Skip to main content

Advertisement

SpringerLink
Log in

Biweekly oxaliplatin plus 1-day infusional fluorouracil/leucovorin followed by metronomic chemotherapy with tegafur/uracil in pretreated metastatic colorectal cancer

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Metronomic chemotherapy, at a minimally toxic dose and with a frequent schedule, is a potentially novel approach to the control of advanced cancer disease via a different mechanism from maximum tolerable doses chemotherapy. Taking advantage of the potential effectiveness of metronomic therapy, tegafur/uracil (UFT) was incorporated into an oxaliplation/infusioanl fluouracil (5-FU)/leucovorin (LV) protocol in this study. The primary endpoints were response rate, time to progression (TTP) and safety profile in 5-FU-pretreated metastatic colorectal cancers (CRCs).

Patients and methods

Twenty-eight patients with metastatic CRCs resistant or refractory to 5-FU/LV were enrolled. Chemotherapy was administrated every 2 weeks sequentially with 2-h infusion of oxaliplatin (85 mg/m2) and LV (200 mg/m2), intravenous bolus 5-FU (400 mg/m2), 22-h infusion of 5-FU (600 mg/m2) on day 1 and then followed by 10-day daily oral UFT (200 mg/m2)/LV (30 mg/m2).

Results

Partial response was seen in ten (35.7%) patients. The median TTP was 5.2 (95% CI: 4.16–6.31) months and the median overall survival was 13.4 (95% CI: 6.39–20.5) months. No grade 3 toxicities above 5% according to National Cancer Institute-Common Toxicity Criteria (NCI-CTC) occurred except sensory neuropathy (10.7%). No grade 4 toxicity, treatment-related mortality or hand–foot syndrome was found.

Conclusions

This study protocol with favorable toxicity profile is thus promisingly effective against 5-FU-pretreated metastatic CRCs. Given the present experience, an evaluation of the regimen as front-line treatment of metastatic CRC is planned.

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

Similar content being viewed by others

References

  1. Saltz LB, Cox JV, Blanke C et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group New Engl J Med 343:905–914

    Article  CAS  Google Scholar 

  2. Tournigand C, Andre T, Achille E et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Onco 22:229–237

    Article  CAS  Google Scholar 

  3. de Gramont A, Vignoud J, Tournigand C et al (1997) Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-h continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 33:214–219

    Article  PubMed  Google Scholar 

  4. Andre T, Bensmaine MA, Louvet C et al (1999) Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 17:3560–3568

    PubMed  CAS  Google Scholar 

  5. Maindrault-Goebel F, de Gramont A, Louvet C et al (2001) High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7). Eur J Cancer 37:1000–1005

    Article  PubMed  CAS  Google Scholar 

  6. Hsieh RK, Chao TY, Chen WS et al (2004) Oxaliplatin added the simplified bimonthly low dose leucovorin and 5- FU on pretreated advanced colorectal cancer is effective and not affected by different previous 5-FU regimens. Cancer Invest 22:171–179

    Article  PubMed  CAS  Google Scholar 

  7. 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 22:23–30

    Article  PubMed  CAS  Google Scholar 

  8. Ferrara N, Hillan KJ, Gerber HP et al (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400

    Article  PubMed  CAS  Google Scholar 

  9. Browder T, Butterfield CE, Kraling BM et al (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886

    PubMed  CAS  Google Scholar 

  10. Klement G, Baruchel S, Rak J et al (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15–R24

    PubMed  CAS  Google Scholar 

  11. Hanahan D, Bergers G, Bergsland E et al (2000) Less is more, regularly: Metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105:1045–1047

    Article  PubMed  CAS  Google Scholar 

  12. Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436

    Article  PubMed  CAS  Google Scholar 

  13. Pietras K, Hanahan DA (2005) Multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23:939–952

    Article  PubMed  CAS  Google Scholar 

  14. Miller KD, Sweeney CJ, Sledge GW et al (2005) Refining the target: chemotherapeutics as antiangiogenics. J Clin Oncol 19:1195–1206

    Google Scholar 

  15. Yonekura K, Basaki Y, Chikahisa L et al (1999) UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin Cancer Res 5:2185–2191

    PubMed  CAS  Google Scholar 

  16. Tanaka F, Yanagihara K, Otake Y et al (2004) Angiogenesis and the efficacy of postoperative administration of UFT in pathologic stage I non-small cell lung cancer. Cancer Sci 95:371–376

    Article  PubMed  CAS  Google Scholar 

  17. Rustum YM (1997) Mechanism-based improvement in the therapeutic selectivity of 5-FU prodrug alone and under conditions of metabolic modulation. Oncology (Karger) 1:7–11

    Article  Google Scholar 

  18. Maehara Y, Kakeji Y, Ohno S et al (1997) Scientific basis for the combination of tegafur with uracil. Oncology (Huntington) 11:14–21

    CAS  Google Scholar 

  19. Rougier P (1998) Clinical efficacy of oxaliplatin monotherapy: phase II trials in advanced colorectal cancer. Semin Oncol 25:23–31

    PubMed  Google Scholar 

  20. 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 20:3617–3627

    Article  PubMed  CAS  Google Scholar 

  21. 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. J Clin Oncol 20:3605–3616

    Article  PubMed  CAS  Google Scholar 

  22. Saltz LB, Leichman CG, Young CW et al (1995) A fixed-ratio combination of uracil and Ftorafur (UFT) with low dose leucovorin. An active oral regimen for advanced colorectal cancer. Cancer 75:782–785

    Article  PubMed  CAS  Google Scholar 

  23. Maroun J, Asche C, Romeyer F et al (2003) A cost comparison of oral tegafur plus uracil/folinic acid and parenteral fluorouracil for colorectal cancer in Canada. Pharmacoeconomics 21:1039–1051

    Article  PubMed  CAS  Google Scholar 

  24. Feliu J, Vicent JM, Garcia-Giron C et al (2004) Phase II study of UFT and oxaliplatin in first-line treatment of advanced colorectal cancer. Br J Cancer 91:1758–1762

    Article  PubMed  CAS  Google Scholar 

  25. Kim K, Nam E, Lee NS et al (2002) Oxaliplatin and UFT combination chemotherapy in patients with metastatic colorectal cancer. Am J Clin Oncol 25:354–357

    Article  PubMed  Google Scholar 

  26. Therasse P, Arbuck SG, Eisenheuer EA et al (2000) New Guide-lines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  27. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10

    Article  PubMed  CAS  Google Scholar 

  28. de Gramont A, Figer A, Seymour M et al ( 2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol.18:2938–2947

    Google Scholar 

  29. Reddy GK (2005) The addition of bevacizumab to FOLFOX4 prolongs survival in relapsed colorectal cancer: interim data from the ECOG 3200 trial. Clin Colorectal Cancer 4:300–301

    PubMed  Google Scholar 

  30. Yoshikawa R, Kusunoki M, Yanagi H et al (2001) Dual antitumor effects of 5-fluorouracil on the cell cycle in colorectal carcinoma cells: a novel target mechanism concept for pharmacokinetic modulating chemotherapy. Cancer Res 61:1029–1037

    PubMed  CAS  Google Scholar 

  31. Borner MM, Schoffski P, de Wit R et al (2002) Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer 38:349–358

    Article  PubMed  CAS  Google Scholar 

  32. Fischel JL, Formento P, Ciccolini J et al (2002) Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity. Br J Cancer 86:1162–1168

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grant VGH-92–254 from Taipei Veterans General Hospital and grant 94003 from Szu-Yuan Research Foundation, Taipei.

Author information

Authors and Affiliations

  1. Division of Medical Oncology, Taipei Veterans General Hospital and National Yang-Ming University, No. 201, Shi-Pai Rd., Sec. 2, Taipei, 112, Taiwan, ROC

    Peng-Chan Lin, Ta-Chung Chao & Jin-Hwang Liu

  2. Division of Hematology and Oncology, Department of Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ROC

    Peng-Chan Lin

  3. Division of Experimental Surgery, Taipei Veterans General Hospital, School of Medicine National Yang-Ming University, Taipei, Taiwan, ROC

    Wei-Shone Chen

  4. Division of Colorectal Surgery, Taipei Veterans General Hospital, School of Medicine National Yang-Ming University, Taipei, Taiwan, ROC

    Wei-Shone Chen & Shung-Haur Yang

  5. Department of Radiology, Taipei Veterans General Hospital, School of Medicine National Yang-Ming University, Taipei, Taiwan, ROC

    Chui-Mei Tiu

Authors
  1. Peng-Chan Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei-Shone Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ta-Chung Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shung-Haur Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chui-Mei Tiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin-Hwang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin-Hwang Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, PC., Chen, WS., Chao, TC. et al. Biweekly oxaliplatin plus 1-day infusional fluorouracil/leucovorin followed by metronomic chemotherapy with tegafur/uracil in pretreated metastatic colorectal cancer. Cancer Chemother Pharmacol 60, 351–356 (2007). https://doi.org/10.1007/s00280-006-0377-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-006-0377-4

Keywords

Search

Navigation