Gemcitabine Alone or in Combination with Cisplatin for AdvancedBiliary Tract Carcinomas: an Overview of Clinical Evidence

Background and Objective: There has been no universally agreed standard chemotherapy regimen for patientswith advanced biliary tract carcinomas (BTC). We aimed to fully display and evaluate the clinical evidencefor gemcitabine or gemcitabine-cisplatin combination for advanced BTC. Methods: Systematic searches wereperformed to identify relevant randomized controlled trials (RCTs) and uncontrolled trials. Overall survival(OS), progression-free survival (PFS), overall response rates (ORR), tumor control rates (TCR), and toxicitywere evaluated. Evidence levels of the results were evaluated with the Grading of Recommendations Assessment,Development and Evaluation (GRADE) approach. Results: Results of the eleven gemcitabine-cisplatin trialsand ten gemcitabine trials showed both chemotherapy regimens had benefits with reference to mean OS (8.63vs. 8.79 months), mean PFS (4.86 vs. 4.72 months), pooled ORR (25.3% vs. 19.6%) and TCR (55.2% vs. 53.1%).Two RCTs showed the gemcitabine-cisplatin combination to prolong the mean PFS (mean difference [MD] 2.57,95%CI 1.69 3.45), substantially increasing the mean OS (MD 3.59, 95% CI 3.48 3.71), and producing a similareffect in ORR (risk ratio [RR] 1.59, 95%CI 1.04 2.43), increasing TCR (RR 1.15, 95%CI 1.02 1.31) comparedwith gemcitabine alone, with generally manageable grade 3 or 4 adverse events. The evidence level of OS wasmoderate, and other outcomes (ORR, PFS, TCR, anaemia, neutropenia) were at low evidence levels. Conclusion:Available evidence was limited with low quality, which showed that both gemcitabine-cisplatin and gemcitabinealone had clinical activity with acceptable safety profiles, and gemcitabine-cisplatin appeared to be more usefulfor advanced BTC patients than gemcitabine alone.     

Current standards and future perspectives in adjuvant treatment for biliary tract cancers

Biliary tract cancer, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC) are rare tumours with a rising incidence. Prognosis is poor, since most patients are diagnosed with advanced disease. Only ~20% of patients are diagnosed with early-stage disease, suitable for curative surgery. Despite surgery performed with potentially-curative intent, relapse rates are high, with around 60–70% of patients expected to have disease recurrence. Most relapses occur in the form of distant metastases, with a predominance of liver spread. In view of high tumour recurrence, adjuvant strategies have been explored for many years, in the form of radiotherapy, chemo-radiotherapy and chemotherapy. Historically, few randomised trials were available, which included a variety of additional tumours (e.g. pancreatic and ampullary tumours); most evidence relied on phase II and retrospective studies, with no high-quality evidence available to define the real benefit derived from adjuvant strategies.Since 2017, three randomised phase III clinical trials have been reported; all recruited patients with resected biliary tract cancer (CCA and GBC) who were randomised to observation alone, or chemotherapy in the form of gemcitabine (BCAT study; included patients diagnosed with extrahepatic CCA only), gemcitabine and oxaliplatin (PRODIGE-12/ACCORD-18; included patients diagnosed with CCA and GBC) or capecitabine (BILCAP; included patients diagnosed with CCA and GBC). While gemcitabine-based chemotherapy failed to show an impact on patient outcome (relapse-free survival (RFS) or overall survival (OS)), the BILCAP study showed a benefit from adjuvant capecitabine in terms of OS (pre-planned sensitivity analysis in the intention-to-treat population and in the per-protocol analysis), with confirmed benefit in terms of RFS. Based on the BILCAP trial, international guidelines recommend adjuvant capecitabine for a period of six months following potentially curative resection of CCA as the current standard of care for resected CCA and GBC. However, BILCAP failed to show OS benefit in the intention-to-treat (non-sensitivity analysis) population (primary end-point), and this finding, as well as some inconsistencies between studies has been criticised and has led to confusion in the biliary tract cancer medical community.This review summarises the adjuvant field in biliary tract cancer, with evidence before and after 2017, and comparison between the latest randomised phase III studies. Potential explanations are presented for differential findings, and future steps are explored.     

GEMOX方案联合重组人血管内皮抑素一线治疗晚期胆系肿瘤的初步观察

目的 观察吉西他滨（GEM）、奥沙利铂（OXA）联合重组人血管内皮抑素（恩度）一线治疗晚期胆系肿瘤（BTCs）的疗效及安全性。方法 回顾性分析2009年1月至2013年8月ⅣB期BTCs患者 48例,分为联合组（n=20）和单纯化疗组（n=28）。联合组：吉西他滨1000mg／m2静滴,d1、d8;奥沙利铂 100mg／m2 静滴 d2,3周为1周期;恩度 15mg 静滴 d1～d14,3周为1周期。单纯化疗组仅给予GEMOX方案化疗,剂量与使用方法同联合组。2个周期后按照RECIST11标准评价近期疗效,参考KPS变化评价生活质量（QoL）,根据NCI CTC30标准评价不良反应,并观察疾病进展时间（TTP）和总生存时间（OS）。结果 联合组获CR 1例、PR 3例、SD 12例、PD 4例,有效率（RR）为200％,疾病控制率（DCR）为80.0％;中位TTP为8.6个月,中位OS为14.0个月;QoL改善稳定率为80.0％。单纯化疗组获CR 1例、PR 5例、SD 15例、PD 7例,RR 为21.5％,DCR 为75.0％;中位TTP为 6.0个月,中位OS 为10.0个月; QoL改善稳定率为71.4％。两组中位TTP和OS的差异有统计学意义（P＜0.05）。两组最常见的不良反应为骨髓抑制,其他不良反应包括恶心呕吐、肝功能损害、外周神经炎、皮肤过敏反应等,以1～2级为主,两组比较差异无统计学意义（P＞0.05）。化疗联合恩度组仅2例出现心电图T波改变,1例出现房性早搏,1例出现轻度血压升高。结论 GEMOX联合恩度方案一线治疗转移性BTCs疗效较好,可以改善或稳定QoL,延长生存时间,且耐受性较好,值得临床推广使用和进一步深入观察。     

GEMOX对比GX方案一线治疗晚期转移性胆系肿瘤的临床观察

目的观察吉西他滨联合奥沙利铂方案（GEMOX组）或希罗达（GX组）方案一线治疗晚期转移性胆系肿瘤（BTCs）的有效性及安全性。方法回顾性分析经病理及影像学检查确诊为原发性胆系肿瘤Ⅳ期的61例患者。其中,GEMOX方案为一线治疗的31例,GX方案为一线治疗的30例。GEMOX组：吉西他滨1 000 mg/m2静脉滴注d1、8,奥沙利铂 100 mg/m²静脉滴注d2。GX组：吉西他滨1 000 mg/m2静脉滴注d1、8;希罗达片1 250 mg/ m² ,口服 2次/日 d1~14。两方案均21天为一周期。至少完成2周期化疗的患者进行疗效、不良反应评价,并分析生存情况。结果GEMOX组完全缓解（CR）2例、部分缓解（PR）6例、稳定（SD）15例,有效率（RR）为25.8％,疾病控制率（DCR）74.2%,中位疾病进展时间（mTTP）6.5月,中位总生存期（mOS）12月;GX方案组CR 1例、PR 5例、SD 16例,RR 20.0％,DCR 73.3%,mTTP为 6月,mOS 为10月。两组的RR、DCR、mTTP、mOS差异均无统计学意义（P>0.05）。两组Ⅲ度白细胞减少分别为6.5% vs. 6.7%,Ⅲ度血小板减少分别为6.5% vs. 3.3%,两组比较差异无统计学意义（P>0.05）。而外周神经炎以GEMOX组显著,手足综合征仅见于GX组。结论GEMOX和GX方案均可作为一线治疗晚期转移性BTCs的推荐方案,两组不良反应均较轻,耐受性好,具体实施应根据患者个体耐受情况及药物毒性进行选择。     

Platinum-based chemotherapy in metastatic breast cancer: current status

Cisplatin and carboplatin are active in previously untreated patients with metastatic breast cancer (MBC) with mean response rates (RRs) of 50 and 32%, respectively. In pretreated patients the RR to cisplatin/carboplatin monotherapy declines markedly to <10%. Cisplatin and carboplatin have been combined with many other cytotoxics. In first-line setting high activity has been observed in combination with taxanes or vinorelbine (RRs consistently approximately 60%). It appears that these newer combinations are superior to older regimens with etoposide (RRs 30 to 50%) or 5-fluorouracil (RRs 40 to 60%). Cisplatin-/carboplatin-based regimens with infusional 5-FU and epirubicin/paclitaxel/vinorelbine achieve high RRs of around 60 to 80%. However these regimens are difficult to administer in all patients because they require central venous access for continuous 5-FU infusion. In pretreated MBC the combinations of cisplatin-taxane/vinorelbine/gemcitabine or carboplatin-docetaxel/vinorelbine yield RRs of 40 to 50%, which are higher than those achieved with platinum-etoposide/5-FU. In locally advanced disease cisplatin-based regimens achieve very high RRs (>80%). This would suggest that in chemotherapy-na?ve patients platinum-based therapy might have an important role to play. Additionally the synergy demonstrated between platinum compounds, taxanes and herceptin, in preclinical and clinical studies is of immense importance and the results of the two ongoing Breast Cancer International Research Group randomized phase III studies are eagerly awaited. These studies may help clarify the role of platinum compounds in the treatment of metastatic and possibly early breast cancer.     

吉西他滨固定剂量率或标准输注联合奥沙利铂方案治疗进展期胆管癌随机对照研究

  目的  探讨奥沙利铂分别与吉西他滨固定剂量率输注、常规输注联合方案对进展期胆管癌化疗疗效、不良反应及其对患者生存时间的影响。  方法  2010年1月至2012年12月南京医科大学附属淮安第一医院病理确诊的93例初治、无手术指征进展期胆管癌和术后复发或转移性胆管癌患者,随机分为研究组（47例）和对照组（46例）。研究组采用吉西他滨固定剂量率即10 mg/（m2·min）输注联合奥沙利铂;对照组采用吉西他滨标准输注（30 min）联合奥沙利铂方案化疗,每21 d重复,每例患者完成至少2个周期化疗,并进行随访。治疗结束后对2组疗效、不良反应进行评价。  结果  治疗前2组患者临床特征具有均衡性（P > 0.05）。客观缓解率、临床获益率研究组高于对照组,差异均有统计学意义（P < 0.05）;研究组的生存时间OS、肿瘤进展时间TTP较对照组明显延长,差异均有统计学意义（P < 0.05）。不良反应主要为血液学毒性,尤其Ⅲ~Ⅳ度白细胞、血小板减少发生率研究组明显高于对照组（P < 0.05）;而非血液学不良反应发生率2组相近（P > 0.05）。  结论  以吉西他滨固定剂量率输注联合奥沙利铂方案治疗进展期胆管癌,方法可行,具有较高的客观缓解效率,延长了OS及TTP;非血液学不良反应发生率较低,患者耐受性较好;但其血液学毒性较为显著,需引起足够重视,值得进一步研究其临床应用价值。      

PGC方案诱导化疗后同步放化疗治疗Ⅲ~ⅣA期鼻咽癌的Ⅱ期单中心前瞻性临床研究

目的 评价脂质体紫杉醇、吉西他滨、卡铂三药联合的诱导化疗（PGC方案）序贯同步放化疗治疗中晚期鼻咽癌患者的疗效及不良反应。方法 对初治Ⅲ~ⅣA期33例鼻咽癌患者, 给予2周期PGC方案新辅助化疗,序贯同步放化疗。诱导化疗方案：脂质体紫杉醇135 mg/m2+吉西他滨1 000 mg/m2+卡铂,血药浓度-时间曲线下面积（area under the curve,AUC）取5,第一天给药,每三周一次。第7周开始调强放射治疗同步化疗,卡铂AUC=5, 每三周一次。结果 在PGC诱导化疗两周期后评价：7例（21%）完全缓解（CR）,21例（64%）部分缓解（PR）,4例（12%）稳定（SD）,1例（3%）进展（多发性肺转移）。放疗完成3月后评价,28（85%）例CR、4（12%）例PR、1例（3% ）PD。1年总生存率100%,1年无病生存率91%。主要不良反应包括白细胞下降,血小板减少反应,肝功能损害,均可逆转。结论 PGC三药方案诱导化疗序贯同步放化疗治疗Ⅲ~ⅣA期鼻咽癌疗效较好,不良反应可耐受。     

含吉西他滨方案和CHOP样方案一线治疗结外NK/T细胞淋巴瘤效果观察

目的 比较含吉西他滨的联合方案和CHOP样联合方案一线治疗结外NK/T细胞淋巴瘤的效果及安全性.方法 回顾性分析河南省人民医院2012年3月至2017年3月39例初治结外NK/T细胞淋巴瘤患者,其中11例采用含吉西他滨联合方案,28例采用CHOP样联合方案.比较两组的完全缓解(CR)率、部分缓解(PR)率、总反应率(ORR)、总生存(OS)率、无进展生存(PFS)率及不良反应.结果吉西他滨组CR 5例,PR 3例;CHOP样组CR 8例,PR 5例;两组CR率和ORR比较,差异均无统计学意义(P=0.453,P=0.073);两组预计3年OS率(75%比33%)、3年PFS率(70%比29%)比较,差异均有统计学意义(χ2=5.606,P=0.018;χ2=3.924,P=0.048).单因素分析结果显示,治疗方案(P=0.018)、乳酸脱氢酶(LDH)升高(P=0.007)影响患者生存预后(均P<0.05).多因素分析结果显示,LDH升高增加患者的死亡风险(RR=6.331,95%CI2.339~17.136,P<0.001),采用含吉西他滨方案治疗降低患者的死亡风险(RR=0.101,95%CI0.023~0.452,P=0.003).不良反应多为1~2级,患者耐受性良好.结论 含吉西他滨联合方案较CHOP样联合方案可延长结外NK/T细胞淋巴瘤患者的生存时间,提高远期疗效.     

Taxanes with anthracyclines as first-line chemotherapy for metastatic breast carcinoma

BACKGROUND: The magnitude of the benefit of adding taxanes to anthracyclines in first-line chemotherapy for metastatic breast carcinoma is still unclear. The authors performed a pooled analysis as well as a meta-analysis of all Phase III trials, to determine whether the combination of anthracyclines plus taxanes provided an advantage over standard anthracyclines-based regimens. METHODS: All Phase III peer-reviewed published or presented trials were considered eligible. A pooled analysis (Method A) and a literature-based meta-analysis (Method B) were accomplished, and event-based relative risk ratios (RR(A-B)) with 95% confidence intervals were derived. Both analyses were performed to examine for significant differences in time to disease progression (TTP), overall response rate (ORR), overall survival (OS), complete response rate (CR), neutropenia, and febrile neutropenia (FN). For both analyses, a heterogeneity test was applied. RESULTS: Seven trials (2805 patients) were gathered. When data were pooled and plotted, significant differences in favor of taxanes were seen for ORR (RR(A-B) 1.21, P<0.001), CR (RR(A) 2.04; RR(B) 1.81, P<0.001), even though they caused a significant increase in neutropenia (RR(A) 1.19; RR(B) 1.15, P<0.001) and FN (RR(A) 2.82; RR(B) 3.44, P<0.001). A borderline significance in favor of taxanes was seen in TTP (RR(A) 1.10, P=0.05; RR(B) 1.06, P=0.07). A nonsignificant trend for taxanes was found in OS. No significant heterogeneity (except for neutropenia, P<0.01) was observed. CONCLUSIONS: The adjunction of taxanes to anthracyclines in first-line chemotherapy for metastatic breast carcinoma yielded a significant benefit in activity (ORR, CR), a slight advantage in TTP, and a trend in OS, although with a significant cost in hematologic toxicity.     

Bevacizumab in combination with different platinum‐based doublets in the first‐line treatment for advanced nonsquamous non‐small‐cell lung cancer: A network meta‐analysis

Platinum‐based doublet chemotherapy with or without bevacizumab is the standard treatment for untreated advanced nonsquamous non‐small‐cell lung cancer (NS‐NSCLC). However, adding bevacizumab to chemotherapies other than paclitaxel–carboplatin is, though widely applied clinically, largely unjustified due to the lack of head‐to‐head data. We performed a Bayesian network meta‐analysis (NMA) to address this important issue. Data of 8,548 patients from 18 randomized controlled trials (RCTs) receiving six treatments, including taxane–platinum (Taxane–Pt), gemcitabine–platinum (Gem–Pt), pemetrexed–platinum (Pem–Pt), taxane–platinum + bevacizumab (Taxane–Pt + B), gemcitabine–platinum + bevacizumab (Gem–Pt + B) and pemetrexed–platinum + bevacizumab (Pem–Pt + B), were incorporated into the analyses. Direct and indirect evidence of overall survival (OS) and progression‐free survival (PFS) were synthesized at the hazard ratio (HR) scale and evidence of objective response rate (ORR) and serious adverse events (SAE) were synthesized at the odds ratio (OR) scale. Taxane–Pt + B showed significant advantages in OS (HR = 0.79, p < 0.001), PFS (HR = 0.54, p < 0.001) and ORR (OR = 2.7, p < 0.001) over Taxane–Pt with comparable tolerability (OR = 3.1, p = 0.08). Gem–Pt + B showed no OS benefit compared to any other treatment. No significant differences were detected between Pem–Pt + B and Pem–Pt in four outcomes. In terms of the benefit‐risk ratio, Pem–Pt and Taxane–Pt + B were ranked the first and second, respectively. In conclusion, in the first‐line treatment for advanced NS‐NSCLC, Taxane–Pt and Gem–Pt are the most and least preferable regimens to be used with bevacizumab, respectively. Adding bevacizumab to Pem–Pt remains unjustified because it fails to improve efficacy or tolerability. In terms of the benefit‐risk ratio, Pem–Pt and Taxane–Pt + B are the best and second‐best treatment for this population.     

Phase II trial of docetaxel and oxaliplatin in patients with advanced gastric cancer and/or adenocarcinoma of the gastroesophageal junction.

BACKGROUND: Platinum-based chemotherapy is the standard treatment for advanced gastric cancer (GC). This trial explored the efficacy and tolerability of combined docetaxel (Taxotere) + oxaliplatin (DOCOX) in GC patients. PATIENTS AND METHODS: Patients with untreated stage IV GC or adenocarcinoma of the gastroesophageal junction (AGEJ) received docetaxel 60 mg/m(2) followed by oxaliplatin 130 mg/m(2) on day 1 of each 21-day cycle until progression or unacceptable toxicity. The primary end points were response rate (RR), toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Baseline characteristics (N = 71): median age 59 years, 72% male, 51% esophagogastric junction cancer, and Eastern Cooperative Oncology Group performance status of zero, one, two were 42%, 51%, 7%, respectively. The median number of cycles was 6 (range, 1-19). Grades 3-4 toxic effects: neutropenia (70%); vomiting (17%); nausea (16%); dehydration, fatigue, or diarrhea (13%, each); and thrombocytopenia or febrile neutropenia (7%, each). Sixty-six patients completed >/=2 cycles. The RR was 36% with 25 partial response (PR) and no complete responses (CRs); stable disease (SD) was 49%. Clinical benefit rate (CBR = CR + PR + SD >/=6 months) was 40%; median PFS was 4.3 months, and OS was 8.5 months. CONCLUSIONS: DOCOX produced manageable toxicity in patients with advanced GC and AGEJ. The confirmed RR of 36%, CBR of 40%, and median survival of 8.5 months are encouraging and comparable to standard front-line regimens.     

吉西他滨联合顺铂治疗晚期非小细胞肺癌的临床研究

目的评价吉西他滨(gemcitabine)联合顺铂治疗晚期非小细胞肺癌的疗效及毒副反应。方法选择经病理证实的晚期非小细胞肺癌41例住院患者采用GP方案行静脉化疗，具体为Gemcitabine 1250mg/m^2d1、d8，DDP30mg/m^2d1-d3，21天重复，至少使用2周期以上。结果完全缓解(CR)4．9％(2／41)，部分缓解(PR)43．9％(18／41)，稳定(SD)34．1％(14／41)，进展(PD)17．00k，(7／41)，总有效率(RR)48．80%；肿瘤控制率(CR PR SD)为82．19％；中位缓解期7．1m，中位生存期11m(4．5～20m)；毒副反应以白细胞及血小板下降、消化道反应、乏力为常见，均可耐受，无化疗相关死亡。结论吉西他滨联合顺铂对晚期非小细胞肺癌有较好疗效，毒副反应可以耐受，值得临床推广。     

尼妥珠单抗联合化疗治疗转移性鼻咽癌的研究

目的观察尼妥珠单抗联合吉西他滨治疗晚期转移性鼻咽癌的近期疗效和不良反应。方法 13例既往接受过多方案化疗的晚期转移性鼻咽癌患者,接受尼妥珠单抗每周200 mg,静脉滴注;吉西他滨1 000 mg/m2,静脉滴注,d1、d8,每3周重复,每2周期评价疗效。结果 全组13例中,CR 2例(15.2%）,PR 6例(46.2%）,CR+PR 61.5%,1年生存率76.9%。不良反应主要为Ⅰ~Ⅱ度骨髓抑制。结论 尼妥珠单抗联合吉西他滨方案治疗晚期转移性鼻咽癌的近期疗效确切,耐受性好。     

吉西他滨联合卡培他滨或替吉奥治疗蒽环类和紫杉类耐药的晚期乳腺癌的临床观察

目的:比较吉西他滨联合卡培他滨或替吉奥治疗蒽环类和紫杉类耐药的晚期乳腺癌的疗效及不良反应。方法:蒽环类和紫杉类耐药的晚期乳腺癌患者90例,随机分为吉西他滨联合卡培他滨组（GX组）和吉西他滨联合替吉奥组（GS组）各45例。GX组患者的具体方案为:吉西他滨1 000 mg/m2静脉滴注,d1、8,卡培他滨1 000 mg/m2口服,每日两次,d1~14;GS组患者的具体方案为:吉西他滨1 000 mg/m2静脉滴注,d1、8,替吉奥60 mg（体表面积≥1.5 m2）,50 mg（1.25 m2<体表面积<1.5 m2）,40 mg（体表面积≤1.25 m2）,每日两次口服,d1~14。所有患者21天为1个治疗周期,治疗2个周期后评价近期疗效,每周期评价不良反应。结果:90例患者均可评价疗效。其中GX组45例患者中CR 4例,PR 18例,SD 17例,PD 6例,有效率(RR)和疾病控制率（DCR）分别为48.9%和86.7%;GS组45例患者中CR 4例,PR 19例,SD 15例,PD 7例,有效率(RR)和疾病控制率（DCR）分别为51.1%和84.4%。两组患者的RR和DCR相比差异无统计学意义（P>0.05）。GX组患者的中位疾病进展时间为8.1个月,与GS组患者（7.7个月）比较,差异无统计学意义（P>0.05）;GX组患者的中位生存时间为31.5个月,与GS组患者（29.8个月）比较,差异无统计学意义（P>0.05）;GX组患者的1年生存率为82.2%,与GS组患者（77.7%）比较,差异无统计学意义（P>0.05）;GX组患者的2年生存率为68.9%,与GS组患者（64.4%）比较,差异无统计学意义（P>0.05）。两组的主要不良反应为骨髓抑制和消化道反应,以Ⅰ-Ⅱ度为主,均可耐受。GX组患者手足综合征的发生率高于GS组,差异有统计学意义（P<0.05）。结论:吉西他滨联合卡培他滨或替吉奥治疗蒽环类和紫杉类耐药的晚期乳腺癌患者的近远期疗效相当,不良反应较轻且均可耐受,吉西他滨联合替吉奥方案的手足综合征发生率较低,两种方案均值得临床进一步研究。     

βV-tubulin expression is associated with outcome following taxane-based chemotherapy in non-small cell lung cancer

Background:Tubulin-binding agents (TBAs) are effective in non-small cell lung cancer (NSCLC) treatment. Both βIII- and βV-tubulins are expressed by cancer cells and may lead to resistance against TBAs.Methods:Pre-treatment samples from 65 locally advanced or oligometastatic NSCLC patients, who underwent uniform induction chemotherapy with paclitaxel and platinum followed by radiochemotherapy with vinorelbine and platinum were retrospectively analysed by immunohistochemistry. Protein expression of βIII- and βV-tubulin was morphometrically quantified.Results:Median pre-treatment H-score for βIII-tubulin was 110 (range: 0-290), and 160 for βV-tubulin (range: 0-290). Low βIII-tubulin expression was associated with improved overall survival (OS) (P=0.0127, hazard ratio (HR): 0.328). An association between high βV-tubulin expression and prolonged progression-free survival (PFS, median 19.2 vs 9.4 months in high vs low expressors; P=0.0315, HR: 1.899) was found. Further, high βV-tubulin expression was associated with objective response (median H-score 172.5 for CR+PR vs 120 for SD+PD patients, P=0.0104) or disease control following induction chemotherapy (170 for CR+PR+SD vs 100 for PD patients, P=0.0081), but not radiochemotherapy.Conclusion:Expression of βV-tubulin was associated with treatment response and PFS following paclitaxel-based chemotherapy of locally advanced and oligometastatic NSCLC patients. Prolonged OS was associated with low levels of βIII-tubulin. Prospective evaluation of βIII/βV-tubulin expression in NSCLC is warranted.     

Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy

Background

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that responds poorly to chemotherapy. Although treatment with pemetrexed in combination with cisplatin serves as first-line chemotherapy for MPM, the optimal second-line and beyond therapy has not yet been fully examined.

Methods

Between March 2008 and October 2011, 17 consecutive Japanese patients pretreated with at least one regimen of platinum plus pemetrexed chemotherapy received gemcitabine and vinorelbine. Responses, survival time, and toxicity were retrospectively evaluated.

Results

Response [partial response (PR) + complete response (CR)] and disease control [stable disease (SD) + PR + CR] rates were 18 and 82 %, respectively. The median progression-free survival (PFS) after combination chemotherapy was 6.0 months, whereas the median overall survival (OS) was 11.2 months. Grade 3 or 4 neutropenia and anemia were observed in 41 and 29 % of patients, respectively, and one patient experienced febrile neutropenia. Grade 3 or 4 nonhematologic toxicities included constipation (6 %) and phlebitis (6 %).

Conclusion

Combination chemotherapy using gemcitabine with vinorelbine was shown to have moderate activity in Japanese MPM patients pretreated with platinum plus pemetrexed chemotherapy. A further multicenter phase II trial is warranted to confirm the efficacy and safety of this combination treatment.     

Systemic therapy for metastatic pancreatic adenocarcinoma

Systemic treatment of metastatic pancreatic adenocarcinoma achieves only modest benefits, with evidence indicating a survival advantage with 5-fluorouracil (5-FU) over best supportive care alone, and further advantage of single-agent gemcitabine over 5-FU. There are very few regimens better than single-agent gemcitabine despite multiple trials of cytotoxic and targeted agents. The addition of a platinum agent has improved response rate but not survival. The addition of erlotinib has improved survival but only by a small margin. The use of gemcitabine in multidrug regimens containing one or more of: a platinum agent; fluoropyrimidine; anthracycline; and taxane has demonstrated advantages in response rate, progression-free survival and, in one randomized study, overall survival. After gemcitabine failure, second-line therapy with oxaliplatin and 5-FU provides a further survival advantage. Further advances depend upon the current and future clinical trials investigating enhanced delivery of current agents, new agents and novel modalities, improved supportive care, and treatment more tailored to the individual patient and tumour.     

Docetaxel and herceptin: foundation for future strategies

Randomized controlled studies have demonstrated that both docetaxel and Herceptin are capable of increasing survival in patients with metastatic breast cancer. The two agents show synergy in vitro, and their use in combination is not likely to be associated with the problem of enhanced cardiotoxicity. In two trials of Herceptin plus docetaxel in patients with advanced breast cancer, preliminary data are available for 35 patients. These early results show that the combination is well-tolerated. No symptomatic cardiotoxicity has occurred. The preliminary response rates (RR) in these first- and second-line patients are 44% in one study and 63% in the other. In the subgroups of patients who were HER-2 3+ overexpressers, the RRs are currently 55% and 73%. In an attempt to maximize the efficacy of Herceptin, its use has also been studied in combination with docetaxel and a platinum salt, producing a preliminary RR of 78% in patients positive for HER-2 on the fluorescence in situ hybridization assay. These data are sufficiently promising to justify a study of the role of Herceptin in combination with adjuvant chemotherapy regimens containing docetaxel or docetaxel plus a platinum. The combination of Herceptin with adjuvant therapy containing docetaxel and a platinum may provide a helpful alternative to the potentially cardiotoxic Herceptin/anthracycline-containing regimens currently under investigation.     

Combination therapy with gemcitabine (GEM) and erlotinib (E) in exocrine pancreatic cancer under special reference to RASH and the tumour marker CA19-9

We report on the results of a prospective treatment of 30 proven metastatic pancreatic cancer patients with the recently described combination of gemcitabine and erlotinib (GEM+E) (24× 1st line therapy, 8× 2nd line therapy). Eight of these patients received GEM+E for treatment of metastastic tumour recurrence after previous resective surgery, followed by adjuvant chemotherapy with gemcitabine. In 2 patients GEM+E was given as 1st line treatment and later, after complete response which was followed by a new recurrence, also as a second line therapy. The evaluation of RASH severity grades, the course of the serum tumour marker CA19-9 were determined every 14 days and the evaluation of the imaging methods CT or MRT, evaluated every 6-8 weeks, revealed the following results: there was a tendency for RASH grades to correlate with the tumour response, however, with observed exceptions. The decision for interruption or maintenance of GEM+E, therefore, should not be based on the RASH phenomenon, but on a detailed follow-up with imaging methods and the relevant tumour markers as in the follow-up before erlotinib introduction into pancreatic cancer therapy. As known from previous studies tumour markers represent more sensitive parameters compared to the imaging methods. GEM+E was active in the whole group of patients, mainly given as 1st line therapy (34% PD, 29% SD, 47% MR, PR, CR), but also in the 2 subgroups: in the patients with GEM+E as 2nd line therapy, as well as in patients after previous adjuvant gemcitabine therapy after tumour resection. In the 2 patients with transient-CR after 1st line therapy with GEM+E the 2nd line therapy also resulted in a CR with long lasting remission. These data should motivate clinicians to focus their interest not only to 1st line therapy regimens with erlotinib, but also to 2nd and 3rd line strategies within the previously published concept of an efficacy-orientated sequential polychemotherapy or multimodal-therapy for pancreatic cancer.     

吉西他滨联合长春瑞滨与联合紫杉醇姑息治疗铂类耐药的Ⅳ期鼻咽癌患者的随机对照试验

目的:观察吉西他滨联合长春瑞滨与联合紫杉醇方案作为姑息治疗方案治疗铂类耐药的Ⅳ期鼻咽癌患者的有效性及安全性。方法:收集2012年7月至2014年7月含铂一线治疗失败的晚期鼻咽癌患者共105例的临床资料,随机分为吉西他滨联合长春瑞滨组（GV组）与吉西他滨联合紫杉醇组（GT组）,比较两方案在总有效率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）、总生存期（OS）及不良反应发生率等方面的差异。采用Log-rank检验比较PFS及OS。结果:两组间的ORR无统计学差异（P=0.491）,DCR存在统计学差异（GT组较优,P=0.034）。两组间的PFS、OS的差别均无统计学意义（P=0.387,P=0.673）。不良反应方面,GV组Ⅰ度感觉异常较多,而GT组Ⅲ度白细胞降低、Ⅰ度疲乏无力、过敏反应、肌肉关节疼痛、脱发及Ⅱ度脱发较多,差别均有统计学意义。结论:GV、GT两种方案治疗铂类耐药的晚期鼻咽癌患者在总有效率、无进展生存期及总生存期上近似,GT方案可提高患者疾病控制率（DCR）,不良反应较GV方案多,多为轻中度,患者可耐受。