Advanced stage ovarian cancer patients with neoadjuvant chemotherapy suffered worse recurrence free survival

Neoadjuvant chemotherapy (NACT) has been applied for the treatment of patients with advanced-stage epithelial ovarian cancer (EOC), fallopian tube cancer, and primary peritoneal cancer, as these patients have a low likelihood of achieving optimal debulking and are thus poor surgical candidates. Herein, we explore the effects of NACT and compare the surgical outcomes and recurrence data in patients who receive interval debulking surgery followed NACT(NACT-IDS) or primary debulking surgery(PDS). Methods A retrospective, single-center, observational study was conducted. Patients with advanced-stage EOC, fallopian tube cancer and primary peritoneal cancer who were treated with NACT or primary debulking surgery were enrolled. The effects of NACT as well as the surgical outcomes and recurrence data were compared between the NACT-IDS and PDS groups.

surgery) followed by platinum-based chemotherapy. The purpose of surgery is ideally to remove the tumor, with less than or equal to 1 cm of residual tumor, which is associated with a survival benefit 3 .
However, more than 75% of OC patients diagnosed with advanced-stage disease have accompanying ascites and hypoalbuminemia, which are predictive of severe postoperative complications 4,5 , and complications that occur after surgery delay adjuvant chemotherapy 6 . Therefore, neoadjuvant chemotherapy followed by interval debulking surgery is suggested 7 for patients with advanced-stage disease who have a low likelihood of achieving optimal debulking and thus are poor surgical candidates. In addition, one study found higher quality of life scores in terms of emotional and cognitive function 5 . Importantly, the survival of patients who receive NACT followed by interval debulking surgery has been found to be no worse than the survival of those treated with PDS 8,9 . Recently, the utilization of NACT has been proven to rapidly decrease 30-and 90-day mortality after surgery 10 .
In this study, we aimed to explore the effects of NACT and to compare the surgical outcomes and long-term recurrence information between an NACT-IDS and a PDS group.

Patient selection
Patients with epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer diagnosed by a pathologist and treated with NACT followed by interval debulking surgery (NACT-IDS) from January 1, 2013, to October 31, 2018, were considered potential participants. We also selected patients treated with primary debulking surgery (PDS) followed by platinum-based adjuvant chemotherapy during the same period for inclusion in the control group. The exclusion criteria were as follows: patients diagnosed with other malignant tumors and patients who did not undergo interval debulking surgery after NACT, or loss of follow-up. Informed consent was obtained.
We collected general information, including age, histology type, FIGO stage, and hemoglobin, albumin, alanine aminotransferase, aspartate aminotransferase, CA12-5, and HE4 levels before and after neoadjuvant therapy/surgery. We also collected information on the duration of surgery and the volume of bleeding during surgery as well as information regarding recurrence, platinum-free interval, and recurrence-free survival.

Follow-up
The follow-up period ended on December 31, 2019, and all included participants underwent regular tests for serum CA12-5 levels and abdominal/pelvic computerized tomography(CT)/ magnetic resonance imaging(MRI). Recurrence was defined as elevated serum CA12-5 levels ( 35 U/ml) as assessed by CT/MRI findings. The recurrence free survival was calculated from date of surgery to date of recurrence, and the platinum-free interval was calculated from the last chemotherapy cycle to the time of recurrence.
Statistical analysis SPSS 19.0 was applied for the statistical analysis, and P 0.05 was considered statistically significant.
We used means ± standard deviations (SD) or medians (interquartile ranges) to express quantitative variables, and qualitative variables were expressed as absolute numbers (percentages). Student's unpaired t test for variables with a normal distribution and the Mann-Whitney U test for variables with a nonnormal distribution were used for the comparison of quantitative variables between the groups, and the Chi-square test was used for qualitative variables. Kaplan-Meier survival analysis was used to analyze recurrence free survival with GraphPad Prism 8.0.

Clinical characteristics of the participators
Twenty-five patients received NACT followed by IDS, and 22 patients treated with PDS as the initial treatment were included. The baseline characteristics of the included patients are listed in Table 1.
The age, FIGO stage, histology type, adjuvant chemotherapy cycle and rate of bowel resection were comparable between the NACT and PDS groups, while the diameters of the mass were larger in the PDS group than in the NACT group (P = 0.000). The effect of NACT In the NACT group, serum markers were selected to evaluate the effect of NACT before and after the course of chemotherapy. Additionally, we found that the albumin level was elevated after chemotherapy (P = 0.001), while the CA12-5 and HE4 levels were obviously decreased posttreatment (P = 0.002, 0.003). In addition, the AST and ALT levels were comparable before and after the invention (P = 0.194, 0.074; Table 2). Table 2 The serum biomarkers tested pre-and post-NACT The surgical outcomes and recurrence data of NACT-IDS and PDS The preoperative hemoglobin and HE4 levels were lower in the NACT-IDS group than in the PDS group Additionally, there were 6/14 (42.86%) patients in the NACT-IDS group whose platinumfree interval was < 6 months and 2/9 (22.22%) patients in the PDS group (P = 0.333) (Table 3).
Kaplan-Meier survival analysis for recurrence free survival demonstrated that patients who received NACT followed by IDS had a poor recurrence free survival (P = 0.0441). (Fig. 1) Table 3 The surgical outcomes and recurrence data of NACT-IDS and PDS

Discussion
Ovarian cancer is the leading cause of death from gynecological malignancy worldwide, as most patients are diagnosed at advanced stages due to a lack of sensitive screening tests and the lack of specific symptoms at early stages. The standard of treatment is surgery followed by platinum-based chemotherapy 11 , and optimal debulking is the goal, as residual tumors decrease progression-free survival and overall survival 12 . To achieve the goal of optimal debulking, multivisceral surgeries such as bowel section and splenectomy are performed 13,14 .
Invasive procedures are associated with high risks of morbidity and mortality; in addition, poor outcomes, such as hypoalbuminemia, are predictive of severe postoperative complications 4 , and complications delay the start of subsequent chemotherapy, which reduces progression-free survival 6 .
Therefore, neoadjuvant chemotherapy offers an alternative treatment for patients with advanced ovarian cancer and makes surgery highly feasible 15 . In our study, we found that the level of albumin was elevated after the course of NACT (37.47 ± 5.42 vs 42.61 ± 3.46, P 0.05). Cancer patients have low preoperative albumin levels, especially those with advanced-stage disease and patients with ascites 16 ; the mechanisms for this low level involve a decrease in amino acid intake and albumin synthesis 17 as well as an increase in albumin leakage to the extravascular space in patients with ascites. There were 21 (80.77%) patients with massive ascites upon diagnosis, and the largest mean diameter of the ascites assessed by ultrasound was 104.05 ± 31.75 mm. After the course of NACT, ascites was not detected in 3 patients, and the largest mean diameter of the remaining cases of ascites was 65.00 ± 35.32 mm (t = 3.636, P = 0.001). Furthermore, decreases in CA12-5 and HE4 levels were found (P 0.05) in the NACT group, and side effects of chemotherapy (lowered hemoglobin levels) also occurred. Previous studies have observed that patients who receive interval debulking surgery after NACT have better surgical outcomes than patients who receive PDS, including less severe surgical complexity, fewer upper abdominal procedures, a shorter surgical duration, a lower amount of perioperative blood loss, a shorter hospital stay 5,8,18 , and reduced surgical morbidity and mortality 7,8 . In our study, there was no difference in the surgical outcomes between the NACT and PDS groups, as NACT may induce fibrosis, which may influence surgical procedures.
The presence of residual disease after surgery largely impact the prognosis of EOC 19 ; one study showed that the 7-year overall survival rate decreased from 73.6% in patients without residual tumors to 21% in patients with any type of residual disease 20 . Therefore, the goal of debulking surgery has been changed from the presence of a residual tumor less than 1 cm in diameter to the presence of no visible tumor 21 ; however, advanced-stage disease is associated with a low rate of complete tumor resection 22 . A previous study demonstrated that patients who received IDS after NACT were likely to achieve optimal cytoreduction 20,23 but that they did not have superior survival 24 , and there was a decreasing trend in median survival with an increase in the number of NACT cycles 24,25 . These studies suggest that NACT impacts the evaluation of tumor spread and leads to incomplete tumor resection in potentially resectable areas.
In addition, patients treated with NACT-IDS suffer from recurrence more often than patients treated with PDS 26  There were some limitations in this study. First, this was a retrospective analysis in a single institution with a small sample size; thus, much stronger evidence is needed to confirm the results. Additionally, due to limited information, we did not compare overall survival between the two groups.

Conclusion
NACT improves the performance of patients, but patients suffered more recurrence during the followup period. NACT should not be applied in all advanced ovarian cancer patients without selected. The Kaplan-Meier curve for RFS

Supplementary Files
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