Surgery Today

, Volume 37, Issue 11, pp 923–943 | Cite as

UFT (Tegafur and Uracil) as Postoperative Adjuvant Chemotherapy for Solid Tumors (Carcinoma of the Lung, Stomach, Colon/Rectum, and Breast): Clinical Evidence, Mechanism of Action, and Future Direction

  • Fumihiro Tanaka
Review Article


UFT (tegafur and uracil) is an oral anticancer drug that has been developed in Japan. Owing to its mild toxicity profile, UFT can be suitable in an adjuvant setting following a complete tumor resection, whereas its direct antitumor effect achieved may be insufficient for advanced unresectable disease. Therefore, a variety of adjuvant chemotherapy trials with UFT have been conducted, and results of well-designed randomized controlled trials have recently shown a survival benefit of postoperative UFT treatment in resected lung, gastric, colorectal, and breast cancer. In the present article, postoperative adjuvant trials with UFT-containing chemotherapy are reviewed, and the mechanism of action and future directions are also discussed.

Key words

Tegafur Uracil UFT Solid tumor Adjuvant chemotherapy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Fujii, S, Kitano, S, Ikenaka, K, Shirasaka, T 1979Effect of coadministration of uracil or cytosine on the anti-tumor activity of clinical doses of 1-(2-tertahydrofuryl)-5-fluorouracil and level of 5-fluorouracil in rodentsGann (Cancer Sci)7020914Google Scholar
  2. 2.
    Tanaka, F, Fukuse, T, Wada, H, Fukushima, M 2000The history, mechanism and clinical use of oral 5-fluorouracil derivative chemotherapeutic agentsCurr Pharm Biotech1137164CrossRefGoogle Scholar
  3. 3.
    Ikenaka, K, Shirasaka, T, Kitano, S, Fujii, S 1979Effect of uracil on metabolism of 5-fluorouracil in vitroGann (Cancer Sci)703539Google Scholar
  4. 4.
    Ho, DH, Pazdur, R, Covington, WP, Brown, N, Huo, YY, Lassere, Y,  et al. 1998Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouraci infusion and oral uracil plus N1-5(2′-Tertahydrofuryl)-5-fluorouracilClin Cancer Res420858PubMedGoogle Scholar
  5. 5.
    Ota, K, Taguchi, T, Kimura, K 1988Report on nationwide pooled data and cohort investigation in UFT phase II studyCancer Chemother Pharmacol223338PubMedCrossRefGoogle Scholar
  6. 6.
    Malik, ST, Talbot, D, Clarke, PI, Osborne, R, Reznek, R, Wrigley, PF,  et al. 1990Phase II trial of UFT in advanced colorectal and gastric cancerBr J Cancer6210235PubMedGoogle Scholar
  7. 7.
    Wada, H, Hitomi, S, Teramatsu, T 1996Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. West Japan Study Group for Lung SurgeryJ Clin Oncol14104854PubMedGoogle Scholar
  8. 8.
    Kato, H, Ichinose, Y, Ohta, M, Hata, E, Tsubota, N, Tada, H,  et al. 2004A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lungN Engl J Med350171321PubMedCrossRefGoogle Scholar
  9. 9.
    Nakagawa, K, Tada, H, Akashi, A, Yasumitsu, T, Iuchi, K, Taki, T,  et al. 2006The Osaka Lung Cancer Study Group, Japan. Randomized study of adjuvant chemotherapy for completely resected p-stage I-IIIA non-small cell lung cancerBr J Cancer9581721PubMedCrossRefGoogle Scholar
  10. 10.
    Kinoshita, T Nakajima, T Ohashi, Y National Surgical Adjuvant Study Group for Gastric Cancer2005N-SAS-GC). Adjuvant chemotherapy with uracil-tegafur (UFT) for serosa negative advanced gastric cancer: results of a randomized trial by the National Surgical Adjuvant Study of Gastric CancerJ Clin Oncol23313sabstract #4021Google Scholar
  11. 11.
    Akasu, T, Moriya, Y, Ohashi, Y, Yoshida, S, Shirao, K, Kodaira, S 2006Adjuvant chemotherapy with uracil-tegafur for pathological stage III rectal cancer after excision with selective lateral pelvic lymphadenectomy: a multicenter randomized controlled trialJpn J Clin Oncol3623744PubMedCrossRefGoogle Scholar
  12. 12.
    Noguchi, S, Koyama, H, Uchino, J, Abe, R, Miura, S, Sugimachi, K,  et al. 2005Postoperative adjuvant therapy with tamoxifen, tegafur plus uracil, or both in women with node-negative breast cancer: a pooled analysis of six randomized controlled trialsJ Clin Oncol10217284CrossRefGoogle Scholar
  13. 13.
    Yonekura, K, Basaki, Y, Chikahisa, L, Okabe, S, Hashimoto, A, Miyadera, K,  et al. 1999UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in miceClin Cancer Res5218591PubMedGoogle Scholar
  14. 14.
    Tanaka, F, Yanagihara, K, Otake, Y, Miyahara, R, Wada, H 2004Angiogenesis and the efficacy of postoperative administration of UFT in pathologic stage-I non-small cell lung cancerCancer Sci953716PubMedCrossRefGoogle Scholar
  15. 15.
    Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, et al. Randomized phase III trial comparing S-1 monotherapy versus surgery alone for stage II/III gastric cancer patients (pts) after curative D2 gastrectomy (ACTS-GC study). Presented at the 2007 Gastrointestinal Cancer Symposium (ASCO) on January 19, 2007 Scholar
  16. 16.
    Mountain, CF 1997Revision in the international system for staging lung cancerChest11617107Google Scholar
  17. 17.
    Naruke, T, Tsuchiya, R, Kondo, H, Asamura, H, Nakayama, H 1997Implication of staging in lung cancerChest112242s248sPubMedGoogle Scholar
  18. 18.
    Tanaka, F, Yanagihara, K, Otake, Y, Miyahara, R, Kawano, Y, Nakagawa, T,  et al. 2000Surgery for non-small cell lung cancer: postoperative survival based on the revised tumor-node-metastasis classification and its time trendEur J Cardiothorac Surg18147155PubMedCrossRefGoogle Scholar
  19. 19.
    Tanaka, F, Yanagihara, K, Ohtake, Y, Fukuse, T, Hitomi, S, Wada, H 1997Time trends and survival after surgery for p-stage IIIa, pN2 non-small cell lung cancer (NSCLC)Eur J Cardiothorac Surg123729PubMedCrossRefGoogle Scholar
  20. 20.
    PORT Meta-analysis Trialists Group1998Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomized controlled trialsLancet35225763CrossRefGoogle Scholar
  21. 21.
    Burdett, L, Stewart, L 2005Postoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data meta-analysisLung Cancer47813PubMedCrossRefGoogle Scholar
  22. 22.
    Non-small Cell Lung Cancer Collaborative Group1995Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trialsBMJ311899909Google Scholar
  23. 23.
    The International Adjuvant Lung Cancer Trial Collaborative Group2004Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancerN Engl J Med35038607CrossRefGoogle Scholar
  24. 24.
    Winton, T, Livingston, R, Johnson, D, Rigas, J, Johnston, M, Butts, C,  et al. 2005Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancerN Engl J Med352258997PubMedCrossRefGoogle Scholar
  25. 25.
    Douillard, JY, Rosell, R, De Lena, M, Carpagnano, F, Ramlau, R, Gonzáles-Larriba, JL,  et al. 2006Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomized controlled trialLancet Oncol771927PubMedCrossRefGoogle Scholar
  26. 26.
    Pignon, JP, Tribodet, H, Scagliotti, GV, Douillard, JY, Shepherd, FA, Stephens, RJ,  et al. 2006Lung Adjuvant Cisplatin Evaluation (LACE): a pooled analysis of five randomized clinical trials including 4584 patientsJ Clin Oncol24s366sabstract #7008Google Scholar
  27. 27.
    Nakagawa, M, Tanaka, F, Tsubota, N, Ohta, M, Takao, M, Wada, H 2005A randomized phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I non-small cell lung cancer: the West Japan Study Group for Lung Cancer Surgery (WJSG) — the 4th studyAnn Oncol167580PubMedCrossRefGoogle Scholar
  28. 28.
    Endo, C, Saito, Y, Iwanami, H, Tsushima, T, Imai, T, Kawamura, M,  et al. 2003A randomized trial of postoperative UFT therapy in p-stage I–II non-small cell lung cancer: North-east Japan Study Group for Lung Cancer SurgeryLung Cancer401816PubMedCrossRefGoogle Scholar
  29. 29.
    Imaizumi, M 2005Postoperative adjuvant cisplatin, vindesine, plus uracil-tegafur chemotherapy increased survival of patients with completely resected p-stage I non-small cell lung cancerLung Cancer498594PubMedCrossRefGoogle Scholar
  30. 30.
    The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan)1995A randomized trial of postoperative adjuvant chemotherapy in non-small cell lung cancer (the second cooperative study)Eur J Surg Oncol216977CrossRefGoogle Scholar
  31. 31.
    Wada, H, Miyahara, R, Tanaka, F, Hitomi, S, Japan, West 1999Study Group for lung cancer surgery (WJSG). Postoperative adjuvant chemotherapy with PVM (Cisplatin + Vindesine + Mitomycin C) and UFT (Uracil + Tegaful): a randomized clinical trialEur J Cardiothorac Surg1543843PubMedCrossRefGoogle Scholar
  32. 32.
    Tanaka, F Tsubota, N Namikawa, S Ohta, M Yamakido, M Hitomi, S Japan Study Group for Lung Cancer Surgery (WJSG) et al. 2005A randomized phase III trial of adjuvant chemotherapy with cisplatin and vindesine followed by UFT for completely resected pathologic (p-) stage IIIA-N2 non-small cell lung cancer (NSCLC): West Japan Study Group for Lung Cancer Surgery (WJSG) — the 5th studyJ Clin Oncol23685sabstract #7262Google Scholar
  33. 33.
    Tsuboi, M, Kato, H, Ichinose, Y, Ohta, M, Hata, E, Tsubota, N,  et al. 2006the Japan Lung Cancer Research Group on Postsurgical Adjuvant ChemotherapyJ Clin Oncol24s413sabstract #7197Google Scholar
  34. 34.
    Hamada, C, Tanaka, F, Ohta, M, Fujimura, S, Kodama, K, Imaizumi, M,  et al. 2005Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancerJ Clin Oncol2349995006PubMedCrossRefGoogle Scholar
  35. 35.
    Ogawa, E, Tanaka, F, Yanagihara, K, Wada, H 2005A phase II trial of adjuvant chemotherapy with weekly paclitaxel (Pac) and carboplatin (Cb) followed by UFT for completely resected pathologic (p-) stage II (N1) and IIIA (N2) non-small cell lung cancer (NSCLC)J Clin Oncol23s698sabstract #7315Google Scholar
  36. 36. Scholar
  37. 37.
    Kinoshita, T, Konishi, M, Nakagohri, T, Takahashi, S, Gotouda, N 2006Gastric cancerJpn J Cancer Chemother3331317Google Scholar
  38. 38.
    Sakamoto, J, Morita, S, Kodera, Y, Rahman, M, Nakao, A 2004Adjuvant chemotherapy for gastric cancer in Japan: global and Japanese perspectivesCancer Chemother Pharmacol54s25s31PubMedGoogle Scholar
  39. 39.
    Hermans, J, Bonekamp, JJ, Boon, MC, Bunt, AM, Ohyama, S, Sasako, M,  et al. 1993Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trialsJ Clin Oncol1114417PubMedGoogle Scholar
  40. 40.
    Pignon, JP, Ducreux, M, Rougier, P 1994Meta-analysis of adjuvant chemotherapy in gastric cancer: a critical reappraisalJ Clin Oncol1287980Google Scholar
  41. 41.
    Earle, CC, Maroun, JA 1999Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: revisting a meta-analysis of randomized trialsEur J Cancer35105964PubMedCrossRefGoogle Scholar
  42. 42.
    Mari, E, Floriani, I, Tinazzi, A, Buda, A, Belfiglio, M, Valentini, M,  et al. 2000Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trialsAnn Oncol1183743PubMedCrossRefGoogle Scholar
  43. 43.
    Panzini, I, Gianni, L, Fattori, PP, Tassinari, D, Imola, M, Fabbri, P,  et al. 2002Adjuvant chemotherapy in gastric cancer: a meta-analysis of randomized trials and comparison with previous meta-analysisTumori88217PubMedGoogle Scholar
  44. 44.
    Janunger, KG, Hafstrom, L, Glimelius, B 2002Chemotherapy in gastric cancer: a review and updated meta-analysisEur J Surg168579608CrossRefGoogle Scholar
  45. 45.
    Macdonald, JS, Smalley, SR, Benedetti, J, Hundahl, SA, Estes, NC, Stemmermann, GN,  et al. 2001Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junctionN Engl J Med34572530PubMedCrossRefGoogle Scholar
  46. 46.
    Nakajima, T, Ota, K, Ishihara, S, Oyama, S, Nishi, M, Hamashima, N 1994Meta-analysis of 10 postoperative adjuvant chemotherapies for gastric cancerJpn J Cancer Chemother2118005Google Scholar
  47. 47.
    Takiuchi, H, Ajani, JA 1998Uracil-tegafur in gastric carcinoma: a comprehensive reviewJ Clin Oncol16287785PubMedGoogle Scholar
  48. 48.
    Furukawa, H, Iwanaga, T, Nakajima, T, Okabayashi, K, Nakazato, H, Hiratsuka, Y,  et al. 1995Randomized study with mitomycin C + 5-fluorouracil + cytosine arabinoside (MFC), MFC + tegafur and uracil (UFT), and MF + UFT in advanced gastric cancer: interinstitutional differences in a multicenter study in JapanJ Surg Oncol605964PubMedCrossRefGoogle Scholar
  49. 49.
    Kitamura, M, Nakajima, T, Ohta, K, Nashimoto, A, Yamamura, Y, Furukawa, H,  et al. 1999Adjuvant chemotherapy of gastric cancer: JCOG experienceNakajima, TYamaguchi,  eds. Multimodality therapy for gastric cancerSpringerTokyo3241Google Scholar
  50. 50.
    Nakajima, T Nashimoto, A Kitamura, M Kito, T Iwanaga, T Okabayashi, K the Gastric Cancer Surgical Study Group et al. 1999Adjuvant mitomycin and fluorouracil followed by oral uracil and tegafur in serosa-negative gastric cancer: a randomized trialLancet3542737PubMedCrossRefGoogle Scholar
  51. 51.
    Nakajima, T 2000Evaluation of adjuvant UFT for gastric cancerOncology1482s96sGoogle Scholar
  52. 52.
    Miyashiro I, Furukawa H, Sasako M, Yamamoto S, Nishimoto A, Nakajima T, et al; Gastric Cancer Surgical Study Group, Japan Clinical Oncology Group. No survival benefit with adjuvant chemotherapy for serosa-positive gastric cancer: randomized trial of adjuvant chemotherapy with cisplatin followed by oral fluorouracil (UFT) in serosa-positive gastric cancer. Japan Clinical Oncology Group 9206-2. Presented at the 2005 Gastrointestinal Cancer Symposium (ASCO). Scholar
  53. 53.
    Sakamoto, J, Morita, S, Kodera, Y, Rahman, M, Nakao, A 2004Adjuvant chemotherapy for gastric cancer in Japan: global and Japanese perspectivesCancer Chemother Pharmacol54s25s31PubMedGoogle Scholar
  54. 54.
    Oba, K, Morita, S, Tsuburaya, A, Kodera, Y, Kobayashi, M, Sakamoto, J 2006Efficacy of adjuvant chemotherapy using oral fluorinated pyrimidines for curatively resected gastric cancer: a meta-analysis of centrally randomized controlled clinical trials in JapanJ Chemother183118PubMedGoogle Scholar
  55. 55.
    Sakamoto, J, Tsuburaya, A, Morita, S, Matsui, T, Oba, K, Kodera, Y,  et al. 2006Adjuvant chemotherapy with tegafur/uracil (UFT) for gastric cancer. A meta-analysis of centrally randomized clinical trialsJ Clin Oncol24s186sabstract #4033Google Scholar
  56. 56.
    Akasu, T 2006Adjuvant chemotherapy for colorectal cancerJpn J Cancer Chemother3330712Google Scholar
  57. 57.
    Benson, AB,III, Schrag, D, Somerfield, MR, Cohen, AM, Figueredo, AT, Flynn, PJ,  et al. 2004American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancerJ Clin Oncol22340819PubMedCrossRefGoogle Scholar
  58. 58.
    Mamounas, E, Wieand, S, Wolmark, N, Bear, HD, Atkins, JN, Song, K,  et al. 1999Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04)J Clin Oncol17134955PubMedGoogle Scholar
  59. 59. Scholar
  60. 60.
    Gill, S, Loprinzi, CL, Sargent, DJ, Thome, SD, Alberts, SR, Haller, DG,  et al. 2004Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?J Clin Oncol221797806PubMedCrossRefGoogle Scholar
  61. 61.
    Wolmark, N, Rockette, H, Fisher, B, Wickerham, DL, Redmond, C, Fisher, ER,  et al. 1993The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: Results from National Surgical Adjuvant Breast and Bowel Project Protocol C-03J Clin Oncol11187987PubMedGoogle Scholar
  62. 62.
    O'Connell, MJ, Wolmark, N, Yothers, G, Haile, S, Colangelo, L, Petrelli, N 2005Durable improvement in disease-free survival (DFS) and overall survival (OS) for stage II or III colon cancer treated with leucovorin-modulated fluorouracil (FU): 10-year follow-up of National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03J Clin Oncol23s248sabstract #3511Google Scholar
  63. 63.
    Wolmark, N, Rockette, H, Mamounas, E, Jones, J, Wieand, S, Wickerham, DL,  et al. 1999Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04J Clin Oncol1735539PubMedGoogle Scholar
  64. 64.
    Sargent, DJ, Goldberg, RM, Jacobson, SD, Macdonald, JS, Labianca, R, Haller, DG,  et al. 2001A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patientsN Engl J Med34510917PubMedCrossRefGoogle Scholar
  65. 65.
    Jessup, JM, Stewart, A, Greene, FL, Minsky, BD 2005Adjuvant chemotherapy for stage III colon cancer. Implications of race/ethnicity, age, and differentiationJAMA294270311PubMedCrossRefGoogle Scholar
  66. 66.
    Haller, DG, Catalano, PJ, Macdonald, JS, O'Rourke, MA, Frontiera, MS, Jackson, DV,  et al. 2005Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089J Clin Oncol2386718PubMedCrossRefGoogle Scholar
  67. 67.
    Wolmark, N, Wieand, HS, Kuebler, JP, Smith, RE 2005A phase III trial comparing FULV to FULV+oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP Protocol C-07J Clin Oncol23s246sabstract #3500Google Scholar
  68. 68.
    Andre, T, Boni, C, Mounedji-Boudiaf, L, Navarro, M, Tabernero, J, Hickish, T,  et al. 2004Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancerN Engl J Med350234351PubMedCrossRefGoogle Scholar
  69. 69.
    Kato, T, Ohashi, Y, Nakazato, H, Koika, A, Saji, S, Suzuki, H,  et al. 2002Efficacy of oral UFT as adjuvant chemotherapy to curative resection of colorectal cancer: multicenter prospective randomized trialLangenbeck's Arch Surg38657581CrossRefGoogle Scholar
  70. 70.
    Lembersky, BC, Wieand, HS, Petrelli, NJ, O'Connell, MJ, Colangelo, LH, Smith, RE,  et al. 2006Oral 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-06J Clin Oncol24205964PubMedCrossRefGoogle Scholar
  71. 71.
    Twelves, C, Wong, A, Nowacki, MP, Abt, M, Burris, H,III, Carrato, A,  et al. 2005Capecitabine as adjuvant treatment for stage III colon cancerN Engl J Med3522696704PubMedCrossRefGoogle Scholar
  72. 72. Scholar
  73. 73.
    Gastrointestinal Tumor Study Group1985Prolongation of the disease-free interval in surgically treated rectal carcinomaN Engl J Med312146572CrossRefGoogle Scholar
  74. 74.
    Krook, JE, Moertel, CG, Gunderson, LL, Wieand, HS, Collins, RT, Beart, RW,  et al. 1991Effective surgical adjuvant therapy for high-risk rectal carcinomaN Engl J Med32470915PubMedCrossRefGoogle Scholar
  75. 75.
    Fisher, B, Wolmark, N, Rockette, H, Redmond, C, Deutsch, M, Wickerham, DL,  et al. 1988Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01J Natl Cancer Inst80219PubMedCrossRefGoogle Scholar
  76. 76.
    Wolmark, N, Wieand, S, Hyams, DM, Colangelo, L, Dimitrov, NV, Romond, EH,  et al. 2000Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02J Natl Cancer Inst9238896PubMedCrossRefGoogle Scholar
  77. 77.
    Mori, T, Takahashi, K, Yasuno, M 1998Radical resection with autonomic nerve preservation and lymph node dissection techniques in lower rectal cancer surgery and its results: the impact of lateral lymph node dissectionLangenbecks Arch Surg38340915PubMedCrossRefGoogle Scholar
  78. 78.
    The Colorectal Cancer Chemotherapy Study Group of Japan1995Five-years results of randomized controlled trial of adjuvant chemotherapy for curatively resected colorectal cancerJpn J Clin Oncol2591103Google Scholar
  79. 79.
    Kodaira, S, Kikuchi, K, Yasutomi, M, Takahashi, T, Hojo, K, Kato, T,  et al. 1998Postoperative adjuvant chemotherapy with mitomycin C and UFT for curatively resected rectal cancer. Results from the Cooperative Project No.7 Group of the Japanese Foundation for Multidisciplinary Treatment of CancerInt J Clin Cancer335764Google Scholar
  80. 80.
    Watanabe, M, Nishida, O, Kunuii, Y, Kodaira, S, Takahashi, T, Tominaga, T,  et al. 2004Randomized controlled trial of the efficacy of adjuvant immunotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil and uracil/tegafurInt J Clin Oncol998106PubMedCrossRefGoogle Scholar
  81. 81.
    Meta-analysis Group of the Japanese Society for Colon and Rectum and the Meta-analysis Group in Japan2004Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trialsJ Clin Oncol2248492Google Scholar
  82. 82.
    Hamada, C, Sakamoto, J, Yasutomi, M, Saji, S, Nakazato, H, Yoshida, S,  et al. 2005Meta-analysis Project Group Japanese Society for Cancer of Colon and RectumJ Clin Oncol23s263sabstract #3571Google Scholar
  83. 83. Scholar
  84. 84.
    Tokudome, N, Ito, N 2006Adjuvant chemotherapy based on evidence-based medicine for breast cancer patientsJpn J Cancer Chemother3331823Google Scholar
  85. 85.
    Goldhirsch, A, Glick, JH, Gelber, RD, Coates, AS, Thurlimann, B, Senn, HJ 2006Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005Ann Oncol16156983CrossRefGoogle Scholar
  86. 86.
    Bonadonna, G, Brusamolino, E, Valagussa, P, Rossi, A, Brugnatelli, L, Brambilla, C,  et al. 1976Combination chemotherapy as an adjuvant treatment in operable breast cancerN Engl J Med29440510PubMedCrossRefGoogle Scholar
  87. 87.
    Early Breast Cancer Trialists' Collaborative Group1998Polychemotherapy for early breast cancer: an overview of the randomised trialsLancet35293042CrossRefGoogle Scholar
  88. 88.
    Early Breast Cancer Trialists' Collaborative Group2005Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trialsLancet36516871717CrossRefGoogle Scholar
  89. 89.
    Levine, MN, Whelan, BM 2006Adjuvant chemotherapy for breast cancer — 30 years laterN Engl J Med35519202PubMedCrossRefGoogle Scholar
  90. 90.
    Henderson, IC, Berry, DA, Demetri, GD, Cirrincione, CT, Goldstein, LJ, Martino, S,  et al. 2003Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancerJ Clin Oncol2197683PubMedCrossRefGoogle Scholar
  91. 91.
    Citron, ML, Berry, DA, Cirrincione, C, Hudis, C, Winer, EP, Gradishar, WJ,  et al. 2003Randomized trial of dose-dense versus convertionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741J Clin Oncol2114319PubMedCrossRefGoogle Scholar
  92. 92.
    Mamounas, E, Bryant, J, Lembersky, B, Fehrenbacher, L, Sedlacek, SM, Fisher, B,  et al. 2005Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28J Clin Oncol23368696PubMedCrossRefGoogle Scholar
  93. 93.
    Roche, H, Fumoleau, P, Spielman, M, Canon, JJ, Delozier, T, Serin, D,  et al. 2006Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 TrialJ Clin Oncol2456645671PubMedCrossRefGoogle Scholar
  94. 94.
    Martin, M, Pienkowski, T, Mackey, J, Pawlicki, M, Guastalla, JP, Weaver, C,  et al. 2005Adjuvant docetaxel for node-positive breast cancerN Engl J Med35223022013PubMedCrossRefGoogle Scholar
  95. 95.
    Jones, SE, Savin, MA, Holmes, SF, O'Shaughnessy, JA, Blum, J, Vukeija, S,  et al. 2006Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancerJ Clin Oncol2453815387PubMedCrossRefGoogle Scholar
  96. 96.
    Joensuu, H, Kellokumpu-Lehtinen, PL, Bono, P, Alanko, T, Kataja, V, Asola, R,  et al. 2006Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancerN Engl J Med354809820PubMedCrossRefGoogle Scholar
  97. 97.
    Takeuchi, H, Okubo, K, Fujiuchi, N, Saeki, T 2006Current status of adjuvant chemotherapy for breast cancerJpn J Cancer Chemother33736741Google Scholar
  98. 98.
    Hutchins, LF, Green, SJ, Ravdin, PM, Lew, D, Martino, S, Abeloff, M,  et al. 2005Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102J Clin Oncol2383138321PubMedCrossRefGoogle Scholar
  99. 99.
    Iglesias, L, Moreno, JA, Torrija, E, Murillo, E, Codes, M, Duque, A,  et al. 1997UFT in combination as adjuvant therapy for breast cancerOncology117481PubMedGoogle Scholar
  100. 100.
    Hata, Y, Uchino, J, Asaishi, K, Kubo, Y, Tanabe, T, Ogita, M,  et al. 1999UFT and mitomycin plus tamoxifen for stage II, ER-positive breast cancer. Hokkaido ACETBC Study GroupOncology13ss91s95Google Scholar
  101. 101.
    Sugimachi, K, Maehara, Y, Akazawa, K, Nomura, Y, Eida, K, Ogawa, M,  et al. 1999Nishinihon Cooperative Study Group of Adjuvant Chemotherapy for Breast Cancer. Postoperative chemo-endocrine treatment with mitomycin C, tamoxifen, and UFT is effective for patients with premenopausal estrogen receptor-positive stage II breast cancerBreast Cancer Res Treat56113124PubMedCrossRefGoogle Scholar
  102. 102.
    Kasumi, F, Yoshimoto, M, Uchino, J, Abe, R, Nomura, Y, Sugimachi, K,  et al. 2003Meta-analysis of five studies on tegafur plus uracil (UFT) as post-operative adjuvant chemotherapy for breast cancerOncology64146153PubMedCrossRefGoogle Scholar
  103. 103.
    Watanabe, T 1998Phase III randomized comparison of postoperative adjuvant chemotherapy with 2-year oral UFT (uracil / tegafur) versus six-cycle CMF (cyclophosphamide / methotrexate / 5fluorouracil) in high-risk-node-negative breast cancer patientsJpn J Clin Oncol287780PubMedCrossRefGoogle Scholar
  104. 104.
    Watanabe, T 1998Phase III randomized comparison of postoperative adjuvant chemotherapy with 2-year oral uracil / tegafur versus 6-cycle cyclophosphamide / methotrexate / 5-fluorouracil in high-risk node-negative breast cancer patientsCancer Chemother Pharmacol42s68s70PubMedCrossRefGoogle Scholar
  105. 105.
    Watanabe, T, Sano, M, Takashima, S, Kitaya, T, Tokuda, Y, Yoshimoto, M,  et al. 2007Oral uracil-tegafur (UFT) compared to classical cyclophosphamide/methotrexate/5-fluorouracil (CMF) as postoperative chemotherapy in patients with node-negative, high-risk breast cancer (BC): Results of the national surgical adjuvant study for breast cancerJ Clin Oncol25551Google Scholar
  106. 106.
    Inaji, H, Park, Y, Okamura, K, Mitsuyama, S, Saito, T, Koh, J,  et al. 2004A randomized controlled study comparing CMF plus TAM with UFT plus TAM as postoperative adjuvant therapy in women with node-positive breast cancerJ Clin Oncol22s23sabstract #586Google Scholar
  107. 107.
    Inaji, H, Sakai, K, Oka, T, Ozawa, K, Saito, Y, Senoo, T,  et al. 2006A randomized controlled study comparing uracil-tegafur (UFT) + tamoxifen (UFT + TAM therapy) with cyclophosphamide + adriamycin + 5-fluorouracil (CAF therapy) for women with stage I, II, or IIIa breast cancer with four more involved nodes in the adjuvant settingJpn J Cancer Chemother3314231429Google Scholar
  108. 108.
    Tanaka, F, Wada, H 2006Efficacy of postoperative adjuvant therapy for resected non-small cell lung cancer. An evidence-based reviewJpn J Cancer Chemother33300306Google Scholar
  109. 109.
    Alam, N, Shepherd, FA, Winton, T, Graham, B, Johnson, D, Livingston, R,  et al. 2005Compliance with post-operative adjuvant chemotherapy in non-small cell lung cancer. An analysis of National Cancer Institute of Canada and intergroup trial JBR.10 and a review of the literatureLung Cancer47385394PubMedCrossRefGoogle Scholar
  110. 110.
    Fukushima, M, Morita, M, Ikeda, K, Nagayama, S 2003Population study of expression of thymidylate synthase and dihydropyrimidine dehydrogenase in patients with solid tumorsInt J Mol Med12839844PubMedGoogle Scholar
  111. 111.
    Basaki, Y, Chikahisa, L, Aoyagi, K, Miyadera, K, Yonekura, K, Hashimoto, A,  et al. 2001gamma-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factorAngiogenesis4163173PubMedCrossRefGoogle Scholar
  112. 112.
    Basaki, Y, Aoyagi, K, Chikahisa, L, Miyadera, K, Hashimoto, A, Yonekura, K,  et al. 2000UFT and its metabiolites inhibit cancer-induced angogenesis. Via a VEGF-related pathwayOncology1468s71sGoogle Scholar
  113. 113.
    Tanaka F, Wada H, Fukushima M. Anti-angiogenic effect of UFT and its clinical significance in postoperative adjuvant therapy for non-small cell lung cancer. Proc ASCO 21(part2);212b(abstract #2669Google Scholar
  114. 114.
    Munoz, R, Man, S, Shaked, Y, Lee, CR, Wong, J, Francia, G,  et al. 2006Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapyCancer Res6633863391PubMedCrossRefGoogle Scholar
  115. 115.
    Folkman, J, Watson, K, Ingiber, D, Hanahan, D 1989Induction of angiogenesis during the transition from hyperplasia to neoplasiaNature3395861PubMedCrossRefGoogle Scholar
  116. 116.
    Folkman, J 1991What is the evidence that tumors are angiogenesis-dependent?J Natl Cancer Inst8246CrossRefGoogle Scholar
  117. 117.
    Naumov, GN, Akslen, LA, Folkman, J 2006Role of angiogenesis in human tumor dormancy: animal models of the angiogenic switchCell Cycle517791787PubMedGoogle Scholar
  118. 118.
    Fukuse, T, Hirata, T, Naiki, H, Hitomi, S, Wada, H 2000Prognostic significance of proliferative activity in pN2 non-small-cell lung carcinomas and their mediastinal lymph node metastasesAnn Surg232112118PubMedCrossRefGoogle Scholar
  119. 119.
    Tanaka, F, Yanagihara, K, Otake, Y, Kawano, Y, Miyahara, R, Takenaka, K,  et al. 2004Prognostic factors in resected pathologic (p-) stage IIIA-N2, non-small cell lung cancer (NSCLC)Ann Surg Oncol11612618PubMedCrossRefGoogle Scholar
  120. 120.
    Carbone, DP, Mitsudomi, T, Chiba, I, Piantadosi, S, Rusch, V, Nowak, JA,  et al. 1994p53 immunostaining positively is associated with reduced survival and imperfectly correlated with gene mutations in resected non-small cell lung cancer. A preliminary report of LCSG 871Chest106377s381sPubMedGoogle Scholar
  121. 121.
    Ebina, M, Steinberg, SM, Mulshine, JL, Linnoila, RI 1994Relationship of p53 overexpression and up-regulation of proliferating cell nuclear antigen with the clinical course of non-small cell lung cancerCancer Res5424962503PubMedGoogle Scholar
  122. 122.
    Tanaka, F, Kawano, Y, Li, M, Takata, T, Miyahara, R, Yanagihara, K,  et al. 1999Prognostic significance of apoptotic index in completely resected non-small-cell lung cancerJ Clin Oncol1727282736PubMedGoogle Scholar
  123. 123.
    Tanaka, F, Otake, Y, Yanagihara, K, Kawano, Y, Miyahara, R, Li, M,  et al. 2003Correlation between apoptotic index and angiogenesis in non-small cell lung cancer (NSCLC): comparison between CD105 and CD34 as a marker of angiogenesisLung Cancer39289296PubMedCrossRefGoogle Scholar
  124. 124.
    Macchiarini, P, Fontanini, G, Hardin, MJ, Squartini, F, Angeletti, CA 1992Relation of neovascularization to metastasis of non-small-cell lung cancerLancet340145146PubMedCrossRefGoogle Scholar
  125. 125.
    Tanaka, F, Otake, Y, Yanagihara, K, Kawano, Y, Miyahara, R, Li, M,  et al. 2001Evaluation of angiogenesis in non-small cell lung cancer: comparison between anti-CD34 antibody and anti-CD105 antibodyClin Cancer Res734103415PubMedGoogle Scholar
  126. 126.
    Tanigawa, N, Amaya, H, Hatsumura, M, Shimomatsuya, T, Horiuchi, T, Muraoka, R,  et al. 1996Extent of tumor vascularization correlates with prognosis and hematogenous metastasis in gastric carcinomasCancer Res5626712676PubMedGoogle Scholar
  127. 127.
    Saclarides, TJ, Speziale, NJ, Drab, E, Szeluga, DJ, Rubin, DB 1994Tumor angiogenesis and rectal carcinomaDis Colon Rectum37921926PubMedCrossRefGoogle Scholar
  128. 128.
    Weidner, N, Semple, JP, Weich, WR, Folkman, J 1991Tumor angiogenesis correlates and metastasis — correlation in invasive breast carcinomaN Engl J Med32418PubMedCrossRefGoogle Scholar
  129. 129.
    Toi, M, Kashitani, J, Tominaga, T 1993Tumor angiogenesis is an independent prognostic indicator in primary breast carcinomaInt J Cancer55371374PubMedCrossRefGoogle Scholar
  130. 130.
    Ferrara, N, Kerbel, RS 2005Angiogenesis as a therapeutic targetNature438967974PubMedCrossRefGoogle Scholar
  131. 131.
    Kerbel, RS 2006Antiangiogenic therapy: a universal chermosensitization strategy for cancer?Science31211711175PubMedCrossRefGoogle Scholar
  132. 132.
    Hurwitz, H, Fehrenbacher, L, Novotny, W, Cartwright, T, Hainsworth, J, Heim, W,  et al. 2004Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancerN Engl J Med35023352342PubMedCrossRefGoogle Scholar
  133. 133.
    Giantonio, BJ, Catalano, PJ, Meropol, NJ, O'Dwyer, PJ, Mitchell, EP,  et al. 2006High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200J Clin Oncol24s1sabstract #2Google Scholar
  134. 134.
    Sandler, A, Gray, R, Perry, MC, Brahmer, J, Schiller, J, Dowlati, A,  et al. 2007Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancerN Engl J Med35525422550CrossRefGoogle Scholar
  135. 135.
    Miller, KD, Chap, LI, Holmes, FA, Cobleigh, MA, Marcom, PK, Fehrenbacher, L,  et al. 2005Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancerJ Clin Oncol23792799PubMedCrossRefGoogle Scholar
  136. 136.
    Miyahara, R, Nakagawa, T, Ishikawa, S, Fukushima, M, Wada, H, Tanaka, F 2005UFT inhibits lung metastases in sponstaneous metastasis model of lung cancerThorac Cardiovasc Surgeon53118121CrossRefGoogle Scholar
  137. 137.
    Tanaka, F, Otake, Y, Yanagihara, K, Kawano, Y, Miyahara, R, Li, M,  et al. 2003Correlation between apoptotic index and angiogenesis in non-small cell lung cancer (NSCLC):comparison between CD105 and CD34 as a marker of angiogenesisLung Cancer39289296PubMedCrossRefGoogle Scholar
  138. 138.
    Tanaka, F, Otake, Y, Yanagihara, K, Yamada, T, Miyahara, R, Kawano, Y,  et al. 2001Apoptosis and p53 status predict the efficacy of postoperative administration of UFT in non-small cell lung cancerBr J Cancer84263269PubMedCrossRefGoogle Scholar
  139. 139.
    Nakagawa, T, Tanaka, F, Tanaka, T, Matsuoka, K, Miyahara, R, Otake, Y,  et al. 2002Predictive value of dihydropyrimidine dehydrogenase expression in tumor tissue regarding the efficacy of post-operatively administered UFT (Tegafur + Uracil) in patients with p-stage I non-small cell lung cancerJ Surg Oncol818792PubMedCrossRefGoogle Scholar
  140. 140.
    Nakano, J, Huang, C, Liu, D, Masuya, D, Nakashima, T, Yokomise, H,  et al. 2006Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFTBr J Cancer95607615PubMedCrossRefGoogle Scholar
  141. 141.
    Shirasaka, T, Nakano, K, Takechi, T, Satake, U, Uchida, J, Fujioka, A,  et al. 1996Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude ratsCancer Res5626022606PubMedGoogle Scholar
  142. 142.
    Takechi, T, Nakano, K, Uchida, J, Mita, A, Toko, K, Takeda, S,  et al. 1997Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in ratsCancer Chemother Pharmacol39205211PubMedCrossRefGoogle Scholar
  143. 143.
    Tatsumi, K, Fukushima, M, Shirasaka, T, Fujii, S 1987Inhibitory effects of pyrimidine, barbituric acid and pyridine derivatives on 5-fluorouracil degradation in rat liver extractsJpn J Cancer Res78748755PubMedGoogle Scholar
  144. 144.
    van Groeningen, CJ, Peters, GJ, Schornagel, JH, Gall, H, Noodhuis, P, de Vries, MJ,  et al. 2000Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumorsJ Clin Oncol1827722779PubMedGoogle Scholar
  145. 145.
    Yamada, Y, Hamaguchi, T, Goto, M, Muro, K, Matsumura, Y, Shimada, Y,  et al. 2003Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infustion of 5-fluorouracilBr J Cancer89816820PubMedCrossRefGoogle Scholar
  146. 146.
    Furuse, K, Kawahara, M, Hasegawa, K, Kudoh, S, Takada, M, Sugiura, T,  et al. 2001Early phase II study of S-1, a new oral fluoropyrimidine, for advanced non-small-cell lung cancerInt J Oncol6236241CrossRefGoogle Scholar
  147. 147.
    Kawahara, M, Furuse, K, Segawa, Y, Segawa, Y, Yoshimori, K, Matsui, K,  et al. 2001Phase II study of S-1, a novel oral fluorouracil, in advanced non-small-cell lung cancerBr J Cancer85939943PubMedCrossRefGoogle Scholar
  148. 148.
    Sakata, Y, Ohtsu, A, Horikoshi, N, Sugimachi, K, Mitachi, Y, Taguchi, T 1998Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patientsEur J Cancer3417151720PubMedCrossRefGoogle Scholar
  149. 149.
    Ohtsu, A, Baba, H, Sakata, Y, Mitachi, Y, Horikoshi, N, Sugimachi, K,  et al. 2000Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study GroupBr J Cancer83141145PubMedCrossRefGoogle Scholar
  150. 150.
    Sasako, M, Saka, M, Fukagawa, T, Katai, H, Sano, T 2006Adjuvant chemotherapy using S-1 for curatively resected gastric cancer- The nationwide clinical trialJpn J Cancer Chemother33110116Google Scholar

Copyright information

© Springer-Verlag Tokyo 2007

Authors and Affiliations

  • Fumihiro Tanaka
    • 1
  1. 1.Department of Thoracic SurgeryHyogo College of MedicineNishinomiyaJapan

Personalised recommendations