Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.

PURPOSE: ABI-007, the first biologically interactive albumin-bound paclitaxel in a nanameter particle, free of solvents, was compared with polyethylated castor oil-based standard paclitaxel in patients with metastatic breast cancer (MBC). This phase III study was performed to confirm preclinical studies demonstrating superior efficacy and reduced toxicity of ABI-007 compared with standard paclitaxel. PATIENTS AND METHODS: Patients were randomly assigned to 3-week cycles of either ABI-007 260 mg/m(2) intravenously without premedication (n = 229) or standard paclitaxel 175 mg/m(2) intravenously with premedication (n = 225). RESULTS: ABI-007 demonstrated significantly higher response rates compared with standard paclitaxel (33% v 19%, respectively; P = .001) and significantly longer time to tumor progression (23.0 v 16.9 weeks, respectively; hazard ratio = 0.75; P = .006). The incidence of grade 4 neutropenia was significantly lower for ABI-007 compared with standard paclitaxel (9% v 22%, respectively; P < .001) despite a 49% higher paclitaxel dose. Febrile neutropenia was uncommon (< 2%), and the incidence did not differ between the two study arms. Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard paclitaxel arm (10% v 2%, respectively; P < .001) but was easily managed and improved rapidly (median, 22 days). No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time. CONCLUSION: ABI-007 demonstrated greater efficacy and a favorable safety profile compared with standard paclitaxel in this patient population. The improved therapeutic index and elimination of corticosteroid premedication required for solvent-based taxanes make the novel albumin-bound paclitaxel ABI-007 an important advance in the treatment of MBC.     

Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies.

PURPOSE: ABI-007 is a novel solvent-free, albumin-bound, 130-nm particle formulation of paclitaxel designed to avoid solvent-related toxicities and to deliver paclitaxel to tumors via molecular pathways involving an endothelial cell-surface albumin receptor (gp60) and an albumin-binding protein expressed by tumor cells and secreted into the tumor interstitium (secreted protein acid rich in cysteine). This study determined the maximum-tolerated dose (MTD) of ABI-007 monotherapy administered weekly (three weekly doses, repeated every 4 weeks) and assessed the pharmacokinetics of paclitaxel administered as ABI-007. PATIENTS AND METHODS: Patients with advanced nonhematologic malignancies received ABI-007 without premedication at dose levels from 80 to 200 mg/m(2) as a 30-minute intravenous infusion once a week for 3 weeks, followed by 1 week of rest (one cycle). RESULTS: Thirty-nine patients were treated with an average of five cycles of ABI-007; 33% of patients received > or = six cycles of treatment. MTDs for heavily and lightly pretreated patients were 100 and 150 mg/m(2), respectively; and the dose-limiting toxicities were grade 4 neutropenia and grade 3 peripheral neuropathy, respectively. Maximum paclitaxel concentration and area under the curve increased linearly with dose. Dose-dependent changes in plasma clearance did not occur. Partial responses were observed in five patients with breast, lung, and ovarian cancers, all of whom had previously been treated with paclitaxel containing polyoxyethylated castor oil in the formulation. CONCLUSION: This study demonstrated that weekly ABI-007 can be administered at doses exceeding those typically used for paclitaxel containing polyoxyethylated castor oil. Pharmacokinetics were linear over the dose range studied. Antitumor responses occurred in patients previously treated with paclitaxel containing polyoxyethylated castor oil.     

Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer.

BACKGROUND: Abraxane (ABI-007) is a novel 130-nm, albumin-bound (nab) particle form of paclitaxel designed to utilize endogenous albumin pathways to increase intratumor concentrations of the active drug. This multicenter phase II study was designed to evaluate the efficacy and safety of Abraxane 260 mg/m2 every 3 weeks in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with histologically confirmed, measurable NSCLC received Abraxane as first-line therapy. RESULTS: Forty-three patients were enrolled. The overall response rate was 16%; the disease control rate was 49%. Median time to progression was 6 months, and median survival was 11 months. The probability of not having progressed by 1 year was 13%; the probability of surviving 1 year was 45%. No severe hypersensitivity reactions were reported despite the lack of premedication; 95% of patients were treated without dose reduction. Two patients (5%) discontinued therapy because of treatment-related toxicities (neuropathy, fatigue [1 each]). No grade 4 treatment-related toxicity occurred. CONCLUSIONS: Abraxane 260 mg/m2 administered IV over 30 min without premedication was well tolerated. Significant tumor responses and prolonged disease control were documented in this group of patients with NSCLC. Exploration of higher doses of ABI-007 alone and in combination with other drugs active in NSCLC is warranted.     

Phase II Trial of Weekly Nanoparticle Albumin-Bound Paclitaxel With Carboplatin and Trastuzumab as First-line Therapy for Women With HER2-Overexpressing Metastatic Breast Cancer

PurposeThis multicenter phase II trial evaluated the efficacy and safety of weekly nanoparticle albumin-bound paclitaxel with carboplatin and weekly trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer (MBC).Patients and MethodsWe treated 32 patients who had measurable MBC that was HER2-positive defined by an immunohistochemical staining score of 3+ or gene amplification by fluorescence in situ hybridization, required for those with an IHC of 2+. Patients were treated with albumin-bound paclitaxel 100 mg/m² and carboplatin at area under the curve (AUC) = 2 on days 1, 8, and 15 of a 28-day cycle. Trastuzumab was administered at 2 mg/kg weekly after a loading dose of 4 mg/kg. Because of hypersensitivity reactions occurring during carboplatin infusion numbers 6–8 in 4 of the first 13 patients with this premedication-free regimen, the protocol was amended for carboplatin and dosed at AUC = 6 day 1 each 28-day cycle, in lieu of introducing steroid prophylaxis. Patients were treated with 6 cycles and allowed to continue with all 3 drugs or trastuzumab alone if free of progression and unacceptable toxicity after 6 cycles.ResultsThe overall response rate (ORR) was 62.5% (95% CI, 45.7%–79.3%) with 3 confirmed complete responders (CRs; 9%) and 17 confirmed partial responses (PRs; 53%). An additional 6 patients (19%) had stable disease (SD) for greater than 16 weeks for a clinical benefit rate (ORR + SD > 16 weeks) of 81%. As of April 16, 2009, 20 patients (63%) had progressed with a median progression-free survival (PFS) of 16.6 months (95% CI, 7.5-26.5 months). Antitumor activity was similar for patients treated with weekly carboplatin and every-4-week carboplatin (ORR, 65% vs. 67%, respectively). Hematologic toxicities were the only grade 4 toxicities noted and were infrequent with grade 4 neutropenia in 3 patients (9%) and 1 febrile neutropenia. Grade 2/3 peripheral neuropathy was uncommon (13%/3%).ConclusionWeekly albumin-bound paclitaxel with carboplatin and trastuzumab is highly active in HER2-overexpressing MBC. In the absence of corticosteroid premedication, which we avoided with albumin-bound paclitaxel, carboplatin seems best dosed every 4 weeks rather than weekly because of carboplatin-associated hypersensitivity reactions. The regimen was very well tolerated with few grade 3 and 4 nonhematologic toxicities experienced, and severe hematologic toxicity and peripheral neuropathy were infrequent.     

Additive effects of a prolactin receptor antagonist,G129R,and herceptin on inhibition of HER2-overexpressing breast cancer cells

Genexol-PM is a novel Cremophor EL-free polymeric micelle formulation of paclitaxel. This single arm, multicenter phase II study was designed to evaluate the efficacy and safety of Genexol-PM in patients with histologically confirmed metastatic breast cancer (MBC). Forty-one women received Genexol-PM by intravenous infusion at 300 mg/m² over 3 h every 3 weeks without premedication until disease progression or intolerability. A total of 331 chemotherapy cycles were administered, with a median of 8 cycles per patient (range, 1–16). Overall response rate was 58.5% (95% CI: 43.5–72.3) with 5 complete responses and 19 partial responses. Thirty-seven patients who received Genexol-PM as a first-line therapy for their metastatic disease showed a response rate of 59.5% (95% CI: 43.5–73.7), and two responses were reported in four patients treated in the second-line setting for their metastatic disease. The median time to progression (TTP) for all patients was 9.0 months (range, 1.0–17.0+ months). Grade 3 non-hematologic toxicities included sensory peripheral neuropathy (51.2%), and myalgia (2.4%). Eight patients (19.5%) experienced hypersensitivity reactions, with grade 3 in two patients. Hematologic toxicities were grade 3 and 4 neutropenia (51.2 and 17.1%, respectively), and grade 1 and 2 thrombocytopenia (22.0%). Notably, no febrile neutropenia was observed. Genexol-PM appears a promising new paclitaxel in view of significant efficacies. Further trials with different dosing schedules, durations of delivery, or in combination with other drugs are warranted.     

Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol).

PURPOSE: To compare the preclinical and clinical pharmacokinetic properties of paclitaxel formulated as a Cremophor-free, albumin-bound nanoparticle (ABI-007) and formulated in Cremophor-ethanol (Taxol). EXPERIMENTAL DESIGN: ABI-007 and Taxol were given i.v. to Harlan Sprague-Dawley male rats to determine pharmacokinetic and drug disposition. Paclitaxel pharmacokinetic properties also were assessed in 27 patients with advanced solid tumors who were randomly assigned to treatment with ABI-007 (260 mg/m(2), 30 minutes; n = 14) or Taxol (175 mg/m(2), 3 hours; n = 13), with cycles repeated every 3 weeks. RESULTS: The volume of distribution at steady state and clearance for paclitaxel formulated as Cremophor-free nanoparticle ABI-007 were significantly greater than those for paclitaxel formulated with Cremophor (Taxol) in rats. Fecal excretion was the main elimination pathway with both formulations. Consistent with the preclinical data, paclitaxel clearance and volume of distribution were significantly higher for ABI-007 than for Taxol in humans [21.13 versus 14.76 L/h/m(2) (P = 0.048) and 663.8 versus 433.4 L/m(2) (P = 0.040), respectively]. CONCLUSIONS: Paclitaxel formulated as ABI-007 differs from paclitaxel formulated as Taxol, with a higher plasma clearance and a larger volume of distribution. This finding is consistent with the absence of paclitaxel-sequestering Cremophor micelles after administration of ABI-007. This unique property of ABI-007 could be important for its therapeutic effectiveness.     

Superior efficacy of a Cremophor-free albumin-bound paclitaxel compared with solvent-based paclitaxel in Chinese patients with metastatic breast cancer

Aim:   In a previous study, a 130-nm nanoparticle albumin-bound paclitaxel ( nab -paclitaxel) demonstrated improved efficacy and safety profile compared with solvent-based paclitaxel (sb-paclitaxel) in Caucasian patients with metastatic breast cancer (MBC). The aim of the present randomized study was to compare the response rates and safety profile of nab -paclitaxel with sb-paclitaxel in Chinese patients with MBC.
Methods:   In the present open-label, multicenter study, 210 patients with MBC were randomly assigned to receive nab -paclitaxel 260 mg/m² intravenously (i.v.) over 30 min every 3 weeks (q3w) with no premedication or sb-paclitaxel 175 mg/m² i.v. over 3 h q3w with standard premedication.
Results:   The overall response rate was 54 and 29% in patients treated with nab -paclitaxel and sb-paclitaxel, respectively ( P  < 0.001). nab -paclitaxel induced a higher response rate in patients who were <65 years old, patients who were receiving first-line therapy, patients who had no prior anthracycline therapy, patients who had ≤ or >3 metastatic lesions, and patients who had visceral disease. The progression-free survival (PFS) period was 7.6 months for nab -paclitaxel and 6.2 months for sb-paclitaxel ( P  = 0.118). Despite the 49% higher paclitaxel dose in patients receiving nab -paclitaxel compared with patients receiving sb-paclitaxel, the safety profile was similar in both treatment groups. The most common grades 3 and 4 adverse event (AE) in both arms was neutropenia. The most common grade 3 nonhematologic AE was peripheral neuropathy, and no grade 4 peripheral neuropathy was observed.
Conclusion:   Compared with sb-paclitaxel, nab -paclitaxel demonstrated superior efficacy, an acceptable safety profile, and a trend toward increased PFS in patients with MBC.     

Nanoparticle albumin-bound paclitaxel (ABI-007): a newer taxane alternative in breast cancer

Breast cancer remains the most common malignancy in women of developed countries. Taxanes are cornerstones in the treatment of breast cancer. Nanoparticle albumin-bound paclitaxel (ABI-007, Abraxane) is a novel taxane that obviates the need of using a toxic solvent such as Cremophor EL leading to a safer administration without standard premedication. Several factors such as the presence of albumin receptors in cell surface, the increased need of nutrients such as albumin by tumor cells and the lack of sequestering Cremophor micelles lead to increased intratumoral concentration of this new taxane. Recent trials have shown that ABI-007 is not only well tolerated but, compared with conventional paclitaxel, is associated with superior response rate, longer time to tumor progression and prolonged survival as second-line therapy in patients with metastatic breast cancer.     

贝伐单抗联合白蛋白结合型紫杉醇治疗难治三阴性乳腺癌的初步临床观察

为了评价贝伐单抗联合白蛋白结合型紫杉醇治疗晚期难治性三阴性乳腺癌的临床效果,选取经病理学确诊的晚期三阴性乳腺癌患者6例(ER、PR和HER-2均为阴性),既往使用过蒽环、紫杉类、吉西他滨及卡培他滨等药物治疗后进展,接受贝伐单抗联合白蛋白结合型紫杉醇方案治疗,其中贝伐单抗7.5 mg/kg,静脉滴入,d1,3周重复;白蛋白结合型紫杉醇260 mg/m2,静脉滴入,d1,3周重复,不做抗过敏预处理.3例患者接受化疗6个周期,3例4个周期.PR 2例,SD 3例,PD 1倒.毒副反应主要是骨髓抑制和神经毒性,其中Ⅳ度粒细胞减少1例,Ⅲ度粒细胞减少2倒,Ⅱ度粒细胞减少2倒,Ⅰ度粒细胞减少1例;Ⅲ度感觉神经病变2例,Ⅱ度感觉神经病变2例,Ⅰ度感觉神经病变2例;高血压1倒,蛋白尿2例.初步研究结果提示,贝伐单抗联合白蛋白结合型紫杉醇治疗晚期难治性三阴性乳腺癌疗效较好,毒副反应可耐受,值得进一步研究.     

Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.

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.     

Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.

ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast congruent with ovary > prostate > colon. The LD(50) and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007.     

Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes

PURPOSE: Nanoparticle albumin-bound paclitaxel, a solvent-free, albumin-bound paclitaxel, demonstrated antitumor activity in patients with taxane-naive metastatic breast cancer (MBC). We examined albumin-bound paclitaxel (100 mg/m2 or 125 mg/m2 administered weekly) to determine the antitumor activity in patients with MBC whose disease progressed despite conventional taxane therapy. PATIENTS AND METHODS: Women with MBC that was previously treated with taxanes were eligible for participation. Taxane failure was defined as metastatic disease progression during taxane therapy or relapse within 12 months of adjuvant taxane therapy. Primary objectives were response rates (RRs) and the safety/tolerability of albumin-bound paclitaxel. RESULTS: Women were treated with albumin-bound paclitaxel 100 mg/m2 (n = 106) or 125 mg/m2 (n = 75) on days 1, 8, and 15 of a 28-day cycle. Response rates were 14% and 16% for the 100-mg/m2 and 125-mg/m2 cohorts, respectively; an additional 12% and 21% of patients, respectively, had stable disease (SD) > or = 16 weeks. Median progression-free survival times were 3 months at 100 mg/m2 and 3.5 months at 125 mg/m2; median survival times were 9.2 months and 9.1 months, respectively. Survival was similar for responding patients and those with SD. No severe hypersensitivity reactions were reported. Patients who developed treatment-limiting peripheral neuropathy typically could be restarted on a reduced dose of albumin-bound paclitaxel after a 1-2-week delay. Grade 4 neutropenia occurred in < 5% of patients. CONCLUSION: Albumin-bound paclitaxel 100 mg/m2 given weekly demonstrated the same antitumor activity as albumin-bound paclitaxel 125 mg/m2 weekly and a more favorable safety profile in patients with MBC that had progressed with previous taxane therapy. Survival of patients with SD > or = 16 weeks was similar to that of responders.     

Multicentric phase II trial of gemcitabine plus epirubicin plus paclitaxel as first-line chemotherapy in metastatic breast cancer

In this phase II, multicentre trial, patients with metastatic breast cancer (MBC) were treated with a combination of gemcitabine, epirubicin and paclitaxel (GET). The primary objective of this study was to determine the tolerability and activity in terms of complete responce (CR) and overall response rate of the GET combination in this patient population. Patients with no prior treatment for MBC, and at least one bidimensionally measurable lesion received gemcitabine 1000 mg m(-2) intravenously (i.v.) over 30 min on days 1 and 4, followed by epirubicin i.v. at 90 mg m(-2) on day 1, and paclitaxel 175 mg m(-2) over 3 h on day 1, every 21 days, up to eight courses. From May 1999 to June 2000, 48 patients were enrolled from seven Italian institutions. A total of 297 chemotherapy courses were administered with a median of six cycles patient(-1) (range 1-8). Seven patients (15%) obtained CR and 27 patients (56%) had partial responce, for an overall response rate of 71% (95% CI: 58.3-83.7). After a median follow-up of 23.7 months (range 7.0-34.4), median progression-free survival was 10.5 months (95% CI: 9.2-11.7), and median overall survival 25.9 months. The main haematological toxicity consisted of grade 3 or 4 neutropenia that occurred in 62% of cycles (22% grade 4 and 40% grade 3). The GET combination is active and well tolerated as first-line chemotherapy for MBC.     

Phase II multicenter trial of albumin-bound paclitaxel and capecitabine in first-line treatment of patients with metastatic breast cancer

BackgroundCapecitabine, a tumor-activated oral fluoropyrimidine, and albumin-bound paclitaxel (ab-paclitaxel) have substantial single-agent activity in patients with metastatic breast cancer (MBC). Taxane and antimetabolite doublets have improved efficacy compared with single agents. This phase II open-label trial was designed to test the safety and efficacy of capecitabine and ab-paclitaxel in previously untreated MBC.Patients and MethodsPatients received capecitabine (825 mg/m² orally twice daily, approximately 12 hours apart, on days 1 to 15) and ab-paclitaxel (125 mg/m² intravenously on days 1 and 8 of each cycle with no premedication) every 3 weeks. The primary endpoint was overall objective response rate (ORR), with evaluation performed after every 2 cycles. Entry criteria included measurable MBC, human epidermal growth factor receptor 2 (HER2) negativity, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, no previous chemotherapy for metastatic disease, and > 6 months since adjuvant fluoropyrimidine or paclitaxel treatment.ResultsFifty patients received at least 1 dose of study drug, with 46 patients evaluable for efficacy evaluation. Three hundred seventy-four cycles of therapy were delivered. Eighty percent of patients completed 8 cycles. The ORR was 61% (complete response [CR], 4%; partial response [PR], 57%), and 7 patients had sustained (≥ 24 weeks) stable disease for a clinical benefit rate of 76.1%. The median progression-free survival (PFS) was 10.6 months, and the median overall survival was 19.9 months. The most common adverse events (AEs) that were ≥ grade 3 were pain, hand-foot syndrome, and neutropenia.ConclusionThe combination of weekly ab-paclitaxel plus daily capecitabine orally at these doses and scheduling was well tolerated and showed substantial efficacy.     

Docetaxel plus epirubicin is a highly active, well-tolerated, first-line chemotherapy for metastatic breast cancer: results of a large, multicentre phase II study

Purpose In this multicentre phase II study, the efficacy and safety profile of the combination of docetaxel and epirubicin as first-line chemotherapy for metastatic breast cancer (MBC) were evaluated.Methods Epirubicin (75 mg/m²) and docetaxel (75 mg/m²) were given intravenously once every 3 weeks for six cycles to 133 patients with MBC.Results The overall clinical response rate was 67% (complete and partial responses were 23% and 44%, respectively). The median time to progression was 10.8 months (95% CI 9.7–12.6) and the median overall survival was 19.5 months. Granulocyte colony-stimulating factor support was administered to 32% of patients and in 22% of cycles. Grade 3/4 neutropenia occurred in 35% of patients and febrile neutropenia in 19%. The most frequent grade 3/4 non-haematological toxicities (as percent of patients) were asthenia (6%), vomiting (5%) and nausea (5%). No patients developed congestive heart failure.Conclusions The combination of docetaxel and epirubicin was highly active as first-line treatment for MBC and showed a manageable toxicity profile.     

Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial.

OBJECTIVES: This phase II study was conducted to evaluate the efficacy and safety of gemcitabine in patients with metastatic breast cancer (MBC). METHODS: Women with histologically or cytologically confirmed bidimensionally measurable MBC not amendable to curative surgery or radiation were eligible. Prior chemotherapy for metastatic disease was not permitted. Patients received gemcitabine 1,200 mg/m(2) on days 1, 8 and 15 for 3 weeks every 28 days for a maximum of 8 cycles. RESULTS: Thirty-nine patients, with a median age of 58 years, were enrolled. The overall response rate for the 35 evaluable patients was 37.1% (95% confidence interval [CI], 21.5-55.1%), with 2 complete responses and 11 partial responses. Median time to progression and survival were 5.1 months (95% CI, 3.5-8.8 months) and 21.1 months (95% CI, 11.0-26.9 months), respectively. Chemotherapy was well tolerated, with a median of 4 cycles completed. Grade 4 toxicities were 1 infection and 1 abnormal pulmonary function. Grade 3 neutropenia and thrombocytopenia occurred in 30.3% and 6.3% of patients, respectively. The most common grade 3 non-hematologic toxicity was nausea/vomiting (10.3%). Five of 21 patients had improved Karnofsky performance status (KPS) scores. CONCLUSION: Single-agent gemcitabine is active and well tolerated as first-line treatment in patients with MBC.     

Phase II trial of outpatient schedule of paclitaxel in patients with previously untreated metastatic, measurable adenocarcinoma of the stomach.

BACKGROUND: Chemotherapy represents the standard treatment for patients with metastatic stomach cancer. Conflicting results have been published regarding the activity of paclitaxel in this setting. Therefore, we developed a phase II study to evaluate an outpatient 3 h infusion of paclitaxel. METHODS: Patients with chemonaive metastatic stomach cancer received paclitaxel 210 mg/m(2) every 3 weeks. Patients with esophageal cancer were not eligible. RESULTS: Twenty-one patients were enrolled. The median age was 55.5 years (range 37-81 years). Two partial responses were observed among the 18 patients evaluable for response and toxicity (response rate 11%, 95% CI: 2-33%). The median time to progression was 10.5 weeks and median survival 23 weeks. There was only one episode of grade IV neutropenia and no episodes of grade 3-4 non-hematological toxicity were observed. CONCLUSION: Paclitaxel exhibited minimal activity in this patient population.     

High efficacy and low toxicity of weekly docetaxel given as first-line treatment for metastatic breast cancer

BACKGROUND: Docetaxel is one of the most effective antitumor agents currently available for the treatment of metastatic breast cancer (MBC). This phase II multicenter study prospectively analyzed the efficacy and toxicity of docetaxel given on a weekly schedule as first-line treatment of metastatic breast cancer. PATIENTS AND METHODS: All patients received docetaxel, 35 mg/m(2) weekly for 6 weeks, followed by 2 weeks of rest. Subsequent cycles (3 weeks of treatment, 2 weeks of rest) were given until a maximum of 5 cycles or disease progression. Premedication consisted of 8 mg dexamethasone intravenously 30 min prior to the infusion of docetaxel. RESULTS: Fifty-four patients at a median age of 58 years with previously untreated MBC were included in the study. A median of 10 doses (median cumulative dose 339 mg/m(2)) was administered (range: 2-18). The overall response rate was 48.1% (95% CI: 34-61%, intent-to-treat). Median survival was 15.8 months and median time to progression was 5.9 months (intent-to-treat). Hematological toxicity was mild with absence of neutropenia-related complications. Grade 3 neutropenia was observed in 3.7% of patients and grade 3 and 4 anemia was observed in 5.6 and 1.9% of patients, respectively. CONCLUSION: The weekly administration of docetaxel is highly efficient and safe as first-line treatment for MBC and may serve as an important treatment option specifically in elderly patients and patients with a reduced performance status.     

Capecitabine plus paclitaxel versus epirubicin plus paclitaxel as first-line treatment for metastatic breast cancer: efficacy and safety results of a randomized, phase III trial by the AGO Breast Cancer Study Group

Capecitabine/taxane combinations are highly active in metastatic breast cancer (MBC). We conducted a randomized, phase III, noninferiority trial comparing capecitabine plus paclitaxel (XP) with epirubicin plus paclitaxel (EP) as first-line therapy for MBC, regarding progression-free survival (PFS) as primary efficacy endpoint. Females who had received no prior chemotherapy for MBC were randomized to six 3-weekly cycles of XP (capecitabine 1000 mg/m² b.i.d., days 1–14; paclitaxel 175 mg/m² 3-h infusion, day 1) or EP (epirubicin 60 mg/m² 1-h infusion, day 1; paclitaxel as above). Secondary endpoints included response rate, overall survival, tolerability, and quality of life (QoL). Each arm included 170 patients, most of whom received all six cycles as planned. The difference in means of (logarithmic) PFS times (?0.205) did not meet the pre-defined level for noninferiority (?0.186). However, PFS was similar in the two arms [HR: XP vs. EP: 1.012 (95 % CI 0.785–1.304); median 10.4 months XP vs. 9.2 months EP]. Overall survival was also similar [HR 1.027 (95 % CI 0.740–1.424); median 22.0 vs. 26.1 months], and response rate was 47 % versus 42 %. Both regimens were tolerable: there were more grade 3/4 diarrhea and grade 3 hand–foot syndromes with XP and more grade 3/4 hematologic toxicities with EP. There were no major differences in QoL. Although, noninferiority of XP to EP was formally not proven, first-line XP was active and feasible. XP is a valid first-line alternative to anthracycline/taxane regimens, especially in patients previously treated with adjuvant anthracyclines.     

Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy

To evaluate the single agent activity, pharmacokinetics and tolerability of the novel tubulin targeted agent vinflunine (VFL) (320 mg m(-2) q 21 days) as second-line chemotherapy in patients with metastatic breast carcinoma (MBC). All patients had disease progression after anthracycline/taxane (A/T) therapy. They could have received a nonanthracycline adjuvant treatment and subsequently received a first-line A/T combination for advanced/metastatic disease; or relapsed >6 months after completion of adjuvant A/T therapy and were subsequently treated with the alternative agent; or relapsed within 6 months from an adjuvant A/T combination. Objective response was documented in 18 of 60 patients enrolled (RR: 30% (95% confidence interval (CI): 18.9-43.2%)). Among the responders, seven patients had relapsed during a period of <3 months from taxane-based regimen yielding a RR of 33.3%. The median duration of response was 4.8 months (95% CI: 4.2-7.2), median progression-free survival was 3.7 months (95% CI: 2.8-4.2) and median overall survival was 14.3 months (95% CI: 9.2-19.6). The most frequent adverse event was neutropenia (grade 3 in 28.3% and grade 4 in 36.7% of patients). No febrile neutropenia was observed. Fatigue (grade 3 in 16.7% of patients) and constipation (grade 3 in 11.7% of patients) were also common; these were non-cumulative and manageable permitting achievement of a good relative dose intensity of 93.5%. Vinflunine is an active agent with acceptable tolerance in the management of MBC patients previously treated with (A/T)-based regimens. These encouraging phase II results warrant further investigation of this novel agent in combination with other active agents in this setting or in earlier stages of disease.