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Alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes

BACKGROUND: 5-fluorouracil (5-FU) and mitomycin-C (MMC) with radiotherapy (RT) remain an established treatment for patients with anal cancer (AC). Genetic mutations in two major metabolizing enzymes for 5-FU; dihydropyrimidine dehydrogenase (DPYD and thymidylate synthetase (TYMS), have been associat...

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Autores principales: Saif, MW, Hamal, Ruchi, Siddiqui, Nauman, Maloney, Antonia, Smith, Melissa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255561/
https://www.ncbi.nlm.nih.gov/pubmed/34276810
http://dx.doi.org/10.1177/17562848211024464
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author Saif, MW
Hamal, Ruchi
Siddiqui, Nauman
Maloney, Antonia
Smith, Melissa
author_facet Saif, MW
Hamal, Ruchi
Siddiqui, Nauman
Maloney, Antonia
Smith, Melissa
author_sort Saif, MW
collection PubMed
description BACKGROUND: 5-fluorouracil (5-FU) and mitomycin-C (MMC) with radiotherapy (RT) remain an established treatment for patients with anal cancer (AC). Genetic mutations in two major metabolizing enzymes for 5-FU; dihydropyrimidine dehydrogenase (DPYD and thymidylate synthetase (TYMS), have been associated with clinical response and toxicity. However, their place in the treatment of AC remains undetermined. METHODS: We retrospectively reviewed 21 patients with AC, including T2-4, N0-1, M0 or T1-4, N2-3, and M0 treated between 2012 and 2018. All patients were treated with 5-FU 1,000 mg/m(2)/day via continuous intravenous (IV) infusion 1–4 and 29–32, MMC 10 mg/m(2) IV bolus days 1 and 29 plus RT. Patients who developed ⩾3 grade toxicities were tested for the DPYD and TYMS genes. Treatment was either modified with reduced doses or changed to MMC 10 mg/m(2) day 1 and 29 with cisplatin 25 mg/m(2)/week plus RT. Toxicities and responses were collected. RESULTS: Six out of 21 patients who developed ⩾3 grade toxicities including pancytopenia, neutropenia, thrombocytopenia, mucositis, nausea, rash, and nephritis were found to have genetic mutations: TYMS 2RG/3RC (n = 2), 3RG/3RC (n = 1), 2R/2R (n = 2), TYMS 3′UTR del/Ins (n = 2), and DPYD c.2864A > T heterozygous (n = 1). Two patients received 5-FU at a 50% reduced dose on days 29–32; one patient refused to receive 5-FU (continued with MMC and RT); one patient received only radiation therapy due to persistent pancytopenia despite the use of growth factors; two patients received an alternative regimen consisting of MMC 10 mg/m(2) on day 29 with cisplatin (CDDP) 25 mg/m(2)/week plus RT; and two patients received cisplatin/MMC with RT from the beginning as they were prospectively detected to have TYMS abnormalities prior to dosing the chemotherapy. These patients tolerated treatment very well with only grade 2 toxicities. All the patients (4/4) on cisplatin/MMC achieved clinical complete response (cCR), while four patients (4/15) on 5-FU/MMC reached cCR at the first assessment. Radiological response showed complete response at the end of 24 weeks assessment. CONCLUSIONS: Molecular testing for DPYD and TYMS genes can allow us to identify patients who are most likely to respond or face severe toxicity to 5-FU in a potentially curable cancer. Combining radiation with CDDP with MMC in patients with AC is feasible. A prospective study based on pharmacogenetic testing comparing MMC/cisplatin with MMC/5-FU is indicated in patients with AC.
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spelling pubmed-82555612021-07-16 Alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes Saif, MW Hamal, Ruchi Siddiqui, Nauman Maloney, Antonia Smith, Melissa Therap Adv Gastroenterol Advances and Future Perspectives in Colorectal Cancer BACKGROUND: 5-fluorouracil (5-FU) and mitomycin-C (MMC) with radiotherapy (RT) remain an established treatment for patients with anal cancer (AC). Genetic mutations in two major metabolizing enzymes for 5-FU; dihydropyrimidine dehydrogenase (DPYD and thymidylate synthetase (TYMS), have been associated with clinical response and toxicity. However, their place in the treatment of AC remains undetermined. METHODS: We retrospectively reviewed 21 patients with AC, including T2-4, N0-1, M0 or T1-4, N2-3, and M0 treated between 2012 and 2018. All patients were treated with 5-FU 1,000 mg/m(2)/day via continuous intravenous (IV) infusion 1–4 and 29–32, MMC 10 mg/m(2) IV bolus days 1 and 29 plus RT. Patients who developed ⩾3 grade toxicities were tested for the DPYD and TYMS genes. Treatment was either modified with reduced doses or changed to MMC 10 mg/m(2) day 1 and 29 with cisplatin 25 mg/m(2)/week plus RT. Toxicities and responses were collected. RESULTS: Six out of 21 patients who developed ⩾3 grade toxicities including pancytopenia, neutropenia, thrombocytopenia, mucositis, nausea, rash, and nephritis were found to have genetic mutations: TYMS 2RG/3RC (n = 2), 3RG/3RC (n = 1), 2R/2R (n = 2), TYMS 3′UTR del/Ins (n = 2), and DPYD c.2864A > T heterozygous (n = 1). Two patients received 5-FU at a 50% reduced dose on days 29–32; one patient refused to receive 5-FU (continued with MMC and RT); one patient received only radiation therapy due to persistent pancytopenia despite the use of growth factors; two patients received an alternative regimen consisting of MMC 10 mg/m(2) on day 29 with cisplatin (CDDP) 25 mg/m(2)/week plus RT; and two patients received cisplatin/MMC with RT from the beginning as they were prospectively detected to have TYMS abnormalities prior to dosing the chemotherapy. These patients tolerated treatment very well with only grade 2 toxicities. All the patients (4/4) on cisplatin/MMC achieved clinical complete response (cCR), while four patients (4/15) on 5-FU/MMC reached cCR at the first assessment. Radiological response showed complete response at the end of 24 weeks assessment. CONCLUSIONS: Molecular testing for DPYD and TYMS genes can allow us to identify patients who are most likely to respond or face severe toxicity to 5-FU in a potentially curable cancer. Combining radiation with CDDP with MMC in patients with AC is feasible. A prospective study based on pharmacogenetic testing comparing MMC/cisplatin with MMC/5-FU is indicated in patients with AC. SAGE Publications 2021-07-03 /pmc/articles/PMC8255561/ /pubmed/34276810 http://dx.doi.org/10.1177/17562848211024464 Text en © The Author(s), 2021 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Advances and Future Perspectives in Colorectal Cancer
Saif, MW
Hamal, Ruchi
Siddiqui, Nauman
Maloney, Antonia
Smith, Melissa
Alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes
title Alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes
title_full Alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes
title_fullStr Alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes
title_full_unstemmed Alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes
title_short Alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes
title_sort alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes
topic Advances and Future Perspectives in Colorectal Cancer
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255561/
https://www.ncbi.nlm.nih.gov/pubmed/34276810
http://dx.doi.org/10.1177/17562848211024464
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