J Gastrointest Canc DOI 10.1007/s12029-010-9207-3
ORIGINAL RESEARCH
Management Strategies for Locoregional Recurrence in Early-Stage Gastric Cancer: Retrospective Analysis and Comprehensive Literature Review Ahmed Salem & Sameh Hashem & Layth Y. I. Mula-Hussain & Issa Mohammed & Ala’a Nour & Wael Shelpai & Faiez Daoud & Basem Morcos & Yasser Yamin & Imad Jaradat & Jamal Khader & Abdelatief Almousa
# Springer Science+Business Media, LLC 2010
Abstract Objective To present a comprehensive account and literature review addressing the anatomical distribution, natural history, and management strategies for locoregional recurrence in early-stage gastric cancer (EGC). Patients and methods Retrospective chart review of patients presenting with EGC recurrence at King Hussein Cancer Center (Amman, Jordan) between July 2006 and May 2009. A literature review of publications addressing recurrence following surgery for EGC was undertaken via a systematic search of PUBMED database and National Comprehensive Cancer Network (NCCN) guideline updates. Results Seventeen patients presented with EGC, three of whom (17.6%) were pathologically staged as T2N1 [1/33 lymph nodes (LNs)], T1N0, and T1N0 were afflicted by recurrence following R0 partial gastrectomy. Literature
review yielded 18 studies specifically addressing recurrence in EGC. Several management strategies have been proposed for isolated recurrence following gastrectomy in EGC. NCCN clinical practice guideline updates do not take into consideration whether the recurrence is isolated or widespread and whether the initial stage is early or advanced. Conclusions While acknowledging the limitations of this study, including the small sample size and the short follow-up period, it appears clear that oncologic treatment is possible for EGC recurrence, particularly, in patients with isolated relapse. Guideline updates should differentiate between management strategies suitable for recurrence occurring in early versus advanced initial cancer stage.
A. Salem : S. Hashem : L. Y. I. Mula-Hussain : I. Mohammed : A. Nour : I. Jaradat : J. Khader : A. Almousa (*) Department of Radiation Oncology, King Hussein Cancer Center, Amman, Jordan e-mail: aalmousa@khcc.jo
Introduction
W. Shelpai Clinical Research and Cancer Registry, King Hussein Cancer Center, Amman, Jordan F. Daoud : B. Morcos Department of Surgical Oncology, King Hussein Cancer Center, Amman, Jordan Y. Yamin Department of Medical Oncology, King Hussein Cancer Center, Amman, Jordan
Keywords Gastric cancer . Recurrence . Radiotherapy . Surgery . Chemotherapy
Gastric adenocarcinoma is currently the fourth most common cancer worldwide with approximately 930,000 new cases and 700,000 deaths per year [1, 2]. Despite the declining incidence in the west, stomach cancer is still considered a significant health challenge because diagnosis is often made at an advanced stage with nodal involvement and/or extension to adjacent organs [3]. Early-stage disease confers excellent long-term outcome if properly treated [4], with surgery being the sole curative modality [5]. Local recurrence is estimated to occur in 30–80% of patients with advanced stage cancer [3]. The incidence, natural history, anatomical distribution and therapeutic modalities for recurrence following curative surgery in early-stage gastric
Alive with disease 18 Observation Asymptomatic Poorly differentiated histology, LVI 30
F
f
2
3
42
pT2N1M0
Partial Gastrectomy and adjuvant CRT (MacDonald protocol)
Regional LNs (Mesentric LNs)
Yes 33
M 1
50
pT1N0M0
Distal Gastrectomy
Regional LNs (Para-aortic LNs)
No
Alive with disease 12 None (refused treatment) Epigastric pain
28 Completion Gasterctomy Epigastric pain
LVI Positive tumor margin not detected by pathologist Poorly differentiated histology Yes 9 Anastomotic site
Location of recurrence Treatment of 1º tumor 1º tumor stage Age Sex
“Early gastric cancer” is a term used infrequently to define tumors which are potentially “curable” by means of surgical resection only [7]. Generally, this term encompasses T1 tumors which are located within the mucosa (T1a) or reach the submucosa (T1b) [8]; however, any potentially curable
Number
Definition of early gastric cancer and the incidence of recurrence
Table 1 Patient characters and outcome
Seventeen patients presented with EGC (7.2%); three of whom (17.6%) pathologically staged as T2N1 [1/33 lymph nodes (LNs)], T1N0 and T1N0 were afflicted by recurrence following R0 partial gastrectomy (Table 1). The first patient received adjuvant chemoradiation according to MacDonald’s protocol [6]. Time to recurrence was 30, 33, and 9 months, respectively. Recurrence was in the regional LNs (mesenteric and para-aortic) in first two patients and in the anastomotic surgical bed in the third. Patients with nodal recurrence opted not to take the proposed chemotherapeutic regimens consequent to informed decision and remain alive with disease 18 and 12 months into follow-up, respectively. The patient with anastomotic recurrence underwent completion gastrectomy and remained alive and free from disease 28 months into follow-up. Literature review yielded 18 studies specifically addressing recurrence in EGC.
Time to recurrence (months)
Results
Partial Gastrectomy
Pathological confirmation of recurrence
Possible cause
Presenting symptom
Treatment of recurrence
Between July 2006 and May 2009, 237 patients with gastric carcinoma were treated at King Hussein Cancer Center (Amman, Jordan). Records of patients with early gastric adenocarcinoma (T1 and 2, N1) were retrospectively reviewed following acquisition of Institutional Review Board approval with special reference to the incidence, location and management of cancer recurrence. Tumors located at the gastroesophageal junction were excluded from this study. A review of literature addressing recurrence following surgery for EGC was undertaken via a systematic search of PUBMED database for English-language articles and abstracts published from July 1987 and National Comprehensive Cancer Network (NCCN) guideline updates. Three abstracts in Japanese and one abstract in Korean addressing the role of surgery and chemotherapy in recurrent gastric cancer were included in this review.
pT1N0M0
Patients and methods
35
Follow-up from recurrence (months)
Outcome
cancer (EGC), however, remain unknown. We present a detailed and comprehensive account of the therapeutic regimens and disease outcome of this poorly reported entity.
Alive NED
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gastric tumor could be included in this definition. Nodal metastasis (N1, 2)—once synonymous with advanced gastric cancer—does not always preclude curative resection. The incidence of EGC has climbed in recent decades consequent to developments in diagnostic approaches [7]. In Japan, screening programs have enabled detection of gastric cancer at very early stages [9]. In comparison, EGC still constitutes less than 10% of gastric cancer cases in the West [8]. Surgical resection is the mainstay of treatment for gastric adenocarcinoma [10]. Less aggressive therapeutic alternatives for EGC, in addition, include endoscopic mucosal resection, wedge resection, and laparoscopic-assisted gastrectomy [11]. The rate of recurrence in EGC treated by D2 gastrectomy is reported to vary between 1.3% to 12.2% [7, 12–17] (Table 2). Median time to recurrence is 16 months, and 82% of patients recur in the first 2 years after surgical treatment [18]. Potential sites for recurrence include the surgical bed, remnant stomach, anastomotic staple line, duodenal stump, and regional LNs [3]. The incidence of lymphogenous recurrence is related to the extent of LN dissection performed [19]. Hematogenous spread, however, is probably the most common pattern of recurrence [12]. In general, gastric cancer recurrence was thought to represent advanced cancer progression [19]. In reality, successful oncologic treatment is often possible, particularly, in patients with isolated relapse of early-stage disease. There are, however, limited reports addressing the outcome, therapeutic regimen, and prognostic factors in such patients [20].
Standard management of early-stage gastric and esophagogastric junction tumors Standard treatment for EGC is complete surgical resection (subtotal or total gastrectomy), D1 or D2 LN dissection, followed by reconstruction with gastrojejunostomy. In the same manner, surgical resection is the mainstay treatment for early esophagogastric junction tumors; however, the required
extent of surgical resection is dependent on the anatomic location of the primary tumor. According to the AEG classification; adenocarcinomas of the distal esophagus (AEG type I) are distinguished from tumors of the anatomical cardia (AEG type II) and subcardiac region (AEG type III). Total gastrectomy with resection of the distal esophagus is a suitable approach for AEG type II and III tumors [21]. Siewert and colleagues [22] confirm such recommendations via reporting the surgical experience of 1,002 patients with adenocarcinoma of the esophagogastric junction. Esophagectomy does not appear to offer any survival benefit over extended gastrectomy in these patients and is associated with significantly higher morbidity [23]. In comparison, AEG type I tumors require an esophagectomy for potential cure [21].
Diagnostic alternatives for detection of recurrence Contrast-enhanced computed tomography (CT) remains the standard radiological method for detection of gastric cancer recurrence irrespective of initial tumor stage. Park et al. [24] suggested a potential role of positron emission tomography (PET)/CT in detection of gastric cancer recurrence; however, more comprehensive reports narrate that the addition of PET/CT does not appear to increase the diagnostic accuracy of contrast-enhanced CT in the detection of recurred gastric malignancy [1]. Definitive diagnosis requires pathological confirmation through CT- or ultrasound-guided needle biopsy and/or reoperation. Even though such approaches often prove to be technically demanding consequent to lesion size, depth, and proximity to great vessels and/or organs, they remain mandatory prior to the delivery of radical therapy.
Isolated versus widespread recurrence in advanced versus early gastric cancer It is estimated that 5% of patients with EGC die from recurrent disease [25]. Survival in our patients contrasts
Table 2 The incidence and location of recurrence in six large EGC series Study
Year
Number of patients
Sano et al. [14]
1993
1,486
Kim et al. [7] Folli et al. [13] Wu et al. [15] Habu et al. [16] Ichiyoshi et al. [17]
2009 1995 2008 1987 1990
1,786 223 245 304 503
Clinical stage
EGC (Stages I–IIc) EGC EGC EGC EGC EGC
Pattern of failure after gastrectomy Total failure
Nodal
20 (1.3%)
4 (20%)
32 22 30 6 17
9 8 – 2 3
(1.79%) (9.9%) (12.24%) (1.97%) (3.4%)
(28.1%) (36.4%) (33.3%) (17.6%)
Nodal and peritoneal
Peritoneal Only
Anastomotic/ gastric stump
Distant
1 (5%)
Not mentioned
13 (65%)
10 (31.3%)
1 (3.1%)
4 (13.3%)
2 (6.7%)
Not mentioned Not mentioned 16 (53.3%)
12 (37.5%) 14 (63.6%) 8 (26.7%) 4 (66.7%) 9 (53%)
2 (10%)
–
–
5 (29.4%)
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median survival following recurrence in advanced gastric cancer which is estimated at 5 months [12, 26]. Similarly, prior reports have narrated that patients with isolated recurrence have a survival rate that is superior to those who presented with multiple or widespread dissemination [20]. More specifically, Park et al. [27] demonstrated superior survival in patients with isolated para-aortic LN (PALN) metastasis than those whose recurrence was located elsewhere. Such observations provide conclusive affirmation that isolated recurrence in EGC more closely represents indolent disease rather than advanced cancer progression.
patterns [5, 28, 29]. On one hand, intestinal-type adenocarcinomas are more prone to hepatic metastases, while diffuse-type adenocarcinomas more frequently result in peritoneal dissemination [2]. Micrometastasis is a possible explanation for recurrence in node-negative EGC [12]. Multiple lymphatic pathways make it difficult to perform complete nodal dissection during gastrectomy providing a potential haven for recurrence in the regional LNs and metastasis elsewhere [30]. On the other hand, vascular invasion of submucosal cancer cells might be implicated as a possible mechanism for distant recurrence [12].
Management alternatives Prevention of recurrence Subsequent to inherent difficulties in successfully treating gastric recurrence, emphasis has currently been focused on presenting therapeutic alternatives that can potentially prevent recurrence of gastric malignancy. Extensive D2 lymphadenectomy improves staging accuracy and might reduce locoregional relapse, particularly, in the lymphatic basins [2]. This is especially true for patients with pT1–2 tumors; a statistically significant negative correlation between the number of dissected LNs and recurrence rate is consistently being reported [25]. Preoperative chemoradiation can decrease the risk of peritoneal seedling at surgery [26]; however, utilization of neo-adjuvant chemoradiation in EGC has not been previously reported. The benefit of adjuvant chemoradiation on locoregional control in advanced gastric cancer is undeniable [2]; nonetheless, postoperative chemoradiation is probably not warranted in patients with EGC owing to the toxicity associated with the former regimen. Risk factors for recurrence include older age, submucosal tumors, lymphatic invasion, and c-erB-2 immunopositivity [7, 12]. Presence of these risks might warrant closer follow-up and consideration for further treatment.
Histological variables relating to recurrence Histological subtypes of gastric cancer exhibit different biological behavior that may reflect altered recurrence
Palliative care has traditionally been offered to patients with nodal metastasis following gastrectomy; however, there is growing consensus to consider isolated gastric cancer recurrence, particularly, in early-stage disease—in similarity to colorectal cancer—potentially salvageable via various therapies [19]. NCCN version 1.2010 clinical practice guidelines [31] dictate that recurrence following gastric cancer is to be treated according to Karnofsky performance status (KPS). Patients with KPS>60% are to be treated by chemotherapy, clinical trials, or best supportive care, while patients with KPS≤60% are to be offered best supportive care. Unfortunately, NCCN updates do not take into consideration whether the recurrence is isolated or widespread, and whether the initial stage is early or advanced.
Surgical Management Repeat surgery for recurrent gastric cancer can serve as a salvage modality for local control or as a palliative alternative for intestinal obstruction, obstructive jaundice and/or uretric obstruction [19]. In such cases, operative management can be technically difficult and is thought to be associated with high mortality. Park et al. [32] reported an operative mortality of 10.5%. Furthermore, complete resection is possible in only 17% of patients [32]. However, and since complete surgical excision has been associated with significant survival benefit, aggressive surgical approaches are strongly recommended [33]. Operative
Table 3 Surgical management for EGC recurrence Study
Year
Number Median Primary tumor Location of of patients age stage recurrence
de Liaño et al. [38] 2008
3
80
Carboni et al. [39]
1
58
2005
T1a-2a, N0-1 (3/39LNs) T2N1
Time to Treatment recurrence
Anastomotic line Not clear Gastric bed
Symptomatic Median relief Survival
Surgical excision 3/3 (100%)
50 months Surgical Not clear excision + CTX
30 months 11 months
GTV: PET/CT visualization of tumor; PTV: GTV plus 2–3 mm margin
Patients did not receive chemoradiation at time of initial disease
Both patients received chemotherapy based on 5-FU before SBRT
b
a
Kim et al. [19] 2009
2
50.5
II
Isolated PALN 28.5 months 46.5/3Fx (SBRT)b
11 (29.7%) 20 (54.1%) 19/21 (90.5%) Five patients had 11.4 months Grade 2 toxicity 2 (100%) 0 2/2 (100%) Grade 1 only 32.5 months In press Sun et al. [30]
The natural history and therapeutic outcome for recurrence following EGC is in variance to recurrence following
Year
Conclusions
Study
Molecular genetic studies are improving our understanding of the biologic profile and clinical behavior of gastric cancer and promise to enhance prognostic stratification of patients with the aim of developing individualized new therapies [2]. Novel alternatives incorporating molecularly directed targeted therapies are set to play an increasing role in the management of gastric cancer [2]. HER-2 is amplified in 18–27% of gastric cancer; however, the role of Trastuzumab, a recombinant humanized anti-HER-2 monoclonal antibody, in recurrent gastric cancer needs further refinement [40].
Table 4 Irradiation for EGC
Future directions
Number Median Primary Location of of patients Age tumor stage recurrence
Time of recurrence
Median RT dose
The role of conventional radiotherapy in recurrent gastric cancer is limited due to the proximity of the involved LNs to critical organs, such as the spinal cord, intestine, and colon, that often prevent the delivery of sufficient radiation dose for adequate local control [19]. The inapplicability of conventional irradiation gradually shifted the attention toward a more stereotactic approach in patients with isolated relapse. Kim et al. [19] reported promising results with stereotactic body radiotherapy using CyberKnifeÂŽ (Accuray Inc., Sunnyvale, CA, USA) at doses between 45 and 51 Gy over three fractions for patients with isolated PALN recurrence (Table 4).
12.2 months 50 Gy/25Fxa
Role of radiotherapy
Regional LNs
Complete response
Partial response
Symtomatic relief
Studies have demonstrated mixed response following administration of chemotherapy for recurrent gastric cancer [29, 35]. Teraishi et al. [36] reported a case of recurrent gastric cancer to the PALNs with marked response to chemotherapy consisting of S-1 with more than 21 months of progressionfree survival. Murakami et al. [37] narrated the successful use of TS-1 in conjunction with 5-fluorouracil, mitomycin C, and cisplatin in patients with liver, PALN, and peritoneal recurrence following gastrectomy for gastric cancer.
TxNO-2
Toxicity
Role of chemotherapy
587
management for isolated nodal recurrence is more appealing. Nashimoto et al. [34] reported a case in which surgical dissection of an isolated PALN metastasis resulted in a 6-year survival (Table 3).
37
Median survival
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advanced stage disease. Oncologic treatment is possible in EGC recurrence, particularly, in patients with isolated relapse. Guideline updates should differentiate between strategies suitable for early rather than advanced initial cancer stage. The presence of the above-stated risk factors might warrant closer follow-up.
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