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观察

背景与目的:贝伐珠单抗是首个抗血管生成的分子靶向药物,可以与多种化疗药物联合用于治疗复发转移性乳腺癌.本研究旨在观察贝伐珠单抗联合多西他赛治疗复发转移性乳腺癌的疗效和不良反应.方法:28例Her-2阴性的复发转移性乳腺癌患者均接受贝伐珠单抗联合多西他赛方案治疗,多西他赛75 mg/m2静滴,第1天:同时给予贝伐珠单抗15 mg/kg,第1天;21 d为1个周期.每个周期评价疗效同时记录不良反应.结果:27例患者可评价疗效和不良反应,其中CR 1例,PR 21例,有效率(CR+PR)为81.5%.粒细胞减少及白细胞减少是主要的不良反应,Ⅳ度粒细胞减少发生率为85.2%.研究中观察到高血压3例,静脉血栓1例,分级均为1级.蛋白尿12例,鼻衄15例,均为1～2级.结论:贝伐珠单抗联合多西他赛是治疗Her-2阴性的复发转移性乳腺癌患者的有效方案,其不良反应能够耐受.     

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。     

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。     

贝伐珠单抗联合FOLFIRl方案一线治疗转移性结直肠癌的临床研究

目的评价贝伐珠单抗联合FOLFIRI方案一线治疗转移性结直肠癌的疗效和安全性。方法将42例转移性结直肠癌患者随机分为FOLFIRI组和FOLFIRI＋贝伐珠单抗组。FOLFIRI组（n=21）采用伊立替康（CPT一11,180mg／m2,d1）＋甲酰四氢叶酸钙（CF,400mg／m2,d1）＋氟尿嘧啶（5-FU,400mg／m2,静脉推注,d1;然后5-FU,2400mg／m2,以微量泵进行持续静脉滴注46小时）。FOLFIRI＋贝伐珠单抗组（n=21）采用贝伐珠单抗（每2周5mg／kg,d1）＋FOLFIRI方案。2周为1个周期,3个周期后评价疗效。两组患者均持续治疗至病情进展或毒性不能耐受。结果42例患者均可评价疗效和不良反应。FOLFIRI组和FOLFIRI＋贝伐珠单抗组的治疗有效率分别为28．6％和61．9％,FOLFIRI＋贝伐珠单抗组的有效率显著高于FOLFIRI组（P=0．03）。FOLFIRI＋贝伐珠单抗组的临床获益率明显高于FOLFIRI组（90．5％US61．9％,P：0．03）。FOLFIRI组和FOLFIRI＋贝伐珠单抗组中位无疾病进展时间（progression—freesurvival,PFS）分别为6．6个月和10．0个月（P=0．000）。两组的主要不良反应为迟发性腹泻和中性粒细胞减少,贝伐珠单抗组增加的不良反应主要有高血压（P=0．002）、出血（P=0．001）和蛋白尿（P=0．035）。结论FOLFIRI方案化疗联用贝伐珠单抗提高了晚期结直肠癌患者治疗的有效率和临床获益率,并延长了PFS,不良反应患者可以耐受。     

靶向药物治疗上皮性卵巢癌的研究进展

约2/3的晚期上皮性卵巢癌患者经标准治疗后最终会复发。标准治疗后使用靶向药物维持治疗可延长无铂间隔,降低出现继发性铂耐药的风险,增加后续治疗时铂类药物的选择,提高患者下次含铂化疗的应答率,可延长患者的无进展生存期和总生存率。继VEGF抑制剂贝伐珠单抗（bevacizumab）被推荐用于上皮性卵巢癌维持治疗后,多项维持治疗研究成果已公布,维持治疗的方案根据乳腺癌易感基因（breast cancer susceptibility gene,BRCA）状态和初治是否使用贝伐珠单抗进行了更新：BRCA 1/2 突变的患者 ,初始治疗中如果使用贝伐珠单抗 ,维持治疗可以用聚二磷酸腺苷核糖聚合酶[poly(ADP-ribose)polymerase,PARP]抑制剂奥拉帕尼联合贝伐珠单抗或者奥拉帕尼单药或者尼拉帕尼单药,而对于初始治疗时未使用贝伐珠单抗的患者,推荐使用奥拉帕尼或者尼拉帕尼维持;无BRCA突变的患者,在初始治疗中如果使用贝伐珠单抗,推荐用奥拉帕尼联合贝伐珠单抗或单药贝伐珠单抗,初始治疗中未使用过贝伐珠单抗的患者推荐使用尼拉帕尼维持。PD-1/PD-L1抑制剂的多项临床研究也正在开展。本文主要对微血管生成抑制剂、PARP抑制剂、PD-1/PD-L1抑制剂治疗上皮性卵巢癌的最新研究进展进行综述。     

贝伐珠单抗联合FOLFOX或FOLFIRI方案治疗转移性结直肠癌的临床研究

目的 观察贝伐珠单抗联合FOLFOX或FOLFIRI方案用于转移性结直肠癌一线及二线治疗的临床疗效和毒副反应。方法 回顾性分析2005年11月至2012年8月接受贝伐珠单抗联合FOLFOX或FOLFIRI方案作为一线及二线治疗的57例转移性结直肠癌患者的临床资料。采用RECIST 1.1版评价疗效,用NCI-CTC 3.0版评价不良反应,用Kaplan-Meier法进行生存分析。结果 57例结直肠癌患者中,19例（33.3％）获PR,28例（49.2％）获SD,有效率（RR）为33.3％,疾病控制率（DCR）为82.5％。贝伐珠单抗联合化疗用于一线与二线治疗患者的RR或DCR差异均无统计学意义（P＞0.05）;贝伐珠单抗联合FOLFOX方案与FOLFIRI方案的RR或DCR差异均无统计学意义（P＞0.05）。57例患者的无进展生存期（PFS）及总生存期（OS）分别为8.83个月及14.80个月。一线与二线治疗及贝伐珠单抗联合FOLFOX方案与FOLFIRI方案的中位PFS或OS差异均无统计学意义（P＞0.05）。主要不良反应包括白细胞减少、血小板减少及恶心呕吐。贝伐珠单抗相关的不良反应主要包括高血压3例,蛋白尿1例,鼻衄2例,均为1～2级,药物可以控制。结论 贝伐珠单抗联合化疗治疗转移性结直肠癌能够提高治疗疗效,不良反应可以耐受。     

贝伐珠单抗治疗脑转移瘤难治性瘤周水肿的疗效分析

目的 观察贝伐珠单抗治疗恶性肿瘤脑转移瘤难治性瘤周水肿的疗效及不良反应。方法 回顾性分析于本院接受贝伐珠单抗治疗的14例伴难治性瘤周水肿的恶性肿瘤脑转移瘤患者的临床资料,包括乳腺癌脑转移7例、肺癌5例、食管癌1例、右上颌窦腺样囊性癌1例。所有患者均为甘露醇、地塞米松等常规治疗无效的难治性脑水肿病例。评估患者在贝伐珠单抗治疗前后的临床症状、生活质量评分及MRI显示的水肿体积,并详细记录治疗相关不良反应。结果 全组患者接受贝伐珠单抗治疗的中位剂量为4.76 mg/kg。全组14例患者中,11例患者在贝伐珠单抗给药后头晕、头痛症状明显减轻,3例患者症状改善不明显。全组14例患者贝伐珠单抗治疗后瘤周水肿体积较治疗前明显减少［（38 804±14 859）mm3 vs.（80 100±28 338）mm3,P=0.02］,水肿指数较治疗前有降低的趋势（15.38±7.12 vs. 26.40±16.52,P＞0.05）,但差异无统计学意义。14例患者中有1例于第2次贝伐珠单抗治疗后出现上颌窦创面大量出血死亡,3例患者出现可控制的高血压,未出现蛋白尿、贫血、口腔炎等其他并发症。结论 贝伐珠单抗可控制恶性肿瘤脑转移的难治性瘤周水肿,为严重脑水肿患者争取放疗机会,但应谨慎掌握适应证,警惕严重不良反应。     

贝伐珠单抗维持治疗小细胞肺癌1例并文献复习

目的:探讨贝伐珠单抗维持治疗小细胞肺癌对无进展生存时间及总生存时间的影响。方法:本文报道1例广泛期小细胞肺癌贝伐珠单抗联合化疗5个周期后继续贝伐珠单抗维持治疗8个周期病例，并对相关文献进行复习。结果:患者无进展生存时间为10个月。结论:贝伐珠单抗维持治疗广泛期小细胞肺癌可以延长无进展生存期，延长生存期。     

AK-HER2与参照药治疗HER2阳性转移性乳腺癌患者的疗效、体内代谢特征、安全性和免疫原性比较：一项多中心、随机、双盲Ⅲ期等效性临床试验

背景与目的：针对人表皮生长因子受体（human epidermal growth factor receptor 2,HER2）阳性转移性乳腺癌患者,曲妥珠单抗治疗能够延长患者总生存期,显著改善患者预后,但是原研曲妥珠单抗价格较高。生物类似药理论上具有相当的疗效和安全性。本临床试验旨在评估曲妥珠单抗生物类似药AK-HER2与原研曲妥珠单抗在HER2阳性转移性乳腺癌患者中的疗效、药代动力学、安全性和免疫原性。方法：这项多中心、随机、双盲Ⅲ期临床试验在中国43个分中心开展。本研究遵从研究方案、赫尔辛基宣言阐明的伦理学原则和药物临床试验质量管理规范,获得医院医学伦理委员会批准,临床试验注册机构为国家药品监督管理局（临床试验批件号为2015L04224,临床试验登记号为CTR20170516）。在入组前获得了受试者的书面知情同意书。入组患者随机分配至AK-HER2组与对照组,分别接受AK-HER2或原研曲妥珠单抗（赫赛汀?,初始负荷剂量8 mg/kg,维持剂量6 mg/kg,每3周为1个治疗周期,总治疗时间为16个周期）与多西他赛（剂量75 mg/m2,治疗持续至少9个周期）联合治疗。本临床试...     

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.     

Switch maintenance therapy with docetaxel and bevacizumab after induction therapy with cisplatin,pemetrexed, and bevacizumab in advanced non-squamous non-small cell lung cancer: a phase II study

Switch maintenance therapy, using alternative agents that were not administered during induction chemotherapy, is a treatment option for advanced non-squamous non-small cell lung cancer (NSCLC). Bevacizumab is known to increase the efficacy of other chemotherapeutic agents; however, switch maintenance therapy with docetaxel and bevacizumab has not been adequately studied. The goal of this study was to evaluate the efficacy and safety of switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab. Chemotherapy-naïve non-squamous NSCLC patients received induction therapy of four cycles of cisplatin (75 mg/m²), pemetrexed (500 mg/m²), and bevacizumab (15 mg/kg). Patients who achieved disease control after induction therapy then received maintenance therapy with docetaxel (50 mg/m²) and bevacizumab (15 mg/kg) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival from enrollment. This study enrolled 49 NSCLC patients, among which 38 (77.6%) completed the four cycles of induction therapy and received maintenance therapy. The median progression-free survival from enrollment was 7.8 months (95% confidence interval: 4.7–11.0 months). The most common toxicities of grade 3 or higher were neutropenia (68.4%), leukopenia (50.0%), febrile neutropenia (31.8%), and hypertension. Switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab demonstrated modest efficacy and frequent hematologic toxicity in non-squamous NSCLC patients.     

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.     

The Breast Avastin Trial: phase II study of bevacizumab maintenance therapy after induction chemotherapy with docetaxel and capecitabine for the first-line treatment of patients with locally recurrent or metastatic breast cancer

Background

Therapeutic approach for patients with metastatic breast cancer (MBC) is still controversial. This study was conducted to assess the efficacy and safety of bevacizumab in combination with docetaxel plus capecitabine as first-line treatment for MBC. The feasibility of bevacizumab maintenance therapy in this setting was also evaluated.

Patients and methods

In this single-arm, multicenter phase II study, patients received bevacizumab 15 mg/kg and docetaxel 60 mg/m² on day 1, plus capecitabine 900 mg/m² twice daily on days 1–14 every 21 days. Treatment was administered for up to 6 cycles, then bevacizumab continued until progressive disease. The primary end point was progression-free survival (PFS); secondary end points were tumor response rate, overall survival, and toxicity.

Results

Seventy-nine eligible patients were treated with bevacizumab in combination with docetaxel plus capecitabine. The overall response rate was 61 %, with a complete response rate of 8 % and a median duration of response of 10 months. At a median follow-up of 28 months, the median PFS was 11 months. Fifty-two (65 %) patients received bevacizumab maintenance therapy for a median duration of 7 months (range 1 to 33+). Neutropenia was the most common grade 3–4 toxicity (28.1 % of patients), and two fatal adverse events occurred (septic shock and gastrointestinal perforation).

Conclusions

Bevacizumab in combination with docetaxel and capecitabine demonstrates significant activity and quite acceptable toxicity profile as first-line treatment of MBC. Subsequent maintenance therapy with bevacizumab is feasible for a long period of stable disease. Results deserve confirmation.     

TCH方案治疗老年HER-2阳性乳腺癌安全性分析

目的：观察TCH方案（多西紫杉醇﹢卡铂﹢赫赛汀）治疗老年人表皮生长因子受体-2（ human epi-dermal growth factor receptor-2，HER-2）阳性乳腺癌的近期化疗毒性及远期心脏毒性。方法：24例老年HER     

曲妥珠单抗对HER-2阳性早期乳腺癌骨髓微转移的影响

目的：检测HER-2阳性的早期乳腺癌患者应用曲妥珠单抗（Trastuzumab）治疗前后骨髓微转移的改变,探讨HER-2基因及Herceptin对骨髓微转移的影响。方法：应用实时定量逆转录-聚合酶链反应（qRT-PCR）方法检测15例HER-2阳性乳腺癌及18例HER-2阴性乳腺癌患者术前及化疗后骨髓CK19的表达水平,其中10例HER-2阳性乳腺癌患者在化疗结束后,继续应用Herceptin治疗,3月后再次抽取骨髓标本,qRT-PCR检测CK19的表达水平。结果：手术前,14例HER-2阳性乳腺癌患者骨髓CK19表达阳性（93.3%）,而HER-2阴性患者8例CK19表达阳性（44.4%）,二者差异显著（P=0.000）。化疗后,12例HER-2阳性乳腺癌患者CK19表达阳性（80.0%）,而HER-2阴性患者3例表达阳性（16.7%）,二者差异显著（P=0.000）。10例HER-2阳性乳腺癌患者化疗后继续应用Herceptin治疗3月后,骨髓CK19的表达明显下降（102.78±98.24 vs 66.92±49.18,P=0.036）。结论：HER-2基因的表达与早期乳腺癌患者骨髓微转移密切相关,而Herceptin可以降低骨髓微转移病灶,提示骨髓微转移情况可以作为Herceptin治疗疗效的早期预测指标。     

不同分子亚型乳腺癌脑转移患者的临床特征和预后分析

目的探讨不同分子亚型乳腺癌脑转移(BCBM)患者的临床特点和预后。方法收集201例BCBM患者的临床资料,根据原发肿瘤激素受体及表皮生长因子受体2(HER-2)表达状态,将患者分为3个不同分子亚型,并分析不同亚型BCBM患者的临床特征及生存情况。结果 201例患者中,Luminal型68例(33.8%),HER-2型87例(43.3%),三阴型46例(22.9%)。全组患者初始转移部位依次为肺68例(33.8%)、骨63例(31.3%)、肝52例(25.9%)和脑27例(13.4%)。不同亚型患者初始转移部位不同(P<0.05),Luminal型患者骨转移的发生率最高(41.2%),HER-2型肝转移的发生率为35.6%,三阴型患者脑转移的发生率为30.4%。不同亚型患者首次复发至出现脑转移时间(TTBM)不同Luminal型为18.1个月,HER-2型为16.8个月,三阴型患者为8.3个月,差异有统计学意义(P=0.005);Luminal型患者总生存时间为95.7个月,HER-2型总生存时间为72.2个月,三阴型患者总生存时间为41.6个月,差异有统计学意义(P=0.002)。HER-2型患者脑转移前采用抗HER-2治疗的TTBM为21.9个月,较未行抗HER-2治疗的TTBM(7.2个月)明显延长(P=0.002)。结论肺、骨、肝和脑是乳腺癌最常见的远处转移部位。三阴型乳腺癌患者容易发生脑转移且预后最差,三阴型和HER-2型未行抗HER-2治疗患者容易早期出现脑转移,抗HER-2治疗可以延缓脑转移的发生。     

多西他赛联合洛铂新辅助化疗方案治疗三阴性乳腺癌的临床观察

目的 探讨多西他赛联合洛铂在三阴性乳腺癌（TNBC）新辅助化疗中的疗效和不良反应。方法30例TNBC患者应用多西他赛联合洛铂行新辅助化疗,具体方案为：多西他赛75mg／m²静滴,d1;洛铂30mg／m²静滴,d1;21天为1周期。按照WHO实体瘤客观疗效评价标准及术后病理组织学检测评价疗效,按照WHO急性及亚急性毒性标准评价毒副反应。结果8、17和5例患者分别完成2、4和6个周期的新辅助化疗,获CR 9例、PR 15例、SD 4例、PD 2例,RR为80.0％;术后病理组织学检测获病理学完全缓解6例。主要不良反应为骨髓抑制：1～2级白细胞减少17例,3～4级5例;1～2级血小板减少7例,3～4级2例;1～2级血红蛋白减少6例。非血液学毒性轻微。结论 多西他赛联合洛铂方案的疗效较好,毒副反应可耐受,是TNBC新辅助化疗方案的一个新选择。     

Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients.

PURPOSE: To evaluate the safety and efficacy of bevacizumab and weekly docetaxel as first- or second-line therapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Twenty-seven MBC patients received i.v. bevacizumab at 10 mg/kg on days 1 and 15 in combination with i.v. docetaxel 35 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Primary end points were to assess toxicity, overall response rate, and progression-free survival. A secondary end point was to assess the relationship between plasma endothelial and cell adhesion markers and clinical outcomes. RESULTS: One-hundred fifty-eight treatment cycles were administered with a median of six cycles (range 1-15 cycles) per patient. The most common grade 4 toxicities per patient were as follows: 2 (7%)-pulmonary embolus, 1 (4%)-febrile neutropenia, and 1 (4%)-infection; grade 3 toxicities were 4 (15%)-neutropenia, 4 (15%)-fatigue, 2 (7%)-neuropathy, 2 (7%)-athralgias, 2 (7%)-stomatitis, 1 (7%)-pleural effusion, and 1 (4%)-hypertension. The overall response rate was 52% [95% confidence interval (95% CI), 32-71%], median response duration was 6.0 months (95% CI, 4.6-6.5 months), and the median progression-free survival was 7.5 months (95% CI, 6.2-8.3 months). In hypothesis-generating univariate and limited multivariate analyses, E-selectin was statistically significantly associated with response to the combination. CONCLUSION: Bevazicumab in combination with weekly docetaxel is active with acceptable toxicities in MBC. Additional studies evaluating E-selectin as a marker of response to bevacizumab-containing chemotherapy are warranted.