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.     

Combination chemotherapy of carboplatin and docetaxel for advanced non-small cell lung cancer (NSCLC)

Since mid-1997, we have treated 60 patients with advanced NSCLC with carboplatin (CBDCA) plus docetaxel (TXT). CBDCA (300-400 mg/m2) and TXT (60 mg/m2) were given on day 1 every 3 weeks. The mean treatment cycle was 2.3 +/- 1.4 (range 1-7). Fifty-four patients had measurable tumors, of whom 2 patients achieved a complete response and 19 patients achieved a partial response (37.0%, 95% CI: 24.3-51.3%) (Ad 12/29, Sq 7/23, Lar 1/2). Median survival time was 12.8 months and 1 year survival was 53.6%. AUC of CBDCA was not related to response (AUC of responders and non-responders was 3.29). Myelosuppression was moderate (WBC 2,284 mm3, range 800-4,700, PLT 16.4 x 10(4) mm3, range 6.6-41.5 x 10(4), Hb 10.9 g/dl, range 6.4-15.8). Leukocytopenia was related to AUC of CBDCA (R2 = 0.1093) but thrombocytopenia was not related to AUC of CBDCA (R2 = 0.0553). Gastrointestinal toxicity was mild (grade 0-1: 57%, grade 2: 35%, grade 3: 8%, grade 4: 0%). Treatment with CBDCA plus TXT combination is safe and effective in patients with NSCLC.     

胸腺肽在晚期非小细胞肺癌化疗中的作用

背景与目的：肺癌的发生、发展与机体的免疫功能状况密切相关,恶性肿瘤患者存在明显的免疫功能紊乱,主要表现为细胞免疫功能下降.本研究评价胸腺肽联合化疗对晚期非小细胞肺癌的疗效、毒副反应、生活质量及免疫功能的影响.方法：42例非小细胞肺癌随机分为2组,治疗组：NP方案＋胸腺肽.长春瑞滨（NVB）25 mg/m^2,静脉滴注,第1、8天,顺铂（DDP）70～80 mg/m^2,静脉滴注,第1天.化疗后第3天每日静脉滴注胸腺肽200 mg,连续7～10 d.对照组：单化疗,用NP方案,剂量、用法同上.结果：治疗组化疗后CD4和NK细胞活性显著高于化疗前和对照组化疗后水平（P＜0.01）,对照组NK细胞活性化疗后显著低于化疗前水平（P＜0.05）.治疗组KPS提高率为61.9%（13/21）,而对照组为28.6%（6/21）,两组差异有显著性（P＜0.05）.治疗组有效率52.4%（11/21）,1年生存率为52.6%.对照组有效率42.9%（9/21）,1年生存率38.8%.两组间疗效、毒副反应及1年生存率比较差异无显著性（P＞0.05）.结论：胸腺肽联合化疗能提高肺癌化疗患者机体的免疫功能,改善患者生存质量.     

Gemcitabine-based chemotherapy for non-small cell lung cancer (NSCLC)--a review of 30 randomized trials

Non-small cell lung cancer (NSCLC) represents a major challenge to oncologists because of its dismal outcomes. Conventional cytotoxic therapies for advanced disease have been unsatisfactory with modest efficacy and high toxicities. The last decade witnessed the introduction of many novel agents with enhanced efficacy and more manageable safety profile than conventional therapies. Gemcitabine is one of these novel agents which was introduced in the mid 1990's in the US/Europe and has been available in Japan since 1999. Due to its unique profile of great efficacy, mild toxicities and combinability with other agents, gemcitabine and its combination have been widely accepted as one of the standard regimens for the treatment of advanced NSCLC. There were multiple clinical trials demonstrated the superiority of gemcitabine or its combination over conventional therapies, especially in terms of increased response, prolonged survival, and quality of life enhancement for these patients. The current review presents an overview of all the randomized clinical trials of gemcitabine and its combination for advanced NSCLC published over the last decade.     

Front-line weekly chemotherapy with gemcitabine for unfit patients with non-small cell lung cancer (NSCLC)

Chemotherapy (CT) for elderly patients is becoming a standard, since the first demonstration by Gridelli and co-workers that chemotherapy (in their case Vinorelbine (VNB), single agent) is capable to produce significant survival benefits. Much less is known concerning the use of CT for unfit patients. The purpose of this phase II trial was to perform a comprehensive evaluation of activity, toxicity, and tolerability of single-agent Gemcitabine (GEM) (Gemzar) as a first-line chemotherapy for unfit patients with inoperable or recurrent non-small cell lung cancer. Patients were eligible if they had a pathological diagnosis and no previous chemotherapy; they should be younger than 76, with a performance status (ECOG-PS) equal to three; informed consent was also required. Gemcitabine was given by intravenous infusion at a weekly dose of 1250 mg/m2, 3 weeks per month, every 28 days. Treatment was given until progression, persistent toxicity, or refusal. Forty-five patients (39 males) entered the study; median age was 73 years (range 45-75); cell types were: adenocarcinoma (21), squamous (18), large cell (6). Previous surgical treatments included three lobectomies and one pneumectomy. Because of rapid clinical deterioration or consent withdrawal, six patients, registered for study, never started their treatment; other six had early chemotherapy suspension. These patients were included in the analysis, on an "intent-to-treatment" basis. The median number of chemotherapy cycles was nine (range 0-15); median dose-intensity was 75% of projected. Toxicity was mild, mainly hematological and never life threatening (only 1 grade 4 toxicity out of 325 pre-chemotherapy evaluations). Four patients obtained a partial response (9%, C.I. 1-17%) and other six patients had some tumor regression (13%, C.I. 3-23%). The estimated median time to progression was 17 weeks (quartile range: 9-24), with a median survival of 35 weeks (quartile rage: 20-51). We have found that single-agent gemcitabine represent a sufficiently safe therapeutic option in unfit patients with inoperable non-small cell carcinoma (NSCLC).     

三维适形放疗和同步化疗治疗局部晚期非小细胞肺癌的临床研究

目的 :比较三维适形放疗与普通放疗结合同步化疗治疗局部晚期非小细胞肺癌(NSCLC)的疗效及毒副反应。方法 :64例ⅢA/ⅢB期NSCLC随机分成两组 ,三维适形放疗组采用三维适形放疗技术 ,每次 3～ 6Gy ,1次 /d ,照射 10～ 2 0次 ,肿瘤灶总生物有效量为 80～ 90Gy。普通放疗组放疗量在60～ 66Gy。两组同时给予长春瑞滨 2 5mg/m2 ,放疗开始的d1、d8、d2 9、d3 6、d57、d64、d85、d92 静脉滴入 ;卡铂 3 0 0mg/m2 ,放疗开始的d1、d2 9、d57、d85静脉滴入。结果 :三维适形放疗组有效率 96 88% (3 1/ 3 2 ) ,其中CR为17例 ,PR为 14例。普通放疗组有效率为81 2 5 % ,其中CR为 9例 ,PR为 15例。三维适形放疗组的有效率明显高于普通放疗组 ,P =0 0 19。三维适形放疗组和普通放疗组的 1、2年生存率分别为 84 3 8%、40 63 %和 78 13 %、2 3 5 6% ,中位生存时间分别为19个月、16个月 ,其差异有统计学意义 ,P =0 0 189。适形放疗组III度放射性食管炎、放射性肺炎发生率分别为 6 2 5 % (2 / 3 2 )、3 13 % (1/ 3 2 ) ,低于普通放疗组的 46.9%(15 / 3 2 )和 18.8% (6/ 3 2 ) ,两组间差异有统计学意义 ,P =0 0 0 0 ,P =0 0 0 1。结论 :三维适形放疗和同步化疗是ⅢA/ⅢB期非小细胞肺癌安全有效的治疗手段 ,值得进一步临     

参芪扶正注射液联合化疗治疗非小细胞肺癌的临床观察

目的:比较参芪扶正注射液联合化疗与单纯化疗治疗非小细胞肺癌的临床疗效及不良反应.方法:60例非小细胞肺癌患者随机分为参芪扶正注射液配合化疗组(治疗组)和单纯化疗组(对照组) ,其中配合化疗组30例,采用紫杉醇135mg/m2+生理盐水500ml静滴3小时以上,第1天,后予顺铂25mg/m2静滴,第1 -3天方案化疗,化疗时常规行预处理,化疗前3天开始静滴参芪扶正注射液250ml,1次/日,连用10天,每21天为1周期.对照组30例化疗方案同治疗组,至少2个周期后评价疗效及生存质量改善情况.结果:参芪扶正注射液配合化疗组总有效率(40.0%)较单纯化疗组(33.3%)高,但差异无统计学意义(P＞ 0.05) ,但在改善患者生活质量、减轻化疗毒性方面明显优于单纯化疗组,差异有显著性(P＜ 0.05) .结论:参芪扶正注射液联合化疗在治疗非小细胞肺癌中可提高化疗疗效,减轻化疗毒性,提高患者生活质量.     

含羟基喜树碱联合方案治疗中晚期非小细胞肺癌

目的 :观察含羟基喜树碱 (HCPT)联合方案治疗中晚期非小细胞肺癌 (NSCLC)患者的客观疗效及毒副作用。方法 :4 6例中晚期非小细胞肺癌患者为治疗组 ,应用含羟基喜树碱方案化疗 ,其中 2 5例肺腺癌患者接受HFAP方案 ,2 1例肺鳞癌患者接受HCAP方案 ,4周为一周期 ,2周期为一疗程 ;以同期住院的未用HCPT联合化疗的同类患者 4 2例作为对照组 ,其剂量、周期、疗程与治疗组相同 ,但不用HCPT。结果 :治疗组 4 3例患者完成一疗程治疗 ,肺腺癌有效率为 5 6 % ,CR 2例 ,PR 12例 ;肺鳞癌有效率为 5 5 5 % ,CR为 0 ,PR 10例 ,总有效率 (CR +PR)为 5 5 8% ;对照组 4 2例均完成一疗程治疗 ,肺腺癌有效率为37 5 % ,CR 1例 ,PR 9例 ;肺鳞癌有效率为 33 3% ,PR 6例 ,有效率 35 7% ;两组间差异显著 (P <0 0 5 )。治疗组和对照组的毒副反应主要表现为食欲不振、脱发、恶心呕吐和白细胞及血小板减少 ,两组毒副反应发生率无显著性差异 (P >0 0 5 )。结论 :羟基喜树碱联合化疗治疗中晚期非小细胞肺癌疗效确切 ,副作用可耐受 ,该药是治疗非小细胞肺癌较为有效的药物 ,值得进一步在临床中观察和研究。     

Evolution of non-small cell lung cancer chemotherapy (Review)

Non-small cell lung cancer (NSCLC) is a common malignancy which has been increasing in incidence over the last decades. In the past, these tumors were considered quite resistant to chemotherapy and until the development of cisplatin 30 years ago, the use of cytotoxic drugs was considered palliative. Cisplatin (CDDP) proved to be an active agent and when combined with other cytotoxic drugs, effectiveness in NSCLC increased. Many trials have taken place during the last 30 years with cisplatin combinations. Despite the effectiveness of cisplatin, the renal toxicity and neurotoxicity that are produced obliged researchers and clinicians to create other combinations without CDDP. Carboplatin, an analogue of CDDP and then taxanes, gemcitabine and vinorelbine, a Vinca alkaloid, that proved to be effective in NSCLC, led to substitute combinations for CDDP. In the present article we review the literature on NSCLC chemotherapy in order to visualize the effectiveness of older drug combinations vs. the newer ones. It seems that combinations with or without cisplatin are of similar effectiveness with respect to response rate and median and overall survival but the toxicity is different with a prevalence of myelotoxicity.     

Adjuvant chemotherapy following SBRT for early stage non-small cell lung cancer (NSCLC) in older patients

Adjuvant chemotherapy improves overall survival (OS) following stereotactic body radiotherapy (SBRT) in patients with early stage non-small cell lung cancer and tumors ≥four cm. Here, we aim to evaluate its role following SBRT in older patients. Patients >70 years diagnosed with clinical stages I-II NSCLC, (N0 disease), who received SBRT, were identified using the National Cancer Database (n = 7042). The Kaplan-Meier method was used to estimate OS, and the log-rank test was used to compare distributions by treatment strategy overall and within clinical stages I and II. There were 3533 female patients (50.2%), and 6074 (86.3%) had stage I disease. Among stage I patients, 643 (10.6%) received adjuvant chemotherapy, compared to 372 stage II patients (38.4%). Median OS was better with SBRT in patients with stage I disease (25.4 vs. 20.3 months; p < .001); while patients with stage II NSCLC had better OS with SBRT + chemotherapy (20.2 vs. 14.2 months; p < .001). On multivariate analysis, patients with stage I NSCLC who received SBRT alone had better overall survival (HR: 0.79; 95% CI, 0.73, 0.87). SBRT alone was associated with an increased risk of death in patients with stage II disease (HR: 1.34; 95% CI, 1.15, 1.55). Patients with tumors ≥4 cm had better OS with SBRT + chemotherapy (18.5 vs. 15.5 months; p = .003), while patients with tumors <4 cm did better with SBRT (median OS of 24.1 vs. 20.3 months; p < .001). In >70 years old patients with tumors ≥4 cm, adjuvant chemotherapy following SBRT was associated with improved OS.     

308例非小细胞肺癌放疗效果的临床因素分析

目的：探讨非小细胞肺癌单纯放疗的生存情况及影响预后的临床因素。方法：回顾性分析1985年1月－1991年12月收治的308例非小细胞肺癌,Ⅰ期11例,Ⅱ期68例,ⅢA期155例,ⅢB期74例。均经病理或细胞学证实,采用10MV－X线或CO－60机照射,常规分割,周剂量7－11,50Gy。有47例放疗开始或半量时按治疗计划布野,全程包括纵隔及原发灶,纵隔剂量大于56Gy其它病例纵隔剂量40Gy,生存率计算采用Kaplan-Meier法及Log-rank检验。结果：全组中位生期期10个月,1、3、5年生存率分别为43％、15％和9％,影响生存的临床因素分析结果表明,临床分期、近期疗效和周剂量和与预后有密切关系（P＜0．05）,而放疗总剂量和纵隔剂量与预后未见明显关系（P＜0．05）。结论：影响肺癌患者放疗预后的临床因素主要是临床分期,近期疗效和周剂量的大小,而放疗总剂量和纵隔剂量高低与生存率无明显关系     

Update on antiangiogenic treatment of advanced non-small cell lung cancer (NSCLC)

Bevacizumab is a monoclonal antibody that specifically inhibits vascular endothelial growth factor, and is the first antiangiogenic agent to be approved for first-line treatment of advanced non-small cell lung cancer (NSCLC). Evidence from two large phase III trials demonstrates that bevacizumab combined with chemotherapy improves outcomes for patients with non-squamous NSCLC. In patients with adenocarcinoma without epidermal growth factor receptor (EGFR) mutation, a median overall survival of 18.0 months is achieved. Several post-registration phase IV studies have confirmed bevacizumab’s efficacy and tolerability profile and have clarified the eligibility criteria. Clinical research is still ongoing to define the role of bevacizumab in different settings, such as single-agent bevacizumab for continuation maintenance therapy in advanced disease, treatment beyond disease progression, adjuvant therapy in early-stage NSCLC, or bevacizumab in combination with other targeted agents. A number of antiangiogenic tyrosine kinase inhibitors (TKI) have also been investigated in phase II and III trials. None of these drugs has proven significant clinical benefit in unselected patient populations. This article reviews the extensive information from randomized trials and large observational studies for bevacizumab in advanced NSCLC, and shortly describes the current clinical development of antiangiogenic monoclonal antibodies, TKIs and related compounds.     

新辅助化疗对围手术期非小细胞肺癌患者的影响

目的 研究新辅助化疗(MVP)是否影响非小细胞肺癌患者围手术期的安全性。方法 所有患者化疗方案均为MVP，即丝裂霉素(MMC) 长春碱胺(VDS) 顺铂(DDP)。将接受2周期术前新辅助化疗、根治性手术和2次术后化疗的患者与接受同样手术和4次术后化疗的患者进行比较。结果 在107例符合要求的病例中，新辅助化疗组有66例，对照组有41例，两组在性别、年龄、肿瘤分期、病理类型上均无统计学差异。新辅助化疗组患者的手术时间(P=0．262)、术中失血量(P=0．704)、术中输血量(P=0．811)、输血总量(P=0．074)比对照组患者略高，术后总引流量(P=0．061)稍低，但其差异均无统计学意义。两组术后死亡率(P=0．674)和并发症：心律失常(P=0．608)、支气管胸膜瘘(P=0．378)、肺炎(P=0．622)、呼吸衰竭(P=0．285)的比较亦均无统计学意义。结论 新辅助化疗对非小细胞肺癌患者围手术期的安全性无显著影响。     

非小细胞肺癌组织成纤维细胞P-gp的表达及意义

目的:研究非小细胞肺癌组织中成纤维细胞P-gp的表达与临床病理特征的关系,探讨其对患者术后早期复发或远处转移的影响。方法:应用Max VisionTM快捷免疫组化检测48例非小细胞肺癌组织和10例非癌肺组织中成纤维细胞P-gp的表达,随访患者并研究其表达水平与术后早期复发的相关性。结果:非小细胞肺癌组织中成纤维细胞P-gp的表达阳性率为70.8%,明显高于非癌肺组织(P<0.01);成纤维细胞P-gp的表达与患者年龄、肿瘤分化程度、临床分期和有无淋巴结转移有关(P<0.05);与患者性别、大小和肿瘤组织类型无关(P>0.05),P-gp阳性患者术后1年内复发或远处转移率明显高于P-gp阴性患者。结论:P-gp参与了肿瘤细胞的耐药性的形成,肿瘤组织成纤维细胞P-gp的表达水平在患者术后早期复发及远处转移中具有重要意义。     

吉西他滨联合顺铂方案二线治疗晚期非小细胞肺癌的临床观察

目的:观察吉西他滨联合顺铂二线治疗晚期非小细胞肺癌的疗效及不良反应.方法:对38例晚期非小细胞肺癌患者采用二线化疗,入组患者均经病理组织学证实,有可测量病灶,方案为吉西他滨1000mg/m2第1、8天,顺铂80mg/m2,分3天应用,21天为1个周期.化疗2个周期后评价疗效及不良反应.结果:所有患者均可评价,共进行108周期的化疗.完全缓解(CR)0例,部分缓解(PR)11例,稳定(SD)12例,进展(PD)15例,总有效率28.9%.中位缓解时间4.5月,中位生存时间7.8月.主要不良反应为血液学毒性,其中Ⅲ/Ⅵ度的中性粒细胞下降、血小板下降和血红蛋白下降分别为18.5%(20/108)、11.1%(12/108)和8.3%(9/108),其次为消化道不良反应,Ⅲ/Ⅵ度的食欲下降和恶心呕吐分别为13.9%(15/108)和12.0%(13/108).结论:吉西他滨联合顺铂对复治晚期非小细胞肺癌有较好疗效,不良反应可以耐受.