ago2012State_of_the_art_classification_and_multimodality_treatment_of_malignant_thymoma

Cancer Treatment Reviews 38 (2012) 540–548

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State-of-the-art classification and multimodality treatment of malignant thymoma q Hannah Koppitz a,h, Jürgen K. Rockstroh b,i, Heinrich Schüller c,j, Jens Standop d,k, Dirk Skowasch e,l, Hans Konrad Müller-Hermelink f,m, Ingo G.H. Schmidt-Wolf g,⇑ a

Medizinische Klinik und Poliklinik III, Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Str. 25, 53105 Bonn, Germany Medizinische Klinik und Poliklinik I, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany Klinik und Poliklinik für Radiologie, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany d Klinik und Poliklinik für Chirurgie, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany e Medizinische Klinik und Poliklinik II, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany f Medizinausschuss der Universitäten Kiel und Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany g Medizinische Klinik und Poliklinik III, Center for Integrated Oncology (CIO) Köln Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany b c

a r t i c l e

i n f o

Article history: Received 29 September 2011 Received in revised form 28 November 2011 Accepted 30 November 2011

Keywords: Classification Review Therapy Thymoma

a b s t r a c t Thymomas are the most common tumors of the anterior mediastinum. Classification, treatment options and understanding of the pathophysiology of thymoma have changed over the past years. It is hoped that novel therapeutic strategies will lead to a survival benefit in these patients. It has turned out that patients with thymoma are best treated with multimodality therapy. In this review, a pathologist, an immunologist, a surgeon, a radiotherapist, a pneumologist and oncologists discuss the current status of classification and strategies for the treatment of thymoma patients. Ó 2011 Elsevier Ltd. All rights reserved.

Approach to thymoma patients Thymoms are derived from epithelial parts of the thymus. Thymoma cells are slowly progressing tumors, 50% of thymomas at diagnosis are incapsulated and do not infiltrate the adjacent tissue.2 Not all thymomas are potentially invasive. Masoka stages I and II are not invasive in most cases.3 Epidemiology and etiology Thymomas account for 0.2–1.5% of all malignancies.4 The incidence is 0.13 of 100,000 persons in the US.5 It has increased in q

This article is an update of our previous review 1.

⇑ Corresponding author. Tel.: +49 228 287 15507; fax: +49 228 287 15849.

E-mail addresses: hkoppitz@uni-bonn.de (H. Koppitz), juergen.rockstroh@ukb. uni-bonn.de (J.K. Rockstroh), heinrich.schueller@ukb.uni-bonn.de (H. Schüller), jens.standop@ukb.uni-bonn.de (J. Standop), dirk.skowasch@ukb.uni-bonn.de (D. Skowasch), konrad.mueller-hermelink@uksh.de (H.K. Müller-Hermelink), Ingo.

Schmidt-Wolf@ukb.uni-bonn.de (I.G.H. Schmidt-Wolf). h Tel.: +49 228 240 68436. i Tel.: +49 228 287x6558; fax: +49 228 287x5034. j Tel.: +49 228 287x15875; fax: +49 228 287x19778. k Tel.: +49 228 287x15857; fax: +49 228 287x14856. l Tel.: +49 228 287x16670. m Tel.: +49 451 500x4488; fax: +49 451 500x4777.

0305-7372/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2011.11.010

the last decades presumably because of a higher life expectancy.

All ages are affected while the highest rate can be detected in the eighth decade.6 The etiology of this disease is not known.

Clinical presentation and differential diagnosis In about half of the cases thymomas are detected by chance in a chest X-ray. In other cases, thymomas lead to chest pain, coughing, dyspnea and signs of upper inflow congestion. It is often associated with paraneoplastic syndroms like myasthenia gravis (MG) which occurs in approximately 45% of patients with thymoma, especially in type B2 and B3 thymoma.7 In 10–15% of MG patients a thymoma can be diagnosed.8 The spectrum of antibodies found in MG patients with thymoma is different from the usual MG cases. The concentration of acetylcholine receptor antibodies is lower and titin and ryanodine receptor antibodies are more frequently found in thymoma patients with MG. Moreover, the higher prevalence for women is not given in thymoma associated MG.9 Other parathymic conditions occurring in only 2–5% of thymoma patients are pure red cell aplasia and hypogammaglobulinemia.8 Thymomas are situated in the anterior compartment of the mediastinum in 75%, in the frontal and upper mediastinum in 15%, in the upper mediastinum in 6%, and at other locations in

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H. Koppitz et al. / Cancer Treatment Reviews 38 (2012) 540–548 Table 1 Localization of thymomas.1,2 Localization

%

Frontal mediastinum Frontal and upper mediastinum Upper mediastinum Other localizations

75 15 6 14

Table 3 WHO classification of thymic epithelial tumors (thymomas).25 In addition to ‘‘labeling’’ a given thymoma as WHO type A, AB, B1–3 thymoma or thymic carcinoma, each pathologist is free to use whatever designation or nomenclature he/she feels most appropriate for a given tumor. In any case of thymic carcinoma it is necessary to further specify the tumor applying conventional terms derived from general tumor pathology (as listed in the lower right column) The clinicopathological classification16 is given for comparison. Ca carcinoma.

Classification of thymoma WHO Type

Table 2 Diagnostic procedures in patients with thymoma.1 Diagnostic procedures Quantitative serum immunoglobulins, immune precipitation for detection of monoclonal Ig Tests for detection of autoimmune disorders according to clinical findings (like acetylcholinic receptor antibodies) Cell blood count and reticulocytes count for detection of pure red cell aplasia LDH, beta HCG, alpha fetoprotein Chest X-ray CT or MRT of the chest Echocardiography CT-controlled core biopsy/surgical biopsy

A AB B1

5–10% (Table 1). For further details we refer to our previous review.1 Diagnostic procedures recommended are presented in Table 2.

To achieve a definitive diagnosis a CT-controlled core biopsy or a surgical biopsy can be used. This would be necessary for example if a nonoperative approach has to be considered due to the extent of the disease or if a lymphoma is a probable differential diagnosis.

Success rates of about 90% are reported for surgical biopsy.8 Despite the significance of a preoperative diagnosis, especially regarding neoadjuvant approaches, the routine histological confirmation before surgery does not seem to have become accepted by the European Society of Thoracic Surgeons according to a survey by Ruffini et al.10 Recently, the use of 18F-FDG-PET-CT for distinction of low risk (A1–B1) and high risk thymoma (B2, B3 and thymic carcinoma)11 and the correlation of tumor size in CT and staging (I–II compared to III–IV) could be shown.12 Differential diagnoses are Hodgkin’s disease, non-Hodgkin’s lymphoma, lung cancer and germ cell tumors.13 B-cell non-Hodgkin’s lymphoma and soft tissue sarcoma seem to be associated malignancies.5 Classification and histology Traditional classification of thymomas14,15 was based on the proportion of non-neoplastic lymphoid cells versus neoplastic epithelial cells. Thymoma subtypes according to this classification were not correlated with prognosis.16–23 This disadvantage appears to have been corrected by the WHO classification of tumors of the thymus which was published in 199924 and revised in 2004.25 The WHO classification appears to have independent prognostic significance26 that is secondary only to tumor stage.3,16,18,21,22,26–28 Genetic studies support the WHO thymoma concept.29–31 The new classification mainly adopted the histological criteria for the thymoma subtypes as previously defined by the Marino–Muller-Hermelink system.10,18,22,32,33 However, the histogenesis of the various thymoma subtypes is still controversial.17,18,21–23 Recent concepts favor an epithelial stem cell derived tumorgenesis. The WHO classification provides abstract ‘‘labels’’ (A, AB, B1–3, thymic carcinoma) to specify thymoma subtypes as given in Table 3. While the WHO subtypes A, AB, B1, B2 and B3 label clearly defined tumor entities, the thymic carcinoma group comprehends histologically and clinically diverse tumors that in the former WHO classification

Malignant thymomas category I

Terminology of the ‘‘histogenetic classification’’ for histological thymoma subtypes Medullary thymoma Mixed thymoma Predominantly cortical

B2 B3

Cortical Well differentiated thymic carcinoma

Rare thymomas

Micronodular thymoma Metaplastic thymoma Microscopic thymoma Sclerosing thymoma Lipofibroadenoma

Thymic carcinoma 2

Clinicopathological Classification16 Benign thymoma

Malignant thymomas category II

Squamous cell carcinoma (Ca) Basaloid Ca Adenoca Papillary adenoca Ca with t(15;19) translocation Lymphoepithelioma-like Ca Sarcomatoid Ca Clear cell Ca Mucoepidermoid Ca Well-differentiated neuroendocrine Ca (typical/ atypical carcinoid) Poorly differentiated neuroendocrine Ca (large cell/ small cell neuroendocrine Ca) Undifferentiated Ca Combined epithelial tumours, including neuroendocrine carcinomas

have been called ‘‘type C thymomas’’ and that now include thymic neuroendocrine tumors as well. Therefore, it is absolutely required that thymic carcinomas are further specified according to the nomenclature of general tumor pathology as listed in Table 3. In conclusion, the new WHO classification25 provides a broadly accepted basis from which prospective clinical studies should be launched.

Staging and prognosis Most thymomas are surrounded by a capsule at first and infiltrate into the adjacent tissue at a later time. Staging of thymomas is outlined in Table 4. Although there is no standardized staging system, the one proposed by Masaoka in 1981 is commonly employed, but several authors find an update desirable. The modification of this system by Koga et al.34 in 1994 is recommended and defined in detail by the ITMIG.35 Moreover, several TNM classification systems have been proposed, among them one presented by Yamakawa and Masaoka in 1991.36 Kondo37 was able to show a significant difference in survival between the stages being the N and M factor more determining for the prognosis than the T factor. The authors consider the TNM classification more useful for thymic carcinoma than for thymoma due to the fact that many thymic carcinomas are in Masaoka stage IVB and can not be further subdivided according to their pro-

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Table 4 Staging of thymoma patients according to Yamakawa et al.36 (above) and Masaoka et al.131 modified by Koga34(below).

TNM classification of thymoma (Yamakawa, Masaoka) T factor

T1 Macroscopically completely encapsulated and microscopically no capsular invasion T2 Macroscopically adhesion or invasion into surrounding fatty tissue or mediastinal pleura, or microscopic invasion into capsule T3 Invasion into neighboring organs, such as pericardium, great vessels, and lung T4 Pleural or pericardial dissemination

N factor

N0 No lymph node metastasis N1 Metastasis to anterior mediastinal lymph nodes N2 Metastasis to intrathoracic lymphnodes except anterior mediastinal lymph nodes N3 Metastasis to extrathoracic lymphnodes

M factor

M0 No hematogenous metastasis M1 Hematogenous metastasis

Masaoka-Koga stage I IIA IIB

III IVA IVB

Extent of disease Grossly and microscopically completely encapsulated tumor Microscopic transcapsular invasion Macroscopic invasion into thymic or surrounding fatty tissue or grossly adherent to but not breaking through mediastinal pleura or pericardium Macroscopic invasion into neighboring organ (i.e., pericardium, great vessel, or lung) Pleural or pericardial implants Lymphogenous or hematogenous metastases

gression.36 Anyway, the TNM classification has not been used in any reported series.

Many articles proved the positive correlation between Masaoka stage and survival.38 Detterbeck used the survival rates published in 10 trials with a total of more than 2000 patients to obtain average rates for 5-year survival of 92%, 82%, 68% and 61% and 10-year survival of 88%, 70%, 57% and 38% for Masaoka stages I–IV, respectively.8 The role of lymphogenous metastasis for prognosis remains unclear due to the rarity of them.38 The completeness of resection and the recurrence rate could be identified to be important prognostic factors for survival.39,3 Most deaths of thymoma patients are related to the tumor itself followed by unrelated causes.8 Genetic aberrations Genetic aberrations are found in up to 87.3% of all thymomas.31 They are in most cases a loss of heterocygosity on chromosome 6q25 followed by 6p21.40 This common genetic alteration could suggest an unknown tumor suppressor gene.41 The number of allelic imbalances correlates with WHO classification and Masaoka stage being most frequent in thymic carcinoma and in Masaoka stage IV thymoma.31,42 Treatment of thymoma Therapy of thymoma patients has to take into account the location of the disease, the stage of the thymoma and treatment options. Generally, the therapeutic goal should be complete removal of the tumor. Treatment options for patients with thymoma are: surgical treatment, irradiation, chemotherapy and symptomatic treatment.

A. General therapeutic options Role of surgery Early stage thymomas are eligable for complete surgical resection, and prognosis is favorable.43 A standardized surgical treatment does not exist. However, a radical resection has to be strived for depending on the localization and the size of the tumor.

The ITMIG recommends en bloc resection including complete thymectomy and resection of the surrounding mediastinal fat because of the possibility of subtle macroscopically invisible transcapsular invasion of the tumor.44 Often, the resection of surrounding structures like pericardium, pleura, lung or pericardiophrenic fatty tissues can be necessary if they are invaded.45 In patients with myasthenia gravis, a removal of the contiguous right and left mediastinal pleura and the dissection of the aorta-pulmonary window are recommended. In case of pleural invasion, the entire pleural space should be explored for possible metastases.44 The most common surgical approach is the median sternotomy.

Other methods like video-assisted thoracoscopy, robotic surgery, transcervical thymectomy and mini-sternotomy have been reported in literature46 and seem to be promising among others in terms of better cosmetic results and better tolerability for comorbid patients.47 The ITMIG recommends these procedures only if involvement of the phrenic nerve and any vein or other major vessels has been ruled out. If the capsule perforates or a complete or en bloc resection cannot be obtained, the minimally invasive approach should be converted into an open one.44 A large percentage of thymomas is resectable (42% in stage IV to 100% in stage I–II in a study of 1320 patients)37 whereas a complete resection can be obtained in only about one third of the cases.

The medium operative mortality reported in literature is 2.5%.8 Role of radiation therapy Generally, thymomas are radiosensitive tumors with radiosensitivity differing only marginally between histological entities.

Therefore, external radiation therapy may be used in combination with other modalities; it may be considered preoperatively to obtain operability48–50 and postoperatively after incomplete resection.51–54 However, side effects of radiation need to be kept in mind at the time of therapeutic decision making. Possible cardiovascular and respiratory side effects may limit the administered dose. Above dose levels of 30 Gy pneumonitis, pericarditis, and, as long-term sequelae, coronary stenoses may occur. It has to be realized, that dose ‘‘threshold’’ values for side effects are in the range of the lowest reported effective dose levels (doses from 30 to 60 Gy are used).

Newer developments in radiological diagnosis and treatment allow a more exact staging and consecutively better protection of noninvolved tissues (conformal radiotherapy, intensity modulated radiotherapy).

Role of chemotherapy Chemotherapy has been reported to induce complete and partial remissions; some of the complete remissions have been pathologically confirmed at subsequent surgery.55 As monotherapy, ifosfamide and cisplatin have been applied.

The effect of cisplatin as monotherapeutic agent is limited.56 The results in combination with prednisone are better.57 In contrast, two phase II trials of ifosfamide reported more satisfying response rates.58,59 Very different remission rates of about 30–100% have been described for chemotherapeutic combinations, most of them

H. Koppitz et al. / Cancer Treatment Reviews 38 (2012) 540–548

platin-based, such as the PAC regimen (cyclophosphamide, cisplatin, doxorubicin) or the ADOC regimen (cyclophosphamide, adriamycin, vincristine and cisplatin). Thymic malignancies that are resistant to these regimens pose a challenge that might be met by target-based therapy.

Neoadjuvant treatment Neoadjuvant chemotherapy has been reported in patients with thymoma.60–63 Still, the role of neoadjuvant chemotherapy is not clear at present. The same holds true for radiation therapy. According to the literature shrinking of tumor size, and thereby operability may be obtained.48–50 Preoperative radiation therapy has been reported to reduce pleural metastases64 while an improvement of survival after preoperative radiation of stage III thymoma could not be detected.65 Korst et al. are exploring the use of neoadjuvant radiochemotherapy for complete resection of locally advanced thymoma in an ongoing trial (ClinicalTrials.gov Identifier: NCT00387868).

Adjuvant treatment Adjuvant therapy should be performed according to histological subtype, clinical stage and most importantly status of resection (R0, R1 or R2).3 Adjuvant radiotherapy is recommended in case of incomplete resection and in case of biopsies through mediastinoscopy.66 Two recent large scale studies were able to show a significant increase of overall survival in patients with stage II–III thymoma who underwent adjuvant radiotherapy, especially after an incomplete resection.51,52 In contrast, no reduction of recurrence rate after adjuvant radiotherapy in patients with completely resected thymoma could be detected.67,39 In a study of 200 patients, Chen et al.28 showed that adjuvant radiotherapy could only improve survival in patients with type B2 and B3 thymoma and thymic carcinoma.

Adjuvant chemotherapy might be considered in Masaoka stage III and IV thymomas as part of a multidisciplinary approach, especially in case of incomplete resection.53,54

Treatment options according to the stage of disease, novel therapeutic concepts and current trials Treatment of noninvasive malignant thymoma (stage I) Standard treatment is surgical resection of the thymoma. Radiation therapy is not indicated following complete resection of a well-encapsulated tumor. However, radiation therapy should be considered in rare cases when a noninvasive thymoma is resected incompletely, and when the patient is inoperable because of his poor surgical risk.53,68

Treatment of malignant thymoma with capsular invasion and/or invasion into thymic or surrounding fat tissue (stage II) Postoperative radiotherapy should be considered in all patients with completely resected stage II thymomas when tumor extension beyond the capsule is documented pathologically.69 In incompletely resected or primary unresectable thymomas radiation therapy or combined radiochemotherapy should be performed.70,71 However, data from Shanghai28 and Wuerzburg3 suggest that in completely resected stage II thymomas of WHO subtype A, AB and B1 adjuvant therapy may not be beneficial.

543

Treatment of invasive malignant thymoma (stages III and IV) Treatment options are en bloc surgical resection if possible and adjuvant radiation therapy.49,55,72,73 Induction chemotherapy may be delivered especially in initially unresectable thymomas to possibly obtain operability.53 If the vena cava is infiltrated, angioplasty with or without reconstruction can be performed and often complete resection can be obtained.65 In case of extensive pleural disease, extrapleural pneumectomy is a treatment option for which complete resection rates of more than 60%74 and 5-year-survival rates of 60% for Masaoka stage IVa are reported.75 Due to the aggressiveness of this operation, only certain patients qualify for it. Thus, less invasive techniques like pleural perfusion thermochemotherapy76,77 or pleurectomy combined with intraoperative photodynamic therapy78 are discussed in literature.

Even if a complete resection may not be achieved, the prognosis for patients with partial resected thymoma is still significantly better than for unoperated patients.39 Nonetheless, in these stages surgical options may be limited and radiochemotherapy is the treatment of choice. An intergroup trial of patients with unresectable tumors who received the PAC regimen (cisplatin, doxorubicin, and cyclophosphamide) followed by thoracic radiation reported a 5-year survival rate of 52%.79 The combination of cisplatin and etoposide chemotherapy is very effective and well tolerated in advanced thymoma.80 In another series of 30 patients with stage IV or locally progressive recurrent tumor following radiation therapy, the PAC regimen achieved a 50% response rate, including three complete responses.

The median duration of response was 12 months and 5-year survival was 32%.81 The ADOC regimen (doxorubicin, cisplatin, vincristine, cyclophosphamide) led to a 92% response rate (34 of 37 patients), including complete responses in 43%82 and an 83% response rate in another trial.83 In combination with surgery Rea et al.61 report a response in each of the 16 treated patients.

Since anthracyclines can cause cardiomyopathy, anthracyclinefree regimens are desirable, especially for patients undergoing radiotherapy as well. The combination of carboplatin and paclitaxel did not show satisfying response rates, particularly for thymic carcinomas.84–86 Another anthracycline-free regimen, VIP (etoposide, ifosfamide and cisplatin) showed similar modest response rates to carboplatin plus paclitaxel.87,88 Since no randomized comparisons have been done, it remains uncertain whether combination chemotherapy regimens are more effective than regimens using single agents. One phase II trial of cisplatin was associated with a partial response rate of only 10%.56 A retrospective analysis of 17 patients treated with cisplatin with or without prednisone over a 10-year period revealed an overall response rate of 64%55,57 Ifosfamide used as a single agent showed overall response rates of 62% in 13 treated patients58 and 46% in 15 treated patients.59 In conclusion, multidisciplinary approaches seem to be necessary for the treatment of invasive thymoma. Kunitoh et al.89 recently reported that in about 50% of patients with initially unresectable thymoma, complete resection was possible after CODE chemotherapy. After some patients received post-operative radiotherapy, a five year survival rate of 85% could be achieved.

In a trial with CAPP regimen followed by surgery, radiotherapy and consolidation chemotherapy the survival rates even reached 95% after 5 years54 (Fig. 1) Treatment of refractory disease and relapse Recurrence of thymoma often can be observed in high stage thymomas and even more frequently in thymic carcinoma. Kondo et al.39 published recurrence rates of 0.9%, 4.1%, 28.4%, and 34.3%

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diagnosis of thymoma

relapse

stage II/III/IV

stage I

resectable

unresectable

chemotherapy radiotherapy single agent: e.g. IFO combination: e.g.ADOC,CAPP targeted therapy

resectable

surgical resection

unresectable

radiotherapy

corticosteroids/ octreotide

incomplete Incomplete resection resection

radiotherapy

surgical resection incomplete resection radio(chemo) therapy Fig. 1. Scheme of treatment for newly diagnosed patients with thymoma.

and 51% for stage I, II, III, and IV thymoma and thymic carcinoma, respectively. The average time to recurrence is approximately 5 years8 and the most common site of recurrence is the pleura.66 The prognosis degrades with an increasing number of recurrent lesions.90 Due to the possibility of late recurrences and subsequent tumors the ITMIG recommends a lifelong follow-up care.91 The decision of how to treat the patient with refractory or recurrent disease is based on the pretreatment of the patient. Therefore, only general advice can be given here.

Recurrent thymoma can be treated by repeated surgical resection especially for local occurrence.91 Davenport et al.46 showed in a review that resection of local recurrence improves prognosis while pleural disease does not respond well to surgery. Surgery is feasible in more than half of all recurrences and total resection can be achieved in 62% of all reoperated patients.8 Postoperative radiation plays a role for patients with incomplete resections and has been employed in selected patients following complete resection of recurrent thymoma.92 If surgical resection is not possible, radiation therapy should be performed when possible based on pretreatment.55 Corticosteroids may be used in unresectable tumors that have been refractory to radiation therapy leading to transient partial responses.55 Two studies reported on the modest activity of somatostatin receptor blockade with octreotide or octreotide analogs combined with prednisone in refractory thymoma.93,94 Docetaxel has been successfully applied to a patient with refractory thymoma95 (Fig. 2).

Novel therapeutic concepts The recently founded International thymic malignancies interest group ITMIG sat as a goal to facilitate the research on this

Fig. 2. Scheme of treatment for relapse in thymoma patients.

subject for example establishing outcome measures and definitions for thymic tumors96 and promoting innovative approaches for clinical research to obtain a larger amount of data.97 Successful treatment of invasive thymoma with high-dose chemotherapy followed by peripheral blood stem cell transplantation (PBSCT) has been reported in several case reports.98–100 Pan et al.101 could show that CD20 is expressed on 90% of mixed spindle/lymphocytic thymomas. Thus, it will be of interest to test the CD20 antibody rituximab in patients with this entity of thymoma. Rituximab may be helpful for the treatment of refractory myasthenia gravis in patients with or without thymoma.102 IL-2 had no significant effect in 14 patients with thymoma103 in contrast to a case report.104 TNP-470, an angiogenesis inhibitor, has been tested in combination with paclitaxel and carboplatin in one patient with thymoma.105 Proton beam radiation might be an option for patients with thymoma.106 A partial response has been reported using pemetrexed.107 Belinostat, a histondeacteylase-Inhibitor, caused a stable disease for 17 months in a thymoma patient.108 Giaccone et al.109 tested belinostat in a phase II trial and reported only a small partial response rate but high rates of stable disease.

In case of overexpression of KIT which was found in 86% by immunohistochemistry and RT-PCR in patients with thymic carcinoma but in none with thymoma110 patients might respond to tyrosine kinase inhibitors such as imatinib111 or to dasatinib.112 Three recent trials could not show activity for the tyrosine kinase inhibitors imatinib113,114 and saracatinib115 despite detected cKIT expression. Three partial responses of four patients treated with sunitinib were reported by Strobel et al.116 In spite of high KIT expression, mutations have been detected in only 7% (5 of 70) of all genotyped thymic carcinomas in literature.42 That might explain the lacking response in past trials. Girard et al. recommend the use of sunitinib or imatinib in patients with KIT mutations corresponding to in vitro testing, case reports and results in other tumors with the same mutation.42 An ongoing trial is investigating the activity of another tyrosine kinase inhibitor in thymic malignancies (ClinicalTrials.gov Identifier: NCT01011439).

The use of multikinase-inhibitors that block various kinases was described in several case reports. Li et al.117 report shrinkage of a

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Table 5 Treatment results of patients with thymoma and thymic carcinoma. If not stated differently, all results after exclusive chemotherapy. Na not available. Modified from Schütte.132 Trial

Number of patients

Single agent chemotherapy Harper 13 Highley 15 Bonomi 20 Park 17 Combined chemotherapy Platin-based Giaccone 16 Hanna 5 Loehrer 26 Loehrer 30 Berruti 6 Fornasiero 37 Rea 16 Furugen 16 Igawa 11 Lemma thymoma 21 Lemma thymic 23 carcinoma Grassin 16 Kurup 21 Kim 22

Chemotherapy regimen

CR [%]

PR [%]

RR [%]

Overall survival [months]

Year of publication

IFO IFO DDP DDP +/- PRED

54 39 0 35

8 8 10 29

62 46 10 64

Na 13+ 19 Na

1991 1999 1993 1994

DDP, VP-16 High-dose carboplatin, VP-16 PAC+ radiation PAC ADOC ADOC ADOC + surgery Car+pac Car+pac Car+pac Car+pac

31 40 22 10 0 43 43 25 0 14,3 0

25 60 48 40 83 48 57 12 4 28,6 21,7

56 100 70 50 83 92 100 37 36 42,9 21,7

52 Na 93 38 15+ 15 Na 49 22,7 Na 20

1996 2001 1997 1994 1993 1991 1993 2011 2010 2011 2011

0 0 14

25 62 63

25 62 77

Na Na Na

2010 2010 2004

50 0 0

25 100 56

75 100 56

Na 8+ 33.8

1988 1991 2011

60 80 0 20 100

100 80 38 40 100

12+ Na Na Na Na

1988 1980 1989 2009 2006

Dy Macchiarini Okuma

4 7 9

VIP CODE + surgery + radiation CAPP + surgery + radiation + consolidation chemotherapy DDP, VLB, BLM DDP, EPI-ADM, ETP DDP, Irinotecan

Not platin-based Kosmidis Evans Goldel Palmieri Nakagawa

5 5 13 15 1

CPM, ADM, VCR CPM, VCR, PROC, PRED CPM, ADM, VCR, PRED, +/- BLM Capecitabine, Gemcitabine Pemetrexed

40 0 38 20 0

Targeted therapy Histondeacetylase-inhibitors Steele 1

Belinostat

Na

2008

Giaccone

Na

2011

Belinostat

Stable disease for 17 months 0 5 5

Tyrosine-kinase-inhibitors Wakelee 21 Strobel 4

Saracatinib Sunitinib

0 0

0 75

0 75

Na Na

2010 2010

EGFR-antibodies Palmieri Farina

2 1

Cetuximab Cetuximab

0 0

100 100

100 100

Na Na

2007 2007

EGFR-inhibitors Kurup Christodoulou Bedano

26 1 18

Gefitinib Erlotinib Erlotinib + Bevacizumab

0 4 4 Symptoms improved 0 0 0

Na Na Na

2004 2008 2008

Multikinase-inhibitors Li

1

Sorafenib

Na

2009

1

Sorafenib

Stable disease for 9 months 0 100 100

Na

2009

13 1

Cixutumumab CP-751,871

0 0 0 Stable disease for >1 year

Na Na

2010 2007

Octreotide, PRED Octreotide +/- PRED

6 5

15 Na

2002 2004

Bisagni IGFR-antibodies Rajan Haluska

41

Somatostatin-receptor-blocker Palmieri 16 Loehrer 38

thymic carcinoma and the metastases with stable disease for 9 months after applying sorafenib. A partial response to sorafenib in a heavily pretreated patient with c-KIT-mutation could be detected.118 In a report, two patients with metastatic heavily pretreated disease were evaluated for EGFR expression in the primitive tumor, being considered this data as a basis for an anti EGFR treatment with the monoclonal antibody cetuximab which targets EGFR. A

31 25

37 30

strong EGFR expression was revealed by immunohistochemistry in the two cases considered, thus the patients received cetuximab and a partial response was reported.119 Farina et al.120 also reported a case of partial remission in a patient with immunohistochemically detected overexpression of EGFR after treatment with cetuximab. An ongoing trial is testing the effect of the PAC regimen combined with cetuximab (ClinicalTrials.gov Identifier: NCT01025089).

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Table 6 List of ongoing clinical trials for patients with thymoma.133.

Title of trial

Eligibility

Recruiting status

Phase II study of trimodality therapy (cisplatin, etoposide and radiation) for patients with thymoma or thymic carcinoma at significant risk for recurrence Multicenter Phase II study of imc-a12 in patients with thymoma and thymic carcinoma who have been previously treated with chemotherapy Phase II study of alimta (pemetrexed) treatment of advanced thymoma and thymic carcinoma A Phase II trial of chemotherapy (cisplatin, doxorubicin & cyclophosphamide) plus cetuximab followed by surgical resection in patients with locally advanced or recurrent thymoma Efficacy of medical treatment with octreotide in patients with primary inoperable thymoma to reduce tumor size A Phase II study of paclitaxel and cisplatin in previously untreated, unresectable invasive thymoma or thymic carcinoma A Phase 1/2 study of pxd101 (belinostat) in combination with cisplatin, doxorubicin and cyclophosphamide in the first line treatment of advanced or recurrent thymic malignancies A Phase I study of intravenous (iv) palifosfamide-tris administered in combination with iv etoposide and iv carboplatin in patients with malignancies for which etoposide and carboplatin are an appropriate choice Phase I dose escalation study of accelerated fractionation with esophageal sparing using intensitymodulated radiation therapy for locally-advanced thoracic malignancies including a prospective assessment of esophageal motion and radiation-induced esophageal injury Radiofrequency ablation in treating patients with refractory or advanced lung cancer

Thymoma, thymic carcinoma

Recruiting

Thymoma and thymic carcinoma previously treated with chemotherapy Advanced thymoma, thymic carcinoma Locally advanced or recurrent thymoma

Recruiting

Inoperable thymoma

Recruiting

Untreated, unresectable thymoma, thymic carcinoma Thymoma, thymic carcinoma

Recruiting

Non small cell lung cancer, small cell lung cancer, testicular cancer, thymoma, ovarian cancer osteosarcoma Non small cell lung cancer, small cell lung cancer, thymoma, thymus neoplasms

Recruiting

Lung cancer, malignant mesothelioma, metastatic cancer, thymoma and thymic carcinoma Lung cancer, esophageal cancer, malignant pleural mesothelioma, thymoma, thymic carcinoma

Ongoing, not recruiting Recruiting

Thymic carcinoma previously treated with chemotherapy Non-small-cell lung cancersmall cell lung cancerthymic malignancies Thymoma, thymic carcinoma Thymoma, thymic carcinoma, lung cancer, carcinoma, non-small-cell lung, mesothelioma

Recruiting

Allogeneic tumor cell vaccine with metronomic oral cyclophosphamide and celecoxib as adjuvant therapy for lung and esophageal cancers, thymic neoplasms, thoracic sarcomas, and malignant pleural mesotheliomas Phase II study of oral PHA-848125AC in patients with thymic carcinoma previously treated with chemotherapy Molecular profiling and targeted therapy for advanced non-small cell lung cancer, small cell lung cancer, and thymic malignancies A Phase II study of amrubicin in relapsed or refractory thymic malignancie Molecular analysis of thoracic malignancies

EGFR-Inhibitors are another answer to EGFR overexpression.

Kurup et al.121 were able to show only one partial response in 26 patients treated with gefitinib. Christodoulou et al.122 reported a case of improvement of myasthenic symptoms after treatment with erlotinib. For the combination of erlotinib with the VEGF-antibody bevacizumab, Bedano et al.123 report stable disease in 60% of 18 treated patients. EGFR mutations seem to be very unfrequent in thymic malignancies (only two mutations in 122 analyzed tumors)42,121,122,124,133 which could explain the low response to EGFR inhibitors. RAS-mutations have been detected in three of 45 thymic malignancies. In other tumors these mutations cause a resistance to anti-EGFR therapy.42 This could be another reason for the trial results.

A recent trial found a high expression of VEGF-A, VEGF-C, VEGFD and of their TK receptors R1, R2 and R3 (67–87% of thymic tumors)125 which could play a role as a target for chemotherapy in future studies.

Another possible target could be the insulin-like growth factor1 receptor. Zucali et al.126 found an expression of this receptor in 20% of 132 patients with thymic malignancies. Recently, a significant correlation between IGF-1R expression and Masaoka stage with higher expression in advanced stages could be detected.127 Rajan et al.128 could not report an objective response in 13 patients treated with the IGFR-antibody cixutumumab and Haluska et al.129 tested another antibody in 24 patients with solid tumors, among them one with thymoma who experienced stable disease for more than a year. An ongoing trial is testing the activity of cixutumumab in thymoma patients (ClinicalTrials.gov Identifier: NCT00965250).

Recently, Breinig et al. found a novel protumorigenic mechanism in thymic malignancies. They were able to detect that Hsp90 supports various oncogenes, like CDK4, EGFR and probably most important for the genesis of thymic malignancies, IGF-1R. Thus, clinical trials testing Hsp90 inhibition are indicated.127 Muta-

Unknown Recruiting

Recruiting

Recruiting

Recruiting Recruiting Not yet recruiting

tional analyses are warranted to allow a target-based therapy in chemotherapy–refractory patients.

Due to the rarity of thymic malignancies, different regimens have never been compared in a randomized setting and there are only studies with a low number of patients or case reports. Therefore, no science-based treatment recommendations exist. We listed the treatment results systematically in Table 5. Among the combination chemotherapies, the ADOC regimen shows the best results in more than one trial. The number of patients is even lower in the trials for targeted therapies. Here, the EGFR-antibodies and the multikinase inhibitors seem to be promising.

Current clinical trials Multicenter co-operative group clinical trials are warranted to assess novel thymoma therapies to maximize patient resources in this uncommon tumor.130 The homepage of the NCI at present lists several trials recruiting patients with thymoma. One trial combines cisplatin with paclitaxel in patients with advanced thymoma. At present, use of etoposide and cisplatin combined with radiotherapy is involved in another trial. A third trial tests the use of cetuximab and the PAC regimen followed by surgical resection in the treatment of patients with metastatic or recurrent thymoma. For further trials we refer to Table 6.

Conclusion and future prospects In this review, a pathologist, an immunologist, a surgeon, a radiotherapist, a pneumologist and oncologists opt for multicenter co-operative group clinical trials that may facilitate novel thymoma treatment strategies to maximize patient resources in this tumor. We hope that novel multimodality therapies will lead to a survival benefit in thymoma patients.

H. Koppitz et al. / Cancer Treatment Reviews 38 (2012) 540–548

Conflict of interest The authors do not have any conflicts of interest to disclose.

Acknowledgements We thank Prof. Dr. P. Brossart, Bonn for carefully reading our manuscript.

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