Neoadjuvant Chemotherapy Followed by Surgery versus Primary Surgery in Advanced Epithelial Ovarian Cancer: A Review of Outcomes at National Institute of Cancer Research Hospital in Bangladesh

Introduction: This study evaluated the difference in operative and clinical outcomes for patients with advanced ovarian cancer after primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) in Bangladesh. Methods: Sixty patients with advanced epithelial ovarian cancer presenting to the department of Gynaecological Oncology at the National Institute of Cancer Research and Hospital were pros-pectively enrolled. Thirty patients underwent primary debulking surgery and thirty patients received NACT followed by IDS. Results: In the PDS and IDS groups respectively, 56.7% and 50% of patients presented with stage IIIC and 67.7% and 56.7% respectively had serious papillary type histopathology. Duration of surgery, amount of blood loss and total hospital stay were significantly lower (p < 0.001) in IDS group than in the PDS group. There was a statistically significant difference in postoperative tumor residuals between IDS and PDS patients. Complete tumor resection (R0) was obtained in 24 (80%) of IDS patients versus 13 (43.3%) Median progression free in was that of the IDS group was There one at 45 days in the PDS group. No other were documented at of a favorable outcome than primary debulking surgery on progression free survival in advanced ovarian cancer patients and permits a less aggressive surgery to be performed in Bangladesh.


Introduction
Ovarian cancer is the deadliest of all gynecological cancers. Even though new treatment approaches have been introduced, the five-year survival is low [1] [2] [3] [4]. Ovarian cancer is commonly diagnosed when it has already spread to the upper abdomen and distant areas because of initial vague and non-specific signs and symptoms. The current standard treatment of advanced ovarian cancer (stage III/IV) can either be primary debulking surgery (PDS) followed by chemotherapy or neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) [5]. Debulking or cytoreductive surgery typically includes a total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO), complete omentectomy and resection of any metastatic disease.
Resectability of disease depends on the skills of the surgeon and the extent of disease. Optimal cytoreduction is difficult if there is an extensive disease involving the upper abdomen or the undersurface of diaphragm. While optimal cytoreduction is an important prognostic factor for the survival of patients, extensive surgical resection increases postoperative morbidity [6] [7].
Neoadjuvant chemotherapy (NACT), followed by surgery is a therapeutic approach for extensive disease when complete surgical resection is not initially possible either due to bulky or diffusely unresectable disease or because of patients' medical comorbidities. NACT significantly reduces the tumor burden before surgery and allows an easier and optimal cytoreduction [8] [9]. It also decreases the morbidity, blood loss, and intensive care unit (ICU) and hospital stays [10].
This study compares the outcomes and peri-operative morbidities of primary debulking surgery versus NACT followed by surgery in Bangladeshi women with advanced ovarian cancer.

Methods
This prospective quasi experimental study was done between November 2017 to October 2019 in the department of Gynaecological Oncology, National Institute of Cancer Research and Hospital (NICRH), Dhaka, Bangladesh. Sixty patients with a diagnosis of ovarian cancer by histopathology, fine needle aspiration cytology (FNAC), and imaging studies such as ultrasound or CT scan were included in the study. Data was collected in a pre-designed data collection form. Patients were divided into two groups and assigned either to primary debulking surgery (PDS) followed by six courses of platinum-based chemotherapy or three courses of neoadjuvant platinum-based chemotherapy followed by interval debulking surgery (IDS), followed by three courses of platinum-based chemotherapy. Eligibility criteria was as follows: Patients were assigned to their treatment group based on both radiological and exam findings. Those patients with a fixed pelvic mass, large ascites, pleural effusions, and/or diaphragmatic disease were assigned to receive neoadjuvant chemotherapy followed by interval debulking surgery.
Patients were regularly evaluated after completion of chemotherapy for evidence of disease recurrence over fifteen months of follow-up. The follow-up schedule was every three months and included clinical examination, transvaginal and transabdominal ultrasound and CA-125 assays. A computed tomography (CT scan)/Magnetic Resonance Imaging (MRI) scan was ordered if clinical examination or laboratory testing was abnormal. Results of the study was calculated and analyzed by standard statistical methods. Data was expressed as mean + SD. A value of p < 0.05 was considered statistically significant. The data was analyzed with the SPSS for Windows (IBM SPSS Statistics for Windows, version 22.0, Armonk, NY: IBM Corp) software.

Results
Median age of the PDS group was 49 years while that of the IDS group was 55 years. Mean body mass indices of both groups were below 25 kg/m 2 which was not statistically significant. Pleural effusion was noted in four patients (13.3%) in the PDS group compared to one patient (3.3%) in the IDS group. Distension of the abdomen with ascites was the chief complaint in both groups (eight in PDS and six in IDS). Pain and palpable abdominal masses were present in five and one patients respectively in PDS and in IDS groups. Median tumor size was 12.12 cm in PDS and 10.85 cm in IDS groups. Pre NACT and post NACT CA-125 blood levels in IDS patients were significantly different (p < 0.001). Twenty-two patients had normalization of CA 125 levels after three cycles of NACT, six women had a reduction in the CA 125, and two women had no change in CA 125 levels. There were no significant differences were found in respect to CEA blood levels ( Table 1). Table 2 summarizes the histopathologic subtypes of epithelial ovarian cancer among the sixty patients. There was no statistical difference between those undergoing upfront versus interval cytoreductive surgeries.
Surgery-related variables are shown in Table 3. In the PDS group, the median length of operations was 2.75 hours compared to 2.5 hours in the IDS group. This difference was statistically significant. The amount of blood loss in PDS patients (720 ml) was significantly higher than IDS patients (496.67 ml) (p < 0.001). The volume of ascitic fluid found in PDS (1038.33 ml) was also significantly higher than the similar fluid found in IDS (86.67 ml) (p < 0.001). A complete cytoreduction (residual disease to R0) occurred in 24 (80%) of IDS patients   The development of tumor or ascites at different follow-ups is presented in Table 5. At six months of follow-up, there was only one instance of a mass or mass with ascites in PDS patients. At nine months of follow-up period, there were two reports of masses and one additional ascites in the PDS group. These differences were statistically not significant. In the last two consecutive follow-ups, significant differences were noted as PDS patients experienced more    Distant recurrences among both groups are summarized in Table 6. Patients undergoing PDS were more likely to have metastases to the liver and supraclavicular lymph nodes than patients in the IDS group. One patient in the PDS group developed lung metastases in addition to hepatic and peritoneal disease.
In the IDS group, patients' complete response (CR) was found in 22 (73.3%) patients while partial response (PR) was noted in six patients (20%). In two patients (6.7%) stable disease (SD) was found. In the IDS group, complete response and partial response were found in 22 (73.3%) and six (20%) patients respectively for patients receiving three cycles of chemotherapy prior to surgery.
The disease-free survival between the groups was compared by using Kaplan-Meier curve. Statistically significant difference in favor of the IDS group was found between the groups by Log Rank (Mantel-Cox) test (χ 2 = 26.274 (df = 1) ; p < 0.001). Median disease-free survival in the PDS group was twelve months while that of the IDS was seventeen months (Figure 1). By 15 months of follow-up, there was one death in the PDS group at 45 days.

Summary of Main Results
Our results demonstrate that NACT is associated with superior optimal cytoreduction, lower peri-operative morbidity as well as post-surgical morality compared to initial surgery in patients with advanced epithelial ovarian cancer. For patients presenting to NICRH in Bangladesh, NACT followed by IDS has a more favourable outcome than PDS on progression free survival in advanced epithelial ovarian cancer.

Results in the Context of Published Literature
In this study median age of women with advanced ovarian cancer patients was 49 years in the PDS group and 55 years in the IDS group. This is a decade younger than the median age reported in the western literature [12]. The exact reason for this age difference is not known; however, this could reflect the overall demographic profile of population with a relatively younger population than the West. However, an Indian study showed that the median age of women with EOC was 52 years [13]. In SCORPION trial it was noted that the median age of PDS group was 54 years and 55 years in NACT-IDS group [14].
In our study no significant difference was noted between body mass indices.
Distension of the abdomen was the chief complain in both groups. Pain and a mass were present in ten and seven patients respectively in the PDS and IDS  [20].
In our study, CA 125 normalized in 73.3% and dropped in 20% patients respectively for patients receiving three cycles of chemotherapy prior to surgery.
The impact of chemotherapy was also seen in the differences in the amount of ascitic fluid found in the PDS group which was significantly higher than in the IDS group. Chemotherapy responsive disease has been reported by other groups as well [21] [22] [23] [24]. Parameters of surgical aggressiveness (blood loss rates, ICU stays, and total hospital stay) were significantly lower in NACT group than PDS group [25]. Journal of Cancer Therapy In current study, the mean follow-up period was 15 months for the entire group. The follow-up range of both subgroups was identical. More instances of recurrence occurred in PDS than IDS patients (p = 0.021). In contrast, in a study conducted in Italy showed that during the study period, 123 recurrences (70.3%) were observed, with a statistically significant higher proportion of patients in the IDS group experiencing recurrent disease compared to women receiving PDS (76.3% vs. 50.0%, p = 0.001) [26]. In this study, progression free survival between the groups was compared by using Kaplan-Meier curve. Statistically significant differences in favor of NACT was found between the groups by Log Rank (Mantel-Cox) test (χ 2 = 26.274 (df = 1) ; p < 0.001). Median progression free survival in PDS group was twelve months while that of the NACT followed by IDS group was seventeen months. In a cohort of Indian patients with advanced epithelial ovarian cancer treated with neoadjuvant chemotherapy, the median progression free survival was 15.15 months 95% confidence interval [CI] and the median overall survival (OS) was 34.73 months [13]. A multivariate analysis of their study revealed that optimal cytoreduction and number of NACT cycles were significantly associated with PFS and optimal cytoreduction. Similarly, in another report, the median overall survival time was 28 months in PDS group and 25 months in NACT group with a p value of 0.5. [25].
Based on the result of meta-analysis of different RCTs, there were no significant differences in the progression free survival (PFS) and overall survival of patients with advanced ovarian cancer based on PDS versus IDS [27] [28] [29]. When deciding whether a patient is a candidate for primary debulking surgery, with an acceptable level of morbidity, the clinician must consider both the burden of disease and the patient's comorbidities. Laparoscopy, in addition to axial CT and MRI may provide information about the disease burden and the ability to surgically resect the disease [12] [14] [30] [31]. The difference between progression free survival among patients undergoing primary versus interval cytoreductive surgery may be in part due to differences in complete resections. In only 43% of the PDS group compared to 80% of the IDS group achieved R0 complete surgical resections. Our data supports the importance of complete surgical cytoreduction as a prognostic indicator.
Strengths and Weaknesses All patients were consecutively operated by gynaecologic-oncologic surgeons. Only patients with FIGO stages III and IV were included in this analysis. The present study had some limitations. The study was conducted in a single centre in Dhaka city which may not be representative for the whole population. The sample size was small in the present study. The study period of present study was short. A longer follow-up will help document overall survival of patients undergoing PDS versus NACT and IDS.

Conclusion
Ovarian cancer frequently presents at an advanced stage, and it may not be possi- ble to remove all this disease during surgery. In Bangladesh, NACT is associated with superior optimal cytoreduction, lower peri-operative morbidity as well as post-surgical morality compared to initial surgery in patients with advanced epithelial ovarian cancer. NACT followed by IDS has a more favorable outcome than PDS on progression free survival in advanced epithelial ovarian cancer. Our study supports the findings of multiple other reports that NACT before surgery is an acceptable standard of care for women with advanced ovarian cancer.

Conflicts of Interest
The authors have no conflicts of interest to disclose.