Novel treatment options for refractory germ cell tumors

u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 8 ) 89–96

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journal homepage: www.updateoncancer.com

Novel treatment options for refractory germ cell tumors G. Varuni Kondagunta a , Guru Sonpavde a,∗ , Matthew D. Galsky a , Mark T. Fleming a , Thomas E. Hutson a , Cora N. Sternberg b a b

Genitourinary Oncology Program, US Oncology Research, Houston, TX, USA San Camillo and Forlanini Hospitals, Rome, Italy

a r t i c l e

i n f o

a b s t r a c t

Keywords:

Although testicular germ cell tumors (GCTs) are a model for a curable neoplasm, a significant

Germ cell tumors

proportion will relapse and require salvage therapy. While currently available conven-

Salvage therapy

tional and high-dose chemotherapy salvage regimens attain durable complete remissions

Novel agents

in a significant proportion of patients, the long-term outcomes are still suboptimal in this young population. Several novel agents are being evaluated for recurrent germ cell tumors, including chemotherapeutic and biologic agents, notably anti-angiogenic agents. A better understanding of biology may lead to enhanced outcomes for cisplatin-refractory patients with germ cell tumors. © 2008 Elsevier Ltd. All rights reserved.

1.

Introduction

Germ cell tumor (GCT) represents the most common malignancy in men ages 15–35 and remains the model of curable malignancy. However, approximately 30% of patients with disseminated disease will fail to achieve a durable complete response (CR) following treatment with cisplatin plus etoposide with or without bleomycin chemotherapy (EP, BEP), with outcomes varying with risk category [1,2]. The routine inclusion of high dose cisplatin or two cycles of highdose chemotherapy and autologous stem cell transplantation (ASCT) in the first-line treatment for poor and intermediate risk metastatic GCT patients did not improve outcomes [3,4]. Residual masses in the post-chemotherapy setting are resected in the case of non-seminomatous (NS)-GCTs, while they may be observed in the case of seminomas (and resected if growing or positive by PET scan) [5–7]. For patients with relapsed or refractory GCTs, the optimal treatment regimen has not yet been established. Therapeutic options based on single arm phase II trials include conventional-dose chemotherapy with cisplatin and ifos-

famide in combination with vinblastine or paclitaxel (VeIP or TIP), high-dose chemotherapy with ASCT, or the use of an intensified regimen of conventional-dose drugs [8–15]. Second-line therapy may attain durable remissions in 25–50% of patients, with patient selection probably impacting on outcomes more than the specific regimens. Of patients who fail conventional-dose salvage chemotherapy, a minority of patients may still be cured by third-line treatment with ASCT [16]. Sixty-three percent of 184 patients achieved a durable complete response to high-dose therapy and ASCT with a median follow-up of 4 years [16]. Of 135 patients who received two consecutive courses of ASCT as second-line therapy, 94 were disease-free, and 22 of 49 patients who received ASCT as third-line or later therapy were disease-free after a median follow-up of 4 years. A prospective, randomized trial of second-line therapy of 280 patients assigned to receive either four cycles of VIP (etoposide, ifosfamide and cisplatin)/VeIP or three such cycles followed by one cycle of ASCT revealed no significant improvements in either 3-year event-free survival (35% vs. 42%; p = .16) or overall survival (53%) [17]. Additionally, one cycle of salvage VIP plus three cycles of high-dose

∗ Corresponding author at: Genitourinary Oncology Program, Texas Oncology, PA, U.S. Oncology Research, 501 Medical Center Blvd., Webster, TX 77598, USA. Tel.: +1 281 332 7505; fax: +1 281 332 8429. E-mail address: [email protected] (G. Sonpavde). 1872-115X/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.uct.2008.10.001

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chemotherapy plus ASCT was less toxic, but did not improve outcomes when compared to three cycles of VIP plus one cycle of high-dose chemotherapy plus ASCT [18]. In contrast, a retrospective matched-pair analysis of patients treated with either ASCT or conventional-dose chemotherapy in the initial salvage setting estimated a modest 10% benefit in 2-year disease-free and overall survival with high-dose chemotherapy [19]. Outcomes for therapy of relapse following ASCT with currently available options are dismal with <5% durable remissions [20]. Surgical salvage therapy retains an important role in patients with completely resectable platinum-refractory disease and those with late relapse beyond 2 years [21–23]. Given the young age of these patients and the poor outcomes for platinum-refractory disease, the discovery of novel active agents is imperative.

primary mediastinal non-seminoma, cisplatin-refractory disease, and ßHCG >1000 U/l as independent adverse prognostic variables for failure-free survival. Three prognostic groups were identified: good-risk disease with no adverse factors, intermediate-risk disease with 1–2 adverse factors, and poorrisk disease with ≥3 factors. These groups demonstrated 2-year failure-free survivals of 51, 27, and 5%, respectively. Indiana University has reported their experience with 1–2 cycles of VeIP/VIP followed by tandem ASCT (two courses) in 80 less-heavily pretreated men, of whom only 46% had received at least two prior regimens [27]. Patients with greater than two points in the Beyer score, platinum-refractory disease, ßHCG >1000 mU/ml, AFP >1000 ng/ml, and primary mediastinal nonseminomas had 2-year failure-free survivals of 30, 37, 26, 18, and 0%, respectively.

2. Prognostic factors for relapsed germ cell tumors

3.

As in the frontline setting, prognostic factors have been determined in the recurrent disease setting [2]. A report identified 164 progressing patients (testicular, 83%; extragonadal, 17%) of 795 patients treated with platinum-based first-line chemotherapy for metastatic GCTs [24]. Three prognostic factors remained in the multivariate analysis: progression-free interval, CR to induction treatment, and the level of serum ßhuman chorionic gonadotropin (ßHCG) and alfa-fetoprotein (AFP) at relapse. Those patients with a progression-free interval of <2 years, less than CR to induction chemotherapy, and high markers at relapse (AFP >100 kU/l or ßHCG >100 IU/l) formed a poor-prognosis group, and none of them survived beyond 3 years. Patients with up to two of these risk factors formed a good-prognosis group, with a 47% 5-year survival. A subset of patients from the good-prognosis group with a progression-free interval of >2 years had a 5-year survival of 61%. In a report of 203 patients treated with second-line VIP or VeIP, four prognostic factors were identified: incomplete response to initial therapy, extragonadal origin, lung metastases, and elevated markers (HCG >10,000 mIU/ml or AFP >1000 ng/ml) [25]. Patients with either marker elevation or extragonadal origin and at least one other poor prognostic factor had a complete response rate of 4%, with no durable remissions, whereas patients with testicular primaries and non-elevated markers displayed a CR rate of 62% and a 3year survival of 43%. In comparing outcomes across trials, patient characteristics that demonstrate the refractory nature of the patient population studied need to be closely examined, especially as many of these trials have varied patient populations. Cisplatin-refractory disease has been defined as progression within 4 weeks of completion of cisplatin-based chemotherapy, while absolutely cisplatin-refractory is defined as progression during cisplatin-based chemotherapy. Three hundred ten patients treated with three cycles of VeIP/VIP followed by a single course of ASCT at four centers in the United States and Europe with more than 85% of patients having received at least two prior regimens were retrospectively evaluated by Beyer et al. [26]. Multivariate analysis identified lack of marker-negative remission with conventional salvage chemotherapy given in preparation for HDCT,

Resistance mechanisms

Adult male GCTs represent a unique system of pluripotent tumor cells that can manifest into various phenotypes. Recent studies into the molecular basis of GCT resistance and sensitivity, differentiation, and transformation revealed that over-expression of cyclin-D2 is an early, possibly oncogenic event in GCT, and appears to forebode a poorer prognosis [28]. Differentiation may be governed by various interacting pathways such as loss of germ cell totipotentiality regulators, and of embryonic development and genomic imprinting. Chemotherapy sensitivity and resistance are likely regulated by a p53-dependent apoptotic pathway. Genetic analysis has revealed that virtually all GCTs show an increased copy number of 12p, as one or more copies of i(12p), as tandem duplications of 12p, or transposed elsewhere in the genome. The gene CCND2, which encodes cyclin D2, mapped to 12p13, may be the abnormal driver responsible for GCT development. Abnormality in the TP53 gene is present in the subset of cisplatin-resistant GCTs, in contrast to the platinum sensitive GCTs which express the wild-type TP53 gene [29,30]. It is possible that due to an abnormality in TP53, GCT cells are unable to properly follow apoptotic pathways after exposure to cisplatin. Other studies have suggested that cisplatin resistance in GCTs arises from the inability to arrest the cell cycle appropriately at the G1/S checkpoint due to abnormalities in the retinoblastoma gene product (RB). Using GCT cell lines, inhibitors of cyclin dependent kinases such as flavopiridol, were studied and induced apoptosis, unrelated to cell cycle arrest. These and other such studies may lead to the study of specific novel agents in this patient population. Studies applying comparative genomic hybridization to a set of cisplatin-sensitive tumors and a set of cisplatinresistant tumors, and identifying specific genes involved in resistance are ongoing [31]. Identifying the function of these genes may help to further understand the mechanisms of cisplatin resistance in GCTs and may help to identify these refractory patients earlier in their course of treatment. These genomic studies may also help shape future prognostic models. Identification of specific genes that play a role in resistance mechanisms may also help identify new targets for novel therapeutics.

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4. Chemotherapeutic regimens for salvage therapy 4.1.

Single-agent chemotherapy

While the aforementioned combination regimens and ASCT are established as salvage regimens, there is a role for single agents in certain settings. Historically, oral etoposide (VP-16) was initially studied in a phase II trial that showed modest activity in patients refractory to cisplatin-based therapy (including 6 of 22 patients that were exposed to ASCT) and had received prior conventional intravenous etoposide [32]. Of 21 evaluable patients, three responded with a >90% decrease in markers and a greater than 50% decrease in measurable radiographic disease. Three other patients responded with a greater than 90% decrease in markers. Therefore, oral VP-16 has remained a palliative option for patients who are refractory to other available treatments.

4.1.1.

Paclitaxel

Single-agent paclitaxel has demonstrated modest activity in patients not previously exposed to paclitaxel. In a trial conducted at Memorial Sloan Kettering Cancer Center (MSKCC) including patients who had received one previous cisplatincontaining regimen, paclitaxel 250 mg/m2 was administered by continuous infusion over 24 h every 3 weeks [33]. Of 31 patients, eight (26%) achieved a partial or complete response. Responses were achieved in those who had failed to respond to VIP and in men with poor prognostic features, including mediastinal primary site, and with an incomplete response to prior cisplatin therapy. In another phase II German trial, 24 patients with relapsed, mostly cisplatin-refractory, metastatic GCTs were treated with 3-h paclitaxel infusions of 225 mg/m2 every 3 weeks [34]. The patients had received a median of seven platinum-containing treatment cycles prior to paclitaxel, and 12 patients had previously received high-dose carboplatin/etoposide-based salvage therapy with autologous stem cell support. Six patients (25%) achieved partial or complete responses. In addition, five patients (21%) displayed stabilization. The median duration of responses to paclitaxel was 8 months.

4.1.2.

Gemcitabine

Gemcitabine, classified as an anti-metabolite, was initially studied in two phase II clinical trials based on an anecdotal experience which showed activity in a cisplatin and paclitaxel refractory GCT patients. The first trial included 20 evaluable patients with advanced metastatic NSGCTs and patients with mediastinal primaries [35]. Sixty-five percent had three prior regimens; 25% had only one cisplatin-based regimen due to absolute refractory status and 13 patients had cisplatin-refractory disease; 11 patients received prior ASCT. Gemcitabine was dosed at 1250 mg/m2 weekly for 3 weeks out of every four. Three patients (15%) achieved a response with one patient achieving a CR. The duration of the CR was 2 months; the durations of partial response (PR) were 2 and 6 months. Three additional patients had minor responses with a decline of tumor markers more than 50% but less than 90% and or regression of tumor; durations of 2, 3, and 5 months.

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Toxicity was tolerable with 30% grade III/IV thrombocytopenia and 10% grade III neutropenia. The second trial included 31 evaluable patients with advanced metastatic NSGCTs who had received a median of seven prior cisplatin-based cycles [36]. Twenty-two (71%) had prior ASCT; 19 (61%) patients had received prior paclitaxelbased therapy; and 17 patients (54%) had cisplatin-refractory or absolute refractory disease. Eight patients had extragonadal primary tumors. Patients were treated with gemcitabine 1000 mg/m2 once weekly for 3 weeks out of every four. Six patients (19%) achieved a partial response with tumor regression and or marker decline of ≥75%. An additional 11 patients (35%) had temporary disease stabilization (mean 3 months; range 2–9+ months). A favorable toxicity profile was described with primarily hematologic toxicity with grade III/IV thrombocytopenia seen in 22% and grade III/IV neutropenia seen in 13%.

4.1.3.

Oxaliplatin

Oxaliplatin is a water soluble derivative of 1,2, diaminocyclohexane platinum which has a more favorable toxicity profile than cisplatin. Based on pre-clinical studies which showed activity in cisplatin-resistant cell lines, oxaliplatin has been studied in various solid tumors. Specifically, there was incomplete cross-resistance with oxaliplatin noted in platinum resistant NSGCT cell lines [37]. These data led to the study of oxaliplatin in refractory GCT in a phase II trial [38]. Thirty-two patients with refractory GCT were treated at two different dosing schedules (60 mg/m2 weekly 3 weeks out of four, or 120 mg/m2 every 2 weeks). The patient population was heavily pre-treated with 25 patients (78%) having had prior high dose chemotherapy and ASCT, 20 patients (64%) with cisplatin-refractory disease and 7 patients (22%) with absolute refractory disease. A majority of patients (69%) were also previously treated with paclitaxel based regimens. Overall, four PRs (13%) were noted with durations of 2, 5, 7 and 8 months. There were an additional two patients who had disease stabilization that lasted 5 and 6 months.

4.1.4.

Other novel chemotherapeutic agents

Both topoisomerase I inhibitors irinotecan and topotecan demonstrated no activity in phase II trials of patients with recurrent GCTs [39,40]. Other small phase II trials have demonstrated marginal or no activity for temozolomide, ixabepilone, capecitabine, bendamustine and pyrazoloacridine [41–45].

4.2.

Combination chemotherapy

4.2.1.

Gemcitabine/oxaliplatin

The combination of gemcitabine and oxaliplatin has been particularly important as neither of these drugs has routinely been part of the first or second-line treatments of patients with GCT. Gemcitabine and oxaliplatin were studied in two separate phase II clinical trials [46,47]. Kollmannsberger et al. reported data on 35 patients with a median follow up of 6 months; 89% of the patients had previously been treated with high dose chemotherapy and ASCT and 63% were considered to be cisplatin refractory or absolutely refractory [46]. Two patients achieved a CR (duration 4 months, 11.9 months) with an additional two patients with marker-negative PR and 11 patients

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with marker positive PR (46% favorable response). Pectasides et al. reported on 29 patients with cisplatin-refractory NSGCTs with the same regimen [47]. Thirty-two percent achieved a favorable response with four CRs (duration 11+, 14+, 19+, and 28+ months) and five PRs. The primary toxicity in both trials was hematologic with 48–62% experiencing grade 3–4 myelosuppresion. One patient in the Kollmannsberger trial died as a result of neutropenic septic shock.

4.2.2.

taxel plus ifosfamide were administered with leukapheresis, followed by three cycles of carboplatin plus etoposide with reinfusion of PBSC. Fifty-five percent of assessable patients achieved a complete response to chemotherapy with or without surgical resection, and 51% achieved durable remissions at a median follow-up of 40 months. Other small reports have employed paclitaxel as an element of salvage high dose therapy with ASCT, although it is difficult to definitively establish a role for paclitaxel in the absence of randomized trials [53,54].

Paclitaxel containing combinations

Other combinations have also been studied in the refractory setting including gemcitabine–paclitaxel, oxaliplatin–paclitaxel and gemcitabine–oxaliplatin–paclitaxel [48–51]. Recent studies evaluating high dose chemotherapy with ASCT have incorporated paclitaxel [52]. However, these combinations may be most effective in patients who have not received paclitaxel. In a phase II trial of paclitaxel-gemcitabine in refractory patients following prior conventional chemotherapy, 6 (21.4%) of 28 responded, including three CRs. Two of the complete responders were continuously disease-free at 15+ and 25+ months [48]. The activity of this combination in patients progressing after ASCT was reported in a separate retrospective report by Einhorn et al. [49]. In 37 refractory but paclitaxelnaive GCT patients, 31% achieved favorable responses; 19% (six patients) CR rate with four patients achieving durable CR with chemotherapy alone. Additionally, the four that remained in CR had a minimal burden of disease and had all achieved prior CR to high dose chemotherapy with ASCT. Oxaliplatin and paclitaxel were combined in a phase II trial in refractory GCT patients [50]. Sixteen patients (59%) were absolute cisplatin refractory and an additional five patients were refractory to high dose chemotherapy with ASCT. One patient achieved a marker positive partial response and nine patients achieved disease stabilization (37%), although no CRs were observed. At a median follow up of 65 months, two patients are alive and disease free. A triplet regimen gemcitabine/oxaliplatin/paclitaxel has also been studied with an overall response rate of 51% in 41 patients with refractory GCT [51]. Five patients (23%) were absolute refractory and nine (23%) had cisplatin-refractory disease. Patients had received a median of two prior platinumbased chemotherapy regimens, 78% had received prior high dose chemotherapy with ASCT and 24% did receive prior paclitaxel-based therapy. A CR was achieved in two patients (5%), and 34% achieved a marker-negative partial response (PR) and an additional 12% achieved a marker positive PR. After a median follow up of 5 months, 27% remain disease free with a median response duration of 8 months (range 3–17+ mo). Grade 3–4 thrombocytopenia occurred in 49% of patients, grade 3–4 anemia in 7% and grade 3–4 leukopenia in 15%. The non-hematologic toxicity profile was favorable with three patients experiencing grade 3 toxicities. Sequential, dose-intense chemotherapy with paclitaxel and ifosfamide followed by carboplatin and etoposide (TICE) plus peripheral-blood stem-cell (PBSC) support in patients with GCTs who are likely to experience treatment failure with conventional-dose salvage treatment [52]. The 48 patients entered onto this trial had progressive GCT and unfavorable prognostic features after chemotherapy. Two cycles of pacli-

4.2.3.

Irinotecan combinations

Single agent irinotecan had negative results in a trial in cisplatin-refractory patients [39]. However, based on preclinical data that suggested synergy between irinotecan and cisplatin, a pilot study was conducted in 18 evaluable patients with cisplatin-refractory GCTs [55]. Two patients achieved a CR, and seven achieved a partial response. At a median follow up of 28 months, nine patients (53%) achieved disease free survival. Pectasides et al. reported a 40% favorable response rate (four CR and three PR) in 18 refractory GCT patients treated with irinotecan and oxaliplatin, with three of the CRs being continuously disease-free for 11+, 14+, and 19+ months [56]. However, this patient population was comprised of less heavily pre-treated patients with most patients (78%) receiving two prior cisplatin-based regimens and none with prior high dose chemotherapy with ASCT.

4.2.4.

Cisplatin plus epirubicin combination regimen

In one series at Indiana University, cisplatin and epirubicin was evaluated in 30 patients; 21 of whom had a late relapse (relapsed disease greater than 2 years after primary therapy) [57]. Previous reports of late relapse patients suggest that paclitaxel-based therapy may offer the possibility of attaining a durable CR. In this series though, several of the patients had not received high dose chemotherapy with ASCT and some had not received paclitaxel. Nine patients achieved a CR; seven of these patients remain without evidence of disease at 25+, 27+, 29+, 44+, 45+, 46+, and 48+ months. One patient remains alive with stable pulmonary nodules at 28+ months. Toxicities were acceptable with primarily hematologic toxicity. Fourteen patients did experience grade-3 non-hematologic toxicities including acute renal failure and gastrointestinal distress, but there were no cardiac toxicities and treatment related deaths.

5.

Novel biologic agents

5.1.

Angiogenesis as a target

As with other tumors, there are data that indicate that GCTs are also strongly reliant on angiogenesis [58]. Olivarez et al. demonstrated in early stage orchiectomy specimens that microvessel count predicted the presence of occult nodal metastases at subsequent retroperitoneal lymph node dissections (RPLND) [59]. As microvessel count had already been proposed as an indicator of angiogenesis, this indicated a role for angiogenesis in the development of metastatic disease in these GCTs. Viglietto et al. showed that a majority of GCTs overexpress vascular endothelial growth factor (VEGF) compared with the normal testis, VEGF expression corre-

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Table 1 – Recent reports of novel single agents as salvage therapy. Author (reference) Kollmannsberger et al. [39] Puc et al. [40] Kollmannsberger et al. [41] Vuky et al. [42] Kondagunta et al. [43] Oechsle et al. [44] Feldman et al. [45] Rick et al. [63] Einhorn et al. [65]

Novel agent

Responses/ total patients

Irinotecan Topotecan Bendamustine Pyrazoloacridine Temozolomide Capecitabine Ixabepilone Thalidomide Imatinib

0/15 0/14 1/19 0/13 0/14 0/14 1/12 5/15 0/18

lates with microvessel density and VEGF receptor tyrosine kinases [60]. Flk-1/KDR and FLT-1 are also overexpressed in GCTs more than in the normal testis. In Orchiectomy GCT specimens, overexpression of VEGF, increased microvessel density, vascular invasion, lymphatic invasion, and histologic subtype correlated with the clinical presence of metastatic disease [61]. These data suggest that GCTs are dependent upon angiogenesis, and that serum expression of ligands and receptors involved in the VEGF pathway may have prognostic significance and correlate with more aggressive disease. There are also data to suggest that interference with the VEGF pathway may be effective in causing regression of GCTs. Bevacizumab was recently reported anecdotally to have activity in GCTs. The authors achieved a partial response in a patient with a chemotherapy-refractory non-seminomatous GCT with the combination of bevacizumab and high dose ifosfamide, carboplatin, and etoposide (HD-ICE) [62]. Most interestingly, the patient had been refractory to three lines of chemotherapy including HD ICE plus paclitaxel (T-ICE). Thalidomide has also been evaluated in a small trial with 5 of 15 patients achieving serological PR and one additional patient had stable disease for 3 months [63]. Sunitinib is currently being studied in the refractory GCT population in separate ongoing clinical trials (Tables 1 and 2). In addition, there is an ongoing trial of oxaliplatin in combination with bevacizumab for this patient population as well (Table 2).

5.2.

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Other novel molecular targets

In a retrospective review of 23 patients GCTs were noted to commonly express c-kit and EGFR in 48 and 65% of patients, respectively, although the clinical relevance of this expression is unknown [64]. Disappointingly, imatinib did not induce any significant responses in recurrent kitexpressing testicular GCTs in a small phase II trial [65]. However, anecdotally, imatinib may have activity in recurrent kit-expressing seminomas and an ongoing trial is further evaluating imatinib in this population (Table 2) [66]. Gefitinib is being evaluated in another trial (Table 2). Anecdotally, trastuzumab has demonstrated activity in HER2-expressing cisplatin-refractory GCT, and may warrant further study [67].

6.

Conclusions

Although GCTs remain a highly curable disease, there remains a subset of patients that have refractory disease despite aggressive treatment with cisplatin-based chemotherapy and even high dose chemotherapy with ASCT. Molecular studies may help identify genes for prognostic purposes and help identify pathways that may lead to new therapeutic options. Discovery of novel agents for this young patient population remains an important area for ongoing clinical research to fulfill an unmet need.

Conflict of interest Mark T. Fleming, MD is on the Speakers bureau for SanofiAventis and Pfizer; Guru Sonpavde, MD, receives research support from Eli Lilly, Pfizer, BMS and Astrazeneca and is on the speakers’ bureau for Pfizer, Sanofi-Aventis and Wyeth; G. Varuni Kondagunta, MD: Speaker’s bureau for Wyeth and Pfizer; Matthew D. Galsky, MD receives research support from Pfizer; advisory board/consultant for Novartis; and is on the speakers’ bureau for Pfizer; Thomas E. Hutson, DO, PharmD, receives research support from Bayer/Onyx, Pfizer, GlaxoSmithKline; advisory board/consultant for Bayer/Onyx, Pfizer, Dendreon, and Sanofi-Aventis; and is on the speakers’ bureau for Bayer/Onyx, Pfizer, Amgen, Sanofi-Aventis, and Genentech; Cora N. Sternberg, MD, FACP, receives research support from Eli Lilly, Sanofi-Aventis, Pharmion, GPC Biotech, Bayer/Onyx and Pfizer.

Table 2 – Ongoing phase II trials of novel agents in recurrent GCTs. Regimen/agent Sunitinib Oxaliplatin–Bevacizumab Gefitinib Imatinibb Docetaxel Aresenic trioxide

Institution MSKCC, CUOGa IU IU CALGB EORTC SWOG

Index: GCT, germ cell tumor; CUOG, Canadian Urologic Oncology Group; SECSG, Southeastern cancer Study Group. a b

Separate phase II trials. Seminomas only.

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