Neoadjuvant chemotherapy versus primary surgery for advanced-stage ovarian cancer: the question remains opened

Neoadjuvant chemotherapy versus primary surgery for advanced-stage ovarian cancer: the question remains opened

1018 Letters to the Editor is arguable that their patients who were completely cytoreduced with interval procedures were a selected group with a fav...

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Letters to the Editor

is arguable that their patients who were completely cytoreduced with interval procedures were a selected group with a favorable prognostic indicator (chemo-sensitivity) and should have an excellent prognosis after additional chemotherapy. However, the reported median survival of 41 months after complete interval cytoreduction was lower than observed median survivals of virtually all primary cytoreductive surgical series that reported survival outcomes of subgroups that had complete cytoreduction [1 –4]. A historical explanation for the apparent reduction of median survival associated with complete interval cytoreduction is that the patients had malignancies with very ‘‘unfavorable tumor biology’’ as manifested by widespread intra-abdominal disease that would require extensive surgery [5]. However, the correlation of specific radiographic and/or laparoscopic observations with findings at laparotomy and primary cytoreductive outcomes has had minimal investigation. Furthermore, retrospective series and a recent prospective one demonstrate that although the extent of intra-abdominal disease may weakly correlate with ‘‘unfavorable tumor biology,’’ the primary cytoreductive outcome has a greater influence on the probability of survival [3,4]. Hence, patients with widespread, extensive metastatic disease that undergo complete primary cytoreduction indeed have survival that is minimally diminished relative to those with small tumor burdens [3,4]. Additionally, resistance to chemotherapy is a manifestation of ‘‘unfavorable’’ or ‘‘aggressive’’ tumor biology that cannot be offset by treatment. Hence, considering that the extent of intra-abdominal disease correlates poorly with ‘‘biological aggressiveness’’ that cannot be offset by treatment and that virtually all of the patients who had complete interval cytoreduction by Mazzeo et al. had disease that was initially chemo-sensitive, it is very unlikely that the relatively poor median survival reported is due to case selection of patients with innately ‘‘biologically aggressive’’ disease. Outcomes reported by Mazzeo et al. strongly suggest that metastatic disease develops resistance to cytotoxic agents when exposed in a neoadjuvant setting. There are no published results of neoadjuvant chemotherapy series that duplicate survival outcomes of the most favorable primary cytoreductive surgical series. Therefore, neoadjuvant chemotherapy should be restricted to patients with absolute contraindications to primary cytoreductive surgery. Efforts should be made to acquire and use all available techniques to achieve complete cytoreduction primarily whenever feasible. It would be helpful to know if the authors operated on any patients thought to be potentially inoperable on the basis of laparoscopic and/or radiographic findings, to confirm the predictive value of such findings in determining whether patients were operable. Additionally, it would be useful to know the author’s opinion about why the reported median survival (41 months) for patients who had complete interval cytoreduction was diminished relative to patients with widespread disease who undergo complete cytoreduction primarily [1 –4].

References [1] Omura GA, Bundy BN, Berek JS, Curry S, Delgado G, Mortel R. Randomized trial of cyclophosphamide plus cisplatin with or without doxirubicin in ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1989;7(4):457 – 65. [2] Alberts DS, Liu PY, Hannigan EV, O’Tolle R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335(4):1950 – 5. [3] Eisenkop SM, Spirtos NM, Friedman RL, Lin WM, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90(4):390 – 6. [4] Le T, Krepart GV, Lotocki RJ, Heywood MS. Does debulking surgery improve survival in biologically aggressive ovarian cancer. Gynecol Oncol 1997;67(4):208 – 14. [5] Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in smallvolume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992;47(4):167 – 71.

Scott M. Eisenkop * Women’s Cancer Center, Tarzana, CA 91356-6125, USA E-mail address: [email protected] 12 September 2003 doi:10.1016/j.ygyno.2003.11.050 * Women’s Cancer Center, Suite 311, 5525 Etiwanda Avenue, Tarzana, CA 91356-6125. Fax: +1-818-774-0804.

Neoadjuvant chemotherapy versus primary surgery for advanced-stage ovarian cancer: the question remains opened We thank Dr. Eisenkop for pushing the discussion further. He suggests that ‘‘our reported median survival of 41 months after complete interval cytoreduction was lower than the observed median survivals of virtually all primary cytoreductive surgical series that reported survival outcomes of subgroups that had complete cytoreduction’’. One explanation proposed by Dr. Eisenkop for this observation is that neoadjuvant chemotherapy may be responsible for the occurrence of ‘‘metastatic disease resistant to cytotoxic agents’’. Although interesting and still possible, we do not think that we can draw such a conclusion from our small retrospective series since the median survival of the patients who underwent complete surgical resection is based on only 24 patients [1]. In addition, 9 patients out of 45 had an AJCC stage IV ovarian cancer and were also included in the analysis. Four of them were completely debulked [1]. The studies, thought by Dr. Eisenkop to

Letters to the Editor

show better results, did not include any stage IV but only stage III and sometimes stage II patients [2– 5]. Therefore, we think that a survival comparison between these subgroups of patients coming from different studies is meaningless due to the low number of patients involved as well as their difference in initial AJCC stage. Recently, Vergote [6] reviewed the retrospective studies in which patients with advanced ovarian cancer were treated with neoadjuvant chemotherapy followed by interval debulking surgery. They censored a total of 648 patients. As our series, some of these studies included patients with stage III and IV disease. For these 648 patients treated by neoadjuvant chemotherapy, the survival results were similar or better than those treated with primary debulking surgery. No firm conclusions can be drawn from these trials, but clearly, these previous published phase II neoadjuvant studies do not support the hypothesis that neoadjuvant chemotherapy is less effective than primary cytoreduction. This question remains opened and is currently tested in prospective randomized trials. If these studies demonstrate that neoadjuvant chemotherapy is inferior to primary surgery, induction of chemoresistance by neoadjuvant chemotherapy may be one of the multiple possible explanations, although speculative. Another valid reason may be that neoadjuvant chemotherapy followed by interval debulking and adjuvant chemotherapy is decreasing the dose intensity received by each individual patient since chemotherapy is stopped during a few weeks to allow surgery. We are convinced that primary cytoreduction, when feasible, remains the standard of care in patients with advanced-stage ovarian cancer. However, when the surgical team estimates that primary optimal cytoreduction will not be achievable safely, neoadjuvant chemotherapy may be an alternative. We agree that resectability criteria can be different from one surgeon to another, and that the laparoscopy and/or radiographic findings, on which we decided to operate or not, should be prospectively validated.

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References [1] Mazzeo F, Berliere M, Kerger J, Squifflet J, Duck L, D’Hondt V, et al. Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer. Gynecol Oncol 2003;90:163 – 9. [2] Omura GA, Bundy BN, Berek JS, Curry S, Delgado G, Mortel R. Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: a gynecologic oncology group study. J Clin Oncol 1989;7:457 – 65. [3] Alberts DS, Liu PY, Hannigan EV, O’Tolle R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950 – 5. [4] Eisenkop SM, Spirtos NM, Friedman RL, Lin WM, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome for patients with advanced ovarian cancer. A prospective study. Gynecol Oncol 2003;90:390 – 6. [5] Le T, Krepart GV, Lotocki RJ, Heywood MS. Does debulking surgery improve survival in biologically aggressive ovarian cancer. Gynecol Oncol 1997;67:208 – 14. [6] Vergote I. Controversies in surgery in ovarian cancer—What is its real role? Eur J Cancer 2003;1(6):S115 – 25.

Jean-Pascal Machiels * Martine Berliere Centre du cancer, Medical Oncology Unit and Gynecology Department, Universite´ Catholique de Louvain, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium E-mail address: [email protected] Filomena Mazzeo Service d’Oncologie, Hoˆpital de Jolimont, Haisne Saint-Paul, Belgium 9 October 2003 doi:10.1016/j.ygyno.2003.11.002 * Corresponding author. Centre du cancer, Medical Oncology Unit and Gynecology Department, Universite´ Catholique de Louvain, Cliniques Universitaires Saint-Luc, 10 Avenue Hippocrate, 1200 Brussels, Belgium. Fax: +32-2-764-54-28.