International Journal of Clinical Oncology

, Volume 23, Issue 2, pp 281–286 | Cite as

MMC/UFT/LV in refractory colorectal cancer: phase II study and analysis of predictive variables of progression

  • Chiara Baratelli
  • Marco Tampellini
  • Massimo Di Maio
  • Azzurra Ottone
  • Maria Pia Brizzi
  • Laura Forti
  • Irene Alabiso
  • Cristina SonettoEmail author
  • Oscar Alabiso
  • Giorgio Vittorio Scagliotti
Original Article



The treatment of refractory metastatic colorectal cancer (rmCRC) and the lack of predictive variables are matters of debate.

Patients and methods

We conducted a multicentre phase II trial assessing the disease control rate (DCR) of the combination of tegafur/uracil and mitomycin C in rmCRC. The number of previous lines of chemotherapy, carcinoembryonic antigen (CEA) levels, progression-free survival of the last chemotherapy regimen (PPFS), and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio at the time of study entry were evaluated as indicators of early progression.


We enrolled 42 patients. The combination was well tolerated with a DCR of 26.2% and median overall survival of 6.9 months. Low CEA levels, PPFS >6 months and low NLR were significantly associated with better prognosis.


The study failed its primary endpoint. However, some putative indicators of early progressive patients have been described.


Colorectal cancer Mitomycin C UFT Predictive markers 


Compliance with ethical standards

Conflict of interest

The authors declare no potential conflict of interest.


  1. 1.
    Torre LA, Bray F, Siegel RL et al (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108CrossRefPubMedGoogle Scholar
  2. 2.
    Goldberg RM, Sargent DJ, Morton RF et al (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22(1):23–30CrossRefPubMedGoogle Scholar
  3. 3.
    Hoff PM, Pazdur R, Benner SE, Canetta R (1998) UFT and leucovorin: a review of its clinical development and therapeutic potential in the oral treatment of cancer. Anticancer 9(6):479–490Google Scholar
  4. 4.
    Douillard JY, Hoff PM, Skillings JR et al (2002) Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. Clin Oncol 20(17):3605–3616CrossRefGoogle Scholar
  5. 5.
    Carmichael J, Popiela T, Radstone D et al (2002) Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20(17):3617–3627CrossRefPubMedGoogle Scholar
  6. 6.
    Paz MM, Zhang X, Lu J, Holmgren A (2012) A new mechanism of action for the anticancer drug mitomycin C: mechanism-based inhibition of thioredoxin reductase. Chem Res Toxicol 25(7):1502–1511CrossRefPubMedGoogle Scholar
  7. 7.
    Verweij J, Pinedo HM (1990) Mitomycin C: mechanism of action, usefulness and limitations. Anticancer Drugs 1(1):5–13CrossRefPubMedGoogle Scholar
  8. 8.
    Ferrarotto R, Machado K, Mak MP et al (2012) A multicenter, multinational analysis of mitomycin C in refractory metastatic colorectal cancer. Eur J Cancer 48(6):820–826CrossRefPubMedGoogle Scholar
  9. 9.
    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(2):228–247CrossRefPubMedGoogle Scholar
  10. 10.
  11. 11.
    Galizia G, Lieto E, Zamboli A et al (2015) Neutrophil to lymphocyte ratio is a strong predictor of tumor recurrence in early colon cancers: a propensity score-matched analysis. Surgery 158(1):112–120CrossRefPubMedGoogle Scholar
  12. 12.
    Absenger G, Szkandera J, Pichler M et al (2013) A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients. Br J Cancer 109(2):395–400CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Neofytou K, Smyth EC, Giakoustidis A et al (2014) Elevated platelet to lymphocyte ratio predicts poor prognosis after hepatectomy for liver-only colorectal metastases, and it is superior to neutrophil to lymphocyte ratio as an adverse prognostic factor. Med Oncol 31(10):239CrossRefPubMedGoogle Scholar
  14. 14.
    Kodaira S (1997) Postoperative adjuvant chemotherapy with mitomycin C and UFT for rectal cancer. Oncology (Williston Park) 11(9 Suppl 10):40–43Google Scholar
  15. 15.
    Nakagoe T, Ishikawa H, Sawai T et al (2000) Multicenter randomized prospective study of adjuvant chemotherapy with UFT and mitomycin C in advanced colorectal cancer. Anticancer Res 20(2B):1069–1075PubMedGoogle Scholar
  16. 16.
    Gyldenkerne N, Glimelius B, Frödin JE et al (2004) A phase II study of UFT and Leucovorin in combination with mitomycin C in patients with metastatic colorectal cancer. Acta Oncol 43(3):276–279CrossRefPubMedGoogle Scholar
  17. 17.
    Vormittag L, Kornek GV, Gruhsmann B et al (2007) UFT/leucovorin and mitomycin C as salvage treatment in patients with advanced colorectal cancer − a retrospective analysis. Anticancer Drugs 18(6):709–712CrossRefPubMedGoogle Scholar
  18. 18.
    Alkis N, Demirci U, Benekli M et al (2011) Mitomycin-C in combination with fluoropyrimidines in the treatment of metastatic colorectal cancer after oxaliplatin and irinotecan failure. J BUON 16(1):80–83PubMedGoogle Scholar
  19. 19.
    Francois E, Smith D, Dahan L et al (2012) Uracil-tegafur/leucovorin and mitomycin C salvage therapy in patients with advanced colorectal cancer: a phase II study. J Chemother 24(4):207–211CrossRefPubMedGoogle Scholar
  20. 20.
    Michalaki V, Gennatas S, Gennatas C (2010) Mitomycin C and UFT/leucovorin as salvage treatment in patients with advanced colorectal cancer. J BUON 15(2):270–273PubMedGoogle Scholar
  21. 21.
    Grothey A, Van Cutsem E, Sobrero A et al (2013) CORRECT Study Group: regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312CrossRefPubMedGoogle Scholar
  22. 22.
    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):1909–1919CrossRefPubMedGoogle Scholar
  23. 23.
    Tampellini M, Ottone A, Alabiso I et al (2015) The prognostic role of baseline CEA and CA 19-9 values and their time-dependent variations in advanced colorectal cancer patients submitted to first-line therapy. Tumour Biol 36(3):1519–1527CrossRefPubMedGoogle Scholar
  24. 24.
    Li MX, Liu XM, Zhang XF et al (2014) Prognostic role of neutrophil-to-lymphocyte ratio in colorectal cancer: a systematic review and meta-analysis. Int J Cancer 134(10):2403–2413CrossRefPubMedGoogle Scholar
  25. 25.
    Del Prete M, Giampieri R, Loupakis F et al (2015) Prognostic clinical factors in pretreated colorectal cancer patients receiving regorafenib: implications for clinical management. Oncotarget 6(32):33982–33992PubMedPubMedCentralGoogle Scholar
  26. 26.
    Petrelli F, Coinu A, Cabiddu M et al (2015) Prognostic factors for survival with bevacizumab-based therapy in colorectal cancer patients: a systematic review and pooled analysis of 11,585 patients. Med Oncol 32(2):456CrossRefPubMedGoogle Scholar
  27. 27.
    Giessen C, Laubender RP, Ankerst DP et al (2015) Surrogate endpoints in second-line treatment for mCRC: a systematic literature-based analysis from 23 randomised trials. Acta Oncol 54:187–193CrossRefPubMedGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2017

Authors and Affiliations

  • Chiara Baratelli
    • 1
  • Marco Tampellini
    • 1
  • Massimo Di Maio
    • 1
  • Azzurra Ottone
    • 1
  • Maria Pia Brizzi
    • 1
  • Laura Forti
    • 1
  • Irene Alabiso
    • 1
  • Cristina Sonetto
    • 1
    Email author
  • Oscar Alabiso
    • 1
  • Giorgio Vittorio Scagliotti
    • 1
  1. 1.Division of Medical Oncology, Department of Oncology, AOU San Luigi di OrbassanoUniversity of TorinoTurinItaly

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