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Purpose: Findings from our previously published phase III randomized trial showed a high pathologic complete remission (CR) rate in patients with human epidermal growth factor receptor 2-positive breast cancer after the concurrent administration of trastuzumab and paclitaxel, followed by concurrent trastuzumab and 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) preoperative chemotherapy. The safety and efficacy data of initial population were updated, with inclusion of additional experience with the same therapy., Study Design: The initial randomized study population of 42 patients were randomly assigned to either four cycles of paclitaxel followed by four cycles of FEC or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. All data were updated through November 2005., Results: Pretreatment characteristics of the initial patients and of the second cohort were similar. In the second cohort, pathologic CR rate was 54.5% (95% confidence interval, 32.2-75.6%) and the pathologic CR rate among all patients treated with chemotherapy plus trastuzumab was 60% (95% confidence interval, 44.3-74.3%). Three patients in the chemotherapy only group have recurred, and one has died. There has been no recurrences in the patients randomized to chemotherapy plus trastuzumab, and the estimated disease-free survival at 1 and 3 years was 100% (P = 0.041). In additional cohort treated with chemotherapy and trastuzumab at the median follow-up of 16.3 months, no patients had recurred. No new safety concerns were observed in this study., Conclusion: Our expanded cardiac safety data and the updated efficacy data showed that the natural history of this subset of breast cancer patients can be substantially modified by this treatment approach.

Purpose: To determine the impact a change in schedule of paclitaxel administration from once every 3 weeks to frequent administration would have on the pathologic complete response (pCR) rate in the breast and lymph nodes for patients with invasive breast cancer treated with primary systemic chemotherapy (PST)., Patients and Methods: Patients with clinical stage I-IIIA breast cancer were randomly assigned to receive PST of paclitaxel doses administered either weekly (for a total of 12 doses of paclitaxel) or once every 3 weeks (four cycles), followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses every 3 weeks. Two different doses of paclitaxel were used based on lymph node status defined by ultrasound and fine needle aspiration. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after completion of all chemotherapy., Results: A total of 258 patients were randomly assigned to receive doses of paclitaxel administered either weekly or once every 3 weeks, followed by FAC. Of these 258 patients, 110 patients had histologic lymph node involvement and 148 patients had clinical N0 disease. Weekly paclitaxel followed by FAC was administered to 127 patients and once-every-3-weeks paclitaxel followed by FAC was administered to 131 patients. Clinical response to treatment was similar between groups (P = .25). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with once-every-3-weeks paclitaxel (15.7%; P = .02), with improved breast conservation rates (P = .05)., Conclusion: The change in schedule of paclitaxel from once every 3 weeks to a more frequent administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes.

In this article, we report on a case of a pregnant patient with synchronous bilateral breast cancer treated with weekly paclitaxel. She presented after right mastectomy and anthracycline-based chemotherapy at an outside facility. Staging studies at our hospital before taxane administration demonstrated a 19-20-week gravid uterus and tumor in the remaining left breast. Weekly paclitaxel was given preoperatively during pregnancy. A normal male infant was delivered. Upon completion of chemotherapy, the patient underwent mastectomy and axillary lymph node dissection followed by comprehensive radiation therapy to the chest wall.

Purpose: This Phase II study was designed to determine the efficacy and toxicity of combination doxorubicin and paclitaxel as front-line treatment for metastatic breast cancer., Experimental Design: Eligible patients had no prior anthracycline or taxane therapy and normal cardiac function. They were treated with bolus doxorubicin 60 mg/m2, followed by paclitaxel 200 mg/m2, as either 1- or 3-h infusions for six to seven cycles. Single-agent paclitaxel was continued thereafter. Serial multiple gated acquisition scans were performed, and endomyocardial biopsies were performed for consenting patients., Results: Eighty-two patients were enrolled with a median age of 53 years (range, 32-78 years). Of 79 evaluable patients, 58.2% had an objective response (3.8% complete response + 54.4% partial response), 34.2% had stable disease, and 7.6% had progressive disease. With median follow-up of 37.5 months, median time to progression was 7 months; median survival was 31 months. Multiple gated acquisition scans were performed in 82 of 82 patients at baseline, 75 of 82 patients at a total doxorubicin dose of 60-180 mg/m2, 62 of 68 patients at 200-300 mg/m2, 18 of 52 patients at 310-360 mg/m2, and 4 of 8 patients at 420 mg/m2. Median ejection fractions were 62.5, 60, 57.5, 52.5, and 32%, respectively. Fifteen of 82 (18.3%) patients had a decrease in ejection fraction > or = 15% to an absolute ejection fraction < or = 50%. Eight of these 15 patients (53%) developed clinical congestive heart failure: 4 of 8 (50%) who received a total doxorubicin dose of 420 mg/m2 versus 4 of 74 (5.4%) who received a dose < or = 360 mg/m2 (P = 0.002)., Conclusions: When the doxorubicin dose exceeds 360 mg/m2, the combination of bolus doxorubicin and paclitaxel presents unacceptable cardiac risk.

Purpose: ABI-007 is a novel Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. The absence of Cremophor EL may permit ABI-007 to be administered without the premedications used routinely for the prevention of hypersensitivity reactions. Furthermore, this novel formulation permits a higher paclitaxel concentration in solution and, thus, a decreased infusion volume and time. This Phase I study examines the toxicity profile, maximum tolerated dose (MTD), and pharmacokinetics of ABI-007., Experimental Design: ABI-007 was administered in the outpatient setting, as a 30-min infusion without premedications. Doses of ABI-007 ranged from 135 (level 0) to 375 mg/m2 (level 3). Sixteen patients participated in pharmacokinetic studies., Results: Nineteen patients were treated. No acute hypersensitivity reactions were observed during the infusion period. Hematological toxicity was mild and not cumulative. Dose-limiting toxicity, which occurred in 3 of 6 patients treated at level 3 (375 mg/m2), consisted of sensory neuropathy (3 patients), stomatitis (2 patients), and superficial keratopathy (2 patients). The MTD was thus determined to be 300 mg/m2 (level 2). Pharmacokinetic analyses revealed paclitaxel C(max) and area under the curve(inf) values to increase linearly over the ABI-007 dose range of 135-300 mg/m2. C(max) and area under the curve(inf) values for individual patients correlated well with toxicity., Conclusions: ABI-007 offers several features of clinical interest, including rapid infusion rate, absence of requirement for premedication, and a high paclitaxel MTD. Our results provide support for Phase II trials to determine the antitumor activity of this drug.

Purpose: Paclitaxel has significant antitumor activity in patients with metastaticbreast cancer who have been previously treated with or exposed to anthracycline-containing chemotherapy. In this prospective randomized trial, the role of paclitaxel was evaluated in an adjuvant setting to determine its impact on reducing the risk of recurrence in patients with operable breast cancer., Experimental Design: Five hundred twenty-four patients were randomized to be treated either with 4 cycles of paclitaxel followed by 4 cycles of combination therapy with 5-fluorouracil, Adriamycin, and cyclophosphamide (Pac/FAC) or with 8 cycles of FAC alone. Patients with intact primary breast cancer received the initial 4 cycles of paclitaxel or 4 cycles of FAC in a neoadjuvant setting. Planned duration of therapy was the same in all patients. After completion of 8 cycles of chemotherapy, those patients who were > or =50 years and whose tumors were positive for estrogen receptors received tamoxifen for 5 years., Results: Ninety-two patients have had a recurrence after a median follow-up of 60 months with a range of 5-89 months. Estimated disease-free survival at 48 months was 0.83 for FAC and 0.86 for Pac/FAC group. The difference between the two groups was not statistically significant (P = 0.09). The overall estimated hazard ratio for Pac/FAC compared with FAC derived by fitting the Cox regression model and incorporating terms for prognostic factors was 0.66., Conclusion: Preliminary results suggest that the addition of paclitaxel to a FAC regimen of adjuvant or neoadjuvant therapy may further reduce the risk of disease recurrence; however, differences were not statistically significant. At the time of this analysis, there have been 47 deaths. The survival data are too preliminary to permit meaningful evaluation of the impact of paclitaxel on mortality.

Background: The authors conducted a single institution Phase II clinical trial to determine whether paclitaxel had antitumor activity in patients with metastatic breast carcinoma that was refractory to standard chemotherapy., Methods: Patients with metastatic breast carcinoma were eligible for the study if they had disease progression after at least 2 prior chemotherapy regimens. Patients who had received three prior regimens were treated in a separate cohort. All patients were required to have received doxorubicin in the past and were not eligible if they had received prior therapy with paclitaxel. The starting dose of paclitaxel for low risk patients was 175 mg/m2, administered as a 24-hour continuous infusion; the starting dose of paclitaxel was 150 mg/m2 for patients who had received > or = 3 prior regimens. Therapy was given every 3 weeks and continued for at least 2 courses unless there was evidence of rapidly progressing disease, for at least 3 courses if there was no change in disease and Grade 3 or 4 (based on National Cancer Institute toxicity criteria) toxicity was not noted, and for 6 courses beyond the maximum response in patients who demonstrated complete or partial responses and showed no evidence of disease progression., Results: Sixty-eight of 69 patients entered in the study were evaluable for response: 35 patients who had received 2 prior chemotherapy regimens for Stage IV disease and 33 patients who had received > or =3 prior regimens. A partial response was observed in 7 patients who had received 2 prior regimens, for an objective response rate of 20% (95% confidence interval [95% CI], 14-26%). In the group who had received > or = 3 prior regimens, a total of 6 partial responses were observed, for an objective response rate of 18% (95% CI, 12-23%). The median response duration was 8.2 months (range, 2.7-10.1 months) for the group who had received 2 prior regimens and 5.8 months (range, 2.1-9.5 months) for patients who received > or = 3 prior regimens. Responses were noted in patients with anthracycline-resistant tumors., Conclusions: Paclitaxel was active in heavily pretreated patients with metastatic breast carcinoma, including anthracycline-resistant breast carcinoma.

Purpose: To compare prospectively the antitumor activity of single-agent paclitaxel to the three-drug combination of fluorouracil, doxorubicin, and cyclophosphamide (FAC) as neoadjuvant therapy in patients with operable breast cancer., Patients and Methods: Patients with T1-3N0-1M0 disease were randomized to receive either paclitaxel (250 mg/m(2)) as 24-hour infusion or FAC in standard doses at every-3-week intervals. Each patient was treated with four cycles of preoperative chemotherapy. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after four cycles of induction chemotherapy., Results: A total of 174 patients were registered, and 87 were randomized to each arm of the study. Clinical response, ie, complete and partial responses, was similar in both arms of the study. Three patients in the FAC arm and one patient in the paclitaxel subgroup had progressive disease. The extent of residual disease by intent-to-treat analysis at the time of surgery was similar between the two arms of the study., Conclusion: The results of this prospective study demonstrated that single-agent paclitaxel as neoadjuvant therapy has significant antitumor activity, and this was clinically comparable to FAC. Similar fractions of patients had clinical complete and partial responses, and very few patients had no response to either therapy. The value of alternate non-cross-resistant therapies as used in this protocol on the clinical course of this disease would require longer follow-up.

The objective of this study was to compare the antitumor activity of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) with that of the 5-fluorouracil/doxorubicin/cyclophosphamide (FAC) combination by evaluating the extent of residual disease in the breast and regional lymph nodes of patients with breast cancer following four cycles of induction chemotherapy. Patients with histologically confirmed invasive but noninflammatory carcinoma of the breast stages T2-3, N0-1, M0 were eligible to enter the study. Patients were treated with four cycles of either FAC or single-agent paclitaxel before local therapy. Following local therapy, treatment of the two arms was identical. Of 104 operable breast cancer patients who were treated with either regimen, 78 were evaluable for response to preoperative chemotherapy and had undergone local therapy. Age, TNM classification, and estrogen receptor status of the patients were similar in the two groups. Following induction chemotherapy, the extent of disease in the breast and the distribution and number of positive nodes were similar between the two treatment arms. Disease progressed in two patients in the FAC arm and in none in the paclitaxel arm during the induction phase of therapy. A higher fraction of patients had neutropenic fever during the paclitaxel treatment. Initial data from this ongoing randomized study show that paclitaxel alone has comparable anticancer activity with FAC in patients with early breast cancer. The degree of cytoreduction was similar with both induction therapies.

Purpose: To determine the efficacy (objective response rate and duration of response and survival) and toxicity of docetaxel in patients with strictly defined anthracycline-resistant metastatic breast cancer (MBC)., Patients and Methods: Thirty-five patients with bidimensionally measurable MBC who had progressive disease while receiving anthracycline-containing chemotherapy were registered onto the phase II trial. Docetaxel was administered at a dose of 100 mg/m2 over 1 hour every 21 days., Results: Thirty-four patients were assessable for disease response; 18 (53%; 95% confidence interval [CI], 35% to 70%) achieved a partial response. The median times to disease progression and survival duration were 7.5 and 13.5 months, respectively, for responding patients. The median overall survival duration was 9 months. Two hundred eight cycles (median, five) of docetaxel were administered. Neutropenia with less than 500 cells/microL developed in 31 of 35 patients; it was complicated by fever in 30 (14%) of 208 cycles and in 18 (51%) of 35 patients, including one treatment-related death. Fluid retention was seen in 15 (43%) of 35 patients, including pleural effusions in 11 patients (31%). Moderate skin toxicity, asthenia, and myalgia were observed in 16%, 58%, and 37% of cycles, respectively., Conclusion: Docetaxel has the highest reported antitumor activity in anthracycline-resistant MBC. High objective response rates were seen in patients with visceral-dominant involvement, multiple metastatic sites, or extensive previous therapy. Docetaxel is associated with severe but reversible neutropenia, asthenia, and cumulative dose-related fluid retention. Dexamethasone decreased the frequency and severity of skin toxicity and appeared to ameliorate fluid retention.

Taxol (paclitaxel) has demonstrated good antitumor activity against metastatic breast cancer (MBC) in phase II trials. The drug is usually well tolerated. However, severe myelosuppression, including rapidly reversible neutropenia, may necessitate dose reductions and may ultimately limit its use as a long-term treatment. Sequential or simultaneous administration of Taxol and doxorubicin may enhance response rates. There appears to be no complete cross-resistance between the two drugs. Current trials are exploring the best way to deliver this combination while keeping dose-limiting toxicity to a minimum. Additionally, single-agent trials are evaluating Taxol in extensively pretreated MBC. The results of these trials are awaited with interest.

Taxol was evaluated in metastatic breast cancer in three trials. In the first, a phase II study, 25 patients who had received only one prior regimen of chemotherapy received Taxol (starting dose of 250 mg/m2). The response rates were 12% complete, 44% partial, and 32% minor. The median duration of response was 9 months (range, 3 to 19 months). The median survival was 20 months (range, 5 to 29+ months). Toxic effects were granulocytopenia less than 500/mm3 in 85% of all courses but serious infection in only 6% of courses, myalgias, and cumulative neuropathy. The second trial was a phase I study of Taxol by 24-hour infusion sequenced with doxorubicin by 48-hour infusion as initial chemotherapy for metastatic disease. In arm 1, Taxol preceded doxorubicin. The starting doses were 125 mg/m2 Taxol, 60 mg/m2 doxorubicin. Neupogen (5 micrograms/kg) was given subcutaneously on days 5 through 19. Ten patients received 96 courses. The maximum tolerated dose was defined by mucositis and infection at the starting dose. Cumulative thrombocytopenia occurred in subsequent courses. The unexpectedly severe toxic effects at doses that were low by comparison to other studies suggested schedule-related toxicity. Therefore, in arm 2 the sequence has been reversed: doxorubicin precedes Taxol. Doses have been escalated to 180 mg/m2 Taxol with 60 mg/m2 doxorubicin without dose-limiting toxic effects occurring. The third trial, a phase II study in patients who have received three or more prior chemotherapy regimens, is ongoing. Twenty-one of a planned 35 patients have been entered. Taxol has shown significant antitumor activity in minimally pretreated patients.(ABSTRACT TRUNCATED AT 250 WORDS)