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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 2033-2035 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.306
In Reply:Heinrich-Heine-University, Düsseldorf, Germany. We read with interest the letter by Drs Geller and Santana regarding our article on ovarian sex cord-stromal tumors (OSCST) in children and adolescents.1 The authors' comments are certainly helpful, because they point to the clinically most problematic group of patients with stage Ic tumors. We agree that in rare tumors such as OSCST, it may sometimes be problematic to arrive at valid conclusions. In addition, it should be considered that patients may have been recruited over a long period of time. As a consequence, the clinical experience may have grown during the observation period, thus leading to changes in therapeutic decisions in borderline patients such as those with stage Ic tumors. Therefore, we have concluded that our data need to be validated in a larger prospective trial,1 and we are going to pursue this issue in the near future, when the world-wide first prospective trial for the treatment of sex cord-stromal tumors in children and adolescents is open for recruitment. We appreciate the author's retabulation of the stage Ic patients with regard to time of tumor rupture and administration of chemotherapy, because this table indeed allows for a quick and clear overview. However, some points need to be clarified in light of the data, as they have been presented in our article. On page 2360, we mention that "we saw no relapses among 12 patients who were categorized as having accidental stage Ic tumors. ... In contrast, five of nine patients with natural stage Ic tumors who experienced preoperative tumor rupture or malignant ascites relapsed. ... This group includes four patients ... treated with adjuvant chemotherapy, among whom, three developed a recurrence. ..." In our most recent pathologic analysis of OSCST registered at the German Pediatric Tumor Registry in Kiel, these data have not been commented on in detail, because surgical records were not available in sufficient numbers of patients; however, no discrepancy was apparent.2 Therefore, the table provided by Geller and Santana must be recalculated and corrected (Table 1).
Geller and Santana critically comment on our recommendation to follow up patients with stage Ic and accidental tumor rupture expectantly. Indeed, we maintain this recommendation, because we have seen no adverse advents in this subgroup of patients, making them prognostically indistinguishable from stage Ia patients.1 This observation is substantiated by the updated analysis of the patients included in the Journal of Clinical Oncology article, which now includes an 18-month longer follow-up period (Fig 1). In this analysis, all stage Ic patients with accidental intraoperative tumor rupture have remained relapse-free. Notably, the minimum follow-up is now at least 1 year longer than the latest relapse observed in stage Ic patients with preoperative rupture or malignant ascites.
Geller and Santana also comment on our conclusion that adjuvant chemotherapy might be suitable in stage Ic tumors with preoperative rupture. We agree that this conclusion cannot be drawn in the perspective of stage Ic patients alone, because the number of patients is small. However, after our correct tabulation of the data presented in our article, we do not see a statistically significant advantage for patients who were followed expectantly compared with the chemotherapeutically treated patients, as it has been suggested by Geller and Santana in light of the false tabulation. In addition, testing this hypothesis is problematic, because the cumulative doses and chemotherapeutic regimens were variable in our patients, as commented upon in our article. Nevertheless, our recommendation to treat stage Ic tumors with preoperative rupture or malignant ascites is based on the observed high recurrence rate in this particular subgroup and on our experience that cisplatin-based chemotherapy can be effective in high-stage tumors. In this context, we do not follow the authors' conclusion that our data can be interpreted that postoperative chemotherapy might better benefit those with accidental stage Ic, whereas chemotherapy is minimally effective in natural stage Ic tumors chosen to receive it up front. In our opinion, the prognosis of accidental stage Ic is superb, and no postoperative adjuvant chemotherapy is required. On the other hand, we have not treated patients with up-front (ie, preoperative) chemotherapy for natural stage Ic tumors, and therefore, no conclusions can be drawn with regard to this aspect. We strongly appreciate the authors' suggestion to comment on the potential impact of mitotic rate on the decision of whether to treat. Indeed, mitotic activity constitutes an important prognostic factor both in adult and in juvenile granulosa cell tumors (GCT).2,3 However, the cutoff level that defines prognostically unfavorable tumors is much lower in adult than in juvenile GCTs. This may be one possible explanation why adult GCTs bear the risk of late recurrence (with a median to relapse of 4 to 6 years),2 which is not characteristic of juvenile GCTs.1 Because of the small numbers of patients and because of the size restriction of the article, we have not performed statistical analysis or even multivariate analysis to elucidate this issue. However, we would like to mention that among stage Ic patients with preoperative rupture, six tumors showed more than 20 mitoses/10 high-power fields, and four of these relapsed. Therefore, there seems to be a biologic and clinical correlation that rapidly proliferating tumors show a higher probability of preoperative rupture and/or tumor spread into the ascites and that both parameters confer a poor prognosis. In conclusion, the evaluation of mitotic activity substantially contributes to risk assessment and may also guide in therapeutic decisions in stage Ic patients. Nevertheless, it must be considered that the number of patients is limited, and therefore we agree with Geller and Santana that strong evidence-based guidelines can certainly not be established for these rare tumors. However, we sincerely hope that the retabulation and updated evaluation of the certainly most problematic group of stage Ic tumors helps to clarify the rationale of our recommendation. Lastly, we are looking forward to the prospective analysis of children and adolescents with OSCST in the sex cord-stromal tumor 2004 trial for testicular and ovarian sex cord-stromal tumors. We would greatly appreciate international collaboration to collect meaningful numbers of patients and to draw more valid conclusions, when more patients have been treated according to a uniform risk-adapted therapeutic strategy (www.uniklinik-duesseldorf.de/scst). Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Schneider DT, Calaminus G, Wessalowski R, et al: Ovarian sex cord-stromal tumors in children and adolescents. J Clin Oncol 21:2357-2363, 2003 2. Schneider DT, Jänig U, Calaminus G, et al: Ovarian sex cord-stromal tumors: A clinicopathologic study of 72 cases from the Kiel Pediatric Tumor Registry. Virchows Arch 443:549-560, 2003[Medline]
3. 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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