Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry (IHC) is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA).
The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15, Sino Biological) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0=none, 1=equivocal/uninterpretable, 2=weak, and 3=intermediate-strong. Those cases with all cores scoring 3 in the epithelial component were categorized as PD-L1high and the remaining as PD-L1low.
PD-L1high scores were more frequent in TETs than controls (68.1% vs. 17.6%, p=0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in WHO B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/gender), PD-L1high TETs had a significantly worse overall survival (HR 5.40, 95% CI 1.13-25.89, p=0.035) and a trend for worse event-free survival (HR 2.94, 95% CI 0.94-9.24, p=0.064).
PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than controls, and PD-L1high TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD1/PD-L1 therapy in this rare tumor type.
Limited treatment options exist for patients with thymic malignancies (TM), and chemotherapy efficacy is often restricted by cumulative toxicity such as neuropathy (taxanes) and cardiomyopathy (anthracyclines). Single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor with minimal cardiac toxicity, was investigated in TM patients in this trial.
This was an open-label single drug trial at two institutions in the United States (Stanford University and Indiana University). Eligible patients had TM [thymoma (T) or thymic carcinoma (TC)] with progression or relapse after at least one prior chemotherapy regimen, and adequate organ function including left ventricular ejection fraction (LVEF) of >50%. The initial treatment plan consisted of amrubicin at 40 mg/m2 IV days 1–3 repeated in 3-week cycles.
From July 2011 to April 2014, a total of 33 patients (14T/19TC) were enrolled. There were 14 women and 19 men; age range of 30–81 years; 9 Asian, 1 African-American, 1 Hispanic and 22 non-Hispanic White patients. A high rate of febrile neutropenia (FN) led to an amended starting dose of 35 mg/m2 days 1–3 repeated in 3-week cycles. In total, 7 patients experienced FN with 1 related death. Other grade 3/4 related events included: thrombocytopenia (n=2), neutropenia without fever (n=3), hyponatremia (n=2), hypokalemia (n=2), anemia (n=7), lethargy/fatigue (n=7), perirectal abscess (n=2), palmar-plantar erythrodysesthesia (n=3), syncope (n=2), venous embolism (n=2), and 1 patient each with sepsis, oral abscess, mucositis, chest pain, and epigastric pain. Other toxicities were generally mild and well tolerated. No significant changes in LVEF were noted on serial echocardiograms. There were 6 partial responses (4T/2TC), 21 with stable disease, and 4 with progressive disease (PD) or death at or before first assessment for a response rate (RR) of 18% and a disease control rate (DCR) of 88% (29%/11% RR in T vs. TC and 100%/78% DCR in T vs. TC). All but 5 patients received at least 4 cycles, and 15 tolerated >10 cycles, with 38 cycles as the highest number to date. Three patients remain on therapy.
Amrubicin, at 35 mg/m2 IV days 1–3 on a 3-week cycle, shows promise as a single agent in pre-treated patients with T and TC with an 18% RR (29% T/11% TC) and no unexpected toxicity. DCRs of 100% in the T patients and 78% in the TC patients were observed. RR and DCR were higher in the T patients compared to the TC patients. Further exploration of amrubicin as a single drug or in combination is warranted in TM.
Amrubicin; thymoma (T); thymic carcinoma (TC); chemotherapy
Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.
Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150 mg erlotinib + 300 mg dovitinib) and cohort -1 (150 mg erlotinib + 200 mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre-and post-dovitinib exposure.
Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308 ± 698 ng/ml and AUC 0–24 41,030 ± 15,577 ng × h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0–24 decreased significantly by 93% (p = 0.02) and 97% (p < 0.01), respectively, during dovitinib co-administration.
This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.
Dovitinib; Erlotinib; TKI 258; NSCLC; Epidermal growth factor receptor (EGFR)
Fluroine-18 flurodeoxyglucose positron emission tomography (FDG-PET) imaging is considered standard for Non-Small Cell Lung Cancer (NSCLC). A retrospective review of 61 patients with NSCLC showed that higher FDG-PET metabolic tumor volume portended worse outcomes overall and in a subset of patients treated definitively.
Fluorine-18 flurodeoxyglucose positron emission tomography (FDG-PET) imaging has rapidly become the standard of care for staging patients with lung cancer. We evaluated the prognostic value of metabolic tumor volume (MTV), a measure of tumor burden on FDG-PET imaging, in patients with non–small-cell lung cancer (NSCLC) treated definitively.
Methods and Materials
A retrospective review identified 61 patients with NSCLC who underwent FDG-PET imaging for pretreatment staging. Metabolically active tumor regions were segmented on the PET scans semiautomatically to calculate the total body MTV. We determined the relationship of overall survival (OS) and progression-free survival (PFS) with MTV in the entire cohort, and in the subgroup treated definitively.
The estimated median PFS and OS for the entire cohort were 11.1 months and 18.9 months. Higher MTV was significantly associated with worse OS (P = 0.00075) and PFS (P = 0.00077). For definitively treated patients, when MTV was analyzed as a binary value above or below the median value, 2-year PFS was 60% versus 39.7% (median PFS 34.9 vs. 11.9 months) and 2-year OS was 79.7% versus 33.3% (median OS 41.9 vs. 18.9 months), respectively (log-rank P = 0.12 for PFS and P = 0.066 for OS). When MTV was analyzed as a continuous variable, multivariate Cox proportional hazards analysis demonstrated a trend to worse PFS (hazard ratio [HR] = 1.31; P = 0.12) and significantly worse OS (HR = 1.53; P = 0.018) with increasing MTV after controlling for known prognostic variables.
Tumor burden as assessed by MTV yields prognostic information on survival beyond that of established prognostic factors in patients with NSCLC treated definitively.
thymic epithelial tumors; autoimmune paraneoplastic disorders; genomic changes; anti-cytokine antibodies; biological therapies
In the REVEL trial, ramucirumab, a monoclonal antibody to VEGFR-2, improved overall survival in combination with docetaxel compared to docetaxel alone in the second-line setting of non-small cell lung cancer (NSCLC). Along with bevacizumab and nintedanib, ramucirumab is the third anti-angiogenic agent that has yielded positive overall survival results in a phase III trial of patients with advanced NSCLC. Given the lack of effective therapies in the relapsed setting and the disappointing results of many other VEGF-targeted agents in lung cancer, the results from REVEL are encouraging. One of the major remaining hurdles is the identification of reliable predictive biomarkers in order to predict which patients are most likely to benefit from anti-angiogenic therapies. Despite the positive results seen in REVEL, the exact role of ramucirumab in the treatment paradigm of lung cancer remains to be seen given the modest survival benefit of 1.4 months and the lack of predictive biomarkers at this time.
Angiogenesis; ramucirumab; lung cancer; VEGF; docetaxel
Bevacizumab improves responses and progression-free survival when added to first-line paclitaxel/carboplatin or cisplatin/gemcitabine for patients with advanced nonsquamous non-small cell lung cancer. This study was designed to evaluate toxicities and efficacy of gemcitabine/carboplatin/bevacizumab.
Patients with untreated advanced nonsquamous non-small cell lung cancer, with no evidence of brain metastases and not on anticoagulation were eligible. Patients received gemcitabine 1000 mg/m2 on days 1 and 8; carboplatin area under the curve 5 day 1; and bevacizumab 15 mg/kg day 1 every 3 weeks for up to six cycles. Bevacizumab was then continued every 3 weeks until disease progression or unacceptable toxicity.
From July 2006 to December 2008, 48 patients were enrolled: 23 (48%) men, 25 (52%) women, and 19 (40%) never smokers. One patient never received therapy and is not included in the analysis. Median cycle number was 8 (1– 42) with 37 patients (78.7%) completing ≥4 cycles of three drugs. Dose reductions occurred in 34 (72.3%) patients. Grade 3/4 toxicities included neutropenia (47%/15%), thrombocytopenia (11%/15%), anemia (6%/0%), dyspnea (6%/2%), bacterial pneumonia (4%/0%), and hypertension (4%/2%). No neutropenic fevers occurred. One patient died of hemoptysis. Grade 3 bleeding occurred in three other patients. There were seven (14.9%) partial responses. Median time to first event (progression/death/toxicity requiring discontinuation) was 6.4 months (95% confidence interval: 4.8 –7.9 months). The median overall survival (OS) was 12.8 months (95% confidence interval: 10.0 –16.5). The OS is 57% at 1 year and 10% at 2 years.
Although perhaps skewed by a high proportion of nonsmokers and women, treatment with gemcitabine/carboplatin/bevacizumab has an acceptable toxicity profile with promising median OS despite a low response rate.
Lung cancer; Non-small cell; Antiangiogenic agents
Circulating tumor DNA (ctDNA) represents a promising biomarker for noninvasive assessment of cancer burden, but existing methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce CAncer Personalized Profiling by deep Sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of stage II–IV and 50% of stage I NSCLC patients, with 96% specificity for mutant allele fractions down to ~0.02%. Levels of ctDNA significantly correlated with tumor volume, distinguished between residual disease and treatment-related imaging changes, and provided earlier response assessment than radiographic approaches. Finally, we explored biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.
The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.
Lung cancer; Non-small cell lung cancer; Targeted therapies; Epidermal growth factor receptor; Epidermal growth factor receptor; Anaplastic lymphoma kinase; Anaplastic lymphoma kinase; Acquired resistance
Hispanics in the United States have lower age-adjusted mortality resulting from non–small-cell lung cancer (NSCLC) compared with non-Hispanic whites (NHWs). The purpose of this study was to evaluate individual, clinical, and neighborhood factors in survival among Hispanics with NSCLC.
Patients and Methods
We performed a retrospective analysis of NHWs and Hispanics with NSCLC between 1998 and 2007 in the California Cancer Registry (follow-up to December 2009). Kaplan-Meier curves depict survival by nativity for Hispanics with NSCLC. Cox proportional hazards models estimated hazard of mortality by race with adjustment for individual (age, sex, marital status), clinical (histologic grade, surgery, irradiation, chemotherapy), and neighborhood factors (neighborhood socioeconomic status, ethnic enclave).
We included 14,280 Hispanic patients with NSCLC. Foreign-born Hispanics had 15% decreased risk of disease-specific mortality resulting from NSCLC compared with NHWs (hazard ratio [HR], 0.85; 95% CI, 0.83 to 0.88) after adjustment for individual, clinical, and neighborhood factors. After adjustment for individual factors, compared with US-born Hispanics, foreign-born Hispanics had 10% decreased risk of disease-specific mortality (HR, 0.90; 95% CI, 0.87 to 0.96). Clinical and neighborhood factors slightly moderated the survival benefit for foreign-born patients. A modestly more pronounced survival advantage was seen for foreign-born Hispanics living in low socioeconomic and high Hispanic enclave neighborhoods as compared with US-born Hispanics (HR, 0.86; 95% CI, 0.81 to 0.90).
Foreign-born Hispanics with NSCLC have a decreased risk of disease-specific mortality compared with NHWs and US-born Hispanics with NSCLC. Neighborhood factors slightly moderate this survival advantage. This survival advantage is slightly more pronounced in lower socioeconomic and higher Hispanic enclave neighborhoods.
Chemotherapy; Molecular subtypes; NSCLC; Pemetrexed; ROS1
Detection and characterization of circulating tumor cells (CTCs) may reveal insights into the diagnosis and treatment of malignant disease. Technologies for isolating CTCs developed thus far suffer from one or more limitations, such as low throughput, inability to release captured cells, and reliance on expensive instrumentation for enrichment or subsequent characterization. We report a continuing development of a magnetic separation device, the magnetic sifter, which is a miniature microfluidic chip with a dense array of magnetic pores. It offers high efficiency capture of tumor cells, labeled with magnetic nanoparticles, from whole blood with high throughput and efficient release of captured cells. For subsequent characterization of CTCs, an assay, using a protein chip with giant magnetoresistive nanosensors, has been implemented for mutational analysis of CTCs enriched with the magnetic sifter. The use of these magnetic technologies, which are separate devices, may lead the way to routine preparation and characterization of “liquid biopsies” from cancer patients.
NSCLC; Choroid; CNS metastases; Chemotherapy
Sorafenib is a raf kinase and angiogenesis inhibitor with activity in multiple cancers. This phase II study in heavily pretreated non-small cell lung cancer (NSCLC) patients (≥ two prior therapies) utilized a randomized discontinuation design.
Patients received 400 mg of sorafenib orally twice daily for two cycles (two months) (Step 1). Responding patients on Step 1 continued on sorafenib; progressing patients went off study, and patients with stable disease were randomized to placebo or sorafenib (Step 2), with crossover from placebo allowed upon progression. The primary endpoint of this study was the proportion of patients having stable or responding disease two months after randomization.
: There were 299 patients evaluated for Step 1 with 81 eligible patients randomized on Step 2 who received sorafenib (n=50) or placebo (n=31). The two-month disease control rates following randomization were 54% and 23% for patients initially receiving sorafenib and placebo respectively, p=0.005. The hazard ratio for progression on Step 2 was 0.51 (95% CI 0.30, 0.87, p=0.014) favoring sorafenib. A trend in favor of overall survival with sorafenib was also observed (13.7 versus 9.0 months from time of randomization), HR 0.67 (95% CI 0.40-1.11), p=0.117. A dispensing error occurred which resulted in unblinding of some patients, but not before completion of the 8 week initial step 2 therapy. Toxicities were manageable and as expected.
: The results of this randomized discontinuation trial suggest that sorafenib has single agent activity in a heavily pretreated, enriched patient population with advanced NSCLC. These results support further investigation with sorafenib as a single agent in larger, randomized studies in NSCLC.
NSCLC; sorafenib; randomized discontinuation trial
Surgery is regarded as the primary treatment modality for early stage non-small cell lung cancer (NSCLC), but even after complete resection, a substantial percentage of these patients eventually develop local recurrence or distant metastases. Therefore more effective treatment strategies to reduce lung cancer mortality and recurrence rate are needed. Only recently has the use of adjuvant chemotherapy become standard in early stage NSCLC, at least for stage II and resected IIIA NSCLC. Controversies remain about the benefit for stage I patients. Five-year survival improvements of 5% to 10% have been reported with cisplatin-based adjuvant chemotherapy from multiple large randomized phase III clinical trials and meta-analyses. Questions remain as to which patients benefit and which regimens are best. In this paper, important clinical research in the field of adjuvant chemotherapy of NSCLC is reviewed.
Non-small cell lung cancer (NSCLC); adjuvant chemotherapy; elderly patient
MET and its ligand hepatocyte growth factor/scatter factor (HGF) influence cell motility and lead to tumor growth, invasion, and angiogenesis. Alterations in MET have been observed in non-small cell lung cancer (NSCLC) tumors, with increased expression associated with more aggressive cancer, as well as acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). MET inhibitors act via two basic mechanisms. Small molecule inhibitors antagonize ATP in the intracellular tyrosine kinase domain of MET, with studies on the following agents reviewed here: tivantinib (ARQ-197), cabozantinib (XL-184), crizotinib (PF-02341066), amuvatinib (MP470), MGCD265, foretinib (EXEL-2880), MK2461, SGX523, PHA665752, JNJ-38877605, SU11274, and K252A. The monoclonal monovalent antibody fragment onartuzumab (MetMAb) is also discussed here, which binds to and prevents the extracellular activation of the receptor by ligand. MET inhibition may both overcome the negative prognostic effect of MET tumor expression as well as antagonize MET-dependent acquired resistance to EGFR inhibitors. Here we discuss MET inhibitors in combination with other therapies in lung cancer.
Non-small cell lung cancer; targeted therapies; tyrosine kinase inhibitors; MET
Lung cancer is the leading cause of cancer death among US Asian/Pacific Islander (API) and Latina women, despite low smoking prevalence. This study examined survival patterns following non-small cell lung cancer in a population-based sample of lung cancer cases from the San Francisco Bay Area Lung Cancer Study (SFBALCS).
Women diagnosed with lung cancer from 1998–2003 and 2005–2008 and identified through the Greater Bay Area Cancer Registry were telephone-screened for eligibility for the SFBALCS. The screener data were linked to the cancer registry data to determine follow-up. This analysis included 187 non-Hispanic White, 23 US-born Latina, 32 foreign-born Latina, 30 US-born API, and 190 foreign-born API never smokers diagnosed with lung cancer and followed through 2008.
All-cause survival was poorer among APIs (hazard ratio (HR) and 95% confidence interval (CI) = 1.7 (1.0–2.8) among US-born APIs; 1.2 (0.9–1.5) among foreign-born APIs), and Latinas (HR (95% CI) = 2.1 (1.2–3.6) among US-born Latinas; 1.4 (0.9–2.3) among foreign-born Latinas), relative to non-Hispanic Whites. These survival differences were not explained by differences in selected sociodemographic or clinical factors.
Further research should focus on factors such as cultural behaviors, access to or attitudes toward health care, and genetic variations, as possible explanations for these striking racial/ethnic differences.
Latina and API female never smokers diagnosed with lung cancer were up to two-times more likely to die than non-Hispanic Whites, highlighting the need for additional research to identify the underlying reasons for the disparities, as well as heightened clinical awareness.
lung cancer survival; Asian; Latina; Hispanic; never smokers; nativity
Enzastaurin, an oral serine/threonine kinase inhibitor, targets the protein kinase C and AKT pathways with anti-tumor and anti-angiogenic effects. Erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, has activity in solid tumors. Based on the promising combination of EGFR inhibitors and anti-angiogenic agents, this phase I trial was initiated.
This single-institution, open-label, non-randomized trial used a standard 3 + 3 dose-escalation model in patients with advanced solid malignancies including non-small-cell lung cancer (NSCLC). Two dose levels of enzastaurin (with loading doses) were explored: 250 mg daily and 500 mg daily. Erlotinib was given at 150 mg daily.
Sixteen patients were enrolled in this study (median age, 64 years). Most patients were heavily pre-treated, female, and Caucasian and had NSCLC. The highest dose of enzastaurin, 500 mg daily, was tolerated with no unexpected adverse events and no alteration in the pharmacokinetics of either drug at this dose level. The mean clearance was 5.75 L/h for erlotinib and 53.8 L/h for enzastaurin. The most common possibly drug-related grade 3–4 adverse events included diarrhea (25.0%), neurologic symptoms (18.8%), and vomiting (18.8%). Activity was noted, with a partial response in one patient and prolonged disease stability for >12 cycles in three patients.
The combination of enzastaurin 500 mg daily and erlotinib 150 mg daily is well tolerated and does not alter the pharmacokinetics of the individual drugs, with clinical activity seen. A phase II trial of this combination has been initiated in patients with advanced-stage NSCLC.
Clinical trial; Enzastaurin; Erlotinib; Pharmacokinetics
In the Women's Health Initiative (WHI) randomized controlled trial, use of estrogen plus progestin increased lung cancer mortality. We conducted post hoc analyses in the WHI trial evaluating estrogen alone to determine whether use of conjugated equine estrogen without progestin had a similar adverse influence on lung cancer.
The WHI study is a randomized, double-blind, placebo-controlled trial conducted in 40 centers in the United States. A total of 10 739 postmenopausal women aged 50–79 years who had a previous hysterectomy were randomly assigned to receive a once-daily 0.625-mg tablet of conjugated equine estrogen (n = 5310) or matching placebo (n = 5429). Incidence and mortality rates for all lung cancers, small cell lung cancers, and non–small cell lung cancers in the two randomization groups were compared by use of hazard ratios (HRs) and 95% confidence intervals (CIs) that were estimated from Cox proportional hazards regression analyses. Analyses were by intention to treat, and all statistical tests were two-sided.
After a mean of 7.9 years (standard deviation = 1.8 years) of follow-up, 61 women in the hormone therapy group were diagnosed with lung cancer compared with 54 in the placebo group (incidence of lung cancer per year = 0.15% vs 0.13%, respectively; HR of incidence = 1.17, 95% CI = 0.81 to 1.69, P = .39). Non–small cell lung cancers were of comparable number, stage, and grade in both groups. Deaths from lung cancer did not differ between the two groups (34 vs 33 deaths in estrogen and placebo groups, respectively; HR of death = 1.07, 95% CI = 0.66 to 1.72, P = .79).
Unlike use of estrogen plus progestin, which increased deaths from lung cancer, use of conjugated equine estrogen alone did not increase incidence or death from lung cancer.
For many years adjuvant chemotherapy has been a standard treatment after complete resection in malignancies such as breast and colon but only recently has its use become standard in early stage non-small cell lung cancer (NSCLC). Although surgery is regarded as the best possible treatment for early stage NSCLC, only 20–25% of patients have resectable disease at presentation. Despite optimal surgical treatment, 5-year survival rates for NSCLC remain 50–60% for stage IB, 40–50% for stage II, and 20–30% for stage III (Kohler et al., 2011; Siegel et al., 2011). Adjuvant chemotherapy provides additional survival benefit in resected NSCLC but questions remain as to how to select patients for therapy and which regimen is best. Other than work with tegafur/uracil in Japan, the positive adjuvant trials have all utilized a cisplatin backbone, but the drug(s) to pair with cisplatin are a matter of debate and will be discussed further in this manuscript.
lung cancer; non-small cell; adjuvant; chemotherapy; early stage