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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 2032-2033 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.281
Tumor Rupture and Mitotic Index in Pediatric Sex Cord-Stromal TumorsSt Jude Children's Research Hospital, Department of Hematology-Oncology and College of Medicine, University of Tennessee Health Science Center, Memphis, TN. To the Editor: In the June 15, 2003, issue of the Journal of Clinical Oncology, Schneider et al1 conclude and recommend that children and adolescents with ovarian sex cord-stromal tumors staged as Ic as a result of accidental tumor rupture (rupture occurring during the time of surgery) should be observed without further therapy, whereas patients for whom the tumor status is staged as Ic because of natural preoperative tumor rupture should receive adjuvant chemotherapy. We commend their contribution in enhancing our current understanding of these rare tumors in children and adolescents.2-4 However, after a careful retabulation and evaluation of their data, in addition to considering a recent publication by the same authors, we question this conclusion, because it is not evidenced-based.2 Our analysis of the stage Ic data presented by the authors with consideration to etiology of tumor rupture is as follows (Table 1). First, we must note that the number of patients included in this subgroup analysis is not sufficient to draw any definitive conclusions. Indeed, the authors acknowledge that a multivariate analysis was not feasible because of this limitation. This fact alone should make one cautious in attributing significance to interpretations of this data. On the basis of this limited data, we can estimate that the event-free survival rates for patients with tumors classified as accidental stage Ic and natural stage Ic are 83.33% (10 of 12 patients) and 66.66% (six of nine patients), respectively. At first glance, this suggests a worse outcome for patients with natural stage Ic tumors, possibly justifying the authors' conclusions. However, one must fully consider the apparent efficacy of chemotherapy in the two groups as well as other possible confounding variables.
When evaluating only the stage Ic patients with natural tumor rupture (n = 9), the data show that one (25%) of four patients who received chemotherapy are event-free, compared with five (100%) of five who did not receive chemotherapy (P = .048; Fisher's exact test). This would seem to imply that no chemotherapy is better than giving chemotherapy in this subgroup, in contrast to the conclusions reached by the authors. We acknowledge that the most appropriate statistical comparison is the exact log-rank test with time-to-event data, but not enough data are provided in the article to apply this tool. Despite the lack of statistical certainty, these observations suggest the presence of selection bias originating in the decision process regarding who received chemotherapy and who did not. In the group of patients with accidental tumor rupture (n = 12), there was no difference in event-free survival (as a binary outcome) in patients treated with chemotherapy (three of three patients; 100%) versus those patients who did not receive chemotherapy (seven of nine patients; 78%; P = .99). Noteworthy, two patients in this subgroup who initially did not receive chemotherapy experienced relapse and ultimately received chemotherapy that proved ineffective as salvage therapy, as both patients succumbed to their cancer. This is in contrast to patients in this subgroup who received up-front adjuvant chemotherapy where no relapses were detected. Although this latter observation did not reach statistical significance, one might interpret the entirety of the data presented in a different light than described by the authors. That is, the data can be interpreted to imply that postoperative chemotherapy might better benefit those with accidental stage Ic tumors in consolidating their remission and ultimately preventing relapse and treatment failure, whereas chemotherapy is minimally effective for those patients with natural stage Ic tumors chosen to receive it up front. In addition, the authors advocate the value of mitotic activity index as a prognostic indicator and provide Kaplan-Meier curves for the entire patient cohort. However, no data are provided on this variable for the individual patient subgroup with tumor rupture. The mitotic activity has recently been reaffirmed by these authors to have prognostic value and specifically has been suggested to be helpful in defining which patients with stage Ic tumors are at high risk of relapse and would potentially benefit from adjuvant therapy.2 The readers of the Journal of Clinical Oncology article would benefit in knowing the mitotic activity data on the tumors associated with stage Ic disease and whether it was used to determine which patients would receive up-front adjuvant chemotherapy. A testable hypothesis is that mitotic activity defines the prognosis of children and adolescents with stage Ic ovarian sex cord-stromal tumors, rather than timing of tumor rupture. Ovarian sex-cord stromal tumors in children are rare and the controversy of how to best treat such patients has been poorly resolved in part because of the rarity of these tumors and the lack of prospective trials designed to assess the value of postoperative adjuvant chemotherapy.5,6 The efforts by the German Society of Pediatric Oncology and Hematology are therefore to be commended. However, the small subsets of patients studied, the lack of information pertaining to the tumor mitotic status, and the lack of further explanations as to why certain patients were selected to receive postoperative chemotherapy while other patients with apparently similar presentations were not warrants caution in interpreting the role of timing of tumor rupture in guiding the management of patients with stage Ic ovarian sex-cord stromal tumors. We look forward to clarification from the authors on these important points. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Schneider DT, Calaminus G, Wessalowksi R, et al: Ovarian sex cord-stromal tumors in children and adolescents. J Clin Oncol 21:2357-2363, 2003 2. Schneider DT, Janig U, Calaminus G, et al: Ovarian sex cord-stromal tumors: A clinicopathological study of 72 cases from the Kiel Pediatric Tumor Registry. Virchows Arch 443:549-560, 2003[Medline] 3. Schneider DT, Calaminus G, Wessalowski R, et al: Klin Padiatr 214:173-178, 2002[Medline] 4. Calaminus G, Wessalowski R, Harms D, et al: Juvenile granulosa cell tumors of the ovary in children and adolescents: Results from 33 patients registered in a prospective cooperative study. Gynecol Oncol 65:447-452, 1997[CrossRef][Medline] 5. Akyuz C, Varan A, Buyukpamukcu N, et al: Malignant ovarian tumors in children: 22 years of experience at a single institution. J Pediatr Hematol Oncol 22:422-427, 2000[Medline]
6. Schumer ST, Cannistra SA: Granulosa cell tumor of the ovary. J Clin Oncol 21:1180-1189, 2003 Related Article
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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