Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan

Abstract

In Japan, the history of postoperative chemotherapy for breast cancer started with 5-fluorouracil (5-FU), launched in the 1980s. Currently, oral fluoropyrimidine-based regimens indicated for the treatment of breast cancer in Japan include tegafur plus uracil (UFT); tegafur, gimeracil, and oteracil (TS-1); doxifluridine; and capecitabine. In particular, UFT represents an important option for long-term treatment because of minimal adverse events and the potential for long-term maintenance of effective plasma concentrations of 5-FU to inhibit micrometastasis after surgery. Therefore, various clinical studies of postoperative adjuvant chemotherapy with UFT have been conducted in patients with completely resected tumors. Recent studies have shown that UFT prolongs survival after tumor resection in patients with gastric cancer, colorectal cancer, and lung cancer. In patients with breast cancer, large clinical trials of UFT-based postoperative chemotherapy conducted in Japan have shown that UFT is useful for the treatment of intermediate-risk patients with no lymph node metastasis. This paper reviews the results of clinical studies of UFT conducted in Japan to assess the therapeutic usefulness of this oral 5-FU. The types of patients most likely to benefit from UFT are discussed on the basis of currently available evidence and a global consensus of treatment recommendations. The optimal timing of endocrine therapy and strategies for postoperative adjuvant chemotherapy with UFT in patients with breast cancer are also discussed.

Figure 1.

Outline of the evolution of oral 5-fluorouracil–based treatments in Japan. Abbreviations: 5-FU, 5-fluorouracil; DPD, dihydropyrimidine dehydrogenase; TS-1, tegafur, gimeracil, and oteracil; UFT, tegafur plus uracil.

Figure 2.

Five-year DFS rates in the third ACETBC trial evaluating mitomycin and tamoxifen with or without UFT. (A): All eligible cases. (B): DFS curve in ER⁺ patients in the Hokkaido region of the third ACETBC study. Abbreviations: ACETBC, Adjuvant Chemoendocrine Therapy for Breast Cancer; DFS, disease-free survival; ER, estrogen receptor; UFT, tegafur plus uracil. Modified from Kasumi F, Yoshimoto M, Uchino J et al. Meta-analysis of five studies on tegafur plus uracil (UFT) as post-operative adjuvant chemotherapy for breast cancer. Oncology 2003;64:146–153, with permission of S. Karger AG, Basel; and from Ogita M, Uchino J, Asaishi K et al. Efficacy of UFT plus tamoxifen for estrogen-receptor-positive breast cancer and tamoxifen plus UFT for estrogen-receptor-negative breast cancer: Adjuvant therapy after administration of mitomycin. Clin Drug Investig 2003;23:689–699, with permission.

Figure 3.

Proportional risk reductions with adjuvant chemotherapy according to age at randomization. (A): Results of the EBCTCG analysis indicate that there was a significant trend toward a lower risk for mortality in older, compared with younger, women mainly treated with CMF-based polychemotherapy. (B): In contrast, data from the fourth ACETBC trial suggest that age at diagnosis does not significantly impact treatment benefit from UFT. Abbreviations: ACETBC, Adjuvant Chemoendocrine Therapy for Breast Cancer; EBCTCG, Early Breast Cancer Trialists' Collaborative Group; O-E, observation-expectation; PPC, polychemotherapy; SD, standard deviation; UFT, tegafur plus uracil; V, variance. Modified from Polychemotherapy for early breast cancer: An overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 1998;352:930–942, with permission; and from Noguchi S, Koyama H, Uchino J et al. 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 2005;23:2172–2184, with permission.

Figure 4.

Relapse-free survival time for patients treated with UFT or CMF participating in the N-SAS-BC 01 trial. Abbreviations: CI, confidence interval; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; N-SAS-BC, National Surgical Adjuvant Study of Breast Cancer; UFT, tegafur plus uracil. Modified from Watanabe T, Sano M, Takashima S et al. 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 2009;27:1368–1374, with permission.

Figure 5.

Five-year relapse-free survival rate in patients taking part in the CUBC trial. (A): All eligible cases. (B): ER⁻ cases. (C): ER⁺ cases. Abbreviations: CI, confidence interval; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; CUBC, Comparative Trial with UFT + TAM and CMF + TAM in Adjuvant Therapy for Breast Cancer; ER, estrogen receptor; HR, hazard ratio; UFT, tegafur plus uracil. Modified from Takatsuka Y, Park Y, Okamura K et al. Relationship between estrogen receptor (ER) status and efficacy of postoperative adjuvant chemotherapy with oral tegafur uracil (UFT) or CMF subset analysis from a randomized controlled trial (CUBC trial in Japan) [poster session at EBCC]. Eur J Cancer Suppl 2008;6:117–118.

Figure 6.

Impact of UFT or CMF on QOL in patients taking part in the N-SAS-BC 01 trial. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Breast 23 scores for social functioning (A), nausea and vomiting (B), and upset by hair loss (C). In the graph for social functioning, a higher score indicates better QOL, whereas for nausea and vomiting and upset by hair loss, lower scores indicate better QOL. (D): FACT-TOI. A higher score indicates better QOL. Data are presented as mean ± standard error. Abbreviations: ANCOVA, analysis of covariance; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; FACT-TOI, Functional Assessment of Cancer Therapy–Breast Total Outcome Index; N-SAS-BC, National Surgical Adjuvant Study of Breast Cancer; QOL, quality of life; UFT, tegafur plus uracil. Modified from Watanabe T, Sano M, Takashima S et al. 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 2009;27:1368–1374, with permission.