Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach 2010 Editor

Yusuf Yildirim Aegean Obstetrics & Gynecology Education and Research Hospital, Department of Gynecologic Oncology, Gaziler Cad., No. 468, Yenisehir, Izmir, Turkey

Transworld Research Network, T.C. 37/661 (2), Fort P.O., Trivandrum-695 023 Kerala, India

Published by Transworld Research Network 2010; Rights Reserved Transworld Research Network T.C. 37/661(2), Fort P.O., Trivandrum-695 023, Kerala, India Editor Yusuf Yildirim Managing Editor S.G. Pandalai Publication Manager A. Gayathri Transworld Research Network and the Editor assume no responsibility for the opinions and statements advanced by contributors ISBN: 978-81-7895-484-4

Contents

Preface Chapter 1 The place of gynaecologic cancers in peritoneal surface oncology concept Naoual Bakrin and Olivier Glehen Chapter 2 Surgical anatomy of upper abdominal solid organs for gynecologic oncologists Yusuf Yildirim and Emre Gultekin Chapter 3 Cytoreductive surgery for ovarian cancer Philipp Harter, Jacobus Pfisterer and Andreas du Bois Chapter 4 Surgical and chemotherapeutic cytoreduction for advanced primary and recurrent ovarian cancer, the Washington Cancer Institute approach Paul H. Sugarbaker Chapter 5 Hyperthermic intraperitoneal chemotherapy (HIPEC) in optimally cytoreduced peritoneal carcinomatosis of gynecology origin: Does it provide survival advantage?

Eelco de Bree, Dimitris D. Tsiftsis and John Melissas Chapter 6 The role of cytoreductive surgery for non-genital tract metastases to the ovary Leszek Gottwald, Janusz Piekarski and Arkadiusz Jeziorski

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Chapter 7 Cytoreductive surgery in endometrial cancer and uterine sarcomas Stefanie M. Ueda and Robert E. Bristow Chapter 8 The role of surgery in the management of high-risk gestational trophoblastic neoplasia John R. Lurain Chapter 9 The role of cytoreductive surgery in cervical cancer: Is there a benefit of retroperitoneal lymph node debulking in advanced disease?

Waldo Jiménez and Allan Covens Chapter 10 The role of cytoreductive surgery in vulvar cancer. Is there an indication for aggressive surgical approach in FIGO Stage III/IV disease?

Anthony Proietto and Ganendra Raj Chapter 11 The place of pelvic exenteration as a cytoreductive procedure in advanced gynaecologic malignancies Markus C. Fleisch, Daniel T. Rein and Wolfgang Janni Chapter 12 The role of video-assisted thoracic surgery (VATS) and intrathoracic cytoreductive surgery in gynecologic malignancies John P. Diaz and Dennis S. Chi Chapter 13 Laparoscopic and robotic assisted laparoscopic cytoreductive surgery in gynecologic oncology Frédéric Marchal, Philippe Rauch and François Guillemin Chapter 14 Critical care and pain management in patients who have undergone cytoreductive surgery for gynecologic malignancies A. Le Gouez, J. Dick and D. Benhamou

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Preface Despite the crucial advancements in treatment with chemotherapy, radiotherapy and biological agents, main treatment method in gynecologic cancers is surgery as in all other solid tumors.

The history of gynecologic cancers is very old. Evidences of first human gynecologic cancers were discovered in Egyptian mummies from the 3000 BC. Granville (1826) dissected mummified remains and discovered an ovarian mass later thought to be a malignant cystadenocarcinoma of the ovary. The history of cytoreductive surgery in gynecologic cancers goes back to the end of the 18th century. The application of modern cytoreductive surgery in gynecologic cancers was initiated in 1834 by Meigs. Later, significant progress was made in cytoreductive surgery by the studies performed by the Gynecologic Oncology Group (GOG) and the International Federation of Gynecology and Obstetrics (FIGO) and many other authors. Currently, resection of almost every organ is performed for cytoreductive surgery of ovarian cancer and every day we witness new technical improvements enforcing the limits of our imagination. Besides, cytoreductive surgery has been applied not only in the treatment of ovarianfallopian-peritoneal cancers, but also in the treatment of endometrial and other gynecologic cancers. Theoretical rationale of cytoreductive surgery is to improve the chemotherapy response (by reducing tumor load before chemotherapy, increasing tumor perfusion and growth fraction), to improve the immune function and to make possible changes in tumor biology.

One of the other recent advances in Gynecologic Oncology is that ovarian cancer has constituted a model within the concept of “Peritoneal Surface Oncology� (Cytoreductive Surgery combined with Hyperthermic Intraperitoneal Chemotherapy-HIPEC) which has been developed since 1990’s for the treatment of peritoneal carcinomatosis. This approach is gradually becoming the standard management both for gynecologic and non-gynecologic peritonitis carcinomatosis cases. Scientific studies on the extensive cytoreductive surgery of ovarian cancer have played a significant role in the development of this concept.

This book aims to introduce the role of cytoreductive surgery in gynecologic cancers through a multi-disciplinary approach. Many famous scientists from US, Canada, European Countries and Australia have participated in this special work. I would like to express my heartfelt thanks to all authors and co-authors who contributed to this book by sparing their valuable time in spite of their busy academic schedules. It has been my pleasure to work with them in this project and I look forward to working together again in other projects in the future.

I hope this book to be useful for the specialists, fellowships and assistants in all disciplines related to the treatment of gynecologic cancers.

I dedicate this book to my beloved wife and son.

January 2010

Izmir

Yusuf Yildirim

Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 1-11 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

1. The place of gynaecologic cancers in peritoneal surface oncology concept 1

Naoual Bakrin1,2 and Olivier Glehen1,2

Department of Oncologic Surgery, Centre Hospitalo-Universitaire Lyon Sud, HCL, 69495, Pierre Bénite cedex, France; 2EA 3738, Université Claude Barnard Lyon 1, Faculté de médecine Lyon Sud 69600, Oullins, France

Abstract. The locoregional progression of gynecological cancer usually results in peritoneal carcinomatosis, condition that may confer a poor prognosis.

Peritoneal carcinomatosis is a common metastatic manifestation of digestive-tract malignancies and gynecological carcinoma.

Primitive peritoneal carcinoma is a rare condition. Tissue of the genital tract plays a definite role in its pathogenesis.

Indeed serous ovarian, Fallopian tube and peritoneal carcinomas share histologic characteristics, natural history and maybe the same tissue origin.

Recent studies shed light on the role of distal Fallopian tube in pelvic serous carcinogenesis, including peritoneal serous papillary carcinoma.

Among gynaecological malignancies, ovarian cancer is responsible for most of peritoneal carcinomatosis. Two ovarian carcinoma groups are distinguished, considering molecular pathogenesis and propensity for peritoneal dissemination.

Embryology and the secondary mullerian system can account for the mullerian-like morphology of ovarian carcinoma and the presence of tumors, histologically identical to ovarian carcinoma, in peritoneal surface, outside the ovary.

Correspondence/Reprint request: Dr. Olivier Glehen, Department of Oncologic Surgery, CHLS, 69495, Pierre Bénite cedex, France. E-mail: olivier.glehen@chu-lyon.fr

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Role of tissue of genital tract and embryology Epithelial ovarian cancer is a highly heterogenous group of cancer and contain 4 subtypes: serous, mucinous, endometrioid and clear cell. Ovary is made up of cortex and inner medulla, ovarian surface epithelium (OSE) is a single layer of cells in continuity with the peritoneal mesothelium.

The Fathalla’s theory of incessant ovulation underline the role of repeated ovulatory mechanical action over a prolonged period of three or four decades [1]. Repeated ovarian epithelial surface disruption and recurrent exposition to oestrogen-rich follicular fluid, are suspected to enhance mitotic activity [2] and consequently increase the risk of unrepaired DNA damages.

Epidemiologic data and animal models support this hypothesis: pregnancy, lactation and oral contraception use, that inhibit ovulation, reduce the risk of developing ovarian carcinoma. It has been demonstrated, so, that poultry hens with hyperovulation are likely to develop peritoneal carcinoma [3].

However, the Fathalla’s theory has been unchallenged for a long time in spite of its inconsistencies. Indeed, it fails to explain the mullerian-like morphology of some ovarian carcinoma whereas ovarian surface epithelium consist of two types of modified mesothelial cells: the first is cuboidal with abundant microvilli and the second is flat squamous [4].

Ovarian carcinomas are more differentiated than OSE, they are made up of cells more specialised than the tissue of origin and express more markers.

This feature distinguishes ovarian carcinomas, since in other solid tumors cells are generally less differentiated than those of normal tissue [5].

Dubeau formulated an hypothesis based on an intermediate step: invasive carcinoma may arise from an ovarian surface epithelial that has undergone a mullerian metaplasia [6].

However, early ovarian neoplastic changes are rarely, if ever, found in OSE, but usually observed in ovarian inclusion cysts lined by a mullerianlike epithelium [7].

Inclusion cysts are a frequent histological feature observed in normal ovaries. Many hypothesis can account for the cysts origin: ovarian surface epithelium is entrapped within the stroma during post-ovulatory reparing process [8], more merely it can be the result of an epithelium invagination that eventually lose its connections with the surface. Lining epithelium cysts contain flat-to-cuboidal cells and sometimes a Fallopian tube –like architecture is observed. Authors have assumed that tubal epithelium cells seeded on ovary surface are entrapped into an ovulation stigma and give rise to a cyst [9].

There are evidences that inclusion cysts are not directly related to the number of ovulation: polycystic ovaries known for low ovulatory activity, present though a high frequency of inclusion cysts. Moreover, mullerian-

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lined cysts can be observed far from ovarian surface, in the deep cortex, in the medulla, in the hilum, in paraovarian and paratubal areas and also in lymph nodes, where there are called endosalpingiosis [6].

This disseminated mullerian tissue, is reffered to as secondary mullerian system [10].

It is essential to shed light on organogenesis of genital tract to understand pathogenesis of pelvic carcinoma.

During the seventh week the canal system of the female genital organ differentiates. The mesonephronic ducts atrophy and the future fallopian tube, the uterus, the upper part of the vagina arise out the paramesonephronic ducts of Mullerian ducts. Primary Mullerian system is composed of upper part of vagina, cervix, uterus and fallopian tubes. The epithelia of mullerian origin can take on different appearances: endometrioid (endometrium), ciliated (fallopian tube) or stratified squamous non cornified (vagina exocervix) or secreting (endocervix), it can express oestrogen and progesterone receptor.

The secondary mullerian system consist of peritoneum, mesothelial inclusions in pelvic lymph nodes and ovarian surface cell layer [10]. It is found outside the mullerian ducts path.

The simple cubic ovarian mesothelium arise out a thickened coelomic epithelium. One describes two type of modified mesothelial cells, one is cuboidal with abundant microvilli and the other is flat squamous with fewer microvilli [11]. This shared origin can explain the mullerian morphology of tumors arising from organs not of mullerian origin.

The metaplastic theory can not be definitely ruled out, but it supposed a pre-existing epithelium, which seems improbable inside lymph nodes for instance [6].

The role of secondary mullerian system in ovarian carcinoma has been little explored. And yet, this hypothesis reaches to explain two main inconsistencies: first, the mullerian morphology of most ovarian carcinoma and second, the presence of carcinomas, clinically and histologically indistinguishable from ovarian carcinoma outside the ovary and even in women with previous oophorectomy.

The common localisation of ovarian carcinoma support the theory of inclusion cysts carcinogenesis. Indeed, at early stage ovarian tumors are frequently found inside ovary stroma and not at the surface.

Role of environmental factors The female peritoneum presents a determining particularity: it is exposed to external environment. Most human cancers arise from epithelial surfaces that are exposed to carcinogen agents. Whereas male peritoneum is a closed

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cavity, in women, fallopian tubes open the peritoneum and connect it to uterine cavity and vagina.

Thus, peritoneum and ovaries are exposed to external agents by vaginal route. Talc use, particularly when contamined with asbestos was suspected to be a valid carcinogen agent of ovary. One found a relationship between talc use and increased risk of developing ovarian carcinoma [10, 12]. Even if asbestos and fiber exposure is known to be associated with higher risk of serosal cancer, the role of talc even fiber-contamined in ovary carcinogenesis is still controversial [13, 14].

The particularity of the female peritoneum must be taken into account, and the role of external agents in peritoneal and ovarian carcinogenesis not definitely ruled out.

Two pathologic categories of ovarian cancers Among gynaecological malignancies, ovarian cancer is responsible for most of peritoneal carcinomatosis. Two pathologic categories have been recently distinguished, considering molecular pathogenesis and trend to extraovarian spread [15].

The type I include borderline malignancy, low grade serous carcinoma, endometrioid and mucinous ovarian carcinoma. Pathologic observation shed light on a pathologic continuum from benign to malignant lesion.

This group is genetically stable and present shared mutations including KRAS, BRAF, PTEN and beta catenin [15]. Studies show that mutation of KRAS is the most frequent genetic alteration found in mucinous tumor [16, 17].

Among mucinous tumors: 80% of advanced stage are associated with pseudomyxoma peritonei. Mucinous carcinoma are often unilateral, well differenciated and grow slowly. An increased rate of KRAS mutation is described respectively in cystadenoma, mucinous borderline and mucinous carcinoma. This data support the theory of a continuum from a benign lesion to a frankly invasive form of mucinous carcinoma [15].

Pseudomyxoma peritonei (PMP) is a condition characterised by an abundant intraperitoneal mucinous material. PMP is from appendiceal origin in more than 90% of cases but also may be due to colonic mucinous tumors [18]. In women, the origin of PMP represent a greater stake since ovary can give rise to mucinous tumor, and further, secondary localisation on ovary can mimic primitive ovarian tumor. Another dilemma is whether the peritoneal localisations associated with PMP are metastasis of the primary mucinous tumor, whether they are expression of a multifocal neoplastic process involving peritoneum and ovarian surface [19].

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Secondary ovarian localisations generally involve both ovaries and when unilateral the tumor is right-sided. Like in peritoneum, implants are confined to the surface epithelium and are never observed deeper than superficial stroma [19]. On contrary, ovarian mucinous low malignant potential is generally unilateral, with the same frequence in each side and involve the entire ovary. Survival for women with stage I MBT is 100% [19], death occur in advanced stage MBT, mostly associated with PMP. These data taken into account, we can assume that MBTs, unlike serous border line tumors, rarely spread beyond the ovary. Authors assume that MBT never spread beyond ovary The type II includes mainly, ovarian serous carcinoma. This entity is aggressive, genetically instable and present TP53 mutations [15]. High grade serous carcinoma is poorly differentiated and display a papillary architecture, the cells have large pleomorphic nuclei, often multinucleated. Mitosis are numerous and abnormal mitotic figures are frequent. Concerning serous carcinoma, several grading system exist [20], the FIGO uses a three-tier classification (poorly, moderately and highly differentiated) based on the amount of solid growth. This classification mean there’s a continuum from well to poorly differentiated sub-type [21]. However, a two-tier system is consistent with the epidemiologic data: the 5-year survival rates ranged from 40% to 56% for low-grade serous carcinoma and 9% to 34% for high grade serous carcinoma [22-24]. As seen above, the molecular characteristics of poorly and well differenciated serous carcinoma are completely different.

It seems that low-grade micropapillary serous carcinoma arise from serous borderline tumor, whereas, no precursor lesion for high-grade serous carcinoma has been yet identified [21]. Regarding molecular and genetic data, the pathway of tumor development are necessarily different. A recent study has shown there is no difference in extreme drug resistance and TP 53 mutation, between poorly and moderately differentiated serous carcinoma.

These results provide strong evidence for a two-tier classification.

Patterns of peritoneal diffusion The ovarian metastatic process consist of cell dissociation, cell seeding and eventually invasion of the peritoneum [25]. At the molecular level, peritoneal seeding is related to impaired cell-cell adhesion. Indeed, tissular cohesion is due to cell adhesion with extracellular matrix and to direct cellcell contact. There are three type of cell junction: tight-junction, adherensjunction and gap-junction. E-Cadherin is a calcium-dependent adherens junction molecule [5]. The invasiviness is the result of a progressive loss of epithelial phenotype and gain of mesenchymal features, also named epithelial-

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mesenchymal transition. Endothelin A receptor/ Endothelin 1axis induces proliferation, survival and loss of intercellular communication. This axis drive EMT by inducing down-regulation of E-Cadherin [26].

Place of tubal in situ carcinoma Serous ovarian carcinoma, fallopian tube carcinoma and primitive peritoneal serous carcinoma display numerous similarities in their morphology and natural history. Insomuch it is often impossible to determine the organ of origin at late stage, when ovaries, abdominal cavity and fallopian tubes are all involved.

Recently, Fallopian tube has been suspected to be original site of pelvic serous carcinoma [27]. Indeed, tubal in situ carcinoma (TIC) shares the same p53 mutation than the synchron associated ovarian carcinoma, suggesting monoclonality and so, a common origin.

Fallopian tubes have three functions: pick up the ovum, transport it and facilitate the fertilisation. The tubal epithelium structure varies with hormonal status and with the tubal segment. Three types of cells are described, ciliated, serous and intercalary.

Few is known about tubal surface epithelium carcinogenesis. In analogy with OSE, we can assume that incessant variation in hormonal levels induce incessant mitotic activity and consequently higher the risk of unrepaired DNA damaged. Even in Fallopian tube removed prophylactically, chromosomal abnormalities are noticed. This may suggest that genetic alterations occur early in the carcinogenesis process of pelvic serous carcinoma. Women with BRCA mutations present an increased risk of developing any form of pelvis serous carcinoma [28]. In this population, TIC is often the only neoplasm diagnosed, which led to assume that TIC is a precursor to pelvic serous carcinoma. However, TIC may be a frequent lesion, under-diagnosed, so it could also coexist with the primitive lesion of ovary or primitive peritoneal carcinoma. Kindelberger and al examined ovaries and fallopian tubes from salpingo-oophorectomy in unselected population. TIC was found coexisting with all forms of pelvis serous carcinoma. The tubes were entirely sectioned, extensively examined according and screened twice. Fimbria where thouroughly examined since it is site of early serous carcinoma in BRCA+ women [29, 30]. Before making a diagnosis of tubal intraepithelial carcinoma pathologist had to ensure that: there was not any site of invasive carcinoma, this lesion was actually primitive and not a secondary localisation or a remote tumor (even if fallopian mucosa is rarely the site for implants of serous neoplasms) [31].

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Uterine serous carcinoma (USC) Uterine serous carcinoma is an aggressive histological type of endometrial carcinoma. It spreads to peritoneal cavity rapidly. Ambros and colleagues have proposed the term of Endometrial intraepithelial carcinoma (EIC) to define a USC without endometrial invasion. Mostly, EIC is associated to USC [32]. USC present loss of heterozigosity at the p53 locus and most EIC contain only one mutated p53 allele [33]. These data suggest that USC originate from EIC. Authors hypothesize that patients with EIC and concomitant pelvic serous carcinoma present actually peritoneal metastasis of a primitive endometrial carcinoma (even non invasive). The p53 data support strongly this hypothesis. The natural history of peritoneal carcinomatosis from endometrial malignancy is unique. Endometrial carcinoma metastasizes by vascular and lymphatic invasion similar to other gynaecological malignancies.

However retrograde transtubal spread is another potential mode of tumor spread.

Transtubal spread has been proposed as a mechanism of tumor dissemination in Uterine Serous Carcinoma (UCS). 62 % of patients with UCS had extrauterine disease at hysterectomy, of which 20% was peritoneal disease without myometrial or lymphatic-vascular invasion [34] Alteration in adhesion molecule expression account for serous carcinoma seeding [35, 36]. Peritoneal deposits of endometrial serous carcinoma and peritoneal serous carcinoma are morphologically similar. However, differences exist: USC typically occur in seventh to eighth decade whereas patient with PSC are one decade younger [37, 38].

Ovarian carcinoma: Paradigm for locoregional treatment?

Ovarian carcinoma is the most lethal gynaecological malignancy, 70% of patient present peritoneal metastasis at diagnosis. OC disseminate preferentially in peritoneal cavity rather than lymphatic and venous route. Even at recurrent stage, ovarian cancer is often a locoregional disease involving only the peritoneum and adjacent intrabdominal organs, making it ideally suited for locoregional therapy. Two therapeutic tools have largely demonstrated their efficiency in the management of peritoneal carcinomatosis: systemic chemotherapy and optimal cytoreductive surgery (CRS) [39]. But despite the high rate of remission obtained following this therapeutic strategy, more than 50% of patients will recur [40].

A new strategy has emerged during the last 20 years: the hyperthermic intraperitoneal chemotherapy (HIPEC). The rationale for locoregional treatment combining CRS and HIPEC is based on the high rate of ovarian cancer recurrence, the results of CRS for recurrent ovarian cancer [41, 42] those of

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CRS with HIPEC in the management of peritoneal carcinomatosis from gastrointestinal cancer [43], and those of intraperitoneal chemotherapy in the first line of treatment [44]. The CRS allows treatment of macroscopic disease and HIPEC is used to treat microscopic diasease. Small phase II studies have already reported interesting survival results with the use of CRS and HIPEC for the treatment of recurrent or chemoresistant ovarian cancers [45-47].

Cisplatinum appears to be the molecule of choice for the treatment of ovarian cancer regarding its cytotoxicitys enhancement by hyperthermia and its pharmacokinetics advantages [46, 48]. But of course this new strategy need to be evaluate into phase III trials.

Conclusions Ovarian, Tubal and endometrial carcinomas natural history leads to peritoneal carcinomatosis. A recent theory assumes that all pelvic carcinomas have a common origin in fimbrial epithelium. Tubal in situ carcinoma, an underrecognised condition, comes out as a consistent precursor of so-called primitive peritoneal carcinoma.

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Deraco M, Rossi CR, Pennacchioli E, Guadagni S, Somers DC, Santoro N, Raspagliesi F, Kusamura S, Vaglini M. Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion in the treatment of recurrent epithelial ovarian cancer: a phase II clinical study. Tumori 2001;87: 120-6.

Panteix G, Beaujard A, Garbit F, Chaduiron-Faye C, Guillaumont M, Gilly F, Baltassat P, Bressolle F. Population pharmacokinetics of cisplatin in patients with advanced ovarian cancer during intraperitoneal hyperthermia chemotherapy.

Anticancer Res 2002;22: 1329-36.

Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 13-34 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

2. Surgical anatomy of upper abdominal solid organs for gynecologic oncologists Yusuf Yildirim and Emre Gultekin

Aegean Obstetrics & Gynecology Education and Research Hospital, Department of Gynecologic Oncology, Gaziler Cad., No 468, Yenisehir, Izmir, Turkey

Abstract. In ovarian cancer standard treatment is cytoreductive surgery followed by platinum-based chemotherapy and residual disease after surgery is generally considered the most important modifiable prognostic factor. Cytoreductive surgery can also be performed for other gynecologic malignancies especially endometrial cancer. Nowadays, in parallel with increasing experiences and developing medical/surgical techniques, gynecologic oncologists have recently performed cytoreductive surgery with increasing frequencies.

Performing cytoreductive surgery for any type of advanced abdominal malignancy is required a comprehensive knowledge about multivisceral organ resections including gastrointestinal resections, diaphragm peritonectomy and/or resection, splenectomy, distal panceatectomy, liver resection, and adrenal/renal resections. Anyone who performs these procedures should have adequate knowledge about surgical anatomy of intraabdominal organs. This chapter presents basic knowledge about surgical anatomy of upper abdominal solid organs for clinicians dealing with gynecologic cancer surgery.

Introduction Numerous studies have documented that extensive cytoreductive surgery followed by platinum-based combination chemotherapy is a cornerstone Correspondence/Reprint request: Dr. Yusuf Yildirim, Aegean Obstetrics & Gynecology Education and Research Hospital, Department of Gynecologic Oncology, Gaziler Cad., No 468, Yenisehir, Izmir, Turkey E-mail: dr.yusufyildirim2@yahoo.com.tr

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approach and optimal cytoreduction (≤ 1 cm residual disease volume) is associated with long-term survival in patients with advanced (FIGO stage III and IV) ovarian cancer. Survival effect of primary maximal/optimal cytoreductive surgery has clearly been established (1-12). Among the well known prognostic factors in ovarian cancer, only amount of residual disease can be influenced by the surgeon and the amount of residual disease after surgery is generally considered the most important modifiable prognostic factor. However, the ability to successfully perform optimal cytoreduction ranges from 20% to 90% (3-10).

Many institutions have recently begun to perform aggressive/ultra-radical procedures to increase their optimal cytoreduction rates. Diaphragm peritonectomy and/or resection, splenectomy, distal panceatectomy, liver resection, and adrenal/renal resections are among the procedures reported to be both feasible and associated with acceptable morbidity for cytoreduction of ovarian cancer (10, 13-33).

In ovarian carcinoma, not only primary cytoreductive surgery but also secondary cytoreductive surgery in the selected cases (e.g., patients with lowvolume disease and a long-term disease-free interval) may improve survival.

As with primary cytoreductive surgery, the optimal resection rates obtained with secondary cytoreductive surgery vary depending on the centers with the reported rates ranging from 29% to 87% (Table 1).

Table 1. Published results on optimal cytoreduction rates during secondary surgery and factors influencing survival after secondary cytoreduction.

Reference

n

Berek (1983) (34) Segna (1993) (35) Gadducci (2000) (36) Eisenkop (2000) (37) Gungor (2005) (38) Pfisterer (2006) (39) Ayhan (2006) (40) Benedetti Panici (2007) (41)

21 100 30 106 44 267 64 47

% optimally cytoreducted 29% 61% 83% 85% 77% 76% 83% 87%

Salani (2007) (42)

55

74.5%

Tebes (2007) (43)

85

86%

Bae (2009) (44)

54

87%

Cheng (2009) (45)

21

67%

Factors influencing survival after secondary surgery RDV-S (p<0.01) RDV-S (p=0.0001) RDV-S (p=0.04) RDV-S (p=0.0007) RDV-S (p=0.007) RDV-S (p<0.0001) RDV-S (p=0.004) RDV-S (p=0.02), CA-125 (p=0.034) RDV-S (p<0.01), DRI (p<0.01), NRCS (p<0.03) DFI (p<0.01), RDV-P (p<0.02), RDV-S (p<0.05) PFS (p=0.043), Site of recurrence (p=0.013) No effect of RDV-S (p>0.05)*

RDV-S=residual disease volume after secondary surgery, RDV-P=residual disease volume after primary surgery, DRI=diagnosis-to-recurrence interval, NRCS=number of radiographic recurrence sites, DFI=disease-free interval before secondary surgery, PFS=progression-free survival before secondary surgery, *: There was no significant statistical difference in median survival between patients with optimal and suboptimal secondary surgical cytoreduction, with an estimated survival of 10 months and 9.8 months, respectively (P>0.05).

Surgical anatomy of upper abdominal solid organs for gynecologic oncologists

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In recent years, cytoreductive surgery including the resection of upper abdominal organs has been increasingly used in endometrial cancers as well as other primary and secondary gynecologic malignancies in addition to ovarian carcinoma (46-49). In parallel with this, gynecologic oncologists have recently performed upper abdominal surgery with increasing frequencies. Therefore, the clinicians practicing gynecologic cancer surgery, especially ovarian carcinoma surgery, should have sufficient knowledge about the surgery of upper abdominal organs. Such an improvement in knowledge makes the gynecologic oncologic surgeons more enthusiastic for optimal cytoreduction, which is associated with improved survival. This chapter presents basic knowledge about surgical anatomy of upper abdominal solid organs for gynecological oncologists.

Surgical anatomy of the liver (50-62) In adults, liver, as the largest solid organ in the body, accounts for about 2% of the total body weight with an average weight of 1350 grams. It is essentially located in the right hypochondria and shows close proximity of the anterior surface of the stomach, the left kidney, and the spleen. Its transverse diameter is approximately 21 to 23 cm and its thickness (at the midline of the right lobe) about 15 cm. The greatest antero-posterior diameter on the level of the upper pole of the right kidney is approximately 10 to 12 cm.

Peritoneal attachments (ligaments), superficial landmarks, and segmental anatomy The surgical anatomy of the liver has been traditionally described based on the regional proximities and superficial landmarks. The dome of the right hepatic lobe is in line with the midclavicular line approximately at the level of the fifth costa. The upper margin at the midline is on where the sternal body and the xiphoid cartilage conjoin. The upper margin of the left lobe is determined with a line from the xipho-sternal conjunction in lateral to the left side of the fifth costal cartilage 5 cm beyond the midline. The right margin of the liver fits with the arcus costarum.

Liver is fixed with the ligamentous structures of the parietal peritoneum extending toward hepatic surface. At the terminal point of both the right and left sides, two leaves of the coronary ligament conjoin in lateral forming the triangular ligaments. Posteriorly, the anterior leaf of the falciform ligament forms a T-shaped appearance together with the smaller

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left triangular ligament and the larger right triangular ligament.

The obliterated umbilical vein on the free margin of the falciform ligament is usually used to distinguish between the right and left ligaments.

This distinction line is in fact on the left to the axis separating the liver into the right and left lobes. The line drawn from two fossae where posteriorly vena cava and anteriorly gall bladder are located is consistent with the true plane separating the liver into two surgical lobes (the right and left lobes). The angle of this plane is 35 degrees vertically, and 20 degrees sagittally. The line drawn between two fissures where ligamentum venosum and ligamentum teres are located separates the left lobe into the medial and lateral segments. The lobus quadratus forms the great portion of the medial segment of the left lobe. Due to its reciprocal blood supply and drainage, the lobus caudatus is a separate lobe not belonging either to the left or right side. Figure 1 shows lobar/ segmental anatomy of the liver.

Figure 1. Lobar/segmental (functional) anatomy of the liver (demonstrating segment I-VIII and principle plan between right and left lobes).

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Hepatic blood supply Hepatic blood supply comes from two sources: hepatic artery (25%) and portal vein (75%). Blood flow emanating from the liver returns to the vena cava through the hepatic veins.

Hepatic arteries Arterial system: “Celiac artery→common hepatic artery→(gastroduodenal, right gastric) →proper hepatic artery→hepatic artery (right, left)”. In twentytwo percent of the people, the left hepatic artery arises from the left gastric artery, and there is only a single left hepatic artery in 50 % of the people. In 17 % of the people, the right hepatic artery arises from the superior mesenteric artery.

The right hepatic artery arises from the a. hepatica propria on the left to the ductus choledochus and proceeds towards the right as from behind this duct. In one half of the cases, cystic artery arises from the right hepatic artery, and there are some variations in the other half. The left hepatic artery supplies blood to the medial and lateral segments of the left lobe. This vessel is relatively short immediately subdividing into terminal branches. Because it progresses obliquely as from the lower surface superiorly and laterally, it makes possible to preserve the lateral segment of the left lobe, thus enabling nearly the total resection of the medial segment. As a rule, the artery is located just under the left hepatic duct. In most cases, the artery gives branches to the lateral and medial segments, thus following the branching of the portal vein and hepatic ducts in general. In 25 % of the cases, a large portion of arterial blood supply to the left lobe (medial segment) comes from the right hepatic artery.

The common hepatic artery is frequently a main branch arising from the celiac arterial stem in the upper side of pancreas. In approximately 3 % of the people, there is an abnormal main hepatic artery which arises from the superior mesenteric artery. It is related to the pancreatic head and neck; it sometimes passes through the head and then behind the portal vein, resulting in the whole blood supply of the duodenum coming from the superior mesenteric artery in such cases. Ligation of this vessel inadvertently not only causes hepatic ischemia and even necrosis, but also endangers duodenum.

More frequently (27%), there may be seen variations in which the right or left hepatic artery arises from the superior mesenteric artery. Its trace is uncertain, but shows proximity to the pancreatic head and neck.

Historically, it was believed that hepatic arteries were end arteries having no anastomosis. Subsequent anatomic studies have demonstrated that there

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are about 25 potential collateral arterial networks coming into liver.

Following a hepatic artery ligation, a number of small collateral vessels begin to appear in the regions of caudate lobe and porta hepatis. Moreover, in 25% of the people, extrahepatic anatomoses have been shown to exist between the left and right hepatic arteries. All these anastomoses are of subcapsular and small diameter, of which many are in areas near lobus caudatus.

Portal vein Of approximately 7 to 8 cm length and containing no valves, the portal vein is formed by the union of superior, splenic and inferior mesenteric veins behind the pancreatic neck at the level of second lumbar vertebra (Figure 2).

In one out of three cases, inferior mesenteric vein directly joins superior mesenteric vein. Additionally, there are a number of small venous structures joining the various parts of the portal vein from the surrounding organs (e.g., abdominal esophagus, stomach, and pancreas).

Portal vein is located in front of vena cava inferior and behind pancreas where hepatic artery and biliary duct are located its left and right sides, respectively. While descending obliquely toward the right side behind the initial part of the duodenum, the portal vein anteriorly intercrosses vena cava inferior and enters the free edge of the small omentum (hepatoduodenal ligament). In this region, the main biliary duct on its right is near the hepatic artery, which is on its behind left. This triple structure forms the anterior edge

Figure 2. Extra-hepatic portal venous system (PV: Portal vein, SMV: Superior mesenteric vein, IMV: Inferior mesenteric vein, SV: Splenic vein).

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of the epiploic fossa (Winslow) together with the peritoneal membrane.

It travels posterior to common bile duct and hepatic artery in porta hepatis, gives off right and left portal branches in liver hilum. The longer left branch is morphologically less effective in terms of blood flow. The left portal vein has two portions: “transverse” portion progressing through the hilum, and “intrahepatic” portion progressing in the fissure of the umbilical vein.

The portal and superior mesenteric veins can be easily detached from the posterior surface of the pancreas in healthy cases. In very rare cases, the portal vein may run along in front of pancreas and duodenum (anterior replacing portal vein). Additionally, the portal vein may drain into superior vena cava or has a congenital stricture.

Hepatic venous drainage The venous return is principally achieved via the right, middle, and left hepatic veins. The posterior segment of the right lobe and a large portion of the upper surface of the anterior segment are drained via the right hepatic vein, the greatest one of these three veins. The middle and left hepatic veins either unite to join vena cava as a single truncus, or join vena cava at the separate but close points (triple confluence). The lower surface of the medial segment of the left lobe, and the lower surface of the anterior segment of the right lobe are drained via the middle hepatic vein. The upper part of the medial segment and the whole lateral segment of the left lobe are drained via the left hepatic vein (Figure 3).

Figure 3. Hepatic venous system (LHV: Left hepatic vein, MHV: Middle hepatic vein, RHV: Right hepatic vein).

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The caudate lobe and some parts of the liver may show a direct drainage to vena cava. The caudate lobe is drained via two or more veins joining vena cava on the left and anteriorly. The posterior and lateral parts of the posterior segment of the right lobe are drained via few veins joining vena cava on the right posterolateral surface. The upper right vein may directly join vena cava, although it usually flows out to the upper side of the right hepatic vein. The upper left vein directly joins vena cava draining the area, which is confined by the left triangular ligament. In some instances, this vein may be ruptured while revealing the esophageal hiatus during the dissection of the left triangular ligament.

Hepatic venous system is valveless. Average blood flow is 1500 mL/min per 1.70 m2 of body surface area. A number of anostomoses have been reported to exist between hepatic veins. In addition, it has been generally accepted that there are associations between the portal and hepatic venous systems. The respective associations are between the afferent venules of the portal system and the sublobular hepatic veins. When performed an injection into the hepatic veins only, the segmental distribution of the drainage can be obviously seen. However, such anatomic distribution is not in parallel with the segmental designation of the portal system. Two systems coalesce with each other such that when both are injected, no lobar or segmental planes can be seen.

Trans-hepatic biliary drainage Intrahepatic biliary network closely follows the hepatic arterial and portal vessels. Unlike arterial system, there is less evidence on the presence of functional anastomosis between the right and left lobes, except the conjunction of the right and left hepatic channels at porta hepatis. When performed an injection, there appears no association between the biliary channels of the anterior and posterior segments of the right lobe through the segmental fissure.

With a length of approximately 9 mm, the right hepatic channel consists of the union of anterior and posterior segmental channels near porta hepatis.

The lateral segment of the left lobe is drained via two segmental channels.

The caudate lobe is drained in a different manner, in which there may be seen a drainage to both right and left hepatic channel systems.

The right and left lobar channels unite to form the right and left hepatic channels. The latters unite to form the choledochal duct. The length of choledochal duct varies (2 to 7 cm), but usually follows a uniform course.

The choledochal duct comes off the conjunction of the common hepatic channel and the cystic channel. It progresses on the free edge of the small omentum passing behind duodenum to open up to the Vaterâ&#x20AC;&#x2122;s ampulla.

Figure 4 shows relationships between choledoc and hepatic artery/portal vein in hepatoduodenal ligament.

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Figure 4. The relationships between choledoc and hepatic artery/portal vein in hepatoduodenal ligament (LHA: Left hepatic artery, AHP: Arteria hepatica propria).

Surgical anatomy of the pancreas (50-61, 63) Pancreas is a solid organ that is transversely located between duodenum on the right and spleen on the left in the retroperitoneal region. It is associated with omental bursa superiorly, transverse mesocolon anteriorly, and large omental pouch inferiorly.

Parts of the pancreas Pancreas consists of head, uncinate process, neck, body, and tail (Figure 5). The anterior surface of the head is adjacent to pylorus and colon.

The anterior pancreaticoduodenal arcade is parallel to the duodenal curvature and associated with the pancreatic surface. The posterior surface of the pancreatic head is associated with the right renal hilus and medial edge, the right renal vessels and inferior vena cava, the right crus of the diaphragm, the posterior pancreaticoduodenal arcade, and the right gonadal vein. The distal part of the common bile duct (choledoc) is less frequently (15%) located behind the pancreatic head, and more frequently (85%) is sunk in the pancreatic body partially or completely.

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Figure 5. Parts of the pancreas (SMV: Superior mesenteric vein, SMA: Superior mesenteric artery).

A projection from the pancreatic head extends toward below and slightly to the left to form the uncinate process. The uncinate process passes anteriorly to the inferior vena cava between the portal vein and superior mesenteric vessels. On the sagittal plane, the uncinate process remains between aorta and superior mesenteric artery where it shows proximity with duodenum superiorly and the left renal vein inferiorly. An uncinate process may not exist or circumscribe the superior mesenteric vessels completely.

The pancreatic neck has a length of approximately 2 cm. It is anteriorly concealed by pylorus to a limited extend, and extends toward to the right until the point where the anterior-superior pancreaticoduodenal artery comes off the gastroduodenal artery. The left edge of the neck is unclear. Behind the neck, the portal vein is formed by the union of superior mesenteric and splenic veins.

The anterior surface of the pancreatic body is covered by the double membrane of the peritoneum of omental bursa, separating the stomach from the pancreas. The body is associated with the transverse mesocolon. Arteria colica media comes off from the bottom of the pancreas and progresses

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between two leaves of the mesocolon. Small pancreatic vessels open up to the splenic vein. These vessels should be ligated to preserve the splenic vein and the spleen during pancreatectomy.

The pancreatic cauda (tail) is relatively mobile. Its end reaches the splenic hilus. It is located between two leaves of the splenorenal ligament together with the beginning of the splenic vein, and the splenic artery. Outer leaf of this ligament is the posterior leaf of the gastrosplenic ligament, thus being avascular.

Pancreatic ducts and related structures The main pancreatic duct (Wirsung) extends from the middle of the upper and lower edges and slight posteriorly along the pancreatic body and tail. The main pancreatic duct and the accessory duct (Santorini) are located in front of the major pancreatic vessels. In the pancreatic body and tail, fifteen to twenty short ductules open up to the main duct. The main duct opens up into duodenum at the level of major papilla (mostly at the level of the second lumbar vertebra). The accessory pancreatic duct (Santorini) drains off the antero-superior part of the pancreatic head into either main pancreatic duct or the duodenum via the minor papilla. The major duodenal papilla is at the distance of 7 to 10 cm from pylorus on the posteromedial wall of the second part of the duodenum. Rarely, papilla may be in the third part of the duodenum. Vaterâ&#x20AC;&#x2122;s ampulla (ampulla) corresponds to an area of expansion of the main pancreaticobiliary duct below the conjunction of two ducts and adjacent to papilla. There may be no ampulla in one out of three cases.

The most common pancreatic duct variation is that the accessory pancreatic duct (Santorini) open up to the duodenum with the minor papilla.

The minor duodenal papilla is located at about 2 cm above the major papilla and slight anteriorly. Unlike the major papilla, it has no characteristic mucosal folds denoting its place, and is smaller than the major papilla.

Currently, it is believed that various sphincters composed of smooth muscle fibers circumscribe the ampulla, the pancreatic duct, and the intramural part of the biliary duct. Considering its contribution to the anatomy of this region, the whole sphincter complex is called Boyden sphincter. The total length of this sphincter complex ranges from 6 mm to 30 mm.

Pancreatic arterial blood supply Pancreatic blood supply comes from both the celiac truncus and the superior mesenteric artery (Figure 6). The pancreatic head and duodenal concave surface is always supplied by two (anterior and posterior)

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Yusuf Yildirim & Emre Gultekin

Figure 6. Arterial blood supply of the pancreas (ASPDA: Anterior superior pancreatico-duodenal artery, PSPDA: Posterior superior pancreatico-duodenal artery, AIPDA: Anterior inferior pancreatico-duodenal artery, PIPDA: Posterior inferior pancreatico-duodenal artery, SMA: Superior mesenteric artery).

pancreatico-duodenal arterial arcades (arcus). Also supplying the duodenal wall, this vascular arcade is the primary obstacle in completing pancreatectomy without duodenectomy.

Gastroduodenal artery is the first large branch of the main hepatic branch of the celiac truncus. It gives the right gastroepiploic artery at about 1 cm away from its beginning, and thereafter subdivides into the posterior and anterior superior pancreaticoduodenal arteries. The anterior superior pancreaticoduodenal artery is on the anterior surface of the pancreas; it gives eight to ten branches to the anterior duodenal surface, an additional branch to the proximal jejunum, and a number of branches to the pancreas. During the resection of the pancreas, duodenal branches may be sacrificed, but jejunal branches should be protected.

This artery enters the pancreas, and then joins the anterior inferior pancreaticoduodenal artery coming from the superior mesenteric artery in the posterior surface. The anterior inferior pancreaticoduodenal artery arises from the superior mesenteric artery at or above the upper edge of the pancreatic neck.

The blood supply of the pancreatic tail comes from the left gastroepiploic artery or a splenic branch at the splenic hilus. It makes anostomoses with the large pancreatic artery branches and other pancreatic arteries. The pancreatic tail artery supplies the accessory splenic tissue when it is at the hilus. There are three major variations of arterial blood supply of distal pancreas. The most

Surgical anatomy of upper abdominal solid organs for gynecologic oncologists

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common type of these is observed in about 50% of people in which dorsal pancreatic artery joins with transverse pancreatic artery inside of the pancreas.

The splenic artery progresses by giving folds on the anterior and posterior surfaces, and below and above the pancreatic tail. The first large branch is the dorsal pancreatic artery, and frequently opens up to the upper posterior arcade after giving the inferior pancreatic branch to the left side.

The ligation of the splenic artery does not require splenectomy. However, the ligation of the splenic vein requires splenectomy.

As mentioned earlier, in approximately 3 % of the people, there is an abnormal main hepatic artery which arises from the superior mesenteric artery.

This aberrant artery is related to the pancreatic head and neck; it sometimes passes through the head and then behind the portal vein, resulting in the whole blood supply of the duodenum coming from the superior mesenteric artery.

Ligation of this vessel inadvertently not only causes hepatic ischemia and even necrosis, but also endangers duodenum.

Pancreatic venous drainage In general, the pancreatic veins are parallel with the arteries and located more superficially. Arteries and veins are behind the pancreatic ducts. These veins are drained by the portal vein, and the superior and inferior mesenteric veins.

Pancreatic lymphatic drainage Pancreatic lymphatic drainage is complex as with the arterial blood supply.

The lymphatic flow is usually parallel with the arterial/venous systems, and there is no standardized classification system for the lymph nodes.

Pancreatic nerves Pancreas is innervated by the splanchnic and vagal nerves from the autonomic nervous system. These nerves usually follow the blood vessels.

These autonomic nerves carry afferent (motor) fibers to the blood vessels and the pancreatic ducts and glands, and contain visceral efferent (pain) fibers whose distribution is not well known.

Pancreatic exploration Pancreas can be reached by separating the gastrohepatic or gastrocolic omentum. Generally, the whole pancreas can be well seen by performing a wide incision of the gastrocolic omentum.

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Yusuf Yildirim & Emre Gultekin

It is essential to liberalize duodenum with the Kocherâ&#x20AC;&#x2122;s maneuver for the palpation of the pancreatic head. The mobilization of the duodenum is obtained by mobilizing the hepatic flexure and then incising the peritoneum from the lateral edge of the second part of the duodenum. Due to its close proximity with superior mesenteric artery and vein, evaluating and revealing the uncinate process is much more difficult.

Surgical anatomy of the spleen (50-61, 64) Spleen is solid organ located in the upper left abdominal quadrant, with a weight of about 100 to150 g. Its lateral surface is in contact with diaphragm at the level of 9th to 11th costae, whereas it is in proximity to the large curvature of the stomach medially. The left kidney is behind the spleen. The lower pole of the spleen is in proximity to the splenic flexure of the colon.

Relation of the spleen to the pancreas The pancreatic tail is so close to the splenic hilus (Figure 7), and in 30% of the people, the pancreatic tail is in a direct contact to the spleen. In most of the cases having no direct contact, the distance between the pancreas and the splenic hilus is less than 1 cm. The close proximity of the pancreas with the splenic arteries and hilus is important for the splenectomy application.

Figure 7. Relations of the spleen to the pancreas, colon and left kidney.

Surgical anatomy of upper abdominal solid organs for gynecologic oncologists

27

Splenic ligaments The peritoneal structures that form the splenic suspensory ligaments hold the spleen in the upper left abdominal quadrant. The peritoneum extends toward the spleen through the anterior and posterior gastric walls and forms the gastrosplenic ligament bearing the short gastric branches of the splenic vessels. Inferiorly, the gastrosplenic (gastrolienal) ligament continues to the splenocolic ligament together with the larger omentum. Portion of the peritoneum in the posterior edge of the lateral surface extends to superior, lateral and inferior regions forming the splenophrenic, splenorenal and splenocolic ligaments, respectively.

Splenic arteries The splenic blood supply comes from the splenic artery, which arises from the celiac axis (Figure 8). Splenic artery gives several branches before entering the spleen. These include the short gastric arteries supplying the upper part of the large curvature of the stomach, and the left gastroepiploic arteries extending to more distant areas of the large curvature and to the large omentum. The main splenic artery usually gives branches at a distance of 3 to 4 cm before the hilus, although there may be branching at a distance of 1 to 12 cm from the hilus.

Due to the embryologic development of spleen, the formation of splenic arteries may occur in two types: marginal and diffuse types. In the marginal type, the main splenic artery gives short terminal branches near the hilus. In the diffuse type, the main splenic artery is short and spreads into the spleen with several long branches.

Figure 8. Splenic artery and vein.

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Splenic veins The splenic vein consists of many branches leaving the spleen. The main branch usually follows a line from the left to the right, below and behind the splenic artery and behind the pancreatic tail and body. The splenic vein gathers the left gastroepiploic, few pancreatic and frequently inferior mesenteric veins, and combines with the superior mesenteric vein to form the portal vein behind the pancreatic neck. Short gastric veins discharge into the branches of the splenic vein or into the spleen directly.

Splenic lymphatics The splenic pulp contains no lymphatic vessels. The present lymphatics exist in the connective tissue and trabecules of the splenic capsule. The lymph nodules near the hilus receive lymphatic drainage from the stomach rather than spleen, and these lymphatics discharge to the lymph nodules accompanying the splenic artery.

Splenic nerves There is a nervous network extending from the celiac plexus near the splenic artery. Experiments carried on mammalians revealed that spleen has only sympathetic innervation. In some species, stimulation of the splenic nerves leads to splenic contractions.

Surgical anatomy of kidneys & adrenals (50-61) Kidneys are retroperitoneal organs located in both sides of the columna vertebralis. Both kidneys have two poles, one superior and the other inferior, two surfaces, namely anterolateral and posteromedial, and a hilus harboring neurovascular structures and pelvis renalis. Because the longitudinal axis of the kidneys is oblique, the superior and inferior poles are about 5 and 8 cm far from the midline, respectively. Due to the different relations to the liver and diaphragm, the right kidney is located at a lower level compared to the left one.

Kidneys are present in a bed composed of transverse fascia, arcuate ligaments, and perirenal fatty tissue in the subdiaphragmatic region. On the right, the anterior surface of the kidney is in close proximity to the right flexura coli and the descending duodenum. There is no peritoneum in these areas. On the left, there is a similar relation between the pancreatic tail and the descending colon.

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The renal fascial ligaments (renal= perirenal= Gerotaâ&#x20AC;&#x2122;s fascia) are originated from the retroperitoneal connective tissue and surround the kidney on the anterior and posterior surfaces.

Approximately 65% of the people, there is a single renal artery. Those arteries called renal accessory or aberrant arteries and usually progressing toward superior or inferior poles are extra or auxiliary arteries being the single arteries supplying their respective segments. After leaving the kidney, the renal vein follows the renal artery and opens up to the inferior vena cava (Figure 9).

Adrenal glands are endocrine organs that are located just over the superior renal poles, with a weight of approximately 3 to 5 g and a size of 5x2x1 cm.

The right adrenal gland is in a close proximity to vena cava. The left adrenal gland is present between aorta and the anteromedial edges of the left kidney. Both glands are in yellow and more solid than perirenal fatty tissue.

On the cross-section of a gland, the outer section is composed of yellowishcolored cortex, whereas the inner section is composed of red-brownish medulla.

The adrenal glands are located over the compartment formed by the renal fascia; their positions are maintained by the vessels and fibrous ligands. The adrenal glands are highly rich in arterial blood supply. Arterial blood supply is

Figure 9. Renal artery and vein.

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Figure 10. Left adrenal artery and vein.

provided by a. phrenica inferior superiorly, aorta centrally, and the branches of a. renalis inferiorly. Whereas the left adrenal vein frequently opens up to the left renal vein or vena cava inferior (Figure 10), many small veins originated from the right adrenal gland directly open to v. cava inferior.

Acknowledgement I would like to acknowledge Bugra Destan, M.D., from the Department of Cardiovascular Surgery for his appreciated contributions in providing figure drawings.

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Griffiths CT, Parker LM, Fuller AF Jr. Role of cytoreductive surgical treatment in the management of advanced ovarian cancer. Cancer Treat Rep 1979; 63: 235-240.

Wakabayashi MT, Lin PS, Hakim AA. The role of cytoreductive/debulking surgery in ovarian cancer. J Natl Compr Canc Netw 2008; 6: 803-10.

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21. Ayhan A, Al RA, Baykal C, Demirtas E, Ayhan A, Yuce K. The influence of splenic metastases on survival in FIGO stage IIIC epithelial ovarian cancer. Int J Gynecol Cancer 2004; 14: 51-6.

22. Chi DS, Abu-Rustum NR, Sonoda Y, et al. Laparoscopic and hand-assisted laparoscopic splenectomy for recurrent and persistent ovarian cancer. Gynecol Oncol 2006; 101: 224-227.

23. Andelson MD. Ultrasonic surgical aspirator in cytoreduction of splenic metastases to avoid splenectomy. J Reprod Med 1992; 37: 917-20.

24. Yildirim Y, Sanci M. The feasibility and morbidity of distal pancreatectomy in extensive cytoreductive surgery for advanced epithelial ovarian cancer. Arch Gynecol Obstet 2005; 272: 31-34.

25. Kehoe SM, Eisenhauer EL, Abu-Rustum NR, et al. Incidence and management of pancreatic leaks after splenectomy with distal pancreatectomy performed during primary cytoreductive surgery for advanced ovarian, peritoneal and fallopian tube cancer. Gynecol Oncol 2009; 112: 496-500.

26. Merideth MA, Cliby WA, Keeney GL, Lesnick TG, Nagorney DM, Podratz KC. Hepatic resection for metachronous metastases from ovarian carcinoma. Gynecol Oncol 2003; 89: 16-21.

27. Bosquet JG, Merideth MA, Podratz KC, Nagorney DM. Hepatic resection for metachronous metastases from ovarian carcinoma. HPB 2006; 8: 93-96.

28. Yoon SS, Jarnagin WR, Fong Y, DeMatteo RP, Barakat RR, Blumgart LH, Chi DS. Resection of recurrent ovarian or fallopian tube carcinoma involving the liver. Gynecol Oncol 2003; 91: 383-388.

29. Abood G, Bowen M, Potkul R, Aranha G, Shoup M. Hepatic resection for recurrent metastatic ovarian cancer. Am J Surg 2008; 195: 370-373.

30. Lim MC, Kang S, Lee KS, Han SS, Park SJ, Seo SS, Park SY. The clinical significance of hepatic parenchymal metastasis in patients with primary epithelial ovarian cancer. Gynecol Oncol 2009; 112: 28-34.

31. Baron M, Hamou L, Laberge S, Callonnec F, Tielmans A, Dessogne P. Metastatic spread of gynaecological neoplasms to the adrenal gland: case reports with a review of the literature. Eur J Gynaecol Oncol 2008; 29: 523-6.

32. Einat S, Amir S, Silvia M, Moshe I. Successful laparoscopic removal of a solitary adrenal metastasis from ovarian carcinoma: a case report. Gynecol Oncol 2002; 85: 201-203.

33. Cortes J, Uriz A, Terrasa J, et al: Ovarian cancer metastatic to the kidney: case report. Eur J Gynaecol Oncol 1986; 7: 206-209.

34. Berek JS, Hacker NF, Lagasse LD, et al. Survival of patients following secondary cytoreductive surgery in ovarian cancer. Obstet Gynecol 1983; 61:189-193.

35. Segna RA, Dottino PR, Mandeli JP, et al. Secondary cytoreduction for ovarian cancer following cisplatin therapy. J Clin Oncol 1993; 11: 434-439.

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36. Gadducci A, Iacconi P, Cosio S, et al. Complete salvage surgical cytoreduction improves further survival of patients with late recurrent ovarian cancer. Gynecol Oncol 2000; 79: 344-349.

37. Eisenkop SM, Friedman RL, Spirtos NM. The role of secondary cytoreductive surgery in the treatment of patients with recurrent epithelial ovarian carcinoma.

Cancer 2000; 88: 144-153.

38. Gungor M, Ortac F, Arvas M, et al. The role of secondary cytoreductive surgery for recurrent ovarian cancer. Gynecol Oncol 2005; 97: 74-79.

39. Pfisterer J, Harter P, Canzler U, et al. The role of surgery in recurrent ovarian cancer. Int J Gynecol Cancer 2005; 15: 195-198.

40. Ayhan A, Gultekin M, Taskiran C, et al. The role of secondary cytoreduction in the treatment of ovarian cancer: Hacettepe University experience. Am J Obstet Gynecol 2006; 194: 49-56.

41. Benedetti Panici P, De Vivo A, Bellati F, Manci N, Perniola G, Basile S, Muzii L, Angioli R. Secondary cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer. Ann Surg Oncol 2007; 14: 1136-42.

42. Salani R, Santillan A, Zahurak ML, Giuntoli RL 2nd, Gardner GJ, Armstrong DK, Bristow RE. Secondary cytoreductive surgery for localized, recurrent epithelial ovarian cancer: analysis of prognostic factors and survival outcome.

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45. Cheng X, Jiang R, Li ZT, Tang J, Cai SM, Zhang ZY, Tian WJ, Zang RY. The role of secondary cytoreductive surgery for recurrent mucinous epithelial ovarian cancer (mEOC). Eur J Surg Oncol 2009 May 12. [Epub ahead of print].

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55. Diagnostic and surgical imaging anatomy: chest, abdomen, pelvis. International Edition Michael P. Federle, Melissa L. Rosado De Christenson, Paula J. Woodward, Gerald F. Abbott, Akram M. Shaaban (Editor). Lippincott Williams & Wilkins, 2006.

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Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 35-49 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

3. Cytoreductive surgery for ovarian cancer 1

Philipp Harter1, Jacobus Pfisterer2 and Andreas du Bois1

HSK, Dr. Horst Schmidt Klinik Wiesbaden, Dept. of Gynecology & Gynecologic Oncology Wiesbaden, Germany; 2Ubbo-Emmius Klinik, Department of Gynecology, Aurich, Germany

Surgical therapy in ovarian cancer contains different types of surgery (Table 1): (1) Surgery for diagnostic purposes: This kind of surgery could be

performed at any time in the course of ovarian cancer (e.g. to get a histological diagnosis). Second-look surgery belongs to this group of procedures. It is an operation performed in patients who are clinically free of disease after the completion of a defined course of chemotherapy with the purpose to confirm the response status (In principle, the removal of the remaining tumor at second-look passes the border of diagnostic procedures).

(2) Staging laparotomy: This surgery should be performed in patients with macroscopically early ovarian cancer limited to the ovaries or the pelvis.

Aim of this surgery is the detection of tumor spread (3) Primary cytoreductive surgery: Surgery with the aim of complete resection of all macroscopic tumors in patients with first diagnosis of ovarian cancer before any other treatment modalities (e.g. chemotherapy).

(4) Secondary surgery/Interval debulking: An operation performed in patients after chemotherapy, usually 2 or 3 cycles, with an attempt to remove any remaining tumor which has not been removed by chemotherapy.

Correspondence/Reprint request: Dr. Philipp Harter, Dept. Gynecology & Gynecologic Oncology, HSK, Dr. Horst Schmidt Klinik, Ludwig-Erhard-Str. 100, D-65199 Wiesbaden, Germany E-mail: philipp.harter@hsk-wiesbaden.de

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(5) Surgery for progressive ovarian cancer: An operation with the purpose of removing obviously resistant tumors which have not responded to chemotherapy and progressed during primary chemotherapy.

(6) Surgery for recurrent ovarian cancer: Surgery aiming for complete resection of all macroscopic tumor in patients with recurrent ovarian cancer after completion of primary therapy including a subsequent period without any signs of disease.

(7) Palliative surgery: An operation performed in patients with symptoms caused by progressive disease or sequels from prior treatment. These operations are performed in an effort to relieve symptoms and do not aim primarily at survival prolongation.

This book chapter wants to focus on cytoreductive surgeries in primary and recurrent ovarian cancer.

Table 1. Different types of surgery in ovarian cancer.

(1) (2) (3) (4) (5) (6) (7)

Surgery for diagnostic purposes Staging laparotomy Primary cytoreductive surgery Secondary surgery/Interval debulking Surgery for progressive ovarian cancer Surgery for recurrent ovarian cancer Palliative surgery

Primary cytoreductive surgery The role of surgery in newly diagnosed ovarian cancer is widely accepted, although there is no Level I evidence for its role, and prospectively randomized phase III studies comparing cytoreductive surgery with no surgery are lacking. However, there is supportive evidence (level II and III) indicating a benefit for primary cytoreductive surgery. Possible benefits of surgery include (1) removal of poorly vascularized tumor whereupon pharmacologic sanctuaries are eliminated, (2) a higher growth fraction in the better perfused small residual tumor masses which favours an increased cell death with chemotherapy, (3) small tumor masses require fewer cycles of chemotherapy so there is less opportunity for induced drug resistance, (4) removal of drug-resistant clonogenic cells, and (5) host immunocompetence enhanced by the removal of large tumor bulk [1]. In 1934, Meigs was the first one who championed cytoreductive surgery in advanced ovarian cancer to enhance the effects of postoperative radiation therapy [2]. The concept of primary cytoreduction was supported when Griffiths showed that survival

Cytoreductive surgery for ovarian cancer

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depends on residual disease [3]. Since then, many other authors and two metaanalyses have confirmed this observation [4, 5, 6, 7, 8, 9, 10, 11, 12, 13]. Whilst in the late 90â&#x20AC;&#x2122;s the aim of primary surgery was defined as residual disease of less than 1 cm (so-called optimal debulking), it seems that this definition has to be rediscussed. Actual data of a meta-analysis of the AGO Study Group including more than 3000 patients with advanced ovarian cancer of 3 large prospective randomized trials show clearly that patients most benefit in case of complete resection [14]. There is still some advantage in case of achieving residual disease of 1-10 mm compared to more than 10 mm, but nevertheless, the advantages in survival in case of complete resection are so impressive, that it is not arguable to deny a patient cytoreductive surgery with complete removal of the tumor if this is technically possible under consideration of co-morbidities and risk factors of the individual patient [15]. The surgical techniques include not only pelvic surgery and bowel resection. Also the addition of upper abdominal surgery, including stripping of the diaphragm or splenectomy, improves survival if these techniques help to achieve lower tumor burden [16].

However, there is some debate about definition of complete debulking: Should systematic lymphadenectomy be included or is it sufficient to remove palpable enlarged lymph nodes. It is known that 81% of patients with advanced disease have lymph node metastases which are often not detectable by palpation.

Furthermore, most of metastatic nodes are localized in the upper para-aortic and interaortocaval region [17] (Figure 1). A recently published prospectively randomized phase III international multicenter study addressed this question [18]. This study compared systematic pelvic and para-aortic lymphadenectomy with removal of enlarged lymph nodes only in FIGO stage III epithelial ovarian cancer and intra-abdominal so-called optimal debulking with tumor residuals up to 1 cm. Patients with systematic lymphadenectomy showed a significant longer progression-free survival (median +7 months adjusted analysis, p = 0.01; +5 months analysis of raw data) and a non-significant benefit regarding median overall survival (+ 2.4 months in adjusted analysis, +5.6 months raw data analysis). In addition, patients who underwent systematic lymphadenectomy had longer operation time and more complications (including blood loss). The lack of any significant survival advantage led some to comment, that systematic lymphadenectomy should not play a role in primary ovarian cancer surgery [19]. However, the authors of the study came to an opposite conclusion and stated that â&#x20AC;&#x153;the therapeutic value of systematic lymphadenectomy in women with advanced ovarian cancer remains controversialâ&#x20AC;?. The latter statement seems more reasonable when analyzing the study carefully. The survival comparison was based on 191 events in only 44.2% of all recruited patients. A clinical relevant impact

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Figure 1. Probability of positive nodes in ovarian cancer patients.

of any procedure cannot be ruled out based on such small numbers; e.g. a risk reduction of 25% or, in other words, an absolute improvement of 13% survival rate would have been missed statistically in such a small cohort.

Furthermore, the composition of the study cohorts might be re-considered.

The role of systematic lymphadenectomy might be to complete â&#x20AC;&#x153;seemingly completeâ&#x20AC;? debulking by removing small tumor residuals in patients who have metastatic but non-palpable lymph nodes (non-palpable lymph node metastases rarely exceed 1 cm by diameter) thus shifting these patient from small volume residual disease to no macroscopic residual disease. This effect could only benefit patients with complete intra-abdominal debulking and no macroscopic residual disease left in the peritoneal cavity. However, two thirds of included patients had intra-abdominal residuals of up to 1 cm.

Lymphadenectomy would not alter their status of residual disease and they still had small volume disease intra-abdominally even if small lymph node metastasis would have been removed. Consequently, only the 37% of included patients who had no visible residuals intra-abdominally could have experienced any benefit from systematic lymphadenectomy with respect to residual tumor. Furthermore, only 28% of patients more had positive nodes in the lymphadenectomy group compared to the patients who had only removal of enlarged lymph nodes (42% vs. 70%) thus making the subgroup who

Cytoreductive surgery for ovarian cancer

39

would (theoretically) benefit from systematic lymphadenectomy even smaller. In conclusion, a trial aiming at an evaluation of a possible impact of systematic lymphadenectomy should â&#x20AC;&#x153;enrichâ&#x20AC;? the study population by patients who could benefit and only enroll patients with complete intraabdominal debulking. The LION-trial which addresses this question has currently started (Figure 2). Until results are available, the role of lymphadenectomy remains a cornerstone of staging in early ovarian cancer and should be discussed with patients balancing side effects and possible benefit. Patients most probable to gain any benefit are those completely debulked intra-abdominally. However, patients with small volume disease still experienced better progression-free survival, which might be of value on its own if not traded for excessive toxicity (which is uncommon in experienced centers for ovarian cancer surgery). An exploratory analysis of the surgical treatment characteristics in a prospective trial compared UK and Non-UK centers [20]. This study showed the following observations: (1) patients recruited from centers outside the UK were more likely to be completely debulked (UK 28.6%, Non-UK 39.9%, p<0.001). (2) Completely debulked patients of Non-UK centers had better PFS compared to UK centers (p=0.01). In Non-UK centers procedures as bowel resection, pelvic, and paraaortic lymphadenectomy have been performed more often (p<0.001), especially in complete debulked patients. It seems that complete debulking without lymphadenectomy is not the same as complete debulking with this procedure. The operation time was shorter in UK centers (95 minutes vs. 135 minutes, p<0.001). Unfortunately morbidity of the surgery is not reported, but more extensive surgery, as performed in Non-UK centers resulted in better PFS (Overall survival was not reported). An exploratory analysis of the AGOOVAR meta-database which contains the data of 3 prospective randomized trials in advanced ovarian cancer, showed that 1003 out of 2924 patients had complete resection. 72% of the patients in this subgroup underwent lymphadenectomy. In multivariate analysis lymph node resection remained an independent prognostic factor (Hazard ratio 0.71, 95% CI: 0.55-0.91). Further prognostic factors were age, performance status, stage, histological subtype, and grading [21]. In conclusion, residual disease after primary surgery is an important prognostic factor. Multiple surgical procedures are necessary to remove all visible tumor. Only complete debulking should be the aim of surgery before start of primary chemotherapy.

Many surgical skills and techniques described in this book are necessary for conducting adequate and successful surgeries in ovarian cancer patients.

Majority of patients are still treated in low-volume hospitals which are not specialized in treating ovarian cancer patients. An actually performed review

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Philipp Harter et al.

Lymphadenectomy In Ovarian Neoplasms LION (AGO-OVAR OP.3)

System. lymphadenectomy • epithelial invasive ovarian cancer

z pelvic

• FIGO IIB - IV

z para-aortic

• ECOG 0/1 without CI for lymphadenectomy • complete resection • absence of “bulky”nodes

R N= 640

No Lymphadenectomy

Figure 2. Design LION.

on specialization has shown that treatment by specialized centers and physicians (Gynecologic Oncologists) lead to a better quality of staging in ovarian cancer and a higher rate of optimal debulking in advanced ovarian cancer [22]. Additionally a national survey in Germany has shown that patients have a higher chance to receive state-of-the art therapy including a successful surgery in clinics involved in ovarian cancer trials [23].

Secondary surgery / Interval debulking The timing of cytoreductive surgery as upfront debulking operation was challenged because (almost) complete removal of the entire visible tumor could only be achieved in a minority of patients outside specialized centers.

At this time, interval cytoreductive surgery seemed to be an attractive option and 2 randomized prospective trials [24, 25] provide some evidence that patients with advanced ovarian cancer benefit from one successful cytoreductive surgery. Whilst van der Burg reported a survival benefit for interval debulking performed in a specialized centre after primary surgery elsewhere, Rose found no benefit for interval debulking, if primary surgery was performed by a gynecologic oncologist. An EORTC-GCG/NCIC-CTG trial has compared primary surgery versus interval debulking in patients with stage IIIC/IV ovarian cancer which has shown non-inferiority of interval debulking compared to upfront surgery [26]. However, this trial included

Cytoreductive surgery for ovarian cancer

41

only patients in whom the treating physicians have expected a low probability to achieve complete resection at primary surgery potentially benefit from neoadjuvant chemotherapy. Optimal debulking (residual disease up to 1 cm) was achieved in only 48% in patients in the primary surgery arm and in 83% after neoadjuvant chemotherapy. The survival rates showed no significant differences between the two arms (29 and 30 months), but are low compared to e.g. the last prospective randomized GCIG Intergroup trial AGO-OVAR 9 reporting a overall survival of 46 and 49 months [27]. Also the median time of surgery with 180 minutes indicates the negative selection bias in this trial population. Postoperative mortality was significantly lower in the interval debulking arm (0.6% vs. 2.7%). It is difficult to interpret this data, but it seems that patients in whom complete resection at primary surgery in experienced centers is not possible could potentially benefit in terms of lower morbidity and mortality by interval debulking. Surgery with maximal effort of cytoreduction before starting primary chemotherapy remains the standard of care in patients in whom complete resection could be achieved. Interval debulking after 2 or 3 courses of systemic therapy is an option for patients in whom surgery with maximal effort is not possible at primary diagnosis (e.g. worse performance status due to cancer symptoms and aim of improvement by “neoadjuvant” chemotherapy). This level II evidence for the role of cytoreductive surgery in advanced ovarian cancer was supported by data from an epidemiologic survey indicating that both optimal surgery and state-of-the-art chemotherapy contribute independently to the outcome in ovarian cancer [23].

Cytoreductive surgery in recurrent ovarian cancer Reviewing the role of secondary cytoreductive surgeries faces obstacles due to the broad variety of definitions used to describe different procedures.

Definitions commonly include different groups of patients, namely patients with recurrent disease and those with persistent disease; the latter might even include patients with either progressive disease at the end of chemotherapy or patients with persisting but not progressing ovarian cancer as well as both patients with small residual tumors that responded to systemic treatment and patients suffering from recurrence after a disease-free period of some weeks or several years [28,29]. There are only a very limited number of reports about surgery for persistent or primary progressive ovarian cancer. One of this series was reported by Morris et al: “The present study provided no evidence that secondary surgery is of significant…” [30]. For this subgroup survival rates up to 9 months are reported which are not justify cytoreductive surgery with a morbidity rate of 24% in this setting.

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Cytoreductive surgery for recurrence is defined as an operation performed in patients with recurrent disease after completion of primary treatment (surgery with or without chemotherapy) and a period without any evidence of disease. It is performed with the purpose of removing as much of the tumor as possible. Although usually not curative, this kind of surgery aims at prolongation of survival and its practice follows similar rules as primary surgery for advanced disease. Unfortunately, the only randomized trial about the role of cytoreductive surgery in recurrent ovarian cancer by the EORTC, the LOROCSON trial, has been aborted prematurely due to low recruitment [pers. communication I. Vergote] This review will present the available evidence about the role of cytoreductive surgery apart from randomized trials and focuses on some relevant questions: Which patients had been offered cytoreductive surgery for recurrence (selection bias?) and what were the surgical achievements?

Some authors defined optimal debulking as removal of all visible tumor while others reported small residuals with varying dimensions of maximum diameters (0.5-2 cm). The complete debulking rate varied between 9 and 82% [31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49]. All series were collected retrospectively and exposed to obvious selection bias.

Unfortunately, information about selection criteria and proportions of patients not offered cytoreductive surgery was lacking. The reported selection rates of patients without being offered surgery varied from 7%-64%.

What was / should be the appropriate endpoint for cytoreductive surgery for recurrence?

The concept of so-called optimal debulking has been introduced for primary cytoreductive surgery in advanced ovarian cancer. Mainly retrospective analyses studies had reported a kind of threshold above which cytoreduction did not result in a more favorable outcome and defined â&#x20AC;&#x153;optimal debulkingâ&#x20AC;? as achieving removal of all tumor lesions with a maximum diameter larger than this cut-off.

More recent studies had used a definition of â&#x2030;¤ 1 cm diameter of residual tumor as cut-off for inclusion criteria [50, 51] or as stratum [52, 53]. However, the concept of optimal debulking has not been very well established in cytoreductive surgery for recurrent disease.

The larger series of patients with cytoreductive surgery for recurrent disease provided controversial findings. Eisenkop and Harter reported a survival benefit only for completely debulked patients whilst Scarabelli and Zang indicated a benefit also for so-called optimally debulked patients.

However, the latter two series reported remarkably lower complete resection

Cytoreductive surgery for ovarian cancer

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rates (11% and 35%) than Harter and Eisenkop (50% and 81%), thus raising the question about different selection criteria, different surgical approaches, and methodological issues. A benefit might be missed if a subgroup bearing a potential prognostic factor is rather small. Another series from GĂźngĂśr et al with 75 patients compared completely debulked patients with patients with residual disease and those treated with chemotherapy only. Again, only patients with complete debulking showed a prolonged survival.

Are there any predictive and/or prognostic factors regarding surgical outcome in recurrent ovarian cancer?

None of the series reported age as predictive factor for resectability. The presence of symptoms, elevated CA 125, localization of disease, number of disease sites, and short treatment free interval were reported in univariate analyses as predictive factor. Only four series reported multivariate analyses of predictive or prognostic factors associated with favorable surgical outcome. Eisenkop identified absence of pre-operative salvage chemotherapy, good performance status and size of recurrent disease less than 10 cm as predictors for complete debulking. In Gronlunds series with 38 patients number of disease sites (solitary vs. multiple) was an independent factor for resectability. Zang reported absence of ascites and residual disease after surgery in primary treatment as predictors for resectability. The DESKTOP trial [36] identified the following predictors: Good performance status, no residual disease after surgery for primary treatment (alternatively, if unknown: early initial FIGO stage) and neither ascites > 500 ml in pre-OP diagnostics. Complete resection was achieved in 79% of patients presenting all these factors. If not all factors were positive, a complete resection was achieved in only 43%. The latter group could be further differentiated: a complete debulking could be achieved in 63% of this subgroup if there was no peritoneal carcinomatosis found intra-operatively; otherwise only 23% could be debulked completely. In the subsequent DESKTOP II trial patients with good performance status (ECOG 0), complete resection at primary surgery, and absence of ascites were defined as score positive and the score was validated in multicentre study. In this setting, the use of this score has shown a complete resection rate of 76% in patients with first relapse and with this result the score was validated successfully [54]. A subsequent randomized phase III trial is planned by the AGO-OVAR. Does favorable surgical outcome translate into survival benefit in recurrent ovarian cancer?

The median survival of completely debulked patients ranged from 16 to 100 months and overlapped with the median survival described in the

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recently reported large prospective trials in recurrent platinum-sensitive ovarian cancer, i.e. ICON4/AGO-OVAR 2.2 [55] and the Gynecologic Cancer Intergroup (GCIG) study AGO-OVAR 2.5 [56]. These studies reported median survival of 18 and 29 months in the respective superior arms. The majority of series of cytoreductive surgery for recurrent ovarian cancer did not report median survival far exceeding the ICON4/AGO-OVAR 2.2 results. Although median survival was on average higher in series with more completely debulked patients, a statistically significant correlation could not be detected. Furthermore, the lack of randomized trials makes it impossible to conclude whether a more favorable outcome in series with high rates of complete debulking could be attributed to biology (i.e. selection bias) or to surgical efforts.

Which prognostic factors are associated with prolonged survival in patients who received cytoreductive surgery for recurrent ovarian cancer?

Almost all series reported a relationship between survival and surgical outcome in univariate analysis. Complete debulking was one of the strongest predictors for survival in all 5 multivariate analyses performed on this question (table 3). All other factors analyzed provided controversial information.

Treatment-free-interval before cytoreductive surgery did not show any significant impact on outcome in univariate analyses of six series but another five series reported a significant role. However, only few patients with rather short treatment-free survival had been included in the respective series and the proportion of patients with less than 6 months ranged from 0 â&#x20AC;&#x201C; 13.5 % only. Therefore, the data about a possible impact of treatment-free-interval are mainly valid for different periods beyond 6 months.

Eisenkop reported a benefit for treatment-free intervals exceeding 36 months compared to shorter intervals (13-36 and 6 â&#x20AC;&#x201C; 12 months). Scarabelli showed a benefit for the subgroup with a recurrence-free-interval of 13 to 24 months but not for patients with longer (> 24 months) or shorter intervals (7-12 months). The DESKTOP trial showed a benefit for a treatment-freeinterval exceeding 6 months but no difference when intervals longer than 6 months were compared in the univariate analysis (6-12 vs. 12-24 vs. longer than 24 months). However, treatment-free-interval did not remain an independent factor in the multivariate analysis. A similar observation was reported by Zang who reported a benefit for longer progression-free-intervals in the univariate analysis which could not be confirmed in the multivariate analysis. A further factor associated with prolonged survival was absence of ascites (2 of 3 series analyzing ascites as factor) and an inverse relation was

Cytoreductive surgery for ovarian cancer

45

reported for pre-operative chemotherapy (2 of 4 series analyzing this issue).

Only three series had evaluated the impact of systemic treatment after surgery and the most recent analysis reported by Harter observed a positive impact of post-operative platinum-based chemotherapy. In addition the influence of pre-operative tumor load on surgical and prognostic outcome was still discussed controversial. An exploratory analysis of the DESKTOP II data has shown that presence of peritoneal carcinomatosis is a significant negative predictor for complete resection. However, if complete resection is achieved despite peritoneal carcinomatosis, there is no difference in survival compared to completely debulked patients without peritoneal carcinomatosis [57].

In conclusion, there is no level I/II evidence for cytoreductive surgery in recurrent ovarian cancer. However, even the most active chemotherapy regimens provided only limited activity with a median survival of 29 months (ICON4/AGO-OVAR 2.2), and improvement is clearly needed. The reported series of surgery for recurrent disease include survival rates up to 100 months, thus far exceeding the median survival rates reported after chemotherapy only. These data stem from highly selected patient cohorts and, therefore, the main question might be: How can we select suitable patients for cytoreductive surgery in recurrent ovarian cancer? The available information is far from being conclusive, but some factors were repeatedly cited as predictors for successful operations. Sound counseling of patients regarding the selection for surgery in recurrent ovarian cancer will only be possible after validation of these predictors in a kind of predictive score which provides an acceptable range of assumed factors regarding favorable outcome of surgery. The DESKTOP I study identified three variables: (1) good performance status, (2) absence of ascites, and (3) complete debulking during primary surgery (or, if unknown, early FIGO stage initially). This predictive score was successfully validated (AGODESKTOP II).

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Hoskins WJ, Bundy BN, Thigpen JT, et al. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: A Gynecologic Oncology Group study. Gynecol Oncol 1992; 47: 159-166.

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Allen DG, Heintz APM, Touw FWMM. A meta-analysis of residual disease and survival in stage III and IV carcinoma on the ovary. Eur J Gynaecol Oncol 1995;16:349-356.

Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta â&#x20AC;&#x201C;analysis. J Clin Oncol 2002; 20: 1248-1259. du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Pfisterer J. The role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer. A combined exploratory analysis of three prospectively randomized phase III multicenter trials by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux pour les Etudes des Cancers de l'Ovaire (GINECO). Cancer (accepted). du Bois A, Quinn M, Thigpen T, et al. 2004 consensus statements on the management of ovarian cancer : final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol 2005 ; 16 Sup18 :viii7-viii12.

Eisenhauer EL, Abu-Rustum NR, Sonoda Y, et al. The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIC-IV epithelial ovarian cancer. Gynecol Oncol 2006; 103:1083-1090.

Harter P, Gnauert K, Hils R, et al. Pattern and clinical predictors of lymph node metastases in epithelial ovarian cancer. Int J Gynecol Cancer 2007; 17:1238-44.

Panici PB, Maggioni A, Hacker N. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomzed clinical trial. J Natl Cancer Inst 2005; 97: 560-566.

Chambers SK. Systematic lymphadenectomy in advanced epithelial ovarian cancer : two decades of uncertainty resolved. J Natl Cancer Inst 2005; 97: 548-549.

Crawford CS, Vasey PA, Paul J, et al. Does aggressive surgery only benefit patients with less advanced ovarian cancer? Results from an international comparison within the SCOTROC-1 trial. J Clin Oncol 2005; 23: 8802-8811.

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21. du Bois A, Reuss A, Harter P, Meier W, Wagner U, Sehouli J, Gropp M, Pfisterer J on behalf of the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR). The role of lymphadenectomy in advanced epithelial ovarian cancer (AOC) in patients with macroscopically complete resection of intraperitoneal disease. Int J Gynecol Cancer 2006, 16 (S3), 601 (#0008).

22. Du Bois A, Rochon J, Pfisterer J, Hoskins WJ. Variations in institutional infrastructure, physician specialisation and experience, and outcome in ovarian cancer. Gynecol Oncol 2009; 112: 422-36.

23. Du Bois A, Rochon J, Lamparter C, Pfisterer J. Pattern of care and impact of participation in clinical studies on the outcome in ovarian cancer. Int J Gynecol Cancer 2005;15: 183-91.

24. Van der Burg MEL, van Lent M, Buyse M, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995; 332: 629-634.

25. Rose PR, Nerenstone F, Brady MS, et al. Secondary surgical cytoreduction for advanced ovarian carcinoma N Engl J Med 2004; 351: 2489-2497.

26. Vergote I, Trope CG, Amant F, et al. EORTC-GCG/NCIC-CTG Randomised trial comparing primary debulking surgery with neoadjuvant chemotherapy in stage IIIC/IV Ovarian, fallopian tube and peritoneal cancer. 12th Biennial meeting of the IGCS, Bangkok 2008.

27. Du Bois A, Kristensen G, Joly F, et al. Randomized phase III GCIG study (AGOOVAR 9, GINECO-TCG, NSGO-OC-0102) : Gemcitabine-paclitaxel-carboplatin vs. Paclitaxel-carboplatin as first line treatment of ovarian cancer. 12th Biennial meeting of the IGCS, Bangkok 2008.

28. Sharp F, Blackett AD, Leake RE, Berek JS. Conclusions and recommendations from the Helene Harris Memorial Trust fifth biennial international forum on ovarian cancer, May 4 â&#x20AC;&#x201C; 7, 1995, Glasgow UK. Int J Gynecol Cancer 1995; 5: 449-458.

29. Berek JS, TropĂŠ C, Vergote I. Surgery during chemotherapy and at relapse of ovarian cancer. Ann Oncol 1999; 10 (suppl 1): 3-7.

30. Morris M, Gershenson DM, Wharton JT. Secondary cytoreductive surgery in epithelial ovarian cancer : nonresponders to first-line therapy. Gynecol Oncol 1989; 33:1-5.

31. Cormio G, di Vagno G, Cazzolla A, et al. Surgical treatment of recurrent ovarian cancer: report of 21 cases and a review of the literature. Eur J Obstet Gynecol Reprod Biology 1999; 86: 185-188.

32. Eisenkop SM, Friedman RL, Spirtos NM. The role of secondary cytoreductive surgery in the treatment of patients with recurrent epithelial ovarian carcinoma.

Cancer 2000; 88: 144-153.

33. Gadduci A, Iacconi P, Cosio S, et al. Complete salvage surgical cytoreduction improves further survival of patients with late recurrent ovarian cancer. Gynecol Oncol 2000; 79: 344-349.

34. Gronlund B, Lundvall L, Christensen IJ, et al. Surgical cytoreduction in recurrent ovarian carcinoma in patients with complete reponse to paclitaxel-platinum. Eur J Surgical Oncology 2005; 31: 67-73.

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35. GĂźngĂśr M, Ortac F, Arvas M et al. The role of secondary cytoreductive surgery for recurrent ovarian cancer. Gynecol Oncol 2005; 97: 74-79.

36. Harter P, du Bois A, Hahmann M, et al. Surgery in Recurrent Ovarian Cancer: The Arbeits gemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR Trial. Ann Surg Oncol 2006; 13: 1702-1710.

37. Jaenicke F, Holscher M, Kuhn W, et al. Radical surgery procedure improves survival time in patients with recurrent ovarian cancer. Cancer 1992; 70: 21292136.

38. Kuhn W, Schmalfeldt B, Pache L, et al. Disease-adapted relapse therapy for ovarian cancer: results of a prospective study. Int J Oncol 1998; 13: 57-63.

39. Leitao MM, Kardos S, Barakat RR, Chi DS. Tertiary cytoreduction in patients with recurrent ovarian cancer. Gynecol Oncol 2004; 95: 181-185.

40. Loehr A, Harter P, Traut A, et al. Cytoreductive surgery in recurrent ovarian cancer. J Cancer Res Clin Oncol 2004; 130 (suppl 1): 122 (abstract OP570).

41. Morris M, Gershenson DM, Wharton JT, et al. Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Gynecol Oncol 1989; 34: 334-338.

42. Munkarah A, Levenback C, Wolf JK, et al. Secondary cytoreductive surgery for localized intra-abdominal recurrences in epithelial ovarian cancer. Gynecol Oncol 2001; 81: 237-241.

43. Onda T, Yoshikawa H, Yasugi T, et al. Secondary cytoreductive surgery for recurrent epithelial ovarian carcinoma: proposal for patients selection. Br J Cancer 2005; 92, 1026-1032.

44. Pecorelli SP, Sartori E, Santin A. Follow-up after primary therapy: management of the symptmatic patient: surgery. Gynecol Onncol 2001; 81: 138-142.

45. Scarabelli C, Gallo A, Carbone A. Secondary cytoreductive surgery for patients with recurrent epithelial ovarian carcinoma. Gynecol Oncol 2001; 83: 504-512.

46. Tay EH, Grant PT, Gebski V, Hacker NF. Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Obstet Gynecol 2002; 99: 1008-1013.

47. Vaccarello L, Rubin SC, Vlamis V, et al. Cytoreductive surgery in ovarian carcinoma patients with a documented previously complete surgical response.

Gynecol Oncol 1995; 57: 61-65.

48. Zang RY, Zhang ZY, Li ZT, et al. Effect of cytoreductive surgery on survival of patients with recurrent epithelial ovarian cancer. J Surg Oncol 2000; 75: 24-30.

49. Zang RY, Li ZT, Tang J, et al. Secondary cytoreductive surgery for patients with relapsed epithelial ovarian carcinoma: who benefits? Cancer 2004; 100: 1152-1161.

50. McGuire WP, Hoskins WJ, Brady MF. Cyclophosphamide and cisplation compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334: 1-6.

51. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimalley resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 2003; 21: 3194-3200.

52. Piccart MJ, Bertelsen K, James K, et al. Randomized Intergroup trial of cisplatinpaclitaxel versus cisplatin-cyclophospahmide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000; 92: 699-708.

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53. du Bois A, Lueck HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003; 95: 1320-1329.

54. Harter P, Sehouli J, Reuss A, et al. Predictive factors for resection in recurrent ovarian cancer. Intergroup study of AGO Kommission Ovar, AGO-OVAR, AGO Austria, MITO and NOGGO. 12th Biennial meeting of the IGCS, Bangkok 2008.

55. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361: 2099-106.

56. Pfisterer J, Plante M, Vergote I, et al. Gemcitabine/carboplatin vs. carboplatin in platinum sensitive recurrent ovarian cancer. Results of a Gynecologic Cancer Intergroup randomized phase III trial of the AGO OVAR, the NCIC CTG and the EORTC GCG. J Clin Oncol 2006;24: 4699-707.

57. Harter P, Hahmann M, Lueck HJ, et al. Surgery for Recurrent Ovarian Cancer: Role of Peritoneal Carcinomatosis: Exploratory Analysis of the DESKTOP I Trial About Risk Factors, Surgical Implications, and Prognostic Value of Peritoneal Carcinomatosis. Ann Surg Oncol 2009; Feb 19: epub ahead of print.

Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 51-71 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

4. Surgical and chemotherapeutic cytoreduction for advanced primary and recurrent ovarian cancer, the Washington Cancer Institute approach Paul H. Sugarbaker Program in Peritoneal Surface Malignancy, Washington Cancer Institute, Washington, DC, USA

Abstract. Ovarian cancer remains the number one cause of death from gynecological malignancies. Currently, the conventional treatment approach for advanced (stage III and IV) ovarian malignancy is surgical debulking and systemic chemotherapy.

Negative second-look laparotomy is attainable in only 20 to 40% of the cases. Up to 47% of these patients relapse within 5 years. In an effort to improve the results of treatment a Comprehensive Approach including cytoreductive surgery and perioperative intraperitoneal chemotherapy has been utilized. This approach is based on the success achieved with other peritoneal surface malignancies.

The goal of these treatments is to surgically eradicate all visible tumor and then to chemically eradicate microscopic residual disease.

Cytoreductive surgery includes peritonectomy procedures and visceral resections. Cisplatin and doxorubicin are administered through the intraperitoneal route with heat during the surgical procedure. In the first five postoperative days patients receive normothermic intraperitoneal paclitaxel.

Results of a phase II trial with this Comprehensive Approach suggests improved survival as compared to historical controls with reasonable morbidity and mortality.

Correspondence/Reprint request: Dr. Paul H. Sugarbaker, Program in Peritoneal Surface Malignancy, Washington Cancer Institute, Washington, DC, USA. E-mail: Paul.Sugarbaker@medstar.net

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Introduction Ovarian cancer is the number one killer among gynecological malignancies. Information from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute (NCI) shows that the incidence of ovarian cancer in the US for all races has been fluctuating between 14 and 16 per 100,000 persons during the 1991-2001 decade.[1] According to the same source, the US Estimated Complete Prevalence Counts on 1/1/2001 were 167,002.[2] Also, a woman age 45 living in the United States has a probability of developing ovarian cancer of 0.117%; and at age 75 a probability of 1%.[3] Ovarian cancer is the fifth more common cause of cancer death in Western countries.[4] Unfortunately, symptoms are generally unspecific. A recent case-control study showed that when either increasing abdominal size, bloating, urinary urgency or pelvic pain occur more frequently, and with more intensity than expected or these symptoms are of recent onset, further investigation searching for an ovarian mass is warranted.[5] In the past, CA-125 tumor marker levels, transvaginal ultrasound, and pelvic examinations were thought to be potential effective screening tools. However, none of them have proved to decrease mortality from ovarian cancer and may lead to unnecessary emotional distress and invasive diagnostic procedures. As a consequence of its internal location and non-specific symptomatology most patients are diagnosed with ovarian cancer in late stages of the disease.

Most tumors are epithelial in origin (approximately 90%) and the minority is either germ cell or stromal tumors (roughly 10%). Once a tumor starts growing in the ovary, spread of cancer cells throughout the abdominopelvic cavity occurs very early in the natural history of the disease probably due to the anatomic structures of the ovary. This organ is covered by a thin layer of visceral peritoneum which is easily disrupted by the expansion and the invasive nature of the cancerous growth. This early intracoelomic dissemination causes ovarian cancer to spread beyond the internal female genitalia at the time of diagnosis in a great majority of patients.[6,7] However, peritoneal implantation is not the only route of dissemination. Depending on the stage, up to 74% of the women with ovarian cancer have pelvic and/or paraaortic lymph nodes involvement.[8] A smaller percentage of these women may develop hematogenous metastases in the liver, lungs, bone marrow, and brain.

In many patients the natural history of ovarian cancer is similar to other secondary peritoneal surface malignancies; for example, carcinomatosis from primary gastric cancer. Carcinomatosis results in debilitating ascites formation and intestinal obstruction in late stages. With knowledge of the

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progression of this disease, the targets of the treatment should be the peritoneal surface spread as well as the systemic metastases. Eradication of the peritoneal surface component of this disease would be a major contribution to the overall management of this disease. Comprehensive management using surgical cytoreduction to decrease the tumor load to a minimum and perioperative intraperitoneal chemotherapy to eliminate macroscopic disease on peritoneal surfaces has the potential to greatly improve quality of life and have some impact on survival in ovarian cancer patients.

A comprehensive approach to ovarian cancer treatment The Program in Peritoneal Surface Malignancy at the Washington Cancer Institute has initiated a treatment strategy that combines as a single event surgery and perioperative chemotherapy. Cytoreductive surgery, including peritonectomy procedures and visceral resections, has been used in a surgical effort to eradicate all visible disease from peritoneal surfaces and from the viscera. Peritonectomies are performed on demand; that is, only when there is visible disease on the peritoneal surface are these membranes stripped by electrosurgical dissection. Also, visceral resections are carried out as needed to clear the abdominal cavity from visible ovarian cancer.

Retroperitoneal and pelvic lymphadenectomy are included to resect palpably involved lymph nodes. After all resections are completed and before any reconstructions, heat-augmented chemotherapy agents are administered in a large volume of chemotherapy solution. The heated intraoperative intraperitoneal chemotherapy (HIPEC) is administered with the goal of destroying microscopic residual disease and preventing cancer cell implantation. As a result of surgical trauma and visceral manipulation, extensive raw tissue surfaces are vulnerable to cancer cell adherence, implantation and progression. This chemotherapeutic cytoreduction is supplemented with the administration of early postoperative intraperitoneal chemotherapy (EPIC) using paclitaxel. EPIC is the use of an additional cell cycle-specific intraperitoneal chemotherapeutic agent during the first five days of the postoperative period.

The intraperitoneal route for administration of chemotherapy has been shown to improve progression-free survival and overall survival as compared to a systemic route in ovarian cancer patients.[9-11] However, a significant contrast exists between this experience and the comprehensive management discussed in this manuscript. As itemized in Table 1, the efficacy and the simplicity of intraperitoneal chemotherapy administration may be greatly augmented by a perioperative timing of the regional drug delivery. Nevertheless, these two intraperitoneal treatments are regarded as complimentary rather than competitive.

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Table 1. Contrast of long-term intraperitoneal chemotherapy and perioperative intraperitoneal chemotherapy for ovarian cancer.

Long-term intraperitoneal chemotherapy Yes

Perioperative intraperitoneal chemotherapy No

Yes

No

No

Yes

Uniform manual distribution of chemotherapy solution possible

No

Yes

Heat targeted systemic chemotherapy possible

No

Yes

Multiple cycles possible Limited distribution because of adhesions Can be readily combined with hyperthermia

Selection criteria and institutional requirements for a comprehensive treatment plan Cytoreductive surgery and perioperative intraperitoneal chemotherapy represents an innovative strategy for treatment of ovarian malignancies, requiring a knowledgeable selection of patients, a strong commitment from the surgical team, and long-term institutional support.

Selection of patients is based on two well-defined criteria: ability of the patient to survive an extensive surgical procedure with acceptable morbidity and mortality and no evidence of clinical findings that would result in a futile surgical procedure with residual cancer present after a best surgical effort.

Patients of advanced age, poor performance status, malnourished or with medical conditions that would decrease the likelihood of postoperative survival should not be selected for combined treatment. Also, patients with systemic metastases, two or more sites of bowel obstruction, common bile duct obstruction or bilateral ureteral obstruction should not be submitted to this comprehensive treatment.

This procedure requires dedication from an oncologic surgeon who must have broad surgical knowledge, a thorough understanding of intraperitoneal chemotherapy, unusual technical skills and the stamina to endure long procedures. Because these interventions are extensive and thereby costly, institutional backing is important. Early in the effort, Institutional Review Board approval is advised to protect the patients, the surgeons and the institution itself.

An effort to educate other physicians involved in this treatment, as well as nurses and ancillary personnel, should occur. Standardized orders for chemotherapy

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and a clear written clinical pathway will help to coordinate the actions of the clinical staff. The learning curve that accompanies a new program requires careful planning and frequent morbidity/mortality review on a regular basis.[12]

Quantitative prognostic indicators The three assessments useful for patient selection in order to treat patients most likely to benefit are the prior surgical score (PSS), the peritoneal cancer index (PCI) and the completeness of cytoreduction score (CC).

The abdominopelvic regions are used to study in a quantitative manner factors that may control the outcome of peritoneal surface malignancy treatments (Figure 1). Two transverse planes and two sagittal planes are used to divide the abdomen into 9 abdomino-pelvic regions (AR 0-8). The upper transverse plane is located at the lowest aspect of the costal margin. The lower transverse plane is placed at the anterior superior iliac spine. The sagittal planes divide the abdomen into 3 equal sectors. These lines define nine regions, which are numbered in a clockwise direction with 0 at the umbilicus and 1 defining the space beneath the right hemidiaphragm. The anatomic structures that are associated with each of these 13 regions have been designated.

Figure 1. The abdomino-pelvic regions.

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Prior surgical score Surgical trauma promotes cancer cell implantation. Prior surgeries may modify the natural history of ovarian cancer by inducing cancer growth at crucial anatomic sites located beyond the peritoneal layer (e.g. ureters and pelvic sidewall). Complete cytoreduction may not be possible if tumor nodules are allowed to implant on vital structures. It is therefore very important to preoperatively assess the extent of prior surgeries before attempting a definitive cytoreductive surgery with perioperative intraperitoneal chemotherapy. The prior surgical score (PSS) uses abdominopelvic regions 0-8 to create an important quantitative prognostic indicator. Patients with no prior abdominopelvic surgery or biopsy only received a PSS of 0, those with up to one abdominopelvic region dissected received a PSS of 1, those with two to five abdominopelvic regions received a PSS of 2 and those with six or more regions dissected received a PSS of 3. Look and colleagues showed that patients who had a PSS of 3 or higher had a significantly reduced survival than those patients with a PSS of 0, 1 or 2.[13]

Peritoneal cancer index The peritoneal cancer index (PCI) is a quantitative prognostic indicator that is useful for patient selection for the Comprehensive Approach. The PCI is determined after abdominal exploration and complete separation of intestinal adhesions. This index combines a size and a distribution parameter to achieve a numerical score. The lesion size score (LS) is used to quantitate the size of peritoneal nodules. LS-0 indicates no tumor seen, LS-1 indicates tumor implants up to 0.5 cm, LS-2 indicates tumor implants between 0.5 cm and 5 cm. LS-3 indicates tumor implants larger than 5 cm or a layering of cancer. The distribution of tumor is determined in the thirteen abdominopelvic regions. In contrast to the PSS, the small bowel is assessed as an additional four abdominopelvic regions, designated AR-9 to AR-12 and includes the upper jejunum, lower jejunum, upper ileum and lower ileum respectively. The summation of the lesion size score in each of the 13 abdominopelvic regions is the peritoneal cancer index (PCI), ranging from 0 to 39 (Figure 2). As discussed later in this manuscript the PCI provides a useful guideline that helps direct the surgeon toward comprehensive treatment when the score is low. A high score would suggest a minimal palliative intervention.

Completeness of cytoreduction score Completeness of cytoreduction (CC) is a quantitative prognostic indicator determined after the surgical resection has been completed. A patient receives a CC-0 score when no visible peritoneal carcinomatosis remains

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Figure 2. Peritoneal cancer index (PCI). The score is a summation of cancer implant lesion size (scored 0 to 3) present in 13 abdominopelvic regions. (From Esquivel J, Sugarbaker PH: Elective surgery in recurrent colon cancer with peritoneal seeding: When to and when not to proceed. Cancer Therapeutics 1998; 1:321-325).

after cytoreduction. CC-1 is recorded when tumor nodules persist after cytoreduction but they measure less than 0.25 cm. CC-2 indicates that residual tumor nodules measure between 0.25 to 2.5 cm. When tumor nodules are greater than 2.5 cm or there is confluence of unresectable tumor, a CC-3 score is given. Several prior studies in ovarian cancer have shown that the size of the cancer nodules remaining after cytoreduction is directly related to the survival. The smaller the residual nodules, the greater the likelihood of a long-term survival.[14,15] By a â&#x20AC;&#x153;log-killâ&#x20AC;? hypothesis one would predict this observation to be true.

Surgical techniques used for a complete cytoreduction in selected patients Patient preparation for surgery Once a decision to proceed with surgery is made, before the surgical intervention the patient follows an exercise program that would improve aerobic capabilities and increase muscular mass. A routine bowel preparation is prescribed for the day prior to the surgery. Under general endotracheal anesthesia with adequate monitoring, the surgical team introduces a doublelumen central venous line for the purpose of both central venous pressure

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monitoring and fluids administration. For the first five postoperative days this line will be used for administration of total parenteral nutrition. Both arms are placed in abduction and the back in extension. Sequential compression boots (SBC Compression Boots, Kendall Co., Ma.) are placed surrounding the calves for deep venous thrombosis prevention. The patient is placed in the lithotomy position using St. Mark’s leg holders (AMSCO, Erie, Pa.) so that weight of the leg is held by the heels and not by the calves.[16] Because the surgical intervention lasts for 8 to 12 hours, it is extremely important to verify that the patient’s position on the table is proper. Decubitus ulcers, nerve damage and compartment syndromes are common and must be avoided. Egg-crate foam padding for arms and legs are used to decrease the risk of these complications. The body temperature must be carefully monitored for low temperature from extensive exposure of viscera during the cytoreductive surgery and for high temperature during heated intraoperative intraperitoneal chemotherapy.

Antibiotics are administered in a prophylactic fashion during the surgery.

The extent of the raw surface after peritonectomies increases the risk of postoperative hemorrhage precluding the use of heparin for deep vein thrombosis prophylaxis for the first four days after surgery. This prevention is limited to the sequential compression boots as described above during this time; heparin is used after bleeding and clotting tests have returned to normal.

Other requirements for a successful cytoreductive surgery are two suction tubes in the operative field, an electrosurgical unit capable of high voltage pure cut and spray coagulation modes, a 3-mm electrosurgical balltip, an electrosurgery tip extender, and at least one smoke evacuator. The temperatures at the electrosurgical dissection plane can be very high and result in heat damage to tubular structures. The second assistant or the scrub nurse frequently irrigates with room temperature normal saline solution.

Frequent large volume irrigation is necessary when dissecting around tubular structures. The irrigation also keeps tissues free of debris and blood, thereby preserving tissue transparency. Residual saline solution in small volume promotes an efficient electrosurgical dissection.

Once the surgical field is properly prepared and draped, the Thompson selfretaining retractor’s frame is placed (Thompson Surgical Instruments, Inc., Traverse City, Mi.). The surgeon may fasten suction tubes, electrosurgery cable, and smoke evacuator hoses to the Thompson retractor’s frame.

Anterior parietal peritonectomy and complete abdominal exploration In order to perform a full abdominal exploration a vertical median xiphopubic incision is performed. The incision should always include the

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umbilicus since, in cases of peritoneal carcinomatosis, this anatomic site is at a very high risk of cancer involvement. When patients desire preservation of the umbilicus for aesthetic reasons a plastic reconstruction can be accomplished.

The incised skin edges are elevated in a symmetrical manner by cutaneous traction sutures (Figure 3). The fascia is incised directly through the linea alba.[17] The posterior rectus sheath is dissected away from the underlying anterior parietal peritoneum towards the left and the right of the midline, initially in a centrifugal fashion. Once the dissection has progressed approximately 10 cm from midline to lateral, the Thompson retractor blades are placed so that they pull back the abdominal wall creating an angle between the peritoneum and the posterior rectus abdominis sheath (Figure 4).

The initial centrifugal dissection continues laterally to the paracolic sulci. In the cephalic direction the resection includes the round and falciform ligaments but not the undersurface of the hemidiaphragms. In the caudal direction the anterior parietal peritoneum specimen is separated from the pelvic peritoneum at the dome of the bladder. The urachus is identified and elevated on a clamp. This will be the lead point for pelvic peritonectomy at a later time.

Figure 3. Cutaneous traction sutures are placed using a strong monofilament suture.

The sutures are placed approximately every 8 cm along the skin edge. The traction sutures are secured to a self-retaining retractor using hemostats.

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Figure 4. Anterior parietal peritonectomy.

Once the anterior parietal peritoneum specimen is removed, the surgeon can perform a complete abdominal exploration. This includes a lysis of all adhesions. At this time, the peritoneal cancer index (PCI) can be determined.

The success of complete cytoreduction and long-term survival can be estimated by assessment of the distribution and the mass of peritoneal surface cancer.[18] The PCI has been established as a quantitative prognostic indicator for advanced ovarian cancer.[19]

Right and left subphrenic peritonectomies The right subphrenic peritonectomy is a centripetal dissection that detaches the peritoneum with its layer of cancer from the undersurface of the right hemidiaphragm (Figure 5). It is also necessary to detach the peritoneum from the liver surface and to electroevaporate any disease from Glissonâ&#x20AC;&#x2122;s capsule. In the retrohepatic space, the dissection extends centripetally to the inferior vena cava. The peritoneum covering the perirenal fat and the right adrenal gland is also detached from the postero-inferior edge of the liver.

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Figure 5. Right upper quadrant peritonectomy.

The duodenum and the porta hepatis constitute the medial border of the right subphrenic peritonectomy.

Also as a centripetal dissection, the left subphrenic peritonectomy includes the undersurface of the left hemidiaphragm. It requires separation of the left lobe of the liver from the triangular ligament that becomes a part of the peritonectomy specimen. Electroevaporation of tumor layering out on the left lobe Glissonsâ&#x20AC;&#x2122;s capsule is required. This dissection liberates the spleen, which at this point in time remains attached to its pedicle, to the greater omentum, and to the lienocolic ligament.

The surgeon must avoid penetrating the pleural cavity because that will allow cancer dissemination within the thoracic cavity. In case of chest penetration through the diaphragm, the heated intraoperative intraperitoneal chemotherapy should be allowed to enter the chest cavity by enlarging the diaphragmatic incision to prevent pleural implantation. The closure of the diaphragm should take place after the HIPEC is completed.

Greater omentectomy and splenectomy The greater omentum is elevated under strong traction as it is detached from the transverse colon along with the visceral peritoneum that covers the anterior aspect of the transverse mesocolon mesentery. The right gastroepiploic

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artery is ligated in continuity and all the small gastroepiploic branches on the greater curvature are also individually ligated as they reach the stomach. The short gastric vessels are also ligated and divided. At this point it is necessary to carefully evaluate the splenic hilum which is prominent site for cancer deposits. If the spleen or its hilum appear to be involved, the splenic artery and veins are individually ligated. In order to complete the greater omentectomy the left gastroepiploic vessels are ligated in continuity and divided.

In all of the left upper quadrant dissection the pancreas needs to be protected from trauma especially when dissecting the splenic vessels.

Cholecystectomy, lesser omentectomy and stripping of the omental bursa The most dependent part of the omental bursa is the space behind the pylorus, called the â&#x20AC;&#x153;retropyloric space.â&#x20AC;? This is a common site in which tumor accumulation takes place. Since the vessels along the greater curvature of the stomach have been divided, the blood supply for the stomach is limited to the right and left gastric arteries. With these crucial concepts in mind the surgeon can continue with the next step. The lesser omentectomy is a circular dissection that starts with a cholecystectomy and dissection of the anterior and posterior aspect of the hepatoduodenal ligament. The gastrohepatic ligament is divided at the peritoneal reflection along the gastrohepatic fissure between the left lateral liver segment and the caudate lobe. An accessory left hepatic artery may occur in the mid-portion of this ligament. After confirmation that the main left hepatic artery is intact, the accessory left hepatic artery can be ligated. The surgical dissection continues at the crus of the diaphragms. In order to protect and preserve the vessels of the lesser curvature (only remaining blood supply to the stomach after the greater omentectomy), the lesser omental fat and adherent tumor is crushed between the thumb and index fingers. This digital dissection exposes the network of vessels between the right and left gastric arteries and therefore the surgeon can resect the lesser omental adipose tissue along with tumor without damage to the vascular arcade.

The last portion of the lesser omental dissection is the stripping of the floor of the omental bursa. The peritoneum is divided at the reflection between the caudate lobe and the left side of the inferior vena cava. Then dissecting in a cephalic direction, the peritoneum covering the right diaphragmatic crus is elevated. The peritoneum can then be bluntly stripped by pulling it in a caudal and external direction. Once it is stripped down to the superior edge of the pancreas, the peritoneum can be incised, keeping in mind the close proximity of the left gastric artery and lymph nodes of the common hepatic artery.

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Pelvic peritonectomy The stripping of the pelvic peritoneum includes the cul-de-sac. Before starting the dissection the surgeon must evaluate tumor involvement of the sigmoid colon and rectum. The epiploic appendages contain a large amount of lymphoid aggregates, which have great absorptive capabilities similar to those of the greater omentum, making it possible that these appendages may require resection. Also, tumor cells accumulate by gravity at dependent sites.

This and the fact that the peritoneal cul-de-sac is intimately attached to the rectum frequently make it impossible for the surgeon to make the patient disease-free without a rectosigmoid resection along with the pelvic peritonectomy.

The centripetal dissection for the pelvic peritonectomy starts with the creation of an anterior flap of peritoneum by separating it from the bladder.

The posterior peritoneal flap starts at the ligament of Treitz. There, the posterior parietal peritoneum is separated from the fourth portion of duodenum, the inferior mesenteric vein is ligated in continuity, and the dissection progresses medially separating the peritoneum from the third portion of the duodenum. The stripping proceeds caudally as the sigmoid colon is divided by a linear stapler and the inferior mesenteric artery is ligated and divided. Both ovarian veins are ligated and divided at the level of the inferior border of the perirenal fat. Left and right ureters are identified in the abdomen as peritoneal stripping continues towards the pelvis. The centripetal dissection joins the anterior and posterior flaps. The anterior pelvic peritonectomy proceeds to go across the vagina reaching the anterior aspect of the rectum by elevating the cul-de-sac. Laterally, the uterine arteries are ligated lateral to the ureters and the vagina is incised. The dissection meets the lateral aspect of the rectum below the peritoneal cul-de-sac. Once the circumferential electroevaporation has freed up the rectum, the organ is divided across the mid-rectum with a linear stapler. The specimen of pelvic peritonectomy contains the pelvic peritoneum, the sigmoid and the upper portion of the rectum, and if they had not been extirpated before, the uterus and both ovaries.

Heated intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC) After the cytoreductive surgeries with peritonectomies have been completed, the chemotherapy washing of the abdomen is performed. Even if a CC-0 score is determined, it is invariably true that invisible to the naked eye, cancer cells remain within the peritoneal cavity. Tumor manipulation,

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transected lymphatic ducts leaking tumor cells throughout the procedure, and small tumor nodules remaining on the abdominal and pelvic surfaces of organs not amenable to peritonectomy procedures, namely small bowel, require the implementation of some method that will cytoreduce residual tumor cells. The technique uses mechanical removal, chemical (chemotherapeutic killing) and physical killing of cancer cells. A well known site for persistent disease are the suture lines; they represent an ideal site for cancer cell implants. Tumor cell entrapment occurs on these raw surfaces with fibrin accumulating and tissues compressed together by stitches or staples. Suture lines are at high risk of recurrence if constructed before the intraperitoneal chemotherapy and therefore not directly treated for residual cancer cells.

HIPEC using an open technique employs mechanical, physical and chemical effects to further cytoreduce cancer cells after surgery. A mechanical effect to eradicate cancer cells trapped in fibrin and tissue debris takes place during 90 minutes of continuous rubbing and washing of the intraabdominal surfaces. Heat, a physical effect, promotes cell death by various mechanisms affecting nucleic acids, cell membranes and the cytoskeleton.[20] The target temperature within the peritoneal cavity is approximately 42째. Some chemotherapeutic agents such as mitomycin C, doxorubicin, cisplatin and melphalan among others, have their cell killing effect enhanced by heat creating a synergistic result.[21] Also, penetration of chemotherapy into tissues is augmented by heat.[22] The intraperitoneal route of chemotherapy administration for carcinomatosis has another advantage. The concentration times time (area under the curve or AUC) of the cytotoxic agent in the peritoneal cavity is many times higher than that in the plasma compartment. The AUC ratio of peritoneal to plasma varies for different drugs, but it can be as high as 1,000 for paclitaxel, for example.[23] This feature of intraperitoneal chemotherapy with selected drugs makes possible high concentration of the agent where the disease is localized, enhancing the cell killing effect and decreasing the systemic toxicity. Ideally, the drug to be used should be active against ovarian cancer, non-toxic for non-cancer cells, of high molecular weight to cause a slow peritoneal clearance, and have a high penetration into tumor tissues.

Several drugs have been used for intraperitoneal irrigation for patients with ovarian cancer: cisplatin alone, carboplatin alone, mitoxantrone alone and cisplatin plus doxorubicin.[24-27] Our group has used a combination of cisplatin (50 mg/m2) and doxorubicin (15 mg/m2). Sugarbaker, after a dose escalation study, determined that a low dose of doxorubicin (15 mg/m2) would result in a thin layering of fibrous tissue on peritoneal surfaces that has not been reported to interfere in any way with subsequent gastrointestinal function.[28]

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There are multiple reasons to recommend doxorubicin as an intraperitoneal chemotherapy agent.[29] Perhaps most important, due to the large molecular size of this drug its clearance from the peritoneal cavity is greatly delayed. It is also known that its penetration is at least five cell layers making it appropriate for the elimination of small volume residual disease postoperatively. It is also augmented in its anticancer effects by heat.[22] Cisplatin has been shown to have improved penetration into cancerous tissue when administered with heat as compared to normothermic conditions.

The increase in cytotoxicity is estimated at 1.8 times.[30] Also, the peritoneum/plasma area under the curve ratio is favorable. These factors plus the activity of this drug both for primary and recurrent ovarian cancer has led to its frequent use by intraperitoneal administration.[31]

Technique for heated intraoperative intraperitoneal chemotherapy An abdominopelvic reservoir is constructed by tenting up the skin edges to a specially designed instrument that allows hand distribution of the chemotherapy agent and total containment.[32] The double-gloved hand guarantees that the perfusate reaches particularly difficult places within the peritoneal cavity, such as the space between the bowel loops, the space behind the liver, and the rectal stump deep within the pelvic cavity.

In order to keep the temperature at a constant 42ยบC, a roller pump forces the solution through a heat exchanger. Then it proceeds to that abdominopelvic cavity through a catheter. The hyperthermic perfusate is drained from the abdomen through drains going back to the heat exchanger, and closing the circuit. The inflow catheter and the closed suction drains are secured watertight with purse-string sutures on the skin of the abdomen to avoid leaks and spillage. The chemotherapy solution circulates for 90 minutes at 42ยบC. After the 90 minutes of HIPEC with manual distribution, the surgeon may assume that fibrin and tissue debris and the microscopic residual disease they contain have been eradicated. At this time, all the anastomosis and any additional reconstruction can occur. Closed-suction drains and an inflow catheter are properly positioned for subsequent EPIC. In the first five postoperative days ovarian cancer patients receive EPIC. This involves normothermic intraperitoneal paclitaxel (20-40 mg/m2/day).

Systemic paclitaxel has been used to treat advanced ovarian cancer alone and in combination with other drugs. In phase III clinical trials the combination resulted in improved response rates and also improved survival.[33] The extremely favorable area under the curve ratio (1000) and the remarkable drug penetration of up to 80 cell layers deserve mention.[34] Mohamed and colleagues studied the use of paclitaxel in 6% hetastarch as a carrier solution. The retention of the high molecular weight carrier solution

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as compared to the salt solution in the abdominopelvic space improved the drug exposure to peritoneal surface cancer nodules without any increase in systemic toxicity.[35] A potential problem with intraperitoneal paclitaxel is the lipid solvent and the fact that carcinogens can be leached out of soft plastic used to administer the infusions. Stuart and colleagues discussed the technical precautions that will minimize this potential hazard.[36] In summary, HIPEC and EPIC combine mechanical, physical and chemical effects for continued tumor cell cytoreduction. They are used as a planned part of the surgical procedure and the postoperative care in the highly controlled environments of the operating room, surgical intensive care unit, and a specialized nursing unit.[34]

Results of comprehensive treatment in advanced primary and recurrent ovarian cancer treated at the Washington Cancer Institute In patients who have failed the standard treatments of primary ovarian cancer the survival is short with an estimated median survival of 8 months.

Figure 6 shows the survival curve of 28 patients with advanced primary and recurrent epithelial ovarian cancer or papillary serous cancer. These patients had exhausted all conventional treatments for ovarian cancer. Median survival was 45.8 months. Further analysis of the clinical features that affected survival determined that extent of prior surgery (PSS), the peritoneal cancer index (PCI) and completeness of cytoreduction (CC) were factors significantly affecting survival.

Those patients with extensive prior surgery, that is with three or more abdominopelvic regions subjected to surgical dissection were less likely to receive a complete cytoreduction and their survival was significantly shorter.[13] Patients with a low prior surgical score (PSS 0 or 1: less than three abdominopelvic regions previously dissected) had a median survival of 6.5 years, compared to 1.5 years for those patients with a higher PSS (p=0.001)(Figure 7).

Patients who had extensive disruption of peritoneal surfaces are not expected to receive maximal benefit from peritonectomy. These observations reported by Look and colleagues have not been previously published. In the past and prior to the utilization of our comprehensive management strategy one assumed that the more aggressive the surgical extirpation of ovarian cancer the greater the likelihood of a prolonged systemic chemotherapy benefit. These new data regarding prior surgical score show that other critical factors concern the survival of ovarian cancer patients when cytoreductive surgery plus perioperative intraperitoneal chemotherapy are directed at patients after standard therapy has failed.

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Figure 6. Overall survival of 28 patients with advanced primary or recurrent epithelial ovarian cancer or papillary serous cancer.

Figure 7. Survival of ovarian cancer by prior surgical score.

Tentes and colleagues reported on the PCI as a quantitative prognostic indicator in 60 women with ovarian cancer.[19] Those patients with a PCI lower than 10 had a median survival of 80 months and a 5-year survival of 65%, while those patients with a PCI greater than 10 had a median survival of 38 months and a 5-year survival rate of 29% (p=0.0253).

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Figure 8. Survival of ovarian cancer by completeness of cytoreduction.

Look and colleagues studied the CC score as a prognostic indicator.[13] The results showed that a complete cytoreduction had a statistically significant improved survival (p=0.049) (Figure 8).

The peritoneum as a first line of defense against carcinomatosis Our hypothesis regards the peritoneum as the human bodyâ&#x20AC;&#x2122;s first line of defense against carcinomatosis. Whenever the peritoneum is violated by surgery, residual cancer cells are implanted and then progress beyond the peritoneum. In the abdomen or pelvis with a high prior surgical score, the peritonectomy becomes technically much more difficult and less likely to be complete. Also, tumor growth deep to the peritoneum at crucial anatomic sites increases the likelihood of severe complications; for example, ureteral and vascular injuries will occur more frequently during the cytoreductive surgery and intestinal fistulas occur more often in the postoperative period.

In summary, in all surgery for ovarian cancer involving stripping of peritoneal surfaces there is a high likelihood of malignant seeding deep to the peritoneum. Based on the data from prior surgical score an attempt should be made at eradicating all tumor to prevent further cancer cell contamination of raw abdominal and pelvic surfaces. This approach employs proper â&#x20AC;&#x153;respect

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for the peritoneumâ&#x20AC;? in patients with carcinomatosis. Complete cytoreduction and intraperitoneal chemotherapy is an essential part of the strategy to use to achieve that goal.

Morbidity and mortality The combination of cytoreductive surgery and perioperative intraperitoneal chemotherapy as previously described is associated with a 30% morbidity and 2% mortality.[37,38] The typical postoperative course for these patients implicates an average 21-day hospital stay. They usually have a prolonged ileus lasting for 10 to 14 days. Nasogastric suction is sustained until the bowel function is recovered. These patients need total parenteral nutrition until intestinal function has returned. After the nasogastric tube is withdrawn oral nutrition is gradually restarted. The most common complications are central line infections, pancreatitis and intestinal fistulas. Anastomotic leak rate is 2%. Mortality was often associated with septic neutropenia and cardiovascular events.

Summary These new concepts regarding the management of the peritoneal surface component of ovarian cancer suggest some major modifications in the surgery for primary disease. First, debulking surgery to resect the ovaries and tubes and greater omentum if it is involved by a large mass of tumor is indicated. This surgery is necessary to achieve an accurate diagnosis and debulk cancer that is easily accessible. By the log-kill hypothesis it may assist in a beneficial systemic chemotherapy response. However, no attempt at aggressive surgical debulking is indicated unless complete cytoreduction to a state of no visible evidence of disease is considered likely. Unless cytoreduction is complete no deeply invasive dissections should occur.

Hysterectomy is not indicated. Pelvic peritoneal stripping with or without rectosigmoid colon resection is not indicated. Small or large bowel surgery should only be performed if there is established or impending intestinal obstruction. Retroperitoneal or pelvic sidewall lymph node dissections are contraindicated. Only enlarged lymph nodes should be biopsied and not resected. Following this minimally aggressive primary cancer surgery the most aggressive systemic chemotherapy is necessary.

In those patients who show stable disease or an objective response, our combined treatment should be initiated 6 to 8 weeks after the completion of systemic chemotherapy. Response must be monitored by CT of chest, abdomen and pelvis and by tumor markers. The patient should be required to

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vigorously pursue a period of physical conditioning to optimize their recovery from a major intervention of both surgery and perioperative intraperitoneal chemotherapy.

In a physically fit patient who has shown control of a cancer mass as a result of systemic chemotherapy, the comprehensive approach may be considered with curative intent. The goal of the cytoreductive surgery with peritonectomy is complete visible removal of all ovarian cancer. The goal of the perioperative intraperitoneal chemotherapy is to cytoreduce microscopic residual disease, especially small cancer nodules that cannot be completely resected from the small bowel surface.

In approximately one-third of these patients an ostomy may be required to protect a low colorectal anastomosis. If this is required the patient returns after full recovery for an ostomy closure. This third intervention may be used as a third look/ostomy closure and additional cytoreduction and additional perioperative intraperitoneal chemotherapy is appropriate if small volume persistent disease is documented.

This highly specialized treatment needs to be performed by qualified surgeons who are knowledgeable about intraperitoneal chemotherapy toxicity as well as the complications of this aggressive surgical approach. Accepting the fact that a systematic review supports this management strategy, the results with this comprehensive treatment are encouraging for ovarian cancer.[39] A large phase II prospective multiinstitutional study would be needed to validate these results and a phase III study may be required in the future.

References 1.

SEER Incidence - AA Rates for White/Black/Other, 1973-2001. In: Surveillance, Epidemiology and End Results Program. National Cancer Institute, 2001.

2. US Estimated Complete Prevalence Counts on 1/1/2001. In: Surveillance, Epidemiology and End Results Program. National Cancer Institute, 2001.

3. SEER 12 Registries Incidence and Mortality (2003 Submission). In: Surveillance, Epidemiology and End Results Program. National Cancer Institute, 2001.

4. Parkin, D.M., Pisani, P., and Ferlay, J. 1999, Int. J. Cancer, 80, 827.

5. Goff, B.A., Mandel, L.S., Melancon, C.H., and Muntz, H.G. 2004, J.A.M.A., 291, 2705.

6. Sampson, J. 1931, J. Pathol., VII, 423.

7. Carmignani, C.P., Sugarbaker, T.A., Bromley, C.M., and Sugarbaker, P.H. 2003, Cancer Metastasis Rev., 22, 465.

8. Delgado, G., Chun, B., Caglar, H., and Bepko, F. 1977, Obstet. Gynecol., 50, 418.

9. Markman, M., Bundy, B.N., Alberts, D.S., et al. 2001, J. Clin. Oncol., 19, 1001.

10. Armstrong, D.K., Bundy, B., Wenzel, L., et al. 2006, N. Engl. J. Med., 354, 34.

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11. Alberts, D.S., Liu, P.Y., Hannigan, E.V., et al. 1996, N. Engl. J. Med., 335, 1950.

12. Gonzalez Bayon, L., Sugarbaker, P.H., Gonzalez Moreno, S., et al. 2003, Surg.

Oncol. Clin. N. Am., 12, 741.

13. Look, M., Chang, D., and Sugarbaker, P.H. 2003, Int. J. Gynecol. Cancer, 13, 764.

14. Young, R., Perez, C., and Hoskins, W. 1993, Cancer of the Ovary, V.T. DeVita, Jr., S. Hellman, S.A. Rosenberg (Eds.), JB Lippincott, Philadelphia, 1226.

15. Zang, R.Y., Zhang, Z.Y., Li, Z.T., et al., 2000, Eur. J. Surg. Oncol., 26, 798.

16. Morris, R.J., and Woodcock, J.P. 2004, Ann. Surg., 239, 162.

17. Sugarbaker, P.H. J. Surg. Oncol. (in press).

18. Esquivel, J., Farinetti, A., and Sugarbaker, P.H. 1999, G. Chir., 20, 81.

19. Tentes, A.A., Tripsiannis, G., Markakidis, S.K., et al. 2003, Eur. J. Surg. Oncol., 29, 69.

20. Christophi, C., Winkworth, A., Muralihdaran, V., and Evans, P. 1998, Surg.

Oncol., 7, 83.

21. Takahashi, I., Emi, Y., Hasuda, S., et al. 2002, Surgery, 131, S78.

22. Jacquet, P., Averbach, A., Stuart, O.A., et al. 1998, Cancer Chemother. Pharmacol., 41, 147.

23. Markman, M., Rowinsky, E., Hakes, T., et al. 1992, .J Clin. Oncol., 10, 1485.

24. van der Vange, N., van Goethem, A.R., Zoetmulder, F.A., et al. 2000, Eur. J. Surg. Oncol., 26, 663.

25. Steller, M.A., Egorin, M.J., Trimble, E.L., et al. 1999, Cancer Chemother.

Pharmacol., 43, 106.

26. Nicoletto, M.O., Padrini, R., Galeotti, F., et al. 2000, Cancer Chemother. Pharmacol., 45, 457.

27. Deraco, M., Rossi, C.R., Pennacchioli, E., et al. 2001, Tumori, 87, 120.

28. Sugarbaker, P.H. 1996, Early postoperative intraperitoneal adriamycin as an adjuvant treatment for visceral and retroperitoneal sarcoma, P.H. Sugarbaker (Ed.), Kluwer, Boston, 15.

29. Ozols, R.F., Locker, G.Y., Doroshow, J.H., et al. 1979, Cancer Res., 39, 3209.

30. Los, G., Sminia, P., Wondergem, J., et al. 1991, Eur. J. Cancer, 27, 472.

31. Panteix, G., Beaujard, A., Garbit, F., et al. 2002, Anticancer Res., 22, 1329.

32. Sugarbaker, P.H., 2005, J. Surg. Oncol., 92, 142.

33. Piccart, M.J., Bertelsen, K., James, K., et al. 2000, J. Natl. Cancer Inst., 92, 699.

34. Kuh, H.J., Jang, S.H., Guillaume Wientjes, M., et al. 1999, J. Pharmacol. Exp. Ther., 290, 871.

35. Mohamed, F., Marchettini, P., Stuart, O.A., and Sugarbaker, P.H. 2003, Cancer Chemother. Pharmacol. 52, 405.

36. Stuart, O.A., Knight, C., and Sugarbaker, P.H. 2005, Oncol. Nurs. Forum, 32, 44.

37. Stephens, A.D., Alderman, R., Chang, D., et al. 1999, Ann. Surg. Oncol., 6, 790.

38. Yan, T.D., Zappa, L., Edwards, G., Alderman, R., Marquardt, C.E., and Sugarbaker, P.H. 2007, J. Surg. Oncol., 96, 102.

39. Bijelic, L., Jonson, A., and Sugarbaker, P.H. 2007, Ann. Oncol., 8, 1943.

Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 73-99 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

5. Hyperthermic intraperitoneal chemotherapy (HIPEC) in optimally cytoreduced peritoneal carcinomatosis of gynecology origin: Does it provide survival advantage?

Eelco de Bree, Dimitris D. Tsiftsis and John Melissas Department of Surgical Oncology, Medical School of Crete â&#x20AC;&#x201C; University Hospital Herakleion, Greece

Abstract. Among the gynecological malignancies, ovarian cancer is most frequently associated with diffuse peritoneal carcinomatosis. Rarely, peritoneal carcinomatosis is caused by other gynecological malignancies, including endometrial, fallopian tube and primary peritoneal cancer as well as malignant mixed mesodermal tumors. Despite progress in cytoreductive surgery and systemic chemotherapy and consequently significant improvement of survival in advanced ovarian cancer, still the majority of patients will ultimately die from this disease. Hence, besides development of novel more effective drugs, alternative routes of administration have been studied. Intraperitoneal chemotherapy is associated with a major pharmacokinetic advantage, with high locoregional drug concentrations and low systemic toxicity. Optimal cytoreductive surgery is a prerequisite because of its limited penetration depth. The addition of postoperative intraperitoneal instillation chemotherapy to the management of primary advanced ovarian Correspondence/Reprint request: Dr. Eelco de Bree, Department of Surgical Oncology, University Hospital, P.O. Box 1352, 71110 Herakleion, Greece. E-mail: debree@edu.uoc.gr

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cancer has been demonstrated to be beneficial in randomized trials and meta-analysis.

Intraoperative application of intraperitoneal chemotherapy has the advantage of improved distribution of the drug solution through the peritoneal cavity and exposure of the entire seroperitoneal surface to the agent. Moreover, intraoperatively it can be combined with hyperthermia by heating the drug solution. Intraperitoneal instillation of certain drugs and hyperthermia are both better tolerated when the patient is under general anesthesia. Hyperthermia is cytotoxic itself and enhances the efficacy of many chemotherapeutic drugs. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been demonstrated to be feasible and associated with acceptable morbidity.

Unfortunately, there are no data from randomized trials available to asses its role in the management of gynecological malignancies with peritoneal dissemination.

Cautious extrapolation of data from simple intraperitoneal instillation chemotherapy and data from phase II and non-randomized comparative studies suggest that HIPEC delivered at the time of surgery for ovarian cancer has definite potential. Further investigation is necessary and only a randomized trial design will adequately answer the question whether the addition of HIPEC actually prolongs survival in selected patients with peritoneal dissemination of ovarian and other gynecological cancer, conditions where outcome remains so poor with conventional therapy.

Introduction Among the gynecological malignancies, ovarian cancer is most frequently associated with diffuse peritoneal carcinomatosis. Rarely, peritoneal carcinomatosis is caused by other gynecological malignancies, including endometrial, fallopian tube and primary peritoneal cancer as well as malignant mixed mesodermal tumors. Ovarian cancer is the second most frequently gynecological malignancy and the eighth most frequent cancer among females with approximately two thirds of the patients presenting with advanced disease, i.e. peritoneal carcinomatosis and/or hematogenous metastases. Ovarian cancer is the fifth most frequent cause of death from cancer and responsible for 6% of all cancer deaths in females. [1] Progress in the treatment of this disease is evident, with an improvement in survival rate during the last 30 years. In the 1960s, the 5-year survival rate for ovarian cancer was 30%, whereas recent statistics indicate an increase to 45% [1]. Improvement of the quality of cytoreductive surgery as well as development of novel drugs and new chemotherapy regimens are the main contributors to this improvement. Prior to 1993, chemotherapy of choice for advanced ovarian cancer was cisplatin or carboplatin in combination with a classic alkylating agent like cyclophosphamide.

Since the mid-1990s cytoreductive surgery and systemic combination chemotherapy with a platinum compound and a taxane have become the standard of care for this disease [2], although a recent trial [3] indicated that in some women systemic chemotherapy with carboplatin alone may provide equivalent disease control with a favorable toxicity profile.

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Despite this progress in systemic chemotherapy, most ovarian cancer patients will ultimately die from their disease. Hence, besides development of novel more effective drugs, alternative routes of administration have been studied. Recently, the addition of intraperitoneal chemotherapy to the management of advanced ovarian cancer has been demonstrated to be potentially beneficial [4,5].

The rationale for intraperitoneal chemotherapy Although usually considered as systemic disease, peritoneal carcinomatosis can be better understood as regional dissemination. Ovarian cancer with tumor implants on peritoneal surfaces may remain confined to the peritoneal cavity for a prolonged period of time. This means that even though it is considered certainly a poor prognostic sign, it is not proof of distant metastases, providing a rationale for regional cancer treatment. Patients with additional hematogenous metastases are usually excluded from such regional treatment modalities, since systemic disease is insufficiently treated by a regional approach and should be treated in a systemic way [6].

Intraperitoneal chemotherapy is a regional treatment modality that has been used for peritoneal carcinomatosis already since 1955 [7]. During the last decades it has subjected to an increasing number of experimental and clinical investigations. The major advantage of intraperitoneal chemotherapy is the regional dose intensity provided, which may overcome the obstacle of relative drug resistance. Assuming the above mentioned dose-effect relation, this will result in a higher efficacy of the cytotoxic drug. The prerequisites for effective intraperitoneal chemotherapy are summarized in table 1 and discussed below.

The pharmacokinetic advantage Following intraperitoneal delivery high regional drug concentrations can be achieved, while systemic drug levels are low. The concentration differential arises because of the relatively slow rate of movement of the drug from the peritoneal cavity into the plasma (peritoneal clearance).

This pharmacokinetic process is based on the characteristics of the peritoneal-plasma barrier, which maintains the continuous high ratio of chemotherapeutic drug concentration between peritoneal cavity and plasma [8,9]. The physical nature of the peritoneal-plasma barrier has not been fully elucidated. At present, it is suspected that a complex diffusion barrier exists that consists of peritoneal mesothelium, subserosal tissue and blood vessel walls. The capillary wall appears to offer the dominant resistance to

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Table 1. Usual preconditions and patient selection for effective intraperitoneal chemotherapy.

• • • • • •

Absence of hematogenous metastases Adequate general condition of patient Lysis of intra-abdominal adhesions Minimal residual disease after cytoreductive surgery Large volume carrier solution Adequate drug choice (see table 2)

the transfer of large molecules. Absence of significant alterations in pharmacokinetics after extensive resections of peritoneum [10], suggests that the mesothelium and peritoneal interstitium impede their movement to a lesser extent. The movement of large drug molecules and hydrophilic agents through this barrier is limited, while the high drug extraction by the liver after absorption from the peritoneal cavity and transport to the portal vein system provides decreased systemic drug exposure. The area under the concentration versus time curve (AUC) gradient of the drugs from the peritoneal cavity to peripheral blood expresses most adequately the pharmacological advantage of intraperitoneal drug administration. Depending on their molecular weight, their affinity to lipids, and first-pass effect and clearance by the liver, the intraperitoneal to plasma drug AUC ratio may exceed a factor of 1000, as observed for taxanes and other drugs. The ratio of maximal intraperitoneal to peak plasma drug levels may reach a similar level [6].

An additional advantage is that the blood drainage of the peritoneal surface through the portal vein to the liver provides, besides the already mentioned first-pass effect, an increased exposure of potential hepatic micrometastases to cytotoxic drugs administered intraperitoneally [11]. Certain drugs are also transported through lymphatics to the systemic circulation and consequently higher drug exposure is achieved in the lymph than in plasma. This provides a strong rationale for treatment of concurrent occult or clinical lymph node metastases by intraperitoneal chemotherapy [12].

Drug tumor penetration depth High intraperitoneal drug concentration and exposure are the two main factors affecting the treatment of free intraperitoneal tumor cells. However, the AUC for peritoneal fluid may not be correlated with the drug amount in tumor deposits. For invasive peritoneal tumor deposits of adenocarcinoma, which grow towards the subperitoneal space, it is more important to achieve satisfactory local tissue penetration and concentration of the drug rather than

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high intraperitoneal fluid drug concentrations only [13]. The agent has to penetrate the peritoneal tumor as well as at the site of the peritoneal cavity as into the peritoneal layer and subperitoneal tissue.

A disadvantage of intracavitary chemotherapy remains to be the limited tissue penetration by the therapeutic agent. Unfortunately, for many agents it is difficult to accurately measure tissue penetration depth and concentration after intraperitoneal chemotherapy and, when possible, there is a large interindividual variation. Nevertheless, the penetration depth of drugs that are intraperitoneally delivered is estimated to be 3 to 5 mm. at maximum [14-19].

This implies the need for meticulous cytoreductive surgery to precede intraperitoneal delivery of drugs. Hence, intraperitoneal chemotherapy may be indicated only following â&#x20AC;&#x2DC;optimalâ&#x20AC;&#x2122; resection of peritoneal disease, leaving no or very small macroscopic disease behind; generally it is not beneficial in cases in which optimal cytoreductive surgery is not achieved and more than minimal residual disease is left behind [6]. Techniques and other aspects of cytoreductive surgery in ovarian and other gynecological cancer are discussed in detail in other chapters of this book.

Intraperitoneal chemotherapy may be combined simultaneously with systemic chemotherapy to optimize treatment efficacy in case of residual tumor after cytoreductive surgery. The intraperitoneally delivered cytotoxic agent penetrates the residual tumor nodules from the site of the peritoneal surface, while intravenous drug administration provides drug distribution by capillary blood flow into the tumor deposits [20-22]. For the same reason, substantial drug absorption from the peritoneal cavity to the systemic compartment may be even beneficial when it leads to adequate plasma concentrations without major systemic toxicity. Hence, peritoneal fluid to plasma maximal concentration and AUC ratios of certain agents may not accurately represent the pharmacokinetic advantage of intraperitoneal drug administration.

Timing of intraperitoneal chemotherapy Homogeneous distribution and drug exposure to the entire seroperitoneal surface is required for optimal efficacy. This implies the need for lysis of intra-abdominal adhesions and the use of large volumes of fluid containing the chemotherapeutic agent. Intraperitoneal chemotherapy has been administered in the preoperative, intraoperative, and early and late postoperative period.

From a distributional point of view, the optimal time is either prior or during surgery to avoid limitation of homogenous distribution by postoperative adhesion formation. Preoperative administration has the objective to facilitate subsequent cytoreductive surgery, but requires small-volume disease and lack

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of extensive adhesions from previous operations. Intraperitoneal chemotherapy is generally used intra- or postoperatively, because the peritoneal surface is usually grossly affected and cytoreductive surgery is required. Intraoperative and early postoperative intraperitoneal chemotherapy are intended to consolidate the effect of surgery by destroying residual small tumor noduli and microscopic intraperitoneal malignant cell nests.

In postoperative intraperitoneal chemotherapy, drugs are preferably administered during the first postoperative days, before any new surgeryrelated adhesions are produced. Late postoperative intraperitoneal chemotherapy, longer than 2 weeks after surgery, is probably associated with diminished therapeutic effect, due to uneven peritoneal distribution, caused by postoperative adhesions, and peritoneal cavity access catheter related problems [6,3,24].

Hyperthermia Besides the realization of optimal conditions for homogenous drug distribution, another advantage of intraoperative application of intraperitoneal chemotherapy is the ability to perform this treatment modality under hyperthermic conditions, which are poorly tolerated by a conscious patient.

The selective effect of hyperthermia on malignant cells and its ability to enhance the efficacy of chemotherapeutic agents make it a valuable adjunct to intraperitoneal chemotherapy in the management of peritoneal carcinomatosis [6,25].

The direct cytotoxic effect of heat has been known since ancient times [6,26]. There is an abundance of experimental and clinical evidence to indicate that malignant cells are selectively destroyed by hyperthermia in the range of 41oC to 43oC. The cellular and molecular basis for this selectivity has been well studied [25-27].

Additionally, hyperthermia enhances chemotherapy efficacy in a number of ways [25]. The combination of heat and chemotherapeutic drugs frequently results in increased cytotoxicity over that predicted for an additive effect. The synergism between both kinds of treatment may be caused by several factors, including increased drug uptake in malignant cells, altered cellular metabolism and cellular drug pharmacokinetics, increased drug penetration in tissue, temperature-dependent increases in drug action and inhibition of repair mechanisms. In many cases, this enhancement of activity and penetration depth of drugs is already seen above 39-40oC [25].

Not all drugs exhibit a synergism with heat, but several agents have been shown to have an apparently improved therapeutic index and efficacy when used with hyperthermia in in vitro and in vivo experimental studies.

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Generally, the highest thermal enhancement ratios have been observed for alkylating agents like melphalan, cyclophosphamide and ifosfamide [28].

There has been some concern regarding lack of thermal enhancement or even an antagonistic effect of hyperthermia on the cytotoxic effect of paclitaxel in in vitro studies [29]. However, in these studies, drug concentrations and duration of exposure to the drug and to heat resembled more the conditions of systemic chemotherapy with a period of external heating of the target area.

It seems that at high paclitaxel drug concentrations under mild hyperthermia for 2 hours, conditions similar to those during HIPEC, is associated with enhancement and certainly not with impairment of cytotoxicity [29].

During hyperthermic intraperitoneal chemotherapy (HIPEC) mild hyperthermia is achieved by heating the drug carrier solution. The desired intra-abdominal temperature differs between centers and varies generally from 40 to 44oC. Heat used during HIPEC has a limited penetration depth, emphasizing also here the need for adequate cytoreductive surgery. In a recent study [30],30 a wide inter-individual variability was noted and a temperature of 39oC or higher was reached to a mean depth of 3.1 mm at the beginning and 5.1 mm at the end of the procedure, when the intraperitoneal temperature fluctuated between 40oC and 41oC.

Techniques for intraperitoneal chemotherapy Uniform exposure of all surfaces within the peritoneal cavity is of critical importance. In postoperative intraperitoneal instillation chemotherapy, infusion of large volumes of fluid (at least 1-2 liters) is necessary to achieve this goal. Access to the peritoneal cavity for instillation of chemotherapeutic solutions is usually achieved by placement of a Tenckhoff catheter or a subcutaneous implantable port and catheter (Port-A-Cath) system. After infusion, the patient is instructed to change frequently body position to promote exposure to the entire seroperitoneal surface. At completion of the treatment, the solution is drained out of the abdominal cavity [31-33].

For HIPEC, after completion of cytoreductive surgery, temperature probes are placed to monitor intra-abdominal temperature and to allow correction of the perfusion pattern in case of unequal thermal distribution. Inflow and outflow catheters are placed in the abdominal cavity. The abdominal cavity is completely filled with the carrier solution, usually being normal saline or dextrose-based peritoneal dialysis solutions. The perfusion is performed using a roller pump, which is connected to a heat exchanger. The cytotoxic drug is added to the perfusate when the target intra-abdominal temperature is reached.

At the end of HIPEC, virtually the whole drug amount is removed by drainage of the perfusate, preventing further systemic absorption. Comprehensive

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discussion of the different chemoperfusion techniques is behind the scope of this chapter, but the two main techniques, the ‘open abdomen technique’ and the ‘closed abdomen technique’, are briefly summarized. During the ‘closed abdomen technique’ the abdominal skin is temporary closed water tight.

Closure of the skin only allows exposure of the remaining laparotomy wound to the perfusate, diminishing the risk of wound recurrence. The abdomen is manually agitated during the perfusion period to promote uniform heat and drug distribution. At the end of the procedure the solution is drained and the abdominal wall is closed in a standard fashion. Advantages of the method are limited heat loss, prevention of drug evaporation, decreased risk of contamination and maintenance of a tight surgical field. The closed abdomen technique seems a safer technique for the theatre personnel due to the minimal drug exposure to them. The main disadvantage is the possible lack of uniform distribution of the perfusate. Others use the ‘open abdomen technique’ in an attempt to optimize exposure of the abdominal organs and the parietal peritoneum to the perfusate. The skin surrounding the abdominal incision is sutured to a retractor ring placed above the anterior surface of the abdomen, causing an elevated rim around the open abdominal cavity. In this way, a ‘Coliseum’ or ‘soup bowl-like’ container is created for instillation of the peritoneal perfusate. The principle benefit of this ‘Coliseum technique’ is the achievement of better exposure of the seroperitoneal surfaces and adequate heat and drug distribution through the entire abdominal cavity by manual stirring of the perfusate, manipulation of the mobile abdominal contents and repositioning of the inflow catheter. Disadvantages of the technique are that the open abdomen naturally leads to heat loss and the exposure of operating room personnel and especially the surgeon, to the cytotoxic drug. Finally, perfusion with an open abdominal cavity may results in incomplete exposure of the laparotomy wound and of the intestine floating on the fluid surface to the perfusate, resulting in a higher incidence of early wound recurrence and possibly an increased occurrence of malignant bowel obstruction. Although each technique has certain advantages and disadvantages, there are yet no sufficient data available to demonstrate one of the methods to be more effective [24].

Drug choice The choice of the chemotherapeutic drug is very important and certain aspects have to be considered (table 2). It is important for the agent to lack severe local toxicity after intraperitoneal administration. Moreover, the drug should have a well established activity against the gynecological malignancy treated. Drugs that have to be metabolized systemically into their active form are inappropriate for intraperitoneal use. Whereas in instillation intraperitoneal

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Table 2. Specific features of cytotoxic agents favorable for intraperitoneal delivery.

• • • • • • • • •

Lack of local toxicity of the agent Documented activity against malignancy to be treated No need for metabolism into active form Experimental or clinical evidence for concentration- or exposuredependent cytotoxicity of the agent Slow clearance from the peritoneal cavity (i.e. high molecular weight, water rather than lipid solubility) Significant and rapid hepatic metabolism to non-cytotoxic metabolite (first-pass effect from the liver) Rapid renal clearance Direct cytotoxic agent (no antimetabolites; only for HIPEC) Synergistic effect with hyperthermia (only for HIPEC)

chemotherapy all categories of active drugs can be used, in HIPECprocedures a direct cytotoxic agent is needed. Anti-metabolites are not suitable for this application, because the exposure duration is too short to be effective. Experimental or clinical evidence should be available suggesting that a concentration- or exposure-dependent cytotoxicity exists for the certain drug. Otherwise, when low target drug levels are equally effective, conventional systemic chemotherapy may be sufficient. Agents with a large molecular weight have more favorable pharmacokinetics, because of limited and delayed absorption from the peritoneal cavity. Drugs highly metabolized in the liver to non-toxic metabolites are preferred because the first-pass effect from the liver decreases further the systemic drug exposure. Additional rapid renal clearance of the drug that has passed the liver may decrease systemic drug exposure. Finally, existence of synergistic effect of the drug with hyperthermia is preferred for HIPEC. In vivo studies on different agents indicate that the drug of choice at physiological temperatures may not be the drug of choice at elevated temperatures [34]. A theoretical prerequisite for HIPEC is the heat stability of the drug that is to be administered, but fortunately nearly all drugs are stable under these moderate hyperthermic conditions [6,35].

For ovarian cancer and other gynecologic malignancies various drugs have been used for intraperitoneal chemotherapy (table 3) [35]. As mentioned before, antimetabolites as methotrexate, 5-fluorouracil, floxuridine and gemcitabine are not effective in intraoperative intraperitoneal chemotherapy, while lack of thermal enhancement makes etoposide not favorable for HIPEC [35]. Most experience with intraperitoneal chemotherapy for gynecological cancer is obtained with platinum-derivates as cisplatin and carboplatin and

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Table 3. Results of pharmacokinetic studies on intraperitoneal administration of various drugs, effective in ovarian cancer [35].

Drug Melphalan Cisplatin Carboplatin Mitomycin-C Adriamycin Mitoxantrone Methotrexate 5-fluorouracil Floxuridine Gemcitabine Topotecan Etoposide Paclitaxel Docetaxel

C max i.p. / C max plasma 93 10-36 100 249-474 72 1000

800-1000 45-200

AUC i.p. / AUC plasma 17-63 12-22 15-20 13-80 162-230 100-1400 117-1400 1000-2700 791 54 2-9 550-2300 150-3000

Mean ratios of studies are mentioned. C = concentration, max = maximal, i.p. = intraperitoneal, AUC = area under concentration versus time curve

taxanes like paclitaxel and docetaxel, drugs that are most effective in systemic chemotherapy for ovarian cancer. Because of their most favorable pharmacokinetic profile and the probable thermal enhancement of its cytotoxicity, taxanes as paclitaxel and docetaxel seems to be rather attractive agents for HIPEC [29,36]. Results of pharmacokinetic studies on intraperitoneal administration of drugs used for gynecological malignancies with peritoneal carcinomatosis are summarized in table 3 [35]. Although mitoxantrone, 5-fluorouracil and floxuridine have pharmacokinetics superior than for example that of platinum compounds, they have not been widely used because their cytotoxic effect on ovarian cancer cells is considerably inferior.

Duration of intraperitoneal chemotherapy While in pre- or postoperative instillation peritoneal chemotherapy the drug solution is usually left in the peritoneal cavity for 4 to more than 24 hours, the duration of HIPEC has been arbitrary and varies from 30 minutes to 2 hours in different centers. No definite data are available to support a certain time period, but taking into account results from pharmacokinetic and experimental hyperthermic studies and taking maximal advantage of drug availability and heat effect, the optimal perfusion duration

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seems to be 90 to 120 minutes [6]. Some, in an attempt to shorten operation time, to decrease costs and meanwhile to obtain an optimal peritoneal fluid AUC, advocate a shorter duration (30 minutes) with higher drug doses [37].

Eligibility and indications for intraperitoneal chemotherapy In order to undergo cytoreductive surgery and intraperitoneal chemotherapy, eligible patients must be sufficient healthy to withstand the surgery and chemotherapy, especially in case of HIPEC. Usually, disease should be confined to the peritoneal cavity and systemic disease should be absent, because intraperitoneal chemotherapy does not treat systemic metastases adequately. Further of major importance is that, when after surgery tumor deposits are left behind, they should not exceed 5 mm in diameter, because of the already mentioned limited penetration depth. Preoperative assessment to identify patients whose disease is not likely to be optimally resectable would enable such patients to avoid morbidity of unnecessary surgery. Although several studies have investigated the accuracy of imaging studies in determining the resectability of ovarian cancer, the factors associated with prediction of suboptimal surgery vary between studies and centers, probably reflecting the surgical philosophy at individual institutions [38].

The level of surgical expertise is of major importance with regard to the operability of advanced ovarian cancer and this will ultimately determine the chance of optimal cytoreductive surgery [39].

There are five time-points in the natural history of gynecological cancer with peritoneal dissemination at which cytoreductive surgery and intraperitoneal chemotherapy can be performed, the latter being either simple instillation intraperitoneal chemotherapy or HIPEC: for primary disease (first-line treatment), which includes during front-line treatment, after interval cytoreductive surgery following initial induction chemotherapy and as consolidation treatment, or for persistent and recurrent disease (second line treatment). Superior outcome is to be expected in the first settings, when disease is mostly chemo-sensitive, and worse in the latter settings, when in a significant portion of patients disease is expected to be resistant to chemotherapy.

An alternative indication is the palliation of debilitating malignant ascites, wherefore HIPEC is highly effective. [40,41]. This indication will not be discussed in detail, but is also extremely effective when performed by minimal invasive surgery in patients who are not candidates for cytoreductive surgery [42,43].

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HIPEC

versus

HIPEC has some advantages over simple intraperitoneal instillation chemotherapy. As discussed above, the most important is the superior distribution of the heated drug solution through the peritoneal cavity and homogenous exposure of the entire seroperitoneal surface to both drug and heat [6]. Further, residual tumor is at the smallest possible volume and treatment would be usually delivered many days to weeks prior to the usual time when postoperative intraperitoneal chemotherapy is given. Another advantage of intraoperative use is that intraperitoneal chemotherapy can be administered with mild hyperthermia, which is directly cytotoxic and enhances the efficacy and penetration depth of many drugs [6,25], but is poorly tolerated by a patient who is awake. Finally, intraperitoneal administration of some agents, including cisplatin and paclitaxel, may cause severe abdominal pain, which is often the dose limiting factor and is better tolerated intraoperatively [44-50].

An argument which may be used against the application of HIPEC instead of instillation intraperitoneal chemotherapy is the substantially shorter tumor exposure time (usually 1-2 hours versus 24 hours). However, experimental studies have demonstrated that even short time exposure of tumor cells to high drug concentrations, as during HIPEC, is extremely sufficient to induce extended cell growth arrest and tumor cell death [51-53].

Another disadvantage is that HIPEC can usually be applied only a single time or the most again when secondary surgery is performed, while simple intraperitoneal instillation chemotherapy is given repetitively. However, it has to be noted, that in a significant number of patients who are considered to be treated with intraperitoneal instillation chemotherapy, treatment can not be started or has to be discontinued because of peritoneal access catheter complications, as obstruction, dysfunction, bowel perforation and infection [54]. Moreover, HIPEC does not exclude postoperative use of intraperitoneal instillation chemotherapy.

Results of intraperitoneal instillation chemotherapy for ovarian cancer Intraperitoneal instillation chemotherapy has been studied much more extensively than HIPEC. Nowadays, there is clear evidence that addition of intraperitoneal instillation chemotherapy to systemic chemotherapy might be beneficial for primary ovarian cancer patients with peritoneal carcinomatosis,

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who underwent optimal cytoreductive surgery. In a recent meta-analysis of different treatment strategies for ovarian cancer [55], addition of intraperitoneal chemotherapy to the management of advanced ovarian cancer was demonstrated to result in significant improvement of survival. When treatment regimens were compared with intravenous single drug chemotherapy which involves neither platinum nor taxane, hazard ratio for death was lowest for platinum-taxane chemotherapy with at least one agent given intraperitoneally (0.45; 95% confidence interval 0.33-0.61). Platinum-based combination intravenous chemotherapy with intraperitoneal chemotherapy with a platinumcompound was associated with a relative risk of death was inferior and similar to that of intravenous platinum-taxane chemotherapy (0.60; 95% confidence interval 0.46-0.79 vs. 0.58; 95% confidence interval 0.49-0.69).

Survival differences were inferior for other treatment regimens. Results were similar when analysis was limited to first-line treatment.

In the past, two large randomized trials (GOG 104 and 114) [56,57] have demonstrated a clear benefit for intraperitoneal instillation chemotherapy in small residual primary ovarian cancer. However, an old systemic chemotherapy regimen and addition of intravenous carboplatin administration only in the experimental arm were important criticisms of these studies. While previously platinum-compounds had been used for intraperitoneal chemotherapy, during the last 15 years paclitaxel has been intraperitoneally administered for the treatment of primary and recurrent advanced ovarian cancer in different studies with favorable pharmacokinetic and promising clinical results. [29] Hence, intraperitoneal administration of paclitaxel was included in the latest large multicentric randomized trial on intraperitoneal chemotherapy for optimally cytoreduced primary ovarian cancer (GOG 172) [44]. Significantly improved survival was noted for the use of intraperitoneal chemotherapy with paxlitaxel and cisplatin. This study revealed an improvement in median progression-free survival from 18.3 to 23.8 months by intraperitoneal chemotherapy and a relative recurrence risk of 0.80 (p=0.05) in favor of intraperitoneal treatment when compared with conventional intravenous chemotherapy. Overall survival data followed a similar trend favoring intraperitoneal chemotherapy with a median overall survival of 65.6 versus 49.7 months and a relative death risk of 0.75 (p=0.03).

This is one of the largest benefits ever observed for a new therapy in gynecologic oncology. Based on the results of this study and meta-analysis of the results of this and seven other trials [58], in 2006 the National Cancer Institute issued a clinical announcement recommending that women with primary stage III ovarian cancer who undergo optimal surgical cytoreduction should be considered for intraperitoneal chemotherapy [59,60]. The referred meta-analysis was criticized by the inclusion of a consolidation treatment

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study among front-line treatment trials. A subsequent systematic review and meta-analysis [50], from which this consolidation treatment study was excluded, demonstrated still a significant overall survival benefit of the addition of intraperitoneal chemotherapy during primary treatment of women with stage III epithelial ovarian cancer (relative risk, 0.88; 95% confidence interval, 0.81-0.95). Concern exists regarding the adverse events and peritoneal access catheter-related complications with intraperitoneal chemotherapy, which were significantly more common and often doselimiting than observed during intravenous treatment alone [50,58]. This needs to be considered well when deciding on the most appropriate treatment for each individual woman. Incidence of catheter-related complications, however, has been dramatically reduced by adequate training of nursing and medical personnel, correct use of the catheter system as well as increased experience [54]. Appropriate clinical and institutional multidisciplinary facilities are needed for the save delivery of this treatment in optimally cytoreduced patients.

For other indications than following primary cytoreductive surgery, no randomized trials examining the role of intraperitoneal chemotherapy in ovarian cancer have been performed. However, encouraging results from phase II studies on intraperitoneal instillation chemotherapy as salvage treatment for persistent or recurrent peritoneal disease, as consolidation treatment after negative second-look surgery and as adjuvant treatment for stage I and II disease have been reported [31-33].

Results of HIPEC for gynecological cancer Although randomized controlled trials have demonstrated a significant benefit of HIPEC in colon cancer with peritoneal dissemination and in highrisk gastric cancer [61-63], unfortunately there are no results of such a study for ovarian cancer. The Italian Society of Integrated Locoregional Therapy (SITILO) initiated a randomized trial to asses the additional role of HIPEC in persistent ovarian cancer [64], but the study was closed prematurely due to lack of accrual. Hence, only data of phase I and II HIPEC studies concerning patients with primary and recurrent ovarian cancer with peritoneal spread are available so far for assessment of its additional benefit. Results of such studies have been summarized in table 4. Since most frequently HIPEC is offered to patients with recurrent and persistent disease, a majority of them having chemotherapy resistant disease, less promising results may be awaited. Heterogeneity among ovarian cancer patients makes interpretation of results and comparison with non-randomized control groups difficult, underlining the need for phase III trials. This heterogeneity of patient populations

Table 4. Results of HIPEC for ovarian cancer with peritoneal carcinomatosis.

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Table 4. Continued

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and differences of the treatment regimens among the studies do also not allow proper comparison of results among these HIPEC studies and metaanalysis. Indications vary and series include patients with primary ovarian cancer, recurrent/persistent disease or both. Further, other patient selection criteria like age, performance status, tumor load, probability of completeness of cytoreductive surgery and other, may differ considerably. Particularly, there is an enormous inter-individual variety in peritoneal tumor load, varying from some small superficial tumor nodules on the peritoneal surface next to the primary tumor site to a peritoneal cavity full of large invasive tumor deposits. Since the HIPEC-procedure has not been standardized yet, this treatment method varies substantially among centers regarding duration of the perfusion, intra-abdominal temperature during hyperthermia, open or closed abdomen technique, selection and dosage of the chemotherapeutic agents. Probably in most, but not all, patients, systemic chemotherapy was administered after cytoreductive surgery and HIPEC, making it nearly impossible in a non-randomized setting to demonstrate whether survival benefit was due to the addition of this procedure or that this was achieved anyhow by systemic chemotherapy only. Finally, the surgeon as a variable parameter leads to potential inconsistency of quality of cytoreductive surgery [39], making comparison between different series unreliable as the quality of surgical cytoreduction is a highly important undependable parameter for outcome, as discussed in a separate chapter of this book.

Recently, a systematic review of cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis in primary and recurrent ovarian cancer identified fourteen studies with adequate quality to be analyzed [91]. Rates of significant morbidity associated with this treatment modality were low, ranging from 5% to 36%. Hematological toxicity was reported up to 15%, depending substantially on its definition, technique, drug and dose. Renal toxicity was observed in 0-8% of cases and is associated with the use of platinum compounds. Pulmonary complications were seen infrequently and include embolus, pleural effusion, pneumonia and central vein thrombosis. Surgical complications were encountered frequently and related to extensive surgery.

The most significant were anastomotic leak, intestinal perforation, abscess, fistula, sepsis, bleeding and wound infection/dehiscence. Reoperation for complications was required in 0-16% of cases. Especially the combination of intestinal perforation or anastomotic leakage with leucopenia is often fatal.

In the analyzed series, the median mortality rate was 3% (range 0%-10%) and might be decreased by improved patient selection. The median overall survival in series with primary and/or recurrent disease ranged from 22 to 54 months and the median disease-free survival from 10 to 26 months.

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Patients with optimal cytoreduction seemed to have the greatest benefit. In a study in which HIPEC was incorporated during planned secondary surgery after primary cytoreductive surgery and conventional systemic chemotherapy, a 5-year overall survival of 63-66% was noted. In series consisting of patients with recurrent and persistent ovarian cancer only, estimated 5-year overall survival was 15% and 42%. The authors concluded that HIPEC following cytoreductive surgery is a treatment option for patients with ovarian cancer that is worthy of further investigation and that selection criteria for patients most likely to benefit need to be defined.

Despite the difficulty in reliable evaluation as discussed earlier, some investigators attempted to compare their outcome after addition of HIPEC with those obtained by traditional treatment in non-randomized control groups. Ryu et al. [78] compared in a retrospective study the results of 57 stage Ic-III ovarian cancer patients treated by surgical cytoreduction and HIPEC at secondary surgery (second-look or secondary cytoreductive surgery) with those of 60 similar patients who underwent during the same period of time conventional surgical cytoreduction and systemic chemotherapy only. Five-year overall survival was significantly better for the HIPEC-group (63.4% vs. 52.8%, p=0.0078). The additional benefit of HIPEC was most obvious in stage III ovarian cancer patients (5-year overall survival rate 53.8% vs. 33.3%, p=0.0015), while the overall survival difference was not significant in stage Ic and II disease (p=0.63). For stage III ovarian cancer patients whose tumor was reduced to less than 1 cm in diameter during a second procedure, the 5-year survival rate 65.6% in patients who underwent HIPEC and 40.7% in control patients (p=0.0046). In multivariate analysis, HIPEC was an independent prognostic factor that was not affected by surgical staging, residual tumor size after secondary surgery or patient age (p=0.0176).

In the same center, a second non-randomized comparative study was performed, including 96 patients with ovarian cancer stage Ic, II and III [85].

All patients underwent primary surgical cytoreduction and systemic chemotherapy, followed by secondary surgery after initial response.

Secondary operation consisted of either secondary cytoreductive surgery when response was partial or second-look surgery when a clinical complete response was achieved. In 29 cases this was followed by systemic chemotherapy only (control group), while in 67 patients HIPEC with paclitaxel (n=22) or carboplatin (n=45) preceded additional systemic chemotherapy. Patient groups were comparable regarding age, histological type, disease stage, completeness of primary surgical cytoreduction and number of chemotherapy cycles per patient. No statistically significant difference in survival was observed for stage Ic and II disease, while outcome

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was considerably superior after HIPEC in stage III disease. Three-year progression-free survival was 56.3% for the HIPEC-group versus 16.7% for the control group (p=0.003) and 5-year overall survival 66.1% versus 32.8% (p=0.0003). The difference in survival outcome between the patients who received paclitaxel and those who received carboplatin during HIPEC was not significant (5-year overall survival 84.6% versus 63.0%, p=0.41). It has to be noted, that the number of patients in both HIPEC-groups was small to show any statistically significant difference. For the relative risk of disease progression yielded from multivariate analyses, hazard ratio for HIPEC with paclitaxel was 0.281 (p=0.004) an that of HIPEC with carboplatin 0.433 (p=0.008). Like HIPEC with carboplatin (hazard ratio: 0.396, p=0.0004), HIPEC with paclitaxel considerably decreased the risk of death (hazard ratio: 0.197, p=0.025).

Gori et al. [80] investigated the effect of HIPEC as consolidation treatment in 29 stage IIIb and IIIc ovarian cancer patients, following cytoreductive surgery and systemic chemotherapy, in a multicentric prospective trial. They compared outcome with that of a control group of 19 similar patients who refused second-look operation and subsequent HIPEC. Disease stage, completeness of cytoreduction, histological grade and histological type were comparable for both groups of patients. Disease-free and overall survival were superior after HIPEC (median: 57.1 vs. 46.4 months and 64.4 vs. 60.1 months, respectively), but the differences were statistically not significant, possibly due to the small number of patients included in their analysis.

Little experience exists regarding HIPEC for other gynecologic malignancies. Helm et al. [92] reported unexpectedly long survival in five patients treated by cytoreductive surgery and HIPEC for peritoneal recurrence of endometrial carcinoma. Others have reported encouraging results of HIPEC for malignant mixed mesodermal (or malignant mixed M端llerian) tumors [93,94]. Although fallopian tube carcinoma and primary cancer of the female peritoneum, have been frequently included in clinical trials concerning intraperitoneal instillation chemotherapy for ovarian cancer [32,44], only a few cases have been reported to be treated by HIPEC for such indications [77,95,96].

Conclusions and future directions Generally, it seems that HIPEC is well tolerated and associated with acceptable morbidity, when patient selection is appropriate and adequate experience is gained in a referral center. However, the most essential question is whether it provides survival advantage. As mentioned before, unfortunately

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there are no data from randomized trials available to asses the definite benefit of incorporation of HIPEC in the management of ovarian cancer. However, the precedent for treatment at different natural history time-points of ovarian cancer has been set by many relatively small phase I/II studies and further study is needed. The variety in details of HIPEC treatment and the heterogeneity of the patients are such that comparison to historical controls is unreliable and only a randomized trial design will adequately answer the question whether the addition of HIPEC actually prolongs survival in patients with peritoneal dissemination of ovarian cancer. It will be extremely difficult to accomplish such a study, since it would require several hundreds patients for each single indication and thorough collaboration between many centers.

In absence of evidence from randomized trials and with difficulties in interpretation of non-randomized HIPEC-studies, cautious extrapolation of outcome data from randomized trials and meta-analyses concerning simple intraperitoneal instillation chemotherapy in ovarian cancer may be validated.

Taking into account the mentioned advantages of HIPEC when compared with intraperitoneal instillation chemotherapy, it is to be expected that HIPEC offers similarly survival benefit for patients with primary ovarian cancer with peritoneal spread with no or small residual disease after cytoreductive surgery. Likewise, it is probably an effective treatment at other natural history time-points. Comparative non-randomized studies have demonstrated improved outcome by performing HIPEC at secondary surgery (i.e. secondary cytoreductive surgery or second-look surgery) in initially stage III ovarian cancer. Data on HIPEC for other gynecological malignancies are too sparse to draw any conclusion.

Despite the overwhelming evidence, unfortunately the medical community has not widely accepted the use of simple intraperitoneal instillation chemotherapy in optimally cytoreduced stage III ovarian cancer.

Reluctance towards this treatment modality exists probably due to several reasons. Firstly, it is a completely novel and different treatment method.

Further, it is more demanding than conventional intravenous treatment, since it is more time consuming and requires more effort from nursing and medical staff. Moreover, the already mentioned initial concern regarding toxicity and complications may have resulted in a reserved attitude towards this technique. However, accumulation of experience and adequate training of involved personnel have led to gradually reduction of toxicity and complications, although optimal technique, agent, dose and schedule have still to be defined. Another reason that intraperitoneal chemotherapy has not become popular is the persisting use of cisplatin by most investigators, despite the availability of new drugs that are probably more efficient.

Moreover, the medical community and the pharmaceutical industry have put

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emphasize on development and intravenous administration of novel agents instead of the use of an alternative delivery route. These issues have to be kept in mind to understand and to attempt to avoid similar reluctance of the medical community towards the incorporation of HIPEC in the treatment of ovarian cancer, especially when well designed studies may offer adequate evidence for its efficacy in the future. Well designed and collaborative studies, treatment in referral centers, adequate patient selection, accurate training and use of new attractive agents as paclitaxel and docetaxel are some of the key issues to attempt to get HIPEC universally accepted.

Most recently, results of the Ovary Consensus Panel convened for the 5th International Workshop on Peritoneal Surface Malignancy (December 2006, Milan) have been reported [97]. Although there was some disagreement regarding indication criteria, they concluded that HIPEC delivered at the time of surgery for ovarian cancer has definite potential. The experts agreed that growing literature documents its relative tolerability and supports the continuation of further research regarding the role of HIPEC in the treatment of ovarian cancer, a disease where outcome remains so poor with conventional therapy.

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Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 101-122 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

6. The role of cytoreductive surgery for non-genital tract metastases to the ovary Leszek Gottwald, Janusz Piekarski and Arkadiusz Jeziorski Chair of Oncology, University Medical School of Lodz, Paderewskiego 4 Str., 93-509 Lodz, Poland

Abstract. Approximately 6-7% of all adnexal masses found during physical examination are actually metastatic ovarian tumors, which often masquerades as the primary ovarian tumor. The circumstances leading to the discovery of these metastatic lesions depends on the site of the primary tumor. The ovaries may be only slightly enlarged or measure 10 cm or more. Ovarian metastases are bilateral in approximately 70%. The routes of tumor spread to the ovary are variable. Lymphatic and haematogenous metastasis to the ovaries is the most common form of dissemination for the vast majority of cases of carcinoma of the breast, stomach, as well as lymphomas and leukemias. Direct extension is a common manner of spread from colorectum and retropritoneal sarcomas. The ovaries can be reached by the transperitoneal route by cancers from abdominal organs, such as the appendix. Carcinoma of the breast, stomach, colon, and endometrium, as well as lymphomas and leukemias account for the vast majority of cases of metastatic ovarian tumors. In cases, when both ovarian and extraovarian involvement is extensive, determination of the origin of the metastatic ovarian tumor may be impossible.

The distinction of metastatic ovarian neoplasm from a primary one is crucial to its subsequent management, and diagnostic misinterpretation may have important adverse consequences for the patient. Although intraoperative frozen-section evaluation is useful Correspondence/Reprint request: Dr. Leszek Gottwald, Chair of Oncology, University Medical School of Lodz Paderewskiego 4 Str., 93-509 Lodz, Poland. E-mail: lgottwald@wp.pl

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for the diagnosis of metastatic tumors of the adnexa, in some cases it is difficult to distinguish primary ovarian tumors from metastatic ones even by histological examination. In such patients the treatment the treatment should be the same as in primary ovarian carcinoma. The treatment of choice is bilateral salphingooophorectomy, hysterectomy, omentectomy and appendectomy. If there is no gross evidence of abdominal metastasis, pelvic lymph node sampling should be done to determine the extent of disease; In cases when complete resection of the adnexal tumor is impossible, cytoreductive surgery reducing tumor mass before chemotherapy is considered the optimal treatment. The cytoreductive surgery is optimal if the diameter of the largest residual tumor is â&#x2030;¤ 1.0 cm, which is assessed by the maximum tumor in the pelvis and abdomen.

In metastatic breast cancer patients ovarian metastases are present in 10-40% of cases, but rarely is the ovarian metastasis evident before the primary tumor is detected. Signs and symptoms of an ovarian tumor are rarely present in patients with breast cancer metastases to the ovaries and microscopic ovarian metastases are occasionally diagnosed at prophylactic oophorectomy by laparoscopy or laparotomy. Ovarian metastases of breast cancer usually are accompanied by other foci of abdominal spread, and the most common treatment modality in such cases is systemic chemotherapy or hormonotherapy. Isolated ovarian metastases occasionally are encountered, and in these cases laparotomy should be performed for optimal cytoreduction.

In patients with gastrointestinal cancer the ovarian metastatic tumor is discovered before, or more frequently, at the same time as the gastrointestinal primary. Most of the literature on metastatic ovarian carcinomas from the gastrointestinal tract has concentrated on mucinous, signet-ring cell adenocarcinomas, called Krukenberg tumors. The Krukenberg tumor is almost always secondary to the gastric carcinoma, but may occasionally originate in the large intestine, appendix, breast or other sites. In 35% of patients with a Krukenberg tumor, the diagnosis of the digestive primary precedes the diagnosis of the ovarian metastasis. In these cases the choice of treatment is difficult and prognosis is worse in most cases with fatal outcome in one year. Early diagnosis and complete resection is the only possible hope. Radical operation such as pelvic exenteration can improve survival only in cases of recurrent solitary ovarian metastasis or local extended disease.

Colonic adenocarcinomas account for 11-45% of all metastatic ovarian tumors.

The addition of prophylactic bilateral oophorectomy as routine in peri-menopausal and post-menopausal women undergoing abdominal surgery for bowel cancer was postulated by many authors. On the contrary, another authors indicated no benefits in survival of these patients. In cases of direct invasion of the contiguous ovary from the colorectal cancer (pT4) or macroscopic metastases (M1) found during the abdominal surgery for bowel cancer the radical resection of ovarian metastases with a curative aim seems to improve overall survival. Women with isolated ovarian metastasis with a long interval between initial diagnosis of colon cancer and recurrence, and women with limited disease that appears amenable to facile surgical resection would seem to be the preferred candidates to cytoreductive surgery. For patients with isolated ovarian metastases from colon cancer the optimal cytoreduction can confer a significant

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survival advantage compared with those patients who are left with bulky residual disease.

Primary tumors of the appendix are rare and most of them are unrecognized preoperatively, presenting as appendicits, pelvic masses or with atypical abdominal pain. The ovarian and appendiceal tumors are histologically similar; usually it is difficult to distinguish in intraoperative frozen-section primary ovarian mucinous tumors from metastatic ones, and surgical procedures due to primary epithelial ovarian cancer are treatment of choice.

Other rare primary tumors reported in the literature are: malignant lymphoma, malignant melanoma, carcinoid tumors, extragenital sarcomas, tumors of the pancreas, gallbladder and bile ducts, pulmonary and mediastinal tumors, renal tumors, adrenal gland tumors, mesothelioma, and peritoneal tumors. Metastases to the ovary other than those already described are of great rarity. In cases of such tumors surgery in the form of a diagnostic laparotomy for the ovarian mass and for symptom relief is often necessary, but the further management of patients depends upon the site of extent of the primary disease. Numerous studies suggest that resection of metastatic ovarian tumors and cytoreductive surgery play a significant role in improving the survival time in patients with no distant metastasis other than to the adnexa. The benefitial role of cytoreductive surgery in malignant melanoma, as well as malignant lymphoma metastatic to the ovary is not confirmed.

Introduction Since the establishment of the metastatic nature of most Krukenberg tumors by Schlagenhaufer in 1902, it has been demonstrated that many carcinomas, including that of thyroid breast, stomach, gallbladder, pancreas, colon, rectum, and malignancies arising from the female genital tract, may metastatize to the ovaries [1]. Approximately 6-7% of all adnexal masses found during physical examination, and 10-30% of all ovarian malignancies are actually metastatic ovarian tumors. The metastatic origin of these tumors is frequently not suspected by gynecologists [2,3,4]. Carcinoma of the stomach, colon, breast and endometrium, as well as lymphomas and leukemias account for the vast majority of such cases [5,6]. Many reports on metastatic ovarian tumors described the most often primary sites of neoplasms in gastrointestinal tract 36-74% (stomach 8-61%; colon 11-45%), breast 13-31%, and gynecologic organs 18-40% [2,5-10]. Women with solid metastases to the ovary of nongenital origin usually have worse prognosis than women with metastatic cancers of genital origin. Their overall five year survival reaches only 10% [11,12]. In cases, when both ovarian and extraovarian involvement is extensive, identification of the origin of the metastatic ovarian tumor may be impossible.

The metastasis often masquerades as the primary ovarian tumor.

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depends on the site of the primary tumor. The metastatic tumors are bilateral in approximately 70%. Macroscopically the ovaries may be normal, may be only slightly enlarged or may measure 10 cm or more [5,6,12]. The routes of tumor spread to the ovary are variable. Lymphatic and haematogenous metastasis to the ovaries is the most common form of dissemination for the vast majority of cases of carcinoma of the breast, stomach, as well as lymphomas and leukemias. Direct extension is a common manner of spread from colorectum and from retroperitoneal sarcomas. The ovaries can be reached by the transperitoneal route by cancers from abdominal organs, such as the appendix [12,13]. Regional lymph node or liver involvement, and abdominal spread frequently occurred in patients with ovarian metastatic cancers [14].

Surgical treatment for primary ovarian cancer is well defined, and cytoreduction to a low residual tumor volume has arbitrary been shown to offer a survival benefit [15]. In the presence of metastatic ovarian tumors, however, diferent guidelines may apply and an aggressive surgical procedures may be less beneficial [16]. Despite of that, the treatment of choice in most such patients remains surgery, which is usually indicated in the form of explorative laparotomy for adnexal mass, and for relief of symptoms [14]. The optimal cytoreductive surgery has an advantage on survival time in selected patients with nongenital metastatic tumors of the ovary, especially of colorectal origin without abdominal dissemination [14].

The distinction of metastatic ovarian neoplasm from a primary one is crucial to its subsequent management, and diagnostic misinterpretation may have important adverse consequences for the patient. The intraoperative frozen-section evaluation is useful for the diagnosis of metastatic tumors of the adnexa with the reported by an 81-98% accuracy rate in detecting metastatic character of the ovarian tumors [10,12,17]. When surgeons encounter metastatic ovarian tumor and it is confirmed by frozen-section evaluation, and the diagnosis of primary disease is not made previously, an intensive search for primary site should be performed [6]. Unfortunately, in some cases it is difficult to distinguish primary ovarian tumors from metastatic ones even by histological examination. In such patients the treatment should be the same as in primary ovarian carcinoma. The treatment of choice is bilateral salphingo-oophorectomy, hysterectomy, omentectomy and appendectomy. If there is no gross evidence of abdominal metastasis, pelvic lymph node sampling should be done to determine the extent of disease. In cases when complete resection of the adnexal tumor is impossible, cytoreductive surgery reducing tumor mass before chemotherapy is considered the optimal treatment. The cytoreductive surgery is optimal if the diameter of the largest residual tumor is â&#x2030;¤ 1.0 cm, which is assessed by the maximum tumor in the pelvis and abdomen [14].

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Ovarian metastasis is a late reprezentation of generalized disease and therefore it is accepted that the prognosis is generally poor. Most patients die within 1 year of the diagnosis of ovarian tumor [2]. Patients with gynecologic tumors have significantly better prognosis than patients with non-gynecologic tumors metastatic to the ovary [3]. The reported 5-year survival after resection of ovarian metastatic tumors from genital tract and from non-genital organs is 47% and 10-36% respectively [2,3]. It is worth to recall that generally reported 5-year survival of patients with primary ovarian cancer is about 40% [3]. Therefore the prognosis of patients with metastasis to ovary from genital tract organs is better, and with metastasis from non-genital organ is worse than prognosis of patients with primary cancer of ovary.

Breast cancer In metastatic breast cancer patients ovarian metastases, ascites, and carcinomatosis are present in 10-40%, 5.4%, and 2.6% of cases, respectively.

It was confirmed by numerous clinical and anatomopathological reports [5,18,19]. Although the risk of breast cancer recurrence diminishes over time, late metachronous ovarian metastases well into the second decade following the initial diagnosis can occur [11,18]. In women treated previously for breast cancer when non-funcional ovarian tumor is detected and the patient is qualified for surgical removal of this tumor, the risk that the tumor is malignant is 50%. Primary ovarian cancer develops in these patients three times more often than metastases of breast cancer to ovary [11,20,21].

Lobular carcinomas, including those of signet-ring cell type, spread to the ovary more frequently than those of ductal type [5,13].

Only in 1.0-2.0% of patients the ovarian metastasis is diagnosed before the diagnosis of primary breast carcinoma [5,22]. Signs and symptoms of an ovarian tumor are rarely present in patients with breast cancer metastases to the ovaries. Ovarian metastases are rather occasionally diagnosed at prophylactic oophorectomy. Indications for prophylactic oophorectomy are well defined in BRCA1 or BRCA2 germline mutations carriers [21,23].

Many authors suggest that in BRCA1/BRCA2 mutation carriers adnexectomy instead of simple oophorectomy should rather be performed. It is because of the increased risk of the fallopian cancer in such women [23]. Moreover adnexectomy is in fact a simple and effective technique which does not increase the risks of complications and ureteral injuries. Moreover, adnexectomy avoids the risk of ovary remnants being left in the mesovarium during the oophorectomy. The procedure can be easily performed using a laparoscopic approach [23]. Bilateral oophorectomy, commonly with peritoneal

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cytology, is proposed by some authors as a therapeutic option in premenopausal patients with localized or advanced breast cancer [19].

Ovarian metastases are found in 15% to 40% of these breast cancer patients undergoing prophylactic surgery [19]. Most of cases of adnexal tumor found at the time of prophylactic oophorectomy are not recognized at the time of surgical procedure itself, because 29-66% of these patients have only microscopic ovarian metastases. Such metastases are found at final histological examination [12,23]. Generally, in breast cancer patients the indications for prophylactic oophorectomy are not well defined and there are no consensus expert statements about its role and beneficial effect on survival in these patients. However, it should be also remembered that oophorectomy may be used as a form of treatment of selected breast cancer patients. Surgical oophorectomy is regarded as an therapeutic option which can be used in premenopausal breast cancer patients, classified as high risk or intermediate risk patients, with highly endocrine responsive or incompletely endocrine responsive breast cancer [24].

Macroscopically the metastatic ovarian tumor in breast cancer patients is usually smooth-surfaced or bosselated mass, and only exceptionally the cystic elements are found. Metastatic tumors are usually small. In one large study, in only 15% of patients the size of the metastatic tumor was larger than 5 cm [22]. The metastases are bilateral in approximately 80% of cases [22], and in almost 75% of cases ovarian metastases are accompanied by other foci of abdominal spread [22,25]. The presence of ovarian metastases from breast cancer is usually a sign of general dissemination of the disease and the involvement of the ovary is not clinically significant. The most common treatment modality in such cases is systemic chemotherapy or hormonal therapy.

The accuracy of intraoperative frozen-section diagnosis of breast carcinoma metastasis to adnexa is 81% [10]. When the intraoperative frozensection diagnosis is breast cancer metastasis, the surgical resection of metastatic tumors should be considered in patients with prolonged time after initial breast cancer diagnosis and with resectable disease [14,20].

Occasionally isolated ovarian metastases are encountered. In these cases laparotomy should be performed and metastatic tumor should be resected.

Abdominal disease outside the pelvis apparently influences the extent of the surgical intervention and most of the patients with disease outside the pelvis cannot be optimally cytoreduced. The extent of surgery should be individualized and balanced against the morbidity of the offered treatment [20]. The prognosis in cases of ovarian metastases of breast cancer is generally poor with the five-year survival 0-27%, and median survival between 12 and 36 months [7,19-21].

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Gastrointestinal tumors The ovary is a common site for spread of carcinomas from the gastrointestinal tract, and ovarian metastases are present in 8-16% of cases. In patients with gastrointestinal cancer the ovarian metastatic tumor is discovered before, or more frequently, at the same time as the gastrointestinal primary [26]. Among all metastatic ovarian tumors, colon, appendiceal, and upper gastrointestinal tract primary tumors have been shown to be the most common primary malignancies associated with clinical findings suggestive of a primary ovarian cancer [27]. The incidence of ovarian metastases from gastrointestinal tumors seems to be higher in young menstruating women [28]. In some patients even long interval between initial diagnosis of gastrointestinal cancer and ovarian recurrence is observed.

Carcinoma of the stomach, including Krukenberg tumor Most of the literature on metastatic ovarian carcinomas from the gastrointestinal tract has concentrated on Krukenberg tumors, first described

by Friedrich Krukenberg in 1896 [4,29]. The World Health Organization reports that following features should be present when making the diagnosis on Krukenberg tumor: 1) the presence of stromal involvement, 2) the presence of mucin-producing neoplastic signet-ring cells, and 3) ovarian stromal sarcomatoid proliferation [30]. The Krukenberg tumor is almost always secondary to the gastric carcinoma, but the large intestine, appendix, breast, pancreas, urinary system, biliary system and uterine cervix have also been reported as primary sites [4,12,13].

In 35% of patients with a Krukenberg tumor, the diagnosis of the digestive primary preceded the diagnosis of the ovarian metastasis [25,3133]. The gastric primary focus can be small, asymptomatic, or can be present as linitis plastica. In these cases the choice of treatment is difficult and prognosis is worse in most cases with fatal outcome in one year. The Krukenberg tumors usually form white masses that may be bosselated and may attain a large size [29,34]. In ultrasound / computer tomography Krukenberg tumor more frequently is presented as a solid mass with an intratumour cyst, when compared to predominantly cystic primary ovarian malignancies [35].

Eighty percent or more of patients with a Krukenberg tumor had bilateral ovarian metastases [22,25,29,34].

Early diagnosis and complete resection is the only possible hope, but most surgeons do not attempt to remove ovarian tumors when Krukenberg tumors are diagnosed preoperatively [36]. In the literature patients survived more than 4 years after resection of metachronous Krukenberg tumors and

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the absence of residual disease after treatment and limited disease extent were reported [37]. Radical operation such as pelvic exenteration can improve survival only in cases of recurrent solitary ovarian metastasis or locally extended disease [37]. However, no optimal treatment strategy for Krukenberg tumors from gastric cancer has been clearly established, and the prognosis in patients with Krukenberg tumors remains generally poor [36].

Intestinal carcinoma Most metastatic ovarian tumors of intestinal origin are from the large intestine, with occasional examples of small intestinal derivation [38,39].

Seventy five percent of these metastatic ovarian tumors are adenocarcinomas of sigmoid and rectal origin. Ovarian metastasis from a duodenal and jejunal cancer is extremely rare with only several cases described, and it is difficult to detect a small bowel lesion preoperatively [39,40]. The rarity of metastatic tumor of small intestine origin should not be surprising as primary adenocarcinoma of the small bowel accounts for only approximately 1-3% of all gastrointestinal malignancies, even though the small bowel constitutes 75% of the length and 90% of the mucosa surface of the alimentary tract.

Colonic adenocarcinomas account for 11-45% of all metastatic ovarian tumors, and in colorectal cancer patients ovarian metastases are present in 28-35% of cases [2,5,7-9]. At the time of initial laparotomy 3.4-10.3% of patients with colon carcinoma have synchronous ovarian metastases [41].

Transcoelomic dissemination and retrograde lymphatic flow are likely to be common metastatic routes for ovarian tumor of gastric and colorectal origin.

The addition of prophylactic bilateral oophorectomy as routine in peri-menopausal and post-menopausal women undergoing abdominal surgery for bowel cancer is postulated by many authors [3,42]. Becker et all. recommended that the performance of adjunctive bilateral oophorectomy should be strongly considered at the time of initial laparotomy due to rectal cancer in the following situations: 1) as therapy when there in gross evidence of benign or malignant ovarian disease, when there is extensive serosal, peritoneal, or regional lymph node invasion of the rectal cancer, and when one or both ovaries or the uterus are adherent to the bowel adjacent to the primary tumor; 2) as prophylaxis in all postmenopausal women, mainly to prevent primary ovarian carcinoma; 3) as prophylaxis in premenopausal women with the confirmed high risk or strong family history of breast, ovarian, endometrial or bowel cancer, and those with stage IV rectal cancer [42]. On the contrary, another authors indicated lack of survival benefit in these patients.

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In patients with gastrointestinal cancer the ovarian metastatic tumor is discovered before, or more frequently, at the same time as the gastrointestinal primary [26]. The tumors can be discovered during surgery for primary ovarian tumor by gynecologists, or by surgeons at the time of initial surgery for newly diagnosed colon cancer [43]. In approximately 60% of cases metastatic ovarian carcinoma of intestinal origin are bilateral, solid, but more often predominantly cystic, frequently large above 10 cm in largest dimention [28,44]. When malignant ovarian tumors encountered at the time of operation are considered, metastases from intestinal carcinomas are almost five times as frequent as those from gastric carcinomas [45,46].

Metastatic colonic carcinomas may simulate clinically, radiologically, and histologically primary ovarian endometrioid or mucinous carcinomas.

In some cases it is difficult to distinguish primary ovarian cancers from metastatic tumors derived from colon cancer, even by histological examination [9]. It was reported that 45% of metastatic ovarian tumors from colon cancer were misdiagnosed as primary ovarian cancers [2,12,41]. The extrapelvic spread is a helpful feature in the distinction of ovarian metastasis from colorectal carcinoma. The omental, hepatic parenchymal metastases, a prominent involvement of the peritoneal surface and the involvement of mesenteric lymphnodes favor an intestinal primary tumor rather than primary ovarian carcinoma [9]. Metastatic colonic carcinomas may simulate primary endometrioid or mucinous ovarian carcinomas on gross and histologic examination [9]. In histologic assessment subgrups of cytokeratins (CKs) have been used to differentiate primary ovarian metastatic carcinomas. CK7 has been shown to be ubiquitously present in primary ovarian carcinomas, and CK20 is well expressed in colorectal carcinomas and their metastases [9].

The problem has practical importance for choice of therapy. Given the maximal cytoreduction as treatment of choice of primary ovarian cancer and inability to guarantee intraoperative pathologic distinction of primary ovarian carcinoma from metastatic colon carcinoma to the ovary even via frozen section examination, many cases of metastatic colon cancer are submitted to cytoreductive surgery [43]. Misdiagnosis may also lead to inappropriate therapy, because in adjuvant chemotherapy colorectal cancer is generally treated with 5-FU, and primary ovarian cancer is generally treated with paclitaxel and platinum agent.

An isolated ovarian metastasis from colorectal cancer is very often an unexpected finding at laparotomy or laparoscopy and it requests an immediate decision about how to proceed. Women with isolated ovarian metastasis with a long interval between initial diagnosis of colon cancer and recurrence, and women with limited disease that appears amenable to facile surgical resection would seem to be the preferred candidates to cytoreductive

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surgery [28,43,47]. Management of colorectal cancers metastatic to the ovary should include: 1) resection of the primary tumor with the 5 cm surgical margin on either side, 2) the ovarian metastasis, and 3) bilateral salphingooophorectomy in the absence of extensive peritoneal spread or liver metastasis. The incidence of bilateral ovarian involvement is significant, thus, even if only one ovary is grossly involved with metastatic cancer, a bilateral oophorectomy should be performed [28]. Pelvic lymphadenectomy should be considered in the absence of peritoneal or hepatic metastasis [41,43,47]. In cases of direct invasion of the contiguous ovary from the colorectal cancer (pT4) or isolated macroscopic metastases (M1) found during the abdominal surgery for bowel cancer the radical en block resection of the primary lesion and all pelvic organs with metastatic disease with a curative aim seems to improve overall survival [16,41]. For patients with isolated ovarian metastases from colon cancer the optimal cytoreduction can confer a significant survival adventage compared with those patients who are left with bulky residual disease [43,47].

Only when surgical expertise to remove all visible evidence of cancer within the abdomen and pelvis is available should definitive cancer resection occur in association to peritonectomy and perioperative intraperitoneal chemotherapy. For patients with bulky ovarian disease, the aim of cytoreductive surgery with the removal of the pelvic tumor is to provide symptomatic pain relief and may relieve obstruction. The cytoreduction also for colon cancer patients who are et high risk for the development of localregional recurrence and carcinomatosis, such as patients with perforated cancers or with adjacent organ involvement can be take into consideration [41,47,48]. In patients with extensive metastatic disease and peritoneal surface dissemination, aggressive tumor reduction with increased risk of surgical morbidity, however, contributes little and systemic therapy is of greater importance. In these patients systemic therapy is treatment of choice [16,47].

Patients with optymally cytoreduced isolated ovarian metastases from colon cancer have a better prognosis than patients with colon cancer metastases elsewhere. Patients with metastases limited to the ovaries who received optimal cytoreduction had a median disease-free survival of 14.5 months and an overall median survival of 61 months and therefore 50% 5-year survival. The optimal cytoreduction can confer a significant survival adventage compared with those patients who are left with bulky residual disease [41,43]. Rayson reported median survival of 31 months in patients who underwent complete metastatectomy compared to those patients with residual disease with median survival of 14 months. The median 5-year survival in patients without optimal cytoreduction ranged 5-23% [7].

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Carcinoid tumors and tumors of the appendix The primary carcinoid of the ovary is a rare malignancy. It represents approximately 0.1% of ovarian neoplasms. Metastatic carcinoid tumors to the ovary typically originate from primary distal ileal tumors, may be even more uncommon; less than 70 cases were reported in medical literature [49]. They are commonly associated with disseminated abdominal disease. Synchronous metastases involve typically peritoneal surfaces â&#x20AC;&#x201C; mesentery, omentum and peritoneum, and liver. Patients typically present with adnexal mass, and only minority develop the carcinoid syndrome consisting of flushing and/or diarrhaea, due to secretion of serotonin directly into the systemic circulation [49].

Primary tumors of the appendix are rare with the most common being carcinoid. Primary appendiceal adenocarcinoma account for less than 0.5% of all gastrointestinal tumors, and 5-8% of primary appendiceal neoplasms.

The reported incidence of ovarian metastasis from appendiceal tumors varies from 59% to 88%, and in cases of diagnosed primary appendiceal malignancy the addition to the right hemicolectomy bilateral oophorectomy is recommended in good surgical candidates [50,51]. Prolonged survival may be associated with cytoreductive surgery and octreotide treatment [49].

Most of appendiceal tumors are unrecognized preoperatively, presenting as appendicits, pelvic masses or with atypical abdominal pain. Rarely is the diagnosis of primary appendiceal malignant tumor made preoperatively. It is because neither ultrasonography and computer tomography can differentiate between appendiceal tumor and more common malignancies, including colonic as well as ovarian carcinoma [51]. The metastatic appendiceal tumors to ovary are typically cystic, often bilateral, average about 10 cm or more in diameter, usually multilocular. In cases of unilateral tumor, the right ovary is more often involved when compared to the left ones, due to its proximity to the appendix [38].

Acute appendicitis with periappendiceal abscess is the clinical presentation in 70% of patients with appendiceal adenocarcinoma. With appendiceal adenocarcinoma there is often associated pseudomyxoma peritonei, characterized by the presence of abundant mucinous material within the abdomen and peritoneal cavity. It is clear, that most cases of pseudomyxoma peritonei are of appendiceal, or more rarely colorectal origin, and that ovarian mucinous tumors are secondary to direct spread and implantation from the appendiceal neoplasms [52]. If a mass of mucoid or fibrous material is removed, this should be carefully examined to identify the appendix. In cases of pseudomyxoma peritonei the surgeon should always remove the appendix, even if the coexistent ovarian tumor is present. In some cases the appendix is grossly normal and a small adenocarcinoid or adenocarcinoma may be identified in histological examination [52].

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Inspection of the appendix should be a part of the initial exploration at the beginning of abdominal procedures, because the primary appendiceal neoplasms in most cases when ovarian metastatic tumors are present, are minimal and show only thickening, induration or firmness. Additionally, usually it is difficult to distinguish in intraoperative frozen-section primary ovarian mucinous tumors from metastatic appendiceal ones. It makes the correct diagnosis difficult, and in these cases the surgical procedures should be the same as in primary epithelial ovarian cancer. Therefore, when frozen section examination of an ovarian tumor reveals metastatic ovarian neoplasm, and obvious primary lesion is apparently absent, routine appendectomy should be recommended, because the neoplastic appendix may appear macroscopically normal. In numerous cases, primary appendiceal tumors have been diagnozed only at second laparotomies. The data from the literature suggest, that right hemicolectomy confers a survival benefit versus simple appendectomy for primary tumor even in advanced disease. Aggressive debulking, oophorectomy and omentectomy are recommended when ovarian metastatic tumors are present [50].

Pancreatic cancer and biliary tract tumors Pancreatic adenocarcinoma uncommonly metastatizes to ovary. The reported incidence of ovarian metastasis from pancreatic adenocarcinoma at autopsy of pancreatic adenocarcinoma patients is 4-6% [52]. In several studies of nongenital cancers metastasized to the ovaries, pancreatic carcinoma was diagnosed as a primary malignancy in 2-19% of patients [14,52].

Adenocaricnoma of pancreas may present as ovarian metastasis in the absence of the known primary [52]. Large, cystic, multiloculated unilateral mucinous ovarian tumor, or bilateral tumors, usually dominate the clinical presentation of the primary disease. In such cases the primary tumor can be missed [34,52,53] and most of patients initially present with advanced disease.

The impact of cytoreductive surgery on survival in metastatic cancer of the pancreas is difficult to assess. Observations by Falchook et al. suggest longer median survival duration in patients who had undergone metastatectomy followed by chemotherapy than patients who had undergone chemotherapy alone (16.5 months vs. 8.5 months). Surgical intervention can be often necessary to remove the large pelvic tumor, to provide symptomatic pain relief and relieve obstruction. Generally, the resection of ovarian metastatic tumors from pancreatic carcinoma plays a palliative role, and may increase the survival time of symptomatic patients [53].

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Ovarian metastatic carcinoma of gallbladder and extrahepatic bile ducts is a very rare disease, and less than 10% of patients are found to have peritoneal carcinomatosis. The cases of ovarian metastases from cholangiocarcinoma are extremely rare. It should be considered when ovarian tumors with widespread carcinomatosis accompanies biliary obstruction. In such cases the prognosis for patients is poor. Surgery in the form of a diagnostic laparotomy for the ovarian mass, and for symptom relief is often necessary, but when diagnosis is confirmed, palliation remains the mainstay of therapy [54].

Malignant lymphomas and leukaemias Involvement of the ovary by malignant lymphoma can present either as a primary lesion, or more frequently as a focus of involvement in cases of disseminated malignancy [55]. Lymphomas represent 2.6-17.1% of metastatic ovarian tumors [12]. The ovaries are most common site of metastatic tumors from malignant lymphoma in genital organs. Ovarian involvement as a manifestation of clinically occult or overt lymphomatous malignancy is well recognized with frequency as high as 26%.

The haematological secondary ovarian tumors, both lymphomatous or leukaemic, are usually bilateral, solid, and in most cases of the large diameter [56,57]. The presence of ovarian involvement by malignant lymphoma or leukaemia usually is the late manifestation of disseminated nodal disease, and the involvement of the ovary can be not clinically significant [58].

Exploratory surgery due to an ovarian tumor is common treatment method to confirm the diagnosis. The bilateral ovarian involvement, peritoneal implant, and ovarian involvement at the time of surgery may be used as an agrument of a secondary character of ovarian haematologic malignancy [58].

The radical surgery is not associated with improved survival of patients, but the removal of ovarian metastasis palliates symptoms and facilitates the response to systemic treatment [14]. Surgical debulking of the tumors is not considered to be related to improved prognosis, and the treatment of choice of lymphomas and leukemias remains systemic chemotherapy [58]. In young women, when the intraoperative diagnosis by frozen-section from the ovarian tumor biopsy confirmes malignant lymphoma metastatic to ovary, the ovaries should be preserved, to allow the possible preservation of ovarian function as well as preservation of fertility in some these patients after systemic treatment [59]. The 47% overall five-years survival in patients suffering from malignant lymphoma and coexistant synchronic ovarian metastastatic tumors is described.

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Considering the role of surgery in patients with haematologic malignancies, the problem of fertility sparing surgical procedures in young patients without synchronous ovarian metastases should be discussed. Over the last years cryopreservation of ovarian tissue is currently practiced in an attempt to preserve fertility before commencing potentially sterilizing chemotherapy, but clinical and laboratory guidelines are needed to standardize the procedure.

The indications and timing of ovarian tissue banking should be individualized.

Patients previously exposed to chemotherapy can consider ovarian tissue freezing. The extent of tissue removed should take into account the large number of follicles lost and the risk of future sterilization. Tissue handling should enable further investigation of primordial follicles and identification of cancer cells. In these patients harvesting of ovarian tissue should be performed during surgery following previous exposure to chemotherapy or shortly after the chemotherapy. Partial oophorectomy on the way of laparoscopy or laparotomy is the preferred surgical procedure [56].

Malignant melanoma Metastatic ovarian malignant melanomas are more common than primary ovarian malignant melanomas. The melanoma metastatic to ovary arise usually from a cutaneous melanoma, but the secondary ovarian tumors can be discovered many years after the diagnosis of the primary lesion. The diagnosis of malignant melanoma metastatic to the ovary is uncommon in living patients, but approximately 20% of patients dying of malignant melanoma have ovarian metastases at postmortem examination [60]. Most of these patients have abdominal dissemination of melanoma disease, and the involvement of the ovary is not clinically significant. It is rare for melanoma to present clinically as an solitary ovarian tumor [61].

Malignant melanoma metastatic to the ovary should be suspected in any patient who presents with an adnexal mass and has a history of malignant melanoma. Pathologically the ovaries are usually enlarged and the unilateral or bilateral lesions are et last partially cystic with a smooth capsule. Only a minority exhibit conspicuous amounts of melanin pigment [61]. The findings from ultrasonography and computer tomography can be nonspecific in these cases, but magnetic resonance imaging allow detection melanin in the melanoma, which can differentiate to produce this substance [61].

The optimal surgical management of metastatic ovarian malignant melanoma is a challenge and it has been not established to date. Some authors suggest, that if the one ovary is the only site of relapse and there is no evidence of involvement of contralateral ovary, unilateral oophorectomy or salphingo-oophorectomy may contribute to long-term survival. When the

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contralateral ovary can be suspected of metastasis, even without frozen section examination, the bilateral oophorectomy or salphingo-oophorectomy should be performed. Another authors recommend the total abdominal hysterectomy and bilateral salphingo-oophorectomy as treatment of choice in malignant melanoma metastatic to the ovary without abdominal dissemination. Unfortunately, the vast majority of cases of malignant melanoma metastatic to the ovary reported in the literature were associated with other, both abdominal and extraabdominal sites of relapse. In these cases surgical treatment can be necessary to provide symptomatic pain relief and relieve obstruction. For these patients chemotherapy should be considered.

However, there is no definitive evidence that it is beneficial, and the patients with multilocular relapse usually die within 2 years from diagnosis of ovarian metastasis [60,61].

Tumors from the urinary tract Renal carcinoma and carcinoma of the urinary bladder uncommonly metastasize to the ovary [62]. The reported rate of ovarian metastases from renal cancer and bladder cancer to ovary are about 0.5% and 4-12.4% respectively [63,64]. Sometimes there is no history of a primary urinary tract neoplasm, and the ovarian metastatic tumor is the first presentation of the disease. The most common histology of the renal cancer metastatic to the ovary is clear cell carcinoma, and metastatic ovarian cancers from urinary bladder are usually of transitional cell subtype. Bilaterality is an favour of a secondary tumor, but some ovarian metastases from primary tumors arising from urinary tract are unilateral [13,52,62,63,65]. Macroscopically, the predominant features of these metastases are tumors without exophytic growth and mixed yellowish solid and cystic areas [64]. Only isolated examples of ovarian metastasis of ureteral or urethral cancer have been reported in the literature [13].

The treatment of choice in most patients with ovarian metastases from urinary system remains surgery. Unfortunately, very often only explorative laparotomy is possible. In cases with solitary adnexal metastases without abdominal dissemination, the resection of metastatic tumors should be performed. Because of rarity of such cases, the indications for cytoreductive surgery should be individualized [65].

Primary peritoneal tumors Primary peritoneal serous carcinoma is a tumor which was first reported

by Swerdlow in 1959. It is the most common peritoneal malignancy, clinically and morphologically identical to primary ovarian serous adenocarcinoma

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[52,66,67]. There appears to be no significalt epidemiological differences between cancers arising primarily within the ovary or the peritoneum [68].

Primary peritoneal serous carcinoma is a tumor that diffusely involves the peritoneal surface whilst there is no or minimal involvement of the ovaries. The peritoneal tumor is generally bulky and widespread, showing extensive peritoneal carcinomatosis. The omentum is almost always involved [68]. The criteria for diagnosis of primary serous peritoneal adenocarcinoma proposed by GOG (Gynecological Oncology Group) are: 1) the ovaries are normal in size or are enlarged by a benign process, 2) the extraovarian site of carcinoma are of significantly greater volume than the tumor present in either ovary, 3). The ovarian tumor components is neither non-existent, confined to the ovarian surface with or without stromal invasion measuring in aggregate less than 5 mm x 5 mm, or within the ovarian substance and measuring less than 5 mm x 5 mm, d) the histologic characteristics indicate serous carcinoma of any grade [69].

This is not a crucial distinction to make since management of both neoplasms is identical, treatment is based on surgical resection associated with adjuvant chemotherapy [52,67]. In surgical treatment the succesive procedures are: the laparotomy via midline vertical incision, peritoneal washings, total abdominal hysterectomy and bilateral salphingooophorectomy, omentectomy, sampling of pelvic / paraaortic lymphnodes when enlarged, maximal cytoreduction [67,68]. Some of the factors that may prevent optimal cytoreduction include extensive nodular infiltration of the mesenteric, visceral and peritoneal surfaces, and involvement of the porta-hepatis, liver, higher paraaortic nodes and stomach [68]. Very little is known about the role of lymphadenectomy in patients with primary peritoneal serous carcinoma, and only few series have adressed the issue of nodal spread in those patients.

Lymphadenectomy should include all pelvic and para-aortic chains up to the level of the right renal vein. The procedure has both a diagnostic and prognostic value. The therapeutic value of lymphadenectomy remains unproven [70]. Although most of investigators reported the optimal cytoreductive surgery as a favourable prognostic factor in patients with primary peritoneal carcinoma, some authors did not found a significant prognostic value for optimal cytoreductive surgery in these cases [67]. In the adjuvant setting the combination of paclitaxel and platinum is a standard of chemotherapy in patients with primary peritoneal carcinoma [15,67]. The value of secondary cytoreductive surgery in patients suffering from primary peritoneal carcinoma is not clearly defined [67].

Ovaries can be even reached by diffuse malignant peritoneal mesothelioma. Usually in these cases there is widespread peritoneal disease with only minimal involvement of the surface of the ovaries. Rarely there is

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prominent ovarian involvement, mimicking a primary ovarian carcinoma, and occasional cases of primary ovarian mesothelioma have been described [52].

Over the past decade, the management of these patients has evolved similarly to ovarian cancer treatment and now involves cytoreductive surgery, heated intraoperative intraperitoneal chemotherapy (HIIC) with cisplatin and doxorubicin, and early postoperative intraperitoneal paclitaxel. These perioperative treatments are followed by adjuvant intraperitoneal paclitaxel and second-look cytoreduction [71].

Another extragenital tumors metastatized to ovaries A variety of other neoplasms rare metastatize to the ovaries and present as an ovarian tumor in a patient with a known extra-ovarian malignancy.

Uncommon cases of ovarian metastasis from the liver, lung, thyroid glands, extragenital sarcomas, adrenal gland tumors, pulmonary, mediastinal and vascular tumors were described [13,34,72,73]. Metastases to the ovary other than those alredy described are of great rarity. In 2.6-16.9% of cases the primary tumor remains unidentified [12,27].

In cases of such tumors surgery in the form of a diagnostic laparotomy for the ovarian mass and for symptom relief is often necessary, but the further management of patients depends upon the site of extent of the primary disease, histopathology of the tumor and general condition of the patient [72].

Numerous studies suggest that resection of metastatic ovarian tumors and cytoreductive surgery play a significant role in improving the survival time in patients with no distant metastasis other than to the adnexa.

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28. Erroi, F, Scarpa, M, Angriman, I, Cecchetto, A, Pasetto, L, Mollica, E, Polese, L, Cillo, U, and D´Amico, F. Ovarian metastasis from colorectal cancer: prognostic value of radical oophorectomy. 2007, J. Surg. Oncol, 96,113.

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35. Kim, S.H., Kim, W.H., Park, K.J., Lee, J.K., and Kim, J.S. CT and MR findings of Krukenberg tumors: comparison with primary ovarian tumors. 1996, J. Comput. Assist. Tomogr., 20, 293.

36. Cheong, J.H., Hyung, W.J., Chen, J., Kim, J., Choi, S.H., and Noh, S.H. Survival benefit of metastatectomy for Krukenberg tumors from gastric cancer. 2004, Gynecol. Oncol., 94, 477.

37. Kim, H.K., Heo, D.S., Bang, Y.J., and Kim, N.K. Prognostic factors of Krukenberg´s tumor. 2001, Gynecol. Oncol., 82, 105.

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41. Wright, J.D., Powell, M.A., Mutch, D.G., Rader, J.S., Gibb, R.K., Huettner, P.C., and Herzog, T.J. Synchronous ovarian metastases at the time of laparotomy for colon cancer. 2004, Gynecol. Oncol., 92, 851.

42. Becker, S.O., Tomacruz, R., Kaufman, K.S., Bristow, R.E., and Montz, F.J. Gynecologic abnormalities in surgically treated women with stage II or III rectal cancer. 2002, J. Am. Coll. Surg., 194, 315.

43. McCornick, C.C., Giuntoli, R.L., Gardner, G.J., Schulick, R.D., Judson, K., Ronnen, B.M., Vang, R., and Bristow, R.E. The role of cytoreductive surgery for colon cancer metastatic to the ovary. 2007, Gynecol. Oncol., 105, 791.

44. Lash, R.H., and Hart, W.R. Intestinal adenocarcinomasmetastatic to the ovaries.

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46. Johansson, H. Clinical aspects of metastatic ovarian cancer of extragenital origin.

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48. Sugarbaker, P.H., Alderman, R., Edwards, G., Marquardt, C.E., Gushchin, V., Esquivel, J., and Chang, D. Prospective morbidity and mortality assessment of cytoreductive surgery plus perioperative intraperitoneal chemotherapy to treat peritoneal dissemination of appendiceal mucinous malignancy. 2006, Ann. Surg.

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50. McBroom, J.W., Parker, M.F., Krivak, T.C. Rose, G.S., and Crothers, B. Primary appendiceal malignancy mimicking advanced stage ovarian carcinoma: a case series. 2000, Gynecol. Oncol., 78, 388.

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66. Dubernard, G., Morice, P., Rey, A., Camatte, S., Pautier, P., Lhomme, C., Duvillard, P., and Castaigne, D. Lymph node spread in stage III or IV primary peritoneal serous papillary carcinoma. 2005, Gynecol. Oncol., 97, 136.

67. Eltabbakh, G.H., Werness, B.A., Piver, S., and Blumenson, L.E. Prognostic factors in extraovarian primary peritoneal carcinoma. 1998, Gynecol. Oncol., 71, 230.

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70. Dubernard, G., Moriice, P., Rey, A., Camatte, S., Pautier, P., Lhomme, C., Duvillard, P., and Costaigne, D. Lymph node spread in stage III or IV primary peritoneal serous papillary carcinoma. 2005, Gynecol. Oncol., 97,136.

71. Sugarbaker, P.H., Acherman, Y.I., Gonzalez-Moreno, S., Ortega-Perez, G., Stuart, O.A., Marchettini, P., and Yoo, D. Diagnosis and treatment of peritoneal mesothelioma: The Washington Cancer Institute experience. 2002, Semin.

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73. Begum, M., Katabuchi, H., Tashiro, H., Suenaga, Y., and Okamura, H. A case of metastatic haemangiopericytoma of the ovary: recurrence after a period of 17 years from intracranial tumor. 2002, Int. J. Gynecol. Cancer, 12, 510.

Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 123-151 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

7. Cytoreductive surgery in endometrial cancer and uterine sarcomas Stefanie M. Ueda and Robert E. Bristow The Kelly Gynecologic Oncology Service, The Johns Hopkins Medical Institutions Baltimore, MD, USA

Abstract. Optimal cytoreductive surgery has an emerging therapeutic role in the management of advanced and recurrent uterine carcinomas, especially if used in conjunction with adjuvant chemotherapy and/or radiation. Theoretically, successful tumor debulking can produce fractional log kill of malignant cells while sensitizing residual nodules to adjuvant therapies, expand tumor perfusion and drug delivery, and decrease the rate of somatic mutations associated with drug resistant phenotypes. Aggressive surgical interventions or salvage operations traditionally have been limited to women with only isolated pelvic disease or centralized, recurrent tumors. However, both extensive node resection as well as upper abdominal and omental assessment appear to benefit a subset of women with bulky metastases and high-risk histologies and perhaps more adequately detects and removes micrometastatic disease. As with epithelial ovarian cancers, more expansive and radical procedures therefore should be considered as treatment options for patients with even widespread or refractory uterine carcinomas, given the potential for improved clinical outcomes in these patients.

Introduction Uterine corpus cancer is the most common gynecologic malignancy in the United States with over 40,000 women diagnosed annually. According to Correspondence/Reprint request: Dr. Robert E. Bristow, The Kelly Gynecologic Oncology Service, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. E-mail: rbristo1@jhmi.edu

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American Cancer Society statistics, the number of deaths has dramatically risen despite a relatively stable number of new cases over the last 20 years, with only 3,000 deaths occurring in 1988 and 7,470 deaths expected in 2008. In the majority of cases, disease is confined to the uterus, but in approximately 20% of patients, tumor spreads to pelvic lymph nodes or more distant sites. The surgical management and treatment for early-stage endometrial cancer are fairly wellestablished, but patients with metastatic and recurrent disease continue to have low response rates to current therapeutic regimens, and optimal management of these patients remains ill-defined.

Advanced stage endometrial cancer, in particular, poses problems from a clinical standpoint because of historically poor outcomes and lack of consensus data for the most effective treatment programs. Patients with Stage III-IV disease, more specifically, account for over 50% of uterine cancer related deaths, with Stage IV disease being associated with five-year survival rates as low as 10â&#x20AC;&#x201C;20% [1,2]. Radical surgery therefore has a promising role in the management of patients with locally or regionally advanced endometrial cancer, especially if utilized in combination with adjuvant radiation or chemotherapy.

Rationale for optimal cytoreductive surgery The Gynecologic Oncology Group (GOG) defines optimal cytoreduction for endometrial cancer as resection of the maximal tumor mass to 1 cm or less. At present, no available technology exists that consistently allows clinicians to anticipate which patients have unresectable disease. The standard operation for women with advanced-stage endometrial cancer consists of removal of the uterus, ovaries, and tubes; pelvic and para-aortic lymphadenectomy; and if possible, resection of all visible tumor. Some physicians also advocate routine omental sampling and peritoneal staging biopsies to define extent of disease, particularly for endometrial cancer with a serous histological subtype. The specific surgical approach does vary across institutions, however, ranging from a simple extrafascial hysterectomy to more aggressive debulking procedures and lymphadenectomies based on intraoperative assessment of extra-pelvic and nodal metastases as well preoperative tumor grading.

Similar to ovarian cancer, the survival benefit associated with successful surgical cytoreduction is thought to be a result of a number of hypothetical mechanisms [3-5]. In theory, successful tumor debulking can produce a three log kill of tumor cells, with smaller, better vascularized residual nodules being more vulnerable to chemotherapy. Resection of large volume disease further diminishes a tumorâ&#x20AC;&#x2122;s adverse metabolic effects, leading to better

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patient performance status, expanded tumor perfusion and drug delivery, and decreased somatic mutations that often perpetuate drug resistance (GoldieColdman model). Given the high risk of recurrence in advanced stage endometrial cancer, a growing body of literature thus supports the concept of debulking surgery for metastatic disease to not only improve survival but also enhance the efficacy.

Role of lymphadenectomy In 1988, the International Federation of Gynecology and Obstetrics (FIGO) changed the staging criteria for uterine corpus carcinoma from a clinical to surgical system. Surgical staging with pelvic and para-aortic lymphadenectomy specifically allows for the identification of patients with microscopic metastatic disease, presumably the group most likely to benefit from adjuvant treatment. Unfortunately, discrepancies between pre-operative histology, intra-operative assessment, and final pathology occasionally occur, and thus the extent of “adequate” lymph node sampling continues to be an area of controversy, with no agreement regarding the number of lymph nodes necessary for ideal evaluation.

Early GOG studies attempting to address this issue proposed only lymph node sampling from the external iliac, obturator, and hypogastric areas, finding that women with grade 1, superficially invasive cancers exhibited a 2–5% risk for nodal involvement [6]. A subsequent large series of 295 clinical Stage I patients with grade 2 or 3 carcinomas likewise revealed an 8% rate of retroperitoneal recurrences originating from sites thought to be “node negative” at the time of surgery [7]. This suggested that a failure to thoroughly assess pelvic and para-aortic nodes resulted in a small but real risk of undetected extrauterine metastasis in patients with supposed “low risk” endometrial cancer.

Later trials and retrospective reviews recommended retrieving a greater number of nodes from multiple sites. The rationale being that systematic lymphadenectomy in uterine cancer staging provided a more accurate assessment of neoplastic spread to permit better individualization of adjuvant therapy. This approach is generally organized into two parts: 1) a pelvic node dissection removing lymphatic tissue from the anterior and medial surfaces of the iliac vessels as well as from the obturator space superior to the obturator nerve and 2) a para-aortic node dissection removing precaval and lower aortic lymphatic tissue to the level of the inferior mesenteric artery. Reported rates of serious morbidity range from 6-19% [8].

Several studies further emphasized a therapeutic benefit to carrying out a systematic lymphadenectomy for endometrial cancer, particularly in cases of

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high-grade disease [9,10]. For instance, among 509 women with apparent clinical Stage I/IIA disease, patients with poorly differentiated cancers undergoing more extensive lymphadenectomy (> 11 pelvic lymph nodes) had improved survival if no gross metastatic disease remained at the time of hysterectomy [8]. By comparison, the number of nodes obtained and the performance of selective para-aortic lymphadenectomy failed to predict either progression-free or overall survival among patients with grade 1 to 2 cancers in this analysis. These findings parallel those in other published series, which indicate no independent prognostic significance associated with histologically positive para-aortic nodes in the presence of positive pelvic nodes [11,12].

While the importance of systematic lymphadenectomy as a diagnostic tool in endometrial cancer is well accepted, the therapeutic relevance of a methodical para-aortic node assessment seems less clear. Although many gynecologists agree that patients with grade 1 endometrioid adenocarcinoma without myometrial invasion do not need complete lymphadenectomy, no standard method is described for determining which patients require an extensive para-aortic node dissection.

Given the low incidence of aortic node metastases in women with endometrial cancer that appears confined to the uterus (3%), some clinicians advocate limiting aortic lymphadenectomy to patients with high-risk features such as deep myometrial invasion (i.e. at least Stage IC) or grade 3 histology.

Unfortunately, no risk factor profile reliably identifies all patients with aortic nodal spread, producing the debate surrounding the necessity for para-aortic lymphadenectomy in select patients. Reviewing the records of 137 high-risk (myometrial invasion >50%, palpable positive pelvic nodes, or positive adnexae) patients, Mariani et al. found that performance of para-aortic lymphadenectomy predicted longer progression free (OR = 0.25, p = 0.01) and overall survival (OR=0.23, p=0.006), with patients with para-aortic nodes not obtained showing a five-year progression-free survival and overall survival of 36 and 42%, in contrast to 76 and 77% for those with para-aortic nodes assessed (p = 0.02 and 0.05, respectively) [13]. Lymph node recurrences also arose in 37% of those without nodes procured but in no patients with nodes assessed (p = 0.01).

Recognition of pathologically positive lymph nodes by gross inspection alone therefore appears to be poor and not easily reproducible, with successful identification in only 39-61% of patients with clinically suspicious adenopathy [7,14-17]. In patients with microscopically positive pelvic nodes, the likelihood of involved para-aortics increases to 38-51% [6], and many investigators subsequently argue that complete para-aortic lymphadenectomy needs to be carried out in most patients to better identify those who require adjuvant chemoradiation and who might otherwise be underdiagnosed by pelvic node sampling alone. With such unreliable detection rates of extrauterine

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disease by intraoperative palpation alone, the decision not to perform a complete node dissection as a part of routine surgical protocol ultimately may result in unrecognized macroscopic residual disease in patients thought to be optimally cytoreduced.

Resection of macroscopic nodal metastases Several reports evaluating the efficacy of radiation therapy show that patients with Stage IIIC endometrial carcinoma initiating treatment with small-volume residual nodal disease experience superior local control and survival rates compared to patients with unresectable bulky adenopathy [11,16,18].

The potential benefit of more extensive lymphadenectomy thus includes the removal of occult small-volume disease undetectable by clinical inspection or palpation.

Amongst those patients with advanced uterine cancer, the advantage of debulking gross nodal metastasis has been validated by several studies. In a series of 96 patients with Stage IIIC disease examined by Havrilesky and colleagues, five-year disease-specific survival reached 63% in 45 patients with microscopic metastatic disease (Figure 1), in contrast to 50% in 44 patients with grossly positive nodes completely resected and 43% in 7 with residual macroscopic disease [19]. Among those with grossly involved lymph nodes, 86% underwent complete resection, and following multivariate analyses, gross nodal disease not debulked (HR=6.85, p=0.009) predicted greater death from disease.

Figure 1. Disease-specific survival among patients with FIGO stage IIIC endometrial cancer stratified according to residual nodal disease, showing improved outcomes with increased resection of nodal metastases. Courtesy of Havrilesky L et al. Gynecol Oncol 2005;99(3):689.

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Similarly, in a review of 41 surgically staged IIIC endometrial cancer patients who received postoperative whole pelvic radiation conducted by Bristow and coworkers, women with completely resected macroscopic lymphadenopathy exhibited a four-fold longer median survival compared to those left with residual nodal disease (37.5 vs. 8.8 months, p=0.006) [20].

Gross residual nodal disease again independently predicted disease specific survival (HR 7.96, 95% CI 2.54â&#x20AC;&#x201C;24.97, p< 0. 001), and the authors advocated carrying out routine and systematic lymphadenectomy when feasible in patients with Stage IIIC endometrial carcinoma to ensure complete cytoreduction in patients with otherwise subclinical nodal disease.

A report by Lambrou et al. evaluating 66 patients with Stage III-IV disease undergoing primary surgery further revealed a higher likelihood of suboptimal debulking and tumor recurrence if bulky adenopathy was noted [21]. Of the six Stage IIIC patients with suboptimal cytoreduction, all demonstrated residual disease in the pelvic or para-aortic region. The presence of upper abdominal metastases, ascites, extra-pelvic disease (including upper abdomen, omentum, gastrointestinal tract other than rectosigmoid, and distant lymph nodes), and positive para-aortic lymph nodes were each significantly associated with suboptimal surgical cytoreduction. When feasible, removal of all grossly positive nodes in this setting led to a greater probability of achieving optimal cytoreduction and subsequent improved survival.

In one of the largest studies of over 12,000 patients utilizing the SEER database, Chan et al. subsequently proposed that a relationship existed between the number of lymph nodes resected and the survival of patients, but only in those patients with intermediate to high risk endometrioid uterine carcinomas [22]. These investigators stratified the total number of lymph nodes resected into three groups (â&#x2030;¤ 10 nodes, 11â&#x20AC;&#x201C;20 nodes, > 20 nodes) and concluded that disease specific survival increased in proportion to the number of nodes removed in intermediate and high risk patients, particularly in those with Stage IIIC-IV disease (Figure 2). In patients with intermediate to high risk disease (defined as Stage IB, grade3 and Stage IC-IV, all grades), a more extensive lymph node resection led to improved five-year survivals ranging from 75.3-86.8% (p<0.01), and in patients with Stage IIIC-IV, survival increased from 51-72% as an more nodes were removed (p<0.01).

A subsequent series of 63 Stage IIIC endometrial carcinoma patients also found that the number of positive pelvic lymph nodes predicted disease specific survival [23]. In this study, the performance of para-aortic lymphadenectomy significantly decreased recurrence risk and lengthened survival in patients with greater than 2 positive nodes beyond that seen with pelvic lymphadenectomy alone (p=0.011). The five-year disease-related survival was 19.4% in the pelvic node only group (n=12) but 59.6% in the

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Figure 2. Disease specific survival increased in proportion to the number of nodes removed in intermediate and high risk but not low risk patients in Stage IIIC-IV patients. Courtesy of Chan J et al. Cancer 2006;107(8):1823.

pelvic and para-aortic group (n=21). Conversely for early stage disease at this same institution, para-aortic lymphadenectomy failed to yield superior outcomes, implying that extensive lymphadenectomy may only be of value in advanced disease.

Smaller, retrospective studies further support full lymphadenectomy for high risk serous cancers in order to guide need for adjuvant chemotherapy.

Overall and progression-free survival significantly improves with pelvic lymph node counts â&#x2030;Ľ12 among women with high-risk histology (p< 0.001) but not among women with low-risk histology [24]. This increased survival potentially reflects a more rigorous evaluation to exclude lymph node metastases while removing histologically occult disease.

Consequently, although surgical treatment of endometrial cancer in the past has ranged from performing lymph node sampling only in high-risk patients to carrying out complete lymphadenectomies in all uterine cancer patients, systematic lymphadenectomy now appears to be the accepted standard in all but superficial grade I disease and appears to be especially

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important in those patients with known bulky nodal metastases. Obtaining a greater number of nodes not only more adequately stages patients to detect and remove micrometastatic disease, but also is associated with prolonged survival in patients with Stage III-IV disease. It remains to be determined, however, if there exists an absolute number of nodes necessary to define a therapeutic lymphadenectomy. Nodal count as well as the comprehensiveness of pathologic analysis, surgical expertise, and anatomical variations probably all contribute to what constitutes an â&#x20AC;&#x153;adequateâ&#x20AC;? nodal dissection, but clearly an appropriate assessment needs to be done intraoperatively to better direct adjuvant treatment.

Assessment of the omentum The 1988 FIGO guidelines do not include omental evaluation as part of the surgical staging criteria for endometrial carcinoma, but omentectomy or omental biopsy is frequently performed in cases of serous histology because of the similar pattern of spread to ovarian cancer. Nonetheless, the rate of microscopic omental metastasis from uterine cancers only ranges from 3-8% [25], and the negative predictive value of a visually normal omentum at the time of surgery approaches 90% in women with serous cancers, suggesting that total omentectomy is not routinely indicated unless the omentum appears abnormal [26]. Despite these findings, omental biopsy or infracolic omentectomy is still commonly carried out as part of the staging procedure for serous uterine cancers, possibly because the associated morbidity is low.

Given the limited patient numbers and rarity of serous endometrial cancers in currently published studies, objective evidence determining whether routine omental sampling provides clinically useful staging information is difficult to attain. Jeffrey et al. first attempted to address this issue, reporting on 5 women who underwent omental evaluation at initial surgical exploration. Three women had gross omental involvement, and two had visually negative omentums that eventually were upstaged based on microscopic invasion. They concluded that total omentectomy should be included in the routine staging for uterine serous carcinoma [27]. In a series of 30 women with uterine serous carcinoma, Kato et al. further described 8 women who underwent either omental biopsy or omentectomy, with 88% of omental specimens containing malignant cells [28]. Their data, however, failed to answer the question of whether routine omentectomy should be performed, as omentums were not clearly delineated as being either grossly or microscopically involved with metastatic disease.

Cirisano et al. later reviewed surgicopathologic characteristics in women with serous and clear cell carcinomas of the uterus in comparison to

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endometrioid carcinomas and found that omental assessment was done more than twice as often in cases of uterine serous cancer [29]. In clinical stage I-II tumors, 21% of omental specimens from patients with uterine serous carcinoma also had evidence of microscopic omental metastases in contrast to only 3-9% of endometrioid specimens, with almost four times as many patients upstaged in serous cases following extensive operations that often incorporated omentectomy and pelvic and para-aortic lymphadenectomy [29].

In an analysis of 65 women, Geisler et al. likewise recommended surgical staging for uterine serous carcinomas to include at least partial omentectomy because of the propensity of this histologic subtype for extrauterine spread.

Approximately 24% of patients exhibited microscopically positive omental or peritoneal biopsies despite negative lymph nodes, and nearly 40% of women with Stage IV disease were correctly diagnosed only after a staging operation similar to that employed for ovarian cancer was performed.

Faratian et al. correspondingly found omental involvement in 29% of 24 patient samples, and observed that women with a negative omental biopsy showed a significantly better progression free and overall survival than those with a positive biopsy. More notably, two recurrences (13%) occurred in biopsy positive omentums not removed by omentectomy, suggesting a potential therapeutic benefit following this procedure through increased abdominal tumor clearance [31].

Consequently, when the omentum is involved in uterine cancer, thereby upstaging the patient, the disease often is diagnosed by gross visualization. At minimum, sampling of the omentum does appear to assist in guiding management by excluding more advanced disease that definitively requires platinum therapy (Table 1). More radical resection, in contrast, should probably be reserved for bulkier disease that can be completely removed, as this possibly decreases tumor burden to sufficiently alter clinical outcome.

Table 1. Microscopic Omental Metastases in Uterine Serous Carcinomas.

Study

Total Number of Patients

Number of Omental Specimens

Visually Normal Omentums

% Subclinical Micrometastases

Gehrig et al Jeffrey et al Kato et al Cirisano et al Geisler et al Faratian et al

65 15 30 53 67 59

52 5 8 19 65 24

34 2 1 19 42 21

6% 100% 0% 21% 24% 29%

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Primary cytoreduction surgery for advanced stage endometrial cancer Surgical Stage III-IV endometrial cancer accounts for just 5-13% of all cases but is responsible for 23% of disease-related deaths. Five-year survival rates range from 10-25%, largely due to the lack of highly effective adjuvant treatment modalities [2,32]. Despite an overall poor prognosis, optimal cytoreductive surgery appears to lead to more favorable responses and improved clinical outcomes [33-35]. Surgery therefore has evolved as a cornerstone of treatment for most women with locally and regionally advanced endometrial cancer, but the appropriate extent of surgery in this setting and the utility of radical upper abdominal procedures in advanced disease are not clear. As with studies of surgery for ovarian cancer, the definition of what constitutes optimal debulking surgery, however, varies between investigators, and this makes it difficult to adequately compare results from different reports.

In one of the earliest reports addressing the issue of residual disease among women with advanced-stage endometrial cancer, Greer and Hamberger described a series of 31 women with Stage III-IV endometrial carcinomas. Ten patients with Stage IV disease undergoing surgical resection to <2 cm residual disease and postoperative radiation demonstrated 70% fiveyear survival, whereas all four patients with residual tumor greater than 2cm eventually died from their disease [35]. Martinez et al. similarly evaluated 25 Stage III/IV patients following cytoreductive surgery to <2 cm and whole abdomen radiation with nodal boost. Five-year relapse-free survival was 68%, but nearly one fourth of patients were left residual disease of up to 2 cm after their initial operation, mostly in the form of nodal disease [36].

Goff et al. later compared 29 patients with Stage IV disease who underwent cytoreductive surgery that left no â&#x20AC;&#x153;bulkyâ&#x20AC;? disease to 18 patients unable to undergo complete tumor reduction [34]. Median survival was 19 months in the surgically resectable group compared to 8 months in those who did not undergo surgery (p=0.0001), and by multivariate analysis, only successful cytoreduction was a significant prognostic variable.

Other publications have drawn more direct comparisons of optimal versus suboptimal cytoreduction in patients with Stage IV endometrial cancer. Chi et al., for instance, evaluated cytoreductive surgery for 55 Stage IV endometrial cancer patients by dividing them into groups according to surgical outcome [33]. Histology included 33 (60%) endometrioid, 12 (22%) serous, and 3 (5%) adenosquamous. Patients with optimal cytoreduction (â&#x2030;¤ 2.0 cm residual disease) were found to have a median survival time of

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31 months, in contrast to a median survival of 12 months for patients with suboptimal cytoreduction (>2.0 cm residual disease) and only 3 months for patients with unresectable carcinomatosis. Interestingly, the authors observed no significant difference in survival rates between those patients with small volume metastatic disease (â&#x2030;¤ 2.0 cm) before surgery and those patients with initially large volume disease who successfully completed optimal cytoreduction.

On multivariate analysis, extent of surgical cytoreduction seemed to be a notable prognosticator, suggesting that aggressive tumor reduction could potentially increase survival in even cases of advanced disease.

Bristow et al. subsequently assessed the role of optimal cytoreductive surgery in 65 patients with Stage IVB endometrial cancer, achieving optimal resection in 55% of cases [37]. Endometrioid histology accounted for 33.8% of patients, serous 32.3%, and mixed 16.9%. Patients undergoing optimal cytoreduction had a medial survival of 34.3 months compared to 11.0 months for those left with suboptimal residual disease (>1.0 cm). Among those optimally resected, patients with only microscopic residual disease survived longer than patients with optimal but macroscopic tumor residual (Figure 3), with lower residual disease, younger age, and better performance status independently predicting superior clinical outcome. The authors thus concluded that maximal cytoreduction at the time of primary surgery should be the goal in advanced uterine carcinomas because of the likely therapeutic benefit.

Figure 3. Stratification of overall survival in Stage IVB endometrial carcinomas by residual disease status (<1 cm, n=36 or >1 cm, n=29). Courtesy of Bristow R et al.

Gynecol Oncol 2000;78(2):85.

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Ayhan et al. further evaluated 37 Stage IVB patients and found a median survival of 25 months for patients undergoing optimal cytoreduction (â&#x2030;¤ 1.0 cm) compared to 10 months for the suboptimal group [38]. Patients left with no visible tumor exhibited a median survival of 48 months. Endometrioid subtype accounted for the majority of tumors. Operative morbidity appeared to be severe in approximately one-fourth of patients, though complicated by very small numbers. By univariate analysis, extra-abdominal metastases, suboptimal cytoreduction, visible tumor mass after cytoreduction, pelvic and para-aortic lymphatic metastases, and cervical extension predicted worse survival. On multivariate analysis, optimal cytoreduction, concomitant cisplatin radiotherapy, and extra-abdominal metastases associated with improved outcome.

Lambrou et al. most recently reported on 85 patients (66 Stage III and 19 Stage IV) with advanced endometrioid adenocarcinoma treated with primary surgery [21]. Overall survival proved lower and morbidity higher in patients suboptimally cytoreduced, with median survival measuring 6.7 months for patients with residual disease and 17.8 months for patients with optimal resection (p = 0.001).

In each of these studies, overall survival increased in women left with small volume disease after initial resection. As with ovarian cancer, surgical cytoreduction to no residual tumor should be the aim for patients with Stage III-IV uterine disease to maximize response to adjuvant therapies. Thus, more expansive preoperative assessment needs to be done to best predict which patients will be candidates for optimal surgical resection â&#x20AC;&#x201C; patients in whom a reasonable attempt at primary surgical intervention may be more appropriate than chemotherapy or radiation.

Serous and clear cell carcinomas of the endometrium Uterine serous carcinoma Uterine serous carcinomas (USC) comprise 3-11% of all uterine cancers, but account for 15-25% of disease-related deaths and a notable proportion of advanced stage disease [39-41]. Paralleling ovarian cancer, USC demonstrates a propensity for more widespread disease and recurrence risk, with lymphovascular invasion and intraperitoneal dissemination seen more frequently in these tumors as compared to endometrioid uterine cancers (39, 42-43). As many as 69-87% of patients exhibiting extracorporeal disease at initial diagnosis [30,34,44].

Studies indicate that surgical staging for USC is critical (perhaps even more so than in endometrioid tumors), as these lesions often metastasize in the presence of minimal uterine disease.

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Unlike endometrioid cancers, grade and depth of myometrial invasion of USC do not always predict extrauterine spread, as approximately 30-40% of patients with no obvious uterine invasion demonstrate advanced stage disease following comprehensive staging that includes omentectomy, peritoneal biopsies, and lymph node dissection [45,46]. Gehrig et al. observed in 69 patients that 67% of clinical Stage I USC cases with no myometrial invasion had distant disease at the time of surgical staging [47]. Moreover, in a metaanalysis by Dunton et al., up to 63% of all USC patients stage higher surgically than clinically suspected [48]. Because of this discrepancy, many authors endorse complete surgical staging for patients with documented USC on preoperative biopsy [47].

Despite five-year survival rates as low as 5%, a growing body of literature also suggests a role for surgical cytoreduction in the management of Stage IV USC patients, given the potential survival advantage in several case series [42,49,50]. However, the rarity of these tumors again makes large, prospective studies difficult.

Bristow et al. initially reported on 31 patients who underwent primary cytoreductive surgery for Stage IV USC [49]. Optimal cytoreduction was defined as residual disease â&#x2030;¤1 cm, and 51.6% of patients successfully completed primary surgery with optimal disease status. The median survival time for those patients optimally resected was 26.2 months, compared with 9.6 months for patients left with suboptimal residual disease (p < 0.001).

More specifically, the median survival time was 30.4 months in patients left with only microscopic residual disease, 20.5 months in patients with optimal but visible residual disease measuring â&#x2030;¤1 cm, and 9.6 months in patients with residual greater than 1 cm (p=0.004). The only significant predictor of suboptimal surgical outcome was the presence of disease in three or more anatomic regions. On multivariable analysis, the lone statistically significant predictor of extended overall survival was cytoreductive surgical outcome, but no single anatomic region appeared predictive of surgical outcome, pointing to the value of decreasing overall tumor burden rather than removing disease from a particular site.

Moller et al. presented a multi-institutional, retrospective review identifying 52 women with Stage IV USC [51]. Twenty-six patients underwent optimal debulking (â&#x2030;¤ 1 cm residual) and 23 suboptimal. Although overall survival failed to correlate with the absolute size of residual disease (15 vs. 8 months, p>0.05), optimal cytoreduction combined with adjuvant platinum chemotherapy demonstrated a trend toward prolonged survival when compared to suboptimal cytoreduction combined with adjuvant therapy.

Memarzadeh et al. analyzed 43 women who underwent surgical cytoreduction for Stage III and IV disease [52]. The median survival for USC

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patients in this series with microscopic residual disease significantly improved compared to those with macroscopic residual disease following primary surgical cytoreduction (43 vs. 10 months, p<0.001). Progression free survival for those left with microscopic disease also proved nearly 3 times longer than those with macroscopic residual disease (22 vs. 8 months, p<0.0001). Survival of patients with advanced UPSC correlated with the extent of residual tumor following primary surgical resection, and the presence of any measurable residual tumor dramatically decreased the median survival and the recurrence-free interval in these patients.

A large series described by Thomas et al. looked at 125 Stage IIIC窶的V USC patients (Stage IIIC=12, Stage IV=58) [53]. Optimal cytoreduction was accomplished in 60% patients, with no visible residual disease in 37%.

Median time to recurrence differed between those optimally resected and those suboptimally cytoreduced (9 months vs. 6 months, p=0.04). Women with no visible residual disease after cytoreduction, moreover, exhibited a longer median survival (51 months), in comparison to 14 months in those optimally cytoreduced albeit with residual disease and 12 months in those suboptimally cytoreduced (Figure 4). No decrease in survival rates occurred when radical procedures (e.g. splenectomy, diaphragmatic stripping, or bowel resection) needed to be done to completely remove all residual disease.

Thus, in the context of resection of all macroscopic tumor, maximal surgical effort, including the use of extended procedures, enhanced clinical outcome.

Figure 4. Kaplan-Meier plot for stage IIIC-IV patients with no residual (51 months), residual<1cm (14 months), and residual>1 cm (12 months). Courtesy of Thomas M et al, Gynecol Oncol 2007;107(2):190.

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The strongest predictor of overall survival for patients with advanced USC therefore seems to be the amount of residual disease left following primary resection, as over 80% of recurrences in these patients are associated with abdominopelvic failures and about one-third with distant metastases [48, 53]. Recommended management for this group of patients consequently should consist of optimal cytoreductive surgery to no residual tumor, including resection of disease in the upper abdomen, followed by platinumbased chemotherapy to maximally impact median and progression-free intervals.

Clear cell carcinoma Uterine clear cell carcinomas similarly tend to spread to distant sites, accounting for 1â&#x20AC;&#x201C;6% of endometrial cancers but linked to five-year prognoses as low as 20% in advanced disease [54]. Like serous carcinomas, occult extrauterine metastasis presents in 40% of patients with disease clinically confined to the uterus [29], and as with other non-endometrioid tumors, comprehensive surgical staging with systematic lymphadenectomy is generally advocated given the high risk of occult metastasis.

The relative rarity of clear cell carcinomas of the uterus, unfortunately, has compelled many investigators to combine examination of these tumors with uterine serous carcinomas. In one of the few multi-institution reviews focusing on uterine clear cell cancers conducted by Thomas et al., 52% of 99 women were upstaged at the time of surgery, with 20% of women found to have lymphatic involvement after pathologic assessment [55]. No patient was upstaged solely on the basis of omentectomy or peritoneal biopsies.

Cytoreduction to no visible disease was achieved in all Stage IIIC and nearly half of Stage IV patients. Women without visible residual disease had a significant improvement in median progression free survival (17 vs. 7 months, p < 0.001) and overall survival (40 vs. 18 months, p = 0.02) when compared to patients left with residual disease; this trend extended to Stage IV patients (Figure 5). Multivariate analysis identified only the absence of residual disease and adjuvant treatment with radiation or chemotherapy as independent predictors of local disease control.

Clear cell carcinomas of the uterus indeed display a propensity for metastatic disease at initial presentation, yet the relative rarity of clear cell tumors has necessitated that it be analyzed together with uterine serous cancers in many previous publications. Both variants have high rates of deep myometrial invasion and extensive lymphovascular space invasion at diagnosis, with increased rates of loco-regional recurrence and reduced overall survival seen in even early stage disease. As in other histologies, cytoreduction to no

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Figure 5. Longer median survival for Stage IIIC-IV patients with clear cell carcinoma left with no residual disease after primary surgery (40 vs. 18 months). Courtesy of Thomas M et al. Gynecol Oncol 2008;108(2):293.

visible tumor appears to be associated with better outcomes for patients with advanced uterine clear cell carcinomas. When feasible, an attempt at optimal resection consequently should be made in these cases, as a therapeutic benefit seems plausible based on the limited studies currently available.

Salvage cytoreductive surgery for recurrent disease Considering all patients with endometrial cancer, the risk of recurrence ranges from 7.7-63.3%, depending on the presence of specific prognostic factors [56,57]. Traditionally, surgical treatment of recurrent disease has been reserved only for patients presenting with a central pelvic recurrence recalcitrant to radiation therapy. In this scenario, exenterative procedures have been associated with long-term survival rates of 20-45%; yet, relatively few patients are candidates for this approach [58,59]. Although recent data support a positive correlation between survival and the successful surgical cytoreduction of advanced stage endometrial cancer, the role of non-exenterative cytoreductive surgery for recurrent disease has been less widely explored.

Central pelvic recurrence of endometrial cancer For a select number of patients with a localized vaginal recurrence, radiation therapy can provide favorable long-term pelvic control and five-year

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survival rates between 31% and 53% [60-62]. However, a significant proportion of patients will have already received pelvic irradiation to maximal doses and salvage chemotherapeutic regimens remain quite limited in this setting. In these patients, Barakat et al. proposed that the only potentially curative option was pelvic exenteration if the tumor was centrally recurrent.

They identified a total of 44 patients in their review and, despite high operative morbidity, found that 9 patients (20%) achieved long-term survival of greater than 5 years [58].

Regional and distant recurrence of endometrial cancer The subset of women with recurrent endometrial cancer that are candidates for pelvic exenteration is very specific. Unfortunately in the majority of patients, regional or distant disease is present at time of re-diagnosis, and treatment alternatives primarily consist of cytotoxic chemotherapy, hormonal treatment, or palliative radiation. The most effective chemotherapeutic agents for advanced or recurrent endometrial tumors include cisplatin, doxorubicin, paclitaxel, and topotecan. Although overall response rates range from 20-37%, stabilization of disease is generally of short duration [63-66]. Hormonal therapy with progestational agents, anti-estrogens, and gonadotropin-releasing analogs produce disappointing response rates ranging from 9-16%, with the likelihood of response correlating with the degree of tumor differentiation [67-70]. As these data indicate, alternative treatment strategies need to be developed to improve patient outcome for patients with recurrent endometrial cancer. Consequently, recent investigators have explored the role of surgical cytoreduction as a means of augmenting the durability of response to salvage therapies.

The first report of secondary cytoreductive surgery for recurrent endometrial cancer was described by Scarabelli et al. in 1998, which detailed a series of 20 patients [71]. Complete resection of all visible tumor was achieved in 65% of patients and was associated with significantly longer progression-free (9.1 months vs. 1.5 months, p<0.05) and overall survival (11.8 months vs. undefined, p<0.01) compared to patients left with residual disease. Several years later, Campagnutta and coworkers reported a larger series of 75 patients undergoing surgical treatment for recurrent disease [72].

Optimal resection to less than 1 cm was accomplished in nearly 75% of cases, and 64.0% of women underwent complete removal of all macroscopic tumor. The only clinical characteristic independently predictive of optimal resection seemed to be solitary rather than multiple sites of tumor recurrence.

For all patients, the post-recurrence survival time measured a median of 19 months, with optimal secondary cytoreduction being associated with a median survival time of 53 months compared to just 9 months for patients left

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with residual disease. On multivariate analysis, complete cytoreduction, the administration of post-operative chemotherapy, and central pelvic recurrence independently and significantly associated with a superior survival outcome.

More recently, Awtrey and colleagues detailed their experience with 27 patients undergoing non-exenterative surgery for recurrent endometrial cancer [73]. Optimal cytoreduction (<2 cm residual disease) occurred in 67% of cases, and 56% of women were left with no gross residual disease. Patients optimally cytoreduced had a longer median survival time (43 months) compared to patients left with suboptimal residual disease (10 months, p<0.05). Following univariate analysis, the amount of residual disease proved to be the sole predictor of progression-free and overall survival.

Bristow et al. subsequently identified 61 patients with recurrent endometrial cancer, 35 of whom underwent salvage cytoreductive surgery [74].

Complete cytoreduction with no gross residual disease was achieved in nearly two-thirds of patients. Women undergoing complete salvage cytoreduction boasted a median post-recurrence survival time of 39 months, nearly three times longer than those with gross residual disease (13 months, p=0.0005). Following multivariate analysis, both successful surgical resection (HR=0.11) and residual tumor volume (HR=6.85) independently predicted post-recurrence survival (Figure 6).

Figure 6. Overall survival in women with recurrent endometrial cancer classified by surgical status and residual disease with those patients with no gross residual tumor demonstrating better clinical outcomes. Courtesy of Bristow R et al. Gynecol Oncol 2006;103:281.

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Although less clearly delineated than in primary debulking, salvage cytoreductive surgery appears justified in a specific subset of patients in whom prolonged post-recurrence survival can be attained. Theoretically, complete surgical resection of recurrent disease can augment chemotherapeutic response by reducing the kinetic and pharmacologic barriers to tumor cytotoxicity. The reported rates of surgical success thereby reflect both the use of discriminating patient selection criteria and recognizing those patients in whom secondary debulking provides an ensuing therapeutic advantage.

Uterine sarcoma Primary cytoreductive surgery for advanced-stage uterine sarcomas Although representing only 1% of uterine cancers, uterine sarcomas continue to be deadly. Five-year survival rates range from 25-75%, with recurrence of pelvic disease ranging from 14-64% [75-77]. Given the scarcity of good adjuvant therapies in uterine sarcomas, aggressive surgical cytoreduction at initial diagnosis offers one of the few treatment options that possibly prolongs survival.

While lymphadenectomy has not been shown to be therapeutically or prognostically helpful in uterine sarcomas [78], visualization and palpation of the peritoneal cavity are often recommended as sufficient for staging.

Multiple studies have proposed that removal of the ovaries in premenopausal women may not be necessary either [79-81]. Berchuck et al., for instance, evaluated 46 patients with uterine sarcomas and demonstrated parallel recurrence rates between 8 patients with ovarian preservation and the entire patient population [81]. Similarly, Gadducci et al. reported that preservation of the ovaries in apparent Stage I patients younger than age 50 did not affect recurrence rates [79]. Larson et al. further examined overall survival in premenopausal women with uterine sarcomas without controlling for stage or grade, showing no difference in overall survival between the 19 patients who underwent bilateral salpingo-oophorectomy and the 31 patients who maintained residual ovarian tissue postoperatively [80].

Surgery remains the treatment of choice for initial therapy in sarcomas, but the lack of efficacious adjuvant therapies in advanced stage disease ultimately leads to recurrence and poor overall survival. In a ten-year, single institution review of 27 patients with leiomyosarcoma, Dinh et al. concluded that patients with visible disease following primary surgery had a better overall outcome than patients who did not achieve surgical remission (p < 0.0003) [82]. Nearly 60% of patients presented with Stage IV disease,

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and chemotherapeutic regimens (which often included doxorubicin and/or ifosfamide) appeared to be minimally effective. Adjuvant therapy after optimal cytoreduction failed to decrease the risk of recurrence, as 80% of treated patients developed progressive disease.

A report by Giuntoli et al. of 208 women with uterine sarcomas mainly assessing the extent of surgical intervention found that initial surgery consisted of simple hysterectomy in 93% of patients [83]. Radical or modified radical hysterectomies were performed in 4% of patients, with 62% of women categorized as Stage I. Ovaries were preserved in 29 patients, and lymph nodes were evaluated in only 36 women. Multivariate analysis revealed that high grade, advanced stage, and oophorectomy were associated with significantly worse disease-specific survival (Figure 7). Consequently, tumor grade and stage (using modified criteria for endometrial cancer) appeared to be valid prognostic indicators for uterine sarcomas, and ovarian preservation seemed plausible in premenopausal patients with early-stage tumors, as the elimination of oophorectomy at therapy did not appear to significantly alter survival.

A subsequent retrospective review performed on 127 patients with histologically verified uterine sarcomas revealed that FIGO stage (p=0.025), depth of myometrial invasion (p=0.004), and complete cytoreduction (p=0.030) significantly lengthened the disease free survival [84]. Adjuvant therapy correspondingly played a limited role in patients with early-stage disease.

Figure 7. Kaplan-Meier analysis for unselected patients stratified by performance of oophorectomy. Courtesy of Giuntoli R et al. Gynecol Oncol 2003;89(3):460.

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Unfortunately, up to 70% of patients with uterine leiomyosarcoma confined to the uterus and nearly all with extrauterine disease at diagnosis eventually recur, with median time to recurrence spanning 8-16 months [75,76,78,79,81]. Chemotherapy, radiation, and hormonal manipulation all have been advocated for the prevention of tumor recurrence, but all with moderate success. Unlike results seen epithelial histologic subtypes, adjuvant chemotherapy appears to be of minimal efficacy in uterine sarcomas, with various regimens recommended for advanced or recurrent disease showing disappointing response rates ranging from 19-30% [85-87]. In effect, while optimal cytoreductive surgery seems to play a role in improving clinical outcome in the primary setting, the ideal adjuvant treatment after surgical extirpation continues to be undefined.

Cytoreductive resection of recurrent uterine sarcomas Several studies also have examined the feasibility of operative resection of metastatic disease in patients with recurrent uterine sarcomas. Surgery has been retrospectively shown to offer a survival advantage in patients with even pulmonary metastasis. Levenback et al. first described 45 patients with recurrent uterine sarcomas who had previously undergone hysterectomy at initial presentation. Among this carefully selected group of patients with isolated pulmonary metastases, surgical resection led to long-term survival in a substantial proportion of patients, with five-year survival rates of approximately 40% [88]. The absence of bilateral disease proved to be the only significant predictor of improved survival, while nodule size, use of adjuvant therapy, histologic type, and age did not influence clinical outcome.

The survival advantage observed following successful resection of thoracic disease is further seen in patients with extrapulmonary metastases.

Leitao et al. examined the effects of secondary cytoreduction in 41 uterine sarcoma patients with both pulmonary and/or extrapulmonary recurrences, 12 of whom had thoracic procedures performed [89]. Following univariate analysis, time to recurrence of less than 12 months and optimal surgical resection predicted better outcome, with overall median survival for the entire group amounting to 3.9 years in comparison to 7-15 months for historical controls receiving chemotherapy alone.

Even in the presence of lung metastases, surgical excision of intraabdominal metastases remains a viable option in light of the lack of response to other treatment modalities. Surgical excision has been tried, for instance, in cases of liver metastases with partial success. In a study of 26 patients by Lang et al., for example, prolonged survival was associated with removal of all metastatic foci, with 20% of patients surviving 5 years after surgery [90].

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In one of the largest series to date, Giuntoli et al. identified 128 patients with recurrent uterine sarcomas [91]. Management of recurrent disease included secondary cytoreductive surgery in 63% of patients, chemotherapy in 55%, and radiation in 26%. Of the 80 patients undergoing secondary cytoreductive surgery, a complete resection with no residual disease was reported in 80%. In contrast to the survival benefit associated with successful secondary cytoreduction in ovarian cancer, however, median survival time in this study was only modestly improved (2.0 versus 1.1 years, p<0.001), with recurrence within 6 months of diagnosis indicating more aggressive disease often poorly responsive to secondary cytoreduction (Figure 8). Upon review, secondary cytoreductive surgery (HR=0.26) and prolonged time to recurrence (HR=0.58) independently predicted superior disease-specific survival, whereas neither chemotherapy nor radiation improved outcome in patients with recurrent disease.

By reducing tumor volume, optimal surgical resection of recurrent disease appears to be associated with extended post-recurrence survival in a select group of patients, although the modest magnitude of this benefit should be considered in selecting patients for surgical intervention. Patients presenting after a prolonged progression-free interval and preferably with an isolated site of recurrence appear to be the best candidates for attempted surgical resection.

Figure 8. Secondary cytoreductive surgery led to significantly improved disease specific survival in patients with recurrent leiomyosarcomas. Courtesy of Giuntoli R et al. Gynecol Oncol 2007;106(1):82.

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Surgical morbidity and postoperative complications Inevitably, surgical and postoperative morbidity are key factors when considering cytoreductive surgery in patients with advanced or recurrent disease. Nevertheless, the value of radical pelvic and abdominal procedures in these patients needs to be balanced against the associated high morbidity and resulting quality of life for the individual woman.

Little data exists unfortunately regarding the true surgical morbidity associated with substantial cytoreductive procedures. Lambrou and coworkers first looked at the complexities of these complications in detail [21]. Even though the suboptimal and optimal groups in their review exhibited statistically similar radical debulking operations, the suboptimal group actually experienced increased morbidity thought secondary to inherent tumor biology rather than the type of surgical procedure performed. The proportion of patients with major postoperative complications (37.5% vs. 7.25%, p=0.005), unplanned postoperative ICU admissions (31.25% vs. 7.25%, p= 0.018), and length of hospital stay exceeding 15 days (31.25% vs. 4.35%, p= 0.005) proved to be much greater in patients left with residual disease. Specifically, the incidence of major adverse events including severe cardiopulmonary compromise, vascular embolus, fascial dehiscence, sepsis, bowel obstruction, and repeat laparotomy occurred significantly more in patients with suboptimal cytoreductive surgery (37.50% vs.

7.25%, p= 0.005), but the incidence of minor complications including febrile episodes, urinary and surgical site, simple pneumonia, and ileus, conversely, did not significantly differ between the two groups.

In advanced stage patients with only resection of nodal metastases, Havrilesky et al. similarly observed adverse events in 24% of patients [19].

Surgical complications included small bowel obstruction requiring surgery (3%), repeat laparatomy (3%), genitourinary obstruction (2%), wound dehiscence (1%), and lymphocyst requiring drainage (1%). Meanwhile, medical events included small bowel obstruction treated conservatively (3%), venous emboli (4%), cardiopulmonary compromise (5%), pneumonia (1%), and pyelonephritis (1%).

In their series, Bristow et al. likewise found excessive hemorrhage (>1 liter) in 11.4% of patients, with 28.6% of women requiring a blood transfusion [74]. No peri-operative deaths took place. Minor postoperative morbidity (e.g. adynamic ileus, urinary tract infection, superficial wound breakdown, pneumonia, deep vein thrombosis) occurred in nearly 30% of patients, while 5% of women experienced more life-threatening complications that included bacteremia, pulmonary emboli, and acute renal failure. The median length of hospitalization for all patients amounted to 6 days, ranging 1-21 days.

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Cytoreductive surgery in women with either advanced or recurrent uterine cancer therefore demonstrates significant but acceptable risks that require thoughtful deliberation, given the potential therapeutic gains of these more expansive procedures. Before contemplating any surgical intervention, however, appropriate diagnostic evaluation, optimization of medical comorbidities, and thorough risk assessment should be undertaken prior to any tumor debulking operation in order to identify patients best suited to benefit in the long-term.

Conclusions and future directions Certainly, women with metastatic, refractory, or chemoresistant uterine carcinomas need to be considered for primary and salvage cytoreductive procedures if deemed medically or technically possible. Only through maximal surgical efforts, in conjunction with the development of novel targeted based adjuvant drugs, will real therapeutic strides be made for these patients in whom prognosis continues to be abysmal.

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52. Memarzadeh S, Holschneider C, et al. (2002). FIGO stage III and IV uterine papillary serous carcinoma: impact of residual disease on survival. Int J Gynecol Cancer 12(5):454.

53. Thomas M, Mariani A, et al. (2007). Role of cytoreduction in stage III and IV uterine papillary serous carcinoma. Gynecol Oncol 107(2):190.

54. Abeler V, Vergote I, et al. (1996). Clear cell carcinoma of the endometrium: prognosis and metastatic pattern. Cancer 78(8):1740.

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57. Aalders J, Abeler V, et al. (1984). Recurrent adenocarcinoma of the endometrium: a clinical and histopathological study of 379 patients. Gynecol Oncol 17(1):85.

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59. Morris M, Alvarez R, et al. (1996). Treatment of recurrent adenocarcinoma of the endometrium with pelvic exenteration. Gynecol Oncol 60: 288.

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8. The role of surgery in the management of high-risk gestational trophoblastic neoplasia John R. Lurain John & Ruth Brewer Professor of Gynecology and Cancer Research, John I. Brewer Trophoblastic Disease Center, Northwestern University Feinberg School of Medicine, 250 E. Superior St. Suite 05-2168, Chicago, IL 60611, USA

Abstract. Despite the success of chemotherapy in inducing remission in most patients with high-risk gestational trophoblastic neoplasia (GTN), surgical procedures often play an important role in the management of these patients. Approximately one half of patients with high-risk GTN will require some form of surgical procedure during the course of therapy to either remove disease or treat complications. Adjuvant surgical procedures, especially hysterectomy and pulmonary resection, are used most frequently to remove foci of chemotherapy-resistant disease in patients with persistent or recurrent GTN. Conservative resection of chemotherapy-resistant disease within the myometrium may be considered in highly selected patients with no other evidence of disease who wish to preserve fertility. Surgery may also be required in the therapy of patients with high-risk GTN as a means of controlling hemorrhage or dealing with other life-threatening complications.

Correspondence/Reprint request: Dr. John R. Lurain, John & Ruth Brewer Professor of Gynecology and Cancer Research, John I. Brewer Trophoblastic Disease Center, Northwestern University Feinberg School of Medicine 250 E. Superior St., Suite 05-2168, Chicago, IL 60611, USA. E-mail: jlurain@nmff.org

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Introduction Despite the success in inducing remission in most patients with gestational trophoblastic neoplasia (GTN), surgical procedures play an important role in management [1]. Approximately one half of patients with high-risk GTN (FIGO stages II â&#x20AC;&#x201C; IV, score > 7) will require some form of surgical procedure during the course of therapy to either remove disease or treat complications.

Adjuvant surgical procedures may be employed to: (1) remove resistant/persistent disease in the uterus or at metastatic sites, (2) decrease tumor burden in the uterus in patients with limited metastatic disease, (3) control tumor hemorrhage, (4) relieve bowel or urinary obstruction, or (5) treat infection [2-5].

In a series of 50 patients with high-risk GTN treated with etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO) as primary or secondary chemotherapy at the John I. Brewer Trophoblastic Disease Center of Northwestern University between 1986 and 2005, 24 (48%) underwent 28 adjuvant surgical procedures [6]. The procedures included hysterectomy (17), lung resection (5), salpingectomy (1), uterine wedge resection (1), small bowel resection (1), suturing of the liver or uterus for bleeding (2), and uterine artery embolization (1). Twenty-one (87.5%) of 24 patients who had surgical procedures as part of their treatment for high-risk GTN survived. Fifteen (88%) of 17 patients who underwent hysterectomy, 4 (80%) of 5 patients who had resistant foci of choriocarcinoma in the lung resected, all 4 of the patients who had suturing of the uterus, uterine artery embolization, small bowel resection or salpingectomy for bleeding, as well as the patient who had uterine wedge resection of resistant choriocarcinoma survived. This series demonstrates that adjuvant surgical procedures, especially hysterectomy and pulmonary resection for chemotherapy resistant disease as well as procedures to control hemorrhage, are important components in the management of high-risk GTN.

Hysterectomy Hysterectomy has an important role in the management of high-risk GTN. Primary hysterectomy may be considered in selected patients with high-risk metastatic disease who have small extrauterine tumor burdens and do not desire to maintain fertility, but in general the procedure is not as beneficial as in patients with nonmetastatic and low-risk metastatic disease. The two most frequent indications for hysterectomy are to remove chemotherapy-resistant disease in the uterus and to control excessive uterine bleeding.

High-risk patients with evidence of uterine disease, but no or very little extrauterine disease, may benefit from hysterectomy. Lurain et al from the

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Brewer Trophoblastic Disease Center reported that 12 (86%) of 14 patients who had hysterectomy for resistant choriocarcinoma survived [6]. Mutch et al reporting curing 10 (71%) of 14 patients who underwent hysterectomy as part of treatment for recurrent GTN at the Southeastern Regional Trophoblastic Disease Center [7]. The Sheffield, U.K., Trophoblastic Disease Center reported that 9 (75%) of 12 patients who underwent hysterectomy because of chemotherapy-resistant uterine disease had a complete clinical response to surgery [8]. The Charing Cross Hospital, London, U.K., group reported using hysterectomy in 9 of 20 patients who developed resistance to EMA-CO after other chemotherapy [9].

The Sheffield group recently updated their data on the role of hysterectomy in managing persistent GTN at their institution [10]. Of 8,860 registered patients, 62 (0.7%) underwent hysterectomy for GTN: 22 (35.5%) for resistance to chemotherapy and 21 (33.9%) for major hemorrhage, while the remainder had hysterectomy as part of their primary treatment for other indications. The overall remission rate in these patients was 93.5%, however, 7 relapsed and 4 (18%) of 22 patients with resistant disease subsequently died.

Deumplis, et al reviewed the role of hysterectomy in the management of 25 patients with GTN at the Charing Cross Trophoblastic Disease Center over a 13-year period [11]. Histology was choriocarcinoma in 9, placental site trophoblastic tumor in 6, and hydatidiform mole in 10. The two main reasons for surgery were chemoresistance during initial treatment and relapse after treatment. Postoperative chemotherapy was given to 21 of the 25 patients, although the hysterectomy appeared to be therapeutic as demonstrated by a rapid return of hCG levels to normal in 22 of the 25 patients. Survival was 88% (22/25). Of the 3 patients who died, all had high-risk, metastatic disease, one of whom had a placental site tumor.

Cagayan and Magallanes from the Philippines performed adjuvant hysterectomy in 129 (32%) of 420 patients managed with GTN at their institution [12]. Indications for hysterectomy were: uterine rupture (31, 24%), vaginal bleeding (13, 10%), chemotherapy resistance (11, 8.5%), and adjuvant therapy at the beginning of treatment to reduce chemotherapy when future pregnancy was not desired (74, 57.4%). The overall survival was 98.4%, with 2 of the 11 patients who had hysterectomy for chemotherapy-resistant disease dying.

Although hysterectomy clearly has a place in the management of highrisk GTN, it is not often indicated in the primary management of patients with widely metastatic disease unless there is a very large uterine tumor causing bleeding in a patient with no desire to maintain fertility. It is also less common to see refractory disease only in the uterus with the use of current multi-agent chemotherapy. Before deciding to perform a hysterectomy for chemotherapy-resistant high-risk GTN, it is imperative to document the

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presence of uterine disease by scans. In the series from the Brewer Center [6] and the Southeastern Regional Center [7], histologic evidence of uterine disease was found in 79% and 83%, respectively, of hysterectomies done for treatment of recurrent or persistent high-risk GTN.

Pulmonary resection Resection of isolated pulmonary metastases via thoracotomy or thoracoscopy in patients with drug-resistant GTN may be successful in inducing remission.

Before performing pulmonary resection, it is important to exclude disease elsewhere as thoroughly as possible with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, chest, abdomen and pelvis.

Tomada et al reviewed their results from planned resection of pulmonary nodules in GTN and proposed guidelines for successful resection: (1) good surgical candidate; (2) primary uterine malignancy controlled; (3) no evidence of other metastatic sites; (4) solitary pulmonary lesion; (5) hCG level < 1,000 mIU/mL. In their series, 14 (93%) of 15 patients who satisfied these criteria were cured by pulmonary resection as compared to none of the patients who had > 1 unfavorable factors [13].

Xu et al from Beijing, China reported 50% survival with resection of pulmonary metastatic choriocarcinoma in 43 drug-resistant patients. They noted improved survival in patients who had a solitary lung lesion without metastases to other organs as well as prior good response to chemotherapy [14]. Several U.S. trophoblastic disease centers have reported successful outcomes with pulmonary resection in the management of patients with high-risk GTN. Lurain et al from the Brewer Center reported curing 4 (80%) of 5 patients who had pulmonary resections for drug-resistant disease [6]. Mutch et al from the Southeastern Regional Trophoblastic Disease Center reported that 4 (44%) of 9 patients who underwent thoracotomy with pulmonary wedge resection of resistant choriocarcinoma survived [7]. Fleming et al from the New England Trophoblastic Disease Center reported that thoracotomy was successful in eradicating drug-resistant pulmonary disease in 10 (91%) of 11 high-risk patients.

Of the patients who survived, only one had disease outside the lung (brain metastasis) at the time of thoracotomy, and all had solitary lung nodules and hCG levels below 1,500 mIU/mL [15]. It has been noted by several groups of investigators that prompt hCG regression within 1 â&#x20AC;&#x201C; 2 weeks of resection of an isolated pulmonary nodule predicts a favorable outcome [4,13,14,16].

Local uterine resection Conservative resection of chemotherapy-resistant GTN within the myometrium may be considered in highly selected patients with no evidence

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of metastatic disease who wish to preserve fertility. There have been several reports of local myometrial resections for nonmetastatic, chemoresistant GTN [6, 7-21]. One of our patients who had persistent uterine disease after sequential single-agent and EMA-CO chemotherapy without evidence of metastatic disease underwent wedge resection of the right cornual portion of her uterus for choriocarcinoma with negative margins. After surgery, she received 3 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy. She has remained without evidence of disease since then and has had 2 normal pregnancies delivered by cesarean section [6].

Patients considered for this procedure should be thoroughly evaluated for systemic metastases, and the uterine lesion should be carefully localized by MRI with or without positron emission tomography (PET), color flow Doppler ultrasound or hysteroscopy. Lesions less than 2 â&#x20AC;&#x201C; 3 cm in diameter associated with low hCG levels are more likely to be completely excised [18]. Most patients undergoing local uterine resection should also receive chemotherapy.

Procedures for tumor hemorrhage Surgical procedures may also play a role in therapy for high-risk GTN as a means of controlling tumor hemorrhage or dealing with other lifethreatening complications [1,2]. Four of the 50 patients with high-risk GTN who we reported from the Brewer Center required surgical procedures for bleeding. These included suturing of the liver for bleeding metastatic choriocarcinoma, suturing of the uterus for perforating choriocarcinoma, small bowel resection for choriocarcinoma metastatic to the small bowel causing gastrointestinal bleeding, and salpingectomy for ruptured tubal ectopic choriocarcinoma [6].

In the series reported from the Philippines, hysterectomy was indicated for uterine rupture in 31 patients (7.4%) and vaginal bleeding in 13 patients (3.1%) out of 420 patients treated for GTN at their institution. This relatively high rate of hysterectomy (10.5%) for control of uterine bleeding in GTN was explained by the authors as due to delayed referral and improper initial management resulting in more advanced disease at presentation to their center [12].

Selective angiographic embolization of the uterine arteries may also be employed to control uterine or pelvic tumor bleeding in lieu of surgical intervention [22-25]. One of our high-risk patients underwent successful uterine artery embolization for intractable uterine bleeding with preservation of fertility [6]. The Charing Cross Hospital group reported on the use of arterial embolization in 14 patients for control of uterine bleeding associated

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with GTN. Hemorrhage was controlled in 11 patients, while 2 patients required hysterectomy and 1 patient underwent uterine artery ligation for persistent uterine bleeding. Five pregnancies, including 3 normal full-term deliveries were achieved in these 11 women [24].

Vaginal metastases in GTN are extremely vascular, friable and capable of inducing severe hemorrhagic complications. While most vaginal metastases respond quickly and completely to systemic chemotherapy, their management often includes surgical and angiographic interventions. Yuigua, et al from Beijing, China reported on 51 patients with vaginal metastases, 18 (35%) of whom had massive hemorrhage. Management in these patients included vaginal packing (16), excision (2), hysterectomy with internal iliac artery ligation (1), and selected angiographic embolization (3) [26]. At the Brewer Center, 13 (36%) of 36 patients with vaginal metastases from GTN had significant bleeding requiring blood transfusion (median 7 units, range 1 â&#x20AC;&#x201C; 26 units). Seven of these patients required 1 or more procedures for control of bleeding when vaginal packing was not sufficient, including excision (3) or suturing (7) of vaginal lesions, bilateral internal iliac artery ligation (1), and angiographic uterine artery embolization (1) [27].

Craniotomy may be indicated for acute surgical decompression of brain metastasis in high-risk GTN patients with signs or symptoms of increased intracranial pressure [28-32]. Rustin, et al from the Charing Cross Hospital recommended an approach of early craniotomy with excision of isolated brain lesions combined with systemic and intrathecal methotrexate [28]. By contrast, most trophoblastic disease centers in the U.S. recommend integration of whole brain or steriotactic irradiation into systemic therapy for high-risk GTN with brain metastasis in an attempt to prevent brain hemorrhage, reserving craniotomy for neurologic deterioration [29, 30]. Both approaches seem to have similar efficacy, with about 75-80% of patients presenting with brain metastases and 50% of patients overall with brain metastases from GTN being cured [28-30]. Craniotomy for resection of drug-resistant brain lesions is only rarely performed [28-30]. In general, craniotomy is usually reserved for patients with GTN who require acute decompression of central nervous system hemorrhagic lesions to allow for stabilization and institution of therapy [31, 32].

Conclusions Intensive multi-modality therapy of patients with high-risk GTN using EMA-CO chemotherapy (or some variation of it) along with adjuvant radiotherapy for brain metastases and surgery for control of hemorrhage results in primary remission rates of 65-80%. Approximately 20 â&#x20AC;&#x201C; 35% of

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high-risk patients will, therefore, fail first-line therapy or relapse from remission. Most of these patients will have a clinicopathologic diagnosis of choriocarcinoma, a large tumor burden reflected by a high hCG level and multiple metastases to sites other than the lung and pelvis, resulting in very high FIGO scores. Salvage chemotherapy with platinum/etoposide-containing drug regimens often combined with surgical resection of sites of persistent tumor (usually in the uterus or lungs), will results in a cure rate approaching 90% in the high-risk patients.

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Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 161-172 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

9. The role of cytoreductive surgery in cervical cancer: Is there a benefit of retroperitoneal lymph node debulking in advanced disease?

Waldo JimĂŠnez and Allan Covens University of Toronto, Division of Gynecologic Oncology, Toronto, Ontario, Canada

Abstract. Cervical carcinoma commonly spreads via the lymphatics, with metastases first occurring in the pelvic lymph nodes, and then sequentially spreading to the paraaortic nodes. Data from retrospective studies suggest that there may be a survival benefit in those patients with macroscopic nodal disease which is debulked to microscopic residual. In patients undergoing chemo-radiation, isolated failure in the lymph nodes is uncommon and is more commonly associated with failure to control the primary tumor. Candidates for surgical debulking of lymph nodes should be selected among patients with a high probability of achieving local control, a low likelihood of developing distant metastases, and lymph nodes of sufficient size that control with chemo-radiation is unlikely.

Introduction Cervical cancer remains the only gynecologic cancer, which is clinically staged by FIGO. This implies that the treatment is frequently driven by characteristics of the primary tumor without accurate knowledge of the tumor extent. As in other gynaecologic malignancies, non invasive diagnostic tests Correspondence/Reprint request: Dr. A. Covens, Toronto Sunnybrook Cancer Center, 2075 Bayview Ave T2051 Toronto, Ontario M4N 3M5, Canada. E-mail: al.covens@sunnybrook.ca

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have not been shown to be accurate in identifying metastatic disease, [1] leaving surgery as the only reliable method of determining exact information regarding local tumor spread, lymph node metastases, and involvement of adjacent organs. Despite this, the value and benefit of surgical staging remain controversial.

To date, there are no randomized data supporting a survival advantage for surgical staging or debulking of lymph nodes; though retrospective data suggests a potential benefit for lymph node debulking in women with bulky metastatic disease [2-7].

Cervical carcinoma commonly spreads via the lymphatics, with metastases first occurring in the pelvic lymph nodes and then sequentially spreading to the paraaortic nodes [8]. The frequency of pelvic and aortic node metastases increases with the stage of disease (table 1).

The sensitivity of various tests in identifying patients with positive lymph nodes is low; 55% for MRI and CT, and 75% for PET [1]. Though most of the false negatives correspond to microscopic disease or a slightly enlarged lymph node measuring less that 2 cm (which is associated with a high degree of success if included in the success field) [10].

Currently the main value of diagnostic imaging in advanced disease is the detection of metastatic lymph nodes outside the pelvis. If debulking of enlarged lymph nodes is performed, then determination of the size and location of the enlarged lymph nodes, and the characteristics of the primary tumor will help identify appropriate surgical candidates for lymph node debulking.

Table 1. Frequency on Pelvic and Aortic Node Metastases Detected with Pretreatment Staging Laparotomy (Data from Morrow et al) [9].

Clinical Stage

Total Cases

Aortic Metastases (%)

Pelvic Metastases (%)

Ib

570

6

-

IIa

174

12

-

IIb

421

21

24

III, IVa

615

31

50

Evidence supporting lymph node debulking in locally advance cervical cancer Six retrospective studies have reported on outcomes after surgical lymph node debulking (table 2) [2-7]. Five of the six studies debulked both pelvic and paraaortic lymph nodes, and the sixth study debulked paraaortic lymph nodes only.

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Table 2. Survival data from studies assessing lymph node debulking.

Author

N

Nodal Sites Surv (-) Node

Surv Mic Nodes

Surv Macr Debulked

Surv Macr Unresect

Morice [6]

421

PLN, PA

94%

75%

40%

—

Hacker[4]

34

PLN, PA

N/A

80%

82–90%

N/A

Downey [3] 156

PLN, PA

85%

57%

51%

0%

Potish [7]

159

PLN, PA

86%

56%

57%

0%

Cosin[2]

266

PLN, PA

75%

43%

50%

0%

Kim[5]

43

PA

N/A

*18 months

24 months

—

*(median survival)

Survival information is provided on patients with negative lymph nodes, microscopically involved nodes, and macroscopically involved nodes in whom the nodes were surgically debulked. Each of the 6 studies demonstrated similar survivals between patients with microscopically involved nodes and patients with macroscopically involved that were successfully debulked. No long term survivors were reported in patients with unresected macroscopic lymph nodes.

Unfortunately, the definition of macroscopic nodal disease was stated in only two of the studies (>1.5 cm) [4, 6].

The inference from these reports is that there may be a survival benefit in patients with macroscopic nodal disease which is debulked to “microscopic residual.” The 5-year survival rates in patients with macroscopically debulked pelvic lymph nodes, stage IB–IVB, ranged from 46 to 90%, and 50-80% for patients with microscopic nodal disease.

Despite these encouraging results, strict selection is required. Patients in whom there is a low likelihood of obtaining pelvic control or have a high probability of harbouring unrecognized distant metastases are not likely to benefit from lymph node debulking. Importantly, patients with mildly enlarged lymph nodes (less than 2 cm) that are likely to be successfully treated with chemo-radiation, will have minimal impact from surgical debulking of lymph nodes on their survival. These different patient populations will be addressed in the following paragraphs.

Identifying the ideal candidate The typical dose that is delivered to the pelvic lymph nodes with acceptable morbidity using external beam radiation is 6000 cGy. This dose

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will control 90% of lesions up to 2 cm in size. However, radiation therapy’s efficacy declines as involved nodal size increases [10] and therefore there is a potential role for surgery. The addition of chemotherapy to radiation has been shown to further decrease local failure by 33–50% [11-14].

As a prerequisite for retroperitoneal lymph node debulking to have a therapeutic benefit, chemo-radiation should have a high chance of sterilizing the primary tumor, and there should be a low risk of unrecognized distant metastatic disease. In this scenario, removing bulky metastatic pelvic nodes should increase pelvic control above that from chemo-radiation alone by improving side wall control as well as theoretcially decreasing extra pelvic failures or distant failures.

Likelihood of achieving tumor control Failure in achieving local control with radiation is a key prognostic factor in advanced stage cervical cancer. Patients with grossly positive hysterectomy specimens after radiation, progress and died at almost 7 times the rate compared to those with negative specimens [15]. Additionally, the incidence of distant metastases is 40 to 60% greater in patients in whom pelvic control is not attained [16] (Table 3).

Tumor size is the most important predictor of pelvic control. In one GOG report evaluating stages IIB–IVA patients treated with radiation and other agents on three GOG trials [17], patients had progressively worsening prognosis with increasing tumor size.

In an attempt to categorize patients by tumour size, 8 cm has been identified as a clinically relevant cutoff. Patients with tumor sizes larger than 8 cm have been associated with worse survival [18] and central tumor control rates [19] when compared with those smaller than 8 cm.

Other tumour factors (table 4), that correlate inversely with achieving tumor control include bilateral pelvic sidewall involvement, hydronephrosis, and lower vaginal involvement [20].

Table 3. Association of pelvic failure and developing distant metastases by different FIGO stages [16].

FIGO Stage IB IIA IIB III IVA

Distant Metastases Local control (%) 11 22 21 34 50

Pelvic failure (%) 76 88 62 87 75

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Table 4. Local tumor factors associated with survival in stage IIIB cervical cancer [20].

Tumor Size (IIIB) <6 6-7.9 â&#x2030;Ľ8

5y-DSS 59 48 30

Extent of Tumor (IIIB) No pelvic wall Fixed to one side Fixed both sides

5y-DSS 34 44 27

Hydronephrosis (IIIB) Absent Present

5y-DSS 40 28

Vagina Lower 1/3 Not involved Involved

5y-DSS 38 25

5y-DSS: 5 years disease specific survival

Patients with high likelihood of distant spread There are 2 patient populations at high risk for development of distant disease; patients with large tumor volume who are unlikely to achieve pelvic control, and women with positive nodes. The location of lymph node metastases along the lymphatic chain correlates with the site of recurrence and survival. Location of enlarged nodes correlates with the likelihood of developing systemic disease and mortality.

Patients with common iliac and paraaortic lymph node metastases have the highest rates of distant spread; up to 60% [21]. Based on the above data, the value of lymph node debulking would be appear to be unjustified in these patients with high level nodal disease due to their significant risk of distant spread.

Residual disease after chemo-radiation. Are all good prognosis patients appropriate candidates for surgery?

In order for lymph node debulking to have a therapeutic role, it should be able to salvage patients whose primary tumor is controlled after radiation, but residual or persistent metastatic disease remains in their lymph nodes.

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We hypothesized in 2002, through mathematical modeling that the benefit of performing a retroperitoneal lymph node dissection in all patients with locally advanced cervical cancer was unjustified given that it benefited only a small proportion of patients [22]. This has been confirmed with data presenting residual disease in the uterus and lymph nodes after treatment with chemo-radiation [23-27] (table 5).

There are several studies evaluating the role of surgery after radiation (and chemo-radiation) that provide important information about persistent disease in the cervix and lymph nodes [23-27] . In these studies the most common site for persistent disease is the primary tumor. Among the group of patients that have persistent disease in the lymph nodes, the majority also have persistent central disease, leaving only a small number of patients with isolated persistent nodal disease. Thus, if one performs a lymphadenectomy on every patient prior to radiation, theoretically only those destined to persist with isolated nodal persistent disease will benefit, which corresponds to approximately 0 to 6 % of all patients.

In the only study where patients with pre-irradiation enlarged lymph nodes were included, there were just 4 among 113 patients with isolated persistent disease in the lymph nodes [25].

Table 5. Residual disease in patients with locally advance cervical cancer treated with surgery after radiation or chemoradiation.

Huguet 2008 [26] Ferrandina 2007 [24] Houvenaeghel 2006[25] Rouzier 2005 [27] Classe 2006 [23]

N

(+) Primary (N)

92

45.6% (42) NA

152 113 360

51% (57) 49.4% (178)

175

61.1% (107)

(+) PLND (N) 6.5% (6) 12.5% (19) 15.9% (18) 27.5% (99) 24% (42)

(+) Primary & PLND (N)

(+) PLND alone (N)

6.5% (6) 9.2% (14) 11.5% (13) 21.4% (77) 23.4% (41)

0 2.6% (4) 3.5% (4) 6.1% (22) 0.6% (1)

PLND: Pelvic lymph nodes

Surgical approaches, feasibility and complications There are four basic approaches to debulking retroperitoneal nodes in cervical cancer patients: extraperitoneal laparotomy, transperitoneal laparotomy, extraperitoneal laparoscopy and transperitoneal laparoscopy. Data from a

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randomized control trial comparing the extraperitoneal to the transperitoneal approach by laparotomy in paraaortic staging of patients with locally advanced cervical cancer reveal both techniques are of similar sensitivity in detecting nodal spread. There is no significant difference in the frequency of surgical complications. Although the proportion of patients receiving an acceptable dosage of radiation therapy was similar, the transperitoneal approach was associated with a higher frequency of post irradiation enteric complications (11.5% vs 3.9%) [28].

No data regarding delays in starting radiation therapy was provided, however the data suggests that the extraperitoneal approach by laparotomy may be preferred when surgical lymph node debulking is performed.

Over the past 10 years, laparoscopy has been used as an alternative to laparotomy for staging of cervical cancer. An Italian randomized control trial in 168 women with stage IB窶的IB cervical carcinoma scheduled for radical hysterectomy and randomized to transperitoneal, extraperitoneal or laparoscopic pelvic lymphadenectomy showed that extraperitoneal and transperitoneal open lymphadenectomy were as feasible and effective as the laparoscopic approach (96%, 93% and 95% respectively) with similar acceptable complication rate [29]. Operative time was longer and length of hospital stay was shorter in the laparoscopic group.

Observational studies addressing staging in advanced stage cervical cancer have shown that the laparoscopic approach is associated with acceptable morbidity and similar success rates compared with laparotomy.

However, there were not enough patients with bulky enlarged nodes to make conclusions regarding debulking enlarged lymph nodes. In a large series of 98 patients with locally advanced cervical cancer, only half of the patients with positive nodes could be resected (19 out of 38 cases) [30]. Querleu in his series of 51 patients, found that only 6 of 9 patients with macroscopically involved lymph nodes could be debulked laparoscopically [31].

In summary, for staging purposes all approaches have shown similar efficacy, but the retroperitoneal approach and the laparoscopic approach have the advantage of less enteric complications from radiation therapy. For debulking purposes there is no comparative data among these techniques and data from observational studies suggest that a laparotomy may be more appropriate.

All series demonstrate that retroperitoneal lymph node dissections can be completed in most patients with locally advanced cervical cancer, with a feasibility ranging from 92 to 100 % (table 6) [2-7]. However, in these series the majority of patients had either normal or microscopically involved lymph nodes.

When analyzing patients with macroscopically involved nodes, feasibility decreases. In a recent publication with 78 patients with enlarged nodes, 16 were considered unresectable during surgery. In this study the

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Table 6. Feasibility and Complication of Lymphadenectomy in Patients with Locally advance Cervical Cancer.

Author

N

Nodal Sites

Succesful procedure

Morice[6]

421

PLN, PA

100%

Hacker[4] Downey[3]

34 156

PLN, PA PLN, PA

100% 94.2%

Cosin[2]

266

PLN, PA

92.5%

Marnitz[32]

84 lpx

PLN, PA

Querleu[31] LeBlanc[33]

53 lpx 181 lpx

PA PA

96% 95%

Zighelboim[34]

104

PLN,PA

85%

Denschlag[35]

59 extraperitoneal open

PLND & PA if + pelvic

100%

Complications lymphocysts 6.2%, urinary tract fistulae 2.8%, bowel obst 0.5% 14.7% (5)1 vascular, 2 infect lymphocyst, 1 fascitis, 1 hepatitis 6.7% (18) drain of lymphocyst 8 drain of lymphocele 1 ureter. 1 hematoma. 2 lymphocyst (req drain). 1 unrelated Bowel obstr 3 6 vascular (repaired intraop) lymphocyst 2%, wound complic 8% lymphocyst 12% (7), wound infect 3%(2), v cava injury 1%(1), blader inj 1%(1)

chance of achieving a successful resection decreased with increasing age and size of largest lymph node. For the 16 patients who had incomplete resections, the median intraoperative size of the largest lymph node was 4.0 cm. The reason given by the operating surgeons for their inability to completely remove the lymph nodes were vascular involvement of the lymph node (37.5%), infiltration into the bone (19%), neural invasion (12.5%) and gross nodal involvement above the superior mesenteric artery (6%) [34].

Surgical staging of women with locally advanced cervical cancer can be performed with acceptable morbidity. The most common complication is lymphocyst; occurring in approximately 10% of cases (particularly when an extraperitoneal lymphadectomy is performed). It is lower for retroperitoneal laparoscopic staging when the peritoneum is perforated (5% incidence) [31].

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Other complications reported include vascular, ureteric, and bladder injuries (0-6%).

There does not appear to be a significant delay in starting radiotherapy after a lymph node dissection. The median time interval between surgery and the start of chemo-radiation using laparoscopy is approximately 10 days [32], and less than 3 weeks for extraperitoneal laparotomy [2, 35, 36].

Conclusion Data analyzed from surgical specimens of the uterus and lymph nodes after chemo-radiation supports the premise that retroperitoneal lymph node dissection in locally advanced cervical cancer is not likely to benefit many patients, as the most common site for persistent disease is the primary tumor. Isolated nodal disease after chemo-radiation presents in only 0 to 6 % of the patients.

Data from debulking lymph nodes prior to radiation suggest that there may be a small number of patients that benefit. In general, these patients have a high likelihood of control of central disease, a high chance of successfully debulking the macroscopically enlarged lymph nodes, and a low probability of distant metastatic disease.

Patients with tumor sizes larger than 8 cm, bilateral pelvic sidewall involvement, hydronephrosis, and lower vaginal involvement [20] have been associated with a worse survival [18] and central tumor control rates [19], and are poor candidates for retroperitoneal debulking.

Additionally, patients at high risk of distant disease should be excluded from lymph node debulking. Distant metastatic disease has been correlated with both primary tumor characteristics and with the site and volume of lymph node disease. Site of lymph node disease correlates with site of recurrence and survival. Patients with paraaortic and common iliac lymph node disease develop distant disease in up to 60% of cases [21, 37, 38].

Thirdly, the likelihood of successfully debulking the macroscopically enlarged lymph nodes should be high. Nodes that on imaging are suspicious for vascular, neural and bone invasion, as well as those larger than 5 cm should be excluded. Unfortunately, preoperative tests are not very accurate in identifying invasion to these structures and it remains for the most part an intra-operative diagnosis.

The ideal candidates for considering lymph node debulking have the following characteristics: Stage IB or IIB, tumour >2 cm and <8 cm, stage IIIB with unilateral disease only, macroscopically enlarged lymph nodes confined to the pelvis (>2 cm and <5 cm), and normal size common iliac and paraaortic nodes.

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Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 173-178 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

10. The role of cytoreductive surgery in vulvar cancer. Is there an indication for aggressive surgical approach in FIGO Stage III/IV disease?

Anthony Proietto and Ganendra Raj Hunter New England Centre for Gynaecological Cancer, John Hunter Hospital Newcastle, NSW, Australia

Abstract. Primary surgery remains the treatment of choice for patients presenting with early stage vulvar cancer. Radiation therapy for early stage disease is generally restricted to patients with close or involved margins or positive nodes.

In patients with locally advanced vulvar cancer, surgery may involve very radical procedures, possibly requiring the permanent diversion of the urinary and/or faecal stream to achieve adequate surgical margins. Where the extent of the primary tumour or groin node metastses, render the tumour inoperable, chemoradiation may be considered for primary treatment. In some circumstances surgery at a later date may be appropriate. This approach reduces the morbidity of surgery and avoids the physical and psychological morbidity of loss of bowel and/or bladder function.

However there is evidence that the complications of neoadjuvant therapy may outweigh those of exenterative surgery.

There may be an argument for primary exenterative surgery in well selected patients with locally advanced disease. Management of these patients is difficult, and will need to be tailored according to their individual needs.

Correspondence/Reprint request: Dr. Anthony Proietto, Hunter New England Centre for Gynaecological Cancer John Hunter Hospital, Newcastle, NSW, Australia. E-mail: aproietto@bigpond.com

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Introduction Although carcinoma of the vulva is uncommon, representing only 5% of gynaecological cancer (1) its location within close proximity of urethra and anus can result in very difficult therapeutic challenges when locally advanced disease occurs. Although vulvar cancers are â&#x20AC;&#x153;surfaceâ&#x20AC;? cancers and therefore readily available for clinical examination, advanced disease (FIGO Sage III or IV) occurs in 30 to 40% of cases at diagnosis. From a surgical perspective, those cases in which a standard radical vulvectomy cannot remove the primary tumour with an adequate margin are considered to be locally advanced. These cases are not infrequently associated with extensive and unresectable groin and pelvic node matastases.

Assessment of patients with vulvar cancer must include careful evaluation of nodal areas, midline structures and whether there is any involvement of urethra, anal sphincter, vagina and pubic bone. Examination under anaesthesia should be performed to determine the feasibility of adequate resection, keeping in mind the need for an adequate margin, that is at least 1cm. It may be helpful to have the radiation oncologist and reconstructive surgeon attend the EUA. Preoperative imaging with CT or MRI, and PET/CT should be considered in order to exclude as far as possible distant spread of disease.

For patients with early stage vulvar cancer, surgical management has become less radical in an effort to reduce the treatment toxicity for these patients without detrimental effect on overall survival.

Stanley Way was the first to describe the radical en bloc vulvectomy with groin node dissection using the butterfly incision which has been modified since (2). Radical en bloc vulvectomy was the standard treatment for all patients with vulvar cancer before the introduction of the less radical local excision which conserves more vulvar skin and makes primary closure easier.

The current trend is to perform a radical local excision of the primary tumour in combination with inguinofemoral lymphadenectomy with separate incisions. Data from observational studies suggest that excision of early lesions with a good margin all around, including the deep margin, does not changed the overall survival compared to more radical procedures but does reduce the incidence of post operative wound break down and infection(3).

The modified radical vulvectomy that is performed currently for women with early vulvar cancer currently aims to ensure a good margin of 1cm all around(8mm for pathology specimen) with the depth of excision taken down all the way to the deep fascia, the inferior fascia of urogenital diaphragm and periosteum of pubic bone. If inguininal nodes are to be removed they are done with seperate incisions. Whether ipsilateral or bilateral inguinal

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lymphadenectomy is performed depends very much on the site and size of the primary vulvar tumour. Superficial and deep inguinal nodes should be removed, as one prospective trial showed an increased rate of groin recurrence in patients with only superficial node dissection performed (4). Alternative approaches such as sentinel node biopsies are under investigation to help reduce the morbidity of lymphoedema associated with a complete inguinal lymhadenectomy. It is not yet the accepted standard of treatment as the magrin for error is narrow and groin recurrences are often fatal (5-8).

Pelvic lymphadenectomy is rarely performed these days unless there are large bulky nodes which will need to be removed. A GOG trial has confirmed that there is no survival advantage in patients having a pelvic lymphadenectomy compared to patients having the pelvic area irradiated(9). Based on the pathological findings and prognostic factors from the surgical specimen obtained, the patient may receive adjuvant radiotherapy either to the primary area from where the tumour was excised (if the excision margins are narrow), to the groins and pelvic area if more than 2 micro metastatic (â&#x2030;¤ 5mm) deposits in the lymph nodes, one macroscopic involvement of a lymph node (â&#x2030;Ľ 10mm) or capsular involvement is found(10-12).

Ultra radical surgery While the treatment of patients with early vulvar cancer has been well defined, the treatment of patients with advanced vulvar cancers (stage III & IV) is not as straight clear. One of the therapeutic options for patients with locally advanced disease has been radical excision of the primary tumour and draining lymph nodes, with the excision extended to include involved adjacent organs such as the bladder or bowel, effectively converting the surgical procedure to some type of exenteration. Such radical procedures, when planned have to consider both the radical excision, which must clearly be feasible with a very high probability of ensuring adequate, indeed generous, margins, and the reconstruction required.

In patients with locally advanced disease, surgery may require not only an en-bloc radical vulvectomy and bilateral inguinofemoral lymphadenectomy, but also some kind of resection of urethra, vagina or anus, up to and including major exenterative surgery. In such circumstances the postoperative complications can be extremely severe and result in death or severe and permanent functional impairment. Furthermore, such ultraradical procedures may require extensive and complex reconstructive procedures, resulting in long hospital stay, multiple operations and significant disruptions to the patientâ&#x20AC;&#x2122;s life, not to mention the high medical cost(13). Despite all the

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problems associated with this procedure it still remains an important option for treatment for women with advanced stage vulvar cancer.

Combined therapy approaches The difficulty of treating surgically patients with locally advanced vulvar cancer and the high morbidity and even mortality associated with exenterative surgery prompted efforts to limit the extend of the surgical procedures needed to control disease. (14,15). Boronow et al. in 1973 was the first to describe the use of a combined radiosurgical approach for patients with advanced vulvar cancer. He described the use of brachytherapy in the form of intracavitary radium alone or with the combination of teletherapy for internal genital disease and then surgery in the form of radical vulvectomy and bilateral inguinal lymphadenectomy (14). In 1984 Hacker et al described 8 patients treated with pre operative external radiation 44 to 54 Gy with one patient receiving brachytherapy in the dose of 24Gy. Satisfactory shrinkage of tumor occurred in seven of the eight patients (87.5%) thus allowing conservative surgical excision. In four of his patients (50%) there was no viable tumour left in the surgical specimen (16).

Another therapeutic option is combined chemoradiation pre operatively to shrink the tumour and then reassess operability. This approach is based on data obtained from studies of patients with anal and cervical cancers treated by this multimodality approach. A phase II GOG trial using preoperative radiation with concurrent cisplatin/5 flurouracil concluded that the therapy is feasible and its use decreased the need for more radical surgery including primary pelvic exenteration(17). Although chemo radiation is increasingly becoming the preferred option of treatment for patients with advanced vulvar cancer, it is not without toxicity. A significant proportion of women who receive this treatment will suffer long term problems with perineal pain, radiation necrosis to the vulvar skin, lymphoedema, lymphorrhea and secondary radiation effects to bowel and bladder. A recent Cochrane meta analysis has cautioned that the use of combination chemoradiation in treating these patients results in significant toxicity which may be as disabling as that of primary radical surgery (18).

In our unit the patients presenting with advanced vulvar cancer undergo careful evaluation and treatment is individualized. The type of treatment recommended depends very much on the patientâ&#x20AC;&#x2122;s age, co-morbidities, site, size and the extent of the primary tumour and the presence of demonstrable metastatic lesions. Surgery is the preferred treatment for patients presenting with primary tumors that can be excised with adequate margins. In patients where the recommended pathological margin of 8 mm cannot be achieved,

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the primary tumor can still be surgically excised so long as the sphincter function can be preserved. Excision of these tumours may improve quality of life and will reduce the bleeding, discharge and foul odor transmitted from these tumors which can be very distressing for these patients. Where surgical margins are narrow, adjuvant radiation can be given to these areas. The inguinofemoral nodes should be assessed clinically and with imaging (CT abdomen and pelvis and preferably PET/CT) before surgery. If enlarged nodes are felt clinically or detected by imaging in the groin area, then excision of these large nodes and frozen section is under taken without proceeding to a full lymphadenectomy if metastatic cancer is confirmed. This will help to reduce the morbidity of lymphoedema post radiotherapy.

Currently chemoradiation is the treatment of choice in patients presenting with primary tumors that cannot be excised without preserving sphinter function. This is also the case in patients presenting with ulcerated fixed nodes. After primary treatment with chemoradiation the primary tumour and the groin nodes are assessed for operability. Debulking of large pelvic nodes should be considered before performing radiotherapy in patients with stage IV disease. These patients usually have a poor prognosis and radiation alone to the pelvic nodes without debulking the large nodes may not change the final prognosis.

In conclusion, surgery remains a vital component in the treatment of vulvar cancer. Unfortunately the radicality of surgery for patients with stage III and IV is associated with significant complications. There is no difference in overall survival, progression free survival and recurrence rate in patients treated with primary surgery or primary chemoradiation(19). The trend of management currently has shifted towards less radical surgery and this has been made possible with the use of chemoradiation as the primary treatment for patients with advanced cancer.

References 1.

2.

3.

4.

M.S Hoffman, D.Cavanagh, W.S Roberts, J.V.Fiorica,M.AFinan Ultraradical surgery for advanced of the vulva: an update. International Journal of Gynecological Cancer 1993; Volume 3, Issue 6, Pages 369-372.

Way, S. The anatomy of the lymphatic drainage of the vulva and its influence on the radical operation for carcinoma. Ann R Coll Surg Engl 1948; 3:187.

DeHullu, JA, Hollema, H, Lolkema, S, et al.Vulvar carcinoma. The price of less radical surgery. Cancer 2002; 95:2331.

Stehman, FB, Bundy, BN, Dvoretsky, PM, Creasman, WT. Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group. Obstet Gynecol 1992;79:490.

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Katz, A, Eifel, PJ, Jhingran, A, Levenback, CF. The role of radiation therapy in preventing regional recurrences of invasive squamous cell carcinoma of the vulva. Int J Radiat Oncol Biol Phys 2003;57:409.

Gonzalez Bosquet, J, Magrina, JF,Gaffey, TA et al. Long â&#x20AC;&#x201C;term survival and disease recurrence in patients with primary squamous cell carcinoma of the vulva.Gynecol Oncol 2005;97:828.

Robison, K, Steinhoff, MM, Granai, CO, et al. Inguinal sentinel node dissection versus standard inguinal node dissection in patients with vulvar cancer. A comparison of the size of metastasis detected in inguinal lymph node nodes.

Gynecol Oncol 2006:101:204.

Mocellin S, Hoon DS, Pilati P, et al. Sentinel lymph node molecular ultrastaging in patients with melanoma : a systematic review and meta-analysis of prognosis.

J Clin Oncol 2007;25:1588.

Homesley, HD, Bundy, BN, Sedlis,A, Adcock, L. Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes.

Obstet Gynecol 1986;68:733.

Parthasarathy, A, Cheung, MK, Osann, K, et al. The benefit of adjuvant radiation therapy in single-node-positive squamous cell vulvar carcinoma, Gynecol Oncol;103:1095.

De Hullu, JA van der, Zee AG. Surgery and radiotherapy in vulvar cancer. Crit Rev Oncol Hematol 2006;60:38.

Le, T, Elsugi, Hopkins, L, et al. The definition of optimal inguinal femoral nodal dissection in the management of vulva squmaous cell carcinoma. Ann Surg Oncol 2007;14:2128.

W. Weikel, M. Hoffmann E. Steiner, P.G Knapstein, H. Koelbl. Reconstructive surgery following resection of primary vulvar cancers. Gynecologic Oncology, Volume 99, Issue 1, October 2005, Pages 92-100.

Boronow RC, Hickman BT, Reagan MT, et al: Combined therapy as an alternative to exenteration for locally advanced vulvo vaginal cancer. II. Results, complications and dosimetric and surgical considerations. Am J Clin Oncol 10 (2): 171-81, 1987.

Anderson JM, Cassady JR, Shimm DS et al: Vulvar carcinoma. Int J Radiat Oncol Biol Phys 32 (5): 1351-7, 1995.

Hacker NF, Berek JS, Juillard GJF, Lasgasse LD. Preoperative radiation therapy for locally advanced vulvar cancer. Cancer 1984;54:2056-2060.

Moore, DH,Thomas, GM, Montana, GS, et al. Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group.

Int J Radiat Oncol Biol Phys 1998;42:79.

Van Doorn, HC, Ansink, A, Verhaar-Langereis, M, staplers, L. Neoadjuvant chemoradiation for advanced primary vulvar cancer. Cochrane Database Syst Rev 2006;3: CD003752.

Lisa M. Landrum, Valerie Skaggs, Natalie Gould, Joan L. Walker, D. Scott McMeekin. Comparison of outcome measures in patients with advanced squamous cell carcinoma of the vulva treated with surgery or primary chemoradiation.

Gynecologic Oncology 2008;108:584-90.

Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 179-200 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

11. The place of pelvic exenteration as a cytoreductive procedure in advanced gynaecologic malignancies Markus C. Fleisch, Daniel T. Rein and Wolfgang Janni Department of Obstetrics and Gynaecology, Heinrich-Heine-University, Düsseldorf (Director: Prof. W. Janni)

Abstract. For now 60 years pelvic exenteration is in the armamentarium of pelvic surgeons for the treatment of advanced pelvic malignancies. The biology of malignant tumors originating in the pelvis - locoregional tumor progression and only late stage distant spread - was the basis for the development of a radical surgical technique removing the tumor en-bloc with the adjacent pelvic organs. The original procedure described by Brunschwig in 1948 comprised the resection of rectum and bladder followed by a “wet” colostomy with implantation of both ureters into the colon.

Originally described for palliation of symptoms this procedure was initially afflicted with a high surgical mortality and morbidity, but on the other hand became the only surgical option offering cure for advanced stage and recurrent pelvic tumors. Over the years, improvements in perioperative management and surgical technique modified the procedure including continent reconstruction techniques for bowel and bladder making the operation more acceptable for patients.

To date more than 95% of patients not only survive the procedure, but may also encounter 5-year survival rates of 40% or more depending on the individual patient selection criteria. This improvement in outcome parameters is paralleled by an increase Correspondence/Reprint request: Dr. Markus C. Fleisch, Department of Obstetrics and Gynaecology, HeinrichHeine-University, Moorenstr. 5, D-40477 Düsseldorf, Germany. E-mail: Fleisch@uni-duesseldorf.de

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in continent urinary and intestinal reconstruction techniques which have made pelvic exenteration in appropriately selected cases not only acceptable but indispensable for the treatment of advanced gynaecologic malignancies.

Introducing the concept of pelvic exenteration The concept of pelvic exenteration (PE) goes back to the 1940s when some centers in the US developed a surgical technique to treat locally advanced or recurrent pelvic cancers. The concept was based on the observation that tumors in the small pelvis, especially cervical and rectal cancers, have common biological features. They show locoregional invasion and metatastatis but distant metastasis only occur at late stage disease as tumors only rarely spread by hematogeneous route. Tumor persistence or recurrence within the pelvis is the major cause of death in patients suffering from cervical cancer (1). Patients with advanced or recurrent disease in the pelvis frequently develop infiltration of neighbouring organs like urinary bladder, ureter or intestine resulting in urinary complications including obstruction, fistula formation, uraemia or intestinal obstruction with ileus and/or fistula formation. These observations allowed the conclusion that an ultra-radical local therapy of advanced or recurrent pelvic malignancies might not only relief symptoms or prevent complications, but might also have significant impact on patients’ prognosis.

The development of the concept of PE is traditionally credited to Alexander Brunschwig (*1901-†1969) (2) who published his first report on this technique in 1948 (3). He described an en-bloc resection of the pelvic viscera including rectum and anus, urinary bladder and parts of the perineum for the treatment of recurrent cervical cancer. Intestinal and urinary deviation was provided in form of a wet colostomy. Surgical mortality (death within 30 days post surgery) of this procedure at that time was high (23%) and longterm survival was short. Over the past 60 years numerous modifications to pelvic exenteration have been introduced with respect to patient selection criteria, perioperative management, surgical technique and methods for the reconstruction of bladder and bowel function. The initial “total” pelvic exenteration had been modified into a procedure preserving either the rectum (i.e. anterior PE) or bladder (i.e. posterior PE). Still, in appropriately selected patients, pelvic exenteration is considered to be the only therapeutic option offering cure.

In the following paragraphs of this chapter we are going to describe the initial surgical technique, its potential indications and modifications over time. We will summarize the published studies with special emphasis on outcome parameters and will highlight current indications and potential future

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prospects for this challenging surgical procedure. As in the field of gynaecologic oncology patients with cervical and endometrial cancers represent the largest group of patients undergoing PE this review will focus on these two entities.

Original technique Alexander Brunschwig, attending surgeon at the New York Memorial Hospital, started in 1946 to treat women with advanced pelvic malignancies with a new ultra-radical en-bloc resection of the pelvic viscera. In his first report, which was published in 1948 (3), he summarized the outcome of 22 patients who underwent exenteration for palliation of symptoms caused by locally advanced malignant disease in the pelvis. These patients were mainly suffering from cervical cancer. Although no patient died during the operation perioperative mortality was 23% with 5 patients dying from early surgery related complications.

In his original report the technique was described as follows: In a first â&#x20AC;&#x2DC;abdominal phaseâ&#x20AC;&#x2122; and after a low midline incision the abdomen is palpated and the bowels are packed upwards. In Trendelenburg position the posterior parietal peritoneum is incised over aorta and the incision is carried down bilaterally to both external iliac arteries. The infundibulo-pelvic ligament is dissected and ligated and the hypogastric artery and vein are ligated and transsected at their origin. A pelvic node dissection along the iliac artery is performed. Then the mesosigmoid is divided over the left common iliac vessels and the sigmoid pushed cephalad. Analogous to the other pelvic side dissection is performed and the hypogastric vessels are cut. After division of the round ligament, on both sides the obturator space is developed and the obturater vessels and the tissue is transected and developed medially under preservation of the obturator nerve. The peritoneal reflection from the anterior abdominal wall onto the bladder is dissected and the bladder completely mobilized except its attachments at the base. Both ureters are then dissected with a sufficient distance to the tumor and the ureters are implanted into the sigmoid colon. The upper pelvic colon is transected and each cut end invaginated by a purse string suture. Then the recto-sigmoid is dissected away from the concavity of the sacrum and mobilized completely to the pelvic floor. This way the specimen is completely mobilized except its attachments to the pelvic floor. The midline incision is closed and the wet colostomy is brought out through the incision.

In the second perineal phase the vaginal introitus and the rectum are closed by continuous suture and an elliptical incision emcompassing introitus and anus preserving the clitoris is performed. The levator ani muscle is

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dissected and the pelvic viscera are removed en-bloc and the perineal wound is closed.

Indications and contraindications General indications for PE in gynaecologic oncology are advanced primary or recurrent tumors of the uterine cervix, corpus and the vulva.

According to their position in the treatment concept procedures can be classified as primary, secondary or palliative. By definition the intent of exenterative procedures labelled as primary or secondary must be to cure the patient from disease.

The fact, that some studies on the outcome after PE also include ovarian cancer cases, makes results hard to compare as its distinct biology and good response to chemotherapy is not comparable with other gynaecologic malignancies. Ovarian cancer debulking can only be considered as indication if it requires a true compartimentalized resection of the inner genitals in combination with bladder and/or rectum. Due to the fact that in most ovarian cancer cases disease is limited to peritoneal cavity with infiltration of the recto-sigmoid at the Site

Primary

Secondary

Cervix

Selected cases FIGO stage IVA, cases with fistula formation if complete resection is probable (Incidental bladder or rectum infiltration during scheduled radical hysterectomy)

- central recurrence or tumor persistence after surgery or chemo- radiation (- recurrence after primary surgery)

Vagina Vulva

Endometrium

Central recurrence

-Soft tissue sarcoma - Melanoma -Neuroendocrine cancers - others

Cases with rectal/bladder infiltration and probability of complete resection, tumors with known radio-resistance Indications for primary, secondary and palliative PE.

Palliative

Probably in highly selected cases with vesico-vaginal or rectovaginal fistula formation

Contraindications

- Distant Metastasis - Positive pelvic lymphnodes - Local irresectability - (Pelvic sidewall infiltration)

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level of the Douglas pouch it rarely requires a pelvic exenteration-like procedure by definition.

Indications for primary exenteration The term â&#x20AC;&#x153;primaryâ&#x20AC;? PE describes exenterations which are performed as the initial treatment after primary diagnosis. The use of exenteration as primary treatment for advanced gynaecologic cancers has been reported by numerous centers worldwide (4-8). Potential indications for primary exenteration are classically FIGO stage IVA cancers of the uterine cervix invading the wall of the bladder or bowel mucosa, patients with bulky tumors having tumor- or therapy-associated fistula formation and such tumors, in which radiation or chemotherapy is not likely to lead to a clinical response as in soft tissue sarcomas or neuroendocrine tumors (9). According to the FIGO annual report 2006 5-year survival is 22% in stage IVA cervical cancer and 21 to 30% in endometrial cancers depending on histological grade (10, 11).

At advanced cancer stages surgical treatments traditionally compete with chemo- and or radiation therapy either in a neoadjuvant or primary setting.

There are numerous trials showing the efficacy of radiation therapy in combination with cis platinum based chemotherapy for advanced stages of cervical cancer (12-15). Several investigators have been favouring primary exenteration as a reasonable first-line therapy (6, 7, 16-18). However, no prospective randomized clinical trial has been performed yet to directly compare the outcome after chemo-radiation and after primary exenteration for FIGO IVA cervical cancers. The only available data so far is based on observational studies and retrospective analyses (7, 8, 17, 18). This is due to some drawbacks related to the design of such a trial: 1.

2.

The number of potential patients to be enrolled into a surgery arm is limited due to some basics characteristics that need to be present like tumor-free pelvic sidewall, the absence of lymph node involvement or extrapelvic spread and a physical performance status which allows major surgery.

Screeening programs in many developed countries, which in general provide the vast majority of clinical studies, have led to a decrease in the total number of advanced stage cases so that a monoinstitutional trial even in major referral centers is unlikely to recruit a sufficient number of patients to detect potentially significant differences in survival and morbidity.

Especially in cases with bulky tumors radiation therapy is likely to result in tissue necrosis potentially leading to fistula formation which impairs patientsâ&#x20AC;&#x2122;

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quality of life (13, 19). The success rate of a local attempt to surgically repair radiation-related fistula is low so that these cases have to be considered for primary PE. It remains debatable if PE is a reasonable option for FIGO IVA endometrial cancer as patients mostly present with metastatic disease. There is no survival data after surgical therapy for this rare subset of patients available so that indication for PE might be limited only to a highly selected subset of patients.

Indications for secondary exenteration Exenterations are termed â&#x20AC;&#x153;secondaryâ&#x20AC;? if they are performed for recurrent or persistent disease after prior radiation or chemo-radiation therapy. Patients with FIGO IB to IIA cervical cancer undergoing radical hysterectomy (Wertheim-procedure) show a recurrence rate of 10-15% with a pelvic localization of the recurrence in 60% of cases. Patients with stage II to stage III cervical cancer primarily treated by radiation relapse in 20-50% (20).

Approximately 70% of patients with locally advanced cervical cancer relapse and most of them die from uncontrollable disease in the pelvis (18, 21). It is commonly accepted that PE is a valid treatment option for patients with a central recurrence or persistent disease after (chemo-) radiation therapy. The survival rates for secondary exenterations are reported between 16 and 60%.

Another unanswered question is the role of PE for the treatment of a local recurrence after surgery without prior radiotherapy. There are no studies available comparing the outcome of PE for this indication with the results of chemo-radiation, so that PE cannot be generally recommended. Some authors suggest that if the recurrence appears to be completely respectable and is not likely to respond to chemo-radiotherapy (cervical adenocarcinoma, tumor size >3cm tumor extension to the pelvic side wall) pelvic exenteration should be considered (4).

Patients with endometrial cancer usually present at an early stage with excellent survival rates after treatment. However, approximately 11% relapse, half of which with a local pelvic recurrence. PE for central recurrence in endometrial cancer without evident lymph node metastasis is also a therapeutic option offering cure with 5-year survival rates between 20 and 40% (22, 23).

Indications for palliative exenteration Although initially developed for the palliation of symptoms of advanced and non-curable pelvic cancers especially its use for palliation remains

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debatable (24, 25). Because of the high postoperative morbidity and mortality rates associated with this procedure some authors do not believe in the use of PE for palliation (26-31). Other authors advocate that PE can improve quality of life and therefore in appropriately selected cases is indicated for palliation (32, 33).

Frequently presented palliative indications are 1) pelvic pain due to infiltration of the nerval plexus, refractory to medical treatment, 2) recurrent severe hemorrhage, 3) entero-vesical, entero-vaginal and vesico-vaginal fistula formation and its related symptoms, 4) abscess formation on the basis of infected tumor necrosis and 5) subtotal or total intestinal obstruction.

Many investigations on palliative exenterations were performed at a time when currently established options for palliation of symptoms were not available. Nowadays novel chemotherapeutics and re-irradiation in combination with surgical suprapelvic diversion can be considered. Patients predominantly suffering from deep visceral pain can benefit from local and systemic analgesia and acute hemorrhage can be addressed by interventional angiographic supra-selective particle embolization techniques so that the by itself questionable concept of palliative exenteration has to be re-evaluated considering alternative current treatment options.

Contraindications Like for other procedures, PE should not be considered if the physical performance status and co-morbidities do not allow a major operation. In addition, classical contraindications for PE are the presence of distant metastasis, peritoneal spread or preoperatively assessed local irresectability.

Some authors advocate that the presence of an isolated distant metastasis in case of recurrent disease is not a contraindication per se as the metastasis could be resected at the time of PE. Also the presence of tumor positive pelvic lymph nodes is associated with a decrease in postoperative survival so that some authors conclude that this condition can be considered as a contraindication for PE (8, 34-38). If complete resection seems unlikely from pelvic examination or imaging studies PE should not be attempted. Especially pelvic sidewall involvement, which is a major reason for irresectability, can be difficult to evaluate and sometimes can only be detected if the procedure is already at an advanced stage so that this condition still represents and obstacle in identifying eligible candidates for this procedure.

Hรถckel developed a surgical technique allowing a laterally extended endopelvic resection (LEER) especially for patients with recurrent cervical carcinomas involving the side wall of an already irradiated pelvis (39). In his feasibility study he showed that extending the lateral resection plane of pelvic

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exenteration to the medial aspects of the lumbosacral plexus, sacrospinous ligament, acetabulum, and obturator membrane enables the complete removal of locally advanced and recurrent tumors fixed to the pelvic wall with free margins (R0) (39). In his series of 36 cases including 7 cases of primary advanced gynaecologic cancers he found a remarkable 5-year survival rate of 49%. Future studies have to demonstrate if this technique will also provide local control for cases with significant parametrial involvement. Albeit the positive initial results of the LEER procedure most authors consider a fixation of the tumor to the pelvic sidewall as contraindication for secondary exenteration (34, 40-43). Along these lines the presence of hydronephrosis and pain caused by infiltration of the lumbar plexus suggests local irresectability and therefore must be considered as contraindications for PE.

Technical modifications Over the last 60 years pelvic exenteration underwent numerous modifications regarding perioperative management and surgical technique.

Modified exenterations The initially described operation termed ‘pelvic exenteration’ comprised the en-bloc resection of the inner genitals the bladder and the bowel (i.e. “total pelvic exenteration”). Over time surgeons tailored this procedure to the amount of disease to be removed. Procedures where resection was limited to the inner genitals in combination with the bladder preserving the rectum were termed “anterior PE”, in combination with recto-sigmoid preserving the bladder “posterior PE”. Some authors also introduced the term ‘composite PE’ to describe cases involving bony resections like the sacrum-coccyx, ischium, pubic symphysis and others.

Intestinal reconstruction The reconstruction of bladder and bowel function is a central part of exenterative procedures. The decrease in postoperative morbidity and mortality over time resulted in an increase in long-term survivors. There for attention had been directed to improve quality of life aspects. Various technical modifications and improvements in urinary and intestinal reconstruction techniques have been introduced aimed to improve quality of life and patients’ acceptance of this initially mutilating procedure. Traditionally total and posterior exenteration required a permanent colostomy which impaired the acceptance of this procedure for affected women (44). The introduction of

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supralevator rectal resections with low colo-rectal anostomosis with or without protective proximal transient colostomy has avoided permanent colostomy in curatively and non-curatively resected patients with total or posterior exenteration (36, 45). Hatch and co-workers first described the preservation of a rectal stump for selected cases and performed a low rectal anastomosis using automated circular stapler devices. In some cases the anastomosis was secured by an omental wrap, some patients also had protective colostomies. In their analysis they showed the feasibility of this intestinal reconstruction technique with acceptable morbidity (32%), mortality (no operative deaths) and survival (68% overall survival). At least in their series protective colostomies did not improve the healing rate of the anastomosis. As a conclusion, the preservation of faecal continence should be considered in every case of PE requiring bowel resection.

Urinary reconstruction Brunschwigsâ&#x20AC;&#x2122; way of urinary diversion was the implantation of both ureters into the sigmoidostomy. Patients frequently suffered from postoperative episodes of pyelonephritis and hypochloremic acidosis so that other options were tested. Bilateral percutaneous urostomies were technically easy to perform but committed patients to a lifetime of double urinary stomas which impairs daily activities and is associated with a high long-term morbidity rate (46, 47). The first milestone in urinary reconstruction was Brickerâ&#x20AC;&#x2122;s development of the ileal conduit (1950) which separated the urinary and faecal stoma (48). Both ureters are implanted into a pouch formed by an isolated segment of the terminal ileum. However, patients still need to wear a bag as the urinary flow was constant. To overcome this issue the use of various other methods of creating a continent urinary conduit have been described including the Indiana pouch (49), the Kock pouch (50), the Florida pouch (51) and the Miami pouch (52). E.g. the Miami pouch has a mean urinary reservoir volume of 650 ml and provides the patient with a convenient emptying frequency. But continent urinary diversion techniques might be limited by extensive adhesion formation, prior bowel operation or irradiation. Especially in cases with prior radiation therapy this technique is afflicted with a high morbidity rate. Therefore the use of various intestinal segments like the transverse, sigmoid and right colon has been described for pouch formation (27, 53-55) with different postoperative morbidity rates.

Nowadays in many centers the creation of an orthotopic neo-bladder has become the urinary diversion technique of choice (8, 41). The pros of the neobladder are the continence and preservation of the body image especially for younger patients. This technique enables patients to perform their routine

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daily activities without the necessity of wearing bags or performing selfcatheterization. Conditions are at least 70 cm of intact small bowel, a tumorfree trigonum and urethra and the absence of preoperative stress incontinence.

The cons of this form of reconstruction technique are that it is technically difficult to perform and that neobladders have a relatively high postoperative complication rate. Approximately 15% of patients suffer from postoperative hypercontinence.

Vaginal reconstruction Another problem that female patients face and which is a considerable source of postoperative psycho-sexual morbidity is the loss of their vagina and thereby the chance of having vaginal intercourse (56, 57). Therefore after careful consideration of both, oncologic and psychologic aspects and after discussing this aspect with the patient vaginal reconstruction should be part of the operative strategy and should be offered whenever possible and reasonable. There are several options for vaginal reconstruction which can be performed either at the time of the exenteration or as a separate delayed procedure. Beemer and co-workers reported their experience with splitthickness skin grafts, which requires a delayed procedure 2 to 8 weeks after the initial operation during which an adequate granulation tissue forms (58).

Alternatively myocutaneous flaps involving the gracilis and the rectus abdominis muscles can be used at the time of the initial operation (59-61).

These flaps do not only allow immediate reconstruction but also help to address the issue of filling the “empty pelvis” which predisposes to abscess and fistula formation and which is source of perineal wound healing problems and intestinal obstruction (30). Accordingly creating a neovagina using myocutaneous flaps has been shown to reduce postoperative morbidity and to decrease pelvic abscess formation (62, 63). However, there is only limited information available with respect to quality and quantity of sexual activity of patients who underwent vaginal reconstruction as part of their treatment concept for gynaecologic cancers.

Minimal-invasive techniques The preoperative assessment of localization and extension of the disease can be challenging as non-invasive imaging techniques like CT or MRI have limited validity especially for the detection of positive lymph nodes (64-66). Koehler and colleagues estimated that 40-60% of patients who are potential candidates for PE by clinical examination and preoperative staging undergo “aborted” laparotomy due to intraoperative detection of unresectability or distant metastasis (67).

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Aborted exenteration is a situation that needs to be avoided as it is not only source of additional frustration and unnecessary morbidity for the patient but it may also result in a delayed initiation of alternative treatment options like radiation therapy. In their series they performed laparoscopy prior to exenteration. By laparoscopy they excluded macroscopic peritoneal disease and performed pelvic and periaortic lymph node dissection. Nodes and other biopsy were sent for frozen section and then the cervico-vesical septum, the cul-de-sac and the rectal pillars were explored and biopsy taken. Then the perivesical and perirectal space were opened and evaluated for tumor involvement. Surgery was discontinued if extrapelvic disease was confirmed. If laparoscopy suggested complete tumor resectability the procedure was converted to laparotomy and PE was performed.

Analyzing their series of 41 patients irresectability was correctly identified with a specificity of 95.2% and resectability with a specificity of 90.4%. Still, like for the exploration in an open procedure, the laparoscopic exploration of the pelvic sidewall is the most difficult aspect of the procedure and remains a challenge. However, in centers performing PE which also have an expertise in advanced laparoscopy a minimal-invasive staging procedure prior to exenteration might be beneficial to identify eligible patients and to avoid unnecessary laparotomies.

As a logical consequence of the general advances in the use of laparoscopic techniques for the treatment of gynaecologic malignancies few centers showed the feasibility of a laparoscopic approach for PE. There are sporadic case reports and small series published on the successful performance of total laparoscopic or laparoscopically assisted PE for various indications (6871). Considering the potential benefits of minimal-invasive procedures in general like lower blood loss, shorter hospital stay, and decreased postoperative pain, these procedures are of considerable interest. It will be almost impossible to statistically compare reliable outcome parameters like morbidity and survival between laparoscopic and open exenterative procedures considering the case number needed for a valid prospective trial. Also, considering the importance of modern continent urinary and intestinal reconstruction techniques it does not only require a laparoscopic surgeon who is skilled to perform the resection but also various reconstructive techniques by laparoscopy. These prerequisites are currently given only in very few oncology centers worldwide.

Outcome and selection criteria Mortality The high perioperative mortality of more than 20% highlighted in the initial reports (72) was result of infectious, metabolic and surgical complications.

Improvements in perioperative management in combination with modifications

Table 1. Mortality, morbidity and survival in various series investigating the outcome after pelvic exenteration. NR= not reported, NA= not applicable, n= number of included patients (number of gynaecologic patients) (modified after (4)).

190 Markus C. Fleisch et al.

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in surgical technique have contributed to a significant decrease in mortality over the last 40 years. The introduction of perioperative antibiotic and thrombosis prophylaxis has reduced the number of infectious and thromb-embolic events after major surgery in general. Improvements in medical care and intensive care therapy have impacted patient selection criteria and improved postoperative surveillance, respectively. All major studies on the outcome after PE published between 1989 and 2007 now report a proportion of postoperative deaths ranging from 1 to 9% (4, 5, 8, 27, 35, 38, 40, 73-77) (see table 1).

Morbidity PE has historically been afflicted with a high perioperative complication rate ranging between 32-84% as presented by various investigators (8, 26-28, 30, 74, 78, 79).

Table 2. Typical early and late complications after various intestinal, urinary and vaginal reconstruction techniques for PE (modified after (4)).

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PEs are major surgical procedures with an average OR time ranging between 5 to 14h, a mean blood loss of 2300 to 4000 cc and historically with a mean hospital stay between 19 to 37 days. Although overall quality of life does not seem to be affected after PE patients tend to develop postoperative physical, sexual and social problems (18).

The most frequent general postoperative complications associated with this procedure are wound infections, hemorrhage and thromboembolism.

Depending on the type of exenteration performed specific early and late complications can occur affecting urinary, intestinal and vaginal reconstruction (table 2). Typical early complications for urinary and intestinal reconstruction include necrosis, retraction, leakage, and fistula formation.

Late complications are stoma and pouch stenosis, hernia, or prolapse (54).

Especially after total PE patients may suffer from severe infectious pelvic complications like abscess formation in the denuded pelvis. Cases with radiation of the pelvis prior to PE are generally afflicted with a higher surgical morbidity rate than primary cases.

Ureteral stricture should be corrected surgically either immediately or after transient percutaneous nephrostomy to preserve renal function.

Intestinal obstruction occurs both as early and as late complication and continues to be a significant source of morbidity in 10-15% of PE patients.

Mostly paralytic ileus problems, which are also partially a consequence of the denuded pelvis, respond to medical therapy in combination with nasogastric decompression. Small anastomotic leaks often heal spontaneously; if major leakage is found or patients suffer from pelvic infection a protective transient colostomy should be performed. Also enteral fistulas often resolve spontaneously under bowel rest and iv-hyperalimentation (88).

Survival In 1965 Brunschwig reported a series more than 430 patients treated by PE which still is the biggest published series to date on this procedure (72).

The overall 5-year survival rate in this mixed cohort was 21%.

Definitive conclusions regarding the survival after primary exenteration for advanced pelvic malignancies cannot be easily drawn due to the paucity of reliable data published. However, the same applies to other treatment options: There is only limited data on survival rates after primary chemoradiation for stage IVA cervical cancer (13, 15, 89, 90) and no data from large randomized trials is available. Marnitz, Deckers and Numa reported a 5-year survival from 43% to 52,5% in selected patients undergoing PE for FIGO IVA cervical cancer (7, 18, 91) and also the results of other small series reporting survival data after primary PE for advanced gynaecologic

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malignancies are in this range (table 1). These results are even better than the 5-year overall survival after chemo-radiation for stage IVA cervical cancer as listed in the latest FIGO annual report (36%) (10).

As mentioned before there is no data available on the survival outcome after PE for FIGO IVA endometrial cancer so that this potential indication remains questionable.

PE for patients with recurrent cervical cancer after chemo-radiation therapy fulfilling the mentioned eligibility criteria results in survival rates between 16 and 60% (1, 7, 8, 18, 36, 37, 40, 77, 92).

Analyzing the literature there are some commonly identified negative prognostic factors in patients undergoing PE. The tumor-involvement of pelvic lymph nodes, tumor fixation to the pelvic side wall and tumor-positive margins of the surgical specimen have been shown to result in a shorter survival (8, 18). In our own mono-institutional analysis of 203 patients undergoing PE for various gynaecologic cancers over 20 years we found that the mean survival of completely resected patients was approximately 2 years longer than in patients with positive margins (8). Mean survival was approximately 3 years, in the series of Berek et al. and Shingleton et al. no patient survived longer than 3 years (40, 76). The use of intraoperative radiation therapy (IORT) might be beneficial for cases with microscopic residual disease (93). The impact of other factors on survival rate like lymphovascular space invasion, histological type and grade, time to recurrence and tumor size is controversely discussed.

Different investigators have different definitions when PE has to be considered as palliative. Magrina considers PE to have a palliative intent if tumor is present in pelvic or periaortic lymph nodes or at the lateral pelvic wall (38).

Lambrou considers tumor-associated fistula, therapy-resistant hemorrhagic cystitis and/pr proctitis as indications for palliative PE (94), Stanhope also includes bone involvement or distant metastasis (95). Accordingly depending on the definition 5-year survival rates range between 10.5 and 27% (18). The reported median survival rates for patients undergoing palliative chemotherapy for recurrent cervical cancer are between 8 and 11 months (18).

The place of pelvic exenteration in the treatment of advanced pelvic malignancies â&#x20AC;&#x201C; past, presence and future 60 years after its conceptual introduction and according to the current literature PE offers cure for approximately 50% of patients with advanced primary or recurrent cancer of the female genital tract eligible for this procedure.

Treatment-related morbidity remains high but mortality has fallen below 5%.

The experiences of various investigators have highlighted the selection criteria

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for patients which will potentially benefit from this procedure. Considering the numerous unanswered questions regarding indications for PE and the outcome parameters in comparison with alternative treatment options the performance of PE should underlie some restrictions.

First, the performance of PE should be limited to referral centers with high case volume. Performing centers should provide all therapeutic options including all forms of continent urinary and intestinal reconstruction techniques and an upto-date radiation therapy facility. Second, the indication for primary, secondary and palliative exenteration should be the individual decision of an interdisciplinary tumor board conference as some centers advocate (9, 18) and should be approved after discussing all available treatment options. The tumor board should at least consist of a gynaecologic oncologist, urologist, GI surgeon, radiation therapist and a pathologist. The recommendation of the tumor board should then be discussed with the patient along with the other available therapeutic options, the procedure related morbidity and mortality rate in order to get his informed consent.

If individual surgeons, like in most institutions, are not capable of offering all reconstructive techniques and in order to provide high standard of care the procedure should be performed in an interdisciplinary approach involving other disciplines as needed (96).

Minimal-invasive techniques to determine extent and resectability of advanced or recurrent tumors can potentially contribute to identify eligible candidates for PE. Laparoscopic approaches are not only limited to diagnostic purposes. A few expert centers have already shown that performing PE by laparoscopy is feasible and might offer specific advantages compared to the conventional approach. Results of numerous studies over the past 40 years show that the significant improvements in perioperative management and surgical technique have not only led to decreased perioperative mortality and increased survival but also improved postoperative quality of life in this group of patients.

In lack of new treatment modalities for locally advanced cancers in the pelvis and considering the potential advantages of a surgical approach in selected patients it is likely that suggests that also in the future PE will have a significant role for the treatment of advanced pelvic malignancies.

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Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 201-212 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

12. The role of video-assisted thoracic surgery (VATS) and intrathoracic cytoreductive surgery in gynecologic malignancies John P. Diaz and Dennis S. Chi Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center New York, NY, USA

Ovarian cancer is the second most common gynecologic malignancy in the United States, affecting 1 in 70 American women. Most women present with advanced-stage disease, which is why ovarian cancer is the most lethal gynecologic malignancy, with an estimated 15,520 deaths in 2008 [1].

While fallopian tube and primary peritoneal cancers are rare malignancies, they are histologically similar to ovarian cancer and are approached using the same treatment strategies.

Primary surgical debulking is a fundamental component of ovarian cancer treatment in the majority of patients with advanced-stage disease at initial presentation. While the definition of optimal debulking has ranged from complete gross resection to < 2 cm, studies have consistently demonstrated that optimal vs. suboptimal debulking is associated with improved overall survival [2-10]. Even among the subset of patients with stage IV disease as evident by malignant pleural effusion, Correspondence/Reprint request: Dr. Dennis S. Chi, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue New York, NY 10065, USA. E-mail: gynbreast@mskcc.org

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intraparenchymal liver metastasis, or other extraperitoneal disease, several authors have reported survival benefits when optimal cytoreduction can be achieved [3, 11-18].

It is estimated that more than one third of patients with stage IV ovarian carcinoma present with pleural effusions [18, 19]. Many patients with malignant pleural effusions are evaluated with a computed tomography (CT) scan to determine whether bulky thoracic disease precludes an attempt at abdominal surgical cytoreduction. It is unclear whether an accurate assessment of intrathoracic disease and extent of diaphragmatic pleural involvement can be made from radiographic studies alone. The presence of macroscopic intrathoracic disease may alter patient management, particularly if unresected > 1-2 cm intrathoracic tumor deposits would leave the patient with suboptimal residual disease at the conclusion of maximal intra-abdominal cytoreduction.

At presentation, stage IV disease is diagnosed in approximately 10% of patients with epithelial ovarian cancer [20]. The role of cytoreductive surgery in this group continues to be debated. Goodman et al. described the role of cytoreductive surgery in the management of stage IV disease. In their initial series evaluating primary and interval debulking in 35 patients with stage IV disease, they reported no difference in survival among patients who had optimal intra-abdominal cytoreduction [21]. Since this early report, several authors have reported improved survival in association with optimal primary debulking (Table 1 [3, 11-15, 17-19, 21]). Among the subgroup of patients classified as having stage IV disease based on malignant pleural effusions alone, the reported rates of optimal primary debulking range from 27-78% [11-14, 16-18].

The benefits of debulking in patients with malignant pleural effusions compared to patients with other stage IV disease criteria have been evaluated, with mixed results. In a study of 84 patients with stage IV disease, including 32 (38%) of 84 patients with malignant pleural effusions, Bristow et al. reported a median survival of 38.4 months in optimally debulked patients (< 1 cm) and 10.3 months in suboptimally debulked patients (P=0.0004).

On univariate analysis, there was no difference in median survival comparing patients with pleural effusion and other stage IV criteria. Munkarah et al. studied 108 women with stage IV ovarian carcinoma. The median survival of the optimally debulked patients was 25 months versus 15 months for the suboptimally debulked patients (P<0.02). However, there was no statistical difference in median progression-free survival between the two groups.

Interestingly, when they compared patients with pleural effusions only to other stage IV patients, they found no difference in survival between optimally debulked patients (median, 25 months) compared to suboptimally (defined as < 2 cm) debulked patients (median, 23 months) (P=0.7) [15]. In contrast, among a

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Table 1. Cytoreductive surgery in patients with stage IV ovarian carcinoma.

Study

Year

No. of patients

Optimal cytoreduction

Goodman et al.

[21] Liu et al. [14] Curtin et al. [13] Munkarah et al.

[15] Bristow et al. [3] Bonnefoi et al.

[19] Naik et al. [17] Akahira et al.

[18] Brunisholz et al.

[12] Aletti et al. [11]

1992

35

2 cm

Survival advantage for optimal debulking no

1997 1997 1997

47 97 100

2 cm 2 cm 2 cm

yes yes yes

1999 1999

84 169

1 cm 2 cm

yes no

2000 2001

37 225

2 cm 2 cm

yes yes

2005

23

2 cm

no

2006

50

1 cm

yes

smaller cohort of 23 patients with stage IV disease, Brunisholz found that 9 patients with pleural effusions had reduced survival compared with that of patients with other sites of distant metastasis [12].

Although several retrospective reviews have demonstrated a survival benefit to optimal intra-abdominal debulking in patients with malignant pleural effusions, these patients still have decreased survival when compared with patients who have disease confined to the abdomen. Eitan et al. compared the survival of optimally cytoreduced stage IIIC and stage IV patients by pleural effusion criteria. The median survival of the optimally cytoreduced stage IIIC patients was 58 months compared to 30 months for the stage IV patients (P=0.0016) [22]. While the poorer prognosis likely reflects the more aggressive and advanced nature of disease, which extends extraperitoneally, the authors of this prior report from our institution also raised the question of whether undetected bulky residual intrathoracic disease contributed to this difference.

Juretzka et al. reported our experience with video-assisted thoracic surgery (VATS) before planned abdominal exploration in 23 patients with moderate to large pleural effusions and advanced ovarian, fallopian tube, primary peritoneal, or other cancers [23]. VATS was performed for right-sided effusions in 17 patients (74%), and a median of 1350 mL (range, 400-3700 mL) of pleural fluid was drained. VATS demonstrated macroscopic disease in 15 patients (65%), with nodules > 1 cm in 11 (73%) of 15 and nodules < 1 cm in 4 (27%) of 15.

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Macroscopic intrathoracic disease was found in 4 (40%) of 10 patients with negative cytology. Intrathoracic cytoreduction was performed in 3 (27%) of 11 patients with intrathoracic disease < 1 cm. After VATS, 12 (52%) of 23 patients underwent primary surgical management, with cytoreduction to < 1 cm achieved in 11 (92%) of 12 patients. The other 11 patients received primary chemotherapy after undergoing diagnostic laparoscopy alone (4/11) or no further abdominal exploration (7/11). Nine of these patients proceeded to interval cytoreduction, while 2 had pathology demonstrating upper gastrointestinal and lymphoma primaries at the time of VATS. Final diagnosis of primary site of disease included the following: ovary, 14 (61%); endometrial, 2 (9%); dual ovarian/endometrial primaries, 1 (4%); fallopian tube, 1 (4%); primary peritoneal, 1 (4%); and other, 4 (17%). Overall, findings at VATS altered primary surgical management in 11 (48%) of 23 patients.

An update of our initial experience examined the primary management and oncologic outcomes of these patients [24]. In this review, 40 patients with advanced ovarian carcinoma and pleural effusions underwent VATS. The primary management of 16 (40%) of these patients was altered based on the findings at the time of VATS. Patients who after VATS were directed to neoadjuvant chemotherapy instead of primary surgical cytoreduction because of findings of pleural disease had a 2-year progression-free survival rate of 17% compared to 40% for the primary cytoreductive group. The improved progression-free survival for the primary cytoreduction group compared to the neoadjuvant group did not reach statistical significance (P=0.10), perhaps related to our small sample size (Figure 1).

The role of cytoreductive surgery in advanced ovarian carcinoma followed by platinum-based chemotherapy has been well established. The goal of cytoreductive surgery is to obtain an optimally debulked status, with no residual tumor > 1 cm. Patients who present with pleural effusions should be evaluated for the presence of malignant pleural effusions and intrathoracic disease > 1 cm. CT scans have been utilized to assess for intrathoracic disease; however, there have been no randomized trials to evaluate their sensitivity or specificity. We can infer from the inability of these scans to accurately predict which patient will have an optimal abdominal debulking that their utility intrathoracically would be similar [11]. As such, we believe that patients who present with suspected advanced ovarian carcinoma and pleural effusions should be assessed with a VATS procedure. The VATS procedure will not only allow for an accurate assessment of intrathoracic disease but provide for an attempt at intrathoracic debulking, if necessary.

Furthermore, VATS provides the opportunity to appropriately triage patients to neoadjuvant chemotherapy who may have otherwise undergone an abdominal cytoreductive procedure that may not have benefitted her due to unknown bulky intrathoracic disease. The suggested treatment paradigm is outlined in Figure 2.

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Figure 1. Progression-free survival after VATS.

Figure 2. Management of suspected advanced ovarian carcinoma with pleural effusions.

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The VATS procedure Indications to perform a VATS procedure for gynecologic malignancies include the following: 1.

2.

3.

4.

Diagnosis of macroscopic intrathoracic malignant disease when pleural effusion is found in a patient with advanced mullerian malignancy (Figure 3) Treatment of malignant pleural effusion Resection of intrathoracic bulky disease and/or ablation of pleuralbased disease in the setting of the maximal debulking effort Assessment of full-thickness diaphragmatic involvement

Figure 3. Upright chest radiograph: Patients with a suspected advanced ovarian malignancy who have moderate to large pleural effusions on an upright chest radiograph should undergo a video-assisted thoracic surgery to evaluate the intrathoracic cavity for macroscopic disease prior to an attempt at an intra-abdominal cytoreductive surgery. Moderate to large pleural effusions are defined as effusions on an upright chest radiograph in which layering fluid occupies 1/3 or greater of the pleural cavity, as seen above.

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Relative contraindications for VATS include the following: 1.

2.

3.

4.

5.

6.

7.

8.

No intra-abdominal surgical effort is planned, except when treating malignant pleural effusion Ventilator dependency Noncompliant lung Severe emphysema Chest wall involvement by tumor Small thoracic cavity or significant anatomic restrictions Hemodynamic instability Coagulopathy

An anesthetic team experienced in thoracic procedures is important, as VATS cannot be performed without unilateral pulmonary atelectasis.

Intubation is preferably performed with a double-lumen tube that allows onelung ventilation and ensures collapse of the chosen lung.

For a diagnostic procedure without a difficult resection, a single surgeon can hold the camera and possibly the biopsy forceps, and one monitor may suffice. If two surgeons are needed, two monitors are placed on either side of the patientâ&#x20AC;&#x2122;s head, providing the best views for both members of the operating team [25, 26].

The patient is placed in the lateral decubitus position as for conventional thoracotomy. To ensure maximal stretching of the intercostal spaces and to avoid obstruction to camera movement, the operating room table is slanted downward on both sides of the center so as to lower the pelvis and head (Figure 4).

Figure 4. Patient in the lateral decubitus position.

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Figure 5. The incision for the first trocar is placed along the mid-axillary line in the sixth intercostal space.

The first trocar is meant for the camera, as in laparoscopy. A 10-mm or 5-mm trocar can be used depending on availability and operator preference.

The first trocar is placed along the mid-axillary line in the sixth intercostal space (Figure 5). This location provides an excellent view of all pleural spaces, the lung parenchyma, and the mediastinum. The skin incision is made parallel and above the seventh rib. A small clamp is introduced through the intercostal muscles and pleura above the rib to avoid the intercostal vessels and neurovascular bundle that run below each rib. The clamp is opened, widening the intercostal space. Some surgeons advocate the direct digital exploration of the pleural cavity beneath the incision. The first trocar is then inserted, again avoiding the blood vessels running inferior to the rib.

If pleural effusion is present, it is drained through the trocar and sent for cytology. The 10- or 5-mm camera is inserted, and video-assisted exploration of the pleural cavity is performed (Figure 6). Operative ports may now be positioned, if needed. The operative ports are usually put along the anterior and posterior axillary line between the fourth and sixth intercostal spaces.

Some surgeons advocate performing the anterior skin incision under the mammary fold to improve the cosmetic result. If malignant lesions are found, they can be biopsied or resected. Care should be taken to avoid seeding of tumor cells during extraction of tissue from the chest. A plastic endobag should be used for the larger specimens.

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Figure 6. Exploration of the pleural cavity and biopsy of suspicious lesions.

Pleural disease can be ablated or resected as peritoneal disease is treated in the abdomen. This can be accomplished using the argon beam coagulator and monopolar electrocautery. Loculations of pleural effusion can be entered and drained.

All of the instruments that might be needed for an emergency thoracotomy must be ready in the operating room, and the staff should be ready for a conversion, if needed. At the end of the procedure, the trocars are removed and the lung is inflated. A chest drainage tube may be placed in the pleural cavity through one of the ports of entry to treat pneumothorax and drain pleural effusion in the postoperative period. All other ports are closed in layers to ensure air-tight closure.

Postoperative management Patients are followed postoperatively with daily chest radiographs to ensure that the pneumothorax is not enlarging and that the chest tube is positioned properly without kinking. In cases of malignant pleural effusions, pleurodesis can be performed with talc or doxycycline. When the pleural

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drainage is less than 200-300 cc per day, the chest tube can be removed at the bedside, making sure the incision is closed immediately after tube removal.

Complications of VATS are similar to those of conventional thoracotomy, such as air leak, postoperative bleeding, wound infections, empyema, and, in rare cases, respiratory failure [27]. Some of the less common complications include pneumonia, atelectasis, arrhythmias, and deep vein thrombosis.

Pulmonary edema is not reported as a VATS-specific complication but is known to be related to pneumonectomies and lobectomies. Fluid overload should be avoided, and any acute respiratory complaint in the first 24-48 hours postoperatively should be worked up thoroughly.

There are, however, complications related to VATS and specifically to the insertion of the thoracoscopy ports. These complications include intercostal neuritis and port site metastasis of tumor.

Port-related complications can be minimized by good surgical technique, and pain can be decreased substantially [26]. Blunt-tip ports designed for thoracoscopy should be used, and the port should be introduced without force and under control. Some surgeons advocate making the skin incision directly over the intercostal space, avoiding oblique access. Excessive spreading of intercostal tissue should be avoided. A retrieval device will minimize the chances of port-site recurrence.

References 1.

2.

3.

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Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71-96.

Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248-59.

Bristow RE, Montz FJ, Lagasse LD, Leuchter RS, Karlan BY. Survival impact of surgical cytoreduction in stage IV epithelial ovarian cancer. Gynecol Oncol 1999;72:278-87.

Chi DS, Eisenhauer EL, Lang J, Huh J, Haddad L, Abu-Rustum NR, et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol 2006;103:559-64.

Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer.

Gynecol Oncol 2000;78:269-74.

Eisenkop SM, Spirtos NM, Montag TW, Nalick RH, Wang HJ. The impact of subspecialty training on the management of advanced ovarian cancer. Gynecol Oncol 1992;47:203-9.

Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, et al. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovariancarcinoma. Am J Obstet Gynecol 1994;170:974-9; discussion 979-80.

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Markman M. Concept of optimal surgical cytoreduction in advanced ovarian cancer: a brief critique and a call for action. J Clin Oncol 2007;25:4168-70.

Piver MS, Baker T. The potential for optimal (less than or equal to 2 cm) cytoreductive surgery in advanced ovarian carcinoma at a tertiary medical center: a prospective study. Gynecol Oncol 1986;24:1-8.

Piver MS, Lele SB, Marchetti DL, Baker TR, Tsukada Y, Emrich LJ. The impact of aggressive debulking surgery and cisplatin-based chemotherapy on progression-free survival in stage III and IV ovarian carcinoma. J Clin Oncol 1988;6:983-9.

Aletti GD, Dowdy SC, Podratz KC, Cliby WA. Surgical treatment of diaphragm disease correlates with improved survival in optimally debulked advanced stage ovarian cancer. Gynecol Oncol 2006;100:283-7.

Brunisholz Y, Miller J, Proietto A. Stage IV ovarian cancer: a retrospective study on patient's management and outcome in a single institution. Int J Gynecol Cancer 2005;15:606-11.

Curtin JP, Malik R, Venkatraman ES, Barakat RR, Hoskins WJ. Stage IV ovarian cancer: impact of surgical debulking. Gynecol Oncol 1997;64:9-12.

Liu PC, Benjamin I, Morgan MA, King SA, Mikuta JJ, Rubin SC. Effect of surgical debulking on survival in stage IV ovarian cancer. Gynecol Oncol 1997; 64:4-8.

Munkarah AR, Hallum AV, 3rd, Morris M, Burke TW, Levenback C, Atkinson EN, et al. Prognostic significance of residual disease in patients with stage IV epithelial ovarian cancer. Gynecol Oncol 1997;64:13-7.

Zang RY, Zhang ZY, Cai SM, Li ZT, Chen J, Tang MQ, Liu Q. Cytoreductive surgery for stage IV epithelial ovarian cancer. J Exp Clin Cancer Res 1999; 18:449-54.

Naik R, Nordin A, Cross PA, Hemming D, de Barros Lopes A, Monaghan JM. Optimal cytoreductive surgery is an independent prognostic indicator in stage IV epithelial ovarian cancer with hepatic metastases. Gynecol Oncol 2000;78:171-5.

Akahira JI, Yoshikawa H, Shimizu Y, Tsunematsu R, Hirakawa T, Kuramoto H, et al. Prognostic factors of stage IV epithelial ovarian cancer: a multicenter retrospective study. Gynecol Oncol 2001;81:398-403.

Bonnefoi H, A'Hern RP, Fisher C, Macfarlane V, Barton D, Blake P, et al. Natural history of stage IV epithelial ovarian cancer. J Clin Oncol 1999;17:767-75.

FIGO (International Federation of Gynecology and Obstetrics) annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 2003;83 Suppl 1: ix-xxii, 1-229.

Goodman HM, Harlow BL, Sheets EE, Muto MG, Brooks S, Steller M, et al. The role of cytoreductive surgery in the management of stage IV epithelial ovarian carcinoma. Gynecol Oncol 1992;46:367-71.

Eitan R, Levine DA, Abu-Rustum N, Sonoda Y, Huh JN, Franklin CC, et al. The clinical significance of malignant pleural effusions in patients with optimally debulked ovarian carcinoma. Cancer 2005;103:1397-401.

Juretzka MM, Abu-Rustum NR, Sonoda Y, Downey RJ, Flores RM, Park BJ, et al. The impact of video-assisted thoracic surgery (VATS) in patients with suspected advanced ovarian malignancies and pleural effusions. Gynecol Oncol 2007;104:670-4.

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24. Diaz JP, Abu-Rustum RN, Sonoda Y, Downey RJ, Park BJ, Flores RM, et al.

Video-assisted thoracic surgery (VATS) evaluation of pleural effusions in patients with newly diagnosed advanced ovarian carcinoma can influence the primary management choice for these patients. Gynecol Oncol 2009;112 (supplement 1):S34.

25. Roviaro G, Varoli F, Vergani C, Maciocco M, Nucca O, Pagano C. Videoassisted thoracic major pulmonary resections: technical aspects, personal series of 259 patients, and review of the literature. Surg Endosc 2004;18:1551-8.

26. Landreneau RJ, Mack MJ, Hazelrigg SR, Dowling RD, Acuff TE, Magee MJ, Ferson PF. Video-assisted thoracic surgery: basic technical concepts and intercostal approach strategies. Ann Thorac Surg 1992;54:800-7.

27. Yim AP, Liu HP. Complications and failures of video-assisted thoracic surgery: experience from two centers in Asia. Ann Thorac Surg 1996;61:538-41.

Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 213-232 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

13. Laparoscopic and robotic assisted laparoscopic cytoreductive surgery in gynecologic oncology Frédéric Marchal, Philippe Rauch and François Guillemin Department of Surgical Oncology, CRAN, Nancy-Université, CNRS, Centre Alexis Vautrin Avenue de Bourgogne, 54511, Vandoeuvre-les-Nancy, France

Abstract. Advanced laparoscopic procedures are increasingly being used as an alternative to laparotomy in gynecologic oncological surgery. The benefits of advanced laparoscopic procedures compared with laparotomy are clear, including decreased pain, decreased surgical site infection rate, decreased length of stay, quicker return to activity and cosmesis. Recently, the da Vinci robotic system (Intuitive Surgical Corporation, Sunnyvale, CA) has been introduced into minimally invasive gynecologic surgery. The robotic surgical system is an innovative technology that addresses the many of the current limitations of conventional laparoscopy.

However, laparoscopic gynecologic oncological surgery is associated with unique challenges and complications compared with the open gynecologic oncological surgery. Principally, this new technique has to address two questions: is the laparoscopic approach a safe procedure and are the oncological results equal to standard surgery? We discuss in this chapter the laparoscopic cytoreductive surgery in gynecologic oncology (uterine and ovarian tumors) and the recent experience and feasibility of integrating robot-assisted technology into minimally invasive gynecologic oncological surgery.

Correspondence/Reprint request: Dr. Frédéric Marchal, Department of Surgical Oncology, CRAN, NancyUniversité, CNRS, Centre Alexis Vautrin, Avenue de Bourgogne, 54511, Vandoeuvre-les-Nancy, France E-mail: f.marchal@nancy.fnclcc.fr

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Introduction Since the introduction of explorative laparoscopy, operative laparoscopic techniques have been applied to a variety of benign adnexal and uterine conditions. These successes have prompted the development of laparoscopic techniques for the exploration, staging and resection of pelvic malignancies.

Techniques range from full laparoscopic to laparoscopic-assisted procedures in which a portion of the procedure is performed vaginally [1]. Albeit the use of laparoscopy for the surgical management of gynaecological cancer is developed since 1990s, it is still unclear whether laparoscopic gynaecological oncology techniques could achieve adequate oncological resection and staging.

Endometrial cancer Laparoscopy has been reported to provide the exact staging and treatment of endometrial cancer patients, with a shorter hospitalization stay, an earlier recovery, and an improved quality of life [1, 2]. Nonetheless, the number of patients included in such series was low and additional data are required concerning long-term survival in patients treated with laparoscopic approach.

Obermair et al. [3] have reported a retrospective study including 510 stages I窶的V endometrial cancer patients who either had a total laparoscopic hysterectomy or a total abdominal hysterectomy. The objective of this study was to evaluate the effect of the laparoscopic approach on patterns of recurrence, disease-free, and overall survival in patients with endometrial cancer. The surgical intent was total laparoscopic hysterectomy in 226 patients (44.3%) and total abdominal hysterectomy in 284 patients (55.7%).

Total laparoscopic hysterectomy was converted to laparotomy in 11 patients.

Patients undergoing total laparoscopic hysterectomy were younger, heavier, with a higher ASA score and were more likely to present early-stage, welldifferentiated tumours, and less likely to have undergone lymphadenectomy.

Such selection biases may limit the interpretation of the study. With a median follow-up of 29 months, disease-free survival and overall survival were adversely and independently affected by increasing age, higher stage, higher grade, and by deeper myometrial invasion, whereas the intention to treat (total laparoscopic hysterectomy versus total abdominal hysterectomy) did not influence disease-free or overall survival. Patterns of recurrence were similar in both groups and no port-site metastasis was noted in the total laparoscopic hysterectomy group.

Kalogiannidis et al. [4] published a prospective cohort study without randomization of 169 consecutive patients. Sixty-nine patients (41%) were

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treated successfully by laparoscopic approach while 100 (59%) by total abdominal hysterectomy. Four out of 73 patients initially approached by laparoscopy were converted to laparotomy (5.5%). Lymphadenectomy was performed in 40% of the laparoscopic group and 57% of abdominal group (P = 0.03). The median number of pelvic lymph nodes removed by laporoscopic approach and laparotomy was 15 (range 2-31) and 21 (range 2-65), respectively (P = 0.05). Operative time was significantly longer with laparoscopy compared with laparotomy, while blood loss and duration of hospitalization was significantly lower in the laparoscopic group. The recurrence rate in the laparoscopic group was 8.7%, compared to 16% in the laparotomy group (not significant). The actuarial overall survival and disease-free survival for the laparoscopic group were 93% and 91% compared respectively to 86% and 84% in the abdominal group (not significant). In the multivariate analyses histological subtype was the only independent prognostic factor for disease-free survival, while surgical technique was not.

Querleu et al. [5] reported three patients with stage I, non-invasive or superficially invasive endometrial cancer with vaginal cuff recurrence within 9 months of treatment. They raised the concern that the obligatory use of a vaginal manipulator at the time of surgery may lead to anterograde and retrograde dispersal of tumour cells, with subsequent vaginal cuff and peritoneal metastasis.

Little evidence exists to link vaginal recurrence with the use of uterine manipulators or with the omission of tubal occlusion. Sonoda et al. [6] showed that the treatment of low-risk endometrial cancer by laparoscopy is associated with a significantly higher incidence of positive peritoneal cytology when compared with patients operated by laparotomy. The use of an intrauterine manipulator is not necessary required to perform an adequate laparoscopicassisted procedure, and could prevent the retrograde dissemination of cancer cells into the peritoneal cavity during uterine manipulation. Post-operative high dose rate brachytherapy is an another solution to prevent vaginal vault recurrences [7, 8].

A large randomized prospective phase III trial comparing the effectiveness of laparoscopic surgery with standard surgery in treating patients with endometrial cancer was conducted by the Gynecologic Oncology Group (GOG-LAP2 trial).

The inclusion of 2616 patients is completed since 2005 and we are expecting the long-term benefit data [9]. Meanwhile, there is no evidence for prohibiting laparoscopic surgery in patients with endometrial cancer.

Ovarian cancer Ovarian cancer is initially managed with surgery to confirm the diagnosis, determine the extent of disease (surgical staging), and to perform a

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tumour cytoreduction. Careful examination, with the advantage of magnification of the peritoneal surface and multiple random or oriented biopsies may be accomplished laparoscopically.

Laparoscopy seems to be an acceptable technical option to perform restaging of apparently early adnexal carcinomas. Peritoneal staging is indicated, in conjunction with node dissection, in the reassessment of inadequately staged adnexal cancer patients. Using laparoscopic techniques, 18% of patients are upstaged and need adjuvant chemotherapy [10]. Patients definitively classified as stage IA or IB after laparoscopic staging have an excellent prognosis. Husain and her colleagues [11] at the Memorial SloanKettering Cancer Center reported their experience with second-look surgical assessment. They found it to be safe, accurate, and with a low incidence of complications, particularly in the group of patients who had already undergone prior abdominal surgery. They found that the rates of negative evaluations and recurrence rates were comparable between patients undergoing laparoscopy and those undergoing laparotomy [11]. Laparoscopic peritoneal staging may also be proposed in the case of inadequately staged borderline ovarian tumors [12]. It spares the patients from the discomfort of repeat laparotomy. Long-term outcome results suggest that laparoscopic staging accurately detects the patients who need chemotherapy and safely select the patients who can be proposed surgery only.

Neoadjuvant chemotherapy is increasingly used in advanced ovarian, tubal or peritoneal carcinomas, when primary surgery cannot reach optimal cytoreduction. The decision to abort an attempt at optimal cytoreductive surgery is based on the presence of extensive growth in the mesentery, lesser omentum, stomach and duodenum, or posterior hemidiaphragm. Laparoscopy is preferable to exploratory laparotomy is this context, with a shorter recovery and quicker start of neoadjuvant chemotherapy [13]. However portsite metastasis can occurs in approximately 10% of laparoscopies in untreated peritoneal carcinomatosis, but is as chemosensitive as the peritoneal disease and never alters the treatment or outcome [14]. In contrast, Huang et al. [15] reported in 2003 that the occurrence of port-site metastasis after laparoscopy for epithelial ovarian cancer was 19% (6/31 patients) and that the presence of abdominal wall metastases in the entry sites of previous laparoscopy was negatively correlated with survival [15].

For stage III窶的V ovarian cancer, a complete cytoreduction is impossible either because of disease extension or because of the health status of the patient. The volume of the mass, the extent of the disease, the insufficient access to peritoneal and retroperitoneal areas, and of course the risk of peritoneal spillage are limiting factors for the use of operative laparoscopy.

However, laparoscopy is probably the most valuable tool for evaluating the

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operability, primarily or at the time of interval debulking surgery [1]. It can therefore be used to select candidates for initial complete debulking or for neoadjuvant chemotherapy [16-18]. The accuracy of imaging to predict the possibility of initial complete debulking is poor and preoperative CT predictors should be used with caution when deciding between surgical cytoreduction and neoadjuvant chemotherapy [19, 20]. Identification of risk factors for suboptimal cytoreduction in all published cohorts, are not reproducible in alternate populations [19]. Until prospective, randomized trials have demonstrated that neoadjuvant chemotherapy followed by interval cytoreduction is equivalent in terms of survival outcomes to primary optimal cytoreduction followed by chemotherapy, extreme caution should be used when applying preoperative imaging predictors to decide between primary surgical exploration and neoadjuvant chemotherapy in the medically fit patient. A number of studies have demonstrated an association between the preoperative CA-125 level and the inability to achieve optimal cytoreduction, yet the overall accuracy rates at predicting surgical outcome (ie, optimal v suboptimal cytoreduction) were only 50% to 78% with most studies using a CA-125 cut off value of 500 U/mL [20, 21].

Cervical carcinoma The issue of laparoscopy in the management of locally advanced cervical cancer has been addressed by several authors. In 1990, Canis and colleagues [22] first described the laparoscopic radical hysterectomy. By 1996, Spirtos et al. [23] described a complete pelvic and aortic lymphadenectomy and type III radical hysterectomy which were performed laparoscopically. Other authors evaluated the feasibility and safety of pretreatment laparoscopic surgical staging in the treatment of locally advanced cervical cancer [24, 25].

They contended that pretreatment laparoscopy is the best guideline for individualized concurrent chemoradiation. When compared with magnetic resonance imaging, CT scan or (18)F-fluorodeoxyglucose positron emission tomography (PET) scan, laparoscopic surgical staging was superior in detecting microscopic lymph node metastases [25]. Information garnered from the pathologic examination of paraaortic lymph nodes impacted treatment planning in up to 58% of women and appropriately extended the field in 24% of women with clinical stages IB2 and IIA cervical cancer while sparing 75% with stages IIB窶的VA [25]. The use of pretherapeutic laparoscopic surgical staging altered the treatment plan 58% of the time [25].

Marnitz et al. [26] investigated 84 patients with locally advanced cervical cancer who were selected for laparoscopic staging for primary chemoradiation.

In that study, they found that removal of more than five pelvic and/or more

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than five para-aortic lymph nodes was associated with significantly longer overall survival. Leblanc et al. [25] demonstrated a therapeutic benefit especially evident in patients with a microscopic involvement of paraaortic nodes – unlikely to be detected by imaging – and postoperatively managed with extended-field chemoradiation. In this subset survival was equivalent to node-negative patient managed with pelvic chemoradiation therapy [25]. The authors, as Marnitz et al. [26], concluded that debulking of tumor-involved lymph nodes should be performed prior to primary chemoradiation in patients with locally advanced cervical cancer [25]. However, Kupets et al. [27], based on their statistical analysis, asserted that 1% of stage IB, 2% of stage IIB, and 4% of stage IIIB patients would benefit from the debulking of pelvic lymph nodes. They also concluded that select patients with small central tumor burden and low-volume nodal involvement, but with tumors >2 cm would benefit from debulking [27]. In contrast, the only randomized prospective study [28] about the effectiveness of extraperitoneal lymph node dissection in cervical carcinoma demonstrated, surprisingly, the detrimental effect of extraperitoneal lymph node dissection on patient survival. This study had to be stopped after interim analysis of the early results due to the significantly low survival rate in the extraperitoneal lymphadenectomy group.

There were some drawbacks of this study, i.e., low number of patients, method of lymph node dissection, and radiotherapy technique, etc.

Chen et al. [29] reported a large series of laparoscopic radical hysterectomy and lymphadenectomy for cervical cancer. Between February 2001 and June 2007, 295 patients with cervical cancer (from FIGO stages Ia to IIIb) underwent a laparoscopic radical hysterectomy. Out of 295 procedures, 290 were successful. Para-aortic lymphadenectomy was performed in 156 patients (52.9%), and pelvic lymphadenectomy was performed in all 295 patients. The median blood loss was 230 mL (range, 501200 mL). The mean operation time was 162 min (range, 110-350), which included the learning curves of 3 surgeons. In 5 cases (1.7%), conversion to open surgery was necessary due to bleeding (3 cases), bowel injury (1 case), and hypercapnia (1 case). Other major intraoperative injuries occurred in 12 patients (4.1%). Positive lymph nodes were detected in 80 cases (27.1%), lymphovascular space invasion in 54 cases (18.3%), and surgical margins were negative for tumor in all patients. The mean hospital stay was 10.3 days.

Postoperative complications occurred in 10.8% patients, ureterovaginal fistula in 5 cases, vesicovaginal fistula in 4, ureterostenosis in 3 cases, deep venous thrombosis in 9 cases, lymphocyst in 4 cases, lymphedema in 5 cases, and 1 case with trocar insertion site metastasis. Other medical problems included 47 cases (15.9%) of bladder dysfunction and 62 cases (21.0%) of rectum dysfunction or constipation. The median follow-up was 36.45 months

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(range, 8-76 months). Recurrences or metastasis occurred in 48 patients (16.3%). Of these patients, 43 (14.6%) have died of their disease, and 5 (1.7%) are alive with disease. The overall disease-free survival was 95.2% for Ia, 96.2% for Ib, 84.5% for IIa, 79.4% for IIb, 66.7% for IIIa, and 60.0% for IIIb. Pomel et al. [30] reported a series of 50 consecutive patients with uterine cervical cancer who underwent a laparoscopic radical hysterectomy between 1993 and 2001 at two cancer centres. Thirty-one patients had had previous brachytherapy. Two patients had major urinary complications; one had a bladder fistula and one a ureteral stenosis. Previous brachytherapy did not affect the feasibility of this radical procedure. With a median follow-up of 44 months, the overall survival rate was 96%. Steed et al. [31] compared the peri-operative morbidity and recurrence-free survival of FIGO stage IA/IB cervical cancer patients treated by laparoscopic-assisted radical vaginal hysterectomy with time-matched radical abdominal hysterectomy controls.

The authors reported that laparoscopic-assisted radical vaginal hysterectomy was associated with less blood loss but more operative time, and more intraoperative complications, including: cystotomy (seven), ureteric injury (one), and bowel injury (one). There was no difference between postoperative infectious and non-infectious complications. Twenty-two per cent of patients received postoperative radiotherapy for high-risk features in both groups. The 2-year DFS and overall survivals were similar in both groups. These data demonstrate in a large series that early cervical cancer can be treated successfully with laparascopic-assisted radical vaginal hysterectomy with efficacy and recurrence rates similar to radical abdominal hysterectomy. In clinical practice, the three ‘‘minimally invasive’’ techniques for radical hysterectomy are not concurrent but complementary, and indication of each method is adapted to the individual patient [13].

Total pelvic exenteration Total pelvic exenteration is one of the most mutilating surgical procedures performed for gynecologic malignancies. Today, 95% of patients undergoing pelvic exenteration for advanced pelvic malignancy are expected to survive surgery, and 40% to 50% of them are alive 5 years later [32].

Pomel was the first to report two cases of laparoscopic exenteration for gynecological cancer [33]. Ferron et al. published 5 cases in 2006 [32] and Puntambekar 16 cases in 2006 [34]. Laparoscopic exenteration is feasible and made easier and faster using combination of perineal or vaginal approach.

Laparoscopic approach seems to be associated with a minimal blood loss (less than 500 cm3) thanks to modern devices such as the use of harmonic scalpel or new bipolar energy and the help of laparoscopic magnification [32,

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33]. However, hospital stay after pelvic exenteration does not decrease after laparoscopic approach, 27 days (range 13 – 33) [32], except for the Indian series with a median postoperative hospital stay of 3 days. Hospital stay is not dependent on the extent of the scar but one the time required to manage complications of the ‘‘pelvic burn syndrome’’ and for postoperative care of urinary diversion (continent or not) and colostomy. Efforts have to be made to improve patient's quality of live. Reconstruction of urinary system is an integral part of anterior or total pelvic exenterative procedures. Continent urinary diversion is a preferred option for urinary tract reconstruction in selected patients. Laparoscopic hand-assisted Indiana Pouch could be performed with less than 2.5 hours [32, 35]. Reconstruction of the vagina has a significant impact on quality of life and body image, especially for young sexually active patient [32].

Operative laparoscopy could prevent unnecessary laparotomies, can reduce morbidity, and leads to a shorter postoperative hospital stay. Patients with recurrent cervical cancer had positive para-aortic lymph nodes in 75 % of cases [36]. Kohler et al. [37] evaluated 41 consecutive patients undergoing explorative laparoscopy to determine eligibility for exenteration. Almost half (48.7%) of the patients avoided unnecessary exenteration for unresectable disease or intra-abdominal spread of disease. Laparoscopic pelvic lymphadenectomies can facilitate detecting patients who are the best candidates for pelvic exenteration [38]. Finally, these preliminary studies have demonstrated that laparoscopic pelvic exenteration is a feasible procedure in experienced hands.

Robotic surgery: A new standard of care?

As total laparoscopic extented hysterectomy is technically a challenging procedure, so far laparoscopic-assisted vaginal hysterectomy is often the techniques of choice, even in adenocarcinoma of the uterus [2]. Laparoscopic surgery has limitations regarding the 2 dimensions (2D) vision, the limited degrees of liberty of the instruments and the discomfort of the surgeon [39].

These factors restrain the development of minimally invasive procedures, specially for complex procedures. Robotic systems have been developed since 1999 in order to overstep these drawbacks, especially for cardiac surgery [39]. The present machines have been called as “robots” but in fact the term of computer-enhanced telemanipulator should be more appropriate [39]. However, the term of robot is commonly accepted. Since the da Vinci surgical system (Intuitive Surgical®, Sunnydale, CA) was approved for gynecology in April 2005, the role of robotic-assisted surgery in gynecologic oncology continues to evolve [40]. While still in its infancy, the published

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literature on robotic application to gynecologic cancer is minimal before 2008 [41-52] and increased quickly later on [40, 53-80].

Robotic systems enhance 3D vision, magnification, dexterity, precision, and might therefore support surgeons in delicate laparoscopic interventions (Figure 1). Robotic surgery can overcome two main problems of laparoscopic surgery, i.e. the limitation of four degrees of freedom of the instruments and the 2D vision on a TV screen. The first application in gynecologic surgery with computerenhanced telemanipulator was microsurgical tubal reanastomosis [81]. The advantages of the robot are evident in this indication, providing stereovision with magnification and instruments 6 degrees of freedom, tremor filtrering, and improving the quality of surgeonâ&#x20AC;&#x2122;s tasks due to a perfect ergonomic position. The second application concerned vaginally assisted hysterectomy [82]. Pelvic and paraaortic lymph node dissections were associated in the procedure. This experience suggested that robotic surgery is a safe and effective alternative to conventional laparoscopic surgery. Robotic assistance enhances the precision of anatomic dissection and increases the feasibility of performing laparoscopic extended hysterectomy for most surgeons. Position and orientation of the robot create an ergonomic environment for the surgeon and the assistant and give a direct pelvic access. The ports must be placed in such a manner to avoid robotic arms interference and to optimize visualization of the operating field. Robotic surgery establishes a straight foot-hand-eye axis that do not exist in conventional and laparoscopic surgery. It restores the three-dimensional view that is lost in laparoscopic surgery. With the da Vinci System, the surgeon is completely immersed in the operative field without external stimulations; in classical laparoscopy, if the surgeon focuses on the TV screen, he has the whole operative

Figure 1. Surgeon using da Vinci Si console in the foreground with nurse at vision cart and the patient cart with the four arms (photo courtesy of intuitive Surgical, Sunnyvale, California).

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theater in his visual field. The system seems to be the most beneficial for intraabdominal microsurgery or for manipulations in a narrow space and difficult of access. The other major advantage is the easiness of suturing in reconstruction such as biliary tract, proximal gastrojejunostomy, pyelo-ureteral syndrome, or as in gynecologic surgery vaginal closure [48]. While a skilled robotic bedside assistant is essential, the robotic surgeon has the additional advantages of a stable camera and direct control of endoscope movement [40].

We think that hysterectomy assisted by the robot has several advantages in comparison with classical laparoscopic hysterectomy: the vaginal time is deleted, the hemostasis is better particularly for paravagin and paracervix hemostasis, the dissection of the ureter after crossing with uterine artery is easier and more precise. However, no objective evidence has shown advantages of the computer enhanced telesurgical device in comparison with classical laparoscopy. Seamon et al. [40] compared outcomes between robotic versus laparoscopic hysterectomy and lymphadenectomy in patients with endometrial cancer A cohort study was performed by prospectively identifying all patients with clinical stage I or occult stage II endometrial cancer who underwent robotic hysterectomy and lymphadenectomy from 2006–2008 and retrospectively comparing data using the same surgeons' laparoscopic hysterectomy and lymphadenectomy cases from 1998–2005, prior to robotic experience. 181 patients (105 robotic and 76 laparoscopic) met inclusion criteria. There was no significant difference between the two groups in median age, uterine weight, bilateral pelvic or aortic lymph node counts, or complication rates in patients whose surgeries were completed minimally invasively. Despite a higher BMI (34 vs. 29, P < 0.001), the estimated blood loss (100 vs. 250 mL, P < 0.001), transfusion rate (3% vs.

18%, RR 0.18, 95%CI 0.05–0.64, P = 0.002), laparotomy conversion rate (12% vs. 26%, RR 0.47, 95%CI 0.25–0.89, P = 0.017), and length of stay (median: 1 vs. 2 nights, P < 0.001) were lower in the robotic patients compared to the laparoscopic cohort. The odds ratio of conversion to laparotomy based on BMI for robotics compared to laparoscopy is 0.20 (95% CI 0.08–0.56, P = 0.002). The mean skin to skin time (242 vs. 287 min, P < 0.001) and total room time (305 vs. 336 min, P b 0.001) was shorter for the robotic cohort. Although this series is limited by its nonrandomized design, the comparison between classical laparoscopy and assisted robotic laparoscopy concerns a new concept of criteria because the benefit of computer enhanced laparoscopy is obvious for the surgeon. With the aid of this robotic system, difficult laparoscopic interventions may become easier and safer to perform with decreased fatigue for the surgeon. The robot leads to surgeon discomfort and risk of chronic musculoskeletal occupational injury, particularly during longer procedures. Indications for minimal invasive

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surgery may be extended. The authors attributed most of the decrease in time to the superiority of the robotic platform and the increased autonomy of the primary surgeon. In addition, a previously skilled laparoscopic surgeon and a consistent and well-trained bedside assistant were also essential to proficiency and may be potential factors accounting for shorter operative times in the robotic cohort. The decreased blood loss and lower transfusion rates were due to advantages afforded by the robotic platform including improved optics and surgeon dexterity. After the first experiences with the robot, a lot of team can perform extended hysterectomy in oncology surgery, as well as through laparotomy.

Although laparoscopic staging for gynecologic malignancies in obese patients is technically possible with 100â&#x20AC;&#x201C;40% of the patients undergoing at least pelvic lymphadenectomy [59], morbid obesity is one of the limiting factors for widespread application of minimally invasive surgery of endometrial cancer. Seamon [40] and Gehrig [59] demonstrates that robotic surgery in obese women is feasible with a potential lower rate of conversion to laparotomy when compared to laparoscopy, and with shorter operative time, less blood loss, increased lymph node retrieval and shorter hospital stay thanks to the robot. While still considered a limitation to minimally invasive surgery, obesity may be less restricted factor for robotic surgery when compared to conventional laparoscopy for endometrial cancer patients.

The rate of complications of robotic hysterectomies ranging from 6 % to 19 % [48, 54, 61, 82, 83] were similar to these for classical laparoscopy, ranging from 6 to 28 % [30, 83, 84]. From some retrospective publications [30], and from the prospective randomized eVALuate study [84], it seems that complication rates have increased in laparoscopic hysterectomies, especially those involving the urinary system and during the learning curve.

As with any surgical procedure, particularly a new technology, complications are seen if enough procedures are performed. The blood loss and the lymph exsudation in series was mainly the consequences of section of the paracervix and paravagin in the extended hysterectomy according to Piver II [48, 82].

The risk of major complications during classical laparoscopic hysterectomy, highlighting in the eVALuate study [84], could decrease with teleroboticassisted laparoscopic, afforded by the robotâ&#x20AC;&#x2122;s magnified three-dimensional view and the enhanced range of motion and dexterity. The conversion for the robotic surgery is between 0 % and 4 % [48, 54, 61, 83, 85] in comparison with laparoscopic surgery within the range of the published studies (range, 023%) [9, 84-86].

Boggess JF et al. recently published a case-control study of roboticassisted type III radical hysterectomy with pelvic lymph node dissection for cervical cancer performed in 51 patients compared with 49 patients who

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underwent open radical hysterectomy [87]. There were significant differences between the groups with regard to operative blood loss (p < 0.0001), operative time (p = 0.0002), and lymph node retrieval (p = 0.0003), all of which were in favor of the robotic cohort. Hospital stay for robotic group was 1 day, compared with a 3.2-day average hospitalization for the open cohort.

The authors' conclusion was that robotic type III radical hysterectomy with pelvic node dissection is feasible and may be preferable over open radical hysterectomy in patients with early-stage cervical cancer. Minimally invasive surgery for oncology diseases progresses cautiously, concerned by the learning curves of specific procedures. In literature, only a few surgeons published about total laparoscopic radical hysterectomy with pelvic lymphadenectomy for malignancy diseases, showing difficulties to repeat, teach and spread this operation. On the contrary, operative efficiencies with the robot can be achieved within the first 15 cases [87], in comparison with the 20 – 100 cases necessary for a surgeon to reach stable operating times and lymph node yields [30, 88-90]. Moreover, as Boggess demonstrated the laparoscopic approach is not necessary in moving to a robotic approach because the Boggess's team did not have experience with laparoscopic radical hysterectomy.

A phase III randomized clinical trial comparing laparoscopic or robotic radical hysterectomy with abdominal radical hysterectomy in patients with early stage cervical cancer is being performed with the group of the American Association of Gynecologic Laparoscopists [70]. The aim of the study was to show the equivalence of the laparoscopic or robotic approach versus the abdominal approach following a 2-phase protocol. 740 patients must be enrolled.

For advanced diseases, only few data are reported in the literature.

Vergote et al. [79] reported the surgical technique used in 5 patients undergoing retroperitoneal para-aortic lymphadenectomy using the robotic Da Vinci system and Magrina et al. developed a robotic technique for extraperitoneal aortic lymphadenectomy in cadavers followed by its application in a patient with an advanced cervical cancer [91]. In the next future, the series about robotic pelvic exenteration will be published [62].

The drawbacks of da Vinci system is a lack of tactile and tensile feedback that accounts for 11 % of ruptured suture material [81]. With animate lab training and 3D imaging, the surgeon can appreciate tension that the robotic arms are exerting and learns to adapt its strength. This process is very close to the one mastered in microsurgery. The second drawback is represented by the cost of the system, 1,6 million euros, with 200 € for each use for each instrument and 10 % of the price for the annual maintenance fee for repair and service as well as software upgrades to the system. Cost

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effectiveness issues will be the major factor limiting the wider use of robotic systems. The equipment is expensive, but costs will decrease as the market expands and when competitors enter the market. Surgical robotics will have longevity only if demonstrated to be ‘‘better medicine’’, not better business [92].

In view of that, it is essential to decide which procedures are most likely to benefit from telerobotic-assisted laparoscopic system. We believe it is justified to use this system in operations that are carried out within confined spaces, like extended hysterectomy with pelvic lymph nodes dissection, where the advantages of the system are clearly appreciable to the surgeon, specifically dexterity enhancement and accuracy. The third drawback is the dimensions of the cart. The improvement could be the integration of robot’s arms in the ceiling of the operative room. A new design of tools with “snake” mobility can adapt to specific conditions. The computer aided ports placement and virtual reality would ease the procedures.

Conclusions Smaller incisions, less postoperative pain, and shorter hospital stays are welcomed by women suffering from gynecologic cancers. Laparoscopic cytoreductive surgery in gynecologic oncology is a feasible and safe procedure that is associated with fewer intraoperative and postoperative complications as opposite to traditional open procedures. Long-term outcomes after laparoscopic surgery are most likely equivalent to those after abdominal surgery for cervix carcinoma. For endometrial cancer, we are waiting the long-term benefit of a randomized trial. Robotic telemanipulation systems have been introduced recently to enhance the surgeon’s dexterity and vizualisation in videoscopic surgery in order to facilitate refined dissection, suturing and knot tying. Robotic surgery clearly introduces new tools for minimally invasive surgery and will expand its technical possibilities and medical indications. Robotic technology better facilitates the surgical approach as compared to laparoscopy for technically challenging operations performed to treat primary, early or advanced gynecologic cancer. Its role in ovarian cancer is just starting to be explored. Although patient advantages are similar or slightly improved with robotics, there are multiple advantages for surgeons. Because of relatively recent incorporation of robotic technology, long-term oncologic results must be examined in the future.

Acknowledgement We wish to thank Dr. Lina Bolotine for her assistance in writing the manuscript.

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57. Dornhofer N, Hockel M: New developments in the surgical therapy of cervical carcinoma. Ann N Y Acad Sci 2008, 1138:233-252.

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59. Gehrig PA, Cantrell LA, Shafer A, Abaid LN, Mendivil A, Boggess JF: What is the optimal minimally invasive surgical procedure for endometrial cancer staging in the obese and morbidly obese woman? Gynecol Oncol 2008, 111(1):41-45.

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62. Lambaudie E, Houvenaeghel G, Walz J, Bannier M, Buttarelli M, Gurriet B, De Laparrent T, Blache JL: Robot-assisted laparoscopy in gynecologic oncology.

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63. Lin PS, Wakabayashi MT, Han ES: Role of Robotic Surgery in Endometrial Cancer. Curr Treat Options Oncol 2009.

64. Lowe MP, Chamberlain DH, Kamelle SA, Johnson PR, Tillmanns TD: A multiinstitutional experience with robotic-assisted radical hysterectomy for early stage cervical cancer. Gynecol Oncol 2009.

65. Mabrouk M, Frumovitz M, Greer M, Sharma S, Schmeler KM, Soliman PT, Ramirez PT: Trends in laparoscopic and robotic surgery among gynecologic oncologists: A survey update. Gynecol Oncol 2009, 112(3):501-505.

66. Magrina JF, Zanagnolo VL: Robotic surgery for cervical cancer. Yonsei Med J 2008, 49(6):879-885.

67. Mettler L, Schollmeyer T, Boggess J, Magrina JF, Oleszczuk A: Robotic assistance in gynecological oncology. Curr Opin Oncol 2008, 20(5):581-589.

68. Nezhat F: Minimally invasive surgery in gynecologic oncology: laparoscopy versus robotics. Gynecol Oncol 2008, 111(2 Suppl):S29-32.

69. Nezhat FR, Datta MS, Liu C, Chuang L, Zakashansky K: Robotic radical hysterectomy versus total laparoscopic radical hysterectomy with pelvic lymphadenectomy for treatment of early cervical cancer. Jsls 2008, 12(3):227-237.

70. Obermair A, Gebski V, Frumovitz M, Soliman PT, Schmeler KM, Levenback C, Ramirez PT: A phase III randomized clinical trial comparing laparoscopic or robotic radical hysterectomy with abdominal radical hysterectomy in patients with early stage cervical cancer. J Minim Invasive Gynecol 2008, 15(5):584-588.

71. Pareja R, Ramirez PT: Robotic radical hysterectomy in the management of gynecologic malignancies. J Minim Invasive Gynecol 2008, 15(6):673-676.

72. Persson J, Kannisto P, Bossmar T: Robot-assisted abdominal laparoscopic radical trachelectomy. Gynecol Oncol 2008, 111(3):564-567.

73. Ramirez PT, Schmeler KM, Wolf JK, Brown J, Soliman PT: Robotic radical parametrectomy and pelvic lymphadenectomy in patients with invasive cervical cancer. Gynecol Oncol 2008, 111(1):18-21.

74. Ramirez PT, Soliman PT, Schmeler KM, dos Reis R, Frumovitz M: Laparoscopic and robotic techniques for radical hysterectomy in patients with early-stage cervical cancer. Gynecol Oncol 2008, 110(3 Suppl 2):S21-24.

75. Seamon LG, Backes F, Resnick K, Cohn DE: Robotic trocar site small bowel evisceration after gynecologic cancer surgery. Obstet Gynecol 2008, 112(2 Pt 2):462-464.

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79. Vergote I, Pouseele B, Van Gorp T, Vanacker B, Leunen K, Cadron I, Neven P, Amant F: Robotic retroperitoneal lower para-aortic lymphadenectomy in cervical carcinoma: first report on the technique used in 5 patients. Acta Obstet Gynecol Scand 2008, 87(7):783-787.

80. Zakashansky K, Bradley WH, Nezhat FR: New techniques in radical hysterectomy. Curr Opin Obstet Gynecol 2008, 20(1):14-19.

81. Degueldre M, Vandromme J, Huong PT, Cadiere GB: Robotically assisted laparoscopic microsurgical tubal reanastomosis: a feasibility study. Fertil Steril 2000, 74:1020-1023.

82. Diaz-Arrastia C, Jurnalov C, Gomez G, Townsend Jr C: Laparoscopic hysterectomy using a computer-enhanced surgical robot. Surg Endosc 2002, 16:1271-1273.

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84. Garry R, Fountain J, Mason S, Hawe J, Napp V, Abbott J, Clayton R, Phillips G, Whittaker M, Lilford R et al: The eVALuate study: two parallel randomised trials, one comparing laparoscopic with abdominal hysterectomy, the other comparing laparoscopic with vaginal hysterectomy. BMJ 2004, 328(7432):129-133.

85. Payne TN, Dauterive FR: A comparison of total laparoscopic hysterectomy to robotically assisted hysterectomy: surgical outcomes in a community practice. J Minim Invasive Gynecol 2008, 15(3):286-291.

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87. Boggess JF, Gehrig PA, Cantrell L, Shafer A, Ridgway M, Skinner EN, Fowler WC: A case-control study of robot-assisted type III radical hysterectomy with pelvic lymph node dissection compared with open radical hysterectomy.

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89. Tozzi R, Malur S, Koehler C, Schneider A: Laparoscopy versus laparotomy in endometrial cancer: first analysis of survival of a randomized prospective study. J Minim Invasive Gynecol 2005, 12(2):130-136.

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Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India

Cytoreductive Surgery in Gynecologic Oncology: A Multidisciplinary Approach, 2010: 233-258 ISBN: 978-81-7895-484-4 Editor: Yusuf Yildirim

14. Critical care and pain management in patients who have undergone cytoreductive surgery for gynecologic malignancies 1

A. Le Gouez1, J. Dick2 and D. Benhamou3

Fellow in Anaesthesia, Département d'Anesthésie-Réanimation, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud, Clamart, France; 2FRCA Consultant Anaesthetist University College Hospital, London, United Kindom; 3Professor of Anaesthesia and Intensive Care and Chairman, Département d'Anesthésie-Réanimation, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris Université Paris-Sud, Le Kremlin Bicêtre, France

Abstract. Surgery plays a central role in the treatment of gynaecological malignancy. It should be as complete as possible and is either performed first or after chemotherapy or neo-adjuvant radiotherapy. The role of the anaesthetist in this context is primarily to conduct a preoperative evaluation and to assess the impact of cancer on the patient. This evaluation must include the pre-operative nutritional status, occurrence of paraneoplasics syndromes, search for metastasis and obesity, which is a risk factor for most gynaecologic cancer.

Chemotherapy, with deleterious side effects and drug interactions which may impact on anaesthesia, is important to evaluate before surgery. Secondary effects from these treatments most important to evaluate because of their anaesthetics’ implications are haematologic, cardiologic, pulmonary and neurological toxicity. Drug interactions between cytotoxic drugs and anaesthetic agents are now well known.

Nitrous oxide should be avoided as it may potentiate the effects of cytotoxic chemotherapy, halogenated agents should be used cautiously Correspondence/Reprint request: Dr. A. Le Gouez, Fellow in Anaesthesia, Département d'Anesthésie-Réanimation Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud, Clamart, France E-mail: agnes.le-gouez@abc.aphp.fr

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in case of hepatotoxicity, local anesthetics may potentiate the cardiac toxicity of anthracyclines, and cyclophosphamide has an anti-cholinesterase effect which can enhance the effect of succinylcholine. Benefits and risks of loco-regional anaesthesia should be discussed in case of chemotherapy induced neurological toxicity.

The second role of the anaesthetist is to determine the technique of anaesthesia and analgesia adapted for the proposed surgery. Either spinal or general anaesthesia may be performed for surgery in case of cancer of the cervix and endometrium. The risk / benefit balance does not appear to be in favour of epidural anaesthesia for surgery for cancer of the uterus. As the surgical treatment of ovarian cancer is very invasive and requires a laparotomy, the use of spinal anaesthesia with morphine alone or epidural anaesthesia appear to be the techniques of choice. Whereas in breast cancer, general anaesthesia is the modality of choice, the paravertebral block remains an interesting technique.

Finally, the postoperative rehabilitation must take into account the pain, which is often marked by a strong psychological component. As post operative pain is commonly intense and predictable, regular measurement of pain is fundamental, with no matter which one among several tools in a repetitive way during hospitalization.

The key word of the pain management is multimodal analgesia, which might remain the gold standard. Post-hysterectomy pain is significant in the 24 to 48 hours after the procedure and necessitates aggressive analgesia which justifies opioids analgesics.

Patient controlled analgesia allows the patient to treat their own pain and satisfaction is increased. The use of local anaesthetic infiltrations or bilateral ilio-inguinal block, for the management of post-operative pain is not routinely use in abdominal hysterectomy but is still useful in patients in whom morphine is contra-indicated.

Spinal anaesthesia appears to be preventative of chronic pain after hysterectomy. On other hand, ovarian cancer surgery is often extensive and requires prolonged laparotomies for which regional anaesthesia is irreplaceable and should be a central element of multimodal analgesia. More over, epidural is supposed to attenuate the metabolic response to surgical stress and has a central role in the early post-operative rehabilitation, like in major visceral surgery. Continuous epidural infusion provides better analgesia than PCEA, but the use of PCEA reduces side-effects of epidural analgesia. In breast surgery, chronic pain has a high incidence of 50-60 %. The paravertebral block is an interesting alternative which can limit the side effects of nausea and vomiting associated with opioids and allows a prolonged duration of analgesia until mobilisation. Continuous infusion of local anaesthetic in the wound via a multi-perforated catheter seems an interesting alternative that is less invasive.

New literature about the influence of pain on tumour progression and the preventative effect of regional anaesthesia on tumour recurrence is now published, but had only been demonstrated on animal models. It is still interesting to keep in mind, considering post-operative analgesia.

In conclusion, anaesthetists and intensivists are frequently involved in the management of patients undergoing gynae-oncology surgery as surgery is a key part of the management. We have discussed the careful preoperative evaluation and choice of anaesthetic technique which takes into account the individual physiological reserve and also neo-adjuvant therapies. In terms of managing postoperative pain the key is in

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a multimodal approach, taking into account the possibility of hyperalgesia and chronic pain and the psychological component associated with this type of pathology.

Introduction Gynaecological cancers are frequently occurring pathologies often affecting relatively young women, whose life expectancy is improved by the evolving treatments of these cancers. The anaesthetist is increasingly faced with these patients. Expert French and American opinion [1] [2] acknowledges the central role surgery plays in the treatment of gynaecological malignancy. Surgery should be as complete as possible.

The treatment of tumours of the breast, endometrial, cervical and ovarian cancer involves invasive surgical techniques, either performed first or after chemotherapy or neo-adjuvant radiotherapy, according to the spread of disease.

The role of the anaesthetist in this context is primarily to conduct a preoperative evaluation and to assess the impact of cancer on the patient who may be extremely undernourished and may have undergone intensive chemotherapy with deleterious side effects. The technique of anaesthesia and analgesia must be adapted for the proposed surgery. Finally, the postoperative rehabilitation of these immunocompromised patients must take into account their pain, which is often marked by a strong psychological component.

I. Preoperative assessment 1. Features common to gynaecological cancers The preoperative evaluation of patients with gynaecological cancers is usually performed during the anaesthesia consultation. Ideally the consultation should be scheduled well in advance to allow for the necessary pre-operative tests to be performed and analysed, in order to assess the impact of cancer as well as pre-existing chronic disease. At the same time one must consider the semiurgency of surgery when requesting additional investigations. In addition to the standard blood tests (full blood count, blood group determination, investigation for coagulopathy) there are some specific associated pathologies to bear in mind; gynaecological malignancies may invade the ureters and cause dilatation of the pelvi-calyceal system. Thus pre-operative investigation should include measurement of creatinine clearance and if necessary imaging of the renal tract.

Furthermore, these cancers all have a significant metastatic potential, including the lungs and spread through the lymphatics. Hence the preoperative assessment of these patients normally includes a chest x-ray to search for lung metastases and a widened mediastinum secondary to mediastinal lymphadenopathy (which can result in compression of the

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tracheo-bronchial tree, vascular axis or cardiac chambers). This latter finding may justify further investigation by contrast CT and an echocardiogram.

Extrinsic compression of the airway can cause tracheal or bronchial problems resulting in life threatening difficulties with intubation as well as ventilation [3] [4]. Because of the risk of liver metastasis, biochemical analysis of liver function is recommended. The preoperative evaluation of the patient must take into account the patientâ&#x20AC;&#x2122;s nutritional status. Indeed, the pre-operative nutritional status may affect the quality of surgical scar closure, wound healing [5], resistance to infection, the occurrence of decubitus ulcers and can lead to impaired muscle function, which may impact on respiratory function post-operatively. This nutritional and metabolic status can be evaluated by weight loss (10 to 20% in 6 months being significant) or more precisely by calculating the BMI (Body Mass Index), where a value of 16 kg/m² or less indicates malnutrition. Only patients with severe malnutrition have an indication for pre-operative enteral nutrition which requires at least 7 days to be effective [6].

Pre-operative investigations include an electrocardiogram systematically performed in patients who are over 50 years. The rest of the cardio-vascular assessment should be determined individually depending on the history of cardiovascular disease and should include NYHA staging for symptoms of dyspnoea.

Paraneoplastics syndromes should be sought out: SIADH (syndrome of inappropriate secretion of anti diuretic hormone) characteristically reveals hyponatraemia, Cushing syndrome hypernatraemia, hyperparathyroidism causes hypercalcemia and Eaton-Lambert syndrome is responsible for a myasthenic picture.

At the end of the anaesthesia consultation an ASA score may be defined, the likelihood of transfusion evaluated. A frank discussion with the patient should be offered (sometimes declined) to allow the patient to discuss details of their perioperative care (pre-medication, vascular access etc.). Specifically this should cover plans for pain relief post-operatively as well as general issues associated with anaesthesia and the possibility of transfusion [2].

2. Different types of gynaecological cancer surgery and their implications for anaesthetists Cancer of the cervix cancer is often detected by the cervical smear and the role of papilloma virus in pathogenesis is becoming increasingly apparent. The patients are mostly young women, the peak incidence is between 48 and 55 years, and usually in good physical condition. They tend to metastasize preferentially to the liver and lungs. Epidermoid or adenocarcinomas (beyond the sub-clinical stages treated at colposcopy) are

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treated according to their TNM staging [7] by vaginal hysterectomy in some cases with aortic and pelvic lymphadenectomy. The skin incision is usually of the Pfannenstiel type, but in certain cases a vaginal hysterectomy with laparoscopy may be considered.

Adenocarcinomas of the endometrium or sarcomas have a different epidemiology with over 90% of women with endometrial cancer over the age of 50 and therefore present a more fragile population. Obesity, combined with the nulliparity and diabetes, are risk factors. Anaesthetic concerns for the obese patient include vascular access, airway and ventilator management and the problem of adjusting dosages. Depending on the volume of the uterus, the invasion of myometrium, adnexae, lymph node involvement, surgery may go as far as total hysterectomy with pelvic and para-aortic lymphadenectomy. Surgery is classically performed abdominally, but the vaginal route may be reserved for frail patients. All efforts are made to prevent dissemination of tumour at operation. Adnexectomy and lymphadenectomy are performed laparascopically.

Tumours of the ovary are mainly primitive epithelial tumours and are the fifth most common neoplasia in women (10/100 000 average incidence in industrialized countries) with a peak incidence among women 60 to 70 years.

This cancer is often diagnosed late with the presence of clinical signs indicating a significant extension in the abdomino-pelvic cavity (ascites, pelvic pain, perception of a pelvic mass, occlusive syndrome). Chest radiography is used to screen for the presence of a pleural effusion that may require a diagnostic puncture. The effusion can be an inflammatory reaction to peritoneal extension of the tumour or carcinomatous pleurisy. Surgery is performed according to the consensus that the goal is complete resection of the lesions (absence of macroscopic residual) since the quantity of residual tumour correlates to survival [8]. Xyphoid-pubic midline laparotomy is the standard procedure for total abdominal hysterectomy with bilateral adnexectomy, omentectomy, appendicectomy and lymph node resection infra-renally with blind peritoneal biopsies. Excision of any other resectable lesions is performed and may include segmentectomy of the bowel. Finally peritoneal lavage is performed for diagnosis and cytolysis of potential tumour [9]. Thus this may constitute extensive and prolonged surgery with the potential for bleeding and post-operative pain in patients who are often elderly. Chemotherapy is almost always with a platinum salt post-operatively. These patients may well undergo a â&#x20AC;&#x2DC;second-lookâ&#x20AC;&#x2122; surgery following chemotherapy, their physical status will then need to be re-evaluated.

Cancer of the vulva and vagina are more rare and tend to require more superficial (although mutilating) surgery. They will not be discussed here.

Breast cancer is the most common female cancers. It affects about one woman in eleven and is responsible for 18% of cancer deaths in women.

Over 50% of cancers are observed after 65 years and nearly 10% before 35 years [10]. Obesity is associated with an increased risk of occurrence of

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breast cancer. Treatment of a hypercholesterolemia should be set at least 7 days before surgery to be effective [11]. The initial surgical treatment is a lumpectomy with contemporaneous histological examination (frozen section) whose aim is to change the course of the intervention. If the nodule is a benign tumour, the intervention is stopped. If the nodule is a carcinoma, an axillary clearance is performed. A mastectomy is performed if the cancer is large or bifocal. The anaesthetic management is simple but may include a semi-sitting position for some mastectomies. This position requires that the tracheal tube is carefully secured and that attention is paid to the position and wellbeing of the arms peri-operatively.

3. Adjunctive therapies and their implications for anaesthesia a. Dose chemotherapy deleterious side effects Cancers of the ovary are very chemosensitive and patients often benefit from adjuvant or neo-treatments, commonly based on platinum salts.

Chemotherapy also has a place in many breast cancers calls for the use of anthracyclines, taxanes, vinorelbine, platinum derivatives, fluorouracil (5FU), and cyclophosphamide. These drugs have important secondary effects as well as drug interactions which may impact on anaesthesia.

Haematologic toxicity is manifested mainly 7 to 14 days after chemotherapy. Neutropenia less than 500/mm3 should delay surgery.

Thrombocytopenia less than 50 000/mm3 justifies a platelet transfusion prior to the operation. Anthracyclines [12] have a cardiac toxicity that can occur early or delayed, depending on its combination with cyclophosphamide or radiotherapy. This cardiotoxicity is increased in the presence of certain risk factors such as extremes of age, gender, combinations of cardiotoxic drugs and with pre-existing cardiovascular disease [13] [14]. The acute clinical picture varies from simple atrial extra-systoles to supraventricular and ventricular tachycardias, and to other repolarization with microvoltage disorders [15]. The most severe form is acute heart failure which appears to arise indepently of the administered dose. The delayed form depends on cumulative doses (550mg/m2 for doxorubicin) and consists of a dilated cardiomyopathy. The search for functional and clinical signs of heart failure should be careful in the anaesthesia consultation and deserves investigation with a 12-lead electrocardiogram, echocardiography and myocardial scintigraphy with evaluation of systolic and diastolic heart. In addition, 5FU can cause coronary spasms leading to coronary heart disease. Nevertheless, it seems that only patients with a history of congestive heart failure are likely to suffer cardiovascular complications in the peri-operative period [16].

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Among the products typically used in gynaecological cancer, the taxanes have acute pulmonary toxicity that manifests in the form of interstitial pneumonitis, a bronchospasm or a pleural effusion, confirming the need for a pre-operative chest X-ray [13]. Alkylating agents and cysplatine are nephrotoxic and the most common pathology is acute tubular necrosis.

Preoperative analysis of serum electrolytes and urea is performed routinely.

Cyclophosphamide produces liver toxicity and investigations for cytolysis should be performed [17].

Signs of neurological toxicity should be documented when epidural analgesia is envisaged. This toxicity may be central (hemiplegia, cerebellar syndrome) for spindle poisons or peripheral (abolition of bone-tendon reflexes, sensitive neuropathy) for platinums, taxanes and vinca-alkaloids [13].

Digestive toxicity with nausea, vomiting and diarrhoea associated with the cytotoxic agents only exists in the hours following administration so should have no effect on airway management at the time of anaesthesia, but it is wise to look out for electrolyte disturbances. b. Corticosteroids Corticosteroids are often used in oncology, particularly in cases of peritoneal carcinomatosis [18]. There is a risk of acute adrenal insufficiency post-operatively requiring dose adjustment and the addition of hydrocortisone peri-operatively. c. The chemo-hyperthermia intra-peritoneal (CHIP) The CHIP is an intense therapy proposed in well-selected cases of localized peritoneal carcinomatosis, i.e. without evidence of visceral extension. An intraperitoneal infusion of chemotherapy combined with hyperthermia (43 째 C) follows immediately after surgical excision of the mass. This technique has severe hemodynamic consequences, and is reserved for those with no preoperative signs of cardiovascular disease.

II. Perioperative techniques and analgesia 1. Pre-emptive analgesia Pre-emptive analgesia is a controversial subject [19]. It prevents sensitisation of both peripheral and central nervous system by the administration before surgery of NSAIDs or local anaesthetics, i.e. treating pain prior to its onset in order to decrease intensity and duration of post-operative pain. It is distinct from preventive analgesia which reduces central sensitization that arises from noxious inputs across the entire perioperative period, beyond the clinical

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Table 1. Pre operative evaluation.

For all patients Interview: search for signs cardiovascular dysfunction, dyspnea, palpitations, chest pain, oedema, hospitalizations for acute pulmonary oedema, cardiovascular history, impaired general condition.

Clinical examination: cardio-pulmonary auscultation, evaluate clinical signs of heart failure right and left, difficult intubation criteria, evaluation of venous access.

Tests: blood group, full blood count with platelets, coagulation profile, serum electrolytes including calcium, magnesium, phosphate, serum creatinine and blood urea, transaminases, total bilirubin free and combined, chest X-ray.

Specific investigations Neurological examination: regional anaesthesia planned and history of neurotoxic chemotherapy Electrocardiogram: if more than 50 years, if clinical signs of CVS disease, cardiovascular history, treatment with anthracyclines Echocardiography, myocardial scintigraphy: cardiovascular history, treatment with anthracyclines, after consulting cardiological Respiratory function tests: clinical, taxanes Nutritional assessment: signs of malnutrition

duration of action of the target preventive drug. One good example is ketamine, whose analgesic effect lasts very long, beyond 5 half lives. Both strategies prevent hyperalgesia. In a meta-analysis on 66 studies of general surgery, Ong et al. found that epidural analgesia resulted in consistent improvement on analgesic consumption, time of first rescue analgesic request, post-operative pain scores [20]. Local anaesthetic wound infiltration and NSAID administration improved analgesic consumption and time of first rescue analgesic request but not post-operative pain scores. The least proof of efficacy was found for opioids and systemic NMDA antagonist. However, ketamine, whose anti-NMDA (N-methyl-D-aspartate) receptor action is well known, appears, in a systematic review of the literature, as an effective prevention for 58% of patients in non-gynaecological surgery [21].

Regarding gynaecologic surgery, certain non-randomized studies reported 40% savings morphine post-operative [22] while another randomized study revealed no beneficial effect on the administration of ketamine before the incision of hysterectomies [23]. Another molecule, gabapentin [24], has analgesic properties in both acute and chronic pain. Oral premedication with gabapentin reduces morphine consumption post-operatively through a central mechanism of action by activation of spinal descending noradrenergic tracts [25]. Gabapentin also decreases hyperalgesia and the risk of subsequent chronic pain through its calcium channel antagonist effect.

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2. Drug interactions between cytotoxic drugs and anaesthetic agents Anaesthesia of such patients may be complicated by the underlying patient state and their chemotherapy. Firstly, peri-operative monitoring will be adapted according to any cardiovascular history of the patient. No particular anaesthetic technique has demonstrated its superiority in terms of reducing occurrence of cardiovascular events per-operatively [16]. However there are some precautions with the use of anesthetic drugs. Nitrous oxide should be avoided as it may potentiate the effects of cytotoxic chemotherapy on bone marrow aplasia. Halogenated agents should be used cautiously in case of hepatotoxicity secondary to chemotherapy, and isoflurane may possibly lengthen QT segment of patients on anthracyclines. Local anesthetics also potentiate the cardiac toxicity of anthracyclines, and less toxic amides should be prefered. Cyclophosphamide has an anticholinesterase effect for up to one month after treatment, which can enhance the effect of succinylcholine [26]. Altogether it is preferable to employ curares metabolized through Hoffmann degradation (as atracurium and cisatracurium) and monitor their effects. In case of kidney failure or nephrotoxic chemotherapy, it is desirable to ensure proper hydration, avoid use of nephrotoxic drugs, and to adjust the doses of drugs according to renal function including antibiotics. Finally, the benefits and risks of regional anaesthesia should be discussed in case of chemotherapy induced neurological toxicity.

3. Anaesthesia and analgesia techniques according to type of surgery The treatment of cancer of the cervix and endometrium is total hysterectomy which can be performed as an open procedure or vaginally.

Several studies show a high level of postoperative pain following hysterectomy, especially by laparotomy [27] [28] [29]. Pain is at its most intense in the first 48 hours after the operation. Many articles seek to highlight the influence of anaesthesia technique on post-operative pain. In a randomized study on patients undergoing abdominal hysterectomy, the use of a spinal with bupivacaine alone before inducing general anaesthesia, can reduce the consumption of morphine PCA in patients without reducing its sides effects [30]. In the same way, spinal anaesthesia can reduce the consumption of morphine following vaginal hysterectomy but the difference is only significant for the first 12 hours in a Canadian study [31]. Intrathecal morphine requires careful monitoring to detect the occurrence of respiratory

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depression, but an intrathecal dose of less than 200 micrograms does not change the respiratory risk compared with other traditional routes of morphine administration. In conclusion, spinal or general anaesthesia may be performed for hysterectomy to resect neoplasia. Combined spinal-epidural anaesthesia with post-operative use of the epidural catheter seems excessive given the intensity of post-operative pain but can be used. Studies on the early rehabilitation after colonic surgery show benefit of the use of epidural versus general anaesthesia on post-operative recovery. However, the beneficial role that epidural analgesia provides is widely reduced when part of a broader early rehabilitation program (fast track surgery) [32]. Thus the risk / benefit balance does not appear to be in favor of epidural anesthesia for surgery for cancer of the uterus.

Surgical treatment of ovarian cancer is very invasive and it requires a laparotomy often with midline incision extending above the umbilicus. This results in painful post-operative rehabilitation similar to upper GI surgery.

This explains why perioperative management of ovarian cancers is based on protocols for post-operative rehabilitation of colon cancer surgery [33].

Intrathecal morphine is sometimes used and produces analgesia of good quality but of too short duration (24 hours). The recommended dose of morphine is about 0.1 to 0.3 mg. By epidural or intrathecal route, morphine does not cause sympathetic or motor block. With the highly lipid-soluble sufentanil or fentanyl, onset and duration of action is much shorter than for morphine (from 3-6hrs compared to 12-24h). The duration of intrathecal analgesia is limited to the duration of the product used. The addition of adrenaline can be used to increase duration of analgesia without significantly increasing side effects [34]. Clonidine has similar properties but increases the risk of sedation and hypotension [35]. Side effects such as respiratory depression, nausea and urinary retention, are dose-dependent which also justifies the use of the lowest effective dose possible. The same effects are found for the use of opiates by epidural route but with a lower frequency [36]. Thus the use of epidural anaesthesia started perioperatively appears to be the technique of choice. Epidural analgesia should combine an opioid and a local anaesthetic. The site of punction should be low thoracic with high concentration of local anaesthetic to reduce motor block and hypotension, compare to lumbar epidural which will need bigger volume for the same level of anaesthesia. It must often be accompanied by general anaesthesia because the first step of the procedure often involves laparoscopy, and general anaesthesia is indicated for patient comfort for cases where surgery may be prolonged.

Optimal treatment for ovarian cancer peritoneal deposits is not well established with weak responses to second line chemotherapy or beyond.

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In this context cytoreducutive surgery associated with peritoneal chemotherapy has been proposed [37]. These operations are long (8 hours on average), invasive (xyphoid-pubic incision) and extremely painful postoperatively. These patients benefit from epidural during the perioperative period. Perioperative management is fairly standard [38], and includes large bore venous access, invasive arterial monitoring, central venous pressure trace and cardiac output (usually by oesophageal Doppler or transoesophageal echocardiography). Such invasive monitoring is warranted because of the haemodynamic variations created by a large third space fluid compartment and large insensible losses secondary to intestinal resection.

Hypotensive episodes limit the perioperative use of the epidural.

Hyperthermia itself is responsible for an increase in insensible losses, an augmentation of microvascular permeability and hypoalbuminaemia, and a reduction in systemic vascular resistance, all of which increase perioperative hypotension. These effects can be offset by carefully guided filling. Both bladder and oesophageal temperatures should be monitored. The liver is also sensitive to hyperthermia which may result in altered pharmacokinetics of anaesthetic agents, notably shortening duration of neuromuscular blockade with vecuronium. A transitory increase in creatinine is expected and may also be offset by maintenance of renal perfusion intraoperatively as well as encouraging diuresis. In addition the detrimental effects of the chemotherapy on diaphragmatic excursion can be countered by using ventilation with PEEP. Finally, it is important to watch out for a coagulopathy secondary to the thermal insults especially at the end of the procedure.

With breast cancer, general anaesthesia is the modality of choice. This is due to the location of the surgery which would require a thoracic epidural if an awake technique were considered, which is thought to be too invasive and uncomfortable for the patient to justify its routine use. Analgesia is usually provided by a multimodal combination of non opioids and morphine.

Paravertebral block may provide very potent anaesthesia [39] but is an invasive technique with risk of pneumothorax (1% in the literature) and with a high failure rate in adults (10.7%) [40] and thus is usually used when morphine is contraindicated. Local anaesthetic creams may also be of use when applied before surgery (See below).

4. Perioperative fluid therapy Patients are required to be fasted for 6 hours for solids prior to elective surgery to ensure an empty stomach. Many studies have shown a benefit from allowing clear liquids to be drunk up until two hours before surgery in terms of reducing postoperative complications [41] [42]. It is imperative to find a

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balance between a restrictive fluid therapy which reduces cardiopulmonary complications which may result in hypovolaemia and a liberal fluid strategy which reduces nausea and vomiting [43] but at the same time may increase hyperchloraemic acidosis [44] [45] and post-operative morbidity and hospital stay in major abdominal surgery [46]. The optimal strategy is â&#x20AC;&#x153;goal directed fluid administrationâ&#x20AC;? whereby cardiac index and oxygen delivery are targeted using colloids to decrease the amount of fluids infused [47].

5. Prophylactic antibiotics Antibiotic therapy should be adjusted to local microbiological cover as well as to suit the type of surgery. The principal agents are penicillins and usually amoxicillin in combination with clavulanic acid. Patients that have a history of recent admissions to hospital may have nosocomial pathogens and adjusting antibiotics accordingly may be required.

6. Cell salvage Autotransfusion of patientsâ&#x20AC;&#x2122; own blood retrieved from the perioperative fields is a controversial issue in cancer surgery as it theoretically exposes the patient to the risk of reinjecting tumour cells into the circulation. There is no rigorous randomised controlled trial in the literature but a review [48] demonstrated that in all of the studies (theoretical and clinical) tumour cells are found in the salvaged blood and in the reinjectate. However, the use of the Cell Saver in six clinical studies with 20 to 55 patients each has not led to dissemination after a 12-60 months follow up [48]. The use of a leucocyte filter significantly reduces the quantity of tumour cells in the salvaged blood whilst irradiation of the blood with 50 Gy prevents further cellular division. At present routine use of the cell saver is not advised with the exception of unexpected haemorrhagic cancer surgery, and then with the use of a leucocyte filter.

III. Postoperative management 1. Pain As post operative pain is commonly intense and predictable [49], post operative care must at first take care of pain relief. A fast recovery is essential to reduce complications related to surgery and prolonged bed-rest and to reduce postoperative morbidity [50]. Gynaecological cancer surgery results in pain with a psychological component [51]. Regular autoevaluation of pain is fundamental to understanding and managing postoperative pain. Pain can be measured using scales which can be verbally reported or expressed by a mark on a line 100mm long (visual analogue scale, VAS). Pain intensity can

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be recorded by best-fit description (no pain, moderate, strong, severe, excruciating) or more precisely using a verbally reported score of 0 to 10 (numeric reporting scale NRS, verbal reporting scaleVRS) where 10 is defined as the worst ever experienced pain and 0 as no pain. The advantage of using continous scales is that it is more precise in registering pain responses to therapy (for example addition of a non-steroidal antiinflammatory alone is unlikely to change a descriptive pain from one category to the next, but may commonly result in a demonstrable change in numeric reporting scale or VAS) [52]. The most important thing is to use these tools systematically and in a repetitive way during hospitalization.

It should be noticed that there is a large inter-individual variability in pain which also follows a diurnal course (maximal in the morning and evening) [53]. This should be taken into account when managing pain.

Gabapentin is used more and more as part of a pre-medication, and has been used for control of pain after hysterectomy [54] where it has an opioid reducing action but at the price of increasing sedation. Multimodal analgesia with two or three different non-opioid analgesics will limit the side effects of each product (for example anti-inflammatory and paracetamol). Non-steroidal antiinflammatories should be given provided there are no concerns about renal function or coagulation. The pharmacokinetics of these agents mean that they are given orally pre-operatively and as soon as the oral route becomes possible postoperatively [55]. Treatment of post-operative pain continues in the anaesthetic recovery room and is usually based on morphine titration according to local protocol [56] which leads to rapid establishment of analgesia. The posology of morphine must be adapted according to the patientâ&#x20AC;&#x2122;s renal function especially considering that some will require prolonged opioid therapy.

A novel concept is emerging in the literature of the influence of pain on tumour progression and of the preventative effect of regional anaesthesia on tumour recurrence [57] [58] [59] [60]. These effects have been well demonstrated on animal models while human studies, although encouraging, have still many limitations to conclusively prove a benefit [61]. a. Specific to hysterectomy Post-hysterectomy pain is significant in the 24 to 48 hours after the procedure and necessitates aggressive multimodal analgesia [29] including opioid analgesics. As before, morphine can be given by the intrathecal route, orally or parenterally (sub-cutaneous, intra-muscular) or intravenously using a controlled administration system (patient-controlled analgesia, PCA). The speed of action and its bioavailability depend on route of administration. By using intravenous titration, one can rapidly establish analgesia on an individual basis [56] after which therapy can be continued by PCA or via

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intermittent injection. The latter is probably the most simple way to provide analgesia as long as the injections are performed regularly [62]. However this technique may be limited by pain between injections, a delay in action and a variable absorption in the post-operative period. The reduced satisfaction experienced with this technique is probably due to a mis-evaluation of the pain intensity of the patient by the nursing staff [63]. Patient controlled analgesia allows the patient to treat their own pain according to parameters set by the doctor. This method allows instant analgesia and relies far less on the immediate presence of nursing staff. With this technique the patient will tolerate higher pain scores as she is in control of her own analgesia [64] and satisfaction is increased [65]. It has been shown that PCA increases the frequency of urinary retention in the first 24-hours after pelvic surgery [66].

Therefore a urinary catheter is usually required for the first 24-72 hours after hysterectomy.

If epidural or combined spinal-epidural anaesthesia duraing surgery is used, then the epidural is used post-operatively for analgesia, which is extremely efficient for controlling pain on rest and on movement. The use of a patient-controlled epidural analgesia program has been shown to reduce secondary effects such as motor block and nausea and vomiting compared with a continuous infusion [67]. There probably also exists a role for preemptive epidural analgesia followed by general anaesthesia for the control of immune response in the post-operative period [58].

For several years there has been increasing interest in the use of local anaesthetic infiltrations for the management of post-operative pain [68].

There are numerous studies looking at the beneficial effects of local anaesthetic infiltration. The large diversity of routes of administration (wall blocks, sub-cutaneous infiltration by catheter, sub-peritoneal route, continuous infusion and boluses) and the various products used make the interpretation of these results difficult. Specifically for abdominal hysterectomies it seems that the beneficial effect on the VAS is not large enough to justify routine use of infiltration catheters [69] [70] [71] [72]. In a double-blind study of patients undergoing abdominal hysterectomy the morphine sparing effect of parietally infiltrated bupivacaine is only significant in the first 4 hours after surgery compared with a placebo control [73]. Numerous placebo-controlled studies have demonstrated that parietal infiltration alone of local anaesthetic after hysterectomy has no analgesic role [72] [74] [75] [76]. However, if this infiltration is performed preemptively then 8 hours morphine sparing effect is noted compared with placebo [77].

On the other hand, some technics employing local anaesthetics have proven their advantages. Bilateral ilio-inguinal block has been shown to lead to reduced morphine consumption for 2 days following surgery but disappointingly

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this is not associated with any reduction in morphine related side effects [78].

In laparoscopic cases, instillation of local anaesthetic directly on the subdiaphragmatic and operative sites by the surgeon is a simple technique. The morphine reducing effect is significant in the first 24 hours [79]. To conclude, it seems still useful to remain aware of these developing techniques and they certainly have a role in combination with non opioids drugs.

Chronic pain affects 5-32% of women undergoing hysterectomy for nonneoplasia pathology [80]. The mechanisms underlying this type of pain are not entirely elucidated but include factors triggering central nervous system sensitization and hyperalgesia. It is associated with intra-operative nerve lesions and an inflammatory response. Risk factors include the intensity of pain pre and post-operatively, as well as the genetic and psychosocial profile.

It is apparent that the psycho-affective dimension of cancer surgery places the patients at high risk of developing chronic pain. Spinal anaesthesia appears to be preventative of chronic pain using multivariate analysis in one nonrandomised study [81]. In the only available randomised trial [Sprung, 2006 #48], it seems that the use of intrathecal morphine decreases pain two weeks after vaginal hysterectomy, however, without effect on either length of hospitalization or patients' postoperative functional status. It has also been shown that epidural anaesthesia reduces chronic pain in major surgery in a non-randomised trial [82]. b. Specific to ovarian cancer Ovarian cancer surgery is often extensive and requires prolonged laparotomies for which regional anaesthesia is irreplaceable. In a metaanalysis of all the randomised studies comparing the efficacity of epidurals and PCA morphine on postoperative analgesia, epidurals are demonstrably superior at all stages [67]. It is important to realise that continuous epidural infusion provides better analgesia than PCEA, and that the use of PCEA reduces drug consumption and side-effects of epidural analgesia. Sole agent use of local anaesthetics in the epidural infusate has been shown to be superior to opioids alone via the same route [67]. However, the combination of an opioid with a local anaesthetic agent (bupivacaine or ropivacaine) is the best means of increasing analgesia and of reducing tachyphylaxis which inevitably arrives with local anaesthetics as sole agents after 12-36 hours of administration. It would appear that there is a real benefit in establishing epidural analgesia pre-emptively before incision [83], by associating local anaesthetic agent and opioid, which will decrease post operative pain scores and systemic morphine consumption. Combinations of local anaesthetic and opioid demonstrate a synergistic effect [84], allowing for a reduction in dose

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of both products. Such an epidural mixture allows excellent analgesia to run for several days in the post-operative period. In abdominal surgery numerous studies have demonstrated the superiority of the epidural route for analgesia [85] and for attenuating the metabolic response to surgical stress [86] which translates into a significantly reduced operative risk [87]. It also allows a faster recovery and better comfort for the patients [88]. The use of epidural opioids excludes opioids being administered by any other route according to the duration of action epidurally. However, duration of action may be short and patients may start to suffer well before reaching the mean duration time of the product. It is therefore essential to anticipate with an emergency prescription of analgesic which may include morphine injection. This is also best avoided by regular systemic administration of non opioids added to the epidural regimen. This is the method of analgesia described in the largest series of early post-operative rehabilitation for major visceral surgery [89].

This multimodal approach influences recovery and morbidity for patients in conjunction with simple measures which do not have any impact individually [32]. Numerous post-operative techniques are perpetuated by habit and go against current evidence such as the continued use of gastric tubes, abdominal drains, urinary catheters, dietary restriction and bedrest. Gastric tubes can increase chest infection rates and should not be maintained in place after gastrointestinal resection. It is now universally agreed that the resumption of oral feeding should be achieved as soon as possible [90], above all in the context of neoplasia and malnutrition. Epidural analgesia allows for early mobilisation in giving high quality analgesia on movement as well as at rest. The urinary catheter should not be a barrier to early mobilisation with epidural analgesia and can be removed expectantly at 24 hours. Early mobilisation counters the negative effect of bedrest which increase loss of muscle mass, affects respiratory function and predisposes to thromboembolism.

Mobilisation will be facilitated by using low concentrations or low volumes in epidural, which limit motor block.

Finally, the use of regional analgesia does not necessitate abandoning other analgesics but on the contrary, regional anaesthesia should be the central element of a multimodal analgesia [91]. This multimodal analgesia can employ numerous molecules having additive or synergistic actions thus reducing opioid consumption and opioid side effects. Various adjuvants can be used separately or combined, and should be started from the beginning of the procedure: paracetamol, nefopam, NSAIDS, ketamine, clonidine, gabapentin, magnesium, intravenous lidocaine [92] [32] [93]. Where epidural analgesia is not used, a multi-holed catheter inserted by the surgeon just after peritoneal closure may lead to satisfactory analgesia, as apparent in studies of visceral surgery [94]. This differs from hysterectomy because the wound is

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larger than the pfannenstiel incision and vertical which is supposed to be painful especially during mobilisations. c. Breast surgery A wide range of surgical procedures may be encountered. For simple, minor procedures, analgesia is managed by oral non-opioid combinations.

For simple mastectomy without lymph node removal, Fassoulaki et al [95] have shown the analgesic efficiency of local anaesthetic cream (EMLA) applied to the surgical site before surgery. The cream is applied all around the surgical zone pre-operatively by the nurse preparing the patient and is continued for 4 days post-operatively. Above all this study showed that this technique can significantly reduce chronic pain. Chronic pain has a high incidence of 50-60 % following the usual management of these cases, but was reduced to 22% in this study. These results need to be confirmed but are very promising at this stage. In extensive breast surgery (radical mastectomy), regional anaesthetic techniques are useful and are associated with better analgesia than PCA [96]. Perioperative use of an epidural infusion also results in less blood loss which adds another advantage to these techniques. Placement of a paravertebral catheter is an interesting alternative which can limit the side effects of nausea and vomiting associated with opioids and allows a prolonged duration of analgesia until mobilisation [40] [97]. These analgesic techniques are very effective but their use is still limited in breast surgery. Indeed paravertebral blocks are an expert technique and as breast surgery has becomes less invasive in the last few years, the perceived benefit of performing these complex and invasive procedures is lesser. The continuous infusion of local anaesthetic via a muti-perforated catheter in the wound seems an interesting alternative that is less invasive and equally effective compared to a â&#x20AC;&#x2DC;single-shotâ&#x20AC;&#x2122; paravertebral technique [98].

2. Deep vein thrombosis (DVT) and pulmonary embolism (PE) The association between cancer and hypercoaguability is well known, due to certain factor growth (V, VIII, IX, XI), disseminated intravascular coagulation (DIC) and a reduction in antithrombotic factors (protein C, protein S, and antithrombin). Thromboembolic risk may also be raised by the simultaneous administration of chemotherapy and hormone therapy.

Moreover, cancer surgeries may be prolonged and intraperitoneal, both factors which increase thrombosis. The incidence of postoperative DVT, clinically diagnosed, is 15-28% according to studies. Prevention of postoperative DVT includes graduated compression stockings (established

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pre-operatively) as well as low molecular weight thromboprophylaxis for four weeks, eg. 40mg enoxaprine sub-cutaneously [99] started 6 to 8 hours after surgery.

3. Antibiotics Patients who have had chemotherapy pre-operatively should be considered as immunocompromised and may receive 48 hours of prolonged antibioprophylaxis.

4. Prevention of postoperative nausea and vomiting (PONV) There is no evidence of an increased incidence of nausea and vomiting in patients on chemotherapy [100]. Thus there are no particular preventative measures to be taken in the context of prevention of nausea and vomiting in this group. Factors that pre-dispose to PONV are well-known and are included in the Apfel score; female sex, non smoker, history of travel sickness and requiring morphine postoperatively. It is notable that most patients undergoing gynaeoncology surgery will have a score of at least 2, i.e. a 40% risk of nausea-vomiting, which justifies the use of a preventative therapy, including at least antiemetic drug. This regimen should be based on a multimodal approach if risks factors are found.

5. Severe malnutrition Artificial nutrition in the postoperative period is indicated for the malnourished, if it is unlikely that they will be able to recover a diet that covers at least 60% of their nutritional requirements within a week of their operation, or in the case of a complication that results in a prolonged period of starvation or in the event of hypermetabolism [101]. The route should be enteral whenever possible. Traditionally, post-operative oral intake is withheld until the return of bowel function in a way to avoid vomiting, pneumonia, wound dehiscence and anastomotic leakage. In gastrointestinal surgery there is a trend for commencing to feed from the first post-operative day before the return of bowel function. It seems logical to do the same for gynaecological surgery all the more so if there has been non surgical disruption of the digestive tract. The idea is to reduce length of stay and postoperative complications associated with extensive surgery [102] [103] [104].

This notion is confirmed in a review of the literature published in 2007 [105], on randomised controlled trials that compared the effect of early versus delayed initiation of oral intake of food and fluids after major abdominal

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gynaecologic surgery. Early feeding was defined as having oral intake within the first 24 hours after surgery. It seems that early feeding is safe, however associated with the increased risk of nausea, and a trend to reduce length of hospital stay in four studies. Empirically, patientâ&#x20AC;&#x2122;s satisfaction should be increased, as long as this approach is individualised, but this hasnâ&#x20AC;&#x2122;t been studied so far.

6. Effect on quality of life of multiple excisions The management of patients undergoing gynae-oncology surgery includes evaluation of the quality of life after surgery, and measures the change in quality of life that are procedure specific eg. splenectomy, multiple gastrointestinal resections and short-bowel syndrome.

7. Specific to intraperitoneal chemotherapy The post operative period is often marked by the occurrence of respiratory complications of variable degree [37] [38] necessitating obligatory monitoring in an intensive care unit. Ileus is common and of variable duration, early feeding being assured by jejunostomy. Finally, the surveillance for thrombocytopenia must not be forgotten. Often platelet count reaches its nadir at 5 days, which may affect the timing of withdrawal of the epidural catheter.

Conclusion Anaesthetists and intensivists are frequently involved in the management of patients undergoing gynae-oncology surgery as surgery is a key part of the management. This surgery is sometimes performed during a window of a course of chemotherapy or radiotherapy. We have discussed the careful preoperative evaluation and choice of anaesthetic technique which takes into account the individual physiological reserve and also neoadjuvant therapies. In terms of managing postoperative pain the key is in a multimodal approach. In fact all the analgesic techniques, infiltration, regional, systemic, pre emptive or preventive have specific advantages and disadvantages. These must be balanced against the intensity of postoperative pain and the possibility of hyperalgesia and chronic pain. As a result it is the combination of techniques and analgesics, with respect to their contra-indications, which provides the key for the optimal management of pain in these patients, without forgetting the psychological component associated with this type of pathology.

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