A multicenter Phase II study evaluating the efficacy, safety and pharmacokinetics of trastuzumab emtansine in Japanese patients with heavily pretreated HER2-positive locally recurrent or metastatic breast cancer.

OBJECTIVE: Trastuzumab emtansine significantly improved progression-free survival and overall survival when compared with lapatinib-capecitabine in pretreated human epidermal growth factor receptor 2-positive advanced breast cancer. However, data in Japanese populations are limited. METHODS: In the single-arm Phase II JO22997 study, Japanese patients with human epidermal growth factor receptor 2-positive inoperable locally advanced/recurrent or metastatic breast cancer previously treated with at least one prior chemotherapy regimen for locally advanced/recurrent or metastatic breast cancer and trastuzumab in any setting received 3.6 mg/kg trastuzumab emtansine every 3 weeks until progression, unacceptable toxicity or consent withdrawal. The primary endpoint was Independent Review Committee-assessed objective response rate. Secondary endpoints included progression-free survival, overall survival, safety and pharmacokinetics. RESULTS: The objective response rate in 73 treated patients was 38.4% (90% confidence interval, 28.8-48.6%), exceeding the prespecified boundary for an objective response rate > 20%. After 6.5 months' median follow-up, median progression-free survival was 5.6 months (95% confidence interval, 4.6-8.2). After 28.9 months' median follow-up, median overall survival was 30.5 months (95% confidence interval 25.2-not reached). There were no treatment-related deaths. The most common Grade 3/4 adverse events were thrombocytopenia (22%) and aspartate aminotransferase elevations (14%). Thrombocytopenia did not require platelet transfusion and typically recovered before the next cycle. There were no substantial differences in trastuzumab emtansine or trastuzumab pharmacokinetic parameters between this study and previous data from non-Japanese patients. CONCLUSIONS: JO22997 results suggest high activity of trastuzumab emtansine in Japanese patients, a safety profile consistent with previous studies in non-Japanese patients, no new safety signals and no evidence of pharmacokinetic differences between Japanese and non-Japanese populations. These results support trastuzumab emtansine therapy for Japanese patients with chemotherapy- and trastuzumab-pretreated human epidermal growth factor receptor 2-positive locally advanced/recurrent or metastatic breast cancer.

Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer.

BACKGROUND: Toremifene, a selective estrogen receptor modulator, is used as adjuvant therapy for postmenopausal patients with breast cancer in Japan. For Japanese patients, however, only limited data are available on the efficacy and safety profile of toremifene. To establish the long term efficacy and safety of toremifene for Japanese patients, we conducted a prospective, multicenter, randomized phase III trial comparing toremifene and tamoxifen. PATIENTS AND METHODS: The subjects were postmenopausal Japanese patients who had undergone surgery for node-negative breast cancer. Toremifene or tamoxifen was administered for 2 years. The primary endpoint was demonstration of the non-inferiority of toremifene compared with tamoxifen in respect of 5-year survival. Secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and adverse events. RESULTS: A total of 253 patients were enrolled. The baseline characteristics of the two treatment groups were well-balanced. Median follow-up was 66.5 months. Five-year survival was similar for toremifene and tamoxifen (97.0 vs. 96.9 %; 90 % confidence interval -3.9 to 4.1), indicating that toremifene is not inferior to tamoxifen for postmenopausal Japanese patients with early breast cancer. Cumulative overall survival and cumulative disease-free survival were also very similar for toremifene and tamoxifen (97.5 vs. 97.3 %, log-rank test P = 0.9458; 88.4 vs. 90.6 %, log-rank test P = 0.3359, respectively). Adverse events in both groups were similar and mostly mild or moderate. Thus, both are equally effective and well tolerated. CONCLUSION: Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer.

Are there high-risk subgroups for isolated locoregional failure in patients who had T1/2 breast cancer with one to three positive lymph nodes and received mastectomy without radiotherapy?

BACKGROUND: To define the factors associated with increased risk of isolated locoregional failure that may justify postmastectomy radiotherapy in patients with T1/2 breast cancer and 1-3 positive lymph nodes. METHODS: Between 1990 and 2002, 248 patients who had pT1-2 breast cancer and 1-3 positive lymph nodes were treated with mastectomy without radiotherapy (age 32-84, median 54). RESULTS: Median follow-up time was 82 months (range 2-189 months). For all patients, the 8-year isolated locoregional failure-free rate was 95 %. In univariate analysis, hormone receptor status and administration of hormone therapy were statistically significant factors, and vascular invasion was the borderline significant factor for isolated locoregional failure-free rates (P = 0.0377, 0.0181, and 0.0555, respectively). The 8-year isolated locoregional failure-free rates were 98 % for patients with positive hormone receptor status and 90 % for patients with negative hormone receptor status, 97 % for patients who received hormone therapy and 89 % for patients who did not receive hormone therapy, 92 % for patients with vascular invasion and 97 % for patients without vascular invasion. In multivariate analysis for hormone receptor status and vascular invasion, the former was statistically significant (P = 0.0491) and the latter was borderline significant (P = 0.0664). When patients had both negative hormone receptor and positive vascular invasion status, the 8-year isolated locoregional failure-free rates decreased to 83 %. CONCLUSIONS: With regard to patients who had pT1/2 breast cancer and 1-3 positive lymph nodes, isolated locoregional failure was not common in general; however, patients who had both negative hormone receptor status and vascular invasion were comparatively high-risk patients for isolated locoregional failure.

Promotion of quality-controlled mammography alone as a screening modality in Japan.

BACKGROUND: The rate of breast cancer screening in Japan has not increased, and it is thought that one of the reasons is the principle that mammography (MMG) and clinical breast examination (CBE) be carried out in combination. Nationwide, there is a shortage of physicians qualified to perform CBE, and in some regions mass-screening is performed by MMG alone out of a mobile MMG bus. In Shikoku, MMG is performed alone as a screening examination in Kochi and Ehime Prefectures. METHODS: A comparative analysis of the data generated by MMG alone in breast cancer screening in the four prefectures of Shikoku during the 2005-2009 period was performed. RESULTS: The overall attendance rates, recall, cancer detection, early-stage cancer detection, and the positive predictive value (PPV) were 16.8-24.5, 6.0-12.8, 0.26-0.37, 63.1-79.7, and 2.8-4.3 %, respectively. Almost no differences were seen between the results for MMG alone and combined MMG/CBE screening. In addition, the cancer detection rates based on the Japan Cancer Society's nationwide data were 0.25 % with combined MMG/CBE screening and 0.21 % with MMG alone, showing almost no difference. CONCLUSIONS: No differences were seen between the results (i.e., recall rate, cancer detection rate, early-stage cancer detection rate, PPV) for MMG alone and MMG/CBE screening in the four prefectures of Shikoku compared with the Japan Cancer Society's nationwide data. In order to improve the mammographic screening rate in Japan, quality-controlled mammography as a stand-alone examination should be promoted, and performed biennially for women aged 50-74 years.

Efficacy and safety of ixabepilone in taxane-resistant patients with metastatic breast cancer previously treated with anthracyclines: results of a phase II study in Japan.

PURPOSE: Anthracycline and taxane resistance is a key issue in the treatment of metastatic breast cancer (MBC), particularly in Asian patients who often present with advanced disease. The objective of this study was to investigate the efficacy and safety of ixabepilone monotherapy in Japanese patients with taxane-resistant MBC previously treated with anthracycline. PATIENTS AND METHODS: Japanese patients with taxane-resistant MBC previously treated with anthracycline were treated with 40 mg/m(2) ixabepilone every 3 weeks. Primary endpoint was overall response rate. Secondary endpoints included duration of response, time to progression (TTP), and safety. RESULTS: Fifty-two patients were treated with ixabepilone. Overall response rate was 11.5 % (95 % confidence interval 4.4-23.4), stable disease rate was 38.5 %, duration of response was 3.6 months (range 2.4-5.3 months), and TTP was 2.8 months (range 0.7-8.1 months). The most frequent grade 3/4 toxicities were neutropenia (82.7 %), leukopenia (75 %), myalgia (19.2 %), and peripheral neuropathy (19.2 %). CONCLUSION: Ixabepilone monotherapy was effective and toxicities were manageable in this phase II study of Japanese patients with taxane-resistant metastatic breast cancer previously treated with anthracyclines.

Impact of aggregate of risk factors for isolated locoregional failure in breast cancer patients treated with mastectomy without radiotherapy.

BACKGROUND: The impact of aggregate of risk factors on isolated locoregional failure after mastectomy without radiotherapy was assessed. METHODS: We reviewed 1091 patients who had stage I-III unilateral breast cancer and received mastectomy between 1990 and 2002. RESULTS: Median follow-up time was 67 (1-175) months. On multivariate analysis, four or more positive axillary lymph nodes (AXLN ≥4), pT4, primary tumor larger than 5 cm (T >5 cm), severe lymphatic invasion (ly2-3), and negative hormone receptor status (HR negative) were the statistically significant risk factors (hazard ratios 5.78, 2.31, 2.47, 2.99, and 3.40, respectively). The 8-year isolated locoregional failure-free rates of patients with single risk factor were 88% for AXLN ≥4, 93% for pT4, 93% for T >5 cm, 98% for ly2-3, and 97% for HR negative. Considering impact on isolated locoregional failure, AXLN ≥4 was termed the major risk factor and other factors were termed minor risk factors. The 8-year isolated locoregional failure-free rates were 98% for patients with only 0-1 minor risk factors (low-risk group), 86% for patients with the major risk factor alone or with only 2-4 minor risk factors (intermediate-risk group), 72% for patients with the major risk factor plus 1-2 minor risk factors (high-risk group), and 28% for patients with the major risk factor plus 3-4 minor risk factors (very high-risk group). CONCLUSIONS: Aggregate of risk factors increased the risk of isolated locoregional failure significantly. Patients with the major risk factor plus one or more minor risk factors seemed to be candidates for postmastectomy radiotherapy.

Identification of candidates for postmastectomy radiotherapy in patients with pT3N0M0 breast cancer.

BACKGROUND: There is still controversy concerning the indication of postmastectomy radiotherapy (PMRT) for pT3N0M0 breast cancer. To identify the candidates for PMRT in this subset, we investigated failure patterns, and searched for risk factors for isolated locoregional failure in pT3N0M0 breast cancer after mastectomy without PMRT. METHODS: Among 1,176 patients who received mastectomy without PMRT for untreated unilateral breast cancer between 1990 and 2002, 64 patients (5%) had pT3N0M0 breast cancer (age 30-81 years; median 52.5 years). RESULTS: Isolated locoregional failure as the initial failure occurred in three patients. For all 64 patients, the 8-year failure-free survival rate, the isolated locoregional failure-free rate, and the distant failure-free rate were 76, 93, and 82%, respectively. Incidence of isolated locoregional failure as the initial failure was 18% (2/11) for patients 40 years or younger and 2% (1/53) for patients older than 40 years. The 8-year isolated locoregional failure-free rates were 73% for patients 40 years or younger and 98% for patients older than 40 years (p = 0.0135). CONCLUSION: Concerning pT3N0M0 breast cancer, incidence of isolated locoregional failure was comparatively low after mastectomy without PMRT. Routine use of PMRT for all pT3N0M0 patients seemed to be unacceptable. PMRT may be useful for younger patients because of the comparatively high incidence of isolated locoregional failure. Because of the small number of cases in our series, further studies are necessary to determine the usefulness of PMRT for younger patients with pT3N0M0 breast cancer.

Long-term gemcitabine administration in heavily pretreated Japanese patients with metastatic breast cancer: additional safety analysis of a phase II study.

BACKGROUND: Recently gemcitabine has been approved for treatment of metastatic or recurrent breast cancer in Japan; however, no systematically investigated safety study of long-term gemcitabine monotherapy has been reported despite its wide use globally for multiple indications. PATIENTS AND METHODS: In a previously reported phase II study, 62 Japanese metastatic breast cancer patients with progressive disease after treatment with anthracyclines and taxanes were treated with gemcitabine 1250 mg/m(2) on days 1 and 8 of a 21-day cycle. For this report we re-analyzed the safety profiles for the 13 patients who received 10 or more cycles of the therapy. RESULTS: Most grade 3/4 adverse events seen after 10 cycles were hematological toxicities. These were similar to those seen before the 10th cycle; however, 2 patients showed grade 3 nonhematological severe adverse events including acute cardiac failure and loss of consciousness. All adverse events were reversible and manageable. One patient received gemcitabine treatment for up to 54 cycles without unmanageable toxicities. CONCLUSION: Toxicities seen in long-term gemcitabine treatment were reversible and manageable in this setting of heavily pretreated Japanese metastatic breast cancer patients.

First-line bevacizumab in combination with weekly paclitaxel for metastatic breast cancer: efficacy and safety results from a large, open-label, single-arm Japanese study.

UNLABELLED: Despite extensive evaluation of first-line bevacizumab-containing therapy in randomized trials in locally recurrent/metastatic breast cancer (LR/mBC), data from Japanese populations are limited. We conducted a phase II study exclusively in Japanese patients to evaluate bevacizumab combined with weekly paclitaxel. Patients with HER2-negative measurable LR/mBC who had received no prior chemotherapy for LR/mBC received bevacizumab 10 mg/kg, days 1 and 15, in combination with paclitaxel 90 mg/m(2), days 1, 8, and 15, repeated every 4 weeks, until disease progression, unacceptable toxicity, or patient/physician decision. Co-primary endpoints of this single-arm open-label phase II study were progression-free survival (PFS) and safety. A total of 120 patients (median age 55 years) received study therapy. At the time of data cut-off, the median duration of therapy was 11.1 months (range 0.5-24.7 months). Median PFS was 12.9 months (95% CI: 11.1-18.2) according to Independent Review Committee assessment and 14.9 months by investigator assessment. Median PFS was 9.6 months in the subgroup of 38 patients with triple-negative LR/mBC. The overall response rate was 74% (95% CI: 64.5-81.2%). Median overall survival (OS) was 35.8 months (95% CI: 26.4-not estimated) and the 1-year OS rate was 88.9% (95% CI: 83.2-94.6). The regimen was well tolerated and the safety profile was generally consistent with previous reports of bevacizumab-paclitaxel combination therapy. Grade 3 hypertension was reported in 17% of patients. Grade 4 hypertension, grade 3/4 proteinuria, and gastrointestinal perforation were absent. There were no new bevacizumab safety signals. In 50 patients (42%), treatment was continued for ≥ 1 year. CONCLUSION: The high activity of first-line bevacizumab in combination with weekly paclitaxel observed in our study confirms the results of the E2100 trial. Our results suggest that the activity and tolerability of first-line bevacizumab-containing regimens demonstrated in E2100 can be reproduced in Japanese populations.

Detection of isolated ipsilateral regional lymph node recurrences by F18-fluorodeoxyglucose positron emission tomography-CT in follow-up of postoperative breast cancer patients.

Imaging diagnostic methods except for mammograms are not recommended for follow-up of postoperative breast cancer patients in order to detect small recurrences because of the poor survival improvement in earlier randomized trials. However, the use of new imaging modalities may improve survival by detection of small isolated regional lymph node recurrences which are potentially curable. Between April 2006 and December 2008, we used PET-CT to find small recurrences in follow-up of 1,907 postoperative breast cancer patients. A total of 3,280 PET-CT imagings were performed. The median age at PET-CT imaging was 58 years, with a median 48-month interval from definitive surgery to the PET-CT imaging. Twenty-two patients were found to have isolated ipsilateral regional recurrences only by PET-CT (axillary node recurrences in 6, infraclavicular node recurrences in 5, supraclavicular node recurrences in 6, and parasternal node recurrences in 5). All of those recurrences were missed by palpation or were nonpalpable. The pathological lymph node status at the definitive surgery for the primary breast cancer of 22 patients with the isolated ipsilateral regional lymph node recurrences was positive in 17 patients. If patients are limited to those who had pathologically positive node(s) at definitive surgery, the incidence of patients with isolated regional lymph node recurrences found only by PET-CT would be 2.6% (17/663 patients). Seventeen other asymptomatic cancers including contralateral breast cancers were found only by PET-CT. Early detection of isolated loco-regional recurrences of breast cancer is suggested to result in improved survival. Therefore, the use of PET-CT in follow-up of postoperative node-positive breast cancer patients may improve their survival because of early detection of isolated regional lymph node recurrences which are still potentially curable, and screening of other asymptomatic cancers.

Suspicious calcifications in benign breast lesions: a radio-pathologic correlation.

BACKGROUND: Breast cancer screening by mammography (MMG) has recently increased in Japan. Suspicious lesions are therefore being detected more and more by MMG and the number of benign biopsies is increasing. It is thus important to examine which pathologically benign lesions were read as suspicious on MMG to reduce the number of biopsies in the case of benign breast lesions. METHODS: Of 299 category 3 or 4 lesions on MMG, 39 histologically benign lesions with calcification were reviewed and compared with the mammograms by a pathologist and a radiologist. The Japan Mammography Guidelines were used for MMG interpretation. RESULTS: In mastopathy lesions, small round segmental calcifications and pleomorphic clustered calcifications were assessed as suspicious. The suspicious type of calcification in fibroadenoma was small round clustered. The calcifications in fibroadenoma may be seen as small round when the fibroadenoma is rather young, and assessed as suspicious. CONCLUSIONS: Some types of calcifications in mastopathy and fibroadenoma were assessed as borderline by MMG. We should therefore collect data from more benign cases with suspicious calcifications on MMG and elucidate the diagnostic criteria in MMG findings of such calcifications.

The efficacy and safety of gemcitabine plus paclitaxel combination first-line therapy for Japanese patients with metastatic breast cancer including triple-negative phenotype.

PURPOSE: Gemcitabine (GEM)-paclitaxel combination therapy has been confirmed as a standard therapy for metastatic/recurrent breast cancer (MBC) in Western countries. This study was conducted to assess the efficacy and safety of GEM-paclitaxel combination therapy in Japanese MBC patients. METHODS: Patients were administered paclitaxel 175 mg/m(2) on day 1, and GEM 1,000 or 1,250 mg/m(2) on days 1 and 8 of 21-day cycle. The primary endpoint of this study was overall response rate; secondary endpoints were duration of response, time to progression, survival time and rate. RESULTS: Paclitaxel 175 mg/m(2) plus GEM 1,250 mg/m(2) was determined as the recommended dose. A total of 56 patients received 506 cycles of treatment (median: 7.5 cycles) with a relative dose intensity of 79.6% for GEM and 85.8% for paclitaxel. The response rate was 44.6% (25/56 patients), median time to progression 8.6 months and median survival time 27.1 months. In triple-negative patients, the response rate was 35.7% (5/14 patients), and the median time to progression was 6.0 months. The most frequent grade ≥ 3 toxicities were neutropenia (82.1%), leukopenia (62.5%) and ALT increase (14.3%). CONCLUSIONS: This study confirmed the efficacy and safety of GEM-paclitaxel combination therapy in Japanese MBC patients.

Endometrial Metastasis from Breast Cancer during Adjuvant Endocrine Therapy.

It is well-known that tamoxifen increases the risk of endometrial cancer. Although metastasis to the uterus from breast cancer is uncommon, there have been some case reports on uterine metastasis. If an endometrial abnormality is detected, the differential diagnosis of whether the uterine tumor is metastatic or primary is very important to determine the course of treatment. We herein report a case in which we detected a uterine tumor during follow-up after treatment with tamoxifen, and demonstrate that GCDFP-15 is useful in diagnosing metastatic uterine tumors arising from breast cancer.

Metastatic Breast Cancer to the Stomach Resembling Early Gastric Cancer.

Breast cancer metastases to the stomach are very rare. As characteristics of breast cancer metastases to the stomach, metastases of lobular carcinoma, mainly with signet ring cells, are frequently observed, and they are often difficult to distinguish from a primary gastric cancer with signet ring cells. Moreover, because no characteristic symptoms are shown and they involve a submucosal lesion, it is difficult to make a radiographic diagnosis. However, if a gastric lesion is observed after breast carcinoma surgery, differentiation between a gastric primary lesion and a metastatic lesion is very important in order to determine treatment. We encountered a case that was diagnosed as early gastric cancer discovered using an endoscope 2 years after surgery and which was found to be breast cancer metastasis to the stomach by gross cystic disease fluid protein (GCDFP) and cytokeratin (CK) 7/20 immunostaining of the biopsy tissue. Here, we report our findings of this unique case.

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.

Pulmonary angioplastic procedure for lung cancer surgery.

PURPOSE: Although bronchoplasty for the treatment of lung cancer is widely accepted as a reliable, safe procedure for the preservation of lung function, there have been only a few reports on pulmonary artery (PA) resection and reconstruction. METHODS: Retrospectively, we reviewed our medical records of pulmonary angioplastic procedures and assessed the results. RESULTS: A total of 25 patients (5 women, 20 men) with a mean age of 68 years (range 44-85 years) underwent a pulmonary angioplastic procedure for lung cancer surgery. Altogether, 13 patients had adenocarcinoma, and 11 had squamous cell carcinoma. The cancers were located in the left lung in 15 cases and in the right lung in 10 cases. The PA reconstructions comprised 4 circumferential resections and anastomoses, 18 wedge resections and end-to-end anastomoses, 2 tangential resections with direct suturing, and 1 wide wedge resection and autologous pericardial patch repair. Six patients underwent concomitant bronchoplasty with pulmonary artery reconstruction. Prior to surgical treatment, seven patients had received neoadjuvant therapy. Although early postoperative complications occurred in eight patients (32%), no operative or in-hospital deaths occurred. All the patients in this series were discharged from hospital and went home. The overall 5-year survival rate was 45%, with a mean 27 months of follow-up. CONCLUSION: Most operative complications after PA reconstruction were controllable despite the high morbidity rate. Pulmonary angioplastic procedures for the surgical treatment of lung cancer are both useful and feasible with good intermediate-term results.

Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan.

BACKGROUND: To compare the cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and the anthracycline-containing regimen cyclophosphamide, epirubicin, and fluorouracil (CEF) to evaluate the efficacy and safety of the latter. METHODS: A total of 294 patients with axillary node-positive primary breast cancer of STAGE I-IIIa were randomly assigned to either CEF [cyclophosphamide (CPA) 500 mg/m(2) i.v. days 1 and 8; epirubicin (EPI) 60 mg/m(2) i.v. day 1; and 5-fluorouracil (5-FU) 500 mg/m(2) i.v. days 1 and 8] or CMF [CPA 500 mg/m(2) i.v. days 1 and 8; methotrexate (MTX) 40 mg/m(2) i.v. days 1 and 8; and 5-FU 500 mg/m(2) i.v. days 1 and 8]. Both treatment regimens were comprised of six cycles at 4-week intervals. Tamoxifen (TAM) 20 mg/day was concomitantly given to estrogen receptor (ER)-positive patients and those with undetermined ER status for 2 years. RESULTS: The overall 5-year survival was 77.1% for CEF and 71.4% for CMF [p = 0.24; hazard ratio 0.79 (95% CI 0.50-1.24)], and the 5-year disease-free survival was 55.7% for CEF and 48.9% for CMF [p = 0.15; hazard ratio 0.80 (95% CI 0.57-1.12)]. Although the log-rank test did not show a significant difference, both overall and disease-free survivals were higher for CEF according to the point estimates. Adverse drug reactions (ADRs) occurred more frequently in CEF. CONCLUSION: Whereas CEF had a good trend compare with CMF, it could not be proven statistically significant. The principal cause of the failure seems to be insufficient power, that is, the dose intensity (EPI: 60 mg/m(2)) set 10 years ago, when the trial began, was low, and the number of trial subjects was small because of the background of the times, which made the accumulation of cases extremely difficult. However, the trial should be considered to be meaningful, as it was the first, formally conducted controlled trial on chemotherapy in Japan.

Efficacy and safety of S-1 in patients with metastatic breast cancer: retrospective review in a single institution.

BACKGROUND: It is extremely difficult to bring about a complete cure of metastatic breast cancer: the purpose of treatment is to prolong the patient's survival while maintaining their quality of life (QOL). The current retrospective study was conducted to find whether S-1, an orally administered 5-FU agent, can produce a therapeutic result in patients with recurrent metastatic breast cancer while maintaining their QOL. METHODS: Among the patients who were diagnosed at our institution to have recurrent metastatic breast cancer between November 2001 and December 2008, those who were treated with S-1 were selected and their records retrospectively reviewed. RESULTS: The analysis was conducted on 33 patients. The median number of regimens that these patients underwent was 2 (range 0-6). The overall response rate (ORR), clinical benefit rate (CBR), median time to treatment failure and overall survival were 30%, 42%, 152 days and 338 days, respectively. Among the 11 patients who were treated with S-1 in the first or the second line, ORR and CBR were 45.5 and 63.6%, respectively. Toxicity more than grade 3, leucopenia, neutropenia diarrhea, mucositis, and hand-foot syndrome were found in only 3%. CONCLUSION: S-1 is well-tolerated by patients, promising a therapy while maintaining their QOL. When applied in the early stage of a disease in particular, the agent promises a very effective anti-tumor effect.

[A case of recurrent breast cancer with extensive liver metastasis successfully treated with endocrine therapy].

A 5 6-year-old woman, who underwent breast-conserving surgery and radiation (60 Gy) therapy in July, 1992, at the age of 40, was diagnosed with pT1aN0M0, pStage I. She was administered tamoxifen (TAM) as adjuvant therapy. However, she underwent microdochectomy for DCIS in her contralateral breast in June, 1998. TAM was given till August, 1999. In June, 2006, at the age of 54, 14 years after initial surgery, CT revealed extensive liver masses which were diagnosed as liver metastasis by liver biopsy. Receptor status was positive for ER and PgR, and negative for HER2. AC was started as a first-line chemotherapy ( 4 courses), but did not prove effective. She refused second-line chemotherapy, so letrozole was selected, and subsequently resulted in PR of the liver metastasis. However, 8 months later, with a liver metastasis relapse, exemestane followed by tamoxifen, medroxyprogesterone acetate, and high-dose toremifene were administered sequentially, resulting in long-time disease control. In conclusion, endocrine therapy might be an effective option even in a visceral crisis, if metastatic tumors have showed slow growth and there is positive hormone receptor status.

Efficacy and tolerability of weekly paclitaxel in combination with high-dose toremifene citrate in patients with metastatic breast cancer.

Toremifene citrate is expected to prevent drug resistance in cancer patients by inhibiting p-glycoprotein activity. The safety and efficacy of combination therapy with high-dose toremifene citrate and paclitaxel were investigated. Between December 2003 and June 2004, 15 women with a mean age of 53 years old with metastatic breast cancer were enrolled. The administration schedule was 80 mg/m2 of paclitaxel given on Days 1, 8, and 15, and 120 mg/day of toremifene citrate orally administered starting on Day 18. On Days 32 and 39, paclitaxel was concurrently administered again. Toxicities, response rate, and time to treatment failure were assessed. All patients had been treated with endocrine or chemotherapy. Grade 3 leukopenia occurred in 2 patients on the administration of paclitaxel alone, and grade 3 febrile neutropenia occurred in 1 patient given the combination therapy. There was no grade 3 or greater non-hematological toxicity. There was no complete response and 1 partial response, producing a response rate of 6.7%. Median time to treatment failure was 2.7 months. Combination therapy of paclitaxel and toremifene was safe and well tolerated with minimal toxicity. Further clinical trials targeting patients with functional p-glycoprotein are warranted.