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Genotype-driven dosing reduces 5-FU, capecitabine toxicity

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Evidence of pharmacogenetic testing benefits

Therapeutic drug monitoring provides an alternative to guide dose adaptations. For capecitabine, because of the intracellular conversion of this prodrug into fluorouracil (5-FU) and cytotoxic metabolites, the utility of therapeutic drug monitoring for dose optimization is unclear. By contrast, therapeutic drug monitoring is well established for infusional 5-FU, with defined target ranges and dosing algorithms available. Therefore, to prevent toxicities during dose escalation, dose titration in DPYD risk variant carriers could be done using infusional 5-FU with a starting dose of 50%, followed by therapeutic drug monitoring.

Prospective evaluation of genotype-guided dosing has been done for very few pharmacogenetic markers. With two prospective studies showing both feasibility and clinical benefit, DPYD genotyping provides a leading example of how prospective pharmacogenetic testing can result in benefits for patients by reducing morbidity and mortality associated with adverse drug effects. With fluoropyrimidines remaining a mainstay of cancer chemotherapy, these benefits will continue to be of relevance for the foreseeable future.

Ursula Amstutz, PhD, and Carlo R Largiadèr, PhD, are from the University Institute of Clinical Chemistry at the University of Bern, Switzerland. Their comments were adapted from an editorial accompanying the study in The Lancet: Oncology. They reported no competing interests.


AT ESMO 2018

– Pretreatment genotyping of patients for a key metabolizing enzyme prior to therapy with a fluoropyrimidine agent can be performed in routine clinical practice and can significantly improve safety of the drugs, investigators reported.

Among 1,103 patients scheduled for fluoropyrimidine-based therapy with either fluorouracil (5-FU) or capecitabine alone or in combination with other therapies, toxicities were highest among patients with two common variant alleles of DPYD, the gene encoding for the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). The risk for toxicity was “markedly reduced” when doses were reduced by 50% in patients carrying the alleles, reported Linda Henricks, PharmD, from the Netherlands Cancer Institute, Amsterdam, and her colleagues.

“Our study was done in a daily clinical care setting in regional general hospitals and a few academic centers, showing the feasibility of implementation of upfront DPYD screening. To make DPYD-guided dosing feasible in all hospitals, the turnaround time for DPYD genotyping must be short to prevent a delay in the start of treatment,” they wrote in a study published in The Lancet Oncology prior to presentation of these data at the European Society of Medical Oncology Congress.

The laboratories participating in their study had turnaround times ranging from a few days up to 1 week, they noted.

Fluoropyrimidines are the backbones of therapy for several different malignancies, but up to 30% of patients treated with these drugs can experience severe toxicities because of reduced DPD activity, primarily caused by genetic variants in DPYD.

The investigators conducted a prospective multicenter study to see whether screening for the four most common variants could help clinicians tailor treatment programs to improve tolerability of fluoropyrimidine-based therapies.

They looked at the incidence of toxicities between patients carrying DPYD variant alleles and DPYD wild-type carriers in an intention-to-treat analysis, and compared relative risks for severe toxicities among patients with those of historical controls – patients with DPYD variant alleles who had been treated with a full-dose fluoropyrimidine in previous studies.

They enrolled 1,181 patients during May 2015–December 2017, of whom 1,103 were evaluable. Of this group, 92% (1,018 patients) had wild-type DPYD, and 8% (85) were heterozygous variant allele carriers.

The four variant alleles the investigators genotyped for were: DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A.

Patients who were heterozygous for c.2846A>T or c.1236G>A received doses reduced by 25%, and patients with DPYD*2A or c.1679T>G received doses reduced by 50%. Patients with DPYD wild-type were treated according to the current standard of care.

The incidence of severe fluoropyrimidine-related toxicity, the primary endpoint, was significantly higher among variant allele carriers compared with patients with wild-type DPYD (39% vs. 23%, respectively, P = .0013).

The relative risk for severe toxicity among patients with DPYD*2A treated in the current study with genotype-guided therapy was 1.31, compared with 2.87 for historical controls carrying the same variant.

Among c.1679T>G carriers, those treated with genotype-guided therapy had no severe toxicity, whereas the relative risk for historical controls was 4.30.

Respective relative risks for c.2846A>T carriers were 2.0 vs. 3.11, and for c.1236G>A carriers were 1.69 vs. 1.72.

“Although our study revealed that the applied approach of genotype-guided adaptive dosing significantly reduced severe fluoropyrimidine-induced toxicity and prevented treatment-related death, additional methods should be explored and prospectively tested to further reduce treatment-related toxicity, not only in DPYD variant allele carriers, but also in DPYD wild-type patients,” Dr. Henricks and her associates wrote.

The study was supported by the Dutch Cancer Society. Dr. Henricks and a coauthor report grants from the Society. One coauthor reported a prior unrestricted grant from Roche and one personal fee from Modra outside the submitted work.

SOURCE: Henricks LM et al. Lancet Oncol. 2018 Oct 19. doi: 10.1016/S1470-2045(18)30686-7.

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