A controlled trial of the effect of 4-hydroxypyrazolopyrimidine (allopurinol) on the toxicity of a single bolus dose of 5-fluorouracil.

Abstract

We have evaluated, in a controlled study, the modification of the toxicity of a single bolus dose of 5-fluorouracil (5-FU) by allopurinol. Patients first received a single dose of 5-FU and were monitored for toxicity. If a measurable nadir in WBC or platelet count occurred, then the same dose of 5-FU was repeated with concurrent allopurinol, given for four consecutive days at an initial dose of 300 mg twice daily, starting the day before the administration of 5-FU. With this schedule, each evaluable patient received courses of 5-FU with and without allopurinol that could be compared for toxicity. Twenty patients received initial 5-FU doses of either 1,200 mg/m2 or 1,500 mg/m2 and later had the same dose repeated with allopurinol. Nineteen of these patients had a higher WBC count with allopurinol than without it. In several patients who received a further course of 5-FU with 900-mg/d allopurinol, the WBC count was yet higher than with 600-mg/d allopurinol. The myelosuppression produced by 5-FU was characterized by a decrease in granulocyte levels that was much greater than the decrease in lymphocyte levels, and the result of allopurinol treatment was to attenuate this effort on granulocytes. In a second part of the trial, the goal was to establish the maximum tolerated dose of 5-FU given with concurrent allopurinol. In this part of the study, all patients entered were given 5-FU, usually 1,200 mg/m2, with allopurinol, usually 600 mg/d for four days. Escalations of one or the other drugs were made on subsequent treatments. The data for 22 patients showed that 1,800 mg/m2 of 5-FU was well tolerated if given with 600 to 1,200 mg of allopurinol per day, and that the WBC count nadirs were no more severe than those of 1,200-mg/m2 5-FU without allopurinol. Neurotoxicity became limiting in some patients treated at these higher doses. We conclude that allopurinol given in the proper dose and schedule can diminish the granulocytopenia produced by bolus doses of 5-FU, thereby allowing a 50% increase in the maximal tolerated dose of 5-FU.

Failure of Allopurinol to Provide Clinically Significant Protection against the Hematologic Toxicity of a Bolus 5-FU Schedule

“…One patient developed unexplained neurologic symp toms 3 weeks after the completion of his 5-FU course which resolved spontaneously within 3 days. This rapid resolution is in contrast to other reported studies where neurologic symptoms generally required several weeks to resolve [8][9][10]. Our use of 7 days of allopurinol pretreatment as well as continuing allopurinol through the entire course of 5-FU and for a week after its completion may have resulted in protection against neurotoxicity.…”

“…Two previous reports of phase I single-dose bolus 5-FU administration in the presence of allopurinol have yielded conflicting results [8,9]. Howell ct al.…”

“…The major toxicity seen in this study was neurotoxicity. In contrast, Wooley et al [9] ad ministered allopurinol for 4 consecutive days begin ning the day before 5-FU and found some protection against myelosuppression in that the nadir leukocyte counts were higher in the presence of allopurinol. A 50% increase in the maximum tolerated dose of a single bolus of 5-FU (1,200 to 1,800 mg/m2) was possible.…”

“…A 50% increase in the maximum tolerated dose of a single bolus of 5-FU (1,200 to 1,800 mg/m2) was possible. Continuation of allopurinol after the ad ministration of 5-FU by Wooley et al [9] was felt to be important and a plausible explanation for the dif ference in these two studies.…”

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

“…For 5-FU, no Slope-value has been reported in patients and therefore the Slopeestimate was derived by testing which value that resulted in similar nadir as those reported in two published studies [28,29] when typical system-related parameter values of 7·10 9 cells/L, 125 h and 0.17 were used for WBC 0 , MTT and γ, respectively.…”