Abdomino-pelvic hyperthermia and intraperitoneal carboplatin in epithelial ovarian cancer: Feasibility, tolerance and pharmacology

Purpose: To investigate the feasibility, toxicity, and pharmacokinetics of intraperitoneal (i.p.) carboplatin (CB) with concomitant abdomino-pelvic hyperthermia (HT) in advanced ovarian cancer patients. Methods and Materials: Patients with residual disease mainly confined to the peritoneal cavity after platinum based chemotherapy received an initial course of i.p. CB for baseline pharmacokinetics followed by three cycles of i.p. CB with concomitant regional hyperthermia. The goal of HT was to achieve at least 45 min of intraperitoneal temperature >42 degrees but <50 degrees C while maintaining normal tissue temperatures <43 degrees C and systemic body temperatures <38 degrees C. No analgesic premedication was used. Thermometry was recorded by multisensor fiberoptic probes placed within the peritoneal cavity, bladder, vagina, and oral cavity. Results: Thirteen patients received a total of 31 sessions. Our intraperitoneal temperature goal could not be achieved because of patient intolerance. At best, we could maintain intraperitoneal temperatures >40 degrees C, for more than 40 min in 7 of 31 sessions. The average values of thermal variables were T-90 = 40 degrees C, T-AVE = 41 degrees C, T-MIN = 38.2 degrees C, and T-MAX = 42.9 degrees C. The mean maximum systemic temperature was 38 degrees C. Acute thermal toxicities requiring early interruption of hyperthermia were systemic temperature exceeding 38 degrees C (11 of 31), abdominal pain or generalized distress (20 of 31), and vomiting (2 of 31). Hematological toxicities were not increased by hyperthermia. Pharmacokinetics were consistent with enhanced clearance of CB by HT. Lower radio frequencies (<75 MHz) achieved better heat deposition in the peritoneal cavity than higher frequencies (>75 MHz). Two of the 13 patients (a Stage III and a Stage IV patient) are alive with no evidence of disease at 40 and 43 months from treatment. Conclusions: Intraperitoneal temperatures in the range of 40 degrees C maintained for approximately 40 min can be achieved within the described setting. The probability of successful induction of therapeutic intraperitoneal temperatures appears to be higher when frequencies below 75 MHz are used. Patients who are potentially platinum sensitive and have minimal residual disease could potentially benefit from the combined treatment under the conditions studied. However, this temperature-time range appears inadequate against platinum resistant disease, and/or bulky residual pelvic disease. Alternative approaches such as whole body hyperthermia and carboplatin are warranted to overcome some of the obstacles observed.