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Eniluracil’s Need for a Targeted Approach: A Lesson in Drug Development

Charles Wood Cancer Center, Glenn Falls Hospital, Glenn Falls, NY

To the Editor:In the February 15, 2002, issue of the Journal of Clinical Oncology, Rivera et al¹ reported a response rate of only 10% with a median survival of 40.4 weeks in patients with anthracycline- and taxane-resistant metastatic breast cancer. In the accompanying editorial, Robert Diasio² comments that "it may be premature to dismiss a drug like eniluracil . . . which may have pharmacologic attributes that would prove useful in the future," but he goes onto conclude that it is unlikely that eniluracil, uracil/tegafur, or S1 fluoropyrimidines will be used in the United States. In my opinion, such an outcome for fluoropyrimidines that possess dihydropyrimidine dehydrogenase (DPD) inhibition would be an unfortunate misfire for drug development and for a select group of patients who might benefit. Trials comparing eniluracil and fluorouracil (5-FU) with 5-FU and leucovorin in colorectal cancer patients showed no advantage for the DPD inhibitor, but the trial design suffered from taking a lowest-common-denominator approach to cancer. Consider, instead, that molecular analyses performed by Salonga et al³ reveal a striking heterogeneity with regard to susceptibility and resistance to 5-FU. Among a group of 33 patients, 12 had a favorable enzyme profile (ie, regarding thymidylate synthase [TS] and DPD expression levels), defined by a response rate of 92% and a median survival of 18 months. In the resistant group, in which no responses occurred and median survival was only approximately 6 months, patients did not respond either because of TS overexpression (39%) or because of DPD overexpression (18%) or both (12%). By extension, these observations could mean that only the group of 18% DPD overexpressors would derive benefit from an eniluracil/5-FU combination compared with 5-FU alone, either because 5-FU is already efficacious for some patients (29%) or because resistance driven by TS overexpression (57%) is not overcome by a pure DPD inhibitor.

Should a drug that can only help a minority of patients be evaluated in a trial that includes a majority for whom there will be no advantage to receiving the drug? Eniluracil was conceived as a molecularly targeted therapy but was taken into clinical trials without investigators bothering to evaluate patients’ potential molecular susceptibility. Plausibly, a drug like trastuzumab might have met with the same demise if it had been given to all breast cancer patients rather than only selectively to the HER2 overexpressing group. On the other hand, there may be an unrealized hope for patients with a DPD overexpression phenotype, a far more compelling group for study with eniluracil rather than patients selected on the basis of resistance to anthracycline and taxanes alone.

Should we test the tissue specimens in Rivera et al’s trial¹ with quantitative assays for TS and DPD levels? Until recently, such a question may have been impractical, but polymerase chain reaction–based technology is commercially available for paraffin-embedded tissues. A correlation between enzyme profile and susceptibility could outline a new strategy for DPD inhibitor development and extend the concept of molecularly targeted therapy to the design of chemotherapeutic trials in general. Conceivably, DPD inhibition is a highly effective treatment strategy for 10% to 20% of patients with breast and colon cancers. It would be a loss for such a promising hypothesis not to have its legitimate day in clinical trials court for this select group.

REFERENCES

1. Rivera E, Sutton L, Colwell B, et al: Multicenter phase II study of a 28-day regimen of orally administered eniluracil and fluorouracil in the treatment of patients with anthracycline- and taxane-resistant advanced breast cancer. J Clin Oncol 20: 987-993, 2002[Abstract/Free Full Text]

2. Diasio RB: An evolving role for oral fluoropyrimidine drugs. J Clin Oncol 20: 894-896, 2002[Free Full Text]

3. Salonga D, Danenberg KD, Johnson M, et al: Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 6: 1322-1327, 2000[Abstract/Free Full Text]

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