A Medical Research Council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma

Abstract

The UK Medical Research Council conducted this trial of carboplatin chemotherapy in advanced seminoma to compare single agent carboplatin with a standard combination of etoposide with cisplatin. The use of single agent carboplatin was expected to be associated with reduced toxicity. A total of 130 patients with advanced seminoma were randomly assigned to treatment with either single agent carboplatin (C) at a dose of 400 mg/m 2 to be corrected for glomerular filtration rate outside the range 81–120 ml min –1 and to be administered on day 1 of a 21 day cycle to a total of 4 cycles or to etoposide + platinum (EP). The trial was designed as an equivalence study aiming to exclude a reduction in the 3-year progression-free survival in patients allocated to carboplatin of between 10 and 15%, requiring initially a target accrual of 250 patients (90% power significance level 5% (one-sided)). The trial closed after 130 patients had been randomized following recommendation by an independent data monitoring committee. At a median follow-up time of 4.5 years, 81% of patients had been followed up for at least 3 years and 19 patients have died. The estimated PFS rate (95% Confidence Intervals (CI)) at 3 years was 71% (60–82%) in patients allocated C and 81% (71–90%) in those allocated EP; the 95% CI for the difference in 3 year PFS was – 6% to +19%. The hazard ratio of 0.64 (95% CI 0.32–1.28) favoured EP but the difference was not statistically significant (log rank chi-squared = 1.59 P = 0.21). The 3-year survival rate was 84% (75–92%) in those allocated C, and 89% (81–96%) in those allocated EP. The hazard ratio for survival was 0.85 with 95% CI, 0.35–2.10, log rank chi-squared = 0.12, P = 0.73. The trial has not demonstrated statistically significant differences in the major survival endpoints comparing single agent carboplatin with a combination of etoposide + cisplatin. This cannot be taken as an indication of equivalence since the limited size of this trial rendered it unable to exclude a 19% lower progression-free survival and survival in those treated with single agent carboplatin which would be important clinically. Standard initial chemotherapy for advanced seminoma should be based on cisplatin combinations and the role of carboplatin awaits the outcome of further studies. © 2000 Cancer Research Campaign http://www.bjcancer.com

Metastatic seminoma treated with either single agent carboplatin or cisplatin-based combination chemotherapy: a pooled analysis of two randomised trials

“…The promising results observed in phase II studies for single agent carboplatin therapy in patients with metastatic seminoma have served as the rationale for two randomised phase III trials conducted in Great Britain and Germany, which compared single agent carboplatin therapy with cisplatin-based combination regimens (Clemm et al, 2000;Horwich et al, 2000). The British trial, however, was prematurely closed due poor accrual and to reports of inferiority of carboplatin-based therapy in patients with metastatic nonseminoma.…”

“…The British trial, however, was prematurely closed due poor accrual and to reports of inferiority of carboplatin-based therapy in patients with metastatic nonseminoma. The analysis of the 130 seminoma patients randomised until closure of the trial revealed a nonsignificant 10% difference in progression-free and a nonsignificant 5% difference in overall survival in favour of the combination of cisplatin/etoposide (Horwich et al, 2000). The results of the German randomised trial based on 250 patients have demonstrated a statistically significant 21% absolute lower progression-free survival rate following carboplatin therapy compared with the combination of cisplatin, etoposide, and ifosfamide (Clemm et al, 2000).…”

“…The individual patient data of 130 patients with advanced seminoma included in the British trial and of 250 patients included in the German randomised phase III trial were obtained (Clemm et al, 2000;Horwich et al, 2000). In total, 19 patients were excluded from the analysis due to missing data.…”

“…In the British trial single agent carboplatin was compared with the combination of cisplatin and etoposide whereas in the German study the combination of cisplatin, etoposide and ifosfamide was chosen as the standard arm. The British seminoma study was closed early after the enrollment of 130 patients due to poor accrual and to results of randomised trials demonstrating inferiority of carboplatin-based combinations compared with cisplatin-based regimens in patients with metastatic nonseminoma (Bokemeyer et al, 1996;Horwich et al, 2000). The final results of the German randomised seminoma trial on single agent carboplatin have not yet been fully published; however, the first analysis after completion of accrual has indicated an inferiority of carboplatin single agent therapy regarding progression-free survival (Clemm et al, 2000).…”

2007 Systematic review: Primary treatments for testicular germ cell tumours after radical orchidectomy. Summary report

“…Patient atteint d'une tumeur germinale sé minomateuse de stade avancé L'analyse a porté sur deux é tudes de qualité mé thodologique critiquable : une é tude ré trospective é valuant la place de la chimiothé rapie (EP ou BEP ou VAB modifié ) par rapport à la radiothé rapie (25 ou 25 Gy + boost de 10 ou 30-45 Gy) chez 128 patients [9] et une analyse poolé e sur donné es individuelles de deux essais randomisé s [11,24] comparant chez 361 patients mé tastatiques une monochimiothé rapie (carboplatine) à une polychimiothé -rapie (VIP ou EP) [7].…”