Elsevier

The Lancet

Volume 361, Issue 9375, 21 June 2003, Pages 2099-2106
The Lancet

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Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial

https://doi.org/10.1016/S0140-6736(03)13718-XGet rights and content

Summary

Background

Despite improvements in the treatment of ovarian cancer, most patients develop recurrent disease within 3 years of diagnosis. There is no agreed second-line treatment at relapse. We assessed paclitaxel plus platinum chemotherapy as such treatment.

Methods

In parallel international, multicentre, randomised trials, between January, 1996, and March, 2002, 802 patients with platinum-sensitive ovarian cancer relapsing after 6 months of being treatment-free were enrolled from 119 hospitals in five countries. Patients were randomly assigned paclitaxel plus platinum chemotherapy or conventional platinum-based chemotherapy. Analysis was by intention to treat, except for toxic effects.

Findings

With a median follow-up of 42 months, 530 patients have died. Survival curves showed a difference in favour of paclitaxel plus platinum (hazard ratio 0·82 [95% CI 0·69–0·97], p=0·02), corresponding to an absolute difference in 2-year survival of 7% between the paclitaxel and conventional treatment groups (57 vs 50% [95% CI for difference 1–12]), and median survival of 5 months (29 vs 24 months [1–11). 717 patients developed progressive disease or died. The progression-free survival curves show a difference in favour of paclitaxel plus platinum (hazard ratio 0·76 [0·66–0·89], p=0·0004), corresponding to an absolute difference in 1-year progression-free survival of 10% (50 vs 40% [4–15]) and in median progression-free survival of 3 months (13 vs 10 months [1–5]).

Interpretation

Paclitaxel plus platinum chemotherapy seems to improve survival and progression-free survival among patients with relapsed platinum-sensitive ovarian cancer compared with conventional platinum-based chemotherapy.

Introduction

Ovarian cancer is the fourth most common cancer in women, and accounted for an estimated 114 000 deaths worldwide in 2000.1 Treatments for this disease have improved over the past 30 years, with advances in surgery and platinum-based chemotherapy, but most women with ovarian cancer still develop recurrent disease and die within 5 years.

No best second-line treatment is agreed on for relapsing disease, although several agents are available. For first-line treatment platinum-based chemotherapy is given, and increasingly carboplatin, with or without a taxane, is used rather than cisplatin, since it has less toxicity and equivalent activity.2, 3 At relapse, the probability of response to re-treatment with platinum-based chemotherapy depends on the platinum-free interval.4 When the interval is longer than 6 months, many clinicians would re-treat patients with platinum with the same drug or alternating between carboplatin and cisplatin. Women whose disease progresses while receiving initial platinum-based treatment, and those who develop recurrent disease within 6 months of platinum-based treatment rarely respond to further platinum-based treatment, and are deemed to have platinum-resistant disease. Paclitaxel is an active drug,5 and was first licensed for such patients. This drug is generally well tolerated, with alopecia, myelosuppression, and neuropathies being the most common side-effects.

Most patients do not have platinum-resistant disease but do relapse 6 or more months after first-line treatment.6 Whether the introduction of a drug such as paclitaxel, which has a different mode of action to platinum, would benefit these patients when given in combination with platinum, more than rechallenge with conventional platinum-based chemotherapy is unclear. In observational studies in relapsing patients with platinum-sensitive disease, response rates of up to 90% have been reported after treatment with carboplatin and paclitaxel.7, 8 However, we know of no previous randomised trial that has compared paclitaxel plus platinum with conventional platinum-based chemotherapy in patients with ovarian cancer relapsing 6 or more months after chemotherapy. In the International Collaborative Ovarian Neoplasm 4 (ICON4) and Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) OVAR-2·2 randomised trials, we assessed the effectiveness of paclitaxel in combination with platinum in previously treated ovarian cancer. We aimed particularly to find out whether paclitaxel should be given in addition to platinum-based chemotherapy in patients who are judged to have platinum-sensitive disease and who would otherwise be treated with more conventional platinum-containing regimens.

Section snippets

Patients and methods

ICON4 and AGO-OVAR-2.2 were run as parallel trials. ICON4 was coordinated by the Istituto Mario Negri, Milan, Italy (IRFMN), and the Medical Research Council's Clinical Trials Unit, London, UK (MRC CTU). AGO-OVAR-2.2 was coordinated by AGO, Karlsruhe, Germany.

Results

802 patients were enrolled in the study. The accrual periods varied in the three protocols: January, 1996, to March, 2002, for the Italian ICON4 group; May, 1996, to March, 2002, for the MRC CTU ICON4 group; and October, 1996, to September, 1999, for AGO. 410 patients were assigned conventional platinum-based chemotherapy and 392 paclitaxel plus platinum chemotherapy (figure 1). Pretreatment characteristics were similar in the two treatment groups (table 1).

The types of treatment recieved are

Discussion

Given the findings for progression-free survival and overall survival, sufficient patients in our study were alive and at risk at 4 years to state that the overall results are reliable up to this time. 90% of the patients were randomised after first relapse, and 75% more than 12 months after completion of platinum-based chemotherapy. These patients would be deemed as having a reasonable outlook. The fact that this is a large trial has allowed us to explore subgroups to assess the consistency of

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