Duration of therapy in metastatic breast cancer: management using Herceptin

Despite progressive developments in therapeutic interventions, including surgery, radiotherapy and chemotherapy, there has been no major improvement in the survival of women with metastatic breast cancer (MBC). Based on knowledge of tumor growth patterns, approaches addressing this issue have included increasing chemotherapy dose or dose density and extending the duration of therapy. However, only the latter approach has resulted in improved clinical benefit, although not survival; and its use is restricted by the cumulative toxicity of chemotherapeutic agents. Therefore, the best hope for improved survival lies with new classes of anticancer drug and particularly biological agents. This review focuses on the first oncogene-targeted therapy for human epidermal growth factor receptor-2 (HER2)+ MBC patients. The humanized anti-HER2 monoclonal antibody Herceptin has proven clinical benefits in HER2+ MBC patients, most importantly improved survival, and is rapidly becoming a standard of care for these patients. In contrast to the fixed number of cycles used for chemotherapeutic agents, Herceptin is administered until disease progression, with some data suggesting that continuation beyond disease progression should be investigated. The preclinical and clinical findings on which the current recommended duration of Herceptin therapy are based are reviewed and alternative strategies are discussed.     

贝伐单抗治疗转移性乳腺癌有效性与安全性的Meta分析

目的：系统评价贝伐单抗治疗转移性乳腺癌的有效性与安全性,以期为临床提供循证参考。方法：计算机检索PubMed、EMbase、The Cochrane Library（2017年第8期）、CBM、CNKI、VIP和WanFang Data,检索时间均从建库至2017年8月。由 2 名研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用RevMan 5.3统计软件进行Meta分析。结果：共纳入6项RCT,共计4 235例患者。Meta分析结果显示：与对照组相比,贝伐单抗组PFS [HR=0.71,95%CI（0.60,0.84）,P<0.000 1]明显延长,客观缓解率ORR[RR=1.42,95%CI（1.27,1.59）,P<0.000 01]、1年生存率[RR=1.06,95%CI（1.02,1.11）,P=0.003]显著提高。而OS[HR=0.92,95%CI（0.84,1.02）,P=0.11]、死亡率[RR=0.88,95%CI（0.75,1.04）,P=0.14]较对照组差异无统计学意义。安全性方面,贝伐单抗组较对照组高血压[RR=1.75,95%CI（1.34,2.28）,P<0.000 01]、蛋白尿[RR=1.75,95%CI（1.34,2.28）,P<0.000 01]发生率增加,同时增加出血、感觉障碍发生风险,差异均有统计学意义。结论：当前证据表明,与传统化疗相比,贝伐单抗联合化疗在转移性乳腺癌治疗中可显著延长PFS,增加客观缓解率、1年生存率,同时降低死亡率。不良反应以高血压、蛋白尿发生最为常见。受纳入研究数量和质量的限制,上述结论尚需开展更多高质量研究予以验证。     

Trials of new combinations of Herceptin in metastatic breast cancer

Herceptin extends survival in human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer patients when administered with paclitaxel or anthracycline/cyclophosphamide (AC), and the combination with 3-weekly paclitaxel is the current standard first-line therapy. However, other combinations may be equally effective. This review provides information on recent and ongoing trials of new Herceptin combinations. Preliminary results indicate that Herceptin plus epirubicin/cyclophosphamide may be effective without the cardiotoxicity of the AC combination. Weekly paclitaxel plus Herceptin has produced responses in 83% of HER2-positive patients treated. Co-administering Herceptin with other cytotoxic agents has also been investigated, with combination partners being chosen based on in vitro synergy with Herceptin, known efficacy as monotherapy and convenience of weekly administration (e.g. docetaxel, vinorelbine). High response rates have been observed in these clinical trials, e.g. up to 80% in combination with vinorelbine. Furthermore, Herceptin in combination with weekly paclitaxel, docetaxel or vinorelbine was well tolerated: there was no significant cardiotoxicity or unexpected toxicity and the combination showed an adverse event profile similar to that seen with monotherapy with the cytotoxic agent. Thus, Herceptin produces additional clinical benefit when added to all the cytotoxic agents with which it has been examined, further demonstrating its potential for use in HER2-positive breast cancer patients.     

Efficacy and toxicity of capecitabine-based chemotherapy in patients with metastatic or advanced breast cancer: results from ten randomized trials

Abstract

Objective:

The efficacy and adverse effects of capecitabine-based chemotherapy versus other regimens reported in previous trials were discordant. The aim of the present study was to determine the efficacy and toxicity profiles of capecitabine-based chemotherapy versus capecitabine-free regimens in patients with metastatic and/or advanced breast cancer.     

郝赛汀治疗HER-2阳性转移性乳腺癌疗效观察

目的探讨郝赛汀治疗HER-2阳性转移性乳腺癌临床疗效。方法将驻马店市中心医院2008年2月至2010年2月收治的172例转移性乳腺癌患者随机分为常规组58例、单药组50例、联合组64例,观察3组临床疗效。结果常规组有效率(RR)27.6%,单药组有效率44.0%,联合组有效率59.4%。结论单用还是联合化疗,赫赛汀都是一个治疗乳腺癌转移的重要药物;联合化疗能显著提高患者的缓解率,延长疾病进展时间,延长存活率,较单用疗效更良好。     

Herceptin: the future in adjuvant breast cancer therapy

New drugs for the treatment of breast cancer are generally introduced into clinical practice in the metastatic setting. However, it is well known that therapeutic response improves when drugs are used earlier in the disease. Therefore, once drugs have shown a major therapeutic impact in the metastatic setting, investigation in the adjuvant setting should be prioritized. Herceptin has shown significant efficacy and an ability to extend survival in human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer patients and is well tolerated. Four major randomized, multicenter adjuvant clinical trials of Herceptin in patients with HER2-positive primary breast cancer have been started or are planned. The designs of these trials are described. With a total of over 12 000 patients, these studies should provide the information necessary to confirm the clinical potential of Herceptin as adjuvant therapy. The inclusion of a variety of regimens, including different durations of Herceptin therapy in the Herceptin Adjuvant (HERA) Trial, will allow the optimal therapeutic approach to be identified, and the size and generally pragmatic designs should encourage clinicians to enroll patients. The establishment of the role of Herceptin in the adjuvant setting will offer women with HER2-positive primary breast cancer the chance for improved survival. This is particularly important given that HER2-positive breast cancer patients form a high-risk group with a poor overall prognosis.     

乳腺癌肝转移介入治疗疗效分析

目的探讨介入治疗对乳腺癌肝转移的治疗效果,并对其在乳腺癌肝转移综合治疗中的价值进行评价。方法对我院2006年1月-2010年12月就诊的46例乳腺癌肝转移患者设为观察组进行介入治疗,药物选择为顺铂、丝裂霉素、阿霉素、5-氟尿嘧啶等,其中38例进行超液化碘油栓塞,与31例采用化学治疗的患者（对照组）进行对比分析。结果本组46例乳腺癌肝转移患者经介入治疗后,完全缓解9例,部分缓解19例,进展7例,无变化11例。结论乳腺癌肝转移的介入治疗疗效显著,毒副作用小,应作为乳腺癌肝转移综合治疗中的主要治疗手段。     

Octreotide as first-line treatment for women with metastatic breast cancer

Summary Octreotide is a synthetic somatostatin analogue which has shown inhibitory activity against human breast cancer cells in culture. Ten patients with metastatic breast cancer and no prior hormonal therapy exposure received octreotide at 150 g subcutaneously thrice daily. No objective responses were observed and the median time to treatment failure was short at 57 days.     

Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic breast cancer

The clinical efficacy and antiangiogenic effect of low-dose, metronomic administration of cyclophosphamide (CTX) and methotrexate (MTX) (CM) have been demonstrated. The authors report results and long-term follow-up for patients with metastatic breast carcinoma who obtained prolonged clinical benefit with CM. Prospectively collected data from two successive clinical trials were evaluated. From July 1997 to October 2003, patients with metastatic breast carcinoma were treated with low-dose oral chemotherapy (MTX 2.5 mg, twice daily on day 1 and day 2 or 4, and CTX 50 mg daily). Patients who achieved prolonged clinical benefit for a duration of 12 months or more (complete remission, partial remission or stabilization of disease) were considered for the analysis. Median follow-up was 23 months. A total of 153 patients were enrolled and are evaluable: Eastern Cooperative Oncology Group performance status 0-1 in 90 patients, two or more sites of metastatic disease in 97 patients, zero regimen for metastatic breast carcinoma in 48 patients. Among 153 patients, five demonstrated complete remission and 25 partial remission. The proportion of patients who achieved prolonged clinical benefit was 15.7% (95% confidence interval 9.9-21.4%). Median time to progression for patients with prolonged clinical benefit was 21 months (range 12-37+ months). One patient maintained complete remission 42 months after therapy discontinuation. At the multivariate analysis endocrine responsiveness and the achievement of an objective response significantly correlated with the achievement of prolonged clinical benefit. Metronomic chemotherapy can induce prolonged clinical benefit in metastatic breast cancer, supporting its role as an additional therapeutic tool in the treatment of patients with metastatic breast carcinoma.     

氟维司群治疗受体阳性转移性乳腺癌患者的疗效及安全性

目的探讨氟维司群（FUL）对受体阳性转移性乳腺癌（MBC）患者的疗效及安全性。方法 24例患者接受氟维司群治疗,0、14及28 d各肌内注射250 mg,随后每28天肌内注射250 mg,直至肿瘤进展。主要研究终点为至疾病进展时间（TTP）,次要终点为客观有效率（ORR）及临床获益率（CBR）。结果本组24例患者中位TTP为4.4个月,ORR为8.3%（2/24）,CBR为25.0%,其中部分缓解（PR）2例,疾病稳定（SD）超过24周4例。氟维司群的疗效与患者术后无病生存期（DFS）及解救治疗线数等因素相关。全组不良反应较轻微。结论氟维司群是治疗MBC患者的有效内分泌治疗药物,安全性较好。     

Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report

Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). We herewith report on a patient suffering from HER2 overexpressing MBC who received intrathecal methotrexate and trastuzumab for meningeal carcinomatosis. A 48-year-old woman was diagnosed with breast cancer in December 2002. Following surgery, six cycles of adjuvant FE100C plus irradiation and, subsequently for 1 year, trastuzumab were given. As a result of disseminated metastatic spread in October 2005, the patient received whole-brain radiotherapy for symptomatic central nervous system involvement, and was put on several trastuzumab-based combination regimens (capecitabine, vinorelbine, paclitaxel). In June 2006, the patient developed clinical signs of terminal cone involvement with overflow incontinence and paraparesis of the legs. Immediate radiation led to partial relief from clinical symptoms. Subsequently, the patient was put on the tyrosine kinase inhibitor lapatinib and capecitabine (August to October 2007), but on November 6th the patient suffered again from overflow incontinence and weakness of the legs. Failing to respond to lapatinib, the patient received gemcitabine/cisplatin and, additionally, was recommenced on intravenous trastuzumab. Owing to progressive leptomeningeal disease, the patient received repeated doses of intrathecal methotrexate and trastuzumab. Within 2 weeks and four intrathecal treatments, cerebrospinal fluid cytology showed the absence of tumor cells. Moreover, a striking clinical improvement with resolution of the paraparesis of the legs and overflow incontinence was observed. This case report gives details regarding the clinical course of a breast cancer patient who received intrathecal trastuzumab and methotrexate via lumbar puncture for meningeal carcinomatosis of HER2-overexpressing MBC.     

The safety of eribulin for the treatment of metastatic breast cancer

Introduction: Eribulin mesylate is a highly potent anticancer agent approved for use in pretreated metastatic breast cancer (MBC). Clinical trials of eribulin in MBC have demonstrated activity against this tumor type, and a phase 3 study in patients with MBC previously treated with an anthracycline and a taxane showed a significant increase in overall survival (OS) with eribulin versus control regimens.

Areas covered: This review presents overviews of the development of eribulin, its pharmacology, and its efficacy in MBC. A detailed review of its safety profile is presented, and the safety of eribulin is compared with other agents commonly used to treat MBC.

Expert opinion: As eribulin is the only drug shown to improve OS in patients with pretreated MBC, it is an important treatment option for many patients. Eribulin is currently considered a second-line (Europe) or third-line (United States) therapy, and studies have been examining use in the first-line setting. The use of eribulin in combination with other therapies is beginning to be explored because its manageable safety profile makes it an ideal combination-treatment partner. Emerging eribulin combination-treatment data suggest a manageable toxicity profile, and eribulin is set to be a key drug for the treatment of MBC in the future.     

信迪利单抗联合常规化疗在复发转移宫颈癌治疗中疗效和安全性研究

目的探究程序性死亡受体 1(PD-1)抑制剂信迪利单抗(达伯舒)联合常规化疗在复发转移宫颈癌治疗中短期疗效、长期疗效和安全性。方法筛选 2019年 3月至 2020年 8月河北北方学院附属第一医院符合纳入、排除标准的复发转移宫颈癌病人 88例,采用中央随机系统分配法分为试验组( n=44)和对照组(n=44)。对照组执行常规化疗方案,试验组执行信迪利单抗联合常规化疗方案。参考实体肿瘤疗效评估标准( RECIST)1.1来评价并比较两组病人短期疗效。通过随访和记录无进展生存期( PFS)来评价并比较两组病人长期疗效。参考常见不良事件评价标准( CTCAE)5.0版来评价两组病人不良事件和安全性。结果短期疗效:试验组客观缓解率为 47.73%,显著高于对照组 18.18%(P=0.035);试验组持久临床受益率为 86.36%,显著高于对照组的 43.18%(P=0.048)。长期疗效:试验组中位 PFS为 7.22个月［ 95%CI:(4.38,14.04)］显著长于对照组的 4.31个月［95%CI:(3.43,9.25)］(P=0.032)。试验组中位总生存期( OS)为 17.30个月［ 95%CI:(14.33,17.58),］死亡风险显著低于对照组的 6.93个月［ 95%CI:(4.89,13.25)］(P=0.039)。 Cox回归分析结果显示肿瘤突变负荷( P=0.036)、化疗,疗程( P=0.022)、组织学类型( P=0.018)和转移灶位点( P=0.035)是试验组治疗效果的独立预后因素。结论信迪利单抗联合常规化疗方案显著提高     

Efficacy and safety of doublet versus single agent as salvage treatment for metastatic breast cancer pretreated with anthracyclines and taxanes: a systematic review and meta-analysis

Aim: To perform a systematic review and meta-analysis of randomized controlled trials to compare the efficacy and safety of doublet versus single agent as salvage treatment for pretreated metastatic breast cancer.

Methods: A comprehensive literature search was performed to identify relevant randomized controlled trials (RCTs). All clinical studies were independently identified by two authors for inclusion. Demographic data, treatment regimens, objective response rate (ORR), and progression-free survival (PFS) and overall survival (OS) were extracted and analyzed using Comprehensive MetaAnalysis software (Version 2.0).

Results: Thirteen RCTs involving 4878 pretreated metastatic breast cancer patients were ultimately identified. The pooled results demonstrated that doublet combination therapy significantly improved ORR (RR 1.13, 95% CI: 1.01–1.27, p?<?.001) and PFS (hazard ration [HR] 0.83, 95% CI: 0.73–0.96, p?=?.011), but not OS (HR 0.93, 95% CI: 0.86–1.01, p?=?.065). Similar results were observed in sub-group analysis according to treatment regimens. Additionally, more incidences of grade 3 or 4 myelosuppression toxicities nausea and fatigue were observed in doublet combination therapy.

Conclusions: In comparison with a single agent alone, doublet combination therapy as salvage treatment for pretreated metastatic breast cancer patients significantly improves ORR and PFS, but not OS. Further studies are recommended to identify patients who will most likely benefit from the appropriate doublet combination therapy.     

Long-term follow-up of patients with metastatic breast cancer: results of a retrospective, single-center analysis from 2000 to 2005

Recent epidemiological studies suggest that chemotherapy for metastatic breast cancer (MBC) has not contributed to a marked improvement in the patient outcome during the last decades. Randomized trials that investigated the efficacy of a first-line schedule for MBC, observed a median survival of 18-24 months. This study aimed to analyze patients with MBC who have been treated in a single university outpatient clinic for survival. Patients with MBC who had received their complete anticancer treatment in our outpatient clinic between 2000 and 2005 were analyzed for treatment schedules and survival. A total of 232 patients [median age, 53 years; range, 27-87 years; estrogen receptor and/or progesterone-positive hormone receptor, n=174 (75%); human epidermal growth factor receptor 2 overexpression (human epidermal growth factor receptor 2 positive), n=79 (34%)] were included in this analysis, of which 43.7% of hormone receptor-positive patients received 1-2, 28.3% received 3-4, and 1.7% received more than four hormonal regimens. In addition, 53.4% of all patients received up to three chemotherapeutic agents in palliative intent, whereas four to six regimens were applied in 22.1, and 12.9% received more than six subsequent regimens. An increased number of regimens were associated with an improvement in survival. The median overall survival was 44 months (95% confidence interval: 39-49). HR positivity, bone only, or single-site metastases were associated with an improved survival. An improved survival was also shown in patients who underwent locoregional procedures for oligometastatic disease (n=31; median overall survival >50 months), whereas triple-negative breast cancer was related to worse outcome (16 months; 95% confidence interval: 7-25). These data collected from a selective patient population of a single center support the hypothesis that the sequential use of all treatment modalities for MBC to its full potential may result in an increased survival. Whether innovative medicine, a step-by-step escalation of all treatment modalities according to standard guidelines and individualized clinical requirements, and a multidisciplinary treatment approach contribute to these good outcomes is debatable.     

Efficacy of gemcitabine-based chemotherapy in metastatic breast cancer: a meta-analysis of randomized controlled trials

Abstract

Objectives:

To compare the effects of gemcitabine-based chemotherapy and gemcitabine-free regimens, a meta-analysis of all relevant randomized controlled trials was performed to investigate the improvement in overall response rate (ORR), time to progression (TTP), and overall survival (OS). A subgroup of gemcitabine-based doublet compared with single agent was also analyzed.     

蒽环类联合紫杉类药物新辅助化疗方案治疗乳腺癌的临床疗效研究

目的研究蒽环类联合紫杉类化疗药新辅助化疗方案治疗乳腺癌的临床疗效和安全性。方法选取2012年1月至2013年6月我院收治的76例乳腺癌患者,依据治疗方案分为观察组和对照组,每组均38例。收集患者年龄、家族史、肿瘤转移等一般临床资料,对比分析两组患者治疗后临床疗效和药物不良反应情况,对比两组患者治疗后总体生存数据。结果观察组的总体治疗有效率(92.1%)显著高于对照组(71.0%),差异有统计学意义(P<0.05)。两组患者用药不良反应发生率比较差异无统计学意义(P>0.05)。随访生存分析结果显示,治疗后观察组患者的总体生存时间为(59.1±4.3)个月,显著长于对照组的(51.3±4.5)个月,差异有统计学意义(P<0.05)。结论蒽环类联合紫杉类化疗药物的新辅助化疗方案治疗乳腺癌疗效较好,安全性高,可提高患者预后生存时间。