Number of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Treatments is Associated with Longer Survival: Analysis of a Large Prospective Cohort of Patients With Unresectable Peritoneal Surface Malignancies.

OBJECTIVE: To analyze the reasons for stopping pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivered for unresectable peritoneal surface malignancies (PSM) and to determine survival in a large patient cohort of an experienced PIPAC center. BACKGROUND: PIPAC alone or combined with systemic chemotherapy was developed to palliatively treat unresectable PSM. Safety, tolerance and promising survival results were already reported, but the reasons for stopping treatment remain unclear and the influence of the number of PIPAC procedures on prognosis has not been evaluated. METHODS: A retrospective analysis of PIPAC procedures from a prospectively maintained single institution PSM database was conducted from January 2016 to January 2023. RESULTS: A total of 346 patients underwent 1200 PIPAC treatments in the defined time period. Two-thirds of the patients completed 3 or more PIPAC procedures, and 2 patients had more than 15 treatment procedures. Reasons for PIPAC cessation were disease progression or complication (56%), reorientation to a potential curative procedure (19%), surgical complications of the procedure (13%), death between procedures (8%) and patient request (3%). PSM origin and receiving 3 or more PIPAC treatments were independently correlated with better survival in the overall population, in the group of ultimately unresectable PSM and after propensity score weighting. CONCLUSION: The main reason for stopping PIPAC treatment in palliative management of PSM is disease progression. When 3 or more PIPAC procedures can be delivered in combination to systemic chemotherapy, survival is significantly improved. Its use should be validated by prospective studies.

Metastatic Colorectal Cancer Treated with Combined Liver Resection, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Predictive Factors for Early Recurrence.

BACKGROUND: Selection of colorectal cancer patients with concomitant peritoneal (PM) and liver metastases (LM) for radical treatment with cytoreductive surgery (CRS), including liver resection and hyperthermic intraperitoneal chemotherapy (HIPEC), needs improvement. This retrospective, monocentric study was designed to evaluate the predictive factors for early recurrence, disease-free survival (DFS), and overall survival (OS) in such patients treated in a referral center. METHODS: Consecutive colorectal cancer patients with concomitant LM and PM treated with curative intent with perioperative systemic chemotherapy, simultaneous complete CRS, liver resection, and HIPEC in 2011-2022 were included. Clinical, radiological (before and after preoperative chemotherapy), surgical, and pathological data were investigated, along with long-term oncologic outcomes. A multivariate analysis was performed to identify predictive factors associated with early recurrence (diagnosed <6 months after surgery), DFS, and OS. RESULTS: Of more than 61 patients included, 31 (47.1%) had pT4 and 27 (40.9%) had pN2 primary tumors. Before preoperative chemotherapy, the median number of LM was 2 (1-4). The median surgical PCI (peritoneal carcinomatosis index) was 3 (5-8.5). The median DFS and OS were 8.15 (95% confidence interval [CI] 5.5-10.1) and 34.1 months (95% CI 28.1-53.5), respectively. In multivariate analysis, pT4 (odds ratio [OR] = 4.14 [1.2-16.78], p = 0.032]) and pN2 (OR = 3.7 [1.08-13.86], p = 0.042) status were independently associated with an early recurrence, whereas retroperitoneal lymph node metastasis (hazard ratio [HR] = 39 [8.67-175.44], p < 0.001) was independently associated with poor OS. CONCLUSIONS: In colorectal cancer patients with concomitant PM and LM, an advanced primary tumor (pT4 and/or pN2) was associated with a higher risk of early recurrence following a radical multimodal treatment, whereas RLN metastases was strongly detrimental for OS.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy to Treat Pseudomyxoma Peritonei of Ovarian Origin: A Retrospective French RENAPE Group Study.

BACKGROUND: Ovarian pseudomyxoma peritonei (OPMP) are rare, without well-defined therapeutic guidelines. We aimed to evaluate cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) to treat OPMP. METHODS: Patients from the French National Network for Rare Peritoneal Tumors (RENAPE) database with proven OPMP treated by CRS/HIPEC and with histologically normal appendix and digestive endoscopy were retrospectively included. Clinical and follow-up data were collected. Histopathological and immunohistochemical features were reviewed. RESULTS: Fifteen patients with a median age of 56 years were included. The median Peritoneal Cancer Index was 16. Following CRS, the completeness of cytoreduction (CC) score was CC-0 for 9/15 (60%) patients, CC-1 for 5/15 (33.3%) patients, and CC-2 for 1/15 (6.7%) patients. The median tumor size was 22.5 cm. After pathological review and immunohistochemical studies, tumors were classified as Group 1 (mucinous ovarian epithelial neoplasms) in 3/15 (20%) patients; Group 2 (mucinous neoplasm in ovarian teratoma) in 4/15 (26.7%) patients; Group 3 (mucinous neoplasm probably arising in ovarian teratoma) in 5/15 (33.3%) patients; and Group 4 (non-specific group) in 3/15 (20%) patients. Peritoneal lesions were OPMP pM1a/acellular, pM1b/grade 1 (hypocellular) and pM1b/grade 3 (signet-ring cells) in 13/15 (86.7%), 1/15 (6.7%) and 1/15 (6.7%) patients, respectively. Disease-free survival analysis showed a difference (p = 0.0463) between OPMP with teratoma/likely-teratoma origin (groups 2 and 3; 100% at 1, 5, and 10 years), and other groups (groups 1 and 4; 100%, 66.6%, and 50% at 1, 5, and 10 years, respectively). CONCLUSION: These results suggested that a primary therapeutic strategy using complete CRS/HIPEC for patients with OPMP led to favorable long-term outcomes.

Eliminating the need for preoperative intravenous hyperhydration: Sodium thiosulfate as nephrotoxicity prevention in HIPEC-treated patients - A retrospective analysis.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment for peritoneal metastases. However, HIPEC with cisplatin is associated with renal toxicity. Sodium thiosulfate (ST) has been shown to prevent cisplatin-induced toxicity. METHODS: A retrospective, single-center analysis of patients treated curatively for peritoneal surface malignancy, who underwent cytoreductive surgery with cisplatin-based HIPEC between 2015 and 2020. Patients were categorized into three groups based on the management of cisplatin-induced renal toxicity: preoperative hyperhydration alone (PHH), preoperative hyperhydration with ST (PHH + ST), and ST alone. Renal function and complications, in terms of Acute (AKI) and chronic kidney injury (CKI), were monitored and analyzed during 3 postoperative months. RESULTS: This study included 220 consecutive patients. Mean serum creatinine levels were 95, 57 and 61 mmol/L, for PHH, PHH + ST and ST groups, respectively (p < 0.001). Glomerular Filtration Rate (GFR) were 96, 94 and 78 ml/min/1.73 m2, respectively (p < 0.001). AKI and CKI are respectively for PHH, PHH + ST and ST groups were 21 % (n = 46), 1 % (n = 2) and 0 % vs 19 % (n = 42), 0 % and 0 % (p < 0.001), for pairwise analysis did not show any difference between PHH + ST and ST alone combination, regarding nephrological outcomes. All patients were followed 3 months postoperatively. CONCLUSION: There is no need for preoperative hyperhydration when sodium-thiosulfate is used to prevent cisplatin-induced nephrotoxicity in patients undergoing cytoreductive surgery with HIPEC. These findings have implications for improving and simplifying the management of patients with peritoneal metastases undergoing HIPEC with cisplatin.

PIPAC in patients with peritoneal metastases from gastrointestinal tract (PIPOX01): An open label, non-comparative phase 1/2 dose escalation and expansion trial.

BACKGROUND: Despite modern systemic chemotherapy, survival remains poor for patients with advanced isolated peritoneal metastases from the gastrointestinal tract. We aimed to assess the safety and efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with oxaliplatin. PATIENTS AND METHODS: We conducted a phase 1/2, open label, non-comparative, dose escalation and expansion trial of PIPAC with oxaliplatin in patients with a peritoneal cancer index (PCI) of more than 5, 13 and 15 for respectively a gastric, small bowel and colorectal primary cancer, and who had received at least three months of systemic chemotherapy. PIPAC cycle lengths were 4-6 weeks with systemic chemotherapy allowed 15 days after each PIPAC. PCI and oxaliplatin tumor concentration were assessed every PIPAC cycle. The main endpoints were tolerability, tumor response, and survival. RESULTS: Between 2017 and 2020, 34 patients were enrolled in three centers, in this phase 1/2 study, of whom 25 were evaluable at the recommended dose determined in the phase I trial (90 mg/m2 plus systemic 5-FU). Before inclusion, patients received a median of 2 [1-4] chemotherapy lines and had a median PCI of 22.5 [7-29]. At this dose, the safety profile showed acceptable tolerability. Eight patients (32 %) had grade 3/4 treatment-related adverse events. Minor (grade 1/2) adverse events were mainly abdominal pain (n = 19, 76 %) and nausea (n = 16, 64 %). Median PFS was 6.1 months and median OS was 13 months. CONCLUSION: In patients with advanced and refractory peritoneal metastasis, PFS of 6.1 months is encouraging. A prospective randomized phase II study is required.

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

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.

Hyperthermic intraperitoneal chemotherapy in colorectal cancer.

BACKGROUND: This study evaluated the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer with peritoneal metastases (pmCRC) in a large international data set of patients. PATIENTS AND METHODS: Patients with pmCRC from 39 centres who underwent cytoreductive surgery with HIPEC between 1991 and 2018 were selected and compared for the HIPEC protocols received-oxaliplatin-HIPEC versus mitomycin-HIPEC. Following analysis of crude data, propensity-score matching (PSM) and Cox-proportional hazard modelling were performed. Outcomes of interest were overall survival (OS), recurrence-free survival (RFS) and the HIPEC dose-response effects (high versus low dose, dose intensification and double drug protocols) on OS, RFS and 90-day morbidity. Furthermore, the impact of the treatment time period was assessed. RESULTS: Of 2760 patients, 2093 patients were included. Median OS was 43 months (95% c.i. 41 to 46 months) with a median RFS of 12 months (95% c.i. 12 to 13 months). The oxaliplatin-HIPEC group had an OS of 47 months (95% c.i. 42 to 53 months) versus 39 months (95% c.i. 36 to 43 months) in the mitomycin-HIPEC group (P = 0.002), aHR 0.77, 95% c.i. 0.67 to 0.90, P < 0.001. The OS benefit persisted after PSM of the oxaliplatin-HIPEC group and mitomycin-HIPEC group (48 months (95% c.i. 42 to 59 months) versus 40 months (95% c.i. 37 to 44 months)), P < 0.001, aHR 0.78 (95% c.i. 0.65 to 0.94), P = 0.009. Similarly, matched RFS was significantly higher for oxaliplatin-HIPEC versus others (13 months (95% c.i. 12 to 15 months) versus 11 months (95% c.i. 10 to 12 months, P = 0.02)). High-dose mitomycin-HIPEC protocols had similar OS compared to oxaliplatin-HIPEC. HIPEC dose intensification within each protocol resulted in improved survival. Oxaliplatin + irinotecan-HIPEC resulted in the most improved OS (61 months (95% c.i. 51 to 101 months)). Ninety-day mortality in both crude and PSM analysis was worse for mitomycin-HIPEC. There was no change in treatment effect depending on the analysed time period. CONCLUSIONS: Oxaliplatin-based HIPEC provided better outcomes compared to mitomycin-based HIPEC. High-dose mitomycin-HIPEC was similar to oxaliplatin-HIPEC. The 90-day mortality difference favours the oxaliplatin-HIPEC group. A trend for dose-response between low- and high-dose HIPEC was reported.