Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: a phase II study in patients with HER2-negative metastatic breast cancer

Purpose

Metronomic combination chemotherapy with the oral fluoropyrimidine doxifluridine/5??-deoxy-5-fluorouridine (5 -DFUR) and oral cyclophosphamide (C) showed promising efficacy in a single-arm study. The oral fluoropyrimidine capecitabine was designed to deliver 5-fluorouracil preferentially to tumors, potentially improving efficacy over doxifluridine. We conducted a phase II multicenter study to evaluate an all-oral XC combination in patients with HER2-negative metastatic breast cancer (MBC).

Materials and methods

Patients received capecitabine 828?mg/m² twice daily with cyclophosphamide 33?mg/m² twice daily, days 1?C14 every 3?weeks. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

Results

Between May 2007 and April 2009, 51 patients were enrolled and 45 were included in the efficacy analysis. The median follow-up was 18.1?months. ORR was 44.4% and stable disease (??24?weeks) was achieved in 13.4%, resulting in a 57.8% clinical benefit response rate. Median PFS was 12.3?months (95% confidence interval: 8.9?C18.9?months). Median PFS was 10.7?months in triple-negative disease and 13.2?months in estrogen-receptor positive, HER2-negative disease. The 1- and 2-year OS rates were 86 and 71%, respectively. Median OS has not been reached. Grade 3 adverse events comprised leukopenia (26%), neutropenia (16%), and decreased hemoglobin (2%). There was no grade 3 hand-foot syndrome.

Conclusions

Oral XC is an effective first- or second-line therapy for MBC, demonstrating high activity in both luminal A and triple-negative disease with few severe side effects. This metronomic oral combination chemotherapy could be beneficial for the treatment of HER2-negative MBC.     

First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients

BackgroundBevacizumab has consistently demonstrated improved progression-free survival (PFS) and response rate when combined with first-line chemotherapy for HER2-negative metastatic breast cancer (mBC). However, the lack of a significant overall survival (OS) difference continues to attract debate, and identification of patients deriving greatest benefit from bevacizumab remains elusive.Patients and methodsIndividual patient data from three randomised phase III trials in the first-line HER2-negative mBC setting were analysed, focusing specifically on efficacy in poor-prognosis patients.ResultsThe meta-analysis (n = 2447) demonstrated a PFS hazard ratio (HR) of 0.64 (95% confidence interval [CI] 0.57–0.71; median 9.2 months with bevacizumab versus 6.7 months with non-bevacizumab therapy) and response rate of 49% versus 32%, respectively. The OS HR was 0.97 (95% CI 0.86–1.08); median 26.7 versus 26.4 months, respectively. In patients with triple-negative mBC, the HRs for PFS and OS were 0.63 (95% CI 0.52–0.76) and 0.96 (95% CI 0.79–1.16), respectively. Median PFS was 8.1 months with bevacizumab versus 5.4 months with chemotherapy alone, median OS was 18.9 versus 17.5 months, respectively, and 1-year OS rates were 71% versus 65%.ConclusionsBevacizumab improves efficacy, including 1-year OS rates, both overall and in subgroups of poor-prognosis patients with limited treatment options.     

Body mass index in HER2-negative metastatic breast cancer treated with first-line paclitaxel and bevacizumab

The evidence emerged from the TOURANDOT trial encourages evaluating the role of anthropometric determinants on treatment outcomes in HER2-negative metastatic breast cancer patients treated with bevacizumab-including regimens. We thus analyzed data from a subgroup of these patients from a larger cohort previously assessed for treatment outcomes. Patients were included in the present analysis if body mass index values had been recorded at baseline. Clinical benefit rates, progression free survival and overall survival were assessed for the overall study population and subgroups defined upon molecular subtype. One hundred ninety six patients were included (N:196). Body mass index showed no impact on clinical benefit rates in the overall study sample and in the luminal cancer subset (p = 0.12 and p = 0.79, respectively), but did so in the triple negative subgroup, with higher rates in patients with body mass index ≥25 (p = 0.03). In the overall study sample, body mass index did no impact progression free or overall survival (p = 0.33 and p = 0.67, respectively). Conversely, in triple negative patients, progression free survival was significantly longer with body mass index ≥25 (6 vs 14 months, p = 0.04). In this subset, overall survival was more favorable (25 vs 19 months, p = 0.02). The impact of the molecular subtype was confirmed in multivariate models including the length of progression free survival, and number of metastatic sites (p < 0.0001). Further studies are warranted to confirm our findings in more adequately sized, ad hoc, prospective studies.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

节拍化疗与转移性乳腺癌

节拍化疗是通过抑制肿瘤新生血管生成发挥抗肿瘤作用.研究表明,运用节拍化疗可明显提高转移性乳腺癌患者的生活质量,耐受性好,且有较高的效应/费用比,有望成为转移性乳腺癌的一种全新治疗模式.     

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。     

索拉非尼对HER2阴性转移性乳腺癌治疗效果Meta分析

目的 索拉非尼是首个获准上市的多靶点酪氨酸激酶抑制剂.近年来探讨索拉非尼治疗HER2阴性转移性乳腺癌的临床试验不断开展,但试验结论并不一致.本研究通过Meta分析评价索拉非尼联合化疗治疗HER2阴性转移性乳腺癌的有效性和安全性.方法 通过检索Pubmed、Embase以及Central等数据库,截止时间为2016-10,筛选索拉非尼联合化疗治疗HER2阴性的转移性乳腺癌的随机对照试验.试验结果应用Review Manager 5.3进行分析.结果 纳入5个临床试验共计1 381例HER2阴性转移性乳腺癌患者,索拉非尼联合化疗与单纯化疗相比,使患者的疾病进展时间(time to progression,TTP)明显延长,2组之间差异有统计学意义,HR=0.77,95％CI为0.60～0.99,P=0.04;而无病生存期(progression-free survival,PFS;HR=0.83,95％CI为0.64～1.07,P=0.14)、总生存期(overall survival,OS;HR=1.06,95％CI为0.90～1.23,P=0.49)、客观反应率(objective response rate,ORR;RR=1.12,95％CI为0.97～1.30,P=0.14)2组之间差异无统计学意义.3～4度的手足综合征、乏力、皮疹、胃炎及贫血发生率明显增多,P＜0.05;而中性粒细胞减少、血小板减少、腹泻以及高血压的发生率并未明显增加,P＞0.05.结论 相比单纯化疗,HER2阴性转移性乳腺癌患者可以从索拉非尼联合化疗治疗中获益,但手足综合征、皮疹等不良事件发生率有所增加.     

贝伐株单抗联合化疗在HER2阴性进展期乳腺癌治疗中的疗效和安全性分析

目的：观察贝伐珠单抗（BV）联合化疗治疗HER2阴性进展期乳腺癌的疗效和安全性。方法回顾性分析接受贝伐株单抗治疗的15例进展期乳腺癌患者的临床资料,按照实体肿瘤疗效评价标准（RECIST 1.1）和美国国立癌症研究所不良反应事件通用术语标准评价疗效和不良反应,每2个月评估疗效,主要观察终点是无进展生存期（progression free survival,PFS）,每个周期评价不良反应。结果15例患者的中位PFS为4个月;治疗10个周期以上的患者为4例,6个周期以上者3例,其余8例均不足4个周期;15例患者均可评价疗效,5例（33.33%）PR中4例伴胸壁转移;5例SD（33.33%）,5例PD（33.33%）;主要不良反应为高血压4例、少量鼻出血3例、蛋白尿2例、贫血2例、血小板减少2例,经对症治疗后均好转,4例停药。结论贝伐珠单抗联合化疗作为二线及以上方案治疗进展期乳腺癌仍有一定疗效,对于伴胸壁转移的患者疗效尤其显著,不良反应可耐受。     

Palbociclib in highly pretreated metastatic ER-positive HER2-negative breast cancer

Purpose

We aimed to investigate the role of palbociclib, a first-in-class cyclin-dependent kinase 4 and 6 inhibitor, in postmenopausal women with highly pretreated endocrine therapy-resistant metastatic breast cancer (MBC).

Methods

Between 28 September 2015 and 14 March 2017, a compassionate use program was established in the University Hospitals Leuven in which 82 postmenopausal women with estrogen receptor-positive, HER2-negative MBC were included after at least four lines of systemic treatment. The efficacy and safety analysis was performed in 82 patients who had received at least one dose of palbociclib and who had at least 6-month follow-up at the data cut-off point. The primary objective was the evaluation of efficacy of the combination of palbociclib and endocrine therapy with clinical benefit as primary endpoint, defined as the absence of progressive disease and being on treatment for at least 6 months. Secondary objectives were the evaluation of toxicity and the identification of potential predictors for clinical benefit.

Results

The median age of the patients was 67.1 years (range 34.8–85.9) at the time of inclusion. The average duration of treatment was 5.6 months (range 1–19), with a median progression-free survival of 3.17 (95% CI 2.76–4.70) months. At the data cut-off point, 10 patients were still on treatment with palbociclib. In this highly pretreated setting, 34 patients experienced no progressive disease within 6 months, resulting in an overall clinical benefit rate (CBR) of 41.5%. 20.7% (17/82) showed stable disease for ≥?9 months and 13.4% for ≥?12 months. None of the investigated predicting factors were significantly associated with clinical benefit at 6 months. For 43.9% of the patients, treatment delay or dose reduction was indicated.

Conclusions

Palbociclib in combination with endocrine therapy shows an unexpectedly high CBR and favorable safety profile in heavily pretreated endocrine-resistant estrogen receptor-positive, HER2-negative MBC patients.

     

Metronomic chemotherapy in metastatic breast cancer: Impact on VEGF

BackgroundAnticancer chemotherapy is thought to be effective by means of direct cytotoxicity on tumor cells. Alternative mechanisms of efficacy have been ascribed to several common anticancer agents; including cyclophosphamide (CTX) and capecitabine (Cap) when given at lower doses for prolonged period (metronomic chemotherapy) postulating an antiangiogenic activity as well.Aim of workTo evaluate the action and tolerability of metronomic chemotherapy (MC) and its impact on serum vascular endothelial growth factor (VEGF) levels in metastatic breast cancer (MBC) patients.Patients and methodsIn this study we evaluated the clinical efficacy and tolerability of low dose, capecitabine (500 mg twice daily) together with oral cyclophosphamide (CTX) (a dose of 50 mg once daily) in patients with metastatic breast cancer. Vascular endothelial growth factor (VEGF), an angiogenic marker, was measured in the serum samples; at base line, and after 2 and 6 months of therapy.ResultsSixty patients were evaluable. One achieved complete response (CR), 12 partial responses (PR), and 21 stable diseases (SD), while 26 were with progressive disease (PD). The overall response rate was 21.7% with overall disease control (CR, PR, and SD) 56.7%. The median time to progression was 7 ± 2.59 months and overall survival 16 ± 8.02 months. Toxicity was mild, Palmar–plantar erythrodythesia was the most common side effect and was observed in 22 patients (37%), leucopenia (G1 + 2) was the most common hematological toxicity, and it was reported in 27% of the cases. The median VEGF level was significantly declined after 2 and 6 months of therapy compared to the base line among the patients with disease control (CR, PR, and SD). In multivariate logistic regression analysis, patients with post-menopausal, positive hormonal receptors, negative HER-2/Neu, and one metastatic site, were statistically significant and have a better disease control rate.ConclusionsMC induced drop in VEGF, and was effective, minimally toxic regimen for the treatment of metastatic breast cancer patients.     

Preoperative bevacizumab combined with letrozole and chemotherapy in locally advanced ER- and/or PgR-positive breast cancer: clinical and biological activity

The antiangiogenic agent bevacizumab showed synergistic effects when combined with chemotherapy in advanced breast cancer. We presently investigated the activity of bevacizumab in combination with chemotherapy, including capecitabine and vinorelbine, and endocrine therapy, including letrozole (+triptorelin in premenopausal women), as primary therapy for patients with ER and/or PgR > or =10% T2-T4a-c, N0-N2, M0 breast cancer. Biological end point included the proliferative activity (Ki67), whereas clinical end points were clinical response rate, pathological complete response (pCR) and tolerability. Circulating endothelial cells (CECs) and their progenitors, as surrogate markers of antiangiogenic activity, were measured at baseline and at surgery.Thirty-six women are evaluable. A clinical response rate of 86% (95% CI, 70-95) and no pCR were observed; Ki67 was significantly decreased by 71% (interquartile range, -82%, -62%). Toxicity was manageable: two grade 3 hypertension, four grade 3 deep venous thrombosis and no grade >2 proteinuria were observed. Treatment significantly decreased the percentage of viable CECs and prevented the chemotherapy-induced mobilisation of circulating progenitors. Basal circulating progenitors were positively associated with clinical response. In conclusion, bevacizumab is feasible and active in association with primary chemoendocrine therapy for ER-positive tumours in terms of proliferation inhibition, clinical response and antiangiogenic activity.