Advances in the treatment of second-line non-small-cell lung cancer

Treatment with third-generation chemotherapy agents improves survival and quality of life of patients with non-small-cell lung cancer (NSCLC). Despite these favorable outcomes, most patients receiving front-line therapy experience disease progression. The availability of many new novel agents with activity in NSCLC has prompted investigators to explore second-line chemotherapy options. For many years, docetaxel was the only approved agent for the second-line treatment of NSCLC. More recently, the multi-targeted antifolate pemetrexed has demonstrated activity in patients previously treated with chemotherapy with locally advanced or metastatic NSCLC. The findings of a phase III trial comparing pemetrexed to docetaxel led to the regulatory approval of pemetrexed as monotherapy for the second-line treatment of NSCLC. Several other novel therapies, including molecular targeting agents such as erlotinib, are under development in clinical trials in patients with NSCLC. One of these trials has subsequently led to the approval of erlotinib as second- or third-line therapy in advanced NSCLC.     

Antimetabolites in the management of non-small cell lung cancer

Opinion statement Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. Although chemotherapy has been shown to increase survival for patients with advanced-stage disease, survival benefits have been modest and come at the cost of significant toxicity. Treatment options in the second-line setting have been limited. Pemetrexed, a multitargeted antifolate, has activity as a single agent and as part of combination chemotherapy against NSCLC. As reported in a recent phase III clinical trial, survival outcomes in the second-line setting for patients treated with pemetrexed or docetaxel are similar. More importantly, major toxicity with the use of pemetrexed with vitamin B₁₂ and folate supplementation is far less than with docetaxel. Based on its single agent activity, ease of administration, and favorable toxicity profile, pemetrexed has the potential to be incorporated in various settings against NSCLC, including metastatic disease, as adjuvant therapy, and for locally advanced disease.     

培美曲塞二钠与多西紫杉醇单药治疗晚期非小细胞肺癌的对比研究

目的:比较培美曲塞二钠和多西紫杉醇对一线化疗失败的晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的疗效与不良反应。方法:84例一线化疗失败或不能耐受的晚期NSCLC患者随机分为培美曲塞二钠组(44例)和多西紫杉醇组(40例),分别接受培美曲塞二钠500 mg/m2治疗和多西紫杉醇75 mg/m2治疗。入选患者均接受2~6个周期化疗。结果:所有患者参与评价,单用培美曲塞二钠组及单用多西紫杉醇组的有效率分别是13.6%(6/44)和10.0%(4/40);疾病控制率分别是54.5%(24/44)和55.0%(22/40),两组的差异均无统计学意义,χ2=0.002,P值分别为0.741和0.967。单用培美曲塞二钠组和多西紫杉醇组患者的中位生存时间分别为8.2和8.1个月,1年生存率分别为27.3%和25.0%,两组的差异均无统计学意义,P值分别为0.258和0.580。两组的不良反应均为骨髓抑制、恶心、呕吐、乏力及脱发。培美曲塞二钠组发生中性粒细胞减少的概率明显低于多西紫杉醇组,Ⅰ~Ⅱ度分别为31.8%(14/44)和65.0%(26/40),χ2=9.249,P=0.002;Ⅲ~Ⅳ度分别为4.5%(2/44)和30.0%(12/40),χ2=9.775,P=0.002。结论:对于一线化疗失败或不能耐受的晚期NSCLC患者,分别使用培美曲塞二钠和多西紫杉醇进行化疗,疗效相似,但使用培美曲塞二钠化疗的不良反应更低,值得临床推广使用。     

Successful treatment using apatinib with or without docetaxel in heavily pretreated advanced non-squamous non-small cell lung cancer: A case report and literature review

Although targeted therapy directed toward driver mutations has produced a significant efficacy benefit for patients with non-small cell lung cancer (NSCLC), many patients do not possess mutations associated with the approved targeted drugs. Angiogenic agents play an important role in the therapeutic strategy for advanced NSCLC. Apatinib is a novel tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2. A phase II clinical trial demonstrated the survival benefit of apatinib monotherapy in advanced NSCLC. Moreover, addition of anti-angiogenic agents to chemotherapy showed robust efficacy in advanced NSCLC, regardless of tumor histology. Here, we present the case of a heavily pretreated lung adenocarcinoma patient who was treated with apatinib and apatinib continuation plus docetaxel re-challenge. He was negative for several driver genes, including EGFR, ALK, KRAS, ROS1, HER2, RET and BRAF. The previous treatment included platinum-based doublets, pemetrexed monotherapy, docetaxel plus bevacizumab, gefitinib monotherapy, nab-paclitaxel monotherapy, irinotecan plus oxaliplatin and radiotherapy. He obtained a partial response after both apatinib monotherapy and apatinib plus docetaxel treatment, with progression-free survival durations of 5 months and 6 months, respectively. This case indicated that apatinib monotherapy or apatinib plus docetaxel might be regarded as a therapeutic option for heavily pretreated patients with advanced non-squamous NSCLC.     

Perspectives on salvage therapy for non-small-cell lung cancer

Platinum-based chemotherapy offers a modest survival advantage over best supportive care in chemotherapy-naive patients with a good performance status and advanced/metastatic non-small-cell lung cancer (NSCLC). Despite the survival benefit associated with first-line chemotherapy, the majority of patients will experience relapse or disease progression. In clinicalpractice, an increasing number of patients maintain a good performance status after first-line treatment and are eligible for further treatments. Docetaxel (Taxotere) at 75 mg/m2 given once every 3 weeks has been the standard of care for second-line chemotherapy since the year 2000. Pemetrexed (Alimta) is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. A large phase 111 study comparing docetaxel to pemetrexed in second-line therapy demonstrated that pemetrexed is equally active and less toxic than docetaxel. Based on these results, pemetrexed is a reasonable second-line chemotherapy option for patients with recurrent, advanced NSCLC. Progress made in the field of molecular biology has led to the identification of drugs active against specific cellular targets. Gefitinib (Iressa) and erlotinib (Tarceva) are both orally active tyrosine kinase inhibitors of the epidermal growth factor receptor. Phase II and III trials have demonstrated that these agents are active particularly in a subgroup of patients with specific biologic characteristics. Both drugs have been approved for the treatment of pretreated NSCLC. Other drugs, such as cetuximab (Erbitux) and bevacizumab (Avastin) have shown promising activity in NSCLC and are currently being tested in clinical trials.     

培美曲塞二钠或多西他赛单药二线治疗晚期非小细胞肺癌的疗效和毒性分析

目的 探讨培美曲塞二钠或多西他赛单药二线治疗晚期非小细胞肺癌的疗效和毒性.方法 选择48例经一线化疗失败的晚期NSCLC患者,按照随机数表法将其分为2组.2组分别实施培美曲塞二钠、多西他赛单药治疗,观察治疗后的不良反应、近期及远期疗效.结果 2组患者化疗后的近期疗效以及远期疗效比较,差异不具有统计学意义(P＞0.05);而培美曲塞二钠组患者化疗后的不良反应远低于多西他赛组,差异具有统计学意义(P＜0.05).结论 培美曲塞二钠在保证对NSCLC的临床治疗效果的同时可以降低其不良反应.     

培美曲塞二钠二线治疗晚期非小细胞肺癌近期疗效观察

目的比较单用培美曲塞二钠及多西紫杉醇应用于一线化疗失败的晚期非小细胞肺癌患者的疗效与安全性。方法42例既往一线化疗失败或不能耐受的Ⅳ期非小细胞肺癌患者分别分入培美曲塞二钠和多西紫杉醇组,22例患者接受培美曲塞二钠500 mg/m2治疗,20例患者接受多西紫杉醇75 mg/m2治疗。入选患者至少接受2个周期以上化疗,最多接受6个周期化疗。结果入组的42例患者均可评价疗效。单用培美曲塞二钠组及单用多西紫杉醇组的总有效率分别是13.6%和10.0%（P=0.716）,疾病控制率分别是54.5%和55.0%（P=0.976）。单用培美曲塞二钠组和多西紫杉醇组患者的中位生存时间分别为8.2和8.1个月（P=0.258）,1年生存率分别为27.3%和25.0%（P=0.580）。两组的不良反应主要为骨髓抑制、恶心/呕吐、乏力及脱发。培美曲塞二钠组发生中性粒细胞减少的机率明显低于多西紫杉醇组（Ⅰ-Ⅱ度：31.8%对65.0%,P=0.032;Ⅲ-Ⅳ度：4.5%对30.0%,P=0.027）。结论对于既往一线化疗失败或不能耐受的Ⅳ期非小细胞肺癌患者,单药使用培美曲塞二钠及单药使用多西紫杉醇进行化疗疗效相似,但使用培美曲塞二钠单药不良反应更低,值得临床推广。     

复治晚期非小细胞肺癌EGFR-TKI治疗失败后培美曲塞与多西他赛挽救性化疗的疗效比较

目的 比较复治晚期非小细胞肺癌（NSCLC）表皮生长因子受体 酪氨酸激酶抑制剂（EGFR TKI）治疗失败后用培美曲塞或多西他赛挽救性化疗的疗效及毒副反应。方法120例复治晚期NSCLC患者于EGFR-TKI治疗失败后分别接受培美曲塞（500mg／m2,d1）或多西他赛（75mg／m2,d1）的挽救性化疗,均21天为1周期。记录并比较两者的疗效和预后。结果培美曲塞组和多西他赛组的有效率（RR）分别为13.4％和5.3％（P=0.307）,疾病控制率（DCR）分别为58.5％和42.1％（P=0.093）,中位无进展生存期（PFS）分别为2.83个月和2.10个月（P=0.862）,中位总生存期（OS）分别为8.40个月和9.10个月（P=0.527）。EGFR-TKI治疗有效和挽救性化疗前行为状态评分（PS）≤1者的中位PFS较长。培美曲塞组1～4级中性粒细胞减少的发生率低于多西他赛组,分别为41.5％和65.8％（P=0.013）。在非血液学毒性方面两组差异均无统计学意义（P＞0.05）。结论 复治晚期NSCLC TKI治疗失败后用培美曲塞或多西他赛挽救性化疗,部分患者仍可以获益,两组疗效相当,且大部分患者能够耐受化疗的毒副反应。对于EGFR-TKI治疗有效、挽救性化疗前PS评分较好的患者,有可能从挽救性化疗中获益更大。     

阿帕替尼治疗多线治疗失败的转移性乳腺癌的疗效观察

目的 观察阿帕替尼治疗难治性乳腺癌的疗效及不良反应.方法 回顾性分析29例经多线治疗失败后进行阿帕替尼化疗的转移性乳腺癌患者的临床资料,分析阿帕替尼单药化疗和阿帕替尼联合化疗患者的无进展生存期(PFS)、客观有效率(ORR)和疾病控制率(DCR).结果 29例患者中,1例死亡,1例由于血小板降低而停止用药,可评价疗效的患者共27例.27例患者的中位PFS为3.1个月(1.0~6.1个月).阿帕替尼联合化疗患者的PFS为3.10个月,阿帕替尼单药化疗患者的中位PFS为3.46个月,差异无统计学意义(P>0.05).治疗后部分缓解3例,疾病稳定12例,疾病进展12例,ORR为11.11%,DCR为55.56%.多因素分析结果显示,既往化疗方案数是影响乳腺癌患者PFS的独立危险因素(P<0.05).化疗后患者的3~4级不良反应包括手足综合征2例(6.90%),高血压2例(6.90%),低血小板血症1例(3.45%).结论 阿帕替尼单药及联合化疗治疗转移性乳腺癌有一定疗效,值得进一步研究.     

Single-agent docetaxel (Taxotere) in the treatment of advanced non small-cell lung cancer: clinical concepts and commentary

Chemotherapy in recurrent or metastatic non small-cell lung cancer (NSCLC) has been shown to im-prove quality of life, and to provide a modest prolongation of survival. Docetaxel is a semisynthetic taxane that is an active agent for the treatment of NSCLC, both in previously untreated patients as well as those who have relapsed or progressed following cisplatin-based chemotherapy. After encouraging results in phase II studies, randomized trials have shown that treatment with single-agent docetaxel is superior to best supportive care for advanced NSCLC in both untreated and previously treated patients. This article will review the published data on the use of single-agent docetaxel in the treatment of advanced NSCLC.     

Antiangiogenic agents in combination with chemotherapy in patients with advanced non-small cell lung cancer

Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC.     

Pemetrexed-Induced Pneumonitis: A Case Report

Pemetrexed is a structurally novel antifolate agent approved in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma who have unresectable disease and for the therapy of previously treated patients with locally advanced or metastatic Non–Small-cell lung cancer (NSCLC) as a single agent or in association with cisplatin as a first-line treatment in patients with nonsquamous histology. Herein, we report a case of pemetrexed-induced pneumonitis. Because pemetrexed is being prescribed with increasing frequency for NSCLC and mesothelioma, we believe that physicians should be aware of this rare but serious complication.     

Treatment rationale and study design for a phase III,double-blind,placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer

Background  

To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed.     

FDA drug approval summary: pemetrexed for injection (Alimta) for the treatment of non-small cell lung cancer

On August 19, 2004, pemetrexed for injection (Alimta); Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com) received accelerated approval as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had received prior chemotherapy. Approval was primarily based on a single, controlled, unblinded trial. Five hundred seventy-one protocol-eligible patients were randomized to receive either pemetrexed or docetaxel (Taxotere); Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharmaus.com). The primary efficacy end point was overall survival. The median survival times were 8.3 months in the pemetrexed arm and 7.9 months in the docetaxel arm. Neither superiority nor noninferiority for overall survival could be demonstrated, the latter because a reliable and consistent survival effect of docetaxel could not be estimated and because of significant crossover of pemetrexed-treated patients to docetaxel after tumor progression. Comparable response rates, 9.1% for pemetrexed and 8.8% for docetaxel, times to progressive disease, and progression-free survival times supported the conclusion that an effect of pemetrexed on survival was reasonably likely, however.In addition, pemetrexed was felt to have a more favorable safety profile than docetaxel. Of greatest importance, pemetrexed caused significantly less neutropenia, febrile neutropenia, neutropenic infections, and need for granulocyte/macrophage colony-stimulating factors.     

A dose-escalation study of pemetrexed and docetaxel in non-small-cell lung cancer

A phase I study was conducted to determine the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLT) of pemetrexed and docetaxel in patients with advanced unresectable or metastatic non-small-cell lung cancer (NSCLC). Patients were treated with escalating doses of pemetrexed (400-600 mg/m(2) as a 10-min intravenous infusion) and docetaxel (65-85 mg/m(2) as a 1-h intravenous infusion) on day 1, every 3 weeks. An expanded accrual at the level of the recommended dose (RD) had been scheduled. Forty-two patients with metastatic NSCLC were enrolled in the phase I study and 20 additional patients at the RD level. The MTD could not be reached even at the doses of 550 and 85 mg/m(2) for pemetrexed and docetaxel, respectively, which are higher than the recommended dose for each drug given as a single agent. Therefore, the RD was defined at 500 mg/m(2) pemetrexed and 75 mg/m(2) docetaxel. Among the 164 administered chemotherapy cycles (phase I part), there were three episodes of febrile neutropenia whereas 13 (7.9%) and 11 (6.7%) cycles were complicated with grade III and IV neutropenia, respectively. Three patients developed grade III/IV thrombocytopenia. Non-hematologic toxicity was mild with grade III fatigue occurring in three (6.7%) patients. There was no toxic death. The favorable toxicity profile of the regimen was confirmed in patients treated at the RD level. Overall, one complete (CR) and 13 partial responses (PR) (overall response rate = 23; 95% C.I:12.4-33.5%] were documented. The combination of pemetrexed and docetaxel seems to be an effective regimen in NSCLC with acceptable and manageable toxicity, which merits further investigation.     

Concurrent docetaxel and thoracic radiation in non-small-cell lung cancer

Locally advanced (stages IIIA and IIIB) non-small-cell lung cancer (NSCLC) represents approximately 25% of new cases of NSCLC diagnosed annually. The treatment strategy for these patients involves combined-modality therapy with chemotherapy and thoracic radiation. Furthermore, a subset of patients with stage IIIA disease undergo surgical resection. Docetaxel is a chemotherapy agent with activity in both first- and second-line treatment of patients with advanced NSCLC. Several recent studies have also incorporated docetaxel in the treatment of patients with stage III NSCLC as neoadjuvant therapy, alone or in combination with cisplatin or carboplatin and thoracic radiation. Docetaxel has also been used as consolidation therapy. This review will summarize the data to date on the use of docetaxel and thoracic radiation in the treatment of patients with stage III NSCLC.     

阿帕替尼联合多西他赛与多西他赛二线治疗晚期非鳞非小细胞肺癌的疗效、安全性及预后对比

目的:对比阿帕替尼联合多西他赛与单纯多西他赛在晚期非鳞非小细胞肺癌(NSCLC)二线治疗中的疗效及安全性,并对预后影响因素进行分析。方法:纳入98例晚期非鳞NSCLC,随机分为治疗组（阿帕替尼联合多西他赛）48例以及对照组（多西他赛）50例,观察客观缓解率（ORR)、疾病控制率（DCR)、无进展生存期（PFS)、总生存期（OS）及不良反应,并将治疗组的临床病理因素纳入单因素及多因素分析。结果:两组患者近期疗效无明显差异;中位PFS分别为4.1个月与3.1个月（P=0.045）;中位OS分别为10.4个月与8.8个月（P=0.023）。两组患者3-4级不良反应发生例数未见明显差异。单因素分析显示中高分化、转移灶≤1个预后较好,多因素分析提示肿瘤分化程度是阿帕替尼联合多西他赛治疗晚期非鳞NSCLC的独立预后因素。结论:在晚期非鳞NSCLC二线治疗中,阿帕替尼联合多西他赛与多西他赛对比有生存获益,且耐受性好,肿瘤分化程度是独立的预后因素。     

Second-line chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC)

An increasing number of patients with advanced non-small cell lung cancer (NSCLC) progressing after front-line chemotherapy are still in good performance status and willing to receive further treatment. Several drugs have been tested in this setting of treatment, but the only agent registered world-wide for second-line chemotherapy of advanced NSCLC is docetaxel. This drug, at dose of 75 mg/m2 every three weeks, has been the standard of care as second-line chemotherapy since 2000, based on two trials that reported improved survival times and quality of life when comparing with best supportive care (TAX 317) and with ifosfamide or vinorelbine (TAX 320). Docetaxel, given at this dose and schedule, resulted in significant haematological toxicity, with many patients at risk for neutropenic fever. Pemetrexed is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. In a phase III study in 571 patients pemetrexed, comparing with docetaxel in second-line chemotherapy, demonstrated clinically equivalent therapeutic outcomes, but a more favourable haematological toxicity profile, with fewer episodes of neutropenia, neutropenic fever, and infections and less use of granulocyte colony-stimulating factor support. Others several agents have been evaluated for the second-line treatment of patients with non-small cell lung cancer, but no comparative phase III studies with docetaxel has been carried out. The epidermal growth factor receptor-tyrosine kinase inhibitors gefitinib (ZD1839, Iressa) and erlotinib (OSI 774, Tarceva) have been evaluated in the second- and third-line setting. Both drugs have demonstrated interesting response rates and toxicity profile and, in particular, erlotinib evidenced a survival advantage of 2 months respect placebo in recent phase III trial. Future developments are likely to value poli-chemotherapy or combination chemotherapy with EGFR tyrosine kinase inhibitors in second-line treatment of advanced NSCLC.     

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.     

培美曲塞治疗19例复发性晚期非小细胞肺癌

背景与目的：晚期复发的非小细胞肺癌治疗效果差,可选择的药物不多。本研究探讨培美曲塞单药或联合顺铂/卡铂治疗晚期复发性非小细胞肺癌（NSCLC）的疗效以及不良反应。方法：经病理学或细胞学确诊的复发性晚期NSCLC患者19例,其中男性9例,女性10例,中位年龄48岁,KPS评分≥70。单药治疗：培美曲塞500mg/m^2,第1天静脉滴注每3周重复;联合治疗：培美曲塞500 mg/m^2第1天＋顺铂60 mg/m^2第2天静脉滴注每3周重复;或培美曲塞500 mg/m^2第1天＋卡铂300 mg/m^2第2天静脉滴注每3周重复。至少2周期以上可评价疗效及不良反应。结果：19例中16例可评价疗效,全组无CR/PR病例,MR 2例,SD 10例,PD 4例,疾病控制率75%（12/16）。中位生存时间9个月,1年生存率为31%（5/16）。主要不良反应为粒细胞下降、贫血和胃肠道反应。结论：培美曲塞单药或联合铂类治疗晚期复发NSCLC疗效确切,不良反应发生率低,耐受性较好。