Page 89 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

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There was no indication of publication bias. Risk of grade ≥ 3 toxicity for c.2846A>T-carriers
compared to *1/*1:
any toxicity
RRadj (95% CI) incidence for *1/*1
(% of
patients) 3.02 (2.22- 25%
4.10) (S)
The heterogeneity between the studies was
significant and strong.
There was no indication of publication bias.
NOTE: c.1236G>A is in complete linkage disequilibrium with c.1129-5923C>G in haplotype B3. Studies analysing both gene variants were pooled.
NOTE: Meta-analysis of 5 studies with in total 3900 patients, 182x *1/*4 and 2x *4/*4, showed no significant association between *4 and grade ≥ 3 toxicity. The only study that found a significant effect (Loganayagam 2013) was the cause of strong heterogeneity between the studies. In addition, results regarding the effect of *4 on DPD activity are inconsistent.
2594 patients were treated with 12 cycles of adjuvant FOLFOX therapy (5-fluorouracil, folinic acid and oxaliplatin; 91.9% of patients) or FOLFIRI therapy (5- fluorouracil, folinic acid and irinotecan; 8.1% of patients) with or without cetuximab. Part of the patients received 6 cycles of FOLFOX followed by six cycles of FOLFIRI with or without cetuximab. 62.0% of patients had any grade ≥ 3 adverse event, with 33.1% having any grade ≥ 3 adverse event common to 5- fluorouracil treatment.
Adverse events classified as common to 5-fluorouracil treatment were fatigue, anorexia, dehydration, diarrhoea, stomatitis/mucositis, nausea/vomiting, leukopenia, neutropenia, febrile neutropenia, thrombocytopenia, and pain. Most frequent 5- fluorouracil adverse events included diarrhoea (12.0%), neutropenia (11.7 %), nausea/vomiting (5.0%), fatigue (4.9%), and mucositis (4.2%). Follow-up for disease free survival was for 5 years. Results were adjusted for clinicopathological factors like age, sex, treatment, total number of treatment cycles and dose modifications. The latter two outcomes (higher percentage of patients with premature continuation and with dose modification) might be results of 5-fluorouracil adverse events instead of causes.
Cetuximab increased the risk of 5-fluorouracil adverse events. OR’s were adjusted for this, but other
4
ref. 10 – FU, comb
Lee AM et al. DPYD variants as predictors of 5- fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147).
J Natl Cancer Inst 2014;106:dju 298. PubMed PMID: 25381393.
Level of evidence score: 3
gene act. 0.5-1: CTC-AE 4
gene act. 0.5 + gene act. 1.5: CTC- AE4
gene act. 0.5:CTC- AE 5(2)#
Authors’ conclusion: ‘Statistically significant associations were found between DPYD variants (DPYD*2A and 2846A>T) and increased incidence of grade 3 or greater 5FU-adverse events in patients treated with adjuvant 5-FU- based combination chemotherapy.’
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