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. 1996 Sep;122(9):554–558. doi: 10.1007/BF01213552

Phase II study of 5-fluoruracil leucovorin and azidothymidine in patients with metastatic colorectal cancer

Jeffrey Clark 1,✉, William Sikov 1, Frank Cummings 1, Marcia Browne 1, Wallace Akerley 1, Harrold Wanebo 1, Alan Weitberg 1, Teresa Kennedy 1, Bernard Cole 1, Joseph Bigley 3, Julie Beitz 1, James Darnowski 1
PMCID: PMC12201401  PMID: 8781570

Abstract

The primary objective of this study was to determine the response rate of patients with metastatic colorectal cancer to combined therapy with 5-fluorouracil (5-FU), leucovorin, and intravenous azidothymidine (AZT), a thymidine nucleoside analog. By itself, AZT has limited antineoplastic efficacy. However, experimental studies indicate that 5-FU enhances the antitumor activity of AZT by inhibiting synthesis of normal thymidine nucleotides with which AZT competes for incorporation into nucleic acids. A phase I study defined the maximum tolerated dose of AZT as 7 g/m2 with hypotension during the infusion being the dose-limiting toxicity. A phase II study was performed with oral leucovorin (100 mg p.o. hourly for 4 h prior to 5-FU and 4 h and 8 h after 5-FU), bolus 5-FU (400 mg/m2) followed 1 h later by a 2-h infusion of AZT (7 g/m2). Treatment was given weekly for 4 weeks followed by a 1-week break, which constituted a cycle of therapy. Responses were evaluated after every two cycles. Patients continued on therapy as long as they tolerated treatment and did not have progressive disease. Of 15 evaluable patients who had received no chemotherapy there was 1 complete response 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. Approximately 50% of treatments were accompanied by mild hypotension, which was easily corrected by increasing the rate of normal saline infusion. There was no difficulty administering this regimen in the outpatient setting. While the overall response rate (29%) is comparable to that seen with combinations of 5-FU and leucovorin alone, in most reported series a considerably higher dose of 5-FU was utilized than in this study. Since patients in the present study experienced relatively little 5-FU toxicity, increasing the dose of 5-FU in this regimen would appear to be feasible and might result in a higher response rate.

Key words: Colon cancer, AZT, Fluorouracil, Leucovorin

Abbreviations

AZT

Azidothymidine

5-FU

fluorouracil

LV

leucovorin

TS

thymidylate synthase

NS

normal saline

MTD

maximum tolerated dose

Footnotes

Supported in part by NIH-P30-CA13943 and CA 55358

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