PHASE-II STUDY OF 5-FLUORURACIL LEUCOVORIN AND AZIDOTHYMIDINE IN PATIENTS WITH METASTATIC COLORECTAL-CANCER

The primary objective of this study was to determine the response rate of patients with metastatic colorectal cancer to combined therapy wit h 5-fluorouracil (5-FU), leucovorin, and intravenous azidothymidine (A ZT), a thymidine nucleoside analog, By itself, AZT has limited antineo plastic efficacy. However, experimental studies indicate that 5-FU enh ances the antitumor activity of AZT by inhibiting synthesis of normal thymidine nucleotides with which AZT competes for incorporation into n ucleic acids. A phase I study defined the maximum tolerated dose of AZ T as 7 g/m(2) with hypotension during the infusion being the dose-limi ting toxicity. A phase II study was performed with oral leucovorin (10 0 mg p.o. hourly for 4 h prior to 5-FU and 4 h and 8 h after 5-FU), bo lus 5-FU (400 mg/m(2)) followed 1 h later by a 2-h infusion of AZT (7 g/m(2)). Treatment was given weekly for 4 weeks followed by a I-week b reak, which constituted a cycle of therapy. Responses were evaluated a fter every two cycles. Patients continued on therapy as long as they t olerated treatment and did not have progressive disease, Of 15 evaluab le patients who had received no chemotherapy there was 1 complete resp onse and 4 partial responses (a 33% response rate), whereas only 1 of 6 patients who had received prior adjuvant chemotherapy had a partial response (17%). An additional 10 patients had stable disease lasting 2 -14 months, Therapy was well tolerated with the only one instance each of grade 3 nausea and vomiting, diarrhea,anemia, and hypotension. App roximately 50% of treatments were accompanied by mild hypotension, whi ch was easily corrected by increasing the rate of normal saline infusi on, There was no difficulty administering this regimen in the outpatie nt setting. While the overall response rate (29%) is comparable to tha t seen with combinations of 5-FU and leucovorin alone, in most reporte d series a considerably higher dose of 5-FU was utilized than in this study. Since patients in the present study experienced relatively litt le 5-FU toxicity, increasing the dose of 5-FU in this regimen would ap pear to be feasible and might result in a higher response rate.