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Medical Oncology

, 36:63 | Cite as

High total bilirubin level is a significant risk factor for severe neutropenia in patients receiving irinotecan-based chemotherapy

  • Yunami Yamada
  • Hironori FujiiEmail author
  • Koichi Ohata
  • Hiroko Kato-Hayashi
  • Daichi Watanabe
  • Takuma Ishihara
  • Shinya Uemura
  • Takuji Iwashita
  • Hisashi Imai
  • Nobuhisa Matsuhashi
  • Takao Takahashi
  • Tadashi Sugiyama
  • Masahito Shimizu
  • Kazuhiro Yoshida
  • Akio Suzuki
Original Paper
  • 80 Downloads

Abstract

Irinotecan is effective for the treatment of metastatic colorectal cancer (mCRC) and advanced pancreatic cancer (aPC). However, these treatments are often limited due to the incidence of severe neutropenia. We identified risk factors for severe neutropenia in patients with mCRC or aPC, receiving irinotecan-based chemotherapy regimens. The study selected 104 patients (mCRC: 53 and aPC: 51) who received irinotecan-based chemotherapy between January 2014 and May 2018 and who were included in the present study. The initial dose of irinotecan was 150 mg/m2 in all patients, and patients with a lower initial dose of irinotecan were excluded. Severe neutropenia (grade ≥ 3) occurred in 56 patients (53.8%). Multivariable Cox proportional hazards analysis indicated that modified FOLFIRINOX (mFOLFIRINOX) and serum total bilirubin (T-Bil) were significant risk factors for severe neutropenia. Moreover, with receiver-operating characteristic (ROC) curve analysis, the cutoff for T-Bil was found to be 0.7 mg/dL. Among patients treated with mFOLFIRINOX therapy, the incidence of severe neutropenia was significantly higher in patients with high level of T-Bil (> 0.7 mg/dL) than in those without it (93.8% vs 55.0%, P = 0.006). A chemotherapy regimen (modified FOLFIRINOX therapy) and T-Bil > 0.7 mg/dL were significant risk factors for severe neutropenia in patients receiving 150 mg/m2 irinotecan.

Keywords

Irinotecan Severe neutropenia High level of total bilirubin Modified FOLFIRINOX Metastatic colorectal cancer Advanced pancreatic cancer 

Notes

Funding

This study did not receive funding from any funding source.

Compliance with ethical standards

Conflict of interest

K Yoshida received grants, personal fees, and nonfinancial support from Chugai Pharmaceutical Co., Ltd. during the conduct of this study; grants and personal fees from Taiho Pharmaceutical Co., Ltd., Pfizer Inc., and Yakult Honsha Co., Ltd.; and grants from Bristol-Myers Squibb and Kyowa Hakko Kirin Co., Ltd. outside the submitted work. He also received honoraria from Taiho Pharmaceutical Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., and Yakult Honsha Co., Ltd., and had a consultant or advisory relationship with Taiho Pharmaceutical Co., Ltd. and La Roche, Ltd. T. Takahashi has received honoraria for lectures from Takeda Pharmaceutical Co., Ltd. The other authors have no conflicts of interest to disclose.

References

  1. 1.
    Shimada Y, Yoshino M, Wakui A, Nakao I, Futatsuki K, Sakata Y, et al. Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group. J Clin Oncol. 1993;11(5):909–13.CrossRefGoogle Scholar
  2. 2.
    Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355(9209):1041–7.CrossRefGoogle Scholar
  3. 3.
    Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229–37.CrossRefGoogle Scholar
  4. 4.
    Yamazaki K, Nagase M, Tamagawa H, Ueda S, Tamura T, Murata K, et al. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol. 2016;27(8):1539–46.CrossRefGoogle Scholar
  5. 5.
    Köhne CH, Hofheinz R, Mineur L, Letocha H, Greil R, Thaler J, et al. First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer. J Cancer Res Clin Oncol. 2012;138(1):65–72.CrossRefGoogle Scholar
  6. 6.
    Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.CrossRefGoogle Scholar
  7. 7.
    Yoshida K, Iwashita T, Uemura S, Maruta A, Okuno M, Ando N, et al. A multicenter prospective phase II study of first-line modified FOLFIRINOX for unresectable advanced pancreatic cancer. Oncotarget. 2017;8(67):111346–55.CrossRefGoogle Scholar
  8. 8.
    Ozaka M, Ishii H, Sato T, Ueno M, Ikeda M, Uesugi K, et al. A phase II study of modified FOLFIRINOX for chemotherapy-naïve patients with metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2018;81(6):1017–23.CrossRefGoogle Scholar
  9. 9.
    Kono A, Hara Y. Conversion of CPT-11 into SN-38 in human tissues. Gan To Kagaku Ryoho. 1991;18(12):2175–8.PubMedGoogle Scholar
  10. 10.
    Kawato Y, Aonuma M, Matsumoto K. Production of SN-38, a main metabolite of the camptothecin derivative CPT-11, and its species and tissue specificities. Gan To Kagaku Ryoho. 1991;6(6):899–907.Google Scholar
  11. 11.
    Minami H, Sai K, Saeki M, Saito Y, Ozawa S, Suzuki K, et al. Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28. Pharmacogenet Genomics. 2007;17(7):497–504.CrossRefGoogle Scholar
  12. 12.
    Sai K, Sawada J, Minami H. Irinotecan pharmacogenetics in Japanese cancer patients: roles of UGT1A1*6 and *28. Yakugaku Zasshi. 2008;128(4):575–84.CrossRefGoogle Scholar
  13. 13.
    Satoh T, Ura T, Yamada Y, Yamazaki K, Tsujinaka T, Munakata M, et al. Genotype-directed, dose-finding study of irinotecan in cancer patients with UGT1A1*28 and/or UGT1A1*6 polymorphisms. Cancer Sci. 2011;102(10):1868–73.CrossRefGoogle Scholar
  14. 14.
    Miyata Y, Touyama T, Kusumi T, Morita Y, Mizunuma N, Taniguchi F, et al. UDP-glucuronosyltransferase 1A1*6 and *28 polymorphisms as indicators of initial dose level of irinotecan to reduce risk of neutropenia in patients receiving FOLFIRI for colorectal cancer. Int J Clin Oncol. 2016;21(4):696–703.CrossRefGoogle Scholar
  15. 15.
    Fujii H, Yamada Y, Watanabe D, Matsuhashi N, Takahashi T, Yoshida K, et al. Dose adjustment of irinotecan based on UGT1A1 polymorphisms in patients with colorectal cancer. Cancer Chemother Pharmacol. 2019;83(1):123–9.CrossRefGoogle Scholar
  16. 16.
    Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004;22(8):1382–8.CrossRefGoogle Scholar
  17. 17.
    Ichikawa W, Uehara K, Minamimura K, Tanaka C, Takii Y, Miyauchi H, et al. An internally and externally validated nomogram for predicting the risk of irinotecan-induced severe neutropenia in advanced colorectal cancer patients. Br J Cancer. 2015;112(10):1709–16.CrossRefGoogle Scholar
  18. 18.
    Innocenti F, Kroetz DL, Schuetz E, Dolan ME, Ramírez J, Relling M, et al. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. J Clin Oncol. 2009;27(16):2604–14.CrossRefGoogle Scholar
  19. 19.
    Negoro Y, Yano R, Watanabe K, Kayano Y, Nakamura T, Masada M, et al. Principal factors of irinotecan-induced severe neutropenia other than UGT1A1 gene polymorphism. Iryo Yakugaku. 2014;40(8):454–62.Google Scholar
  20. 20.
    Makihara K, Azuma S, Kawato N, Ueno H, Nakata I. Pre-treatment serum total bilirubin level as an indicator of optimal CPT-11 dosage. Cancer Chemother Pharmacol. 2015;75(2):273–9.CrossRefGoogle Scholar
  21. 21.
    van der Bol J, Mathijssen RH, Loos WJ, Friberg LE, van Schaik RH, de Jonge MJ, et al. Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia. J Clin Oncol. 2007;25(19):2719–26.CrossRefGoogle Scholar
  22. 22.
    Hajian-Tilaki K. Receiver operating characteristic (ROC) curve analysis for medical diagnostic test evaluation. Casp J Intern Med. 2013;4(2):627–35.Google Scholar
  23. 23.
    Raijmakers MT, Jansen PL, Steegers EA, Peters WH. Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene. J Hepatol. 2000;33(3):348–51.CrossRefGoogle Scholar
  24. 24.
    Tanaka H, Saito K, Mino K, Izumi K, Harada M, Isobe H. Assessment of total bilirubin or SN-38/SN-38G ratio as a predictor of severe irinotecan toxicity. Gan To Kagaku Ryoho. 2009;36(9):1505–9.PubMedGoogle Scholar
  25. 25.
    Carlini LE, Meropol NJ, Bever J, Andria ML, Hill T, Gold P, et al. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Cancer Res. 2005;11(3):1226–36.Google Scholar
  26. 26.
    Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H, et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res. 2000;60(24):6921–6.PubMedGoogle Scholar
  27. 27.
    Kitagawa C, Ando M, Ando Y, Sekido Y, Wakai K, Imaizumi K, et al. Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics. 2005;15(1):35–41.CrossRefGoogle Scholar
  28. 28.
    Xiang X, Jada SR, Li HH, Fan L, Tham LS, Wong CI, et al. Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients. Pharmacogenet Genomics. 2006;16(9):683–91.CrossRefGoogle Scholar
  29. 29.
    Han JY, Lim HS, Shin ES, Yoo YK, Park YH, Lee JE, et al. Influence of the organic anion-transporting polypeptide 1B1 (OATP1B1) polymorphisms on irinotecan-pharmacokinetics and clinical outcome of patients with advanced non-small cell lung cancer. Lung Cancer. 2008;59(1):69–75.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yunami Yamada
    • 1
  • Hironori Fujii
    • 1
    Email author
  • Koichi Ohata
    • 1
  • Hiroko Kato-Hayashi
    • 1
  • Daichi Watanabe
    • 1
  • Takuma Ishihara
    • 2
  • Shinya Uemura
    • 3
  • Takuji Iwashita
    • 3
  • Hisashi Imai
    • 4
  • Nobuhisa Matsuhashi
    • 4
  • Takao Takahashi
    • 4
  • Tadashi Sugiyama
    • 5
  • Masahito Shimizu
    • 3
  • Kazuhiro Yoshida
    • 4
  • Akio Suzuki
    • 1
  1. 1.Department of PharmacyGifu University HospitalGifuJapan
  2. 2.Gifu University Hospital Innovative and Clinical Research Promotion Center Gifu UniversityGifuJapan
  3. 3.First Department of Internal MedicineGifu University HospitalGifuJapan
  4. 4.Department of Surgical OncologyGifu University Graduate School of MedicineGifuJapan
  5. 5.Laboratory of Pharmacy Practice and Social ScienceGifu Pharmaceutical UniversityGifuJapan

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