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Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer
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Gynecologic Oncology 90 (2003) 163–169
www.elsevier.com/locate/ygyno
Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer Filomena Mazzeo,a Martine Berlie`re,b Joseph Kerger,c Jean Squifflet,b Lionel Duck,a Ve´ronique D’Hondt,a Yves Humblet,a Jacques Donnez,b and Jean-Pascal Machielsa,* a
b
Medical Oncology Unit, Centre du Cancer, Universite´ Catholique de Louvain, Brussels, Belgium Department of Gynecology, Centre du Cancer, Universite´ Catholique de Louvain, Brussels, Belgium c Medical Oncology Unit, Universite´ Catholique de Louvain, Mont-Godinne, Belgium Received 16 October 2002
Abstract Objective. The aim of this review is to report our experience and the feasibility of neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer. Methods. Forty-five patients with primarily unresectable advanced-stage epithelial ovarian cancer were treated in our center between 1995 and 2002 by platinum-based neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. Their files were reviewed retrospectively. Results. At the end of neoadjuvant chemotherapy, according to RECIST criteria, 1 patient (2.2%) had achieved a clinical complete response (CR), 33 (73.4%) a partial response (PR), and 8 (17.8%) had stable disease (SD). Only 3 (6.6%) patients showed disease progression (PD). Surgery was performed in patients with objective response or SD after a median number of 4 courses (range: 2– 6) of induction chemotherapy. A complete macroscopic debulking was achieved in 24 (53.3%) out of 39 patients in whom cytoreductive surgery was performed. For the entire group, median overall survival was 29 months. Survival was significantly improved in patients with optimal debulking compared to patients with persistent tumor after surgery: 41 months versus 23 months (P ⫽ 0.0062). Median survival for patients responding to neoadjuvant chemotherapy (CR and PR) was 44 months compared to 27 months for patients with SD or PD after initial chemotherapy (P ⫽ 0.01). Neither treatment-related deaths nor significant toxicities were observed. Conclusion. Neoadjuvant chemotherapy followed by optimal debulking may be a safe and valuable treatment alternative in patients with primarily unresectable advanced-stage bulky ovarian cancer. Patients with an objective response to chemotherapy or absence of macroscopic residual tumor after surgery have a better outcome. This approach is currently being tested in large, prospective randomized clinical trials. © 2003 Elsevier Science (USA). All rights reserved.
Introduction Primary surgical cytoreduction followed by platinum-based chemotherapy represents the standard therapy for patients with advanced epithelial ovarian cancer [1–5]. However, despite this therapeutic strategy, most patients with International Fed-
* Corresponding author. Medical Oncology Unit, Universite´ Catholique de Louvain, Cliniques Universitaires Saint-Luc, 10, avenue Hippocrate, 1200 Brussels, Belgium. Fax: ⫹32-2-764-54-28. E-mail address: [email protected] (J.-P. Machiels).
eration of Gynecology and Obstetrics (FIGO) stage III or IV disease will relapse and eventually die of progressive disease. Current literature shows an inverse relationship between residual tumor diameter after surgery and survival [2]. These data suggest that patients with advanced-stage ovarian cancer could only benefit from an optimal surgical debulking. No clear survival benefit has been demonstrated in patients with residual tumor larger than 2 cm in diameter after debulking in FIGO stages III–IV ovarian cancer [6], and optimal cytoreductive surgery may often be difficult to achieve due to the initial extent of the disease. Thus primary surgery for this subset of patients may be questionable.
0090-8258/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0090-8258(03)00249-X
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Ovarian cancer is a chemosensitive disease and approximately 80% of patients will achieve an objective response with platinum-based regimens [7]. In this patient population, neoadjuvant chemotherapy may significantly reduce the tumor burden before surgery and allow for an easier optimal cytoreduction. The feasibility of this treatment modality has been demonstrated in previous reports [7–15]. Recently a clinical trial suggested that neoadjuvant chemotherapy followed by debulking might prolong survival for patients with ascitis and FIGO stage IIIC ovarian cancer [16]. In this paper, we report our experience with neoadjuvant chemotherapy in patients with FIGO stage IIIC or IV initially unresectable ovarian cancer. Complete macroscopic resection can be achieved in about 70% of patients responding to neoadjuvant chemotherapy and patients with an objective response to initial chemotherapy and complete debulking have a prolonged survival compared to those with chemoresistant disease or incomplete surgery.
Patients and methods This review includes 45 patients with FIGO stage IIIC and IV epithelial ovarian cancer treated at our institution between 1995 and 2002. To be eligible for analysis, patients should (i) have measurable bulky tumor masses on the initial abdominal and pelvic CT scan, (ii) be operable without medical contraindication for surgery at diagnosis, and (iii) be considered as unresectable at the initial staging procedure by our surgical team. Patients were classified as initially unresectable when our surgical team (including at least two surgeons: J.D., J.S., or M.B.) considered that an optimal cytoreduction (defined as no residual tumor mass greater than 2 cm in dimension) was not safely feasible with standard surgical procedures. The main reason for unresectability was the presence of (i) dense and vascularized adhesions between bowel and omental masses, (ii) large nodules adherent to intra-abdominal structures (rectum, bladder, . . .), or (iii) multiple, disseminated nodules of carcinomatosis at the surface of the small and large bowel. Standard ovarian cancer surgery at our institution includes total hysterectomy, bilateral ovariectomy, infragastric omentectomy, and resection of all intraabdominal visible lesions (inspection, palpation, peritoneal washing, . . .). Para-aortic lymphadenectomy was not routinely performed unless clear lymph node involvement was demonstrated by the abdominal CT scan or noted during the surgical procedure. Platinum-based neoadjuvant chemotherapy was administered as primary treatment. Carboplatin was given at area under the curve of 6 or cisplatin at the dosage of 75 mg/m2 in association with paclitaxel at 175 mg/m2, or cyclophosphamide at 600 mg/m2 and, in one case, doxorubicin at 35 mg/m2. Courses were repeated every 3 weeks. Response to the neoadjuvant chemotherapy was analyzed on abdominal
Table 1 Patient characteristics (n ⫽ 45) Median age (years) Histological type Serous Unspecified adenocarcinoma Clear cell Endometrial Mucinous FIGO stage IIIC IV Staging procedure Surgical (laparoscopy) Nonsurgical Neoadjuvant chemotherapy regimen Carboplatin–paclitaxel Cisplatin–cyclophosphamide Cisplatin–cyclophosphamide–doxorubicin Cisplatin–paclitaxel Carboplatin alone Adjuvant chemotherapy regimen Carboplatin–paclitaxel Topotecan Cisplatin–cyclophosphamide Paclitaxel No adjuvant chemotherapy
68 (range 28–80) 28 (62.2%) 10 (22.2%) 3 (6.6%) 2 (4.5%) 2 (4.5%) 36 (80.0%) 9 (20.0%) 32 (71.1%) 13 (28.9%) 35 (77.7%) 7 (15.5%) 1 (2.2%) 1 (2.2%) 1 (2.2%) 26 (57.8%) 9 (20.0%) 7 (15.5%) 2 (4.5%) 1 (2.2%)
CT scan using RECIST criteria. Then, surgery was performed in patients showing tumor response or disease stabilization after a median number of 4 courses (range: 2– 6) of initial chemotherapy. After surgery, adjuvant chemotherapy was administered in all cases except in one patient who refused any further treatment. Patients with progressive disease did not undergo surgery, because an optimal and complete surgical procedure was not safely feasible, and therefore underwent second-line chemotherapy, mainly topotecan at 1.5 mg/m2 daily during 5 days every 4 weeks. Kaplan–Meier analyses were used to determine diseasefree survival and overall survival. The log-rank test was used for survival comparison. A P value ⬍0.05 was considered statistically significant.
Results Patient characteristics and staging procedure Patient characteristics are summarized in Table 1. During the enrolment period, 45 patients presenting with advancedstage ovarian cancer had been classified as unresectable by our surgical and medical gynecology oncology team according to the criteria developed in the method section. Median age was 68 years (range 28 – 80). The most frequent histological type was serous adenocarcinoma (62.2%). Thirty-six (80%) patients had FIGO stage IIIC ovarian cancer and 9 (20%) patients FIGO stage IV disease (8 with malignant pleural effusion, 1 with hepatic metastases).
F. Mazzeo et al. / Gynecologic Oncology 90 (2003) 163–169 Table 2 Radiological response rate to chemotherapy (RECIST criteria) (n ⫽ 45) N (%) CR PR SD PD
1 (2.2%) 33 (73.4%) 8 (17.8%) 3 (6.6%)
Note. CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease.
Staging was performed by surgical laparoscopy with multiple biopsies in the majority of patients (n ⫽ 32 or 71.1%). Surgical staging was not performed in 13 (28.9%) patients. In these patients, abdominal CT scan showed ascitis, bowel involvement, and peritoneal implants larger than 2 cm in diameter or cytologically proven pleural involvement, and laparoscopy was not performed because the gynecologic and medical oncology team estimated that this procedure would not have modified the treatment strategy and that the disease was unresectable whatever the results of the laparoscopy. In these cases, either a positive cytology or a CT scan guided biopsy of one of the lesions was obtained before the start of chemotherapy and the histological examination had to be compatible with ovarian adenocarcinoma. The ovarian cancer was histologically confirmed at the debulking surgery in all these patients who had not undergone primary surgical staging. Response to neoadjuvant chemotherapy All patients received a platinum-based induction chemotherapy starting within 2 weeks following the initial diagnosis and staging (Table 1). The median number of courses of neoadjuvant chemotherapy was 4 (range: 2– 6). Since most of the patients were included after 1996, the majority (n ⫽ 35 or 77.8%) received paclitaxel– carboplatin combination chemotherapy. Seven (15.6%) patients were treated with cyclophosphamide– cisplatin, 1 (2.2%) with cyclophosphamide– doxorubicin– cisplatin, 1 (2.2%) with paclitaxel– cisplatin, and one 80-year-old patient (2.2%) with carboplatin monotherapy. Response to neoadjuvant chemotherapy was first evaluated by abdominal CT scan using the RECIST criteria (Table 2). After neoadjuvant chemotherapy, one complete response (2.2%) was observed, 33 (73.4%) patients achieved a partial response (PR), and 8 (17.8%) had stable disease (SD). Only 3 (6.6%) patients progressed (PD) during the initial chemotherapy. Debulking surgery Surgical debulking was proposed to all patients responding to neoadjuvant chemotherapy and was also attempted in patients with SD. One patient with SD did not undergo surgery due to ischemic heart failure diagnosed during che-
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motherapy (survival: 28 months). Another patient with PR refused surgery as well as any further treatment. She died 37 months after the diagnosis. The 3 patients with PD were not debulked, because an optimal resection would not have been safely possible, and received palliative second-line chemotherapy. As a consequence, in our series, 39 patients finally underwent surgery. The duration of the surgical procedure ranged from 150 to 240 min. No major complications were recorded during debulking surgery. After surgery, two patients developed an adynamic ileus that lasted for more than 7 days, but these complications resolved spontaneously or with medical supportive measures within 2 weeks. At surgery, no pathological complete response was noted, and residual ovarian cancer was present in all cases. Out of the 39 patients in which cytoreduction was performed, a complete macroscopic surgical resection could be achieved in 24 (53.3% of the whole population) (Table 3). Seven additional patients (15.6%) had less than 2 cm of residual tumor masses at the end of the surgical procedure. The debulking could not be complete in any of the patients with SD after neoadjuvant chemotherapy except in one case. In contrast, 22 patients out of 33 in PR after induction chemotherapy were free of macroscopic residual disease after surgery. Interestingly, 4 patients out of the 9 (44.5%) with stage IV disease achieved a CR status after induction chemotherapy and surgery. These four patients had a malignant pleural effusion confirmed by a cytological analysis prior to neoadjuvant chemotherapy. Among these complete responders, two relapsed at 6 and 17 months after diagnosis, respectively, whereas the two others were still in CR at 5 and 18 months of follow-up. Adjuvant chemotherapy Adjuvant chemotherapy regimens are described in Table 1. Patients who responded to neoadjuvant chemotherapy received a median of 4 (range: 2– 6) additional adjuvant courses of the same chemotherapy regimen. Nonresponding patients or patients with stable disease after neoadjuvant therapy were treated with second-line chemotherapy. The choice of second-line chemotherapy regimen was let to the discretion of the treating medical oncologist and mainly consisted of an intravenous topotecan regimen. Table 3 Residual tumor size after neoadjuvant chemotherapy and surgery (n ⫽ 45) Residual tumor size
N (%)
Complete macroscopic resection (R0) ⬍0.5 cm 0.5–2 cm ⬎2 cm No surgical evaluation Unknown
24 (53.3%) 2 (4.5%) 5 (11.1%) 8 (17.8%) 5 (11.1%) 1 (2.2%)
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Table 4 Sites of relapse for the patients with no residual tumor (n ⫽ 15) Site
N (%)
Peritoneum Liver Pleural
12 (79.9%) 2 (13.4%) 1 (6.7%)
Toxicity There were no treatment-related deaths. The toxicities of the chemotherapy were as expected with these chemotherapy regimens. In this review, only toxicities requiring dose adjustment or hospitalization could be reliably recorded. In this context, we noted 6 episodes of febrile neutropenia with two septicemia (bacteroides fragilis and E. coli), 1 grade IV and 2 grade III thrombocytopenia, 4 grade IV neutropenia, 1 grade III mucositis, and 1 grade IV vomiting. These toxicities were managed at the discretion of the treating physician by dose reduction or by delaying treatment, when necessary. Disease-free interval and survival analysis Fifteen out of the 24 patients in CR at the end of treatment relapsed after a median disease-free interval of 12 months (median follow-up: 11 months). Most of these recurrences (80%) occurred in the peritoneal cavity (Table 4). At the time of analysis, the median follow-up for the whole group was 21.5 months. The projected overall median survival time was 29 months. Survival probability was calculated according to different prognostic parameters (Fig. 1). Survival was significantly better in patients with no residual disease after debulking compared to the patients with persistence of macroscopic residual disease after surgery (41 versus 23 months; P ⫽ 0.0062). Patients responding to neoadjuvant chemotherapy had a median survival of 44 months. In contrast, patients with SD or PD after initial chemotherapy had a median survival of 27 months. This difference was statistically significant (P ⫽ 0.01). Finally, patients with normal CA-125 value (normal ⬍ 35 U/ml) at the end of neoadjuvant chemotherapy also had a significantly increased survival compared to patients with a pathologic CA-125 at this point in time: 44 versus 24 months (P ⫽ 0.03). However, the initial level of CA-125 (ranging from normal to 85,000 U/mL) was not a prognostic determinant. A multivariate analysis was not performed since this would have been irrelevant due to the low number of events and patients included in this retrospective analysis. Other prognostic factors studied in this analysis were presence of malignant ascitis, performance status, histological grade, increased LDH level, and anemia. None of these parameters seem to correlate with survival in this small retrospective series.
Discussion Surgical debulking followed by platinum-based chemotherapy is the standard of care for patients with stage III ovarian carcinoma. Neoadjuvant chemotherapy followed by interval debulking surgery may reduce the tumor burden and allow for an easier and complete surgical cytoreduction, at least in patients with chemosensitive disease. In our experience, the therapeutic sequence of neoadjuvant chemotherapy followed by surgical debulking and adjuvant chemotherapy showed to be feasible and effective. Neither treatment-related deaths nor major complications were encountered. About 75% of patients included showed an objective response to neoadjuvant chemotherapy. Median overall survival of the entire group was 29 months, which is in the expected range for such advanced-stage disease [2,7,16]. In our study, patients without macroscopic residual disease after surgery had a significantly better survival compared to patients with incomplete surgery. This is in accordance with previously published data and, like these studies, supports maximal cytoreduction as the ideal objective to achieve in these patients [2,7]. In addition, survival was also significantly longer in patients who were in PR or CR after induction chemotherapy compared to those with SD or PD. Complete surgical reduction was obtained in 23 (67%) out of 34 patients in PR or CR and only in one out of 8 (12.5%) patients with SD. Our data suggest that an objective response to neoadjuvant chemotherapy may facilitate the subsequent surgical cytoreduction, although only a prospective randomized study will definitively be able to prove this point. Four patients out of 9 (44.5%) with stage IV disease (malignant pleural effusion) achieved a CR status after chemotherapy and surgery. Among these complete responders, 2 relapsed at 6 and 17 months after diagnosis, respectively. The 2 others were still in CR at 5 and 18 months of follow-up. These observations confirm that primary chemotherapy followed by surgery might also be a valid approach in carefully selected patients with stage IV disease. The relative contribution of maximal cytoreductive surgery and platinum-based adjuvant chemotherapy to the survival of patients with advanced ovarian cancer is still a matter of debate. Some studies have tried to clarify the relative contribution of surgery and platinum-based chemotherapy to the survival of patients with advanced ovarian carcinoma [17]. Indeed, the survival advantage associated with complete surgery may rather be related to the inherent biology of the tumor as well as its chemosensitivity than to maximum cytoreductive surgery and skills of the surgeon [18]. Hunter et al. showed that platinum-based chemotherapy improved median survival in a greater proportion than maximal surgery [17]. In this meta-analysis, the use of platinum chemotherapy increased median survival by 53% and each 10% increase in maximal cytoreduction by only 4.1%. Other authors reached similar conclusions [19,20]. In
Fig. 1. (A) Survival according to complete debulking. (B) Survival according to CA-125 level after neoadjuvant chemotherapy. (C) Survival according to response to chemotherapy.
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contrast, some publications suggested that neither platinum dose intensity nor cumulative platinum dose was a statistically significant predictor of survival, but that maximal cytoreductive surgery was the most powerful independent determinant of survival [2,5,21,22]. In our series, patients who normalized their CA-125 level during induction chemotherapy also had a better survival. This probably reflects the chemosensitivity of the disease and corroborates the fact that patients showing an objective response to chemotherapy with conventional measurement criteria also have a better outcome. Others authors previously suggested that CA-125 might be a good surrogate marker to assess the tumor response in patients receiving platinum–paclitaxel combination regimens [23–25]. Although not studied prospectively, our results support these findings in the neoadjuvant setting. If validated, CA-125 may provide a cheaper and easier way to assess the tumor response. In our cohort, an attempt to perform debulking surgery was proposed to the patients in SD after initial chemotherapy. These patients could not be completely resected except in one case and clearly had a poorer prognosis. The value or importance of interval debulking in this subgroup of patients remains questionable since most of them had persistent residual bulky masses after the surgical procedure. Although speculative, it might be possible that administration of second-line chemotherapy without interval debulking could achieve similar outcome in these instances. For these patients with a very poor prognosis, the main goal of treatment may be quality of life. Thus it would be necessary to prospectively evaluate if surgery in this setting is able to improve quality of life by decreasing the number of complications such as the risk of intestinal obstruction, for instance. Of course, this review has some flaws: it was a small retrospective series with a long period of inclusion and a heterogeneity of chemotherapy regimens. Some of the patients with stage III, initially unresectable ovarian carinoma did not undergo a surgical staging, which clearly is not standard in this disease. How these parameters could have influenced our results is unknown. Many questions remain concerning the optimal number of induction chemotherapy courses and the value of adjuvant chemotherapy in this context. Would this approach really improve survival of this poor prognosis population or just help to identify patients with chemosensitive disease? As most recurrences were observed in the peritoneal cavity, would intraperitoneal chemotherapy improve survival? Many studies have already shown that this sequential approach is safe and seems to produce at least similar or equivalent results compared to initial surgery followed by adjuvant chemotherapy [7–16,26 –27]. However, these studies are heterogeneous and the definition of unresectability is likely to be different from one study to another and to be mainly dependent on the skills and the experience of the
individual surgeon as shown by the wide disparity in surgical success rates reported. A small study suggested that patients with stage IIIC ovarian carcinoma with large ascitis volume (⬎500 mL) might have an increased survival when treated with neoadjuvant chemotherapy followed by surgery compared to primary debulking [16]. This approach is now being evaluated in large randomized trials. In addition, identification of predictive factors of chemosensitivity may represent an important goal for medical oncologists, especially in the neoadjuvant setting. In the future, development of the microarray technology may identify gene-expression profile of chemosensitive disease and help to individualize and to select the best therapeutic approach and strategy for each patient.
References [1] Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 1975;42:101– 4. [2] Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248 –59. [3] Bertelsen K. Tumor reduction surgery and long-term survival in advanced ovarian cancer: a DACOVA study. Gynecol Oncol 1990; 38:203–9. [4] Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992;47:159 – 66. [5] Allen DG, Heintz AP, Touw FW. A meta-analysis of residual disease and survival in stage III and IV carcinoma of the ovary. Eur J Gynaecol Oncol 1995;16:349 –56. [6] Hoskins WJ, Lawton FG. Primary cytoreductive surgery for advanced stage disease. In: Gershenson DM, McGuire, editors. Ovarian cancer. New York: Churchill Livingstone; 1998, p. 65– 84. [7] Ansquer Y, Leblanc E, Clough K, Morice P, Dauplat J, Mathevet P, Lhomme C, Scherer C, Tigaud JD, Benchaib M, Fourme E, Castaigne D, Querleu D, Dargent D. Neoadjuvant chemotherapy for unresectable ovarian cancer: a French multicenter study. Cancer 2001;9: 2329 –34. [8] Vergote IB, De Wever I, Decloedt J, Tjalma W, Van Gramberen M, van Dam P. Neoadjuvant chemotherapy versus primary debulking surgery in advanced ovarian cancer. Semin Oncol 2000;27:31– 6. [9] Vergote IB, De Wever I, Decloedt J, Tjalma W, Van Gramberen M, van Dam P. Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: a retrospective analysis of 285 patients. Gynecol Oncol 1998;71:431– 6 (doi:10.1006/gyno.1998.5213). [10] Onnis A, Marchetti M, Padovan P, Castellan L. Neoadjuvant chemotherapy in advanced ovarian cancer. Eur J Gynaecol Oncol 1996;17: 393–96. [11] Recchia F, De Filippis S, Rosselli M, Saggio G, Carta G, Rea S. Primary chemotherapy in stage IV ovarian cancer. A prospective phase II study. Eur J Gynaecol Oncol 2001;22:287–91. [12] Kayikcioglu F, Kose MF, Boran N, Caliskan E, Tulunay G. Neoadjuvant chemotherapy or primary surgery in advanced epithelial ovarian carcinoma. Int J Gynecol Cancer 2001;11:466 –70. [13] Schwartz PE, Rutherford TJ, Chambers JT, Kohorn EI, Thiel RP. Neoadjuvant chemotherapy for advanced ovarian cancer: long term survival. Gynecol Oncol 1999;72:93–9 (doi:10.1006/gyno.1998.5236).
F. Mazzeo et al. / Gynecologic Oncology 90 (2003) 163–169 [14] Jacob JH, Gehenson DM, Morris M, Copeland LJ, Burke TW, Wharton JT. Neoadjuvant chemotherapy and interval debulking for advanced epithelial ovarian cancer. Gynecol Oncol 1991;42:146 –50. [15] Chambers JT, Chambers SK, Voynick IM, Schwartz PE. Neoadjuvant chemotherapy in stage X ovarian carcinoma. Gynecol Oncol 1990; 37:327–31. [16] Kuhn W, Rutke S, Spa¨ the K, Schmalfeldt B, Florack G, von Hundelshausen B, Pachyn D, Ulm K, Graeff H. Neoadjuvant chemotherapy followed by tumor debulking prolongs survival for patients with poor prognosis in International Federation of Gynecology and Obstetrics Stage IIIC ovarian carcinoma. Cancer 2001;92:2585–91. [17] Hunter RW, Alexander NDE, Soutter WP. Meta-analysis of surgery in advanced ovarian cancer: is maximum cytoreductive surgery an independent determinant of prognosis? Am J Obstet Gynecol 1992; 166:504 –11. [18] Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol 2000;78:269–74 (doi:10.1006/gyno.2000.5926). [19] Venesmaa P. Epithelial ovarian cancer: impact of surgery and chemotherapy on survival during 1977–1990. Obstet Gynecol 1994;84: 8 –11. [20] Hogberg T. Primary surgery in ovarian cancer: current opinions. Ann Med 1995;27:95–100. [21] Voest EE, van Houwelingen JC, Neijt JP. A meta-analysis of prognostic factors in advanced ovarian cancer with median survival and
[22]
[23]
[24]
[25]
[26]
[27]
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overall survival (measured with the log [relative risk] as main objectives. Eur J Cancer Clin Oncol 1989;25:711–20. Ben-David Y, Rosen B, Franssen E, Einarson T, Szyfer L. Metaanalysis comparing cisplatin total dose intensity and survival. Gynecol Oncol 1995;59:93–101 (doi:10.1006/gyno.1995.1273). Rustin GJ, Nelstrop AE, McClean P, Brady MF, McGuire WP, Hoskins WJ, Mitchell H, Lambert HE. Defining response of ovarian carcinoma to initial chemotherapy according to serum CA-125. J Clin Oncol 1996;14:1545–51. Bridgewater JA, Nelstrop AE, Rustin GJS, Gore ME, McGuire WP, Hoskins WJ. Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxel. J Clin Oncol 1999;17:501– 8. Tuxen MK, Soletormos G, Dombernowsky P. Serum tumour marker CA-125 in monitoring ovarian cancer during first-line chemotherapy. Br J Cancer 2001;84:1301–7 (doi:10.1054/bjoc.2001.1787). Van Den Burg MEL, Van Lent M, Buyse M, Kobierska A, Colombo N, Favalli G, Lacave AJ, Nardi M, Renard J, Pecorelli S. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995;332:629–34. Rose PG, Nerenstone S, Brady M, Clarke-Pearson D, Olt G, Rubin SC, Moore DH. A phase III randomised study of interval secondary cytoreduction in patients with advanced stage ovarian carcinoma with suboptimal residual disease: a Gynaecologic Oncology Group Study. Proc Am Assoc Clin Oncol 2002; 201a: abstract 802.
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Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer Filomena Mazzeo,a Martine Berlie`re,b Joseph Kerger,c Jean Squifflet,b Lionel Duck,a Ve´ronique D’Hondt,a Yves Humblet,a Jacques Donnez,b and Jean-Pascal Machielsa,* a
b
Medical Oncology Unit, Centre du Cancer, Universite´ Catholique de Louvain, Brussels, Belgium Department of Gynecology, Centre du Cancer, Universite´ Catholique de Louvain, Brussels, Belgium c Medical Oncology Unit, Universite´ Catholique de Louvain, Mont-Godinne, Belgium Received 16 October 2002
Abstract Objective. The aim of this review is to report our experience and the feasibility of neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer. Methods. Forty-five patients with primarily unresectable advanced-stage epithelial ovarian cancer were treated in our center between 1995 and 2002 by platinum-based neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. Their files were reviewed retrospectively. Results. At the end of neoadjuvant chemotherapy, according to RECIST criteria, 1 patient (2.2%) had achieved a clinical complete response (CR), 33 (73.4%) a partial response (PR), and 8 (17.8%) had stable disease (SD). Only 3 (6.6%) patients showed disease progression (PD). Surgery was performed in patients with objective response or SD after a median number of 4 courses (range: 2– 6) of induction chemotherapy. A complete macroscopic debulking was achieved in 24 (53.3%) out of 39 patients in whom cytoreductive surgery was performed. For the entire group, median overall survival was 29 months. Survival was significantly improved in patients with optimal debulking compared to patients with persistent tumor after surgery: 41 months versus 23 months (P ⫽ 0.0062). Median survival for patients responding to neoadjuvant chemotherapy (CR and PR) was 44 months compared to 27 months for patients with SD or PD after initial chemotherapy (P ⫽ 0.01). Neither treatment-related deaths nor significant toxicities were observed. Conclusion. Neoadjuvant chemotherapy followed by optimal debulking may be a safe and valuable treatment alternative in patients with primarily unresectable advanced-stage bulky ovarian cancer. Patients with an objective response to chemotherapy or absence of macroscopic residual tumor after surgery have a better outcome. This approach is currently being tested in large, prospective randomized clinical trials. © 2003 Elsevier Science (USA). All rights reserved.
Introduction Primary surgical cytoreduction followed by platinum-based chemotherapy represents the standard therapy for patients with advanced epithelial ovarian cancer [1–5]. However, despite this therapeutic strategy, most patients with International Fed-
* Corresponding author. Medical Oncology Unit, Universite´ Catholique de Louvain, Cliniques Universitaires Saint-Luc, 10, avenue Hippocrate, 1200 Brussels, Belgium. Fax: ⫹32-2-764-54-28. E-mail address: [email protected] (J.-P. Machiels).
eration of Gynecology and Obstetrics (FIGO) stage III or IV disease will relapse and eventually die of progressive disease. Current literature shows an inverse relationship between residual tumor diameter after surgery and survival [2]. These data suggest that patients with advanced-stage ovarian cancer could only benefit from an optimal surgical debulking. No clear survival benefit has been demonstrated in patients with residual tumor larger than 2 cm in diameter after debulking in FIGO stages III–IV ovarian cancer [6], and optimal cytoreductive surgery may often be difficult to achieve due to the initial extent of the disease. Thus primary surgery for this subset of patients may be questionable.
0090-8258/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0090-8258(03)00249-X
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Ovarian cancer is a chemosensitive disease and approximately 80% of patients will achieve an objective response with platinum-based regimens [7]. In this patient population, neoadjuvant chemotherapy may significantly reduce the tumor burden before surgery and allow for an easier optimal cytoreduction. The feasibility of this treatment modality has been demonstrated in previous reports [7–15]. Recently a clinical trial suggested that neoadjuvant chemotherapy followed by debulking might prolong survival for patients with ascitis and FIGO stage IIIC ovarian cancer [16]. In this paper, we report our experience with neoadjuvant chemotherapy in patients with FIGO stage IIIC or IV initially unresectable ovarian cancer. Complete macroscopic resection can be achieved in about 70% of patients responding to neoadjuvant chemotherapy and patients with an objective response to initial chemotherapy and complete debulking have a prolonged survival compared to those with chemoresistant disease or incomplete surgery.
Patients and methods This review includes 45 patients with FIGO stage IIIC and IV epithelial ovarian cancer treated at our institution between 1995 and 2002. To be eligible for analysis, patients should (i) have measurable bulky tumor masses on the initial abdominal and pelvic CT scan, (ii) be operable without medical contraindication for surgery at diagnosis, and (iii) be considered as unresectable at the initial staging procedure by our surgical team. Patients were classified as initially unresectable when our surgical team (including at least two surgeons: J.D., J.S., or M.B.) considered that an optimal cytoreduction (defined as no residual tumor mass greater than 2 cm in dimension) was not safely feasible with standard surgical procedures. The main reason for unresectability was the presence of (i) dense and vascularized adhesions between bowel and omental masses, (ii) large nodules adherent to intra-abdominal structures (rectum, bladder, . . .), or (iii) multiple, disseminated nodules of carcinomatosis at the surface of the small and large bowel. Standard ovarian cancer surgery at our institution includes total hysterectomy, bilateral ovariectomy, infragastric omentectomy, and resection of all intraabdominal visible lesions (inspection, palpation, peritoneal washing, . . .). Para-aortic lymphadenectomy was not routinely performed unless clear lymph node involvement was demonstrated by the abdominal CT scan or noted during the surgical procedure. Platinum-based neoadjuvant chemotherapy was administered as primary treatment. Carboplatin was given at area under the curve of 6 or cisplatin at the dosage of 75 mg/m2 in association with paclitaxel at 175 mg/m2, or cyclophosphamide at 600 mg/m2 and, in one case, doxorubicin at 35 mg/m2. Courses were repeated every 3 weeks. Response to the neoadjuvant chemotherapy was analyzed on abdominal
Table 1 Patient characteristics (n ⫽ 45) Median age (years) Histological type Serous Unspecified adenocarcinoma Clear cell Endometrial Mucinous FIGO stage IIIC IV Staging procedure Surgical (laparoscopy) Nonsurgical Neoadjuvant chemotherapy regimen Carboplatin–paclitaxel Cisplatin–cyclophosphamide Cisplatin–cyclophosphamide–doxorubicin Cisplatin–paclitaxel Carboplatin alone Adjuvant chemotherapy regimen Carboplatin–paclitaxel Topotecan Cisplatin–cyclophosphamide Paclitaxel No adjuvant chemotherapy
68 (range 28–80) 28 (62.2%) 10 (22.2%) 3 (6.6%) 2 (4.5%) 2 (4.5%) 36 (80.0%) 9 (20.0%) 32 (71.1%) 13 (28.9%) 35 (77.7%) 7 (15.5%) 1 (2.2%) 1 (2.2%) 1 (2.2%) 26 (57.8%) 9 (20.0%) 7 (15.5%) 2 (4.5%) 1 (2.2%)
CT scan using RECIST criteria. Then, surgery was performed in patients showing tumor response or disease stabilization after a median number of 4 courses (range: 2– 6) of initial chemotherapy. After surgery, adjuvant chemotherapy was administered in all cases except in one patient who refused any further treatment. Patients with progressive disease did not undergo surgery, because an optimal and complete surgical procedure was not safely feasible, and therefore underwent second-line chemotherapy, mainly topotecan at 1.5 mg/m2 daily during 5 days every 4 weeks. Kaplan–Meier analyses were used to determine diseasefree survival and overall survival. The log-rank test was used for survival comparison. A P value ⬍0.05 was considered statistically significant.
Results Patient characteristics and staging procedure Patient characteristics are summarized in Table 1. During the enrolment period, 45 patients presenting with advancedstage ovarian cancer had been classified as unresectable by our surgical and medical gynecology oncology team according to the criteria developed in the method section. Median age was 68 years (range 28 – 80). The most frequent histological type was serous adenocarcinoma (62.2%). Thirty-six (80%) patients had FIGO stage IIIC ovarian cancer and 9 (20%) patients FIGO stage IV disease (8 with malignant pleural effusion, 1 with hepatic metastases).
F. Mazzeo et al. / Gynecologic Oncology 90 (2003) 163–169 Table 2 Radiological response rate to chemotherapy (RECIST criteria) (n ⫽ 45) N (%) CR PR SD PD
1 (2.2%) 33 (73.4%) 8 (17.8%) 3 (6.6%)
Note. CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease.
Staging was performed by surgical laparoscopy with multiple biopsies in the majority of patients (n ⫽ 32 or 71.1%). Surgical staging was not performed in 13 (28.9%) patients. In these patients, abdominal CT scan showed ascitis, bowel involvement, and peritoneal implants larger than 2 cm in diameter or cytologically proven pleural involvement, and laparoscopy was not performed because the gynecologic and medical oncology team estimated that this procedure would not have modified the treatment strategy and that the disease was unresectable whatever the results of the laparoscopy. In these cases, either a positive cytology or a CT scan guided biopsy of one of the lesions was obtained before the start of chemotherapy and the histological examination had to be compatible with ovarian adenocarcinoma. The ovarian cancer was histologically confirmed at the debulking surgery in all these patients who had not undergone primary surgical staging. Response to neoadjuvant chemotherapy All patients received a platinum-based induction chemotherapy starting within 2 weeks following the initial diagnosis and staging (Table 1). The median number of courses of neoadjuvant chemotherapy was 4 (range: 2– 6). Since most of the patients were included after 1996, the majority (n ⫽ 35 or 77.8%) received paclitaxel– carboplatin combination chemotherapy. Seven (15.6%) patients were treated with cyclophosphamide– cisplatin, 1 (2.2%) with cyclophosphamide– doxorubicin– cisplatin, 1 (2.2%) with paclitaxel– cisplatin, and one 80-year-old patient (2.2%) with carboplatin monotherapy. Response to neoadjuvant chemotherapy was first evaluated by abdominal CT scan using the RECIST criteria (Table 2). After neoadjuvant chemotherapy, one complete response (2.2%) was observed, 33 (73.4%) patients achieved a partial response (PR), and 8 (17.8%) had stable disease (SD). Only 3 (6.6%) patients progressed (PD) during the initial chemotherapy. Debulking surgery Surgical debulking was proposed to all patients responding to neoadjuvant chemotherapy and was also attempted in patients with SD. One patient with SD did not undergo surgery due to ischemic heart failure diagnosed during che-
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motherapy (survival: 28 months). Another patient with PR refused surgery as well as any further treatment. She died 37 months after the diagnosis. The 3 patients with PD were not debulked, because an optimal resection would not have been safely possible, and received palliative second-line chemotherapy. As a consequence, in our series, 39 patients finally underwent surgery. The duration of the surgical procedure ranged from 150 to 240 min. No major complications were recorded during debulking surgery. After surgery, two patients developed an adynamic ileus that lasted for more than 7 days, but these complications resolved spontaneously or with medical supportive measures within 2 weeks. At surgery, no pathological complete response was noted, and residual ovarian cancer was present in all cases. Out of the 39 patients in which cytoreduction was performed, a complete macroscopic surgical resection could be achieved in 24 (53.3% of the whole population) (Table 3). Seven additional patients (15.6%) had less than 2 cm of residual tumor masses at the end of the surgical procedure. The debulking could not be complete in any of the patients with SD after neoadjuvant chemotherapy except in one case. In contrast, 22 patients out of 33 in PR after induction chemotherapy were free of macroscopic residual disease after surgery. Interestingly, 4 patients out of the 9 (44.5%) with stage IV disease achieved a CR status after induction chemotherapy and surgery. These four patients had a malignant pleural effusion confirmed by a cytological analysis prior to neoadjuvant chemotherapy. Among these complete responders, two relapsed at 6 and 17 months after diagnosis, respectively, whereas the two others were still in CR at 5 and 18 months of follow-up. Adjuvant chemotherapy Adjuvant chemotherapy regimens are described in Table 1. Patients who responded to neoadjuvant chemotherapy received a median of 4 (range: 2– 6) additional adjuvant courses of the same chemotherapy regimen. Nonresponding patients or patients with stable disease after neoadjuvant therapy were treated with second-line chemotherapy. The choice of second-line chemotherapy regimen was let to the discretion of the treating medical oncologist and mainly consisted of an intravenous topotecan regimen. Table 3 Residual tumor size after neoadjuvant chemotherapy and surgery (n ⫽ 45) Residual tumor size
N (%)
Complete macroscopic resection (R0) ⬍0.5 cm 0.5–2 cm ⬎2 cm No surgical evaluation Unknown
24 (53.3%) 2 (4.5%) 5 (11.1%) 8 (17.8%) 5 (11.1%) 1 (2.2%)
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Table 4 Sites of relapse for the patients with no residual tumor (n ⫽ 15) Site
N (%)
Peritoneum Liver Pleural
12 (79.9%) 2 (13.4%) 1 (6.7%)
Toxicity There were no treatment-related deaths. The toxicities of the chemotherapy were as expected with these chemotherapy regimens. In this review, only toxicities requiring dose adjustment or hospitalization could be reliably recorded. In this context, we noted 6 episodes of febrile neutropenia with two septicemia (bacteroides fragilis and E. coli), 1 grade IV and 2 grade III thrombocytopenia, 4 grade IV neutropenia, 1 grade III mucositis, and 1 grade IV vomiting. These toxicities were managed at the discretion of the treating physician by dose reduction or by delaying treatment, when necessary. Disease-free interval and survival analysis Fifteen out of the 24 patients in CR at the end of treatment relapsed after a median disease-free interval of 12 months (median follow-up: 11 months). Most of these recurrences (80%) occurred in the peritoneal cavity (Table 4). At the time of analysis, the median follow-up for the whole group was 21.5 months. The projected overall median survival time was 29 months. Survival probability was calculated according to different prognostic parameters (Fig. 1). Survival was significantly better in patients with no residual disease after debulking compared to the patients with persistence of macroscopic residual disease after surgery (41 versus 23 months; P ⫽ 0.0062). Patients responding to neoadjuvant chemotherapy had a median survival of 44 months. In contrast, patients with SD or PD after initial chemotherapy had a median survival of 27 months. This difference was statistically significant (P ⫽ 0.01). Finally, patients with normal CA-125 value (normal ⬍ 35 U/ml) at the end of neoadjuvant chemotherapy also had a significantly increased survival compared to patients with a pathologic CA-125 at this point in time: 44 versus 24 months (P ⫽ 0.03). However, the initial level of CA-125 (ranging from normal to 85,000 U/mL) was not a prognostic determinant. A multivariate analysis was not performed since this would have been irrelevant due to the low number of events and patients included in this retrospective analysis. Other prognostic factors studied in this analysis were presence of malignant ascitis, performance status, histological grade, increased LDH level, and anemia. None of these parameters seem to correlate with survival in this small retrospective series.
Discussion Surgical debulking followed by platinum-based chemotherapy is the standard of care for patients with stage III ovarian carcinoma. Neoadjuvant chemotherapy followed by interval debulking surgery may reduce the tumor burden and allow for an easier and complete surgical cytoreduction, at least in patients with chemosensitive disease. In our experience, the therapeutic sequence of neoadjuvant chemotherapy followed by surgical debulking and adjuvant chemotherapy showed to be feasible and effective. Neither treatment-related deaths nor major complications were encountered. About 75% of patients included showed an objective response to neoadjuvant chemotherapy. Median overall survival of the entire group was 29 months, which is in the expected range for such advanced-stage disease [2,7,16]. In our study, patients without macroscopic residual disease after surgery had a significantly better survival compared to patients with incomplete surgery. This is in accordance with previously published data and, like these studies, supports maximal cytoreduction as the ideal objective to achieve in these patients [2,7]. In addition, survival was also significantly longer in patients who were in PR or CR after induction chemotherapy compared to those with SD or PD. Complete surgical reduction was obtained in 23 (67%) out of 34 patients in PR or CR and only in one out of 8 (12.5%) patients with SD. Our data suggest that an objective response to neoadjuvant chemotherapy may facilitate the subsequent surgical cytoreduction, although only a prospective randomized study will definitively be able to prove this point. Four patients out of 9 (44.5%) with stage IV disease (malignant pleural effusion) achieved a CR status after chemotherapy and surgery. Among these complete responders, 2 relapsed at 6 and 17 months after diagnosis, respectively. The 2 others were still in CR at 5 and 18 months of follow-up. These observations confirm that primary chemotherapy followed by surgery might also be a valid approach in carefully selected patients with stage IV disease. The relative contribution of maximal cytoreductive surgery and platinum-based adjuvant chemotherapy to the survival of patients with advanced ovarian cancer is still a matter of debate. Some studies have tried to clarify the relative contribution of surgery and platinum-based chemotherapy to the survival of patients with advanced ovarian carcinoma [17]. Indeed, the survival advantage associated with complete surgery may rather be related to the inherent biology of the tumor as well as its chemosensitivity than to maximum cytoreductive surgery and skills of the surgeon [18]. Hunter et al. showed that platinum-based chemotherapy improved median survival in a greater proportion than maximal surgery [17]. In this meta-analysis, the use of platinum chemotherapy increased median survival by 53% and each 10% increase in maximal cytoreduction by only 4.1%. Other authors reached similar conclusions [19,20]. In
Fig. 1. (A) Survival according to complete debulking. (B) Survival according to CA-125 level after neoadjuvant chemotherapy. (C) Survival according to response to chemotherapy.
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contrast, some publications suggested that neither platinum dose intensity nor cumulative platinum dose was a statistically significant predictor of survival, but that maximal cytoreductive surgery was the most powerful independent determinant of survival [2,5,21,22]. In our series, patients who normalized their CA-125 level during induction chemotherapy also had a better survival. This probably reflects the chemosensitivity of the disease and corroborates the fact that patients showing an objective response to chemotherapy with conventional measurement criteria also have a better outcome. Others authors previously suggested that CA-125 might be a good surrogate marker to assess the tumor response in patients receiving platinum–paclitaxel combination regimens [23–25]. Although not studied prospectively, our results support these findings in the neoadjuvant setting. If validated, CA-125 may provide a cheaper and easier way to assess the tumor response. In our cohort, an attempt to perform debulking surgery was proposed to the patients in SD after initial chemotherapy. These patients could not be completely resected except in one case and clearly had a poorer prognosis. The value or importance of interval debulking in this subgroup of patients remains questionable since most of them had persistent residual bulky masses after the surgical procedure. Although speculative, it might be possible that administration of second-line chemotherapy without interval debulking could achieve similar outcome in these instances. For these patients with a very poor prognosis, the main goal of treatment may be quality of life. Thus it would be necessary to prospectively evaluate if surgery in this setting is able to improve quality of life by decreasing the number of complications such as the risk of intestinal obstruction, for instance. Of course, this review has some flaws: it was a small retrospective series with a long period of inclusion and a heterogeneity of chemotherapy regimens. Some of the patients with stage III, initially unresectable ovarian carinoma did not undergo a surgical staging, which clearly is not standard in this disease. How these parameters could have influenced our results is unknown. Many questions remain concerning the optimal number of induction chemotherapy courses and the value of adjuvant chemotherapy in this context. Would this approach really improve survival of this poor prognosis population or just help to identify patients with chemosensitive disease? As most recurrences were observed in the peritoneal cavity, would intraperitoneal chemotherapy improve survival? Many studies have already shown that this sequential approach is safe and seems to produce at least similar or equivalent results compared to initial surgery followed by adjuvant chemotherapy [7–16,26 –27]. However, these studies are heterogeneous and the definition of unresectability is likely to be different from one study to another and to be mainly dependent on the skills and the experience of the
individual surgeon as shown by the wide disparity in surgical success rates reported. A small study suggested that patients with stage IIIC ovarian carcinoma with large ascitis volume (⬎500 mL) might have an increased survival when treated with neoadjuvant chemotherapy followed by surgery compared to primary debulking [16]. This approach is now being evaluated in large randomized trials. In addition, identification of predictive factors of chemosensitivity may represent an important goal for medical oncologists, especially in the neoadjuvant setting. In the future, development of the microarray technology may identify gene-expression profile of chemosensitive disease and help to individualize and to select the best therapeutic approach and strategy for each patient.
References [1] Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 1975;42:101– 4. [2] Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248 –59. [3] Bertelsen K. Tumor reduction surgery and long-term survival in advanced ovarian cancer: a DACOVA study. Gynecol Oncol 1990; 38:203–9. [4] Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992;47:159 – 66. [5] Allen DG, Heintz AP, Touw FW. A meta-analysis of residual disease and survival in stage III and IV carcinoma of the ovary. Eur J Gynaecol Oncol 1995;16:349 –56. [6] Hoskins WJ, Lawton FG. Primary cytoreductive surgery for advanced stage disease. In: Gershenson DM, McGuire, editors. Ovarian cancer. New York: Churchill Livingstone; 1998, p. 65– 84. [7] Ansquer Y, Leblanc E, Clough K, Morice P, Dauplat J, Mathevet P, Lhomme C, Scherer C, Tigaud JD, Benchaib M, Fourme E, Castaigne D, Querleu D, Dargent D. Neoadjuvant chemotherapy for unresectable ovarian cancer: a French multicenter study. Cancer 2001;9: 2329 –34. [8] Vergote IB, De Wever I, Decloedt J, Tjalma W, Van Gramberen M, van Dam P. Neoadjuvant chemotherapy versus primary debulking surgery in advanced ovarian cancer. Semin Oncol 2000;27:31– 6. [9] Vergote IB, De Wever I, Decloedt J, Tjalma W, Van Gramberen M, van Dam P. Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: a retrospective analysis of 285 patients. Gynecol Oncol 1998;71:431– 6 (doi:10.1006/gyno.1998.5213). [10] Onnis A, Marchetti M, Padovan P, Castellan L. Neoadjuvant chemotherapy in advanced ovarian cancer. Eur J Gynaecol Oncol 1996;17: 393–96. [11] Recchia F, De Filippis S, Rosselli M, Saggio G, Carta G, Rea S. Primary chemotherapy in stage IV ovarian cancer. A prospective phase II study. Eur J Gynaecol Oncol 2001;22:287–91. [12] Kayikcioglu F, Kose MF, Boran N, Caliskan E, Tulunay G. Neoadjuvant chemotherapy or primary surgery in advanced epithelial ovarian carcinoma. Int J Gynecol Cancer 2001;11:466 –70. [13] Schwartz PE, Rutherford TJ, Chambers JT, Kohorn EI, Thiel RP. Neoadjuvant chemotherapy for advanced ovarian cancer: long term survival. Gynecol Oncol 1999;72:93–9 (doi:10.1006/gyno.1998.5236).
F. Mazzeo et al. / Gynecologic Oncology 90 (2003) 163–169 [14] Jacob JH, Gehenson DM, Morris M, Copeland LJ, Burke TW, Wharton JT. Neoadjuvant chemotherapy and interval debulking for advanced epithelial ovarian cancer. Gynecol Oncol 1991;42:146 –50. [15] Chambers JT, Chambers SK, Voynick IM, Schwartz PE. Neoadjuvant chemotherapy in stage X ovarian carcinoma. Gynecol Oncol 1990; 37:327–31. [16] Kuhn W, Rutke S, Spa¨ the K, Schmalfeldt B, Florack G, von Hundelshausen B, Pachyn D, Ulm K, Graeff H. Neoadjuvant chemotherapy followed by tumor debulking prolongs survival for patients with poor prognosis in International Federation of Gynecology and Obstetrics Stage IIIC ovarian carcinoma. Cancer 2001;92:2585–91. [17] Hunter RW, Alexander NDE, Soutter WP. Meta-analysis of surgery in advanced ovarian cancer: is maximum cytoreductive surgery an independent determinant of prognosis? Am J Obstet Gynecol 1992; 166:504 –11. [18] Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol 2000;78:269–74 (doi:10.1006/gyno.2000.5926). [19] Venesmaa P. Epithelial ovarian cancer: impact of surgery and chemotherapy on survival during 1977–1990. Obstet Gynecol 1994;84: 8 –11. [20] Hogberg T. Primary surgery in ovarian cancer: current opinions. Ann Med 1995;27:95–100. [21] Voest EE, van Houwelingen JC, Neijt JP. A meta-analysis of prognostic factors in advanced ovarian cancer with median survival and
[22]
[23]
[24]
[25]
[26]
[27]
169
overall survival (measured with the log [relative risk] as main objectives. Eur J Cancer Clin Oncol 1989;25:711–20. Ben-David Y, Rosen B, Franssen E, Einarson T, Szyfer L. Metaanalysis comparing cisplatin total dose intensity and survival. Gynecol Oncol 1995;59:93–101 (doi:10.1006/gyno.1995.1273). Rustin GJ, Nelstrop AE, McClean P, Brady MF, McGuire WP, Hoskins WJ, Mitchell H, Lambert HE. Defining response of ovarian carcinoma to initial chemotherapy according to serum CA-125. J Clin Oncol 1996;14:1545–51. Bridgewater JA, Nelstrop AE, Rustin GJS, Gore ME, McGuire WP, Hoskins WJ. Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxel. J Clin Oncol 1999;17:501– 8. Tuxen MK, Soletormos G, Dombernowsky P. Serum tumour marker CA-125 in monitoring ovarian cancer during first-line chemotherapy. Br J Cancer 2001;84:1301–7 (doi:10.1054/bjoc.2001.1787). Van Den Burg MEL, Van Lent M, Buyse M, Kobierska A, Colombo N, Favalli G, Lacave AJ, Nardi M, Renard J, Pecorelli S. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995;332:629–34. Rose PG, Nerenstone S, Brady M, Clarke-Pearson D, Olt G, Rubin SC, Moore DH. A phase III randomised study of interval secondary cytoreduction in patients with advanced stage ovarian carcinoma with suboptimal residual disease: a Gynaecologic Oncology Group Study. Proc Am Assoc Clin Oncol 2002; 201a: abstract 802.