Clinical benefits of symptom resolution after palliative surgery in advanced cancer: A single-center experience.

BACKGROUND: Palliative surgery (PS) is defined as any surgical procedure aimed at improving quality of life or relieving symptoms caused by an advanced or metastatic cancer. The involvement of patients, caregivers, and other professional figures is crucial for obtaining optimal symptom relief and avoiding complications. This study aims to evaluate the short-term outcome and related factors in patients undergoing PS. PATIENTS AND METHODS: A retrospective analysis was performed in consecutive patients who underwent palliative gastrointestinal surgery at our surgical unit during the period June 2018 to May 2023. Demographic, clinical, pathological and follow-up data were collected from a prospectively maintained department database. The main outcomes were complications, symptoms palliation, symptoms recurrence and return to systemic chemotherapy. Standard statistical analysis was performed. RESULTS: During the study period, 127 patients underwent palliative surgery. The Clavien-Dindo 3-5 complication rate and mortality rate were 19.7 % and 6 %, respectively. The resolution of symptoms was achieved in 109 patients (89 %). Successful symptom palliation was significantly related to the possibility of returning to systemic chemotherapy (SC) (OR 9.30 95 % CI 0.1.83-47.18, p 0.007). The only factor related to survival in multivariate analysis was the return to systemic chemotherapy (HR 0.25 95 % CI 0.15-0.42 0.001). CONCLUSION: PS in selected patients is effective for symptom resolution and improving overall survival, if the result is making anticancer therapy possible. Prospective data collection is in any case warranted in every institution performing PS for the purpose of monitoring appropriateness and quality of surgical care.

Doxorubicin as Risk Factor for Fascial Dehiscence After CRS-HIPEC for Peritoneal Metastases.

BACKGROUND/AIM: Among postoperative complications, fascial dehiscence (FD) is registered in up to 10% of patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). This study aimed to evaluate the risk factors related to FD after CRS-HIPEC. PATIENTS AND METHODS: A retrospective analysis of a prospectively maintained database of consecutive patients who underwent CRS-HIPEC between 2015 and 2023 was performed. For each patient, risk factors for postoperative fascial dehiscence were identified using multivariate analysis. RESULTS: During the study period (2018-2023), 217 patients were treated with CRS-HIPEC. The incidence of FD was observed in seven cases (3.2%), which were reoperated with direct fascial closure. In three cases, FD was associated with other grade III-IV complications. Body mass index, (BMI; p=0.024), doxorubicin-based HIPEC (p=0.005), and open technique (p=0.004) were identified as risk factors for FD in univariate analysis. Systemic chemotherapy, prior surgical score, and peritoneal cancer index (PCI) were not associated with an increased risk of FD. In multivariable regression analysis, doxorubicin-based HIPEC and open technique were confirmed as risk factors for FD. CONCLUSION: Although FD is a relatively rare event after CRS-HIPEC, open technique and doxorubicin-based HIPEC were significant predictors of this complication. Specific fascial closure techniques and proper wound care should be considered in high-risk patients.

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.

Laparoscopic Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Peritoneal Metastasis: Improved Short-term Outcomes Revealed Through Propensity Score Matching Analysis.

INTRODUCTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the standard of care for selected cases of primary or secondary peritoneal surface malignancies. The study aims to verify the postoperative advantages of laparoscopic CRS-HIPEC. METHODS: A retrospective analysis of patients who underwent CRS-HIPEC at our institution was performed. Records were extracted from a prospectively maintained database. Patients were divided into two groups, laparoscopic CRS-HIPEC and open CRS-HIPEC, and matched for age, ASA, comorbidities, Prior Surgical Score (PSS), and Peritoneal Cancer Index (PCI) using propensity score analysis. Demographics, clinical, and operative data were compared between the two groups using chi-square or Fisher's exact test and T-test or Mann-Whitney U test. RESULTS: Between 2016 and 2022, 13 patients underwent laparoscopic CRS-HIPEC. These were matched to 32 open CRS-HIPEC patients (1:2.5), obtaining comparable demographics and clinical and preoperative variables. The two groups had a similar duration and complexity of surgery; however, the mean estimated blood loss was lower during laparoscopic procedures (p = 0.008). Overall morbidity rates were lower after laparoscopic CRS-HIPEC (p = 0.043); however, grade III-IV complications, reintervention, and 90-day readmission rates were comparable between the two groups. A faster postoperative recovery in all aspects of the postoperative course was observed, including hospital length of stay (6 vs. 9.5 days, p = 0.003). CONCLUSIONS: Laparoscopic CRS-HIPEC is a feasible and safe procedure and shows improved short-term postoperative outcomes in selected patients with limited peritoneal disease compared to the open approach.

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

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

The impact of preoperative nutritional screening, ERAS protocol, and mini-invasive surgery in surgical oncology: A multi-institutional SEM analysis of patients with digestive cancer.

Background: Mini-invasive surgery (MIS), ERAS, and preoperative nutritional screening are currently used to reduce complications and the length of hospital stay (LOS); however, inter-variable correlations have seldom been explored. This research aimed to define inter-variable correlations in a large series of patients with gastrointestinal cancer and their impact on outcomes. Methods: Patients with consecutive cancer who underwent radical gastrointestinal surgery between 2019 and 2020 were analyzed. Age, BMI, comorbidities, ERAS, nutritional screening, and MIS were evaluated to determine their impact on 30-day complications and LOS. Inter-variable correlations were measured, and a latent variable was computed to define the patients' performance status using nutritional screening and comorbidity. Analyses were conducted using structural equation modeling (SEM). Results: Of the 1,968 eligible patients, 1,648 were analyzed. Univariable analyses documented the benefit of nutritional screening for LOS and MIS and ERAS (≥7 items) for LOS and complications; conversely, being male and comorbidities correlated with complications, while increased age and BMI correlated with worse outcomes. SEM analysis revealed that (a) the latent variable is explained by the use of nutritional screening (p0·004); (b) the variables were correlated (age-comorbidity, ERAS-MIS, and ERAS-nutritional screening, p < 0·001); and (c) their impact on the outcomes was based on direct effects (complications: sex, p0·001), indirect effects (LOS: MIS-ERAS-nutritional screening, p < 0·001; complications: MIS-ERAS, p0·001), and regression-based effects (LOS: ERAS, MIS, p < 0·001, nutritional screening, p0·021; complications: ERAS, MIS, p < 0·001, sex, p0·001). Finally, LOS and complications were correlated (p < 0·001). Conclusion: Enhanced recovery after surgery (ERAS), MIS, and nutritional screening are beneficial in surgical oncology; however, the inter-variable correlation is reliable, underlying the importance of the multidisciplinary approach.

Enhanced Recovery after Surgery (ERAS) Program for Patients with Peritoneal Surface Malignancies Undergoing Cytoreductive Surgery with or without HIPEC: A Systematic Review and a Meta-Analysis.

Enhanced recovery after surgery (ERAS) program refers to a multimodal intervention to reduce the length of stay and postoperative complications; it has been effective in different kinds of major surgery including colorectal, gynaecologic and gastric cancer surgery. Its impact in terms of safety and efficacy in the treatment of peritoneal surface malignancies is still unclear. A systematic review and a meta-analysis were conducted to evaluate the effect of ERAS after cytoreductive surgery with or without HIPEC for peritoneal metastases. MEDLINE, PubMed, EMBASE, Google Scholar and Cochrane Database were searched from January 2010 and December 2021. Single and double-cohort studies about ERAS application in the treatment of peritoneal cancer were considered. Outcomes included the postoperative length of stay (LOS), postoperative morbidity and mortality rates and the early readmission rate. Twenty-four studies involving 5131 patients were considered, 7 about ERAS in cytoreductive surgery (CRS) + HIPEC and 17 about cytoreductive alone; the case histories of two Italian referral centers in the management of peritoneal cancer were included. ERAS adoption reduced the LOS (-3.17, 95% CrI -4.68 to -1.69 in CRS + HIPEC and -1.65, 95% CrI -2.32 to -1.06 in CRS alone in the meta-analysis including 6 and 17 studies respectively. Non negligible lower postoperative morbidity was also in the meta-analysis including the case histories of two Italian referral centers. Implementation of an ERAS protocol may reduce LOS, postoperative complications after CRS with or without HIPEC compared to conventional recovery.

Repeated Cytoreduction Combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Selected Patients Affected by Peritoneal Metastases: Italian PSM Oncoteam Evidence.

The reiteration of surgical cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients affected by recurrent peritoneal metastases is still questioned regarding safety and effectiveness. This study evaluates the safety, efficacy, and associated factors of iterative CRS combined with HIPEC. This multicentric retrospective study collected data from four surgical oncology centers, on iterative HIPEC. We gathered data on patient and cancer characteristics, the peritoneal cancer index (PCI), completeness of cytoreduction (CC), postoperative complications, and overall survival (OS). In the study period, 141 CRS-plus-HIPECs were performed on 65 patients. Nine patients underwent three iterative procedures, and one underwent five. No increased incidence of complications after the second or third procedure was observed. Furthermore, operative time and hospitalization stay were significantly shorter after the second than after the first procedure (p < 0.05). Optimal cytoreduction was achieved in more than 90% of cases in each procedure, whether first, second, or third. A five-year (5 y) OS represented 100% of the cases of diffuse malignant-peritoneal-mesotheliomas, 81.39% of pseudomyxoma peritonei, 34.67% of colorectal cancer (CRC), and 52.50% of ovarian cancer. During the second CRS combined with HIPEC, we observed a lower rate of complete cytoreduction and a non-significantly better survival in cases with complete cytoreduction (5 y-OS CC-0 56.51% vs. 37.82%, p = 0.061). Concomitant hepatic-CRC-metastasis did not compromise the CRS-plus-HIPEC safety and efficacy. This multicentric experience encourages repeated CRS-plus-HIPEC, showing promising results.

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.

HIPEC as a risk factor for postoperative coagulopathy after cytoreductive surgery for peritoneal metastases.

AIM OF THE STUDY: Postoperative coagulopathy is a poorly investigated condition after Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC). This study aims to evaluate the occurrence and risk factors of coagulative disorders after surgery for peritoneal metastases. PATIENTS AND METHODS: The records were extracted from a prospectively maintained database of consecutive patients who underwent CRS between January 2018 and September 2020. The study was approved by the local Ethics Committee. For each patient, the coagulation profile (CP), which included international normalized ratio (INR), partial thromboplastin time (aPTT), and platelets (PLTS) before surgery, intensive care unit admission,1st, 3rd, 5th postoperative day (POD) and the day before discharge was collected. Risk factors for postoperative coagulopathy were identified at multivariate analysis. RESULTS: During the study period, 125 patients were included in the study. Among these, 48 (38.4%) underwent CRS only, and 77 (61.6%) CRS followed by HIPEC. Twenty-one patients (16.8%) developed severe coagulopathy, 5 (10.4%) after CRS and 16 (20.8%) after CRS-HIPEC. At multivariate analysis, HIPEC and blood loss ≥ 500 ml represented independent risk factors for severe alteration of INR > 1.5 (p = 0.05, OR 1.2) and PLTS < 75 109/L (p = 0.03, OR 1.3), respectively. CONCLUSION: HIPEC is an independent risk factor for postoperative coagulopathy after CRS. Further studies are necessary to assess the usefulness of the point-of-care test in patients treated with CRS-HIPEC.

Complete pathological response of colorectal peritoneal metastases in Lynch syndrome after immunotherapy case report: is a paradigm shift in cytoreductive surgery needed?

BACKGROUND: We report the first case of a patient affected by peritoneal metastases from colon cancer, arising in the context of Lynch syndrome with pathological complete response. The patient was treated with immunotherapy and cytoreductive surgery. This paper discusses the implications of these novel therapies for the management of PM. CASE PRESENTATION: A 50-year-old man affected by Lynch syndrome was referred to our institution for metachronous peritoneal recurrence of ascending colon adenocarcinoma. As a second-line treatment, he received Nivolumab therapy with stable disease. Patient underwent cytoreductive surgery with residual disease and a pathological complete response. Flow cytometry described a particular immune sub-population response. There was no evidence of disease progression after nine months. CONCLUSION: This is the first report of a Lynch patient affected by peritoneal metastases of colorectal cancer, treated with cytoreductive surgery (CRS) and resulting in a pathological complete response after immune checkpoint inhibitors treatment (ICIs). This case report may suggest that patients with peculiar immunological features could benefit from a tailored approach, since "classical" CRS paradigms may not effectively predict the clinical outcome. Further large-scale studies are needed to determine the correct operative management of such patients (tailored or "standard" CRS), defining the correct surgical timing and eventual discontinuation of ICI therapy after surgery.

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

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

Colorectal Cancer with Peritoneal Metastases: The Impact of the Results of PROPHYLOCHIP, COLOPEC, and PRODIGE 7 Trials on Peritoneal Disease Management.

HIPEC is a potentially useful locoregional treatment combined with cytoreduction in patients with peritoneal colorectal metastases. Despite being widely used in several cancer centers around the world, its role had never been investigated before the results of three important RCTs appeared on this topic. The PRODIGE 7 trial clarified the role of oxaliplatin-based HIPEC in patients treated with radical surgery. Conversely, the PROPHYLOCHIP and the COLOPEC were designed to chair the role of HIPEC in patients at high risk of developing peritoneal metastases. Although all three trials demonstrated the relative ineffectiveness of HIPEC for treating or preventing peritoneal metastases, these results are not sufficient to abandon this technique. In addition to some criticisms relating to the design of the trials and their statistical value, the oxaliplatin-based HIPEC was found to be ineffective in preventing or treating peritoneal colorectal metastases, especially in patients already treated with systemic platinum-based chemotherapy. Several studies are ongoing investigating further HIPEC drugs and regimens. The review deeply discussed all the aspects and relapses of this new evidence.

Laparoscopic Cytoreduction Combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Peritoneal Surface Malignancies (PSM): Italian PSM Oncoteam Evidence and Literature Review.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has gained increasing acceptance in clinical practice. Performing CRS and HIPEC laparoscopically represents a challenging and intriguing technical evolution. However, the experiences are limited, and the evidence is low. This retrospective analysis was performed on patients treated with laparoscopic CRS-HIPEC within the Italian Peritoneal Surface Malignancies Oncoteam. Clinical, perioperative, and follow-up data were extracted and collected on prospectively maintained databases. We added a systematic review according to the PRISMA method for English-language articles through April 2022 using the keywords laparoscopic, hyperthermic, HIPEC, and chemotherapy. From 2016 to 2022, fourteen patients were treated with Lap-CRS-HIPEC with curative intent within the Italian centers. No conversion to open was observed. The median duration of surgery was 487.5 min. The median Peritoneal Cancer Index (PCI) was 3, and complete cytoreduction was achieved in all patients. Two patients (14.3%) had major postoperative complications, one requiring reintervention. After a median follow-up of 16.9 months, eleven patients were alive without disease (78.6%), two patients developed recurrence (14.3%), and one patient died for unrelated causes (7.1%). The literature review confirmed these results. In conclusion, current evidence shows that Lap-CRS-HIPEC is feasible, safe, and associated with a favorable outcome in selected patients. An accurate patient selection will continue to be paramount in choosing this treatment.

Novel Perspectives in Pseudomyxoma Peritonei Treatment.

Pseudomyxoma Peritonei (PMP) is an anatomo-clinical condition characterized by the implantation of neoplastic cells on peritoneal surfaces with the production of a large amount of mucin. The rarity of the disease precludes the evaluation of treatment strategies within randomized controlled trials. Cytoreductive Surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) has proven to be the only therapeutic option with potential chances of cure and long-term disease control. The present review discusses the epidemiology, pathogenesis, clinical presentation and treatment of PMP, focusing on the molecular factors involved in tumor progression and mucin production that could be used, in the upcoming future, to improve patient selection for surgery and to expand the therapeutic armamentarium.