Population pharmacokinetics of cisplatin in patients with advanced ovarian cancer during intraperitoneal hyperthermia chemotherapy.

The objective of this study was to determine the pharmacokinetic profile of total platinum administered by hyperthermic peritoneal perfusion (HPP) in 16 patients with ovarian cancer. The patients had a performance status of lIIalpha/b/c on the FIGO scale. They received 60, 80 or 100 mg of cisplatin. The percent of cisplatin remaining in the body after the peritoneum was emptied averaged 65% (41.7-85.4%). The average ratio between peritoneal drug concentrations and plasma concentrations was 73. A Bayesian estimation of individual phamacokinetic parameters was carried out using the non-linear mixed-effect modeling approach as implemented in the NONMEM computer program. A two-compartment model with an additional peritoneal cavity compartment was used to fit the data. Large interindividual variability of the pharmacokinetic parameters occurred The maximum platinum concentration in plasma was reached between 1 and 1.5 hours after the beginning of administration; it ranged from 0.37 to 1.7 microg/ml (1.9 to 8.72 microM). The elimination half-life was 80 hours (48-152 hours and the area under the plasma concentration time curve normalized to a 100 mg cisplatin dose was 79 mg/liter x hours. The simultaneous fit of perfusate and plasma concentrations allowed us to estimate the percent of cisplatin that reached the systemic circulation at about 20%. At time infinity, the urinary cisplatin recovery accounted for only 20% of the administered dose. The results in this study showed that a high proportion of the cisplatin dose was absorbed by target tumor cells. In spite of the advanced disease of patients at the time of HPP, 37.5% of them were still alive three years after HPP (ie., 3-6 years after cancer diagnosis) and 12.5%, 7 years after HPP (i.e., 8 years after cancer diagnosis).

Intraperitoneal chemohyperthermia with mitomycin C for digestive tract cancer patients with peritoneal carcinomatosis.

BACKGROUND: Most patients with peritoneal carcinomatosis of digestive tract origin die within 6 months. Intraperitoneal chemohyperthermia (IPCH) associated with surgery has been reported as a possible new therapeutic approach. METHODS: A prospective Phase II trial was carried out with 83 patients who had digestive tract cancer and peritoneal carcinomatosis to evaluate the tolerance and efficacy of IPCH with mitomycin C (MMC) associated with surgery. Eighty-six IPCH treatments with MMC were given as complementary therapy after surgery (peritoneal perfusate with a 10 mg/L dose of MMC; inflow temperature, 46-49 degrees C; use of a closed circuit; duration, 90 minutes). Primary tumors were mainly gastric (in 42 cases) or colorectal (in 27 cases). RESULTS: Mortality and morbidity occurred in 3 of 83 cases and 8 of 83 cases, respectively. For patients with resectable tumors, the median survival time was 16 months when carcinomatosis was Stage I and II (malignant granulations less than 5 mm in greatest dimension), whereas it was 6 months when carcinomatosis was Stage III and IV (malignant granulations more than 5 mm in greatest dimension). For patients with resectable gastric cancer and Stage I and II carcinomatosis, 1-, 2-, and 3-year actuarial survival rates were 80%, 61%, and 41%, respectively, whereas the rate was 10% at 1 year for patients with bulky disease (Stage III and IV). CONCLUSIONS: IPCH appears to be a promising new approach to treating patients with digestive tract cancers and peritoneal carcinomatosis with small, malignant granulations (Stage I and II).

Peritonectomy combined with intraperitoneal chemohyperthermia in abdominal cancer with peritoneal carcinomatosis: phase I-II study.

OBJECTIVE: To evaluate the feasibility and the tolerance of Peritonectomy Procedure (PP) combined with Intraperitoneal Chemohyperthermia (IPCH) in patients with peritoneal carcinomatosis, a phase I-II study has been realised from January 1997 to September 1998. METHODS: Eighteen patients were included for peritoneal carcinomatosis from colorectal cancer (13), ovarian cancer (2), gallbladder cancer (1), gastric cancer (1) and peritoneal mesothelioma (1). Peritoneal carcinomatosis were mainly advanced disease (16 stage 3 and 4, 2 stage 2). All the patients underwent surgical resection of their primary tumor with PP as described by Sugarbaker and IPCH (with Mitomycin C, Cisplatinum or both). IPCH used in this study was a "closed sterile circuit" device with inflow temperatures ranging from 46 to 48 degrees C. IPCH was performed on the same day as PP (8118) or delayed (10/18). RESULTS: Significant down-staging of peritoneal carcinomatosis was achieved for 16 patients. One patient died postoperatively, while the morbidity rate was 6/18 (long postoperative ileus, grade 3 leucopenia and anastomotic leakage). CONCLUSIONS: Combination of PP and IPCH could achieve significant tumoral volume reduction in peritoneal carcinomatosis. This aggressive treatment must be employed selectively because of its morbidity. Larger phase III studies are now needed.

Intraperitoneal chemo-hyperthermia with mitomycin C for gastric cancer patients with peritoneal carcinomatosis.

OBJECTIVE: This study evaluates the tolerance and efficacy of Intraperitoneal Chemo-hyperthermia (IPCH) with Mitomycin C (MMC) associated with surgery, in peritoneal carcinomatosis of gastric origin. BACKGROUND: Most patients with peritoneal carcinomatosis of gastric origin die within 6 months, and IPCH associated with surgery has been reported as a possible new therapeutic approach. METHODS: A prospective non randomized trial was carried out on 42 patients with gastric cancers and peritoneal carcinomatosis. Fourty-three IPCH with MMC were used as complementary treatment after surgery (peritoneal perfusate with a 10 mg/l dose of MMC, inflow temperature 46 to 49 degrees C, use of a closed circuit, duration 90 minutes). Fourteen primary tumors were unresectable ones and 12 patients had large malignant preoperative ascites. RESULTS: Mortality and morbidity rates were 2/42 and 4/42 respectively. For resectable gastric cancers with stage 1 and 2 carcinomatosis (malignant granulations less than 5 mm in diameter), one, two and three year survival rates were 80, 61 and 41% respectively. For unresectable primary tumors and for stage 3 and 4 carcinomatosis (granulations larger than 5 mm in diameter), six and twelve month survival rates were 50% and 10% respectively. CONCLUSIONS: IPCH appears as a safe new therapeutic approach in gastric cancers with peritoneal carcinomatosis with small malignant granulations (stage 1 and 2) and randomized trials are now needed to clearly evaluate its efficacy.

[Intraperitoneal chemo-hyperthermia with mitomycin C in cancer of the stomach with peritoneal carcinosis]. / Chimiohyperthermie intrapéritonéale avec mitomycine C dans les cancers de l'estomac avec carcinose péritonéale.

We report 42 cases of gastric cancer with peritoneal carcinosis treated with intraperitoneal chemohyperthermia. Intraperitoneal chemohyperthermia was achieved with a closed sterile circuit containing mitomycin C, 10 mg/l producing an input temperature varying from 46 to 49 degrees C for 90 minutes. There were three postoperative deaths: one pulmonary embolism at day 4, one multiple organ failure et day 4, and one septic shock at day 25 due to a colonic fistula. Two patients suffered complications: one opening of the duodenal stump requiring reoperation on day 5, and one prolonged postoperative ileus lasting to day 10. Of the 12 patients with ascites, resorption was achieved in 8. In patients with early-stage peritoneal carcinosis (granulations less than 5 mm) survival at 1, 2 and 3 years was 90%, 61% and 41% respectively. For those with more extensive carcinosis, survival at 1 year was 10%. Five patients survived more than 30 months, three have survived to 34, 43 and 73 months. Intraperitoneal chemohyperthermia is a new treatment for carcinosis of gastric origin. These early results must be assessed further with larger controlled.