Up-front Genotyping Reduces Fluoropyrimidine Toxicity

Alexander M. Castellino, PhD

December 03, 2015

Severe and life-threatening toxicity of 5-fluorouracil (5-FU) is strongly associated with a genetic polymorphism in the 5-FU metabolizing enzyme dihydropyrimidine dehydrogenase, specifically, DPYD*A2.

Screening for DPYD*A2 provides genotype-guided dosing, and by reducing drug exposure, reduces the toxicity seen, reports a study published online November 16 in the Journal of Clinical Oncology.

"In contrast to the long-lasting and life-threatening toxicity that typically occurs with full dosing, the observed toxicity with genotype-guided dosing was short in duration and well controlled with general supportive care," corresponding author Jan H. M. Schellens, MD, PhD, of the Netherlands Cancer Institute, Amsterdam, and his colleagues write in their discussion.

"The results presented in this study are an encouraging step toward the therapeutic individualization of 5-FU," commented Robert B. Diasio, MD, William J. and Charles H. Mayo Professor and director of the Mayo Clinic Cancer Center, Rochester, Minnesota. He was not involved in the study and was approached for comment by Medscape Medical News.

Severe Toxicity in 5% to 10% of Patients

The authors explain that in approximately 5% to 10% of patients, administration of 5-FU is associated with severe toxicity early during treatment, leading to dose interruptions or even discontinuations. Much of this is associated with genetic polymorphism in DPYD, with DPYD*2A being the most relevant. That polymorphism results in an enzyme with reduced activity, owing to a truncated protein produced from alternate splicing.

In several studies and case reports, severe toxicity has been reported with standard-dose 5-FU. "We hypothesized that upfront genotyping of DPYD*2A followed by individualized dose adjustment would improve safety of fluoropyrimidine therapy for patients and reduce overall treatment cost," Dr Schellens and colleagues write in their introduction.

The Dutch Study

In a multicenter study, 2038 consecutive patients who were prescribed 5-FU-based chemotherapy underwent prospective genotyping for DPYD*2A before therapy was initiated.

A total of 22 patients (1.1%) were heterozygotes for DPYD*2A, having one active gene and one gene with reduced activity. Of 2038 patients, 1631 (80%) received full-dose 5-FU. Colorectal cancer was the most common cancer treated; 90% of patients were treated with capecitabine (Xeloda, F. Hoffman-La Roche, Ltd), an orally administered prodrug of 5-FU, and 10% of patients received intravenous 5-FU.

Of 22 patients who were heterozygous for DPYD*2A, 18 (80%) received reduced doses of 5-FU; four patients did not receive 5-FU-based therapy.

Of these 18 patients, two (11%) experienced grade 0 toxicity; 11 (61%), grade 1 toxicity; and five (28%), grade ≥3 toxicity.

Because a randomized study was considered unethical, the toxicity for the 18 patients from this study was compared with that for historic controls — patients with DPYD*2A genotype whose cases were reported in published studies and who received full-dose 5-FU.

The historic control comprised 48 patients from 14 studies, which included a total of 3974 patients.

Incidence of ≥grade 3 toxicity was reduced from the 73% in historic control patients who received standard-dose 5-FU to 28% in the 18 patients from this study who received genotype-guided reduced dosing. In addition, 10% of patients in the historic cohort died from grade 5 toxicity, compared with 0% in the current cohort.

In a second comparison, the Dutch investigators reported that a genotype-guided reduced-dosing strategy in patients heterozygous for DPYD*2A resulted in toxicity rates comparable with that in patients with wild-type DPYD*2A who received full-dose 5-FU.

In a secondary endpoint cost analysis, the Dutch investigators reported a cost saving of $61 (€56.47) per patient in favor of the screening strategy.

"The results of this study show that upfront genotyping of DPYD*2A is feasible, improves safety of fluoropyrimidine therapy for patients, and is more likely cost saving," Dr Schellens and colleagues write in their discussion.

Significance to Clinical Practice

"This study demonstrates for the first time to our knowledge the feasibility of upfront genotyping in daily practice, without delaying start of treatment," Dr Schellens and colleagues write.

"In our trial, we demonstrated that patients can be safely treated with starting doses reduced by 50%," they state.

"While this study was able to evaluate toxicity following the administration of a reduced dose of 5-FU, limited data pertaining to the therapeutic efficacy of this reduced dose were available for inclusion in the report," Dr Diasio told Medscape Medical News when approached for comment on the study.

"Additional long-term follow-up studies will be necessary to determine what effects the reduced dose has on efficacy outcomes," he added.

But the authors indicate that the primary objective of the study was to determine the safety of DPYD*2A genotype-guided dosing. They emphasize that given the low frequency of DPYD*2A, a study with efficacy as the coprimary endpoint or even the secondary endpoint is not feasible.

"[P]rospective screening for DPYD*2A is life saving, feasible, and cost saving, outweighing screening costs. It should therefore become standard of care in treatment with fluoropyrimidines," Dr Schellens and colleagues conclude.

The potential of this approach is pertinent to clinical practice in the United States, Dr Diasio indicated.

"However, additional studies are needed to better understand the mechanisms that are responsible 5-FU-induced toxicity and to identify additional predictive tests that might permit prevention of life-threatening toxicity," Dr Diasio told Medscape Medical News.

The authors and Dr Diasio have disclosed no relevant financial relationships.

J Clin Oncol. Published online November 19, 2015. Abstract

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