International Collaborative Ovarian Neoplasm Trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm Trial

Abstract & Commentary

The investigators of 2 major and parallel European randomized clinical trials focused on early-stage epithelial ovarian cancer (International Collaborative Ovarian Neoplasm 1 [ICON1] and Adjuvant ChemoTherapy In Ovarian Neoplasm [ACTION]) performed a combined analysis. Both trials compared platinum-based adjuvant chemotherapy with observation following primary surgery. Between 1990 and 2000, 925 patients (477 in ICON1 and 448 in ACTION) who had surgery for early stage ovarian cancer were randomly assigned to receive platinum-based adjuvant chemotherapy (n = 465) or observation (n = 460) until chemotherapy was indicated. After a median follow-up of more than 4 years, 245 patients had died or had a recurrence (ICON1: 33, ACTION: 112). Overall survival at 5 years was 82% in the chemotherapy arm and 74% in the observation arm (difference = 8%; [95% confidence interval (CI) = 2-12%]; hazard ratio [HR] = 0.67; 95% CI = 0.50-0.90; P = .008). Recurrence-free survival at 5 years was also better in the adjuvant chemotherapy arm than it was in the observation arm (76% vs 65%; difference = 11% [95% CI = 5-16]; HR = 0.64; 95% CI = 0.50-0.82; P = .001). Subgroup analysis provided no evidence of a difference in the size of effect of chemotherapy on survival in any pretreatment subcategory (age, tumor stage, histologic cell type, and differentiation grade). The trial concluded that platinum-based adjuvant chemotherapy improved overall survival and recurrence-free survival at 5 years in this combined group of patients with early stage ovarian cancer defined by the inclusion criteria of the ICON1 and ACTION trials (International Collaborative Ovarian Neoplasm 1 [ICON1] and European Organisation for Research and Treatment of Cancer Collaborators-Adjuvant ChemoTherapy In Ovarian Neoplasm [EORTC-ACTION]. J Natl Cancer Inst. 2003;95:105-112).

Comment by David M. Gershenson, MD

Approximately 30% of women with epithelial ovarian cancer have stage I or II disease. Although the overall survival of patients with stage I disease is 80-90% and the overall survival of patients with stage II disease is 50-70%, there is still a wide range of survival times for various subsets of patients within this category. Over the past 2 decades or so, experts have been able to reach a consensus on the definition of "high-risk" early stage disease that is associated with a worse outcome. Most agree that high-risk early stage ovarian cancer includes stage Ia and Ib, grades 2 and 3; all clear cell carcinomas; and all stages Ic and II. There has been a difference in philosophy between the American and the European perspective regarding the conduct of early stage ovarian cancer trials. The Europeans have maintained historically that, prior to the findings of these trials, there was no evidence of benefit from adjuvant therapy; thus, their clinical trials, as demonstrated by these studies, have generally included a comparison of treatment vs observation. On the other hand, the Americans have made the assumption that the prognosis of high-risk early stage patients is not so wonderful, thereby choosing to design trials comparing 2 different treatments. Now that these trials have seemingly established the benefits of adjuvant therapy once and for all, most future trials will assume the American design. However, as always, the details are important. In the ICON1 trial, patients with well-differentiated tumors and stage III disease were included. In the ACTION trial, where eligibility criteria were more restrictive, the benefit of adjuvant chemotherapy was limited to patients with nonoptimal staging. Of course, this just underscores the fact that all clinical trials have flaws—some more major than others. In this case, the true value of adjuvant chemotherapy for patients with high-risk early stage ovarian cancer still remains somewhat uncertain. The goal of future trials will be to tease out those patients who do not require adjuvant treatment, and most of us believe that the identification of these good-prognosis patients will be based on some, as yet unknown, molecular biomarker.

Dr. Gershenson is Professor and Chairman, Department of Gynecology, M.D. Anderson Cancer Center, Houston.