Page 222 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 8
Table 3. DPYD variants
DPYD variant
DPYD*2A (c.1905+1G>A) DPYD*13 (c.1679T>G) c.2846A>T
c.1236G>A
Total
SNPs (N)
6
0
1
8
15 (N=14)
Tested patients (N)
275
214
214
109
275
LUMC (%)
2.2 0 0.5 7.3 5.1
Literature (%) Ref.
DPYD variants found in LUMC patients and these numbers compared with frequencies in the literature.
The follow-up of the dose recommendations by oncologists
Dose reduction was advised after the first administration of 5-FU or capecitabine (post- dose) for two patients. The medical record of the first patient showed that the initial screening result became available after the start of therapy. Dose adjustments could not be applied, toxicity occurred and the advised dose reduction was applied in the second cycle (Table 4, patient 12). The other patient was screened after start of therapy, but stopped therapy completely due to toxicity, thus applying a dose reduction was not applicable. For this patient the reason not to screen prospectively was absent in the medical record (Table 4, patient 2).
For eleven patients a dose reduction was recommended prior to the start of therapy (prospective). This resulted in an initial dose reduction in eight of 11 patients. For one patient the recommend dose reduction was not applied and full dose was given (Table 4, patient 13). In two patients the recommended dose reduction could not be applied since they did not start therapy. One patient did not start therapy due to renal failure and the presence of a DPYD variant (Table 4, patient 14), and one patient refused to start therapy (Table 4, patient 5). Also one patient was genotyped prospectively, but received a recommendation for phenotyping due to compound heterozygosity (Table 4, patient 9). This patient started treatment with a 50% reduced dose at the oncologists discretion. An overview of the above mentioned data are displayed in Table 4. The adherence to the dose recommendations (pre- and post-dose) is 90% (9 out of 10).
Analysis of results on clinical outcomes
The explorative analysis showed that the prospective dose recommendations given, resulted in initial dose reductions in eight patients. None of these eight patients developed severe toxicity (grade ≥3) during the first cycle. After the first or second cycle it was possible to increase the dosages, guided by toxicity. Dosages were increased in four patients (from 50% up to 60, 80 and 100%, and from 75 to 100%, respectively, all receiving capecitabine). However, this led to the development of severe toxicity in two DPYD*2A carrying patients (80% capecitabine led to diarrhea grade 3 followed by 31 days of hospitalization and 100% capecitabine led to hand-foot syndrome grade 3). Toxicity data can be found in Table 4.
In one patient with a DPYD*2A variant who received capecitabine in combination with radiotherapy, the dose recommendation was not followed by the physician and this patient experienced diarrhea (grade 4), enteritis and leukopenia, for which hospitalization of 18
220
~1.0–1.8 ~0.1 ~1.0–1.4 ~2.6–4.9 4.7–8.2
10,20 12 10,12 10,21