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

Abstract

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. 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. 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). 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. See related commentary by Kollmannsberger et al., p. 257.