Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial.

PURPOSE: This phase III trial compared the efficacy and safety of doxorubicin and paclitaxel (AT) to 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line therapy for women with metastatic breast cancer. PATIENTS AND METHODS: A total of 267 women with metastatic breast cancer were randomized to receive either AT (doxorubicin 50 mg/m(2) followed 24 hours later by paclitaxel 220 mg/m(2)) or FAC (5-fluorouracil 500 mg/m(2), doxorubicin 50 mg/m(2), cyclophosphamide 500 mg/m(2)), each administered every 3 weeks for up to eight cycles. Patients had to have measurable disease and an Eastern Cooperative Oncology Group performance status of 0 to 2. Only one prior non-anthracycline, nontaxane-containing adjuvant chemotherapy regimen was allowed. RESULTS: Overall response rates for patients randomized to AT and FAC were 68% and 55%, respectively (P =.032). Median time to progression and overall survival were significantly longer for AT compared with FAC (time to progression 8.3 months v 6.2 months [P =.034]; overall survival 23.3 months v 18.3 months [P =.013]). Therapy was generally well-tolerated (median of eight cycles delivered in each arm). Grade 3 or 4 neutropenia was more common with AT than with FAC (89% v 65%; P <.001); however, the incidence of fever and infection was low. Grade 3 or 4 arthralgia and myalgia, peripheral neuropathy, and diarrhea were more common with AT, whereas nausea and vomiting were more common with FAC. The incidence of cardiotoxicity was low in both arms. CONCLUSION: AT conferred a significant advantage in response rate, time to progression, and overall survival compared with FAC. Treatment was well-tolerated with no unexpected toxicities.     

A phase II trial of paclitaxel and epirubicin in advanced breast cancer

Initial trials of paclitaxel and doxorubicin in advanced breast cancer yielded high response rates but significant cardiac toxicity was observed. In this phase II trial we investigated the efficacy and safety of paclitaxel combined with epirubicin. Patients with advanced breast cancer, performance status 0-2, measurable disease, and a normal left ventricular ejection fraction, who may have received adjuvant chemotherapy were treated with epirubicin 75 mg m(-2) followed by a 3-h infusion of paclitaxel 175 mg m(-2) repeated every 3 weeks. Forty-three eligible patients were treated at six centres. 67% patients received the maximum of six cycles. The response rate was 54% (95% CI 38-69%), 12% CR and 42% PR. Estimated median progression-free survival was 6.9 months (95% CI 5.4-10.0) and estimated median overall survival was 17.9 months (95% CI 14.2-25.7). Four patients had a decrease in the left ventricular ejection fraction (LVEF) of > or =20% of baseline value, and in two patients the LVEF decreased to below the lower limit of normal, but no patient developed clinical evidence of cardiac failure. Grade 4 neutropenia occurred in 56% cycles, but only 4% of cycles were complicated by febrile neutropenia. Grade 3 or 4 non-haematologic toxicity was uncommon. In conclusion, paclitaxel 175 mg m(-2) and epirubicin 75 mg m(-2) is a well tolerated, promising regimen for the treatment of advanced breast cancer.     

Phase II multicenter trial of a weekly paclitaxel and carboplatin regimen in patients with advanced breast cancer.

PURPOSE: To determine the activity of weekly paclitaxel plus carboplatin as first-line therapy in patients with advanced breast cancer (ABC) by assessing response rate, survival, and safety. PATIENTS AND METHODS: One hundred patients with ABC received paclitaxel 135 mg/m(2) (group 1, n = 20) and carboplatin area under the concentration-time curve (AUC) of 2. Paclitaxel was subsequently reduced to 100 mg/m(2) (group 2, n = 80) because of toxicity. The median age was 58.5 years, and most patients had an Eastern Cooperative Oncology Group performance status of 相似文献   

Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic

BACKGROUND:: Pacitaxel has shown activity in metastatic breast cancer, includinganthracycline-resistant breast cancer. The efficacy, toxicityand optimal scheduling of the combina tion of the two drugsneeds to be defined. PATIENTS AND METHODS:: Thirty women with advanced breast cancer who had undergone atmost one prior adjuvant chemotherapy regimen, were treated atthree different dose levels with doxorubicin (50, 60 and 60mg/m²) followed 30 minutes later by paclitaxel (155, 175 and200 mg/m², respectively) every 3 weeks. RESULTS:: The overall response rate was 83% (95% CI: 64–94), with24% of patients achieving CR. The median response duration forcomplete responders was 11 months (range 4–14+) and mediansurvival 18 months (range 3–28+). Two hundred sixty-fivetreatment courses were given (median 9, range 3–13) andthe median cumulative dose of doxorubicin was 369 mg/m² (range114–550). The main toxicities were neutropenia, parestesia,nausea/vomiting, alopecia, myalgia and cardiotoxicity. Fifteenpatients (50%) had reductions of left ventricular ejection fractionto below normal levels and 6 of these patients (20%) developedcongestive heart failure. CONCLUSIONS:: The combination of doxorubicin and paclitaxel is highly active,but is accompanied by the dose-limiting toxic effects of neutropenia,neuropathy and cardiotoxicity. advanced breast cancer, cardiotoxicity, doxorubicin, paclitaxel     

A phase II study of gemcitabine plus paclitaxel in patients with metastatic breast cancer and prior anthracycline treatment

Aim: To investigate the efficacy and safety of gemcitabine‐paclitaxel in Chinese patients with metastatic breast cancer following anthracycline failure in a multicenter, open‐label, single‐arm, phase II clinical trial. Methods: Chinese female patients with unresectable, locally recurrent or metastatic breast cancer who had relapsed after neo‐adjuvant anthracycline‐based chemotherapy were included. All patients had measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 at baseline. Gemcitabine (1250 mg/m²)‐paclitaxel (175 mg/m²) was administered on a 3‐weekly schedule until disease progression, and patients were followed up for 12 months (post‐enrolment). The primary end point was objective response rate; secondary end points included duration of response, progression‐free survival and overall survival. Results: Overall 60 patients were enrolled. Their mean age was 46.9 (SD ± 9.0) years and 90% of patients had metastatic disease. All patients had previously received chemotherapy. A total of 48 patients (80%) completed the 12‐month follow up, and 40 patients (67%) completed at least six cycles of study therapy. The objective response rate (complete response + partial response) was 50% (95% CI: 36.6–63.4). Median duration of response was 5.6 months (95% CI: 4.4–7.6) and median progression‐free survival was 7.6 months (95% CI: 5.8–8.8). Overall survival at 12 months was 87% (95% CI: 77.9–95.2). Laboratory toxicities were primarily hematologic, including Grade 3 and 4 neutropenia (n = 27 [45%]) and leukopenia (n = 18 [30%]). Eight patient deaths (13%) were not treatment‐related. Conclusion: Gemcitabine‐paclitaxel combination therapy is an active and well‐tolerated chemotherapy regimen, with expected and manageable toxicity in Chinese patients with metastatic breast cancer.     

Combining platinum, paclitaxel and anthracycline in patients with advanced gynaecological malignancy

Two meta-analyses have suggested that the addition of an anthracycline to platinum-based chemotherapy may improve survival in advanced ovarian cancer, and two randomised trials have demonstrated superiority of paclitaxel over cyclophosphamide in platinum combinations. A combination of platinum, anthracycline and paclitaxel would, therefore, be a reasonable experimental arm of any future randomised trial in patients with epithelial ovarian carcinoma (EOC). Patients who required chemotherapy for EOC but were ineligible for standard trials or had other gynaecological tumours that required similar platinum-based chemotherapy were considered for this pilot. The platinum/anthracycline/paclitaxel regimen (G-CAT) was given 3-weekly and consisted of doxorubicin 50 mg/m(2) or epirubicin 60 mg/m(2) intravenously (i.v.) bolus, paclitaxel 175 mg/m(2) (i.v.) over 3 h and either cisplatin 75 mg/m(2) (i.v.) or carboplatin AUC 6, with granulocyte colony-stimulating factor (G-CSF) at the neutrophil nadir. Different combinations were used in order to determine the least toxic regimen. Toxicity and response were assessed according to CTC and WHO criteria, respectively. 26 patients entered the study, 13 with EOC and 13 with other gynaecological cancers (peritoneal, fallopian tube, mixed Mullerian). Median age was 49 years (range: 27-67). 8 patients received carboplatin/doxorubicin/paclitaxel, 8 cisplatin/doxorubicin/paclitaxel and 10 carboplatin/epirubicin/paclitaxel. A total of 135 cycles of chemotherapy were delivered, with a median of 6 cycles per patient (range: 2-6). 54 (40%) cycles required G-CSF support and 17 (65%) patients required at least one dose reduction. All patients experienced grade 4 neutropenia and 13 (50%) patients developed grade 3-4 thrombocytopenia (12 of whom had received carboplatin). There were 4 (15%) patients with grade 3/4 infections but no septic deaths. Non-haematological toxicities were manageable, lethargy occurred in 75% of cisplatin-treated patients. Grade 1/2 cardiotoxicity, as assessed pre- and post-treatment by left ventricular ejection fraction, was observed in 6/13 (46%) patients who had received doxorubicin and 2/7 (29%) epirubicin-treated patients. No clinically detectable cardiac toxicity was encountered. The response rate in 25 evaluable patients was 76% (12 CR, 7 PR). Dose intensity was highest in the carboplatin/epirubicin/paclitaxel combination. G-CAT shows high activity and can be administered safely, but only very fit patients are suitable for this regimen as it is associated with considerable toxicity. Carboplatin/epirubicin/paclitaxel was the best tolerated regimen overall.     

Phase II trial of high-dose liposome-encapsulated doxorubicin with granulocyte colony-stimulating factor in metastatic breast cancer. TLC D-99 Study Group.

PURPOSE: To estimate the toxicity and response rate of high-dose liposome-encapsulated doxorubicin (TLC D-99, Evacet, The Liposome Company Inc, Princeton, NJ) in patients with advanced breast cancer. PATIENTS AND METHODS: Fifty-two breast cancer patients with bidimensionally measurable metastatic disease and no prior chemotherapy for metastatic disease received a 135 mg/m2 intravenous (i.v.) bolus of TLC D-99 with 5 microg/kg of granulocyte colony-stimulating factor via subcutaneous injection every 21 days. RESULTS: The median number of treatment cycles of TLC D-99 was three (range, one to 10 cycles), and the median total cumulative dose of TLC D-99 was 405 mg/m2 (range, 135 to 1,065 mg/m2). Grade IV neutropenia, thrombocytopenia, and mucositis were experienced by 48 (92%), 46 (88%), and 10 (19%) patients, respectively. Twenty (38%) of patients experienced cardiac toxicity: four (8%) experienced a decrease of 20% or more in left ventricular ejection fraction (LVEF) to a final value > or = 50%, nine (17%) experienced a decrease of 10% or more in LVEF to a final value less than 50%, and seven (13%) developed symptomatic congestive heart failure (CHF), including one patient who died of cardiomyopathy after receiving a total dose of 1,035 mg/m2. In a stepwise logistic regression model, the significant risk factors for the development of CHF were the cumulative dose of prior adjuvant doxorubicin (P = .007) and the total cumulative dose of TLC D-99 (P = .032). The overall response rate was 46% (95% confidence interval [CI], 32% to 61%) on an intent-to-treat basis. The median duration of response was 7.4 months (95% CI, 6.1 to 19.6 months) and the median progression-free survival was 6.1 months (95% CI, 5.4 to 7.5 months). CONCLUSION: There was no added therapeutic benefit to the dose escalation of TLC D-99 in this study. A high rate of cardiotoxicity was also observed, especially among patients who had received prior adjuvant doxorubicin. This was probably attributable to the dose and schedule of TLC D-99 used in this trial, as well as the patient's lifetime cumulative doxorubicin dose. Administration of high-dose TLC D-99 at 135 mg/m2 every 3 weeks by i.v. bolus infusion does not warrant further investigation.     

Mitoxantrone and paclitaxel combination chemotherapy in metastatic breast cancer

This study evaluated mitoxantrone and paclitaxel combination chemotherapy in the treatment of patients with metastatic breast cancer. Thirty-seven patients who had developed progressive disease after prior chemotherapy were treated with mitoxantrone (14 mg/m²) and paclitaxel (150 mg/m²) every 21 days for a maximum of six cycles. The most frequent grade 3 or 4 nonhematological toxicities were fever and nausea. Grade 4 neutropenia occurred in 71% of patients. Cardiotoxicity occurred in 2 patients, both of whom had previously received doxorubicin. Objective response was achieved in 35% of patients (5% complete response and 30% partial response) and 41% had stable disease. Median time to disease progression and median survival were 6 and 12 months, respectively. The percent of patients with an objective response was not different for those who had received prior doxorubicin or had chemotherapy in the preceding 6 months. This regimen appears to be effective and well tolerated as salvage therapy and merits further evaluation.     

Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy.

BACKGROUND: An every-2-week regimen of gemcitabine and paclitaxel was adapted for patients with advanced transitional cell carcinoma (TCC) who had received prior cisplatin-based chemotherapy. METHODS: Forty-one patients with advanced or metastatic TCC who had received prior cisplatin-based systemic chemotherapy were treated with an outpatient regimen of gemcitabine 2500-3000 mg/m(2) and paclitaxel 150 mg/m(2) every 2 weeks. RESULTS: Forty of 41 patients had measurable disease. Response was observed in 24 patients (60%; 95% confidence interval [CI], 45-75%). Eleven (28%) achieved complete response, and 13 (33%) obtained partial response. Twenty of 25 patients (80%; 95% CI, 64-96%) who had been previously treated in the neoadjuvant or adjuvant setting responded versus 4 of 15 (27%; 95% CI, 5-49%) in patients who received prior methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC) for metastatic disease. The median duration of survival for patients given gemcitabine and paclitaxel after failing neoadjuvant or adjuvant M-VAC was 12 months (range, 2-43+), as compared with only 8 months (range, 2-28) for patients who had been treated after failure of prior therapy for metastatic disease. For all patients, the median duration of response was 6.4 months (range, 2-43.3+ months), and the median survival was 14.4 months (range, 2-43+). Thirteen patients (32%) developed World Health Organization Grade 3-4 neutropenia, with febrile neutropenia in 3 (7%) patients. Granulocyte colony-stimulating factor was given to 10 (24%) patients. There was no Grade 3-4 anemia or thrombocytopenia. CONCLUSIONS: The combination of gemcitabine and taxol in previously treated patients with recurrent TCC is highly effective and produces objective durable responses. This every-2-week schedule is a well tolerated outpatient regimen with minimal toxicity.     

A Phase II trial of pegylated liposomal doxorubicin,vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients

BACKGROUND: Patients with multiple myeloma (MM) have increased bone marrow angiogenesis, a low plasma cell labeling index, and multidrug resistance (the primary cause of chemotherapy failure). MM patients receiving the vincristine, doxorubicin, and dexamethasone (VAD) regimen develop resistance and cardiac and steroid toxicity. Pegylated liposomal doxorubicin (Doxil/CAELYX) could potentially extend the duration of malignant plasma cell exposure to therapeutic levels of doxorubicin. This Phase II study evaluates combination pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone in MM patients. METHODS: Thirty-three newly diagnosed patients with MM received intravenous pegylated liposomal doxorubicin (40 mg/m(2)), vincristine (2.0 mg, Day 1), and oral or intravenous dexamethasone (40 mg per day for 4 days) every 4 weeks for six or more cycles and/or for two cycles after the best response. RESULTS: The overall response rate was 88%: 4 (12%) patients achieved a complete response, 18 (55%) a major response, and 7 (21%) a minor response. Three patients (9%) had stable and one (3%) had progressive disease. The median time to progression was 23.1 months, with 2-year and 3-year progression-free survival rates of 42% and 23%, respectively. The patient survival rate at 3 years was 67%. No patients discontinued treatment due to adverse events. Myelosuppression was manageable. The most common toxicities were Grade 3 palmar-plantar erythrodysesthesia, mucositis, and neutropenia. Only one patient experienced cardiotoxicity. CONCLUSIONS: Substituting pegylated liposomal doxorubicin for doxorubicin in the VAD regimen and reducing the dose of dexamethasone in patients with MM improve the safety profile and convenience of the treatment regimen without compromising efficacy.     

Phase II study of doxorubicin and paclitaxel as second-line chemotherapy of small-cell lung cancer: a Hoosier Oncology Group Trial

Forty-six evaluable patients with recurrent small-cell lung cancer were entered on a phase II Hoosier Oncology Group (HOG) protocol evaluating bolus doxorubicin 40 mg/m2 followed by paclitaxel 175 mg/m2 over 3 hours. Courses were repeated every 3 weeks for a maximum of 6 courses. Therapy was well-tolerated with grade III neurotoxicity in 5 patients (11%), grade III/IV emesis in 5 (11%), and grade III mucositis in 2 patients. One patient had grade IV myalgias and one patient had grade III cardiotoxicity. The main toxicity was myelosuppression. Twenty-nine patients (63%) had grade IV and 8 (17%) grade III granulocytopenia. Nine patients (20%) were hospitalized for granulocytopenic fever. There was no treatment-related mortality. Nineteen of 46 patients (41%) had an objective response, including 3 complete remissions. Two of 14 patients with refractory disease (progression less than 3 months after initial therapy) responded, compared to 17 of 32 (52%) with sensitive disease (progression beyond 3 months of initial chemotherapy regimen).     

Amifostine as chemoprotectant in metastatic breast cancer patients treated with doxorubicin

Amifostine has shown to selectively protect normal tissues against cytotoxic and mutagenic effects of several anti-neoplastic drugs, such as alkylating agents, organoplatinum compounds, anthracyclines, taxanes, and ionising radiation. This cytoprotection is broad-spectrum and selective, without loss of therapeutic efficacy. In this study we have treated 31 patients affected with inoperable or metastatic breast cancer, not previously submitted to chemotherapy for advanced disease, with amifostine 910 mg/m(2) followed by doxorubicin 75 mg/m(2). The overall response rate was 52% with a median response duration of 13 months (range 6-53+) and a median overall survival of 21 months (range 3-59+). With regard to toxicity, 14 patients (45%) experienced transient g4 neutropenia which was febrile only in one case (3%). Grade 3-4 thrombocytopenia was not recorded. Nausea and vomiting occurred in 14% of cycles. Grade 3 mucositis was observed in only 1 patient, whereas 2 patients (6%) developed an asymptomatic drop of left ventricular ejection fraction (LVEF) >10% below basal value. In conclusion, this study suggests that amifostine can reduce doxorubicin related toxicity, thus improving the patients' quality of life and the efficacy/toxicity ratio of this drug.     

Paclitaxel by 24-hour infusion with doxorubicin by 48-hour infusion as initial therapy for metastatic breast cancer: Phase I results

Purpose: We and others have demonstrated the antineoplastic efficacy of paclitaxel as a single agent in metastatic breast cancer. We performed this phase I trial to evaluate the combination of paclitaxel with doxorubicin.Patients and methods: Eligible patients had measurable or evaluable metastatic breast cancer for which this was the initial cytotoxic treatment. They may have received adjuvant chemotherapy with other drugs. The study had four parts. In part 1, the patients received paclitaxel by 24-hour infusion followed by doxorubicin by 48-hour infusion. The paclitaxel dose was to be escalated from a starting dose of 125 mg/m2, and the doxorubicin dose was to remain constant at 60 mg/m2 with treatment repeated every three weeks. The results of part 1 prompted part 2 which was a study of the reverse sequence. Part 3 was a formal study of pharmacology and has been reported (J Clin Oncol 14: 2713–21, 1996). In part 4, patients received doxorubicin 50 mg/m2 by bolus followed by paclitaxel 150 mg/m2 by 24-hour infusion for courses 1 and 2. In all subsequent courses doxorubicin was administered by 48-hour infusion. All patients in all four parts of the study had baseline cardiac scans. All patients received standard premedication for paclitaxel.Results: Forty-eight patients were treated in all four parts of the study. In part 1 (10 patients), the maximum tolerated dose (MTD) was paclitaxel 125 mg/m2/24 hours followed by doxorubicin 48 mg/m2/48 hours as defined by dose-limiting mucositis and neutropenic fever which occurred at the starting dose. For part 2 (21 patients), the MTD was doxorubicin 60 mg/m2/48 hours followed by paclitaxel 160 mg/m2/24 hours. In part 4 (seven patients), the MTD was doxorubicin 50 mg/m2/bolus followed by paclitaxel 135 mg/m2/24 hours. In parts 2 and 4, the dose-limiting toxic effect was neutropenia. Of the entire cohort of 48 patients, seven (15%) had a complete response (one persists at five years without intervening therapy), 26 (54%) had a partial response for an objective response rate of 69% (95% confidence interval (95% CI): 54%–81%). The median follow-up of all living patients is 38+ months (range 20+ to 62+); the median response duration is seven months (range 2–33.7+); the median overall survival is 20.5 months (range 5–54+). The median time to progression is 9.6 months (range 1–33.7+ months). Two patients developed congestive heart failure, one at 24 months after her final dose of doxorubicin which amounted to a cumulative lifetime total doxorubicin dose of 870 mg/m2, one after a total of 660 mg/m2. In both, cardiac symptoms were controlled with medications.Conclusions: The combination of paclitaxel/24 hours with doxorubicin/48 hours is an effective antineoplastic treatment for metastatic breast cancer. However, the incidence of complete response, the median overall survival, and time to progression were not greater than for standard doxorubicin-based combinations. Additionally, a sequence-dependent interaction between paclitaxel and doxorubicin, given in the schedule described here, was defined. Other strategies and schedules should be evaluated to maximize the antineoplastic efficacy of these two potent agents.     

A phase II randomized study of two taxanes and cisplatin for metastatic breast cancer after anthracycline: a final analysis

OBJECTIVE: The purpose of the study is to compare two taxanes/cisplatin combinations for metastatic breast cancer in terms of time to disease progression, response rates and toxicity. METHODS: Between April 2000 and December 2002, 101 patients with advanced breast carcinoma, previously treated with an anthracycline but not with a taxane, were enrolled. Fifty patients were treated with docetaxel 60 mg/m2 and cisplatin 50 mg/m2, and 51 patients were treated with paclitaxel 175 mg/m2 and cisplatin 50 mg/m2. Each cycle repeated every 3 weeks. RESULTS: The overall response rate was 62.5 and 42.6% in the docetaxel and palcitaxel groups respectively (P = 0.06). Median time to disease progression was 9.8 and 6.5 months in docetaxel and paclitaxel groups respectively (P = 0.15). The median overall survival time was 22.7 months in the docetaxel arm and 22.4 months in the paclitaxel arm. Grade 3/4 arthralgia/myalgia, sensory neuropathy and anemia occurred more frequently in the paclitaxel arm, while more mucositis, fatigue and neutropenia occurred in the docetaxel arm. CONCLUSION: Taxane/cisplatin combinations were active for advanced breast cancer, while there appeared to be evidence in favor of a docetaxel/cisplatin combination. The toxicity in favor of docetaxel/cisplatin warrants future first-line clinical trials.     

Gemcitabine plus paclitaxel as first-line chemotherapy for patients with advanced breast cancer

OBJECTIVES: To assess the efficacy and tolerability of gemcitabine and paclitaxel as first-line treatment in advanced breast cancer. METHODS: Patients with histologically confirmed metastatic or metastatic plus locally advanced breast cancer received gemcitabine 1,200 mg/m(2) on days 1 and 8 and paclitaxel 175 mg/m(2) on day 1 every 21 days for 8 cycles. RESULTS: From December 1999 to August 2001, 45 patients, with a median age of 53.5 years (range, 22-77), received a total of 260 cycles. All were assessable for response and toxicity. Twenty-seven patients had prior adjuvant therapy. Hormonal receptor status was positive in 31.1% and negative in 40.0% of patients. Main metastatic sites included soft tissue (62.2%) and lung (53.3%). The objective response rate was 66.7%; complete response, 22.2%; partial response, 44.4%; stable disease, 15.6%; progressive disease, 17.8%. Median duration of response was 18 months and median time to tumor progression was 11 months. Grade 3/4 leukopenia, neutropenia, and thrombocytopenia developed in 13.3% of patients, and 15.5% developed grade 3/4 mucositis. No treatment-related deaths occurred. Median overall survival was 19 months. CONCLUSIONS: Gemcitabine plus paclitaxel is an active combination with a favorable toxicity profile as first-line treatment for patients with advanced breast cancer.     

A phase II evaluation of a 3-hour infusion of paclitaxel, cisplatin, and 5-fluorouracil in patients with advanced or recurrent squamous cell carcinoma of the head and neck: Southwest Oncology Group study 0007

BACKGROUND: Previous data from an institutional pilot study in patients with advanced or recurrent squamous cell carcinoma of the head and neck (SCCHN) who received treated a combined chemotherapy regimen of paclitaxel, cisplatin, and 5-fluorouracil indicated an overall response rate of 60% and a median survival of 6 months. To validate these results and to determine the feasibility of this combination, a Phase II study was conducted by the Southwest Oncology Group (SWOG S0007). METHODS: Patients with advanced or recurrent SCCHN were eligible if they had received 1 previous regimen of induction/adjuvant chemotherapy or no prior systemic therapy. Patients received treatment with paclitaxel (135 mg/m(2) on Day 1), followed by cisplatin (75 mg/m(2) on Day 1), and 5-fluorouracil (1000 mg/m(2)per day as a 96-hour continuous infusion on Days 1-4) every 21 days. RESULTS: Seventy-six patients received a combined total of 286 cycles of chemotherapy. Sixty-nine patients were evaluable for response. There were 5 complete responses (7%) and 23 partial responses (33%) partial responses, for an overall response rate of 41%. The median progression-free survival was 4 months, and the median overall survival was 10 months. Six treatment-related deaths were documented, including deaths in 2 patients who had a Zubrod PS of 2. Grade 3 or 4 neutropenia (according to National Cancer Institute Common Toxicity Criteria [version 2.0]) was observed in 47% of patients. Other Grade 3 or 4 adverse events included mucositis (34% of patients), nausea (20% of patients), anemia (9% of patients), and neuropathy (8% of patients). CONCLUSIONS: The combination of paclitaxel, cisplatin, and 5-fluorouracil had efficacy similar to that of standard treatment regimens in patients with advanced or recurrent SCCHN but with increased toxicity.     

Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer.

PURPOSE: To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS: Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m(2) of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m(2) of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival. RESULTS: Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P =.0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m(2) for MC versus 480 mg/m(2) for AC (P =.0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months. CONCLUSION: Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.     

Toxicity of doxorubicin and cyclophosphamide (60 mg/600 mg/m2) in adjuvant chemotherapy for breast cancer

We evaluated the toxicity of 4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (AC 60/600) in adjuvant chemotherapy for breast cancer. Between 1994 and 2003, 62 patients received 6 cycles of doxorubicin (40 mg/m2) and cyclophosphamide (500 mg/m2) every 3 weeks (AC 40/500), and 106 patients received AC 60/600 as adjuvant chemotherapy for breast cancer. The performance status of all patients was 0 or 1. Toxicity was determined using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) ver. 2. Grade 3/4 neutropenia was frequent in AC 60/600 (6.5% vs 24.3%, p < 0.001). However, febrile neutropenia was not significant in either group (1.6% vs 3.8%, p = 0.39). There was also no statistical difference in the toxicity greater than grade 3 of anemia, nausea, vomiting, fatigue, diarrhea and cardiotoxicity. There was no treatment-related death in both groups. The number of patients who completed chemotherapy was higher in those receiving AC 60/600 than in those receiving AC 40/500 (91.9% vs 99.1%, p = 0.026). AC 60/600 is tolerated and feasible in adjuvant chemotherapy of breast cancer in Japanese patients from the viewpoint of toxicities.     

紫杉醇联合顺铂治疗晚期食管鳞癌

目的研究紫杉醇联合顺铂治疗晚期食管癌的疗效和毒副反应。方法30例晚期食管磷癌患者中,27例为初次化疗患者,3例患者曾接受术后辅助化疗。中位年龄58岁。紫杉醇175mg／m^2,d1,静脉滴注3h;顺铂40mg/m^2,d2,d3;21d为1个周期。结果30例患者共完成89个化疗周期。在可评价疗效的27例患者中,完全缓解5例(18．5％),部分缓解11例(40．7％),有效率为59．3％。中位疾病进展时间为5．0个月,中位生存时间9．7个月。可评价毒副反应28例,其主要的毒副反应为脱发,有5例(17．9％)患者出现Ⅲ-Ⅳ度中性粒细胞降低。结论紫杉醇联合顺铂对晚期食管癌疗效肯定,可以考虑作为治疗晚期食管癌的主要治疗方案。     

Phase II trial of gemcitabine/doxorubicin/paclitaxel administered every other week in patients with metastatic breast cancer

The present trial was designed to determine the efficacy of the combination of gemcitabine/doxorubicin/paclitaxel (GAT) delivered every other week as first-line therapy in patients with metastatic breast cancer. From February 1998 to September 1999, 41 patients were included in this trial. Doses delivered were doxorubicin 30 mg/m2 on day 1 and paclitaxel 135 mg/m2 plus gemcitabine 2500 mg/m2 both given on day 2, every 14 days. Doses were selected from a previous phase I trial conducted at our institution. Eligibility criteria for the phase II trial included histologically confirmed metastatic breast cancer with bidimensionally measurable lesions; no prior therapy for metastatic disease; adjuvant or neoadjuvant chemotherapy was allowed if given more than 1 year before and cumulative doses of doxorubicin or epirubicin were less than 200 mg/m2 or 360 mg/m2, respectively; Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less; and adequate hematological, hepatic, and renal function. Prophylactic use of granulocyte colony-simulating factor (G-CSF) was allowed if patients were not fully recovered (absolute neutrophil count greater than 1500/microL) from chemotherapy administration before the next dose. Left ventricular ejection fraction was determined initially, at the end of the study, and every 6 months thereafter. The patients' median age was 55 years (range, 33-68 years), and their median ECOG performance status was 0 (range, 0-1). Twenty-eight patients had received adjuvant therapy, 17 with epirubicin (none with doxorubicin). Metastases were present in the bone (19 patients), lung (19 patients), liver (11 patients), and soft tissues (18 patients). Twenty patients had one metastatic site and 21 had two or more sites. Efficacy was assessed on an intent-to-treat basis. A total of 216 cycles of GAT were given. Twenty-two percent of the courses were delayed or given at reduced doses mostly due to neutropenia or thrombocytopenia. G-CSF was required in 58% of the cycles. Grade 3/4 neutropenia was the main toxicity and appeared in 17 patients, one of whom had an episode of febrile neutropenia. Nonhematological toxicities consisted mainly of neurotoxicity and myalgias. A drop of 10%-20% in the left ventricular ejection fraction was detected in two patients and another patient had a decrease greater than 20%, although none developed symptoms of heart failure. Overall response rate was 80.4% (95% confidence interval: 68.3-92.5), with 15 patients (36.6%) achieving a complete response. Median survival time was 27 months and median time to progression was 15 months. The GAT combination is feasible and very active in patients with metastatic breast cancer, with an encouraging response rate including a high rate of complete responses. No congestive heart failure was documented and other toxicities were mild, with the exception of neutropenia.