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Stratification of patients with colorectal peritoneal metastases (CRPM) using RAS/BRAF mutational status may refine patient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This study aimed to analyse the association of RAS/BRAF status and their variants, with clinicopathological variables and survival outcomes in patients who have undergone CRS ± HIPEC.A single centre, peritonectomy database was interrogated for patients with CRPM who underwent peritonectomy procedures between 2010 and 2020.During the study period, 174 patients were included. Molecular status was obtained on 169 patients, with 68 (40.5%) KRAS, 25 (14.8%) BRAF and 6 (3.6%) NRAS mutations detected. Patients with BRAF mutations were more likely to be mismatch repair deficient (dMMR) (BRAF 20%, KRAS 4.4%, wild type 8.6%, p = 0.015). Most common BRAF and KRAS variants were, V600E (80%) and G12D (39.7%), respectively. BRAF V600E was independently associated with worse overall (median: 28 months, multivariate: HR 2.29, p = 0.026) and disease-free survival (median: 8 months, multivariate: HR 1.8, p = 0.047). KRAS G12V was a strong prognostic factor associated with disease-free survival (median: 9 months, HR 2.63, p = 0.016). dMMR patients (14/161, 8.7%) exhibited worse median overall survival compared to those with proficient MMR (dMMR 27 months, pMMR 29 months p = 0.025).This study highlights the importance of molecular analysis in CRPM stratification. BRAF V600E mutations predict poor outcomes post CRS and HIPEC and may help refine patient selection for this procedure. Molecular analysis should be performed preoperatively to characterise prognosis and guide perioperative therapeutic options.

The prevalence of elderly patients with resectable colorectal peritoneal metastases (CRPM) is increasing. This study aimed to compare short and long-term outcomes of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for CRPM in patients above and below 70 years of age.This was a retrospective, 10-year analysis of 90-day major morbidity and mortality, and long-term survival.Thirty-two (21.3%) of 150 consecutive patients who underwent CRS and HIPEC during the study period were aged 70 and older. PCI (P = 0.04), perioperative chemotherapy use (P 0.01) and organ resections (rectum P = 0.04, diaphragm P = 0.03) were less in the over 70 group. There was no significant differences in major morbidity (P = 0.19) and mortality (P = 0.32). There was also no difference in 5-year overall survival (OS) (≥70: 26% vs.70: 39%; P = 0.68) and disease-free survival (DFS) (≥70: 25% vs.70: 14%; P = 0.22). Age above 70 was not independently associated with worse OS (HR 1.55, P = 0.20) and DFS (HR 1.07, P = 0.81).The surgical management of CRPM appears safe and feasible in this elderly population. Appropriate selection of elderly patients for such radical intervention is reinforced by the comparable survival with those under 70.

Background Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-recognised treatment option for the management of colorectal peritoneal metastases (CRPM). However, incorporating the routine use of neoadjuvant chemotherapy (NAC) into this management plan is controversial. Methods A systematic review and meta-analysis were conducted to evaluate the impact of neoadjuvant chemotherapy on perioperative morbidity and mortality, and long-term survival of patients with CRPM undergoing CRS and HIPEC. Results Twelve studies met the inclusion criteria (n = 2,463 patients). Ten were retrospective cohort, one was prospective cohort, and one was a prospective randomised by design. Patients who received NAC followed by CRS and HIPEC experienced no difference in major perioperative morbidity and mortality compared with patients who underwent surgery first (SF). There was no difference in overall survival at 3 years, but at 5 years NAC patients had superior survival (relative risk [RR] 1.31; 95% confidence interval [CI] 1.11–1.54, P < 0.001). There were no differences in 1- and 3-year, disease-free survival (DFS) between groups. Study heterogeneity was generally high across all outcome measures. Conclusions Patients who received neoadjuvant chemotherapy did not experience any increase in perioperative morbidity or mortality. The potential improvement in 5-year overall survival in patients receiving NAC is based on limited confidence due to several limitations in the data, but not sufficiently enough to curtail its use. The practice of NAC in this setting will remain heterogeneous and guided by retrospective evidence until prospective, randomised data are reported.

Extended peritonoid drug sensitivity data

Patient characteristics & analyses.

Purpose:Patients with colorectal cancer with peritoneal metastases (CRPMs) have limited treatment options and the lowest colorectal cancer survival rates. We aimed to determine whether organoid testing could help guide precision treatment for patients with CRPMs, as the clinical utility of prospective, functional drug screening including nonstandard agents is unknown.Experimental Design:CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing.Results:Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for two patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications.Conclusions:Our approach is feasible, reproducible, and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.

Supplementary Methods

Pseudomyxoma peritonei (PMP) is a rare clinical entity, commonly derived from a mucin-producing tumour of the appendix. International consensus is unclear on the role of positron emission tomography (PET) in preoperative staging. This study aimed to assess the ability of preoperative PET in predicting the histological grade of PMP.All patients scheduled for cytoreductive surgery (CRS) +/- hyperthermic intraperitoneal chemotherapy (HIPEC) for PMP who underwent preoperative PET at a single centre between June 2007 and June 2020 were included. A nuclear medicine physician, blinded to patient outcomes, retrospectively reviewed imaging studies to assess for maximum tumour standardised uptake value (SUV) to mean liver SUV ratio (SUVBetween April 2007 and December 2020, a total of 204 patients underwent surgical intervention for PMP. Of these, 124 (60.8%) met the inclusion criteria. Median peritoneal carcinomatosis index for the entire cohort was 9 and complete cytoreduction (CC0/1) was achieved in 109 (88%) patients. Patients with high-grade PMP were more likely to have diffuse peritoneal disease (p 0.001) and higher SUVPreoperative PET showed positive correlation with high-grade PMP and acceptable sensitivity and specificity as a diagnostic tool. PET should be considered a useful adjunct to standard imaging for predicting histological grade in the staging of patients with PMP.

Pelvic exenteration (PE) for locally advanced pelvic malignancy is well established, though high rates of morbidity and mortality exist. Such a complication profile has often deterred the surgical community from offering exenteration in combination with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). We aimed to evaluate the perioperative outcomes following pelvic exenteration when combined with CRS and HIPEC for peritoneal surface malignancy (PSM) in a tertiary referral centre.A review of a prospectively maintained PSM database from June 2015 to December 2020 at a tertiary referral institution was performed. Patients who underwent CRS, PE, and HIPEC were matched with patients who underwent PE alone. Primary endpoints were perioperative morbidity and mortality.From June 2015 to December 2020, 20 patients required PE as part of their CRS and HIPEC for PSM. The majority of patients were female (n = 16, 80%) with a median age of 52 (range 21-70). Colorectal cancer was the predominant pathology (n = 12, 60%). Median PCI was 11.5 (range 3-39). CC0 and R0 resections were achieved in all patients. CRS, PE, and HIPEC and PE-alone groups were well matched for clinicopathological variables. There was no difference in perioperative major morbidity (HIPEC: 30% vs PE: 15% p = 0.256) and mortality (HIPEC: 0 vs PE: 5% p = 0.311) between groups. Median follow-up was 17.5 months (range 7-68). Eight patients (40%) died from disease-related issues during the study period.An aggressive surgical strategy with complete resection is feasible and safe in select patients with complex PSM involving the pelvis.

BACKGROUND: Synchronous liver resection, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy for colorectal liver and peritoneal metastases have traditionally been contraindicated. More recent clinical practice has begun to promote this aggressive treatment in select patients. OBJECTIVE: This study aimed to investigate the perioperative and oncological outcomes of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, with and without liver resection, in the management of metastatic colorectal cancer. DATA SOURCES: Medline, Embase, and Cochrane Library databases were searched up to July 2020. STUDY SELECTION: Cohort studies comparing outcomes following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with and without liver resection for metastatic colorectal cancer were reviewed. No randomized controlled trials were available. INTERVENTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with or without synchronous liver resection were compared. MAIN OUTCOME MEASURES: The primary outcome measures were perioperative mortality and major morbidity. Secondary outcomes included 3- and 5-year overall survival and 1- and 3-year disease-free survival. RESULTS: Fourteen studies fitted the inclusion criteria, with 8 studies included in the meta-analysis. On pooled analysis, there was no significant difference in perioperative morbidity and mortality between the two groups. Patients that underwent concomitant liver resection had worse 1- and 3-year disease-free survival and 3- and 5-year overall survival. LIMITATIONS: Only a limited number of studies were available, with a moderate degree of heterogeneity. CONCLUSIONS: The addition of synchronous liver resection to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of resectable metastatic colorectal cancer was not associated with increased perioperative major morbidity and mortality in comparison with cytoreduction and hyperthermic intraperitoneal chemotherapy alone. However, the presence of liver metastases was associated with inferior disease-free and overall survival. These data support the continued practice of liver resection, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy in the management of select patients with such stage IV disease.