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Efficacy of oral tegafur-uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in early breast cancer: a pooled analysis of two randomized controlled trials (N·SAS-BC 01 trial and CUBC trial)

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Abstract

Two randomized clinical studies comparing the efficacy of oral UFT (2 years) with that of classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (six courses) have been conducted in patients with resected early breast cancer. We have performed a pooled analysis of these two randomized studies. A pooled analysis was performed using individual patient data from the two trials. Hazard ratios (HRs) were determined with a Cox model stratified by study and adjusted for clinical characteristics. We preplanned to verify the following two hypotheses: UFT is non-inferior to CMF in all patients (hypothesis 1) or in ER-positive patients (hypothesis 2) with respect to relapse-free survival (RFS). Non-inferiority of UFT versus CMF was established if the upper limit of the two-sided confidence interval (CI) of the HR for RFS did not exceed 1.30. Hochberg multiplicity adjustment for the significance level was performed. A total of 1,057 patients were analyzed (CMF, n = 528; UFT, n = 529). Median follow-up time was 5.6 years. The HR for RFS was 1.04 (95% CI, 0.78–1.40) in all patients and 0.79 (97.5% CI, 0.49–1.27) in ER-positive patients. UFT was shown to be non-inferior to CMF in ER-positive patients. An exploratory subgroup analysis showed that RFS was better with UFT than with CMF in ER-positive patients who were 50 years or older (HR, 0.58; 95% CI, 0.34–1.01). UFT is non-inferior to CMF in terms of inhibiting recurrence of ER-positive, early breast cancer.

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References

  1. Clarke M, Coates AS, Darby SC, Davies C, Gelber RD, Godwin J, Goldhirsch A, Gray R, Peto R, Pritchard KI, Wood WC (2008) Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta-analysis of randomised trials. Lancet 371(9606):29–40. doi:10.1016/S0140-6736(08)60069-0

    Article  CAS  PubMed  Google Scholar 

  2. Nakajima T, Kinoshita T, Nashimoto A, Sairenji M, Yamaguchi T, Sakamoto J, Fujiya T, Inada T, Sasako M, Ohashi Y (2007) Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer. Br J Surg 94(12):1468–1476. doi:10.1002/bjs.5996

    Article  CAS  PubMed  Google Scholar 

  3. Akasu T, Moriya Y, Ohashi Y, Yoshida S, Shirao K, Kodaira S (2006) Adjuvant chemotherapy with uracil-tegafur for pathological stage III rectal cancer after mesorectal excision with selective lateral pelvic lymphadenectomy: a multicenter randomized controlled trial. Jpn J Clin Oncol 36(4):237–244. doi:10.1093/jjco/hyl014

    Article  PubMed  Google Scholar 

  4. Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N (2004) A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350(17):1713–1721. doi:10.1056/NEJMoa032792

    Article  CAS  PubMed  Google Scholar 

  5. Lembersky BC, Wieand HS, Petrelli NJ, O’Connell MJ, Colangelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME, Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N (2006) Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast And Bowel Project Protocol C-06. J Clin Oncol 24(13):2059–2064. doi:10.1200/JCO.2005.04.7498

    Article  CAS  PubMed  Google Scholar 

  6. Ota K, Taguchi T, Kimura K (1988) Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer Chemother Pharmacol 22(4):333–338

    Article  CAS  PubMed  Google Scholar 

  7. Tashiro H, Nomura Y, Ohsaki A (1994) A double blind comparative study of tegafur (FT) and UFT (a combination of Tegafur and uracil) in advanced breast cancer. Jpn J Clin Oncol 24(4):212–217

    CAS  PubMed  Google Scholar 

  8. Kasumi F, Yoshimoto M, Uchino J, Abe R, Nomura Y, Sugimachi K, Nakazato H, Abe O (2003) Meta-analysis of five studies on tegafur plus uracil (UFT) as post-operative adjuvant chemotherapy for breast cancer. Oncology 64(2):146–153. doi:10.1159/000067763

    Article  CAS  PubMed  Google Scholar 

  9. Noguchi S, Koyama H, Uchino J, Abe R, Miura S, Sugimachi K, Akazawa K, Abe O (2005) Postoperative adjuvant therapy with tamoxifen, tegafur plus uracil, or both in women with node-negative breast cancer: a pooled analysis of six randomized controlled trials. J Clin Oncol 23(10):2172–2184. doi:10.1200/JCO.2005.02.158

    Article  CAS  PubMed  Google Scholar 

  10. Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, Kohno N, Nakagami K, Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto G, Ohashi Y (2009) Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial. J Clin Oncol 27(9):1368–1374. doi:10.1200/JCO.2008.18.3939

    Article  CAS  PubMed  Google Scholar 

  11. Park Y, Okamura K, Mitsuyama S, Saito T, Koh J, Kyono S, Higaki K, Ogita M, Asaga T, Inaji H, Komichi H, Kohno N, Yamazaki K, Tanaka F, Ito T, Nishikawa H, Osaki A, Koyama H, Suzuki T (2009) Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study. Br J Cancer 101(4):598–604. doi:10.1038/sj.bjc.6605218

    Article  CAS  PubMed  Google Scholar 

  12. Hochberg Y (1988) A sharper Bonferroni procedure for multiple tests of significance. Biometrika 75(4):800–802. doi:10.1093/biomet/75.4.800

    Article  Google Scholar 

  13. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C (1995) Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 332(14):901–906

    Article  CAS  PubMed  Google Scholar 

  14. Nakamura S, Abe O, Ikeda T, Toi M (2006) Postoperative adjuvant therapy with tamoxifen, tegafur-uracil (UFT), or both in women with node-negative breast cancer: a pooled analysis of six randomized controlled trials (relapse-free survival data). Proc Am Soc Clin Oncol 24:18s (abstr 633)

    Google Scholar 

  15. Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP (2009) Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 360(20):2055–2065. doi:10.1056/NEJMoa0810266

    Article  CAS  PubMed  Google Scholar 

  16. Kurebayashi J, Nukatsuka M, Nagase H, Nomura T, Hirono M, Yamamoto Y, Sugimoto Y, Oka T, Sonoo H (2007) Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells. Cancer Chemother Pharmacol 59(4):515–525. doi:10.1007/s00280-006-0293-7

    Article  CAS  PubMed  Google Scholar 

  17. Kurebayashi J, Nukatsuka M, Sonoo H, Uchida J, Kiniwa M (2009) Preclinical rationale for combined use of endocrine therapy and 5-fluorouracil but neither doxorubicin nor paclitaxel in the treatment of endocrine-responsive breast cancer. Cancer Chemother Pharmacol. doi: 10.1007/s00280-009-1024-7

  18. Toi M, Ikeda T, Akiyama F, Kurosumi M, Tsuda H, Sakamoto G, Abe O (2007) Predictive implications of nucleoside metabolizing enzymes in premenopausal women with node-positive primary breast cancer who were randomly assigned to receive tamoxifen alone or tamoxifen plus tegafur-uracil as adjuvant therapy. Int J Oncol 31(4):899–906

    CAS  PubMed  Google Scholar 

  19. Gennari A, Sormani MP, Pronzato P, Puntoni M, Colozza M, Pfeffer U, Bruzzi P (2008) HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100(1):14–20. doi:10.1093/jnci/djm252

    Article  CAS  PubMed  Google Scholar 

  20. Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, Martino S, Perez EA, Muss HB, Norton L, Hudis C, Winer EP (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295(14):1658–1667. doi:10.1001/jama.295.14.1658

    Article  CAS  PubMed  Google Scholar 

  21. Hayes DF, Thor AD, Dressler LG, Weaver D, Edgerton S, Cowan D, Broadwater G, Goldstein LJ, Martino S, Ingle JN, Henderson IC, Norton L, Winer EP, Hudis CA, Ellis MJ, Berry DA (2007) HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 357(15):1496–1506. doi:10.1056/NEJMoa071167

    Article  CAS  PubMed  Google Scholar 

  22. Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O’Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM (2009) Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet 373(9676):1681–1692. doi:10.1016/S0140-6736(09)60740-6

    Article  CAS  PubMed  Google Scholar 

  23. Duric VM, Stockler MR, Heritier S, Boyle F, Beith J, Sullivan A, Wilcken N, Coates AS, Simes RJ (2005) Patients’ preferences for adjuvant chemotherapy in early breast cancer: what makes AC and CMF worthwhile now? Ann Oncol 16(11):1786–1794. doi:10.1093/annonc/mdi370

    Article  CAS  PubMed  Google Scholar 

  24. Yen-Revollo JL, Goldberg RM, McLeod HL (2008) Can inhibiting dihydropyrimidine dehydrogenase limit hand-foot syndrome caused by fluoropyrimidines? Clin Cancer Res 14(1):8–13. doi:10.1158/1078-0432.CCR-07-1225

    Article  CAS  PubMed  Google Scholar 

  25. Sparano JA, Paik S (2008) Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol 26(5):721–728. doi:10.1200/JCO.2007.15.1068

    Article  PubMed  Google Scholar 

  26. Liu G, Franssen E, Fitch MI, Warner E (1997) Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 15(1):110–115

    CAS  PubMed  Google Scholar 

  27. Saif MW, Syrigos KN, Katirtzoglou NA (2009) S-1: a promising new oral fluoropyrimidine derivative. Expert Opin Investig Drugs 18(3):335–348. doi:10.1517/13543780902729412

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The National Surgical Adjuvant Study (N-SAS) Group received governmental research grants from the Ministry of Health and Welfare in 1995 and 1996. The N-SAS-BC 01 trial and the CUBC trial were financially supported by Taiho Pharmaceutical Co., Ltd.

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Authors and Affiliations

  1. Department of Biostatistics, School of Public Health, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Yasuo Ohashi

  2. Department of Medical Oncology, Hamamatsu Oncology Center, 3-6-13 Chuo, Naka-ku, Hamamatsu, Shizuoka, 430-0929, Japan

    Toru Watanabe

  3. Department of Surgery, Niigata Cancer Center Hospital, 2-15-3 Kawagishi-chyo, Chuo-ku, Niigata-city, Niigata, 951-8566, Japan

    Muneaki Sano

  4. Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari, Osaka-city, Osaka, 537-8511, Japan

    Hiroki Koyama & Hideo Inaji

  5. Department of Cancer Control and Statistics, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka-city, Osaka, 537-8511, Japan

    Takaichiro Suzuki

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  1. Yasuo Ohashi
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Correspondence to Yasuo Ohashi.

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Ohashi, Y., Watanabe, T., Sano, M. et al. Efficacy of oral tegafur-uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in early breast cancer: a pooled analysis of two randomized controlled trials (N·SAS-BC 01 trial and CUBC trial). Breast Cancer Res Treat 119, 633–641 (2010). https://doi.org/10.1007/s10549-009-0635-3

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