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.

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.

Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer With Peritoneal Metastases (CYTO-CHIP study): A Propensity Score Analysis.

PURPOSE: Gastric cancer (GC) with peritoneal metastases (PMs) is a poor prognostic evolution. Cytoreductive surgery (CRS) yields promising results, but the impact of hyperthermic intraperitoneal chemotherapy (HIPEC) remains controversial. Here we aimed to compare outcomes between CRS-HIPEC versus CRS alone (CRSa) among patients with PMs from GC. PATIENTS AND METHODS: From prospective databases, we identified 277 patients with PMs from GC who were treated with complete CRS with curative intent (no residual nodules > 2.5 mm) at 19 French centers from 1989 to 2014. Of these patients, 180 underwent CRS-HIPEC and 97 CRSa. Tumor burden was assessed using the peritoneal cancer index. A Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) based on propensity score was used to assess the effect of HIPEC and account for confounding factors. RESULTS: After IPTW adjustment, the groups were similar, except that median peritoneal cancer index remained higher in the CRS-HIPEC group (6 v 2; P = .003). CRS-HIPEC improved overall survival (OS) in both crude and IPTW models. Upon IPTW analysis, in CRS-HIPEC and CRSa groups, median OS was 18.8 versus 12.1 months, 3- and 5-year OS rates were 26.21% and 19.87% versus 10.82% and 6.43% (adjusted hazard ratio, 0.60; 95% CI, 0.42 to 0.86; P = .005), and 3- and 5-year recurrence-free survival rates were 20.40% and 17.05% versus 5.87% and 3.76% (P = .001), respectively; the groups did not differ regarding 90-day mortality (7.4% v 10.1%, respectively; P = .820) or major complication rate (53.7% v 55.3%, respectively; P = .496). CONCLUSION: Compared with CRSa, CRS-HIPEC improved OS and recurrence-free survival, without additional morbidity or mortality. When complete CRS is possible, CRS-HIPEC may be considered a valuable therapy for strictly selected patients with limited PMs from GC.

FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer.

BACKGROUND: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer. METHODS: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. RESULTS: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis). CONCLUSIONS: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).

High pressure enhances the effect of hyperthermia in intraperitoneal chemotherapy with oxaliplatin: an experimental study.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) achieve good results in selected patients with peritoneal carcinomatosis. High intra-abdominal pressure could enhance the penetration of chemotherapy drugs. The aim of this study was to compare the effects of high pressure and hyperthermia when used separately and when combined in terms of blood and tissue absorption of oxaliplatin in a swine model of intraperitoneal chemotherapy. METHODS: Four groups of 5 pigs each underwent laparotomy and open intraperitoneal chemotherapy with oxaliplatin at a constant concentration (150 mg/L) for 30 minutes in normothermia and atmospheric pressure (group 1), or hyperthermia (42°C) and atmospheric pressure (group 2), or normothermia and high pressure (25 cm H2O) (group 3), or hyperthermia and high pressure (group 4). High pressure was achieved thorough a water column over the abdomen. Systemic absorption and abdominal tissue mapping of the penetration of oxaliplatin in each group were studied. RESULTS: Blood concentrations of oxaliplatin were similar in the different groups. Hyperthermia achieved higher concentrations in visceral surfaces (P = 0.0014), but not in parietal surfaces. High pressure enhanced diffusion of the drug in both the visceral and parietal peritoneum (P = 0.0058 and P = 0.0044, respectively). The combination of hyperthermia and high pressure significantly increased the penetration of oxaliplatin and achieved the highest tissue concentrations (10.39 mg/kg vs 5.48 mg/kg; P = 0.00001 in the visceral peritoneum, and 66.16 mg/kg vs 35.62 mg/kg; P = 0.0003 in the parietal peritoneum). CONCLUSIONS: Open high-pressure HIPEC with oxaliplatin is feasible in the pig. Hyperthermia enhances diffusion in the visceral peritoneum, whereas high pressure is effective in the visceral and parietal peritoneum. The combination of the two achieves the highest tissue concentrations of oxaliplatin.

Childbearing after hyperthermic intraperitoneal chemotherapy: results from an international survey.

BACKGROUND: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) can improve survival in selected patients with primary or secondary peritoneal malignancies. With the opportunity for long-term survival, questions about the impact of those procedures in fertility in women of childbearing age can be raised. MATERIALS AND METHODS: An international survey was performed among all teams participating in the International Peritoneal Surface Malignancy Group in order to collect data about pregnancies and their outcome in women having undergone previous CRS with adjuvant HIPEC. RESULTS: There were 7 pregnancies reported after CRS and HIPEC in women treated for peritoneal malignancies. All these women conceived spontaneously, most of them within 2 years after the procedure. They delivered most often by vaginal way after an uneventful pregnancy. Their newborns were healthy, except 1 case of congenital diaphragmatic hernia requiring emergent surgery. There were 2 additional uneventful pregnancies reported after the diagnosis of pseudomyxoma peritonei and before CRS and HIPEC, with the support of the medical team. Another woman having undergone oocytes retrieval and embryo cryopreservation prior to the surgery was mother of twins after the procedure via a surrogate mother. CONCLUSION: Childbearing after cytoreductive surgery and heated intraperitoneal chemotherapy is possible in women conserving their genital organs after the procedure. The question of fertility should be considered and discussed in women in reproductive age prior to cytoreductive surgery and heated intraperitoneal chemotherapy. Different options could be offered in this setting. Multidisciplinary decision making involving surgical oncologists and fertility specialists is important.

Comparison of hyperthermia and adrenaline to enhance the intratumoral accumulation of cisplatin in a murine model of peritoneal carcinomatosis.

BACKGROUND: The best method to deliver intraperitoneal chemotherapy (IPC) for peritoneal carcinomatosis from ovarian cancer is not well defined. The aim of this study was to assess the ability of hyperthermia and adrenaline to enhance the intratumoral accumulation of cisplatin in a rat model of peritoneal carcinomatosis. METHODS: Four groups of 5 BDIX rats with ovarian peritoneal carcinomatosis underwent IPC with 30 mg/l of cisplatin according to the following conditions: normothermia at 37° for 1 or 2 hours, hyperthermia at 42°C for 1 hour or normothermia at 37°C for 2 hours with 2 mg/l adrenaline. Tissue platinum content was measured by atomic absorption spectroscopy. The effect of hyperthermia, adrenaline and the duration of exposure to the drug was measured in vivo (tissue concentration of platinum in tumor, abdominal and extra abdominal tissues) and in vitro (cytotoxicity on human ovarian cancer cells). RESULTS: In vitro, hyperthermia and longer exposure enhanced the accumulation and the cytotoxic effect of cisplatin on cancer cells. In vivo, only the 2 hours treatment with adrenaline resulted in increased platinum concentrations. The rats treated with adrenaline showed significantly lower concentrations of cisplatin in extra peritoneal tissues than those treated with hyperthermia. CONCLUSION: Adrenaline is more effective than hyperthermia in order to enhance the intratumoral concentration of cisplatin in rats with peritoneal carcinomatosis from ovarian origin. It may also decrease the systemic absorption of the drug.

Which method to deliver hyperthermic intraperitoneal chemotherapy with oxaliplatin? An experimental comparison of open and closed techniques.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) achieves good results in selected patients with peritoneal carcinomatosis. There are two main procedures to deliver this therapy: the open abdomen and the closed abdomen techniques. A true comparison of the two techniques has never been performed. The aim of this study was to compare blood and abdominal tissue concentrations of oxaliplatin after open and closed techniques to deliver HIPEC. METHODS: Nine pigs underwent HIPEC at 42-43 degrees C for 30 min with oxaliplatin (400 mg/m(2)) according to two techniques: closed (three animals) or open (six animals). The open technique used either an external heater with a pump (three animals) or an intra-abdominal heating cable (three animals) to achieve hyperthermia. Temperature homogeneity, systemic absorption, and abdominal tissue mapping of the penetration of oxaliplatin with each technique were studied. Two additional pigs underwent hyperthermia with dyes instead of oxaliplatin to depict the distribution of the liquid within the abdomen with both techniques. RESULTS: Hyperthermia was satisfactory with both techniques. The closed technique achieved higher temperatures within the diaphragmatic area, while the open technique obtained higher temperatures in the mid and lower abdomen (P < 0.001 for both comparisons). The systemic absorption of oxaliplatin was higher with the open technique (P < 0.04 for all comparisons), as was the accumulation within the abdominal cavity. The operating time for the two techniques was not greatly different. CONCLUSIONS: Intraperitoneal hyperthermia can be achieved with both techniques. The open technique had far higher systemic absorption and abdominal tissue penetration of oxaliplatin than the closed technique.

Closed hyperthermic intraperitoneal chemotherapy with open abdomen: a novel technique to reduce exposure of the surgical team to chemotherapy drugs.

BACKGROUND: Exposure of the surgical team to toxic drugs during hyperthermic intraperitoneal chemotherapy (HIPEC) remains a matter of great concern. During closed-abdomen HIPEC, operating room staff are not exposed to drugs, but the distribution of the heated liquid within the abdomen is not optimal. With open-abdomen HIPEC, the opposite is true. Although the open-abdomen method is potentially more effective, it has not become a standard procedure because of the risk of exposure of members of the team to drugs. METHODS: We present a new technique (closed HIPEC with open abdomen) which ensures protection against potentially contaminating exposure to liquids, vapours and aerosols, and allows permanent access to the whole abdominal cavity. Its principle is to extend the abdominal surgical wound upwards with a sort of "glove-box". The cutaneous edges of the laparotomy are stapled to a latex "wall expander". The expander is draped over a special L-section metal frame placed above the abdomen. A transparent cover containing a "hand-access" port, like those used in laparoscopic surgery, is fixed inside the frame. RESULTS: In 10 patients, this device proved to be hermetic for both liquids and vapours. Intra-abdominal temperature was maintained between 42 and 43 degrees C during most of the procedure. The whole abdominal cavity was accessible to the surgeon, allowing optimal exposure of all peritoneal surfaces. CONCLUSION: This technique allows optimal HIPEC, while limiting the potential toxic effects for the surgical, medical and paramedical teams.