ArticlesComparison of two standard chemotherapy regimens for good-prognosis germ-cell tumours: a randomised trial
Introduction
Germ-cell tumours most commonly arise in the testis and are the most frequent malignancies affecting adult men younger than 35 years in western societies.1, 2 In the late 1970s, the addition of cisplatin to existing chemotherapy (vinblastine and bleomycin) substantially improved the results of treatment for patients with metastatic germ-cell tumours.3 With this three-drug regimen, cure was achievable in more than 70% of cases.
A rational and well-conducted series of clinical trials further refined management. These trials showed that a brief course of chemotherapy was adequate4, 5, 6, that etoposide was preferable to vinblastine,5, 7, 8 and that prognostic classification on the basis of clinical characteristics was worthwhile.9, 10 An international consensus judged that the optimum chemotherapy for good-prognosis germ-cell tumours comprises three or four cycles of cisplatin and etoposide with or without bleomycin.11 However, there remained significant variation in the dose and schedules of these drugs and in the criteria used to classify prognosis.11
A survey of treatment patterns in Australia by the Australian and New Zealand Germ Cell Trial Group (AGCTG) in the early 1990s revealed substantial variations in management at participating centres. About half of the centres used a 5-day chemotherapy regimen incorporating 500 mg/m2 etoposide per cycle, as used in the USA. The remaining centres generally used a 3-day chemotherapy regimen incorporating etoposide at a dose of 360 mg/m2 per cycle, based on regimens commonly used in the UK. On the basis of the results of a previous AGCTG study,12 almost all centres used bleomycin, but many investigators were uncertain about the optimum dose and schedule in view of the unpredictable toxicity of this drug.
The AGCTG decided to compare two “standard” regimens of chemotherapy, each incorporating cisplatin, etoposide, and bleomycin, in a randomised clinical trial. The first regimen was based on treatment recommendations from Indiana University, USA,13 and is referred to as regimen A. The second regimen was based on the control treatment of a UK Medical Research Council and European Organisation for Research and Treatment of Cancer (MRC/EOTRC) clinical trial that was underway at that time. The results of that trial have since been published and show 97% survival at 3 years in the control group.14 This regimen is referred to as regimen B.
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Patients
Eligible patients had a histologically confirmed germ-cell tumour (seminoma or non-seminoma) with: measurable disease or raised concentrations of tumour markers in serum; adequate haematological, renal, and hepatic function; and good prognostic features as defined below. Patients with a histological diagnosis of seminoma but a raised serum a-fetoprotein concentration were classified as having non-seminoma. Classification of good prognosis was based on modified Memorial Sloan-Kettering Cancer
Interim analyses
166 patients were randomised from February, 1994, to April, 2000, when recruitment was suspended after the second planned interim analysis. This analysis in March, 2000, suggested superior survival for regimen A (two vs 13 deaths among 148 patients, log-rank p=0–004), and as a result, the independent safety and data monitoring committee recommended that the trial executive review the data. The executive suspended recruitment and instigated an additional analysis with further follow-up. This
Discussion
The use of three or four cycles of cisplatin and etoposide chemotherapy, with or without bleomycin, represents the standard of care for patients with metastatic germ-cell tumours with a good prognosis requiring chemotherapy.11 The dose of etoposide used traditionally in many UK and European centres has been 360 mg/m2 divided over 3 days. In contrast, the US practice has been to give etoposide at a dose of 500 mg/m2 divided over 5 days. The role of bleomycin has been a source of substantial
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