sirolimus and Intestinal-Perforation

Temsirolimus (CCI-779) is a novel inhibitor of the mammalian target of rapamycin. This Phase 1 study was aimed at investigating the maximum-tolerated dose, toxicity, pharmacokinetics and antitumor activity in Japanese patients with advanced solid tumors.. Temsirolimus was given as a 30 min intravenous infusion once a week. Patients with solid tumors not amenable to standard forms of treatment were eligible. Dose escalation of temsirolimus was planned from 15, 45, 80 to 165 mg/m(2). The pharmacokinetics of temsirolimus and sirolimus in whole blood were examined for cycles 1, 2, 4 and 5 of treatment.. Ten patients (median age 60.5 years; range 41-69 years) with advanced solid tumors were enrolled. Their primary cancers were renal cell carcinoma (five patients), lung cancer (three patients) and colorectal cancer (two patients). The major toxicities were hypophosphatemia diarrhea, hyperglycemia, stomatitis, pyrexia, elevated aspartate aminotransferase, rash, reduced neutrophil count, elevated alanine aminotransferase, anorexia, hypertriglyceridemia and somnolence. Two of three patients who received temsirolimus 45 mg/m(2) developed dose-limiting toxicities of Grade 3 stomatitis (one patient) and Grade 3 diarrhea (two patients). The maximum-tolerated dose was 15 mg/m(2). The peak blood concentrations of temsirolimus and sirolimus, a major active metabolite, increased in a dose-dependent manner. The area under the concentration-versus-time curve of sirolimus, but not temsirolimus, increased in a dose-dependent manner.. The recommended dose for Phase 2 clinical studies of temsirolimus in Japanese patients with advanced solid tumors is 15 mg/m(2) intravenously once a week.

Topics: Adult; Aged; Anti-Allergic Agents; Antineoplastic Agents; Area Under Curve; Carcinoma, Renal Cell; Colorectal Neoplasms; Diarrhea; Diphenhydramine; Disorders of Excessive Somnolence; Drug Administration Schedule; Drug Eruptions; Fever; Humans; Hyperglycemia; Hypertriglyceridemia; Hypophosphatemia; Infusions, Intravenous; Intestinal Perforation; Kidney Neoplasms; Lung Neoplasms; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Premedication; Sirolimus; Stomatitis; Treatment Outcome

A probable case of bowel perforation associated with temsirolimus use in a patient with uterine leiomyosarcoma is reported.. A 45-year-old Hispanic woman reported acute abdominal pain one day after receiving her third weekly i.v. infusion of temsirolimus, a mammalian target of rapamycin inhibitor increasingly used against a variety of cancers, including renal cell carcinoma and soft tissue sarcomas. Temsirolimus had been initiated three weeks previously in an attempt to control retroperitoneal metastases of uterine leiomyosarcoma, which had progressed despite surgical resection, six cycles of adjuvant chemotherapy, and pelvic irradiation. A computed tomography scan revealed a large pelvic mass with foci of gas, fluid collection, and other findings highly suggestive of an abscess due to bowel perforation. Application of the adverse drug reaction probability scale of Naranjo et al. in this case indicated a probable relationship between the bowel perforation and temsirolimus use; a literature search identified no other reported cases of temsirolimus-associated bowel perforation in association with uterine leiomyosarcoma. It is suspected that the patient's recent course of pelvic radiotherapy may have played a role in predisposing her to bowel perforation during temsirolimus use. While the mechanism of bowel perforations associated with temsirolimus therapy remains unclear, it is possible that due to its inhibitory effects on vascular endothelial growth factor (VEGF), temsirolimus use may result in gastrointestinal stresses and weaknesses similar to those attributed to bevacizumab, a VEGF-targeted angiogenesis inhibitor that has been linked to chemotherapy-induced bowel perforation.. A woman who recently received pelvic radiation experienced a bowel perforation after three infusions of temsirolimus for the treatment of metastatic leiomyosarcoma.

Topics: Antineoplastic Agents; Female; Humans; Intestinal Perforation; Leiomyosarcoma; Middle Aged; Pelvis; Sirolimus; TOR Serine-Threonine Kinases; Uterine Neoplasms