Oncological Outcomes in Patients with Delayed Cytoreductive Surgery During COVID Times

Abstract

ESMO ESGO guidelines recommend standard 3–4 cycles of neoadjuvant chemotherapy (NACT) for advanced epithelial ovarian cancers (EOC); however, the ideal number of cycles is still debatable. Literature regarding survival after 5 or more cycles is conflicting. COVID pandemic saw several oncosurgeries postponed due to healthcare crises. The present study was undertaken to evaluate oncological outcomes in patients undergoing delayed cytoreductive surgery (CRS) in advanced Epithelial Ovarian Cancer. This was a hospital-based, retrospective, observational study done at tertiary cancer institute. Objectives were to evaluate progression free survival (PFS) and overall survival (OS) according to timing of surgery and to identify prognostic factors for OS and PFS. The study group included patients undergoing delayed CRS (defined as CRS done after more than 5 cycles of NACT), and the control group is comprised of CRS done after 3–4 cycles NACT. A total of 29 patients underwent delayed CRS. Of these, 58% (n = 17) patients had COVID-related causes for delay in surgery. On comparing with the control group (n = 98), the study group had lower rates of complete cytoreduction (50% vs 71%, p = 0.012). Similarly complete chemotherapy response score was observed in lower proportion of delayed CRS (24.13% vs 28.15%, p = 0.003). Mean CA 125 levels were 89.32 and 148.45 in cases and controls respectively (p = 0.090). PFS of the patients with delayed CRS (7 months) versus the interval CRS group (16 months) showed a statistically significant difference between the two group (p = 0.0001). Also, the OS for the control group was longer (55 months) than cases (34 months) (p ≤ 0.0001). Administration of additional cycles of chemotherapy beyond 3–4 cycles seemed to decrease survival in Ovarian Cancer patients. This approach however, may be beneficial in increasing the survival of patients who are deemed inoperable after 3–4 cycles of chemotherapy.

Introduction

Epithelial ovarian cancer remains one of the most lethal gynaecological malignancies despite several advances in our understanding of the disease biology and chemotherapeutic drugs. The decision of timing of surgery in the chronology of a patient with epithelial ovarian cancer is dependent on multiple factors, which include patient’s general condition, extent of disease, surgical competence, and availability of advanced intensive care facilities, amongst many others. In essence, regardless of the timing of surgery, the aim all cytoreductive procedures is complete cytoreduction with no residual disease and tolerable morbidity, irrespective of the number of neoadjuvant chemotherapy cycles [1].

Although the European Society of Medical Oncology and European Society of Gynaecological Oncology (ESMO ESGO) have recommended a standard of 3–4 cycles of neoadjuvant chemotherapy (NACT) for advanced epithelial ovarian cancers (EOC) [2], the ideal number of such cycles is still debatable. There are contradictory reports in literature regarding the effect of more than or equal to 5 cycles on progression free survival or overall survival and prognosis in general [3, 4]. COVID pandemic saw several oncosurgeries postponed due to healthcare crises, and several patients underwent delayed cytoreductive surgery (CRS).

Methodology

This was a hospital-based, retrospective, observational cohort study done at a tertiary care cancer institute of Northeast India between January 2019 and December 2021, with follow-up till May 2023.

The aim of the study was to evaluate the oncological outcomes and impact on survival in patients who have undergone delayed CRS in advanced EOC. The objective was to evaluate progression free survival (PFS) and overall survival (OS) according to the timing of surgery.

The study group is comprised of patients undergoing Delayed CRS, which was defined as CRS done after 5 or more cycles of NACT. The chemotherapy agents administered were intravenous Paclitaxel (175 mg/m²) and Carboplatin (AUC 5/6). The cause was administration of additional cycles broadly categorized into COVID-related factors (including unavailability of dates for surgery) and disease-related factors (such as inoperability, poor general condition of the patient, and poor responders to chemotherapy), while the control group is comprised of CRS done after 3–4 cycles NACT. Patients with non-epithelial malignancies, or those who did not undergo CRS due to progressive disease or any other cause, were excluded from the study.

The electronic case records were analysed in detail, including the clinical history and examination, imaging, endoscopy, biopsy, and histopathological reports. Progression free survival (PFS) was defined as the time from debulking surgery to the first documented date of progression, or death from any cause, whichever occurred first (the last date of follow-up being censored). Overall survival (OS) was defined as the time from the date of surgery to death from any cause, the last date of follow-up being censored. Median follow-up time in our patients was 12 months (range: 2–38 months).

The following parameters were collected, age and stage at diagnosis, number, dose and type of chemotherapeutic drug used, fall in CA 125 levels after chemotherapy. Radiological response after chemotherapy was reported according to RECIST 1.1 protocol [5]. Intra-operative findings were documented with PCI (peritoneal carcinomatosis index) and CC (completeness of cytoreduction) scores. Time to subsequent recurrence, sites of recurrence and overall survival were recorded. The reporting of the study was done according to STROBE guidelines. [6].

Statistical Analysis

Statistical analysis was performed by RStudio Version 1.2.1335 for Mac iOS. The data was collected in Excel worksheets. Continuous variables are described by the number of observations (N), the median, minimum, maximum, mean and standard deviation. The Student t-test or Wilcoxon test was used to compare the distribution of continuous variables. Categorical variables were described by the number of observations (N) and the frequency (%) of each modality. The Kaplan–Meier method was used to estimate survival rates and median survival times and their associated 95% confidence interval (95% CI). A Cox proportional hazard analysis was performed to identify OS and PFS prognostic factors. All statistical tests were two-sided, and the significance threshold was set at 5% (i.e. p < 0.05).

Results

During the study period, a total of 29 patients underwent delayed CRS. In order to prognosticate these cases, they were compared with the control group comprising 103 patients who were operated after 3 cycles of NACT, within the same study period. Out of the study group, 17 (58%) patients had COVID-related causes for delay in surgery, while in 12 (41.3%) patients the reasons for delay were related to disease factors, such as stable disease or partial response to chemotherapy, not amenable to cytoreduction (Fig. 1).

Fig. 1.

Scheme layout of study group and control group (interval CRS: CRS done after 3–4 cycles of NACT; delayed CRS: CRS done after 5–6 cycles of NACT; COVID group: patients with COVID-related factors like unavailability of OT; non-COVID group: patients with disease factors, such as stable disease or not amenable to CRS)

On comparison between the two groups, lower rates of complete cytoreduction (50% vs 71%, p = 0.012) were achieved in the study group. Similarly, complete chemotherapy response score was observed in lower proportion of delayed CRS (24.13% vs 28.15%, p = 0.003). Mean CA 125 levels were 89.32 mIU/mL and 148.45 mIU/mL in cases and controls respectively, however these mean values were not statistically significant (p = 0.090) (Table 1).

Table 1.

Description of characteristics of the two groups

S No	Value	Cases (N = 29)	Controls (N = 103)	p value
1	Mean age	50.82 years (range: 31–77)	47.80 years (range: 25–71)	0.20
2	Mean CA 125 levels	89.32 mIU/mL (SD 187.95; range 5.2–1001)	148.45 mIU/mL (SD 223.87; range 3–1001)	0.09
3	Stage at presentation			< 0.001
	Stage II	–	1
	Stage III	16	90
	Stage IV	13	12
4	RECIST 1.1			< 0.001
	CR	-	78
	PR	27	23
	SD	2	2
5	CRS			0.003
	1	6	70
	2	15	4
	3	7	29
6	CC score			0.01269
	0	14	71
	1	5	20
	2	9	9

RECIST 1.1 Response Evaluation Criteria in Solid Tumors 1.1, CR complete response, PR partial response, SD stable disease, Prog progressive disease, CRS chemotherapy response score, CC Score completeness of cytoreduction score.

PFS of the patients with delayed CRS (7 months) versus the interval CRS group (16 months) showed a statistically significant difference between the two groups (Fig. 2). Similarly, the OS for the control group was longer (55 months) than those with delayed CRS (34 months) (Fig. 3).

Fig. 2.

PFS cases vs controls

Fig. 3.

OS cases vs controls

Since the cases contained both COVID patients and non-COVID group of patients who had undergone a delayed CRS, a subgroup analysis was done between controls and COVID-related subgroup to exclude the bias due to disease factors such as inoperability and poor chemo responders. The control group showed a better overall survival than the COVID group (36 months vs 20 months, p = 0.052), as well as PFS (16 months vs 10 months, p ≤ 0.001) (Figs. 4 and 5).

Fig. 4.

OS control vs COVID

Fig. 5.

PFS control vs COVID

Discussion

Our study was a retrospective study that aimed to evaluate the impact of additional cycles of NACT on oncological outcomes that had to be administered to patients during the COVID times owing to logistical constraints. The study group with delayed CRS exhibited poor oncological outcomes in terms of both OS and PFS. Completeness of cytoreduction remains the most vital factor in oncological outcomes; however, the two groups had comparable CC scores, which does not reflect in the OS and PFS data. Thus, it would seem prudent to assume that the delay in CRS has been detrimental to the study group.

A multicentre Italian study published similar decrease in overall survival when additional chemotherapy after 3 cycles was administered to the EOC patients [7]. Several underlying mechanisms may be responsible, including the oft quoted ‘selection of platinum resistant clones’ in the neoadjuvant chemotherapy group [8], and the preference for primary cytoreduction over interval cytoreduction itself [9]; however, the jury is still out on that pending results from future prospective trials [10].

Our observation that additional cycles of chemotherapy would render a suboptimal cytoreductive surgery as operable may presently be the only indication for which a delayed cytoreduction may be chosen. There were no significant differences between the morbidity data in the two groups. Our data showed similar PFS and OS outcomes for both COVID and non-COVID groups. With only 4 events occurring in 16 patients, the median OS was 20 months in the COVID subgroup, and with 5 events out of 12 patients in the non-COVID subgroup, the median OS was 34 months (p-value: 0.8). Inferring statistics in such low sample sizes is not possible to give any definitive results.

The strength of this study lies in its retrospective nature making the processes blind to study outcome. In turn, this also provided us an opportunity to study the impact of delayed CRS in a real-world scenario as compared to a controlled trial, where numerous factors have been meticulously arranged. Our study has some drawbacks. Bevacizumab as a component of neoadjuvant chemotherapy may have influenced rates of cytoreduction and PFS [11, 12]; however, this has not been has not been compared in our study groups.

At present, there are two multicentre prospective trials trying to answer the dilemma of timing of cytoreductive surgery; one is the GO SOAR 2 (Global Gynecological Oncology Surgical Outcomes Collaborative) study, an international, multicentre mixed cohort trial to compare survival following interval and delayed cytoreductive surgery, between delayed cytoreductive surgery and no surgery (chemotherapy alone) [13]. Another trial, CHRONO (CHROnology of surgery after Neoadjuvant chemotherapy for Ovarian cancer), is a multicentre Phase III study planned to assess the efficacy of delayed surgery after six cycles of neoadjuvant chemotherapy on progression free survival [14]. The results of these may hopefully shed more light in this regard.

Conclusion

Administration of additional cycles of chemotherapy beyond 3–4 cycles in our study seemed to decrease the survival in EOC patients. This approach, however, may be beneficial in increasing the survival of patients who are deemed inoperable after 3–4 cycles of chemotherapy. Further prospective trials may resolve this question better in the future.

Data Availability

The data that support the findings of this study are available on request from the corresponding author.

Declarations

Ethics Approval

The study was approved by the Institutional Ethics Committee of Dr B Borooah Cancer Institute, Guwahati.

Competing Interests

The authors declare no competing interests.