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

Purpose: Sequential high-dose chemotherapy (HDC) using carboplatin/etoposide 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. Patients and Methods: Trial eligibility included second or later relapse or poor-risk first relapse and adequate end-organ function. Treatment consisted of sequential bevacizumab-GemDMC (HDC cycle 1) and bevacizumab-ifosfamide/carboplatin/etoposide (C2) in three 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 relapse-free survival rate from an expected <25%. We validated its results in an off-trial fourth cohort treated the same as cohort 3. Results: We treated 165 male patients (65 trial and 100 cohort 4 patients), after a median of three prior therapy lines, mostly with cisplatin-refractory tumors at relapse (45% refractory and 23% absolutely refractory) and 19% primary mediastinal tumors. The overall response rate was 84.5% (77% complete response/partial response with negative markers). 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 relapse-free survival 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 and 2) and those not receiving it (cohorts 3 and 4). Conclusions: Sequential GemDMC-carboplatin/etoposide with or without ifosfamide shows outcomes that exceed the anticipated results in multiply, poor-risk relapsed GCT. Bevacizumab did not improve outcomes.