Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial

Abstract

Background Poor-prognosis germ-cell tumours (GCT) are associated with only a 50% cure rate. Our hypothesis was that treatment intensification based on an early tumour marker decline will improve progression-free survival (PFS). Methods In this phase III, multicentre, international trial (NCT00104676 ; EU-20502), after patients with poor-prognosis GCT defined according to the International Germ-Cell Cancer Consensus Group (IGCCCG) had received one cycle of cisplatin (20 mg/m2/day × 5 days), etoposide (100 mg/m2/day × 5 days), and bleomycin (30 mg/week) (BEP), AFP and hCG were assessed between day 18 and 21: 1) patients with a favourable decline continued BEP (Fav-BEP); 2) patients with an unfavourable decline were randomised to receive either BEP (Unfav-BEP) or a dose-dense regimen (Unfav-dose-dense), consisting of paclitaxel (175 mg/ m2 day 1)-BEP plus oxaliplatin (130 mg/ m2 day 10) (2 cycles), followed by cisplatin (100 mg/ m2 day 1), ifosfamide (2 g/ m2 on days 10, 12, 14 + mesna), and bleomycin (25 units/day, by continuous infusion × 5 days on day 10 to 14) (2 cycles), with G-CSF support. Centrally blocked randomisation stratified by centre was used. The primary endpoint was PFS and the efficacy analysis was conducted on an intention-to-treat basis i.e. it included all randomised patients. The planned trial accrual was completed in May 2012 and follow-up is ongoing. Results 263 patients were enrolled and 203 had an unfavourable tumour marker decline (randomised: 105 Unfav-dose-dense arm, 98 Unfav-BEP arm). The 3-year PFS rate was 59% [95% Confidence Interval (CI): 49–68] in the Unfav-dose-dense arm versus 48% [95% CI: 38–59] in the Unfav-BEP arm (p=0.05; HR: 0.66 [95% CI: 0.44–1.00]). The 3-year PFS rate was 70% [95% CI: 57%–81%] for patients in the Fav-BEP arm (p=0.01 for PFS compared with the Unfav-BEP arm). More grade 3–4 neurotoxicity (7 [7%] vs 1 [1%]) and greater haematotoxicity occurred in the dose-dense arm, with no excess febrile neutropenia (18 [17%] vs 18 [18%]) or toxic deaths (1 each arm). Salvage high-dose chemotherapy + a stem-cell transplant were required in 6 [6%] in the Unfav-dose-dense arm and 16 [16%] patients in the Unfav-BEP arm (p=0.015). Conclusion Personalising treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor-prognosis GCT and an unfavourable tumour marker decline.

Guidelines on Testicular Cancer: 2015 Update

“…An international randomised phase 3 trial conducted in 263 patients with IGCCCG poor-risk NSGCT demonstrated that intensifying treatment with dose-dense chemotherapy improves PFS but not OS in patients with an early unfavourable decline in tumour marker levels [65]. On the basis of results from this trial, patients with an unfavourable decline in tumour marker levels after one cycle of BEP should be switched to a more intensive chemotherapy regimen [66].…”

Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With Intermediate- or Poor-Risk Germ Cell Tumors

“…[9][10][11] Surgical expertise at the two high-volume institutions that enrolled patients in this study may have contributed to the excellent outcomes observed with TIP. However, it should be noted that only two patients who achieved a CR had viable disease resected at postchemotherapy surgery.…”

Disease characteristics and survival outcomes of extragonadal primary germ cell tumour in two Canadian tertiary cancer centres

“…24 Recent large trials, such as EORTC 30983 and GETUG 13, reported improved DFS, but similar OS with more intensive chemotherapy regimens in patients with high-risk GGCT. 25,26 More studies are needed to elucidate whether more intensive chemotherapy or targeted therapy can improve outcomes in patients with EGCTs.…”