International Cancer Conference Journal

, Volume 7, Issue 4, pp 125–129 | Cite as

Severe adverse events due to dihydropyrimidine dehydrogenase deficiency in a Japanese patient with colon cancer taking capecitabine: a case report

  • Mai Tsutsui
  • Seiichiro YamamotoEmail author
  • Yusuke Yoshikawa
  • Ryo Nakanishi
  • Kiminori Takano
  • Koji Osumi
  • Tomotaka Akatsu
  • Kimiyasu Yoneyama
  • Motohito Nakagawa
  • Toshio Kanai
Case report


Fluoropyrimidine has been commonly used not only in unresectable cases of metastatic colorectal cancer, but also in adjuvant therapy. Dihydropyrimidine dehydrogenase (DPD) is an enzyme encoded by the DPYD gene, which is responsible for the rate-limiting step in pyrimidine catabolism and breaks down more than 80% of standard doses of 5-fluorouracil (5-FU) and capecitabine, an oral prodrug of 5-FU. The lack of enzymatic activity increases the half-life of the drug, resulting in excess drug accumulation and toxicity which may lead to life-threatening side effects. There have been several published case reports about DPD deficiency in patients with colorectal cancer in Western countries. However, case reports of DPD deficiency in Japanese patients with colorectal cancer are rare because measuring DPD activity is not covered by public medical insurance in Japan, and it is not examined in our daily clinical practice currently. Therefore, we think that it is important to accumulate such case reports for further understanding. This report describes the case of a Japanese patient with colon cancer who experienced severe side effects while taking capecitabine, due to DPD deficiency. A 68-year-old man with ascending colon cancer underwent curative laparoscopic right hemicolectomy. Because final pathologic staging was Stage IIIa, standard adjuvant chemotherapy with capecitabine (3600 mg/body/day, days 1–14, every 3 weeks) was started on postoperative day 50. After 2 weeks, he started to experience Grade 3 diarrhea and was admitted to the hospital on postoperative day 66. On day 70, the patient had Grade 4 febrile neutropenia. Antibiotics and granulocyte-colony-stimulating factor were administered until his blood tests recovered to the normal degree. After 1 week of diarrhea, antidiarrheal agents were administered, and the patient gradually recovered. During the occurrence of diarrhea, specimen cultures were negative for infection. He was discharged on day 21 of the hospital stay. DPD deficiency was suspected, and 2 weeks later the DPD activity of the peripheral blood mononucleocytes was examined. The result was 10.3 U/mg protein which was remarkedly low (reference range 22.6–183.6 U/mg protein), and DPD deficiency was diagnosed. We always must consider the possibility of DPD deficiency in patients who experience severe side effects while taking capecitabine.


Fluoropyrimidines Dihydropyrimidine dehydrogenase deficiency Colon cancer Capecitabin Side effects 





Japanese Society for Cancer of the Colon and Rectum


Common Terminology Criteria for Adverse Events


White cell count


C-reactive protein




Granulocyte-colony stimulating factor


Computed tomography




Enzyme-linked immunosorbent assay


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Informed consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.


  1. 1.
    Vital, Health and Social Statistics Office to the Counsellor for Vital, Health and Social Statistics to the Director-General for Statistics and Information Policy, Ministry of Health, Labour and Welfare: Vital Statistics in JAPAN (2016)
  2. 2.
    Watanabe T, Muro K, Ajioka Y et al (2017) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer. JSCRR Guidelines 2016 for the Treatment of Colorectal Cancer. Int J Clin Oncol. (Epub ahead of print)CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Mori K, Hasegawa M, Nishida M, et at (2000) Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues. Int J Oncol 17:33–38PubMedGoogle Scholar
  4. 4.
    Gross E, Busse B, Riemenschneider M et al (2008) Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. PLoS One 3(12):e4003CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Amstutz U, Froehlich TK, Largiadèr CR (2011) Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics 12(9):1321–1336CrossRefPubMedGoogle Scholar
  6. 6.
    Kim SR, Park CH, Park S et al (2010) Genetic polymorphisms associated with 5-Fluorouracil-induced neurotoxicity. Chemotherapy 56(4):313–317CrossRefPubMedGoogle Scholar
  7. 7.
    Rumiato E, Boldrin E, Amadori A et al (2013) DMET™ (Drug-Metabolizing Enzymes and Transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity. Cancer Chemother Pharmacol 72(2):483–488CrossRefPubMedGoogle Scholar
  8. 8.
    Japanese Society for Cancer of the Colon and Rectum (2013) Japanese classification of Colorectal Carcrinoma (Eighth Edition)Google Scholar
  9. 9.
    Mori K, Hasegawa M, Nishida M et al (2000) Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tissues. Int J Clin Oncol 17:33–38Google Scholar
  10. 10.
    Law K, Rogers J, Eng C (2014) Delayed presentation of DPD deficiency in colorectal cancer. J Adv Pract Oncol 5:205–210PubMedPubMedCentralGoogle Scholar
  11. 11.
    Mitake Y, Hiramatsu K, Kato T et al (2015) A case of low dihydropyrimidine dehydrogenase activity with septic shock caused by enterocolitis during adjuvant chemotherapy for Stage II colon cancer. J Jpn Surg Assoc 76(9):2247–2251CrossRefGoogle Scholar
  12. 12.
    Ogura K (2006) Dihydropyrimidine dehydrogenase activity and its genetic aberrations. Jpn J Cancer Chemother 33(8):1041–1048Google Scholar
  13. 13.
    Ezzeldin H, Daiso R (2004) Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracl administration. Clin Conorectal Cancer 4(3):181–189CrossRefGoogle Scholar
  14. 14.
    Bakkeren JA, De Abreu RA, Sengers RC,et al (1984) Elevated urine, blood and cerebrospinal fluid levels of uracil and thymine in a child with dihydrothymine dehydrogenase deficiency. Clin Chim Acta 140(3):247–256CrossRefPubMedGoogle Scholar
  15. 15.
    Lee A, Ezzeldin H, Fourie J,et al (2004) Dihydropyrimidine dehydrogenase deficiency: impact of pharmacogenetics on 5-fluorouracil therapy. Clin Adv Hematol Oncol 2(8):527–532PubMedGoogle Scholar
  16. 16.
    Van Kuilenburg AB, Haasjes J, Richel DJ et al. (2000) Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res. 4705–4712Google Scholar
  17. 17.
    Schwab M, Zanger UM, Marx C et al (2008) Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 26(13):2131–2138CrossRefPubMedGoogle Scholar
  18. 18.
    Jhonson MR, Wang K, Daisio B (2011) Profound dihydropyrimidine dehydrogenase: its role in fluorouracil clinical toxicity and tumor resistance. Clin Cancer Res 17(19):3455–3468Google Scholar
  19. 19.
    Mercier C, Ciccolini J (2006) Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy. Clin Colorectal Cancer 6(4):288–296CrossRefPubMedGoogle Scholar
  20. 20.
    Ogura K, Ohnuma T, Minamide Y et al (2005) Dihydropyrimidine dehydrogenase activity in 150 healthy Japanese volunteers and identification of novel mutations. Clin Cancer Res 11(14):5104–5111CrossRefPubMedGoogle Scholar
  21. 21.
    Toshima T, Yamashita H, Ooishi M et al (2013) A case in which dihydropyrimidine dehydrogenase deficiency was strongly suspected during adjuvant chemotherapy with capecitabine for colon cancer. Jpn J Cancer Chemother 40(11):1549–1552Google Scholar
  22. 22.
    Sakaguchi H, Miyamoto H, Oono K (2014) A case of suspected dihydropyrimidine dehydrogenase (DPD) deficiency in which severe adverse events occurred during postoperative adjuvant chemotherapy with capecitabine. J Clin Surg 69(5):617–620Google Scholar
  23. 23.
    Yoshida Y, Ogura K, Hiratsuka A et al (2015) 5-fluorouracil chemotherapy for dihydropyrimidine dehydrogenase-deficient patients: potential of the dose-escalation method. Anticancer Res 35(9):4881–4887PubMedGoogle Scholar

Copyright information

© The Japan Society of Clinical Oncology 2018
corrected publication July 2018

Authors and Affiliations

  • Mai Tsutsui
    • 1
  • Seiichiro Yamamoto
    • 1
    Email author
  • Yusuke Yoshikawa
    • 1
  • Ryo Nakanishi
    • 1
  • Kiminori Takano
    • 1
  • Koji Osumi
    • 1
  • Tomotaka Akatsu
    • 1
  • Kimiyasu Yoneyama
    • 1
  • Motohito Nakagawa
    • 1
  • Toshio Kanai
    • 1
  1. 1.Department of SurgeryHiratsuka City HospitalHiratsukaJapan

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