Elsevier

The Lancet

Volume 357, Issue 9258, 10 March 2001, Pages 739-745
The Lancet

Articles
Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumours: a randomised trial

https://doi.org/10.1016/S0140-6736(00)04165-9Get rights and content

Summary

Background

Most patients with metastatic germ-cell tumours are cured with chemotherapy. However, the optimum chemotherapy regimen is uncertain, and there is variation in international practice. We did a multicentre randomised trial to compare two standard chemotherapy regimens for men with good-prognosis germ-cell tumours.

Methods

Good prognosis was defined by modified Memorial Sloan-Kettering criteria. The first regimen (regimen A) was based on treatment recommendations from Indiana University and comprised three cycles of 20 mg/m2 cisplatin on days 1–5, 100 mg/m2 etoposide on days 1–5, and 30 kU bleomycin on days 1, 8, and 15, repeated every 21 days. The second regimen (regimen B) was based on the control regimen of a published randomised clinical trial and comprised four cycles of 100 mg/m2 cisplatin on day 1, 120 mg/m2 etoposide on days 1–3, and 30 kU bleomycin on day 1, repeated every 21 days. The primary outcome measure was overall survival. Analysis was by intention to treat.

Findings

166 patients were randomised, 83 to each regimen. The trial was stopped when the second planned interim analysis met predefined stopping rules. The median follow-up was 33 months. Overall survival was substantially better with regimen A (three vs 13 deaths, hazard ratio 0·22 [95% CI 0·06–0·77], p=0·008). This difference was due to deaths from cancer (one vs nine), and not deaths from treatment (two vs two) and remained significant after adjustment for other prognostic factors (0·25 [0·07–0·88], p=0·03).

Interpretation

In men with good-prognosis germ-cell tumours, the regimen developed at Indiana University is superior to the alternative regimen studied in this trial. The lower total dose and dose-intensity of bleomycin and the lower dose-intensity of etoposide in regimen B could be responsible for the worse outcome.

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.

Section snippets

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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