Systemic chemotherapy in addition to CRS-HIPEC for colorectal peritoneal metastases: A critical systematic review on the impact on overall survival.

In patients with resectable colorectal peritoneal metastases, it is unclear whether systemic chemotherapy, in addition to cytoreductive surgery-hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), improves overall survival (OS). This systematic review of 12 retrospective studies involving 3721 patients aimed to summarize the available evidence. Contradictory results were found regarding the effectiveness of neoadjuvant, adjuvant, and perioperative systemic therapies on OS, with a high risk of bias. Available evidence remains inconclusive, stressing the need for prospective, randomized trials, like the ongoing Dutch CAIRO6-trial.

Patient-reported outcomes during first-line palliative systemic therapy alternated with pressurized intraperitoneal aerosol chemotherapy for unresectable colorectal peritoneal metastases: a single-arm phase II trial (CRC-PIPAC-II).

BACKGROUND: The CRC-PIPAC-II study prospectively assessed bidirectional therapy (BT) consisting of first-line palliative systemic therapy and electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC-OX) in patients with unresectable colorectal peritoneal metastases (CPM). This study describes the exploration of patient-reported outcomes (PROs). METHODS: In this phase II trial, 20 patients with isolated CPM were treated with up to three cycles of BT, each cycle consisting of two to three courses of systemic therapy, followed by ePIPAC-OX (92 mg/m2). Patients were asked to complete the EuroQoL EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-CR29 questionnaires at baseline, during the first cycle of BT, and one and four weeks after each consecutive BT cycle. PRO scores were calculated and compared between baseline and each subsequent time point using linear-mixed modeling (LMM). PROs were categorized into symptom scales and function scales. Symptom scales ranged from 0 to 100, with 100 representing the maximum symptom load. Function scales ranged from 0 to 100, with 100 representing optimal functioning. RESULTS: Twenty patients underwent a total of 52 cycles of bidirectional therapy. Most PROs (29 of 37, 78%) were not significantly affected during trial treatment. In total, only eight PROs (22%) were significantly affected during trial treatment: Six PROs (index value, global health status, emotional functioning, C30, appetite, and insomnia) showed transient improvement at different time points. Two PROs transiently deteriorated: pain initially improved during the first BT cycle [- 16, p < 0.001] yet worsened temporarily one week after the first two BT cycles (+ 20, p < 0.001; + 17, p = 0.004; respectively). Abdominal pain worsened temporarily one week after the first BT cycle (+ 16, p = 0.004), before improving again four weeks after treatment ended (- 10, p = 0.004). All significant effects on Pros were clinically significant and all deteriorations in PROs were of temporary nature. DISCUSSION: Patients undergoing BT for unresectable CPM had significant, but reversible alterations in several PROs. Most affected PROs concerned improvements and only two PROs showed deteriorations. Both deteriorated PROs returned to baseline after trial treatment and were of a temporary nature. These outcomes help to design future studies on the role of ePIPAC in the palliative setting.

An observational cohort of patients with colorectal peritoneal metastases or pseudomyxoma peritonei treated with CRS-HIPEC: Development and first results of the Dutch CRS-HIPEC quality registry.

INTRODUCTION: To improve care for patients with colorectal peritoneal metastases (CRC-PM) or pseudomyxoma peritonei (PMP), the Dutch CRS-HIPEC quality registry was initiated in 2019. The aims are to describe the development and content of this registry and to give insight into the data collected during the first years. MATERIALS AND METHODS: The registry is an observational cohort in the Netherlands. All patients with CRC-PM or PMP who intend to undergo cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) from 6 hospitals are included. Clinical data and outcomes (including hospital variation) were analyzed. RESULTS: In 2019-2022, 889 patients were included in the CRS-HIPEC quality registry: 749 (84 %) with CRC-PM and 140 (16 %) with PMP. Peritoneal metastases were diagnosed synchronously in 51 % of CRC-PM patients and in 94 % of PMP patients. In patients undergoing complete CRS, the median peritoneal cancer index was 8 (IQR 4-13) for CRC-PM and 15 (IQR 6-26) for PMP. Complete cytoreduction was achieved in 639 CRC-PM patients (97 %) and 108 PMP patients (82 %). HIPEC was mainly performed with mitomycin C (CRC-PM: 94 %, PMP: 92 %). Major postoperative complications (Clavien-Dindo grade ≥3) occurred in 148 CRC-PM patients (22 %) and 30 PMP patients (23 %) with 90-day mortality rates of 2 %. In CRC-PM, differences between hospitals were observed regarding proportions of diagnostic laparoscopies/laparotomies, (neo)adjuvant treatment, ostomy formations and re-admissions. CONCLUSION: The CRS-HIPEC quality registry provides insight into the outcomes of CRS-HIPEC and enables clinical auditing and observational cohort studies aiming to improve treatment outcomes for patients with CRC-PM and PMP.

First-line palliative systemic therapy alternated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for unresectable colorectal peritoneal metastases: A single-arm phase II trial (CRC-PIPAC-II).

BACKGROUND: Palliative systemic therapy alternated with electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC) has never been prospectively investigated in patients with unresectable colorectal peritoneal metastases (CPM). The CRC-PIPAC-II study aimed to assess safety, feasibility and efficacy of such bidirectional therapy. METHODS: This two-center, single-arm, phase II trial enrolled chemotherapy-naïve patients to undergo three treatment cycles, consisting of systemic therapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI, all with bevacizumab) and oxaliplatin-based ePIPAC (92 mg/m2) with intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Primary outcome were major treatment-related adverse events. Secondary outcomes included minor events, tumor response, progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients completed 52 treatment cycles. Fifteen major events occurred in 7 patients (35 %): 5 events (33 %) related to systemic therapy; 5 (33 %) related to ePIPAC; and 5 (33 %) were biochemical events. No treatment-related deaths occurred. All patients experienced minor events, mostly abdominal pain, nausea and peripheral sensory neuropathy. After treatment, radiological, pathological, cytological, and biochemical response was observed in 0 %, 88 %, 38 %, and 31 % of patients respectively. Curative surgery was achieved in one patient. Median PFS was 10.0 months (95 % confidence interval [CI] 8.0-13.0) and median OS was 17.5 months (95 % CI 13.0-not reached). CONCLUSIONS: Combining palliative systemic therapy with oxaliplatin-based ePIPAC in patients with unresectable CPM was feasible and showed an acceptable safety profile. Treatment-induced response and survival are promising, yet further research is required to determine the additional value of ePIPAC to systemic therapy.

Towards Equal Access to Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy and Survival in Patients with Isolated Colorectal Peritoneal Metastases: A Nationwide Population-Based Study.

BACKGROUND: Before 2016, patients with isolated synchronous colorectal peritoneal metastases (PMCRC) diagnosed in expert centers had a higher odds of undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) and better overall survival (OS) than those diagnosed in referring centers. Nationwide efforts were initiated to increase awareness and improve referral networks. METHODS: This nationwide study aimed to evaluate whether the between-center differences in odds of undergoing CRS-HIPEC and OS have reduced since these national efforts were initiated. All patients with isolated synchronous PMCRC diagnosed between 2009 and 2021 were identified from the Netherlands Cancer Registry. Associations between hospital of diagnosis and the odds of undergoing CRS-HIPEC, as well as OS, were assessed using multilevel multivariable regression analyses for two periods (2009-2015 and 2016-2021). RESULTS: In total, 3948 patients were included. The percentage of patients undergoing CRS-HIPEC increased from 17.2% in 2009-2015 (25.4% in expert centers, 16.5% in referring centers), to 23.4% in 2016-2021 (30.2% in expert centers, 22.6% in referring centers). In 2009-2015, compared with diagnosis in a referring center, diagnosis in a HIPEC center showed a higher odds of undergoing CRS-HIPEC (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.02-2.67) and better survival (hazard ratio [HR] 0.80, 95% CI 0.66-0.96). In 2016-2021, there were no differences in the odds of undergoing CRS-HIPEC between patients diagnosed in HIPEC centers versus referring centers (OR 1.27, 95% CI 0.76-2.13) and survival (HR 1.00, 95% CI 0.76-1.32). CONCLUSION: Previously observed differences in odds of undergoing CRS-HIPEC were no longer present. Increased awareness and the harmonization of treatment for PMCRC may have contributed to equal access to care and a similar chance of survival at a national level.

Comparing patient reported abdominal pain between patients treated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) and primary colorectal cancer surgery.

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).

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.

The Impact of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS-HIPEC) versus Conventional Surgery on Patient-Reported Outcomes: A Comparative Cohort Study between the CAIRO6 Trial and the PROCORE Study.

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.

Consensus statement for treatment protocols in pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Objectives: Safe implementation and thorough evaluation of new treatments require prospective data monitoring and standardization of treatments. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a promising alternative for the treatment of patients with peritoneal disease with an increasing number of suggested drug regimens. The aim was to reach expert consensus on current PIPAC treatment protocols and to define the most important research topics. Methods: The expert panel included the most active PIPAC centers, organizers of PIPAC courses and principal investigators of prospective studies on PIPAC. A comprehensive literature review served as base for a two-day hybrid consensus meeting which was accompanied by a modified three-round Delphi process. Consensus bar was set at 70% for combined (strong and weak) positive or negative votes according to GRADE. Research questions were prioritized from 0 to 10 (highest importance). Results: Twenty-two out of 26 invited experts completed the entire consensus process. Consensus was reached for 10/10 final questions. The combination of doxorubicin (2.1 mg/m2) and cisplatin (10.5 mg/m2) was endorsed by 20/22 experts (90.9%). 16/22 (72.7%) supported oxaliplatin at 120 with potential reduction to 90 mg/m2 (frail patients), and 77.2% suggested PIPAC-Ox in combination with 5-FU. Mitomycin-C and Nab-paclitaxel were favoured as alternative regimens. The most important research questions concerned PIPAC conditions (n=3), standard (n=4) and alternative regimens (n=5) and efficacy of PIPAC treatment (n=2); 8/14 were given a priority of ≥8/10. Conclusions: The current consensus should help to limit heterogeneity of treatment protocols but underlines the utmost importance of further research.

Patient-reported outcomes during repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for isolated unresectable colorectal peritoneal metastases in a multicenter, single-arm, phase 2 trial (CRC-PIPAC).

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/m2). 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.

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.

The emergence of pressurized intraperitoneal aerosol chemotherapy as a palliative treatment option for patients with diffuse peritoneal metastases: a narrative review.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an emerging palliative treatment for patients with unresectable peritoneal metastases. Potential advantages of PIPAC over current treatment options are a homogeneous intraperitoneal distribution, low local and systemic toxicity, and enhanced tumour penetration. Given these possible benefits, PIPAC is increasingly implemented in many centres worldwide. Scientific research into PIPAC is currently available from in vitro/in vivo/in animal studies, retrospective cohorts in humans, and phase I and II studies in humans. There are no results from randomised trials comparing PIPAC with conventional treatment, such as palliative systemic therapy. This narrative review aimed to provide an overview of the currently available literature on PIPAC. In general, repetitive PIPAC was feasible and safe for patients and operating room personnel. Primary and secondary non-access rates varied from 0-17% and 0-15%, respectively. Iatrogenic bowel injury was observed in 0-3% of PIPAC procedures. CTCAE grade 1-2 complications were common, mostly consisting of abdominal pain, nausea, vomiting, and fatigue. CTCAE grade 3-4 complications were uncommon, occurring on 0-15% of PIPAC procedures. Post-operative mortality rates of 0-2% were reported. The risk of occupational exposure to cytotoxic drugs was very low when strict safety guidelines were followed. Clinical heterogeneity was high in most studies, since, in general, patients with unresectable peritoneal metastases from a variety of primary tumours were included. Also, patients received either PIPAC monotherapy or PIPAC combined with concomitant systemic therapy, and were able to receive PIPAC in any line of palliative treatment. Since the results were generally not stratified for these three important factors, this severely complicates the interpretation of results. Based on the current literature, PIPAC may be regarded as a promising palliative treatment option in patients with diffuse peritoneal metastases. Initial results show that it is feasible and safe. However, well designed and (ideally) randomized controlled trials are urgently needed to determine the additional value of PIPAC in this setting. Until then, PIPAC should preferably be performed in the setting of clinical trials.

Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (PIPAC-OX) in patients with colorectal peritoneal metastases-a systematic review.

Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (PIPAC-OX) is increasingly used as a palliative treatment option for patients with colorectal peritoneal metastases (CPM). The present study aimed to systematically review all clinical studies reporting safety and efficacy outcomes of PIPAC-OX in patients with CPM. PubMed, EMBASE, The Cochrane Library, and CINAHL were systematically searched to identify all clinical studies that included at least one patient with CPM treated with PIPAC-OX and reported one of the following outcomes: adverse events, tumor response, quality of life, secondary cytoreductive surgery, progression-free survival, overall survival, and environmental safety of PIPAC-OX. Results were narratively described. Of 28 included studies, only 14 non-comparative studies separately reported at least one outcome of PIPAC-OX for CPM, of which only two studies specifically focused on this group. These 14 studies reported adverse events (5 studies), tumor response (5 studies), secondary cytoreductive surgery (4 studies), progression-free survival (1 study), overall survival (5 studies), and environmental safety (2 studies). Except for 5 studies (describing 26 patients), none of the included studies stratified their results for PIPAC-OX monotherapy and PIPAC-OX with concomitant systemic therapy, and none of the studies reporting survival outcomes stratified results for line of palliative treatment, complicating interpretation. No PIPAC-OX related deaths were reported. No occupational platinum was detected during PIPAC-OX. The available evidence regarding PIPAC-OX for CPM is limited and difficult to interpret. Despite these limitations, PIPAC-OX appears safe in patients with CPM and safe for operating personnel. To increase insight in the role of PIPAC-OX in this setting, investigators of ongoing and future studies are encouraged to report separate outcomes of PIPAC-OX for CPM, to stratify their results for PIPAC-OX monotherapy and PIPAC-OX with concomitant systemic therapy, and to stratify survival results for line of palliative treatment.

Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases: A Phase 2 Randomized Clinical Trial.

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.