BACKGROUND. The objective of this study was to determine the impact of malignant

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1 1397 The Clinical Significance of Malignant Pleural Effusions in Patients with Optimally Debulked Ovarian Carcinoma Ram Eitan, M.D. Douglas A. Levine, M.D. Nadeem Abu-Rustum, M.D. Yukio Sonoda, M.D. Jae N. Huh, B.A. Corinna C. Franklin, B.A. Tobey A. Stevens, M.D. Richard R. Barakat, M.D. Dennis S. Chi, M.D. Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. BACKGROUND. The objective of this study was to determine the impact of malignant pleural effusions on survival in patients with optimally debulked, advanced epithelial ovarian carcinoma. METHODS. The authors conducted a retrospective review of all patients with advanced epithelial ovarian carcinoma who underwent optimal primary cytoreduction at their institution between January 1987 and August Survival rates were compared between pts with optimally debulked Stage IIIC epithelial ovarian carcinoma and patients with optimally debulked Stage IV epithelial ovarian carcinoma (according to the International Federation of Gynecology and Obstetrics [FIGO] staging system) based on cytology-proven malignant pleural effusions. RESULTS. Ninety-nine patients were identified, and 97 of those patients were evaluable. The group with Stage IIIC disease included 76 patients, and the group with Stage IV disease included 21 patients. The median age at diagnosis was 55 years (range, years). The majority of patients received platinum-based chemotherapy after undergoing optimal primary cytoreduction. Age, tumor grade and histology, and the percentage of patients with ascites were similar in the two groups. The median survival rate was 58 months for patients who had Stage IIIC disease and 30 months for patients who had Stage IV disease (P 0.016). CONCLUSIONS. Although both groups underwent optimal cytoreduction in the abdomen/pelvis and were treated in a similar fashion, the median survival rate of patients with malignant pleural effusions was significantly shorter than the survival of patients without effusions. Many factors that led to or were manifested by pleural effusions, such as undetected bulky residual intrathoracic disease, may have been the cause for this survival difference. In the patients with effusions, one or more of these contributing factors may have led to the observed decreased survival rate, warranting further investigation. Cancer 2005;103: American Cancer Society. KEYWORDS: ovarian carcinoma, pleural effusion, survival, optimal debulking. Address for reprints: Dennis S. Chi, M.D., Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, MRI-1026, New York, NY 10021; Fax: (212) ; gynbreast@mskcc.org Received July 21, 2004; revision received December 3, 2004; accepted December 3, The majority of women who develop epithelial ovarian carcinoma will present with advanced Stage III or IV disease. 1 Stage III disease has been defined by the International Federation of Gynecology and Obstetrics (FIGO) as histologically proven, microscopic, extrapelvic spread (Stage IIIA); extrapelvic disease measuring 2 cm (Stage IIIB); and extrapelvic disease measuring 2 cm in size or positive retroperitoneal or inguinal lymph nodes (Stage IIIC). Stage IV disease has been defined as parenchymal liver metastasis, malignant pleural effusion, or other distant extraabdominal sites of disease. No substaging has been set for Stage IV in the FIGO staging system. In the 1998 FIGO annual report concerning the results of treat American Cancer Society DOI /cncr Published online 22 February 2005 in Wiley InterScience (

2 1398 CANCER April 1, 2005 / Volume 103 / Number 7 ment in gynecologic malignancies, 2 among nearly 3000 patients with ovarian carcinoma who were diagnosed between 1990 and 1992, it was shown that patients who had Stage IV disease fare much worse (11% survival) compared with patients who had Stage III disease (25% survival). This also was demonstrated by Heintz et al., 3 who reported that Stage IV confers a worse survival than Stage III disease (17% vs % 5-year survival, respectively). In those reports, no differentiation was made between patients diagnosed with Stage IV disease based on malignant pleural effusion and those with parenchymal liver, lung, or other extraperitoneal spread. The few reports on the survival in the subclasses of patients with Stage IV disease reported conflicting results, with some reporting a better prognosis for patients with pleural effusions, 4 and some reporting no difference in survival. 5 Over the past 3 decades, it has been established that 1 of the most important prognostic factors in patients with advanced epithelial ovarian carcinoma is optimal abdominal cytoreduction at initial surgery. 6 8 This benefit also has been shown for patients with Stage IV epithelial ovarian carcinoma, 9 13 although, in these patients, disease has spread to sites outside the abdomen. Patients with a malignant pleural effusion at the time of diagnosis but with no evidence of bulky disease outside the abdomen usually undergo surgery with the intent of optimal abdominopelvic debulking. The pleural effusion, although it upstages the patient, is considered to be similar to ascites and usually will not deter the surgeon from proceeding with planned abdominal cytoreduction. It is believed that this patient subpopulation may benefit from cytoreduction, similar to patients with bulky abdominal disease and ascites but without pleural effusion. However, it must be determined whether the malignant pleural effusion is a sign of bulkier, pleural-based disease or of extraabdominal disease that is not detected otherwise. Although historically it was considered part of the Stage IV category in the FIGO staging system, it is not clear whether the prognosis for patients with malignant pleural effusion differs from the prognosis for patients with Stage IIIC disease. The objective of the current study was to test the hypothesis that patients with Stage IV (due to malignant pleural effusion) optimally debulked epithelial ovarian carcinoma only will have survival similar to the survival of patients with optimally debulked Stage III epithelial ovarian carcinoma. MATERIALS AND METHODS After obtaining Institutional Review Board approval, we used the Virginia K. Pierce Gynecology Service prospectively acquired data base to identify all patients diagnosed with Stage IIIC epithelial ovarian carcinoma and Stage IV epithelial ovarian carcinoma based on cytology-proven, malignant pleural effusions only who underwent primary optimal cytoreductive surgery at our institution between January 1987 and August We performed a retrospective chart review and collected all demographic, clinical, surgical, and pathologic information. Patients with Stage IV epithelial ovarian carcinoma not due to malignant pleural effusions alone and patients with epithelial ovarian carcinoma of low-malignant potential were excluded from the analysis. All patients were staged according to the criteria set by FIGO. 14 Overall survival and progression-free survival were calculated from the date of initial surgery to death or diagnosis of recurrent epithelial ovarian carcinoma, respectively, or to the date of the last follow-up visit for those patients who were still alive. A standard censoring technique was used. Optimal cytoreduction was defined as surgery that left residual disease measuring 1 cm in greatest dimension. Standard two-sided statistical tests were used to compare clinical characteristics between the two groups. Survival was calculated using the Kaplan Meier method, and differences in survival were compared using the log-rank test. RESULTS In total, 99 patients were identified within the study period, and 97 of those patients were evaluable. Seventy-six patients had Stage IIIC disease based on upper abdominal disease that measured 2 cm and comprised the Stage IIIC patient group. The 21 patients who had Stage IV disease based on cytologically confirmed, malignant pleural effusions comprised the Stage IV patient group. All patients underwent a laparotomy with optimal debulking of their tumor to 1 cm of residual disease. Patient characteristics are presented in Table 1. No difference was found in patient age, tumor grade, tumor histology, or percentage of patients with ascites between the two groups. Serous histology was found in 55% and 62% of patients with Stage IIIC and Stage IV disease, respectively. Architecture Grade 3 tumors were found in 58% of patients with Stage IIIC disease and in 62% of patients with Stage IV disease. The majority of patients in both groups received platinumbased chemotherapy after surgical debulking (in combination with paclitaxel, cyclophosphamide, or alone). Most patients received a full course of platinum-based chemotherapy ( 6 cycles), including 62 patients in the Stage IIIC group (82%) and 16 patients in the Stage IV group (80%).

3 Pleural Effusion in Ovarian Ca/Eitan et al TABLE 1 Patient Characteristics a Characteristic Group 1: Stage IIIC b (n 76 patients) No. of patients (%) Group 2: Stage IV (n 21 patients) Age (yrs) Median Range Histology Serous 42 (55) 13 (62) Mucinous 2 (3) 1 (5) Endometrioid 17 (22) 6 (28) Clear cell 6 (8) 0 (0) Mixed 4 (5) 1 (5) Other 5 (6) 0 (0) Grade 1 4 (5) 2 (9) 2 24 (32) 6 (29) 3 44 (58) 13 (62) Unknown 4 (5) 0 (0) Ascites Yes 59 (78) 19 (91) No 9 (12) 2 (9) Unknown 8 (10) 0 (0) CA 125 (units/ml) Median Range 30 10, ,600 Primary chemotherapy Platinum-based 68 (89) 20 (95) cyclophosphamide alone 3 (4) 1 (5) No chemotherapy 2 (3) 0 (0) Unknown 3 (4) 0 (0) a P values were not statistically significant. b Staging was performed according to the International Federation of Gynecology and Obstetrics (FIGO). TABLE 2 Recurrence Patterns in Optimally Debulked Patients with Stage IIIC and IV Epithelial Ovarian Carcinoma Variable Stage IIIC a (n 76 patients) Stage IV (n 21 patients) P value No. of patients who presented with recurrent epithelial ovarian carcinoma 53 (70%) 15 (71%) NS Time to recurrence (mos) Mean SD % CI NS: not significant; SD: standard deviation; 95% CI: 95% confidence interval. a Staging was performed according to the International Federation of Gynecology and Obstetrics (FIGO). When they were evaluated at the end of primary chemotherapy, 57% of patients in each group were assessed clinically with no evidence of disease (NED) (negative scans, normal CA 125 levels). One patient in each group had residual disease in the chest found at this point (5% of patients in the Stage IV group who were not assessed with NED and 3% of patients in the Stage IIIC group). Eight patients in the Stage IV group and 52 patients in the Stage IIIC group underwent second-look surgery at the end of primary chemotherapy (38% and 67%, respectively). Surprisingly, only 1 patient in the Stage IV group, compared with 20 patients in the Stage IIIC group, were identified as negative for disease at second-look surgery (12% and 38%, respectively). The median CA 125 levels at the time patients were diagnosed with epithelial ovarian carcinoma were higher in the Stage IIIC group compared with the Stage IV group, with a wide range of results but without a statistically significant difference noted between the groups (P 0.59) (Table 1). The median follow-up was 48 months for patients with Stage IIIC disease and 35 months for patients with Stage IV disease. Table 2 describes disease recurrence patterns in both groups. Patients in both groups had the same likelihood of overall recurrence, although recurrences in patients with Stage IV disease developed significantly earlier compared with recurrences in patients with Stage IIIC disease (12 months vs. 21 months, respectively; P 0.04). This difference in progression-free survival also is demonstrated graphically in Figure 1. Three patients in each group were identified with disease in the chest as the first site of recurrence (14% of patients in the Stage IV group and 5% of patients in the Stage IIIC group; P 0.15). In addition, 47% of patients in the Stage IV group developed recurrences in the abdomen, compared with 65% of patients in the Stage IIIC group (P 0.25). Overall survival is demonstrated in Figure 2. The median overall survival was 58 months for the Stage IIIC group compared with 30 months for the Stage IV group based on malignant pleural effusions (P 0.016) (Fig. 2). DISCUSSION Cytoreductive surgery followed by platinum-based chemotherapy has become the standard of care for advanced-stage epithelial ovarian carcinoma. 15 All patients diagnosed with what appears to be resectable disease undergo surgery with the intent of performing optimal abdominopelvic cytoreductive surgery. We believe that a maximal surgical effort should be employed, and we recently reported a statistically significant increase in optimal debulking rates at our institution by incorporating extensive upper abdominal procedures into our surgical approach. 16

4 1400 CANCER April 1, 2005 / Volume 103 / Number 7 FIGURE 1. Progression-free survival for patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IIIC versus Stage IV, optimally debulked epithelial ovarian carcinoma. FIGURE 2. Overall survival for patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IIIC versus Stage IV, optimally debulked epithelial ovarian carcinoma. Malignant pleural effusion in a patient diagnosed with epithelial ovarian carcinoma confers Stage IV disease but does not preclude optimal debulking Our data show that patients with optimally debulked, Stage IV disease based on malignant pleural effusions have a shorter time to recurrence and decreased overall survival compared with optimally debulked patients who have Stage IIIC disease. The main factor that leads to the poorer prognosis for patients with pleural effusions is not known. Are the tumors presenting with pleural effusion inherently more aggressive? Do these tumors present enhanced resistance to chemotherapy? Are more invasive genes being overexpressed in these patients? Microarray studies performed at our institution and others comparing tissue from patients with Stage III and Stage IV epithelial ovarian carcinoma hopefully will answer some of these questions. However, those studies may find that there is no difference in gene expression between these groups and the biology of their tumors is similar. Other factors to consider are surgeon bias when confronting a patient with disease that already has spread outside the abdomen. Is the surgical effort similar in both groups? Because the optimal debulking parameters are the only tool we currently have to assess for residual disease after surgical debulking procedures for epithelial ovarian carcinoma, this bias hopefully was eliminated from the current study, in which all patients underwent optimal debulking at the same institution. With that in mind, it is clear that more patients in the Stage IIIC group were offered second-look surgery (67% vs. 38%). It also is possible to speculate that some patients with malignant pleural effusions may have harbored bulky (suboptimal), pleural-based disease that was not diagnosed radiographically. Only two patients in the Stage IV group and no patients in the Stage IIIC group underwent computed tomography (CT) scans of the chest before surgery. Pleural effusions were diagnosed using plain chest X-rays only. Therefore, we cannot comment on the value of chest CT scanning before surgery in patients with Stage IV disease, although we now perform chest CT scans on all patients with epithelial ovarian carcinoma at the time of diagnosis. In patients with malignant pleural effusions, the benefits of optimal abdominopelvic cytoreduction may be blunted or negated altogether due to undiagnosed intrathoracic disease. Fifty-seven percent of patients were classified clinically with NED at the end of primary treatment, although it was found that more patients in the Stage IV group harbored disease when they underwent thorough second-look surgery. The question of increased tumor resistance to cytotoxic agents is raised again. No difference was found in the rates of chest residual disease at the completion of chemotherapy, nor was any difference found in the rates of first recurrence in the chest between the two groups. Again, it appears likely that the malignant pleural effusion is a sign of a more aggressive tumor. We recently reported our experience with the performance of video-assisted thoracoscopic surgery (VATS) prior to abdominal exploration in 12 patients with suspected advanced-stage ovarian carcinoma and moderate-to-large pleural effusions. 17 In 50% of those patients, solid pleural-based tumor was identified that was not observed previously on diagnostic imaging studies, and in 25% of patients, the tumor nodules measured 1 cm in greatest dimension. Moreover, on final analysis, six of those patients had advanced ovarian or fallopian tube carcinoma and

5 Pleural Effusion in Ovarian Ca/Eitan et al malignant pleural effusions. In 5 of those 6 patients (83%), solid tumor was discovered at VATS and in 3 patients (50%), a tumor measuring 1 cm was identified. Therefore, it is our impression that patients with moderate-to-large pleural effusions may benefit from a VATS procedure prior to abdominal exploration. If solid tumor measuring 1 cm is detected at the time of VATS, then an option of intrathoracic cytoreduction, as described by Eisenkop, 18 could be considered. To our knowledge, although neoadjuvant chemotherapy has been discussed in the literature extensively, the indications for its use in patients with epithelial ovarian carcinoma still are not clear. If the reason for decreased survival in patients with Stage IV disease is a decreased sensitivity to cytotoxic agents, then will neoadjuvant treatment be of benefit in this group? This question remains to be answered; however, we believe that the small benefit offered to these patients by surgery is a factor toward considering them for neoadjuvant chemotherapy In the current retrospective cohort study, the survival of optimally cytoreduced patients with malignant pleural effusions was significantly shorter compared with the survival of patients with Stage IIIC, optimally cytoreduced disease without effusions. Selection bias and other confounders found in retrospective studies also were possibilities in this study, and we made efforts to minimize them as much as possible. Prospective data regarding this issue currently are lacking, and the current study provided further evidence to support the current FIGO staging system in which patients who have pleural effusions are upstaged and are expected to have a worse prognosis compared with patients who do not have extraperitoneal disease. The question of whether Stage IV disease should be subdivided based on sites of extraperitoneal spread remains open. The cause for this survival difference currently is not known and regardless of whether it is more aggressive disease or undetected intrathoracic disease in the patients with effusions, methods such as VATS to detect occult disease in this patient population should be considered to delineate the extent of disease better prior to the initiation of therapy; this is an area of ongoing investigation. REFERENCES 1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, CA Cancer J Clin. 2004;54: [No authors listed.] FIGO annual report on the results of treatment in gynecologic cancer. J Epidemiol Biostat. 1998; 3: Heintz AP, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. J Epidemiol Biostat. 2001;6: Penson RT, Skates SJ, Fuller AJ Jr., Seiden MV. Clinical course of Stage IV epithelial ovarian cancer. J Clin Oncol. 1999;17: Bonnefoi H, A Hern RP, Fisher C, et al. 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