High-Dose Chemotherapy for Multiply or Poor-Risk Relapsed Germ-Cell Tumors

Purpose: Sequential high-dose chemotherapy (HDC) using carboplatin/etoposide (CE) with autologous stem-cell transplant can be curative in relapsed germ-cell tumors (GCT). However, outcomes are poor for multiply relapsed/refractory tumors. We studied gemcitabine/docetaxel/melphalan/carboplatin (GemDMC), which exploits DNA damage repair inhibition. We hypothesized that concurrent bevacizumab, targeting the high vascularity of GCT, would synergize with HDC. Methods: Trial eligibility included 2nd or later relapse or poor-risk 1st relapse, and adequate end-organ function. Treatment consisted of sequential bevacizumab-GemDMC (HDC cycle 1, C1) and bevacizumab-ifosfamide/carboplatin/etoposide (ICE) (C2), in 3 consecutive cohorts: bevacizumab/full-dose GemDMC (cohort 1), bevacizumab/reduced-dose GemDMC (cohort 2), and no bevacizumab/reduced-dose GemDMC (cohort 3). The trial was powered to distinguish a target 50% 2-year RFS rate from an expected <25%. We validated its results in an off-trial 4th cohort treated the same as cohort 3. Findings: We treated 165 male patients (65 trial, 100 cohort 4), after a median of 3 prior therapy lines; mostly cisplatin-refractory tumors at relapse (45% refractory, 23% absolutely refractory); 19% primary mediastinal tumors. Overall response rate: 84.5% (77% CR/PRm-). The treatment-related mortality rates in cohorts 1 to 4 were 13%, 8%, 4%, and 4%, respectively. Resection of residual lesions in 74 patients found no viable GCT in 76%. The 5-year RFS and overall survival rates were 57.1% and 58.3%, respectively, without differences between trial and cohort 4 patients, or between patients receiving bevacizumab (cohorts 1/2) or not (cohorts 3/4). Conclusions: Sequential GemDMC-(I)CE in multiply poor-risk relapsed GCT shows outcomes that exceed the anticipated results. Bevacizumab did not improve outcomes.