Page 102 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
ref. 22 – FU, comb Mercier C et al. Prospective phenotypic screening for DPD deficiency prior to 5-FU administratio n:
decrease in toxicity, not in efficacy.
J Clin Oncol 2008;26(May 20 suppl):abstr 14556. (meeting abstract)
ref. 23 – FU, comb
Jatoi A et al. Paclitaxel, carboplatin, 5-fluoroura- cil, and radiation for locally advanced esophageal cancer: phase II results of preliminary pharmacologi c and molecular efforts to mitigate toxicity and predict outcomes: North Central Cancer
Level of evidence score: 3
Inclusion of the additional variants only led to a marginal improvement in the prediction of overall toxicity.
The method of administration is an independent risk factor: the risk of grade III/IV toxicity was greater for the bolus Mayo regimen than for the high-dose infusion (OR=2.44 [95% CI 1.52-3.91]).
59 French patients with inoperable head and neck cancer; determination of DPD activity (dihydrouracil/uracil ratio) prior to FU combination therapy or radio-chemotherapy; mild DPD deficiency (dihydrouracil/uracil ratio < 0.5): FU dose was 80% of the standard dose, severe DPD deficiency (ratio < 0.33): FU dose was 50% of the standard dose, complete DPD deficiency: no FU.
- 25% of the patients had mild and 22% severe DPD deficiency.
- 12% of the patients with DPD deficiency and dose reduction showed severe toxicity. The incidence of severe toxicity was twofold lower in the overall group compared to the regimen without dose reduction.
- There were no toxicity-induced fatalities.
- The effectiveness was similar to the regimen without dose reduction (percentages of responders 64% and 81% for first-line chemotherapy and radio- chemotherapy and 50% and 38% for treatment for relapsed cancer).
50 American patients with locally advanced oesophageal cancer (11x *1/*1, 1x *1/*2A, 16x *1/*5, 3x *1/*6, 13x *1/*9A, 4x *9A/*9A, 1x *5/*5) participating in a phase II study received FU 225 mg/m2 per day by continuous infusion in combination with carboplatin, paclitaxel and radiotherapy; FU was temporarily discontinued in the event of FU-related grade III-IV toxicity, after which the dose was decreased by 20%; patients received median 81% and 66% of the standard FU dose during 1 and 2 cycles respectively; screening for *2A (IVS14+1G>A), *5 (1627A>G), *6 (2194G>A) and *9A (85T>C).
- Almost all patients (94%) had at least 1 incident of grade III-IV toxicity, including 3 fatalities.
- No significant associations of the polymorphisms with pathological complete response, time to progression/relapse of cancer, overall survival or grade III/IV toxicity.
NB: *5, *6 and *9A do not have reduced DPD activity.
Authors’ conclusion: “5-FU dose tailoring based upon DPD status evaluation led to 2 fold decrease in occurrence of severe toxicities without impairing efficacy.”
Level of evidence score: 3
gene act. 1: Clinical Relevanc e Score: AA
Authors’ conclusion: “Genotyping for polymorphisms
of dihydropyrimidine dehydrogenase, cytochrome P3A4, and glutathione-S- transferase did not predict tumour response or serious adverse events.”
100
table continues