Interval or Late Debulking Surgery in Advanced Ovarian Cancer: Progression Free and Overall Survival Advantages

Med. J. Cairo Univ., Vol. 83, No. 2, March: 63-68, 2015 www.medicaljournalofcairouniversity.net Interval or Late Debulking Surgery in Advanced Ovarian Cancer: Progression Free and Overall Survival Advantages LOAIE EL-HELW, M.D. 1, 2 and HANAA EL-KHENINI, Ph.D. 3, 4 The Department of Medical Oncology, Mansoura University, Egypt 1 & the City General Hospital, University Hospitals of North Staffordshire, Stoke-On-Trent, UK 2 and the Departments of Public Health, Mansoura University, Egypt 3 & E-Health, the University of Manchester, UK 4 Abstract Purpose: Interval (IDS) or late debulking surgery (LDS) following neoadjuvant chemotherapy (NAC) may have a role in treating advanced epithelial ovarian cancer (AEOC) where primary debulking surgery is not possible. We aimed to study the outcome of such patients who were treated in our centre during the last 3 years. Methods: This was retrospective study of AEOC patients who had NAC with or without IDS/LDS in the City General Hospital, Stoke-On-Trent between May 2011 and July 2014. Results: Forty six patients with AEOC were treated under our oncology team during that period. Thirty one patients (67.4%) were in stages III and 15 were in stage IV (32.6%). All patients were recommended NAC; 30 patients (65.2%) had paclitaxel and carboplatin regimen and 16 (34.8%) single agent carboplatin. Response to chemotherapy was assessed after 2 cycles. Twenty seven patients (58.7%) had partial response, 16 (34.8%) stable disease and 3 (6.5%) progressive disease. Seventeen patients (37%) proceeded to IDS after cycle 3 and 4 patients (8.7%) to LDS after cycle 6. After a median follow-up period of 12 months, 39 patients (84.8%) had relapsing/progressive disease. The median progression free survival duration (PFS) for all patients was 9 months and 2 years PFS probability was 4.5%. The median PFS was 10 months for patients who had either IDS or LDS compared to 8 months for no debulking. The median overall survival (OS) duration was not reached yet but the 2 years OS probability was 76% for all patients; 94% for patients who had IDS and 58% for no debulking. One year OS probability for patients who had late debulking was 100%. Conclusion: In our study, we documented PFS and OS advantages for patients who IDS or LDS and therefore should be considered whenever possible as part of the primary treatment of AEOC patients. Key Words: Advanced ovarian cancer Neoadjuvant chemotherapy Debulking surgery. Correspondence to: Dr. Loaie M. El-Helw, E-Mail: loaieelhelw@hotmail.com, loaie.elhelw@uhns.nhs.uk Introduction APPROXIMATELY 70% to 80% of the ovarian cancer patients are in stage III or IV when first diagnosed. The current standard treatment for epithelial ovarian cancer (EOC) consists of primary debulking surgery (PDS) followed by paclitaxel and platinum chemotherapy. Optimal cytoreduction-in those patients-to no macroscopic residual disease is difficult to achieve with reported rate of less than 25% despite maximal efforts [1]. Also, most patients diagnosed with advanced epithelial ovarian cancer (AEOC) are elderly, with multiple comorbidities, and poor performance status. Therefore aggressive surgery is significantly limited in these patients. Neoadjuvant chemotherapy (NAC) is associated with 70-80% response rate in AEOC and can result in adequate tumour shrinkage. Therefore, NAC followed by interval debulking surgery (IDS) has been considered as an alternative to conventional PDS in treating AEOC [2,3]. The timing of IDS is usually after 2-4 cycles of chemotherapy. The value of late debulking surgery (LDS) after 6 cycles is not clear as there is a chance of emergence of more chemotherapy resistant tumour clones. Therefore, in our study we reviewed the management of our patients who presented with AEOC and were not candidate for PDS. We studied their outcome in relation to timing of debulking surgeries. Patients and Methods Retrospective study of patients with advanced ovarian cancer who had NAC with or without IDS/LDS treated in our centre in the City General Hospital, the University Hospital of North Staffordshire since May 2011 till July 2014. Electronic patients and gynaecology multidisciplinary (GM- 63

64 Interval or Late Debulking Surgery in Advanced Ovarian Cancer DT) meetings records were reviewed. Data analysis was performed using SPSS statistical package version 16. Overall survival (OS) and progressionfree survival (PFS) probabilities were analysed using the Kaplan-Meier method. The log-rank test and Cox-regression multivariate analysis were used to investigate the differences in survival between the study groups. p<5 was considered statistically significant. Results Demographic data: Table (1) describes the demographic features of the patient in the study. Forty six patients with AEOC who were not candidate for PDS were included. The median age was 71 years old (range 37-86). Thirty one patients presented in clinical stage (CS) III (67.4%) and 15 (32.6%) CS IV. Serous papillary adenocarcinoma was the most common histologic subtype (91.3%). Four patients (8.7%) presented with primary peritoneal carcinomatosis (PPC) but the majority had advanced ovarian cancer presenting with adnexal masses and wide spread diseases. Table (1): Demographic data of the 46 studied patients. Variables Number Percent Clinical stage: III 31 67.4 IV 15 32.6 Grade: Grade 1 1 2.8 Grade 3 35 97.2 Missing data 10 Histology: Serous 42 91.3 Clear cells 2 4.3 Mucinous 1 2.2 Undetermined subtypes 1 2.2 Clinical subtypes: EOC 42 91.3 PPC 4 8.7 GMDT plan: NAC/IDS 42 91.3 Palliative chemotherapy 4 8.7 NAC: Paclitaxel and carboplatin 30 65.2 Carboplatin 16 34.8 EOC : Epithelial ovarian cancer. PPC : Primary peritoneal carcinoma. NAC : Neoadjuvant chemotherapy. IDS : Interval debulking surgery. All our patients were discussed in the GMDT meetings on initial presentations where their management plans were decided. Forty two (91.3%) patients were decided to have NAC/IDS and 4 patients (8.7%) were to have palliative chemotherapy only due to poor performance status (PS) although all patients were reviewed once again after 2 cycles of chemotherapy for possibility of IDS. Paclitaxel and carboplatin regimen was the most commonly used NAC (65.2%) and single agent carboplatin was used in the rest of patients (34.8%). Response and outcome: Response to chemotherapy was assessed after 2 cycles of chemotherapy and patients were rediscussed in the GMDT meetings. Twenty seven patients (58.7%) had partial response (PR) to chemotherapy, 16 (34.8%) stable disease (SD) and 3 (6.5%) progressive disease (PD). Only 17 patients (37%) were recommended to proceed to IDS. Further 18 (39.1 %) were not suitable for IDS but were recommended to continue chemotherapy with further review following cycle 5; only 4 (8.7%) of them proceeded to LDS. Overall 21 patients (45.7%) had IDS/LDS. More patients with clinical stage III proceeded to have debulking surgery than CS IV; nearly 48% of patients with CS III had IDS and 6.5% had LDS. For patients with CS IV, 13.3% had IDS and 13.3% LDS. Complete surgical cytoreduction was achieved in 16 patients (34.8%) but 5 patients (1%) had suboptimal debulking with residual macroscopic disease. Maximal cytoreduction was achieved in all of the 4 patients (100%) who had LDS and in 12 of the 17 who had IDS (7%) (Table 2). After a median follow-up period of 12 months (range 5-40), 39 patients (84.8%) had relapsing/ progressive disease and had a median of 2 (range 1-4) further lines of systemic anticancer treatment (SACT). All patients who had IDS and 1 out 4 patients (25%) who had LDS, have eventually relapsed and 21 of 25 patients (84%) who did not have any debulking surgery had PD. Only 2 patients (4.4%) had single area of relapse and underwent further surgical resection followed by chemotherapy. Fifteen patients (83.3%) with IDS/LDS had platinum free interval (PFI) of >_6 months compared to only 47.6% for patients with no debulking surgery (p-19 Pearson Chi-Square) (Table 3). Survival data: The median progression free survival duration (PFS) for all patients was 9 months (range 8-10 months) and 2 years PFS probability was 4.5% Fig. (1). The median PFS was 10 months (range 8-11) for patients who had IDS or LDS compared to 8 months (range 6-9) for no debulking (p-5) Fig. (2). The median PFS durations were 11, 10 and 8 months for patients who had complete, in-

Loaie El-Helw & Hanaa El-Khenini 65 complete cytoreduction or no debulking respectively (p-3) although the difference in median PFS for complete and incomplete cytoreduction was statistically insignificant (p-01) Fig. (3). The median PFS for patients who had debulking (IDS/ LDS) compared to no debulking were (10 and 8 months; p-15). None was statistically significant in Cox-regression analysis. Over the follow-up period, 1 patient of 17 (5.9%) patients who had IDS and 7 of the 25 who had no debulking (28%) have died. All patients with LDS are still alive. Table (2): Response and outcome. Variables Number Percent Response after 2 cycles: PR 27 58.7 SD 16 34.8 PD 3 6.5 GMDT decisions after 2 cycles: Proceed to IDS 17 37.0 Review after 5 th cycle 18 39.1 No debulking 11 23.9 Number of cycles to debulking: 3 Cycles (IDS) 17 37 6 cycles (LDS) 4 8.7 No debulking 25 54.3 Debulking in relation to stage: Clinical stage III (31 patients): IDS (after 3 cycles NAC) 15 48.4 LDS (after 6 cycles NAC) 2 6.5 No debulking 14 45.1 Clinical stage IV (15 patients): IDS (after 3 cycles NAC) 2 13.3 LDS (after 6 cycles NAC) 2 13.3 No debulking 11 73.4 Surgical Cytoreduction: Complete 16 34.8 Incomplete (residual disease) 5 1 No debulking 25 54.3 Debulking in relation to cytoreduction: IDS (17 patients): Complete 12 7 Incomplete 5 29.4 LDS (4 patients): Complete 4 100 Incomplete 0 0 NAC : Neoadjuvant chemotherapy. IDS : Interval debulking surgery (after 3 cycles). PR : Partial response. SD : Stable disease. PD : Progressive disease. LDS : Late debulking surgery (after 6 cycles). The median overall survival (OS) data were not reached yet but the 2 years OS probability was 76% Fig. (4). The 2-years survival probability was 94% for patients who had IDS after 3 cycles compared to 58% for no debulking (p-9 Log Rank). One year OS probability for patients who had late debulking was 100% Fig. (5). The relation of OS to degree of cytoreduction is shown in Fig. (6) where 2 years OS probability was 94% for complete cytoreduction compared to 58% for no debulking (p-9). All patients with suboptimal debulking are still surviving at 1.5 years of follow-up. Patients who had platinum free interval (PFI) of > 12 months have the highest survival probability compared to PFI of 6-12 months and <6 months (p.008) Fig. (7). In Cox-regression multivariate analysis, none of these variables was statistically significant. Table (3): Relapse data among the studied patients. Variables Number Percent Relapse/progression: Yes 39 84.8 No 7 15.2 Relapse in relation to IDS/LDS: IDS & relapse (17 patients): Yes 17 100 No 0 0 LDS & relapse (4 patients): Yes 1 25 No 3 75 No debulking (25 patients): Yes 21 84 No 4 16 Pattern of relapse: Isolated site 2 4.4 Multiple areas 44 95.6 Further debulking surgery at relapse: Yes 2 4.4 No 44 95.6 Platinum free interval: IDS/LDS (18 relapsed patients): <6 months/refractory 3 16.7 6-12 months 9 50 >12 months 6 33.3 No debulking (21 relapsed patients): <6 months/refractory 11 52.4 6-12 months 10 47.6 >12 months IDS : Interval debulking surgery. LDS : late debulking surgery. SACT : Systemic anticancer treatment.

66 Interval or Late Debulking Surgery in Advanced Ovarian Cancer N cycles to Debulking 3 cycles (IDS) 6 cycles (LDS) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Fig. (1): Primary progression free survival for all studied patients. 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Fig. (2): Primary progression free survival in relation to timing of Debulking surgery. Surgical cytoreduction Complete Incomplete (residual disease) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Fig. (3): Primary progression free survival in relation to degree of cytoreduction. Fig. (4): Overall survival in the studied patients. N cycles to Debulking 3 cycles (IDS) 6 cycles (LDS) Surgical cytoreduction Complete Incomplete (residual disease) Fig. (5): Overall survival in relation to timing of Debulking surgery. Fig. (6): Overall survival in relation to degree of cytoreduction.

Loaie El-Helw & Hanaa El-Khenini 67 Platinum free interval >12 months 6-12 months <6 months Fig. (7): Overall survival in relation to platinum free inteeval. Overall, higher PFS was achieved for patients who had IDS/LDS compared to no debulking (10 and 8 months respectively). The median survival duration for the studied patients has not been reached yet. All patients with LDS are still surviving at 1 year (100% OS) as well as 94% of patients who had IDS. Of note that the 4 patients who had LDS were diagnosed in 2013 and early 2014, therefore their follow-up period is still short (median 10 months; range 9-12). The 1 and 2 years OS for the no debulking patients group was 58%. These findings emphasize the importance of debulking surgeries whether IDS or LDS as they are associated with better PFS and OS compared with no debulking. Discussion Neoadjuvant chemotherapy and interval debulking surgery (NAC/IDS) is an acceptable safe approach to achieve optimal cytoreduction in patients with advanced epithelial ovarian cancer who are not candidate for primary debulking surgery [4-6]. The best timing to perform cytoreductive surgery after NAC is still unclear. In a meta-analysis by Bristow and Chi, it was found that increasing the number of chemotherapy cycles prior to the debulking surgery had a negative survival effect. Thus, a definitive operative intervention should be undertaken early in the treatment program as possible [7]. That concept was also reported by Colombo and colleagues who found that patients with AEOC receiving complete IDS after more than 4 cycles of NAC have poor prognosis [8]. However, another meta-analysis did not show that increasing the number of NAC cycles adversely affected OS [3]. In our study, 46 patients with stage III and IV AEOC were not candidate for primary debulking surgery (PDS) and therefore were offered NAC and consideration of IDS. All patients were rediscussed in our GMDT meetings after 2 cycles of NAC and accordingly 17 patients (37%) had adequate response and proceeded to IDS after 3 NAC cycles. Eleven patients (23.9%) were not candidateat all-for debulking surgery for wide spread disease distribution and/or inadequate response to NAC. The rest of our patients (18; 39.1%) showed slow response to NAC based on radiological or laparoscopic assessment and therefore complete cytoreduction was considered non-achievable at that stage. They have been further reassessed following cycle 5 of NAC and only 4 were selected for LDS. The definition of 'optimal cytoreduction' has moved from its former meaning of a cytoreduction to 1cm of residual disease to no residual disease [9,10]. Tumour resection with >1cm of residual disease (15-30% of patients) places these patients at risk of morbidities of the cytoreductive attempt without survival benefit [11]. In agreement with that, our patients who had optimal debulking surgeries, had significantly longer median PFS compared to patients who had suboptimal debulking surgeries or no debulking at all (11, 10 and 8 months respectively). Patients, who had IDS/LDS, had higher chance of having platinum sensitive disease when they relapsed with platinum free interval (PFI) of more than 6 months. Also, 1.5 years OS probabilities were higher for our patients who had optimal and suboptimal debulking surgeries compared to patients who had no debulking. Patients with PFI of more than 6 months had higher OS compared to patients with platinum resistant ovarian cancer. On conclusion, IDS and LDS offer better PFS and OS for patients with AEOC who are not candidate for PDS. Debulking surgeries in patients with AEOC increase the percentage of patients who have platinum free interval of >_6 months and therefore have more chances to respond to further platinum regimens. References 1- GALLO A. and FRIGERIO L.: Neoadjuvant chemotherapy and surgical considerations in ovarian cancer. Curr. Opin. Obstet. Gynecol., 15 (1): 25-31, 2003. 2- MORICE P., DUBERNARD G., REY A., et al.: Results of interval debulking surgery compared with primary debulking surgery in advanced stage ovarian cancer. J. Am. Coll. Surg., 197 (6): 955-63, 2003.

68 Interval or Late Debulking Surgery in Advanced Ovarian Cancer 3- KANG S. and NAM B.H.: Does neoadjuvant chemotherapy increase optimal cytoreduction rate in advanced ovarian cancer? Meta-analysis of 21 studies. Ann. Surg. Oncol., 16 (8): 2315-20, 2009. 4- ZHENG H. and GAO Y.: Primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery for patients with advanced ovarian cancer. Chin., J. Cancer Res., 24 (4): 304-9, 2012. 5- KEYVER-P., ZIVANOVIC O. and RUDLOWSKI C.: Interval debulking surgery in patients with Federation of Gynecology and Obstetrics (FIGO) stage IIIC and IV ovarian cancer. Onkologie., 36 (6): 324-32, 2013. 6- MARKAUSKAS A., MOGENSEN O., DEPONT CHRIS- TENSEN R., et al.: Primary surgery or interval debulking for advanced epithelial ovarian cancer: Does it matter. Int. J. Gynecol. Cancer., 24 (8): 1420-8, 2014. 7- BRISTOW R.E. and CHI D.S.: Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: A meta-analysis. Gynecol. Oncol., 103 (3): 1070-6, 2006. 8- COLOMBO P.E., LABAKI M., FABBRO M., et al.: Impact of neoadjuvant chemotherapy cycles prior to interval surgery in patients with advanced epithelial ovarian cancer Gynecol. Oncol., S0090-8258 (14) 01305-5, 2014. 9- THIGPEN T., DUBOIS A., MCALPINE J., et al.: Firstline therapy in ovarian cancer trials. Int. J. Gynecol. Cancer, 21 (4): 756-62, 2011. 10- VERGOTE I., TROPÉ C. and AMANT F.: Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N. Engl. J. Med., 363 (10): 943-53, 2010. 11- CHANG S. and BRISTOW R.: Evolution of surgical treatment paradigms for advanced-stage ovarian cancer: Redefining 'optimal' residual disease. Gynecol. Oncol., 125 (2): 483-92, 2012.