Is CBOP/BEP an alternative to BEP for patients with poor prognosis metastatic germ cell tumours?

Correspondence to A Addeo; alfredo.addeo@ uhbristol.nhs.uk The management of metastatic germ cell tumours (GCTs) with platinum-based chemotherapy represents a major success story. However, patients with poor-prognosis nonseminomatous GCTs (NSGCTs) with high tumour markers, non-pulmonary visceral metastases, or a mediastinal primary site at presentation have a less certain outcome. This group achieved cure rates <50% in an international pooled analysis despite being treated with standard bleomycin, cisplatin and etoposide chemotherapy (BEP). There have been no clear improvements in the efficacy of first-line chemotherapy since the introduction of BEP in the mid-1980s. Four cycles of BEP given every 3 weeks remain the internationally accepted, standard of care for intermediate-prognosis and poor-prognosis patients, and three cycles of BEP given every 3 weeks is the most commonly endorsed regimen for good-prognosis patients. Attempts to improve survival have included use of multiagent regimens (eg, cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, etoposide (POMB/ACE); bleomycin, vincristine, cisplatin/etoposide, ifosfamide, cisplatin, and bleomycin (BOP/VIP-B)); newer drugs such as ifosfamide, paclitaxel and high-dose chemotherapy. None have proved superior to BEP for overall survival (OS) in randomised trials and all are more toxic. Although the chemotherapy sensitivity of GCTs is a strong rationale for testing highdose chemotherapy, this approach has been hampered by greater toxicity and some early deaths. 14 An alternative approach has been to shorten the interval between courses of chemotherapy rather than increase the doses, but even this has been limited by toxicity. In order to improve survival for patients with poor-prognosis disease there is a need to better understand which patients will respond well to BEP and which patients need more intensive treatment. A retrospective study with 653 patients proposed that a subgroup with poor-prognosis NSGCT and an improved outcome could be identified based on tumour marker decline assessed 3 weeks after the start of chemotherapy. Patients with an unfavourable decrease had a 4-year progression-free survival (PFS) of 38% and those with a favourable decrease had a 4-year PFS of 64% (p=0.01): 4-year OS was 58% in patients with unfavourable decrease and 83% in those with a favourable one (p=0.02). Based on this the randomised phase III GETUG 13 trial was designed for patients with poor-prognosis GCTs. After one cycle of standard BEP, patients’ human chorionic gonadotropin (HCG) and α-fetoprotein (AFP) concentrations were measured. Patients with a favourable decline in HCG and AFP, calculated from a logarithmic formula using baseline and day 18–21 marker values, continued BEP (Fav-BEP group) for three additional cycles. Patients with an unfavourable decline were randomly assigned (1:1) to receive either BEP (Unfav-BEP group) or a sequential dosedense regimen (Unfav-dose-dense group), consisting of two cycles of paclitaxel (T)-BEP-oxaliplatin followed by two cycles of cisplatin, bleomycin and ifosfamide. Of the 263 patients recruited 254 were evaluable for tumour marker decline. Fifty-one patients had a favourable marker assessment, and 203 (80%) had an unfavourable decline; 105 were randomly assigned to the Unfav-dose-dense group and 98 to the Unfav-BEP group. Three-year PFS was 59% (95% CI 49% to 68%) in the Unfav-dose-dense group versus 48% (38% to 59%) in the Unfav-BEP group (HR 0.66, 95% CI 0.44 to 1.00, p=0.05). Three-year PFS was 70% (95% CI 57% to 81%) in the Fav-BEP group (HR 0.66, 95% CI 0.49 to 0.88, p=0.01 for PFS compared with the Unfav-BEP group). More grade 3–4 neurotoxic events (7% vs 1%) and haematological