International Collaborative Ovarian Neoplasm (ICON1) Collaborators1
Affiliations of Writing Committee: N. Colombo, European Institute of Oncology, Milan, Italy; D. Guthrie, M. Parmar, W. Qian, A. M. Swart, Medical Research Council Clinical Trials Unit, London, U.K.; S. Chiari, A. Lissoni, C. Bonazzi, Ospedale San Gerado, Monza, Italy; V. Torri, Mario Negri Institute, Milan; C. Williams, Cochrane Cancer Network, Oxford, U.K.
Correspondence to: Mahesh Parmar, Ph.D., Medical Research Council Clinical Trials Unit, 222 Euston Rd., London NW1 2DA, U.K. (MP{at}ctu.mrc.ac.uk).
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ABSTRACT |
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INTRODUCTION |
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The question of whether immediate adjuvant chemotherapy after surgery would prolong the time to recurrence and improve survival in patients with early-stage epithelial ovarian carcinoma was identified in 1990 by the Advanced Ovarian Cancer Trialists Group (AOCTG) as requiring investigation. In response, the International Collaborative Ovarian Neoplasm (ICON) collaborators initiated a randomized trial in 1991 of immediate adjuvant chemotherapy for early-stage ovarian cancer (ICON1). At the same time, the European Organisation for Research and Treatment of Cancer (EORTC) initiated a similar trial on Adjuvant ChemoTherapy In Ovarian Neoplasm (ACTION), the results of which are reported in this issue (5). Early in the course of both trials, it was planned that a single independent data-monitoring committee would review the combined accumulating data from both the ICON1 and ACTION trials.
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PATIENTS AND METHODS |
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The rate of recurrence and death in early-stage ovarian cancer patients is low, and because differences in outcomes between the two treatments were likely to be modest, a large number of patients was required. Therefore, the eligibility criteria were kept as simple as possible. The ICON studies consisted of two independent trials of chemotherapy that were initiated at the same time; one for earlier stage disease (ICON1) and one for more advanced-stage disease (ICON2). The trials were designed to be complementary so that every patient with epithelial ovarian cancer could be considered for entry into one of these randomized trials.
The protocol asked the following question of clinicians: In the opinion of the responsible clinician, does the patient require immediate chemotherapy? If the clinician was uncertain, he or she was asked to consider entering the patient into ICON1, the earlier stage trial. If the clinician was certain about the need for immediate chemotherapy, he or she was asked to consider entering the patient into ICON2, the more advanced-stage trial, which compared single-agent carboplatin with a three-drug combination of cyclophosphamide + doxorubicin + cisplatin (CAP) (16).
The most important eligibility criteria for ICON1 were that the patient had histologically confirmed ovarian carcinoma of epithelial origin and that the clinician was uncertain as to whether to offer immediate adjuvant chemotherapy. Other criteria were that the patient was fit to receive chemotherapy, had no previous malignant disease (except nonmelanoma skin cancer), had no previous radiation therapy or chemotherapy, and had given her written informed consent to enter the trial. Approval by the ethics committee of the local institution was required before any patient could be entered in the trial.
Surgery
All visible tumor had to be removed. Thorough surgical staging, where possible, with total hysterectomy and bilateral salpingo-oophorectomy, where appropriate, and omentectomy was recommended as the minimum procedures.
Randomization and Data Collection
ICON1 was run as three parallel trials through the Istituto Mario Negri in Milan, Italy; the Swiss Group for Clinical Cancer Research (SAKK) in Bern, Switzerland; and the Clinical Trials Unit of the Medical Research Council (MRC CTU), Cancer Division London, U.K. (formerly Cancer Trials Office, Cambridge, UK). Random assignment was performed in Italy for all Italian patients and in the United Kingdom for all other patients. The randomization procedure used a method of minimization stratified by center, FIGO stage (17), and degree of tumor differentiation. The same stratification factors were used in both randomization centers. The allocation sequence for randomization was generated on a computer by the MRC CTU and Istituto Mario Negri. The trial was open in that after patients were randomly assigned to one of the trial arms there was no blinding of treatment allocation to investigators, patients, or trial center staff.
Pretreatment data collected at the time of random assignment included age, stage, histologic cell type and degree of tumor differentiation (18), and planned chemotherapy regimen. Treatment and initial follow-up data were collected 6 months after randomization, and further follow-up data were collected 12 months after randomization and annually thereafter. Information on the patients vital and disease status and date of disease recurrence, if applicable, was collected at intervals of 6 months for the first year and annually thereafter. Follow-up data included information on disease and vital status and treatment for recurrence. All follow-up data were collected either by the Istituto Mario Negri (Italian centers) or by the MRC CTU (all other centers).
Adjuvant Chemotherapy
Six cycles of chemotherapy with single-agent carboplatin or CAP at intervals of 3 weeks were recommended, although other regimens that included platinum (combination carboplatin or single-agent cisplatin) were also allowed. The recommended dose of carboplatin when used as a single agent was based on the dose required to obtain an area under the curve (AUC) of 5 mg/mL; the recommended dose of carboplatin when used in combination was 4 mg/mL using the AUC method of Calvert et al. (19), in which the dose required is obtained by the formula (GFR + 25) x 5, where GFR is the measured glomerular filtration rate. The recommended dose of cisplatin when used as a single agent was 70 mg/m2. The recommended doses for the CAP regimen were cyclophosphamide at 500 mg/m2, doxorubicin at 50 mg/m2, and cisplatin at 50 mg/m2. The type of planned chemotherapy regimen for an individual patient had to be registered at the randomizing center at allocation before each patient was assigned to one of the trial arms.
Statistical Methods and Analysis
The calculation of sample size was complicated by the fact that survival was likely to vary with tumor stage and it was difficult to estimate a priori the proportions of patients at each stage. It was originally planned that 2000 patients would be accrued to ICON1, which would provide 90% power to detect an absolute increase in 5-year survival of 7% (a survival improvement from 60% to 67%) at a 5% statistical significance level (two-sided test of significance).
Originally, guidelines to consider stopping the trial were stated in the ICON1 protocol as using conservative statistical significance tests (i.e., if P<.01, consideration would be given to stopping the trial) and in the ACTION trial protocol as following the OBrien and Fleming rule (20). However, before the first analysis the investigators of both trials agreed that a single independent data-monitoring committee would monitor the combined data from both trials as it accumulated. This data-monitoring committee followed an informal guideline that they would not stop the trials unless the results were extremely positive, for example, a P value of less than .001.
During the accrual period, the data-monitoring committee noted that survival in the no-adjuvant-chemotherapy arm of the combined trials was better than anticipated and that accrual was slow. Therefore, in June of 1999, the investigators of the two trials agreed that the sample size combined across both trials could be reduced to 900 patients, with approximately 450 patients to be accrued in each trial. In a combined analysis, this would provide a sufficient number of events to detect an increase in absolute 3-year survival of 6% (a survival improvement from 85% to 91%), with 90% power at a 5% statistical significance level.
The primary outcome measure was overall survival, defined as time from randomization to death from any cause. Patients who were still alive at the time of analysis were censored on the date of their last follow-up. The secondary outcome measure was recurrence-free survival, defined as the time to clinically defined recurrence or death from any cause. KaplanMeier curves of overall survival and recurrence-free survival were compared using the MantelCox version of the log-rank test (21). The stratified log-rank test was used to allow for possible differences across the two randomizing centers. All the statistical tests were two-sided, and all analyses were performed on an intention-to-treat basis.
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RESULTS |
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Between August 1991 and January 2000, 477 patients were entered into the ICON1 trial from 84 centers in five countries (U.K., Ireland, Brazil, Switzerland, and Italy; Table 1). Two hundred forty-one patients were randomly assigned to immediate platinum-based adjuvant chemotherapy and 236 to observation until chemotherapy was indicated (i.e., no immediate adjuvant chemotherapy) (Fig. 1
). For the analysis presented here, all data collected to March 2001 (in Italy) and December 2001 (data held by the MRC) was included.
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Ninety-three percent of patients had FIGO stage I disease, and 73% had intermediate or well-differentiated tumors (Table 1). At randomization, six patients were classified as having stage III disease with no residual bulk. However, following randomization one of these patients was found to have had lung metastases and, in fact, had stage IV disease with residual bulk of more than 2 cm. Two other patients who were classified as having stage Ic and stage IIa disease, respectively, with no residual bulk, were found on review to have had stage III disease, with one patient having residual bulk of more than 2 cm.
Adjuvant Chemotherapy Received
Two hundred forty-one patients were allocated to the adjuvant chemotherapy arm. As Fig. 1 shows, 44 of these patients either did not receive adjuvant chemotherapy or did not have full information available. Of the 197 patients known to have received chemotherapy (i.e., who had a documented chemotherapy regimen), 171 (87%) patients were given single-agent carboplatin, 21 (11%) were given combination cisplatin, three (2%) were given combination carboplatin, one (<1%) was given single-agent cisplatin, and one (<1%) was given an unspecified regimen. A total of 168 patients (85%) received all six cycles of chemotherapy, although 65 of these patients had some treatment modification. A total of 29 of the 197 patients who received chemotherapy (15%) received fewer than six cycles of chemotherapy. Compliance with chemotherapy and reasons for modification are summarized in Table 2
. Six patients who were allocated to the no-adjuvant-chemotherapy arm actually received adjuvant chemotherapy.
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After a median follow-up (for patients still alive) of 51 months, a total of 103 patients died (42 in the immediate adjuvant chemotherapy arm, 61 in the no immediate adjuvant chemotherapy arm). Patients in the adjuvant chemotherapy arm had better overall survival than patients in the no-adjuvant-chemotherapy arm (hazard ratio [HR] of 0.66, 95% CI = 0.45 to 0.97; P = .03). These results translate into 5-year overall survival figures of 79% for patients who received adjuvant chemotherapy and 70% for patients who did not receive adjuvant chemotherapy, a difference of 9% (95% CI = 1% to 15%) (Fig. 2). A larger number of patients died without recurrence in the no-adjuvant-chemotherapy arm than in the adjuvant chemotherapy arm (Table 3
), and a greater number had missing information on cause of death. However, the numbers of patients who died for reasons not thought to be related to ovarian cancer were similar. The causes of death are consistent with the frequency of comorbid conditions in this patient population.
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Three hundred forty-four patients (72%) were alive and recurrence free at the time of this analysis. Of the other 133 (28%) patients whose events are included in this analysis, 107 (80%) had disease recurrence (47 in the adjuvant chemotherapy arm and 60 in the no-adjuvant-chemotherapy arm) and 26 (20%) had died without recurrence (eight in the adjuvant chemotherapy arm and 18 in the no-adjuvant-chemotherapy arm). Thus the preponderance of events in the recurrence-free survival analysis was recurrences occurring sometime before death. The KaplanMeier curves for recurrence-free survival of both trial arms are shown in Fig. 3. Patients in the adjuvant chemotherapy arm had better recurrence-free survival than patients in the no-adjuvant-chemotherapy arm (HR = 0.65, 95% CI = 0.46 to 0.91; P = .01). These results translate into 5-year recurrence-free survival figures of 73% for patients who received adjuvant chemotherapy and 62% for patients in who did not receive adjuvant chemotherapy, an improvement in recurrence-free survival of 11% (95% CI = 3% to 18%).
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DISCUSSION |
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When ICON1 was launched there were only three small randomized trials in early-stage ovarian cancer comparing immediate treatment with adjuvant chemotherapy following surgery with no immediate treatment (4, 7, 15). Two other small randomized studies comparing immediate with deferred platinum-based adjuvant chemotherapy in patients with early-stage epithelial ovarian cancer were inconclusive (8, 14). A full summary and formal meta-analysis of all of these trials of platinum-based adjuvant chemotherapy (20) lend further support to the conclusion that patients with early-stage epithelial ovarian cancer can benefit from chemotherapy and provide no evidence to support the notion that relative effects of chemotherapy vary according to patient characteristics.
ICON1 was a large trial, with simple entry criteria. If the clinician was uncertain whether a patient with early-stage ovarian cancer would benefit from treatment with platinum-based adjuvant chemotherapy following surgery, the patient could be entered into the trial. There was no restriction on FIGO stage or tumor grade. However, most patients were of early stage, with more than 90% of patients classified as having stages IIc. The results are, therefore, representative of the likely effects of chemotherapy in clinical practice.
The ICON1 trial did have some possible limitations. First, this trial was an open study. However, the main outcomeoverall survivalis unlikely to have been affected by ascertainment bias. With respect to bias in ascertaining recurrence of disease, recurrence of ovarian cancer is usually symptomless and is diagnosed on clinical or radiologic examination, and all patients were followed up at the same time interval regardless of treatment arm. Therefore, such bias was also unlikely. A second possible limitation was that there was a small amount of crossover from one treatment arm to the other. However, crossover would have had the effect of reducing the estimated effect of chemotherapy that was observed between the two groups. Therefore, it is likely that the effect of immediate adjuvant chemotherapy was, if anything, underestimated in this trial.
In conclusion, the findings of this trial indicate that all patients with early-stage ovarian cancer should be considered for platinum-based adjuvant chemotherapy after removal of all visible tumor. Given that the majority of centers in this international trial chose single-agent carboplatin, this becomes, by definition, the treatment of choice. The risks and benefits of other regimens including taxanes have not been assessed in this population, and extrapolation from trials of later disease may not be appropriate. Future studies should investigate ways of further improving outcomes for women with early-stage ovarian cancer.
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APPENDIX: ICON1 TRIAL COLLABORATORS AND AFFILIATIONS |
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NOTES |
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Supported in Italy by Fondazione Nerina e Mario Mattioli, in the U.K. by the U.K. Medical Research Council, and in Switzerland by the Swiss Group for Clinical Cancer Research.
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Manuscript received April 17, 2002; revised November 7, 2002; accepted November 14, 2002.
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