The favorable results observed in the relapsed and refractory setting soon prompted investigators to expand their studies of HDCT to the first-line treatment of advanced GCT. This was facilitated further by more uniform pretreatment risk stratification, specifically the development of the universally accepted IGCCCG classification scheme [5
] that enabled oncologists to identify poor-risk patients prior to the initiation of systemic therapy. Several groups have published single-arm Phase II trials of HDCT as first-line treatment in GCT patients with poor prognosis [54
]. Response rates and survival data of early studies were encouraging, when compared with historical controls of studies using CDCT in poor risk patients. As expected, these studies reported less toxicity when using HDCT upfront rather than in the salvage setting [35
]. A matched pair analysis of 147 consecutive patients treated with high-dose VIP in a German multicenter trial and 309 patients treated with CD VIP or BEP at the Indiana University was reported in 1999 [60
]. Multivariate analysis indicated that first-line HDCT in patients with poor-prognosis GCT may result in a significant improvement of progression-free and overall survival. These findings led to Phase III trials which evaluated the role of HDCT in first-line treatment of poor-risk GCT.
In one randomized trial performed by the Genitourinary Group of the French Federation of Cancer Centers, 114 previously untreated patients with poor-prognosis nonseminomatous GCT received either three or four cycles of double-dose cisplatin in combination with vinblastine, etoposide and bleomycin (P200VeBV) or two cycles of modified P200VeBV followed by a single cycle of double-dose cisplatin (200 mg/m2
) in combination with high-dose etoposide (1750 mg/m2
) and cyclophosphamide (6400 mg/m2
) supported by autologous stem cell transplantation (ASCT) [61
]. The initial report failed to demonstrate significant differences in relapse-free survival or OS () [62
]. This negative result was later confirmed after a median follow-up of 9.7 years [62
]; in fact, there was a trend toward superior OS in the standard-dose arm. The study has been criticized in that the high-dose arm used double-dose cisplatin, which has been shown to have no greater efficacy than single-dose cisplatin [65
]; the standard arm did not include BEP chemotherapy, the current standard of care for first-line treatment of poor-risk disease; and a significant proportion of patients in the high-dose arm did not complete HDCT. It is therefore felt that this trial did not adequately address the issue of first-line HDCT in poor-risk GCT.
Phase III trials first-line high-dose chemotherapy.
The German Testicular Cancer Study Group developed a sequential high-dose VIP regimen composed of three to four cycles of conventional-dose cisplatin plus dose-escalated etoposide and ifosfamide followed by ASCT. In a Phase I/II trial treating 221 patients with IGCCCG poor-risk disease, PFS and disease-specific survival were 68 and 73%, respectively, at 5 years, with limited severe toxicity [57
]. This Phase I/II trial demonstrated that high-dose VIP was tolerable, achieved more responses than historical controls with conventional-dose therapy, and could be administered at multiple centers [57
]. Based on these results, a randomized Phase III trial (EORTC 30974) for patients with poor-risk GCT was designed in Europe to compare standard BEP versus one cycle of standard VIP plus three cycles of high-dose VIP (etoposide 1500 mg/m2
, ifosfamide 12 g/m2
and cisplatin100 mg/m2
) with ASCT. This study closed prematurely due to slow accrual, and instead of the 222 patients estimated necessary to adequately prove superiority, only 137 patients were enrolled and treated. Preliminary data was reported at the 2010 ASCO meeting. With 4.4 year median follow-up, neither the 2-year FFS nor the 2-year OS differed significantly between the two treatment arms [63
The largest randomized Phase III trial (n = 219) to evaluate the benefit of HDCT and autologous stem cell support in the first-line setting was published in the year 2007 [64
]. This was a multi-institutional intergroup study (MSKCC, Southwestern Oncology Group, Eastern Cooperative Oncology Group, and Cancer and Leukemia Group B) comparing standard BEP × four to two cycles of BEP, followed by two sequential cycles of high-dose CECy (carboplatin 1800 mg/m2
, etoposide 1800 mg/m2
and cyclophosphamide 200 mg/kg), each supported by autologous stem cell reinfusion. Similar to previous reports, accrual to this trial was challenging, and even with modification of the eligibility criteria to include intermediate-risk patients, this study did not reach its target accrual of 270 patients. No significant differences were observed between the two arms in the rate of CR, 2-year durable DFS or 2-year OS. In addition, toxicity was worse in the HDCT arm [64
]. Secondary analysis in this study prospectively validated the prognostic significance of the rate of tumor marker decline following the initial two cycles of BEP, an adverse feature that these authors had used for patient selection in two prior Phase II trials [54
]. In this Phase III study, patients with appropriate marker decline had a significantly longer survival and time to treatment failure compared with patients with an unsatisfactory rate of decline. The 1-year durable CR proportion for the 70 unsatisfactory decline patients was significantly higher with HDCT than with BEP (61 vs 34%; p = 0.03); however, 2-year OS only showed a trend towards better outcome (78 vs 55%; p = 0.1). Given the modest sample size of patients in this specific subgroup, these findings are not sufficiently robust to draw definite conclusions for clinical practice.
Scandinavian investigators have also examined the utility of using marker decline to help guide treatment selection in the first-line setting. Results of a multicenter protocol conducted by the Swedish Norwegian Testicular Cancer Group (SWENOTECA) were presented at the 2009 ASCO meeting [66
]. Investigators treated 602 patients with metastatic NSGCT. Treatment was individually adjusted according to AFP and β-HCG decline (satisfactory decline defined as half-life for AFP ≤7 days and/or β-HCG ≤3 days), and patients with unsatisfactory response after two courses of standard BEP received intensified treatment with addition of ifosfamide. If marker decline remained unsatisfactory, treatment was further escalated to HDCT with stem cell rescue. A total of 19% of patients were intensified in the first step and 6% in the second step. In a preliminary analysis, the results were encouraging with 5-year PFS of 89.5, 85.4 and 64.9% for IGCCCG good-, intermediate- and poor-risk groups, respectively. The lack of significant difference between the good- and intermediate-risk group suggests that intermediate-risk patients may specifically benefit from this approach.
In the light of the overall disappointing Phase III data, there is currently no role for the routine incorporation of HDCT into the first-line treatment of patients with GCT. Further studies are ongoing testing new regimens; however, until adequately powered randomized Phase III trials demonstrate a superior outcome, the standard of care for intermediate- and poor-risk GCT remains four cycles of BEP chemotherapy.