Development of a prediction model for recurrence in patients with colorectal peritoneal metastases undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

INTRODUCTION: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes for selected patients with colorectal peritoneal metastases (PM), but recurrence rates are high. The aim of this study was to develop a tool to predict recurrence in patients with colorectal PM that undergo CRS-HIPEC. MATERIALS AND METHODS: For this retrospective cohort study, data of patients that underwent CRS-HIPEC for colorectal PM from four Dutch HIPEC centers were used. Exclusion criteria were perioperative systemic therapy and peritoneal cancer index (PCI) ≥20. Nine previously identified factors were considered as predictors: gender, age, primary tumor characteristics (location, nodal stage, differentiation, and mutation status), synchronous liver metastases, preoperative Carcino-Embryonal Antigen (CEA), and peritoneal cancer index (PCI). The prediction model was developed using multivariable Cox regression and validated internally using bootstrapping. The performance of the model was evaluated by discrimination and calibration. RESULTS: In total, 408 patients were included. During the follow-up, recurrence of disease occurred in 318 patients (78%). Significant predictors of recurrence were PCI (HR 1.075, 95% CI 1.044-1.108) and primary tumor location (left sided HR 0.719, 95% CI 0.550-0.939). The prediction model for recurrence showed fair discrimination with a C-index of 0.64 (95% CI 0.62, 0.66) after internal validation. The model was well-calibrated with good agreement between the predicted and observed probabilities. CONCLUSION: We developed a prediction tool that could aid in the prediction of recurrence in patients with colorectal PM who undergo CRS-HIPEC.

Intraperitoneal irinotecan with concomitant FOLFOX and bevacizumab for patients with unresectable colorectal peritoneal metastases: protocol of the multicentre, open-label, phase II, INTERACT-II trial.

INTRODUCTION: The peritoneum is the second most affected organ for the dissemination of colorectal cancer (CRC). Patients with colorectal peritoneal metastases (CPM) face a poor prognosis, despite the majority of patients being treated with palliative systemic therapy. The efficacy of palliative systemic therapy is limited due to the plasma-peritoneum barrier. The poor prognosis of unresectable CPM patients has resulted in the development of new treatment strategies where systemic therapy is combined with local, intraperitoneal chemotherapy. In the recently published phase I study, the maximum tolerated dose and thus the recommended phase II dose of intraperitoneal irinotecan was investigated and determined to be 75 mg. In the present study, the overall survival after treatment with 75 mg irinotecan with concomitant mFOLFOX4 and bevacizumab will be investigated. MATERIALS AND METHODS: In this single-arm phase II study in two Dutch tertiary referral centres, 85 patients are enrolled. Eligibility criteria are an adequate performance status and organ function, histologically confirmed microsatellite stable and unresectable CPM, no previous palliative therapy for CRC, no systemic therapy<6 months for CRC prior to enrolment and no previous cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS and HIPEC). Patients will undergo a diagnostic laparoscopy as standard work-up for CPM and if the peritoneal disease is considered unresectable (eg, Peritoneal Cancer Index (PCI)>20, too extensive small bowel involvement), a peritoneal access port and a port-a-cath are placed for administration of intraperitoneal and intravenous chemotherapy, respectively. Patients may undergo up to 12 cycles of study treatment. Each cycle consists of intravenous mFOLFOX4 with bevacizumab and concomitant intraperitoneal irinotecan (75 mg), which is repeated every 2 weeks, with a maximum of 12 cycles. Modified FOLFOX-4 regimen consists of 85 mg/m2 oxaliplatin plus 200 mg/m2 LV and 5-FU 400 mg/m2 bolus on day 1 followed by 1600 mg/m2 5-FU as a 46 hours infusion. Study treatment ends after the 12th cycle, or earlier in case of disease progression or unacceptable toxicity. The primary outcome is overall survival and key secondary outcomes are progression-free survival, safety (measured by the amount of grade ≥3 adverse events (Common Terminology Criteria for Adverse Events V.5.0)), patient-reported outcomes and pharmacokinetics of irinotecan. It is hypothesised that the trial treatment will lead to a 4 month increase in overall survival; from a median of 12.2 to 16.2 months. ETHICS AND DISSEMINATION: This study is approved by the Dutch Authority (CCMO, the Hague, the Netherlands), by a central medical ethics committee (MEC-U, Nieuwegein, the Netherlands) and by the institutional research boards of both research centres. Results will be submitted for publication in peer-reviewed medical journals and presented to patients and healthcare professionals. TRIAL REGISTRATION NUMBER: NCT06003998.

Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Locally Advanced Colon Cancer (COLOPEC): 5-Year Results of a Randomized Multicenter Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Whether adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) might prevent peritoneal metastases after curative surgery for high-risk colon cancer is an ongoing debate. This study aimed to determine 5-year oncologic outcomes of the randomized multicenter COLOPEC trial, which included patients with clinical or pathologic T4N0-2M0 or perforated colon cancer and randomly assigned (1:1) to either adjuvant systemic chemotherapy and HIPEC (n = 100) or adjuvant systemic chemotherapy alone (n = 102). HIPEC was performed using a one-time administration of oxaliplatin (460 mg/m2, 30 minutes, 42°C, concurrent fluorouracil/leucovorin intravenously), either simultaneously (9%) or within 5-8 weeks (91%) after primary tumor resection. Outcomes were analyzed according to the intention-to-treat principle. Long-term data were available of all 202 patients included in the COLOPEC trial, with a median follow-up of 59 months (IQR, 54.5-64.5). No significant difference was found in 5-year overall survival rate between patients assigned to adjuvant HIPEC followed by systemic chemotherapy or only adjuvant systemic chemotherapy (69.6% v 70.9%, log-rank; P = .692). Five-year peritoneal metastases rates were 63.9% and 63.2% (P = .907) and 5-year disease-free survival was 55.7% and 52.3% (log-rank; P = .875), respectively. No differences in quality-of-life outcomes were found. Our findings implicate that adjuvant HIPEC should still be performed in trial setting only.

Adjuvant dendritic cell-based immunotherapy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with malignant peritoneal mesothelioma: a phase II clinical trial.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is an aggressive malignancy with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes, but recurrence rates remain high. Dendritic cell-based immunotherapy (DCBI) showed promising results in patients with pleural mesothelioma. The primary aim of this trial was to determine feasibility of adjuvant DCBI after CRS-HIPEC. METHODS: This open-label, single-center, phase II clinical trial, performed in the Erasmus MC Cancer Institute Rotterdam, the Netherlands, included patients with epithelioid MPM. 4-6 weeks before CRS-HIPEC leukapheresis was performed. 8-10 weeks after surgery, DCBI was administered three times biweekly. Feasibility was defined as administration of at least three adjuvant vaccinations in 75% of patients. Comprehensive immune cell profiling was performed on peripheral blood samples prior to and during treatment. RESULTS: All patients who received CRS-HIPEC (n=16) were successfully treated with adjuvant DCBI. No severe toxicity related to DCBI was observed. Median progression-free survival (PFS) was 12 months (IQR 5-23) and median overall survival was not reached. DCBI was associated with increased proliferation of circulating natural killer cells and CD4+ T-helper (Th) cells. Co-stimulatory molecules, including ICOS, HLA-DR, and CD28 were upregulated predominantly on memory or proliferating Th-cells and minimally on CD8+ cytotoxic T-lymphocytes (CTLs) after treatment. However, an increase in CD8+ terminally differentiated effector memory (Temra) cells positively correlated with PFS, whereas co-expression of ICOS and Ki67 on CTLs trended towards a positive correlation. CONCLUSIONS: Adjuvant DCBI after CRS-HIPEC in patients with MPM was feasible and safe, and showed promising survival outcomes. DCBI had an immune modulatory effect on lymphoid cells and induced memory T-cell activation. Moreover, an increase of CD8+ Temra cells was more pronounced in patients with longer PFS. These data provide rationale for future combination treatment strategies. TRIAL REGISTRATION NUMBER: NTR7060; Dutch Trial Register (NTR).

Phase I study of intraperitoneal irinotecan combined with palliative systemic chemotherapy in patients with colorectal peritoneal metastases.

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.

Patients with extensive colorectal peritoneal metastases who are not eligible for surgery and heated intraperitoneal chemotherapy have poor survival. The authors tried to improve the survival of these patients by adding intraperitoneal (inside the abdominal cavity) chemotherapy to standard palliative chemotherapy which is administered into the bloodstream. In this trial, irinotecan (a type of chemotherapy) was administered into the abdomen of patients with extensive colorectal peritoneal metastases. The authors investigated which dose could be administered safely in combination with standard palliative chemotherapy. They also looked into toxicity, safety, benefit, and movement of the drug in the body. Eighteen patients were treated in this study. The maximum tolerated dose of intraperitoneal irinotecan was 75 mg. It was well tolerated and could be administered safely. The intra-abdominal amount of irinotecan was high, whereas the amount of irinotecan in the blood remained low. The benefits of intra-abdominal irinotecan were promising. Because of this, a new study has been started to further investigate this new combination chemotherapy for colorectal cancer.

Intraperitoneal Chemotherapy for Unresectable Peritoneal Surface Malignancies.

Malignancies of the peritoneal cavity are associated with a dismal prognosis. Systemic chemotherapy is the gold standard for patients with unresectable peritoneal disease, but its intraperitoneal effect is hampered by the peritoneal-plasma barrier. Intraperitoneal chemotherapy, which is administered repeatedly into the peritoneal cavity through a peritoneal implanted port, could provide a novel treatment modality for this patient population. This review provides a systematic overview of intraperitoneal used drugs, the performed clinical studies so far, and the complications of the peritoneal implemental ports. Several anticancer drugs have been studied for intraperitoneal application, with the taxanes paclitaxel and docetaxel as the most commonly used drug. Repeated intraperitoneal chemotherapy, mostly in combination with systemic chemotherapy, has shown promising results in Phase I and Phase II studies for several tumor types, such as gastric cancer, ovarian cancer, colorectal cancer, and pancreatic cancer. Two Phase III studies for intraperitoneal chemotherapy in gastric cancer have been performed so far, but the results regarding the superiority over standard systemic chemotherapy alone, are contradictory. Pressurized intraperitoneal administration, known as PIPAC, is an alternative way of administering intraperitoneal chemotherapy, and the first prospective studies have shown a tolerable safety profile. Although intraperitoneal chemotherapy might be a standard treatment option for patients with unresectable peritoneal disease, more Phase II and Phase III studies focusing on tolerability profiles, survival rates, and quality of life are warranted in order to establish optimal treatment schedules and to establish a potential role for intraperitoneal chemotherapy in the approach to unresectable peritoneal disease.

Impact of centralization of care for malignant peritoneal mesothelioma: A historical cohort study from the Dutch mesothelioma expert centers.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare and aggressive cancer that has a poor prognosis. An earlier population-based study found that the majority of Dutch patients do not receive anti-cancer treatment. In 2015, Dutch Malignant Mesothelioma care was centralized in two expert centers. We reviewed treatment patterns at these centers, to assess the impact of centralization of MPM care in the Netherlands. METHODS: Data from all patients referred to the Dutch MPM expert centers from 2014 to 2020, were retrospectively collected. Descriptive statistics regarding referrals, patient and tumor characteristics, and treatment patterns were provided. Population-based incidence rates were provided by the Netherlands Cancer Registry. RESULTS: From 2014 to 2020, 78 patients were referred to the Dutch Mesothelioma expert centers, of whom 32 were female (41%). From 2014 to 2017, 27 patients were referred, whereas 51 patients were referred from 2018 to 2020. This represents about 24% and 61% of the estimated population incidence, respectively. Treatment patterns were comparable between both periods. Between 2014 and 2018, 33% of patients underwent surgery, 44% systemic therapy, and 22% received best supportive care (BSC), while this was 29%, 37%, and 33% respectively from 2018 to 2020. CONCLUSION: Centralization of care for patients with MPM resulted in an increase of annual referrals to the Dutch mesothelioma expert centers. While population-based incidence did not change during the study period, the absolute number of patients receiving treatment at our centers did increase. This might be considered a first important step towards better treatment for patients with this fatal disease.

Treatment and Survival Outcomes for Patients with Colorectal Peritoneal Metastases Deemed Ineligible for Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Results of a Retrospective Study.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for selected patients with colorectal peritoneal metastases (PM). This report provides an overview of treatment and survival outcomes for patients deemed ineligible for CRS-HIPEC. METHODS: Colorectal PM patients referred to a tertiary center from 2014 to 2020 that were ineligible for CRS-HIPEC were included. Patient, tumor, and treatment characteristics were provided. Survival analyses were performed using the Kaplan-Meier method. RESULTS: Of 476 patients referred for CRS-HIPEC, 227 (48%) were deemed ineligible. Median follow-up was 15 months [IQR 10-22]. Data on follow-up treatment was available for 198 patients, of which 73% received systemic therapy. These patients had a median overall survival (OS) of 17 months [IQR 9-25]. For patients receiving best supportive care (BSC) median OS was 4 months [IQR 2-9]. The main reason for ineligibility was extensive PM (42%), with a median OS of 11 months [IQR 5-18]. Patients deemed ineligible due to (extensive) liver (9%) or lung metastases (8%) showed longer OS (median 22 months, IQR 8-27, and 24 months, IQR 12-29, respectively) than patients with extensive PM (median 11 months, IQR 5-18) or distant lymph node metastases (median 14 months, IQR 4-25). CONCLUSION: The main reason for CRS-HIPEC ineligibility was extensive PM. The majority of patients received systemic therapy. Patients deemed ineligible due to extra-peritoneal metastases had better survival outcomes than patients deemed ineligible due to extensive PM.

The Impact of Low Skeletal Muscle Mass on Short- and Long-Term Outcomes After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a potentially curative treatment for peritoneal metastases from colorectal cancer (CRC) or pseudomyxoma peritonei (PMP). Because of the considerable morbidity of this treatment, optimal patient selection is key. This study aimed to assess the impact of low skeletal muscle mass (SMM) on outcomes after CRS-HIPEC. METHODS: Patients who underwent CRS-HIPEC between 2014 and 2020 at a tertiary center were included. SMM was measured on computed tomography by means of the L3 muscle index. Postoperative complications and survival outcomes were compared between groups by use of logistic regression and Kaplan-Meier survival analyses. RESULTS: Of 284 included patients, 149 had low SMM. Occurrence of severe postoperative complications did not differ between groups (28.9% for patients with low vs. 34.1% for patients with normal SMM). Low SMM was not associated with postoperative complications (p = 0.344). For CRC patients, no significant differences were observed in disease-free (DFS) or overall survival (OS) between patients with low (median DFS 7 months [IQR 4-14], median OS 33 months [IQR 14-NR]) and patients with normal SMM (median DFS 8 months [IQR 5-20], median OS 35 months [IQR 18-NR]). Regarding PMP, survival outcomes did not significantly differ between groups (3-year DFS 47.3% for patients with low SMM vs. 54.5% for patients with normal SMM, p = 0.676; 3-year OS 70.8% vs. 90.9% respectively, p = 0.172). CONCLUSIONS: Low SMM could not be identified as a predictor of severe complications or survival outcomes after CRS-HIPEC.

Intraperitoneal paclitaxel for patients with primary malignant peritoneal mesothelioma: a phase I/II dose escalation and safety study-INTERACT MESO.

INTRODUCTION: Malignant peritoneal mesothelioma (MPM) is a rare, aggressive tumour arising primarily from the peritoneum. The only potentially curative treatment is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the majority of patients are not eligible to undergo this treatment. The benefit of systemic treatment for these patients is limited at the cost of considerable morbidity. Hence, there is a need for appropriate palliative treatment options for patients with MPM. As MPM rarely disseminates outside the abdominal cavity, these patients might benefit from local treatment. A higher, more effective dose of chemotherapy can directly be delivered at the site of the disease. Systemic uptake will be limited, likely resulting in less toxicity. The aim of the INTERACT MESO trial is to determine the maximum tolerable dose of intraperitoneal paclitaxel monotherapy in patients with MPM. Secondary endpoints are to assess safety and toxicity, feasibility and the pharmacokinetic profile of this treatment. METHODS AND ANALYSIS: The INTERACT MESO trial is a prospective, open-label, single-centre, phase I study with a classic three-plus-three dose escalation design. The study population consists of adult patients with primary MPM, without extra-abdominal disease, who are not eligible to undergo CRS-HIPEC. According to standard of care work-up for CRS-HIPEC, patients will undergo diagnostic laparoscopy to determine the feasibility of CRS-HIPEC. In case CRS-HIPEC is not considered feasible, a peritoneal port-a-cath (PAC) system will be placed. Through this PAC, 8-16 weekly cycles of intraperitoneal chemotherapy will be administered. ETHICS AND DISSEMINATION: The Central Committee on Research Involving Human Subjects (CCMO, The Hague, The Netherlands) and the Medical Research Ethics Committee (METC, Rotterdam, The Netherlands) have granted permission to carry out this study protocol. The results of this trial will be submitted for publication in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NL9718. EudraCT: 2021-003637-11.

Survival Outcomes After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy in Patients with Synchronous Versus Metachronous Onset of Peritoneal Metastases of Colorectal Carcinoma.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for peritoneal metastases (PM) from colorectal carcinoma (CRC). Because of considerable morbidity, optimal patient selection is essential. This study was designed to determine the impact of the onset of PM (synchronous vs. metachronous) on survival outcomes after CRS-HIPEC. METHODS: Patients undergoing CRS-HIPEC for colorectal PM in two academic centers in the Netherlands between 2010 and 2020 were eligible for inclusion. Patients were classified as synchronous (s-PM, i.e., diagnosis at time of presentation, staging, or primary surgery) or metachronous onset (m-PM, i.e., diagnosis during follow-up) of colorectal PM. Survival outcomes were compared between groups by Kaplan-Meier survival and Cox regression analyses. RESULTS: Of 390 included patients, 179 (45.9%) had synchronous onset of colorectal PM. These patients more often presented with higher TN-stage and poor differentiation/signet cell histology. Treatment with perioperative chemotherapy was more common in s-PM patients. m-PM patients experienced more serious postoperative complications (Clavien-Dindo ≥ III). There was no significant difference in disease-free survival (DFS) between s-PM (median 9 months, interquartile range [IQR] 5-15) and m-PM patients (median 8 months, IQR 5-17). Overall survival (OS) was significantly shorter for s-PM (median 28 months, IQR 11-48) versus m-PM patients (median 33 months, IQR 18-66, p = 0.049). Synchronous onset of PM was not independently associated with OS in a multivariable analysis. CONCLUSIONS: Synchronous onset of colorectal PM was associated with poor tumor characteristics and more advanced disease, but was not an independent predictor of survival outcomes after CRS-HIPEC.

Nasogastric- vs. percutaneous gastrostomy tube for prophylactic gastric decompression after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

OBJECTIVES: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with postoperative gastroparesis and ileus. In 2015, our practice shifted from using percutaneous gastrostomy tubes (PGT), to nasogastric tubes (NGT) for prophylactic gastric decompression after CRS-HIPEC. This study aimed to compare these methods for length of stay (LOS) and associated complications. METHODS: Patients that underwent CRS-HIPEC for peritoneal metastases from colorectal cancer between 2014 and 2019 were included. Cases were grouped based on receiving NGT or PGT postoperatively. Multivariable linear regression determined the independent effect of decompression method on LOS, thereby adjusting for confounders. RESULTS: In total, 179 patients were included in the analyses. Median age was 64 years [IQR:54-71]. Altogether, 135 (75.4%) received a NGT and 44 (24.6%) received a PGT. Gastroparesis occurred significantly more often in the PGT group (18.2 vs. 7.4%, p=0.039). Median LOS was significantly shorter for patients with a NGT (15 [IQR:12-19] vs. 18.5 [IQR:17-25.5], p<0.001). PGT was independently associated with longer LOS in multivariable analysis (Beta=4.224 [95%CI 1.243-7.204]). There was no difference regarding aspiration, pneumonia and postoperative mortality between groups. CONCLUSIONS: NGT should be preferred over PGT for gastric decompression after CRS-HIPEC as it is associated with fewer gastroparesis and shorter LOS.

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.

The Accuracy of the Surgical Peritoneal Cancer Index in Patients with Peritoneal Metastases of Colorectal Cancer.

INTRODUCTION: The peritoneal cancer index (PCI) is one of the most important prognostic factors in patients with peritoneal metastases from colorectal cancer undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). The PCI is determined during laparotomy by 2 experienced surgeons and plays a major role in the decision to proceed with CRS-HIPEC. The primary objective of this study was to determine the accuracy of the surgical PCI (sPCI) by comparing it with the PCI confirmed by the pathologist (pPCI). METHODS: All consecutive patients who underwent CRS-HIPEC for colorectal peritoneal metastases between February 2015 and June 2018 were identified. Relevant patient- and tumor-related characteristics were collected. RESULTS: In total, 119 patients were included, 60 males (50.4%). The median age was 64 (IQR 55-71). The median sPCI (sPCI = 11, IQR 6-16) was significantly higher than the median pPCI (pPCI = 8, IQR 3-13, p < 0.001). The total pPCI was lower than the total sPCI in 80 patients (67.2%). In 21 patients (17.6%), the sPCI was overestimated with ≥5 points. Small lesions are more likely to be negative. In patients that underwent resection of their primary tumor prior to CRS-HIPEC, the difference between the sPCI and pPCI was significantly larger (p < 0.05). CONCLUSIONS: Surgical calculation of the PCI often results in overestimation. Far-reaching consequences are tied to the macroscopic evaluation of the sPCI, but this evaluation seems not very reliable.

Monitoring of mitochondrial oxygenation during perioperative blood loss.

One of the challenges in the management of acute blood loss is to differentiate whether blood transfusion is required or not. The sole use of haemoglobin values might lead to unnecessary transfusion in individual cases. The suggestion is that mitochondrial oxygen tension can be used as an additional monitoring technique to determine when blood transfusion is required. In this case report, we report mitochondrial oxygen measurements in a patient with perioperative blood loss requiring blood transfusion.

Predictive Ability of C-Reactive Protein in Detecting Short-Term Complications After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Retrospective Cross-Sectional Study.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a potentially curative treatment for peritoneal carcinomatosis. OBJECTIVE: The aim of this study was to determine the predictive value of postoperative inflammatory biomarkers in assessing complications after CRS and HIPEC. METHODS: A prospective database of 181 patients, who underwent CRS-HIPEC between March 2014 through April 2018 in the Erasmus MC, was retrospectively analyzed. Postoperative complications were defined according to the serious adverse event (SAE) grading system. Levels of C-reactive protein (CRP) and white blood cell (WBC) count were compared between patients with SAE grade < 3 and SAE grade ≥ 3. The area under the receiver operating characteristic curve (AUC) was calculated for CRP and WBC against SAE ≥ 3 and various intra-abdominal complications. RESULTS: SAE ≥ 3 postoperative complications occurred in 50 patients. From the second until the fifth postoperative day (POD), CRP levels were significantly higher (p = 0.023, p < 0.001, p = 0.002, and p = 0.002, respectively) in these patients. CRP concentrations above 166 mg/L on POD3 (AUC 0.75) and 116 mg/L on POD4 (AUC 0.70) were associated with the highest risk of an SAE ≥ 3. Postoperative WBC levels were not significantly different between patients with SAE < 3 and SAE ≥ 3 complications. CONCLUSION: Data from our hospital suggest that CRP levels that continue to rise after POD2 or that are ≥ 166 mg/L at POD3 or ≥ 116 mg/L at POD4, indicate a considerable risk for developing high-grade SAEs. The cut-off values we found can potentially be used as a threshold for additional diagnostic interventions, after they have been validated in external data.

A population-based study on the prognostic impact of primary tumor sidedness in patients with peritoneal metastases from colon cancer.

Primary tumor location is an established prognostic factor in patients with (metastatic) colon cancer. Colon tumors can be divided into left-sided and right-sided tumors. The aim of this study was to determine the impact of primary tumor location on treatment and overall survival (OS) in patients with peritoneal metastases (PM) from colon cancer. This study is a retrospective, population-based cohort study. Records of patients diagnosed with colon cancer and synchronous PM, from 1995 through 2016, were retrieved from the Netherlands Cancer Registry (NCR). Data on diagnosis, staging, and treatment were extracted from the medical records by specifically trained NCR personnel. Information on survival status was updated annually using a computerized link with the national civil registry. In total, 7930 patients were included in this study; 4555 (57.4%) had a right-sided and 3375 (42.6%) had a left-sided primary tumor. In multivariable analysis right-sided primary tumor was associated with worse OS (HR: 1.11, 95% CI 1.03-1.19, P = .007). Of all patients diagnosed with PM, 564 (7.1%) underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Patients with left-sided primary tumors were more often candidates for CRS-HIPEC (6.5% vs. 8.0%, P = .008). OS of patients with right- and left-sided tumors who underwent CRS-HIPEC did not significantly differ. In conclusion, primary right-sided colon cancer was an independent prognostic factor for decreased OS in patients diagnosed with synchronous PM. In patients treated with CRS-HIPEC location of the primary tumor did not influence survival.

Concomitant intraperitoneal and systemic chemotherapy for extensive peritoneal metastases of colorectal origin: protocol of the multicentre, open-label, phase I, dose-escalation INTERACT trial.

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.

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 .