Fast track — ArticlesPaclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial
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.
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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
References (19)
- et al.
Cancer burden in the year 2000: the global picture
Eur J Cancer
(2001) ICON2: randomised trial of single–agent carboplatin against three–drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer
Lancet
(1998)Chemotherapy in advanced ovarian cancer: four systematic meta–analyses of individual patient data from 37 randomized trials
BrJ Cancer
(1998)- et al.
Second–line platinum therapy in patients with ovarian cancer previously treated with cisplatin
J Clin Oncol
(1991) - et al.
Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103
J Clin Oncol
(1993) Paclitaxel plus carboplatin versus standard chemotherapy with either single–agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial
Lancet
(2002)- et al.
Second-line therapy with paclitaxel and carboplatin for recurrent disease following first-line therapy with paclitaxel and platinum in ovarian or peritoneal carcinoma
J Clin Oncol
(1998) - et al.
Retrospective analysis of carboplatin and paclitaxel as initial second-line therapy for recurrent epithelial ovarian carcinoma: application toward a dynamic disease state model of ovarian cancer
J Clin Oncol
(2002) - et al.
Carboplatin dosage: prospective evaluation of a simple formula based on renal function
J Clin Oncol
(1987)