Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has shown survival benefits in select patients with peritoneal metastases (PM) from colorectal cancer (CRC). Molecular alterations, particularly RAS/BRAF mutations and Microsatellite Instability (MSI), play crucial roles in prognostic stratification and treatment planning, influencing both disease-free survival (DFS) and overall survival (OS). This scoping review evaluates the prognostic role of MSI and RAS/BRAF mutations in patients with PM-CRC treated with CRS-HIPEC.

A literature search was conducted across several databases to identify papers published between 2000 and September 2024. We selected 18 publications that considered DFS and OS as primary or secondary outcomes in patients with RAS/BRAF mutations and MSI following CRS-HIPEC treatment. Studies involving appendiceal cancer, peritoneal disease from non-CRC, pediatric patients, or subjects not treated with CRS-HIPEC were excluded.

Most studies suggest that RAS and BRAF mutations have a negative influence on survival outcomes. While inconsistencies exist, RAS mutations are generally associated with worse DFS. Specific KRAS subtypes such as KRASMUT2 or KRAS G12V and the BRAF V600 variant correlate with poorer prognosis. MSI status appears to attenuate the adverse effects of RAS/BRAF mutations on survival, although conflicting data persist.

RAS and BRAF mutations correlate with poorer outcomes in PM-CRC, underscoring the need for mutation-informed strategies to refine HIPEC and systemic therapies. Recognizing subtypes may improve patient selection for CRS-HIPEC, optimizing both local disease control and long-term survival. Future research should incorporate these molecular profiles to enhance therapeutic decision-making and better address this challenging condition.

Peritoneal carcinomatosis (PC) represents a challenge in the management of metastatic colorectal cancer (mCRC) because of the difficulties in diagnosis, tumor burden assessment, and in selecting the optimal treatments. A critical limitation is the lack of robust prognostic and predictive biomarkers, largely relying on serum markers (e.g., carcinoembryonic antigen) or the peritoneal carcinomatosis index (PCI) for disease extent. Circulating tumor DNA (ctDNA)-genomic fragments shed by tumor cells into the bloodstream-is now recommended by international guidelines for mCRC management. Its potential extends to PC, where it may enhance diagnostic, therapeutic, and follow-up strategies. However, PC from CRC (PC-CRC) is associated with lower ctDNA levels and detection rates compared to other metastatic sites, posing a challenge for its clinical utility. To address these limitations, peritoneal fluid analysis has emerged as a promising alternative, with peritoneal tumor DNA (ptDNA) detected at higher concentrations in this anatomical space. Integrating ctDNA and ptDNA may offer a deeper understanding of PC-CRC biology and provide more precise tools for managing this complex disease. This approach has the potential to revolutionize the treatment paradigm for PC-CRC, bringing precision medicine even to this subgroup of patients traditionally associated with poor outcomes. This review aims to evaluate the diagnostic, prognostic, and therapeutic implications of ctDNA and ptDNA in PC-CRC, highlighting current limitations and future directions.

Colorectal cancer (CRC) represents a major global public health issue, ranking as the third most common cancer worldwide. Given the substantial prevalence of CRC, there is a critical need to identify precise prognostic and predictive biomarker tools for better treatment outcomes. Phase angle (PA) has been proposed as a prognostic marker in various non-malignant and malignant clinical conditions.

To investigate the relationship between PA and survival outcomes in the first-line treatment of metastatic CRC (mCRC).

In this prospective observational study, we obtained data on patients who started first-line systemic chemotherapy from the beginning of 2020 until the end of 2022. The PA, assessed by the bioelectrical impedance analysis scale, was evaluated as a possible prognostic factor for treatment outcomes, which were measured as progression-free survival (PFS) and objective response rate (ORR).

Using the cut-point value for PA set at 4.60°, 144 patients were divided into two cohorts. The high PA group of patients exhibited a significantly longer median PFS than the low PA group, 14.8 vs 10.5 months, respectively. No difference in ORR was observed. However, patients with PA ≥ 4.60° had a higher disease control rate.

PA represents a novel and objective pre-chemotherapy prognostic factor to identify mCRC patients who are at increased risk of a worse survival outcome.

Peritoneal metastases from colorectal cancer (PMCRC) present a complex treatment challenge requiring multidisciplinary expertise. Significant controversy exists regarding the optimal management of PMCRC patients. In this article, we seek to review the currently available evidence and discuss key components of patient workup, treatment, and management.

About a quarter of patients with locally advanced colon cancer (pT4) develop locoregional recurrence, including peritoneal metastases. The aim of this individual patient data meta-analysis (IPDMA) was to evaluate the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) with regard to reducing the locoregional recurrence rate in the overall population and high-risk subgroups of patients with locally advanced colon cancer.

A systematic literature search was conducted in July 2024 to identify RCTs on adjuvant HIPEC in addition to routine adjuvant systemic chemotherapy in locally advanced colon carcinoma. An IPDMA was performed, with the locoregional recurrence rate as the primary endpoint and disease-free survival (DFS) and overall survival (OS) as secondary endpoints.

The search identified two trials (COLOPEC and HIPECT4). Individual patient data were pooled for 386 patients, of whom 189 patients received adjuvant HIPEC and 197 patients constituted the control group. The median follow-up was 36 (interquartile range 32-60) months. A modified intention-to-treat analysis showed a 36-month locoregional recurrence rate of 16.0% for HIPEC patients and 21.2% for control patients (P = 0.295). Predefined subgroup analyses revealed a significant reduction in locoregional recurrence after HIPEC in patients with right-sided tumours (HR 0.56 (95% c.i. 0.48 to 0.67)) (P < 0.001). No significant differences in survival were found for the overall study population; low event rates in subgroups did not allow for survival analyses.

Adjuvant HIPEC significantly reduced the locoregional recurrence rate in right-sided locally advanced colon cancer, but not in the overall study population. Definitive conclusions on DFS and OS require longer follow-up.

Background: T4 colorectal cancer (CRC) is associated with an increased risk of peritoneal metastases (PM), but it is currently not possible to accurately predict which patients with T4 CRC develop PM. We investigated the occurrence and risk factors for PM in these patients. Methods: A mono-institutional prospective database of 352 patients undergoing T4 primary CRC resection from 2012 to 2021 was reviewed. Clinico-pathological variables potentially associated with synchronous or metachronous PM were tested by univariate and multivariate analyses. Results: The prevalence of synchronous PM was 73/352 (20.7%) and was significantly associated with age (p = 0.037), primary site (p = 0.002), positive nodes (p = 0.005), elevated CA19.9 (p = 0.001), and non-intestinal histology (p = 0.001). After a median follow-up of 35.9 months (95% confidence interval [CI] = 29.5-44.9), metachronous CRC-PM occurred in 36/164 patients (22.0%) with available data, accounting for a three-year cumulative incidence of 21.5% (95% CI = 14.3-28.1). Metachronous CRC-PM occurred in 3/48 patients (6.2%) with negative nodes and normal CEA, as compared with 33/116 patients (28.4%) with positive nodes and/or elevated CEA (p < 0.001). Combined nodal and CEA status (hazard ratio [HR] = 1.27; 95% CI = 1.02-1.59; p = 0.033), postoperative chemotherapy (HR= 0.51; 95% CI = 0.33-0.77; p = 0.001), and positive resection margins (HR = 2.01; 95% CI = 1.20-3.39; p = 0.008) were significantly associated with PM. Conclusions: The peritoneum is a major site for treatment failure in T4 CRC. Patients with normal CEA and negative lymph nodes are associated with a significantly lower risk for metachronous CRC-PM. These findings may help in refining patient selection for integrated approaches aiming at the prevention or early treatment of CRC-PM, which are pending validation in prospective studies.

Selection of suitable candidates for intraoperative tumour detection and cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is important for improving outcomes for patients with colorectal peritoneal metastases. Previous research demonstrated the use of single-photon emission computed tomography (SPECT), intraoperative radiodetection, and near-infrared fluorescence (NIRF)-guided surgery with a dual-labelled 111In-labelled dodecane tetra-acetic acid (DOTA)-labetuzumab-IRDye800CW tracer to detect peritoneal metastases before operation. The aim of this study was to validate these results.

A single-centre phase II study was conducted to evaluate the safety and feasibility of 111In-labelled DOTA-labetuzumab-IRDye800CW in patients with colorectal peritoneal metastases undergoing CRS-HIPEC. SPECT/computed tomography (CT) was undertaken before surgery, after intravenous administration of 10 mg 111In-labelled DOTA-labetuzumab-IRDye800CW (mean 101.25 MBq). During surgery, radiodetection and NIRF imaging were used for tumour detection. Adverse events were assessed, and tumour-to-background ratios (TBRs) and peritoneal cancer index scores were analysed.

Seven patients were included. No study-related severe adverse events were reported. Imaging before surgery revealed previously undetected metastases in one patient. The mean(standard deviation, s.d.) SPECT/CT peritoneal cancer index score was 3(2), and the intraoperative score was 14(7) (P = 0.032). A total of 52 lesions were removed during CRS, of which 37 were malignant. With NIRF imaging, 34 (92%) of 37 malignant lesions were detectable. Of 52 fluorescent lesions, 4 were false-positive. Mean(s.d.) fluorescence TBR was 3.4(1.8) and mean radiodetection TBR was 4.4(1.4).

This study confirmed the safety and feasibility of multimodal image-guided surgery in patients with peritoneal metastases.

Peritoneal metastasis (PM) is common in colorectal cancer (CRC), yet its underlying mechanisms are poorly understood. Here, we explored the transcriptional profile of CRC, PM and adjacent tissues revealing key players that facilitate PM. Single-cell analysis of 48 matched samples from 12 patients revealed that remodeling of malignant cells and the tumor microenvironment promotes CRC progression and metastasis. Multiplexed imaging confirmed depletion in PM by enrichment in CRC tissues of neutrophils associated with mucosal immunity disruption, intestinal microbiota dysbiosis and mesenchymal transition of both cancerous and mesothelial cells. Functional analyses in cell lines, organoids and in vivo models demonstrated that dysbiosis promoted inflammation and protumor neutrophil recruitment, while coupled mesenchymal transition of malignant and mesothelial cells disrupted the stromal structure and increased cancer cell invasiveness. Our findings suggest that targeting mesothelial cells and tumor microenvironment remodeling may offer therapeutic strategies for CRC-PM.

Data in the literature suggest that obstruction is an independent predictor of poor prognosis in colon cancer. Of all possible sites of recurrence, peritoneal metastases are associated with worse survival. Our aim was to report the incidence of metachronous peritoneal metastases from a cohort of patients undergoing resection of obstructive colon cancer with curative intent and to identify predictive factors for metachronous peritoneal metastases.

From 2000 to 2015, a total of 2,325 patients were treated for obstructive colon cancer in French surgical centers, members of the French National Surgical Association (AFC). Patients with palliative management, synchronous metastatic disease, and with postoperative mortality were excluded. A multivariate analysis was performed to determine independent predictive factors of metachronous peritoneal metastases.

The cohort included 1,085 patients. The median follow-up was 21.5 months. Metachronous peritoneal metastases occurred in 12% of patients and were diagnosed after a median interval of 13.5 months. The cumulative 3-year metachronous peritoneal metastasis rate was 10.9%. Three-year overall survival was 85% for patients who did not develop recurrence, 71% for those who develop recurrence without peritoneal metastases, and 56% for those with metachronous peritoneal metastases (P < .0001). In multivariate analysis, 3 variables were identified as independent risk factors for metachronous peritoneal metastases: pT4 stage (odds ratio: 1.98; 95% confidence interval: 1.17-3.36; P = .011), pN2 stage (odds ratio: 2.57; 95% confidence interval: 1.89-4.45; P = .0007), and fewer than 12 lymph nodes examined (odds ratio: 2.01; 95% confidence interval: 1.08-3.74; P = .028).

This study showed a significant risk of metachronous peritoneal metastases after curative-intent resection of obstructive colon cancer. The awareness of factors predisposing to metachronous peritoneal metastases could improve the treatment strategy of these patients.

Increased survival can be achieved in patients with colorectal cancer peritoneal metastases (CRPM) treated with cytoreductive surgery. The benefit of this strategy remains uncertain when CRPM are associated with extraperitoneal metastases (EPM). The aim of this study was to compare short- and long-term outcomes of patients treated with CRS for CRPM, with or without EPM.

This study included 413 consecutive patients who underwent CRS for CRPM: 120 with EPM (EPM+) and 293 without (EPM-). Patients with isolated ovarian metastases were included in EPM-group (n = 83).

EPM were mainly located to the liver (66 %,n = 79), retroperitoneal lymph nodes (33 %,n = 40); less frequently to the spleen (9 %,n = 12), lung (9 %,n = 10) or pleura (1 %,n = 1). Ovarian metastases were present in 126 patients (83 in EMP-, 43 in EPM+). Peritoneal carcinomatosis index (PCI) was similar in EPM- (8 [4-14]) and EPM+ (8 [3-13],p = 0.335) groups, as postoperative mortality (3 % vs 3 %,p = 1) and major morbidity rates (28 % vs 35 %,p = 0.223). Median overall survival (mOS) and disease-free survival were significantly higher in the EPM-group (58m vs 39m, and 16m vs 10m,p = 0.003). We highlighted 3 prognostic groups 1) EPM-with PCI<10 (mOS 93m), 2) EPM+ with PCI<10 (mOS 57m), 3) EPM-with 1015 regardless EPM (mOS 26m, p < 0.001).

Complete cytoreductive surgery seems to be feasible in patients with EPM, without increase in postoperative morbidity and mortality compared to patients without EPM. This strategy provides prolonged survival in selected patients with limited peritoneal metastases from colorectal cancer.

The peritoneal metastasized colorectal cancer (pmCRC) represents a serious health problem worldwide with a special emphasis in the developed countries. Several guidelines recognize the role of multimodal therapy consisting of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of pmCRC. New data suggests that some other factors, eg, tumor biology, immune profile, neoadjuvant chemotherapy may play a predictive role for the oncological outcome of these patients.

The presence at diagnosis, or development of, colorectal peritoneal metastases (CPM) is common in colorectal cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) show promising results in selected patients with CPM. The current study aimed to describe oncologic outcomes of patients with CPM, focusing on recurrence patterns and risk factors for adverse events.

We conducted a retrospective review of patients with CPM treated by CRS and HIPEC at a single institution between 2000 and 2021.

A total of 555 patients were included, of whom 480 (86.5%) had complete cytoreduction, with a median age of 59 years and median Peritoneal Cancer Index (PCI) of 6. Following complete cytoreduction, 5-year overall survival (OS) and disease-free survival (DFS) were 51% and 31%, respectively. In multivariable Cox regression, PCI >6 (hazard ratio [HR] 2.25), pathological node positivity (pN+; HR 1.94), and perineural invasion (HR 1.85) were associated with decreased OS, while PCI >6, pN+, and previous systemic metastases resulted in reduced DFS. Overall, 284 (62%) patients developed recurrence, of whom 97 (34%) had local recurrence (LR), 100 (35%) had systemic recurrence (SR), and 87 (31%) had combined recurrence (5-year OS: 49.3%, 46%, and 37.4%, respectively). Mutated KRAS (mKRAS) was associated with lower 5-year OS (55.8%) and DFS (27.9%) compared with wild-type KRAS (wtKRAS; 70.7% and 37.6%, respectively). In multivariable analyses, mKRAS was related to decreased OS (HR 1.82), DFS (HR 1.55), and SR (OS 1.89), but not to LR.

Complete cytoreduction results in good survival outcomes for patients with CPM. Burden of peritoneal disease and tumor biology are the main predictors of survival. Patients with mKRAS are a high-risk cohort, with increased probability of SR and reduced survival.

This study aimed to investigate the risk factors for peritoneal recurrence (PR) in patients with stage II to III colorectal cancer who underwent colorectal surgery.

A retrospective study was conducted on 232 patients who underwent colorectal surgery for stage II to III colorectal cancer. Univariate and multivariate analyses were performed to determine risk factors for PR.

The overall incidence of PR was 8.2 % (19/232). A univariate Cox regression analysis showed that a higher level of carcinoembryonic antigen (CEA) (P = 0.039), higher levels of carbohydrate antigen 19-9 (CA19-9) (P < 0.001), preoperative bowel obstruction (P = 0.011), tumor invasion of T4 category (P = 0.019), lymph node metastasis (P = 0.016), poorly differentiated, mucinous or signet-ring histological type (P = 0.010), larger amount of intraoperative bleeding (P = 0.002), R1 resection (P = 0.003), anastomotic leakage Clavien-Dindo classification (CD) ≥2 (P = 0.018), longer postoperative stay (P = 0.002), and recurrence of other organs preceding disseminated recurrence (P = 0.004) were observed significantly more frequently in patients with PR than in patients without PR. A multivariate Cox regression analysis revealed that poorly differentiated, mucinous, or signet-ring histological type (HR: 5.067, 95 % CI: 1.192-21.534, P = 0.028) and intraoperative bleeding (HR: 1.003, 95 % CI: 1.000-1.005, P = 0.017) were independent risk factors for PR. Peritoneal recurrence-free survival curves generated using the Kaplan-Meier method gradually worsened with increasing intraoperative bleeding (P < 0.001). In addition, the sub-analyses between stage II and stage III and between ≤ cT3 and cT4 also demonstrated that peritoneal recurrence-free survival worsened with increasing intraoperative bleeding.

Our findings suggest that histological type, and intraoperative bleeding are risk factors for PR in patients who undergo colorectal surgery for stage II to III colorectal cancer. In particular, peritoneal recurrence is associated with increased intraoperative bleeding.

We compared the relative benefits, harms and cost-effectiveness of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery ± systemic chemotherapy versus cytoreductive surgery ± systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric or ovarian cancers by a systematic review, meta-analysis and model-based cost-utility analysis.

We searched MEDLINE, EMBASE, Cochrane Library and the Science Citation Index, ClinicalTrials.gov and WHO ICTRP trial registers until 14 April 2022. We included only randomised controlled trials addressing the research objectives. We used the Cochrane risk of bias tool version 2 to assess the risk of bias in randomised controlled trials. We used the random-effects model for data synthesis when applicable. For the cost-effectiveness analysis, we performed a model-based cost-utility analysis using methods recommended by The National Institute for Health and Care Excellence.

The systematic review included a total of eight randomised controlled trials (seven randomised controlled trials, 955 participants included in the quantitative analysis). All comparisons other than those for stage III or greater epithelial ovarian cancer contained only one trial, indicating the paucity of randomised controlled trials that provided data. For colorectal cancer, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably results in little to no difference in all-cause mortality (60.6% vs. 60.6%; hazard ratio 1.00, 95% confidence interval 0.63 to 1.58) and may increase the serious adverse event proportions compared to cytoreductive surgery ± systemic chemotherapy (25.6% vs. 15.2%; risk ratio 1.69, 95% confidence interval 1.03 to 2.77). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone (40.8% vs. 60.8%; hazard ratio 0.55, 95% confidence interval 0.32 to 0.95). For gastric cancer, there is high uncertainty about the effects of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy versus cytoreductive surgery + systemic chemotherapy or systemic chemotherapy alone on all-cause mortality. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to cytoreductive surgery + systemic chemotherapy (46.3% vs. 57.4%; hazard ratio 0.73, 95% confidence interval 0.57 to 0.93). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy may not be cost-effective versus cytoreductive surgery + systemic chemotherapy for colorectal cancer but may be cost-effective for the remaining comparisons.

We were unable to obtain individual participant data as planned. The limited number of randomised controlled trials for each comparison and the paucity of data on health-related quality of life mean that the recommendations may change as new evidence (from trials with a low risk of bias) emerges.

In people with peritoneal metastases from colorectal cancer with limited peritoneal metastases and who are likely to withstand major surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should not be used in routine clinical practice (strong recommendation). There is considerable uncertainty as to whether hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy or cytoreductive surgery + systemic chemotherapy should be offered to patients with gastric cancer and peritoneal metastases (no recommendation). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should be offered routinely to women with stage III or greater epithelial ovarian cancer and metastases confined to the abdomen requiring and likely to withstand interval cytoreductive surgery after chemotherapy (strong recommendation).

More randomised controlled trials are necessary.

This study is registered as PROSPERO CRD42019130504.

This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/135/02) and is published in full in Health Technology Assessment; Vol. 28, No. 51. See the NIHR Funding and Awards website for further award information.

Cytoreductive surgery and chemotherapy reportedly improve the prognosis of patients with metachronous peritoneal metastases. However, the types of peritoneal metastases indicated for cytoreductive surgery remains unclear. Therefore, we aimed to clarify the category of cases for which cytoreductive surgery would be effective and report the prognosis associated with cytoreductive surgery for metachronous peritoneal metastases.

This study included 52 consecutive patients who underwent cytoreductive surgery for metachronous peritoneal metastases caused by colorectal cancer between January 2005 and December 2018 and fulfilled the selection criteria. The median follow-up period was 54.9 months. Relapse-free survival was calculated as the time from cytoreductive surgery of metachronous peritoneal metastases to recurrence. Overall survival was defined as the time from cytoreductive surgery of metachronous peritoneal metastases to death or the end of the follow-up period.

The 5-year relapse-free survival rate was 30.0% and the 5-year overall survival rate was 72.3%. None of the patients underwent hyperthermic intraperitoneal chemotherapy. The analysis indicated no potential risk factors for 5-year relapse-free survival. However, for 5-year overall survival, the multivariate analysis revealed that time to diagnosis of metachronous peritoneal metastases of < 2 years after primary surgery (hazard ratio = 4.1, 95% confidence interval = 2.0-8.6, p = 0.0002) and number of metachronous peritoneal metastases ≥ 3 (hazard ratio = 9.8, 95% confidence interval = 2.3-42.3, p = 0.002) as independent factors associated with a poor prognosis.

Long intervals of more than 2 years after primary surgery and 2 or less metachronous peritoneal metastases were good selection criteria for cytoreductive surgery for metachronous peritoneal metastases from colorectal cancer.

Even with systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC), peritoneal metastases (PM) remain a common site of disease progression for colorectal cancer (CRC) and are frequently associated with a poor prognosis. The mass spectrometry (MS) method known as Matrix-Assisted Laser Desorption/Ionization - Time of Flight (MALDI-TOF) is frequently used in medicine to identify structural compounds and biomarkers. It has been demonstrated that lipids are crucial in mediating the aggressive growth of tumors. In order to investigate the lipid profiles, particularly with regard to histological distribution, we used MALDI-TOF MS (MALDI-MS) and MALDI-TOF imaging MS (MALDI-IMS) on patient-derived tumor organoids (PDOs) and PM clinical samples. According to the MALDI-IMS research shown here, the predominant lipid signature of PDOs in PM tissues, glycosphingolipid (GSL) sulfates or sulfatides, or STs, is unique to the areas containing tumor cells and absent from the surrounding stromal compartments. Bioactive lipids are derived from arachidonic acid (AA), and AA-containing phosphatidylinositol (PI), or PI (18:0-20:4), is shown to be highly expressed in the stromal components. On the other hand, the tumor components contained a higher abundance of PI species with shorter and more saturated acyl chains (C34 and C36 carbons). The cellular subversion of PI and ST species may alter in ways that promote the growth, aggressiveness, and metastasis of tumor cells. Together, these findings suggest that the GSL/ST metabolic programming of PM may contain novel therapeutic targets to impede or halt PM progression.

There is uncertainty in the relative benefits and harms of hyperthermic intraoperative peritoneal chemotherapy (HIPEC) when added to cytoreductive surgery (CRS) +/- systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric, or ovarian cancers.

We searched randomized controlled trials (RCTs) in the medical literature until April 14, 2022 and applied methods used for high-quality systematic reviews.

We included a total of eight RCTs (seven RCTs included in quantitative analysis as one RCT did not provide data in an analyzable format). All comparisons other than ovarian cancer contained only one trial. For gastric cancer, there is high uncertainty about the effect of CRS + HIPEC + systemic chemotherapy. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, CRS + HIPEC + systemic chemotherapy probably decreases all-cause mortality compared to CRS + systemic chemotherapy. For colorectal cancer, CRS + HIPEC + systemic chemotherapy probably results in little to no difference in all-cause mortality and may increase the serious adverse events proportions compared to CRS +/- systemic chemotherapy, but probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone.

The role of CRS + HIPEC in gastric peritoneal metastases is uncertain. CRS + HIPEC should be standard of care in women with stage III or greater epithelial ovarian cancer undergoing interval CRS. CRS + systemic chemotherapy should be standard of care for people with colorectal peritoneal metastases, with HIPEC given only as part of a RCT focusing on subgroups and regimes.

CRD42019130504.

Peritoneal metastases (PM) in colorectal cancer (CRC) is associated with a dismal prognosis. Identifying and exploiting new biomarkers, signatures, and molecular targets for personalised interventions in the treatment of PM in CRC is imperative. We conducted transcriptomic profiling using RNA-seq data generated from the primary tissues of 19 CRC patients with PM. Using our dataset established in a previous study, we identified 1422 differentially expressed genes compared to non-metastatic CRC. The profiling demonstrated no differential expression in liver and lung metastatic CRC. We selected 12 genes based on stringent criteria and evaluated their expression patterns in a validation cohort of 32 PM patients and 84 without PM using real-time reverse transcription-polymerase chain reaction. We selected cartilage intermediate layer protein 2 (CILP2) because of high mRNA expression in PM patients in our validation cohort and its association with a poor prognosis in The Cancer Genome Atlas. Kaplan-Meier survival analysis in our validation cohort demonstrated that CRC patients with high CILP2 expression had significantly poor survival outcomes. Knockdown of CILP2 significantly reduced the proliferation, colony-forming ability, invasiveness, and migratory capacity and downregulated the expression of molecules related to epithelial-mesenchymal transition in HCT116 cells. In an in vivo peritoneal dissemination mouse knockdown of CILP2 also inhibited CRC growth. Therefore, CILP2 is a promising biomarker for the prediction and treatment of PM in CRC.

Neoadjuvant therapy has an established role in the treatment of patients with colorectal cancer. However, its role continues to evolve due to both advances in the available treatment modalities, and refinements in the indications for neoadjuvant treatment and subsequent surgery.

A narrative review of the most recent relevant literature was conducted.

Short-course radiotherapy and long-course chemoradiotherapy have an established role in improving local but not systemic disease control in patients with rectal cancer. Total neoadjuvant therapy offers advantages over short-course radiotherapy and long-course chemoradiotherapy, not only in terms of increased local response but also in reducing the risk of systemic relapses. Non-operative management is increasingly preferred to surgery in patients with rectal cancer and clinical complete responses but is still associated with some negative impacts on functional outcomes. Neoadjuvant chemotherapy may be of some benefit in patients with locally advanced colon cancer with proficient mismatch repair, although patient selection is a major challenge. Neoadjuvant immunotherapy in patients with deficient mismatch repair cancers in the colon or rectum is altering the treatment paradigm for these patients.

Neoadjuvant treatments for patients with colon or rectal cancers continue to evolve, increasing the complexity of decision-making for patients and clinicians alike. This review describes the current guidance and most recent developments.

Treatment of peritoneal surface malignancies makes physicians face demanding and new-fangled problems, as there are many uncertain aspects considering the outcomes of affected patients' prognoses. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are associated with favorable long-term outcomes in carefully selected patients with peritoneal metastases (PM). We aim to summarize the current results about the initial malignancies and their peritoneal spreads. The current literature has been scrutinized, and studies between 2016 and 2022 were included wherein long-term, progression-free (PFS), and overall survival (OS) data were considered relevant information. Medline, Embase, and Google Scholar have been the main sources. Hereby, we cover all the primer malignancies: gastric, ovarian, and colorectal cancers with peritoneal metastases (PM), malignant peritoneal mesothelioma, and pseudomyxoma peritonei. Examining the advances in the current peer-reviewed literature about the indications of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), target groups, risk factors, and other influencing elements, we intend to provide a complex state-of-the-art report, establishing the relevant aspects of that emerging treatment method.

Peritoneal metastases from colon cancer are a particularly challenging disease process given the limited response to systemic chemotherapy. In patients with isolated peritoneal metastases, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy offers a potential treatment option to these patients with limited peritoneal metastases as long as a complete cytoreduction is achieved. Decision about a patient's candidacy for this treatment modality should be undertaken by a multidisciplinary group at expert centers.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Whether adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) might prevent peritoneal metastases after curative surgery for high-risk colon cancer is an ongoing debate. This study aimed to determine 5-year oncologic outcomes of the randomized multicenter COLOPEC trial, which included patients with clinical or pathologic T4N0-2M0 or perforated colon cancer and randomly assigned (1:1) to either adjuvant systemic chemotherapy and HIPEC (n = 100) or adjuvant systemic chemotherapy alone (n = 102). HIPEC was performed using a one-time administration of oxaliplatin (460 mg/m2, 30 minutes, 42°C, concurrent fluorouracil/leucovorin intravenously), either simultaneously (9%) or within 5-8 weeks (91%) after primary tumor resection. Outcomes were analyzed according to the intention-to-treat principle. Long-term data were available of all 202 patients included in the COLOPEC trial, with a median follow-up of 59 months (IQR, 54.5-64.5). No significant difference was found in 5-year overall survival rate between patients assigned to adjuvant HIPEC followed by systemic chemotherapy or only adjuvant systemic chemotherapy (69.6% v 70.9%, log-rank; P = .692). Five-year peritoneal metastases rates were 63.9% and 63.2% (P = .907) and 5-year disease-free survival was 55.7% and 52.3% (log-rank; P = .875), respectively. No differences in quality-of-life outcomes were found. Our findings implicate that adjuvant HIPEC should still be performed in trial setting only.

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.

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.

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.

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.

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.

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.

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.

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).

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.

Prognostic scores are developed to facilitate the selection of patients with colorectal cancer peritoneal metastases (CRPM) for treatment with cytoreductive surgery (CRS) ± intraperitoneal chemotherapy (IPC). Three prominent prognostic scores are the Peritoneal Surface Disease Severity Score (PSDSS), the Colorectal Peritoneal Metastases Prognostic Surgical Score (COMPASS), and the modified COloREctal-Pc (mCOREP). We externally validate these scores and compare their predictive accuracy.

Data from consecutive CRPM patients who underwent CRS/IPC from 1996 to 2018 was used to externally validate COMPASS, PSDSS, and mCOREP. Analysis evaluated the efficacy of each score in predicting (1) open-close laparotomy-those found at laparotomy to not be eligible for curative intent CRS/IPC, (2) surgical futility-those who underwent open-close laparotomy, palliative debulking surgery, or had an overall survival of less than 12 months, and (3) overall and recurrence-free survival (OS, RFS).

Prognostic scores were calculated for the 174-patient external validation cohort. COMPASS was most accurate in predicting open-close laparotomy, futile surgery, and survival (OS and RFS). Area under the curve (AUC) for open-close prediction was 0.78 (95% confidence interval, CI: 0.68-0.87), representing useful discrimination. However, AUC for futility prediction was 0.62 (95% CI: 0.52-0.71), and C-statistic for OS was 0.65 indicating only possibly helpful discrimination. C-statistic for RFS was 0.59 indicating poor discrimination.

While COMPASS showed the best statistical behavior, accuracy for several clinically relevant outcomes remains low, and thus applicability to clinical practice limited.

Metachronous peritoneal metastases (MPM) following a curative surgery procedure for pT4 colon cancer is a challenging condition. Current epidemiological studies on this topic are scarce.

A retrospective multicentre trial was designed. All consecutive patients who underwent operations to treat pT4 cancers between 2015 and 2017 were reviewed. Demographic, clinical, operative, pathological and oncological follow-up variables were included. MPM were described as any oncological disease at the peritoneum, clearly different from a local recurrence. Univariate and multivariate Cox regression models were constructed. A risk stratification model was created on a cumulative factor basis. According to the calculated hazard ratio (HR), a scoring system was designed (HR < 3, 1 point; HR > 3, 2 points) and a scale from 0 to 6 was calculated for peritoneal disease-free rate (PDF-R). A risk stratification model was also created on the basis of these calculations.

Fifty different hospitals were involved, which included a total of 1356 patients. Incidence of MPM was 13.6% at 50 months median follow-up. The strongest independent risk factors for MPM were positive pN stage [HR 3.72 (95% CI 2.56-5.41; p < 0.01) for stage III disease], tumour perforation [HR 1.91 (95% CI 1.26-2.87; p < 0.01)], mucinous or signet ring cell histology [HR 1.68 (95% CI 1.1-2.58; p = 0.02)], poorly differentiated tumours [HR 1.54 (95% CI 1.1-2.2; p = 0.02)] and emergency surgery [HR 1.42 (95% CI 1.01-2.01; p = 0.049)]. In the absence of additional risk factors, pT4 tumours showed 98% and 96% PDF-R in 1-year and 5-year periods based on Kaplan-Meier curves.

Cumulative MPM incidence was 13.6% at 5-year follow-up. The sole presence of a pT4 tumour resulted in high rates of PDF-R at 1-year and 5-year follow-up (98% and 96% respectively). Five additional risk factors different from pT4 status itself were identified as possible MPM indicators during follow-up.

Early detection and intervention could significantly improve the prognosis of patients with peritoneal metastasis (PM). Our main purpose was to develop a model to predict the risk of PM in patients with colorectal cancer (CRC).

Patients from the Surveillance, Epidemiology, and End Results (SEER) database with CRC classified according to the AJCC 8th TNM staging system were selected for the study. After data pre-processing, the dataset was divided into a training set and a validation set. In the training set, univariate logistic analysis and stepwise multivariate logistic regression analysis were utilized to screen clinical features and construct a risk prediction model. Then, we validated the model using the confusion matrix, receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves to examine its performance.

The model constructed using stepwise multivariate logistic regression analysis incorporated the following eight clinical features: age, tumor location, histological type, T stage, carcinoembryonic antigen (CEA) level, tumor deposits (TDs), log odds (LODDS) of metastatic lymph nodes, and extraperitoneal metastasis (EM). The areas under the curve (AUCs) of the model in the training and validation sets were 0.924 and 0.912, respectively. The accuracy and the recall ratio were higher than 0.8 in both cohorts. DCA and the calibration curves also confirmed its excellent predictive power.

Our model can effectively predict the risk of PM in CRC patients, which is of great significance for the timely identification of patients at high risk of PM and further clinical decision-making.

Despite improvements in characterization of CRC heterogeneity, appropriate risk stratification tools are still lacking in clinical practice. This study aimed to elucidate the primary tumor transcriptomic signatures associated with distinct metastatic routes.

Primary tumor specimens obtained from CRC patients with either isolated LM (CRC-Liver) or PM (CRC-Peritoneum) were analyzed by transcriptomic mRNA sequencing, gene set enrichment analyses (GSEA) and immunohistochemistry. We further assessed the clinico-pathological associations and prognostic value of our signature in the COAD-TCGA independent cohort.

We identified a significantly different distribution of Consensus Molecular Subtypes between CRC-Liver and CRC-peritoneum groups. A transcriptomic signature based on 61 genes discriminated between liver and peritoneal metastatic routes. GSEA showed a higher expression of immune response and epithelial invasion pathways in CRC-Peritoneum samples and activation of proliferation and metabolic pathways in CRC-Liver samples. The biological relevance of RNA-Seq results was validated by the immunohistochemical expression of three significantly differentially expressed genes (ACE2, CLDN18 and DUSP4) in our signature. In silico analysis of the COAD-TCGA showed that the CRC-Peritoneum signature was associated with negative prognostic factors and poor overall and disease-free survivals.

CRC primary tumors spreading to the liver and peritoneum display significantly different transcriptomic profiles. The implementation of this signature in clinical practice could contribute to identify new therapeutic targets for stage IV CRC and to define individualized follow-up programs in stage II-III CRC.

Metastatic colorectal cancer (CRC) is a common cause of cancer-related mortality, of which peritoneal metastases (PMs) have the worse outcome. Metastasis-specific markers may help predict the spread of tumor cells and select patients for preventive strategies. This exploratory pilot study aimed to gain more insight into genetic alterations in primary CRC tumors, which might be a predictive factor for the development of PM. Forty patients with T3 stage CRC were retrospectively divided in three groups: without metachronous metastases during 5-year follow-up (M0, n = 20), with metachronous liver metastases (LM, n = 10) and with metachronous PM (PM, n = 10). Patients with synchronous metastases were excluded. Primary formalin-fixed paraffin-embedded tumor samples were analyzed via comprehensive genome sequencing (TSO500 analysis) to identify DNA alterations and RNA fusion transcripts in 523 genes and 55 genes, respectively. Thirty-eight samples were included for final analysis. Four M0 tumors and one PM tumor were microsatellite instable. BRAF mutations were uniquely identified in three microsatellite-stable (MSS) PM tumors (37.5%, p = 0.010). RNA analysis showed an additional FAM198A-RAF1 fusion in one PM sample. BRAF p.V600E mutations were only present in PM patients with MSS tumors. Greater attention should be paid to BRAF-mutated tumors in relation to the development of metachronous PM.

With better patient selection and the increasing experience in patients undergoing hyperthermic intraperitoneal chemotherapy (HIPEC) combined surgery, the rate of severe postoperative complications and mortality decreased significantly. However, leukopenia and neutropenia were still a particular concern, and their relation to sarcopenia was not clarified.

Data of consecutive patients who underwent HIPEC for gastrointestinal cancer were collected and analyzed retrospectively between September 2020 and August 2022. Sarcopenia was assessed using psoas muscle index (PMI) at the L3 level on preoperative computed tomography (CT).

Among 103 patients enrolled, 37 (35.9%) were classified as sarcopenic. Most leukopenia and neutropenia occurred during the hospital leaving period after HIPEC and surgery. Before the first time of postoperative chemotherapy, the blood tests revealed 11 (29.73%) and 6 (9.09%) patients were diagnosed with neutropenia in sarcopenia and no sarcopenia groups, respectively. Logistic regression analysis revealed sarcopenia was independently associated with the increased risk of neutropenia (OR 5.58, 95% CI 1.70-18.29, p = 0.005). An incremental albumin level was protective against the occurrence of leukopenia and neutropenia.

Sarcopenia and low albumin level were significantly associated with an increased rate of delayed neutropenia after HIPEC in that disease setting and could be the preoperative risk predictors.

The drug selection of radical surgery (RS), with hyperthermic intraperitoneal chemotherapy (HIPEC), in pT4 colorectal cancer (CRC) remains controversial.

Adverse events after HIPEC were estimated by common terminology criteria for adverse events version 5.0. The efficacy was evaluated using overall survival (OS) and recurrence-free rate (RFR). Propensity score matching (PSM) was used to reduce the influence of confounders between Mitomycin and Lobaplatin groups.

Of the 146 patients, from April 2020 to March 2021, 47 were managed with mitomycin and 99 with lobaplatin. There was no significant difference in the incidence of all adverse events between the two groups after PSM. OS and RFR were not significantly different between the two groups at 22 months (p = 0.410; p = 0.310). OS and RFR of the two groups also showed no significant difference for patients with T4a or T4b stage, tumor size < or ≥ 5 cm. Among patients with colon cancer, RFR at 22 months of the two groups was significantly different (100.0% vs. 63.2%, p = 0.028).

In summary, the safety of mitomycin and lobaplatin for HIPEC was not different. Compared with lobaplatin, mitomycin for HIPEC after RS could benefit patients with colon cancer in RFR.

As colorectal cancer (CRC) patients with peritoneal metastases (PM) have a poor prognosis, new treatment options are currently being investigated for CRC patients. Specific biomarkers in the primary tumor could serve as a prediction tool to estimate the risk of distant metastatic spread. This would help identify patients eligible for early treatment.

To give an overview of previously studied DNA and RNA alterations in the primary tumor correlated to colorectal PM and investigate which gene mutations should be further studied.

A systematic review of all published studies reporting genomic analyses on the primary tissue of CRC tumors in relation to PM was undertaken according to PRISMA guidelines.

Overall, 32 studies with 18,906 patients were included. BRAF mutations were analyzed in 17 articles, of which 10 found a significant association with PM. For all other reported genes, no association with PM was found. Two analyses with broader cancer panels did not reveal any new biomarkers.

An association of specific biomarkers in the primary tumors of CRC patients with metastatic spread into peritoneum could not be proven. The role of BRAF mutations should be further investigated. In addition, studies searching for potential novel biomarkers are still required.