Metachronous Peritoneal Metastases Research Articles

Effectiveness of peritoneal lavage fluid circulating tumour cells and circulating tumour DNA in the prediction of metachronous peritoneal metastasis of gastric cancer (pT4NxM0/pT1-3N+M0) after radical resection: protocol of a prospective single-centre clinical study

BackgroundGastric cancer (GC) is the fourth leading cause of cancer mortality worldwide. Peritoneal metastasis (PM) is a significant cause of death in patients with GC, and presents a major challenge...

Anastomotic leakage following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: A clinical cohort study

BackgroundExtended oncological resections for colorectal cancer surgery are associated with a high rate of complications, especially anastomotic leakage (AL). This study determines the incidence of risk factors for postoperative complications following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer (CRC). MethodsIn this cohort study, the clinical data of all patients with CRC, treated with CRS and HIPEC, from 2011 to 2021 was analyzed. We considered patients' characteristics, tumor-specific features, postoperative complications, and hospital stay using Chi-Square-test or Fisher's exact test. The Mann-Whitney-U-test was used to measure the probability of differences between two sets of data. ResultsOf 1089 HIPEC procedures performed in the study center, 185 patients with CRC and peritoneal metastasis were treated with CRS and HIPEC after formation of at least one anastomosis and therefore included in this study. This included synchronous and metachronous peritoneal metastasis with a mean peritoneal cancer index of 8.67 ± 5.22. In this cohort, AL occurred in 12 (6.5 %) patients. There was no correlation between the number of anastomoses and the occurrence of an AL (p = 0.401). ConclusionThis study reports a low risk of AL after CRS with HIPEC for CRC, comparable to other published data. If a complete cytoreduction seems possible, the risk of anastomotic leakage should not negatively influence the decision to resect. Further studies on this subject are essential to validate our findings.

Peritoneal metastases in patients with neuroendocrine neoplasms: a challenging site of metastases with clinical and prognostic implications.

Peritoneal metastases (PM) of neuroendocrine neoplasm (NEN) origin are identified with increasing frequency and exert a significant effect on quality of life and clinical status of the patients. The aim of this study was to identify the characteristics and the prognostic significance of PM in patients with NENs. A retrospective analysis of the data of patients from two tertiary referral centers was performed. We defined a control group of age- and gender-matched NEN patients with comparable stage IV disease but no PM. We analysed 70 patients (41 females) with PM. Small intestine was the most common primary NEN site (87.1%). PM prevalence was 10.3%. Forty-four patients presented with synchronous PM, whereas 26 developed metachronous PM. The majority of patients had other concomitant metastases (50 hepatic, 6 lung and 12 bone metastases). Twelve patients developed intestinal obstruction. After PM diagnosis, 76% of patients received treatment with somatostatin analogues while six patients (8.6%) were treated with peptide receptor radionuclide therapy (PRRT). The median progression-free survival (PFS) in the PRRT-treated group was 15months (95% CI 2-28). Median overall survival (OS) in the PM group was 142months [95% CI 71-213] while it was not reached in the control group. Peritoneal metastases show low prevalence among NEN patients and are most likely to develop in patients with small intestinal NENs and advanced metastatic disease. The presence of PM does seem to be associated with a negative prognostic impact on OS of NEN patients and their identification and prompt treatment is of major importance.

Recurrence and Survival Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Synchronous and Metachronous Peritoneal Metastases of Colorectal Origin

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has improved the 5-year survival for colorectal cancer (CRC) patients with peritoneal metastases (PM). Little is known about recurrence patterns and recurrence rates between synchronous (S) and metachronous (M) PM following CRS+HIPEC. We aimed to describe the recurrence patterns, overall survival (OS) and disease-free survival (DFS) in S-PM and M-PM patients after complete CRS+HIPEC. From June 2006 to December 2020, a prospective cohort study included 310 CRC patients, where 181 patients had S-PM (58.4%) and 129 patients had M-PM (41.6%). After a median 10.3-month follow-up, 247/310 (79.7%) patients experienced recurrence, and recurrence sites included isolated peritoneal (32.4%), multifocal (peritoneal and liver and/or lung(s)) (22.7%), isolated liver (17.8%), isolated lung (10.5%) and other (16.6%) sites. Recurrence patterns did not differ between S-PM and M-PM. M-PM patients had an impaired DFS compared to S-PM patients (9.4 months (95% CI: 7.3–12.1) vs. 12.5 months (95% CI: 11.2–13.9), p = 0.01). The median OS was similar for S-PM and M-PM (38.4 months (95% CI: 31.2–46.8) vs. 40.8 months (95% CI: 28.8–46.8), p = 0.86). Despite frequent recurrence at extraperitoneal locations, long-term survival was achievable after CRS+HIPEC in CRC patients with PM. The recurrence patterns and OS did not differ between groups, yet M-PM patients had a shorter DFS.

Oncogenic aberrations in primary gastric cancer tumors to predict metachronous peritoneal metastasis.

392 Background: Peritoneal metastases (PM) in gastric cancer (GC) portend a poor prognosis. Yet, there are a paucity of data on underlying genomic alterations predictive of GCPM. Methods: Two-hundred and nine patients who underwent primary tumor (PT) surgical resection were included in the prospective cohort. Whole exome sequencing (WES) of these resected PT GC specimens (average coverage 129X for tumor samples, 70X coverage for matched normal/blood controls) were undertaken. Participants were followed-up longitudinally for peritoneal metastases. Results: Fifty-one (51/209, 24.4%) patients developed PM after a median follow-up duration of 87.0 months and had poorer survival outcomes compared to patients without metastasis (log-rank, p<0.001). Patients with bulkier and more advanced tumors were at increased hazard of PM (T-stage and N-stage stratified analysis, log-rank, p<0.0001). Consistent with known clinical outcomes, The Cancer Genome Atlas (TCGA) genomically stable (GS) subtype (log-rank, p=0.0059) and mesenchymal subtype GC were associated with a higher proclivity for peritoneal organotropism (log-rank, p=0.020). Among patients who developed PM, TP53 was the most commonly altered driver mutation (25/51, 49.0%), followed by ARID1A (9/51, 17.6%), CDH1 (8/51, 15.7%), PIK3CA (6/51, 11.8%). Comparing the PTs of patients with PM against those PTs without PM, ELF3, CDH1 and PIGR were significantly associated with PM (all adjusted p<0.05). Amongst TCGA GS tumors, ARID1A mutations (p=0.018) were significantly associated with PM compared to patients with GS tumors with no metastasis. CDH1 mutations were found to significantly co-occur with PIGR and RHOA mutations and was mutually exclusive to TP53. ARID1A mutations were also found to significantly co-occur with multiple other mutations such as PTEN, PIK3CA, ERBB2, and KRAS. Conclusions: CDH1, PIGR, ELF3 mutations in primary GC tumors were found to be significantly associated with metachronous PM.

OGC P19 Peritoneal metastases from gastric cancer in a nationwide cohort: incidence, treatment and survival

Abstract Background The aims of this study were to investigate incidence, risk factors and treatment of synchronous or metachronous peritoneal metastases (PM) from gastric cancer and to estimate survival of these patients using population-based data. Methods Patients diagnosed with gastric cancer in 2015-2016 were selected from the Netherlands Cancer Registry. The incidence of synchronous and metachronous PM were calculated. Multivariable regression analyses were performed to identify factors associated with the occurrence of PM. Treatment and survival were compared between patients with synchronous and metachronous PM. Results Of 2147 patients with gastric cancer, 656 (31%) were diagnosed with PM. Of these, 498 (23%) had synchronous PM. The cumulative incidence of metachronous PM in patients who underwent potentially curative treatment (n=675) was 22.8% at 3 years. A factor associated with synchronous and metachronous PM was diffuse type histology. Patients diagnosed with synchronous PM more often received systemic treatment than patients with metachronous PM (35% vs. 18% respectively, p<0.001). Median overall survival was comparable between synchronous and metachronous PM (3.2 vs. 2.3 months respectively, p=0.731). Conclusions Approximately one third of all patients with gastric cancer are diagnosed with PM, either at primary diagnosis or during 3-year follow-up after potentially curative treatment. Patients with metachronous PM less often received systemic treatment than those with synchronous PM but survival was comparable between both groups. Future trials are warranted to detect gastric cancer at an earlier stage and to examine strategies that lower the risk of peritoneal dissemination. Also, specific treatment options for patients with gastric PM should be further investigated.

Peritoneal metastases from gastric cancer in a nationwide cohort: Incidence, treatment and survival.

The aims of this study were to investigate incidence, risk factors and treatment of synchronous or metachronous peritoneal metastases (PM) from gastric cancer and to estimate survival of these patients using population-based data. Patients diagnosed with gastric cancer in 2015 to 2016 were selected from the Netherlands Cancer Registry. The incidence of synchronous and metachronous PM were calculated. Multivariable regression analyses were performed to identify factors associated with the occurrence of PM. Treatment and survival were compared between patients with synchronous and metachronous PM. Of 2206 patients with gastric cancer, 741 (34%) were diagnosed with PM. Of these, 498 (23%) had synchronous PM. The cumulative incidence of metachronous PM in patients who underwent potentially curative treatment (n = 675) was 22.8% at 3 years. A factor associated with synchronous and metachronous PM was diffuse type histology. Patients diagnosed with synchronous PM more often received systemic treatment than patients with metachronous PM (35% vs 18%, respectively, P < .001). Median overall survival was comparable between synchronous and metachronous PM (3.2 vs 2.3 months, respectively, P = .731). Approximately one third of all patients with gastric cancer are diagnosed with PM, either at primary diagnosis or during 3-year follow-up after potentially curative treatment. Patients with metachronous PM less often received systemic treatment than those with synchronous PM but survival was comparable between both groups. Future trials are warranted to detect gastric cancer at an earlier stage and to examine strategies that lower the risk of peritoneal dissemination. Also, specific treatment options for patients with gastric PM should be further investigated.

ASO Author Reflections: Localized Synchronous and Metachronous Peritoneal Metastases from Colorectal Cancer-Are They Candidates for Radical Resection?

ASO Author Reflections: Localized Synchronous and Metachronous Peritoneal Metastases from Colorectal Cancer-Are They Candidates for Radical Resection?

Clinical Impact of Radical Resection of Synchronous and Metachronous Peritoneal Metastases from Colorectal Cancer.

According to some case series, patients with colorectal cancer (CRC) who underwent radical resection of synchronous peritoneal metastases (PM) with the primary tumor had better survival than patients who underwent non-surgical treatment. However, little evidence exists regarding the significance of radical resection for metachronous PM. This study aimed to evaluate the clinical significance of surgical intervention for isolated PM from CRC, with a particular focus on time to PM. A total of 74 consecutive patients with isolated PM from CRC, including 40 and 34 patients with synchronous and metachronous PM, respectively, treated between 2007 and 2018 were retrospectively analyzed. The primary outcome measure was overall survival (OS) from diagnosis, and the OS was compared between radical resection and palliative chemotherapy. Five-year OS was 39.7% for all patients. Patients with radical resection had significantly better 5-year OS compared with those with palliative chemotherapy (62.8% vs. 11.0%; p<0.0001). According to time to PM, patients with radical resection had significantly better 5-year OS compared with those with palliative chemotherapy for both synchronous PM (47.6% vs. 0%; p=0.019) and metachronous PM (77.2% vs. 15.2%; p<0.0001). Multivariable analysis stratified by time to PM revealed that surgical intervention is a significant favorable prognostic factor only in patients with metachronous PM (hazard ratio 0.117, 95% confidence interval 0.020-0.678; p=0.017). Patients with radical resection of PM had good survival compared with those with chemotherapy alone, especially for metachronous PM. Surgical intervention should be considered for isolated metachronous PM when radical resection is feasible.

Predictive Genetic Biomarkers for the Development of Peritoneal Metastases in Colorectal Cancer.

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.

15-month safety and efficacy data after intraperitoneal treatment with 224Radium-labelled microparticles after CRS-HIPEC for peritoneal metastasis from colorectal cancer.

3518 Background: Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis. Improved survival can be achieved by extensive cytoreductive surgery (CRS), frequently used together with hyperthermic intraperitoneal chemotherapy (HIPEC), with median time to recurrence around 12 months. Radspherin is a novel treatment principle based on the delivery of short range and cytotoxic alpha particles emitted during the decay of 224Ra. Alpha particles have high linear energy transfer and a radiation range less than 100 µm (3-10 cell diameters), generating highly localized and effective radiation with non-repairable double-strand DNA breaks in affected cells. Our hypothesis is that Radspherin produces an alpha-particle radiation field exclusively to the surfaces and liquid volumes of the peritoneum, delivering lethal doses to remaining micrometastasis in the peritoneal linings and eradicate free-floating tumor cells after surgical resection, thus assumingly prolonging time to recurrence and potentially overall survival. Methods: A phase 1/2a study (EudraCT 2018-002803-33) is ongoing to evaluate safety, tolerability and signal of efficacy of Radspherin injected intraperitoneally two days after CRS-HIPEC. After completion of dose escalation (1-2-4-7 MBq), an activity-dose of 7 MBq was recommended. Assessment of safety and efficacy (diagnostic imaging) was performed every three months. Safety data and progression-free survival (PFS) at 15 months are presented. Results: Twenty-three patients (pts) were enrolled across cohorts (safety population), of these 12 pts received the recommended dose of 7MBq, 9 pts single dose and 3 pts split dose (3,5 MBq x2). Twelve pts had synchronous PM and 11 metachronous PM. Median age was 64 years (28-78), 70 % were female and median peritoneal cancer index was 7 (3-19). To date, 271 adverse events (AE) were reported, whereof only 7 (all grade 1-2) were deemed related to Radspherin. Fourteen serious adverse events (SAEs) in 8 pts have been reported, none considered related to Radspherin. At 15 months, 9 out of 23 pts (39 %) had recurred, whereof 4 pts recurred in the peritoneum. In the expansion cohort (7MBq), 3 out of 12 pts (25 %) had recurred and none of these pts had peritoneal recurrences. Median PFS was not reached in the two populations. Conclusions: Radspherin was well tolerated with no related SAEs reported. At 15 months median PFS has not been reached and none of the patients at recommended dose had peritoneal recurrences. The results are encouraging and warrant further exploration of Radspherin as a novel treatment principle in clinical trials. Clinical trial information: NCT03732781 .

Development and validation of a nomogram for predicting metachronous peritoneal metastasis in colorectal cancer: A retrospective study.

Peritoneal metastasis (PM) after primary surgery for colorectal cancer (CRC) has the worst prognosis. Prediction and early detection of metachronous PM (m-PM) have an important role in improving postoperative prognosis of CRC. However, commonly used imaging methods have limited sensitivity to detect PM early. We aimed to establish a nomogram model to evaluate the individual probability of m-PM to facilitate early interventions for high-risk patients. To establish and validate a nomogram model for predicting the occurrence of m-PM in CRC within 3 years after surgery. We used the clinical data of 878 patients at the Second Hospital of Jilin University, between January 1, 2014 and January 31, 2019. The patients were randomly divided into training and validation cohorts at a ratio of 2:1. The least absolute shrinkage and selection operator (LASSO) regression was performed to identify the variables with nonzero coefficients to predict the risk of m-PM. Multivariate logistic regression was used to verify the selected variables and to develop the predictive nomogram model. Harrell's concordance index, receiver operating characteristic curve, Brier score, and decision curve analysis (DCA) were used to evaluate discrimination, distinctiveness, validity, and clinical utility of this nomogram model. The model was verified internally using bootstrapping method and verified externally using validation cohort. LASSO regression analysis identified six potential risk factors with nonzero coefficients. Multivariate logistic regression confirmed the risk factors to be independent. Based on the results of two regression analyses, a nomogram model was established. The nomogram included six predictors: Tumor site, histological type, pathological T stage, carbohydrate antigen 125, v-raf murine sarcoma viral oncogene homolog B mutation and microsatellite instability status. The model achieved good predictive accuracy on both the training and validation datasets. The C-index, area under the curve, and Brier scores were 0.796, 0.796 [95% confidence interval (CI) 0.735-0.856], and 0.081 for the training cohort and 0.782, 0.782 (95%CI 0.690-0.874), and 0.089 for the validation cohort, respectively. DCA showed that when the threshold probability was between 0.01 and 0.90, using this model to predict m-PM achieved a net clinical benefit. We have established and validated a nomogram model to predict m-PM in patients undergoing curative surgery, which shows good discrimination and high accuracy.

Prolonged Survival in Peritoneal Metastatic Appendiceal Carcinoma Patients Treated With Combined Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

IntroductionPrimary treatment for peritoneal dissemination of appendiceal cancer is the combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. The endpoints were overall survival and evaluation of prognostic factors. MethodsClinicopathological and treatment-related factors were obtained from a prospective database. A total of 84 patients, 55 (65%) primary and 29 (35%) recurrent malignant appendiceal carcinomas with synchronous and metachronous peritoneal metastases, underwent multimodal treatment between 2011 and 2021. The endpoints of the study were overall survival and evaluation of prognostic factors. ResultsThe median follow-up was 4.8 y; the mean age was 54.5 y (range 25-77), with a sex distribution of 69% female and 31% male. The mean peritoneal cancer index was 11.3. The proportion of mucinous, intestinal-type, signet ring cell, and goblet cell carcinoma was 56%, 23%, 11%, and 10%, respectively. The 5-y survival rate of the whole cohort was 56.7%. In primary and recurrent diseases, the overall median survival was 8.4 and 4.9 y. Significantly improved survival was detected after complete cytoreduction resection (hazard ratio [HR] for CCR-2 versus CCR-0: 9.388, 95% confidence interval [CI] 3.026-29.124, P = 0.001) and initial local operation with undelayed admission to the center (HR 0.262, 95% CI 0.089-0.773; P = 0.015). The five independent factors in Kaplan–Meier analysis and univariable Cox regression analysis associated with significant adverse survival were cancer antigen (CA) 19-9 over 37 IU/mL, signet ring cell and intestinal-type histology, positive nodal status, grading, and peritoneal cancer index >20. Neoadjuvant chemotherapy administration did not impact survival (HR 1.220, 95% CI 0.612-2.432, P = 0.571). ConclusionsWith multimodal treatment, prolonged survival is attainable in stage IV primary and recurrent appendiceal carcinoma with peritoneal dissemination. Direct referral to specialized centers after confirmation of peritoneal metastasis is recommended because prompt definitive treatment may significantly improve survival.

Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery for gastric carcinoma at high risk of peritoneal carcinomatosis: short and long-term outcomes (GOETH STUDY)—a collaborative randomized controlled trial by ACOI, FONDAZIONE AIOM, SIC, SICE, and SICO

IntroductionAt the time of diagnosis, 15–20% of gastric carcinomas are in stage T4 or T4b. Furthermore, 5–20% of patients undergoing potentially curative surgery suffer from synchronous or metachronous peritoneal metastases. To date, neither surgery nor systemic chemotherapy successfully controls peritoneal dissemination, offering a limited impact on survival. Peritoneal metastases are in fact responsible for death in around 60% of gastric cancer patients.Several Eastern studies in the past have focused on hyperthermic intraperitoneal chemotherapy (HIPEC) as a prophylactic measure in patients with serosal extension, nodal involvement, and positive peritoneal fluid cytology. Therefore, a new multimodal therapeutic strategy based on aggressive surgery plus new locoregional treatment may prolong survival in this particular clinical scenario.MethodsThis study compares the efficacy of prophylactic surgery (radical gastric resection, appendectomy, resection of the round ligament of the liver, and bilateral adnexectomy) plus hybrid CO2 HIPEC system versus standard surgery in patients with T3-T4 N0-N + gastric adenocarcinoma. Patients will be randomly assigned (1:1 ratio) to the experimental arm or standard surgery. The primary endpoint is to establish the difference in disease-free survival between the groups. The secondary objective is to compare the safety and tolerability of prophylactic surgery plus HIPEC CO2 versus standard surgery.DiscussionConsidering the poor prognosis of patients with peritoneal dissemination from gastric cancer, a prophylactic strategy to prevent peritoneal metastases may be beneficial. In patients with gastric cancer at high risk of peritoneal carcinomatosis, we propose aggressive surgical treatment with radical gastrectomy, removal of organs at risk of harbouring tumour cells, and HIPEC.Trial registrationClinicalTrials.gov NCT03917173. Registered on 16 April 2019.Protocol version: v1, March 27, 2019.Protocol number: IRFMN-GCC-7813.EudraCT number: 2019–001478-27.

Prognostic Factors of Survival in Patients with Peritoneal Metastasis from Colorectal Cancer.

Objectives: The aim of this study was to analyze the prognostic factors of survival in patients with peritoneal metastasis (PM) from colorectal cancer (CRC). The type of relationship between survival and the PM time of detection was used to determine whether it was synchronous with the primary tumor or metachronous. Patients and Methods: Retrospective observational study. It included patients treated for colorectal adenocarcinoma diagnosed between January 2005 and December 2019 who presented PM at the time of diagnosis or during follow-up. Variables, such as sex, age, differentiation grade, positive adenopathy (pN+), tumor size (pT), tumor location, mucinous component, peritoneal carcinomatosis index (PCI), and KRAS mutational status, were analyzed. Results: During the study period, 1882 patients were surgically treated for CRC in our hospital. Of these, 240 patients (12.8%) were included in the study after evidence of PM. The mean age was 67 ± 12 years (range: 32–92 years), and 114 patients were female (47.5%). The mean follow-up was 20 ± 13 months (median 12 months). The Kaplan–Meier survival at 36 months was higher in patients with metachronous PM (24% vs. 8%; p = 0.002), WT-KRAS tumors (31% vs. 15%; p < 0.001), N0 stage (30% vs. 19%; p < 0.001), T3 stage tumors (18% vs. 19% in T4A and 3% in T4B; p > 0.001), and tumors with classic adenocarcinoma histology (18% vs. 8%; p = 0.011). Patients with a PCI of 1–10 showed a likelihood of survival at 36 months of 56%, which was longer than that found in patients with a PCI of 11–20 (8%) or a PCI of >20 (0%) (p < 0.001). In the multiple regression analysis, the factors with an independent prognostic value were: poor grade of differentiation (HR 1.995; 95% CI: 1.294–3.077), KRAS mutation (HR 1.751; 95% CI: 1.188–2.581), PCI 11–20 (HR: 9.935; 95% CI: 5.204–18.966) and PCI > 20 (HR: 4.011; 95% CI: 2.291–7.023). Conclusions: PCI should continue as the as the most useful prognostic indicator in order to assess prognostic estimations as well as therapeutic and surgical decisions, but tumor grade and KRAS mutational status may help in the treatment decision process by providing complementary information. The time of PM detection did not achieve statistical significance in the multiple regression analysis.

Patients with Metachronous Peritoneal Metastatic Mucinous Colorectal Adenocarcinoma Benefit More from Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) than Their Synchronous Counterparts

Simple SummaryMucinous adenocarcinoma develops in 10–20% of all colorectal cancer (CRC) cases. This subtype is characterized by its worse clinicopathological features, including but not limited to more advanced stages at the time of tumor diagnosis, it being more frequent in the proximal colon, it showing mutation more frequently in CRC-specific protooncogenes, and its impaired response rate to various oncological treatments. Although several studies have investigated the benefits of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) in peritoneal metastatic CRC, limited data exist on the effect of mucinous CRC. Therefore, a retrospective study was conducted, and the following novel results were obtained. CRS + HIPEC is advantageous for both mucinous and non-mucinous CRC in metachronous cases, but the same cannot be said for those patients with synchronous metastases: the survival of mucinous CRC patients with synchronous peritoneal metastases was significantly worse despite the use of CRS + HPEC treatment.Background: Mucinous adenocarcinoma is a frequent subtype in colorectal cancer (CRC). A higher initial T-stage, poorer differentiation, worse response to anti-tumor therapies, and shorter survival are characteristic of mucinous CRC. Moreover, the therapeutic benefit of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) in mucinous CRC has not been significantly investigated. Methods: A retrospective analysis of 218 CRC patients with synchronous or metachronous peritoneal metastases was conducted. Results: 129 and 89 patients had synchronous and metachronous metastases, and 36 (27.8%) and 22 (24.8%) of these were mucinous CRC, respectively. Mucinous CRC was more frequent in the proximal colon, with a higher T-stage and N-stage and with an average peritoneal carcinomatosis index that was 2 values higher. Disease-specific survival was significantly worse in the synchronous mucinous group (median survival: 22.4 months vs. 36.3 months, p = 0.0229). In contrast, no such difference was observed in the metachronous cohort (32.6 months vs. 34.4 months, p = 0.6490). Conclusions: In the case of synchronous peritoneal metastases originating from mucinous CRC, the positive effect of CRS+HIPEC cannot be verified, and the added value of this highly invasive treatment is therefore somewhat questioned. However, CRS + HIPEC is recommended for metachronous metastases, since no difference between the two CRC-subtypes could be verified.

Analysis of perioperative efficacy and safety of cytoreductive surgery in the treatment of colorectal cancer peritoneal metastases

Objective: To analyzed perioperative safety of cytoreductive surgery (CRS) for patients with colorectal cancer peritoneal metastasis (CRPM) and to construct a predictive model for serious advese events (SAE). Methods: A descriptive case-series study was conducted to retrospectively collect the clinicopathological data and treatment status (operation time, number of organ resection, number of peritoneal resection, and blood loss, etc.) of 100 patients with peritoneal metastases from colorectal cancer or appendix mucinous adenocarcinoma who underwent CRS at the Sixth Affiliated Hospital of Sun Yat-sen University from January 2019 to August 2021. There were 53 males and 47 females. The median age was 52.0 (39.0-61.8) years old. Fifty-two patients had synchronous peritoneal metastasis and 48 had metachronous peritoneal metastasis. Fifty-two patients received preoperative neoadjuvant therapy. Primary tumor was located in the left colon, the right colon and the rectum in 43, 28 and 14 cases, respectively. Fifteen patients had appendix mucinous adenocarcinoma. Measures of skewed distribution are expressed as M (range). Perioperative safety was analyzed, perioperative grade III or higher was defined as SAE. Risk factors associated with the occurrence of SAEs were analyzed using multivariate logistic regression. A nomogram was plotted by R software to predict SAE, the efficacy of which was evaluated using the area under the ROC curve (AUC) and correction curves. Results: The median peritoneal cancer index (PCI) score was 16 (1-39). Sixty-eight (68.0%) patients achieved complete tumor reduction (tumor reduction score: 0-1). Sixty-two patients were treated with intraperitoneal hyperthermic perfusion chemotherapy (HIPEC). Twenty-one (21.0%) patients developed 37 SAEs of grade III-IV, including 2 cases of ureteral injury, 6 cases of perioperative massive hemorrhage or anemia, 7 cases of digestive system, 15 cases of respiratory system, 4 cases of cardiovascular system, 1 case of skin incision dehiscence, and 2 cases of abdominal infection. No grade V SAE was found. Multivariate logistic regression analysis showed that CEA (OR: 8.980, 95%CI: 1.428-56.457, P=0.019), PCI score (OR: 7.924, 95%CI: 1.486-42.259, P=0.015), intraoperative albumin infusion (OR: 48.959, 95%CI: 2.115-1133.289, P=0.015) and total volume of infusion (OR: 24.729, 95%CI: 3.956-154.562, P=0.001) were independent risk factors for perioperative SAE in CRS (all P<0.05). Based on the result of multivariate regression models, a predictive nomogram was constructed. Internal verification showed that the AUC of the nomogram was 0.926 (95%CI: 0.872-0.980), indicating good prediction accuracy and consistency. Conclusions: CRS is a safe and effective method to treat CRPM. Strict screening of patients and perioperative fluid management are important guarantees for reducing the morbidity of SAE.

First experience with 224Radium-labelled microparticles (radspherin) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study).

3599 Background: Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis. Improved survival can be achieved by combining extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). However, median time to recurrence is short (11-12 months) and there is a need for novel therapies to prevent subsequent PM. Radspherin consists of the α-emitting radionuclide radium-224 (224Ra), half-life 3.6 days, adsorbed to a suspension of biodegradable calcium carbonate microparticles, designed to give short-range radiation to the serosal peritoneal surface, aiming to kill remaining free cancer cells and small tumor cell clusters. Methods: A first-in-man phase 1 study (EudraCT 2018-002803-33) was conducted at two specialized CRS-HIPEC centers. Radspherin was injected in the abdominal cavity through a catheter 2 days after CRS-HIPEC. Dose escalation at increasing dose levels of 1-2-4-7-MBq, repeated injection and expansion cohorts evaluated the safety and tolerability of Radspherin, explored maximal tolerated dose and biodistribution by using single photon-emission computed tomography/computed tomography (SPECT/CT) imaging. Results from the planned safety interim analysis after completion of the dose-limiting toxicity (DLT) period are presented. Results: Twenty-three patients were enrolled, dose escalation cohort (14), repeated cohort (3) and expansion cohort (6). Nineteen patients were treated in Oslo/ 4 in Uppsala. Twelve patients had synchronous PM Stage IV and 11 metachronous PM (Stage II (6), Stage III (5). Disease-free interval 15 months (3-39); males (7), females (16); median age 64 years (28-78). Peritoneal cancer index was median 7 (3-19), operation time 395 minutes (194-515) and hospital stay 12 days (7-37). Accordion ≥3 grade events (6); including anastomotic leaks (2); abscess (1); drains (2) and missed lesion (1), all reported as serious adverse events (SAEs). The 7MBq dose was selected as recommended dose as no DLT was observed. A total of 185 treatment emergent adverse effects (TEAE) were recorded, most were of low grade and considered related to CRS and/or HIPEC. Few patients (7) had TEAEs considered related to a combined impact of Radspherin and CRS-HIPEC. The biodistribution of Radspherin showed a relatively even peritoneal distribution, and no patients had compartments of the abdominal cavity without radioactivity (cold spots), and low number had hot spots. Long-term safety, dosimetry and first efficacy results of Radspherin will be reported after 12 months follow up period. Conclusions: All dose levels of Radspherin were well tolerated with DLT not reached. No deaths occurred and no SAEs were considered related to Radspherin. The biodistribution of Radspherin showed good peritoneal distribution of the radiolabeled microparticles. Clinical trial information: 2018-002803-33.

The impact of BMI on the development of metachronous peritoneal metastases – results from a population-based cohort study in colorectal cancer patients

Background: This study aimed to assess the impact of body mass index (BMI) on the chance to develop metachronous peritoneal metastasis (CPM) in a nationwide cohort of colorectal cancer patients treated with curative intent.

Role of Early Bedside HIPEC as Adjuvant Treatment in Colorectal Peritoneal Metastasis

Objectives: Peritoneal metastasis (PM) is a poor prognostic factor for all malignancies and remains difficult to treat with systemic chemotherapy because of poor peritoneal vascularization, resulting in limited drug delivery and penetration into tissues. Our study aims to investigate the efficacy and safety of different locoregional treatment protocols with hyperthermic intraperitoneal chemotherapy (HIPEC), Early Peritoneal Chemotherapy (EPIC), Pressurized Intraperitoneal Chemotherapy (PIPAC) in the management of advanced colorectal cancer with metachronous PM. Methods: A total of 42 patients were divided into three groups, as follows. Group A: After neoadjuvant systemic chemotherapy, 15 patients received cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) and then adjuvant systemic chemotherapy. Group B: After neoadjuvant systemic chemotherapy, 12 patients received CRS + HIPEC + early postoperative intraperitoneal chemotherapy for 5 postoperative days and then adjuvant systemic chemotherapy. Group C: After neoadjuvant chemotherapy, 15 patients received CRS + HIPEC and then an adjuvant bedside HIPEC on the 10th postoperative day combined with postoperative adjuvant chemotherapy. Results: Patients in group A had a median overall survival (OS) of 33 months; however, log-rank tests showed that survival distributions of the three groups were not statistically significant different for both OS and disease-free survival. Conclusion: In conclusion, CRS plus HIPEC remains an alternative to locoregional treatment in well-selected patients with PM in combination with systemic neoadjuvant and adjuvant chemotherapy. Keywords: Hyperthermic Intraperitoneal Chemotherapy (HIPEC), Cytoreductive Surgery (CRS), Peritoneal Metastasis (PM), Colorectal Cancer (CRC), adjuvant treatment