Japanese Journal of Clinical Oncology

IDENTIFICATION NUMBER

N·SASBC-01 (National Surgical Adjuvant Study of Breast Cancer Protocol 01)

CHIEF INVESTIGATOR

Toru Watanabe, MD, PhD
Department of Medical Oncology,
National Cancer Center Hospital,
Tokyo, Japan

DATE ACTIVATED

October 14, 1996

THERAPY MODALITY

Chemotherapy, postoperative adjuvant therapy, post-marketing clinical trial

BACKGROUND

Use of surgical adjuvant chemotherapy employing a combination of cytotoxic drugs, e.g. CMF (cyclophosphamide/methotrexate/5-fluorouracil)-type regimens, in certain subsets of patients with axillary lymph node-negative breast cancer has been established internationally by consensus, based on data obtained from large-scale clinical trials and their meta-analysis (1,2).

Japan has long had a unique standpoint on this issue. There are two prominent views on the evaluation of postoperative chemotherapy for breast cancer patients. The first view is that breast cancer in Japanese women is biologically less aggressive than that in Caucasian women. Evidence supporting this view is that 5-year disease-free survival rate in Japanese node-negative breast cancer patients is [sim]90%, which is apparently better than that observed in European or American women (3). The dominant opinion amongst Japanese surgeons is that cytotoxic chemotherapy is not indicated in node-negative breast cancer patients.

The second unique situation in Japan is that oral fluoropyrimidine compounds, e.g. UFT (Taiho Pharmaceutical, Tokyo) and doxifluridine (Japan Rosch, Tokyo) are widely used for breast cancer patients, both in adjuvant and metastatic settings, because of their low toxicity and because continued administration of them is easy. UFT is a combination of tegafur [1-(2-tetrahydrofuranyl)-5-fluorouracil]and uracil in molar ratio of 1:4. Tegafur is a prodrug and is slowly metabolized to 5-fluorouracil (5-FU). Preclinical studies indicated that UFT resulted in significantly higher tumor to serum 5-FU ratios than observed with tegafur alone. UFT is administered orally and is effective in gastric, colon, rectum and breast cancers (4). It is reported that gastrointestinal toxicity such as nausea/vomiting and diarrhea are the major side-effects but these occurred in less than 10% of patients who received oral UFT at a dose of 300-400 mg/day for 2 years (5). Although oral UFT has been evaluated for its anti-tumor activity in metastatic breast cancer (6) and prolongation of disease-free survival time in patients with stage II breast cancer (7), insufficient data are yet available to justify replacing the CMF-type regimen with oral UFT in postoperative chemotherapy of breast cancer patients.

In order to assess the usefulness of antineoplastic agents which are already available on the market, a government-funded program for developing a guideline for appropriately conducting clinical trials of those agents in the context of surgical adjuvant therapy (Chairperson: Kaoru Abe, President of the National Cancer Center) was founded in 1995. In accordance with the guideline draft, National Surgical Adjuvant Study Group (N·SAS) was organized to conduct clinical trials of post-operative adjuvant chemotherapy for breast cancer (N·SAS-BC), colon cancer (N·SAS-CC) and gastric cancer (N·SAS-GC). Initially, UFT was selected as the trial drug and nation-wide multi-institutional trials supported by a trust fund from Taiho Pharmaceutical were designed for the three cancers mentioned above.

The presence or absence of metastasis in the axillary lymph nodes is the most powerful prognostic indicator available in patients with primary breast cancer. Even in node-negative breast cancer patients, 5- and 10-year disease-free survival rates are 92 and 83%, respectively, according to the National Cancer Center database. Where there is considered to be a high risk of node-negative breast cancer recurring in patients, tumor size, estrogen receptor status and pathological tumor grade are recommended as the principal focuses for assessment. Because no reliable criterion for evaluating pathological grade has been established, the N·SAS-BC Pathology Committee developed new grading criteria for this study, which categorize node-negative breast cancer on a scale of 1 to 3. This is based on the nuclear grade, which is composed of nuclear atypia and mitotic counts. Research revealed that 75-80% of the patients categorized as nuclear grade 2 or 3 survived for 5 years and remained disease free. Therefore, by extrapolation, the 10-year disease-free survival rate is expected to be between 60 and 70%. Patients with grade 2 or 3 breast cancer, according to the N·SAS-BC pathological grade criteria, are likely to suffer recurrence in a ratio of 2-2.5:1 amongst all axillary lymph node-negative cancer patients.

For high-risk node-negative breast cancer patients selected by the grading criteria, a study protocol of a proposed randomized trial was designed, using surgical adjuvant chemotherapy comparing 2-year oral UFT versus six-course CMF. In order to compare the effectiveness of the two regimens and improve on the number of patients who survive and remain disease free for 5 years, a `test for the equivalency concept' was employed for this study. Clinically acceptable range was first determined for UFT by issuing a questionnaire to 78 N·SAS contributing doctors. Resulting data indicated that in a patient population where 5-year disease-free survival is 67% with no surgical adjuvant chemotherapy and 75% with CMF, the upper and lower expected limits of 5-year disease-free survival rate with UFT were 82.5 and 67.5%, respectively. This translates to a hazard ratio of recurrence of UFT to CMF of between 0.77 and 1.30. Where [alpha] error = 0.05 and [beta] error = 0.20, the required sample size in each treatment group was calculated to be 650 (8). The follow-up duration was set for 5-10 years depending on the number of recurrences observed in the period.

OBJECTIVES

1.   To compare disease-free survival with overall survival resulting from 2-year oral UFT (300 mg/m²) versus six courses of CMF in women with node-negative high-risk breast cancer.

2.   To assess side-effects, quality of life and cost-effectiveness of patient treatment when this protocol is used.

PROTOCOL ENTRY CRITERIA