CORRESPONDENCE

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

John A. Green

Correspondence to: John A. Green, M.B., Ch.B., D.M., Department of Medicine, University of Liverpool, Liverpool, L69 3GA, United Kingdom (e-mail: J.A.Green{at}liverpool.ac.uk).

The authors of the two largest randomized trials (1,2) addressing the use of adjuvant chemotherapy in early-stage ovarian cancer are to be congratulated for seeing them through to publication after 12 years. The addition of two earlier trials of adjuvant chemotherapy in early-stage ovarian cancer in the meta-analysis presented in the combined analysis of the two trials (3) only reinforced the authors’ most important conclusion that, in early-stage disease, the small number of events limits statistical and clinical interpretation. The demonstration of a modest benefit of adjuvant chemotherapy for overall survival (8% at 5 years) and recurrence-free survival (11% at 5 years), based on 245 events, is important enough to influence clinical decision making (3).

However, uncertainties remain. First, the chemotherapy regimens used for ovarian cancer have changed in the past 12 years, with modifications in dose intensity, development of new drug analogs, and the incorporation of additional agents into the management of advanced disease. Extrapolation to early-stage disease may be problematic, not least because the additional late toxicity from drug combinations is a greater factor in stage I and II disease where more than 70% of patients survive 5 years (3).

Second, there have been developments in histopathologic assessment. Borderline tumors, a category of tumors that was excluded from both trials (1,2), are subject to considerable interobserver variation (4), and clear-cell carcinomas, which make up 15%–20% of early-stage disease, have a poorer prognosis and respond less well to chemotherapy than other epithelial types. Unfortunately, neither of these two trials used centralized histopathologic review of the diagnostic category or grade of tumors.

Finally, the text of the three articles (13) suggests differing views on the issue of surgical staging between the two research groups, and it is widely recognized that there are divergent opinions both in Europe and the United States on the optimal surgical approach to staging in ovarian cancer. Interestingly, there is evidence suggesting variation in overall survival associated with the expertise of the gynecologist performing the surgical procedure and, in early-stage ovarian cancer, a substantial proportion of patients are operated on by nonspecialist physicians (1,5). There was little difference between the minimum requirements for surgical staging in both the International Collaborative Ovarian Neoplasm 1 (ICON1) and the Adjuvant ChemoTherapy In Ovarian Neoplasm (ACTION) trials; both required clearance of all macroscopic disease. However, in the ICON1 trial, surgical staging data were not recorded, whereas the physicians participating in the ACTION trial were strongly advised to consider performing more comprehensive staging.

A post hoc subgroup analysis of optimally staged patients, which was based on only one-third (151 case patients, 18 events) of the ACTION trial’s patients, led the authors of that trial to conclude that adjuvant chemotherapy may not benefit optimally staged patients. The practical question is whether restaging of non-optimally staged patients, which may increase the stage category in 20% of patients, is worth the effort and risk. The expected gain in survival is likely to be small, and it may be argued that the benefits of cytotoxic chemotherapy have improved survival to the extent that the differences between small macroscopic and microscopic disease are overcome by chemotherapy.

Oncologists should, therefore, accept the findings of these two trials (1,2) and the conclusions of the meta-analysis (3) as the best evidence currently available for the benefit of adjuvant chemotherapy and adopt it, with the exception of stage 1a and b grade 1 tumors, as standard-of-care for early-stage ovarian cancer (6). At a minimum, the standard chemotherapy regimen should contain carboplatin at an area under the curve dose level of 6 mg · min/mL, which has been shown to have acceptable morbidity (3). Furthermore, pragmatic surgical staging guidelines, which are achievable in 80% of ovarian cancer cases, should be agreed on internationally, and mechanisms should be devised to ensure that tumor tissue can be stored and exchanged on a global basis for analysis at both the morphologic and molecular level.

REFERENCES

1 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]

2 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]

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 Buttin BM, Herzog TJ, Powell MA, Rader JS, Mutch DG. Epithelial ovarian tumors of low malignant potential: the role of microinvasion. Obstet Gynecol 2002;99:11–7.[Abstract/Free Full Text]

5 Junor EJ, Hole DJ, McNulty L, Mason M, Young J. Specialist gynaecologist and survival outcome in ovarian cancer: a Scottish National Study of 1866 patients. Br J Obstet Gynaecol 1999;106:1130–6.[ISI][Medline]

6 Vergote I, De Brabander J, Fyles A, Bertelsen K, Einhorn N, Sevelda P, et al. Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 2001;357:176–82.[CrossRef][ISI][Medline]



             
Copyright © 2003 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement