CORRESPONDENCE

RESPONSE: Re: Adjuvant Chemotherapy in Patients With Early-Stage Ovarian Cancer

David Guthrie
On Behalf of the ICON1 Collaborators

Correspondence to: David Guthrie, M.B., B.S., Ph.D, F.R.C.O.G., F.R.C.R., Medical Research Council Clinical Trials Unit, 222 Euston Rd., London, NW1 2DA, United Kingdom (e-mail: DGJCGuthrie{at}aol.com).

Dr. Green states that the change in chemotherapy regimens used for ovarian cancer over the past 12 years creates problems in interpreting the results of the International Collaborative Ovarian Neoplasm 1 (ICON1) (1) and Adjuvant ChemoTherapy In Ovarian Neoplasm (ACTION) (2) trials. We agree that it would be difficult to interpret these results if no effect of chemotherapy had been observed; however, because overall survival was improved and the platinum-based chemotherapy used in these trials remains the mainstay of treatment, the findings of the two trials remain relevant and provide important evidence for determining the best treatment for women with early-stage ovarian cancer. Furthermore, the fact that the majority of patients in both trials (57%) received single-agent carboplatin makes this chemotherapy regimen the recommended treatment. We do agree that our findings should not be extrapolated to other chemotherapy regimens. Results of clinical trials with evidence of more effective chemotherapy regimens or more effective new drug analogs than single-agent carboplatin are not available in the early disease setting.

The criticism that centralized pathologic review was not performed in the ICON1 and ACTION trials has no impact on their findings. Centralized histopathologic review does not take place in the real world, and these were real world trials. Randomization within large trials ensures that potential misclassification is equally distributed between treatment arms. Moreover, there was no evidence from the planned subgroup analyses of the combined trials (3) that any tumor subtypes, including clear-cell tumors, responded differently to treatment than other tumor types.

It is true that there were differing views between the ICON1 (1) and the ACTION (2) investigators on whether patients who are optimally surgically staged benefit from adjuvant chemotherapy. The authors of the ACTION trial chose to draw conclusions from a small, unplanned subgroup analysis of 151 patients with optimal disease staging (one-third of the patients in the trial) who contributed only 18 events to the survival analysis. Although the hazard ratio for the risk of death in this group suggests a 24% reduction in the relevant risk of death in favor of no chemotherapy (using the Mantel–Haenszel version of the log-rank test) (4), the 95% confidence intervals [CIs] are wide (95% CI = 0.51 to 3.15), ranging from a twofold reduction in the relative risk of death with adjuvant chemotherapy to a twofold increase in the relative risk of death with adjuvant chemotherapy.

The suggestion that the findings of the ICON1 (1) and ACTION (2) trials should not be applied to patients with stage Ia or Ib ovarian cancer is not founded on evidence from those trials, which included 430 stage Ia and Ib patients (47%). In addition, there was no evidence of heterogeneity of the treatment effect according to disease stage (shown in Fig. 3 of the combined analysis) (3); the test for interaction was not statistically significant (P = .73). Therefore, all patients are likely to benefit from adjuvant chemotherapy by the same relative amount, and the findings apply equally to all patients with early-stage ovarian cancer.

This fact still allows for the interpretation that, for patients with a good prognosis (i.e., a 90%–95% survival rate), the relative benefit of adjuvant chemotherapy may translate into only a small absolute benefit in survival of 1%–2%. In these circumstances, some doctors and patients may not believe that adjuvant chemotherapy is worthwhile. Hence, the decision whether to give and/or receive adjuvant chemotherapy must be made according to the expected risks and benefits for an individual patient—a clinical judgment similar to the one made when deciding to conserve an ovary in a young woman with ovarian cancer who wishes to have children. Therefore, the conclusion that all patients with early-stage disease should be considered for adjuvant chemotherapy stands.

REFERENCES

1 Colombo N, Guthrie D, Chiari S, Parmar M, Qian W, Swart AM, et al. International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst 2003;95:125–32.[Abstract/Free Full Text]

2 Trimbos JB, Vergote I, Bolis G, Vermorken JB, Mangioni C, Madronal C, et al. Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst 2003;95:113–25.[Abstract/Free Full Text]

3 Trimbos JB, Parmar M, Vergote I, Guthrie D, Bolis G, Colombo N, Vermorken JB, et al. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 2003;95:105–12.[Abstract/Free Full Text]

4 Parmar M, Machin D. Survival analysis: a practical approach. New York (NY): John Wiley & Sons; 1995. p. 81.



             
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