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.

The impact of hospital experience in bariatric surgery on short-term outcomes after minimally invasive esophagectomy: a nationwide analysis.

BACKGROUND: Minimally invasive esophagectomy (MIE) is a technically challenging procedure with a substantial learning curve. Composite volume of upper gastrointestinal (upper GI) procedures for cancer has been previously linked to postoperative outcomes. This study aimed to investigate an association between hospital experience in bariatric surgery and short-term outcomes in MIE. METHOD: Data on esophagectomy patients between 2016 and 2020 were collected from the Dutch Upper Gastrointestinal Cancer Audit, a mandatory nationwide registry. Hospitals were categorized as bariatric or non-bariatric. Multivariable logistic regression investigated short-term postoperative outcomes, adjusting for case mix. RESULTS: Of 3371 patients undergoing esophagectomy in sixteen hospitals, 2450 (72.7%) underwent MIE. Bariatric hospitals (N = 6) accounted for 1057 (43.1%) MIE. Annual volume of bariatric procedures was median 523 and esophagectomies 42. In non-bariatric hospitals, volume of esophagectomies was median 52 (P = 0.145). Overall postoperative complication rate was lower in bariatric hospitals (59.2% vs. 65.9%, P < 0.001). Bariatric hospitals were associated with a reduced risk of overall complications (aOR 0.76 [95% CI 0.62-0.92]), length of hospital (aOR 0.79 [95% CI 0.65-0.95]), and ICU stay (aOR 0.81 [95% CI 0.67-0.98]) after MIE. Surgical radicality (R0) did not differ. Lymph node yield (≥ 15) was lower in bariatric hospitals (90.0% vs. 94.7%, P < 0.001). Over the years, several short-term outcomes improved in bariatric hospitals compared to non-bariatric hospitals. CONCLUSION: In this nationwide analysis, there was an association between bariatric hospitals and improved short-term outcomes after MIE. Characteristics of bariatric hospitals that could explain this phenomenon and whether this translates to other upper GI procedures may be warranted to identify.

Primary tumor resection or systemic treatment as palliative treatment for patients with isolated synchronous colorectal cancer peritoneal metastases in a nationwide cohort study.

Limited data are available to guide the decision-making process for clinicians and their patients regarding palliative treatment options for patients with isolated synchronous colorectal cancer peritoneal metastases (CRC-PM). Therefore, the aim of this study is to analyze the outcome of the different palliative treatments for these patients. All patients diagnosed with isolated synchronous CRC-PM between 2009 and 2020 (Netherlands Cancer Registry) who underwent palliative treatment were included. Patients who underwent emergency surgery or curative intent treatment were excluded. Patients were categorized into upfront palliative primary tumor resection (with or without additional systemic treatment) or palliative systemic treatment only. Overall survival (OS) was compared between both groups and multivariable cox regression analysis was performed. Of 1031 included patients, 364 (35%) patients underwent primary tumor resection and 667 (65%) patients received systemic treatment only. Sixty-day mortality was 9% in the primary tumor resection group and 5% in the systemic treatment group (P = 0.007). OS was 13.8 months in the primary tumor resection group and 10.3 months in the systemic treatment group (P < 0.001). Multivariable analysis showed that primary tumor resection was associated with improved OS (HR 0.68; 95%CI 0.57-0.81; P < 0.001). Palliative primary tumor resection appeared to be associated with improved survival compared to palliative systemic treatment alone in patients with isolated synchronous CRC-PM despite a higher 60-day mortality. This finding must be interpreted with care as residual bias probably played a significant role. Nevertheless, this option may be considered in the decision-making process by clinicians and their patients.

Intraperitoneal drug delivery systems releasing cytostatic agents to target gastro-intestinal peritoneal metastases in laboratory animals: a systematic review.

For peritoneal metastases (PM), there are few curative treatment options, and they are only available for a select patient group. Recently, new therapies have been developed to deliver intraperitoneal chemotherapy for a prolonged period, suitable for a larger patient group. These drug delivery systems (DDSs) seem promising in the experimental setting. Many types of DDSs have been explored in a variety of animal models, using different cytostatics. This review aimed to provide an overview of animal studies using DDSs containing cytostatics for the treatment of gastro-intestinal PM and identify the most promising therapeutic combinations. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) guidelines. The 35 studies included revealed similar results: using a cytostatic-loaded DDS to treat PM resulted in a higher median survival time (MST) and a lower intraperitoneal tumor load compared to no treatment or treatment with a 'free' cytostatic or an unloaded DDS. In 65% of the studies, the MST was significantly longer and in 24% the tumor load was significantly lower in the animals treated with cytostatic-loaded DDS. The large variety of experimental setups made it impossible to identify the most promising DDS-cytostatic combination. In most studies, the risk of bias was unclear due to poor reporting. Future studies should focus more on improving the clinical relevance of the experiments, standardizing the experimental study setup, and improving their methodological quality and reporting.

Effective Strategies to Predict Survival of Colorectal Peritoneal Metastases Patients Eligible for Cytoreductive Surgery and HIPEC.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), often combined with systemic therapy, can be offered to selected colorectal peritoneal metastases (PM) patients. However, clinical heterogeneity and the lack of high-level evidence challenges determination of the correct treatment strategy. This review aims to provide an overview of current strategies to predict survival of colorectal PM patients treated with CRS and HIPEC, guiding clinicians to select a suitable treatment-strategy and to inform patients about their prognosis. First, the prognostic relevance of several clinicopathological prognostic factors, such as extent of PM, location of primary tumor, histology type, and the presence of lymph node or liver metastases will be discussed. Subsequently, special attention will be given to recent developments in several aspects of tumor biology such as RAF/RAS mutations, circulating tumor DNA, immunoprofiling, and consensus molecular subtypes. Finally, currently available prognostic models to predict survival will be evaluated, concluding these models perform moderate to good, but most of them partly rely on intra-operative data. New insights in tumor biology, as well as the reliable assessment of extent of peritoneal disease by diffusion weighted MRI pose promising opportunities to establish an adequate and clinically meaningful preoperative prognostic model in the near future.

Systemic therapy in addition to cytoreduction and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: recent insights from clinical studies and translational research.

There is a lack of randomized or high-quality intention-to-treat cohort studies addressing the role of systemic therapy in addition to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) as part of the treatment of colorectal peritoneal metastases (PM). Therefore, the choice whether or not to treat patients with systemic therapy is currently mainly based on expert opinion. As a result, treatment with neoadjuvant and/or adjuvant systemic therapy is implemented in various ways around the world. The aim of this review was to provide an overview of recent insights with regard to the systemic treatment of PM of colorectal origin obtained from clinical studies and translational research.

Adjuvant Systemic Chemotherapy vs Active Surveillance Following Up-front Resection of Isolated Synchronous Colorectal Peritoneal Metastases.

Importance: To date, there are no data on the value of adjuvant systemic chemotherapy following up-front resection of isolated synchronous colorectal peritoneal metastases. Objective: To assess the association between adjuvant systemic chemotherapy and overall survival following up-front resection of isolated synchronous colorectal peritoneal metastases. Design, Setting, and Participants: In this population-based, observational cohort study using nationwide data from the Netherlands Cancer Registry (diagnoses between January 1, 2005, and December 31, 2017; follow-up until January 31, 2019), 393 patients with isolated synchronous colorectal peritoneal metastases who were alive 3 months after up-front complete cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were included. Patients allocated to the adjuvant systemic chemotherapy group were matched (1:1) with those allocated to the active surveillance group by propensity scores based on patient-, tumor-, and treatment-level covariates. Exposures: Adjuvant systemic chemotherapy, defined as systemic chemotherapy without targeted therapy, starting within 3 months postoperatively. Main Outcomes and Measures: Overall survival was compared between matched groups using Cox proportional hazards regression analysis adjusted for residual imbalance. A landmark analysis was performed by excluding patients who died within 6 months postoperatively. A sensitivity analysis was performed to adjust for unmeasured confounding by major postoperative morbidity. Results: Of 393 patients (mean [SD] age, 61 [10] years; 181 [46%] men), 172 patients (44%) were allocated to the adjuvant systemic chemotherapy group. After propensity score matching of 142 patients in the adjuvant systemic chemotherapy group with 142 patients in the active surveillance group, adjuvant systemic chemotherapy was associated with improved overall survival compared with active surveillance (median, 39.2 [interquartile range, 21.1-111.1] months vs 24.8 [interquartile range, 15.0-58.4] months; adjusted hazard ratio [aHR], 0.66; 95% CI, 0.49-0.88; P = .006), which remained consistent after excluding patients who died within 6 months postoperatively (aHR, 0.68; 95% CI, 0.50-0.93; P = .02) and after adjustment for major postoperative morbidity (aHR, 0.71; 95% CI, 0.53-0.95). Conclusions and Relevance: Findings of this study suggest that in patients undergoing up-front resection of isolated synchronous colorectal peritoneal metastases, adjuvant systemic chemotherapy appeared to be associated with improved overall survival. Although randomized trials are needed to address the influence of potential residual confounding and allocation bias on this association, results of this study may be used for clinical decision-making in this patient group for whom no data are available.

Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parallel-group, phase II-III, randomised, superiority study (CAIRO6)

BACKGROUND: Upfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes. METHODS: This open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0-10 or 11-20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician's discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates. DISCUSSION: This is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM. TRIAL REGISTRATION: Clinicaltrials.gov/ NCT02758951 , NTR/ NTR6301 , ISRCTN/ ISRCTN15977568 , EudraCT/ 2016-001865-99 .

Comparison of 2 Perioperative Management Protocols and Their Influence on Postoperative Recovery after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Standard Parenteral Nutrition, Selective Bowel Decontamination and Suprapubic Catheters?

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is associated with considerable postoperative morbidity, including ileus and infectious complications. Perioperative care is believed to be an important factor for the development and treatment of postoperative morbidity. PATIENTS AND METHODS: Data on case-matched patients from a retrospective database of 2 Dutch HIPEC centres was compared. Patient selection and procedures were identical in both hospitals although perioperative management items differ slightly. In centre B, immediate total parenteral nutrition (TPN), suprapubic urine bladder catheter placement (SPCs) and selective decontamination of the digestive-tract are standard care for CRS-HIPEC patients, while in centre A, they are not. RESULTS: From a total of 223 patients, 68 consecutive patients from centre B were compared to 68 matched patients from centre A. TPN was administered to 54.4% of patients in centre A because of prolonged ileus, whereas it was standard of care in centre B. In all, 105 (77.2%) patients experienced postoperative complications including 17.6% who had a grades III-IV complication. The incidence of grade III-V complications was 18 (26.4%) in centre A and 8 (11.8%) in centre B (p = 0.03). Median hospital stay was 12 days (7-84) in A and 11(6-80) in centre B (p = 0.546). CONCLUSIONS: Gastrointestinal recovery after CRS-HIPEC seems to take longer as compared to other surgical procedures. Between the 2 centres, a significant difference in severe complications was found, while standard TPN, selective bowel decontamination and SPCs were the only identified differences in perioperative care.

Major influence of postoperative complications on costs of cytoreductive surgery and HIPEC in patients with colorectal peritoneal metastases.

Complications after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) result in impaired short- and long-term outcomes. However, financial consequences of complications after CRS and HIPEC in a European health care setting are unknown. This study aims to assess the consequences of complications on hospital costs after CRS and HIPEC.In this prospective observational cohort study, patients with colorectal peritoneal metastases treated with CRS and HIPEC were included. Financial information was collected according to the Dutch manual for costs analyses. Costs were compared between patients without complications (NC), minor complications (MC), or severe complications (SC), according to the Clavien-Dindo classification.One hundred and sixty-one patients were included, of whom 42% experienced NC, 27% MC and 31% SC. Mean hospital costs were &OV0556;9.406 ±â€Š2.235 in NC patients, &OV0556;12.471 ±â€Š3.893 in MC patients, and &OV0556;29.409 ±â€Š22.340 in SC patients. The 31% of patients with severe complications accounted for 56% of all hospital costs. Hospital admission costs in SC patients were 320% higher compared to NC patients. Costs of complications were estimated to be 43% of all admission costs.Severe postoperative complications have major influence on costs after CRS and HIPEC and result in a threefold increase of hospital costs in affected patients. This finding stresses the need for adequate risk assessment of developing severe complications after CRS and HIPEC.

Synchronous peritoneal metastases of small bowel adenocarcinoma: Insights into an underexposed clinical phenomenon.

BACKGROUND: The aim of this population-based study was to provide insight into the incidence, risk factors and treatment-related survival of patients with peritoneal metastases (PM) of small bowel adenocarcinoma (SBA). METHODS: Data from the Netherlands Cancer Registry were used. All patients diagnosed with SBA between 2005 and 2014 were included. The influence of patient and tumour characteristics on the odds of developing PM was analysed. Subsequently, for all further analyses, patients without synchronous PM of SBA were excluded. The log-rank test and Kaplan-Meier analyses were conducted to estimate survival, and the Cox proportional hazards model was used to evaluate the risk of death. RESULTS: Of the 1428 included patients diagnosed with SBA, 181 (13%) presented with synchronous PM. Synchronous PM was found in 9% of the duodenal tumours and in 17% of the more distal tumours. Median overall survival of all patients with PM was 5.9 months, whereas survival of both 11 months was observed in patients treated with primary tumour resection or palliative chemotherapy and 32 months after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS+HIPEC). Poor prognostic factors for survival were age ≥70 years (hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.1-2.2), systemic metastases other than PM (HR 2.0, 95% CI 1.4-2.9) and an advanced (HR 1.9, 95% CI 1.3-3.0) or unknown T-stage (HR 2.1, 95% CI 1.2-3.5). CONCLUSIONS: Synchronous PM was frequently encountered in SBA. Without treatment, prognosis was extremely poor. Survival was higher after primary tumour resection, palliative chemotherapy and CRS+HIPEC, but selection bias probably played a significant role calling for further clinical research.

Patient selection for cytoreductive surgery and HIPEC for the treatment of peritoneal metastases from colorectal cancer.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a viable option for selected patients with peritoneal metastases (PM) from colorectal origin, resulting in long-term survival and even cure in some cases. However, adequate patient selection for this treatment is currently one of the major challenges. The aim of this review is to provide a comprehensive overview of clinically relevant factors associated with overall survival. This may help to guide clinicians through the complex interplay of patient, tumor, and treatment characteristics to adequately select patients who benefit the most from this extensive surgical treatment. First, basic principles of colorectal PM and the CRS and HIPEC treatment will be discussed. According to available literature, especially extent of peritoneal disease, completeness of cytoreduction, and signet ring cell histology have great influence on the outcome after CRS and HIPEC. Other factors that seem to have a negative prognostic value are the presence of liver metastases and the absence of treatment with neo-adjuvant systemic therapy. Prognostic models combining the above-mentioned factors, such as the Colorectal Peritoneal Metastases Prognostic Surgical Score nomogram, may provide clinically relevant tools to use in everyday practice.

Perioperative systemic therapy for resectable colorectal peritoneal metastases: Sufficient evidence for its widespread use? A critical systematic review.

BACKGROUND/PURPOSE: Despite its widespread use, no randomised studies have investigated the value of perioperative systemic therapy as adjunct to cytoreduction and HIPEC for colorectal peritoneal metastases. This systematic review evaluated the available evidence, which consists of non-randomised studies only. METHODS: A systematic search identified studies that investigated the influence of neoadjuvant, adjuvant, or perioperative systemic therapy on overall survival (OS). RESULTS: The 11 included studies (n=1708) were clinically heterogeneous and subject to selection bias. Studies on neoadjuvant systemic therapy revealed OS benefit (n=3), no OS benefit (n=1), and superiority of chemotherapy with bevacizumab vs. chemotherapy (n=2). Studies on adjuvant systemic therapy showed no OS benefit (n=3). Studies on perioperative systemic therapy demonstrated OS benefit (n=1), and superiority of modern vs. conventional systemic therapy(n=1). CONCLUSION: Significant limitations of available evidence question the widespread use of perioperative systemic therapy in this setting, stress the need for randomised studies, and impede conclusions regarding optimal timing and regimens. Included studies may suggest a survival benefit of neoadjuvant systemic therapy.

Survival of patients with colorectal peritoneal metastases is affected by treatment disparities among hospitals of diagnosis: A nationwide population-based study.

BACKGROUND: In the Netherlands, surgery for peritoneal metastases of colorectal cancer (PMCRC) is centralised, whereas PMCRC is diagnosed in all hospitals. This study assessed whether hospital of diagnosis affects treatment selection and overall survival (OS). METHODS: Between 2005 and 2015, all patients with synchronous PMCRC without systemic metastases were selected from the Netherlands Cancer Registry. Treatment was classified as cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), systemic therapy or other/no treatment. Hospitals of diagnosis were classified as: (1) non-teaching or academic/teaching hospital and (2) HIPEC centre or referring hospital. Referring hospitals were further classified based on the frequency of CRS/HIPEC as high-, medium- or low-frequency hospital. Multivariable regression analyses were used to assess the independent influence of hospital categories on the likelihood of CRS/HIPEC and OS. RESULTS: A total of 2661 patients, diagnosed in 89 hospitals, were included. At individual hospital level, CRS/HIPEC and systemic therapy ranged from 0% to 50% and 6% to 67%, respectively. Hospital of diagnosis influenced the likelihood of CRS/HIPEC: 33% versus 13% for HIPEC centres versus referring hospitals (odds ratio (OR) 3.66 [2.40-5.58]) and 11% versus 17% for non-teaching hospitals versus academic/teaching hospitals (OR 0.60 [0.47-0.77]). Hospital of diagnosis affected median OS: 14.1 versus 9.6 months for HIPEC centres versus referring hospitals (hazard ratio (HR) 0.82 [0.67-0.99]) and 8.7 versus 11.5 months for non-teaching hospitals versus academic/teaching hospitals (HR 1.15 [1.06-1.26]). Compared with diagnosis in medium-frequency referring hospitals, median OS was increased in high-frequency referring hospitals (12.6 months, HR 0.82 [0.73-0.91]) and reduced in low-frequency referring hospitals (8.1 months, HR 1.12 [1.01-1.24]). CONCLUSION: Treatment disparities among hospitals of diagnosis and their impact on survival indicate suboptimal treatment selection for PMCRC.

Short-term outcome in patients treated with cytoreduction and HIPEC compared to conventional colon cancer surgery.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an extensive procedure with considerable morbidity. Since only few hospitals perform CRS + HIPEC, this might lead to confounded outcomes between hospitals when audited. This study aims to compare outcomes between peritoneally metastasized (PM) colon cancer patients treated with CRS + HIPEC and patients undergoing conventional colon surgery. Furthermore, the impact of CRS + HIPEC on the risk of postoperative complications will be assessed, probably leading to better insight into how to report on postoperative outcomes in this distinct group of patients undergoing extensive colon surgery.All patients with primary colon cancer who underwent segmental colon resection in a tertiary referral hospital between 2011 and 2014 were included in this prospective cohort study. Outcome after surgery was compared between patients who underwent additional CRS + HIPEC treatment or conventional surgery.Consequently, 371 patients underwent surgery, of which 43 (12%) underwent CRS + HIPEC. These patients were younger and healthier than patients undergoing conventional surgery. Tumor characteristics were less favorable and surgery was more extensive in CRS + HIPEC patients. The morbidity rate was also higher in CRS + HIPEC patients (70% vs 41%; P < 0.001). CRS + HIPEC was an independent predictor of postoperative complications (odds ratio 6.4), but was not associated with more severe postoperative complications or higher treatment-related mortality.Although patients with colonic PM undergoing CRS + HIPEC treatment were younger and healthier, the postoperative outcome was worse. This is most probably due to less favorable tumor characteristics and more extensive surgery. Nevertheless, CRS + HIPEC treatment was not associated with severe complications or increased treatment-related mortality. These results stress the need for adequate case-mix correction in colorectal surgery audits.

Cytoreductive surgery and HIPEC offers similar outcomes in patients with rectal peritoneal metastases compared to colon cancer patients: a matched case control study.

BACKGROUND & OBJECTIVES: The effect of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with rectal peritoneal metastases (PM) is unclear. This case-control study aims to assess the results of cytoreduction and HIPEC in patients with rectal PM compared to colon PM patients. METHODS: Colorectal PM patients treated with complete macroscopic cytoreduction and HIPEC were included. Two colon cancer patients were case-matched for each rectal cancer patient, based on prognostic factors (T stage, N stage, histology type, and extent of PM). Short- and long-term outcomes were compared between both groups. RESULTS: From 317 patients treated with complete macroscopic cytoreduction and HIPEC, 29 patients (9.1%) had rectal PM. Fifty-eight colon cases were selected as control patients. Baseline characteristics were similar between groups. Major morbidity was 27.6% and 34.5% in the rectal and colon group, respectively (P = 0.516). Median disease-free survival was 13.5 months in the rectal group and 13.6 months in the colon group (P = 0.621). Two- and five-year overall survival rates were 54%/32% in rectal cancer patients, and 61%/24% in colon cancer patients (P = 0.987). CONCLUSIONS: Cytoreduction and HIPEC in selected patients with rectal PM is feasible and provides similar outcomes as in colon cancer patients. Rectal PM should not be regarded a contra-indication for cytoreduction and HIPEC in selected patients. J. Surg. Oncol. 2016;113:548-553. © 2016 Wiley Periodicals, Inc.

Development of a Prognostic Nomogram for Patients with Peritoneally Metastasized Colorectal Cancer Treated with Cytoreductive Surgery and HIPEC.

BACKGROUND: With the introduction of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), long-term survival can be achieved in selected patients with colorectal peritoneal metastases (PM). Patient selection and outcome may be improved significantly with a tool that adequately predicts survival in these patients. This study was designed to validate the peritoneal surface disease severity score (PSDSS) in patients with colorectal PM treated with CRS + HIPEC. If performance of the PSDSS was suboptimal (c < 0.7), we aimed to develop a new prognostic model. METHODS: Patients were included if they had colorectal PM and underwent CRS + HIPEC with intended complete cytoreduction in a Dutch tertiary hospital between 2007 and 2015. Statistical analyses were performed with R-software. RESULTS: A total of 200 patients underwent CRS + HIPEC. External validation of the PSDSS showed a Harrell's c statistic of 0.62. After analysis, four parameters appeared prognostically relevant factors for overall survival: age, PCI score, locoregional lymph node status, and signet ring cell histology. The weighted relevance of these parameters was turned into a prognostic nomogram that we termed colorectal peritoneal metastases prognostic surgical score (COMPASS). The COMPASS differentiated well and showed a Harrell's c statistic of 0.72 with a calibration plot showing good agreement. CONCLUSIONS: This study externally validated the PSDSS and developed a new prognostic score, the COMPASS. This pre-cytoreduction nomogram was more accurate than PSDSS in predicting survival of patients undergoing CRS + HIPEC. It can be used as tool to assist in the decision about continuing cytoreduction and HIPEC and can provide valuable information in the follow-up period after CRS + HIPEC.

Predictors of Severe Morbidity After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Patients With Colorectal Peritoneal Carcinomatosis.

BACKGROUND: Severe morbidity after cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is, besides the obvious short-term consequences, associated with impaired long-term outcomes. The risk factors for severe morbidity in patients with peritoneal carcinomatosis (PC) of colorectal origin are poorly defined. This study aimed to identify risk factors for severe morbidity after CRS + HIPEC in patients with colorectal PC. METHODS: Patients with colorectal PC who underwent CRS + HIPEC between 2007 and 2015 were categorized and compared between those with and those without severe morbidity. Risk factors were identified using logistic regression analysis. Morbidity was graded according to the Clavien-Dindo classification, with grade 3 or higher indicating severe morbidity. RESULTS: This study included 211 patients, of whom 53 patients (25.1%) experienced morbidity of grade 3 or higher. The identified risk factors for severe morbidity were extensive prior surgery [odds ratio (OR) 4.3], a positive recent smoking history (OR 4.0), a poor physical performance status (OR 2.9), and extensive cytoreduction (OR 1.2 per additional resection). Patients with a greater number of risk factors more often had severe morbidity and higher reoperation, readmission, and mortality rates. Furthermore, an internally validated preoperative prediction model for severe morbidity with an area under the curve of 70% was constructed. CONCLUSION: The current study identified risk factors for severe morbidity after CRS + HIPEC in patients with colorectal PC. Patients with a combination of risk factors have a substantial risk of severe morbidity and therefore should be carefully selected for CRS + HIPEC. The preoperative decision model can be a valuable additional tool in this process of patient selection.

Treatment-Related Mortality After Cytoreductive Surgery and HIPEC in Patients with Colorectal Peritoneal Carcinomatosis is Underestimated by Conventional Parameters.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as treatment for patients with colorectal peritoneal carcinomatosis (PC) is regarded as an extensive procedure. The risk of postoperative mortality after major abdominal surgery might be substantially higher than described by the 30-day mortality. This study aims to identify causes of 1-year mortality, thereby assessing a more accurate treatment-related mortality rate after CRS + HIPEC. METHODS: All subsequent patients with colorectal PC treated with CRS + HIPEC with complete macroscopic cytoreduction in two tertiary hospitals between April 2005 and April 2013 were included in this study. Causes of 1-year mortality were carefully analyzed and patient data were compared between patients who died or did not die within 12 months after CRS + HIPEC. RESULTS: Of the 245 included patients, 34 (13.9 %) died within 12 months after CRS + HIPEC. The overall treatment-related mortality rate was 4.9 % (n = 12), and the 30-day and in-hospital mortality rates were 1.6 % (n = 4) and 2.4 % (n = 6), respectively. Furthermore, 18 patients (7.3 %) died due to early recurrent disease. Three patients (1.2 %) died of cardiovascular events, unrelated to CRS + HIPEC. The 1-year mortality group had more extensive peritoneal disease (p = 0.02) and the operative time in this group was longer (p < 0.001). CONCLUSIONS: Overall treatment-related mortality was considerably higher than described by the 30-day and in-hospital mortality rate. However, even though complete macroscopic cytoreduction was achieved in every patient, the main cause of 1-year mortality was early recurrent disease. Both findings are valuable in preoperative patient selection, as well as in preoperative counseling of patients undergoing a CRS + HIPEC procedure.

Serious Postoperative Complications Affect Early Recurrence After Cytoreductive Surgery and HIPEC for Colorectal Peritoneal Carcinomatosis.

BACKGROUND: The prognosis of patients with peritoneally metastasized colorectal cancer has improved significantly with the introduction of cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Although a macroscopically complete resection is achieved in nearly every patient, recurrence rates are high. This study aims to identify risk factors for early recurrence, thereby offering ways to reduce its occurrence. METHODS: All patients with colorectal peritoneal carcinomatosis treated with CRS + HIPEC and a minimum follow-up of 12 months, in April 2014, were analyzed. Patient data were compared between patients with or without recurrence within 12 months after CRS + HIPEC. Risk factors were determined using logistic regression analysis. Postoperative complications were graded according to the serious adverse events (SAEs) score, with grade 3 or higher indicating complications requiring intervention. RESULTS: A complete macroscopic cytoreduction was achieved in 96 % of all patients treated with CRS + HIPEC. Forty-six of 133 patients (35 %) developed recurrence within 12 months. An SAE ≥3 after CRS + HIPEC was the only significant risk factor found for early recurrence (odds ratio 2.3; p = 0.046). Median survival in the early recurrence group was 19.3 months compared with 43.2 months in the group without early recurrence (p < 0.001). Patients with an SAE ≥3 showed a reduced survival compared with patients without such complications (22.1 vs. 31.0 months, respectively; p = 0.02). CONCLUSIONS: Early recurrence after CRS + HIPEC is associated with a significant reduction in overall survival. This study identifies postoperative complications requiring intervention as the only significant risk factor for early recurrence, independent of the extent of peritoneal disease, highlighting the importance of minimizing the risk of postoperative complications.