Affiliations of authors: J. B. Trimbos, Leiden University Medical Center, Leiden, The Netherlands; I. Vergote, University Hospitals, Leuven, Belgium.
Correspondence to: J. Baptist Trimbos, MD, Ph.D., Department of Gynecology, Leiden University Medical Center, POB 9600, 2300 RC, Leiden, The Netherlands (e-mail: J.B.M.Z.Trimbos{at}lumc.nl).
We thank Dr. Green for his compliments regarding the publication of the European Organisation for Research and Treatment of Cancer (EORTC)Adjuvant ChemoTherapy In Ovarian Neoplasm (ACTION) trial (1). Nevertheless, there are a number of comments with which we disagree.
Dr. Green supports the notion that the benefit of adjuvant chemotherapy is important enough to influence clinical decision making based on the overall and recurrence-free survival results of the combined analysis of the ACTION and International Collaborative Ovarian Neoplasm 1 (ICON1) trials (2). We concur with that statement; however, it is crucial in any extrapolation of research findings to the general population to appreciate the features of the study population. We have argued that the vast majority of patients in the combined analysis would have been non-optimally staged, thus defining this population as a mixed group of patients that has an appreciable portion of patients with undetected residual disease in the abdominal cavity (3). Therefore, the patient population in both ICON1 (4) and the combined analyses (2) might be considered as patients with "supposed" early-stage ovarian cancer. Supposed early-stage ovarian cancer is clearly different from "proven" early-stage ovarian cancer on the basis of comprehensive surgical staging.
Variability in the pathologic assessment of ovarian cancer is predominantly in distinguishing the difference between borderline and grade I tumors (5). ICON1, which allowed all early-stage ovarian cancer patients to be included, comprised 32% of well-differentiated (i.e., grade I) tumors (4). Therefore, the risk of including borderline ovarian tumors in that study may have been substantial. In contrast, the ACTION trial (1), which allowed only medium- to high-risk early-stage ovarian cancer patients to be included, and that comprised only 12% of well-differentiated tumors, made the risk of including borderline tumors much smaller.
Another comment in Dr. Greens correspondence is that there are different opinions about optimal surgical staging in Europe and the United States. The EORTC clearly defined its staging guidelines in the early 1990s (6), and they are virtually identical to those of the United States-based Gynecologic Oncology Group (GOG) (7). Dr. Green also commented that there was little difference between the minimum requirements for surgical staging in both the ACTION (1) and ICON1 (4) trials. On the contrary, we believe there was a large difference in the requirements for surgical staging between the two trials. In the ACTION trial, the necessary surgical staging steps were provided in the protocol, and optimal surgical staging was strongly recommended; surgical performance was also comprehensively monitored and analyzed. In the ICON1 trial, surgical staging was not emphasized, not defined, and not even monitored. Therefore, it would be difficult to describe the ICON1 patient population as true early-stage ovarian cancer patients. This notion is supported by a comparison of all ICON1 patients and non-optimally staged ACTION patients in the observation arms (Fig. 1) in which the overall survival curves are almost identical, even though the ICON1 trial included low-risk patients (i.e., stage Ia, Ib, grade I) in 15% of their study population and the ACTION trial did not. These factors strongly suggest that the ICON1 patients should be regarded as predominantly non-optimally staged, limiting the extrapolation of their results and thus, that of the combined analysis (2), to other patient populations.
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Finally, Dr. Green suggested that pragmatic surgical staging guidelines, which are achievable in 80% of ovarian cancer cases, need to be agreed on internationally. This statement seems hard to defend because accurate surgical staging should be based on knowledge of tumor spread and tumor behavior and not on the feasibility of the procedure.
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;95:11325.
2 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;95:10512.
3 Trimbos JB, Zanaboni F. Some afterthoughts on two randomized European trials in early ovarian cancer. Am J Oncol Rev 2003;2:22839.
4 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;95:12532.
5 Trimbos JB, Schueler JA, van der Burg M, Hermans J, van Lent M, Heintz AP, Fleuren GJ. Watch and wait after careful surgical treatment and staging in well-differentiated early ovarian cancer. Cancer 1991;67:597602.[ISI][Medline]
6 Trimbos JB, Bolis G, Pecorelli S. The surgical staging of ovarian cancer--current practice in 15 European countries. Int J Gynecol Cancer 1991;1:8993.[ISI]
7 Buchsbaum HJ, Brady MF, Delgado G, Miller A, Hoskins WJ, Manetta A, et al. Surgical staging of carcinoma of the ovaries. Surg Gynecol Obstet 1989;169:22632.[ISI][Medline]
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