Docetaxel in second-line treatment of non-small-cell lung cancer

The survival and quality-of-life benefits of docetaxel in the second-line treatment of non-small-cell lung cancer (NSCLC) are supported by two phase III trials: TAX 317 and TAX 320. In TAX 317, 204 patients were randomized to receive either docetaxel 100 mg/m2 (D100) or 75 mg/m2 (D75) intravenously every 3 weeks, or best supportive care (BSC). Median survival was 9.0 months with D75 versus 4.6 months for BSC (P = 0.016); 1-year survival was 40% for D75 versus 16% for BSC (P = 0.016). Quality-of-life analysis showed significant improvement in several disease-related symptoms in patients who received docetaxel. TAX 320 was a supportive trial, in which 373 patients were randomized to receive D100, D75, or the control treatment of vinorelbine or ifosfamide (V/I). The partial response rate was 12% with D100 and 8% with D75 versus 1% with V/I (D100, P = 0.001 and D75, P = 0.036). Median response duration was 7+ months. One-year survival was 32% with D75 and 19% with V/I (P = 0.025). In TAX 320, prior paclitaxel exposure had no bearing on the response rate and survival advantage of second-line treatment with docetaxel. Response rates to docetaxel were equivalent in the cohort of patients who had received prior paclitaxel (10.5%) and the group of patients who had not received prior paclitaxel (8.5%). Furthermore, 1-year survival rates for patients with no prior paclitaxel therapy were 33% (D75) and 20% (V/I); 1-year survival rates for patients who had received prior paclitaxel were 30% (D75) and 17% (V/I). Docetaxel at a dose of 75 mg/m2 every 3 weeks offers a clinically meaningful improvement in response rate, time to progression, survival, and quality of life in the second-line treatment of advanced NSCLC. Furthermore, prior paclitaxel did not decrease the likelihood of response to docetaxel, nor did it lessen the survival advantage seen with docetaxel.     

Therapeutic advances in second-line treatment of advanced non-small-cell lung cancer

A majority of patients with lung cancer present with advanced disease: approximately 30% with locally advanced disease and 45% with metastatic disease. The prognosis for these patients is poor, with 5-year survival rates ranging from 5% to 15% for stage IIIB disease and < 5% for stage IV disease. For patients confronting advanced disease, chemotherapy is an essential option for disease control and palliation. Although a number of effective first-line regimens exist, virtually all patients with advanced non-small-cell lung cancer (NSCLC) will have disease relapse. For these patients, identifying the optimal treatment course remains a challenge. This article reviews approved and investigational second-line therapeutic options in patients with relapsed advanced NSCLC. Recently, docetaxel has been shown to improve survival in patients with advanced NSCLC who had progressive disease following treatment with platinum-containing chemotherapy. Subsequently, permetrexed was compared with docetaxel in a second-line treatment study that showed survival for both patient groups was virtually identical. Recently, erlotinib was associated with significantly longer survival compared with best supportive care in the second- or third-line treatment settings. Salvage treatment for NSCLC is reviewed, and the relative merits of the currently available treatments as well as agents that are pending Food and Drug Administration approval as second-line treatments are discussed.     

New avenues for second-line treatment of metastatic non-small-cell lung cancer

Platinum-based doublets are the standard first-line therapy for patients with advanced non-small-cell lung cancer, with approximately a third of patients obtaining an objective response with first-line chemotherapy and another 20–30% achieving temporary disease stabilization. However, all patients inevitably experience disease progression. Three agents are approved for treating patients who progress after one prior regimen: docetaxel, pemetrexed and erlotinib. Erlotinib is the only agent approved for use in the third-line setting. Although these agents have yielded similar outcomes in terms of anti-tumor activity and efficacy, they have different toxicity profiles, and some factors that can help in the choice among them have begun to emerge, such as smoking history and histotype. Several new molecularly targeted agents have shown activity in Phase II trials and may be integrated into second-line therapy as single agents or in combination with current agents in the future. In particular, the most encouraging data in this clinical setting have been reported with the antiangiogenetic drugs bevacizumab (already approved for use in the first-line setting), vandetanib and sunitinib. Phase III trials with these agents are ongoing.     

Nintedanib in combination with docetaxel for second-line treatment of advanced non-small-cell lung cancer

Non-small lung cancer (NSCLC) is a lethal malignancy when diagnosed in advanced stage. The evolution of chemotherapy and the development of agents targeting certain molecular pathways involved in tumor progression improved the prognosis. Nintedanib is a new tyrosine kinase inhibitor, which exerts its activity by blocking VEGF, FGF and PDGF receptors and inhibits the angiogenic signaling by preventing receptor dimerization. Several Phase I and II studies proved its safety and efficacy in diverse solid tumors. In patients with advanced NSCLC, the administration of nintedanib may offer an additional chemotherapy benefit in terms of response rate, progression-free survival and overall survival particularly in patients with adenocarcinoma histology, with manageable toxicity. Here, we present an analytical review of literature regarding nintedanib and we focus on its particular importance in NSCLC treatment.     

Retrospective practice review of treatment of metastatic non-small-cell lung cancer with second-line erlotinib

Background

Epidermal growth factor receptor tyrosine kinase inhibitors (egfr-tkis) and chemotherapy have both demonstrated efficacy in recurrent metastatic non-small-cell lung cancer (nsclc) following failure of first-line platinum-based chemotherapy. Although the 3 available therapeutic agents—docetaxel, erlotinib, and pemetrexed—have significantly changed the treatment landscape for recurrent nsclc, the optimal selection of second- and third-line therapy has not been established. This practice review examines the outcomes in clinical practice of using second-line erlotinib followed by third-line chemotherapy in the treatment of recurrent metastatic nsclc.

Methods

We conducted a retrospective review of nsclc patient charts at three Canadian institutions. Patients with recurrent nsclc who had received second-line erlotinib therapy followed by third-line chemotherapy were selected by census. A chart review assessed key outcomes that included time to progression (ttp), response, and change in performance status. Outcomes for specific patient subgroups were also examined.

Results

We identified 35 patients for this retrospective practice review. First-line platinum-doublet therapy demonstrated a mean ttp of 6.6 months and a 46% overall response rate (15 partial responses and 1 complete response). Second-line treatment with erlotinib produced the highest mean ttp of all lines of therapy (9.2 months) and an overall response rate of 40% (all being partial responses). In the third-line setting, in which most patients received docetaxel, the mean ttp was 4.3 months and the overall response rate was 18% (all being partial responses). Subgroup analysis showed that all patient subgroups demonstrated benefit from second-line erlotinib treatment; improved benefit was observed in patients who developed rash, in female patients, in never smokers, in Asian patients, in patients with positive egfr status, and in patients with adenocarcinoma histology.

Conclusions

For patients with advanced nsclc who progressed following first-line platinum-based chemotherapy, the data demonstrate that second-line egfr-tki treatment is efficacious and well-tolerated and that it does not appear to diminish the benefit of third-line chemotherapy.     

吉西他滨用于非小细胞肺癌治疗的研究进展

吉西他滨（健择,GEM）是治疗非小细胞肺癌（NSCLC）的有效新药。GEM＋顺铂联合化疗（GP方案）治疗晚期NSCLC的有效率31％－54％,中位生存期8．4－15．4个月,一年生存率30％－59％,化疗毒性反应可接受。GP方案可被认为是NSCLC 的标准化疗方案。GP方案21天与28天用药方法的疗效基本相同。随机对照研究GP方案的顺铂用药时序,GEM放射增敏,GEM与其他新药联合疗等问题值得进一步研究。     

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m(-2) PPX or 75 mg m(-2) docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m(-2) resulted in increased neurotoxicity compared with docetaxel.     

小细胞肺癌二线治疗进展

小细胞肺癌(SCLC)是一种恶性程度较高的肿瘤,一线放化疗非常敏感,但容易复发转移,预后差.SCLC二线治疗进展缓慢,拓扑替康是目前唯一被美国食品和药物管理局批准的二线标准治疗药物.大量关于分子靶向治疗和免疫治疗的研究正在进行中,但大多疗效欠佳.2016年美国临床肿瘤学会年会上公布的靶向Delta样蛋白3的抗体药物耦联物rovalpituzumab tesirine(Rova-T)显示了良好的抗肿瘤活性,似乎为分子靶向治疗带来了新的曙光.     

中晚期非小细胞肺癌化疗和放疗综合治疗进展

肺癌确诊时大部分已属中晚期,不宜手术治疗,只宜非手术治疗,肺癌的治疗效果近数十年来没有显著提高,总的治愈率约１０％,化疗和放疗的综合治疗有可能提高局控率和生存率。其综合应用有３种方式;序贯、同期、交替治疗。本文综述了近年来中晚期非小细胞肺癌的化疗和放疗综合应用的理论基础与临床研究;并指出了今后的方向。     

Meta-analysis of docetaxel-based doublet versus docetaxel alone as second-line treatment for advanced non-small-cell lung cancer

Purpose  

To compare docetaxel-based doublet with single-agent docetaxel as second-line treatment in non-small-cell lung cancer (NSCLC).     

A randomized phase II trial of oral topotecan versus docetaxel in the second-line treatment of non-small-cell lung cancer

BACKGROUND: This randomized phase II trial evaluated the efficacy and toxicity of oral topotecan compared with intravenous docetaxel in the second-line treatment of patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eighty patients were randomized to receive topotecan (2 mg per day or 2.5 mg per day fixed dose for 5 of 7 days for 2 weeks) or docetaxel (75 mg/m2) every 21 days. Thirty-nine patients received 138 cycles of topotecan. RESULTS: The overall response rate (RR; ORR) was 8%, median time to progression (TTP) was 1.6 months, median survival was 8.4 months, and the 1- and 2-year survival rates were 36% and 13%, respectively, for patients receiving topotecan. Forty-one patients were randomized, but only 38 patients were actually treated with 136 cycles of docetaxel. The ORR was 8% (7% intent to treat RR), median TTP was 1.4 months, median survival was 7.6 months, and the 1- and 2-year survival rates were 29% and 13%, respectively, for patients receiving docetaxel. CONCLUSION: Oral topotecan appears to be active and well tolerated when administered as a fixed dose daily for 5 of every 7 days for 2 weeks every 21 days and might provide another treatment alternative for patients with advanced-stage NSCLC.     

Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: A phase II trial.

PURPOSE: To investigate the activity and toxicity of gemcitabine as a single agent in patients with advanced non-small-cell lung cancer (NSCLC) after recurrence or failure of previous treatment with a platinum-containing regimen. PATIENTS AND METHODS: From November 1995 to October 1997, 83 patients with stage IIIB or IV NSCLC received gemcitabine 1,000 mg/m(2) once a week for 3 weeks every 28 days. Responses were assessed every two treatment courses. The median age of the patients was 63 years; Eastern Cooperative Oncology Group performance status was 0 to 1 in 62 patients and 2 in 21 patients. The predominant histology was squamous (39 patients); 49 patients had stage IV disease and 34 patients had stage III disease (33 stage IIIB and one stage IIIA). RESULTS: Sixteen patients (19%) achieved a partial response to treatment; the median duration of response was 29 weeks (range, 6 to 50 weeks). Treatment was well tolerated: grade 2 to 3 (World Health Organization standardized response criteria) leukopenia and thrombocytopenia occurred in 23% and 20% of patients, respectively. Mild asthenia was observed in 16% of patients, and peripheral edema in 5% of patients. Nausea and vomiting were present in 16% of patients. CONCLUSION: In this experience, gemcitabine showed significant activity without relevant toxicity, mainly in patients who were previously responsive to chemotherapy. This suggests a possible role for gemcitabine as a second-line treatment in patients who had a previous response or achieved stable disease with a platinum-containing regimen.     

国产奈达铂联合多西他赛二线治疗非小细胞肺癌

目的观察国产奈达铂（NDP）联合多西他赛二线治疗非小细胞肺癌的疗效和毒副反应。方法对57例ⅢB期和Ⅳ期非小细胞肺癌,应用奈达铂80mg／m^2-100mg／m^2,d1,多西他赛75mg／m^2,d1,21d为1个周期,至少接受2个周期化疗。结果57例患者均可评价疗效,其中,CR4例,PR16例,NC24例,PC13例,客观有效率（CR＋PR）35．1％,疾病控制率（CR＋PR＋SD）77．2％;中位疾病进展时间（TTP）为4．3个月,中位生存期为7．4个月,1年生存率为34．2％。本组血液学不良反应发生率较高,非血液学毒性方面恶心、呕吐,总发生率较高。结论国产奈达铂联合多西他赛二线治疗非小细胞肺癌是一种有效的方法,毒性反应轻,病人耐受良好。     

非小细胞肺癌表皮生长因子受体靶向治疗

表皮生长因子受体(EGFR)对于正常上皮细胞的生长是不可缺少的,但其异常表达会影响细胞的增殖和凋亡.EGFR突变和过表达是许多肿瘤的特征之一.因此针对EGFR的靶向治疗,包括小分子酪氨酸激酶抑制剂和单克隆抗体,已成为治疗非小细胞肺癌(NSCLC)的研究方向.     

血管内皮抑制素在非小细胞肺癌中的应用

Endostatin is a novel anti-angiogenic drug which through multiple pathway inhibits vascular endothelial growth factor expression, to achieve the purpose of the inhibition of tumor angiogenesis. The drug in the treatment of non-small-cell lung cancer in pre-clinical study and clinical application show that: used alone have anti-tumor effect; combined with radiotherapy and chemotherapy can obtain short-term curative effect, and does not increase treatment related toxicity. The adverse effect of the drug is mild and can be well tolerated.     

Activity of single-agent gemcitabine as second-line treatment after previous chemotherapy or radiotherapy in advanced non-small-cell lung cancer

The aim of the study was to evaluate activity, toxicity and health-related quality of life (HRQL) with gemcitabine as second-line treatment after previous chemo- or radiotherapy in non-small-cell lung cancer (NSCLC). Patients with previously treated NSCLC were treated with gemcitabine (1000 mg/m(2)) on days 1, 8 and 15 in a 28-day cycle. Eighty patients were included; median age was 57 years (range 38-77). Prior treatment consisted of platinum-containing chemotherapy in 29 patients and high-dose thoracic radiotherapy in 51 patients. Median number of cycles was three (range 1-6). Granulocytopenia CTC grade 3 and 4 occurred in 9% and thrombocytopenia CTC grade 3 and 4 in 9% of cycles. Non-haematological toxicity was mild. Tumour response was achieved in 13% of the patients (95% CI 7-20), median survival time was 26 weeks and 1-year survival was 22%. Tumour response to second-line gemcitabine could not be predicted from response to first-line therapy, first-line treatment modality or treatment interval. In a subset of 35 patients HRQL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-LC13 questionnaires and showed improvement or control of symptoms and functioning in approximately 30% of patients. We conclude that gemcitabine in second-line treatment has modest anti-tumour activity, is well tolerated, and may control tumour-related symptoms and improve HRQL in a significant minority of patients.     

Bevacizumab in the treatment of non-small-cell lung cancer

Lung cancer is the leading cause of cancer death in the United States. The majority of patients present with advanced disease, and treatment with standard cytotoxic chemotherapy improves survival and quality of life in patients with a preserved functional status. However, the prognosis is poor with the majority of patients dying in less than a year. Treatment with standard cytotoxic chemotherapy has reached a therapeutic plateau, and new therapeutic approaches have investigated therapies that target the specific molecular pathways involved in carcinogenesis and angiogenesis. The most promising strategy for inhibiting angiogenesis involves agents that either target the proangiogenesis growth factor, vascular endothelial growth factor A (VEGF) by preventing binding to the receptor or inhibiting the downstream signaling of the vascular endothelial growth factor receptor. The only therapeutic agent approved for the treatment of lung cancer is bevacizumab, a monoclonal antibody that binds to VEGF. A recent phase III trial revealed a statistically significant improvement in response rate, progression free and overall survival with combination of bevacizumab with chemotherapy over chemotherapy alone. Attempts to identify surrogate markers of antiangiogenesis activity are currently ongoing, and may assist in the selection of patients for antiangiogenesis therapy and the development of this class of agents.