DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity

  title={DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity},
  author={Chen Yang and Joseph Ciccolini and Aurore Blesius and Laetitia Dahan and Danielle Bagarry-Liegey and Caroline Brunet and Arthur Varoquaux and Nicolas Frances and Hafedh Marouani and Antoine Giovanni and Rose-Marie Ferri-Dessens and Mohamed Chefrour and Roger Favre and Florence Duffaud and Jean François Seitz and Michel Zanaret and Bruno Lacarelle and C{\'e}dric Mercier},
  journal={Cancer Chemotherapy and Pharmacology},
BackgroundFluoropyrimidine drugs are widely used in head and neck cancer (HNC). DPD deficiency is a pharmacogenetics syndrome associated with severe/lethal toxicities upon 5-FU or capecitabine intake. We have developed a simple, rapid, and inexpensive functional testing for DPD activity, as a means to identify deficient patients and to anticipate subsequent 5-FU-related toxicities. We present here the impact of fluoropyrimidine dose tailoring based on DPD functional screening in a prospective… 


This study shows that 5-FU-related toxicities can be greatly reduced in routine clinical practice by the upfront detection of DPD deficient patients with simple adaptive dosing strategy.

Beating the odds: efficacy and toxicity of dihydropyrimidine dehydrogenase-driven adaptive dosing of 5-FU in patients with digestive cancer.

This feasibility study shows how simplified DPD-based adaptive dosing of 5-FU can reduce sharply the incidence of treatment-related severe toxicities while maintaining efficacy as part of routine clinical practice in digestive oncology.

DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update

The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and

Capecitabine—A “Permanent Mission” in Head and Neck Cancers “War Council”?

An approach including routine testing of dihydropyrimidine dehydrogenase or even the thymidine phosphorylase (TP)/DPD ratio and the inclusion of miRNAs, imaging and radiomics parameters in multi-omics models will help implement “precision chemotherapy” in HNC, a concept supported by the importance of avoiding interruptions or treatment delays in this type of cancer.

Dihydropyrimidine dehydrogenase mutation in neoadjuvant chemotherapy in head and neck cancers: Myth or reality?

It seems that the incidence of DPD mutation is more common in Indian then it′s in the Caucasian population, and clinical toxicity criteria can accurately predict for D PD mutation.

Routine dihydropyrimidine dehydrogenase testing for anticipating 5-fluorouracil-related severe toxicities: hype or hope?

This review covers the limits and achievements of the various strategies proposed so far for determining DPD status in patients scheduled for 5-FU therapy and technical consensus on the best way to identify patients with DPD deficiency before administrating5-FU is far from being achieved.

Screening for dihydropyrimidine dehydrogenase deficiency to prevent severe 5-fluorouracil and capeciatbine-associated toxicity

A number of phenotype-based screening approaches to detect DPD-deficient patients warrant further clinical validation and appear to be well suited for clinical laboratories and which are an attractive option for monitoring of the DPD status.

5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases

5-FU standard dosage administration may lead to strong overexposure, responsible for the severe toxicities observed, including the neurological features, implies that DPD deficiency can cause neurotoxicity in 5-FU-treated patients and advocates for the prospective screening of D PD deficiency before starting any 5-fu-containing chemotherapy so as to prevent such side effects in the future.



A Rapid and Inexpensive Method for Anticipating Severe Toxicity to Fluorouracil and Fluorouracil-based Chemotherapy

Comparison of the U/UH2 ratios with a reference, non-toxic population, showed abnormal values suggesting impaired DPD activity in 57 out of the 80 toxic patients included in this study, and in 4 out of 5 patients with a fatal outcome.

Pharmacodynamics of fluorouracil-based induction chemotherapy in advanced head and neck cancer.

  • E. VokesR. Mick M. Ratain
  • Medicine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 1996
L-PFL-IFN is active in stage IV head and neck cancer and is a significant predictor of toxicity, and in women, optimization of response outcome requires a higher 5-FU concentration.

Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy.

A wide range of techniques available to establish DPD status in patients with cancer are covered, including genotypic or phenotypic, which would allow identification of those at risk and help in subsequent dose adjustment or selection of other treatment modalities.

Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced head and neck carcinomas.

  • R. FétyF. Rolland G. Milano
  • Medicine
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 1998
The present study is the first to demonstrate, in a randomized design, the clinical interest of an individual 5FU dose adaptation based on pharmacokinetic survey, in terms of therapeutic index improvement.

Determination of uracil/UH2 ratio as a potential surrogate for DPD status in cancer patients presenting with severe toxicities during fluoropyrimidine treatment.

  • C. MercierC. Yang R. Favre
  • Medicine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2006
The data indicate U/UH2 ratio appears to be frequently implicated in the occurrence of iatrogenic events with fluoropyrimidine therapy, and this simple and rapid HPLC method may meet the requirements of routine screening, allowing identification of patients who might be at risk of severe toxicity during fluoropyridine administration, at relatively low cost.

[Pharmacokinetic monitoring with dosage adjustment of 5 fluorouracil administered by continuous infusion].

Pharmacokinetic follow-up of 5-FU has proved to be an objective means to significantly reduce haematological and/or digestive tract toxicity and to reduce the median survival time in patients with head and neck cancer.

5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer.

Pharmacokinetic follow-up of these patients has proved to be an objective means to improve therapeutic index significantly and the benefit of such data for real-time therapy management is reported.

Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil.

The first known cancer patient who developed life-threatening complications after treatment with topical 5-FU and was shown subsequently to have profound DPD deficiency is reported, suggesting that degradation by the ubiquitin-proteosome-mediated system plays a role in the elimination of the DPD protein.

Phase II trial of cisplatin, fluorouracil, and pure folinic acid for locally advanced head and neck cancer: a pharmacokinetic and clinical survey.

  • M. SchneiderM. Etienne F. Demard
  • Medicine, Biology
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 1995
A significant correlation was demonstrated between FU concentration and hematologic toxicity grade, mucositis grade, and nausea-vomiting/diarrhea grade and patients who failed to respond significantly exhibited lower FU and total folate concentrations than patients with a CR or PR.

Clinical pharmacokinetic study of 5-FU in continuous 5-day infusions for head and neck cancer

A close relationship was demonstrated between elevated 5-FU CxT values and the frequency of cycles in which signs of toxicity (myelosuppression, mucositis, diarrhea) were observed and no obvious association was noted between response to treatment and systemic5-FU exposure.