Skip to main content

Advertisement

SpringerLink
Log in

Biweekly TAS-102 and bevacizumab as third-line chemotherapy for advanced or recurrent colorectal cancer: a phase II, multicenter, clinical trial (TAS-CC4 study)

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

TAS-102 improves overall survival (OS) of patients with refractory colorectal cancer (CRC), resulting in median progression-free survival (PFS) of 2.0 months (RECOURSE trial). Subsequently, a combination of TAS-102 and bevacizumab was shown to extend median PFS by 3.7 months. However, approximately half of these patients experience grade 3/4 neutropenia. In this study, we evaluated whether biweekly TAS-102 and bevacizumab therapy has efficacy equal to that of conventional TAS-102 and bevacizumab therapy and whether it reduces adverse hematological effects.

Methods

This phase II, investigator-initiated, open-label, single-arm, multicenter study was conducted in Japan. Eligible patients had previously received first- and second-line chemotherapy for metastatic CRC. TAS-102 (35 mg/m2) was given twice daily on days 1–5 and days 15–19 in a 4-week cycle, and bevacizumab (5 mg/kg) was administered by intravenous infusion for 30 min every 2 weeks. The primary end point was progression-free survival (PFS), and secondary end points were time-to-treatment failure (TTF), response rate (RR), OS, and safety.

Results

44 patients with metastatic colorectal cancer were enrolled in this study. Median PFS was 4.6 months (95% confidence interval [95% CI] 3.6–5.3) and median OS was 10.5 months (95% CI 9.6–11.4). A partial response was observed in 2 patients (4.5%, 95% CI 0.4–16.0%). The most common adverse event above grade 3 was neutropenia (7 patients, 15.9%, 95% CI 7.6–29.7%).

Conclusions

Biweekly TAS-102 and bevacizumab therapy as third-line chemotherapy appears as effective as conventional TAS-102 and bevacizumab therapy, and this approach reduces adverse hematological effects.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    Article  PubMed  Google Scholar 

  2. Fakih MG (2015) Metastatic colorectal cancer: current state and future directions. J Clin Oncol Off J Am Soc Clin Oncol 33(16):1809–1824. https://doi.org/10.1200/jco.2014.59.7633

    Article  CAS  Google Scholar 

  3. Van Cutsem E, Cervantes A, Adam R et al (2016) ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol Off J Eur Soc Med Oncol ESMO 27(8):1386–1422. https://doi.org/10.1093/annonc/mdw235

    Article  Google Scholar 

  4. Grothey A, Van Cutsem E, Sobrero A et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312. https://doi.org/10.1016/s0140-6736(12)61900-x

    Article  CAS  PubMed  Google Scholar 

  5. Emura T, Murakami Y, Nakagawa F et al (2004) A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells. Int J Mol Med 13(4):545–549

    CAS  PubMed  Google Scholar 

  6. Mayer RJ, Van Cutsem E, Falcone A et al (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372(20):1909–1919. https://doi.org/10.1056/NEJMoa1414325

    Article  PubMed  Google Scholar 

  7. Kuboki Y, Nishina T, Shinozaki E et al (2017) TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study. Lancet Oncol 18(9):1172–1181. https://doi.org/10.1016/S1470-2045(17)30425-4

    Article  CAS  PubMed  Google Scholar 

  8. Yoshida Y, Yamada T, Kamiyama H et al (2021) Combination of TAS-102 and bevacizumab as third-line treatment for metastatic colorectal cancer: TAS-CC3 study. Int J Clin Oncol 26(1):111–117. https://doi.org/10.1007/s10147-020-01794-8

    Article  CAS  PubMed  Google Scholar 

  9. Yoshida Y, Sakamoto R, Kajitani R et al (2018) Biweekly administration of TAS-102 for neutropenia prevention in patients with colorectal cancer. Anticancer Res 38(7):4367–4373. https://doi.org/10.21873/anticanres.12738

    Article  CAS  PubMed  Google Scholar 

  10. Yoshida Y, Yamada T, Matsuoka H et al (2019) A trial protocol of biweekly TAS-102 and bevacizumab as third-line chemotherapy for advanced/recurrent colorectal cancer: a phase II multicenter clinical trial (the TAS-CC4 study). J Anus Rectum Colon 3(3):136–141. https://doi.org/10.23922/jarc.2018-043

    Article  PubMed  PubMed Central  Google Scholar 

  11. Satake H, Kato T, Oba K et al (2020) Phase Ib/II study of biweekly TAS-102 in combination with bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (BiTS study). Oncologist 25(12):e1855–e1863. https://doi.org/10.1634/theoncologist.2020-0643

    Article  CAS  PubMed  Google Scholar 

  12. Pfeiffer P, Yilmaz M, Möller S et al (2020) TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol 21(3):412–420. https://doi.org/10.1016/s1470-2045(19)30827-7

    Article  CAS  PubMed  Google Scholar 

  13. Kotani D, Kuboki Y, Horasawa S et al (2019) Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer. BMC Cancer 19(1):1253–1253. https://doi.org/10.1186/s12885-019-6475-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fujii H, Matsuhashi N, Kitahora M et al (2019) Bevacizumab in combination with TAS-102 improves clinical outcomes in patients with refractory metastatic colorectal cancer: a retrospective study. Oncologist Theoncologist. https://doi.org/10.1634/theoncologist.2019-0541

    Article  Google Scholar 

  15. Matsuhashi N, Takahashi T, Fujii H et al (2019) Combination chemotherapy with TAS-102 plus bevacizumab in salvage-line treatment of metastatic colorectal cancer: a single-center, retrospective study examining the prognostic value of the modified Glasgow Prognostic Score in salvage-line therapy of metastatic colorectal cancer. Mol Clin Oncol 11(4):390–396. https://doi.org/10.3892/mco.2019.1899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Xu J, Kim TW, Shen L et al (2017) Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study. J Clin Oncol Off J Am Soc Clin Oncol. https://doi.org/10.1200/jco.2017.74.3245

    Article  Google Scholar 

  17. Grothey A, Sugrue MM, Purdie DM et al (2008) Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol Off J Am Soc Clin Oncol 26(33):5326–5334. https://doi.org/10.1200/jco.2008.16.3212

    Article  CAS  Google Scholar 

  18. Bennouna J, Sastre J, Arnold D et al (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 14(1):29–37. https://doi.org/10.1016/s1470-2045(12)70477-1

    Article  CAS  PubMed  Google Scholar 

  19. Grothey A, Flick ED, Cohn AL et al (2014) Bevacizumab exposure beyond first disease progression in patients with metastatic colorectal cancer: analyses of the ARIES observational cohort study. Pharmacoepidemiol Drug Saf 23(7):726–734. https://doi.org/10.1002/pds.3633

    Article  CAS  PubMed  Google Scholar 

  20. Takahashi T, Yamazaki K, Oki E et al (2021) Phase II study of trifluridine/tipiracil plus bevacizumab by RAS mutation status in patients with metastatic colorectal cancer refractory to standard therapies: JFMC51-1702-C7. ESMO Open 6(2):1000093

    Article  Google Scholar 

  21. Moriwaki T, Fukuoka S, Taniguchi H et al (2018) Propensity score analysis of regorafenib versus trifluridine/tipiracil in patients with metastatic colorectal cancer refractory to standard chemotherapy (REGOTAS): a Japanese Society for Cancer of the colon and rectum multicenter observational study. Oncologist 23(1):7–15. https://doi.org/10.1634/theoncologist.2017-0275

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all patients and co-workers for their participation and cooperation in the TAS-CC4 study.

Funding

The authors received no financial support for the research, authorship, or publication of this article.

Author information

Author notes

  1. Hiroshi Matsuoka and Takeshi Yamada contributed equally to this work.

Authors and Affiliations

  1. Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan

    Hiroshi Matsuoka & Takeshi Yamada

  2. Department of Surgery, Fujita Health University, Nagoya, Aichi, Japan

    Takeshi Yamada, Ryo Ohta, Akihisa Matsuda, Hiromichi Sonoda & Hiroshi Yoshida

  3. Department of Gastroenterological Surgery, Fukuoka University Faculty of Medicine, Fukuoka, Japan

    Yoichiro Yoshida & Suguru Hasegawa

  4. Third Department of Internal Medicine, University of Occupational and Environmental Health, Fukuoka, Japan

    Tatsuyuki Watanabe

  5. Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan

    Makoto Takahashi & Kazuhiro Sakamoto

  6. Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba, Japan

    Chihiro Kosugi & Keiji Koda

  7. Department of Gastroenterological Surgery, Iwata City Hospital, Shizuoka, Japan

    Atsuko Fukazawa

  8. Department of Chemotherapy, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Chiba, Japan

    Hidekazu Kuramochi

  9. Deparment of Hygiene and Public Health, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan

    Toshiaki Otsuka

  10. First Department of Surgery, University of Occupational and Environmental Health, Fukuoka, Japan

    Keiji Hirata

Authors
  1. Hiroshi Matsuoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeshi Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryo Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoichiro Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tatsuyuki Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Makoto Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chihiro Kosugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Atsuko Fukazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hidekazu Kuramochi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Akihisa Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiromichi Sonoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hiroshi Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Suguru Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kazuhiro Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Toshiaki Otsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Keiji Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Keiji Koda
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the TAS CC4 Study Group

Contributions

Conception and design: YY, TY, KS, and KK. Acquisition of data: RO, YY, HM, and HK. Analysis and interpretation of data: RO, TY, and YY. Writing, review, and/or revision of the manuscript: TY, RO, and HM. Administrative, technical, or material support: TY and AM. Study supervision: KS, HY, KH, and KK. Other (recruitment of study subjects and oversight of study participants): HM, YY, TY, MT, CK, AF, HK, HS, RO, and AM.

Corresponding author

Correspondence to Takeshi Yamada.

Ethics declarations

Conflict of interest

Suguru Hasegawa has received research funding from Taiho Pharmaceutical Industry and Takeda Pharmaceutical. Hidekazu Kuramochi has received scholarship donations from Taiho Pharmaceutical Industry and Chugai Pharmaceutical. The other authors declare that they have no competing interests.

Additional information

Publisher's Note

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

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matsuoka, H., Yamada, T., Ohta, R. et al. Biweekly TAS-102 and bevacizumab as third-line chemotherapy for advanced or recurrent colorectal cancer: a phase II, multicenter, clinical trial (TAS-CC4 study). Int J Clin Oncol 27, 1859–1866 (2022). https://doi.org/10.1007/s10147-022-02243-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-022-02243-4

Keywords

Search

Navigation