Molecular profiling to optimize treatment in non-small cell lung cancer: a review of potential molecular targets for radiation therapy by the translational research program of the radiation therapy oncology group

Therapeutic decisions in non-small cell lung cancer (NSCLC) have been mainly based on disease stage, performance status, and co-morbidities, and rarely on histological or molecular classification. Rather than applying broad treatments to unselected patients that may result in survival increase of only weeks to months, research efforts should be, and are being, focused on identifying predictive markers for molecularly targeted therapy and determining genomic signatures that predict survival and response to specific therapies. The availability of such targeted biologics requires their use to be matched to tumors of corresponding molecular vulnerability for maximum efficacy. Molecular markers such as epidermal growth factor receptor (EGFR), K-ras, vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and anaplastic lymphoma kinase (ALK) represent potential parameters guide treatment decisions. Ultimately, identifying patients who will respond to specific therapies will allow optimal efficacy with minimal toxicity, which will result in more judicious and effective application of expensive targeted therapy as the new paradigm of personalized medicine develops.     

A model combining age,equivalent uniform dose and IL-8 may predict radiation esophagitis in patients with non-small cell lung cancer

Background and purpose

To study whether cytokine markers may improve predictive accuracy of radiation esophagitis (RE) in non-small cell lung cancer (NSCLC) patients.

吉非替尼治疗化疗失败的局部晚期或转移性非小细胞肺癌疗效及生存的预测因素

背景与目的吉非替尼是一种选择性表皮生长因子受体酪氨酸激酶抑制剂(EGFRTKI),已被证实为治疗化疗失败的晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的有效药物,其治疗亚洲晚期NSCLC患者的疗效与联合化疗的疗效相当。国外的临床研究结果显示,种族、性别、吸烟史及组织病理类型被认为是吉非替尼疗效及生存的相关因素。但在亚洲人群中,吉非替尼疗效及生存的预测因素尚未清楚。本研究回顾分析了中国153例局部晚期或转移性NSCLC患者的接受吉非替尼治疗的情况,旨在分析疗效与生存的预测因素。方法对2003年11月至2004年6月,参加吉非替尼在中国的注册临床研究的153例NSCLC患者的临床、病理特征与疗效及生存的相关情况进行了回顾性分析。疗效相关性采用χ2检验及Logistic回归分析分别进行单因素及多因素分析;生存分析运用Logrank检验及Kaplan-Meier、Cox回归分析分别进行单因素及多因素分析。结果153例可评价的患者中,多因素分析显示年龄≤65岁及从初诊到吉非替尼治疗的时间间隔≥6个月者,与客观有效率明显相关(P<0.05)。中位随访时间10.0个月(0.5~16.8个月),中位生存期为10.3个月(95%CI,8.1~12.6个月),1年生存率为44.1%。COX回归分析显示,PS评分0~1、末次化疗达疾病控制以及吉非替尼治疗达疾病控制是生存的独立预后因素(P<0.05)。结论吉非替尼对既往化疗失败的局部晚期或转移性NSCLC的中国患者有较好的疗效。年龄≤65岁及从初诊到吉非替尼治疗的时间间隔为≥6个月是吉非替尼疗效的预测因素。PS评分0~1、末次化疗达疾病控制及吉非替尼治疗达疾病控制是生存的独立预后因素。     

Swedish lung cancer radiation study group: predictive value of histology for radiotherapy response in patients with non-small cell lung cancer

The aim of the present study was to evaluate the potential predictive value of histology in non-small cell lung cancer (NSCLC) treated with curatively intended radiotherapy. In a collaborative effort among all the Swedish Oncology Departments, clinical data were collected for 1146 patients with a diagnosed non-small cell lung cancer subjected to curatively intended irradiation (?50 Gy) during the years 1990 to 2000. The included patients were identified based on a manual search of all medical and radiation charts at the oncology departments from which the individual patient data were collected. Only patients who did not have a histological diagnosis date and death date/last follow-up date were excluded (n = 141). Among the 1146 patients with non-small cell carcinoma eligible for analysis, 919 were diagnosed with either adenocarcinoma (n = 323) or squamous cell carcinoma (n = 596) and included in this study. The median survival for the 919 patients was 14.8 months, while the 5-year survival rate was 9.5%. Patients with adenocarcinoma had a significantly better overall survival compared with patients with squamous cell carcinoma (p = 0.0062, log-rank test). When comparing different stages, this survival benefit was most pronounced for stages IIA–IIB (p < 0.0001, log-rank test). The difference in survival between the two histological groups was statistically significant in a univariate Cox analysis (p = 0.0063) as well as in two multivariate Cox analyses including demographic and treatment variables (p = 0.037 and p = 0.048, respectively). In this large population based retrospective study we describe for the first time that patients with adenocarcinoma have a better survival after curatively intended radiation therapy in comparison with squamous cell carcinoma patients, particularly those with clinical stages IIA–IIB.     

Genetic variants of the LIN28B gene predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy

BackgroundLIN28 is an RNA-binding protein that not only plays key roles in multiple cellular developmental processes and tumourigenesis, but also is involved in tissue inflammatory response. However, no published study has investigated associations between genetic variants in LIN28 and radiation-induced pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with definitive radiation therapy.MethodsWe genotyped eight potentially functional single nucleotide polymorphisms (SNPs) of LIN28A (rs11247946 T>C, rs3811464 C>T, rs11581746 T>C, and rs12728900 G>A) and LIN28B (rs314280 G>A, rs12194974 G>A, rs17065417 A>C and rs314276 C>A) in 362 patients with NSCLC, who received definitive radio(chemo)therapy. The associations between RP risk and genotypes were assessed by hazards ratio (HR) in Cox proportional hazards regression analysis with time to event considered with and without adjustment for potential confounders.ResultsMultivariate analyses found that patients carrying LIN28B rs314280 AG and AA/AG or rs314276 AC and AA/AC genotypes had a higher risk of grade ⩾3 RP (for rs314280 AG and AA/AG versus GG, adjusted HR = 2.97 and 2.23, 95% confidence interval (CI) = 1.32–6.72 and 1.01–4.94, P = 0.009 and 0.048, respectively; for rs314276 AC and AA/AC versus CC, adjusted HR = 2.30 and 2.00, 95% CI = 1.24–4.28 and 1.11–3.62, and P = 0.008 and 0.022, respectively). Further stratified analyses showed a more consistent and profound risk in the subgroups of age <65 years, males, stage III/IV, ever smokers, having radio-chemotherapy and mean lung dose (MLD) ⩾19.0 Gy.ConclusionGenetic variants of LIN28B, but not LIN28A, may be biomarkers for susceptibility to severe RP in NSCLC patients. Large, prospective studies are needed to confirm our findings.     

Current treatment landscape for oligometastatic non-small cell lung cancer

The management of patients with advanced non-small cell lung carcinoma (NSCLC) has undergone major changes in recent years. On the one hand, improved sensitivity of diagnostic tests, both radiological and endoscopic, has altered the way patients are staged. On the other hand, the arrival of new drugs with antitumoral activity, such as targeted therapies or immunotherapy, has changed the prognosis of patients, improving disease control and prolonging survival. Finally, the development of radiotherapy and surgical and interventional radiology techniques means that radical ablative treatments can be performed on metastases in any location in the body. All of these advances have impacted the treatment of patients with advanced lung cancer, especially in a subgroup of these patients in which all of these treatment modalities converge. This poses a challenge for physicians who must decide upon the best treatment strategy for each patient, without solid evidence for one optimal mode of treatment in this patient population. The aim of this article is to review, from a practical and multidisciplinary perspective, published evidence on the management of oligometastatic NSCLC patients. We evaluate the different alternatives for radical ablative treatments, the role of primary tumor resection or radiation, the impact of systemic treatments, and the therapeutic sequence. In short, the present document aims to provide clinicians with a practical guide for the treatment of oligometastatic patients in routine clinical practice.     

非小细胞肺癌放化综合治疗的前瞻性随机研究

目的 对比观察非小细胞肺癌单纯放疗和放化综合治疗的疗效。方法 从１９９５年１月 到１９９７年１２月,将符合入组条件的８２例非小细胞肺癌患者随机分为放疗组和化放疗综合治疗组。其中完成治疗计划的有７４例,３５例属单纯放疗组,３９例属化放疗综合治疗组。综合治疗组中２１例为增敏化疗（氟脲嘧啶、顺铂）,在放疗的第１、４周给药;１８例为联合方案化疗,在放疗前、中、后进行,最少两周期,药物为卡铂、顺铂、足叶乙甙     

Serum inflammatory miRNAs predict radiation esophagitis in patients receiving definitive radiochemotherapy for non-small cell lung cancer

Background and purposeMicroRNAs (miRNAs) are small, highly conserved non-coding RNAs that regulate many biological processes. We sought to investigate whether three serum miRNAs related to immunity or inflammation were associated with esophagitis induced by chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC).Material and methodsWe measured serum miR-155, miR-221 and miR-21, before and during week 1–2 of CRT for 101 NSCLC patients by real-time PCR. Associations between miRNA and severe radiation-induced esophageal toxicity (RIET) were analyzed by logistic regression.ResultsWe found that patients with stage IIIB–IV disease, higher mean esophagus dose or esophageal V₅₀ had higher rates of severe RIET. Furthermore, high levels of miR-155 and miR-221 at week 1–2 of CRT were also risk factors for severe RIET (miR-155: OR = 1.53, 95% CI: 1.04–2.25, P = 0.03; miR-221: OR = 2.07, 95% CI: 1.17–3.64, P = 0.012). In addition, the fold change of miR-221 was also predictive of severe RIET (OR = 1.18, 95% CI: 1.02–1.37, P = 0.026). However, pretreatment miRNAs was not predictive of severe RIET.ConclusionsHigh serum miR-155 and miR-221 during the first 2 weeks of CRT were associated with the development of severe RIET, suggesting that these miRNAs may be useful as an early surrogate for this form of toxicity.     

Role of pemetrexed in non-small cell lung cancer

Pemetrexed was approved for the treatment of relapsed or chemotherapy refractory non-small cell lung cancer patients, as it produced similar response and survival outcomes and less toxicity as compared to taxotere. Pemetrexed in combination with platinum analogs or with gemcitabine or vinorelbine, produce equivalent responses and overall survival results compared to combinations of platinum analogs with other drugs. The role of bevacizumab and the inhibitors of epithelial growth factor receptor also should be evaluated in selected patients with NSCLC treated with pemetrexed combinations. Further increases in drug dose may be possible using transfer of drug resistance genes in hematopoietic stem cells.     

中国的非小细胞肺癌Gefitinib分子靶向治疗

目的 探讨非小细胞肺癌gefitinib分子靶向治疗的国内经验。方法 收集国内7个医院未经正式发表的用gefitinib治疗晚期非小细胞肺癌的资料，重点分析广东省肺癌研究所的病例情况。结果 自2001年7月至2003年12月．共有282例晚期非小细胞肺癌接受gefitinib治疗。有效率为22．2％～47．7％，疾病控制率为62．6％～81．8％。没有观察到明显的毒副作用。结论 gefitinib可安全有效地用于国内的晚期非小细胞肺癌。     

BIM联合Scribble预测晚期非小细胞肺癌化疗效果

背景与目的：BIM基因和Scribble均是参与细胞凋亡的重要介质。BIM基因的BH3域缺失,可引起凋亡受阻。Scribble低表达对肿瘤细胞增殖、肿瘤转移和耐药有促进作用。通过检测BIM基因多态性和Scribble表达,探讨其与晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）化疗效果的关系。方法：收集2014年1月—2015年12月于复旦大学附属中山医院就诊的96例晚期NSCLC患者,所有患者均一线接受含铂方案化疗。采用聚合酶链反应（polymerase chain reaction,PCR）检测NSCLC患者组织标本中的BIM基因多态性,采用免疫组织化学法检测标本中的Scribble表达水平,然后评估BIM基因多态性和Scribble表达与化疗疗效的关系。结果：BIM基因野生型组化疗的中位无进展生存期（progression-free survival,PFS）优于BIM基因缺失组（5.0个月 vs 2.7个月,P=0.01）。Scribble高表达组化疗的中位PFS优于Scribble低表达组（7.0个月 vs 4.0个月,P<0.001）。BIM基因野生型且Scribble高表达组（BIM-WT-Scrib-H）化疗的中位PFS优于BIM基因野生型或Scribble高表达组（BIM-WT/Scrib-H）和BIM基因缺失型且Scribble低表达组（BIM-del-Scrib-L）（10.0个月 vs 4.5个月 vs 2.0个月,P<0.001）。多因素分析结果显示,BIM基因缺失型为化疗具有更短PFS的独立预测因素（HR=3.221,P<0.001）;Scribble低表达为化疗具有更短PFS的独立预测因素（HR=3.312,P<0.001）。结论：BIM基因缺失型和Scribble低表达是晚期NSCLC化疗效果不佳的独立预测因素,两者联合应用有更好的预测价值。     

A phase II trial of accelerated hypofractionated three-dimensional conformal radiation therapy in locally advanced non-small cell lung cancer

Purpose

The aim of this study is to evaluate the safety and efficacy of accelerated hypofractionated radiotherapy (HypoRT) combined with sequential chemotherapy in locally advanced non-small cell lung cancer (NSCLC).

Materials and methods

A total of 34 patients with stage III NSCLC were enrolled. All patients received accelerated HypoRT (initially 50 Gy/20 fractions, then a fraction dose of 3 Gy) using three-dimensional conformal radiation therapy (3D-CRT), omitting elective nodal irradiation (ENI), to a total dose of 65-68 Gy. All patients received two cycles of induction chemotherapy; 1-2 cycles of consolidation chemotherapy were given to 31 patients. The primary outcome measure was a profile of radiation toxicity. The secondary endpoints included overall survival (OS), progression-free survival (PFS), locoregional PFS (LR-PFS) and the pattern of initial failure.

Results

Radiation toxicity was minimal. The median and 3-year OS, PFS were 19.0 months, 32.1%; 10.0 months, 29.8%, respectively. The 1-, 2-, and 3-year LR-PFS were 69.6%, 60.9% and 60.9%, respectively. No patient experienced isolated elective nodal failure as the first site of failure.

Conclusion

This study suggests that accelerated HypoRT using 3D-CRT omitting ENI can be used in combination with sequential chemotherapy in locally advanced NSCLC.     

吉非替尼治疗晚期非小细胞肺癌的临床研究

目的:总结吉非替尼治疗晚期非小细胞肺癌的近期疗效及副作用。方法:40例经放化疗失败的非小细胞肺癌患者进入本研究,其中8例局限于胸腔内,32例已有远处转移。口服吉非替尼250mg/次,每天1次。全组服药的中位时间为5个月。按照WHO标准统一评定疗效及副反应。结果:40例可评价病例中完全缓解2例,部分缓解10例,病情稳定12例,病情进展16例。全组有效率为30%,疾病控制率为60%,症状缓解率为30%,缓解最明显的症状为咳嗽和疼痛。中位生存期5·6个月(1~20个月),中位进展时间(TTP)为(6·6±1·8)个月,1年生存率为45%。主要的毒副作用是皮疹,共发生25例,占全组的62·5%,其它副作用有腹泻、恶心、脱发,无1例因毒副反应退出。结论:吉非替尼对晚期非小细胞肺癌有明显的抗肿瘤作用,是一种有效且具有良好耐受性的治疗药物。     

局部晚期非小细胞肺癌外科治疗中的气道重建

背景与目的部分局部晚期非小细胞肺癌患者需要采取不同的气道重建方式，以彻底切除病变并最大限度保存肺功能。本研究旨在探讨气道重建中的外科相关问题。方法回顾分析研究2003年1月～2005年6月2206例肺癌手术中100例气道重建患者的临床资料，其中鳞癌42例，腺鳞癌23例，腺癌11例，粘液表皮样癌5例，腺样囊性癌4例，类癌3例及其它混合散在分布类型12例。ⅠB期34例，ⅡB期23例，ⅢA期23例，ⅢB期20例。主要手术方式包括：右上叶袖状切除42例，右下叶袖状切除1例，左上叶袖状切除24例，左下叶袖状切除4例。两叶袖状切除8例，隆凸成形重建17例，肺叶袖状切除合并肺动脉成形4例。结果97例患者为完全性切除（R0），3例为不完全性切除（R1）。术后5例出现并发症，分别为肺部感染2例，胸腔感染1例，支气管胸膜瘘1例，肺泡胸膜瘘1例，并发症发生率为5％。术后住院日为4～27日（中位11日）。99例治愈出院，肺部感染导致死亡1例，手术死亡率为1％。结论对局部晚期非小细胞肺癌采取适当的气道重建方式，符合外科手术原则，可取得较满意的治疗效果。对血管、气管、支气管的处理技巧是手术获得成功的关键。     

吉非替尼治疗晚期非小细胞肺癌53例临床观察

目的观察吉非替尼(易瑞沙)治疗国人非小细胞肺癌(NSCLC)的疗效及毒副作用。方法本研究为阿斯利康公司的扩大记名供应(ExpandedAccessProgramme,EAP)研究的一部分。自2003年2月~2005年12月口服易瑞沙250mg,每日1次,治疗经放化疗失败或不适宜放化疗的晚期NSCLC患者共91例。对服药超过16周的患者进行客观疗效及毒副反应评价。结果91例患者中可评价疗效者53例,获得CR1例(1.9%),PR15例(28.3%),RR(CR PR)16例(30.2%),SD26例(49.1%),疾病控制率(DCR)42例(79.2%),PD11例(20.8%)。肿瘤进展时间(TTP)3.5~25个月,中位TTP7.0个月。生存期4.5~32个月,中位生存期(MST)11个月。1年生存率47.2%(25/53),2年生存率3.8%(2/53)。与药物相关的不良反应依次为痤疮样皮疹25例(47.2%)、皮肤干燥5例(9.4%)、口腔溃疡4例(7.5%)、恶心10例(18.9%),腹泻6例(11.3%),肝功能显著异常(SGPT升高)4例(7.5%)。结论吉非替尼治疗国人晚期NSCLC有效,毒副反应轻微,患者耐受性和依从性好。     

香菇多糖联合化疗治疗晚期非小细胞肺癌

背景与目的 香菇多糖作为一种生物免疫调节剂日益受到药学界与临床的广泛重视，目前中国和日本都将其作为一种抗肿瘤辅助药品广泛应用。本研究旨在观察香菇多糖联合化疗治疗Ⅲ、Ⅳ期非小细胞肺癌的治疗效果。方法 81例Ⅲ、Ⅳ期非小细胞肺癌患者随机分为A、B两组，A组（42例）采用香菇多糖加化疗，B组（39例）采用单纯化疗。两组患者在治疗前后测定外周血T淋巴细胞亚群（CD3、CD4、CD4／CDR）和NK细胞活性，并以正常人（30例）作为对照，对患者疗效、免疫功能、生活质量及不良反应进行评价。结果 治疗后A、B两组的有效率分别为50％和33％（P＜0．05）；A组的T淋巴细胞亚群和NK细胞活性明显高于治疗前（P＜0．01），CDR明显低于治疗前（P＜0．05），而B组无明显变化（P〉0．05）；A组的Karnofsky评分上升率（52％）高于B组（23％）（P〈0．01）；B组的Ⅱ～Ⅳ度白细胞减少及恶心呕吐反应发生率（分别为51和44例次）高于A组（分别为39和24例次）（P＜0．05）。结论香菇多糖联合化疗治疗Ⅲ、Ⅳ期非小细胞肺癌的疗效优于单纯化疗。     

A Phase Ⅱ Trial of Gefitinib as Maintenance Therapy after First-Line Chemotherapy for Advanced Non-Small Cell Lung Cancer in China

Objective:To investigate the efficacy and safety of gefitinib as maintenance therapy for advanced non-small cell lung cancer (NSCLC) patients who obtained disease control (DC) after first-line chemotherapy in Chinese population. Methods:Chinese patients with advanced NSCLC treated with standard chemotherapy and obtained DC were assigned to receive gefitinib as maintenance treatment. The primary end point was overall survival time (OS), the second end point was disease control rate (DCR) and progression-free survival time (PFS). DCR included complete response (CR) plus partial response (PR) and plus stable disease (SD). The impact of epidermal growth factor receptor (EGFR) mutation status on the treatment as exploratory point was also evaluated by denaturing high-performance liquid chromatography (DHPLC). Results:Among 75 enrolled patients, the overall response rate was 37% and the DCR (CR + PR +SD) was 66%. The median PFS and OS were 17.13 months and 26.13 months respectively, with 1- and 2-year survival rates 89.3% and 34.7%. Patients harboring somatic EGFR mutations obtained a prolonged median PFS and OS compared with EGFR wide type (25.1 vs. 13.0 months, P=0.019 and 33.37 vs. 25.57 months, P=0.014, respectively). In COX regression model, only EGFR mutation status was the independently factor influencing both PFS and OS (P=0.029 and 0.017, respectively), however, rash status was the predictor in terms of PFS (P=0.027).Conclusion:Gefitinib produced encouraging survival when delivered as maintenance therapy in Chinese patients obtaining DC after first-line chemotherapy, especially for patients carrying somatic EGFR mutations. EGFR mutation is an independently predictive factor of survival.