Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer

We report the first results from a phase II, open-label study designed to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab and capecitabine as first-line therapy for human epidermal growth factor receptor (HER)-2-positive locally recurrent (LR) or metastatic breast cancer (MBC). Patients were aged ≥18 years with confirmed breast adenocarcinoma, measurable LR/MBC and documented HER-2-positive disease. Patients received bevacizumab (15 mg/kg on day 1) plus trastuzumab (8 mg/kg on day 1 of cycle 1, 6 mg/kg on day 1 of each subsequent cycle) plus capecitabine (1,000 mg/m2 twice daily, days 1-14) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal. Eighty-eight patients were enrolled; 40 (46%) are still on study treatment. The median follow-up was 8.8 months (range, 0.9-17.1 months). The overall response rate, the primary endpoint, was 73% (95% confidence interval [CI], 62%-82%), comprising 7% complete and 66% partial responses. The median progression-free survival interval was 14.4 months (95% CI, 10.4 months to not reached [NR]), with 35 events. The median time to progression was 14.5 months (95% CI, 10.5 months to NR), with 33 events. Treatment was well tolerated; main side effects were grade 3 hand-foot syndrome (22%), grade ≥3 diarrhea (9%), and grade ≥3 hypertension (7%). Overall, 44% of patients experienced grade ≥3 treatment-related adverse events and 13 patients discontinued capecitabine because of toxicity, but continued with bevacizumab and trastuzumab. Heart failure was seen in two patients. The combination of bevacizumab, trastuzumab, and capecitabine was clinically active as first-line therapy for patients with HER-2-positive MBC, with an acceptable safety profile and no unexpected toxicities.     

Paclitaxel and bevacizumab with or without capecitabine as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: A multicentre,open-label,randomised phase 2 trial

BackgroundThe addition of bevacizumab to paclitaxel or capecitabine has demonstrated improved progression-free survival (PFS) and objective response rate (ORR) as compared with chemotherapy alone in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC). We evaluated the efficacy and safety of first-line therapy of paclitaxel and bevacizumab with or without capecitabine in patients with HER2-negative LR/MBC.MethodsIn this multicentre, open-label, randomised phase II trial, women with HER2-negative LR/MBC were randomly assigned in a 1:1 ratio to paclitaxel (90 mg/m² intravenously [IV] on days 1, 8, and 15) and bevacizumab (10 mg/kg IV on days 1 and 15) every 4 weeks for six cycles, followed by bevacizumab (15 mg/kg IV on day 1) every 3 weeks (AT) or to paclitaxel (90 mg/m² IV on days 1 and 8), bevacizumab (15 mg/kg IV on day 1) and capecitabine (825 mg/m² orally twice daily on days 1–14) every 3 weeks for eight cycles, followed by bevacizumab and capecitabine at the same doses every 3 weeks (ATX). The primary end-point was investigator-assessed PFS. Secondary end-points included ORR, duration of response, overall survival (OS) and safety. Exploratory analyses were conducted to evaluate the impact of capecitabine on OS and to validate a novel prognostic model. This trial is registered with EudraCT, number 2006-006058-83.FindingsMedian PFS was significantly longer in ATX as compared with AT (11.2 months versus 8.4 months; stratified hazard ratio (HR), 0.52; 95% confidence interval (CI), 0.41–0.67; p < 0.0001). The ORR in ATX patients with measurable disease (n = 268) was higher than that in AT (69% versus 51%; p = 0.01). The median duration of response was 6.8 versus 5.4 months for, respectively, ATX and AT (p < 0.0001). Median OS was 24.2 months for ATX and 23.1 months for AT (p = 0.53). The increased rate of grade 3–4 adverse events related to the addition of capecitabine, being hand-foot syndrome (34% versus 0% for AT) and neutropenia (20% versus 12% for AT), generally did not preclude continuation of treatment. Exploratory analyses indicated that 1) patients receiving capecitabine at some line for treatment have significantly improved OS and 2) a prognostic model can classify patients into three risk groups associated with OS.InterpretationIn patients with HER2-negative LR/MBC, addition of capecitabine to paclitaxel and bevacizumab significantly improved PFS, ORR and response duration. This combination was reasonably well tolerated and may be considered of use as first-line treatment in rapidly progressive disease.FundingF. Hoffmann-La Roche Ltd, the Netherlands.     

多西紫杉醇为主的联合方案治疗转移性乳腺癌

目的:探讨多西紫杉醇为主的联合化疗方案治疗转移性乳腺癌的疗效及毒副反应。方法:49例转移性乳腺癌患者中,22例既往使用蒽环类治疗失败,予多西紫杉醇联合顺铂或希罗达治疗;27例既往未曾采用蒽环类治疗,予多西紫杉醇联合阿霉素治疗。21天为1周期,2周期后评价疗效,有效者化疗4周期以上。结果:49例患者中,治疗后完全缓解(CR)11例,部分缓解(PR)23例,稳定(SD)8例,进展(PD)7例,有效率为69·3%(34/49)。中位疾病进展时间为8·5个月,中位生存时间为18·3个月。主要毒副反应为白细胞减少,其中Ⅲ~Ⅳ度占51·0%。结论:多西紫杉醇为主的联合化疗方案治疗转移性乳腺癌疗效确切,毒性反应可耐受。     

贝伐珠单抗联合多西他赛治疗HER-2阴性复发转移性乳腺癌的临床疗效

目的 观察贝伐珠单抗联合多西他赛治疗人表皮生长因子受体-2（human epidermal growth factor receptor-2,HER-2）阴性复发转移性乳腺癌的临床疗效。方法  79例HER-2阴性复发转移性乳腺癌患者根据不同化疗方案分为两组,观察组42例给予贝伐珠单抗联合多西他赛治疗,对照组37例给予多西他赛单药治疗,观察两组患者治疗后的临床疗效和1年、2年生存率及生存期。 结果 观察组总有效率为59.52%,对照组为37.84%,两组比较差异无统计学意义（P＞0.05）;观察组患者部分缓解率为47.62%,显著高于对照组的24.32%（P＜0.05）;观察组患者2年生存率为40.28%,高于对照组的16.22%（P＜0.05）;观察组患者贫血、血小板减少的发生率显著高于对照组（P＜0.05）。 结论 贝伐珠单抗联合多西他赛治疗HER-2阴性复发转移性乳腺癌的疗效较好,可提高患者生存率和生存期,但对患者血液系统影响较为明显,值得临床重视。     

多西他赛联合贝伐珠单抗及其单药维持治疗转移性乳腺癌的临床观察

目的 探讨多西他赛联合贝伐珠单抗一线治疗序贯应用贝伐珠单抗单药维持治疗转移性乳腺癌的疗效和安全性。方法 8例转移性乳腺癌患者均为女性,年龄34～62岁,中位年龄为53岁,均经改良根治术后病理组织学确诊,免疫组化检查HER-2为（-）或（+）。治疗方案：贝伐珠单抗15mg／kg d1,多西他赛 75mg／m2 d1,3周为1周期。治疗6个周期未出现病情进展者应用贝伐珠单抗（15mg/kg）单药维持治疗,每3周1次。结果 全组8例中获CR 1例,PR 3例,SD 4例。有效率（RR）为50％,疾病控制率（DCR）为100％。7例经联合治疗6～9个周期后用贝伐珠单抗维持治疗,维持治疗时间为2～31.3个月,中位维持治疗时间为15.3个月,中位无进展生存期为22.3个月。全组5例发生3、4级中性粒细胞减少,其中2例伴发热;5例患者出现指甲毒性,其中3例1、2级,2例3级。贝伐珠单抗应用4～36.5个月过程中,1例发生血栓3级,1例高血压2级,1例高血压3级,2例蛋白尿2级。结论 多西他赛联合贝伐珠单抗一线治疗序贯应用贝伐珠单抗单药维持治疗HER 2阴性转移性乳腺癌的疗效好,毒副反应可耐受,值得临床进一步应用。     

Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer

Background:

Combining bevacizumab with first-line chemotherapy significantly improves progression-free survival (PFS) in HER2-negative metastatic breast cancer (mBC). However, identification of patients benefitting most from bevacizumab remains elusive. The AVADO trial included an extensive optional exploratory biomarker programme.

Methods:

Patients with HER2-negative mBC were randomised to receive docetaxel with placebo or bevacizumab. The primary end point was PFS. Plasma samples were analysed using a multiplex ELISA. Blood mRNA expression was assessed using quantitative PCR. Tumour tissue samples were analysed by immunohistochemistry. Single-nucleotide polymorphisms (SNPs) involved in the VEGF pathway were analysed in germline DNA.

Results:

Samples for biomarker analysis were available from 24–54% of the 736 treated patients (depending on specimen type). The most consistent potential predictive effect was observed with plasma VEGF-A and VEGFR-2; high baseline concentrations were associated with greater treatment effect. Blood mRNA analyses suggested a greater bevacizumab effect in patients with high VEGF₁₂₁. No consistent predictive effect was seen for tumour neuropilin or other candidate tumour markers by immunohistochemistry, or for any of the SNPs investigated.

Conclusion:

Plasma VEGF-A and VEGFR-2 are potential predictive markers for bevacizumab efficacy, supporting findings in gastric and pancreatic cancers. Plasma VEGF-A is being evaluated prospectively in mBC in the MERiDiAN trial.     

Capecitabine plus docetaxel combination chemotherapy for metastatic breast cancer

Doxifluridine(5'-DFUR)is converted to its metabolite 5-FU by the enzyme thymidine phosphorylase(TP). TP is expressed significantly higher in tumor tissue than in normal tissue. Capecitabine(N4-pentoxylcarbonyl -5'-deoxy-5-fluorocytidine)is a pro-drug of 5'-DFUR and a novel fluoropyrimidine carbamate that is converted to 5-FU preferentially in tumor tissue through a three-step enzymatic cascade. Expression of TP in tumor tissue may clinically predict efficacy of capecitabine. Induction of TP activity has brought about enhancement of capecitabine efficacy by taxanes in human cancer xenografts. In addition, a phase III study directly comparison docetaxel monotherapy and docetaxel plus capecitabine has been conducted for metastatic breast cancer patients who had received anthracyclines. The overall response rate of the combination group was 42%(n=255), and that of the monotherapy group was 30%(n=256)(p=0.006). The primary endpoints were time to disease progression, and time to treatment failure, and these parameters were superior in the combination arm than in the single arm, suggesting that capecitabine sensitization by docetaxel might be a new approach to breast cancer treatment.     

Phase I study of docetaxel and cyclophosphamide in patients with advanced or recurrent breast cancer

BACKGROUND: A phase I clinical study of combination chemotherapy with docetaxel and cyclophosphamide (CPA) was performed to determine the maximum tolerated dose (MTD), the incidence and severity of toxicities and the pharmacokinetics in patients with advanced or recurrent breast cancer. METHODS: Docetaxel was administered by intravenous drip infusion over 60 minutes, followed by intravenous bolus injection of CPA every 3-4 weeks. The dosage of docetaxel/CPA was 40/200, 40/400, 50/400, or 60/400 mg/m(2)/day. RESULTS: Fifteen patients were enrolled and received a total of 33 cycles of the combined therapy. The dose limiting toxicities (DLTs) were leukopenia, neutropenia and thrombocytopenia. The MTD was estimated to be docetaxel 60 mg/m(2) in combination with CPA 400 mg/m(2) per day. Plasma clearance of both drugs was similar regardless of dose. The recommended doses of docetaxel/CPA for a phase Utrial are 50/400 mg/m(2)/day every 3-4 weeks. CONCLUSION: The MTD of this combined therapy was docetaxel 60 mg/m(2) and CPA 400 mg/m(2). Neutropenia and leukopeina were common and severe. It is important to stress the need for modification of the dosing scheme.     

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.     

DC方案与DE方案一线治疗转移性乳腺癌的对比研究

目的　比较多西紫杉醇联合卡培他滨（ＤＣ方案）与多西紫杉醇联合表柔比星（ＤＥ方案）一线治疗转移性乳腺癌的疗效及不良反应。方法　６５例转移性乳腺癌患者分别接受ＤＣ方案和ＤＥ方案治疗。ＤＣ方案组：多西紫杉醇７５ｍｇ／ｍ２静滴,ｄ１;卡培他滨２０００ｍｇ／（ｍ２·ｄ）,分两次口服,ｄ１～ｄ１４。ＤＥ方案组：多西紫杉醇７５ｍｇ／ｍ２静滴,ｄ１;表柔比星７５ｍｇ／ｍ２静推,ｄ１。两方案均以２１天为１个周期。结果　ＤＣ方案组有效率高于ＤＥ方案组（６０.６％ ｖｓ．４６.９％,Ｐ＞０.０５）,其中ＤＣ方案组完全缓解率高于ＤＥ方案组（２４.２％ ｖｓ．６.３％）,两组比较差异有统计学意义（Ｐ＜０.０５）。ＤＣ方案组的６个月后疾病无进展率（ＰＦＲ）优于ＤＥ方案组（７２.７％ ｖｓ．６２.５％,Ｐ＞０.０５）。中位无进展生存期（ＰＦＳ）ＤＣ方案组长于ＤＥ方案组（１１.４个月ｖｓ．７.６个月）,两组比较差异有统计学意义（Ｐ＜０.０５）。不良反应以骨髓抑制、胃肠道反应和脱发为主,３、４级手足综合征发生率ＤＣ方案组（２７.３％,９／３３）高于ＤＥ方案组（０）,差异有统计学意义（Ｐ＜０.０５）。结论　ＤＣ方案及ＤＥ方案一线治疗转移性乳腺癌均取得较好疗效,ＤＣ方案可以作为非蒽环类药物有效的一线治疗方案。     

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.     

Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer

Purpose To evaluate the efficacy and safety of erlotinib in advanced breast cancer. Experimental design Multicenter, phase II study of erlotinib (150 mg orally daily). Cohort 1: progression after anthracyclines, taxanes, and capecitabine (n = 47). Cohort 2: progression after >1 chemotherapy for advanced-stage disease (n = 22). Primary endpoint was response rate (World Health Organization criteria). Secondary endpoints were safety, time to progression, and survival. Results One patient in each cohort (n = 2, 3.0%) had a partial response. Response duration was 17 weeks for the Cohort 1 patient and 32 weeks for the Cohort 2 patient. Median time to progression was 43 days for Cohort 1 (range 1–204) and 43 days for Cohort 2 (range 25–419). Common adverse events were diarrhea, rash, dry skin, asthenia, nausea, anorexia. Conclusion Erlotinib had minimal activity in unselected previously treated women with advanced breast cancer. Predictive factors are needed to identify breast cancer patients who may derive benefit from erlotinib treatment.     

Vinorelbine/docetaxel combination treatment of metastatic breast cancer: a phase I study

Purpose The aim of this study was to investigate the combination of vinorelbine (VRL) alternating intravenous (i.v.) and oral in combination with docetaxel (DCT) as first-line chemotherapy of patients with metastatic breast cancer. Patients and methods Tested doses were 60 or 70 mg m⁻² given on day 1 for DCT, 20 to 25 mg m⁻² for i.v. VRL on day 1, 60 mg m⁻² on day 8 or day 15 for oral VRL. Day 1 was administered every 3 weeks. Three to six patients were treated per dose level. Results The median age of the 30 treated patients was 60 years. Four patients were non evaluable for the maximum tolerated dose (MTD) and were replaced. Reported dose-limiting toxicities were 11 omissions of oral VRL for neutropenia, two cases of febrile neutropenia and two grade 4 neutropenia ≥7 days. Dose levels using DCT doses >60 mg m⁻² and/or i.v. VRL doses >20 mg m⁻² met the criteria for MTD. Most frequent toxicities were febrile neutropenia in seven patients and neutropenic infection in four patients (one fatal). Therefore, the recommended schedule was established at i.v. VRL 20 mg m⁻² with DCT 60 mg m⁻² on day 1 and oral VRL 60 mg m⁻² given on day 15 every 3 weeks. At this recommended schedule, only one of six patients experienced febrile neutropenia. Among 22 patients evaluable for tumour response, 2 complete and 10 partial responses were reported. Pharmacokinetics of combined VRL and DCT demonstrated the absence of mutual interaction. Conclusions This phase I study established the recommended doses and schedules of the combination alternating i.v. and oral VRL with DCT, this recommended regimen being further explored in a phase II study.     

A phase II study of weekly docetaxel in patients with anthracycline pretreated metastatic breast cancer

Background: Docetaxel has significant activity in metastatic breast cancer and weekly schedules are associated with less myelosuppression than 3-weekly schedules. We evaluated the toxicity and the activity of weekly docetaxel in anthracycline-pretreated patients. Patients and methods: A total of 42 patients were studied. Treatment consisted of docetaxel 35 mg/m² weekly as a 30-min infusion for 6 weeks followed by a 2-week rest, with dexamethasone 8 mg i.v. pre-medication and 4 mg orally 12-hourly for 48 h following treatment. Results: The median age of the patients was 53 years (range 34–74). Twenty-six (62%) patients had received prior chemotherapy for advanced disease. Patients received a median 10 weeks of treatment (range 1–24). 11 had a partial response (ORR 26%; 95% CI 13–39%), five of whom had relapsed <12 months since the end of previous anthracycline-based chemotherapy. In addition six patients (14%) had stable disease for >16 weeks. Myelosuppression was rare with only 2 patients (5%) experiencing grade 3 neutropenia (no grade 4 neutropenia). Non-haematological grade III toxicities were as follows: fatigue 17%, neuropathy 0%, hyperlacrimation 5%, stomatitis 7%, diarrhoea 14%, and cutaneous toxicity 19%. Skin toxicity consisted of limb/palmar–plantar erythematous reactions, or fixed-plaque erythrodysaesthesia. Conclusions: Weekly docetaxel has moderate activity in women with anthracycline pre-treated breast cancer. Although the level of myelosuppression is lower than 3-weekly regimens, this weekly regimen cannot be recommended due to the significant non-haematological toxicities associated with the treatment.     

The safety and efficacy of bevacizumab in the treatment of patients with recurrent or metastatic cervical cancer

Introduction: Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF). (Avastin; Genetech, Inc, San Francisco, CA) Angiogenesis is blocked by the binding of bevacizumab to VEGF, inhibiting the binding of this ligand to the VEGF receptor. On 14 August 2014 the Food and Drug Administration (FDA) approved use of bevacizumab in persistent, recurrent, or metastatic cervical cancer.

Areas covered: Herein we review pharmacodynamics and kinetics, clinical data and treatment-related toxicities of bevacizumab in the treatment of metastatic, recurrent or persistent cervical cancer. Additionally, future areas of development are reviewed.

Expert commentary: Anti-angiogenesis therapy with bevacizumab is central to metastatic, persistent, and recurrent cervical cancer treatment. Additional anti-angiogenesis drugs are in development. Future studies will need to establish if the addition of multiple anti-angiogenesis agents or anti-angiogenesis in combination with immunotherapy is more effective than bevacizumab with chemotherapy.     

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

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

Efficacy of S-1 in heavily pretreated patients with metastatic breast cancer: cross-resistance to capecitabine

Background  It is not clear what the optimal treatment of chemotherapy is for patients with heavily treated metastatic breast cancer (MBC). We have retrospectively examined the efficacy and safety of S-1 in patients with MBC who had been previously treated with anthracycline, taxane, and capecitabine. Methods  Patients with MBC who had been administered S-1, an oral modulated compound containing a fluoropyrimidine derivative, between November 2001 and June 2003 at the Cancer Institute Hospital were retrospectively reviewed. S-1 at a standard dose of 50 mg/body was administered twice daily for four weeks, followed by a two-week rest period. This was repeated every six weeks until disease progression or unacceptable toxicity. Results  Thirty-five patients were assessed. The patients were heavily pretreated with anthracycline (100%), taxane (paclitaxel or docetaxel) (100%), capecitabine (100%), vinorelbine (71%), and mitomycin (69%). Median follow-up time of patients was 9.6 months (range, 1.2–26.6). ORR was 3% (95% confidence interval: 0–9%), and CBR was 20% (95% confidence interval: 6–33%). Time to treatment failure was 2.8 months. Overall survival was 21.4 months. Grade 1 or 2 adverse events were observed in 17% and 13%, respectively. Grade 3 events occurred as anorexia (9%), nausea (9%), vomiting (9%), diarrhea (14%), fatigue (3%), and elevation of AST/ALT (3%). No grade 3 was seen as hand-foot syndrome. Neither grade 3 nor 4 was observed in bone marrow suppression. Conclusions  S-1 was fairly well tolerated, but demonstrated very limited activity in capecitabine-pretreated patients who had already been exposed to anthracycline and taxane. It was suggested that S-1 clinically exhibited cross-resistance to capecitabine.     

Treatment of metastatic breast cancer: looking towards the future

The armamentarium for the treatment of metastatic breast cancer is increasing with the introduction of newer chemotherapeutic agents and the development of molecular targeted therapies. The clinical utility of anthracyclines in advanced breast cancer has been limited by significant adverse events; therefore the taxanes are increasingly used in the metastatic setting. Trastuzumab with a taxane as first-line therapy is now standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Other targeted therapies, including the antiangiogenesis agents such as bevacizumab, are being investigated both as monotherapy and in combination regimens. While the number of available agents is growing rapidly, challenges remain concerning appropriate dose, schedule, treatment duration and management of drug resistance. This paper reviews recent data regarding the established and investigational medical treatments for endocrine-refractory metastatic breast cancer, and presents treatment recommendations.     

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.     

多西他赛解救治疗不同年龄组转移性乳腺癌的临床研究

目的 评估多西他赛解救治疗不同年龄组转移性乳腺癌患者的临床疗效及血液学毒性。方法 回顾性分析3个年龄组单药多西他赛解救治疗转移性乳腺癌患者的临床资料,对临床疗效等进行统计分析。结果 ≤45岁年龄组的客观缓解率(Objective reponse rate,ORR)和临床获益率(Clinical benefit rate,CBR)分别为30.6%和38.7%,46~59岁年龄组ORR和CBR分别为27.6%和35.7%,而≥60岁年龄组ORR和CBR分为20.0%和27.5%。三组中位无进展生存期(Progression free survival,PFS)分别为6.0(2.9~9.1)个月、5.0(2.9~7.1)个月及4.0(3.3~4.7)个月,三年龄组ORR、CBR及PFS均无统计学差异(P=0.477,0.492,0.460)。多因素COX回归分析显示不同年龄组多西他赛解救治疗PFS与临床分期、病理类型、同侧腋窝淋巴结转移数目、无病生存期、单位体表面积剂量、解救治疗线数、复发转移部位数目等因素均无关。血液学毒性主要表现为白细胞及中性粒细胞减少,多西他赛对血红蛋白及血小板影响较小。结论 多西他赛临床疗效及血液学毒性与年龄有一定程度的相关,随着年龄的增加,显现出临床疗效降低,血液毒性加重的趋势。