Survival outcomes following interval versus primary debulking surgery in advanced epithelial ovarian cancer: A retrospective cohort study in Lagos, Southwest Nigeria

Background: There is conflicting evidence regarding the survival benefit of interval debulking surgery (IDS) compared to conventional treatment with primary debulking surgery (PDS) in women with advanced epithelial ovarian cancer (EOC). Objectives: We compared the survivals following PDS followed by adjuvant chemotherapy (ACT) versus IDS after neoadjuvant chemotherapy (NACT) in women with advanced EOC at the gynaecological oncology unit of a tertiary referral centre in Lagos, Southwest Nigeria. Methods: The data of 126 women with advanced EOC who had standard treatment with either PDS and ACT or NACT and IDS between January 2008 and December 2017 were analyzed. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) time stratified by the types of upfront debulking surgery were calculated and compared by employing the log-rank test statistics. Cox proportional hazard models were then used to estimate hazard ratios of the association between the type of surgical debulking and survivals while adjusting for all necessary covariates. Results: We recorded no statistically significant differences in PFS (adjusted hazard ratio=1.28, 95% confidence interval 0.82–2.01, P=0.282) and OS (adjusted hazard ratio=1.23, 95% confidence interval 0.68–2.25, P=0.491) between IDS and PDS among women with advanced EOC. Conclusions: There is a need for a larger prospective multicenter study to further compare the impact of upfront surgical debulking types on the survival of women with advanced EOC in our setting. In the meantime, giving interval debulking surgery after a few courses of neoadjuvant chemotherapy should be an acceptable standard of care for women with advanced EOC.


Introduction
In 2020, ovarian cancer ranked as the eighth most commonly diagnosed cancer among women, with 313,959 new cases and 207,252 recorded deaths worldwide. 1It is the leading cause of death in women diagnosed with gynaecological cancers. 1 Most cases of ovarian cancer are epithelial in origin 2 with more than 70-80 % f these cases diagnosed at the later stages thus leading to poor outcomes for patients. 3,4is is because early-stage diseases are mostly asymptomatic or characterized by non-speci c symptomatology making diagnosis very challenging.Ovarian cancer, therefore, remains an unresolved global health problem. 5,68][9] Primary debulking surgery (PDS) followed by adjuvant platinum-based chemotherapy (ACT) constitutes the primary treatment approach for ovarian cancer as this treatment aims to eliminate any gross or microscopic residual tumour. 9Optimal surgical debulking is not always possible for advanced-stage diseases, especially in women with very extensive diseases beyond the pelvis 9 or those with a major medical condition that may impair their performance status and inability to withstand an extensive PDS. 10 In such instances, surgery can be intricate, occasionally necessitating substantial bowel resection and signi cant blood loss, posing a considerable risk of morbidity and mortality. 9,11,12When PDS is not feasible, secondary surgery referred to as interval debulking surgery (IDS) may be carried out after an initial tumour response in between a few courses of chemotherapy.
Although there is no optimal timing of IDS, it is usually performed after two to four courses of neoadjuvant chemotherapy (NACT). 9S after NACT has demonstrated improved tumour resectability and response rates. 13,14However, there is still con icting evidence regarding its survival bene ts compared to conventional treatment with PDS followed by adjuvant chemotherapy, 11,12,15 especially in resource-limited settings including Nigeria.Therefore, this current study compared the survival outcomes (progression-free and overall survivals) in women with advanced EOC who had either PDS and ACT or NACT and IDS over 10 years at the women's cancer unit of a tertiary referral centre in Nigeria.

Study design and settings
This was a retrospective cohort study of all advanced epithelial ovarian cancer (EOC) cases that had the standard treatment with either primary debulking surgery (PDS) and adjuvant chemotherapy (ACT) or neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) at a gynaecological oncology unit of a referral hospital in Lagos, Southwest Nigeria between January 2008 and December 2017.The hospital is a leading tertiary healthcare facility in Southwest Nigeria, primarily functioning as a specialized referral centre for government-owned and private hospitals in Lagos, Ogun, and Oyo States.The hospital's gynaecologic oncology unit comprising four consultant gynaecologic oncologists and up to 15 resident doctors provides various in-patient and out-patient multidisciplinary oncology services including the screening and treatment of different premalignant and malignant diseases of the female genital tract. 16

Eligibility criteria
We retrieved data from the medical records of women diagnosed and treated for EOC in the women's cancer unit from January 2008 to December 2017.We also extracted data on tumour recurrence and death for each patient for up to three years of follow-up after completion of rst-line treatment until December 2020.The inclusion criteria were: patients with the surgico-pathological diagnosis of advanced EOC de ned as the International Federation of Gynecology and Obstetrics (FIGO) stages 3 and 4; 17 women who received complete standard treatment consisting of either PDS and postoperative ACT or preoperative NACT, IDS and postoperative ACT; and those with complete medical records and laboratory test results required in the nal data analyses.Women who did not complete their treatment were excluded from the study.

Study procedure and data collection
We included n = 126 women with the surgico-pathological diagnosis of advanced EOC data in the study.We retrieved data from the gynaecological oncology ward register and patients' medical records such as age, menstrual status, parity, body mass index (BMI), coexisting morbidity (such as hypertension, diabetes mellitus, kidney, and liver disease), presence of ascites, preoperative serum CA-125 levels and tumour recurrence and timing of recurrence.Obesity was de ned as a BMI greater than or equal to 30 kg/m 2 . 18We de ned tumour recurrence as the clinical and/or radiologic evidence of tumour regrowth after a period of remission or death within three years of completion of standard rst-line treatment.

Study outcomes
We evaluated two study endpoints: progression-free survival (PFS), characterized as the duration from the conclusion of primary treatment to the initial indication of disease progression, as determined by clinical examination, elevated tumour marker (serum CA125 levels), and/or radiological studies; and overall survival (OS), de ned as the duration from the completion of primary treatment to death from any cause or the last follow-up for patients still alive after completing treatment.Survival data were censored after a three-year follow-up period. 19

Statistical analyses
Data analyses were performed using SPSS version 28.0 for Windows (IBM Corp., Armonk, NY, USA) and descriptive statistics were computed for patients' relevant sociodemographic, and clinical characteristics.Baseline patient characteristics were described using mean and standard deviation (for normally distributed variables) or median and interquartile range (for skewed variables) for continuous parameters.
Categorical variables were presented using frequencies and percentages.Kaplan-Meier estimates of PFS and OS time, strati ed by the types of upfront debulking surgery, were computed and compared using logrank test statistics. 20Cox proportional hazard models using backward stepwise conditional techniques were then used to estimate hazard ratios (HR) of the association between the type of surgical debulking and survivals (PFS and OS) while adjusting for the participants' clinicopathologic characteristics.
Variables with P < 0.20 were built into the nal multivariable models.Statistical signi cance for associations was reported when the P-value was less than 0.05.

Ethical considerations
The research protocol for this study was approved by the Research Ethics Committee of the hospital (ADM/DCST/HREC/APP/3699) according to the Declaration of Helsinki before access to the patient's medical records and subsequent data collection.Strict con dentiality measures were maintained for patients' information throughout and following the conclusion of the study.

Results
We retrieved the data of n = 213 women diagnosed with epithelial ovarian cancer (EOC) and managed with the standard rst-line treatment during the review period.Based on the study eligibility, the datasets of n = 126 women who had advanced EOC were included in the nal data analyses [Figure 1].
As shown in Fig. 2, the Kaplan-Meier survival analysis recorded an overall median progression-free survival (PFS) of 17.0 months (95% con dence interval 10.8, 23.2).There was no statistically signi cant difference in median PFS after three years between women who had interval debulking surgery after preoperative neoadjuvant chemotherapy and those who had primary debulking surgery followed by postoperative adjuvant chemotherapy (17.0 vs. 15.0 months, P = 0.348).As shown in Table 2, the majority of the women in the study had PDS as their upfront surgical treatment (n = 67, 53.2%).Tumour recurrence was recorded in 83 (65.9%) women during the period under review.Following adjustments for age, parity, BMI, co-morbidity and tumour histological subtype, there was no statistically signi cant difference in PFS between women in the IDS arm and those in the PDS arm (adjusted hazard ratio = 1.28, 95% con dence interval = 0.82-2.01,P = 0.282).
In Fig. 3, the Kaplan-Meier survival analysis showed a median overall survival (OS) of 30.1 months (95% con dence interval 28.6, 31.7).There was no statistically signi cant difference in median OS after three years between women who had interval debulking surgery and those who had primary debulking surgery as their rst-line upfront surgical treatment (30.0 vs. 30.2months, P = 0.616).Fifty-one of the 126 women (40.5%) in the study died within three years of completion of their primary treatment.On adjustments for covariates including menstrual status, BMI, co-morbidity, FIGO stage and presence of ascites, there was no statistically signi cant difference in the OS between women in the IDS arm and those in the PDS arm (adjusted hazard ratio = 1.23, 95% con dence interval 0.68-2.25,P = 0.491) [Table 3].

Discussion
Investigations have indicated that an advanced FIGO stage independently worsened PFS [21][22][23] and OS 24 in patients with EOC.On this premise, our current study examined the impact of the type of upfront debulking surgery on these survival outcomes by comparing the survivals of women with advanced EOC who had interval debulking surgery after neoadjuvant chemotherapy with women who had the standard rst-line treatment with primary debulking surgery followed by adjuvant chemotherapy.We recorded no signi cant differences in survival outcomes among women in both treatment groups.
The impact of early tumour recurrence on the overall survival of patients with EOC is widely acknowledged. 25In this study, we recorded a tumour recurrence rate of 65.9%, which is much lower than the rate of 100% recorded in a similar cohort of women with advanced EOC in a previous study conducted in the same setting in Lagos, Nigeria. 23The rate is however lower than the disease recurrence rate of over 70% within the rst 5 years reported in most series involving women with advanced EOC who achieved a full remission following rst-line therapy. 8,26In addition, the relatively high death rate recorded in this study may point to the category of women included in the study which further suggests that an advanced stage may be associated with poor survival outcomes. 23However, the variation in study ndings, especially with regards to recurrence, may be due to the different follow-up periods adopted in our study and that of previous studies as the risk of disease recurrence and death increases with increasing duration since completion of rst-line treatment.
Studies have reported that the primary independent prognostic factor in advanced ovarian cancer is the complete removal of all macroscopic disease during debulking surgery. 27,28A di cult optimal resection of macroscopic disease due to pelvic and peritoneal brosis after neoadjuvant chemotherapy has been hypothesized as a potential drawback of upfront IDS. 15 However, this was not corroborated by our current study where women who had IDS compared to PDS have an unadjusted higher optimal surgical debulking rate (44.1% versus 17.9%).This is similar to previous studies that showed that women with advanced FIGO stage of EOC who had NACT followed by IDS showed statistically and clinically improved optimal cytoreduction, 12,15 perioperative complications, and mortality 29,30 compared to patients who had PDS and postoperative ACT.However, these did not translate to differences in survival bene ts as our current study and previous randomized controlled trials conducted by Vergote et al. in 2010 15 and Kehoe et al. in 2015 12 reported that survival with IDS is similar to PDS in women with stage III or IV EOC.An almost similar nding to our study was also reported in a retrospective study conducted in Slovenia and published by Kobal et al. in 2018 31 that showed no signi cant differences in terms of PFS (17.3 versus 18.3 months) and OS (41.3 versus 34.5 months) in the PDS and IDS arms.This thus suggests that no differences in survival duration in women with advanced ovarian diseases regardless of the geographical settings where treatment is received.
These ndings draw attention to the ndings from the Gynecologic Oncology Group (GOG) 32 and European Organization for Research and Treatment of Cancer (EORTC) 33 trials that suggested the need for optimal tumour response to chemotherapy before IDS.This is because women with advanced diseases in these trials whose tumour masses were chemo-reduced to less than 1 cm before IDS had better survival than women who had PDS followed by chemotherapy.Even though the associations between upfront surgery type and survival outcomes in our study were not in uenced by the disease debulking status, we suggest that the potential of a woman with either FIGO stage 3 or 4 diseases to respond to an initial chemo-reduction should still be used as a criterion for selecting treatment that would achieve optimal survival bene ts.
There are some limitations in this study.First, there are potential selection biases limited by the singlecentre study.Second, the retrospective design of the study with no power calculation could result in inadequate sample size thus limiting the statistical power of the study.Third, the restriction of the study follow-up period to three years instead of the standard survival assessment after ve years could make comparison to previous studies di cult.Fourth, we did not assess the in uence of baseline performance status on the type of treatment selection and the introduction of second-line treatment during follow-up and their consequent impact on patients' survival data. 24Finally, there could be variations in the expertise and/or the level of training of surgeons who performed the upfront debulking surgical procedures during the review period which could have some in uence on our reported ndings.However, our study is the rst to examine survival outcomes based on upfront surgical treatment in women with advanced EOC in sub-Saharan Africa, and therefore, our nding would add to the growing body of literature in this important area of ovarian cancer management.

Conclusions
We found no evidence that IDS between cycles of chemotherapy compared with conventional treatment using PDS followed by postoperative ACT improved survivals in women with advanced EOC.We, therefore, suggest the need for a larger prospective multicenter study to further compare the impact of upfront surgical debulking types on the survival of women with advanced EOC in our setting with adjustments for important covariates that may in uence survival such as patients' baseline performance status and use of second-line treatment during follow-up.In addition, this study should examine the adverse effects, quality of life, or postoperative morbidity or mortality pro les of these treatment modalities.In the meantime, giving interval debulking surgery after a few courses of neoadjuvant chemotherapy should be an acceptable standard of care for women with advanced EOC.There was no signi cant difference in PFS between interval and primary debulking surgery (P =0.348).

Figures
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Figure 1 Study
Figure 1

Table 2
Univariable and multivariable analyses of type of upfront surgery and progression-free survival Abbreviations: BMI, body mass index; CA, cancer antigen; CI, con dence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; NA, not applicable; PDS; primary debulking surgery; Type I includes low-grade serous carcinomas and others; Type II includes high-grade serous carcinomas.

Table 3
Univariable and multivariable analyses of type of upfront surgery and overall survival Abbreviations: BMI, body mass index; CA, cancer antigen; CI, con dence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; NA, not applicable; PDS; primary debulking surgery; Type I includes low-grade serous carcinomas and others; Type II includes high-grade serous carcinomas.
Abbreviations: BMI, body mass index; CA, cancer antigen; CI, con dence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; NA, not applicable; PDS; primary debulking surgery; Type I includes low-grade serous carcinomas and others; Type II includes high-grade serous carcinomas.