B. Baron

Prospective randomised study of split-course radiotherapy versus cisplatin plus split-course radiotherapy in inoperable squamous cell carcinoma of the oesophagus.

Between 1983 and 1989, 211 patients with inoperable squamous cell carcinoma of the oesophagus were randomised in a study comparing split-course irradiation (two courses of 20 Gy in five fractions of 4 Gy, separated by a rest of 2 weeks) (arm A) and the same split-course irradiation in combination with cisplatin (CDDP) (3-4 days before each of the two courses of radiotherapy, repeated every 3-4 weeks, for a total of six cycles) (arm B). The Coxs regression model with retrospective stratification was used to compare the two arms to correct for the imbalance at randomisation of the T classification. The median overall survival was 7.9 (95% confidence interval (CI) 7.3-9.4) months in arm A and 9.6 (95% CI 8-13.5) months in arm B. The difference in overall survival was only borderline significant (P=0.048) with a reduction of the instantaneous rate of death of 24%. The 1 and 2 year overall survival rate were respectively 29% (95% CI 21-37%) and 15% (95% CI 8-22%) in arm A and 45% (95% CI 36-54%) and 20% (95% CI 13-27%) in arm B; thereafter, the survival curves became similar. The median progression free survival (PFS) was 5.0 (95% CI 4.6-5.7) versus 6.9 (95% CI 5.3-8.7) months (P=0.028) and the median time to local progression was 6.2 (95% CI 5.1-7.6) months versus 10.9 (95% CI 8.1-15.5) months (P=0.018), respectively, in arms A and B. Haematological toxicities were slightly more commonly observed in the combined group (1% versus 6%). This study shows that split-course irradiation in combination with CDDP is very well tolerated and should be preferred to radiotherapy alone.

Results of a randomised phase II study of cisplatin plus 5-fluorouracil versus cisplatin plus 5-fluorouracil with α-interferon in metastatic pancreatic cancer: an EORTC gastrointestinal tract cancer group trial

A randomised phase II study of 5-fluorouracil (5-FU) plus cisplatin (CDDP) with or without alpha-interferon 2b was performed in patients with pancreatic cancer with measurable metastatic disease outside the pancreas. The treatment in arm A consisted of cisplatin (100 mg/m(2)) on day 1, followed by a continuous infusion of 5-FU 1000 mg/m(2) for 4 days and in arm B the same treatment was given plus alpha-interferon 2b in a dose of 3 million Units/day subcutaneously (s.c.) from day 1 for 5 days. 36 patients were entered in the trial, 18 in each arm. In arm B only 15 patients were eligible. No responses were observed in the 5-FU/CDDP arm and only 2 partial responses were achieved in the interferon-arm, lasting 27 and 32 weeks, respectively. Both treatment arms showed considerable toxicity. It has to be concluded that both treatment regimens have little activity and cannot be recommended.

Statistical methodology of phase III cancer clinical trials: advances and future perspectives

The methodology for conducting cancer clinical trials has undergone enormous changes over the past 25-30 years since the EORTC Data Center was created. The purpose of this paper is to highlight and to provide a historical perspective for the main methodological concepts, both practical and theoretical, which form the basis for the design and analysis of phase III cancer clinical trials within the EORTC Data Center. Some statistical aspects of other associated topics such as quality of life, health economics, meta-analysis and treatment outcome will also be briefly discussed. Finally, some future perspectives and topics for further statistical methodological research will be presented in order to spur statisticians to meet the challenge of efficiently designing and analysing the clinical trials of tomorrow.

Phase II study on 9-nitrocamptothecin (RFS 2000) in patients with advanced or metastatic urothelial tract tumors

Objective: To investigate the antitumor activity and the safety of RFS2000, an oral topoisomerase I inhibitor, in patients with advanced or metastatic urothelial tract tumors refractory to one prior chemotherapy regimen. Patients and methods: Eligible patients were to have failed first line treatment for advanced or metastatic disease. Patients received RFS2000 as one daily oral intake at the dose of 1.5 mg/m2/day according to a “5 days on/2 days” off schedule continuously. One cycle was arbitrarily defined as a 3 week period. Sufficient oral fluid intake to prevent cystitis previously described in phase I trials with RFS2000 was recommended. Gehan design was used for sample size determination. Anti-tumor activity was evaluated according to the RECIST criteria and toxicity according to CTC version 2. Results: Twenty patients received a total of 57 cycles (range 1–8). Grade 3–4 toxicity was observed in 10 patients requiring dose or schedule modifications. Hematological grade 3–4 toxicity was observed in 16% of the cycles. Only one patient experienced a partial response. Conclusions: RFS2000 could be administered orally as a “5 days on/2 days off” schedule continuously with a median dose intensity of 90.6% with an acceptable toxicity profile. However, RFS2000 did not exert significant activity in patients with advanced/metastatic urothelial tract tumors failing prior chemotherapy. The results of this study do not suggest further investigation of RFS2000 at the present dose and schedule for the treatment of urothelial tract tumors in this refractory population.