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

Watanabe, Tôru; Sano, Muneaki; Takashima, Shigemitsu; Kitaya, Tomoki; Tokuda, Yutaka; Yoshimoto, Masataka; Kohno, Norio; Nakagami, Kazuhiko; Iwata, Hiroji; Shimozuma, Kojiro; Sonoo, Hiroshi; Tsuda, Hitoshi; Sakamoto, Goi; Ohashi, Yasuo

doi:10.1200/jco.2008.18.3939

Cited by 88 publications

(57 citation statements)

References 27 publications

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“…Similar findings were recently reported in a randomised study of stage I -IIIA node-negative, pathologically high-risk breast cancer, which compared a 2-year administration of UFT with 6 cycles of CMF (Watanabe et al, 2009). Results indicated that the efficacy of UFT as an adjuvant treatment was comparable with that of CMF.…”

Section: Resultssupporting

confidence: 86%

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

et al. 2009

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BACKGROUND: It has been reported that treatment with uracil-tegafur (UFT) has shown significantly better survival and relapse-free survival (RFS) than surgery alone. Therefore, we compared UFT with a combination therapy of cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients who had undergone curative surgery for axillary lymph node-positive breast cancer. METHODS: A total of 377 node-positive patients with stage I, II, or IIIA disease were registered from September 1996 through July 2000 and were randomly assigned to either 6 cycles of CMF or 2 years of UFT. In both arms, tamoxifen (TAM) was concurrently administered for 2 years. The primary end point in this study was the non-inferiority of UFT to CMF. RESULTS: No statistically significant difference between the two groups was observed with regard to the 5-year RFS rate (72.2% in the UFT and 76.3% in the CMF). Adverse event profiles differed between the two groups, with a significantly lower incidence of leukopenia and anaemia in the UFT group, as well as anorexia, nausea/vomiting, stomatitis, and alopecia, which have implications for quality of life. CONCLUSION: UFT administered in combination with TAM holds promise in the treatment of lymph node-positive early breast cancer. On stratified analysis, the recurrence rate in the UFT group was found to be better in oestrogen receptor (ER)-positive patients. Tegafur-based treatment should be evaluated by a prospective randomised trial conducted in ER-positive patients.

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Section: Resultssupporting

confidence: 86%

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

et al. 2009

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“…Only 7 of these trials provided reference to historical data. A trial in breast cancer determined the noninferiority margin by a clinically leastacceptable HR of tegafur-uracil as compared with cyclophosphamide þ methotrexate þ 5-fluorouracil (5-FU; CMF), derived from a structured questionnaire among investigators (21). Among the 6 trials using the effect retention method, a retention proportion of 50% was most frequent (5 trials).…”

Section: Methods For Selecting a Noninferiority Marginmentioning

confidence: 99%

Statistical Issues and Recommendations for Noninferiority Trials in Oncology: A Systematic Review

Tanaka

Kinjo

Kataoka

et al. 2012

Clinical Cancer Research

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To provide an overview of noninferiority trials in oncology with a special emphasis on methodologic issues, we conducted a systematic review of randomized trials assessing noninferiority of antineoplastic treatments. We identified 72 articles, of which 65 were randomized phase III trials with a single control arm, 3 were factorial phase III trials, and 4 were randomized phase II trials. Forty-six were trials in lung, colorectal, or breast cancer. The quality of reporting was improved chronologically (P < 0.01); the major deficiencies were claims of noninferiority when the results did not meet statistical criteria for noninferiority (7 articles) or when the noninferiority margin was not prespecified (5 articles). Four trials (6%) presented plans for switching from superiority to noninferiority. The analysis populations were intent to treat (ITT) in 52, perprotocol set (PPS) in 6, and both ITT and PPS in 11 trials. Noninferiority margins were set in 68 trials (94%); 1 trial used both of the conventional and effect retention methods, 17 trials used the conventional method, 5 trials used the effect retention method, and in 45 trials, the method was not specified. Some trials used margins that possibly were larger than the assured effects of the active controls. No trials explicitly took into consideration uncertainty in historical data. Two trials (3%) specified 2 values of margins. Our findings highlight critical deficiencies in design and reporting of noninferiority trials. Seven practical recommendations are presented.

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“…In 2009, the results of the National Surgical Adjuvant Study for Breast Cancer 01 Trial (NSAS-BC01) [7] and the Comparative Trial of UFT + Tamoxifen with CMF + Tamoxifen in Adjuvant Therapy for Breast Cancer (CUBC) [8] -two recent Japanese clinical trials designed to establish whether intravenous or oral treatment was superior for postoperative adjuvant chemotherapy -were reported. The NSAS-BC01 trial compared CMF with UFT in high-risk patients with axillary node negative breast cancer.…”

Section: Chemotherapymentioning

confidence: 99%

Current status of therapy for breast cancer worldwide and in Japan

Park

Kitahara²,

Takagi³

et al. 2011

WJCO

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The results of clinical trials conducted in Europe and North America have been incorporated into treatment strategies for breast cancer in Japan. Despite the use of similar treatment regimens, why has mortality from breast cancer been increasing in Japan? Procedures for surgical treatment and sentinel lymph node biopsy in breast cancer do not differ between Japan and Western countries, but the strategies for radiotherapy differ slightly. Hormonal therapy is now selected on the basis of scientific evidence, and similar regimens are used in Japan and Western countries. As for postoperative adjuvant chemotherapy, an anthracycline plus cyclophosphamide and taxane-based regimens are standard treatments in Japan and Western countries. In 2009, however, the results of two large clinical studies designed to determine whether intravenous or oral treatment was superior for postoperative adjuvant chemotherapy were reported in Japan. Both studies showed that relapsefree survival and overall survival (OS) at 5 years after surgery were similar for a combination of cyclophosphamide, methotrexate, and 5-fluorouracil and for tegafur/uracil. Many chemotherapeutic agents that are used to treat recurrent or metastatic breast cancer have not yet been approved in Japan. As for molecular targeted therapy, some agents that target the human epidermal growth factor receptor family have been approved in Japan, whereas angiogenesis inhibitors have not. The results of many clinical trials have been incorporated into clinical practice in Japan, therefore, the outcomes of breast cancer therapy have surpassed those in other countries. Many pivotal clinical trials have been conducted outside Japan. Treatment regimens that have been developed on the basis of these studies might be suitable for the management of breast cancer in Western women, but not for Japanese women because of differences in genetic factors, physique, body mass index, pharmacokinetics, and drug metabolism. Such regimens should be modified on the basis of the characteristics of breast cancer in Japan to develop treatment that is optimally suited for Japanese women. In particular, local studies of pharmacokinetics, pharmacodynamics, and optimal dose levels and treatment intervals should be carefully performed. The establishment of treatment regimens optimally suited for Japanese patients with breast cancer could put the brakes on the trend towards increasing mortality from breast cancer in Japan.

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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

Abstract: RFS and OS with oral UFT were similar to those with classical CMF. Given the higher QOL scores, oral UFT is a promising alternative to CMF for postoperative adjuvant chemotherapy in women with node-negative, high-risk breast cancer.

Cited by 88 publications

References 27 publications

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

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

Statistical Issues and Recommendations for Noninferiority Trials in Oncology: A Systematic Review

Current status of therapy for breast cancer worldwide and in Japan

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