Elsevier

The Lancet

Volume 360, Issue 9332, 17 August 2002, Pages 505-515
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(02)09738-6Get rights and content

Summary

Background

Previously, we have shown that the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) and singleagent carboplatin produce similar survival and progression-free survival rates in women with ovarian cancer. Subsequently, paclitaxel combined with platinum has become a widely accepted treatment for the disease. We aimed to compare the safety and efficacy of paclitaxel plus carboplatin with a control of either CAP or carboplatin alone.

Methods

Between February, 1995, and October, 1998, we enrolled 2074 patients from 130 centres in eight countries. Women were randomly assigned paclitaxel plus carboplatin or control, the control (CAP or single-agent carboplatin) being chosen by the patient and clinician before randomisation. The primary outcome measure was overall survival. Secondary outcomes were progression-free survival and toxicity. Analysis was by intention to treat.

Findings

With a median follow-up of 51 months, 1265 patients had died, and survival curves showed no evidence of a difference in overall survival between paclitaxel plus carboplatin and control (hazard ratio 0·98, 95% CI 0·87–1·10, p=0·74). The median overall survival was 36·1 months on paclitaxel plus carboplatin and 35·4 months on control (difference 0·7 months, 95% CI −3·6 to 4·7). 1538 patients had progressive disease or died, and again, Kaplan-Meier curves showed no evidence of a difference between the groups (hazard ratio 0·93, 95% CI 0·84–1·03, p=0·16). Median progression-free survival was 17·3 months on paclitaxel plus carboplatin and 16·1 months on control (difference 1·2 months, 95% CI −0·5 to 2·8). Paclitaxel plus carboplatin caused more alopecia, fever, and sensory neuropathy than carboplatin alone, and more sensory neuropathy than CAP. CAP was associated with more fever than paclitaxel plus carboplatin.

Interpretation

Single-agent carboplatin and CAP are as effective as paclitaxel plus carboplatin as first-line treatment for women requiring chemotherapy for ovarian cancer. The favourable toxicity profile of single-agent carboplatin suggests that this drug is a reasonable option as first-line chemotherapy for ovarian cancer.

Introduction

Ovarian carcinoma is the sixth most common cancer of women worldwide and accounts for the greatest number of deaths from gynaecological malignancy in Europe and North America. About 165 000 women are diagnosed in these countries each year, at a median age of 55 years.1, 2

Primary treatment for all stages of disease usually consists of surgery, typically including a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy with or without lymphadenectomy. Most women are offered some form of chemotherapy after surgery, but the prognosis for patients who present with advanced disease is poor, with about 30% surviving for 5 years after diagnosis.3

Ovarian cancer was one of the first solid malignant tumours to be treated by chemotherapy, and single alkylating agents (eg, cyclophosphamide, melphalan, and chlorambucil) were used in treatment until the mid-1970s. Since then, the platinum compound cisplatin has become the mainstay of treatment for women with advanced disease. Several meta-analyses published in the 1990s4, 5, 6 helped to clarify the roles of cisplatin, its analogue carboplatin, and the anthracycline doxorubicin in this disease. These meta-analyses led directly to the ICON2 trial, which compared the three-drug combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) against carboplatin given at an optimum dose as a single agent. With 1526 patients randomised, ICON2 showed reliably that there was no evidence of a difference between these two regimens in terms of progression-free survival and overall survival.7

Also in the early 1990s, the drug paclitaxel was first tested in ovarian cancer, and a Gynaecological Oncology Group trial (GOG-111) compared cisplatin (75 mg/m2) plus cyclophosphamide (750 mg/m2) with cisplatin (75 mg/m2) plus paclitaxel (135 mg/m2 over 24 h) in 410 women with suboptimally debulked ovarian cancer of International Federation of Gynecology and Obstetrics (FIGO) stage III or IV.8 The results of GOG-111 gave a hazard ratio of 0·66 (95% CI 0·53–0·83) for progression-free survival and of 0·61 (0·47–0·79) for overall survival, both in favour of paclitaxel plus cisplatin. These results translate into an absolute improvement in median progression-free and overall survival of 5 months (13 vs 18 months) and 14 months (24 vs 38 months), respectively, for women who received paclitaxel plus cisplatin.

Two further randomised trials comparing paclitaxel plus cisplatin against a cisplatin-based control group have also been reported. A European-Canadian Intergroup trial (OV10)9 with a similar design to GOG-111, but with paclitaxel used at 175 mg/m2 over 3 h and including a broader range of patients, gave similar results in 680 women. Hazard ratios were 0·74 (0·63–0·88) and 0·73 (0·60–0·89) for progression-free and overall survival, respectively. These results translate into absolute improvements in median progression-free and overall survival of 4 months (12 vs 16 months) and 10 months (25 vs 35 months), respectively. By contrast, in a further GOG trial (GOG-132),10 in which 645 women were randomised between three treatment groups, there was no evidence of a difference in survival between cisplatin alone (at 100 mg/m2) and the combination of paclitaxel (135 mg/m2, over 24 h) and cisplatin (75 mg/m2), with hazard ratios of 1·06 (0·86–1·30) and 0·99 (0·80–1·23) for progression-free and overall survival, respectively. These ratios translate into absolute differences in median progression-free survival and overall survival of 0·9 months (16·0 vs 15·1 months) in favour of cisplatin alone and 0·3 months (30·0 vs 30·3 months) in favour of the combination regimen.

The interpretation of these three trials has been discussed in detail elsewhere.11, 12 As a consequence of these trials, some have suggested that paclitaxel plus cisplatin should be the standard first-line treatment for women with advanced ovarian cancer.13 However, because of concern over neurotoxicity with the paclitaxel plus cisplatin combination and evidence of the approximate equivalence of cisplatin and carboplatin from metaanalyses,4 many countries and centres now use paclitaxel and carboplatin as routine treatment for these women.13 Preliminary results from three randomised trials comparing paclitaxel plus carboplatin with paclitaxel plus cisplatin suggest that they are similar in terms of progression-free and overall survival, but with a reduced incidence of neurotoxicity with the carboplatin combination.14, 15, 16

In ICON3, we aimed to compare paclitaxel plus carboplatin against a (non-taxane-containing) platinumbased control group. When ICON3 was launched, the results of ICON2 were immature but suggested that single-agent carboplatin and the three-drug combination of CAP were both appropriate control groups. Thus, clinicians were allowed to choose which of these control regimens they were going to use for each patient, but this choice had to be specified before randomisation. The mature results of ICON2 showed no evidence of a difference in survival or progression-free survival between carboplatin and CAP, and thus the choice between the two control regimens was allowed throughout ICON3.

Section snippets

Patients

The main eligibility criteria were that: the clinician was certain that the patient required, and was fit to receive, chemotherapy; the patient had histologically confirmed invasive ovarian cancer of epithelial origin; there was no concomitant or previous malignant disease likely to interfere with treatment or outcomes; the patient had not received any previous radiotherapy or chemotherapy, and the patient had given her informed consent to enter the trial. There were no restrictions on the

Patients and treatment received

Between February, 1995, and October, 1998, 2074 patients were entered from 130 centres in eight countries. The accrual periods varied in the different randomising centres: February, 1995, to June, 1998, for the MRC; August, 1995, to October, 1998, for the Istituto Mario Negri; December, 1996, to May, 1998, for SAKK; and April, 1997, to May, 1998, for the NSGO. Of the 2074 patients, 1421 were randomised between single-agent carboplatin and paclitaxel plus carboplatin. The remaining 653 patients

Discussion

Our results show that the combination of paclitaxel and carboplatin was not superior to either CAP or singleagent carboplatin as a first-line treatment for women requiring chemotherapy for ovarian cancer. However, we found evidence which confirms that paclitaxel plus carboplatin was more toxic than carboplatin alone, in particular causing more alopecia, fever, and sensory neuropathy. Comparing CAP and paclitaxel plus carboplatin, CAP was associated with more fever and paclitaxel plus

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