Non-Small Cell Lung Cancer
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There are many different types of lung cancer. Non-Small Cell Lung Cancers (NSCLC) are grouped together because they tend to be treated in the same way, which is different to Small Cell Lung Cancer. NSCLCs account for abour 85% of all lung cancer cases. The most common types of NSCLC are Adenocarcinoma, Squamous cell (epidermoid) carcinoma, and large cell carcinoma. Less common types of NSCLC include: pleomorphic, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma of the lung.

Note: most of the resources on the general Lung Cancer page are relevant to NSCLC.

Menu: Non-Small Cell Lung Cancer

Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Lung Cancer

Information Patients and the Public (7 links)


Information for Health Professionals / Researchers (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Laterza MM, Chiurazzi B, Brangi M, et al.
Gefitinib in non-small cell lung carcinoma: a case report of an unusual side effect and complete response in advanced disease.
Tumori. 2013 Jan-Feb; 99(1):3e-5e [PubMed]
Gefitinib is a tyrosine kinase inhibitor, indicated in advanced non-small cell lung cancer in all lines of treatment for patients harboring EGFR mutations. It has a favorable toxicity profile but may induce unexpected adverse effects, such as an infiammatory reaction in the bladder. We report a rare case of hemorrhagic cystitis, an unusual side effect, in a patient with non-small cell lung cancer treated with gefitinib, which did not compromise the clinical response.


Sardenberg RA, Pinto C, Bueno CA, Younes RN
Non-small cell lung cancer stage IV long-term survival with isolated spleen metastasis.
Ann Thorac Surg. 2013; 95(4):1432-4 [PubMed]
Splenic metastasis is rare and generally associated with disseminated disease, often seen in breast cancer, colorectal and ovarian carcinoma, and melanoma. Isolated metastasis to the spleen is rare, with only 93 cases from all sources having been reported up to 2007. Moreover, isolated splenic metastasis from primary lung cancer is extremely rare, with only 11 cases reported to date. We report a case of isolated splenic metastasis in a woman 8 months after lobectomy for an adenocarcinoma in the right lung completely resected. After 8 years of follow-up, the patient is still alive with no evidence of metastatic recurrence.


Acharyya S, Sau S, Dasgupta P, et al.
Skin rash as a surrogate marker of clinical response of targeted therapy using gefitinib in advanced or metastatic non-small-cell lung cancer--a retrospective study.
J Indian Med Assoc. 2012; 110(7):474-6, 493 [PubMed]
This retrospective review of a single institution case series study was conducted to correlate the objective response and skin rash of gefitinib in patients with advanced or metastatic non-small-cell lung cancer(NSCLC). One hundred and forty-nine patients with advanced or metastatic NSCLC were treated with gefitinib (250 mg/day) as second line systemic therapy. Baseline patient characteristics were: More than 75% patients were above 50 years of age, males 64%; adenocarcinoma 52%. Sixty-one patients were excluded from the analysis due to varying reasons; only 88 remaining in the analysis. Partial response was observed in 15 patients (17%), and 34 patients (38.6%) had stable disease. The rest 39 patients (44.3%) had progressive disease on gefitinib therapy. There was a significantly longer median time to progression (TTP) of 7 months in females as compared to 5 months in males (p = 0.001). A highly significant association (p = 0.001) was observed between the grade of skin toxicity and the median time to disease progression, with the median TTP being 4 months in patients experiencing no skin toxicity as compared to 7 months with those grade 2 skin toxicity and 12 months with grade 3 skin toxicity. Gender (p = 0.003), and presence of skin toxicity (p = 0.0001) were having significant difference in median overall survival. On multivariate testing of the same using Cox regression analysis only presence of skin toxicity (p = 0.012) and gender (p = 0.003) was found to significant factors. Thus it can be concluded that occurrence of skin rash and female gender were associated with improved survival with gefitinib for recurrent NSCLC patients.


Friboulet L, Olaussen KA, Pignon JP, et al.
ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.
N Engl J Med. 2013; 368(12):1101-10 [PubMed]
BACKGROUND: The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation.
METHODS: We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage.
RESULTS: We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance.
CONCLUSIONS: Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).


Minomo S, Asami K, Okishio K, et al.
Phase II study of triplet chemotherapy using Tegafur-Uracil, Vinorelbine, Gemcitabine for advanced non-small cell lung cancer.
Anticancer Res. 2013; 33(3):1163-7 [PubMed]
AIM: To evaluate the efficacy and toxicity of triplet chemotherapy using tegafur-uracil (UFT), vinorelbine, and gemcitabine for patients with stage IIIB or IV non-small cell lung cancer.
PATIENTS AND METHODS: A total of 32 patients were enrolled in this study. The patients were subjected to a treatment regimen consisting of intravenous vinorelbine and gemcitabine on days 6 and 13, and oral UFT on days 1-5 and 8-12. This treatment was repeated every three weeks.
RESULTS: All patients had an initial performance status of 0 to 1. The objective response rate was 21.9%, median survival time was 13.9 months, and the one-year survival rate was 56.7%. Grade 3/4 toxicities (% of patients) consisted of leukocytopenia (40.6%), neutropenia (56.3%), thrombocytopenia (3.1%), infection (9.4%), hypoxia (6.3%) and dyspnea (3.1%).
CONCLUSION: Triplet chemotherapy using UFT, vinorelbine, and gemcitabine was well-tolerated, with an acceptable toxicity profile. However, the response rate and median survival did not encourage for additional investigation.


Yokomise H, Liu D, Chang S, et al.
Biomarkers as prognostic factors for cN2 or 3 non-small cell lung cancer treated by induction chemoradiotherapy and surgery.
Anticancer Res. 2013; 33(3):1107-15 [PubMed]
BACKGROUND: We have reported promising results of surgery after induction chemoradiotherapy (carboplatin-taxane, 50 Gy radiation) for cN2,3 non-small cell lung cancer (NSCLC). In order to understand the underlying mechanism, expression of excision repair cross-complementing 1 (ERCC1), class III β-tubulin (tubulin), thymidylate synthase (TYMS), and ribonucleotide reductase M1 (RRM1) were investigated.
PATIENTS AND METHODS: Immunohistochemistry was performed in 45 patients with cN2,3 NSCLC, but only in twelve pathologically-complete response cases to evaluate intratumoral expression of these biomarkers.
RESULTS: High expression of ERCC1, tubulin, TYMS and RRM1 was observed in 25 (55.6%), 19 (42.2%), 20 (44.4%) and 25 (55.6%) patients, respectively. Low expressions of ERCC1, tubulin, TYMS and RRM1 were favorable prognostic factors (p=0.044, p=0.025, p=0.039 and p=0.037, respectively). The simultaneously low expression of ERCC1 and tubulin was observed to be the most significant prognostic factor, by Cox regression analysis (hazard ratio=2.381; p=0.0059).
CONCLUSION: Patients with simultaneous low expression of ERCC1 and tubulin are promising candidates for surgery after carboplatin-taxane chemoradiotherapy. For patients with high expression of ERCC1 and tubulin, uracil-tegafur, pemetrexed, and gemcitabine may be the alternative agents for personalized chemotherapy.


Gottschling S, Jensen K, Herth FJ, et al.
Lack of prognostic significance of neuroendocrine differentiation and stem cell antigen co-expression in resected early-stage non-small cell lung cancer.
Anticancer Res. 2013; 33(3):981-90 [PubMed]
BACKGROUND: Neuroendocrine (NE) carcinomas of the lung exhibit expression of various stem cell antigens, and except for carcinoid tumours, carry a poor prognosis. Despite the fact that 10%-30% of all non-small cell lung carcinomas (NSCLC) which are not classified as NE carcinomas also show expression of NE markers, data on their prognostic significance are conflicting and analyses of the expression and relevance of stem cell antigens in this subgroup are lacking.
MATERIALS AND METHODS: Tissue specimens of 100 resected early-stage NSCLC were analyzed by immunohistochemistry for the expression and prognostic significance of NE markers. Moreover, the subgroup of NSCLC with NE differentiation (ND) were assessed for the expression and prognostic significance of the stem cell antigens CD117, CD133 and breast cancer resistance protein-1 (ABCG2).
RESULTS: ND correlated significantly with adenocarcinoma histology (p=0.035), but not with prognosis. In the subgroup of ND-NSCLC (n=80), the stem cell antigens CD117, CD133 and ABCG2 were expressed in 51%, 14% and 33% of the cases, but likewise, showed no association with prognosis or clinicopathological characteristics.
CONCLUSION: This study indicates that neither ND, nor co-expression of the stem cell antigens CD117, CD133 or ABCG2, have a prognostic significance in resected early-stage NSCLC.


Werynska B, Pula B, Muszczynska-Bernhard B, et al.
Expression of metallothionein-III in patients with non-small cell lung cancer.
Anticancer Res. 2013; 33(3):965-74 [PubMed]
BACKGROUND: Currently, there is little knowledge concerning expression of metallothionein-III (MT-III), also known as growth-inhibitory factor, in non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS: In this study, we evaluated MT-III expression in 184 patients using immunohistochemistry and in 61 cases using real-time polymerase chain reaction.
RESULTS: MT-III mRNA expression was significantly higher in NSCLC as compared to non-malignant lung tissues (NMLT; p<0.0086). MT-III expression was noted in the cytoplasm and nucleus of cancer cells. Significantly lower nuclear MT-III (p<0.0001) expression and significantly higher cytoplasmic MT-III (p=0.0068) expression was noted in the pneumocytes of NMLT, as compared to NSCLC. Nuclear MT-III expression was significantly higher in G1 cases as compared to G2 (p=0.0308) and G3 (p=0.0194) cases. Low cytoplasmic MT-III expression was associated with larger primary tumour size (p=0.0378). Lower MT-III mRNA and cytoplasmic MT-III expression was associated with poor patient outcome (p=0.0410 and p=0.0347, respectively).
CONCLUSION: MT-III expression may have an impact on the pathogenesis of NSCLC.


Zheng YW, Li RM, Zhang XW, Ren XB
Current adoptive immunotherapy in non-small cell lung cancer and potential influence of therapy outcome.
Cancer Invest. 2013; 31(3):197-205 [PubMed]
Non-small cell lung cancer (NSCLC) is found worldwide with high incidence and poor prognoses. Nowadays, insights in the interaction between tumors and immune system have led to the development of immunotherapy as a fundamentally new concept for the treatment of NSCLC. Adoptive cell transfer represents an important advancement in cancer immunotherapy such as cytokine-induced killer and γδ T-cells. Recent clinical research studies provide evidence for the positive effects of adoptive immunotherapy, which is probably associated with levels of cytokines, cell doses, and immune microenvironment. This review summarizes the current condition of adoptive immunotherapy in NSCLC and the long-standing confusion in this field.


Houghton AM
Mechanistic links between COPD and lung cancer.
Nat Rev Cancer. 2013; 13(4):233-45 [PubMed]
Numerous epidemiological studies have consistently linked the presence of chronic obstructive pulmonary disease (COPD) to the development of lung cancer, independently of cigarette smoking dosage. The mechanistic explanation for this remains poorly understood. Progress towards uncovering this link has been hampered by the heterogeneous nature of the two disorders: each is characterized by multiple sub-phenotypes of disease. In this Review, I discuss the nature of the link between the two diseases and consider specific mechanisms that operate in both COPD and lung cancer, some of which might represent either chemopreventive or chemotherapeutic targets.


Chatterjee S, Heukamp LC, Siobal M, et al.
Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer.
J Clin Invest. 2013; 123(4):1732-40 [PubMed] Free Access to Full Article
The molecular mechanisms that control the balance between antiangiogenic and proangiogenic factors and initiate the angiogenic switch in tumors remain poorly defined. By combining chemical genetics with multimodal imaging, we have identified an autocrine feed-forward loop in tumor cells in which tumor-derived VEGF stimulates VEGF production via VEGFR2-dependent activation of mTOR, substantially amplifying the initial proangiogenic signal. Disruption of this feed-forward loop by chemical perturbation or knockdown of VEGFR2 in tumor cells dramatically inhibited production of VEGF in vitro and in vivo. This disruption was sufficient to prevent tumor growth in vivo. In patients with lung cancer, we found that this VEGF:VEGFR2 feed-forward loop was active, as the level of VEGF/VEGFR2 binding in tumor cells was highly correlated to tumor angiogenesis. We further demonstrated that inhibition of tumor cell VEGFR2 induces feedback activation of the IRS/MAPK signaling cascade. Most strikingly, combined pharmacological inhibition of VEGFR2 (ZD6474) and MEK (PD0325901) in tumor cells resulted in dramatic tumor shrinkage, whereas monotherapy only modestly slowed tumor growth. Thus, a tumor cell-autonomous VEGF:VEGFR2 feed-forward loop provides signal amplification required for the establishment of fully angiogenic tumors in lung cancer. Interrupting this feed-forward loop switches tumor cells from an angiogenic to a proliferative phenotype that sensitizes tumor cells to MAPK inhibition.


Onishi H, Araki T
Stereotactic body radiation therapy for stage I non-small-cell lung cancer: a historical overview of clinical studies.
Jpn J Clin Oncol. 2013; 43(4):345-50 [PubMed]
Because of difficulties with stabilization, breathing motion and dosimetry, stereotactic body radiotherapy for lung cancer has only been practiced for the past 15 years. However, a large amount of case data has rapidly been accumulated in recent years. Stereotactic body radiotherapy for Stage I non-small-cell lung cancer has been actively investigated in inoperable patients since around 1995, and a number of clinical trials have been undertaken. Early studies from 2001 presented a 3-year local control rate of 94% and a 3-year overall survival rate of 66% for patients receiving 50-60 Gy in 10 fractions. Another study in 2005, using 48 Gy in four fractions, presented a 3-year local control rate of 98% and 3-year overall survival rates of 83% for Stage IA patients and 72% for Stage IB patients. A multi-institutional study showed favorable local control and survival rates in a group receiving a biologically effective dose of 100 Gy. A dose-escalation study in the USA suggested a maximum tolerated dose of 60 Gy in three fractions. A Phase II clinical trial (RTOG0236) followed, with a reported 3-year local control rate of 98% and a 3-year overall survival rate of 56% for patients who received 60 Gy in three fractions. A Japanese Phase II clinical trial (JCOG0403) investigated a dose of 48 Gy in four fractions among 165 Stage IA patients, showing a 3-year survival rate of 76% and a 3-year locally progression-free survival rate of 69% for the operable group. An overview of past clinical trials in stereotactic body radiotherapy for Stage I non-small-cell lung cancer and current issues is presented and discussed.


Davison J, Mercier G, Russo G, Subramaniam RM
PET-based primary tumor volumetric parameters and survival of patients with non-small cell lung carcinoma.
AJR Am J Roentgenol. 2013; 200(3):635-40 [PubMed]
OBJECTIVE: The purpose of the study was to assess metabolic tumor volume and total glycolytic activity of the primary tumor as prognostic parameters for outcome in patients with non-small cell lung carcinoma (NSCLC).
MATERIALS AND METHODS: Thirty-nine patients who had undergone a baseline staging PET/CT examination at our institution for the diagnosis of NSCLC were retrospectively identified. The maximum standardized uptake value (SUV(max)), metabolic tumor volume, and total glycolytic activity were segmented from PET using the gradient method; 12-month survival and overall survival at the end of follow-up were used as outcome measures. Multivariate logistic regression, receiver operating characteristic curve analysis, and Kaplan-Meier curves for survival analysis were generated and compared using the Mantel-Cox log-rank test.
RESULTS: The mean gradient-based metabolic tumor volume and gradient-based total glycolytic activity were significantly greater in the patients who died (93.3 mL and 597.5 g) than in those who survived (19.3 mL and 193.9 g, respectively) (p < 0.003 and p < 0.031). There was no statistically significant difference in the mean SUV(max) between the patients who survived (12.7) at 12 months and those who had died (13.1) (p = 0.85). On multivariate analysis, gradient-based metabolic tumor volume was the only variable associated with 12-month mortality when adjusted for all other factors.(.) The area under the curve (AUC) for gradient-based metabolic tumor volume was 0.77 (p < 0.006). A significant difference in the time to survival was observed between high and low gradient-based metabolic tumor volume (log-rank p < 0.05) cohorts using the median gradient-based metabolic tumor volume (9.7 mL) as the cut point.
CONCLUSION: PET-based volumetric imaging parameters are potential prognostic markers of outcome in patients with NSCLC.


Campian JL, Ye X, Brock M, Grossman SA
Treatment-related lymphopenia in patients with stage III non-small-cell lung cancer.
Cancer Invest. 2013; 31(3):183-8 [PubMed]
BACKGROUND: This study sought to estimate the severity, etiology, and clinical importance of treatment-related lymphopenia in patients with stage III non-small-cell lung cancer.
METHODS: Serial lymphocyte counts and survival were analyzed retrospectively in 47 patients accounting for known prognostic factors.
RESULTS: Total lymphocyte counts (TLCs) were normal before therapy and did not change following neoadjuvant chemotherapy. Following radiation, TLC fell by 67% (median 500 cells/mm(3), p <.00001). Multivariate analysis revealed an association between severe TLC and survival (HR 1.70, 95% CI: 0.8-3.6).
CONCLUSIONS: Rapid and severe lymphopenia occurred in 50% of patients following radiation which was associated with reduced survival.


Cho A, Hur J, Hong YJ, et al.
NSCLC subtype prediction using cytologic fluid specimens from needle aspiration biopsies.
Am J Clin Pathol. 2013; 139(3):309-16 [PubMed]
This study evaluated the diagnostic usefulness of tumor marker concentrations in cytologic fluids (CF) for subtyping non-small cell lung cancer (NSCLC) and assessed the relationship between fluorine-18-fluorodeoxyglucose ((18)F-FDG) uptake with serum and CF tumor marker levels. This prospective study included 88 patients diagnosed with adenocarcinoma or squamous cell carcinoma (SCC). Cytokeratin-19 fragment (CYFRA 21-1), carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCCA) concentrations in the CF samples were correlated with serum tumor marker concentrations, (18)F-FDG uptake, and NSCLC subtype. Fifty-eight patients were diagnosed with adenocarcinoma. Multivariate analysis revealed higher CF and serum SCCA levels; smoking status predicted SCC from adenocarcinoma. CF SCCA showed the highest accuracy (83%) in distinguishing between SCC and adenocarcinoma. CF samples obtained during routine needle aspiration biopsy procedure contain tumor marker levels sufficient to distinguish between SCC and adenocarcinoma; CF SCCA had the highest diagnostic accuracy.


Yoshida A, Kohno T, Tsuta K, et al.
ROS1-rearranged lung cancer: a clinicopathologic and molecular study of 15 surgical cases.
Am J Surg Pathol. 2013; 37(4):554-62 [PubMed]
Recent discovery of ROS1 gene fusion in a subset of lung cancers has raised clinical interest, because ROS1 fusion-positive cancers are reportedly sensitive to kinase inhibitors. To better understand these tumors, we examined 799 surgically resected non-small cell lung cancers by reverse transcriptase polymerase chain reaction and identified 15 tumors harboring ROS1 fusion transcripts (2.5% of adenocarcinomas). The most frequent fusion partner was CD74 followed by EZR. The affected patients were often younger nonsmoking female individuals, and they had overall survival rates similar to those of the ROS1 fusion-negative cancer patients. All the ROS1 fusion-positive tumors were adenocarcinomas except 1, which was an adenosquamous carcinoma. Histologic examination identified an at least focal presence of either solid growth with signet-ring cells or cribriform architecture with abundant extracellular mucus in 53% of the cases. These 2 patterns are reportedly also characteristic of anaplastic lymphoma kinase (ALK)-rearranged lung cancers, and our data suggest a phenotypic resemblance between the ROS1-rearranged and ALK-rearranged tumors. All tumors except 1 were immunoreactive to thyroid transcription factor-1. Fluorescence in situ hybridization using ROS1 break-apart probes revealed positive rearrangement signals in 23% to 93% of the tumor cells in ROS1 fusion-positive cancers, which were readily distinguished using a 15% cutoff value from 50 ROS1 fusion-negative tumors tested, which showed 0% to 6% rearrangement signals. However, this perfect test performance was achieved only when isolated 3' signals were included along with classic split signals in the definition of rearrangement positivity. Fluorescence in situ hybridization signal patterns were unrelated to 5' fusion partner genes. All ROS1 fusion-positive tumors lacked alteration of EGFR, KRAS, HER2, ALK, and RET genes.


Groth SS, Al-Refaie WB, Zhong W, et al.
Effect of insurance status on the surgical treatment of early-stage non-small cell lung cancer.
Ann Thorac Surg. 2013; 95(4):1221-6 [PubMed]
BACKGROUND: Social disparities permeate non-small cell lung cancer (NSCLC) treatment, yet little is known about the effect of insurance status on the delivery of guideline surgical treatment for early-stage (I or II) NSCLC.
METHODS: We used the California Cancer Registry (1996 through 2008) to identify patients 50 to 94 years old with early-stage NSCLC. We used logistic regression models to assess whether or not insurance status (private insurance, Medicare, Medicaid, no insurance, and unknown) had an effect on whether or not a lobectomy (or bilobectomy) is performed.
RESULTS: A total of 10,854 patients met our inclusion criteria. Compared with patients with private insurance, we found that patients with Medicare (adjusted odds ratio [aOR] 0.87; 95% confidence interval [CI]: 0.79 to 0.95), Medicaid (aOR 0.45; 95% CI: 0.36 to 0.57), or no insurance (aOR 0.45; 95% CI: 0.29 to 0.70) were significantly less likely to undergo lobectomy, even after adjusting for patient factors (age, race, and gender) and tumor characteristics (histology and tumor size). Increasing age, African American race, squamous cell carcinoma, and increasing tumor size were significant independent negative predictors of whether or not a lobectomy was performed.
CONCLUSIONS: Patients without private insurance were significantly less likely than patients with private insurance to undergo a lobectomy for early-stage NSCLC. The variables(s) contributing to this disparity have yet to be elucidated.


Hamaji M, Allen MS, Cassivi SD, et al.
Surgical treatment of metachronous second primary lung cancer after complete resection of non-small cell lung cancer.
J Thorac Cardiovasc Surg. 2013; 145(3):683-90; discussion 690-1 [PubMed]
OBJECTIVE: To clarify the perioperative and oncologic outcome of pulmonary resection for a metachronous second primary lung cancer (MSPLC) following resection of an initial non-small cell lung cancer (NSCLC).
METHODS: Retrospective chart review identified 161 patients (88 men and 73 women) with a median age of 70 years (range, 34-88 years) who underwent pulmonary resection for MSPLC between January 2000 and December 2009. Operative morbidity, mortality, and relevant factors were analyzed with χ(2) test or Fisher exact test and Mann-Whitney U test. Survival was analyzed with Kaplan-Meier and Cox proportional hazard method.
RESULTS: The median interval between the initial and subsequent resection for MSPLC was 42.7 months (range, 7-205 months). There was no operative mortality and postoperative complication rate was 29%. In multivariate analysis, ipsilateral operation (P = .0002) and a lower predicted preoperative percent forced expiratory volume in the first second (P = .0035) were significant risk factors for postoperative complications. Five-year overall survival rates after resection of the initial and second metachronous NSCLC were 87.4% and 60.8%, respectively. Significant negative long-term prognostic factors for survival following resection of a MSPLC in multivariate analysis were tumor size >2 cm (P = .003) and number of pack years of smoking (P = .005). Metastatic nodal disease (P = .19) or a sublobar resection (P = .17) were not associated with worse survival.
CONCLUSIONS: Surgical treatment of a MSPLC can be undertaken with 5-year survival rate of 60%. Expected operative morbidity and mortality are comparable to primary surgery. Tumors 2 cm or smaller are associated with improved survival and freedom from recurrence. Close long-term follow-up of patients who have undergone resection of NSCLC is recommended.


Peng J, Yang LX, Zhao XY, et al.
VCP gene variation predicts outcome of advanced non-small-cell lung cancer platinum-based chemotherapy.
Tumour Biol. 2013; 34(2):953-61 [PubMed]
Valosin-containing protein (VCP), or p97, is a member of the ATP-binding protein family, and is involved in numerous cellular events, such as, protein degradation, membrane fusion, and chaperone activity. VCP has been demonstrated playing a critical role in non-small-cell lung cancer (NSCLC) pathogenesis and progression recently. We investigated the association between VCP polymorphisms and clinical outcome in advanced NSCLC patients undergoing platinum-based chemotherapy. We recruited 663 Chinese advanced NSCLC patients who were treated with platinum-based regimens, and using their clinical data, we assessed the efficacy and side effects of their treatment. Three tag-single nucleotide polymorphisms (SNPs) of VCP were genotyped. SNP rs2074549 showed a significant association with severe neutropenia. Its G/G genotype increased the risk of grade 3 or 4 neutropenia compared with wild-type homozygotes A/A (P = .001, odds ratio = 2.975). Haplotype association analysis revealed that CGA was associated with the increased incidence of severe neutropenia (P = .041, odds ratio = 1.439). However, no significant relationship was found between the presence of VCP polymorphisms and treatment efficacy when objective response, progression-free survival, and overall survival (OS) were evaluated. Our study is the first to provide evidence that VCP polymorphisms are associated with a severe chemotherapy-related adverse outcome in platinum-treated advanced NSCLC patients.


Sadiq AA, Salgia R
MET as a possible target for non-small-cell lung cancer.
J Clin Oncol. 2013; 31(8):1089-96 [PubMed] Article available free on PMC after 10/03/2014
Lung cancer is a heterogeneous group of disorders that is now being subdivided into molecular subtypes with dedicated targeted therapies. The MET receptor tyrosine kinase has been identified as aberrantly overexpressed, potentially having activating mutations, and amplified in certain subsets of lung cancers. The ligand hepatocyte growth factor (HGF) can also be overexpressed in lung cancer or expressed in stroma, and both the MET receptor and the HGF ligand can be targets for therapeutics, especially in lung cancer. Activation of MET leads to a plethora of biochemical and biologic changes both in normal and cancerous cells. Preclinically, it has been shown that silencing or inactivating MET leads to decreased viability of cancer cells. There are a number of compounds against MET/HGF in clinical trials that have been shown to be active in lung cancers. This review will summarize the biology of MET as well as its therapeutic inhibition in lung cancer.


Laurie SA, Goss GD
Role of epidermal growth factor receptor inhibitors in epidermal growth factor receptor wild-type non-small-cell lung cancer.
J Clin Oncol. 2013; 31(8):1061-9 [PubMed]
Worldwide, the majority of patients with advanced non-small-cell lung cancer (NSCLC) do not have activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). These wild-type patients comprise a significant proportion of those treated with inhibitors of this pathway, and data from randomized trials suggest that some of these wild-type patients will derive a modest benefit from these agents. Although the detection of an activating mutation predicts for a greater likelihood of response and longer progression-free survival from an EGFR tyrosine kinase inhibitor, currently there are no biomarkers that consistently and reproducibly predict for lack of benefit in wild-type patients. Several strategies to increase the efficacy of these inhibitors in wild-type NSCLC are the subject of ongoing investigations.


Ohashi K, Maruvka YE, Michor F, Pao W
Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease.
J Clin Oncol. 2013; 31(8):1070-80 [PubMed] Article available free on PMC after 10/03/2014
PURPOSE: EGFR-mutant lung cancer was first described as a new clinical entity in 2004. Here, we present an update on new controversies and conclusions regarding the disease.
METHODS: This article reviews the clinical implications of EGFR mutations in lung cancer with a focus on epidermal growth factor receptor tyrosine kinase inhibitor resistance.
RESULTS: The discovery of EGFR mutations has altered the ways in which we consider and treat non-small-cell lung cancer (NSCLC). Patients whose metastatic tumors harbor EGFR mutations are expected to live longer than 2 years, more than double the previous survival rates for lung cancer.
CONCLUSION: The information presented in this review can guide practitioners and help them inform their patients about EGFR mutations and their impact on the treatment of NSCLC. Efforts should now concentrate on making EGFR-mutant lung cancer a chronic rather than fatal disease.


Salama JK, Vokes EE
New radiotherapy and chemoradiotherapy approaches for non-small-cell lung cancer.
J Clin Oncol. 2013; 31(8):1029-38 [PubMed]
Recent advances in systemic cytotoxic and molecularly targeted therapies coupled with technologic strides in radiotherapy have the potential to improve outcomes for patients with non-small-cell lung cancer (NSCLC). Investigations are ongoing to identify optimal cytotoxin-based chemoradiotherapy platforms. The influence of specific histologic and molecular mutation status on the combination of targeted therapies and radiotherapy is also being actively studied. Although there are no convincing randomized phase III data to date supporting a survival advantage for combining molecularly targeted agents with radiation or chemoradiotherapy in the setting of locally advanced NSCLC, phase II and III studies targeted to elderly patients and those with poor performance status are elucidating preferred chemoradiotherapy strategies. Radiotherapy dose escalation did not improve chemoradiotherapy outcomes, although increasing radiation dose-intensity with modern techniques is being actively studied. As modern radiotherapy techniques have been shown to improve outcomes of some patients with limited metastatic disease, investigations are ongoing regarding how to optimally integrate them with standard chemotherapy platforms.


Mok T, Yang JJ, Lam KC
Treating patients with EGFR-sensitizing mutations: first line or second line--is there a difference?
J Clin Oncol. 2013; 31(8):1081-8 [PubMed]
First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is a standard treatment for patients with activating EGFR mutations. Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. The only reason to consider EGFR TKI as second-line therapy is that none of the six comparative studies has shown improvement in overall survival, which can be explained by the high proportion of patients from the chemotherapy arm crossing over to the EGFR TKI arm on progression. It is true that patients with EGFR mutations may benefit from second-line EGFR TKI therapy, but we cannot conclude that the benefit is either equal to or inferior to first-line EGFR TKI therapy. To date, there are no direct comparative data between first- and second-line EGFR TKI in patients with activating EGFR mutations. Tumor response rates to second-line EGFR TKI have been inconsistent, which could potentially be explained by the impact of first-line chemotherapy on the abundance of tumor cells with activating EGFR mutations. However, numerous arguments, including assurance on drug exposure, improvement in quality of life, better tolerance by patients with poor performance status, and deferral of whole-brain radiation therapy for patients with brain metastasis, support the general application of first-line EGFR TKI.


Oxnard GR, Binder A, Jänne PA
New targetable oncogenes in non-small-cell lung cancer.
J Clin Oncol. 2013; 31(8):1097-104 [PubMed] Article available free on PMC after 10/03/2014
The identification of oncogenic driver mutations underlying sensitivity to epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors has led to a surge of interest in identifying additional targetable oncogenes in non-small-cell lung cancer. A number of new potentially oncogenic gene alterations have been characterized in recent years, including BRAF mutations, HER2 insertions, PIK3CA mutations, FGFR1 amplifications, DDR2 mutations, ROS1 rearrangements, and RET rearrangements. In this review, we will discuss the techniques used to discover each of these candidate oncogenes, the prevalence of each in non-small-cell lung cancer, the preclinical data supporting their role in lung cancer, and data on small molecular inhibitors in development.


Gerber DE, Schiller JH
Maintenance chemotherapy for advanced non-small-cell lung cancer: new life for an old idea.
J Clin Oncol. 2013; 31(8):1009-20 [PubMed] Article available free on PMC after 10/03/2014
Although well established for the treatment of certain hematologic malignancies, maintenance therapy has only recently become a treatment paradigm for advanced non-small-cell lung cancer. Maintenance therapy, which is designed to prolong a clinically favorable state after completion of a predefined number of induction chemotherapy cycles, has two principal paradigms. Continuation maintenance therapy entails the ongoing administration of a component of the initial chemotherapy regimen, generally the nonplatinum cytotoxic drug or a molecular targeted agent. With switch maintenance (also known as sequential therapy), a new and potentially non-cross-resistant agent is introduced immediately on completion of first-line chemotherapy. Potential rationales for maintenance therapy include increased exposure to effective therapies, decreasing chemotherapy resistance, optimizing efficacy of chemotherapeutic agents, antiangiogenic effects, and altering antitumor immunity. To date, switch maintenance therapy strategies with pemetrexed and erlotinib have demonstrated improved overall survival, resulting in US Food and Drug Administration approval for this indication. Recently, continuation maintenance with pemetrexed was found to prolong overall survival as well. Factors predicting benefit from maintenance chemotherapy include the degree of response to first-line therapy, performance status, the likelihood of receiving further therapy at the time of progression, and tumor histology and molecular characteristics. Several aspects of maintenance therapy have raised considerable debate in the thoracic oncology community, including clinical trial end points, the prevalence of second-line chemotherapy administration, the role of treatment-free intervals, quality of life, economic considerations, and whether progression-free survival is a worthy therapeutic goal in this disease setting.


Roberts PJ, Stinchcombe TE
KRAS mutation: should we test for it, and does it matter?
J Clin Oncol. 2013; 31(8):1112-21 [PubMed]
Lung cancer is the leading cause of cancer mortality in the United States and worldwide. Previously, lung cancer was simplistically divided into non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, in the last decade, we have gone from a simplistic binary system of classifying lung cancer to defining NSCLC on the basis of molecular subsets. KRAS mutations represent the most common molecular change in NSCLC. The presence of KRAS mutation has been shown to be associated with a poor prognosis in NSCLC, but this is of little clinical utility. More important is determining the clinical utility of KRAS mutational analysis for predicting benefit of chemotherapy, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), anti-EGFR monoclonal antibodies, or other novel therapeutics. Current data does not support the routine use of KRAS mutational analysis for predicting chemotherapy benefit. Additionally, there was significant interest in using KRAS status to select patients for EGFR TKI and anti-EGFR monoclonal antibodies. However, the EGFR mutational status has demonstrated significant predictive value in the selection of patients for EGFR TKI therapy and is now the preferred test. An association between KRAS mutational status and benefit of anti-EGFR monoclonal antibodies has not been demonstrated in NSCLC. Here we review, in the context of NSCLC, the underlying biology of KRAS mutations, the predictive value of KRAS mutations for therapeutic intervention, and the integration of KRAS mutational testing into our current clinical paradigms.


Besse B, Olaussen KA, Soria JC
ERCC1 and RRM1: ready for prime time?
J Clin Oncol. 2013; 31(8):1050-60 [PubMed]
The quest for markers of sensitivity to cytotoxic agents has been ongoing for decades. In non-small-cell lung cancer, platinum compounds represent the cornerstone of systemic therapy. They target DNA and induce damage that cancer cells struggle to overcome. Somatic excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), and ribonucleotide reductase M1 (RRM1) expression levels have been extensively explored as markers of DNA repair capacity in tumor cells. Although low ERCC1 and/or RRM1 expression is generally associated with sensitivity to platinum, the results published in retrospective and prospective studies are not always consistent. Against this background, we will examine in this review the function of these two biomarkers as well as the tools available for their assessment and the associated technical issues. Their prognostic and predictive values will be summarized and considered in terms of customizing systemic therapy according to biomarker (ERCC1 and RRM1) expression levels. We will also discuss why the use of both markers should at this point be restricted to clinical research and underline that functional readouts of DNA repair will help boost future strategies for biomarker discovery in the field.


Goldstraw P
New staging system: how does it affect our practice?
J Clin Oncol. 2013; 31(8):984-91 [PubMed]
The anatomic extent of disease, as described by the TNM classification, remains the most powerful prognostic indicator for lung cancer. It is used daily by specialists in all branches of lung cancer care and research. Any new edition of the TNM classification is therefore an important event in the thoracic oncology community and one greeted with mixed feelings. The changes introduced in the seventh edition were the first for 13 years and arguably the most profound since the first data-driven revision more than 40 years earlier. Inevitably there will be concerns that any change in the T, N, or M descriptors and resultant stage groupings will have implications for previous treatment pathways. In this article, the changes to the classification are described, and their possible impacts on clinical care and research are discussed.


Shaw AT, Engelman JA
ALK in lung cancer: past, present, and future.
J Clin Oncol. 2013; 31(8):1105-11 [PubMed]
In 2007, scientists discovered that anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non-small-cell lung cancers. ALK-positive cancers are highly sensitive to small-molecule ALK kinase inhibitors, such as crizotinib. Phase I and II studies of crizotinib in ALK-positive lung cancer demonstrated impressive activity and clinical benefit, leading to rapid US Food and Drug Administration approval in 2011. Although crizotinib induces remissions and extends the lives of patients, cures are not achieved as resistance to therapy develops. In this review, we will discuss the history of this field, current diagnostic and treatment practices, and future challenges and opportunities to advance outcomes for patients with ALK-positive lung cancers.


This page last updated: 22nd May 2013
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