Olivier Glehen

Intraperitoneal Nivolumab after Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy in Advanced Ovarian Cancer: A Phase I Study with Expansion Cohort

Abstract Purpose: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are expected to be synergistic with intraperitoneal (IP) immunotherapy by increasing tumor antigen expression and mutational load. We assessed the feasibility and safety of IP nivolumab following complete CRS and HIPEC in pretreated patients with recurrent ovarian cancer (ClinicalTrials.gov identifier: NCT03959761). Patients and Methods: Patients received IP nivolumab (0.5, 1, or 3 mg/kg) using a 3 + 3 dose-escalation design, starting 5 to 7 days after CRS and HIPEC. Four IP Q2W (once every 2 weeks) nivolumab infusions were planned. The primary objective was to demonstrate the feasibility of IP nivolumab based on dose-limiting toxicity. Secondary objectives were to assess changes in tolerance of CRS and HIPEC. Results: A total of 17 patients were enrolled including 10 patients in the dose escalation and 7 patients in the expansion phase. No dose-limiting toxicity was observed at any dose level in the 9 evaluable patients. Six of the 17 patients (35%) did not complete all planned infusions: 4 (23.5%) due to peritoneal catheter complications and 2 (11.8%) due to early progression. No procedure-related deaths occurred. Eleven patients (65%) experienced serious adverse events (SAE), mainly transitory grade 3 to 4 transaminase elevations (6/11) and surgery-related (9/11). Four SAEs were related to the peritoneal catheter and two to HIPEC. No SAEs/grade 3 to 4 adverse events related to IP nivolumab occurred. Conclusions: This is the first study demonstrating the feasibility of IP nivolumab in patients with relapsed advanced ovarian cancer. Further investigation at 3 mg/kg is warranted.

Distribution of residual disease in the peritoneum following neoadjuvant chemotherapy in advanced epithelial ovarian cancer and its potential therapeutic implications

Residual disease in 'normal appearing' peritoneum is seen in nearly 30% of the patients following neoadjuvant chemotherapy (NACT) for advanced ovarian cancer. The goal was to study the sequence of response in different regions, the commonest sites of occult residual disease, its incidence in different peritoneal regions and the potential therapeutic implications of these. This was a prospective multi-centre study (July 2018-June 2019). Pathological evaluation of cytoreductive surgery specimens was performed according to a fixed protocol. Prevalence of residual disease in different regions was used to study patterns of response and distribution of residual disease. In 85 patients treated between July 2018 to June 2019, microscopic disease in 'normal appearing' peritoneal regions was seen in 22 (25.2%) and in normal peritoneum around tumor nodules in 30 (35.2%) patients. Regions 4 and 8 of Sugarbaker's PCI had the highest incidence of occult disease and regions 9 and 10 the lowest. The response to chemotherapy occurred in a similar manner in over 95%- the least common site of residual disease was the small bowel mesentery, followed by upper regions (regions 1-3), omentum and middle regions (regions 0, 4, 8), lower regions (regions 5-7) and lastly the ovaries. During interval CRS, based on the disease mapping provided in this manuscript, regions that have a high probability of residual disease should be explored and dissected. Complete resection of involved the peritoneal region can completely address the occult disease. The role of resection of the entire region as well as 'normal appearing' parietal peritoneal regions should be prospectively evaluated.

Decision-Making Analysis for Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer: A Survey by the Executive Committee of the Peritoneal Surface Oncology Group International (PSOGI)

<b><i>Objectives:</i></b> To assess the individual treatment strategies among international experts in peritoneal carcinosis, specifically their decision-making in the process of patient selection for hyperthermic intraperitoneal chemotherapy (HIPEC) in women suffering from ovarian cancer, to identify relevant decision-making criteria, and to quantify the level of consensus for or against HIPEC. <b><i>Methods:</i></b> The members of the executive committee of the Peritoneal Surface Oncology Group International (PSOGI) were asked to describe the clinical conditions under which they would recommend HIPEC in patients with ovarian cancer and to describe any disease or patient characteristics relevant to their decision. All answers were then merged and converted into decision trees. The decision trees were then analyzed by applying the objective consensus methodology. <b><i>Results:</i></b> Nine experts in surgical oncology provided information on their multidisciplinary treatment strategy including HIPEC for patients with advanced ovarian cancer. Three of the total of 12 experts did not perform HIPEC. Five criteria relevant to the decision on whether HIPEC is performed were applied. In patients with resectable disease, a peritoneal cancer index (PCI) <21, and epithelial ovarian cancer without distant metastasis, consent was received by 75% to perform HIPEC for women suffering from recurrent disease. Furthermore, in the primary disease setting, consent was received by 67% to perform HIPEC according to the same criteria. <b><i>Discussion and Conclusion:</i></b> Among surgical oncology experts in peritoneal surface malignancy and HIPEC, HIPEC plays an important role in primary and recurrent ovarian cancer, and the PCI is the most important criterion in this decision.

Extent and distribution of peritoneal disease in patients undergoing cytoreductive surgery for first platinum sensitive recurrence in ovarian cancer and its potential therapeutic implications

Selected patients with platinum sensitive recurrent ovarian cancer may benefit from cytoreductive surgery (CRS). The aim was to study the pattern of peritoneal involvement in these patients that has not been done before. A comparison was made between the surgical and pathological findings in 60 patients undergoing salvage CRS from July 2018 to December 2019. The sites of residual disease, correlation with surgical and pathological peritoneal cancer index (PCI), small bowel involvement and regional lymph node involvement were studied. Fifty-eight (96.6%) had serous carcinoma and 2 (3.4%) clear cell carcinoma. The median surgical PCI (sPCI) was 7 [range 0-27] and median pathological PCI (pPCI) 4 [range 0-21]. CC-0 resection was performed in 81.6%. The upper regions (region 1,2,3) were the commonest sites of residual disease (63.3%) followed by lower regions (region 5,6,7) in 55.0%, middle regions (regions 0,4,8) in 53.3% and small bowel regions (regions 9-12) in 26.6%. Small bowel involvement was associated with a higher sPCI and pPCI (p < 0.001 for both). Regional nodes were involved in 46.6%. A pathological complete response was seen in 8 (13.3%) patients of which 2 had residual disease in regional nodes. Microscopic disease in 'normal appearing' peritoneum was seen in 21%. The parietal peritoneum was the commonest site of recurrence. Small bowel involvement occurred late and was associated with more extensive disease. Regional lymph node involvement was seen nearly 50% and was a common site for occult disease. The role of more extensive parietal peritoneal resection for recurrent disease should be evaluated prospectively.

Feasibility of ERAS guidelines for cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (CRS-HIPEC): An international multicenter study

Enhanced Recovery After Surgery (ERAS) protocols aim to optimize perioperative care and improve recovery after major surgery. While ERAS pathways are well established in several oncologic disciplines, their feasibility and consistency in the setting of cytoreductive surgery, with or without hyperthermic intraperitoneal chemotherapy (CRS ± HIPEC), remain uncertain due to the complexity and heterogeneity of these procedures. A prospective multicenter observational study was conducted across 10 expert CRS-HIPEC centers to assess the feasibility and real-world implementation of the ERAS Society guidelines for cytoreductive surgery, with or without hyperthermic intraperitoneal chemotherapy. Perioperative practices were compared before (PRE-ERAS) and after (POST-ERAS) structured ERAS guideline implementation. ERAS adherence, clinical outcomes, and predictors of 90-day postoperative complications and prolonged length of stay were analyzed using multivariable logistic regression models. In addition, a predefined subgroup analysis compared outcomes between ovarian and non-ovarian primary tumors. Between 2021 and 2022, 497 patients were included (PRE-ERAS: 288; POST-ERAS: 209). Baseline characteristics were similar except for more ovarian primaries in POST-ERAS (26.4% vs 44%, p = 0.004). POST-ERAS patients showed higher adherence to anemia screening (60% vs 69%, p = 0.042), carbohydrate loading (4% vs 30%, p 70% ERAS adherence (OR 0.19, 95% CI 0.06-0.54, p = 0.003) predicted fewer complications. Ovarian primary (OR 0.50, 95% CI 0.28-0.87, p = 0.016), >70% adherence (OR 0.33, 95% CI 0.12-0.82, p = 0.025), and POST-ERAS status (OR 0.61, 95% CI 0.37-0.99, p = 0.046) correlated with shorter LOS. ERAS implementation for CRS ± HIPEC shortened hospital stay but remained incomplete and was associated with increased readmissions, without reducing complication rates. These findings highlight the need to focus on a pragmatic set of high-impact ERAS elements to improve feasibility in complex cytoreductive surgery.

Tolerance of Intraperitoneal (IP) Nivolumab After Extensive Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients With Advanced Ovarian Carcinoma

Spread pattern, the lack of alternative treatments, and emerging data on the activity of anti-Programmed death ligand 1 (PDL1) targeted checkpoint inhibitor therapy in gynecological cancers provide the rationale for this investigation. Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) are likely to increase the tumor-antigen expression and the mutational load. As a result, it would be interesting to combine this approach with immunotherapy. Moreover, Intraperitoneal (IP) infusion will directly target the peritoneal cavity and potentially enhance the immune response. Indeed some recent papers indicate that the peritoneum could be considered as a lymphoid organ, involving "milky spots", thus able to produce a better immune response when immunotherapy is given by IP route rather than intravenous (IV) route. The investigating team in Lyon, France is one of the major groups for HIPEC research in Europe (Pr O. Glehen et al) - Reference center for the tumors of the peritoneum (French National Cancer Institute). The aim of this study is to assess in this I/II phase study, the feasibility of extensive debulking surgery and HIPEC followed by Intraperitoneal (IP) nivolumab dose escalation in patients with advanced ovarian carcinoma.