Assuring the optimal use of serotonin antagonist antiemetics: the process for development and implementation of institutional antiemetic guidelines at Memorial Sloan-Kettering Cancer Center.

PURPOSE: The need to foster the appropriate and cost-effective use of serotonin-antagonist antiemetic drugs spurred the creation of guidelines. The process by which institution-wide guidelines at Sloan-Kettering were developed, implemented, assessed, and modified is described. METHODS: A multidisciplinary group working with disease-specific management teams assigned the emetic potential of chemotherapy programs to one of five categories. Antiemetic regimens, including a specified dose and schedule of a serotonin-antagonist and dexamethasone, were assigned to each emetic category. The information was collated by disease site and chemotherapy program into hospital-wide antiemetic regimen recommendations. Quality assessment was conducted initially and repeated each time the guidelines were modified. RESULTS: Patient surveys demonstrated a high level of satisfaction with emetic control, which was similar to reported results. Data from the latest survey showed zero emetic episodes in 93% and 87% of participants given moderate and highly emetogenic chemotherapy, respectively. Compliance with the guidelines, initially in 73%, has been improved using a standardized chemotherapy order "check box" labeled, "Antiemetics as per Guidelines." Antiemetic drug expenditures decreased from a projected $2.8 million to $1.3 million annually. CONCLUSION: The guidelines became an educational tool that ensured the delivery of optimal antiemetic therapy chosen by professionals with the greatest knowledge of both the particular chemotherapy regimen and cancer site. Implementation of the guidelines resulted in substantial savings while treating more patients. The guidelines were easily modified as new chemotherapeutic agents and antiemetic drugs became available.

9-Aminocamptothecin by 72-hour continuous intravenous infusion is inactive in the treatment of patients with 5-fluorouracil-refractory colorectal carcinoma.

BACKGROUND: 9-Aminocamptothecin (9AC) and its parent compound, camptothecin, have shown outstanding preclinical activity against colorectal carcinoma. Irinotecan (CPT-11), another camptothecin derivative, has demonstrated clinical activity in patients with 5-fluorouracil (5-FU)-refractory colorectal carcinoma. METHODS: The authors performed a Phase II trial of 9AC involving patients with measurable metastatic colorectal carcinoma who had progressed through only one prior regimen of 5-FU-based chemotherapy. 9AC was given initially at a dose of 59 microg/m2/hour by continuous intravenous infusion for 72 hours, with treatments repeated every 14 days. Granulocyte-colony stimulating factor was given on Days 5-12. RESULTS: Sixteen patients were treated on this trial. Fourteen were evaluable for response. Contrary to expectations, no major objective antitumor responses were observed. Eight patients experienced stable disease for a median of 4.1 months (range, 2.2-9.5 months). Toxicities, especially myelosuppression, were severe and necessitated a 15% reduction in the initial dose after the first 9 patients. Toxicities at this reduced dose remained unacceptable. CONCLUSIONS: 9AC did not demonstrate substantial activity against 5-FU-refractory colorectal carcinoma on the schedule studied. Toxicities at the doses and schedule studied were unacceptable in this patient population. Based on their results, the authors consider it unlikely that 9AC administered as a 72-hour continuous intravenous infusion will play a major role in the treatment of colorectal carcinoma.

Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors.

PURPOSE: To determine the maximum-tolerable dose (MTD) of fluorouracil (5FU) when given with fixed doses of leucovorin and irinotecan (CPT-11), to define the dose-limiting toxicities of this combination, and to evaluate the effect of 5FU on the pharmacokinetics of CPT-11. PATIENTS AND METHODS: CPT-11, leucovorin, and 5FU were administered in repeated 6-week cycles that consisted of weekly treatment with all three drugs for 4 consecutive weeks followed by a 2-week break. On day 1 of treatment, CPT-11 alone was given by 90-minute infusion, and pharmacokinetic sampling was performed over 24 hours. Leucovorin and 5FU were administered by brief intravenous injection on day 2. On days 8, 15, and 22, CPT-11 infusion was immediately followed by leucovorin and then 5FU. A second 24-hour pharmacokinetic sampling was performed on day 8, which permitted comparison of the pharmacokinetics of CPT-11 with and without 5FU. For the second 6-week cycle, leucovorin was administered first, followed by 5FU and then CPT-11, and a third pharmacokinetic sampling was performed. RESULTS: Forty-two patients were entered onto this trial. The CPT-11 dose was initially fixed at 100 mg/m2. Leucovorin was fixed at 20 mg/m2. 5FU doses of 210, 265, 340, 425, and 500 mg/m2 were studied. When the 500-mg/m2 dose of 5FU was found to be tolerable, this was then maintained and CPT-11 was escalated to 125 and then 150 mg/m2. This final CPT-11 dose exceeded the MTD. Neutropenia was the major dose-limiting toxicity. Diarrhea was common, but was rarely dose-limiting. Coadministration of 5FU had no substantial effect on the pharmacokinetics of CPT-11 or SN-38. Among the 38 patients with colorectal cancer, six partial responses (PRs) were seen in this predominantly 5FU-refractory patient population. CONCLUSION: 5FU does not substantially affect the metabolism of CPT-11 to its active metabolite, SN-38. The combination of CPT-11125 mg/m2, 5FU 500 mg/m2, and leucovorin 20 mg/m2 is feasible and tolerable on this schedule.