Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 1, pp 115–122 | Cite as

Regorafenib or rechallenge chemotherapy: which is more effective in the third-line treatment of metastatic colorectal cancer?

  • Osman KöstekEmail author
  • Muhammet Bekir Hacıoğlu
  • Abdullah Sakin
  • Tarık Demir
  • Murat Sarı
  • Ozlem Ozkul
  • Murat Araz
  • Aysun Fatma Doğan
  • Nazım Can Demircan
  • Sernaz Uzunoğlu
  • İrfan Çiçin
  • Bülent Erdoğan
Original Article



To assess the efficacy and safety of regorafenib versus rechallenge chemotherapy in previously treated mCRC patients in third-line setting.

Materials and methods

The data of 104 patients diagnosed with mCRC enrolled from 2010 to 2017 in six oncology centers were analyzed. Tumor treatment options were obtained from follow-up and treatment files. Rechallenge chemotherapy was identified as the re-use of the regimen which was previously administered to patients in one of the therapy lines and obtained disease control, these were the patients whose disease did not progress within 3 months.


A total of 104 patients had received previously two lines of chemotherapy regimens for mCRC. Of these, 73 patients with mCRC who received regorafenib and 31 those who received rechallenge chemotherapy in third-line therapy were analyzed. Overall survival was better with rechallenge than it was with regorafenib (HR 0.29 95% CI 0.16–0.54, p < 0.001). Median OS was 12.0 months (95% CI 8.1–15.9) in rechallenge versus 6.6 months (95% CI 6.0–7.3) in regorafenib group (p < 0.001). Progression-free survival in the rechallenge group showed a higher median value of 9.16 months (95% CI 7.15–11.18) versus with that recorded in the regorafenib group of 3.41 months (95% CI 3.01–3.82), in favor of rechallenge chemotherapy. The most common adverse events of regorafenib was liver function test abnormality and hand–foot syndrome. Although grade 3 or 4 adverse events were similar, non-hematologic toxicities were more common than those of rechallenge.


Rechallenge is still a valuable option against regorafenib in patients who achieved disease control in one of the first two lines of therapy. Even though mCRC patients treated with regorafenib benefited clinically from this treatment, we revealed that chemotherapy rechallenge compared to regorafenib was more effective in the third-line treatment for mCRC patients.


Rechallenge Regorafenib Metastatic colorectal cancer Overall survival Progression-free survival Third-line 




Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Shah MA, Renfro LA, Allegra CJ et al (2016) Impact of patient factors on recurrence risk and time dependency of oxaliplatin benefit in patients with colon cancer: analysis from modern-era adjuvant studies in the Adjuvant Colon Cancer End Points (ACCENT) database. J Clin Oncol 34:843–853CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Heinemann V, von Weikersthal LF, Decker T et al (2014) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15:1065–1075CrossRefPubMedGoogle Scholar
  3. 3.
    Venook AP, Niedzwiecki D, Lenz HJ et al (2017) Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA 317:2392–2401CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Giantonio BJ, Catalano PJ, Meropol NJ et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 5:1539–1544CrossRefGoogle Scholar
  5. 5.
    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):303–312CrossRefPubMedGoogle Scholar
  6. 6.
    Li J, Qin S, Xu R et al (2015) Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 16:619–629CrossRefPubMedGoogle Scholar
  7. 7.
    Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Arnold D, Prager GW, Quintela A et al (2018) Beyond second-line therapy in patients with metastatic colorectal cancer: a systematic review. Ann Oncol 29(4):835–856CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Patel AK, Duh MS, Barghout V et al (2018) Real-world treatment patterns among patients with colorectal cancer treated with trifluridine/tipiracil and regorafenib. Clin Colorectal Cancer 17(3):531–539CrossRefGoogle Scholar
  10. 10.
    Matsuda C, Honda M, Tanaka C et al (2016) Multicenter randomized phase II clinical trial of oxaliplatin reintroduction as a third- or later-line therapy for metastatic colorectal cancer-biweekly versus standard triweekly XELOX (The ORION Study). Int J Clin Oncol 21(3):566–572CrossRefPubMedGoogle Scholar
  11. 11.
    Hartmann JT, Oechsle K, Jager E et al (2004) Prospective multicenter phase II study of irinotecan as third-line therapy in metastatic colorectal cancer and progression after bolus and infusional 5-fluorouracil. Anticancer Drugs 15(5):473–477CrossRefPubMedGoogle Scholar
  12. 12.
    Suenaga M, Mizunuma N, Matsusaka S et al (2015) Phase II study of reintroduction of oxaliplatin for advanced colorectal cancer in patients previously treated with oxaliplatin and irinotecan: rE-OPEN study. Drug Des Devel Ther 9:3099–3108CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Gebbia V, Del Prete S, Borsellino N et al (2006) Efficacy and safety of cetuximab/irinotecan in chemotherapy-refractory metastatic colorectal adenocarcinomas: a clinical practice setting, multicenter experience. Clin Colorectal Cancer 5(6):422–428CrossRefPubMedGoogle Scholar
  14. 14.
    Lievre A, Samalin E, Mitry E et al (2009) Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study. BMC Cancer 9:347CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chaix M, Vincent J, Lorgis V, Ghiringhelli F (2014) FOLFIRINOX bevacizumab is a promising therapy for chemorefractory metastatic colorectal cancer. Oncology 87(3):148–158CrossRefPubMedGoogle Scholar
  16. 16.
    Larsen FO, Boisen MK, Fromm AL, Jensen BV (2012) Capecitabine and bevacizumab in heavily pre-treated patients with advanced colorectal cancer. Acta Oncol 51(2):231–233CrossRefPubMedGoogle Scholar
  17. 17.
    Jime´nez-Fonseca P, Solis MP, Garrido M et al (2015) Gemcitabine plus capecitabine (Gem-Cape) biweekly in chemorefractory metastatic colorectal cancer. Clin Transl Oncol 17(5):384–392CrossRefGoogle Scholar
  18. 18.
    Yoshida M, Takagane A, Miyake Y et al (2016) A phase II study of third-line combination chemotherapy with bevacizumab plus S-1 for metastatic colorectal cancer with mutated KRAS (SAVIOR study). Oncology 91(1):24–30CrossRefPubMedGoogle Scholar
  19. 19.
    Kwon HC, Oh SY, Lee S, Kim SH, Kim HJ (2007) Bevacizumab plus infusional 5-fluorouracil, leucovorin and irinotecan for advanced colorectal cancer that progressed after oxaliplatin and irinotecan chemotherapy: a pilot study. World J Gastroenterol 13(46):6231–6235CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Osman Köstek
    • 1
    Email author
  • Muhammet Bekir Hacıoğlu
    • 2
  • Abdullah Sakin
    • 3
  • Tarık Demir
    • 4
  • Murat Sarı
    • 5
  • Ozlem Ozkul
    • 6
  • Murat Araz
    • 7
  • Aysun Fatma Doğan
    • 1
  • Nazım Can Demircan
    • 1
  • Sernaz Uzunoğlu
    • 1
  • İrfan Çiçin
    • 1
  • Bülent Erdoğan
    • 1
  1. 1.Department of Medical OncologyTrakya UniversityEdirneTurkey
  2. 2.Clinic of Medical OncologyKonya Training and Research HospitalKonyaTurkey
  3. 3.Okmeydanı Training and Research HospitalClinic of Medical OncologyIstanbulTurkey
  4. 4.Department of Medical OncologyBezmi Alem Vakıf UniversityIstanbulTurkey
  5. 5.Department of Medical OncologyIstanbul UniversityIstanbulTurkey
  6. 6.Department of Medical OncologySakarya UniversitySakaryaTurkey
  7. 7.Department of Medical OncologyAfyon Kocatepe UniversityAfyonTurkey

Personalised recommendations