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Background: Despite thorough preoperative work-up for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), so called open-close (OC) procedures as a result of irresectable disease remain common. Currently, diagnostic laparoscopy (DLS) is considered the gold standard, and consequently overrules the results of computed tomography (CT) scans; however, certain regions of the abdomen are difficult to assess and postoperative adhesion formation may further compromise staging during DLS., Purpose: To determine whether better clinical assessment could be achieved by combining the results of DLS and preoperative CT scans during a multidisciplinary team (MDT) meeting., Material and Methods: All patients who were eligible for CRS-HIPEC after DLS, but eventually underwent an OC procedure between 2010 and 2018 were selected. Radiological reassessment of CT scans was performed and combined with assessment of the DLS during a MDT meeting. The MDT was blinded for the outcome of the procedure (OC vs. CRS-HIPEC)., Results: The majority of the OC procedures (69%) was correctly predicted by the MDT. In most patients (88%), this conclusion was based on the combination of the radiological and surgical peritoneal cancer index (PCI). CT was particularly accurate for detection of larger tumor deposits in the abdominal regions, as 84%-86% was detected. Assessment of lesions in the small bowel regions is troublesome; 72% of lesions are missed on the preoperative CT scan., Conclusions: A combination of radiological and surgical assessment of the PCI may lead to improved preoperative patient selection for CRS-HIPEC., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) is an emerging palliative treatment for patients with unresectable colorectal peritoneal metastases. Previously, our study group reported that patients experienced abdominal pain for several weeks after PIPAC-OX. However, it is unknown how this compares to abdominal pain after regular colorectal cancer surgery. To provide some perspective, this study compared the presence of abdominal pain after PIPAC-OX to the presence of abdominal pain after primary tumor surgery. Patient reported abdominal pain scores (EORTC QLQ-CR-29), from two prospective, Dutch cohorts were used in this study. Scores ranged from 0 to 100, a higher score represents more abdominal pain. Abdominal pain at baseline and at four weeks after treatment were compared between the two groups. Twenty patients who underwent PIPAC-OX and 322 patients who underwent primary tumor surgery were included in the analysis. At baseline, there were no differences in abdominal pain between both groups (mean 20 vs. 18, respectively; p = 0.688). Four weeks after treatment, abdominal pain was significantly worse in the PIPAC group (39 vs 15, respectively; p < 0.001; Cohen's d = 0.99). The differential effect over time for abdominal pain differed significantly between both groups (mean difference: 19 vs - 3, respectively; p = 0.004; Cohen's d = 0.88). PIPAC-OX resulted in significantly worse postoperative abdominal pain than primary tumor surgery. These results can be used for patient counseling and stress the need for adequate analgesia during and after PIPAC-OX. Further research is required to prevent or reduce abdominal pain after PIPAC-OX.Trial registration CRC-PIPAC: Clinicaltrails.gov NCT03246321 (01-10-2017)., (© 2023. The Author(s).)

Background: Patients with colorectal peritoneal metastases who are not eligible for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) owing to extensive peritoneal disease have a poor prognosis. It was hypothesized that these patients may benefit from the addition of intraperitoneal irinotecan to standard palliative systemic chemotherapy., Methods: This was a classical 3 + 3 phase I dose-escalation trial in patients with colorectal peritoneal metastases who were not eligible for CRS-HIPEC. Intraperitoneal irinotecan was administered every 2 weeks, concomitantly with systemic FOLFOX (5-fluorouracil, folinic acid, oxaliplatin)-bevacizumab. The primary objective was to determine the maximum tolerated dose and dose-limiting toxicities. Secondary objectives were to elucidate the systemic and intraperitoneal pharmacokinetics, safety profile, and efficacy., Results: Eighteen patients were treated. No dose-limiting toxicities were observed with 50 mg (4 patients) and 75 mg (9 patients) intraperitoneal irinotecan. Two dose-limiting toxicities occurred with 100 mg irinotecan among five patients. The maximum tolerated dose of intraperitoneal irinotecan was established to be 75 mg, and it was well tolerated. Intraperitoneal exposure to SN-38 (active metabolite of irinotecan) was high compared with systemic exposure (median intraperitoneal area under the curve (AUC) to systemic AUC ratio 4.6). Thirteen patients had a partial radiological response and five had stable disease. Four patients showed a complete response during post-treatment diagnostic laparoscopy. Five patients underwent salvage resection or CRS-HIPEC. Median overall survival was 23.9 months., Conclusion: Administration of 75 mg intraperitoneal irinotecan concomitantly with systemic FOLFOX-bevacizumab was safe and well tolerated. Intraperitoneal SN-38 exposure was high and prolonged. As oncological outcomes were promising, intraperitoneal administration of irinotecan may be a good alternative to other, more invasive and costly treatment options. A phase II study is currently accruing., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: - This population-based study aimed to investigate incidence, risk factors, treatment, and survival of synchronous peritoneal metastases (PM) of hepatobiliary origin., Methods: - All Dutch patients diagnosed with hepatobiliary cancer between 2009 and 2018 were selected. Factors associated with PM were identified with logistic regression analyses. Treatments for patients with PM were categorized into local therapy, systemic therapy, and best supportive care (BSC). Overall survival (OS) was investigated using log-rank test., Results: - In total, 12 649 patients were diagnosed with hepatobiliary cancer of whom 8% (n = 1066) were diagnosed with synchronous PM (12% [n = 882/6519] in biliary tract cancer [BTC] vs. 4% [n = 184/5248] in hepatocellular carcinoma [HCC]). Factors that were positively associated with PM were the female sex (OR 1.18, 95% CI 1.03-1.35), BTC (OR 2.93, 95% CI 2.46-3.50), diagnosis in more recent years (2013-2015: OR 1.42, 95% CI 1.20-1.68; 2016-2018: OR 1.48, 95% CI 1.26-1.75), T3/T4 stage (OR 1.84, 95% CI 1.55-2.18), N1/N2 stage (OR 1.31, 95% CI 1.12-1.53) and other synchronous systemic metastases (OR 1.85, 95% CI 1.62-2.12). Of all PM patients, 723 (68%) received BSC only. Median OS was 2.7 months (IQR 0.9-8.2) in PM patients., Conclusion: - Synchronous PM were found in 8% of all hepatobiliary cancer patients and occurred more often in BTC than in HCC. Most patients with PM received BSC only. Given the high incidence and dismal prognosis of PM patients, extended research in hepatobiliary PM is needed to achieve better outcome in these patients., Competing Interests: Declaration of competing interest IHJTdH: An unrestricted research grant for unrelated research from RanD Biotech and ROCHE, paid to the institute. JdV has served as a consultant for Amgen, AstraZeneca, MSD, Pierre Fabre, and Servier, and has received institutional research funding from Servier. HJK: has served in an advisory board for Jansen, IPSEN and Astra Zeneca, paid to institute. Has received speakers fee from Medtalks and CCO, paid to institute. All outside the submitted work. The other authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

The reported incidence of synchronous and metachronous ovarian metastases (OM) from colorectal cancer (CRC) is ~3.4%. OM from CRC are often considered sanctuary sites due to their lower sensitivity to systemic treatment. It has thus been hypothesized that the presence of OM decreases overall survival. Therefore, the purpose of our study was to evaluate the impact of synchronous OM on overall survival in female patients with stage IV CRC treated with systemic therapy alone with palliative intent. The present study used data from the Netherlands Cancer Registry and included female CRC patients with synchronous systemic metastases who were treated with systemic therapy between 2008 and 2018. A subsample was created using propensity score matching to create comparable groups. Propensity scores were determined using a logistic regression model in which the dependent variable was the presence of OM and the independent variables were the variables that differed significantly between both groups. Our study included 5253 patients with stage IV CRC that received systemic therapy. Among these patients, 161 (3%) had OM while 5092 (97%) had extra-ovarian metastases only. Three-year overall survival rates did not show a significant difference between patients with OM compared to patients without ovarian metastases. Moreover, the propensity score-matched analysis showed that the presence of OM in patients treated with systemic therapy for stage IV CRC disease was not associated with decreased 3-year overall survival. However, the results of the present study should be interpreted with caution, due to its observational character and used selection criteria., (© 2022 UICC.)

Purpose-To compare patient-reported outcomes (PROs) of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for colorectal peritoneal metastases to PROs of colorectal cancer (CRC) patients undergoing conventional surgery. Methods-Data were extracted from the CAIRO6 trial (CRS-HIPEC group) and the PROCORE study (conventional surgery group). Nine predefined PROs (derived from the EORTC QLQ-C30 questionnaire) were compared at baseline, in the early postoperative period and one year postoperatively, with correction for treatment with systemic therapy using linear mixed modeling. Results-In total, 331 patients were included: 71 in the CRS-HIPEC group and 260 in the conventional surgery group. All predefined PROs (fatigue, diarrhea, C30 summary score, Global Health Status, physical, role, emotional, cognitive, and social functioning) did not differ significantly between the groups at all three timepoints, and differential effects over time for all PROs did not differ significantly between the groups. Significant worsening of fatigue, C30 summary score, physical and role functioning (both groups), and cognitive and social functioning (conventional surgery group only) was present in the early postoperative period. All scores returned to baseline at one year postoperatively, except for physical and cognitive functioning in the conventional surgery group. Emotional functioning improved postoperatively in both groups compared to baseline. Conclusion-Despite a more extensive procedure with greater risk of morbidity, CRS-HIPEC in patients with colorectal peritoneal metastases did not have a greater negative impact on PROs than conventional surgery in patients with CRC. Further, systemic therapy did not affect these PROs. These findings may facilitate future patient counseling and shared decision making in clinical practice.

Background: This study aimed to assess the impact of open or laparoscopic resection of primary colorectal cancer (CRC) on the development of metachronous colorectal peritoneal metastases (CPM) in a population-based cohort., Materials and Methods: This was a retrospective, population-based study of CRC patients who underwent open or laparoscopic resection of the primary tumour in the Netherlands between January 1st and June 30th 2015. Patients with synchronous metastases were excluded. CPM were considered metachronous if diagnosed ≥ 90 days after resection of primary CRC. Multivariable cox regression analysis was performed to correct for tumour location, histology, differentiation, and stage, nodal stage, tumour perforation, primary surgery type, and unclear resection margins., Results: In total, 1516 CRC patients underwent open resection and 3236 CRC patients underwent laparoscopic resection, with a 3-year cumulative incidence of metachronous CPM of 7.3% and 3.7%, respectively (p < 0.001), after median follow-up of 42 months. Open surgical approach was significantly associated with the development of metachronous CPM: HR 1.4 [95%CI 1.1-1.8]. Other prognostic factors were mucinous adenocarcinoma histology (HR 1.6, 95%CI 1.0-2.5), T4 stage (HR 3.2, 95%CI 2.3-4.5), N1 stage (HR 2.9, 95%CI 2.1-4.0), and N2 stage (HR 4.2, 95%CI 2.9-6.1)., Conclusions: Patients treated with open resection had a significantly higher risk to develop metachronous CPM than patients treated with laparoscopic resection. The mechanisms underlying this phenomenon remain unknown but might be related to differences in per-operative specimen handling, tumour spill, surgical trauma and pro-inflammatory response. This finding might imply the need for a personalized follow-up after primary resection of CRC., (© 2022. The Author(s).)

Background: CRC-PIPAC prospectively assessed repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) as a palliative monotherapy (i.e., without concomitant systemic therapy in between subsequent procedures) for unresectable colorectal peritoneal metastases (CPM). The present study explored patient-reported outcomes (PROs) during trial treatment., Methods: In this single-arm phase 2 trial in two tertiary centers, patients with isolated unresectable CPM received 6-weekly PIPAC-OX (92 mg/m 2 ). PROs (calculated from EQ-5D-5L, and EORTC QLQ-C30 and QLQ-CR29) were compared between baseline and 1 and 4 weeks after the first three procedures using linear mixed modeling with determination of clinical relevance (Cohen's D ≥ 0.50) of statistically significant differences., Results: Twenty patients underwent 59 procedures (median 3 [range 1-6]). Several PROs solely worsened 1 week after the first procedure (index value - 0.10, p < 0.001; physical functioning - 20, p < 0.001; role functioning - 27, p < 0.001; social functioning - 18, p < 0.001; C30 summary score - 16, p < 0.001; appetite loss + 15, p = 0.007; diarrhea + 15, p = 0.002; urinary frequency + 13, p = 0.004; flatulence + 13, p = 0.001). These PROs returned to baseline at subsequent time points. Other PROs worsened 1 week after the first procedure (fatigue + 23, p < 0.001; pain + 29, p < 0.001; abdominal pain + 32, p < 0.001), second procedure (fatigue + 20, p < 0.001; pain + 21, p < 0.001; abdominal pain + 20, p = 0.002), and third procedure (pain + 22, p < 0.001; abdominal pain + 22, p = 0.002). Except for appetite loss, all changes were clinically relevant. All analyzed PROs returned to baseline 4 weeks after the third procedure., Conclusions: Patients receiving repetitive PIPAC-OX monotherapy for unresectable CPM had clinically relevant but reversible worsening of several PROs, mainly 1 week after the first procedure., Trial Registration: Clinicaltrials.gov: NCT03246321; Netherlands trial register: NL6426., (© 2021. The Author(s).)

Background and Purpose: In female colorectal cancer patients, a mean proportion of synchronous and/or metachronous ovarian metastases of 3.4% was described. Previous literature showed that young or premenopausal women (≤ 55 years of age) may be more frequently affected. Once ovarian metastases are diagnosed, the prognosis of the patient is generally dismal, with 5-year survival varying from 12 to 27%. The present study is aimed at determining the proportion of young or premenopausal women diagnosed with colorectal cancer who presented with or developed ovarian metastases by reviewing the current literature on this topic., Methods: This review was performed by querying MEDLINE and EMBASE databases using a combination of terms: "colorectal neoplasms, colorectal cancer, ovarian neoplasms, Krukenberg tumor, young adult, young age, premenopause." Studies that indicated ovarian metastases, either synchronous or metachronous (or a combination of the two), in young women were retrieved and analyzed., Results: The review identified 14 studies encompassing 3379 young or premenopausal female colorectal cancer patients. In this selected group of patients, a mean proportion of ovarian metastases of 4.6% [95% CI: 4.0;5.4] was found., Conclusions: This review showed that approximately one in twenty young female colorectal cancer patients will present with or develop ovarian metastases. Since outcome of this specific oncological pathology is often dismal, this finding is clinically relevant. It demonstrates the need to develop strategies to lower the incidence of ovarian metastases with adequate treatment and counseling of these patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM)., Objective: To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment., Design, Setting, and Participants: An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment., Interventions: Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles., Main Outcomes and Measures: Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm)., Results: In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively., Conclusions and Relevance: In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial., Trial Registration: ClinicalTrials.gov Identifier: NCT02758951.

Objective: The aim of the study was to gain insight in the incidence, treatment, and survival of patients with synchronous pancreatic peritoneal metastases., Methods: All patients diagnosed with pancreatic cancer between 2008 and 2018 in the Netherlands Cancer Registry were evaluated. The patients were subcategorized as (1) synchronous peritoneal metastases, (2) synchronous systemic metastases, and (3) no metastases., Results: In total, 25,334 patients with pancreatic cancer were included. Among them, 3524 (14%) presented with synchronous peritoneal metastases, 10,659 (42%) with systemic metastases, and 11,151 (44%) without metastases at the time of diagnosis. The proportion of the patients diagnosed with peritoneal metastases increased over time (11%, 2008; 16%, 2018; P < 0.001). Of these patients, 964 (27%) received cancer treatment and 2560 (73%) received best supportive care. The median overall survival in patients with peritoneal metastases, systemic metastases, and without metastases was 1.9, 2.4, and 8.0 months, respectively (P < 0.001). In the patients with peritoneal metastases, the median overall survival was 5.0 months when undergoing cancer treatment and 1.3 months with best supportive care (P < 0.001)., Conclusions: Patients with pancreatic cancer are increasingly diagnosed with synchronous peritoneal metastases. Given the current dismal prognosis, research to improve treatment is designated for this patient category., Competing Interests: I.H.J.T.d.H. received an unrestricted research grant for unrelated research from RanD Biotech and ROCHE, paid to the institute. J.d.V.-G. has served as a consultant for AstraZeneca, MSD, Pierre Fabre, and Servier and has received institutional research funding from Servier (all outside the submitted work). The other authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Peritoneal metastases (PM) from lung cancer are rare and it is unknown how they affect the prognosis of patients with lung cancer. This population-based study aimed to assess the incidence, associated factors, treatment and prognosis of PM from lung cancer. Data from the Netherlands Cancer Registry were used. All patients diagnosed with lung cancer between 2008 and 2018 were included. Logistic regression analysis was performed to identify factors associated with the presence of PM. Cox regression analysis was performed to identify factors associated with the overall survival (OS) of patients with PM. Between 2008 and 2018, 129,651 patients were diagnosed with lung cancer, of whom 2533 (2.0%) patients were diagnosed with PM. The European Standardized Rate of PM increased significantly from 0.6 in 2008 to 1.4 in 2018 (p < 0.001). Age between 50 and 74 years, T3-4 tumour stage, N2-3 nodal stage, tumour morphology of a small cell lung cancer or adenocarcinoma, and the presence of systemic metastases were associated with the presence of PM. The median OS of patients with PM was 2.5 months. Older age, male sex, T3-4 tumour stage, N2-3 nodal stage, not receiving systemic treatment, and the presence of systemic metastases were associated with a worse OS. Synchronous PM were diagnosed in 2.0% of patients with lung cancer and resulted in a very poor survival.

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., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jgo-20-133). The focused issue was sponsored by the Peritoneal Surface Oncology Group International (PSOGI). IHJTDH reports a unrestricted grant was paid to the institute by RanD Biotech and QP&S. The authors have no other conflicts of interest to declare., (2021 Journal of Gastrointestinal Oncology. All rights reserved.)

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.

Introduction: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has become standard of care for patients with peritoneal metastases of colorectal origin with a low/moderate abdominal disease load. In case of a peritoneal cancer index (PCI) score >20, CRS-HIPEC is not considered to be beneficial. Patients with a PCI >20 are currently offered palliative systemic chemotherapy. Previous studies have shown that systemic chemotherapy is less effective against peritoneal metastases than it is against haematogenous spread of colorectal cancer. It is suggested that patients with peritoneal metastases may benefit from the addition of intraperitoneal chemotherapy to systemic chemotherapy. Aim of this study is to establish the maximum tolerated dose of intraperitoneal irinotecan, added to standard of care systemic therapy for colorectal cancer. Secondary endpoints are to determine the safety and feasibility of this treatment and to establish the pharmacokinetic profile of intraperitoneally administered irinotecan., Methods and Analysis: This phase I, '3+3' dose-escalation, study is performed in two Dutch tertiary referral centres. The study population consists of adult patients with extensive peritoneal metastases of colorectal origin who have a good performance status and no extra-abdominal metastases. According to standard work-up for CRS-HIPEC, patients will undergo a diagnostic laparoscopy to score the PCI. In case of a PCI >20, a peritoneal access port will be placed in the abdomen of the patient. Through this port we will administer intraperitoneal irinotecan, in combination with standard systemic treatment consisting of 5-fluorouracil/leucovorin with oxaliplatin and the targeted agent bevacizumab. Therapy consists of a maximum of 12 cycles 2-weekly., Ethics and Dissemination: This study protocol is approved by a research medical ethics committee (Rotterdam, Netherlands) and the Dutch Competent Authority (CCMO, The Hague, Netherlands). The results of this trial will be submitted for publication in a peer-reviewed scientific journal., Trail Registration Number: NL6988 and NL2018-000479-33; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 .