This replaced the previous standard of cisplatin, vinblastine and bleomycin in 1987 when it was shown to have similar (low risk disease) or greater (high risk disease) efficacy and less toxicity, particularly neuromuscular.r Multiple phase II and III trials attempting to define superior regimens in higher risk disease have not shown benefit over BEP. Strategies including the use of alternative or additional chemotherapy agents,rr more complex multi-drug regimens,rrrr and most recently, very high dose chemotherapy with stem cell supportr are more toxic but no more effective than BEP.
A randomised trial conducted by the Australia New Zealand Germ Cell Trials Group (ANZGCTG, now incorporated in the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Ltd [ANZUP]), has shown that the dose and dose intensity of BEP is important. A survey of treatment patterns in Australia conducted by the(ANZGCTG) in the early 1990s demonstrated considerable variations in management at participating centres. Approximately half of the centres used a five-day chemotherapy regimen incorporating etoposide 500 mg/m2/cycle, as used in the United States (US). The remaining centres generally used a three-day chemotherapy regimen incorporating etoposide at a dose of 360 mg/m2/cycle, based on regimens commonly used in Britain. Based on the results of a previous ANZGCTG study almost all centres used bleomycin, but many investigators were uncertain about the optimal dose and schedule in view of the unpredictable toxicity of this drug.
The ANZGCTG decided to compare two “standard” regimens of chemotherapy, each incorporating cisplatin, etoposide and bleomycin, in a randomised clinical trial for good-prognosis disease as defined by modified Memorial Sloan-Kettering criteria.r The first regimen was based on treatment recommendations from Indiana University, and referred to as “US PEB”, and comprised 3 cycles of cisplatin 20 mg/m2 days 1 to 5, etoposide 100 mg/m2 days 1 to 5, and bleomycin 30,000 International Units days 1, 8 and 15, repeated every 21 days (3B90E500P).
The second regimen was based on the control arm of a published European clinical trial, and referred to as “European BEP”, and comprised 4 cycles of cisplatin 100 mg/m2 day 1, etoposide 120 mg/m2 days 1 to 3, and bleomycin 30,000 International Units day 1, repeated every 21 days (4B30E360P).
The trial was stopped after the second planned interim analysis met predefined stopping rules. 166 patients were randomised, 83 to each arm. Baseline characteristics were reasonably balanced between the 2 arms.
After a median follow up of 8.5 years, the OS rate at 8 years remained superior in patients treated with 3B90E500P vs the 4B30E360P regimen (92% vs 83%; HR=0.38; p=0.037). The PFS rate at 8 years was better with 3B90E500P than the 4B30E360P regimen, but the difference did not reach statistical significance.r
From multiple studies, it has been shown that prognostic groups as defined by the International Germ Cell Consensus Classificationr dictate response. Good-risk patients have a 90% cure rate with BEP. Intermediate-risk patients have a 80% cure rate with BEP. Poor-risk patients such as non-Seminomatous Germ Cell Tumours (NSGCT) with high tumour markers, nonpulmonary visceral metastases, or a mediastinal primary site at presentation only have a 50% cure rate with BEP. Consider alternative regimens on trial for intermediate and poor-risk patients.
Overall Survival (all patients):r
© Lancet 2001
||Regimen A (%)
||Regimen B (%)
|Grade 3 and 4
|Grade 2, 3 and 4
|Nausea and vomiting
* includes constipation, headache, indigestion, lethargy and dizziness
Regimen A: 3 cycles of cisplatin 20 mg/m2 on days 1 to 5, etoposide 100 mg/m2 days 1 to 5 and bleomycin 30,000 International units days 1, 8 and 15 repeated every 21 days
Regimen B: 4 cycles of cisplatin 100 mg/m2 day 1, etoposide 120 mg/m2 days 1 to 3 and bleomycin 30,000 International units day 1 and repeated every 21 days
Four deaths (2 in each group) were related to the study treatment. Three deaths in the 3B90E500P group and ten deaths in the 4B30E360P group were associated with disease progression.
HRQL scores for eight side effects associated with chemotherapy (as assessed by the GLQ-8 questionnaires were available for 149 patients (90%)). HRQL scores were similar for both regimens.
The primary differences in HRQL between the groups at 3, 6, and 12 weeks occurred in scores for numbness or pins-and-needles sensations (p=0.003), hair loss (p=0.04), and Spitzer Quality of Life Index (p=0.05), which were better in the 3B90E500P group. Scores for most scales returned to baseline levels at 6 months.r
Also consider potential long-term toxicity of BEP including infertility, ototoxicity, Raynaud’s phenomenon, peripheral neuropathy, lung disease, cardiovascular disease and secondary malignancies.r