Olaparib for the treatment of breast cancer

Introduction: Mutations in BRCA1 and BRCA2 genes account for around 2–3% of breast cancer events and more than 10% of triple negative breast cancers. Olaparib (Lynparza®), an orally administered PARP inhibitor, demonstrated clinical benefit in a phase III trial for mutated BRCA-positive HER2 negative metastatic breast cancer.

Areas covered: This review gives an overview of available preclinical and clinical data regarding olaparib, including its chemistry, mechanism of action, pharmacokinetics and pharmacodynamics, and evidence supporting antitumor efficacy and safety profile in breast cancer patients.

Expert commentary: Olaparib improves progression-free survival in germline BRCA mutated HER2 negative metastatic breast cancer patients as compared to standard chemotherapy, with a manageable toxicity profile. Efficacy is of clinical relevance especially in the context of triple negative breast cancer. However, several aspects, such as sequencing or combination of these agents with other anticancer agents and identification of appropriate biomarkers, still need to be clearly defined.     

The Future of Targeted Therapies in Ovarian Cancer

Ovarian cancer is the second most common gynecological malignancy and the leading cause of death from gynecological cancer. Most women present with advanced disease with little prospect for cure. There have been some advances in surgical and chemotherapeutic strategies, but these approaches have led to only minor improvements in outcome. There remains a significant risk for recurrence and resistance to therapy, and hence there is a need to improve upon the current treatment options. Molecularly directed therapy aims to target tumor cells and the tumor microenvironment by blocking specific molecular changes in the cancer. The most promising agents so far are the antiangiogenic agents and polyadenosine diphosphate‐ribose polymerase inhibitors. This article reviews the various targeted therapeutic approaches under clinical investigation in ovarian cancer and the challenges facing their future success in the clinic.     

贝伐珠单抗联合紫杉类药物一线治疗局部复发或转移性乳腺癌患者的安全性及疗效

[目的]研究贝伐珠单抗联合紫杉类药物一线治疗Her-2阴性的局部复发或转移性乳腺癌患者的安全性和疗效。[方法]32例Her-2阴性的复发或转移性乳腺癌患者,一线接受贝伐珠单抗联合紫杉类方案的化疗,直至疾病进展或不良反应不能耐受或患者要求出组。研究者选择化疗方案：贝伐珠单抗15mg／kg静滴d1,多西他赛75mg／m^2,静滴d1,21d为一个周期;或贝伐珠单抗10mg／kg静滴d1,15紫杉醇80mg／m^2,静滴d1,8,15,为一个周期。每3个周期评价疗效。[结果]32例可评价疗效和副作用,PR16例,SD15例,PD1例,总有效率50％,中位TTP为7.25个月。3级以上不良反应为阴道出血、粒细胞下降以及腹泻。[结论]贝伐珠单抗联合紫杉类药物治疗晚期乳腺癌不良反应可以耐受,具有一定疗效。     

FDA Approval Summary: Atezolizumab and Durvalumab in Combination with Platinum-Based Chemotherapy in Extensive Stage Small Cell Lung Cancer

The U.S. Food and Drug Administration (FDA) granted approval to atezolizumab and durvalumab in March of 2019 and 2020, respectively, for use in combination with chemotherapy for first‐line treatment of patients with extensive stage small cell lung cancer. These approvals were based on data from two randomized controlled trials, IMpower133 (atezolizumab) and CASPIAN (durvalumab). Both trials demonstrated an improvement in overall survival (OS) with anti–programmed death ligand 1 antibodies when added to platinum‐based chemotherapy as compared with chemotherapy alone. In IMpower133, patients receiving atezolizumab with etoposide and carboplatin demonstrated improved OS (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.54–0.91; p = .0069), with median OS of 12.3 months compared with 10.3 months in patients receiving etoposide and carboplatin. In CASPIAN, patients receiving durvalumab with etoposide and either cisplatin or carboplatin also demonstrated improved OS (HR, 0.73; 95% CI, 0.59–0.91; p = .0047) with median OS of 13.0 months compared with 10.3 months in patients receiving etoposide and either cisplatin or carboplatin. The safety profiles of both drugs were generally consistent with known toxicities of immune‐checkpoint inhibitor therapies. This review summarizes the FDA perspective and data supporting the approval of these two agents.Implications for PracticeEffective therapeutic options for small cell lung cancer (SCLC) are limited, and there has been modest improvement in the overall survival (OS) of patients with SCLC over the past 3 decades. The approvals of atezolizumab and of durvalumab in combination with chemotherapy for first‐line treatment of patients with extensive stage SCLC represent the first approved therapies with OS benefit for this patient population since the approval of etoposide in combination with other approved chemotherapeutic agents. Additionally, the efficacy results from IMpower133 and CASPIAN lay the groundwork for possible further evaluation in other treatment settings in this disease.     

Bevacizumab in Combination with Metronomic Chemotherapy in Patients with Anthracycline- and Taxane-Refractory Breast Cancer

Abstract

A vascular endothelial growth factor (VEGF) inhibitor might enhance metronomic chemotherapy in previously treated metastatic breast cancer (MBC) patients. Anthra-cycline and taxane refractory MBC patients were given cyclophosphamide 50 mg p.o. daily, methotrexate 1 mg/kg i.v. every 14 days, and bevacizumab 10 mg/kg i.v. every 14 days. Trastuzumab was added in HER2-overexpressing tumors. 24 patients were enrolled and 22 were evaluable. All tumors had histologic grade II-III and most patients had ≥2 metastatic sites. After a median follow-up of 7.7 months the response rates were: complete response (CR) 0%, partial response (PR) 31.8% (95% CI 13.9-54.9%), stable disease for ≥24 weeks (SD) 31.8% (95% CI 13.9-54.9%). Clinical benefit (CB= CR + PR + SD>24w) 63.6% (95% CI 40.7-82.8%). Median progression-free survival (PFS) was 7.5 months; overall survival (OS) was 13.6 months. HER2-overex-pressing or high proliferative-index tumors had better 6-month PFS (75% vs. 34% in HER-negative tumors P= 0.043; 67% vs. 0% in Ki-67 ≥20% tumors, P = 0.015). Adverse effects were mild. The combination of bevacizumab and a metronomic-based chemotherapy was effective, well tolerated and provided clinical benefit in heavily-treated MBC patients.     

贝伐单抗联合多西他赛化疗方案对转移性乳腺癌患者的临床疗效

目的 探讨贝伐单抗联合多西他赛化疗方案对转移性乳腺癌患者的临床疗效.方法 入组87例患者依据随机数字表法随机分为观察组(45例)和对照组(42例).观察组采用贝伐单抗联合多西他赛化疗,对照组采用卡培他滨联合多西他赛化疗.2组均以21 d为1周期,共化疗3周期.对比分析2组总有效率、生活质量以及不良反应.结果 观察组有效率(64.45%)显著高于对照组(40.47%),差异有统计学意义(P<0.05);观察组生活质量改善率(68.89%)高于对照组(40.48%),差异有统计学意义(P<0.05);观察组胃肠道反应、骨髓抑制、手足综合征等不良反应发生率均低于对照组,差异有统计学意义(P均< 0.05);2组1 a生存率比较差异无统计学意义(P>0.05).结论 贝伐单抗联合多西他赛化疗方案对转移性乳腺癌患者临床疗效显著,可明显改善患者生活质量,降低不良反应发生率,值得进一步推广应用.     

贝伐单抗联合白蛋白结合型紫杉醇治疗复发性卵巢癌的临床观察

目的 比较贝伐单抗联合白蛋白结合型紫杉醇与贝伐单抗治疗卵巢癌的疗效及不良反应.方法 60例经病理组织学和(或)细胞学检查确诊的ⅢB期或Ⅳ期复发型卵巢癌患者,其中多伐单抗联合白蛋白结合型紫杉醇组(联合组)28例,贝伐单抗组32例,分别给予贝伐单抗联合白蛋白结合型紫杉醇和贝伐单抗方案进行4个周期的治疗.评估两种治疗方法的近期疗效和不良反应.结果 联合组和贝伐单抗组的疾病控制率分别为85.7％和81.2％,部分缓解率分别为46.4％和43.7％.贝伐单抗组OS为7.0个月,联合组OS为7.3个月;P=0.63.贝伐单抗组与联合组中性粒细胞减少发生率分别为50.0％和42.8％,3～4级白细胞减少发生率分别为43.8％和24.9％ (P=0.001),两组比较差异具统计学意义,血小板减少发生率分别为53.0％和25.0％,差异具有统计学意义.结论 贝伐单抗联合白蛋白结合型紫杉醇治疗复发型卵巢癌疗效良好,不良反应少,安全性更好.     

吉西他滨联合顺铂治疗老年晚期恶性肿瘤的临床观察

目的观察吉西他滨联合顺铂治疗老年晚期恶性肿瘤的临床疗效,毒副反应,临床收益反应。方法吉西他滨800mg/m2静脉点滴第1,8,15天;顺铂30mg/m2静脉点滴第2~4天,28天为1周期,完成2周期后评价疗效。至少治疗2个周期。结果64例均可评价,总有效率为46.9%,其中非小细胞肺癌28例,有效率为46.4%,胰腺癌18例,有效率为44.4%,乳腺癌18例,有效率为50%,中位生存期为11个月,疾病进展时间为6.2个月,1年生存率及2年生存率分别为43.8%和23.4%。疾病相关症状显著改善,体力状态改善率62.5%,主要不良反应为骨髓抑制及消化道反应。无治疗相关性死亡。结论吉西他滨联合顺铂化疗治疗老年晚期恶性肿瘤近期有效率较高。毒副反应轻,耐受性好,并可以改善疾病相关症状,值得临床应用。     

Palliative Chemotherapy in Pretreated Patients with Advanced Cancer: Oral Trofosfamide Is Effective in Ovarian Carcinoma

Thirty-four patients with advanced cancer of various origins and documented disease progression were treated with continuous daily doses of 50-150 mg of oral trofosfamide (TRO). Of 31 evaluable patients, 5 responded to this treatment (1 complete remission and 4 partial remissions) and 12 patients had stable disease. Four of 9 patients with advanced ovarian cancer resistant to platinum-containing regimens and paclitaxel responded to oral TRO. The median treatment duration was 26 weeks for responders and 6 weeks for nonresponders, with cumulative doses of up to 46.000 mg TRO. Response duration was 11-47 weeks. No significant side effects were observed. Oral TRO given in the outpatient setting seems to be an attractive therapeutic option for heavily pretreated cancer patients, and it has remarkable antitumor effects in patients with ovarian cancer.     

Front-Line Bevacizumab plus Chemotherapy with or without Maintenance Therapy for Metastatic Breast Cancer: An Observational Study by the Hellenic Oncology Research Group

Front-line bevacizumab (BEV) in combination with taxanes offers benefit in progression-free survival (PFS) in metastatic breast cancer (mBC). The medical records of mBC patients, treated with front-line BEV-based chemotherapy, were retrospectively reviewed in order to generate real life safety and efficacy data. Patients with human epidermal growth factor receptor 2 (HER2)-negative mBC treated with front-line BEV in combination with chemotherapy were eligible. Maintenance therapy with BEV and/or hormonal agents was at the physicians’ discretion. Among the 387 included patients, the most common adverse events were anemia (61.9%, mainly grade 1), grade 3/4 neutropenia (16.5%), grade 1/2 fatigue (22.3%), and grade 1/2 neuropathy (19.6%). Dose reductions were required in 164 cycles (7.1%) and toxicity led to treatment discontinuation in 21 patients (5.4%). The median PFS and the median overall survival (OS) were 13.3 (95% CI: 11.7–14.8) and 32.3 months (95% CI: 27.7–36.9), respectively. Maintenance therapy, with hormonal agents (ET) and/or BEV, was associated with longer OS versus no maintenance therapy (47.2 versus 23.6 months; p < 0.001) in patients with hormone receptor (HR)-positive disease and BEV maintenance offered longer OS versus no maintenance in patients with HR-negative disease (52.8 versus 23.3; p = 0.023). These real-life data show that front-line BEV-based chemotherapy in HER2-negative mBC patients is an effective treatment with an acceptable toxicity profile. The potential benefit of maintenance treatment, especially ET, is important and warrants further research.     

晚期上皮性卵巢癌术前新辅助化疗的临床总结

探讨晚期卵巢癌能否行手术治疗的预测因素及新辅助化疗在晚期卵巢癌中的临床价值。方法：回顾性分析了大连医科大学附属第一医院1996年1月至2008年12月收治的Ⅲ～Ⅳ期晚期卵巢癌病例92例,其中18例接受新辅助化疗（NAC组）,74例接受初次手术（PCS组）。结果：使初次肿瘤细胞减灭术满意率降低的因素：伴有合并症（P=0.022）;初次治疗时存在胸腔积液（P=0.011）;CA125>1 000 U/L（P=0.030）;有肝、肺转移的Ⅳ期患者（P=0.031）。新辅助化疗的总有效率为66.7%。新辅助化疗可以提高肿瘤细胞减灭术的满意率（P=0.022）,缩短引流管置留天数（P=0.011）,减少腹水量（P=0.005）、术中出血量（P=0.048）,但在手术时间、输血量、平均住院天数、患者生存时间方面,NAC组与PCS组的差异无统计学意义（P>0.05）。结论：伴有合并症、胸腔积液、CA125>1 000 U/L、临床分期为Ⅳ期、表现为肝、肺转移的患者适合新辅助化疗。新辅助化疗可以提高肿瘤细胞减灭术的满意率,减少术中、术后并发症,可能会改善患者预后。     

XELOX Plus Bevacizumab vs. FOLFIRI Plus Bevacizumab Treatment for First-line Chemotherapy in Metastatic Colon Cancer: a Retrospective Study of the Anatolian Society of Medical Oncology

Background: XELOX plus bevacizumab (XELOX-Bev) and FOLFIRI plus Bevacizumab (FOLFIRI - Bev)treatments are an effective strategies patients with metastatic colorectal cancer (mCRC).The aim of this studywas to compare efficacy of first-line XELOX-Bev treatment vs FOLFIRI-Bev treatment for mCRC. Materialsand Methods: A total of 409 patients with mCRC who received chemotherapy were included and divided into 2groups. Group 1 (n=298) received XELOX-Bev and Group 2 (n=111) FOLFIRI-Bev. Comparisons were made interms of overall (OS) and progression-free (PFS) survival, response rate (RR), and grade 3-4 toxicity. Results:Median follow-up was 11 months in Group 1 and 15 months for Group 2. Complete remission was observed in29 (9.7%) and 2 (1.8%) patients, partial remission in 139 (46.6%) and 27 (24.5%) , stable disease in 88 (29.5%)and 49 (44.1%) and progressive disease in 42 (14.1%) and 33 (30.0%) patients in Group 1 and 2, respectively.Median OS was 25 months (range 2-57 months, 95%CI; 22.2-27.7) for Group 1 and 20 months (range 1-67 months,95%CI; 16.8-23.1) for Group 2 (p=0.036). Median PFS was 9.6 months (range 2-36 months, 95%CI; 8.8-10.4) forGroup 1 and 9 months (range 1-44 months, 95%CI; 7.4-10.5) for Group 2 (p=0.019). Objective RR was 56.4%in Group 1 and 26.1% in Group 2 (p<0.001). Conclusions: First-line XELOX-Bev is more effective with a betterresponse rate, prolongation of median PFS/OS, and a superior safety profile compared with FOLFIRI-Bev.     

超选择髂内动脉插管治疗中晚期卵巢癌

 目的:探讨超选择髂内动脉插管治疗中晚期卵巢癌的疗效及其影响因素。方法:对31例中晚期卵巢癌进行双侧髂内动脉超选择化疗并栓塞83次, 全部病例均经随访。 结果:近期疗效较好, 有效率为77.4%。 结论:超选择髂内动脉插管是治疗中晚期卵巢癌的一种新而有效的方法, 影响疗效的因素有:①导管能否超选择; ②肿瘤的大小、临床分期及血管构型; ③药物及栓塞材料的选择; ①病人的自身情况。