Ovarian cancer is the most lethal gynecologic malignancy

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1 Original Research Laparoscopy Compared With Laparotomy for Debulking Ovarian Cancer After Neoadjuvant Chemotherapy Alexander Melamed, MD, MPH, Roni Nitecki, MD, David M. Boruta II, MD, Marcela G. del Carmen, MD, MPH, Rachel M. Clark, MD, Whitfield B. Growdon, MD, Annekathryn Goodman, MD, John O. Schorge, MD, and J. Alejandro Rauh-Hain, MD OBJECTIVE: To compare 3-year survival, length of hospitalization, perioperative mortality, risk of readmission, and residual disease associated with laparoscopic and laparotomic interval debulking surgery among women with epithelial ovarian cancer. METHODS: We used the National Cancer Database to identify a cohort of patients diagnosed with stage IIIC and IV epithelial ovarian cancer between 2010 and 2012 who underwent neoadjuvant chemotherapy and interval debulking surgery. We compared 3-year overall survival, duration of postoperative hospitalization, 90-day postoperative mortality, and residual disease status between women who underwent interval debulking by laparoscopy and by laparotomy. We used the Kaplan-Meier method and Cox regression models in survival analyses. At a significance of.05, this study had 80% power to detect an 8% difference in 3-year survival. The main analysis was intention to treat. From the Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, and Department of Obstetrics and Gynecology, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts. Supported by grant R25CA from the National Cancer Institute at the National Institutes of Health, and the Deborah Kelly Center for Outcomes Research at Massachusetts General Hospital. Presented at the Annual Meeting of the Society for Gynecologic Oncology, March 12 15, 2017, Washington, DC. Each author has indicated that he or she has met the journal s requirements for authorship. Corresponding author: Alexander Melamed, MD, MPH, Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, 55 Fruit Street, YAW-9-9E, Boston, MA 02114; alexander.melamed@ mgh.harvard.edu. Financial Disclosure The authors did not report any potential conflicts of interest by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: /17 RESULTS: We identified 3,071 women meeting inclusion criteria, of whom 450 (15%) underwent surgery initiated laparoscopically. There was no difference in 3-year survival between patients undergoing laparoscopy [47.5%; 95% confidence interval (CI) ] and laparotomy (52.6%; 95% CI ; P5.12). Survival did not differ after adjustment for demographic characteristics, facility type, presence of comorbidities, and stage (adjusted hazard ratio, 1.09; 95% CI ; P5.26). Postoperative hospitalization was slightly shorter in the laparoscopy group (median 4 compared with 5 days, P,.001). Frequency of readmission (5.3% compared with 3.7%; P5.26), death within 90 days of surgery (2.8% compared with 2.9%, P5.93), and suboptimal debulking (20.6% compared with 22.6%, P5.29) did not differ between patients undergoing laparoscopy and laparotomy. CONCLUSION: Ovarian cancer patients selected for laparoscopic interval debulking surgery after neoadjuvant chemotherapy have 3-year survival rates similar to women who undergo interval debulking by laparotomy. Laparoscopy is associated with a modestly shorter postoperative hospitalization, whereas readmission rates and risk of perioperative death are similar for the surgeries. (Obstet Gynecol 2017;0:1 9) DOI: /AOG Ovarian cancer is the most lethal gynecologic malignancy and is usually diagnosed after the cancer has spread within the peritoneal cavity. 1 Two phase III trials have found that women with advanced ovarian cancer randomly assigned to neoadjuvant chemotherapy followed by interval debulking surgery have survival equivalent to those assigned to primary debulking surgery and adjuvant chemotherapy. 2,3 Although primary debulking surgery was the traditional treatment for advanced ovarian cancer, utilization of neoadjuvant chemotherapy has increased substantially in the United States. 4 Recent VOL. 0, NO. 0, MONTH 2017 OBSTETRICS & GYNECOLOGY 1

2 guidelines from the American Society for Clinical Oncology and the Society for Gynecologic Oncology recommend neoadjuvant chemotherapy and interval surgery for women with high perioperative risk or low likelihood of achieving optimal cytoreduction at primary surgery. 5 Laparoscopic interval debulking surgery is an appealing alternative to laparotomy among elderly and infirmed patients who are frequently selected for neoadjuvant chemotherapy; however, little is known about the safety and effectiveness of this approach. 6 9 Two small, uncontrolled studies investigated the feasibility of laparoscopic interval debulking surgery and showed promising perioperative and short-term survival outcomes. 7,8 A small, historically controlled study, which included 10 women who underwent laparoscopic interval debulking and 11 women in the control group, found a nonsignificant decrease in recurrence-free survival and increased cancer-specific mortality. 9 To investigate the safety and effectiveness of laparoscopic interval debulking surgery, this study compared 3-year survival, length of hospitalization, perioperative mortality, risk of readmission, and residual disease between patients who underwent laparoscopic and laparotomic interval debulking surgery in anationalcancerregistry. MATERIALS AND METHODS We conducted a retrospective cohort study using data from the National Cancer Database. The National Cancer Database is a joint program of the American College of Surgeons Commission on Cancer and the American Cancer Society. This program aggregates data from more than 1,500 hospital tumor registries and includes 70% of all incident cancer diagnoses in the United States. 10 The National Cancer Database collects data on demographics, tumor characteristics, cancer-directed therapies, hospital characteristics, and overall survival. Because this investigation used an existing deidentified database, the study protocol was granted exempt status by the Partners Human Research Committee under federal regulation 45 CFR (b). Figure 1 shows the study cohort flow diagram. We identified all patients diagnosed with malignant stage IIIC and IV epithelial ovarian cancer from 2010 to 2012 in the 2013 National Cancer Database public use data file. Because pathologic stage is sometimes not known until after initiation of treatment, the stage was defined as American Joint Committee on Cancer 7th-edition clinical stage IIIC or IV when available or as American Joint Committee on Cancer or International Federation of Gynecology and Obstetrics pathologic stage IIIC or IV when clinical stage was not recorded. 11,12 We defined epithelial histology using International Classification of Diseases for Oncology, Third Edition codes corresponding to serous, mucinous, clear cell, endometrioid, or other adenocarcinoma of the ovary (Table 1). Fig. 1. Flow diagram of the study population. *These exclusions are not mutually exclusive. Melamed. Laparoscopic Interval Debulking Surgery. Obstet Gynecol Melamed et al Laparoscopic Interval Debulking Surgery OBSTETRICS & GYNECOLOGY

3 Table 1. Histologic Types of Epithelial Ovarian Cancer Histologic Type ICD-O-3 Code Serous carcinoma 8441, Mucinous carcinoma , 8480, 8481 Endometrioid carcinoma Clear cell carcinoma 8310, 8313 Other adenocarcinoma 8050, 8140, 8144, 8255, 8260, 8263, 8290, 8320, 8323, 8340, 8440, 8450, 8490, 8560, 8574, 8940 ICD-O-3, International Classification of Diseases for Oncology, Third Edition. We excluded all patients without microscopically confirmed cancer, who had pre-existing cancer diagnoses, who did not undergo definitive surgery for ovarian cancer, or who did not receive chemotherapy. To define a cohort of patients who underwent neoadjuvant chemotherapy followed by interval debulking surgery, we excluded all patients who had surgery before initiating chemotherapy and all those in whom the sequence of surgery and chemotherapy was unknown. Finally, we excluded all patients in whom the surgical approach (laparoscopy or laparotomy) was unknown. The primary analysis was based on the intended surgical approach. All patients whose surgery was initiated with a minimally invasive modality (traditional or robot-assisted laparoscopy) were categorized as having undergone a planned laparoscopic procedure, irrespective of conversion to laparotomy. Surgical approach was abstracted from medical records by the cancer registrar. The primary outcome was overall survival defined as months from cancer diagnosis to death or the date of last contact as reported by the cancer registry. Overall survival was examined as probability of survival 3 years after diagnosis (3-year survival) and the hazard of death from any cause during follow-up. Secondary outcomes of interest included median survival, frequency of death within 90 days of surgery, residual disease status after surgery, frequency of unplanned readmission within 30 days of surgical discharge, and length of hospital admission after surgery. We categorized patient age at the time of diagnosis as less than 40, 40 49, 50 59, 60 69, 70 79, and 80 years or older. Race-ethnicity was defined as Hispanic, non-hispanic white, non-hispanic black, non- Hispanic Asian, or other or unknown. We classified tumor grade using a three-point scale. A Charlson Deyo score of one or greater defined the presence of a comorbidity. 13,14 We categorized the location of the treating facility by U.S. Census Region (Northeast, South, Midwest, and West). 15 Rural urban status was determined by using patients county of residence and classified as metropolitan, adjacent to a metropolitan area, or nonmetropolitan by using the U.S. Department of Agriculture s Economic Research Service rural urban continuum codes. 16 The median household income in the participant s ZIP code was used as a proxy for participant income and categorized according to quartiles across all U.S. ZIP codes as estimated by the 2012 American Community Survey. We categorized insurance status as uninsured, privately insured, insured by Medicare, or having another type of government insurance (military or Medicaid). The treating facility was classified as a community cancer program, an academic research program, an integrated network cancer program, or other. Surgical procedure was categorized as excision of gynecologic organs only (adnexal surgery with or without hysterectomy) or surgery that involved additional cytoreductive maneuvers (including omentectomy or other debulking). Patient characteristics were compared by using the t test and x 2 test for continuous and categorical variables. To explore independent predictors of laparoscopic interval debulking surgery, we developed a multivariable logistic regression model. Covariates in the logistic regression model were selected a priori and included age group, race, facility type, urban status, median ZIP code income, year of diagnosis, insurance type, presence of comorbid conditions, and stage. We used the Kaplan-Meier method to plot survival functions for women who underwent interval surgery by laparotomy and laparoscopy and compared these using the log rank test. We estimated the probability of survival 3 years after diagnosis for each group, associated 95% confidence intervals (CIs), and compared these with the Z test for independent proportions. We also estimated the hazard ratio (HR) for overall mortality after planned laparoscopic interval debulking surgery with a univariable Cox proportional hazards model with planned laparotomy serving as the referent group. To adjust for potential confounding we also calculated the HR for overall mortality after planned laparoscopic staging using a Cox proportional hazard model adjusting for covariates that were selected a priori and included age group, race ethnicity, region, type of facility, urban status, income, presence of comorbidities, year of diagnosis, and cancer stage. Missing data were coded as indicator variables. Differences in frequency of readmission, 90-day mortality, and residual disease status were compared with the x 2 test, and the VOL. 0, NO. 0, MONTH 2017 Melamed et al Laparoscopic Interval Debulking Surgery 3

4 Wilcoxon rank sum test was used to compare length of postoperative hospitalizations. We conducted a sensitivity analysis in which patients who underwent conversion from laparoscopy to laparotomy were excluded to assess whether the main results persisted in this subset of patients. A post hoc power calculation was based on the proportional hazard model and used the approach described by Schoenfeld and Richter 17 and implemented by Dupont and Plummer. 18 RESULTS We identified, 3,071 women with stage IIIC and IV epithelial ovarian cancer who received neoadjuvant chemotherapy followed by interval debulking surgery between 2010 and 2012 and who met all inclusion criteria (Fig. 1). Debulking surgery was initiated laparoscopically in 450 women (15%), and robotic-assisted laparoscopy comprised 27% of these cases (122 patients). Debulking surgery was completed laparoscopically in 378 women (84% of cases initiated laparoscopically), and conversion to laparotomy was more frequent among those who underwent traditional laparoscopy than among those who underwent robotic-assisted laparoscopic surgery (20% compared with 5%, P,.001). In univariable analysis (Table 2) we found that laparoscopic interval surgery was associated with region (P5.003) and was used more frequently in the Northeastern and Southern (18% and 15%, respectively) than in the Western and Midwestern regions of the United States (11% and 13%, respectively). Patients living in or adjacent to a metropolitan area were nearly twice as likely to have had laparoscopic interval surgery as those in nonmetropolitan counties (8% compared with 15%, P5.04). We observed a significant increase in the frequency of laparoscopic interval debulking from 2010 to 2012 (11 16%, P,.001). Patients with one or more comorbidities underwent laparoscopic interval surgery more frequently than those without comorbidities (17% compared with 14%, P5.05). Laparoscopic surgery was performed more frequently at community and integrated network cancer programs (15% and 16%, respectively) than academic centers (13%, P5.04) and more frequently among women with stage IV than among those with stage IIIC cancer (16% compared with 13%, P5.02). To explore which factors were independently associated with receipt of laparoscopic interval debulking surgery, we conducted a multivariable analysis (Table 3). After controlling for demographic, clinical, and hospital-level variables, region, facility type, stage, and year of diagnosis were independent predictors of laparoscopic interval debulking surgery. Table 4 tabulates surgical characteristics and outcomes among women who underwent planned interval laparoscopic surgery and laparotomy. There were no significant differences in frequency of readmission (5.3% compared with 3.7%) or death within 90 days of surgery (2.8% compared with 2.9%). Compared with women who underwent laparotomy, those who had laparoscopic procedures had significantly shorter postoperative hospitalizations (median 4 compared with 5 days, P,.001). Women who underwent laparoscopic interval debulking surgery had procedures that were limited to excision of gynecologic structures only (no omentectomy or additional cytoreductive maneuvers) more frequently than women who had laparotomy (16.7% compared with 10.1%, P,.001). Residual disease status was available in 1,595 patients (60.9%) who underwent planned laparotomy and in 277 patients (61.6%) who underwent planned laparoscopic interval surgery. Among those with known residual disease status, we observed no difference in the frequency of complete gross resection, optimal cytoreduction (residual disease, 1 cm or less), and suboptimal debulking (residual disease greater than 1 cm), by surgical approach (P5.29). Survival information was available in 445 patients (98.9%) who underwent planned laparoscopic interval debulking surgery and for 2,598 patients (99.1%) who had planned laparotomy. Median follow-up was 32.0 months (95% CI ). We observed 183 deaths among women who underwent planned laparoscopy and 1,045 among those who had laparotomy. Figure 2 illustrates the survival functions for patients by planned surgical approach. We found no significant difference in unadjusted survival between women who underwent planned laparoscopic approach and those who underwent laparotomy (HR 1.12; 95% CI ; P5.15). Median survival was 33.8 months (95% CI ) and 37.6 months (95% CI ) for women who underwent planned laparoscopy and laparotomy, respectively. The probability of surviving 3 years after diagnosis was 47.5% (95% CI ) for patients who underwent planned interval laparoscopy and 52.6% (95% CI ) for those who had planned laparotomy (P5.12). Adjustment for age group, race, region, facility type, urban status, income, presence of comorbidities, year of diagnosis, and stage did not alter the association between planned laparoscopic surgery and overall survival (adjusted HR 1.09; 95% CI ; P5.26). When we excluded from the analysis women who underwent conversion from laparoscopy to laparotomy, we found no significant difference in 4 Melamed et al Laparoscopic Interval Debulking Surgery OBSTETRICS & GYNECOLOGY

5 Table 2. Patient and Tumor Characteristics in Patients Undergoing Interval Surgery After Neoadjuvant Chemotherapy for Advanced Ovarian Cancer Characteristic Laparotomy (n52,621) Laparoscopy (n5450) P Age (y) * Race ethnicity.94 Asian 98 (3.7) 14 (3.1) Black 216 (8.2) 41 (9.1) Hispanic 165 (6.3) 28 (6.2) White 2,104 (80.3) 361 (80.2) Other or unknown 38 (1.4) 6 (1.3) Region.003 Midwest 575 (21.9) 74 (16.4) Northeast 541 (20.6) 120 (26.7) South 877 (33.5) 162 (36.0) West 628 (24.0) 94 (20.9) Year of diagnosis (31.3) 103 (22.9) (33.0) 164 (36.4) (35.7) 183 (40.7) Comorbidities present 525 (20.0) 108 (24.0).05 Median ZIP code income ($).07 Less than 38, (15.3) 57 (12.7) 38,000 47, (22.0) 86 (19.1) 48,000 62, (26.9) 123 (27.3) 63,000 or more 917 (35.0) 177 (39.3) Unknown 19 (0.7) 7 (1.6) Insurance type Private 1,130 (43.1) 190 (42.2).10 Medicare 1,101 (42.0) 201 (44.7) Medicaid and other government 234 (8.9) 35 (7.8) None 86 (3.3) 20 (4.4) Unknown 70 (2.7) 4 (0.9) Urban status.04 Metropolitan 2,134 (81.4) 376 (83.6) Adjacent to metropolitan 288 (11.0) 44 (9.8) Nonmetropolitan 121 (4.6) 10 (2.2) Unknown 78 (3.0) 20 (4.4) Facility type.04 Academic 1,370 (52.3) 212 (47.1) Community 1,032 (39.4) 192 (42.7) Integrated network 215 (8.2) 43 (9.6) Other 4 (0.2) 3 (0.7) Stage.02 IIIC 1,500 (57.2) 231 (51.3) IV 1,121 (42.8) 219 (48.7) Histologic type.92 Serous 2,114 (80.7) 357 (79.3) Mucinous 25 (1.0) 6 (1.3) Clear cell 60 (2.3) 11 (2.4) Endometrioid 50 (1.9) 8 (1.8) Other or unspecified adenocarcinoma 372 (14.2) 68 (15.1) Data are mean6standard deviation or n (%) unless otherwise specified. * Based on two-sample t test. Based on x 2 test. unadjusted (HR 1.16; 95% CI ; P5.08) or adjusted (adjusted HR 1.12; 95% CI ; P5.20) survival estimates by surgical approach. Post hoc power analysis demonstrated that with 1,231 deaths at a significance level of 0.05, this study had 80% power to detect an 8% difference in 3-year survival between the laparoscopy and laparotomy groups (53% compared with 45%). VOL. 0, NO. 0, MONTH 2017 Melamed et al Laparoscopic Interval Debulking Surgery 5

6 Table 3. Multivariable Analysis of Predictors of Surgical Approach for Interval Debulking, Laparoscopy Versus Laparotomy Characteristic % (95% CI) Adjusted OR* (95% CI) P Age group (y).13 Less than ( ) 1.73 ( ) ( ) 0.97 ( ) ( ) 0.93 ( ) ( ) Ref ( ) 1.35 ( ) 80 or older 6.7 ( ) 1.3 ( ) Race ethnicity.95 Asian 3.7 ( ) 0.82 ( ) Black 8.4 ( ) 1.08 ( ) Hispanic 6.3 ( ) 1.04 ( ) White 80.3 ( ) Ref Other or unknown 1.4 ( ) 0.90 ( ) Region.003 Midwest 21.2 ( ) 0.85 ( ) Northeast 21.5 ( ) 1.49 ( ) South 33.8 ( ) 1.25 ( ) West 23.5 ( ) Ref Year of diagnosis ( ) 0.64 ( ) ( ) 0.99 ( ) ( ) Ref Comorbidities present 20.6 ( ) 1.25 ( ).08 Median annual income in ZIP code ($).23 Less than 38, ( ) Ref 38,000 47, ( ) 1.06 ( ) 48,000 62, ( ) 1.23 ( ) 63,000 or more 35.7 ( ) 1.34 ( ) Unknown 0.8 ( ) 2.63 ( ) Insurance type.18 Private 43 ( ) Ref Medicare 42.4 ( ) 0.92 ( ) Medicaid or other government 8.8 ( ) 0.96 ( ) No insurance 3.5 ( ) 1.40 ( ) Unknown 2.4 ( ) 0.34 ( ) Urban status.48 Metropolitan 81.8 ( ) Ref Adjacent to metropolitan 10.8 ( ) 1.18 ( ) Nonmetropolitan 4.2 ( ) 1.01 ( ) Unknown 3.2 ( ) 0.61 ( ) Facility type.02 Academic 51.6 ( ) Ref Community program 39.8 ( ) 1.24 ( ) Integrated network 8.4 ( ) 1.36 ( ) Other or unknown 0.2 ( ) 6.31 ( ) Stage.01 IIIC 56.4 ( ) 0.76 ( ) IV 43.6 ( ) Ref OR, odds ratio; CI, Confidence interval; Ref, reference. * Odd ratios are for odds of undergoing laparoscopic interval debulking surgery, and are adjusted for all characteristics in the table. All P values are based on the Wald test. DISCUSSION In this cohort study, we investigated the use and effectiveness of laparoscopic interval debulking surgery in women who received neoadjuvant chemotherapy for advanced epithelial ovarian cancer. We found that interval surgery was initiated laparoscopically in 15% of patients and completed laparoscopically in 11% of patients. We observed no benefit or detriment in survival associated with receipt of laparoscopic interval debulking surgery. Additionally, 6 Melamed et al Laparoscopic Interval Debulking Surgery OBSTETRICS & GYNECOLOGY

7 Table 4. Surgical Characteristics and Outcomes in Women Undergoing Interval Surgery After Neoadjuvant Chemotherapy for Advanced Epithelial Ovarian Cancer Characteristic or Outcome Laparotomy (n52,621) Laparoscopy (n5450) P Extent of surgery*,.001 Gynecologic only 266 (10.2) 75 (16.8) Additional cytoreductive maneuvers 2,338 (89.8) 371 (83.2) Residual disease.29 No gross disease 789 (49.5) 130 (46.9) Gross disease 1.0 cm or less 445 (27.9) 90 (32.5) Gross disease more than 1.0 cm 361 (22.6) 57 (20.6) 90-day mortality 73 (2.9) 12 (2.8) day readmission 97 (3.7) 24 (5.3).26 Length of stay (d) 5 (4 7) 4 (2 6),.001 Data are n (%) or median (interquartile range) unless otherwise specified. * Extent of surgery was unknown in 17 patients undergoing laparotomy and in four patients undergoing laparoscopy. Based on the x 2 test. Residual disease was unknown in 1,026 patients who underwent laparotomy and in 173 who underwent laparoscopy. Based on the Wilcoxon rank sum test. we observed shorter postoperative hospitalization after laparoscopic surgery and no difference in risk of unplanned readmission or perioperative death. These findings suggest that in well-selected patients, such as those who have a complete response to neoadjuvant chemotherapy, laparoscopic interval debulking may be a safe and effective alternative to laparotomy. The feasibility of laparoscopic debulking surgery after neoadjuvant chemotherapy has been demonstrated previously in several small studies. 7 9 In a prospective observational study, Gueli Alletti et al 7 performed laparoscopic interval debulking in 30 women with clinical response to neoadjuvant chemotherapy, achieving resection of all visible disease in 29 women. All patients were alive with a median followup of 10.5 months. 7 In a retrospective study of 30 women, Corrado et al 8 found that laparoscopic cytoreduction was associated with low rates of intraoperative and postoperative complications (3.3% and 6.6%, respectively). At study completion, 26 of 30 patients were alive without recurrence with a median followup of 15 months. 8 In a historically controlled study of 10 women who underwent laparoscopic interval debulking and 11 women who had laparotomy, Favero et al 9 found a nonsignificant decrease in cancer-specific Fig. 2. Comparison of survival curves for laparoscopic and laparotomic interval debulking surgery after neoadjuvant chemotherapy for stage IIIC and IV epithelial ovarian cancer. The reported P value is based on the log rank test. Melamed. Laparoscopic Interval Debulking Surgery. Obstet Gynecol VOL. 0, NO. 0, MONTH 2017 Melamed et al Laparoscopic Interval Debulking Surgery 7

8 survival and a nonsignificant reduction in the chemotherapy-free interval among women undergoing laparoscopy. Although these studies suggest that laparoscopic debulking may be feasible, small sample size and the absence of any control group in all but the smallest study preclude meaningful comparison between laparoscopy and laparotomy. 7 9 In the current study, we observed no difference in survival between women who underwent laparoscopic interval debulking and those who underwent laparotomy. These results were consistent in the primary intention-to-treat analysis and after excluding cases in which laparoscopic procedures were converted to a laparotomy. Survival between the groups remained equivalent after controlling for a range of potential confounders, including age, facility type, comorbidities, and stage. Among the 61% of women with known residual disease status, the mode of interval surgery did not alter the frequency of optimal cytoreduction. This finding is consistent with the prior series that reported high rates of complete cytoreduction achieved with laparoscopic interval debulking. 7,8 Interestingly, we found that surgeons performing laparoscopic interval debulking surgery were more likely to omit resection of extrapelvic structures, yet this did not affect the extent of residual disease or survival among women undergoing laparoscopic interval surgery. These findings suggest that patients selected for laparoscopic debulking may have a lower burden of disease than those who underwent laparotomy. Alternatively, it is possible that disease that would have been palpable at laparotomy was not visualized during laparoscopy and was, therefore, underreported. The results of this study should be interpreted in light of important limitations, including the lack of random allocation and our inability to verify registry data. Estimates of the association of laparoscopic interval surgery with survival may be biased from patient selection based on factors that are not measured in the data, including burden of disease or functional status. However, because patients selected for laparoscopy tended to have more advanced disease and more comorbidities, we expect such bias to overestimate harm associated with laparoscopic staging. Moreover, we cannot verify surgeon intention in cases that were initiated laparoscopically but completed via laparotomy; it is possible that surgeons initiated some procedures laparoscopically to assess feasibility of open interval debulking. Reassuringly, our findings were not affected by exclusion of such cases. Residual disease status was missing in 39% of cases, calling into question conclusions related to this variable. However, the concordance of residual disease and survival results argues against bias in the missing data. This study has relatively short follow-up, and it is possible that survival difference may emerge with further observation. Additionally, this study had power to detect an 8% difference in 3-year survival, and smaller differences may be clinically relevant. Furthermore, the study was likely underpowered for small difference in the frequency of rare events, such as readmission and perioperative death. We could not investigate the effect of laparoscopic debulking on recurrence-free or disease-specific survival because these outcomes are not reported in the National Cancer Database. Finally, this investigation does not provide evidence for or against the use of neoadjuvant chemotherapy in advanced ovarian cancer. REFERENCES 1. Cannistra SA. Cancer of the ovary [published erratum appears in N Engl J Med 2005;352:104]. N Engl J Med 2004;351: Kehoe S, Hook J, Nankivell M, Jayson GC, Kitchener H, Lopes T, et al. 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9 11. Edge SB, Burd DR, Compton CC, Fritz AG, Greene FL CC, Trotti A, editors. AJCC cancer staging manual. 7th ed. New York (NY): Springer; Prat J; FIGO Committee on Gynecologic Oncology. Abridged republication of FIGO s staging classification for cancer of the ovary, fallopian tube, and peritoneum. Cancer 2015;121: Klabunde CN, Potosky AL, Legler JM, Warren JL. Development of a comorbidity index using physician claims data. J Clin Epidemiol 2000;53: Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40: United States Census Bureau. Census Regions and Divisions of the United States. Available at: www2.census.gov/geo/pdfs/ maps-data/maps/reference/us_regdiv.pdf. Retrieved September 15, United States Department of Agriculture Economic Research Service. Rural urban continuum codes. Available at: Retrieved September 15, Schoenfeld DA, Richter JR. Nomograms for calculating the number of patients needed for a clinical trial with survival as an endpoint. Biometrics 1982;38: Dupont WD, Plummer WD. Power and sample size calculations: a review and computer program. Control Clin Trials 1990;11: VOL. 0, NO. 0, MONTH 2017 Melamed et al Laparoscopic Interval Debulking Surgery 9

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