Efficacy and safety of intraperitoneal chemotherapy for pancreatic cancer.

Pancreatic cancer is a highly aggressive cancer with unfavorable prognosis despite the therapeutic interventions. Intraperitoneal chemotherapy has recently shown potential outcomes in the presence of peritoneal metastases. However, a consensus is still lacking on different methods for intraperitoneal chemotherapy in pancreatic cancer. A variety of drugs and doses via three types of intraperitoneal chemotherapy have been studied. The prognosis and treatment strategies for pancreatic ductal adenocarcinoma (PDAC) will be significantly influenced by peritoneal dissemination and resectability of the macroscopic disease. Normothermic intraperitoneal chemotherapy (NIPEC) has been used for the treatment of peritoneal metastases of pancreatic carcinomas. Intraperitoneal chemotherapy is often combined with systemic therapies or surgical procedures which may lead to favorable combination therapies such as cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a relatively new approach that provides a homogenous and deep penetration of the chemotherapy into the peritoneum by producing aerosols. The present study aims to review the literature for recent evidence on intraperitoneal chemotherapy in pancreatic cancer.

CD8 + T-cells restrict the development of peritoneal metastasis and support the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC).

Multimodal therapy for peritoneal metastasis (PM) including cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provides long-term survival in highly selected colorectal cancer patients. Mechanisms behind HIPEC are unknown and may include induction of adaptive immunity. We therefore analyzed human PM samples and explored the impact of HIPEC in experimental models. Human samples from colorectal primary tumors (n = 19) and PM lesions (n = 37) were examined for the presence of CD8 + T-cells and their association with disease free (DFS) and overall survival (OS). CD8 + T cell response after HIPEC was assessed using an in-vivo PM mouse model, tumor cell lines and patient-derived tumor organoids. Patients with high intraepithelial CD8 + T cell counts showed longer DFS and OS. In the mouse model, HIPEC controlled growth of PM and increased numbers of functional granzyme positive CD8 + T cells within tumors. Cell lines and human organoids that were treated with heated chemotherapies showed immunogenic changes, reflected by significantly higher levels of MHC-class I molecules and expression of Cancer Testis Antigens Cyclin A1 and SSX-4. Using in-vitro co-culture assays, we noticed that cancer cells treated with heated chemotherapy primed dendritic cells, which subsequently enhanced effector functions of CD8 + T cells. The presence of CD8 + T-cells within PM lesions is associated with prolonged survival of patients with PM. Data from PM mouse model and in-vitro assay show that heated chemotherapies induce immunogenic changes on cancer cells leading to induction of CD8 + T-cells mediated immunity, which seems to control growth of PM lesions in mice after HIPEC.

Delay in Time to Adjuvant Chemotherapy and its Impact on Oncological Outcomes in Patients Undergoing Optimal Cytoreductive Surgery for Advanced Ovarian Cancer: Analysis of 1480 Cases From the Indian HIPEC Registry.

BACKGROUND AND OBJECTIVES: The impact of delay in initiation of adjuvant chemotherapy following optimal CRS in different settings of treatment for advanced ovarian cancer needs to be studied with special reference to CRS HIPEC. METHODS: The 1480 advanced EOC patients underwent optimal CRS, followed by adjuvant chemotheraphy, with or without intraperitoneal (IP) chemotherapy in Normothermic or Hyperthermic form. Interval between the day of surgery and start of adjuvant chemotherapy and its impact on outcome was analyzed. RESULTS: CRS, CRS with IP or HIPEC was done in 400, 480, and 600 patients respectively. Median interval of starting adjuvant chemotherapy was 32 days CRS group, 34 days CRS + IP group and 41 days CRS + HIPEC group. Delay in chemotherapy impacted on recurrence free survival (RFS) in CRS + IV group (36 vs. 17 months: p = 0.02) and some impact in CRS + IP group (38 vs. 28 months; P 0.78) and no impact on CRS + HIPEC group (35 vs. 32 months; p = 0.17). CONCLUSIONS: Delay in starting adjuvant chemotherapy adversely affects RFS in patients undergoing optimal CRS alone. However, the delay didn't have an impact in the CRS + HIPEC group. Well-designed clinical studies are required to evaluate the impact of single dose of HIPEC.

The rare occurrence of unifocal peritoneal mesothelioma: a case report, literature review, and future directions.

Background: Mesothelioma is a rare, aggressive disease originating from mesothelial cells and carries a poor prognosis. Mesothelioma may arise from the pleura, pericardium, or peritoneum. Peritoneal mesothelioma (PM) usually spreads in a diffuse manner; however, a localized unifocal form of PM may occur. Literature on unifocal mesothelioma remains scarce. Case Description: Herein, we highlight a case of localized epithelioid PM in an 81-year-old gentleman with the unique challenges faced during management. The pelvic mass was 7 cm, well-circumscribed, and hyper-vascular with fibrous attachments to the abdominal wall. The patient had a peritoneal cancer index (PCI) of 4 on initial diagnostic laparoscopy. Diagnosis was confirmed by histology. Resection of the mass with a partial omentectomy was performed. Months later, the patient developed recurrence detected on follow-up imaging in the peri-splenic region. The patient underwent cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) for 60 minutes using mitomycin C and cisplatin followed by an uneventful recovery. Our case report is followed by a review of literature on disease pathophysiology, treatment options, and recently promising immunotherapy approaches. Conclusions: CRS and HIPEC remains the standard treatment regimen for patients with PM. Nonetheless, a more nuanced approach might be indicated in specific patients with localized unifocal PM. Disease distribution and burden may impact the decision on surgical management in selected patients.

Long-Term Outcomes following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Colorectal Origin.

BACKGROUND: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a major treatment of colorectal peritoneal carcinomatosis (CPC). The aim was to determine the disease-free survival (DFS) and overall survival (OS) of patients undergoing CRS-HIPEC for CPC and factors associated with long-term survival (LTS). METHODS: consecutive CPC patients who underwent CRS-HIPEC at a HIPEC center between 2007 and 2021 were included. Actual survival was calculated, and Cox proportional hazards models were used to identify factors associated with OS, DFS and LTS. RESULTS: there were 125 patients with CPC who underwent primary CRS-HIPEC, with mean age of 54.5 years. Median follow-up was 31 months. Average intraoperative PCI was 11, and complete cytoreduction (CC-0) was achieved in 96.8%. Median OS was 41.6 months (6-196). The 2-year and 5-year OS were 68% and 24.8%, respectively, and the 2-year DFS was 28.8%. Factors associated with worse OS included pre-HIPEC systemic therapy, synchronous extraperitoneal metastasis, and PCI ≥ 20 (p < 0.05). Progression prior to CRS-HIPEC was associated with worse DFS (p < 0.05). Lower PCI, fewer complications, lower recurrence and longer DFS were associated with LTS (p < 0.05). CONCLUSION: CRS and HIPEC improve OS in CPC patients but they have high disease recurrence. Outcomes depend on preoperative therapy response, extraperitoneal metastasis, and peritoneal disease burden.

Peritoneal Carcinomatosis in Colorectal Cancer: Review and Update of Current Clinical Data.

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.

Prognostic value of specific KRAS mutations in patients with colorectal peritoneal metastases.

BACKGROUND: There is little evidence on KRAS mutational profiles in colorectal cancer (CRC) peritoneal metastases (PM). This study aims to determine the prevalence of specific KRAS mutations and their prognostic value in a homogeneous cohort of patients with isolated CRC PM treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. MATERIALS AND METHODS: Data were collected from 13 Italian centers, gathered in a collaborative group of the Italian Society of Surgical Oncology. KRAS mutation subtypes have been correlated with clinical and pathological characteristics and survival [overall survival (OS), local (peritoneal) disease-free survival (LDFS) and disease-free survival (DFS)]. RESULTS: KRAS mutations occurred in 172 patients (47.5%) out of the 362 analyzed. Two different prognostic groups of KRAS mutation subtypes were identified: KRASMUT1 (G12R, G13A, G13C, G13V, Q61H, K117N, A146V), median OS > 120 months and KRASMUT2 (G12A, G12C, G12D, G12S, G12V, G13D, A59E, A59V, A146T), OS: 31.2 months. KRASMUT2 mutations mainly occurred in the P-loop region (P < 0.001) with decreased guanosine triphosphate (GTP) hydrolysis activity (P < 0.001) and were more frequently related to size (P < 0.001) and polarity change (P < 0.001) of the substituted amino acid (AA). When KRASMUT1 and KRASMUT2 were combined with other known prognostic factors (peritoneal cancer index, completeness of cytoreduction score, grading, signet ring cell, N status) in multivariate analysis, KRASMUT1 showed a similar survival rate to KRASWT patients, whereas KRASMUT2 was independently associated with poorer prognosis (hazard ratios: OS 2.1, P < 0.001; DFS 1.9, P < 0.001; LDFS 2.5, P < 0.0001). CONCLUSIONS: In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

Systemic Chemotherapy in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery: Systematic Review and Meta-Analysis.

BACKGROUND: For patients with colorectal cancer (CRC) peritoneal metastases (PM) who are eligible for cytoreductive surgery (CRS), the indication and timing of systemic chemotherapy (SC) are still under debate. This study aims to analyze the role of pre, post or perioperative SC on the survival and surgical complications of patients treated with CRS-HIPEC. METHODS: After a systematic search in MEDLINE, Cochrane Database of Systematic Reviews, Scopus, Web of Science and Embase, a meta-analysis was performed to compare postoperative complications, disease-free survival (DFS) and overall survival (OS) according to SC administration and timing. PROSPERO: CRD42023478977. RESULTS: Of 1203 studies screened, 15 were included in the meta-analysis (4523 patients). Post-operative SC was associated with increased overall survival (post-SC vs. no post-SC: HR 0.81, p = 0.00001, I2 = 0%; pre-SC vs. post-SC: HR 0.65, p = 0.01, I2 = 28%), whereas SC (pre or post) or pre-SC compared to surgery alone was not (SC vs. no SC: p = 0.29, I2 = 80%; pre-SC vs. no pre-SC: p = 0.59, I2 = 58%). Similar results were seen for DFS. SC was not associated with an increased complication rate (p = 0.47, I2 = 64%). CONCLUSIONS: Systemic chemotherapy administration in patients undergoing radical surgery for colorectal peritoneal metastases is associated with increased survival only in the adjuvant/post-operative setting. Considering the limitations of the included studies, further trials are needed to answer this unresolved question.

Outcomes of preoperative chemotherapy for colorectal cancer with peritoneal metastasis underwent cytoreductive surgery

Background This study aims to assess and compare the extent to which preoperative chemotherapy prior to CRS improves survival in patients diagnosed with CRCPM. Methods We included 251 patients from 2012 to 2019 in our center. Inverse probability of treatment weighting (IPTW) analysis was used to minimize the selection bias. Survival analysis was performed to compare the survival outcomes. Multivariate Cox regression analysis was conducted to identify prognostic factors. Result The baseline characteristics were well balanced using IPTW (standardized mean difference < 0.1). Preoperative chemotherapy cannot significantly improve overall survival (HR, 1.03; 95% CI 0.71–1.49; P = 0.88). In subgroup analysis, we found that intestinal obstruction after preoperative chemotherapy significantly reduced survival (HR, 2.25; 95% CI 1.01–5.03; P = 0.048), while in the upfront surgery group, intestinal obstruction had no impact on prognosis. Conclusion For CRCPM patients treated with CRS, preoperative chemotherapy does not seem to prolong overall survival. Furthermore, the emergence of intestinal obstruction after chemotherapy may compromise the effectiveness of treatment, resulting in a worse prognosis. This finding has important clinical implications for treatment decisions (AU)

Outcomes of preoperative chemotherapy for colorectal cancer with peritoneal metastasis underwent cytoreductive surgery.

BACKGROUND: This study aims to assess and compare the extent to which preoperative chemotherapy prior to CRS improves survival in patients diagnosed with CRCPM. METHODS: We included 251 patients from 2012 to 2019 in our center. Inverse probability of treatment weighting (IPTW) analysis was used to minimize the selection bias. Survival analysis was performed to compare the survival outcomes. Multivariate Cox regression analysis was conducted to identify prognostic factors. RESULT: The baseline characteristics were well balanced using IPTW (standardized mean difference < 0.1). Preoperative chemotherapy cannot significantly improve overall survival (HR, 1.03; 95% CI 0.71-1.49; P = 0.88). In subgroup analysis, we found that intestinal obstruction after preoperative chemotherapy significantly reduced survival (HR, 2.25; 95% CI 1.01-5.03; P = 0.048), while in the upfront surgery group, intestinal obstruction had no impact on prognosis. CONCLUSION: For CRCPM patients treated with CRS, preoperative chemotherapy does not seem to prolong overall survival. Furthermore, the emergence of intestinal obstruction after chemotherapy may compromise the effectiveness of treatment, resulting in a worse prognosis. This finding has important clinical implications for treatment decisions.

Peritoneal Metastasis: A Dilemma and Challenge in the Treatment of Metastatic Colorectal Cancer.

Peritoneal metastasis (PM) is a common mode of distant metastasis in colorectal cancer (CRC) and has a poorer prognosis compared to other metastatic sites. The formation of PM foci depends on the synergistic effect of multiple molecules and the modulation of various components of the tumor microenvironment. The current treatment of CRC-PM is based on systemic chemotherapy. However, recent developments in local therapeutic modalities, such as cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC), have improved the survival of these patients. This article reviews the research progress on the mechanism, characteristics, diagnosis, and treatment strategies of CRC-PM, and discusses the current challenges, so as to deepen the understanding of CRC-PM among clinicians.

Hyperthermic intrapleural chemotherapy: an update.

The safety and efficacy of hyperthermic intrathoracic chemotherapy (HITHOC) as an adjunct to cytoreductive surgery (CRS) in pleural malignancies has been well demonstrated. This is most often described in cases of mesothelioma, thymoma, or other secondary pleural metastases. The utilization of a direct cytotoxic agent with increased penetration secondary to a hyperthermic environment is especially beneficial in pleural malignancy as a microscopic resection remains immensely challenging. Despite favorable outcomes with a limited associated risk profile, there persists a variety in utilization and technique of HITHOC described in current literature. National Comprehensive Cancer Network (NCCN) guidelines state that though intraoperative adjuvant therapies such as HITHOC have been studied, they remain of unclear benefit and definitive recommendations do not currently exist. This ambiguity limits the standardization of HITHOC, thus hindering its further application in a patient population with exceedingly poor outcomes within current guideline-based therapy. As the prevalence of pleural malignancies necessitating CRS with adjuvant HITHOC remains quite low, we believe a task force initiative to further investigate the role of HITHOC in surgical management of pleural malignancies would enable wider utility of this promising technique. Additionally, we propose that the creation of a pleural cancer index could aid in standardization of HITHOC in those with pleural malignancy.

Race and Ethnicity Impacts Overall Survival of Patients with Appendiceal Cancer Who Undergo Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.

Appendiceal cancer treatment may include cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We investigated whether patient race/ethnicity influences outcomes and overall survival for patients with appendiceal cancer who undergo CRS/HIPEC. We queried the National Cancer Database for adult patients with appendiceal cancer treated with CRS/HIPEC from 2006 to 2018. Patients were stratified by race/ethnicity: non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic, and Other. Sociodemographics and outcomes were compared using descriptive statistics. Kaplan-Meier survival analysis and Log-rank tests assessed differences in overall survival (OS). Cox Multivariate Regression evaluated factors associated with OS. In total, 2532 patients were identified: 2098 (82.9%) NHW, 186 (7.3%) NHB, 127 (5.0%) Hispanic, and 121 (4.8%) Other patients. The sociodemographics were statistically different across groups. The perioperative and postoperative outcomes were similar. OS was significantly different by race/ethnicity (p = 0.0029). NHB patients compared to Hispanic patients had the shortest median OS (106.7 vs. 145.9 months, p = 0.0093). Race/ethnicity was independently associated with OS: NHB (HR: 2.117 [1.306, 3.431], p = 0.0023) and NHW (HR: 1.549 [1.007, 2.383], p = 0.0463) patients compared to Hispanic patients had worse survival rates. Racial/ethnic disparities exist for patients with appendiceal cancer undergoing CRS/HIPEC. Despite having similar tumor and treatment characteristics, OS is associated with patient race/ethnicity.

Enhanced recovery after surgery in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: national survey of peri-operative practice by Indian society of peritoneal surface malignancies.

Objectives: The Enhanced recovery after surgery (ERAS) program is designed to achieve faster recovery by maintaining pre-operative organ function and reducing stress response following surgery. A two part ERAS guidelines specific for Cytoreductive surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) was recently published with intent of extending the benefit to patients with peritoneal surface malignancies. This survey was performed to examine clinicians' knowledge, practice and obstacles about ERAS implementation in patients undergoing CRS and HIPEC. Methods: Requests to participate in survey of ERAS practices were sent to 238 members of Indian Society of Peritoneal Surface malignancies (ISPSM) via email. They were requested to answer a 37-item questionnaire on elements of preoperative (n=7), intraoperative (n=10) and postoperative (n=11) practices. It also queried demographic information and individual attitudes to ERAS. Results: Data from 164 respondents were analysed. 27.4 % were aware of the formal ERAS protocol for CRS and HIPEC. 88.4 % of respondents reported implementing ERAS practices for CRS and HIPEC either, completely (20.7 %) or partially (67.7 %). The adherence to the protocol among the respondents were as follows: pre operative (55.5-97.6 %), intra operative (32.6-84.8 %) and post operative (25.6-89 %). While most respondents considered implementation of ERAS for CRS and HIPEC in the present format, 34.1 % felt certain aspects of perioperative practice have potential for improvement. The main barriers to implementation were difficulty in adhering to all elements (65.2 %), insufficient evidence to apply in clinical practice (32.4 %), safety concerns (50.6 %) and administrative issues (47.6 %). Conclusions: Majority agreed the implementation of ERAS guidelines is beneficial but are followed by HIPEC centres partially. Efforts are required to overcome barriers like improving certain aspects of perioperative practice to increase the adherence, confirming the benefit and safety of protocol with level I evidence and solving administrative issues by setting up dedicated multi-disciplinary ERAS teams.

Surgical Options for Peritoneal Surface Metastases from Digestive Malignancies-A Comprehensive Review.

The peritoneum is a common site for the dissemination of digestive malignancies, particularly gastric, colorectal, appendix, or pancreatic cancer. Other tumors such as cholangiocarcinomas, digestive neuroendocrine tumors, or gastrointestinal stromal tumors (GIST) may also associate with peritoneal surface metastases (PSM). Peritoneal dissemination is proven to worsen the prognosis of these patients. Cytoreductive surgery (CRS), along with systemic chemotherapy, have been shown to constitute a survival benefit in selected patients with PSM. Furthermore, the association of CRS with hyperthermic intraperitoneal chemotherapy (HIPEC) seems to significantly improve the prognosis of patients with certain types of digestive malignancies associated with PSM. However, the benefit of CRS with HIPEC is still controversial, especially due to the significant morbidity associated with this procedure. According to the results of the PRODIGE 7 trial, CRS for PSM from colorectal cancer (CRC) achieved overall survival (OS) rates higher than 40 months, but the addition of oxaliplatin-based HIPEC failed to improve the long-term outcomes. Furthermore, the PROPHYLOCHIP and COLOPEC trials failed to demonstrate the effectiveness of oxaliplatin-based HIPEC for preventing peritoneal metastases development in high-risk patients operated for CRC. In this review, we discuss the limitations of these studies and the reasons why these results are not sufficient to refute this technique, until future well-designed trials evaluate the impact of different HIPEC regimens. In contrast, in pseudomyxoma peritonei, CRS plus HIPEC represents the gold standard therapy, which is able to achieve 10-year OS rates ranging between 70 and 80%. For patients with PSM from gastric carcinoma, CRS plus HIPEC achieved median OS rates higher than 40 months after complete cytoreduction in patients with a peritoneal cancer index (PCI) ≤6. However, the data have not yet been validated in randomized clinical trials. In this review, we discuss the controversies regarding the most efficient drugs that should be used for HIPEC and the duration of the procedure. We also discuss the current evidence and controversies related to the benefit of CRS (and HIPEC) in patients with PSM from other digestive malignancies. Although it is a palliative treatment, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) significantly increases OS in patients with unresectable PSM from gastric cancer and represents a promising approach for patients with PSM from other digestive cancers.

Significance of laparoscopic cytoreductive surgery for appendiceal pseudomyxoma peritonei with limited disease and low tumor burden.

OBJECTIVE: To investigate the clinical value of laparoscopic cytoreductive surgery (CRS) in treating of appendiceal pseudomyxoma peritonei with limited disease and low tumor burden. METHODS: The clinical data of patients with appendiceal pseudomyxoma peritonei treated by surgery with CRS at the Aerospace Center Hospital from January 2018 to December 2021 were retrospectively analyzed. The patients were divided into laparoscopic or open CRS groups according to the operation method. A propensity score-matched (PSM) analysis (1:1) was performed, the related clinical variables were compared between the two groups, and the effect on progression-free survival (PFS) was also analyzed. RESULTS: One hundred and eight patients were included in this study. After PSM, 33 patients were selected from each group and the age and peritoneal cancer index were matched between the two groups. There were significant differences in operation time (P < 0.001), intraoperative bleeding (P < 0.001), intraoperative blood transfusion (P = 0.007), hospital stay (P < 0.001). The analysis of PFS showed that there was no significant difference between the two operation methods. After multivariate analysis, the pathologic subtype (P = 0.012) was identified as an independent prognostic factor for PFS. CONCLUSION: The curative effect of laparoscopic CRS is like that of open operation, which can significantly shorten the operation time and hospital stay and reduce intraoperative bleeding and blood transfusion event. The laparoscopic CRS is safe and feasible in strictly selected patients. The pathologic subtype is an independent factor affecting the prognosis for PFS.

External validation of COMPASS and BIOSCOPE prognostic scores in colorectal peritoneal metastases treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).

INTRODUCTION: The selection of patients undergoing cytoreductive- surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is crucial. BIOSCOPE and COMPASS are prognostic scores designed to stratify survival into four classes according to clinical and pathological features. The purpose of this study is to analyze the prognostic role of these scores using a large cohort of patients as an external reference. METHODS: Overall survival analysis was performed using Log-Rank and Kaplan-Meier curves for each score. The probability of survival at 12, 36, and 60 months was tested using receiver operating characteristic (ROC) curves to determine sensitivity and specificity. RESULTS: From the validation cohort of 437 patients, the analysis included 410 patients in the COMPASS group and 364 patients in the BIOSCOPE group (100% data completeness). We observed a different patient distribution between classes (high-risk for BIOSCOPE compared to COMPASS, p = 0.0001). Nevertheless, both COMPASS and BIOSCOPE effectively stratified overall survival (Log-Rank, p = 0.0001 in both cases), with a lack of discrimination between COMPASS classes II and III (p = n.s.). COMPASS at 12 m and BIOSCOPE at 60 m showed the best performance in terms of survival prediction (AUC of 0.82 and 0.81). The specificity of the two tests is good (median 81.3%), whereas sensibility is quite low (median 64.2%). CONCLUSION: Following external validation in a large population of patients with CRC-PM who are eligible for surgery, the COMPASS and BIOSCOPE scores exhibit high inter-test variability but effectively stratify cancer-related mortality risk. While the quality of the scores is similar, BIOSCOPE shows better inter-tier differentiation, suggesting that tumor molecular classification could improve test discrimination capability. More powerful stratification scores with the inclusion of novel predictors are needed.