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Irinotecan-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses

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Abstract

Irinotecan chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. This systematic review of systematic reviews synthesises all meta-analyses on biomarkers for irinotecan toxicity across all genetic models for Asians, Caucasians, low dose, medium/high dose and regimens with and without fluorouracil. False-positive findings are a problem in pharmacogenetics, increasing the importance of systematic reviews. Four systematic reviews that investigated the effect of the polymorphisms UGT1A1*6 and/or*28 on neutropenia or diarrhoea toxicity were included. Both UGT1A1*6 and *28 were reliably demonstrated to be risk factors for irinotecan-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. UGT1A1*6 and *28 were also related to diarrhoea toxicity; however, at low doses of irinotecan there was evidence that UGT1A1*28 was not. In synthesising the best available evidence, this umbrella systematic review provides a novel reference for clinicians applying personalised medicine and identifies important research gaps.

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References

  1. Marsh S, Hoskins JM . Irinotecan pharmacogenomics. Pharmacogenomics 2010; 11: 1003–1010.

    Article  CAS  PubMed  Google Scholar 

  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: 1041–1047.

    Article  CAS  PubMed  Google Scholar 

  3. Ratain MJ . Irinotecan dosing: does the CPT in CPT-11 stand for "Can't Predict Toxicity"? J Clin Oncol 2002; 20: 7–8.

    Article  PubMed  Google Scholar 

  4. Nakayama G, Tanaka C, Uehara K, Mashita N, Hayashi N, Kobayashi D et al. The impact of dose/time modification in irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal cancer. Cancer Chemother Pharmacol 2014; 73: 847–855.

    Article  CAS  PubMed  Google Scholar 

  5. Shiozawa T, Tadokoro J, Fujiki T, Fujino K, Kakihata K, Masatani S et al. Risk factors for severe adverse effects and treatment-related deaths in Japanese patients treated with irinotecan-based chemotherapy: a postmarketing survey. Jpn J Clin Oncol 2013; 43: 483–491.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Palomaki GE, Bradley LA, Douglas MP, Kolor K, Dotson WD . Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review. Genet Med 2009; 11: 21–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ . Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 1994; 54: 3723–3725.

    CAS  PubMed  Google Scholar 

  8. Cote JF, Kirzin S, Kramar A, Mosnier JF, Diebold MD, Soubeyran I et al. UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan. Clin Cancer Res 2007; 13: 3269–3275.

    Article  CAS  PubMed  Google Scholar 

  9. Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR et al. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 1998; 101: 847–854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Marcuello E, Altes A, Menoyo A, Del Rio E, Gomez-Pardo M, Baiget M . UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer 2004; 91: 678–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rouits E, Charasson V, Petain A, Boisdron-Celle M, Delord JP, Fonck M et al. Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients. Br J Cancer 2008; 99: 1239–1245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Toffoli G, Cecchin E, Corona G, Russo A, Buonadonna A, D'Andrea M et al. The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 2006; 24: 3061–3068.

    Article  CAS  PubMed  Google Scholar 

  13. Campbell JM, Bateman E, Peters MD, Bowen JM, Keefe DM, Stephenson MD . Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Pharmacogenomics 2016; 17: 435–451.

    Article  CAS  PubMed  Google Scholar 

  14. Dias MM, McKinnon RA, Sorich MJ . Impact of the UGT1A1*28 allele on response to irinotecan: a systematic review and meta-analysis. Pharmacogenomics 2012; 13: 889–899.

    Article  CAS  PubMed  Google Scholar 

  15. Dias MM, Pignon JP, Karapetis CS, Boige V, Glimelius B, Kweekel DM et al. The effect of the UGT1A1*28 allele on survival after irinotecan-based chemotherapy: a collaborative meta-analysis. Pharmacogenomics J 2014; 14: 424–431.

    Article  CAS  PubMed  Google Scholar 

  16. Ratain MJ . From bedside to bench to bedside to clinical practice: an odyssey with irinotecan. Clin Cancer Res 2006; 12: 1658–1660.

    Article  PubMed  Google Scholar 

  17. Studies N-NWGoRiA, Chanock SJ, Manolio T, Boehnke M, Boerwinkle E, Hunter DJ et al. Replicating genotype-phenotype associations. Nature 2007; 447: 655–660.

    Article  Google Scholar 

  18. Liu JY, Qu K, Sferruzza AD, Bender RA . Distribution of the UGT1A1*28 polymorphism in Caucasian and Asian populations in the US: a genomic analysis of 138 healthy individuals. Anticancer Drugs 2007; 18: 693–696.

    Article  CAS  PubMed  Google Scholar 

  19. Aromataris E, Fernandez R, Godfrey CM, Holly C, Khalil H, Tungpunkom P . Summarizing systematic reviews: methodological development, conduct and reporting of an umbrella review approach. Int J Evid Based Healthc 2015; 13: 132–140.

    Article  PubMed  Google Scholar 

  20. Campbell JM, Peters MDJ . The association of chemotherapy-induced toxicities with germline polymorphisms: an umbrella review of systematic reviews and meta-analyses. JBI Database System Rev Implement Rep 2014; 12: 40–46.

    Article  Google Scholar 

  21. Institute. TJBMethodology for JBI Umbrella ReviewsJoanna Briggs Institute Reviewers' Manual: 2014. The Joanna Briggs Institute: Adelaide, 2014.

  22. Cheng L, Li M, Hu J, Ren W, Xie L, Sun ZP et al. UGT1A1*6 polymorphisms are correlated with irinotecan-induced toxicity: a system review and meta-analysis in Asians. Cancer Chemother Pharmacol 2014; 73: 551–560.

    Article  CAS  PubMed  Google Scholar 

  23. Han FF, Guo CL, Yu D, Zhu J, Gong LL, Li GR et al. Associations between UGT1A1*6 or UGT1A1*6/*28 polymorphisms and irinotecan-induced neutropenia in Asian cancer patients. Cancer Chemother Pharmacol 2014; 73: 779–788.

    Article  CAS  PubMed  Google Scholar 

  24. Hu ZY, Yu Q, Zhao YS . Dose-dependent association between UGT1A1*28 polymorphism and irinotecan-induced diarrhoea: a meta-analysis. Eur J Cancer 2010; 46: 1856–1865.

    Article  CAS  PubMed  Google Scholar 

  25. Li P, Chen Q, Wang YD, Ha MW . Effects of MTHFR genetic polymorphisms on toxicity and clinical response of irinotecan-based chemotherapy in patients with colorectal cancer. Genet Test Mol Biomarkers 2014; 18: 313–322.

    Article  CAS  PubMed  Google Scholar 

  26. Liu X, Cheng D, Kuang Q, Liu G, Xu W . Association of UGT1A1*28 polymorphisms with irinotecan-induced toxicities in colorectal cancer: a meta-analysis in Caucasians. Pharmacogenomics J 2014; 14: 120–129.

    Article  CAS  PubMed  Google Scholar 

  27. Barnett GC, Elliott RM, Alsner J, Andreassen CN, Abdelhay O, Burnet NG et al. Individual patient data meta-analysis shows no association between the SNP rs1800469 in TGFB and late radiotherapy toxicity. Radiother Oncol 2012; 105: 289–295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Diaz-Padilla I, Amir E, Marsh S, Liu G, MacKay H . Genetic polymorphisms as predictive and prognostic biomarkers in gynecological cancers: a systematic review. Gynecol Oncol 2012; 124: 354–365.

    Article  CAS  PubMed  Google Scholar 

  29. Frank M, Mittendorf T . Influence of pharmacogenomic profiling prior to pharmaceutical treatment in metastatic colorectal cancer on cost effectiveness: a systematic review. Pharmacoeconomics 2013; 31: 215–228.

    Article  PubMed  Google Scholar 

  30. Horgan AM, Yang B, Azad AK, Amir E, John T, Cescon DW et al. Pharmacogenetic and germline prognostic markers of lung cancer. J Thorac Oncol 2011; 6: 296–304.

    Article  PubMed  Google Scholar 

  31. Meggitt SJ, Anstey AV, Mohd Mustapa MF, Reynolds NJ, Wakelin S . British Association of Dermatologists' guidelines for the safe and effective prescribing of azathioprine 2011. Br J Dermatol 2011; 165: 711–734.

    Article  CAS  PubMed  Google Scholar 

  32. Palomaki GE, Bradley LA, Douglas MP, Kolor K, Dotson WD . Can UCT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review. Genet Med 2009; 11: 21–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Scartozzi M, Bittoni A, Pistelli M, Galizia E, Berardi R, Giampieri R et al. Toward molecularly selected chemotherapy for advanced gastric cancer: state of the art and future perspectives. Cancer Treat Rev 2009; 35: 451–462.

    Article  CAS  PubMed  Google Scholar 

  34. Spyridopoulou KP, Dimou NL, Hamodrakas SJ, Bagos PG . Methylene tetrahydrofolate reductase gene polymorphisms and their association with methotrexate toxicity: a meta-analysis. Pharmacogenet Genomics 2012; 22: 117–133.

    Article  CAS  PubMed  Google Scholar 

  35. Stingl JC, Bartels H, Viviani R, Lehmann ML, Brockmoller J . Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: a quantitative systematic review. Pharmacol Ther 2014; 141: 92–116.

    Article  CAS  PubMed  Google Scholar 

  36. Trammel M, Roederer M, Patel J, McLeod H . Does pharmacogenomics account for variability in control of acute chemotherapy-induced nausea and vomiting with 5-hydroxytryptamine type 3 receptor antagonists? Curr Oncol Rep 2013; 15: 276–285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wheeler HE, Gamazon ER, Stark AL, O'Donnell PH, Gorsic LK, Huang RS et al. Genome-wide meta-analysis identifies variants associated with platinating agent susceptibility across populations. Pharmacogenomics J 2013; 13: 35–43.

    Article  CAS  PubMed  Google Scholar 

  38. Zhao RR, Niu ZX . Association of UGT1A1*28 polymorphism with the efficacy and toxicity of irinotecan chemotherapy. Chinese J Cancer Prev Treat 2013; 20: 717–720.

    CAS  Google Scholar 

  39. Zhong DN, Wu JZ, Li GJ . Association between CYP2C8 (rs1934951) polymorphism and bisphosphonate-related osteonecrosis of the jaws in patients on bisphosphonate therapy: a meta-analysis. Acta Haematol 2013; 129: 90–95.

    Article  CAS  PubMed  Google Scholar 

  40. Innocenti F, Schilsky RL, Ramirez J, Janisch L, Undevia S, House LK et al. Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer. J Clin Oncol 2014; 32: 2328–2334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Phelps MA, Sparreboom A . Irinotecan pharmacogenetics: a finished puzzle? J Clin Oncol 2014; 32: 2287–2289.

    Article  CAS  PubMed  Google Scholar 

  42. 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: 1868–1873.

    Article  CAS  PubMed  Google Scholar 

  43. Amadio A, Burkes R, Bailie T, McLean M, Coleman B . Impact of granulocyte colony-stimulating factors in metastatic colorectal cancer patients. Curr Oncol 2014; 21: e52–e61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stein A, Voigt W, Jordan K . Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol 2010; 2: 51–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gold HT, Hall MJ, Blinder V, Schackman BR . Cost effectiveness of pharmacogenetic testing for uridine diphosphate glucuronosyltransferase 1A1 before irinotecan administration for metastatic colorectal cancer. Cancer 2009; 115: 3858–3867.

    Article  CAS  PubMed  Google Scholar 

  46. Martinez-Balibrea E, Abad A, Valladares M, Martinez-Villacampa M, Aranda E, Marcuello E et al. Pharmacogenetic analysis of TS and UGT1A polymorphisms predictive for response and toxicity in Spanish patients with advanced colorectal cancer treated with first-line irinotecan and 5-fluorouracil. J Clin Oncol 2009; 27: 4066.

    Google Scholar 

  47. Levesque E, Belanger A, Couture F, Jonker DJ, Villeneuve L, Harvey M et al. The contribution of UGT1A and ABCB1 to irinotecan-induced toxicity: a prospective pharmacogenetic study of patients with metastatic colorectal cancer. J Clin Oncol 2010; 28: 15s (suppl; abstr 3101).

    Article  Google Scholar 

  48. Lamas MJ, Duran G, Balboa E, Bernardez B, Candamio S, Vidal Y et al. The value of genetic polymorphisms to predict toxicity in metastatic colorectal patients with irinotecan-based regimens. Cancer Chemother Pharmacol 2012; 69: 1591–1599.

    Article  CAS  PubMed  Google Scholar 

  49. Inoue K, Sonobe M, Kawamura Y, Etoh T, Takagi M, Matsumura T et al. Polymorphisms of the UDP-glucuronosyl transferase 1A genes are associated with adverse events in cancer patients receiving irinotecan-based chemotherapy. Tohoku J Exp Med 2013; 229: 107–114.

    Article  CAS  PubMed  Google Scholar 

  50. Massacesi C, Terrazzino S, Marcucci F, Rocchi MB, Lippe P, Bisonni R et al. Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy. Cancer 2006; 106: 1007–1016.

    Article  CAS  PubMed  Google Scholar 

  51. Wang Y, Shen L, Xu N, Wang JW, Jiao SC, Liu ZY et al. UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil. World J Gastroenterol 2012; 18: 6635–6644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Innocenti F, Rosner GL, Qiao W, De Graan AM, Ratain MJ, Van Schaik RHN et al. An independent, external validation study of proposed genetic biomarkers of irinotecan toxicity and pharmacokinetics. J Clin Oncol 2011; 29: 15.

    Article  Google Scholar 

  53. Glimelius B, Garmo H, Berglund A, Fredriksson LA, Berglund M, Kohnke H et al. Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer. Pharmacogenomics J 2011; 11: 61–71.

    Article  CAS  PubMed  Google Scholar 

  54. Boige V, Mendiboure J, Pignon JP, Loriot MA, Castaing M, Barrois M et al. Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05. J Clin Oncol 2010; 28: 2556–2564.

    Article  CAS  PubMed  Google Scholar 

  55. Braun MS, Richman SD, Thompson L, Daly CL, Meade AM, Adlard JW et al. Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: The FOCUS trial. J Clin Oncol 2009; 27: 5519–5528.

    Article  CAS  PubMed  Google Scholar 

  56. Low SK, Chung S, Takahashi A, Zembutsu H, Mushiroda T, Kubo M et al. Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. Cancer Sci 2013; 104: 1074–1082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Katikireddi SV, Egan M, Petticrew M . How do systematic reviews incorporate risk of bias assessments into the synthesis of evidence? A methodological study. J Epidemiol Community Health 2015; 69: 189–195.

    Article  PubMed  Google Scholar 

  58. Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. Br Med J 2008; 336: 601–605.

    Article  Google Scholar 

  59. Balk EM, Bonis PAL, Moskowitz H, Schmid CH, Ioannidis JPA, Wang CC et al. Correlation of quality measures with estimates of treatment effect in meta-analyses of randomized controlled trials. JAMA 2002; 287: 2973–2982.

    Article  PubMed  Google Scholar 

  60. Aromataris E, Fernandez R, Godfrey C, Holly C, Khalil H, Tungpunkom P. Methodology for JBI Umbrella ReviewsThe Joanna Briggs Institute Reviewer's Manual 2014. The Joanna Briggs Institute: Australia, 2014.

    Google Scholar 

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Authors and Affiliations

  1. The Joanna Briggs Institute, Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia

    J M Campbell, M D Stephenson & M D J Peters

  2. School of Medicine, Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia

    E Bateman, D M Keefe & J M Bowen

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  1. J M Campbell
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  2. M D Stephenson
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Correspondence to J M Campbell.

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Campbell, J., Stephenson, M., Bateman, E. et al. Irinotecan-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Pharmacogenomics J 17, 21–28 (2017). https://doi.org/10.1038/tpj.2016.58

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