Good manners for the pharmaceutical industry

THE LANCET

Good manners for the pharmaceutical industry SIR—The results of two randomised studies of cisplatin-cyclophosphamide versus cisplatin-paclitaxel in advanced epithelial ovarian cancer are now available (Gynecologic Oncology Group trial no 111 and the Intergroup trial).1,2 Your June 7 editorial3 makes two inaccurate statements: these studies are not “relatively small” since their combined total is over 1000 patients, and to describe the Intergroup results as preliminary is misleading since it implies that the interpretation may change with further follow-up. This is unlikely because the primary endpoint is progression-free survival and 469 events have occurred (data presented in May, 1997, at the American Society for Clinical Oncology meeting). Response rates and progression-free survival show an impressive advantage for cisplatinpaclitaxel (table). A third study, also presented at ASCO, GOG no 132,4 randomised patients to cisplatin-paclitaxel or singleagent cisplatin or paclitaxel. Response rates to single-agent paclitaxel were significantly lower than those observed in the other two arms, but there was no difference between the three in terms of progression-free or overall survival. This trial has been used to justify not adopting cisplatin-paclitaxel as standard. However, in GOG-132 half the patients crossed over to one of the other treatment groups and this sometimes happened before progression was documented, which calls into question the progression-free survival data. GOG132 is therefore essentially a study of sequential cisplatin-paclitaxel versus first-line treatment with the two drugs combined. It has been difficult to demonstrate an overall survival benefit for individual chemotherapy agents in ovarian cancer because of the relative salvage effect of “crossover” treatment. Advanced Ovarian Cancer Trialists Group5 metaanalysis failed to prove a survival benefit for platinum-based regiments compared with non-platinum-based chemotherapy yet everyone accepts Treatment

platinum as standard. This explains the excitement over GOG-111 and the immediate adoption of the cisplatinpaclitaxel regimen in some quarters. We were unhappy with this change, based on only one trial, and said so at the International Gynaecological Cancer Society in September, 1995. ICON 3 was designed to detect a 10% difference in 2-year survival. 1254 patients have been recruited but with only about 100 events, there is little to analyse. The data monitoring committee has recommended a further 800 patients to allow 4–5% difference in survival to be detected and to permit subset analysis of the two treatments on the main prognostic indicator, the bulk of residual disease after initial surgery. If we assume a range of possible 5-year survivals of 40% down to 15%, a 50% baseline survival at two years (ICON 3 protocol), and statistical power of 90% we calculate that only a 1–2% extra survival benefit can be detected by the addition of 800 patients. The AOCTG overview strongly suggests that carboplatin and cisplatin are of similar efficacy5 (updated by L Stewart in 1997) and there are obvious advantages to carboplatin including reduced neurotoxicity, ototoxicity, and renal toxicity and avoidance of intravenous hydration before and after treatment. Also single-arm carboplatin-paclitaxel dose-escalation phase I/II studies show this to be a well-tolerated regimen. The problem facing ICON 3 investigators is that two good trials already show an impressive advantage in terms of response rates and progression-free survival for cisplatin-paclitaxel over a standard platinum combination regimen. First-line treatment with carboplatin-paclitaxel could therefore be advocated with its low toxicity. ICON 3 is an important trial but crossover treatment may confound the survival data and a further 800 patients are not going to help with the statistical evaluation of any impact on survival. *Martin Gore, Roger A’Hern, Kenneth Swenerton *Royal Marsden Hospital, London SW3 6JJ, UK; and BC Cancer Agency, Vancouver Cancer Centre, BC, Canada

Responses

Progression-free survival

No

%

HR (95% CI)

p

No

Median mo

HR (95% CI)

GOG 111 PC PP

116 100

60 73

Intergroup PC PP

151 149

Overall PC PP

267 249

p

1·76 (1·00–3·09)

<0·05

202 184

13 18

0·7 (0·5–0·8)

<0·001

66 77

1·71 (1·04–2·83)

<0·05

330 338

11 14

0·66 (0·52–0·77)

<0·0001

64 75

1·73 (1·19–2·52)

<0·004

532 522

.. ..

0·68 (0·58–0·79)

<0·000001

PC=cisplatin-cyclophosphamide, PP=cisplatin-paclitaxel, HR=hazard ratio (and 95 % confidence interval).

Response rates and progression-free survival in GOG-111 and Intergroup studies

370

1

2

3

4

5

McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334: 1–6. Piccart MJ, Bertelsen K, Stuart G, et al. Is cisplatin-paclitaxel the standard in first-line treatment of advanced ovarian cancer? The EORTC-GCCG, NOCOVA, NCI-C and Scottish intergroup experience. Proc ASCO 1997; 16: 1258. Editorial. Good manners for the pharmaceutical industry. Lancet 1997; 349: 1635. Muggia FM, Braly PS, Brady MF, et al. Phase III of cisplatin or paclitaxel, versus their combination in suboptimal stage III and IV epithelial ovarian cancer: Gynecologic Oncology Group study 132. Proc ASCO 1997; 16: 1257. Advanced Ovarian Cancer Trialists Group. Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. BMJ 1991; 303: 884–93.

SIR—Your June 7 editorial,1 discusses the negative response of Bristol-Myers Squibb to the recommendation by the independent data monitoring committee that the ICON 3 trial should continue. In this trial patients with epithelial ovarian cancer are randomised to receive paclitaxel plus carboplatin or an appropriate platinum control. As one of the larger contributors to the ICON 3 trial, I wish to disagree with the position taken by Bristol-Myers Squibb. The presentation of early data from the Intergroup study2 at the American Society of Clinical Oncology meeting in May, 1997, which confirmed the improvement in progression-free survival study previously shown by the GOG-111 trial3 lends support to the use of paclitaxel in the first-line treatment of patients with epithelial ovarian cancer. However, the publication of data from GOG-1324 at the same meeting demonstrated just how difficult it is to draw conclusions from the results of individual clinical trials. In GOG-132 patients with advanced disease were randomised three ways, and received full-dose single agent cisplatin, paclitaxel 200 mg/m2 given as a 24-h infusion, or a combination of cisplatin and paclitaxel as used previously in GOG-111. Progression-free survival for the two platinum containing arms of the trial was significantly better than in the single agent paclitaxel arm (11·4 months), but there was no difference between single-agent cisplatin and the cisplatin-paclitaxel combination (16·4 and 14·1 months, respectively). There was no difference between the three arms in the survival analysis (paclitaxel 25·9 months, cisplatin 30·2 months, cisplatin-paclitaxel 26·6 months). One of the main differences between GOG132 and both the Intergroup study and GOG-111 is the widespread use of paclitaxel as a salvage treatment. In the UK carboplatin is the most

Vol 350 • August 2, 1997