BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) enzyme is the rate limiting step in the metabolism of capecitabine, and its deficiency leads to severe toxicities and rarely, death. METHODS: A total of 506 patients were treated in the GI Medical Oncology unit of our institution with capecitabine containing regimens with a dose range of 1,250 to 2,000 mg/m(2)/day during the period from June 2013 to June 2015. Patients with grade (Gr) 3/4 toxicities requiring in-patient care (life threatening complications) were planned for DPD activity testing by peripheral blood PCR sequencing. RESULTS: Thirty-one patients developed Gr 3/4 toxicities during cycle 1 of capecitabine. This included mucositis in 24 (77%), diarrhea in 29 (94%), hand-foot syndrome (HFS) in 13 (42%) and myelosuppression in 5 (16%) patients. Twenty-two (81.4%) were found to be DPD deficient with 6 patients negative for DPD mutation. Three patients did not undergo the DPD analysis as advised. More than one mutation was seen in 11 patients. The relative frequencies of the mutations were IVS14+1G→A in 39%, with 13% having homozygosity, 85 T→C in 36%, 1627 A→G in 32%, 496 A→G in 18% and 2194 G→A in 18%, respectively. After dose reduction in cycle 2 in 17 patients of the DPD mutation positive cohort, statistically significant reduction in the toxicities was seen. CONCLUSIONS: Dose reduction in DPD deficient patients, reduces risk of life threatening complications significantly but not completely. Upfront screening for DPD deficiency in Indian patients should be evaluated further in view of potentially high homozygous DPD mutation prevalence.
BACKGROUND:Dihydropyrimidine dehydrogenase (DPD) enzyme is the rate limiting step in the metabolism of capecitabine, and its deficiency leads to severe toxicities and rarely, death. METHODS: A total of 506 patients were treated in the GI Medical Oncology unit of our institution with capecitabine containing regimens with a dose range of 1,250 to 2,000 mg/m(2)/day during the period from June 2013 to June 2015. Patients with grade (Gr) 3/4 toxicities requiring in-patient care (life threatening complications) were planned for DPD activity testing by peripheral blood PCR sequencing. RESULTS: Thirty-one patients developed Gr 3/4 toxicities during cycle 1 of capecitabine. This included mucositis in 24 (77%), diarrhea in 29 (94%), hand-foot syndrome (HFS) in 13 (42%) and myelosuppression in 5 (16%) patients. Twenty-two (81.4%) were found to be DPD deficient with 6 patients negative for DPD mutation. Three patients did not undergo the DPD analysis as advised. More than one mutation was seen in 11 patients. The relative frequencies of the mutations were IVS14+1G→A in 39%, with 13% having homozygosity, 85 T→C in 36%, 1627 A→G in 32%, 496 A→G in 18% and 2194 G→A in 18%, respectively. After dose reduction in cycle 2 in 17 patients of the DPD mutation positive cohort, statistically significant reduction in the toxicities was seen. CONCLUSIONS: Dose reduction in DPD deficientpatients, reduces risk of life threatening complications significantly but not completely. Upfront screening for DPD deficiency in Indian patients should be evaluated further in view of potentially high homozygous DPD mutation prevalence.
Authors: P M Hoff; R Ansari; G Batist; J Cox; W Kocha; M Kuperminc; J Maroun; D Walde; C Weaver; E Harrison; H U Burger; B Osterwalder; A O Wong; R Wong Journal: J Clin Oncol Date: 2001-04-15 Impact factor: 44.544
Authors: E Van Cutsem; C Twelves; J Cassidy; D Allman; E Bajetta; M Boyer; R Bugat; M Findlay; S Frings; M Jahn; J McKendrick; B Osterwalder; G Perez-Manga; R Rosso; P Rougier; W H Schmiegel; J F Seitz; P Thompson; J M Vieitez; C Weitzel; P Harper Journal: J Clin Oncol Date: 2001-11-01 Impact factor: 44.544
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Authors: A David McCollum; Paul J Catalano; Daniel G Haller; Robert J Mayer; John S Macdonald; Al B Benson; Charles S Fuchs Journal: J Natl Cancer Inst Date: 2002-08-07 Impact factor: 13.506
Authors: M Miwa; M Ura; M Nishida; N Sawada; T Ishikawa; K Mori; N Shimma; I Umeda; H Ishitsuka Journal: Eur J Cancer Date: 1998-07 Impact factor: 9.162
Authors: David Cunningham; Naureen Starling; Sheela Rao; Timothy Iveson; Marianne Nicolson; Fareeda Coxon; Gary Middleton; Francis Daniel; Jacqueline Oates; Andrew Richard Norman Journal: N Engl J Med Date: 2008-01-03 Impact factor: 91.245