Advertisement

International Journal of Clinical Oncology

, Volume 24, Issue 2, pp 222–230 | Cite as

Coadministration of cytotoxic chemotherapeutic agents with irinotecan is a risk factor for irinotecan-induced cholinergic syndrome in Japanese patients with cancer

  • Ayako Tsuboya
  • Ken-ichi FujitaEmail author
  • Yutaro Kubota
  • Hiroo Ishida
  • Iori Taki-Takemoto
  • Daisuke Kamei
  • Shinichi Iwai
  • Yasutsuna Sasaki
Original Article

Abstract

Background

Cholinergic syndrome is an acute adverse event frequently observed in patients administered irinotecan, and can sometimes negatively affect their quality of life. In some manifestations of the syndrome such as bradycardia, careful monitoring of patients is advised. In this study, we retrospectively investigated the risk factors associated with irinotecan-induced cholinergic syndrome in Japanese patients with cancer.

Methods

Patients who received irinotecan-based chemotherapy between April 2014 and June 2018 were examined. Patient backgrounds and clinical data during the first cycle of an irinotecan-containing regimen, including cholinergic syndrome manifestation within 24 h after the start of treatment, were collected from medical records. Univariate and multivariate analyses were performed to assess the risk of irinotecan-induced cholinergic syndrome.

Results

Among 179 patients administered an irinotecan-containing regimen, 51 experienced cholinergic syndrome after the initiation of treatment. The most common symptom was sweating followed by diarrhea, abdominal pain, lacrimation, and nasal discharge. 42 patients developed symptoms of cholinergic syndrome during their first treatment with irinotecan. Multivariate analyses revealed that the incidences of cholinergic syndrome in patients administered 2 or 3 chemotherapeutic agents; i.e., irinotecan plus 1 or 2 other cytotoxic anticancer drug(s), were significantly higher than that in patients administered irinotecan alone [odds ratio (OR) 4.35, 95% confidence interval (CI) 1.5–12, p = 0.0053 and OR 4.50, 95% CI 1.5–14, p = 0.0093, respectively]. The addition of a molecularly targeted drug did not affect the incidence of cholinergic syndrome.

Conclusion

The incidence rate of irinotecan-induced cholinergic syndrome increased concomitantly with the addition of cytotoxic chemotherapeutic agents administered.

Keywords

Adverse events Chemotherapeutic agents Cholinergic syndrome Irinotecan Risk factors 

Notes

Acknowledgements

The authors would like to thank all the staff members of Showa University Hospital who cooperated in this study.

Compliance with ethical standards

Conflict of interest

All authors have no conflict of interest to declare in association with this study.

References

  1. 1.
    Fujita K, Kubota Y, Ishida H et al (2015) Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer. World J Gastroenterol 21(43):12234–12248.  https://doi.org/10.3748/wjg.v21.i43.12234 CrossRefGoogle Scholar
  2. 2.
    Mathijssen RH, van Alphen RJ, Verweij J et al (2001) Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 7(8):2182–2194Google Scholar
  3. 3.
    Ando Y, Saka H, Ando M et al (2000) Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 60(24):6921–6926Google Scholar
  4. 4.
    Innocenti F, Undevia SD, Iyer L et al (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22(8):1382–1388.  https://doi.org/10.1200/JCO.2004.07.173 CrossRefGoogle Scholar
  5. 5.
    Araki K, Fujita K, Ando Y et al (2006) Pharmacogenetic impact of polymorphisms in the coding region of the UGT1A1 gene on SN-38 glucuronidation in Japanese patients with cancer. Cancer Sci 97(11):1255–1259.  https://doi.org/10.1111/j.1349-7006.2006.00321.x CrossRefGoogle Scholar
  6. 6.
    Minami H, Sai K, Saeki M et al (2007) Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28. Pharmacogenet Genom 17(7):497–504.  https://doi.org/10.1097/FPC.0b013e328014341f CrossRefGoogle Scholar
  7. 7.
    Gandia D, Abigerges D, Armand JP et al (1993) CPT-11-induced cholinergic effects in cancer patients. J Clin Oncol 11(1):196–197.  https://doi.org/10.1200/JCO.1993.11.1.196 CrossRefGoogle Scholar
  8. 8.
    Miya T, Fujikawa R, Fukushima J et al (1998) Bradycardia induced by irinotecan: a case report. Jpn J Clin Oncol 28(11):709–711CrossRefGoogle Scholar
  9. 9.
    Fujii H, Hirata T, Mura T et al (2018) Relation between irinotecan-induced cholinergic syndrome and prognosis of colorectal cancer patients. J Clin Oncol 36(4_suppl):859.  https://doi.org/10.1200/JCO.2018.36.4_suppl.859 CrossRefGoogle Scholar
  10. 10.
    Kanbayashi Y, Ishikawa T, Kanazawa M et al (2018) Predictive factors for the development of irinotecan-related cholinergic syndrome using ordered logistic regression analysis. Med Oncol 35(6):82.  https://doi.org/10.1007/s12032-018-1142-3 CrossRefGoogle Scholar
  11. 11.
    Pitot HC, Goldberg RM, Reid JM et al (2000) Phase I dose-finding and pharmacokinetic trial of irinotecan hydrochloride (CPT-11) using a once-every-three-week dosing schedule for patients with advanced solid tumor malignancy. Clin Cancer Res 6(6):2236–2244Google Scholar
  12. 12.
    Blandizzi C, De Paolis B, Colucci R et al (2001) Acetylcholinesterase blockade does not account for the adverse cardiovascular effects of the antitumor drug irinotecan: a preclinical study. Toxicol Appl Pharmacol 177(2):149–156.  https://doi.org/10.1006/taap.2001.9293 CrossRefGoogle Scholar
  13. 13.
    Tsavaris N, Ziras N, Kosmas C et al (2003) Two different schedules of irinotecan (CPT-11) in patients with advanced colorectal carcinoma relapsing after a 5-fluorouracil and leucovorin combination. A randomized study. Cancer Chemother Pharmacol 52(6):514–519.  https://doi.org/10.1007/s00280-003-0659-z CrossRefGoogle Scholar
  14. 14.
    Schoemaker NE, Kuppens IE, Moiseyenko V et al (2004) A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer. Br J Cancer 91(8):1434–1441.  https://doi.org/10.1038/sj.bjc.6602172 CrossRefGoogle Scholar
  15. 15.
    Tournigand C, André T, Achille E et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22(2):229–237.  https://doi.org/10.1200/JCO.2004.05.113 CrossRefGoogle Scholar
  16. 16.
    Noda K, Nishiwaki Y, Kawahara M et al (2002) Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346(2):85–91.  https://doi.org/10.1056/NEJMoa003034 CrossRefGoogle Scholar
  17. 17.
    Yoshida K, Iwashita T, Uemura S et al (2017) A multicenter prospective phase II study of first-line modified FOLFIRINOX for unresectable advanced pancreatic cancer. Oncotarget 8(67):111346–111355.  https://doi.org/10.18632/oncotarget.22795 CrossRefGoogle Scholar
  18. 18.
    Sunakawa Y, Fujita K, Ichikawa W et al (2012) A phase I study of infusional 5-fluorouracil, leucovorin, oxaliplatin and irinotecan in Japanese patients with advanced colorectal cancer who harbor UGT1A1*1/*1,*1/*6 or *1/*28. Oncology 82(4):242–248.  https://doi.org/10.1159/000337225 CrossRefGoogle Scholar
  19. 19.
    Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–345.  https://doi.org/10.1056/NEJMoa033025 CrossRefGoogle Scholar
  20. 20.
    Peeters M, Price TJ, Cervantes A et al (2010) Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28(31):4706–4713.  https://doi.org/10.1200/JCO.2009.27.6055 CrossRefGoogle Scholar
  21. 21.
    Yamazaki K, Nagase M, Tamagawa H et al (2016) 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 27(8):1539–1546.  https://doi.org/10.1093/annonc/mdw206 CrossRefGoogle Scholar
  22. 22.
    Van Cutsem E, Tabernero J, Lakomy R et al (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30(28):3499–3506.  https://doi.org/10.1200/JCO.2012.42.8201 CrossRefGoogle Scholar
  23. 23.
    Tabernero J, Yoshino T, Cohn AL et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16(5):499–508.  https://doi.org/10.1016/S1470-2045(15)70127-0 CrossRefGoogle Scholar
  24. 24.
    Matsumoto K, Katsumata N, Yamanaka Y et al (2006) The safety and efficacy of the weekly dosing of irinotecan for platinum- and taxanes-resistant epithelial ovarian cancer. Gynecol Oncol 100(2):412–416.  https://doi.org/10.1016/j.ygyno.2005.10.013 CrossRefGoogle Scholar
  25. 25.
    Hironaka S, Ueda S, Yasui H et al (2013) Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol 31(35):4438–4444.  https://doi.org/10.1200/JCO.2012.48.5805 CrossRefGoogle Scholar
  26. 26.
    Shimada Y, Yoshino M, Wakui A et al (1993) Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group. J Clin Oncol 11(5):909–913.  https://doi.org/10.1200/JCO.1993.11.5.909 CrossRefGoogle Scholar
  27. 27.
    Muro K, Boku N, Shimada Y et al (2010) Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol 11(9):853–860.  https://doi.org/10.1016/S1470-2045(10)70181-9 CrossRefGoogle Scholar
  28. 28.
    Valencak J, Raderer M, Kornek GV et al (1998) Irinotecan-related cholinergic syndrome induced by coadministration of oxaliplatin. J Natl Cancer Inst 90(2):160CrossRefGoogle Scholar
  29. 29.
    Cheng C, Lau JE, Earl MA (2015) Use of atropine-diphenoxylate compared with hyoscyamine to decrease rates of irinotecan-related cholinergic syndrome. J Commun Support Oncol 13(1):3–7.  https://doi.org/10.12788/jcso.0099 CrossRefGoogle Scholar
  30. 30.
    Marsh ReW, Talamonti MS, Katz MH et al (2015) Pancreatic cancer and FOLFIRINOX: a new era and new questions. Cancer Med 4(6):853–863.  https://doi.org/10.1002/cam4.433 CrossRefGoogle Scholar
  31. 31.
    Lambert A, Gavoille C, Conroy T (2017) Current status on the place of FOLFIRINOX in metastatic pancreatic cancer and future directions. Therap Adv Gastroenterol 10(8):631–645.  https://doi.org/10.1177/1756283X17713879 CrossRefGoogle Scholar
  32. 32.
    Fujita K, Sasaki Y (2014) Optimization of cancer chemotherapy on the basis of pharmacokinetics and pharmacodynamics: from patients enrolled in clinical trials to those in the ‘real world’. Drug Metab Pharmacokinet 29(1):20–28CrossRefGoogle Scholar
  33. 33.
    Blandizzi C, Danesi R, De Paolis B et al (2002) Cholinergic toxic syndrome by the anticancer drug irinotecan: acetylcholinesterase does not play a major role. Clin Pharmacol Ther 71(4):263–271.  https://doi.org/10.1067/mcp.2002.121909 CrossRefGoogle Scholar
  34. 34.
    Akiyama Y, Fujita K, Nagashima F et al (2008) Genetic testing for UGT1A1*28 and *6 in Japanese patients who receive irinotecan chemotherapy. Ann Oncol 19(12):2089–2090.  https://doi.org/10.1093/annonc/mdn645 CrossRefGoogle Scholar
  35. 35.
    Beutler E, Gelbart T, Demina A (1998) Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci USA 95(14):8170–8174CrossRefGoogle Scholar
  36. 36.
    de Jong FA, van der Bol JM, Mathijssen RH et al (2008) Renal function as a predictor of irinotecan-induced neutropenia. Clin Pharmacol Ther 84(2):254–262.  https://doi.org/10.1038/sj.clpt.6100513 CrossRefGoogle Scholar
  37. 37.
    van der Bol JM, Mathijssen RH, Loos WJ et al (2007) Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia. J Clin Oncol 25(19):2719–2726.  https://doi.org/10.1200/JCO.2006.09.6115 CrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2018

Authors and Affiliations

  • Ayako Tsuboya
    • 1
    • 2
  • Ken-ichi Fujita
    • 3
    Email author
  • Yutaro Kubota
    • 4
  • Hiroo Ishida
    • 4
  • Iori Taki-Takemoto
    • 1
  • Daisuke Kamei
    • 1
  • Shinichi Iwai
    • 1
  • Yasutsuna Sasaki
    • 3
    • 4
  1. 1.Division of Community Healthcare and Pharmacy, Department of Healthcare and Regulatory SciencesShowa University School of PharmacyTokyoJapan
  2. 2.Department of PharmacyKawasaki Municipal Tama HospitalKawasakiJapan
  3. 3.Institute of Molecular OncologyShowa UniversityTokyoJapan
  4. 4.Division of Medical Oncology, Department of medicineShowa University School of MedicineTokyoJapan

Personalised recommendations