Gynecologic Oncology 103 (2006) 1083 1090 www.elsevier.com/locate/ygyno The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC IV epithelial ovarian cancer Eric L. Eisenhauer a, Nadeem R. Abu-Rustum a, Yukio Sonoda a, Douglas A. Levine a, Elizabeth A. Poynor a, Carol Aghajanian b, William R. Jarnagin c, Ronald P. DeMatteo c, Michael I. D'Angelica c, Richard R. Barakat a, Dennis S. Chi a, a Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, MRI-1026, New York, NY 10021, USA b Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA c Hepatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA Received 8 March 2006 Available online 4 August 2006 Abstract Objectives. To determine the survival impact of adding extensive upper abdominal surgical cytoreduction to standard surgical techniques for advanced ovarian cancer. Methods. The records of all patients with stages IIIC IVepithelial ovarian cancer who underwent primary surgery at our institution from 1998 to 2003 were reviewed. The cohort was divided into 3 groups. Group 1 patients required extensive upper abdominal surgery, such as diaphragm peritonectomy/resection, resection of parenchymal liver or porta hepatis disease and/or splenectomy with or without distal pancreatectomy, to achieve optimal cytoreduction (residual disease 1 cm). Group 2 patients were optimally cytoreduced by standard surgical techniques, including hysterectomy, oophorectomy, omentectomy, and bowel resection. Group 3 patients were suboptimally cytoreduced. Primary outcome measures were response to primary chemotherapy, progression-free survival, and overall survival. Results. The cohort of 262 patients was divided as follows: Group 1, 57 patients; Group 2, 122 patients; and Group 3, 83 patients. The median follow-up was 36 months (range, 1 94 months). Frequency of clinical complete response in Groups 1, 2, and 3 was 82%, 78%, and 57%, respectively. The median progression-free survival for Groups 1, 2, and 3 was 24, 23, and 11 months, respectively. Progression-free survival for Groups 1 and 2 were equivalent (P=0.53) and were significantly longer than for Group 3 (P<0.001). The median overall survival was 84 and 38 months for Groups 2 and 3, respectively, and had not been reached for Group 1 by 68 months. Patients in Group 1 had equivalent overall survival to patients in Group 2 (P=0.74) and improved survival over patients in Group 3 (P<0.001). Prognostic factors significant on multivariate analysis included stage, optimal status, and ascites. Conclusions. Patients requiring extensive upper abdominal procedures to achieve optimal cytoreduction demonstrated a similar initial response, progression-free survival, and overall survival to patients optimally cytoreduced by standard surgical techniques. The presence of bulky upper abdominal disease alone did not appear to indicate poor tumor biology. This initial maximal surgical effort was associated with improved survival in patients who would have otherwise been suboptimally cytoreduced. 2006 Elsevier Inc. All rights reserved. Keywords: Ovarian cancer; Cytoreduction; Upper abdominal; Survival Introduction Presented at the Thirty-Seventh Annual Meeting of the Society of Gynecologic Oncologists; Palm Springs, CA; March 22 26, 2006. Corresponding author. Fax: +1 212 717 3214. E-mail address: gynbreast@mskcc.org (D.S. Chi). The majority of women who develop epithelial ovarian cancer present with advanced-stage disease [1]. For these patients, standard initial therapy consists of cytoreductive surgery followed by combination platinum taxane chemo- 0090-8258/$ - see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.06.028
1084 E.L. Eisenhauer et al. / Gynecologic Oncology 103 (2006) 1083 1090 therapy [2]. Many pretreatment prognostic factors have been found to impact overall survival [3 7]. Few, however, have had the durable effect of optimal cytoreduction at primary surgery. Because the advent of platinum-based chemotherapy for ovarian cancer, optimal primary cytoreduction has been associated repeatedly with improved survival [8]. Optimal cytoreduction to 1 cm residual disease is most easily achieved in patients with limited initial tumor burden [5,9,10]. The question has been posed as to whether more extensive metastatic spread is a reflection of aggressive tumor biology that may benefit less directly from surgical resection [11]. However, numerous studies have demonstrated that optimal cytoreduction in these patients is associated with long-term survival [12 14]. For patients presenting with widespread upper abdominal disease, the complexity of procedures required to accomplish optimal cytoreduction understandably increases. Diaphragm peritonectomy and/or resection [15 17], splenectomy [18,19], and liver resection [20] are among the procedures reported to be both feasible and associated with acceptable morbidity for cytoreduction of ovarian cancer. Recently, accumulated evidence has suggested an associated survival benefit to these interventions in appropriate patients [20 22]. In 2000, our service expanded our surgical approach in order to improve the optimal cytoreduction rate in our patients with advanced ovarian cancer [23]. This approach incorporated extensive upper abdominal resections when these procedures would help attain optimal residual disease status and demonstrated to be both feasible and associated with acceptable additional morbidity. These patients would have been rendered suboptimal without upper abdominal resection, and the question remained as to whether this intervention had improved their survival. This study focuses on the characteristics, treatment course, and survival of patients who required extensive upper abdominal procedures for optimal cytoreduction, in comparison to patients who were optimally or suboptimally cytoreduced by standard surgical techniques. Methods After obtaining Institutional Review Board approval, the prospectively maintained Virginia K. Pierce Gynecology Service Database was used to identify all patients who had undergone primary cytoreductive surgery at our institution for epithelial ovarian cancer between January 1, 1998, and December 31, 2003. Exclusion criteria included prior surgical exploration at another institution, histology consistent with non-epithelial, mucinous or borderline carcinoma, pathology consistent with primary peritoneal or fallopian tube carcinoma, neoadjuvant chemotherapy, and stages IA IIIB cancers, as well as patients classified as stage IIIC based on nodal metastases only. The records of all patients with stages IIIC and IVepithelial ovarian cancers who had undergone primary surgical exploration were then reviewed and divided into three groups based on extent of surgery and postoperative residual disease. Group 1 consisted of all patients who required more extensive surgery, such as diaphragm peritonectomy or full-thickness resection, splenectomy with or without distal pancreatectomy, cholecystectomy for gallbladder surface tumor, or resection of parenchymal liver or porta hepatis disease, in order to achieve optimal cytoreduction. Bulky upper abdominal disease was defined as >1 cm in largest diameter such that the patient would have been rendered suboptimal were it not removed. Patients who had undergone ablative upper abdominal procedures only, including those with electrocautery, the Cavitron ultrasonic aspirator (CUSA), or the argon-beam coagulator (ABC), were not assigned to Group 1. Group 2 included all patients who were optimally cytoreduced by standard surgical techniques alone, including hysterectomy, oophorectomy, omentectomy, and/or bowel resection. Group 3 consisted of all patients who had >1 cm residual disease after an attempted cytoreduction. Individual records for all patients were reviewed and the following preoperative information collected: age at surgery, date of surgery, and serum level of CA-125. Intraoperative information recorded included presence and volume of ascites, estimated blood loss (EBL), operative time, surgical procedures performed, and diameter of largest residual tumor nodule. Information obtained from the final pathology report included stage, tumor histology, and tumor grade. Major surgical complications were reviewed at a weekly tumor board conference and graded by a previously published institutional scoring system [23]. Postoperative information collected included the interval from surgery to the start of chemotherapy, Karnofsky performance score (KPS) at start of chemotherapy, number of cycles, type of primary and consolidation chemotherapy, initial response, second-look surgery, platinum sensitivity or resistance at 6 months, all available CA-125 levels and radiographic imaging reports, time to progression, and date of last follow-up or death. All patients were staged according to the International Federation of Gynecology and Obstetrics (FIGO) system. Optimal cytoreduction was defined as no residual tumor nodule measuring greater than 1 cm in largest dimension at the completion of surgery. The best overall response to primary chemotherapy was determined by computed tomography (CT) scan results and/or serum CA-125 levels [24]. Complete response (CR) was defined as complete disappearance of all target or non-target lesions, and/or normalization of the serum CA-125 level to 35 U/mL. Partial response (PR) was defined as at least a 30% decrease in the sum of the longest diameter of all target lesions, persistence of one or more non-target lesions, and/or maintenance of serum CA-125 levels above 35 U/mL after an initial 50% decrease. Progressive disease (PD) was defined as at least a 20% increase in the sum of the longest diameter of target lesions, the appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions. CT scan results, if applicable, superseded serum CA-125 levels in determining response. Patients were classified according to whether they had platinum-sensitive, platinum-resistant, or platinum-refractory disease at the time of relapse. Platinum-resistant disease was defined as progression within 6 months of receiving last platinum treatment. Platinum-refractory disease was defined as progression while on platinum treatment. Date of progression was determined by CT scan and/or CA-125 levels. When determined by CT scan, the date of progression was taken as the first appearance of one or more new lesions or increased size of known existing lesions. When determined by CA-125 level, date of progression was defined as the first date of the initial CA-125 of greater than or equal to two times the nadir value or upper limit of normal, as applicable [25,26]. When a subsequent CT scan confirmed that the rise in CA- 125 indicated progression, the date of progression was defined as the date of CA-125 rise. Patients were evaluated as part of the 3 aforementioned groups, and statistical tests were performed as appropriate for the data distribution. Categorical variables were evaluated by χ 2 analysis or Fisher's exact test, as appropriate, for category size. Continuous variables were evaluated by ANOVA or the Kruskal Wallis test for normally or non-normally distributed variables, respectively. All statistical tests were two-sided, and differences were considered statistically significant at P<0.05. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of initial cytoreductive surgery. The Kaplan Meier method was used to estimate the PFS and OS curves for the 3 patient groups [27]. The log-rank test was used to detect differences between survival curves for stratified variables [28]. Cox proportional hazards regression was performed to identify independent prognostic variables for OS by univariate and multivariate analysis, as well as to evaluate the effect of these variables on the group comparison [29]. Continuous variables that were not normally distributed (age, CA-125, and ascites volume) were analyzed as categorical variables greater or less than the median value for the cohort. The factors analyzed included age or >60 years, stage, serous histology, tumor grade, CA- 125 or >1000 U/mL, ascites or >1000 ml, operative time (log value), EBL (log value), bowel resection, lymph node dissection, and group designation. Factors with P<0.10 in the univariate analysis were included in the multivariate model. Kaplan Meier curves were plotted using SPSS statistical software
E.L. Eisenhauer et al. / Gynecologic Oncology 103 (2006) 1083 1090 1085 (version 12.0, SPSS, Inc., Chicago, IL). All other data analyses were performed with Stata statistical software (version 8.2, StataCorp LP, College Station, TX). Results Of the 262 consecutive patients who met our study criteria, 179 (68%) were optimally cytoreduced. Because our service did not begin performing extensive upper abdominal procedures systematically until May 1, 2000, Group 1 patients all had their cytoreductive surgery performed after this date. Patients in Groups 2 and 3 were included from January 1, 1998. Prior to May 1, 2000, 64 patients (53%) were optimally cytoreduced and 57 patients (47%) were suboptimally cytoreduced. After May 1, 2000, 115 patients (82%) were optimally cytoreduced 57 (41%) by extensive techniques and 58 (41%) by standard techniques whereas 26 patients (18%) could not be optimally cytoreduced. Patient characteristics, tumor features, and intraoperative findings between the 3 groups are compared in Table 1. Extensive upper abdominal procedures were required in 57 (32%) of 179 patients in order to achieve optimal cytoreduction (Group 1). In comparison to patients optimally cytoreduced by standard surgical techniques (Group 2), Group 1 patients were more likely to have stage IV disease, higher CA-125 levels, and larger volume ascites. They had similar proportions of no Table 1 Patient characteristics, tumor features, and intraoperative findings Variable Group 1 (n=57) Group 2 (n=122) Group 3 (n=83) P value Median age (range) 59 years 58 years 60 years 0.07 (41 81) (25 83) (36 88) Stage of disease 0.002 IIIC 41 (72%) 112 (92%) 69 (83%) IV 16 (28%) 10 (8%) 14 (17%) Tumor grade 0.72 1 2 (4%) 3 (2%) 1 (1%) 2 7 (12%) 22 (18%) 10 (12%) 3 46 (81%) 91 (75%) 70 (84%) None 2 (4%) 6 (5%) 2 (2%) Histologic type 0.07 Serous 51 (89%) 86 (70%) 59 (71%) Endometrioid 0 (0%) 13 (11%) 8 (10%) Clear cell 0 (0%) 5 (4%) 5 (6%) Mixed 6 (11%) 18 (15%) 11 (13%) Preoperative serum CA-125 Median serum 1124 U/mL 590 U/mL 1226 U/mL 0.007 level (range) (18 20,888) (5 13,150) (76 16,200) Serum level > 33 (58%) 59 (48%) 49 (59%) 0.25 1000 U/mL Ascites Median volume 3000 ml 300 ml 2000 ml <0.001 (range) (0 10,000) (0 9000) (0 15,000) Volume >1000 ml 38 (67%) 44 (36%) 54 (65%) <0.001 Residual disease No visible residual 13 (23%) 37 (30%) 0 (0%) <0.001 <0.5 cm 27 (47%) 40 (33%) 0 (0%) 0.5 1.0 cm 17 (30%) 45 (37%) 0 (0%) 1.0 2.0 cm 0 (0%) 0 (0%) 10 (12%) >2.0 cm 0 (0%) 0 (0%) 73 (88%) Table 2 Cytoreductive procedures performed Procedures performed Group 1 (n=57) Group 2 (n=122) Group 3 (n=83) Standard Hysterectomy 56 (98%) 110 (90%) 59 (71%) USO/BSO 57 (100%) 122 (100%) 82 (99%) Omentectomy 57 (100%) 119 (98%) 74 (89%) Small-bowel resection 4 (7%) 7 (6%) 0 Large-bowel resection 31 (54%) 26 (21%) 15 (18%) Appendectomy 12 (21%) 20 (16%) 5 (6%) Pelvic lymph node dissection 17 (30%) 25 (20%) 4 (5%) Para-aortic lymph node dissection 14 (25%) 29 (24%) 1 (1%) Extensive upper abdominal Diaphragm peritonectomy/resection 52 (91%) 0 0 Splenectomy 17 (30%) 0 0 Distal pancreatectomy 6 (11%) 0 0 Liver resection 9 (16%) 0 0 Resection porta hepatis tumor 8 (14%) 0 0 Cholecystectomy 8 (14%) 3 (2%) 0 USO, unilateral salpingo-oophorectomy. BSO, bilateral salpingo-oophorectomy. visible, 0.5 cm, and 0.6 1.0 cm residual disease at the end of the procedure. In contrast, their CA-125 levels and ascites volume were similar to the group that was suboptimally cytoreduced (Group 3). Age, tumor grade, and tumor histology were not significantly different between the 3 groups. The majority of patients in all 3 groups had multiple cytoreductive procedures performed (Table 2). There was no significant difference between Groups 1 and 2 in the frequency of each standard procedure performed except for large-bowel resections (P < 0.001), which were performed more often in the extensive surgery group. Lymph node dissections were performed with equivalent frequencies in Groups 1 and 2 but were performed less frequently in Group 3. Diaphragm peritonectomy and/or full-thickness resection was the most common upper abdominal procedure performed and was the only upper abdominal procedure performed in 28 patients (49%). The second most common procedure was splenectomy, which was combined with a distal pancreatectomy in 6 patients. Three patients in Group 2 had cholecystectomy performed for cholelithiasis. These patients were included in Group 2 to distinguish them from the patients in Group 1 who had cholecystectomy performed for cytoreduction due to tumor involving the surface of the gallbladder and/or the gallbladder fossa. More extensive procedures were associated with longer median operative time (P < 0.001) and higher median EBL (P<0.001). Median operative time in minutes for the three groups was as follows: Group 1, 320 (range, 115 750); Group 2, 230 (range, 85 480); and Group 3, 150 (range, 60 534). Median EBL in ml for the three groups was as follows: Group 1, 1000 (range, 200 7000); Group 2, 600 (range, 100 7500); and Group 3, 400 (range, 50 3000). The rate of major surgical complications for the three groups was available for all patients undergoing surgery after December 2000. Since that time, the major surgical complications for the three groups have been as follows: Group 1, 7 (12%); Group 2, 5 (7%); and Group 3, 4
1086 E.L. Eisenhauer et al. / Gynecologic Oncology 103 (2006) 1083 1090 Table 3 Postoperative chemotherapy and response Variable Group 1 (n=57) Group 2 (n=122) Group 3 (n=83) P value Days, surgery to chemotherapy Median (range) 24 (7 74) 21 (4 53) 8 (4 50) <0.001 KPS at start of chemotherapy 0.99 >70 48 (86%) 98 (85%) 66 (86%) 70 8 (14%) 17 (15%) 11 (14%) Initial cycles Median (range) 6 (0 9) 6 (0 9) 6 (0 9) 0.26 Received platinum 56 (98%) 116 (95%) 78 (94%) 0.48 Received taxane 55 (97%) 116 (95%) 77 (93%) 0.61 Response to chemotherapy <0.001 Complete response (CR) 47 (82%) 95 (78%) 47 (57%) Partial response 4 (7%) 13 (11%) 15 (18%) Progressive disease 1 (2%) 4 (3%) 15 (18%) Not assessable 5 (9%) 10 (8%) 6 (7%) Second-look surgery after CR 30 (64%) 70 (74%) 38 (81%) 0.17 Positive second-look surgery 17 (57%) 33 (47%) 23 (61%) 0.37 Consolidation Any 32 (56%) 64 (52%) 37 (45%) 0.36 Single-agent platinum 22 (39%) 52 (43%) 28 (34%) 0.33 Intraperitoneal platinum 21 (37%) 49 (40%) 27 (33%) 0.34 Single-agent taxane 5 (9%) 10 (8%) 6 (7%) 0.96 Total platinum cycles Median (range) 7 (0 12) 6 (0 12) 6 (0 12) 0.16 Platinum status at 6 months Sensitive 40 (70%) 81 (66%) 35 (42%) 0.001 Resistant 11 (19%) 22 (18%) 22 (27%) Refractory 2 (4%) 9 (7%) 20 (24%) Not assessable 4 (7%) 10 (8%) 6 (7%) KPS, Karnofsky performance score. (8%). The rate of major surgical complications was not significantly different between groups (P = 0.54). The postoperative treatment course in the 3 groups was similar, with patients receiving equivalent primary chemotherapy regimens, numbers of cycles, consolidation therapy, and type of consolidation (Table 3). The suboptimal patients started their chemotherapy more quickly, but patients in both optimally cytoreduced groups began chemotherapy after a similar interval. Consolidation regimens were employed in approximately half of the patients in each group. This was most commonly 1 5 cycles of intraperitoneal cisplatin after secondlook surgery, and the median total number of platinum cycles received did not differ between groups. After platinum consolidation, the second most common regimen of either weekly or monthly intravenous taxane was used with similar frequency in each group. Groups 1 and 2 had similar frequencies of achieving a clinical CR (82% vs. 78%, respectively) and remaining recurrence-free at 6 months (70% vs. 66%, respectively). Patients in Group 3 were less likely to achieve a clinical CR (57%; P<0.001) and were less likely to be recurrence-free at 6 months (42%; P=0.001). Despite similarities in some pretreatment factors, survival outcomes for patients in Group 1 were much improved over patients in Group 3. At a median follow-up for the entire cohort of 36 months (range, 1 95 months), Group 3 patients recurred after a shorter interval (Fig. 1) and had significantly decreased OS (Fig. 2). Of the 83 patients in Group 3, 57 (69%) had surgery prior to May 1, 2000, when upper abdominal procedures began to be utilized; 26 (31%) had surgery in the time period since. When stratified by these time periods, suboptimally cytoreduced patients demonstrated equivalent PFS (log-rank P=0.63) and OS (log-rank P=0.59) before and after these extensive procedures were implemented. In contrast to the suboptimal patients, Groups 1 and 2 exhibited similar survival endpoints. PFS for Groups 1 and 2 was equivalent (Fig. 1), with median PFS of 24 and 23 months, respectively (Table 4). Subsequent OS for Groups 1 and 2 was also equivalent (Fig. 2), with the median OS not yet reached for Group 1, and 84 months for Group 2. Moreover, patients requiring upper abdominal procedures derived the same benefit from complete cytoreduction as Group 2 patients. When stratified by residual disease categories, Groups 1 and 2 showed Fig. 1. Progression-free survival, in months, by group assignment.
E.L. Eisenhauer et al. / Gynecologic Oncology 103 (2006) 1083 1090 1087 Fig. 2. Overall survival, in months, by group assignment. equivalent OS for both no visible residual (log-rank P = 0.95) and 0.1 1.0 cm residual disease (log-rank P = 0.81) categories. Cox regression revealed that the equivalent survival of Groups 1 and 2 was independent of the effect of the other studied variables. On univariate analysis, factors significantly associated with decreased survival included stage IV disease, ascites >1000 ml, and suboptimal status (Table 5). Age greater than the median, tumor grade, histology, CA-125 greater than the median, EBL, operative time, and whether bowel resection or lymph node dissection was performed did not significantly influence survival. Multivariate analysis (Table 6) confirmed the independent association of stage IV disease (hazard ratio [HR] =2.48; 95% CI, 1.50 4.09), ascites >1000 ml (HR=1.52; 95% CI, 1.03 2.25), and suboptimal status (HR = 2.99; 95% CI, 1.64 5.45). After including the effect of stage and ascites volume in the multivariate model, overall survival for Groups 1 and 2 was equivalent. Discussion Evidence that patients with advanced ovarian cancer benefit from surgical cytoreduction arose from the observation that resection of bulky disease prior to chemotherapy improved their survival [30]. This initial observation has been confirmed by multiple subsequent studies and has formed the current Table 4 Survival endpoints, by group PFS (months) OS (months) Follow-up (months) Median 95% CI Median 95% CI Median Range Group 1 24 17 31 NR 31 1 68 Group 2 23 18 28 84 NA 42 1 95 Group 3 11 10 13 37 30 46 35 1 91 PFS, progression-free survival. OS, overall survival. NR, not reached. NA, not available. treatment paradigm for patients with advanced ovarian cancer [7,8,31]. After primary cytoreduction, the effect of chemotherapy is likely enhanced by a smaller and more homogeneous tumor burden [32]. In the current era of highly active chemotherapy, the result of primary cytoreductive surgery sets the stage for further postoperative treatment and subsequent survival. In 2000, our service expanded our surgical approach to patients with widespread upper abdominal disease [23]. The rationale for this shift was the hypothesis that additional surgical intervention would change the disease course in patients who would have been previously rendered suboptimal on the basis of their upper abdominal disease. It was based on the accumulating evidence that extensive upper abdominal resection was both feasible and safe [5,15,16,18 20] and the assumption that upper abdominal metastases resulted from increased tumor burden rather than inherent biological aggressiveness. If widespread upper abdominal disease arose because those tumors had a more virulent genetic composition, additional surgical intervention Table 5 Univariate cox regression for overall survival Variable Risk ratio 95% CI P value Age, > vs. 60 years 1.24 0.86 1.78 0.25 Stage, IV vs. IIIC 2.15 1.34 3.45 0.001 Histologic grade, 3 vs. 1 or 2 1.02 0.65 1.60 0.92 Histology, serous vs. other 0.86 0.58 1.27 0.44 CA-125, > vs. 1000 U/mL 0.83 0.60 1.30 0.53 Ascites, > vs. 1000 ml 1.48 1.03 2.14 0.04 Bowel resection, yes vs. no 1.04 0.68 1.60 0.87 LND, yes vs. no 1.06 0.65 1.72 0.82 EBL (log) 0.89/mL 0.70 1.13 0.33 Operative time (log) 0.83/min 0.53 1.29 0.41 Group Group 2 vs. Group 1 1.14 0.62 2.08 0.67 Group 3 vs. Group 1 2.53 1.40 4.57 0.002 LND, lymph node dissection. EBL, estimated blood loss.
1088 E.L. Eisenhauer et al. / Gynecologic Oncology 103 (2006) 1083 1090 Table 6 Multivariate cox regression for overall survival Variable Risk ratio 95% CI P value Stage, IV vs. IIIC 2.48 1.50 4.09 <0.001 Ascites, > vs. 1000 ml 1.52 1.03 2.25 0.04 Group Group 2 vs. Group 1 1.63 0.86 3.10 0.14 Group 3 vs. Group 1 2.99 1.64 5.45 <0.001 might not change the disease course. However, if upper abdominal disease was largely a reflection of tumor burden, subsequent optimal cytoreduction should result in a similar response to initial chemotherapy and subsequent survival to advanced-stage patients without this upper abdominal disease burden who were optimally cytoreduced. To evaluate this, we studied all appropriate patients with advanced ovarian cancer in a representative time period. By definition, upper abdominal cytoreduction of bulky metastases applied only to patients with stages IIIC and IV disease. Patients classified as stage IIIC based on nodal metastases only were excluded to evaluate a more homogeneous population of patients with bulky abdominal disease. Non-epithelial and borderline tumors were excluded to limit heterogeneity, and mucinous tumors were excluded based on their disparate response to chemotherapy [4,33]. Similarly, patients with primary peritoneal and fallopian tube cancers were excluded due to lack of uniformity as to their prognosis compared to patients with ovarian cancer [34,35]. Group 1 was chosen to evaluate those patients who would have been suboptimally cytoreduced without extensive upper abdominal procedures. Removal of metastatic deposits by CUSA or ABC has recognized utility [36,37]; in our study, these techniques were used alone in the upper abdomen only in patients with small-volume disease and were therefore not included in Group 1. Although bowel resection has been reported to have a negative effect on survival [38], this was not demonstrated in our survival analysis, and bowel resection was not used as a procedure for group assignment. In contrast to patients optimally cytoreduced by standard techniques, Group 1 patients exhibited two characteristics that were poor prognostic factors on multivariate analysis a greater proportion of patients with stage IV disease and a larger median ascites volume. The negative effects of stage IV disease and ascites have been previously described [3 7,39]. The higher incidence of stage IV disease reflects both their larger baseline tumor burden, as well as our increased ability to optimally cytoreduce these patients with diaphragm or liver resections. Their increased median ascites volume is also suggestive of their greater tumor burden. The similar outcomes seen in Groups 1 and 2 suggest that extensive upper abdominal cytoreduction improved the negative effect of these factors. Lymph node status in ovarian cancer patients with non-bulky nodes has been reported to affect prognosis, and systematic lymphadenectomy has been associated with an improvement in progression-free but not overall survival versus resection of bulky nodes alone [40]. In our series, lymph node dissection was performed in the majority of cases for bulky nodal disease. Patients in Groups 1 and 2 had similar frequencies of lymph node dissection (32% vs. 25%) and positive lymph nodes (25% vs. 21%). On univariate analysis, neither lymph node dissection (P=0.82) nor positive lymph nodes (P=0.93) was associated with improved overall survival. As systematic lymphadenectomy was not performed in all cases, the true lymph node positivity rate could not be determined. However, differences in lymph node positivity did not appear to account for survival differences between patient groups. Differences in primary or consolidation chemotherapy received by patients in the three groups were unlikely to account for the differences seen. Primary combination intravenous platinum taxane chemotherapy was used in almost all patients, and there were no significant differences between groups in the initial therapy received or the median number of cycles. Similarly, consolidation regimens used in patients after a clinical complete response were equivalent. The frequency of patients receiving intravenous or intraperitoneal single-agent platinum or intravenous single-agent taxane was equivalent between groups. No other consolidation regimen was used often enough to significantly affect the group comparison. As the majority of patients in all 3 groups received at least 6 cycles of combination intravenous platinum taxane chemotherapy, the differences in response and platinum sensitivity were notable. Patients in Groups 1 and 2 had a similar frequency of clinical CR, demonstrating the association between optimal cytoreduction and improved initial response. Patients in Group 3 showed a response to combination platinum taxane similar to the 43 67% range seen in patients with measurable disease in the initial Gynecologic Oncology Group (GOG) 9202 pilot study [41] and the GOG 132 study of suboptimal stages III IV patients [42]. Platinum resistance was significantly less likely in Groups 1 and 2. Although an imperfect surrogate for ultimate survival, patients who progress on treatment or recur within 6 months after completion of therapy are thought to be platinum resistant and felt to have a worse prognosis [43,44]. In our study, the durable effect of optimal cytoreduction in Group 1 was reflected again in platinum sensitivity similar to Group 2 and significantly greater than Group 3. This benefit was further demonstrated in the equivalent PFS and OS in Groups 1 and 2. Median PFS in Groups 1 and 2 was similar to the 21 22 month PFS reported for platinum paclitaxel after optimal cytoreduction in the GOG 114 and GOG 152 studies [2,45]. The observed median survival was longer than the 52- to 57-month median OS reported in these GOG trials [2,45]; however, our study was not designed to control for the various second- and further-line treatment regimens. OS for patients in Group 1 was significantly improved over patients in Group 3. Because PFS was also significantly improved, and their primary treatment regimens were similar, this subsequently improved OS was more likely an effect of the initial surgery than second-line therapy. Limitations of this study include those inherent in the study design. As a retrospective study, there is the potential for selection bias in the data recorded. However, the records of all patients meeting inclusion criteria in the study period were reviewed, and the variables evaluated were documented in a
E.L. Eisenhauer et al. / Gynecologic Oncology 103 (2006) 1083 1090 1089 standard fashion at the time of treatment. A study comparing different treatment types would benefit from randomization; however, it would be unreasonable to randomize patients to less than the most complete cytoreduction possible. Therefore, the control groups chosen were the most valid retrospective surrogates. Patients in Group 1 were included over a shorter time period than those in Groups 2 and 3 due to the incorporation of extensive upper abdominal techniques in the time period since May 2000. Group 3 therefore included patients prior to May 2000, who might have been optimally cytoreduced with extensive upper abdominal surgery, whereas those included after this point were suboptimally cytoreduced despite the availability of these procedures. Despite this inherent selection bias, survival probabilities for Group 3 patients in these two time periods were equivalent. This suggests that patients who went on to upper abdominal cytoreduction were not selected for having an inherently better prognosis, which was then attributed to their extensive surgery. Whether Group 3 truly represents all suboptimal patients does not detract from the equivalent outcomes seen in Groups 1 and 2. Although imperfect, these comparisons demonstrate that patients who were optimally cytoreduced had equivalent outcomes, and that extensive upper abdominal procedures were essential to achieve optimal cytoreduction in a significant number of patients with advanced ovarian cancer. Conclusion Our analysis demonstrated that the addition of extensive upper abdominal cytoreduction was associated with improved survival in patients with stages IIIC IV epithelial ovarian cancer. 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