Summary Background The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery has been associated with encouraging survival results in some patients with colorectal peritoneal metastases who were eligible for complete macroscopic resection We aimed to assess the specific benefit of adding HIPEC to cytoreductive surgery compared with receiving cytoreductive surgery alone Methods We did a randomised, open-label, phase 3 trial at 17 cancer centres in France Eligible patients were aged 18–70 years and had histologically proven colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, a Peritoneal Cancer Index of 25 or less, and were eligible to receive systemic chemotherapy for 6 months (ie, they had adequate organ function and life expectancy of at least 12 weeks) Patients in whom complete macroscopic resection or surgical resection with less than 1 mm residual tumour tissue was completed were randomly assigned (1:1) to cytoreductive surgery with or without oxaliplatin-based HIPEC Randomisation was done centrally using minimisation, and stratified by centre, completeness of cytoreduction, number of previous systemic chemotherapy lines, and timing of protocol-mandated systemic chemotherapy Oxaliplatin HIPEC was administered by the closed (360 mg/m2) or open (460 mg/m2) abdomen techniques, and systemic chemotherapy (400 mg/m2 fluorouracil and 20 mg/m2 folinic acid) was delivered intravenously 20 min before HIPEC All individuals received systemic chemotherapy (of investigators' choosing) with or without targeted therapy before or after surgery, or both The primary endpoint was overall survival, which was analysed in the intention-to-treat population Safety was assessed in all patients who received surgery This trial is registed with ClinicalTrialsgov , NCT00769405 , and is now completed Findings Between Feb 11, 2008, and Jan 6, 2014, 265 patients were included and randomly assigned, 133 to the cytoreductive surgery plus HIPEC group and 132 to the cytoreductive surgery alone group After median follow-up of 63·8 months (IQR 53·0–77·1), median overall survival was 41·7 months (95% CI 36·2–53·8) in the cytoreductive surgery plus HIPEC group and 41·2 months (35·1–49·7) in the cytoreductive surgery group (hazard ratio 1·00 [95·37% CI 0·63–1·58]; stratified log-rank p=0·99) At 30 days, two (2%) treatment-related deaths had occurred in each group Grade 3 or worse adverse events at 30 days were similar in frequency between groups (56 [42%] of 133 patients in the cytoreductive surgery plus HIPEC group vs 42 [32%] of 132 patients in the cytoreductive surgery group; p=0·083); however, at 60 days, grade 3 or worse adverse events were more common in the cytoreductive surgery plus HIPEC group (34 [26%] of 131 vs 20 [15%] of 130; p=0·035) Interpretation Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases Funding Institut National du Cancer, Programme Hospitalier de Recherche Clinique du Cancer, Ligue Contre le Cancer

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial.

The therapeutic application of heat is very effective in cancer treatment Both hyperthermia, ie, heating to 39-45 °C to induce sensitization to radiotherapy and chemotherapy, and thermal ablation, where temperatures beyond 50 °C destroy tumor cells directly are frequently applied in the clinic Achievement of an effective treatment requires high quality heating equipment, precise thermal dosimetry, and adequate quality assurance Several types of devices, antennas and heating or power delivery systems have been proposed and developed in recent decades These vary considerably in technique, heating depth, ability to focus, and in the size of the heating focus Clinically used heating techniques involve electromagnetic and ultrasonic heating, hyperthermic perfusion and conductive heating Depending on clinical objectives and available technology, thermal therapies can be subdivided into three broad categories: local, locoregional, or whole body heating Clinically used local heating techniques include interstitial hyperthermia and ablation, high intensity focused ultrasound (HIFU), scanned focused ultrasound (SFUS), electroporation, nanoparticle heating, intraluminal heating and superficial heating Locoregional heating techniques include phased array systems, capacitive systems and isolated perfusion Whole body techniques focus on prevention of heat loss supplemented with energy deposition in the body, eg, by infrared radiation This review presents an overview of clinical hyperthermia and ablation devices used for local, locoregional, and whole body therapy Proven and experimental clinical applications of thermal ablation and hyperthermia are listed Methods for temperature measurement and the role of treatment planning to control treatments are discussed briefly, as well as future perspectives for heating technology for the treatment of tumors

https://biblio.ugent.be/publication/8672203/file/8672204.pdf

Heating technology for malignant tumors: a review

Summary Background Diagnosis and treatment of colorectal peritoneal metastases at an early stage, before the onset of signs, could improve patient survival. We aimed to compare the survival benefit of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC), with surveillance, in patients at high risk of developing colorectal peritoneal metastases. Methods We did an open-label, randomised, phase 3 study in 23 hospitals in France. Eligible patients were aged 18–70 years and had a primary colorectal cancer with synchronous and localised colorectal peritoneal metastases removed during tumour resection, resected ovarian metastases, or a perforated tumour. Patients were randomly assigned (1:1) to surveillance or second-look surgery plus oxaliplatin-HIPEC (oxaliplatin 460 mg/m2, or oxaliplatin 300 mg/m2 plus irinotecan 200 mg/m2, plus intravenous fluorouracil 400 mg/m2), or mitomycin-HIPEC (mitomycin 35 mg/m2) alone in case of neuropathy, after 6 months of adjuvant systemic chemotherapy with no signs of disease recurrence. Randomisation was done via a web-based system, with stratification by treatment centre, nodal status, and risk factors for colorectal peritoneal metastases. Second-look surgery consisted of a complete exploration of the abdominal cavity via xyphopubic incision, and resection of all peritoneal implants if resectable. Surveillance after resection of colorectal cancer was done according to the French Guidelines. The primary outcome was 3-year disease-free survival, defined as the time from randomisation to peritoneal or distant disease recurrence, or death from any cause, whichever occurred first, analysed by intention to treat. Surgical complications were assessed in the second-look surgery group only. This study was registered at ClinicalTrials.gov , NCT01226394 . Findings Between June 11, 2010, and March 31, 2015, 150 patients were recruited and randomly assigned to a treatment group (75 per group). After a median follow-up of 50·8 months (IQR 47·0–54·8), 3-year disease-free survival was 53% (95% CI 41–64) in the surveillance group versus 44% (33–56) in the second-look surgery group (hazard ratio 0·97, 95% CI 0·61–1·56). No treatment-related deaths were reported. 29 (41%) of 71 patients in the second-look surgery group had grade 3–4 complications. The most common grade 3–4 complications were intra-abdominal adverse events (haemorrhage, digestive leakage) in 12 (23%) of 71 patients and haematological adverse events in 13 (18%) of 71 patients. Interpretation Systematic second-look surgery plus oxaliplatin-HIPEC did not improve disease-free survival compared with standard surveillance. Currently, essential surveillance of patients at high risk of developing colorectal peritoneal metastases appears to be adequate and effective in terms of survival outcomes. Funding French National Cancer Institute.

Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP-PRODIGE 15): a randomised, phase 3 study.

Molecular and biological rationale of hyperthermia as radio- and chemosensitizer.

Indications for hyperthermic intraperitoneal chemotherapy with cytoreductive surgery: a systematic review.

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

Mandy Zournas

Papers

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