Feasibility of AC/EC followed by weekly paclitaxel in node-positive breast cancer in Japan.

UNLABELLED: The feasibility and efficacy of adriamycin or epirubicin in combination with cyclophosphamide followed by weekly paclitaxel (AC/EC-weekly PAC) as adjuvant chemotherapy for breast cancer was investigated. PATIENTS AND METHODS: Node-positive breast cancer was treated with AC/ EC-weekly PAC, namely AC at 60/600 mg/m(2) or EC at 90/600 mg/m(2) x4 at three-week intervals, followed by weekly PAC (80 mg/m(2)) x 12, namely four cycles of single weekly administration for three weeks followed by a one-week rest (3 x 4 PAC) or single weekly administration for 12 consecutive weeks (12 PAC). RESULTS: One hundred and three of 109 consecutive patients enrolled were analyzed, of whom 96 (93.2%) completed the regimen. Grade 3/4 neutropenia occurred in 52.4% receiving AC/EC, and 10.9% of 55 receiving 12 PAC but only 2.1% of 48 receiving 3 x 4 PAC. Neuropathy disorders occurred in more than half receiving PAC, which did not improve after one-week rest in 3 x 4 PAC. CONCLUSION: AC/EC-weekly PAC is feasible and without serious complications.

Dofequidar fumarate (MS-209) in combination with cyclophosphamide, doxorubicin, and fluorouracil for patients with advanced or recurrent breast cancer.

PURPOSE: To evaluate the efficacy and tolerability of dofequidar plus cyclophosphamide, doxorubicin, and fluorouracil (CAF) therapy in comparison with CAF alone, in patients with advanced or recurrent breast cancer. Dofequidar is a novel, orally active quinoline derivative that reverses multidrug resistance. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled trial, patients were treated with six cycles of CAF therapy: 28 days/cycle, with doxorubicin (25 mg/m2) and fluorouracil (500 mg/m2) administered on days 1 and 8 and cyclophosphamide (100 mg orally [PO]) administered on day 1 through 14. Patients received dofequidar (900 mg PO) 30 minutes before each dose of doxorubicin. Primary end point was overall response rate (ORR; partial or complete response). In total, 221 patients were assessable. RESULTS: ORR was 42.6% for CAF compared with 53.1% for dofequidar + CAF, a 24.6% relative improvement and 10.5% absolute increase (P = .077). There was a trend for prolonged progression-free survival (PFS; median 241 days for CAF v 366 days for dofequidar + CAF; P = .145). In retrospectively defined subgroups, significant improvement in PFS in favor of dofequidar was observed in patients who were premenopausal, had no prior therapy, and were stage IV at diagnosis with an intact primary tumor. Except for neutropenia and leukopenia, there was no statistically significant excess of grade 3/4 adverse events compared with CAF. Treatment with dofequidar did not affect the plasma concentration of doxorubicin. CONCLUSION: Dofequidar + CAF was well tolerated and is suggested to have efficacy in patients who had not received prior therapy.

[Multicenter phase II trial of thrice-weekly docetaxel and weekly trastuzumab as preoperative chemotherapy in patients with HER 2-overexpressing breast cancer--Japan East Cancer Center Breast Cancer Consortium (JECBC) 02 Trial].

The efficacy and safety of combination therapy of 4 cycles with docetaxel 70 mg/m(2)every 3 weeks and trastuzumab as primary chemotherapy for operable breast cancer was determined in 21 patients (pts) by assessing the pathological complete response (pCR) rate, clinical response rate (RR), breast conservation surgery (BCS) rate and toxicities. To date, 19 pts have completed surgery. The pCR rate was 21% [95% CI 6%-46%] . The overall RR was 90% [95% CI 67%-99%] , with 5 CR, 12 PR, 2 SD and 0 PD. Grade 3 or 4 adverse events were leukopenia 48%, neutropenia 67%, hemoglobin 5%, and febrile neutropenia 10%. All non-hematological toxicities were mild and manageable. The pCR rate is not as low as that achieved in previous international studies. The combination of docetaxel and trastuzumab was a well-tolerated and very active regimen for the treatment of patients with HER 2-overexpressing operable breast cancer. This regimen promises to be one of the leading future treatments for progressive breast cancer.

Combination docetaxel and trastuzumab treatment for patients with HER-2-overexpressing metastatic breast cancer: a multicenter, phase-II study.

BACKGROUND: Pre-clinical and clinical studies indicate that a combination of docetaxel and trastuzumab may effectively treat patients with human epidermal growth factor receptor-2 (HER-2) overexpressing metastatic breast cancer. We evaluated the efficacy and safety of this combination in a multicenter, open-label phase II study in Japan. METHODS: Women with metastatic breast cancer whose tumors overexpressed HER-2, as assessed by immunohistochemistry and by fluorescence in situ hybridisation, received 2 to 6 cycles of docetaxel (70 mg/m2, every 3 weeks) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). The primary endpoint was tumor response. Secondary endpoints were time to disease progression and adverse events. RESULTS: Of the 40 women enrolled in the study, 27 (68%) completed 6 cycles of treatment. Three patients discontinued the study before the second cycle. Median follow-up was 20.8 months (range, 0.6 to 30.9 months). The overall response rate was 65% (26/40; 95% CI, 48% to 79%). The median time to progression was 6.8 months (range, 0.6 to 21.2 months). Of the 40 patients, 35 (88%) had grade 3 or 4 leukopenia, and 33 (83%) had grade 3 or 4 neutropenia. Most instances of leukopenia and neutropenia were manageable by reducing the dose of docetaxel or by treatment with granulocyte colony-stimulating factor. In 4 patients, left ventricular ejection fraction decreased by more than 10% from baseline. CONCLUSIONS: The combination of docetaxel and trastuzumab was as effective as reported in other similar studies and was well tolerated in these patients.

Late phase II clinical study of vinorelbine monotherapy in advanced or recurrent breast cancer previously treated with anthracyclines and taxanes.

BACKGROUND: At present, it is one of the most important issues for the treatment of breast cancer to develop the standard therapy for patients previously treated with anthracyclines and taxanes. With the objective of determining the usefulness of vinorelbine monotherapy in patients with advanced or recurrent breast cancer after standard therapy, we evaluated the efficacy and safety of vinorelbine in patients previously treated with anthracyclines and taxanes. METHODS: Vinorelbine was administered at a dose level of 25 mg/m(2) intravenously on days 1 and 8 of a 3 week cycle. Patients were given three or more cycles in the absence of tumor progression. A maximum of nine cycles were administered. RESULTS: The response rate in 50 evaluable patients was 20.0% (10 out of 50; 95% confidence interval, 10.0-33.7%). Responders plus those who had minor response (MR) or no change (NC) accounted for 58.0% [10 partial responses (PRs) + one MR + 18 NCs out of 50]. The Kaplan-Meier estimate (50% point) of time to progression (TTP) was 115.0 days. The response rate in the visceral organs was 17.3% (nine PRs out of 52). The major toxicity was myelosuppression, which was reversible and did not require discontinuation of treatment. CONCLUSION: The results of this study show that vinorelbine monotherapy is useful in patients with advanced or recurrent breast cancer previously exposed to both anthracyclines and taxanes.

[Study of three-weekly docetaxel and weekly trastuzumab treatment in HER 2-overexpressing metastatic breast cancer patients].

Docetaxel and trastuzumab can be considered to be active drugs for HER 2-overexpressing metastatic breast cancer (MBC). This study was conducted to determine the activity of combination therapy with docetaxel and trastuzumab in MBC patients (pts) by assessing the response rate (RR), time to progression (TTP) and safety. We administered the combination of docetaxel 70 mg/m2 every 3 weeks and trastuzumab using a 4 mg/kg loading dose and thereafter 2 mg/kg weekly. One cycle was three weeks. Between March 2002 and May 2003, 40 pts with HER 2-positive (3+by immunohistochemistry 39, FISH+1) MBC were enrolled in this study, and 39 pts proved eligible. The overall RR was 72% (28/39) [95%CI 55.1%-85.0%], with 6 CR, 22 PR, 7 SD, 1 PD and 3 NE. The median follow-up time was 14.3 months, while the TTP was 6.5 months (range, 0.6-19.8), median OS has not yet been reached. The number of pts assessable for safety was 40. Hematological Grade 3-4 toxicities were leukopenia 87.5% (35/40) and neutropenia 82.5% (33/40). Non-hematological Grade 3 toxicities were weight gain in 2 pts, and anorexia, neuropathy, fever and rash in one pt each. The combination of docetaxel and trastuzumab was a well-tolerated and very active regimen for the treatment of pts with HER 2-overexpressing MBC.

Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial.

PURPOSE: To investigate the efficacy and safety of zoledronic acid for the treatment of bone metastases from breast cancer. PATIENTS AND METHODS: Women with bone metastases (N = 228) were randomly assigned to receive 4 mg zoledronic acid (n = 114) or placebo (n = 114) via 15-minute infusions every 4 weeks for 1 year. The primary efficacy end point was the skeletal-related event (SRE) rate ratio between treatment groups. An SRE was defined as pathologic fracture, spinal cord compression, and radiation or surgery to bone. Secondary end points included percentage of patients with at least one SRE, time-to-first SRE, and Andersen-Gill multiple-event analysis. RESULTS: The SRE rate ratio at 1 year (excluding HCM and adjusted for prior fracture) was 0.61 (permutation test; P = .027), indicating that zoledronic acid reduced the rate of SRE by 39% compared with placebo. The percentage of patients with at least one SRE (excluding HCM) was significantly reduced by 20% by zoledronic acid (29.8% v 49.6% for placebo; P = .003). Zoledronic acid significantly delayed time-to-first SRE (median not reached v 364 days; Cox regression; P = .007) and reduced the risk of SREs by 41% in multiple event analysis (risk ratio = 0.59; P = .019) compared with placebo. Zoledronic acid was well tolerated with a safety profile similar to placebo. No patient treated with zoledronic acid had grade 3 or 4 serum creatinine increase. CONCLUSION: Zoledronic acid significantly reduced skeletal complications compared with placebo across multiple end points in Japanese women with bone metastases from breast cancer.

Sentinel lymphoscintigraphy in patients with breast cancer undergoing excisional biopsy.

UNLABELLED: Some small tumors of the breast cannot be diagnosed by needle biopsy, and an excisional biopsy is occasionally needed for the diagnosis. Sentinel node navigation surgery is frequently suitable for patients with such small breast cancers. The purpose of this study was to compare sentinel lymphoscintigrams in breast cancer patients who had previously undergone excisional biopsy with sentinel lymphoscintigrams in patients undergoing no excisional biopsy. We also investigated the possibility of clinical application of the sentinel node navigation procedure in the former group of patients. METHODS: Sentinel lymphoscintigrams of 43 patients with breast cancer undergoing excisional biopsy were compared to those of 116 patients without excisional biopsy. Lymphoscintigrams were obtained by using intradermal and/or subdermal injections of technetium-99m labeled phytate at 2 points on each side of the dermal incision in patients after excisional biopsy. Injections were performed at 2 points of the skin over the tumor in the patients who had not undergone excisional biopsy. RESULTS: Axillary lymph nodes were visualized in 42 of 43 patients undergoing excisional biopsy (98%) and in 115 of 116 patients without excisional biopsy (99%). The number of visualized axillary nodes was 1 to 5 (mean +/- SD = 2.1 +/- 1.0) and 1 to 5 (mean +/- SD = 1.9 +/- 1.0) in the two groups, respectively. No significant difference was determined between the two groups. Parasternal lymph nodes were depicted in 3 patients after excisional biopsy who had the tumor in the outer half of the breast, in contrast to 4 without excisional biopsy who had the tumor in the inner half. Intramammary hot spots were observed in 5 patients after excisional biopsy and in 2 without excisional biopsy. Lymphatic vessels were observed in 23 patients (53%) who had the excisional biopsy, and in 37 (32%) who did not have the biopsy. The former figure was significantly higher than the latter (p < 0.02). CONCLUSION: Sentinel node navigation surgery for axillary nodes was shown to be possible in patients undergoing excisional biopsy. However, the visualization of parasternal nodes, intramammary hot spots and lymphatic vessels tended to increase in number, and care must be exercised in the management of these patients.

A multicenter phase II study of docetaxel 60 mg/m2 as first-line chemotherapy in patients with advanced or recurrent breast cancer.

PURPOSE: Docetaxel is an active agent as first-line chemotherapy in patients with advanced breast cancer at a dosage of 100 mg/m2. However, the efficacy of this agent as a first-line drug when used at a lower dosage is unclear. This study was performed to evaluate the clinical efficacy and safety of 60 mg/m2 docetaxel for the treatment of breast cancer. PATIENTS AND METHODS: This study enrolled 23 patients with advanced and/or metastatic breast cancer, who had not been treated with an anthracycline or taxane previously. Treatment with docetaxel was continued in patients showing a response until there was evidence of disease progression or unacceptable toxicity. RESULTS: Among 20 fully evaluated patients, the overall response rate was 50.0% and the median time to progression was 31 weeks. The most commonly observed adverse events were neutropenia (78.2%) and fatigue (60.9%). Fluid retention occurred in only 8.7% of the patients. Adverse events did not cause discontinuation of the treatment. CONCLUSION: Docetaxel achieved good disease control with mild adverse events in first-line treatment at a dosage of 60 mg/m2.

1-hexylcarbamoyl-5-fluorouracil + cyclophosphamide + tamoxifen versus CMF + tamoxifen in women with lymph node-positive breast cancer after primary surgery: a randomized controlled trial.

We studied the usefulness of the oral 5-FU anti-cancer drug 1-hexylcarbamoyl-5-fluorouracil (HCFU) + cyclophosphamide (CPM) + tamoxifen (TAM) (HCT group) in comparison with CMF + TAM (CMFT group) in adjuvant therapy for breast cancer by a non-inferiority study based on a multi-institutional joint study. Clinical stage I, II primary breast cancers with histologically positive axillary lymph node metastasis were randomly assigned to the HCT group or the CMFT group after primary surgery. We registered 136 cases (HCT group 68 cases, CMFT group 68 cases). No significant difference in the 5-year overall survival rate (OS) and the 5-year disease-free survival rate (DFS) was found between the two groups. In the stratified analysis, DFS in cases in which the number of metastatic lymph nodes was 1-3 was significantly better in the HCT group (HCT group 84.3%, CMFT group 69.4%, log-rank test p=0.0496). No significant difference in the total incidence of adverse effects was found between the two groups, but there were significantly less adverse effects of grade 2 or over in the HCT group (p=0.034). The QOL survey at 3 months after surgery showed a significant decline of the QOL regarding lassitude, degree of difficulty in daily life, satisfaction with treatment and present mood in the CMFT group. Study results suggest that 2-year HCT therapy including the oral 5-FU anti-cancer drug HCFU is a useful adjuvant therapy which can replace CMFT therapy in early breast cancer cases with 3 or lower metastatic lymph nodes.

Combination chemotherapy with docetaxel and doxifluridine showed a beneficial outcome in advanced or recurrent breast cancer patients with longer disease-free interval.

UNLABELLED: Fundamental studies have confirmed that combination chemotherapy with docetaxel and doxifluridine (a capecitabine metabolite) is very useful in the treatment of breast cancer. This study investigated the usefulness and tolerability of a combination chemotherapy consisting of docetaxel administration on day 8 of doxifluridine therapy in 40 advanced/recurrent breast cancer patients. The overall response rate was 41.0% in 39 eligible patients. The median time to progression (TTP) for all patients was 295 days. Many responders had lung metastasis, soft tissue metastasis or a good performance status, whereas the clinical response showed no correlations with the estrogen receptor status or prior treatment with an anthracycline. The most common hematological toxicities were leukopenia and neutropenia, but dose reduction or delay of administration of either drug was unnecessary. CONCLUSION: The good response rate and long TTP of this doxifluridine plus docetaxel regimen indicate its potential as a first- or second-line treatment for advanced/recurrent breast cancer patients.