Is Systemic Chemotherapy Useful in Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Colorectal Peritoneal Metastases? A Propensity-Score Analysis.

PURPOSE: Multimodal treatment of colorectal (CRC) peritoneal metastases (PM) includes systemic chemotherapy (SC) and surgical cytoreduction (CRS), eventually with hyperthermic intraperitoneal chemotherapy (HIPEC), in select patients. Considering lack of clear guidelines, this study was designed to analyze the role of chemotherapy and its timing in patients treated with CRS-HIPEC. METHODS: Data from 13 Italian centers with PM expertise were collected by a collaborative group of the Italian Society of Surgical Oncology (SICO). Clinicopathological variables, SC use, and timing of administration were correlated with overall survival (OS), disease-free survival (DFS), and local (peritoneal) DFS (LDFS) after propensity-score (PS) weighting to reduce confounding factors. RESULTS: A total of 367 patients treated with CRS-HIPEC were included in the propensity-score weighting. Of the total patients, 19.9% did not receive chemotherapy within 6 months of surgery, 32.4% received chemotherapy before surgery (pregroup), 28.9% after (post), and 18.8% received both pre- and post-CRS-HIPEC treatment (peri). SC was preferentially administered to younger (p = 0.02) and node-positive (p = 0.010) patients. Preoperative SC is associated with increased rate of major complications (26.9 vs. 11.3%, p = 0.0009). After PS weighting, there were no differences in OS, DFS, or LDFS (p = 0.56, 0.50, and 0.17) between chemotherapy-treated and untreated patients. Considering SC timing, the post CRS-HIPEC group had a longer DFS and LDFS than the pre-group (median DFS 15.4 vs. 9.8 m, p = 0.003; median LDFS 26.3 vs. 15.8 m, p = 0.026). CONCLUSIONS: In patients with CRC-PM treated with CRS-HIPEC, systemic chemotherapy was not associated with overall survival benefit. The adjuvant schedule was related to prolonged disease-free intervals. Additional, randomized studies are required to clarify the role and timing of systemic chemotherapy in this patient subset.

Gastric cancer with peritoneal metastases: a single center outline and comparison of different surgical and intraperitoneal treatments.

INTRODUCTION: Gastric cancer with peritoneal metastasis (GCPM) has an unfavourable prognosis. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are promising treatment options that have been shown to improve survival. The aim of this study was to assess the impact of different treatments such as systemic chemotherapy, systemic chemotherapy + PIPAC, and CRS + HIPEC in patients with GCPM. MATERIAL AND METHODS: This single-centre retrospective study included 82 patients with GCPM treated between January 2016 and June 2021. After first-line chemotherapy, depending on disease response and burden, the patients were divided into three treatment groups: chemotherapy alone, chemotherapy + PIPAC, and CRS + HIPEC. The primary outcome was overall survival (OS) from diagnosis, which was compared among the treatment groups. RESULTS: Thirty-seven (45.1%) patients were administered systemic chemotherapy alone, 25 (30.4%) received chemotherapy + PIPAC, and 20 (24.4%) underwent CRS + HIPEC. The CRS + HIPEC group had better OS (median 24 months) than the PIPAC group (15 months, p = 0.01) and chemotherapy group (5 months, p = 0.0001). Following CRS + HIPEC, the postoperative grade 3-4 complication rate was 25%, and no postoperative in-hospital deaths occurred. The median disease-free survival (DFS) was 12 months. Multivariate analysis identified peritoneal carcinomatosis index (PCI) > 7 as an independent predictor of worse DFS. No independent predictors of OS were identified. CONCLUSION: Among patients with GCPM, we identified a highly selected population with oligometastatic disease. In this group, CRS + HIPEC provided a significant survival advantage with an acceptable major complication rate compared with other available therapies (systemic chemotherapy alone or in combination with PIPAC).

Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery in colorectal carcinoma at high risk of peritoneal carcinomatosis: short-term and long-term outcomes from the CHECK study - protocol for a randomised, multicentre, phase 3 trial.

INTRODUCTION: Up to one-fifth of patients with colorectal cancer will develop peritoneal metastases, frequently without other districts' involvement. Despite the recent unsuccesses of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer peritoneal metastases treatment, the rationale in the prophylactic setting remains strong. Several clinical and pharmacokinetic data suggest that the efficacy of intraperitoneal chemotherapy is highest when the disease is microscopic. However, robust evidence demonstrating whether the addition of HIPEC for high-risk colorectal cancers offers better control of local recurrence is lacking. METHODS AND ANALYSIS: This is a multicentre randomised phase 3 trial comparing prophylactic surgery plus HIPEC CO2 with mitomycin, over standard surgical excision in patients with colorectal cancer at high risk of peritoneal carcinomatosis; 388 patients will be included in this study. The primary objective is to compare the efficacy of prophylactic surgery (radical colorectal resection, omentectomy, appendectomy, round ligament of the liver resection and bilateral adnexectomy) plus HIPEC CO2 with mitomycin and standard surgery in terms of local recurrence-free survival. The main secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. The primary endpoint will be described with a cumulative incidence function and will be analysed with Grey test to take account of the competing risks. DFS and OS will be described with the Kaplan-Meier method. ETHICS AND DISSEMINATION: This trial has been evaluated by the Italian Medicines Agency, local ethics committees and will be submitted to the Ministry of Health to notify the start of the trial according to the regulation of trials on devices with CE mark/certification.The results will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal, whatever the findings. TRIAL REGISTRATION NUMBER: NCT03914820.

The prognostic value of skeletal muscle index on clinical and survival outcomes after cytoreduction and HIPEC for peritoneal metastases from colorectal cancer: A systematic review and meta-analysis.

BACKGROUND: Cytoreductive surgery (CRS) and hypertermic intraperitoneal chemotherapy (HIPEC) represent the most effective strategy to manage peritoneal metastases (PM). This systematic review and meta-analysis aimed to assess the impact of body composition on clinical outcomes in patients with PM. METHODS: A systematic literature search was performed using Medline, Web of Science and EMBASE databases from inception to the 20st August 2020. Data were independently extracted by 3 authors. Newcastle-Ottawa Scale was used to assess quality and risk of bias of studies. Pooled analyses were performed using Mantel-Haenszel method to estimate overall effect size with mean differences or odd ratios (ORs) and 95% confidence interval (CI). The primary outcome was postoperative complication (POC) rate, while secondary outcomes were severe POC and postoperative mortality. RESULTS: A total of 4 studies were included in the systematic review and meta-analysis, including 582 patients. A significant association between low skeletal muscle mass and POC was found (OR 1.45, 95% CI 1.04 to 2.03; p = 0.03), while no differences were found in terms operative time, estimated blood loss, length of hospital stay, and postoperative mortality (p > 0.05). CONCLUSIONS: Low skeletal muscle mass at diagnosis is a valid prognostic factor for POC development in colorectal and PM patients undergoing CRS. Prospective and larger studies are needed to better investigate the role of CT scan derived body composition and to understand how to implement this tool in clinical practice.

Microsatellite and RAS/RAF Mutational Status as Prognostic Factors in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS. METHODS: Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS). RESULTS: The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4-51.2 months], and the median DFS was 13.6 months (95% CI, 12.3-14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4-24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS. CONCLUSION: For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.

Clinical and Molecular Features in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinosis from Colorectal Cancer.

PURPOSE: Careful patient selection plays a crucial role in avoiding overtreatment and further increases survival rates in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer (CRC) with peritoneal metastases (PM). METHODS: The clinical and molecular factors influencing survival in patients who had undergone CRS with HIPEC between January 2015 and December 2018 were analyzed. RESULTS: Sixty-six patients underwent CRS with HIPEC during the study period. The median overall survival (OS) was 36 months, with a 3-year OS of 43%. Multivariate analysis revealed increased PCI (HR: 1.21; 95% CI: 1.02-1.41; p = 0.020), right-sided primary tumor (HR: 3.01; 95% CI: 1.27-7.13; p = 0.017), and BRAF V600E mutation (HR: 4.55; 95% CI: 1.21-17.21; p = 0.025) as independent predictors for worse OS. CONCLUSION: In addition to confirming the prognostic role of PCI, our study extends the role of BRAF mutation and right primary tumor location as markers for worse prognosis.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer with Synchronous Peritoneal Metastases: Multicenter Study of 'Italian Peritoneal Surface Malignancies Oncoteam-S.I.C.O.'

BACKGROUND: The development of multimodality treatment, including cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC), has led to promising results in selected patients with peritoneal disease of gastric origin. The aim of this study was to investigate the short- and long-term outcomes of CRS/HIPEC in the treatment of synchronous peritoneal metastasis in gastric cancer. METHODS: The Italian Peritoneal Surface Malignancies Oncoteam-S.I.C.O. retrospective registry included patients with synchronous peritoneal malignancy from gastric cancer submitted to gastrectomy with CRS and HIPEC between 2005 and 2018 from 11 high-volume, specialized centers. RESULTS: A total of 91 patients with a median age of 58 years (range 26-75) were enrolled. The median overall survival (OS) time for the whole group of patients was 20.2 months (95% confidence interval [CI] 11.8-28.5] and the median recurrence-free survival (RFS) was 7.3 months (95% CI 4-10.6). The completeness of cytoreduction score (CCS) of 0 and Peritoneal Cancer Index (PCI) score of ≤ 6 groups showed a significantly better long-term survival (median OS 40.7 and 44.3 months, respectively) compared with the incomplete resected groups (median OS 10.7 months, p = 0.003) and PCI score of > 6 group (median OS 13.4 months, p = 0.005). A significant difference was observed in the survival rate according to neoadjuvant treatment (untreated patients: 10.7 months, 95% CI 5.1-16.2; treated patients: 35.3 months, 95% CI 2.8-67.8; p = 0.022). CONCLUSIONS: In referral centers, CRS and HIPEC after neoadjuvant treatment significantly improved survival in selected patients. Patients with a PCI score ≤ 6, complete cytoreduction, negative nodal involvements, and negative cytology had encouraging results, showing a clinically meaningful survival.

Cytoreductive surgery and mitomycin C hyperthermic intraperitoneal chemotherapy with CO2 recirculation (HIPEC-CO2) for colorectal cancer peritoneal metastases: analysis of short-term outcomes.

Peritoneal dissemination from colorectal cancer (CRC) has long been associated with unfavorable prognosis. However, in the last decades, the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was able to obtain up to 30% 5-year survival rate in selected centers. Despite the wide diffusion of CRS and HIPEC, until now, there are no clear recommendations on the drug of choice for HIPEC nor its technique, and safety and efficacy data of HIPEC regimens and techniques are lacking. We performed a retrospective analysis of a prospectively maintained database of 26 CRS and mitomycin C HIPEC with CO2 recirculation (HIPEC-CO2) for CRC peritoneal metastasis (PM) performed at our center. The main endpoints were morbidity, mortality, the temperature of perfusate during HIPEC and metabolic changes throughout the procedure. Morbidity was assessed by analysis of postoperative adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Continuous variables of Arterial Blood Gas (ABG) analysis at three time-points were compared by the Student t test. There were no postoperative deaths. The overall grade 3-4 CTCAE complications rate at 30 days was 38.4%, with ten severe adverse events occurring to six (23.0%) patients. The temperature within HIPEC perfusion maintained between 41 and 42 °C in all cases and we experienced no HIPEC-related intraoperative complications. We observed a significant difference between all baseline and pre-HIPEC ABG parameters evaluated but no statistically significant differences between pre- and post-HIPEC ABG outcomes. This study shows that mitomycin C HIPEC-CO2 is feasible and has a safety profile comparable to that of other HIPEC techniques reported in the literature. Further research is needed to validate prospectively the safety and efficacy of this technique.

Prognostic factors value of germline and somatic brca in patients undergoing surgery for recurrent ovarian cancer with liver metastases.

OBJECTIVE: To describe accurately the oncological outcomes after hepatic resection (HR) in recurrent ovarian carcinoma (ROC) evaluating clinic-pathological variables and mutational status of BRCA1/2. Although HR is considered a challenging situation in ROC patients, assessment of BRCA1/2 mutational status seems to have a relevant clinical value to guide surgical therapy. METHODS: Patients who underwent HR for ROC at the Catholic University of Rome, between June 2012 and October 2017 were included. Exclusion criteria were represented by extra-abdominal disease and presence of diffuse peritoneal carcinomatosis requiring more than 2 bowel resections. Details relative to HR were collected and BRCA analysis was performed. Predictive factors of post-HR progression free survival (PHR-PFS) were assessed by univariate analyses using Cox-proportional hazard regression models. RESULTS: Thirty-four patients undewent HR within secondary cytoreductive surgery (SCS). Six patients (17.6%) presented with hepatic relapse only, while the remaining 28 patients (82.4%) had concomitant extra-hepatic disease. In the whole series, the 3-yr PHR-PFS was 49.1% and the 3-yr post-HR overall survival was 72.9%. Univariate analysis of variables conditioning PHR-PFS showed that only BRCA mutational status played a statistically significant favourable role: the 3-yr PHR-PFS rate was 81.0% in BRCA mutated patient compared to 15.2% in wild type ones (p value: 0.001). CONCLUSIONS: Our clinical analyses suggest that in ROC patients with liver disease the assessment of germline and somatic BRCA mutational status can help to select patients elegible for SCS.

A novel HIPEC technique using hybrid CO2 recirculation system: intra-abdominal diffusion test in a porcine model.

The role of loco-regional treatment of peritoneal carcinomatosis using intraperitoneal chemotherapy is still investigated. Actually, new technologies are suitable for these procedures, especially a new hybrid system using CO2 called Peritoneal Recirculation System (PRS-1.0 Combat). A HIPEC procedure in a porcine model using the PRS system was conducted. The objective of experimentation was to assess the distribution of liquid inside the abdomen, by using methylene blue instead of chemotherapy. Moreover, we positioned six different thermal probes in different abdominal regions inside the abdomen to measure the temperature during procedure. During the procedure, all thermal probes recorded an average temperature of 41.5°. At the end of infusion, the abdomen was emptied and then opened; the tracer distribution was recorded. No technical problems were recorded during the procedure. Good distribution of tracer was recorded. More studies are needed to investigate better this new technology.