2022 Peritoneal Surface Oncology Group International Consensus on HIPEC Regimens for Peritoneal Malignancies: Colorectal Cancer.

BACKGROUND: Selected patients with peritoneal metastases of colorectal cancer (PM-CRC) can benefit from potentially curative cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC), with a median overall survival (OS) of more than 40 months. OBJECTIVE: The aims of this evidence-based consensus were to define the indications for HIPEC, to select the preferred HIPEC regimens, and to define research priorities regarding the use of HIPEC for PM-CRC. METHODS: The consensus steering committee elaborated and formulated pertinent clinical questions according to the PICO (patient, intervention, comparator, outcome) method and assessed the evidence according to the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Standardized evidence tables were presented to an international expert panel to reach a consensus (4-point, weak and strong positive/negative) on HIPEC regimens and research priorities through a two-round Delphi process. The consensus was defined as ≥ 50% agreement for the 4-point consensus grading or ≥ 70% for either of the two combinations. RESULTS: Evidence was weak or very weak for 9/10 clinical questions. In total, 70/90 eligible panelists replied to both Delphi rounds (78%), with a consensus for 10/10 questions on HIPEC regimens. There was strong negative consensus concerning the short duration, high-dose oxaliplatin (OX) protocol (55.7%), and a weak positive vote (53.8-64.3%) in favor of mitomycin-C (MMC)-based HIPEC (preferred choice: Dutch protocol: 35 mg/m2, 90 min, three fractions), both for primary cytoreduction and recurrence. Determining the role of HIPEC after CRS was considered the most important research question, regarded as essential by 85.7% of the panelists. Furthermore, over 90% of experts suggest performing HIPEC after primary and secondary CRS for recurrence > 1 year after the index surgery. CONCLUSIONS: Based on the available evidence, despite the negative results of PRODIGE 7, HIPEC could be conditionally recommended to patients with PM-CRC after CRS. While more preclinical and clinical data are eagerly awaited to harmonize the procedure further, the MMC-based Dutch protocol remains the preferred regimen after primary and secondary CRS.

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.

The 2022 PSOGI International Consensus on HIPEC Regimens for Peritoneal Malignancies: Methodology.

BACKGROUND: A group of experts from the Peritoneal Surface Oncology Group International (PSOGI) and the BIG-RENAPE group carried out a consensus among surgeons experienced in treating peritoneal malignancies from around the world to derive recommendations on indications of hyperthermic intraperitoneal chemotherapy (HIPEC), choice and details of HIPEC regimens, and areas for future research. This manuscript describes the methodology of achieving this consensus and the degree of participation of experts. METHODS: The Delphi technique was used and the questionnaire comprised three categories: evidence-based recommendations using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system with the PICO (patient, intervention, comparison, and outcome) method, an opinion survey, and research recommendations. A consensus was achieved if any one option had >50% of votes, or positive or negative recommendations combined had > 70% of votes. RESULTS: Of the 145 experts solicited, 71.1% in round I and 72.2% in round II took the survey. Participation was highest among surgeons treating both gastrointestinal and gynecological malignancies. Of 113 questions, after round I, a consensus was achieved for 72 (63.7%) questions, and after the second round, consensus was achieved for another 22 (19.4%) questions, making a total of 94 (83.1%) questions for which a consensus was achieved. CONCLUSION: This consensus was carried out using a thorough review of literature and robust rating of evidence, and included key experts and opinion leaders from across the world. The results could guide clinicians on the use of HIPEC, both in their day-to-day clinical practice and in designing clinical trials.

The 2022 PSOGI International Consensus on HIPEC Regimens for Peritoneal Malignancies: Epithelial Ovarian Cancer.

BACKGROUND AND AIM: We report the results of an international consensus on hyperthermic intraperitoneal chemotherapy (HIPEC) regimens for epithelial ovarian cancer (EOC) performed with the following goals: To define the indications for HIPEC To identify the most suitable HIPEC regimens for each indication in EOC To identify areas of future research on HIPEC To provide recommendations for some aspects of perioperative care for HIPEC METHODS: The Delphi technique was used with two rounds of voting. There were three categories of questions: evidence-based recommendations [using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system with the patient, intervention, comparator, and outcome (PICO) method], an opinion survey, and research recommendations. RESULTS: Seventy-three (67.5%) of 108 invited experts responded in round I, and 68 (62.9%) in round II. Consensus was achieved for 34/38 (94.7%) questions. However, a strong positive consensus that would lead to inclusion in routine care was reached for only 6/38 (15.7%) questions. HIPEC in addition to interval cytoreductive surgery (CRS) received a strong positive recommendation that merits inclusion in routine care. Single-agent cisplatin was the only drug recommended for routine care, and OVHIPEC-1 was the most preferred regimen. The panel recommended performing HIPEC for a minimum of 60 min with a recommended minimum intraabdominal temperature of 41°C. Nephroprotection with sodium thiosulfate should be used for cisplatin HIPEC. CONCLUSIONS: The results of this consensus should guide clinical decisions on indications of HIPEC and the choice and various parameters of HIPEC regimens and could fill current knowledge gaps. These outcomes should be the basis for designing future clinical trials on HIPEC in EOC.

Comparison of Neoadjuvant Systemic Chemotherapy Protocols for the Curative-Intent Management of Peritoneal Metastases from Colorectal Cancer, Regarding Morphological Response, Pathological Response, and Long-Term Outcomes: A Retrospective Study.

BACKGROUND: Selected patients with colorectal cancer peritoneal metastases (CRPM) could be offered a curative-intent strategy based on complete cytoreductive surgery (CRS), potentially combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and perioperative systemic chemotherapy. The impact of different neoadjuvant systemic chemotherapy (NACT) regimens remains unclear due to a lack of comparative data. METHODS: Consecutive CRPM patients from a monocentric database who were treated with complete CRS after single-line NACT were included in this study. Chemotherapy regimens were tailored as a doublet drug (FOLFOX/FOLFIRI) with/without targeted therapy (anti-epidermal growth factor receptor/bevacizumab) and triplet-drug combination (FOLFIRINOX). Morphological response (MR) was assessed using the Response Evaluation Criteria in Solid Tumors criteria, and pathological response (PR) was assessed using the Peritoneal Regression Grading Score (PRGS). Long-term oncologic outcomes were compared. RESULTS: The cohort comprised 388 patients, including 127, 202, and 59 patients in the doublet, doublet + targeted, and triplet groups, respectively. MR rates were higher in the triplet (68.0%) and doublet + targeted groups (64.2%) when compared with the doublet group (42.4%, p = 0.003). Complete and major PRs were observed in 13.6% and 32.0% of patients, respectively. Higher MR rates were observed after doublet + targeted or triplet regimens, while no difference was observed for PR rates. In multivariate analysis, FOLFIRINOX was independently associated with better overall survival (hazard ratio 0.49, 95% confidence interval 0.25-0.96; p = 0.037). FOLFIRINOX also resulted in a higher rate of severe postoperative complications. CONCLUSIONS: In this retrospective study, a FOLFIRINOX regimen as NACT seemed to result in better long-term outcomes for CRPM patients after complete CRS/HIPEC, although with higher morbidity. Prospective studies are needed, including groups without NACT and those with FOLFIRINOX + bevacizumab.

Influence of Extraperitoneal Metastases on the Curative-Intent Management of Colorectal Peritoneal Metastases.

BACKGROUND: Selected patients with colorectal cancer peritoneal metastasis (CRPM) and extraperitoneal disease could be treated radically with a multimodal approach combining complete cytoreductive surgery, thermoablation, radiotherapy, and systemic and intraperitoneal chemotherapy. The impact of extraperitoneal metastatic sites (EPMS) in this setting remains unclear. PATIENTS AND METHODS: Patients with CRPM undergoing complete cytoreduction in 2005-2018 were grouped in: peritoneal disease only (PDO), one EPMS (1 + EPMS), two or more EPMS (2 + EPMS). A retrospective analysis compared overall survival (OS) and postoperative outcomes. RESULTS: Of 433 patients, 109 had 1 + EPMS and 31 had 2 + EPMS. Overall, 101 patients had liver metastasis, 19 lung metastasis, and 30 retroperitoneal lymph node (RLN) invasion. The median OS was 56.9 months. There was no significant OS difference between PDO and 1 + EPMS groups (64.6 and 57.9 months, respectively), whereas OS was lower in the 2 + EPMS group (29.4 months, p = 0.005). In multivariate analysis, 2 + EPMS [hazard ratio (HR) 2.86, 95% confidence interval (CI) 1.33-6.12, p = 0.007], Sugarbaker's Peritoneal Carcinomatosis Index (PCI) > 15 (HR 3.86, 95% CI 2.04-7.32, p < 0.001), poorly differentiated tumors (HR 2.62, 95% CI 1.21-5.66, p = 0.015), and BRAF mutation (HR 2.10, 95% CI 1.11-3.99, p = 0.024) were independent poor prognostic factors, while adjuvant chemotherapy was beneficial (HR 0.33, 95% CI 0.20-0.56, p < 0.001). Patients with liver resection did not show higher severe complication rates. CONCLUSION: In patients with CRPM selected for a radical surgical approach, limited extraperitoneal disease involving one site, notably the liver, does not seem to significantly impair postoperative results. RLN invasion appeared as a poor prognostic factor in this population.

Delaying Surgery After Neoadjuvant Chemotherapy Affects Survival in Patients with Colorectal Peritoneal Metastases: A BIG-RENAPE Network Multicentric Study.

BACKGROUND: Multimodal treatment for patients with peritoneal metastases (PM) from colorectal cancer (CRC), including perioperative chemotherapy (CT) plus complete resection, is associated with prolonged survival. The oncologic impact of therapeutic delays is unknown. OBJECTIVE: The aim of this study was to assess the survival impact of delaying surgery and CT. METHODS: Medical records from the national BIG RENAPE network database of patients with complete cytoreductive (CC0-1) surgery of synchronous PM from CRC who received at least one neoadjuvant CT cycle plus one adjuvant CT cycle were retrospectively reviewed. The optimal interval between the end of neoadjuvant CT to surgery, surgery to adjuvant CT, and total interval without systemic CT were estimated using Contal and O'Quigley's method plus restricted cubic spline methods. RESULTS: From 2007 to 2019, 227 patients were identified. After a median follow-up of 45.7 months, the median overall survival (OS) and progression-free survival (PFS) was 47.6 and 10.9 months, respectively. The best cut-off period was 42 days in the preoperative interval, no cut-off period was optimal in the postoperative interval, and the best cut-off period in the total interval without CT was 102 days. In multivariate analysis, age, biologic agent use, high peritoneal cancer index, primary T4 or N2 staging, and delay to surgery of more than 42 days (median OS 63 vs. 32.9 months; p = 0.032) were significantly associated with worse OS. Preoperative delay of surgery was also significantly associated with PFS, but only in univariate analysis. CONCLUSION: In selected patients undergoing complete resection plus perioperative CT, a period of more than 6 weeks from completion of neoadjuvant CT to cytoreductive surgery was independently associated with worse OS.

Role of Hyperthermic Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery as Consolidation Therapy for Advanced Epithelial Ovarian Cancer.

BACKGROUND: Patients with advanced epithelial ovarian cancer who undergo incomplete surgery followed by six cycles of chemotherapy could benefit from second-look or consolidation cytoreductive surgery (CCRS). The primary goal of this study was to evaluate the overall survival (OS) in patients undergoing complete CCRS and the factors affecting survival. The secondary goal was to study the benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. METHODS: This was a retrospective analysis of 173 patients with CCRS with (n = 118) or without (n = 55) HIPEC treated at 12 French centers. Only patients having a completeness of cytoreduction (CC) 0/1 resection and a minimum of 5 years of follow-up were included. HIPEC was performed systematically for all patients except those treated at the four centers that did not perform HIPEC. RESULTS: The median Peritoneal Cancer Index was 6 (range 0-33). Closed HIPEC was performed in 59 (34.1%) patients and open HIPEC was performed in 56 (32.3%) patients. Grade 3-4 complications occurred in 64 (36.9%) patients. The median OS was 35.67 months (95% confidence interval [CI] 29.8-46.1) and was significantly longer for CCRS + HIPEC (31.4 months without HIPEC and 42.5 months with HIPEC; p = 0.022). On multivariate analysis, closed HIPEC (hazard ratio [HR] 0.46, 95% CI 0.29-0.73; p < 0.001) resulted in a longer OS, and age > 65 years (HR 2.17, 95% CI 1.14-4.11; p = 0.018) and bowel resection (HR 1.98, 95% CI 1.27-3.08; p = 0.020) led to a shorter OS. On multivariate logistic regression analysis, closed HIPEC (odds ratio 0.18; p = 0.001) was associated with a lower risk of dying at 5 years. CONCLUSIONS: CCRS was performed with an acceptable morbidity and resulted in good overall survival. The role of HIPEC in addition to CCRS should be evaluated in prospective, randomized studies and the closed technique prospectively compared with the open technique.

Chronic Exposure to Secondary Organic Aerosols Causes Lung Tissue Damage.

Recently, secondary organic aerosols (SOAs) emerged as a predominant component of fine particulate matter. However, the pathogenic mechanism(s) of SOAs are still poorly understood. Herein, we show that chronic exposure of mice to SOAs resulted in lung inflammation and tissue destruction. Histological analyses found lung airspace enlargement associated with massive inflammatory cell recruitment predominated by macrophages. Concomitant with such cell influx, our results found changes in the levels of a series of inflammatory mediators in response to SOA. Interestingly, we observed that the expression of the genes encoding for TNF-α and IL-6 increased significantly after one month of exposure to SOAs; mediators that have been largely documented to play a role in chronic pulmonary inflammatory pathologies. Cell culture studies confirmed these in vivo findings. Of importance as well, our study indicates increased matrix metalloproteinase proteolytic activity suggesting its contribution to lung tissue inflammation and degradation. Our work represents the first in vivo study, which reports that chronic exposure to SOAs leads to lung inflammation and tissue injury. Thus, we hope that these data will foster new studies to enhance our understanding of the underlying pathogenic mechanisms of SOAs and perhaps help in the design of therapeutic strategies against SOA-mediated lung injury.

Negative-Pressure Wound Therapy for Open Abdomen in Surgical Reintervention after Curative Surgery of Peritoneal Malignancy Increases the Risk of Recurrence.

OBJECTIVE: Negative-pressure wound therapy for open abdomen (NPWTOA) helps reduce the risk of abdominal compartment syndrome. However, the risk of recurrence of cancer is unclear when NPWTOA is applied after oncologic resection. The aim of this study was to evaluate the effects of NPWTOA used for major complications on patients treated with cytoreductive surgery for peritoneal malignancy (PM). METHODS: All patients who underwent an NPWTOA after potentially curative surgery of PM in a single institution were included. These patients were pair matched 1:3 on the Peritoneal Cancer Index, completeness of cytoreduction using a scoring index, and PM origin with patients who underwent surgical reintervention without NPWTOA after curative surgery of PM. Survival among the two groups was compared using the Kaplan-Meier method. RESULTS: Between 2011 and 2017, among 719 curative surgeries for PM, 13 patients underwent an NPWTOA after surgical reintervention. Researchers paired 9 of these patients to 27 others without NPWTOA after surgical reintervention. Median overall survival was 4.8 and 35 months (P = .391), and median disease-free survival was 4.0 and 13.9 months (P = .022) for the NPWTOA and non-NPWTOA groups, respectively. CONCLUSIONS: The use of the NPWTOA during surgical reintervention after curative surgery for PM may increase the risk of early recurrence.

RAS/TP53 Co-mutation is Associated With Worse Survival After Concurrent Resection of Colorectal Liver Metastases and Extrahepatic Disease.

OBJECTIVE: To determine if tumor genetics are associated with overall survival (OS) after concurrent resection of colorectal liver metastases (CLM) and extrahepatic disease (EHD). SUMMARY BACKGROUND DATA: The prognosis for patients who undergo concurrent resection of CLM/EHD is unclear and the impact of somatic mutations has not been reported. METHODS: Patients undergoing concurrent resection of CLM and EHD from 2007 to 2017 were identified from 2 academic centers. From 1 center, patients were selected from a pre-existing database of patients undergoing cytore-ductive surgery with hyperthermic intraperitoneal chemotherapy. The Kaplan-Meier method was used to construct survival curves, compared using the log-rank test. Multivariable Cox analysis for OS was performed. RESULTS: One hundred nine patients were included. Most common EHD sites included lung (33 patients), peritoneum (32), and portal lymph nodes (14). TP53 mutation was the most common mutation, identified in 75 patients (69%), and RAS/TP53 co-mutation was identified in 31 patients (28%). The median OS was 49 months (interquartile range, 24-125), and 3- and 5-year OS rates were 66% and 44%, respectively. Compared to patients without RAS/ TP53 co-mutation, patients with RAS/TP53 co-mutation had lower median OS: 39 vs. 51 months ( P = 0.02). On multivariable analysis, lung EHD [hazard ratio (HR), 0.7; 95% confidence intervals (CI), 0.3-1.4], peritoneal EHD (HR, 2.2; 95% CI, 1.1-4.2) and RAS/TP53 co-mutation (HR, 2.8; 95% CI, 1.1-7.2) were independently associated with OS. CONCLUSIONS: RAS/TP53 co-mutation is associated with worse OS after concurrent CLM/EHD resection. Mutational status and site of EHD should be included in the evaluation of patients considered for concurrent resection.

Non-resectable Malignant Peritoneal Mesothelioma Treated with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Plus Systemic Chemotherapy Could Lead to Secondary Complete Cytoreductive Surgery: A Cohort Study.

BACKGROUND: Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive primary peritoneal neoplasia. At diagnosis, few patients are eligible for a recommended cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Among neoadjuvant strategies, pressurized intraperitoneal aerosol chemotherapy (PIPAC) combined with systemic chemotherapy has been recently proposed. This study evaluated this strategy in a cohort of DMPM patients. METHODS: Patients with DMPM and primary or recurrent non-resectable diseases who received at least one PIPAC procedure in alternation with systemic chemotherapy were included in this retrospective study to analyze oncologic outcomes. RESULTS: Overall, 26 DMPM patients were treated with at least one PIPAC, including 20 patients with no previous CRS. Of 22 patients (85%) who had symptoms, 9 had perceptible ascites. Overall, 79 PIPAC procedures were performed, with half of the patients receiving three PIPAC procedures or more. Among eight patients (31%), 10 adverse events (13% of procedures) were reported, including two severe complications, both corresponding to digestive perforations. Improvement of symptoms was reported for 32% of the patients, whereas control of ascites was noted in 46%. All but one procedure among 14 patients (54%) secondarily treated by CRS-HIPEC were considered complete resections. After a median follow-up period of 29.6 months (95% confidence interval [CI], 17.6-not reached [NR]), the median overall survival period was 12 months (95% CI 11.1-NR). The median progression-free survival (PFS) was significantly better among the patients who underwent resection than among those who did not (33.5 vs 7.4 months; hazard ratio [HR], 0.18; 95% CI 0.06-0.755; p < 0.001). CONCLUSIONS: For patients with initially non-resectable DMPM, PIPAC is feasible for treatment with neoadjuvant intent and could facilitate complete secondary resection.

Feasibility and Safety of Oxaliplatin-Based Pressurized Intraperitoneal Aerosol Chemotherapy With or Without Intraoperative Intravenous 5-Fluorouracil and Leucovorin for Colorectal Peritoneal Metastases: A Multicenter Comparative Cohort Study.

BACKGROUND: This retrospective multicenter cohort study compared the feasibility and safety of oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-Ox) with or without intraoperative intravenous 5-fluorouracil (5-FU) and leucovorin (L). METHODS: Our study included consecutive patients with histologically proven unresectable and isolated colorectal peritoneal metastases (cPM) treated with PIPAC-Ox in seven tertiary referral centers between January 2015 and April 2020. Toxicity events and oncological outcomes (histological response, progression-free survival, and overall survival) were compared between patients who received intraoperative intravenous 5-FU/L (PIPAC-Ox + 5-FU/L group) and patients who did not (PIPAC-Ox group). RESULTS: In total, 101 patients (263 procedures) were included in the PIPAC-Ox group and 30 patients (80 procedures) were included in the PIPAC-Ox + 5-FU/L group. Common Terminology Criteria for Adverse Events v4.0 grade 2 or higher adverse events occurred in 48 of 101 (47.5%) patients in the PIPAC-Ox group and in 13 of 30 (43.3%) patients in the PIPAC-Ox + 5-FU/L group (p = 0.73). The complete histological response rates according to the peritoneal regression grading score were 27% for the PIPAC-Ox + 5-FU/L group and 18% for the PIPAC-Ox group (p = 0.74). No statistically significant differences were observed in overall or progression-free survival between the two groups. CONCLUSIONS: The safety and feasibility of PIPAC-Ox + 5-FU/L appears to be similar to the safety and feasibility of PIPAC-Ox alone in patients with unresectable cPM. Oncological outcomes must be evaluated in larger studies.

Pathogenic Mechanisms of Secondary Organic Aerosols.

Air pollution represents a major health problem and an economic burden. In recent years, advances in air pollution research has allowed particle fractionation and identification of secondary organic aerosol (SOA). SOA is formed from either biogenic or anthropogenic emissions, through a mass transfer from the gaseous mass to the particulate phase in the atmosphere. They can have deleterious impact on health and the mortality of individuals with chronic inflammatory diseases. The pleiotropic effects of SOA could involve different and interconnected pathogenic mechanisms ranging from oxidative stress, inflammation, and immune system dysfunction. The purpose of this review is to present recent findings about SOA pathogenic roles and potential underlying mechanisms focusing on the lungs; the latter being the primary exposed organ to atmospheric pollutants.

Assessment of postoperative pain after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in the treatment of peritoneal metastasis.

PURPOSE: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique, for the treatment of initially unresectable peritoneal metastasis (PM). Our objective was to assess postoperative pain and morbidity. METHODS: Between July 2016 and September 2020, data from 100 consecutive PIPAC procedures with oxaliplatin (PIPAC Ox) or doxorubicin-cisplatin (PIPAC C/D) in 49 patients with PM (all etiologies) were analyzed. Pain was self-assessed using a visual analog scale (VAS) of 0-10. RESULTS: The median PIPAC procedures per patient were 2 [1-3]. Patients indicated greatest pain at 4 pm on the day of the procedure (D0) and on postoperative D1 at 8 am and 4 pm. Postprocedural moderate-to-severe pain (VAS 4-10) was more frequent with PIPAC Ox than with PIPAC C/D, respectively 14 (36.8%) vs 7 (13.5%); p = 0.010. Hospitalization was longer for patients with moderate-to-severe pain than for others (median 4 days [3-7] vs 3 days [2-4], p = 0.004). Multivariate analysis identified oxaliplatin as a factor associated with greater pain (OR [95% CI], 2.95 [1.10-7.89]. Opiate administration was similar after PIPAC Ox and PIPAC C/D procedures, p = 0.477. CONCLUSION: PIPAC was well-tolerated, and pain was well-controlled in the majority of patients. Pain was greatest at 4 pm on D0 and 8 am and 4 pm on D1. PIPAC Ox is associated with greater pain than PIPAC C/D, independently of opiate treatment. Moderate-to-severe pain was associated with longer hospital stays.

An International Registry of Peritoneal Carcinomatosis from Appendiceal Goblet Cell Carcinoma Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

PURPOSE: Peritoneal carcinomatosis from appendiceal goblet cell carcinoma (A-GCC) is a rare and aggressive form of appendiceal tumor. Cytoreductive surgery (CRS) and hyperthermic intra peritoneal chemotherapy (HIPEC) was reported as an interesting alternative regarding survival compared to surgery without HIPEC and/or systemic chemotherapy. Our aim was to evaluate the impact of CRS and HIPEC for patients presenting A-GCC through an international registry. METHODS: A prospective multicenter international database was retrospectively searched to identify all patients with A-GCC tumor and peritoneal metastases who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI). The post-operative complications, long-term results, and principal prognostic factors were analyzed. RESULTS: The analysis included 83 patients. After a median follow-up of 47 months, the median overall survival (OS) was 34.6 months. The 3- and 5-year OS was 48.5% and 35.7%, respectively. Patients who underwent complete macroscopic CRS had a significantly better survival than those treated with incomplete CRS. The 5-year OS was 44% and 0% for patients who underwent complete, and incomplete CRS, respectively (HR 9.65, p < 0.001). Lymph node involvement and preoperative chemotherapy were also predictive of a worse prognosis. There were 3 postoperative deaths, and 30% of the patients had major complications. CONCLUSION: CRS and HIPEC may increase long-term survival in selected patients with peritoneal metastases of A-GCC origin, especially when complete CRS is achieved. Ideally, randomized control trials or more retrospective data are needed to confirm CRS and HIPEC as the gold standard in this pathology.

What is the effectiveness and safety of mirtazapine versus escitalopram in alleviating cancer-associated poly-symptomatology (the MIR-P study)? A mixed-method randomized controlled trial protocol.

BACKGROUND: Advanced cancer patients often experience multiple symptoms at a same time. This might lead to polypharmacy and increase adverse events representing major threats to the quality of health care, especially in palliative care situations. Mirtazapine, an antidepressant agent, has been suggested as a potential relevant drug to alleviate multiple cancer-related symptoms at a same time. Therefore, the present study aims to assess the effectiveness of mirtazapine in alleviating multiple symptoms at a same time in advanced cancer patients suffering from a major depressive episode compared to a group receiving escitalopram, another antidepressant agent. METHODS: Multicentre, prospective, randomized, controlled trial in 12 palliative care services in France. The study will be based on a mixed-method methodology using parallel groups, of oral mirtazapine compared with oral escitalopram, with a 56 day follow-up. The primary outcome will be an improvement of the Global health Status (issued from the EORTC-QLQ-C30) on day 56. 418 participants will be clinically followed-up on day 7 and 56 and will have a telephonic assessment on days 14 and 28. A sub-sample of participants will be invited to take part in semi-structured qualitative interviews at baseline and day 56. For the qualitative part, purposeful sampling will be used. DISCUSSION: This study will provide evidence for the pharmaceutics management of poly-symptomatology in advanced cancer patients. This could lead to important changes in the management of those patients by using a single molecule to alleviate multiple symptoms at a same time, potentially improving medication adherence, symptoms' control, and reducing the risk of medications adverse events. TRIAL REGISTRATION: Trial registration: NCT04763135 . Registered 18 March 2021.

Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) vs CRS alone for treatment of endometrial cancer with peritoneal metastases: a multi-institutional study from PSOGI and BIG RENAPE groups.

OBJECTIVE: To investigate the benefit of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of endometrial peritoneal carcinomatosis compared to CRS alone. METHODS: We conducted a retrospective multicentre study of patients from experienced centres in treating peritoneal malignancies from 2002 to 2015. Patients who underwent surgery for peritoneal evolution of endometrial cancer (EC) were included. Two groups of 30 women were matched and compared: "CRS + HIPEC" which used HIPEC after CRS, and "CRS only" which did not use HIPEC. We analysed clinical, pathologic and treatment data for patients with peritoneal metastases from EC. The outcome measures were morbidity, overall survival (OS), and progression-free survival (PFS). RESULTS: In "CRS plus HIPEC" group, 96.7% of women were treated for recurrence, while in "CRS only" 83.3 were treated for primary disease. There was no significant difference between Peritoneal Carcinomatosis Index at laparotomy or Completeness of Cytoreduction score. Grade III and IV complications rates did not significantly differ between "CRS plus HIPEC" group and "CRS only" group (20.7% vs 20.7%, p = 0.739). Survival analysis showed no statistical difference between both groups. Median OS time was 19.2 months in "CRS plus HIPEC" group and 29.7 months in "CRS only" group (p = 0.606). Median PFS survival time was 10.7 months in "CRS plus HIPEC" group and 13.1 months in "CRS only" group (p = 0.511). CONCLUSION: The use of HIPEC combined to CRS did not have any significance as regard the DFS and OS over CRS alone in patients with primary or recurrent peritoneal metastasis of endometrial cancer.

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery has been associated with encouraging survival results in some patients with colorectal peritoneal metastases who were eligible for complete macroscopic resection. We aimed to assess the specific benefit of adding HIPEC to cytoreductive surgery compared with receiving cytoreductive surgery alone. METHODS: We did a randomised, open-label, phase 3 trial at 17 cancer centres in France. Eligible patients were aged 18-70 years and had histologically proven colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, a Peritoneal Cancer Index of 25 or less, and were eligible to receive systemic chemotherapy for 6 months (ie, they had adequate organ function and life expectancy of at least 12 weeks). Patients in whom complete macroscopic resection or surgical resection with less than 1 mm residual tumour tissue was completed were randomly assigned (1:1) to cytoreductive surgery with or without oxaliplatin-based HIPEC. Randomisation was done centrally using minimisation, and stratified by centre, completeness of cytoreduction, number of previous systemic chemotherapy lines, and timing of protocol-mandated systemic chemotherapy. Oxaliplatin HIPEC was administered by the closed (360 mg/m2) or open (460 mg/m2) abdomen techniques, and systemic chemotherapy (400 mg/m2 fluorouracil and 20 mg/m2 folinic acid) was delivered intravenously 20 min before HIPEC. All individuals received systemic chemotherapy (of investigators' choosing) with or without targeted therapy before or after surgery, or both. The primary endpoint was overall survival, which was analysed in the intention-to-treat population. Safety was assessed in all patients who received surgery. This trial is registed with ClinicalTrials.gov, NCT00769405, and is now completed. FINDINGS: Between Feb 11, 2008, and Jan 6, 2014, 265 patients were included and randomly assigned, 133 to the cytoreductive surgery plus HIPEC group and 132 to the cytoreductive surgery alone group. After median follow-up of 63·8 months (IQR 53·0-77·1), median overall survival was 41·7 months (95% CI 36·2-53·8) in the cytoreductive surgery plus HIPEC group and 41·2 months (35·1-49·7) in the cytoreductive surgery group (hazard ratio 1·00 [95·37% CI 0·63-1·58]; stratified log-rank p=0·99). At 30 days, two (2%) treatment-related deaths had occurred in each group.. Grade 3 or worse adverse events at 30 days were similar in frequency between groups (56 [42%] of 133 patients in the cytoreductive surgery plus HIPEC group vs 42 [32%] of 132 patients in the cytoreductive surgery group; p=0·083); however, at 60 days, grade 3 or worse adverse events were more common in the cytoreductive surgery plus HIPEC group (34 [26%] of 131 vs 20 [15%] of 130; p=0·035). INTERPRETATION: Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases. FUNDING: Institut National du Cancer, Programme Hospitalier de Recherche Clinique du Cancer, Ligue Contre le Cancer.