国产长春瑞滨联合阿霉素治疗转移性乳腺癌的临床观察

目的：观察国产长春瑞滨（盖诺）联合阿霉素方案治疗转移性乳腺癌的临床疗效。方法：运用国产长春瑞滨（25mg/m^2 iv dl,5)加阿霉素（40mg/m^2iv dl)治疗转移性乳腺癌28例，结果：取得CR4例，PR13例，总有效率（CR＋PR）达60．7％；主要毒副反应为白细胞减少，发生率为92．8％，其中Ⅲ-Ⅳ度骨髓抑制占64．2％，结论：国产长春瑞滨加阿霉素方案对转移性乳腺癌疗效明确，血骨髓抑制明显。     

A randomized phase II study of paclitaxel and bevacizumab with and without gemcitabine as first-line treatment for metastatic breast cancer

Background

The addition of bevacizumab to paclitaxel improved progression-free survival (PFS) of patients with metastatic breast cancer (MBC). We examined the efficacy and safety of adding gemcitabine to paclitaxel/bevacizumab (PB).

Patients and Methods

In this multicenter, open-label, randomized phase II trial, women with locally advanced or MBC were randomly assigned to receive paclitaxel 90 mg/m² (days 1, 8, 15) and bevacizumab 10 mg/kg (days 1, 15) with or without gemcitabine 1500 mg/m² (days 1, 15) in 28-day cycles. Patients with prior cytotoxic therapy for MBC were ineligible. The primary endpoint was investigator-assessed overall response rate (ORR); secondary endpoints were PFS, overall survival (OS), safety, and quality of life.

Results

Ninety-four patients received PB, and 93 received paclitaxel/bevacizumab/gemcitabine (PB+G). The ORRs were 48.9% (95% confidence interval [CI], 38.5%-59.5%) and 58.7% (95% CI, 47.9%-68.9%; P = .117) with PB and PB+G, respectively. The median PFS was 8.8 months (95% CI, 8.1-10.4 months) and 11.3 months (95% CI, 9.7-12.7 months; P = .247; hazard ratio, 0.82); the median OS was 25.0 months (95% CI, 18.8-not assessable [N/A] months) and 24.3 months (95% CI, 20.3-N/A months; P = .475; hazard ratio, 0.84), with PB and PB+G, respectively. There was significantly more grade 3-4 neutropenia (P = .001) and dyspnea (P = .014) with PB+G. Patients treated with PB experienced more improvement in total FACT-B (Functional Assessment of Cancer Therapy-Breast) (P = .021), FACT-B Social/Family Well-being (P = .041), and Breast Cancer-Additional Concerns (P = .008) scores than patients treated with PB+G.

Conclusion

The addition of gemcitabine to PB was not associated with a statistically significant improvement in ORR. Treatment with PB+G increased the incidence of severe neutropenia and dyspnea, although the regimen generally was well tolerated.     

A phase I/II trial of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab as first-line treatment in HER-2-positive locally advanced or metastatic breast cancer

Aim

To assess the activity and safety of non-pegylated liposomal doxorubicin (Myocet®) in combination with docetaxel and trastuzumab as first-line treatment of patients with HER-2/neu-positive metastatic breast cancer (MBC).

Patients and methods

The maximum tolerated dose of the combination was defined in the phase I part of the study. In the phase II part, 45 HER-2/neu-positive MBC patients were enrolled to receive 6-8 cycles of Myocet® 50 mg/m² (day 1), docetaxel 30 mg/m² (days 2 and 9) plus trastuzumab (day 2, 4 mg/kg followed by 2 mg/kg/week) every 21 d until unacceptable toxicity or progression occurred. Objective response (primary end-point) and treatment tolerability were assessed according to World Health Organisation criteria. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure and/or a decrease in left ventricular ejection fraction (LVEF).

Results

The overall response rate was 55.6% (complete response 8.9%, partial response 46.7%), with a median time-to-progression of 10.9 months (C.I. 8.7-15.0). Median overall survival was not reached. The most frequent grade 3-4 adverse events were granulocytopaenia (60.0%), leukocytopenia (43.2%) and alopecia (35.6%). Grade 3-4 diarrhoea, pain, oral and skin toxicity (4.4%, each) and nausea/vomiting, thrombocytopenia and elevated alkaline phosphatase (2.2%, each) were also reported. In 2 patients LVEF fell to <50%, with a decrease from baseline >15%. LVEF median values remained stable from baseline to the end of the study (60%).

Conclusions

The combination of Myocet®, docetaxel and trastuzumab is safe and shows promising activity as first-line treatment of HER-2-positive MBC.     

A dose-escalating pilot study of sterically stabilized, pegylated liposomal doxorubicin (Lipo-Dox) in patients with metastatic breast cancer

Doxorubicin is considered among the most active single agents used against advanced breast cancer. Recent advances in the design of liposomes as carriers of cytotoxic drugs have resulted in a new formulation of doxorubicin with improved pharmacokinetic and tumor-localizing properties. The objectives of this dose-escalating pilot study were to evaluate the efficacy and safety of the sterically stabilized, pegylated liposomal doxorubicin (Lipo-Dox) for the treatment of metastatic breast cancer. Lipo-Dox was given at the dosage of 45 mg/m² over 1 hr of intravenous infusion every 4 weeks initially and could be escalated up to a maximum of 60 mg/m². Response was assessable in 17 of 19 intent-to-treat patients. An objective response was achieved in 41.2% (95% confidence interval: 17.8%-64.6%) of patients (5.9% complete response and 35.3% partial response), and 23.5% had stable disease. Median time to disease progression was 163 days. Major treatment-related toxicities included neutropenia, stomatitis, and skin toxicity in this dose-escalation program. Impressively, no grade 4 toxicities have ever been observed. The only grade 3 nonhematological toxicity ever to occur was reversible skin toxicity, presented as palmar-plantar erythrodysthesia. No severe nausea/vomiting, wig-necessary alopecia, or significant cardiac function change were encountered. In conclusion, Lipo-Dox is shown by this first reported pilot study to be an active agent for treatment of advanced breast cancer with a safety profile that differs markedly from free doxorubicin. The dosage of 45-60 mg/m² every 4 weeks was well tolerated. Because myelosuppression and other nonhematological toxicities associated with Lipo-Dox were generally mild and acceptable, further assessment of this drug particularly in combination with other chemotherapeutic drugs in the management of early or advanced breast cancer is suggested.     

Oral vinorelbine/paclitaxel combination treatment of metastatic breast cancer: a phase I study

Purpose Intravenous (i.v.) vinorelbine (VRL) generally given on days 1 and 8 of an every three-week cycle in combination with paclitaxel (PTX) is an effective option for the treatment of metastatic breast cancer (MBC). In an effort to improve both patient and chemotherapy unit convenience, oral VRL was used at equivalent doses of i.v. VRL. Patients and methods The maximal tolerated dose (MTD) was determined during the first cycle of oral VRL given on days 1 and 8 or 15 and PTX infused over 3 h on day 1 every 3 weeks, maximum of 6 cycles. The dose of oral VRL was escalated from 60 to 80 mg/m² in 10 mg/m² increments. Paclitaxel was administered at 110 and then 135 mg/m². The combination regimen was given as first-line chemotherapy of MBC. Three to six patients per cohort were treated. Results Twenty-two patients were treated in the first four cohorts (oral VRL/PTX): 60/110, 70/110, 80/110 and 80/135. In cohort 4, seven patients were treated, one patient being non-evaluable for MTD, three of them presented a dose-limiting toxicity (DLT) consisting of febrile neutropenia and neutropenic infection. Therefore 80/135 was the MTD. Because 36% of oral VRL administrations on day 8 were delayed to day 15 at 80/110, two additional cohorts were tested: in cohort 5, oral VRL 60 mg/m² on days 1 and 15 and PTX 135 mg/m² on day 1 and in cohort 6, oral VRL 80 mg/m² on days 1 and 15 and PTX 110 mg/m² on day 1, every 3 weeks. In cohort 5, six out of eight patients had DLTs: omission of oral VRL on day 15 for five patients, grade 4 neutropenia >7 days for another one. Therefore the recommended dose (RD) for further clinical testing was oral VRL 80 mg/m² on days 1 and 15 and PTX 110 mg/m² on day 1 of an every 3-week cycle. Two of the three evaluable patients treated at the RD had a partial response. The pharmacokinetics of VRL and PTX is being analysed and will be further presented in a separate publication. Conclusions This phase I study has determined the doses of oral VRL and PTX to be used in combination for the benefit of the patient and of the chemotherapy unit in term of nurse’s workload. The recommended regimen of oral VRL 80 mg/m² on days 1 and 15 and PTX 110 mg/m² on day 1 given every 3 weeks will be further tested in phase II.     

Efficacy and toxicity of vinorelbine with doxorubicin/cyclophosphamide combination chemotherapy in a phase I-II study for advanced or recurrent breast cancer patients

BACKGROUND: To evaluate the efficacy and toxicity of vinorelbine (VNB) with doxorubicin/cyclophosphamide (AC) combination chemotherapy, a phase I-II study was carried out in patients with advanced or recurrent breast cancer. METHODS: The phase I part of this study was carried out to determine the treatment schedule and acceptable dose of VNB for the phase II study. In phase I, VNB was initially given as a short infusion on days 1, 8 and 15, every 4 weeks. The initial dose of vinorelbine was 15 mg/m2. In the AC regimen, 20 mg/m2 of doxorubicin (ADM) was given intravenously (i.v.) on days 1 and 8, and 100 mg/body of cyclophosphamide (CPA) was administered orally from days 1 to 14. Subsequently, a phase II study was carried out at the maximum acceptable dose (MAD). RESULTS: Twenty-three patients were entered into this study. In patients receiving VNB at a dose of 15 mg/m2, neutropenia (> or = grade 3) frequently occurred on day 15. The treatment schedule of this study was therefore changed to VNB given i.v. on days 1 and 8 with AC combination chemotherapy. In this treatment schedule, grade 4 neutropenia lasting for more than 4 days occurred in patients given VNB at a dose of 20 mg/m2 with AC more frequently than in those given 15 mg/m2 of VNB. Therefore, the MAD of VNB was determined to be 20 mg/m2 in this regimen. At this recommended dose, there were 1 complete (CR) and 8 partial responses (PRs) in 15 patients, with an overall response rate of 60.0%. No treatment-related death occurred. CONCLUSIONS: These data indicate that VNB plus AC combination chemotherapy was effective and well tolerated for breast cancer patients. A randomized trial of VNB plus AC vs. AC combination chemotherapy may be required to ascertain the benefit of this regimen for advanced or recurrent breast cancer patients.     

Sequential doxorubicin and docetaxel as first-line treatment in metastatic breast cancer: a GEICAM-9801 phase II study

Purpose. To evaluate the efficacy and the toxicity profile of the sequential administration of doxorubicin and docetaxel as first-line chemotherapy in metastatic breast cancer (MBC). Patients and methods. Eighty-one patients received a total of 436 cycles of chemotherapy: 236 of doxorubicin (75 mg/m²) and 200 of docetaxel (100 mg/m² every 21 days). The first 35 patients received doxorubicin every 14 days with G-CSF support, and in the other 46 cases doxorubicin was administered every 21 days without G-CSF. Results. After entire treatment the overall response rate was 65% (18 complete responses). With a median follow-up of 19 months (range, 1–48 months), the median time to progression was 11.3 months and the median survival time was 31 months. As expected, febrile neutropenia was the most important toxicity and it appeared in 26 cycles (6%) and 19 patients (23%). In the patients that received doxorubicin every 14 days, the febrile neutropenia incidence was higher during docetaxel treatment, especially after its first administration. Conclusions. The dose and schedule of doxorubicin and docetaxel used in this trial seems to be active in first-line treatment of patients with MBC. The toxicity profile appears to be better than observed with concomitant schedules.     

A phase II trial of weekly paclitaxel, 5-fluorouracil,and leucovorin as first-line treatment for metastatic breast cancer

Purpose. This phase II multicenter trial evaluated the efficacy and toxicity of weekly paclitaxel, 5-fluorouracil, and leucovorin administered as first-line therapy for metastatic breast cancer. Patients and methods. The study enrolled 155 women with pathologically confirmed and measurable metastatic adenocarcinoma of the breast. Treatment consisted of paclitaxel 80 mg/m², 5-fluorouracil 425 mg/m², and leucovorin 20 mg/m² administered weekly 4 × per 4-week cycle in the first 40 patients enrolled (group 1), and weekly 3 × per 4-week cycle in the subsequent 115 patients (group 2) enrolled. Hematologic growth factor support was not routinely used. Twenty patients with hepatic dysfunction were enrolled to assess the tolerability of the regimen in this population. All therapies were delivered in an outpatient setting. Results. The overall response rate was 48%, with 12-month estimated survival rates of 53% and 65% for treatment groups 1 and 2, respectively. Response rates were not statistically different between the two treatment schedules. Therapy was well tolerated when delivered on the every 3 of 4-week schedule, including patients with hepatic involvement and those age q 65. Conclusion. Weekly therapy with paclitaxel and 5-fluorouracil with leucovorin is active as first-line therapy for metastatic breast cancer. Use of this regimen should be given consideration, particularly in patients who are not candidates for anthracycline-based therapy.     

Phase I studies of fluorouracil, doxorubicin and vinorelbine without (FAN) and with (SUPERFAN) folinic acid in patients with advanced breast cancer

Purpose: The Breast Cancer Site Group of the National Cancer Institute of Canada – Clinical Trials Group (NCIC-CTG) undertook two parallel phase I studies to determine the maximum tolerated dose (MTD) and recommended phase II dose of vinorelbine in combination with doxorubicin and fluorouracil (with or without folinic acid) in metastatic breast cancer. Methods: Cohorts of five patients were to receive: (a) fluorouracil 500 mg/m² and doxorubicin 50 mg/m² on day 1 only and escalating doses of vinorelbine (15, 20, 25, 30 mg/m²) on days 1, 8 and 15 every 3 weeks (FAN regimen), or (b) fluorouracil 340 mg/m² and folinic acid 200 mg/m² on days 1, 2, 3, 4 and 5, doxorubicin 40 mg/m² on day 1 only and escalating doses of vinorelbine (15, 20, 25, 30 mg/m²) on day 1 and again on day 5 every 4 weeks (SUPERFAN regimen). Eligibility included measurable or evaluable metastatic breast cancer and having received neither previous chemotherapy for metastatic disease nor anthracycline-containing adjuvant therapy. Results: Of 26 and 12 patients enrolled in the FAN and SUPERFAN regimens, 26 and 12 were evaluable for toxicity and 21 and 9 for response, respectively. Median ages were 60.3 years (41–71 years) and 64.2 years (51–73 years). Both regimens required amendment after the first cohort with an original day-15 vinorelbine dose omitted from the FAN regimen and more prolonged nadir granulocyte counts allowed. Myelosuppression was dose limiting. MTDs in the FAN and SUPERFAN regimens were vinorelbine 25 mg/m² and 20 mg/m². Other toxicities included mucositis, septicemia and febrile neutropenia. Peripheral neuropathy and constipation were mild. Of the 21 FAN patients evaluable for response, 3 (14%) had complete responses and 7 (33%) had partial responses, for an overall response rate of 48%; 9 (43%) had stable disease and 2 (9%) had progressive disease as their best response. Of the nine SUPERFAN patients evaluable for response, none had a complete response. There were two (22%) with partial responses, and six (67%) had stable disease and one (11%) had progressive disease as their best response. Conclusions: The SUPERFAN regimen was too toxic to pursue even at the lowest dose. The recommended phase II starting dose for the FAN regimen was vinorelbine 20 mg/m². Although these were phase I studies response rates in evaluable patients were less than expected and toxicity did not allow the use of as much vinorelbine in the combinations as had been anticipated. The limited response data from our study would imply that combining vinorelbine with more toxic agents may not enhance response rates and may defeat the advantage of tolerability, especially in elderly patients. Received: 7 December 1996 / Accepted: 8 May 1997     

Phase II study of vinorelbine (alternating intravenous and oral) in combination with docetaxel as first-line chemotherapy in metastatic breast cancer

Purpose  Combination of intravenous (i.v.) vinorelbine and docetaxel was shown to be feasible and effective in metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated in first-line treatment a regimen alternating i.v. and oral vinorelbine in combination with docetaxel. Patients and methods  Forty-nine patients (median age, 53 years) with MBC received a maximum of 6 cycles consisting of i.v. vinorelbine 20 mg/m2 plus docetaxel 60 mg/m2 given on day 1, and oral vinorelbine 60 mg/m2 on day 15 every 3 weeks in an open-label, multicentre phase II study (recommended dose established in phase I study [1]). Results  Sixty-three percent of the patient had received prior adjuvant chemotherapy and 78% presented visceral involvement. Twenty-four responses were documented and validated by an independent panel review, yielding response rates of 49% (95% CI: 34–64) in the 49 enrolled patients and 55.8% (95% CI: 40–71) in the 43 evaluable patients. Median duration of response was 9.4 months. Median progression-free survival and median overall survival were 5.5 and 33.2 months, respectively. Neutropenia was the main dose-limiting toxicity but complications were uncommon, four patients having experienced febrile neutropenia and one having developed neutropenic infection. Other frequently reported adverse events included alopecia, fatigue, stomatitis, constipation, diarrhoea and nausea, which were rarely severe. Conclusions  This regimen alternating oral and i.v. vinorelbine in combination with docetaxel is effective and manageable. Vinorelbine i.v. per oral day 1 per day 15-docetaxel day 1 every 3 weeks represents a convenient option to combine docetaxel and vinorelbine for the palliative treatment of MBC.     

Second line chemotherapy with 5 fluorouracil and vinorelbine in anthracycline and taxane pretreated patients with metastatic breast cancer

Purpose. 5-Fluorouracil (5-FU) and Vinorelbine (Vin) are active in the second line therapy of metastatic breast cancer (MBC). We conducted a multi-institutional phase II study to assess the activity of the combination of 5-FU and Vin in anthracycline and taxane pretreated patients with MBC. Patients and Methods. Patients with MBC previously treated with anthracyclines and taxanes, who had measurable or evaluable disease, were treated with folinic acid 200 mg/m² IV, 5-FU 400 mg/m² IV bolus, and 5-FU 600 mg/m² continuous infusion over 24 hours on days 1, 2, 15, and 16 and Vin 25 mg/m² on days 1 and 15 of a 28-day cycle, for six cycles. Response rate, time to disease progression, overall survival, and toxicity were evaluated. Results. Thirty-eight patients were enrolled and 35 were evaluable for response. Grade III and IV neutropenia was seen in four and three patients, respectively. At a median follow-up of 19.5 months, 33 patients have progressed, 14 during treatment and 19 during the follow-up period, and 23 have died for an overall survival of 12.3 months. The time to progression was six months. Eight patients had a partial response and 14 had stable disease for a clinical benefit rate of 63%. Conclusion. The combination of 5-FU and Vin is well tolerated and is a good option for the palliative care of patients with MBC.     

Predictive factors of response to first-line chemotherapy in 1426 women with metastatic breast cancer

Since response to chemotherapy is a major determinant of survival in metastatic breast cancer, the purpose of our study was to analyse the predictive factors of response. 1426 patients enrolled into eight consecutive randomised trials of anthracycline-based first-line chemotherapy in metastatic breast cancer, between 1977 and 1992, were analysed. A forward stepwise logistic regression analysis was used. The objective response rate (ORR) to chemotherapy in the total population was 63.6% (95% confidence interval (CI): 61.5–67.7). The complete response rate was 17.5%. Multivariate analysis defined adjuvant chemotherapy, lactate dehydrogenase (LDH), Karnofsky index (KI), and pleural and lung metastases to be the five main variables correlated with ORR. A predictive score was calculated using the coefficient of these five variables. The score was established as follows: −1.32+0.54 (if prior adjuvant chemotherapy)+0.80 (low KI)+0.75 (raised LDH)+0.49 (lung metastases)+0.51 (pleural metastases). A low score (less than −0.78) was associated with an ORR greater than 70.0%, representing 41.2% of our population. An intermediate score (between −0.78 and 0) was associated with an ORR of 50 to 70%, representing 37.5% of our population and a positive score was associated with an ORR of less than 50%, representing 21.3% of our population. This score can be used to predict objective response rates to first-line anthracycline-based chemotherapy. This method now needs to be evaluated prospectively in phase II trials. Identification of various risk groups may also be useful for interpretation and design of clinical trials.     

Myotax: a phase II trial of docetaxel plus non-pegylated liposomal doxorubicin as first-line therapy of metastatic breast cancer previously treated with adjuvant anthracyclines

Aim

Non-pegylated liposomal doxorubicin (NPLD) has demonstrated equivalent antitumour activity to conventional doxorubicin and a significantly lower risk of cardiotoxicity when given as a single agent or in combination with cyclophosphamide. This phase II trial was performed to evaluate the efficacy and the safety of NPLD and docetaxel combination in patients with metastatic breast cancer previously exposed to adjuvant anthracyclines.

Patients and methods

Thirty-four patients received NPLD 60 mg/m² and docetaxel 75 mg/m² in a 21-day cycle as first-line therapy of metastatic breast cancer. Treatment was planned for six cycles and was continued until progression or toxicity.

Results

Objective response rate among response-assessable patients was 79% (95% CI (confidence interval), 64–94%) and 27% (95% CI, 11–43%) presented a complete response. Median progression free survival was 11.3 months (95% CI, 6.2–13.3 months) and median overall survival was 28.2 months (95% CI, 16–36.4 months). Symptomatic grade 3 cardiotoxicity occurred in 15% of cases and febrile neutropenia in 47% of the patients.

Conclusions

The combination of NPLD and docetaxel demonstrated high antitumour activity in a population of metastatic breast cancer patients exposed to adjuvant anthracyclines and showed an unexpected and unexplained 15% symptomatic left ventricular systolic dysfunction rate.     

洛铂联合长春瑞滨治疗晚期乳腺癌33例的临床疗效

目的:观察长春瑞滨(NVB)联合洛铂(LBP)组成NL方案治疗晚期乳腺癌的疗效和不良反应。方法:从2004年1月~2005年10月,采用NVB加LBP的联合化疗方案治疗晚期乳腺癌33例,LBP30mg/m2,第1天,静脉滴注3小时;NVB25mg/m2,第1、8天,静脉滴注30分钟,21天为1周期。结果:全组33例共完成105个周期,中位3周期(2~4周期),均可评价疗效。获CR1例,PR13例,SD11例,PD8例,RR为42·4%,肿瘤控制率DCR(CR PR SD)为75·8%,中位缓解期为4个月(1~17个月)。主要不良反应为骨髓抑制,其中Ⅲ~Ⅳ度粒细胞减少发生率为57·6%,Ⅲ度血小板减少发生率为9·1%;非血液学毒性轻微,可以耐受。结论:洛铂联合长春瑞滨组成NL方案治疗局部晚期及转移性乳腺癌疗效较好,不良反应可以耐受,在加强支持治疗(应用造血因子)的基础上,可以考虑作为二线治疗或解救化疗方案。     

Non-pegylated liposomal doxorubicin combined with gemcitabine as first-line treatment for metastatic or locally advanced breast cancer. Final results of a phase I/II trial

Doxorubicin and gemcitabine are active as single agents in breast cancer, have different mechanisms of action, and mainly have non-overlapping side effects. Dose-dependent doxorubicin-related cardiac toxicity is the principal limitation in the metastatic setting. This open, multicenter, single-arm phase I/II study assessed the safety and activity of gemcitabine in combination with non-pegylated liposomal doxorubicin (Myocet), a more cardiac-friendly anthracycline, in the first-line treatment of patients with advanced breast cancer. We aimed to determine the optimal recommended dose (RD) of gemcitabine combined with Myocet in a population, with performance status >or=2 and LVEF >or=50%. A formal phase II study was performed afterwards. A total of 53 patients were recruited. Gemcitabine 900 mg/m(2) intravenously day 1 and 8 combined with Myocet 55 mg/m(2) intravenously day 1, every 21 days, was the final RD. The principal toxicity observed was hematological, and 48% of patients developed grade 3-4 neutropenia. Other toxicities were mild and infrequent, including nausea and vomiting. There were no symptomatic cardiac events despite the fact that 36% of the patients had received prior treatment with adjuvant anthracyclines. Objective responses were observed in 51.1% of 47 evaluable patients (95% CI: 36-66%), including two complete response. In addition, 14 patients (29.8%) demonstrated stable disease. The combination of Myocet and gemcitabine at the RD is safe and has encouraging clinical activity in patients with advanced breast cancer, without apparent cardiac toxicity in anthracycline-pretreated patients. These data support further development of this combination.     

A randomized phase II study of combination, alternating and sequential regimens of doxorubicin and docetaxel as first-line chemotherapy for women with metastatic breast cancer.

BACKGROUND: This randomized phase II study was conducted to evaluate the efficacy of doxorubicin and docetaxel (DOC) administered either as a combination, an alternating or a sequential regimen in women with metastatic breast cancer. Secondary objectives included overall response, time to progression, survival and safety. PATIENTS AND METHODS: Patients with breast cancer (n=123) were randomized to receive doxorubicin and DOC either in combination (60 mg/m2 of each drug), or by alternated or sequential schedule (100 mg/m2 DOC and 75 mg/m2 doxorubicin) every 3 weeks for a maximum of eight cycles as first chemotherapy for stage IV disease. A second randomization allocated patients from each arm to receive prophylactic oral ciprofloxacin or no therapy to prevent febrile neutropenia. RESULTS: Patients received a median of eight cycles. In an intention-to-treat analysis, the overall response was 63%, 52% and 61% in the combination, alternating and sequential schedules, respectively. Corresponding rates of complete response were 15%, 14% and 11%. Grade 4 neutropenia was common in all arms (81%) and, together with febrile neutropenia, was significantly more frequent with the combination. Prophylaxis with ciprofloxacin did not reduce the incidence of febrile neutropenia or infection. Other frequent non-hematological adverse events included alopecia, nausea, vomiting, stomatitis and asthenia. Congestive heart failure only occurred in the combination arm (10%). CONCLUSION: All three schedules are feasible and endowed of good therapeutic activity. In view of the more pronounced toxicity and the risk of cardiac events because of the higher exposure to doxorubicin, the combination should be least favored when treating women with metastatic breast cancer. Prophylaxis with ciprofloxacin was ineffective and is not recommended.     

Phase I dose-finding and pharmacokinetic study of docetaxel and vinorelbine as first-line chemotherapy for metastatic breast cancer

Background and purpose:Anthracycline-containing regimens arewidely used in advanced breast cancer. However, there is a need for new,non-anthracycline regimens that are active in patients for whom anthracyclinesare contraindicated. The aim of this study was to determine the maximumtolerated dose (MTD), the dose-limiting toxicities (DLTs) and recommendeddoses of docetaxel and vinorelbine as first-line chemotherapy in patients withmetastatic breast cancer. The pharmacokinetics of both drugs was alsoevaluated. Patients and methods:Thirty-four women with first-line metastaticbreast cancer were treated with docetaxel, 60–100 mg/m² (day1), and vinorelbine, 20–22.5 mg/m² (days 1 and 5), repeatedevery three weeks and administered on an outpatient basis. Results:Two MTDs were determined: MTD1 was defined at the doselevel using docetaxel 75 mg/m², and vinorelbine 22.5mg/m²; DLT being a grade 3 stomatitis that was more related to thedose of vinorelbine than that of docetaxel. Therefore, the study continuedwith a fixed dose of vinorelbine, 20 mg/m², and docetaxel85–100 mg/m². MTD2 was defined at the dose level combiningdocetaxel, 100 mg/m², and vinorelbine, 20 mg/m²; DLTswere grade 3 stomatitis and severe asthenia. Fluid retention was observed in41% of patients but was never severe or a reason for patientdiscontinuation. In comparison with historical experience, Daflon 500® didnot seem to increase the efficacy of the three-day corticosteroidpremedication by further reducing the incidence or severity of fluidretention. No significant neurotoxicity was observed and no patientdiscontinued the study due to this site effect. Activity was observed at alldose levels and at all metastatic sites, with an overall response rate of71% (95% CI: 52.0%–85.8%). The median timeto progression was 31.4 weeks (95% CI: 12–48 weeks) and mediansurvival was 15.6 months (95% CI: 2.6–26.6 months). Thepharmacokinetics of docetaxel and vinorelbine were not modified between day1 and day 3 when the two drugs were combined with the day 1 administrationschedule used in this study. Conclusion:The recommended doses for phase II studies aredocetaxel, 75 mg/m² (day 1), plus vinorelbine, 20 mg/m²(days 1 and 5), repeated every three weeks. At these doses, the combinationwas found to be active and well tolerated.     

吉西他滨联合长春瑞滨治疗晚期三阴性乳腺癌的临床观察

目的：观察吉西他滨联合长春瑞滨（ＧＮ方案）治疗ＥＲ、ＰＲ、ＨＥＲ ２均阴性（三阴性）晚期转移性乳腺癌的疗效与安全性。方法：２００４年１月～２００８年１月共３７例经免疫组化证实ＥＲ、ＰＲ、ＨＥＲ ２均阴性的晚期转移性乳腺癌复治患者参与研究。患者接受吉西他滨联合长春瑞滨方案治疗：吉西他滨１ ０００ｍｇ／ｍ２,静脉滴注３０ｍｉｎ,ｄ_１、ｄ_８;长春瑞滨２５ｍｇ／ｍ^２静脉滴注１５ｍｉｎ,ｄ_１、ｄ_８。２１天重复。结果：全组３７例共完成１３６个周期的治疗,中位数４个周期,范围２～６个周期,均可评价疗效。完全缓解１例（２.７％）,部分缓解８例（２１.６％）,病情稳定２０例（５１.４％）,病情进展９例（２１.６％）,客观有效率为２４.３％;中位疾病进展时间（ｍＴＴＰ）６个月（９５％ ＣＩ：４～８个月）,中位生存期（ＯＳ）２４个月（９５％ ＣＩ：１１～３７个月）,１年生存率为（６６.２４±８.４３）％,３年生存率为（２８.７７±１１.９６）％。毒副反应主要为Ⅰ ～Ⅱ度骨髓抑制、末梢神经毒性、胃肠道反应、流感样症状、轻度肝功能损伤等。结论：吉西他滨联合长春瑞滨治疗晚期三阴性乳腺癌患者,初步观察有一定的疗效,其毒副作用患者可以耐受。     

A multicentre dose-escalating study of cabazitaxel (XRP6258) in combination with capecitabine in patients with metastatic breast cancer progressing after anthracycline and taxane treatment: a phase I/II study

Background

Most patients with metastatic breast cancer (MBC) progress after chemotherapy. Cabazitaxel (XRP6258) is a new taxoid that is active in chemotherapy-resistant tumour cell lines. The objectives of this phase I/II study were to assess the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and activity of cabazitaxel plus capecitabine in patients with MBC who had been previously treated with taxanes and anthracyclines.

Patients and methods

In part I, we used a 3 + 3 dose-escalation scheme to assess the MTD of intravenous cabazitaxel (day 1) with oral capecitabine twice daily (days 1-14) every 3 weeks. In part II, we evaluated the objective response rate (ORR) at the MTD.

Results

Thirty-three patients were enrolled and treated (15 in part I; 18 in part II). Cabazitaxel 20 mg/m² plus capecitabine 1000 mg/m² was the MTD. Pharmacokinetic analysis showed no apparent drug-drug interaction. In all patients, the main grade 3-4 toxicities were asthenia (n = 5), hand-foot syndrome (n = 5), neutropenia (n = 21), neutropenic infection (n = 1), and neutropenic colitis (n = 1). One patient had febrile neutropenia. Antitumour activity was observed at all dose-levels with two complete responses, five partial responses (PRs), and 20 disease stabilisations (seven unconfirmed PR). At the MTD, 21 patients were evaluable for efficacy. The ORR was 23.8% (95% CI: 8.2-47.2%). The median response duration was 3.1 months (95% CI: 2.1-8.4 months), with four of five lasting for more than 3 months. Median time to progression was 4.9 months.

Conclusions

Cabazitaxel combined with capecitabine is active, has a safety profile consistent with a taxane plus capecitabine combination and warrants further investigation in patients with MBC.     

A phase I-II study of bi-weekly paclitaxel as first-line treatment in metastatic breast cancer

Background: Single-agent bi-weekly paclitaxel was studied as first-line metastatic treatment for breast cancer in a phase I–II trial.Patients and methods: Thirty-eight women with metastatic breast cancer were enrolled. Thirty-seven are evaluable for toxicity, 35 for response.Results: The MTD was defined at 160 mg/m2 q two weeks with dose limiting toxicity in two patients consisting of hematological toxicity (1) and neurotoxicity (2). Twenty patients were treated at 150 mg/m2, the recommended dose. Response rates were two CRs and nine PRs (overall 61%) at the RD of 150 mg/m2 and three CRs and 11 PRs for an overall RR of 67% for the two top doses.Conclusions: The good drug tolerance, response rates, and convenience over weekly treatment suggest this may be a worthwhile regimen.