Secondary cytoreductive surgery with and without hyperthermic intraperitoneal chemotherapy for recurrent ovarian cancer

Introduction

Ovarian cancer is a lethal malignant gynecological cancer known to impact women (1). Optimal cytoreductive surgery (CRS) followed by platinum-based chemotherapy is considered the standard of treatment for advanced ovarian cancer (2,3). In addition, the administration of maintenance therapy with drugs such as bevacizumab and poly (ADP-ribose) polymerase (PARP) inhibitors is gradually increasing (4). However, approximately 60–80% of patients with advanced-stage ovarian cancer experience relapse after complete remission, even after optimal primary treatment (5,6).

Recurrent ovarian cancer typically relies on systemic chemotherapy. However, recent research has revealed that CRS followed by chemotherapy can achieve improved survival outcomes when compared with those with chemotherapy alone (7), thereby highlighting the critical role of secondary CRS. Previous randomized clinical trial suggested a benefit for hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent ovarian cancer (8), but this publication raised multiple questions including methodological and statistical issues, randomization process, unclear end point definition, hamper the interpretation of results (9). In patients with ovarian cancer, improved progression-free survival (PFS) and overall survival (OS) have been documented in patients who underwent HIPEC during interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) (10,11). In patients with peritoneal metastasis arising from gastric cancer, CRS plus HIPEC was found to improve OS and recurrence-free survival when compared with CRS alone (12). In the CRS plus HIPEC and CRS alone groups, the authors reported 5-year OS rates of 19.87% and 6.43% (P=0.005), respectively, along with recurrence-free survival rates of 17.05% and 3.76% (P=0.001) (12). However, regarding the implementation of secondary CRS in patients with recurrent ovarian cancer, comparisons of HIPEC outcomes have not been reported.

The objective of the present study was to compare survival outcomes in patients with recurrent ovarian cancer who underwent secondary CRS with and without HIPEC. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-23-293/rc).

Methods

Study population

This retrospective study was conducted at Yonsei Cancer Center of Severance Hospital in South Korea between January 2006 and February 2021. We compared the outcomes of patients who underwent secondary CRS combined with HIPEC (secondary CRS-plus-HIPEC group) and those who underwent secondary CRS alone (secondary CRS-only group) in the first-relapse ovarian cancer group. Eligible patients were those diagnosed with ovarian, fallopian tubal, or peritoneal cancer who underwent primary debulking or IDS and had a history of recurrence. Figure 1 presents a flowchart of the patients. All patients were initially diagnosed according to the International Federation of Gynecology and Obstetrics (FIGO) stage. Most patients received platinum-based systemic chemotherapy after debulking surgery. All patients underwent CRS to remove visible tumors. The complexity of the procedures used during CRS was classified in accordance with previously published protocols as low [surgical complexity score (SCS) 1 to 3], intermediate (SCS 4 to 7), or high (SCS ≥8) (13). Complete resection was defined as the removal of all residual tumors, and optimal CRS was defined as a residual tumor measuring <1 cm. Patients who did not undergo surgery after the first recurrence but underwent subsequent surgery were excluded from the study inclusion.

Figure 1 Flow chart of patient enrollment. HIPEC, hyperthermic intraperitoneal chemotherapy.

HIPEC was performed using the open technique, and peritoneal fluid perfusion was performed for 90 min. Chemotherapy was performed using cisplatin (100 mg/m²) or paclitaxel (175 mg/m²), which was diluted in 3 L of a 1.5% dextrose solution for peritoneal dialysis. Initially, 3 L of heated perfusion solution was infused into the abdominal cavity at a rate of 800–1,000 mL/min through the inflow tube using a Belmont Hyperthermic Pump (Belmont Instrument Corporation, Billerica, MA, USA). Three intra-abdominal thermometers (one positioned in the pelvis and two in the diaphragm area) were used to monitor the temperature within the abdominal cavity during the infusion, maintained at 42 °C constantly (14,15).

This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was reviewed and approved by the Institutional Review Board at Severance Hospital, Yonsei University Health System, Seoul, Korea (IRB number: 4-2023-0443). Informed consent for this retrospective study was waived.

Outcomes

PFS was defined as the time from the date of disease progression to death from any cause. Progression of disease was clinically defined using the Response Evaluation Criteria in Solid Tumors, version 1.1 (16), or based on an increased CA 125 level exceeding the upper limit of the normal range. OS was defined as the time from diagnosis to death from any cause. Survival data were censored at the last contact or follow-up for surviving patients.

Statistical analysis

The Kaplan-Meier method and log-rank test were used to estimate and compare survival between the CRS-plus-HIPEC and CRS-only groups. Additional subgroup analysis (in epithelial ovarian cancer only) was performed using the Kaplan-Meier method and log-rank test. Statistical significance was set at P<0.05, and all statistical analyses were conducted using the SPSS statistical software (version 21.0; IBM Corp., Armonk, NY, USA).

Results

Patients

Between January 2006 and February 2021, 73 patients underwent CRS after recurrence at Yonsei Cancer Center. Of the 73 patients, 46 underwent CRS after the first recurrence. The secondary CRS-plus-HIPEC and secondary CRS-only groups comprised 20 and 26 patients, respectively. There were no significant differences in patient characteristics, including age, FIGO stage, histologic type, BRCA mutation, recurrence site, and chemotherapy regimen, between the two groups (Table 1). In both groups, the recurrence locations in the abdominal cavity were similar, there was no difference in surgical procedures, and surgery was performed optimally according to the recurrence sites. Of the 46 patients, most (89.1%) received platinum-based chemotherapy during the initial treatment prior to the first recurrence. Overall, 32.6% of patients received maintenance therapy with drugs such as bevacizumab or PARP inhibitors.

Outcomes

Of the 46 patients, 20 (43.5%) were assigned to the secondary CRS-plus-HIPEC group and 26 (56.5%) to the secondary CRS-only group. The median follow-up duration from recurrence to the last follow-up was 15.9 months. The median PFS was 32.7 and 25.1 months in the secondary CRS-plus-HIPEC and secondary CRS-only groups, respectively. The median OS was not achieved in either group. The Kaplan-Meier analysis revealed that HIPEC did not significantly impact PFS (P=0.587) or OS (P=0.239) (Figure 2). Of the 46 patients, 37 (80.4%) had epithelial ovarian cancer. Of these 37 patients, 15 (40.5%) were in the secondary CRS-plus-HIPEC group, and 22 (59.5%) were in the secondary CRS-only group.

Figure 2 Kaplan-Meier curves of PFS and OS according to HIPEC in patients who underwent secondary CRS (A,B). CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy; PFS, progression-free survival; OS, overall survival.

In the subgroup analyses of epithelial histologic type ovarian cancer, the median PFS was not reached in the secondary CRS-plus-HIPEC group and was 25.1 months in the secondary CRS-only group. The median OS was not achieved in either group. Based on the Kaplan-Meier analysis, HIPEC did not significantly impact PFS (P=0.244) and OS (P=0.352) (Figure 3). Of the 46 patients, 41 (89.1%) received platinum-based chemotherapy after primary cytoreduction. Of these 41 patients, 36 (87.8%) patients were sensitive to the initial platinum treatment. The median time to recurrence (defined as the time from the date of last chemotherapy done to first recurrence) was 27.4 months in platinum-sensitive group. In patients with platinum-sensitive recurrent, 32 (88.9%) patients experienced secondary platinum-sensitive recurrence. Most of the platinum-sensitive patients were still platinum-sensitive after secondary CRS with or without HIPEC.

Figure 3 Kaplan-Meier curves of PFS and OS according to HIPEC in patients who underwent secondary CRS in the subgroup analyses of epithelial ovarian cancer (A,B). CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy; PFS, progression-free survival; OS, overall survival.

Discussion

In the present study, we evaluated whether incorporating HIPEC into CRS has prognostic relevance in patients with recurrent ovarian cancer. In patients with recurrent ovarian cancer who underwent secondary CRS, HIPEC had no benefits in terms of PFS or OS. However, when analyzing a subgroup of patients with epithelial ovarian cancer, the addition of HIPEC to secondary CRS showed a greater tendency to improve PFS; no favorable tendency was observed in terms of OS.

A randomized study (7) has reported that CRS with systemic chemotherapy could improve OS when compared with systemic chemotherapy alone in patients with recurrent ovarian cancer; however, the trial was limited to complete macroscopic resections. Of the 407 patients, 206 were assigned to the surgery and chemotherapy groups and 201 to the chemotherapy-alone group. The CRS and chemotherapy group had a longer median OS than the chemotherapy-alone group (53.7 vs. 46.0 months, P=0.02). In another randomized trial, the PFS results revealed the benefits of adding secondary CRS to chemotherapy (17). Therefore, secondary CRS is an important treatment, similar to systemic chemotherapy, and complete resection is an important prognostic factor.

It is necessary to think about the feasibility of minimally invasive surgery like laparoscopic or robotic surgery when doing secondary CRS. The performance of minimally invasive surgery can be confirmed in previous studies on the safety and availability of minimally invasive surgery for optimal cytoreduction (18). However, since this is possible in localized recurrent ovarian cancer, which is a case of recurrence on a single nodule or single organ site (19), it would be meaningful to do the minimally invasive surgery in such a specific case. The BRCA status can be selection criterion in the application of CRS and HIPEC on patients with recurrent ovarian cancer. In recurrent ovarian cancer, BRCA status did not have a significant association with PFS after salvage lymphadenectomy (20), but after hepatic resection, PFS was significantly favorable (21). Therefore, we believe that the BRCA status can help us decide whether to apply cytoreduction and HIPEC.

HIPEC plays an important role in the treatment of advanced primary ovarian cancer. HIPEC was reportedly effective only in patients who underwent IDS after recent NAC (10). Hyperthermia can activate systemic immune responses by stimulating proteins that are immune modulators involved in innate and adaptive immune responses. In addition, HIPEC can activate proteins, thereby inducing the maturation of dendritic cells to enhance antitumor responses (22). The role of HIPEC in patients with recurrent ovarian cancer has been actively studied in recent years. In platinum-sensitive recurrent ovarian cancer, the use of CRS plus HIPEC with oxaliplatin (460 mg/m²) represents a safe treatment that can substantially influence survival rates when compared with chemotherapy alone or surgery plus standard chemotherapy (median disease-free survival and OS of 24 and 38 months, respectively) (23). However, this was a retrospective study with a small sample size, and oxaliplatin was used instead of cisplatin, which is mainly used in HIPEC of ovarian cancer patients. Spiliotis et al. (8) have reported the effectiveness of CRS with HIPEC followed by subsequent second- or third-line systemic chemotherapy in patients with recurrent ovarian cancer. The authors compared survival outcomes between the CRS followed by HIPEC and CRS-only groups. CRS with HIPEC significantly improved survival in patients with recurrent ovarian cancer (mean survival 26.7 vs. 13.4 months, P<0.006). However, this study raised multiple questions, including unclear end point definition, statistical analysis, and randomization process.

In the present study, we detected no significant difference in survival between the CRS-plus-HIPEC and CRS-only groups. Recently, maintenance therapies such as bevacizumab or PARP inhibitors have been used after CRS, followed by chemotherapy in advanced/recurrent ovarian cancer. Treatment with PARP inhibitors was shown to exert considerable survival benefits in primary or recurrent ovarian cancer, particularly in patients with BRCA mutations or similar genes associated with a defect in DNA repair, known as homologous recombination deficiency (24-27). Moreover, bevacizumab could improve PFS in patients with recurrent ovarian cancer (28-30). However, in the GOG 213 trial, the lack of survival benefit in the secondary CRS group, compared with the chemotherapy-only group, was attributed to treatment with bevacizumab (31). In the current study, 33% of patients received maintenance therapy after secondary CRS with or without HIPEC, which might partially explain the lack of any difference in survival rates between the CRS-plus-HIPEC and CRS-only groups.

This retrospective study has several limitations. First, the sample size was small, given the limited number of patients. Second, the follow-up period was short; therefore, a longer follow-up period could elucidate a relevant outcome. Notably, HIPEC could exert potential benefits in patients with recurrent epithelial ovarian cancer. Our study did not perform further analysis by subdividing patients according to BRCA mutation or homologous recombination deficiency. Accordingly, treatment outcomes might differ significantly between the two groups, although we did not detect any statistical difference between the two groups.

Further studies are needed to determine whether CRS and HIPEC can exert benefits following second, third, and subsequent recurrences. A longer follow-up period and larger sample size should be considered to comprehensively clarify the observed findings in patients with recurrent epithelial ovarian cancer who undergo secondary CRS with or without HIPEC.

Conclusions

In the current retrospective study, secondary CRS with HIPEC did not improve survival when compared with CRS without HIPEC in patients with recurrent ovarian cancer. However, when assessing a subgroup of patients with epithelial ovarian cancer, the addition of HIPEC to secondary CRS tended to improve PFS. Thus, HIPEC may be beneficial in patients with epithelial ovarian cancer.

Acknowledgments

Funding: This study was supported by a grant from the Industry-Academic Cooperation Foundation, Yonsei University, Shin Poong Pharmaceutical Co. Ltd. (No. 2022-31-1712).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-23-293/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-23-293/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-23-293/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-23-293/coif). All authors receive article processing charges from Shin Poong Pharmaceutical Co. Ltd. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was reviewed and approved by the Institutional Review Board at Severance Hospital, Yonsei University Health System, Seoul, Korea (IRB number: 4-2023-0443). Informed consent for this retrospective study was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sant M, Chirlaque Lopez MD, Agresti R, et al. Survival of women with cancers of breast and genital organs in Europe 1999-2007: Results of the EUROCARE-5 study. Eur J Cancer 2015;51:2191-205. [Crossref] [PubMed]
2. Kyrgiou M, Salanti G, Pavlidis N, et al. Survival benefits with diverse chemotherapy regimens for ovarian cancer: meta-analysis of multiple treatments. J Natl Cancer Inst 2006;98:1655-63. [Crossref] [PubMed]
3. Lee YJ, Lee JY, Nam EJ, et al. Rethinking Radical Surgery in Interval Debulking Surgery for Advanced-Stage Ovarian Cancer Patients Undergoing Neoadjuvant Chemotherapy. J Clin Med 2020;9:1235. [Crossref] [PubMed]
4. Cortez AJ, Tudrej P, Kujawa KA, et al. Advances in ovarian cancer therapy. Cancer Chemother Pharmacol 2018;81:17-38. [Crossref] [PubMed]
5. Morgan RJ Jr, Alvarez RD, Armstrong DK, et al. Ovarian cancer, version 2.2013. J Natl Compr Canc Netw 2013;11:1199-209. [Crossref] [PubMed]
6. Lee YJ, Woo HY, Kim YN, et al. Dynamics of the Tumor Immune Microenvironment during Neoadjuvant Chemotherapy of High-Grade Serous Ovarian Cancer. Cancers (Basel) 2022;14:2308. [Crossref] [PubMed]
7. Harter P, Sehouli J, Vergote I, et al. Randomized Trial of Cytoreductive Surgery for Relapsed Ovarian Cancer. N Engl J Med 2021;385:2123-31. [Crossref] [PubMed]
8. Spiliotis J, Halkia E, Lianos E, et al. Cytoreductive surgery and HIPEC in recurrent epithelial ovarian cancer: a prospective randomized phase III study. Ann Surg Oncol 2015;22:1570-5. [Crossref] [PubMed]
9. Harter P, Reuss A, Sehouli J, et al. Int J Gynecol Cancer 2017;27:246-7. [Crossref] [PubMed]
10. Lim MC, Chang SJ, Park B, et al. Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer: A Randomized Clinical Trial. JAMA Surg 2022;157:374-83. [Crossref] [PubMed]
11. van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med 2018;378:230-40. [Crossref] [PubMed]
12. Bonnot PE, Piessen G, Kepenekian V, et al. Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer With Peritoneal Metastases (CYTO-CHIP study): A Propensity Score Analysis. J Clin Oncol 2019;37:2028-40. [Crossref] [PubMed]
13. Aletti GD, Eisenhauer EL, Santillan A, et al. Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment. Gynecol Oncol 2011;120:23-8. [Crossref] [PubMed]
14. Lee YJ, Seon KE, Jung DC, et al. Interval debulking surgery with or without hyperthermic intraperitoneal chemotherapy in advanced-stage ovarian cancer: Single-institution cohort study. Front Oncol 2022;12:936099. [Crossref] [PubMed]
15. Lee YJ, Lee JY, Cho MS, et al. Incorporation of paclitaxel-based hyperthermic intraperitoneal chemotherapy in patients with advanced-stage ovarian cancer treated with neoadjuvant chemotherapy followed by interval debulking surgery: a protocol-based pilot study. J Gynecol Oncol 2019;30:e3. [Crossref] [PubMed]
16. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. [Crossref] [PubMed]
17. Shi T, Zhu J, Feng Y, et al. Secondary cytoreduction followed by chemotherapy versus chemotherapy alone in platinum-sensitive relapsed ovarian cancer (SOC-1): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2021;22:439-49. [Crossref] [PubMed]
18. Fagotti A, Petrillo M, Costantini B, et al. Minimally invasive secondary cytoreduction plus HIPEC for recurrent ovarian cancer: a case series. Gynecol Oncol 2014;132:303-6. [Crossref] [PubMed]
19. Gallotta V, Fagotti A, Fanfani F, et al. Laparoscopic surgical management of localized recurrent ovarian cancer: a single-institution experience. Surg Endosc 2014;28:1808-15. [Crossref] [PubMed]
20. Gallotta V, Bruno M, Conte C, et al. Salvage lymphadenectomy in recurrent ovarian cancer patients: Analysis of clinical outcome and BRCA1/2 gene mutational status. Eur J Surg Oncol 2020;46:1327-33. [Crossref] [PubMed]
21. Gallotta V, Conte C, D'Indinosante M, et al. Prognostic factors value of germline and somatic brca in patients undergoing surgery for recurrent ovarian cancer with liver metastases. Eur J Surg Oncol 2019;45:2096-102. [Crossref] [PubMed]
22. Oei AL, Vriend LEM, Krawczyk PM, et al. Targeting therapy-resistant cancer stem cells by hyperthermia. Int J Hyperthermia 2017;33:419-27. [Crossref] [PubMed]
23. Fagotti A, Costantini B, Vizzielli G, et al. HIPEC in recurrent ovarian cancer patients: morbidity-related treatment and long-term analysis of clinical outcome. Gynecol Oncol 2011;122:221-5. [Crossref] [PubMed]
24. Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 2018;379:2495-505. [Crossref] [PubMed]
25. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 2019;381:2391-402. [Crossref] [PubMed]
26. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med 2016;375:2154-64. [Crossref] [PubMed]
27. Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017;18:1274-84. [Crossref] [PubMed]
28. Aghajanian C, Goff B, Nycum LR, et al. Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol 2015;139:10-6. [Crossref] [PubMed]
29. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2017;18:779-91. [Crossref] [PubMed]
30. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 2014;32:1302-8. [Crossref] [PubMed]
31. Coleman RL, Spirtos NM, Enserro D, et al. Secondary Surgical Cytoreduction for Recurrent Ovarian Cancer. N Engl J Med 2019;381:1929-39. [Crossref] [PubMed]