A Pooled Analysis of Gemcitabine Plus Docetaxel Versus Capecitabine Plus Docetaxel in Metastatic Breast Cancer

Introduction.

In two randomized phase III trials of patients with metastatic breast cancer (MBC), gemcitabine-docetaxel (GD) and capecitabine-docetaxel (CD) had similar efficacy, but distinct safety profiles.

Methods.

Data from two GD versus CD studies were pooled; overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) were determined. Cox proportional hazards models identified prognostic factors associated with improved OS and PFS. Using a multivariate prognostic model incorporating identified adverse prognostic factors, we grouped MBC patients into low-, intermediate-, and high-risk categories. Hazard ratios (HRs) of GD over CD for OS and PFS were determined for subsets of patients.

Results.

Baseline demographics of the pooled population were mostly well balanced. In the pooled population, there were no significant differences between GD versus CD for OS (HR = 1.02; p = .824), PFS (HR = 1.15; p = .079), and ORR (p = .526). In the pooled crossover population, there were trends toward improved OS (HR = 0.82; p = .171) and PFS (HR = 0.93; p = .557) with GD. Several prognostic factors (including prior adjuvant taxane) for improved OS or PFS were identified; however, there were no significant interactions between treatment arms and prognostic factors for PFS or OS, except number of metastatic sites. In the prognostic model, median OS and PFS were numerically lower in the high-risk group versus the intermediate- and low-risk groups.

Conclusion.

This analysis confirms the lack of efficacy difference between GD and CD in the pooled population, crossover population, and almost all subpopulations. Several prognostic factors were associated with improved outcomes in the pooled population.     

卡培他滨维持治疗老年晚期转移性结直肠癌的生存分析

目的 评价卡培他滨维持治疗老年晚期转移性结直肠癌的疗效及安全性。方法 自2007年8月1日—2011年8月1日在辽宁医学院附属第一医院完成一线化疗后达到疾病控制（CR+PR+SD）的老年晚期转移性结直肠癌患者接受两种不同的治疗策略（按患者自己意愿）。治疗组30例,予卡培他滨维持治疗（卡培他滨常规量为1 000 mg/m2,每日2次,连用2周,休息1周,每21天为1周期）;对照组48例,观察直至疾病进展再接受进一步治疗。观察两组患者的疾病进展时间（TTP）、总生存期（OS）及不良反应。结果 维持治疗组和对照组的中位疾病进展时间分别为10.3月、6.5月,差异有统计学意义（P=0.000231）;中位总生存期分别为31.4月、18.4月,差异有统计学意义（P=0.000319）。维持治疗组的主要不良反应为手足综合征、消化道反应、较轻的血液学毒性及肝肾功能损害。结论 卡培他滨维持治疗通过延长老年晚期转移性结直肠癌患者的疾病进展时间和总生存期可使其获益且耐受性良好,值得扩大样本进一步研究。     

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。     

Prognostic Value of the Combination of Circulating Tumor Cells Plus KRAS in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab

ObjectiveCirculating tumor cells (CTCs) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) status were identified as prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer treated with chemotherapy and bevacizumab in analyses of the MACRO (Maintenance Treatment in Advanced Colorectal Cancer) trial. In this post hoc analysis of the MACRO trial, the potential additive effect of these 2 factors on patient outcomes was explored.MethodsA total of 158 of the 480 patients involved in the MACRO trial were included in the biological marker substudy. CTC isolation and enumeration were centralized and performed using the CellSearch System (Veridex LLC, Raritan, NJ) in 7.5 mL of whole blood. Evaluation of KRAS status was performed retrospectively by the standard method used at each center. PFS and OS were analyzed by the Kaplan–Meier method according to CTC count and KRAS status.ResultsPatients with < 3 CTC per 7.5 mL blood at baseline and KRAS wild-type tumors had a median PFS of 14.2 months compared with 6.2 months in patients with ≥ 3 CTCs and KRAS mutated tumors (P < .0001; hazard ratio, 3.0; 95% confidence interval, 1.8-5.2). Similar findings were observed for OS (28.9 and 13.7 months, respectively, P = .0004; hazard ratio 2.8; 95% confidence interval, 1.6-4.9). Multivariate analyses showed that CTC count ≥ 3 and KRAS status were the only independent prognostic factors for both PFS and OS.ConclusionsThis post hoc analysis showed that CTC count and KRAS status were independent prognostic factors for outcomes in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy. These factors should be taken into account in the design of future phase III trials.     

Phase I/II Trial of Vinorelbine and Sorafenib in Metastatic Breast Cancer

PurposeWe investigated the efficacy and toxicity of sorafenib, a multikinase inhibitor of vascular endothelial growth factor receptor tyrosine kinase, in combination with vinorelbine therapy in a phase I/II trial in patients with metastatic breast cancer.Patients and MethodsWe enrolled 11 patients in the phase I portion to determine the maximum tolerated dose (MTD) of the combination, followed by 35 extra patients treated at the MTD in phase II. The median age of patients was 54 years old (range, 31-72 years old). Tumors were estrogen receptor and progesterone receptor (ER/PR) positive in 54% (22/54) of patients, and triple negative (ER⁻, PR⁻, HER2⁻) in 41% (17/54) of patients. Of all patients, 22% received sorafenib and vinorelbine as first-line therapy, 37% as second-line therapy, and 41% as third-line therapy.ResultsIn total, 41 patients were treated at the MTD (6 during phase I; 35 in phase II). The observed 44% 4-month progression-free survival rate was similar to the estimated historical rate of 43% with vinorelbine treatment. The combination was tolerated with expected toxicities. Patients treated at the MTD who had received prior bevacizumab treatment received a median of 1.5 cycles (range, 1-10 cycles) compared with a median of 5 cycles (range, 2-12 cycles) for patients without prior bevacizumab treatment.ConclusionFurther evaluation of vinorelbine and sorafenib in bevacizumab-naive patients may be of interest if specific biomarkers guiding patient selection can be identified.     

First-in-Human Phase 1b Trial of Quinacrine Plus Capecitabine in Patients With Refractory Metastatic Colorectal Cancer

BackgroundQuinacrine plus a fluoropyrimidine has in vivo efficacy against metastatic colorectal cancer (mCRC). This phase 1b trial evaluated the combination of quinacrine plus capecitabine in patients with treatment-refractory mCRC.Patients and MethodsUsing a modified Simon accelerated titration design, adults with treatment-refractory mCRC were treated with capecitabine 1000 mg/m² twice daily for 14/21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg twice daily, and 200 mg twice daily for 21 days. The primary endpoint was identifying the maximum tolerated dose, determining tolerability and safety. In an expansion cohort, it was overall response rate and time to tumor progression (TTP).ResultsTen patients (median age of 60 years) were treated in phase 1b. The first 2 quinacrine dosing levels were well tolerated. Dose-limiting toxicities were seen in 3 patients treated with quinacrine 200 mg twice daily. Five additional patients tolerated quinacrine 100 mg twice daily without further dose-limiting toxicities, thus establishing the maximum tolerated dose. Seven additional expansion-cohort patients enrolled onto the study before quinacrine manufacturing ceased within the United States. Five patients experienced stable disease, 1 partial response, and 10 disease progression. Median TTP overall was 2.12 months and median overall survival 5.22 months for the 17 patients.ConclusionCapecitabine and quinacrine can be safely administered at the maximum tolerated dose of capecitabine 1000 mg/m² by mouth twice daily on days 1-14 and quinacrine 100 mg by mouth twice daily on days 1-21 of a 21-day cycle in mCRC patients. Although the expansion study was halted early, TTP was in line with other studies of refractory mCRC, suggesting activity of this regimen in heavily pretreated patients.     

Sorafenib Plus Irinotecan Combination in Patients With RAS-mutated Metastatic Colorectal Cancer Refractory To Standard Combined Chemotherapies: A Multicenter,Randomized Phase 2 Trial (NEXIRI-2/PRODIGE 27)

BackgroundNo treatment option was available for patients with RAS-mutated (RASmt) metastatic colorectal cancer (mCRC) who progress after standard combined chemotherapies at the time of the study. After promising results in phase II, the aim of the present NEXIRI-2/PRODIGE 27 trial was to assess the 2-month non-progression rate for sorafenib (NEX) plus irinotecan (IRI), that is, NEXIRI, treatment.MethodsPatients with RASmt mCRC after failure of oxaliplatin, IRI, fluoropyrimidines, and bevacizumab were randomized between NEXIRI (IRI 120-180 mg/m² intravenous, D1 = D15 plus oral NEX 400 mg twice a day) versus IRI (180 mg/m²) versus NEX. Primary endpoint was the 2-month non-progression rate. Secondary endpoints included progression-free and overall survival (PFS and OS), safety, and germline cyclin D1 (CCND1) rs9344 polymorphisms analyses.ResultsA total of 173 patients were included, 59 in NEXIRI, 57 in IRI, and 57 in NEX arms. The 2-month non-progression rate was 52.6% (95% confidence interval [CI]: 39%–66%), 21.4% (10%–33%), and 19.3% (9%–30%) for NEXIRI, IRI, and NEX. Median PFS was 3.6 (95% CI: 2–4.2), 1.7 (1.7–1.8), and 2 (1.8–2.3) months and the median OS was 7.2 (5.8–9.4), 6.3 (4.8–8), and 5.6 (3.9–7.7) months for NEXIRI, IRI, and NEX, respectively. For NEXIRI rs9344CCND1 A/A genotype patients, OS was 19.6 months (95% CI: 4.8–not reached). Main grade 3 toxicities included neutropenia, febrile neutropenia, diarrhea, hand-foot syndrome, and hypertension.ConclusionsIn patients with RASmt mCRC who progressed after standard combined chemotherapies, the results of 2-month non-progression rate and median PFS in the NEXIRI arm were in favor of an increase of the time before progression.     

A Pilot Study of Apatinib as Third-Line Treatment in Patients With Heavily Treated Metastatic Colorectal Cancer

Background

Antiangiogenic therapy has shown improved clinical outcome in metastatic colorectal cancer (mCRC). After the failure of standard treatments, regorafenib and TAS-102 would be recommended for patients with mCRC, however, they have not been approved in China during this study period.

Haematologic Parameters in Metastatic Colorectal Cancer Patients Treated with Capecitabine Combination Therapy

Background: The standard treatment in the metastatic colorectal cancer consists of 5-FU based infusionalregimens. However, with oral fluoropyrimidines, equal tumor responses may be obtained. Capecitabine causesmacrocytosis of the cells by inhibition of DNA synthesis. In this context, a relationship was found between meancorpuscular volume (MCV) and response to therapy in breast cancer patients treated with Capecitabine, butwhether this relationship also pertains in colorectal cancer has not been established. Materials and Methods: Atotal of 102 metastatic colorectal cancer patients treated with a oxaliplatin (XELOX)±Bevacizumab combinationwere retrospectively evaluated. Patients were randomized into three groups. Hematological parameters (MCV,MPV, PCT, PLT, NLR) were recorded retrospectively, before treatment and after 3 cycles of chemotherapy.Results: After three cycles of therapy, 20 (19.6%) patients had progressive disease (PD), 41 (40.1%) hadstable disease (SD), and 41 (40.1%) demonstrated a partial response (PR). In 62 (60.7%) treatment was withcapesitabin plus XELOX therapy, and in 40 (39.2%) it was XELOX-Bevacizumab combination therapy. Therewas no difference among three groups before the treatment in terms of MCV, MPV, PCT, PLT, and NLR.MCV showed significant increase in chemotherapy response groups (PR and SD). In addition, a significantdecrease was observed for platelet count in chemotherapy response groups. While NLR decrease was seen inonly a PR group, PCT decrease was observed in all three groups. PCT and PLT values were higher in patientsreceiving Bevacizumab. Conclusions: PLT, PCT, MPV, and NLR values were decreased due to Capecitabinebasedchemotherapy, however MCV was increased. PCT and PLT values were higher in patients who receivedBevacizumab than those who did not. MCV, PLT, and NLR can be considered as important factors in predictingresponse to colorectal carcinoma treatment.     

Capecitabine maintenance therapy after first-line chemotherapy in patients with metastatic colorectal cancer

Objective  

To evaluate the efficacy and toxicity of capecitabine maintenance therapy in metastatic colorectal cancer (mCRC) patients.     

多西紫杉醇联合卡培他滨治疗转移性乳腺癌的疗效分析

目的探讨多西紫杉醇联合卡培他滨（DC方案）治疗转移性乳腺癌的临床疗效。方法选择79例转移性乳腺癌患者,均采用DC方案化疗,然后评价患者的临床疗效及不良反应。结果79例患者在本研究中共完成300个化疗周期,中位化疗周期数3．8个。总有效率为50．6％,其中CR3例（3．8％）。化疗主要不良反应有乏力、骨髓抑制、手足综合征、胃肠道反应、口腔黏膜炎等。65例患者出现中性粒细胞下降,其中5例达Ⅳ度骨髓抑制。中位随访时间为10．5个月,中位无进展生存期（progression—free survival,PFS）为5．8个月。结论多西紫杉醇联合卡培他滨方案治疗转移性乳腺癌的有效率高,疗效肯定,不良反应可以耐受,是治疗转移性乳腺癌的有效方案。     

S-1与卡培他滨或氟尿嘧啶治疗晚期结直肠癌的疗效对比Meta分析

目的 利用现有文献资料,对S-1与卡培他滨或氟尿嘧啶治疗晚期结直肠癌的治疗数据进行对比荟萃分析,以此论证S-1替代卡培他滨或氟尿嘧啶的可行性。方法 在PubMed、Cochrane Library、Embase、CNKI数据库中检索已发表的文献,在临床试验中心（https://www.clinicaltrials.gov/）中搜寻符合要求的对照试验。资料的提取和质量评价是依据Cochrane Handbook 5.1.0,并使用RevMan 5.3软件对相关病例对照研究进行Meta分析。结果 来自11项随机对照研究的3 462名患者的数据纳入分析。与卡培他滨或氟尿嘧啶方案相比,S-1治疗组的OS得到改善,但PFS、DCR、ORR并不具有统计学意义。在不良反应中,S-1组的腹泻、肾功能不全和手足综合征的发生率较对照组低。但在合理的对比剂量下S-1组血小板降低的发生率高于对照组。结论 晚期结直肠癌的治疗中,S-1替换常规化疗方案中的卡培他滨或氟尿嘧啶有一定的疗效优势。     

RAS突变型转移性结直肠癌的精准治疗

转移性结直肠癌(mCRC)是一种异质性疾病,临床表现和分子分型差异大.目前,mCRC在治疗前需要常规行大鼠肉瘤病毒(RAS)基因检测.RAS突变状态与患者预后显著相关并能预测抗表皮生长因子受体(EGFR)治疗的疗效,然而仍缺乏针对RAS靶点的特异性治疗手段.既往研究表明直接抑制RAS蛋白带来的临床获益非常有限,最近报道...