Morihiko Kimura

A Phase II Study of S-1 in Patients with Metastatic Breast Cancer : A Japanese Trial by the S-1 Cooperative Study Group, Breast Cancer Working Group

BackgroundS-l is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoro-pyrimidine drug consisting of 1 M tegafur (FT), 0.4 M 5-chloro-2, 4-dihydroxypyrimidine (gimeracil), and 1 M potassium oxonate (oteracil), with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric, head and neck cancers. We investigated its clinical efficacy against metastatic breast cancer.MethodsA non-blind phase II study was carried out to evaluate the efficacy and toxicity in metastatic breast cancer patients. Patients with measurable metastasis foci (n = 111) were enrolled, and 108 patients were regarded as eligible. S-l was administered orally at a standard dose of 80 mg/m2/day b.i.d. One course consisted of 28 consecutive days of administration followed by a 14-day rest, and courses were repeated up to six times.ResultsAmong the eligible patients, 10 had a complete response and 35 had a partial response, with an overall response rate (CRplus PR) of 41.7% (95% confidence interval: CI, 32.3–51.5%). The incidences of toxicity (≧ grade 3) were neutropenia 9.1%, anemia 0.9%, anorexia 3.6%, stomatitis 1.8%, nausea/vomiting 1.8%, diarrhea 0.9%, and fatigue 2.7%, however no treatment-related deaths were observed. The median survival time was 872 days (95% CI, 572-1,110 days). There was no difference in response rate or toxicity between the under 65-year-old group and the older group.ConclusionS-l was demonstrated to have high efficacy with low gastrointestinal toxicity even in older patients and will be a promising new chemotherapy drug for metastatic breast cancer.

Effects of toremifene (TOR) and tamoxifen (TAM) on serum lipids in postmenopausal patients with breast cancer.

This study clarified the difference in the effects on serum lipids between toremifene (TOR) and tamoxifen (TAM). To remove influencing factors, we investigated adjuvant therapy for hormone receptor-positive patients with breast cancer without lymph node metastasis. The subjects were 65 patients who were enrolled in a multicenter randomized comparative study between April 1997 and March 2001. As adjuvant therapy, 20 mg of TAM or 40 mg of TOR was administered for 1 year. The levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-1 (Apo A-1), apolipoprotein A(Apo B), and lipoprotein a (Lp(a)) were measured prior to administration and 3, 6, and 12 months after the start of administration. TC, LDL-C, Lp(a) and Apo B significantly decreased from the third month of administration compared with values before the start of administration in both the TOR and TAM groups. HDL-C significantly increased from the third month only in the TOR group. TG significantly increased in the TAM group but significantly decreased in the TOR group in the 12th month of administration. When these two groups were compared, HDL-C was significantly higher ( p < 0.01) and TG was significantly lower ( p < 0.01) in the TOR group in the 12th month. Improvement of abnormal values of TG, HDL-C and LDL-C was better in the TOR group than in the TAM group after administration for 12 months. The effect on lipid metabolism showed different profiles between the two selective estrogen receptor modulators (SERMs), and TOR gave better results than TAM.

Outstanding problems with response evaluation criteria in solid tumors (RECIST) in breast cancer.

BackgroundIn 1999 European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States and National Cancer Institute of Canada published Response Evaluation Criteria in Solid Tumors (RECIST) as a revision of the WHO criteria to achieve a unified, objective set of criteria for assessing antitumor activity. The present paper discusses breast cancer assessment using RECIST and discusses various outstanding problems in breast cancer therapy.MethodsThe subjects were 50 advanced/recurrent breast cancer patients who were eligible/completed cases and were registered in various clinical trials at Gunma Cancer Center from 1995-2000. The subjects were investigated with regard to the application of RECIST to evaluate the appropriateness and efficacy of the criteria for these patients, in comparison with General Rules for Clinical and Pathological Recording of Breast Cancer formulated by the Japanese Breast Cancer Society QBCS). In addition, a study was conducted of the survival rate as a function of the initial site of metastasis in 258 recurrent cases.ResultsOf the 50 cases judged to be eligible by the JBCS General Rules, 16 cases (32%) were judged to be ineligible by RECIST. The results using the two sets of criteria were the same for CR and PD, while there were some differences in PR and SD/NC.ConclusionTo fully adopt RECIST for breast cancer, the following should be discussed further: (1) the exclusion of bone lesions (2) assessment of long NC (3) difference in survival by metastatic lesion site (4) eligible cases are reduced due to the exclusion of target lesions having a diameter of less than 2.0 cm.

Tuberculosis of axillary lymph nodes with primary breast cancer.

A rare case of tuberculosis of axillary lymph nodes occurring with primary breast cancer is presented. A 78-year-old woman with no history of pulmonary tuberculosis was admitted to our hospital to undergo examination for a lump in her right breast. The tumor was in the upper outer quadrant of the right breast. On palpation, the tumor was 1.2 cm in diameter and axillary lymph node swelling was noted. Mammography disclosed a spiculated mass and swelling and calcification of the axillary lymph nodes. Sonography showed an irregular hypoechoic mass in the right breast and lymph node swelling in the right axilla, indicating breast cancer with axillary lymph nodes metastases. Chest X-ray showed clustered calcifications in the right axilla and a granular shadow in the right upper lobe. Breast conserving therapy was carried out. Invasive papillotubular carcinoma of the right breast and granulomas with calcification of lymph nodes, compatible with tuberculosis, was diagnosed. Tubercle bacillis were detected by culture of lymph nodes. This case suggests that X-ray is useful for diagnosing lymph node tuberculosis. Lymph node tuberculosis should be suspected when lymph node swelling is noted and X-ray shows clustered calcifications in axillary lymph nodes.

Effects of toremifene and tamoxifen on lipid profiles in post-menopausal patients with early breast cancer: interim results from a Japanese phase III trial.

OBJECTIVE Toremifene and tamoxifen have been used for adjuvant therapy in post-menopausal patients with breast cancer in Japan. Dyslipidemias are common in post-menopausal women. However, limited data are available on the effects of these agents on lipid profiles in Japanese patients. The Japan Toremifene Cooperative Study Group has been conducting a Phase III randomized trial of post-menopausal patients with breast cancer. One of its secondary endpoints is to confirm the effects of these agents on serum lipid profiles. METHODS The subjects were post-menopausal Japanese patients who had undergone surgery for early breast cancer. Toremifene or tamoxifen was administered for 2 years. Lipid levels were measured before and up to 24 months after initiation. RESULTS Compared with baseline, at 24 months, the toremifene group (n = 123) showed significantly decreased total cholesterol (P < 0.001) and low-density lipoprotein cholesterol levels (P < 0.001), and significantly increased high-density lipoprotein cholesterol levels (P < 0.001). Their triglyceride levels were not affected (P = 0.677). The tamoxifen group (n = 120) also showed significantly decreased total cholesterol (P < 0.001) and low-density lipoprotein cholesterol levels (P < 0.001); no significant changes occurred in high-density lipoprotein cholesterol (P = 0.297) or triglyceride levels (P = 0.120). CONCLUSIONS Distinct differences between two selective estrogen receptor modulators on lipids were observed. Toremifene improved lipid profiles, particularly as an enhancer of high-density lipoprotein cholesterol. To a large extent, tamoxifen improved low-density lipoprotein cholesterol levels. The impact of these improved lipid profiles on the risk of cardiovascular diseases needs further confirmation.

Clinicopathological Study of Unilateral Multiple Breast Cancer

BackgroundThe tendency for breast cancer to form multiple lesions is important to consider when planning breast-conserving surgery. However, many unknowns remain regarding the pathology and prognosis of multiple breast cancer, and therefore it is clinically significant to investigate its clinicopathological properties.MethodsOver the past 25 years, in the period between April 1972 and March 1997, we investigated the clinicopathological findings including the 5-year and 10-year survival rates of 66 patients treated for unilateral multiple breast cancer.ResultsOf the total of 1,334 female patients with unilateral breast cancer who underwent curative surgery at our hospital, we identified 66 (5.0%) patients with unilateral multiple cancer. The incidence of such cancer has been higher in recent years. Of the 66 patients, 50 (75.8%) were premenopausal, and the remaining patients were postmenopausal, but multiple cancer among postmenopausal women is a recent phenomenon. The ER positivity rate of the main lesion in patients with multiple breast cancer was 69.2% and that of PgR was 50.0%. The 5-and 10-year overall survival rate in all 66 patients with multiple breast cancer was 90.8% and 79.7%, respectively.ConclusionIn the past, multiple breast cancer was frequently identified in premenopausal women. However, the current findings indicate that its incidence among postmenopausal women has increased in recent years. In addition, prognoses were comparable for patients with multiple or solitary breast cancer, a relevant finding in the planning of breast-conserving surgery.

Efficacy of doxifluridine combined with weekly paclitaxel therapy in the treatment of advanced or recurrent breast cancer: results of the JMTO BC01 phase II trial.

We conducted a phase II study to determine the availability and safety of combination chemotherapy with weekly paclitaxel and doxifluridine (a capecitabine metabolite) in the treatment of advanced or recurrent breast cancer. Patients were treated with a combination chemotherapy regimen: doxifluridine was orally administered at 800 mg/day for 14 days, followed by a 7-day washout period. Paclitaxel was given intravenously on days 1 and 8 at 80 mg/m2 for 1 h, followed by a 1-week washout period. This 3-week cycle of therapy was repeated as long as possible (at least eight cycles) until the progression of the tumor and drug-related adverse effects were no longer observed. From May 2003 to December 2005, 26 patients were enrolled in the study. The overall response rate was 53.8% (95% confidence interval, 33.4–73.4%). The clinical benefit rate, including long-term no change, was 65.4% (95% confidence interval, 44.3–82.8%). Time to progression and survival time were 297 and 1182 days, respectively, for the 26 enrolled patients. No severe toxicities were observed. Grade 3/4 leucopenia in three patients, neutropenia in five patients, increased serum creatinine in three patients, hypercalemia in one patient, hypocalcemia in one patient, nausea/vomiting in two patients, and diarrhea in one patient. The good response rate and long time to progression and overall survival time of this doxifluridine combined with weekly paclitaxel therapy indicate its potential as a first-line or second-line treatment for advanced or recurrent breast cancer patients.