Skip to main content

Advertisement

Log in

Efficacy and safety of trifluridine/tipiracil in third-line and beyond for the treatment of patients with metastatic colorectal cancer in routine clinical practice: patterns of use and prognostic nomogram

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Introduction

Trifluridine/tipiracil combination has shown a benefit over placebo in the treatment of patients with chemorefractory metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of this combination in the real-life setting at eight Galician centers in Spain.

Patients and methods

This is a retrospective study of a cohort of patients with mCRC in treatment with trifluridine/tipiracil within usual clinical practice who have been previously treated or are not considered candidates for treatment with available therapies.

Results

A total of 160 mCRC patients were included. Our data showed that 11.9% of patients achieved disease control. Median progression-free survival was 2.75 months; at 5.66 months follow-up, median overall survival was 7.94 months. Asthenia and neutropenia (48.1% both) were the most frequent adverse events. Overall survival was lower in patients with ECOG 2, multiple metastatic sites, platelets count 350,000/µl, alkaline phosphatase > 500 IU/l, and carcinoembryonic antigen > 10 ng/ml.

Conclusion

The results of this study confirm the efficacy and safety of trifluridine/tipiracil in chemorefractory mCRC patients. However, patients in clinical practice differ from patients in clinical trials. Due to this, prognostic factors have special importance to offer the best therapeutic approach.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C et al. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012 v0. International Agency for Research on Cancer, Lyon, France. 2018. https://globocan.iarc.fr. Accessed 11 Dec 2018.

  2. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49:1374–403.

    Article  CAS  Google Scholar 

  3. Sociedad Español de Oncología Médica. 2017. Las cifras del cáncer en España. 2017. https://www.seom.org/seomcms/images/stories/recursos/Las_cifras_del_cancer_en_Esp_2017.pdf. Accessed 11 Dec 2018.

  4. Surveillance Epidemiology and End Results Program. 2018. SEER stat fact sheets: colon and rectum. https://seer.cancer.gov/statfacts/html/colorect.html. Accessed 17 Dec 2018.

  5. Gill S, Blackstock AW, Goldberg RM. Colorectal cancer. Mayo Clin Proc. 2007;82:114–29.

    Article  CAS  Google Scholar 

  6. American Cancer Society. Colorectal Cancer. 2018. Facts & figures 2011–2013. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/colorectal-cancer-facts-and-figures/colorectal-cancer-facts-and-figures-2011-2013.pdf. Accessed 11 Dec 2018.

  7. Cartwright TH. Treatment decisions after diagnosis of metastatic colorectal cancer. Clin Colorectal Cancer. 2012;11:155–66.

    Article  Google Scholar 

  8. Venook A. Critical evaluation of current treatments in metastatic colorectal cancer. Oncologist. 2005;10:250–61.

    Article  CAS  Google Scholar 

  9. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343:905–14.

    Article  CAS  Google Scholar 

  10. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18:2938–47.

    Article  Google Scholar 

  11. 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;355:1041–7.

    Article  CAS  Google Scholar 

  12. van Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25:iii1–9.

  13. Lopez A, Harada K, Vasilakopoulou M, Shanbhag N, Ajani JA. Targeting angiogenesis in colorectal carcinoma. Drugs. 2019;79:63–74.

    Article  CAS  Google Scholar 

  14. Grothey A, van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–12.

    Article  CAS  Google Scholar 

  15. Mayer RJ, van Cutsem E, Falcone A, Yoshino T, García-Carbonero R, Mizunuma N, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372:1909–19.

    Article  Google Scholar 

  16. Product information: regorafenib (Stivarga®). 2018. https://www.ema.europa.eu/documents/product-information/stivarga-epar-product-information_en.pdf. Accessed 17 Dec 2018.

  17. Product information: trifluridine and tipiracil (Lonsurf®). 2018. https://www.ema.europa.eu/documents/product-information/lonsurf-epar-product-information_en.pdf. Accessed 17 Dec 2018.

  18. Casado-Saenz E, Feliu J, Gómez-España MA, Sánchez-Gastaldo A, García-Carbonero R, SEOM. SEOM clinical guidelines for the treatment of advanced colorectal cancer 2013. Clin Transl Oncol. 2013;15:996–1003.

    Article  CAS  Google Scholar 

  19. Fukushima M, Suzuki N, Emura T, Yano S, Kazuno H, Tada Y, et al. Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2'-deoxyribonucleosides. Biochem Pharmacol. 2000;59:1227–366.

    Article  CAS  Google Scholar 

  20. Heidelberger C, Parsons DG, Remy DC. Syntheses of 5-Trifluoromethyluracil and 5-Trifluoromethyl-2'-Deoxyuridine. J Med Chem. 1964;7:1–5.

    Article  CAS  Google Scholar 

  21. Fujiwara Y, Oki T, Heidelberger C. Fluorinated pyrimidines. XXXVII. Effects of 5-trifluoromethyl-2'-deoxyuridine on the synthesis of deoxyribonucleic acid of mammalian cells in culture. Mol Pharmacol. 1970;6:273–80.

  22. Emura T, Murakami Y, Nakagawa F, Fukushima M, Kitazato K. A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells. Int J Mol Med. 2004;13:545–9.

    CAS  PubMed  Google Scholar 

  23. Emura T, Suzuki N, Yamaguchi M, Ohshimo H, Fukushima M. A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA. Int J Oncol. 2004;25:571–8.

    CAS  PubMed  Google Scholar 

  24. Hong DS, Abbruzzese JL, Bogaard K, Lassere Y, Fukushima M, Mita A, et al. Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors. Cancer. 2006;107:1383–90.

    Article  CAS  Google Scholar 

  25. Overman MJ, Varadhachary G, Kopetz S, Thomas MB, Fukushima M, Kuwata K, et al. Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors. Invest New Drugs. 2008;26:445–54.

    Article  CAS  Google Scholar 

  26. Overman MJ, Kopetz S, Varadhachary G, Fukushima M, Kuwata K, Mita A, et al. Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Invest. 2008;26:794–9.

    Article  CAS  Google Scholar 

  27. Green MC, Pusztai L, Theriault RL, Adinin RB, Hofweber M, Fukushima M et al. Phase I study to determine the safety of oral administration of TAS-102 on a twice daily (BID) schedule for five days a week (wk) followed by two days rest for two wks, every (Q) four wks in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol. 2006;24:Abstract 10576.

  28. Patel MR, Bendell JC, Mayer RJ, Benedetti FM, Rosen LS. A phase I dose-escalation study of TAS-102 in patients (pts) with refractory metastatic colorectal cancer (mCRC). J Clin Oncol. 2012;30:Abstract 3631.

  29. Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, et al. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012;13:993–1001.

    Article  CAS  Google Scholar 

  30. Yuki S, Komatsu Y, Yagisawa M, Tsuji Y, Harada K, Hatanaka K, et al. A retrospective cohort study evaluating the safety and efficacy of TAS-102 in patients with metastatic colorectal cancer [HGCSG1503]: updated analysis (Poster 604P). Ann Oncol. 2017;28:158–208.

    Google Scholar 

  31. Falcone A, Taieb J, Price TJ, Seitz JF, Wyrwicz L, Becquart M, et al. Quality of life at baseline in the international open-label early-access program of trifluridine/tipiracil in previously treated metastatic colorectal cancer (phase IIIb). J Clin Oncol. 2018;36:803.

    Article  Google Scholar 

  32. Borelli B, Zucchelli G, Rossini D, Cremolini C, Antoniotti C, Moretto R et al. A retrospective study of trifluridine/tipiracil in pretreated metastatic colorectal cancer patients in clinical practice. Colorectal Cancer. 2018;7:CRC01.

    Article  Google Scholar 

  33. Tanaka A, Sadahiro S, Suzuki T, Okada K, Saito G, Miyakita H. Retrospective study of regorafenib and trifluridine/tipiracil efficacy as a third-line or later chemotherapy regimen for refractory metastatic colorectal cancer. Oncol Lett. 2018;16:6589–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kimura M, Go M, Iwai M, Ito D, Asano H, Usami E, et al. Safety of an oral anticancer agent (trifluridine/tipiracil combination tablet) in patients with advanced and recurrent colorectal cancer. Pharmazie. 2016;71:218–21.

    CAS  PubMed  Google Scholar 

  35. Kimura M, Usami E, Iwai M, Teramachi H, Yoshimura T. Severe neutropenia: a prognosticator in patients with advanced/recurrent colorectal cancer under oral trifluridine-tipiracil (TAS-102) chemotherapy. Pharmazie. 2017;72:49–52.

    CAS  PubMed  Google Scholar 

  36. Hamauchi S, Yamazaki K, Masuishi T, Kito Y, Komori A, Tsushima T, et al. Neutropenia as a predictive factor in metastatic colorectal cancer treated with TAS-102. Clin Colorectal Cancer. 2017;16:51–7.

    Article  Google Scholar 

  37. Ohtsu A, Yoshino T, Falcone A, García-Carbonero R, Argiles G, Sobrero A, et al. Onset of neutropenia as an indicator of treatment response in the phase 3 RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo in patients with metastatic colorectal cancer. J Clin Oncol. 2017;34:775.

    Article  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Dr. Fernando Sánchez-Barbero and Springer Healthcare for his help in the preparation of the manuscript. Medical writing assistance was funded by Servier.

Funding

The study did not receive any grant from any funding agency in the public, commercial or not-for-profit sectors.

Author information

Authors and Affiliations

Authors

Contributions

Design: Ana Fernández Montes, Nieves Martínez Lago, Antía Cousillas Castiñeiras. Enrolled patients: all. Performed analyses: Ana Fernández Montes. Preparation of the manuscript: Francisca Vázquez, Ana Fernández Montes, and Nieves Martínez Lago.

Corresponding author

Correspondence to A. Fernandez Montes.

Ethics declarations

Conflicts of interest

AFM has been consultant for Sanofi, Celgene, Roche, Amgen, Servier, Bristol-Myers Squibb, and Lilly. PGV has been consultant for Amgen, and Lilly. The other authors declare that they have no competing interest.

Ethical approval

The study was approved by the Galician Regional Research Ethics Committee (Reference Number 2018/230) and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study. Eligible patients should give their consent to participate in the study and to allow their medical records to be reviewed after having been informed and having had sufficient time to decide on their inclusion in the study. Each center's ethics committee was asked to waive the signing of informed consent for those patients who had died at the start of the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fernandez Montes, A., Vazquez Rivera, F., Martinez Lago, N. et al. Efficacy and safety of trifluridine/tipiracil in third-line and beyond for the treatment of patients with metastatic colorectal cancer in routine clinical practice: patterns of use and prognostic nomogram. Clin Transl Oncol 22, 351–359 (2020). https://doi.org/10.1007/s12094-019-02130-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-019-02130-x

Keywords

Navigation