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

Abstract

Purpose: The docetaxel, 5-fluorouracil (5-FU), and cisplatin (TPF) regimen in India is associated with high percentages of Grade 3-4 toxicity. This analysis was planned to evaluate the incidence of dihydropyrimidine dehydrogenase (DPD) mutation in patients with severe gastrointestinal toxicity, to assess whether the mutation could be predicted by a set of clinical criteria and whether it has any impact on postneoadjuvant chemotherapy response. Methods: All consecutive patients who received TPF regimen in head and neck cancers between January 2015 and April 2015 were selected. Patients who had predefined set of toxicities in Cycle 1 were selected for DPD mutation testing. Depending on the results, C2 doses were modified. Postcompletion of two cycles, patients underwent radiological response assessment. Descriptive statistics has been performed. The normally distributed continuous variables were compared by unpaired Student′s t-test, whereas variables which were not normally distributed by Wilcoxon sum rank test. For noncontinuous variables, comparison was performed by Fisher′s exact test. Results: Out of 34 patients, who received TPF, 12 were selected for DPD testing, and 11 (32.4%, 95% confidence interval [95% CI]: 19.1-49.3%) had DPD mutation. The predictive accuracy of the criteria for the tested DPD mutations was 81.3% (95% CI: 62.1-100%). Of the 11 DPD mutation positive patients, except for one patient, all others received the second cycle of TPF. The dose adjustments done in 5-FU were 50% dose reduction in 9 patients and no dose reduction in one patient. The response rate in DPD mutated patients was 27.3% (3/11) and that in DPD nonmutated/nontested was 39.1% (9/23) (P = 0.70). Conclusion: In this small study, it seems that the incidence of DPD mutation is more common in Indian then it′s in the Caucasian population. Clinical toxicity criteria can accurately predict for DPD mutation. Postdose adjustments of 5-FU from C2 onward, TPF can safely be delivered in the majority of patients with DPD heterozygous mutations without decrement in efficacy.

Key words

5-fluorouracil - dihydropyrimidine dehydrogenase mutation - head and neck cancers - neoadjuvant chemotherapy - toxicity

• References

• 1 Pfister DG, Ang KK, Brizel DM, Burtness BA, Busse PM, Caudell JJ, et al. Head and neck cancers, version 2.2013. Featured updates to the NCCN guidelines. J Natl Compr Canc Netw 2013;11:917-23.
• 2 Caudell JJ, Hamilton RD, Otto KJ, Jennelle RL, Pitman KT, Vijayakumar S. Induction docetaxel, cisplatin, and 5-fluorouracil precludes definitive chemoradiotherapy in a substantial proportion of patients with head and neck cancer in a low socioeconomic status population. Am J Clin Oncol 2014;37:332-6.
• 3 Patil VM, Noronha V, Joshi A, Muddu VK, Gulia S, Bhosale B, et al. Induction chemotherapy in technically unresectable locally advanced oral cavity cancers: Does it make a difference? Indian J Cancer 2013;50:1-8.
• 4 Somani N, Goyal S, Pasricha R, Khuteta N, Agarwal P, Garg AK, et al. Sequential therapy (triple drug-based induction chemotherapy followed by concurrent chemoradiotherapy) in locally advanced inoperable head and neck cancer patients - Single institute experience. Indian J Med Paediatr Oncol 2011;32:86-91.
• 5 Noronha V, Patil VM, Joshi A, Krishna MV, Dhumal S, Juvekar S, et al. Induction chemotherapy in technically unresectable locally advanced carcinoma of maxillary sinus. Chemother Res Pract 2014;2014:487872.
• 6 Joshi A, Patil VM, Noronha V, Juvekar S, Deshmukh A, Chatturvedi P, et al. Is there a role of induction chemotherapy followed by resection in T4b oral cavity cancers? Indian J Cancer 2013;50:349-55.
• 7 Patil VM, Prabhash K, Noronha V, Joshi A, Muddu V, Dhumal S, et al. Neoadjuvant chemotherapy followed by surgery in very locally advanced technically unresectable oral cavity cancers. Oral Oncol 2014;50:1000-4.
• 8 Patil VM, Noronha V, Joshi A, Muddu VK, Dhumal S, Arya S, et al. Weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer for patients ineligible for 3 weekly maximum tolerable dose chemotherapy. Indian J Cancer 2014;51:20-4.
• 9 van Kuilenburg AB, De Abreu RA, van Gennip AH. Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency. Ann Clin Biochem 2003;40(Pt 1):41-5.
• 10 Van Kuilenburg AB, Meinsma R, Zoetekouw L, Van Gennip AH. Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: High prevalence of the IVS14+1g>a mutation. Int J Cancer 2002;101:253-8.
• 11 Van Kuilenburg AB, Meinsma R, Zoetekouw L, Van Gennip AH. High prevalence of the IVS14 + 1G>A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity. Pharmacogenetics 2002;12:555-8.
• 12 Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, et al. Clinical pharmacogenetics implementation consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther 2013;94:640-5.
• 13 Extra JM, Rousseau F, Bruno R, Clavel M, Le Bail N, Marty M. Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion. Cancer Res 1993;53:1037-42.
• 14 Fraile RJ, Baker LH, Buroker TR, Horwitz J, Vaitkevicius VK. Pharmacokinetics of 5-fluorouracil administered orally, by rapid intravenous and by slow infusion. Cancer Res 1980;40:2223-8.
• 15 Etienne MC, Lagrange JL, Dassonville O, Fleming R, Thyss A, Renée N, et al. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol 1994;12:2248-53.
• 16 van Staveren MC, Guchelaar HJ, van Kuilenburg AB, Gelderblom H, Maring JG. Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency. Pharmacogenomics J 2013;13:389-95.
• 17 Morsman JM, Sludden J, Ameyaw MM, Githang′A J, Indalo A, Ofori-Adjei D, et al. Evaluation of dihydropyrimidine dehydrogenase activity in South-west Asian, Kenyan and Ghanaian populations. Br J Clin Pharmacol 2000;50:269-72.
• 18 Yang CG, Ciccolini J, Blesius A, Dahan L, Bagarry-Liegey D, Brunet C, et al. DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: Impact on treatment efficacy and toxicity. Cancer Chemother Pharmacol 2011;67:49-56.
• 19 Terrazzino S, Cargnin S, Del Re M, Danesi R, Canonico PL, Genazzani AA. DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: A meta-analysis. Pharmacogenomics 2013;14:1255-72.
• 20 Raida M, Schwabe W, Häusler P, Van Kuilenburg AB, Van Gennip AH, Behnke D, et al. Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5′-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)- related toxicity compared with controls. Clin Cancer Res 2001;7:2832-9.
• 21 Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.
• 22 Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695-704.
• 23 Magnani E, Farnetti E, Nicoli D, Casali B, Savoldi L, Focaccetti C, et al. Fluoropyrimidine toxicity in patients with dihydropyrimidine dehydrogenase splice site variant: The need for further revision of dose and schedule. Intern Emerg Med 2013;8:417-23.
• 24 Kalia M. Biomarkers for personalized oncology: Recent advances and future challenges. Metabolism 2015;64 3 Suppl 1:S16-21.
• 25 Patil VM, Noronha V, Joshi A, Krishna VM, Dhumal S, Chaudhary V, et al. Referral pattern for neoadjuvant chemotherapy in the head and neck cancers in a tertiary care center. Indian J Cancer 2014;51:100-3.