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。     

A Multicenter Phase II Study of Docetaxel 60 mg/m2 as First-Line Chemotherapy in Patients with Advanced or Recurrent Breast Cancer

PURPOSE: Docetaxel is an active agent as first-line chemotherapy in patients with advanced breast cancer at a dosage of 100 mg/m2. However, the efficacy of this agent as a first-line drug when used at a lower dosage is unclear. This study was performed to evaluate the clinical efficacy and safety of 60 mg/m2 docetaxel for the treatment of breast cancer. PATIENTS AND METHODS: This study enrolled 23 patients with advanced and/or metastatic breast cancer, who had not been treated with an anthracycline or taxane previously. Treatment with docetaxel was continued in patients showing a response until there was evidence of disease progression or unacceptable toxicity. RESULTS: Among 20 fully evaluated patients, the overall response rate was 50.0% and the median time to progression was 31 weeks. The most commonly observed adverse events were neutropenia (78.2%) and fatigue (60.9%). Fluid retention occurred in only 8.7% of the patients. Adverse events did not cause discontinuation of the treatment. CONCLUSION: Docetaxel achieved good disease control with mild adverse events in first-line treatment at a dosage of 60 mg/m2.     

Combined Targeted Therapies for First-line Treatment of Metastatic Triple Negative Breast Cancer—A Phase II Trial of Weekly Nab-Paclitaxel and Bevacizumab Followed by Maintenance Targeted Therapy With Bevacizumab and Erlotinib

Introduction

Angiogenesis and epidermal growth factor receptor signaling are potential therapeutic targets in triple negative breast cancer (TNBC). We hypothesized that targeting these critical pathways would prolong progression-free survival with first-line therapy for metastatic TNBC.

吉西他滨联合顺铂治疗三阴性和非三阴性乳腺癌的临床疗效及安全性分析

目的 探讨晚期三阴性乳腺癌(TNBC)和非三阴性乳腺癌(non-TNBC)使用吉西他滨联合顺铂治疗的临床疗效及临床安全性.方法 选择晚期乳腺癌患者120例,按照免疫组化表达分为TNBC组(52例)和non-TNBC组(68例).化疗方案为:第1、8天给予静脉滴注吉西他滨1000 mg/m2.顺铂一般80～100 mg/m2,每3周1次;或20 mg/m2,连用5天,每3～4周重复1次.分析2组患者临床病理特征、近期疗效及不良反应.结果 TNBC组有效率为38.5％(20/52),控制率为75.0％ (39/52);non-TNBC组有效率为22.1％ (15/68),控制率为57.4％ (39/68).2组患者有效率和控制率的组间比较均存在统计学差异(P＜0.05);患者无进展生存期的组间比较也存在统计学差异(P＜0.05).吉西他滨联合顺铂化疗方案的不良反应主要为胃肠道反应和血液学毒性,2组患者的不良反应的组间比较无统计学差异(P＞0.05).结论 吉西他滨联合顺铂化疗对TNBC和non-TNBC患者均有效,而TNBC患者的近期疗效优于non-TNBC患者;在不良反应方面TNBC和non-TNBC患者则没有明显差别,2组患者均能对化疗药的毒副作用耐受,其安全性较好.     

Docetaxel-Ifosfamide Combination in Patients with Advanced Breast Cancer Failing Prior Anthracycline- Based Regimens: Results of a Phase I-II Study

Abstract

The established clinical activity of docetaxel and ifosfamide as single agents in anthracycline pre-treated breast cancer, led us to conduct a phase I-II study to define the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and clinical activity of the docetaxel+ifosfamide combination in this setting. Patients with histologically confirmed metastatic breast cancer, after failure on prior anthracycline-based chemotherapy, were treated at successive dose levels (DLs) in cohorts of 3-6 with escalated doses of docetaxel 70-100 mg/m² over 1 h on day 1 followed by ifosfamide 5-6 g/m² divided over days 1+2 (2.5-3.0 g/m²/day over 1 h), every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. Between March 1997 and December 2002, 65 patients with a median age of 57 years (range, 32-72) and performance status (WHO) of 1 (range, 0-2) were treated at 5 DLs as follows; 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 44 were treated at DL4 (total of 50 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 62 for response. DLT (with the addition of G-CSF after DL2) was reached at DL5 with 2/3 initial patients developing febrile neutropenia. Clinical response rates (RRs), on an intention-to-treat basis, in phase II were: 56%; (95% CI, 42.2- 69.7%); 4 CRs, 24 PRs, 10 SD and 12 PD. The median response duration was 7 mo (3-24 mo), median TTP 6.5 mo (0.1-26 mo), and median OS 13 mo (0.1-33 mo). Grade 3/4 toxicities included: neutropenia in 72% of patients, with 60% developing grade 4 neutropenia (≤7 days) and in 10% of these febrile neutropenia, while no grade 3/4 thrombocytopenia was observed. Other toxicities included peripheral neuropathy grade 2 only in 10%, grade 1/2 reversible CNS toxicity in 16%, no renal toxicity, grade 2 myalgias in 8%, grade 3 diarrhea in 8%, skin/nail toxicity in 14%, and grade 2 fluid retention in 2% of patients. One patient in the study treated at phase II died as a result of acute liver failure after the first cycle.

The present phase I-II study has determined the feasibility, defined the MTD and demonstrated the encouraging activity of the docetaxel-ifosfamide combination in the phase II part of the study. Therefore, future randomized phase III studies versus single-agent docetaxel or combinations of the latter with other active agents are warranted.     

Neratinib in Combination With Trastuzumab for the Treatment of Patients With Advanced HER2-positive Breast Cancer: A Phase I/II Study

Background

Despite the availability of several human epidermal growth factor receptor 2 (HER2)-directed treatments, many HER2-positive (HER2⁺) breast cancers eventually progress because of primary or acquired resistance.

Phase II Study of Paclitaxel and Dasatinib in Metastatic Breast Cancer

Background

Overexpression and activation of tyrosine kinase Src has been linked to breast carcinogenesis and bone metastases. We showed the feasibility of combining the SRC inhibitor dasatinib with weekly paclitaxel in patients with metastatic breast cancer (MBC) and herein report the subsequent phase II trial.

中等剂量卡培他滨单药治疗转移性乳腺癌的疗效及安全性

目的观察中等剂量［2 000 mg/(m²·d)］卡培他滨治疗转移性乳腺癌的疗效和不良反应。方法卡培他滨单药治疗43例转移性乳腺癌,2000 mg/(m²·d),d1～14,每3周为1周期。结果43例患者平均行8周期卡培他滨治疗,客观缓解率（CR+PR）为18.6%,临床获益率（CR+PR+SD）为86.0%。整体的中位无进展生存期（PFS）为7.1月（95%CI：5.8～8.4）,在一线治疗、二线治疗和三线及以上治疗亚组中差异无统计学意义,分别为7.1月、6.1月和8.1月（P=0.390）。在蒽环类药物与紫杉类药物治疗均失败的患者中,PFS明显缩短（6.1月 vs.7.1月,P=0.038）。大于65岁的患者PFS显著延长（8.1月 vs.6.1月,P=0.045）。主要不良反应为手足综合征19例（44.2%）。结论中等剂量［2 000 mg/(m²·d)］卡培他滨单药治疗转移性乳腺癌安全、有效。     

国产长春瑞滨联合顺铂治疗转移性乳腺癌的临床观察

目的：观察国产长春瑞滨(盖诺)联合顺铂方案治疗转移性乳腺癌的临床疗效。方法：运用盖诺(25mg／m^2 IV dl，d8)加顺铂(DDP80mg／m^32 IV d1)治疗转移性乳腺癌26例。结果：取得CR3例(11．5％)，PR12例(46．1％)，总有效率RR(CR PR)达57．6％。主要毒副作用为骨髓抑制，胃肠道反应和静脉炎。白细胞减少的发生率100％，其中Ⅲ-Ⅳ度达57．7％。恶心、呕吐的发生率92．3％，Ⅲ-Ⅳ度达11．5％。静脉炎的发生率15．4％。结论：国产长春瑞滨联合顺铂对转移性乳腺癌疗效确切，且毒性可以耐受，可以作为对蒽环类药物治疗后复发，转移乳腺癌患者的二线治疗方案。     

希罗达为主的联合方案治疗蒽环类耐药的复发转移性乳腺癌

目的 探讨希罗达为主的联合化疗方案治疗复发转移性乳腺癌的疗效及毒副反应.方法 42例复发转移性乳腺癌患者中,21例予以希罗达联合诺维本治疗;14例予以希罗达联合多西紫杉醇治疗;7例予以希罗达联合吉西他滨治疗.21 d为1周期,2周期后评价疗效.结果 41例可评价患者中,治疗后完全缓解(CR)8例,部分缓解(PR)16例,稳定(SD)9例,进展(PD)8例,有效率为58.54%.中位疾病进展时间为7.4个月,中位生存时间15.3个月.主要毒副反应为白细胞减少,其中Ⅲ～Ⅳ度占41.46%.结论 希罗达为主的联合化疗方案治疗复发转移性乳腺癌疗效确切,毒性反应可耐受.     

A Phase II Open Label Study of Everolimus in Combination With Endocrine Therapy in Resistant Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer

BackgroundTherapies targeting estrogen receptor signaling are standard for patients with hormone receptor (HR)-positive (HR⁺) metastatic breast cancer (MBC). Dysregulation of the phosphoinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is associated with treatment resistance. Addition of the mTOR inhibitor, everolimus, to exemestane doubled progression-free survival (PFS) in HR⁺/HER2⁻ MBC patients whose disease had previously progressed during endocrine therapy. In this phase II study, we used everolimus in addition to the most recent endocrine therapy during which a patient's disease progressed, in an attempt to restore and extend the benefit of the antiestrogen therapy in patients with HR⁺/HER2⁻ MBC.Patients and MethodsPatients with HR⁺ MBC who progressed on antiestrogen therapy received everolimus (10 mg orally daily) in combination with the antiestrogen therapy most recently administered. Treatment was administered in 4-week cycles and continued until disease progression or unacceptable toxicity. Blood and archival tumor specimens were collected for VeriStrat (Biodesix, Inc) and Foundation One (Foundation Medicine) assays, respectively. Accrual of 42 evaluable patients allowed detection of improvement in median PFS from 2.8 months (expected with hormonal treatment alone) to 5 months (power 80%, α = 5%).ResultsForty-seven patients were enrolled and treated. After a median follow-up of 22.2 months, median PFS was 6.6 months. Secondary efficacy end points included: overall response rate, 6%; clinical benefit rate, 40%; and median overall survival, 21.1 months. No unexpected toxicity was observed. Efficacy could not be correlated with PI3K/AKT/mTOR alterations or VeriStrat (Biodesix, Inc) prognostic signatures.ConclusionAfter progression during antiestrogen therapy, the addition of everolimus, without changing the hormonal therapy, resulted in a median PFS of 6.6 months, suggesting efficacy in patients with HR⁺/HER2⁻ MBC.     

Nab-Paclitaxel/Bevacizumab/Carboplatin Chemotherapy in First-Line Triple Negative Metastatic Breast Cancer

BackgroundTriple negative metastatic breast cancer can be difficult to treat with primarily cytotoxic options. Nab-paclitaxel has demonstrated improved PFS and tolerability compared with standard cremophor-solubilized paclitaxel; based on this, we examined the efficacy and safety of combining weekly nab-paclitaxel with carboplatin and bevacizumab in TNMBC.Patients and MethodsIn this phase II, multicenter trial, patients with first-line TNMBC received nab-paclitaxel (100 mg/m²) and carboplatin (area under the curve = 2) on days 1, 8, 15, and bevacizumab (10 mg/kg) on days 1 and 15 of a 28-day cycle. The primary end point was safety and tolerability and secondary end points included PFS, ORR, and CBR. PFS was calculated using the Kaplan-Meier method.ResultsBetween July 16, 2007, and October 3, 2011, 34 patients were enrolled at 4 centers. Median age was 50.0 (range, 30-76) years and 77% (n = 26) of patients received previous adjuvant therapy. Median PFS was 9.2 months (95% confidence interval [CI], 7.8-25.1 months). The CBR was 94% (95% CI, 80%-99%), and ORR was 85% (95% CI, 69%-95%) for the combination. The regimen was well tolerated with the most common grade 3/4 adverse events being neutropenia (n = 18; 53%) and thrombocytopenia (n = 6; 18%), with other serous events including 1 grade 3 and 1 grade 4 thrombotic event and 1 febrile neutropenia.ConclusionThe combination of nab-paclitaxel, bevacizumab, and carboplatin as first-line treatment for TNMBC was efficacious and well tolerated. The PFS, CBR, and ORR, and tolerability of the regimen, compares favorably with other standard first-line therapies.     

Safety and Efficacy of Crizotinib in Patients With Advanced or Metastatic ROS1-Rearranged Lung Cancer (EUCROSS): A European Phase II Clinical Trial

IntroductionROS1 rearrangements are found in 1% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS).Patients and MethodsThe trial was a multicenter, single-arm phase II trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization). Treatment included 250 mg crizotinib twice daily. The primary endpoint was investigator-assessed objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors, version 1.1). Key secondary endpoints were progression-free survival (PFS), overall survival, efficacy by independent radiologic review, safety, health-related quality of life, and molecular characterization of tumor tissue.ResultsThirty-four patients received treatment. Four patients were excluded from efficacy analysis. Investigator ORR was 70% (95% confidence interval [CI]: 51–85; 21 of 30 patients) and median PFS was 20.0 months (95% CI: 10.1–not reached). Two patients with ROS1 wild-type sequences assessed by DNA sequencing had progression as best response. CD74-ROS1-positive patients had a trend towards a higher ORR and longer median PFS. TP53-co-mutant patients had a significantly shorter median PFS than wild-type patients (7.0 months, 95% CI: 1.7–20.0 versus 24.1 months, 95% CI: 10.1–not reached; p = 0.022). Treatment-related adverse events were documented in 33 of 34 patients (97%).ConclusionsCrizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-co-aberrant patients had a significantly worse outcome compared to TP53 wild-type patients.     

紫杉醇为主的联合化疗治疗晚期乳腺癌的临床研究

目的：评价以紫杉醇为主的联合化疗对晚期乳腺癌患者的疗效和不良反应。方法：对２５ 例晚期或复发的乳腺癌患者行以紫杉醇为主的联合化疗,随机分成两组,Ａ 组：行以紫杉醇与顺铂、鬼臼乙叉甙的联合化疗;Ｂ组：行以紫杉醇与吡喃阿霉素的联合化疗。结果：初治组１０ 例,ＣＲ３ 例,ＰＲ４ 例,总有效率７００ ％ ;复治组１５ 例,ＰＲ６ 例,总有效率４００ ％ 。紫杉醇与顺铂、鬼臼乙叉甙联合化疗及紫杉醇与吡喃阿霉素联合化疗,两组疗效相近,但紫杉醇与吡喃阿霉素联合化疗骨髓抑制及消化道的不良反应相对较轻。结论：紫杉醇为主的联合化疗对晚期乳腺癌应是首选的治疗方法之一     

Phase II Study of S-1 Combined With Low-Dose Docetaxel as Neoadjuvant Chemotherapy for Operable Breast Cancer Patients (N-1 Study)

Background

To improve the pathological complete response (pCR) rate, we devised new neoadjuvant chemotherapy. Efficacy and safety of the oral fluoropyrimidine derivative S-1 (Taiho Pharmaceutical Co, Tokyo, Japan) combined with low-dose docetaxel (S-1+DOC) were evaluated.

国产多西他赛为主的联合化疗治疗转移性乳腺癌

 目的 观察国产多西他赛为主的联合化疗治疗转移性乳腺癌的疗效、毒副反应和临床受益反应（Clinical　benefit　response，CBR），并以进口多西他赛作对照。方法 A组30例转移性乳腺癌患者，既往未采用蒽环类药物治疗的14例采用国产多西他赛联合阿霉素治疗（A1组），既往蒽环类药物治疗失败的16例采用国产多西他赛联合卡培他滨治疗（A2组）；B组25例转移性乳腺癌患者作对照，其中未采用蒽环类药物治疗的11例采用进口多西他赛联合阿霉素治疗（BI组），既往蒽环类药物治疗失败的14例采用进口多西他赛联合卡培他滨治疗（B2组）；3周为1个周期，2周期评价疗效，记录毒副反应。结果 A组有效率（CR＋PR）66．7％，肿瘤控制率（CR＋PR＋SD）93．3％。毒副反应主要为骨髓抑制和脱发，可耐受，无治疗相关性死亡。CBR评价有效者73．3％；B组有效率68％，肿瘤控制率92％。毒副反应与A组相似。CBR评价有效者72％。结论 国产多西他赛为主的联合化疗治疗转移性乳腺癌有较好的疗效，毒副反应可耐受，临床受益反应良好，与进口多西他赛的疗效和不良反应相似。