埃克替尼联合放疗治疗晚期非小细胞肺癌的研究进展

研究证实埃克替尼治疗表皮生长因子受体突变的非小细胞肺癌(NSCLC)患者疗效明确,并具有放疗增敏效果。国内有大量的研究表明埃克替尼联合放疗能显著提高NSCLC患者生存时间,特别是对老年患者或脑转移患者,且不良反应较小。因此,埃克替尼联合放疗有可能成为治疗晚期NSCLC患者的有效治疗手段。现对其相关研究进展作一综述。     

Targeted drugs for unselected patients with advanced non-small-cell lung cancer: a network meta-analysis

Background

Currently, targeted therapy has shown encouraging treatment benefits in selected patients with advanced non-small cell lung cancer (NSCLC). However, the comparative benefits of targeted drugs and chemotherapy (CT) treatments in unselected patients are not clear. We therefore conduct a network meta-analysis to assess the relative efficacy and safety of these regimens.

Methods

PubMed, EMBASE, Cochrane Library and abstracts from major scientific meetings were searched for eligible literatures. The odds ratio (OR) for objective response rate (ORR) and safety was used for pooling effect sizes. Bayesian network meta-analysis was conducted to calculate the efficacy and safety of all included treatments. All tests of statistical significance were two sided.

Results

A total of 13,060 patients from 24 randomized controlled trials (RCT) were assessed. The targeted agents included bevacizumab (Bev), gefitinib (Gef), erlotinib (Erl) and cetuximab (Cet). Network meta-analysis showed that Bev + CT had a statistically significantly higher incidence of ORR relative to the other six different treatments, including placebo (OR =6.47; 95% CI, 3.85–10.29), Erl (OR =2.81; 95% CI, 2.08–3.70), CT (OR =1.92; 95% CI, 1.61–2.28), Gef (OR =1.40; 95% CI, 1.10–1.75), Erl + CT (OR =1.46; 95% CI, 1.17–1.80) and Gef + CT (OR =1.75; 95% CI, 1.36–2.22), whereas placebo and Erl were associated with statistically significantly lower incidence of ORR. Trend analyses of rank probability revealed that Bev + CT had the highest probability of being the best treatment arm in term of ORR, followed by Cet + CT. Meanwhile, Cet + CT showed significant severer rash and thrombocytopenia compared with Bev + CT. Gef was probable to be the rank 3 for ORR but was associated with relatively low risk for grade ≥3 toxicities.

Conclusions

Our study suggested that Bev + CT may offer better ORR in the treatment of unselected patients with advanced NSCLC. Future studies will be needed to investigate whether the increase of ORR with targeted drugs would be translated into survival benefits.     

Risk factors for brain metastases from non-small-cell lung cancer: A protocol for observational study

Brain metastasis is a common site of distant metastasis of non-small-cell lung cancer (NSCLC) that greatly reduces the prognosis of patients. In this study, we explored the correlation between different clinical factors and secondary brain metastases in NSCLC in an attempt to identify NSCLC patient populations at high risk of metastasis to the central nervous system.We collected data for 350 NSCLC patients from the medical record system of the First Affiliated Hospital of Nanchang University from June 2015 to June 2019, and these patients had pathologically verified diagnoses. The correlations between age at the time of diagnosis, sex, histological type, calcium concentration, hemoglobin (HB), fibrinogen (Fbg), activated partial thromboplastin time (APTT), alkaline phosphatase (ALP), carcinoembryonic antigen (CEA), CA125, and CA199 levels and brain metastasis were analyzed. Multivariate logistic regression analysis was used to identify risk factors for NSCLC brain metastasis. A receiver operating characteristic (ROC) curve was used to calculate the cutoff, sensitivity, and specificity of the independent related factors.Of the 350 patients, 57 were diagnosed with brain metastases. Univariate and multivariate logistic regression analysis indicated that lesion diameter, calcium concentration, and CEA level were independent risk factors correlated with brain metastasis (P < .05). There were no significant differences in age, sex, type of histopathology, presence or absence of mediastinal lymph node metastasis, HB, Fbg, APTT, ALP, cancer antigen 125 (CA-125), or cancer antigen 199 (CA-199) levels between patients with brain metastases and patients without brain metastases (P > .05, respectively). ROC curves demonstrated that these factors had comparable accuracy in predicting brain metastasis (area under the curve [AUCs] were 0.620, 0.661, and 0.729, respectively). The cutoff values for lesion diameter, calcium, and CEA were 5.050 cm, 2.295 mmol/L, and 11.160 ng/mL, respectively. The sensitivities for prediction brain metastasis were 59.6%, 64.9%, and 73.3%, with specificities of 63.1%, 59.2%, and 70.3%, respectively.According to our study, lesion diameter, calcium concentration, and CEA level are independent risk factors for brain metastases in NSCLC patients. Thus, we can strengthen the regular follow-up of NSCLC patients with tumor diameter > 5.050 cm, calcium > 2.295 mmol/L, CEA > 11.160 ng/mL, and use these factors as a reference for preventive treatments.     

Proton beam radiotherapy for patients with early-stage and advanced lung cancer: a narrative review with contemporary clinical recommendations

Although lung cancer rates are decreasing nationally, lung cancer remains the leading cause of cancer related death. Despite advancements in treatment and technology, overall survival (OS) for lung cancer remains poor. Proton beam therapy (PBT) is an advanced radiation therapy (RT) modality for treatment of lung cancer with the potential to achieve dose escalation to tumor while sparing critical structures due to higher target conformality. In early and late-stage non-small cell lung cancer (NSCLC), dosimetric studies demonstrated reduced doses to organs at risk (OARs) such as the lung, spinal cord, and heart, and clinical studies report limited toxicities with PBT, including hypofractionated regimens. In limited-stage SCLC, studies showed that regimens chemo RT including PBT were well tolerated, which may help optimize clinical outcomes. Improved toxicity profiles may be beneficial in post-operative radiotherapy, for which initial dosimetric and clinical data are encouraging. Sparing of OARs may also increase the proportion of patients able to complete reirradiation for recurrent disease. However, there are various challenges of using PBT including a higher financial burden on healthcare and limited data supporting its cost-effectiveness. Further studies are needed to identify subgroups that benefit from PBT based on prognostic factors, and to evaluate PBT combined with immunotherapy, in order to elucidate the benefit that PBT may offer future lung cancer patients.     

Successful treatment of 2 patients with brain metastases from non-small cell lung cancer with epidermal growth factor receptor mutation receiving dacomitinib: A case report

Rationale:Approximately 20% of patients with non-small cell lung cancer (NSCLC) are diagnosed with brain metastasis, which is related to poor survival outcomes. The ability of tyrosine kinase inhibitor drugs to penetrate the blood–brain barrier makes them a potential option for intracranial metastases. Dacomitinib, an irreversible second-generation pan-HER tyrosine kinase inhibitor, has become a standard therapy for patients with epidermal growth factor receptor mutations. However, its efficacy in patients with brain metastases (BMs) is not yet established. Here, we present 2 patients with epidermal growth factor receptor-mutant NSCLC with brain metastasis. After initiation of dacomitinib as first-line treatment, a significant clinical response was achieved, and a long-lasting complete remission was achieved in 1 patient up to this date.Patient concern:Case 1 was a 47-year-old man who was admittedtothe hospital because of recurrent cough and expectoration for >1 year. Chest computed tomography scans revealed a high-density shadow in the left upper lobe. Cranial magnetic resonance imaging indicated an abnormal nodular enhancement in the right cerebellar hemisphere. Case 2 was a 55-year-old man with a chief complaint of intermittent cough and expectoration for >1 month. Chest computed tomography revealed a high-density mass in the left superior lobe. Magnetic resonance imaging of the central nervous system revealed 2 abnormal nodular enhancements in the left frontal lobe.Diagnosis:Both patients were diagnosed with lung adenocarcinoma by bronchoscopy and lymph node biopsy.Interventions:Both patients received dacomitinib 30 mg once daily as first-line therapy for 8 and 11 months, respectively until disease progression.Outcome:After treatment with dacomitinib, both patients achieved complete response in BMs. Progression-free survival was 11 and 8 months, respectively.Lessons:Dacomitinib strongly controlled BMs in patients with advanced NSCLC, and the adverse reactions were tolerable. Dacomitinib may be considered a new treatment option for these patients. Further prospective studies are recommended to confirm this conclusion.     

Impact of EGFR mutation status on tumor response and progression free survival after first-line chemotherapy in patients with advanced non-small-cell lung cancer: a meta-analysis

Objectives

Non-small-cell lung cancer (NSCLC) patients harboring sensitive epidermal growth factor receptor (EGFR) mutations derive greater benefits from EGFR-tyrosine kinase inhibitors (EGFR-TKIs) than those with wild type tumors. However, whether EGFR mutation status is associated with the efficacy of cytotoxic chemotherapy or prognosis in advanced NSCLC patients remained controversial. Thus, we sought to conduct a meta-analysis to answer this question.

Methods

Electronic databases were searched for eligible literatures. The primary outcomes were objective response rate (ORR) and 6-month progression-free survival (PFS) rate. The pooled odds ratio (OR) was calculated using random-effects model. Subgroup analyses stratified by study types, EGFR mutation detection methods, chemotherapy regimens, and patient origins were proposed.

Results

A total of 14 studies involving 1,772 advanced NSCLC patients with known EGFR mutation status who had received first-line chemotherapy were included. Patients with positive EGFR mutation had numerically higher ORR than wild type patients (36.2% vs. 30.1%) without significant differences (OR 1.24, 95% CI, 0.90 to 1.70; P=0.19). However, patients with EGFR mutants had significantly superior 6-month PFS rate than wild-type patients (58.6% vs. 47.2%; OR 1.88, 95% CI, 1.33 to 2.65; P=0.0003). Results of the subgroup analyses were concordant with the overall ones.

Conclusions

This comprehensive analysis revealed that advanced NSCLC patients with sensitivity EGFR mutation had higher 6-month PFS rate and potentially greater ORR compared with wild-type patients after first-line chemotherapy. It suggested that EGFR mutation status should be considered a significant factor for patient stratification in evaluating the efficacy of antitumor agents in addition to EGFR-TKIs.     

厄洛替尼一线对老年中晚期非小细胞肺癌的疗效分析

目的探讨厄洛替尼一线化疗方案对于老年中晚期非小细胞肺癌患者的临床疗效及安全性。方法对收治78例老年中晚期非小细胞肺癌患者,随机分为实验组和对照组。实验组患者给予厄洛替尼化疗,对照组给予紫杉醇化疗。比较两组患者治疗的有效率、疾病控制率、无进展生存期、总生存期以及不良反应的发生情况。结果实验组患者有效率、疾病控制率、无进展生存期、总生存期分别为28.2%、76.9%、(168.3±21.4)d、(287.7±39.3)d,对照组患者为20.5%、74.4%(149.23±19.7)d、(243.7±12.6)d,实验组有效率、无进展生存期、总生存期显著高于对照组(P<0.05),两组疾病控制率无显著差别(P>0.05)。结论厄洛替尼一线化疗方案对于不愿接受传统化疗的老年中晚期非小细胞肺癌患者疗效显著,且不良反应可以耐受。     

Clustered incidence of acute promyelocytic leukemia during gefitinib treatment for non-small-cell lung cancer: experience at a single institution

Although gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been shown a significant activity for recurrent non-small-cell lung cancer (NSCLC), its long-term adverse effect with its continuous usage has hitherto not been clearly elucidated. Subjects were 108 consecutive NSCLC cases who were treated with gefitinib between November 2001 and December 2004 at our single institution. A crude incidence rate ratio was calculated by ratio of crude incidence rate in our subject to population-based incident rate of all leukemia (ICD: C91-95) in the same region. The 95% confidence intervals (CIs) were calculated based upon a Poisson distribution. Three cases of acute promyelocytic leukemia (APL) occurred during gefitinib treatment, and these patients' past treatment histories are presented herein. No other malignancy was identified. All of the cases were diagnosed at the stage of mild-to-moderate cytopenia, especially thrombocytopenia, without disseminated intravascular coagulation. All presented a normal karyotype with positive PML-RARalpha in RT-PCR, indicating submicroscopic translocation. They responded well to APL treatments, including all-trans-retinoic acid. The crude incident rate ratio was 639.9 (95% confidence interval: 131.6-1,878.9, P < 0.0001) when the APL incidence in this cohort was compared to all leukemia cases in the general population in the same district in Japan. Thus we had three cases of secondary APL patients within the gefitinib-treated NSCLC cohort. Although we cannot exclude an effect of past exposure of other cytotoxic agents and radiotherapy as a cause of APL, APL inducibility of gefitinib should be clarified in the further study.     

Traditional herbal medicine combined with first-line platinum-based chemotherapy for advanced non-small-cell lung cancer: A PRISMA-compliant systematic review and meta-analysis

Background:Non-small-cell lung cancer (NSCLC) is a major health burden in many countries. This review aimed to evaluate the efficacy of traditional herbal medicine (THM) combined with first-line platinum-based chemotherapy (PBCT) for the treatment of advanced NSCLC.Methods:From inception to April 2021, relevant studies were retrieved from 9 electronic databases. Randomized controlled trials (RCTs) comparing survival outcomes of THM + PBCT treatment with PBCT treatment in patients with advanced NSCLC were reviewed. The risk of bias was evaluated using the Cochrane Risk of Bias Tool. Overall survival, 1-year survival, progression-free survival or time to progression, tumor response rate, and adverse effects were analyzed.Results:Sixteen RCTs comprising 1445 patients were included. The meta-analysis indicated that THM + PBCT treatment, compared to PBCT alone, could improve overall survival (median survival ratio = 1.24, 95% confidence intervals [CI] [1.11, 1.39], P < .001), progression-free survival/time to progression (median survival ratio = 1.22, 95% CI [1.09, 1.37], P < .001), and the 1-year survival rate (risk ratio [RR] = 1.56, 95% CI [1.31, 1.86], P < .001). THM + PBCT also led to a higher tumor response rate (RR = 1.39, 95% CI [1.22, 1.59], P < .001) and lower incidence of thrombocytopenia (RR = 0.72, 95% CI [0.56, 0.92], P = .009) and nausea/vomiting (RR = 0.35, 95% CI [0.21, 0.57], P < .001), while there was no significant effect observed on leukopenia (RR = 0.68, 95% CI [0.34, 1.36], P = .27).Conclusion:THM, when used in combination with PBCT, might increase survival and the tumor response rate while decreasing the side effects caused by chemotherapy in patients with advanced NSCLC. However, considering the limited methodological qualities of the included trials, more rigorous RCTs are needed.     

Clinical features and intervention timing in patients with pregnancy-associated non-small-cell lung cancer

BackgroundThere is no standard procedure available to diagnose and treat with pregnancy-associated non-small cell lung cancer (NSCLC). The present study was to investigate the clinical and molecular features, and the proper intervention timing for this population.MethodsThis is a retrospective, pooled analysis. Cases from Guangdong Lung Cancer Institute and other published cases were collected and reviewed. The overall survival (OS) was analyzed according to the diagnosis timing, the treatment timing and the molecular character. The safety profile during pregnancy was also evaluated.ResultsSeventy-seven cases were collected including 11 patients from our center. The anaplastic lymphoma kinase (ALK) gene rearrangement and epidermal growth factor receptor (EGFR) mutation rates were 47% and 32%, respectively. The OS of patients treated during pregnancy, after delivery, and those not treated differed significantly [12 months vs. not reached (NR) vs. 1 month; P<0.001]. However, the OS between patients treated during pregnancy and after delivery was similar (P=0.173). Patients with ALK or EGFR exhibited a significantly better OS than those with wild-type [NR vs. 22 months vs. 8 months; P<0.001; hazard ratio (HR) =0.02, 95% confidence interval (CI): 0.00–0.22; HR =0.08, 95% CI: 0.01–0.76]. Fetal complications were observed in babies whose mothers were treated during pregnancy.ConclusionsThe pregnancy-associated NSCLC population exhibited a high prevalence of driver genes and a promising effect of targeted therapy. No significant difference in the OS was observed between patients treated during pregnancy and patients treated after delivery.     

厄洛替尼治疗晚期非小细胞肺癌36例临床观察

目的探讨厄洛替尼单药一线或二线治疗晚期非小细胞肺癌的疗效及不良反应。方法收集36例我科就诊的ⅢB期或者Ⅳ期非小细胞肺癌病例:所有患者均为病理学确诊,患者因体力状态较低一线选择厄洛替尼或至少接受1～2个周期化疗,治疗失败或因毒副反应不能耐受后二线选择口服厄洛替尼,具体用法:150 mg/qd,直至病情进展或者不能耐受副反应。结果在36例患者中,CR0例,PR 9例(25.0%),SD17例(45.2%),PD10例(27.8%),ORR为25.0%,DCR为72.2%。中位TTP为5.3个月,统计学结果显示:病理学类型与患者的DCR有关(P=0.029),腺癌的DCR较高。最常见的不良反应为皮疹及腹泻,经对症处理后可好转。结论厄洛替尼治疗晚期非小细胞肺癌疗效较好,不良反应较轻。     

Transformation of NSCLC to SCLC after 1st- and 3rd-generation EGFR-TKI resistance and response to EP regimen and erlotinib: 2 CARE-compliant case reports

Rationale:Genotypic and histological evolution of non-small-cell lung cancer (NSCLC) into small-cell lung cancer (SCLC) has been described as a mechanism of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy. However, the number of clinical cases is rare.Patient concerns:Two lung adenocarcinoma patients with EGFR mutations who recurred after radical resection transformed into SCLC under treatment with the sequential first- and third-generation EGFR-TKIs.Diagnosis:The 2 cases were both confirmed as SCLC by pathological rebiopsy after EGFR-TKIs resistance.Interventions:Case 1 was treated with etoposide plus cisplatin (EP) regimen and erlotinib, while case 2 was treated with erlotinib and EP followed by oral etoposide.Outcomes:Case 1 treated with EP only achieved 3-month progression-free survival (PFS), which is the first case that reported T790 M/C797S cis-mutation for osimertinib resistance before the SCLC transformation. However, case 2 treated with erlotinib and EP followed by oral etoposide, PFS lasted for 8 months.Lessons:The cases highlighted the importance of rebiopsy that identified pathologically SCLC transformation after EGFR-TKI resistance, and suggested the treatment of erlotinib plus EP followed by etoposide, which could provide a reference for such phenotype.     

厄洛替尼与化疗治疗晚期非小细胞肺癌的临床观察

目的观察厄洛替尼与含铂化疗方案治疗晚期非小细胞肺癌的疗效和安全性。方法对我院晚期NSCLC给予化疗组30例,服用厄洛替尼组27例定期随访,观察疗效与不良反应。结果 57例可评价疗效的患者中,化疗组30例:CR:0例,PR:6例,SD:10例,PD:14例;缓解率6/30(20%),疾病控制率16/30(53.3%);服用厄洛替尼组27例:CR:2例,PR:8例,SD:14例,PD:3例;缓解率:10/27(37.1%),疾病控制率24/27(88.9%);不良反应主要表现在骨髓抑制、胃肠道反应以及皮疹,发生率在化疗组和厄洛替尼组分别为76.7%、80%、13.3%及3.71%、40.7%、66.7%,三者之间均有显著性差异。结论厄洛替尼治疗晚期NSCLC患者的疗效较化疗组好,且安全性高。     

Bone metastases in non-small cell lung cancer: a narrative review

Background and ObjectiveBone metastases are common in patients with non-small cell lung cancer (NSCLC) and remain a significant source of morbidity, mortality, and diminished quality of life, despite the considerable progress made in the overall management of patients with metastatic NSCLC over the last decade. Understanding the molecular pathogenesis of bone metastases is critical to improving survival, preserving function, and managing symptoms in this patient population. The objective of our review is to provide a comprehensive review of the pathophysiology, clinical presentation, management, and factors predicting the development and prognosis of patients with NSCLC with bone metastases.MethodsAn online electronic search was performed on PubMed and Google Scholar of all English-language literature using combinations of the following keywords: bone metastases, non-small cell lung cancer, pathophysiology, skeletal related events, response to therapy, predictive factors, and immunotherapy. Bibliographies of identified papers were reviewed for additional articles of interest. Observational cohort, retrospective studies, randomized controlled trials (RCTs), meta-analyses, and review articles were examined for this review.Key Content and FindingsBone metastases in lung cancer patients remain a common occurrence, impacting morbidity, mortality, and quality of life. Patients with skeletal related events (SREs) have worse prognosis. There is data supporting use of bisphosphonates and/or denosumab, and these should be considered in all patients with bone metastases. Novel studies comparing the genomic alterations of skeletal metastases and primary tumors are needed. As therapy for patients with advanced disease evolves, more studies are needed to evaluate the interplay between immunotherapy and bone metastases, and in determining the response to treatment in bone.ConclusionsPredicting development and progression of bone metastases could allow earlier and targeted therapy in patients with bone metastases. Predicting and evaluating response to conventional chemotherapy and immune checkpoint inhibitors in NSCLC patients with bone metastases remains an unmet need and merits further study.     

Clinical efficacy of crizotinib in Chinese patients with ALK-positive non-small-cell lung cancer with brain metastases

Background

Crizotinib has been associated with intracranial disease control in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients with brain metastases. Continued crizotinib treatment has also been used for prolonged disease control in patients experiencing isolated central nervous system (CNS) failure. However, there are few studies of crizotinib efficacy in ALK-positive Chinese patients. Thus, we retrospectively investigated the clinical efficacy of crizotinib in Chinese ALK-positive NSCLC patients with brain metastases at baseline, and evaluated the clinical benefit of continuing crizotinib beyond CNS failure.

Methods

A total of 120 advanced ALK-positive NSCLC patients treated with crizotinib were enrolled with 38 having brain metastases at baseline. The objective response rate (ORR) and progression-free survival (PFS) were compared between patients with and without brain metastases at baseline. A subset of patients who developed CNS failure continued crizotinib treatment beyond progressive disease (PD), and the second PFS from the time of the first progression was also evaluated.

Results

The ORR of crizotinib was similar between patients with and without brain metastases at baseline (68.4% vs. 69.5%, P=0.904). However, the patients without brain metastases at baseline experienced a longer median PFS [10.0 months, 95% confidence interval (CI), 7.6-12.5 vs. 7.0 months, 95% CI, 6.4-7.6; P=0.021]. Among 88 patients with PD defined Response Evaluation Criteria in Solid Tumors (RECIST), 33 developed CNS failure. A total of 24 patients who developed CNS failure continued crizotinib treatment beyond PD, and they achieved a second median PFS of 6.3 months (95% CI, 2.9-9.7).

Conclusions

Chinese ALK-positive NSCLC patients with brain metastases achieved a similar response to crizotinib and significantly shorter PFS compared to those without brain metastases at baseline. Continuous administration of crizotinib beyond PD in patients developing CNS failure appeared to be a valid treatment strategy.     

Peripheral blood eosinophilia may be a prognostic biomarker in non-small cell lung cancer patients treated with immunotherapy

BackgroundEosinophils have been traditionally associated with the initiation and propagation of inflammatory responses, particularly in allergic diseases and helminth infections. More recently, an association between eosinophils and cancer has been the focus of several studies, but controversial results have emerged. This study aims to evaluate the prognostic role of peripheral blood eosinophilia in non-small cell lung cancer (NSCLC) patients receiving immunotherapy (IO). We also evaluated the impact of peripheral eosinophilia on the occurrence of immune-related adverse effects (irAEs).MethodsAdvanced NSCLC patients under IO were included in a retrospective single-center study. Peripheral blood eosinophilia was defined by a count greater than 500/µL. Patients were analyzed for eosinophil counts, overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR).ResultsA total of 121 NSCLC patients receiving IO were included. Thirty-three (27.3%) patients presented peripheral blood eosinophilia during treatment. Patients with peripheral eosinophilia presented more frequently non-progression as best overall response to IO (83.3% vs. 58.1%, P=0.014), higher median OS (26.6 vs. 9.5 months, P=0.022) and higher median PFS (13.8 vs. 4.6 months, P=0.013). IrAEs were more common in patients with peripheral eosinophilia (66.7% vs. 36.4%, P=0.003).ConclusionsThis study suggests that peripheral blood eosinophilia may predict better outcomes in NSCLC patients receiving IO, despite being associated with an increased risk of irAEs. According to our findings eosinophils may be involved in immune response against tumor. Routine eosinophils count assessment may be an additional prognostic tool in NSCLC patients receiving IO.     

Post-study therapy as a source of confounding in survival analysis of first-line studies in patients with advanced non-small-cell lung cancer

Clinical trials exploring the long-term effects of first-line therapy in patients with advanced non-small-cell lung cancer generally disregard subsequent treatment although most patients receive second and third-line therapies. The choice of further therapy depends on critical intermediate events such as disease progression and it is usually left at the physician's discretion. Time-dependent confounding may then arise with standard survival analyses producing biased effect estimates, even in randomized trials. Herein we describe the concept of time-dependent confounding in detail and discuss whether the response to first-line treatment may be a potential time-dependent confounding factor for survival in the context of subsequent therapy. A prospective observational study of 406 patients with advanced non-small-cell lung cancer served as an example base. There is evidence that time-dependent confounding may occur in multivariate survival analysis after first-line therapy when disregarding subsequent treatment. In the light of this important but underestimated aspect some of the large and meaningful recent clinical first-line lung cancer studies are discussed, focussing on subsequent treatment and its potential impact on the survival of the study patients. No recently performed lung cancer trial applied adequate statistical analyses despite the frequent use of subsequent therapies. In conclusion, effect estimates from standard survival analysis may be biased even in randomized controlled trials because of time-dependent confounding. To adequately assess treatment effects on long-term outcomes appropriate statistical analyses need to take subsequent treatment into account.     

吉非替尼单药治疗老年晚期非小细胞肺癌患者的临床观察

目的观察吉非替尼单药治疗老年晚期非小细胞肺癌（NSCLC）患者的有效性与安全性。方法北京协和医院呼吸科收治的63例老年晚期NSCLC患者接受吉非替尼250mg／d治疗,观察患者的一般情况,记录不良反应,并进行疗效评价。中位生存期采用Kaplan-Meier方法计算,不同因素分层生存期比较采用多因素Cox回归分析。结果不良反应一般较轻（1度或2度）,停药后可缓解,最常见的不良反应为皮疹76．8％（43／56）和腹泻35．7％（20／56）。疾病客观有效率、稳定率分别为25．4％、55．6％。所有患者的中位生存期为15．3个月（11．8～18．8个月）。1年生存率为53％。多因素Cox回归分析显示,ECOG体能评分2分以上、有肝脏转移、有胸腔积液、疾病于化疗后复发、吉非替尼治疗的客观疗效是影响生存期的因素。化疗后疾病稳定的23例患者与化疗后疾病进展的24例患者接受吉非替尼治疗后,其两者的生存期比较差异有统计学意义。治疗后出现皮疹与客观疗效相关。结论老年晚期NSCLC患者对吉非替尼的治疗能很好耐受,可延长患者的生存时间。     

Prognostic value of lactate dehydrogenase in non-small cell lung cancer patients with brain metastases: a retrospective cohort study

BackgroundAt present, although there are some known molecular markers for the prognosis of non-small cell lung cancer (NSCLC) brain metastases, but there are still shortcomings in sensitivity and specificity. Lactate dehydrogenase (LDH) is one of the key enzymes involved in malignancy vital glycolytic pathway. Elevated serum LDH levels are reported significantly associated with a poor prognosis in various malignancies. However, there is currently no consensus regarding the prognostic value of LDH in NSCLC patients with brain metastases.MethodsWe retrospectively analyzed 224 patients diagnosed with lung cancer brain metastases between January 2006 and June 2020 after excluding patients meeting combined with other malignancies and inaccurate clinical information. The LDH cutoff values were obtained using a restricted cubic spline (RCS) model, and the patients were divided into two groups according to the optimal cut-off value (180 U/L). 107 patients with LDH ≤180 (47.77%) and 117 patients with LDH >180 (52.23%) were identified. Univariate and multivariate logistic regression analyses were performed to identify the risk factors. The overall survival (OS) time was defined as the time from the first diagnosis of brain metastases to the last follow-up or death. Of the included patients, 147 survived and 77 died. The Kaplan-Meier method was used to illustrate the OS difference between the two groups. Finally, sensitivity analysis was employed to evaluate the robustness of the results.ResultsThe OS rate was significantly lower in the high LDH group versus the low LDH group (P=0.009). The median survival times of the high and low LDH groups were approximately 16 and 33 months, respectively. Multivariate analysis showed that high LDH was associated with a significantly worse OS [adjusted hazard ratio (aHR), 1.567; 95% confidence interval (CI): 1.058 to 2.32, P=0.025] with adjustment for covariables that P<0.05 in univariate analysis. Sensitivity analysis indicated that the results of this study are robust, despite potential unmeasured confounders.ConclusionsHigh level of serum LDH indicates poor prognosis for patients with NSCLC brain metastases. This finding may provide useful prognostic information for patients and clinicians to choose more aggressive treatment strategies.