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.

Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial.

BACKGROUND: Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer. METHODS: This multicentre, open-label trial was done in nine hospitals that specialised in HIPEC in the Netherlands. Patients with clinical or pathological T4N0-2M0-stage tumours or perforated colon cancer were randomly assigned (1:1), with a web-based randomisation application, before resection of the primary tumour, to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). Patients were stratified by tumour characteristic (T4 or perforation), age (<65 years or ≥65 years), and surgical approach of the primary tumour resection (laparoscopic or open). Key eligibility criteria included age between 18 and 75 years, adequate clinical condition for HIPEC, and intention to start adjuvant systemic chemotherapy. Patients with metastatic disease were ineligible. Adjuvant HIPEC consisted of fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) delivered intravenously followed by intraperitoneal delivery of oxaliplatin (460 mg/m2) for 30 min at 42°C, delivered simultaneously or within 5-8 weeks after primary tumour resection. In all patients without evidence of recurrent disease at 18 months, a diagnostic laparoscopy was done. The primary endpoint was peritoneal metastasis free-survival at 18 months, measured in the intention-to-treat population, with the Kaplan-Meier method. Adverse events were assessed in all patients who received assigned treatment. This study is registered with ClinicalTrials.gov, number NCT02231086. FINDINGS: Between April 1, 2015, and Feb 20, 2017, 204 patients were randomly assigned to treatment (102 in each group). In the HIPEC group, two patients withdrew consent after randomisation. In this group, 19 (19%) of 100 patients were diagnosed with peritoneal metastases: nine (47%) during surgical exploration preceding intentional adjuvant HIPEC, eight (42%) during routine follow-up, and two (11%) during diagnostic laparoscopy at 18-months. In the control group, 23 (23%) of 102 patients were diagnosed with peritoneal metastases, of whom seven (30%) were diagnosed by laparoscopy at 18-months and 16 during regular follow-up (therefore making them ineligible for diagnostic laparoscopy). In the intention-to-treat analysis (n=202), there was no difference in peritoneal-free survival at 18-months (80·9% [95% CI 73·3-88·5] for the experimental group vs 76·2% [68·0-84·4] for the control group, log-rank one-sided p=0·28). 12 (14%) of 87 patients who received adjuvant HIPEC developed postoperative complications and one (1%) encapsulating peritoneal sclerosis. INTERPRETATION: In patients with T4 or perforated colon cancer, treatment with adjuvant HIPEC with oxaliplatin did not improve peritoneal metastasis-free survival at 18 months. Routine use of adjuvant HIPEC is not advocated on the basis of this trial. FUNDING: Organization for Health Research and Development and the Dutch Cancer Society.

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 .

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

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

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

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

Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial.

BACKGROUND: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay. METHODS/DESIGN: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 °C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. DISCUSSION: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival. TRIAL REGISTRATION NUMBER: NCT02231086 (Clinicaltrials.gov).

Cytoreductive surgery and HIPEC in treatment of colorectal peritoneal carcinomatosis: experiment or standard care? A survey among oncologic surgeons and medical oncologists.

BACKGROUND: Controversy still exists regarding the position of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastasis of colorectal carcinoma. The goal of the current study was to evaluate the opinions about this treatment among Dutch oncologic surgeons and medical oncologists. METHODS: An online survey was sent to all known Dutch oncologic surgeons (n = 459) and medical oncologists (n = 363) representing the respective departments of 84 hospitals. A comparison was made between surgeons and oncologists. RESULTS: 185 eligible responses were received from 71 hospitals, resulting in a response rate of 23 % for individuals and a response rate of 85 % for hospitals. Overall, 65 % of respondents regarded CRS+HIPEC as effective with sufficient evidence, 29 % responded that CRS+HIPEC is probably effective without sufficient evidence, and 7 % of respondents regards HIPEC as probably ineffective. Medical oncologists were less convinced of the effectiveness of CRS+HIPEC than surgeons (P = 0.006). Of all the respondents, 68 % indicated that they regard CRS+HIPEC as a standard treatment for patients with peritoneal dissemination of colorectal carcinoma (77 % of surgeons vs 54 % of oncologists, P = 0.001). Additionally, 68 % of respondents regard CRS+HIPEC as potentially curative (77 % of surgeons vs 54 % of oncologists, P = 0.001). CONCLUSIONS: Approximately 30 % of physicians who treat colorectal carcinoma do not regard CRS+HIPEC as standard care. Surgeons appear to be significantly more in favor of this treatment than medical oncologists. This study shows that efforts should be made to improve knowledge and increase acceptance of CRS and HIPEC in colorectal cancer treatment among medical oncologists and surgeons.

Skeletal Muscle Depletion is Associated with Severe Postoperative Complications in Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Colorectal Cancer.

BACKGROUND: In patients undergoing colorectal cancer surgery, skeletal muscle depletion (sarcopenia) is associated with impaired postoperative recovery and decreased survival. This study aimed to determine whether skeletal muscle depletion can predict postoperative complications for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for peritoneal carcinomatosis of colorectal cancer. METHODS: All consecutive patients with an available preoperative computed tomography (CT) scan who underwent CRS-HIPEC for peritoneal carcinomatosis of colorectal cancer in two centers were analyzed. Skeletal muscle mass was determined using the L3 muscle index on the preoperative CT scan. The cutoff values defined by Prado et al. were used to classify the patients as sarcopenic or nonsarcopenic. RESULTS: Of the study's 206 patients, 90 (43.7 %) were classified as sarcopenic. The sarcopenic patients underwent significantly more reoperations than the nonsarcopenic patients (25.6 vs. 12.1 %; p = 0.012). The mean L3 muscle index was significantly lower for the patients who experienced severe postoperative complications than for the patients without severe postoperative complications (85.6 vs. 110.2 cm(2)/m(2); p = 0.008). In a multivariable logistic regression model, L3 muscle index was the only parameter independently associated with the risk of severe postoperative complications (odds ratio 0.93; 95 % confidence interval 0.87-0.99; p = 0.018). CONCLUSION: Skeletal muscle mass depletion, assessed using CT-based muscle mass measurements, is associated with an increased risk of severe postoperative complications in patients undergoing CRS-HIPEC for colorectal peritoneal carcinomatosis and could therefore be used in preoperative risk assessment.

Urological procedures in patients with peritoneal carcinomatosis of colorectal cancer treated with HIPEC: morbidity and survival analysis.

AIM: To investigate whether cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) is a feasible and effective option for patients with urological involvement of peritoneal carcinomatosis from colorectal cancer (CRC-PC). PATIENTS AND METHODS: The characteristics of patients with CRC-PC treated with CRS+HIPEC, with or without a urological procedure, between April 2005 and June 2013 in two tertiary Centres were analyzed. RESULTS: Thirty-eight patients (14%) out of 267 CRC-PC patients treated with CRS+HIPEC had a urological procedure during cytoreduction. The median survival was not significantly different between patients with or without a urological procedure (26.9 versus 32.1 months, p=0.29). Severe complications occurred more in patients with a urological procedure (47% versus 20%, p<0.001). In patients with a urological procedure, the most frequent complications were gastrointestinal leakage (n=9) and intra-abdominal abscess formation (n=5). CONCLUSION: Urological resections as a part of CRS+HIPEC in patients with peritoneal carcinomatosis of colorectal origin are feasible and effective. Severe complications are prevalent in these patients but survival is comparable to patients without involvement of the urinary system.

Implementation of a standardized HIPEC protocol improves outcome for peritoneal malignancy.

BACKGROUND: Experience with Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in a pioneer hospital resulted in a treatment protocol that has become the standard in the Netherlands. Outcome of CRS and HIPEC was reviewed to assure differences between the pioneer phase and the period wherein the Dutch HIPEC protocol was clinically implemented. METHODS: The first consecutive 100 CRS and HIPEC procedures performed in the Netherlands were included as pioneer cohort (1995-1999). Two-hundred and seventy-two procedures that were performed in three participating HIPEC centres after the implementation of the Dutch HIPEC protocol were included as the implementation cohort (2005-2012). Another 100 recent patients of the first centre were included as a control group (2009-2011). Indications for the CRS and HIPEC treatment were peritoneal carcinomatosis (PC) from colorectal carcinoma and pseudomyxoma peritonei (PMP). RESULTS: Of the 472 included procedures, 327 (69 %) procedures were performed for PC from colorectal carcinoma and 145 for PMP (31 %). Compared with the implementation phase, the pioneer phase was characterized by more affected abdominal regions (mean 4.3 vs. 3.5, p < 0.001), more resections (mean 3.8 vs. 3.4, p < 0.001), less macroscopic radical cytoreductions (66 vs. 86 %, p < 0.001) and more patients with major morbidity (grade III-V) (64 vs. 32 %, p < 0.001). Other determinants of morbidity were high tumour load and multiple organ resections. Outcome of the implementation phase was similar to the control group. CONCLUSIONS: This study determined that outcome had improved ever since the Dutch HIPEC protocol has been implemented based on completeness of cytoreduction and decreasing morbidity.

Patterns of recurrence following complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer.

BACKGROUND AND OBJECTIVES: CytoReductive Surgery (CRS) combined with Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) has an established role in the treatment of peritoneally metastasized colorectal cancer. The aim of the study was to describe the recurrence patterns and to evaluate treatment options and related survival. METHODS: Patients treated with CRS + HIPEC in two tertiary referral centers between April 2005 and March 2013 were analyzed retrospectively. The prognostic value of several parameters was calculated using Cox Regression. RESULTS: One hundred thirty two of 287 patients (46%) with peritoneal carcinomatosis treated with complete CRS and HIPEC were diagnosed with recurrent disease, after a median disease-free interval of 11.4 months. Recurrence were locoregional (43%), distant metastases (26%) or both (31%). Thirty-two of the 132 patients with recurrences (24%) were treated surgically with curative intent, which extended the median survival from 12 months to 43 months, compared to palliative treatment (best supportive care or chemotherapy; P < 0.001). Initial nodal status (P = 0.01) and the number of affected regions at initial CRS (P = 0.02) were significantly correlated to survival after disease recurrence. CONCLUSION: Disease recurrence after CRS and HIPEC is common; in selected patients, an aggressive surgical approach may be beneficial and extend survival.

Cytoreduction and hyperthermic intraperitoneal chemotherapy: a feasible and effective option for colorectal cancer patients after emergency surgery in the presence of peritoneal carcinomatosis.

BACKGROUND: When peritoneal carcinomatosis (PC) is diagnosed during emergency surgery for colorectal cancer (CRC), further treatment with curative intent may seem futile given the known poor prognosis of both PC and emergency surgery. The aim of the current study was to investigate the feasibility and effectiveness of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for CRC patients who previously underwent emergency surgery in the presence of PC. METHODS: All patients with synchronous PC of CRC referred to two tertiary centers between April 2005 and November 2013 were included in this study. Operative, postoperative and survival details were compared between patients presenting in an emergency or elective setting. RESULTS: In total, 149 patients with synchronous PC underwent CRS and HIPEC. Amongst these patients, 36 (24.2 %) initially presented with acute symptoms requiring emergency surgery. Acute presentation did not result in a longer interval between the initial operation and HIPEC (2.2 vs. 2.1 months; P = 0.09). When comparing operative outcomes, no significant differences were found in blood loss (P = 0.47), operation time (P = 0.39), or completeness of cytoreduction (P = 0.97). In addition, complication rates, degree and types of complication did not differ between the groups. Median survival was 36.1 months for emergency presentation compared with 32.1 in the elective group (P = 0.73). CONCLUSION: CRS + HIPEC may be performed safely in patients with PC of colorectal origin presenting with acute symptoms requiring emergency surgery. More importantly, the 5-year survival rate in these patients was equal to elective cases. This should be regarded as promising and therefore considered for these patients.