Lung Cancer
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Lung Cancer

Lung cancer is one of the most common types of cancer. The lungs are a pair of cone-shaped organs situated inside the chest, they bring oxygen into the body and take out waste carbon dioxide. There is a strong link between smoking and lung cancer. There are two main categories of lung cancer; Small Cell Lung Cancer (SCLC) , and Non-Small Cell Lung Cancer (NSCLC).

Around 42,000 people are diagnosed with lung cancer each year. (Source: Cancer Research UK)

This page shows only UK resources. For a more extensive list of resources from around the world see CancerIndex: Lung Cancer Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications

Information Patients and the Public (7 links)

Information for Health Professionals / Researchers (5 links)

  • PubMed search for publications about Lung Cancer - Limit search to: [Reviews]

    PubMed Central search for free-access publications about Lung Cancer
    MeSH term: Lung Neoplasms
    International US National Library of Medicine
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Latest Research Publications

Showing publications with corresponding authors from the UK (Source: PubMed).

Sharma P, Mehta M, Dhanjal DS, et al.
Emerging trends in the novel drug delivery approaches for the treatment of lung cancer.
Chem Biol Interact. 2019; 309:108720 [PubMed] Related Publications
Cancer is one of the major diseases that cause a high number of deaths globally. Of the major types of cancers, lung cancer is known to be the most chronic form of cancer in the world. The conventional management of lung cancer includes different medical interventions like chemotherapy, surgical removal, and radiation therapy. However, this type of approach lacks specificity and also harms the adjacent normal cells. Lately, nanotechnology has emerged as a promising intervention in the management and treatment of lung cancers. Nanotechnology has revolutionized the existing modalities and focuses primarily on reducing toxicity and improving the bioavailability of anticancer drugs to the target tumor cells. Nanocarrier systems are being currently used extensively to exploit and to overcome the obstructions induced by cancers in the lungs. The nano-carrier-loaded therapeutic drug delivery methods have shown promising potential in treating lung cancer as its target is to control the growth of tumor cells. In this review, various modes of nano drug delivery options like liposomes, dendrimers, quantum dots, carbon nanotubes and metallic nanoparticles have been discussed. Nano-carrier drug delivery systems emerge as a promising approach and thus is expected to provide newer and advanced avenues in cancer therapeutics.

Albers J, Parker W, Kildea J, et al.
Chest wall pain following lung stereotactic body radiation therapy using 48Gy in three fractions: A search for predictors.
Cancer Radiother. 2019; 23(2):98-103 [PubMed] Related Publications
PURPOSE: Chest wall pain is an uncommon but bothersome late complication following lung stereotactic body radiation therapy. Despite numerous studies investigating predictors of chest wall pain, no clear consensus has been established for a chest wall constraint. The aim of our study was to investigate factors related to chest wall pain in a homogeneous group of patients treated at our institution.
PATIENTS AND METHODS: All 122 patients were treated with the same stereotactic body radiation therapy regimen of 48Gy in three fractions, seen for at least 6 months of follow-up, and planned with heterogeneity correction. Chest wall pain was scored according to the Common Terminology Criteria for Adverse Events classification v3.0. Patient (age, sex, diabetes, osteoporosis), tumour (planning target volume, volume of the overlapping region between planning target volume and chest wall) and chest wall dosimetric parameters (volumes receiving at least 30, 40, and 50Gy, the minimal doses received by the highest irradiated 1, 2, and 5cm
RESULTS: Median follow-up was 18 months (range: 6-56 months). Twelve patients out of 122 developed chest wall pain of any grade (seven with grade 1, three with grade 2 and two with grade 3 pain). In univariate analysis, only the volume receiving 30Gy or more (P=0.034) and the volume of the overlapping region between the planning target volume and chest wall (P=0.038) significantly predicted chest wall pain, but these variables were later proved non-significant in multivariate regression.
CONCLUSION: Our analysis could not find any correlation between the studied parameters and chest wall pain. Considering our present study and the wide range of differing results from the literature, a reasonable conclusion is that a constraint for chest wall pain is yet to be defined.

Abdelrady H, Hathout RM, Osman R, et al.
Exploiting gelatin nanocarriers in the pulmonary delivery of methotrexate for lung cancer therapy.
Eur J Pharm Sci. 2019; 133:115-126 [PubMed] Related Publications
Gelatin has many merits that encourage its use in the pulmonary delivery of anticancer drugs. It is a biodegradable denatured protein which possesses several functional groups that could be modified. Additionally, it has balanced hydrophilic and hydrophobic characters, which facilitate the loading of chemotherapeutic agents. Accordingly, the purpose of the current work was to exploit this valuable biomaterial in the efficient pulmonary delivery of methotrexate in case of lung cancer. Gelatin nanoparticles were prepared via a desolvation method and the fabrication process was optimized using Box Behnken design of experiment. A comparative study on uptake of gelatin nanoparticles by lung adenocarcinoma cells and macrophages was implemented using flow cytometry. Investigation of the effect of different methotrexate loading techniques: encapsulation, post loading and chemical conjugation on the nanoparticles characteristics and cellular cytotoxicity was performed. Nano-in-microparticles were prepared by co-spray drying optimized nanoparticles with leucine. Results showed that Box Behnken design was able to optimize preparation parameters to yield uniform nanoparticles with suitable particle size for cancer cells uptake. The prepared nanoparticles demonstrated a preferential uptake by lung cancer cells. Additionally, methotrexate loaded nanoparticles demonstrated up to four fold significant reduction in methotrexate IC

Adderley H, Blackhall FH, Lindsay CR
KRAS-mutant non-small cell lung cancer: Converging small molecules and immune checkpoint inhibition.
EBioMedicine. 2019; 41:711-716 [PubMed] Free Access to Full Article Related Publications
KRAS is the most frequent oncogene in non-small cell lung cancer (NSCLC), a molecular subset characterized by historical disappointments in targeted treatment approaches such as farnesyl transferase inhibition, downstream MEK inhibition, and synthetic lethality screens. Unlike other important mutational subtypes of NSCLC, preclinical work supports the hypothesis that KRAS mutations may be vulnerable to immunotherapy approaches, an efficacy associated in particular with TP53 co-mutation. In this review we detail reasons for previous failures in KRAS-mutant NSCLC, evidence to suggest that KRAS mutation is a genetic marker of benefit from immune checkpoint inhibition, and emerging direct inhibitors of K-Ras which will soon be combined with immunotherapy during clinical development. With signs of real progress in this subgroup of unmet need, we anticipate that KRAS mutant NSCLC will be the most important molecular subset of cancer to evaluate the combination of small molecules and immune checkpoint inhibitors (CPI).

Oswald N, Halle-Smith J, Kerr A, et al.
Perioperative immune function and pain control may underlie early hospital readmission and 90 day mortality following lung cancer resection: A prospective cohort study of 932 patients.
Eur J Surg Oncol. 2019; 45(5):863-869 [PubMed] Related Publications
BACKGROUND: Mortality following lung cancer resection has been shown to double between 30 and 90 days and readmission following surgery is associated with an increased risk of mortality. The aim of this study was to describe the causes of readmission and mortality and enable the identification of potentially modifiable factors associated with these events.
METHODS: Prospective cohort study at a United Kingdom tertiary referral centre conducted over 55 months. Binary logistic regression was used to identify factors associated with death within 90 days of surgery.
RESULTS: The 30 day and 90 day mortality rates were 1.4% and 3.3% respectively. The most common causes of death were pneumonia, lung cancer and Acute Respiratory Distress Syndrome/Multi Organ Failure. Potentially modifiable risk factors for death identified were: Postoperative pulmonary complications (Odds ratio 6.1), preoperative lymphocyte count (OR 0.25), readmission within 30 days (OR 4.2) and type of postoperative analgesia (OR for intrathecal morphine 4.8). The most common causes of readmission were pneumonia, shortness of breath and pain.
CONCLUSIONS: Postoperative mortality is not simply due to fixed factors; the impacts of age, gender and surgical procedure on postoperative survival are reduced when the postoperative course of recovery is examined. Perioperative immune function, as portrayed by the occurrence of infection and lower lymphocyte count in the immediate perioperative period, and pain control method are strongly associated with 90 day mortality; further studies in these fields are indicated as are studies of psychological factors in recovery.

Jawiarczyk-Przybyłowska A, Wojtczak B, Whitworth J, et al.
Acromegaly associated with GIST, non-small cell lung carcinoma, clear cell renal carcinoma, multiple myeloma, medulla oblongata tumour, adrenal adenoma, and follicular thyroid nodules.
Endokrynol Pol. 2019; 70(2):213-217 [PubMed] Related Publications
Acromegaly is associated with increased growth hormone (GH) and insulin-like growth factor-I (IGF-I) secretion which may support tumour development and growth. A 68-year-old woman was diagnosed with acromegaly due to typical clinical and hormonal characteristics. While contrast-enhanced MRI at diagnosis did not reveal a pituitary adenoma, a 5-mm lesion was identified on repeat scanning 13 months later. Abdominal and chest CT showed tumours of the stomach, right adrenal gland, and right lung. The CT also showed a hypodense lesion in the liver and heterogeneous echostructure of the thyroid gland with left lobe solid-cystic tumour. Somatostatin receptor scintigraphy revealed increased tracer accumulation in the right thyroid lobe. No tracer accumulation was noted at the location of the other tumours. The resected stomach, adrenal, chest, and thyroid lesions did not show GH secretion. The patient refused pituitary surgery, and her acromegaly is currently well-controlled with somatostatin analogue therapy. A CT scan 19 months later revealed a contrast-enhancing left kidney tumour that was a G1-grade clear cell carcinoma. Four years after the acromegaly diagnosis multiple myeloma were diagnosed with secondary renal amyloidosis. Genetic screening for a paraganglioma gene panel, AIP, MEN1, and CDKN1B mutations were negative. A next-generation cancer panel containing 94 cancer genes did not identify any possible unifying gene abnormality in her germline DNA. Coexistence of acromegaly and numerous other tumours suggests a common aetiology of these disorders. However, no genetic abnormality could be identified with the tests that have been performed.

Watte G, Nunes CHA, Sidney-Filho LA, et al.
Proportional weight loss in six months as a risk factor for mortality in stage IV non-small cell lung cancer.
J Bras Pneumol. 2018 Nov-Dec; 44(6):505-509 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To evaluate different weight loss (WL) cut-off points as prognostic markers of 3-month survival after diagnosis of stage IV non-small cell lung cancer (NSCLC).
METHODS: This was a prospective study involving 104 patients with metastatic (stage IV) NSCLC who were admitted to a cancer treatment center in southern Brazil between January of 2014 and November of 2016. We evaluated total WL and WL per month, as well as WL and WL per month in the 6 months preceding the diagnosis. The patients were followed for 3 months after diagnosis. A Cox proportional hazards regression model and Kaplan-Meier curves were used in order to evaluate 3-month survival.
RESULTS: The median WL in the 6 months preceding the diagnosis was 6% (interquartile range, 0.0-12.9%). Patients with WL ≥ 5% had a median survival of 78 days, compared with 85 days for those with WL < 5% (p = 0.047). Survival at 3 months was 72% for the patients with WL ≥ 5% (p = 0.047), 61% for those with WL ≥ 10% (p < 0.001), and 45% for those with WL ≥ 15% (p < 0.001). In the multivariate analysis, the hazard ratio for risk of death was 4.51 (95% CI: 1.32-15.39) for the patients with WL ≥ 5%, 6.34 (95% CI: 2.31-17.40) for those with WL ≥ 10%, and 14.17 (95% CI: 5.06-39.65) for those with WL ≥ 15%.
CONCLUSIONS: WL in the 6 months preceding the diagnosis of NSCLC is a relevant prognostic factor and appears to be directly proportional to the rate of survival at 3 months.

Ramsingh J, O'Dwyer P, Watson C
Survival outcomes following adrenalectomy for isolated metastases to the adrenal gland.
Eur J Surg Oncol. 2019; 45(4):631-634 [PubMed] Related Publications
BACKGROUND: Adrenal metastases can arise from different primary sites. Surgical resection of the adrenal gland in patients with isolated metastases may offer improved survival in many of these patients. However, the benefit of surgery in this heterogenous group is often disputed. The aim of this study was to identify patients undergoing adrenalectomy for isolated metastases and to describe survival outcomes based on origin of the primary malignancy.
METHODS: Patients undergoing surgery for isolated adrenal metastases were retrospectively analysed from a prospectively kept database. Data collected included the age of the patient, gender, size and functional status of the tumour and the site of the primary malignancy. Overall survival and survival based on the primary tumour were calculated using Kaplan-Meier survival analyses.
RESULTS: 42 patients were included for analysis. The median tumour size was 40 mm. 91% (n = 38) of operations were performed laparoscopically. Metastases were from the following primary organs: kidney (n = 22), lung (n = 11), breast (n = 2), gastric (n = 1), skin (n = 3), liver (n = 2) and neuroendocrine (n = 1). Overall median survival was 56 (19-93) months with 95% of patients followed up for >6 months. There was a significant difference in median survival between primary organs of origin: 83(42-123), 14(9-18), 15 and 12(3-20) months (p < 0.05) for kidney, lung, breast and skin respectively.
CONCLUSION: There is a potential survival benefit for patients undergoing surgery for isolated adrenal metastases; however this survival benefit is greater in patients undergoing resection for metastases arising from kidney primaries. A selective approach should be adopted to identify patients that will clearly benefit from surgery.

Jiang T, Zhao J, Zhao C, et al.
Dynamic Monitoring and Predictive Value of Circulating Tumor Cells in EGFR-Mutated Advanced Non-Small-Cell Lung Cancer Patients Treated With First-Line EGFR Tyrosine Kinase Inhibitors.
Clin Lung Cancer. 2019; 20(2):124-133.e2 [PubMed] Related Publications
BACKGROUND: There is an urgent need to develop a convenient and less invasive technique to monitor the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). We proposed folate receptor-based assay to count circulating tumor cells (CTCs) to predict and dynamically monitor the therapeutic response to first-line EGFR-TKIs in patients with EGFR-mutated NSCLC.
PATIENTS AND METHODS: Eligible patients were enrolled, and 3 mL of blood was obtained before initial treatment, 1 month after treatment, and every 2 months thereafter. CTCs were isolated on the basis of negative enrichment by immunomagnetic beads and detected by a ligand-targeted PCR method.
RESULTS: A total of 232 patients with EGFR-mutated NSCLC and treated with first-line EGFR-TKIs were included. Patients with low baseline CTC count had a markedly longer progression-free survival (hazard ratio = 0.48; P < .001) and overall survival (hazard ratio = 0.52; P = .002) than those with high count. This difference remained significant in multivariate analysis. Dynamic change of CTC count was significantly associated with partial response (P = .042) and stable disease/progressive disease (P = .032). Notably, dynamic monitoring of CTC provided evidence of resistance to EGFR-TKIs before computed tomographic scanning with a median lead time of 113 days (range, 45-169 days).
CONCLUSION: The current evidence suggests that folate receptor-positive CTC counts can be used for both the dynamic monitoring and prediction of outcome in EGFR-mutated NSCLC patients treated with EGFR-TKIs, which could serve as an alternative or supplement to computed tomographic scanning.

Jeon YJ, Kim T, Park D, et al.
miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC.
Nat Commun. 2018; 9(1):5110 [PubMed] Free Access to Full Article Related Publications
Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.

Menten MJ, Fast MF, Wetscherek A, et al.
The impact of 2D cine MR imaging parameters on automated tumor and organ localization for MR-guided real-time adaptive radiotherapy.
Phys Med Biol. 2018; 63(23):235005 [PubMed] Free Access to Full Article Related Publications
2D cine MR imaging may be utilized to monitor rapidly moving tumors and organs-at-risk for real-time adaptive radiotherapy. This study systematically investigates the impact of geometric imaging parameters on the ability of 2D cine MR imaging to guide template-matching-driven autocontouring of lung tumors and abdominal organs. Abdominal 4D MR images were acquired of six healthy volunteers and thoracic 4D MR images were obtained of eight lung cancer patients. At each breathing phase of the images, the left kidney and gallbladder or lung tumor, respectively, were outlined as volumes of interest. These images and contours were used to create artificial 2D cine MR images, while simultaneously serving as 3D ground truth. We explored the impact of five different imaging parameters (pixel size, slice thickness, imaging plane orientation, number and relative alignment of images as well as strategies to create training images). For each possible combination of imaging parameters, we generated artificial 2D cine MR images as training and test images. A template-matching algorithm used the training images to determine the tumor or organ position in the test images. Subsequently, a 3D base contour was shifted to the determined position and compared to the ground truth via centroid distance and Dice similarity coefficient. The median centroid distance between adapted and ground truth contours was 1.56 mm for the kidney, 3.81 mm for the gallbladder and 1.03 mm for the lung tumor (median Dice similarity coefficient: 0.95, 0.72 and 0.93). We observed that a decrease in image resolution led to a modest decrease in localization accuracy, especially for the small gallbladder. However, for all volumes of interest localization accuracy varied substantially more between subjects than due to the different imaging parameters. Automated tumor and organ localization using 2D cine MR imaging and template-matching-based autocontouring is robust against variation of geometric imaging parameters. Future work and optimization efforts of 2D cine MR imaging for real-time adaptive radiotherapy is needed to characterize the influence of sequence- and anatomical site-specific imaging contrast.

Okoli GN, Kostopoulou O, Delaney BC
Is symptom-based diagnosis of lung cancer possible? A systematic review and meta-analysis of symptomatic lung cancer prior to diagnosis for comparison with real-time data from routine general practice.
PLoS One. 2018; 13(11):e0207686 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lung cancer is a good example of the potential benefit of symptom-based diagnosis, as it is the commonest cancer worldwide, with the highest mortality from late diagnosis and poor symptom recognition. The diagnosis and risk assessment tools currently available have been shown to require further validation. In this study, we determine the symptoms associated with lung cancer prior to diagnosis and demonstrate that by separating prior risk based on factors such as smoking history and age, from presenting symptoms and combining them at the individual patient level, we can make greater use of this knowledge to create a practical framework for the symptomatic diagnosis of individual patients presenting in primary care.
AIM: To provide an evidence-based analysis of symptoms observed in lung cancer patients prior to diagnosis.
DESIGN AND SETTING: Systematic review and meta-analysis of primary and secondary care data.
METHOD: Seven databases were searched (MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, Health Management Information Consortium, Web of Science, British Nursing Index and Cochrane Library). Thirteen studies were selected based on predetermined eligibility and quality criteria for diagnostic assessment to establish the value of symptom-based diagnosis using diagnosistic odds ratio (DOR) and summary receiver operating characteristic (SROC) curve. In addition, routinely collated real-time data from primary care electronic health records (EHR), TransHis, was analysed to compare with our findings.
RESULTS: Haemoptysis was found to have the greatest diagnostic value for lung cancer, diagnostic odds ratio (DOR) 6.39 (3.32-12.28), followed by dyspnoea 2.73 (1.54-4.85) then cough 2.64 (1.24-5.64) and lastly chest pain 2.02 (0.88-4.60). The use of symptom-based diagnosis to accurately diagnose lung cancer cases from non-cases was determined using the summary receiver operating characteristic (SROC) curve, the area under the curve (AUC) was consistently above 0.6 for each of the symptoms described, indicating reasonable discriminatory power. The positive predictive value (PPV) of diagnostic symptoms depends on an individual's prior risk of lung cancer, as well as their presenting symptom pattern. For at risk individuals we calculated prior risk using validated epidemiological models for risk factors such as age and smoking history, then combined with the calculated likelihood ratios for each symptom to establish posterior risk or positive predictive value (PPV).
CONCLUSION: Our findings show that there is diagnostic value in the clinical symptoms associated with lung cancer and the potential benefit of characterising these symptoms using routine data studies to identify high-risk patients.

McKelvie J, McLintock C, Elalfy M
Bilateral Ulcerative Keratitis Associated With Afatinib Treatment for Non-Small-cell Lung Carcinoma.
Cornea. 2019; 38(3):384-385 [PubMed] Related Publications
PURPOSE: To report a case of afatinib-related bilateral ulcerative keratitis.
METHODS: An 85-year-old female patient on treatment with afatinib for non-small-cell lung carcinoma presented with progressive redness, pain, and decreased vision in both eyes. Four weeks before the onset of symptoms, afatinib therapy had been commenced at a dose of 40 mg, once daily. Clinical examination, OCT imaging, photographs, and corneal scrapes were completed at presentation. Afatinib was discontinued. Topical and oral therapy were commenced to treat ulcerative keratitis with close monitoring for signs of progression or corneal perforation.
RESULTS: Significant stromal thinning was detected in the inferior cornea of both eyes with an overlying epithelial defect and no infiltrate. No organisms were identified from the corneal scrapes. The patient responded well to treatment, and her vision returned to baseline 4 months after presentation.
CONCLUSIONS: To the best of our knowledge, this is the first case in the literature that reports afatinib-related ulcerative keratitis. Careful monitoring for signs of ocular adverse events is recommended during treatment with afatinib for non-small-cell lung carcinoma.

Roman M, Labbouz S, Valtzoglou V, et al.
Lobectomy vs. segmentectomy. A propensity score matched comparison of outcomes.
Eur J Surg Oncol. 2019; 45(5):845-850 [PubMed] Related Publications
BACKGROUND: Segmentectomy has emerged as a lung parenchymal sparring alternative to the gold standard lobectomy in non-small cell lung cancer (NSCLC) patients. We hypothesized that there is parity between functional, local recurrence and survival outcomes.
PATIENTS AND METHODS: Parenchymal sparring procedures including anatomical segmentectomies were propensity score matched 1:1 with lobectomies (n = 64). The primary outcomes included survival, functional and oncological outcomes. The oncological outcomes were: post-operative histology, clear margins and local recurrence rates. Kaplan Meier survival curves were used to compare the survival. Oncological and functional variables were assessed by Fischer exact test and t-test.
RESULTS: The pre-operative performance status, ASA grade, lung function, risk factors, surgical approach and tumour histology were similar between the groups. The tumour size was significantly higher for lobectomies (32.4 ± 17 vs. 24.6 ± 12 mm, p = 0.01). The tumour staging in the segmentectomy group was similar to the lobectomy group (Ia; 50 vs. 34%; Ib: 29 vs. 37%; IIa 11 vs. 9.3%; IIb 5 vs. 14%; IIIa 5 vs. 4.6%, p = 0.83). The loco-regional recurrence was lower in the segmentectomy group (1.5 vs. 3.1%, p = 0.69). The up-staging and down-staging post-surgery was similar in both groups, while neo-adjuvant therapy was used in 5 lobectomy and 3 segmentectomy cases. The survival was similar at 1 year between the groups (88 vs. 92%, p = 0.65). Between 4 and 5 years, the survival reduced in the parenchymal sparing group to 39% vs. 68% in the lobectomy group (p = 0.04).
CONCLUSION: Surgical selection bias could be an important confounder in the selection of patients undergoing segmentectomy. Similar up and down staging were demonstrated in the two groups. This is one of the first studies to investigate the results of segmentectomy versus lobectomy in stage II/IIIa NSCLC tumours. No significant differences were found in functional outcomes, but the survival decreased after 4 years in the segmentectomy group, which could be explained by lower survival in the stage II/IIIa tumours treated with segmentectomy.

Amelio I, Mancini M, Petrova V, et al.
p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression.
Proc Natl Acad Sci U S A. 2018; 115(46):E10869-E10878 [PubMed] Free Access to Full Article Related Publications
Mutations in the

Lee PN, Djurdjevic S, Weitkunat R, Baker G
Estimating the population health impact of introducing a reduced-risk tobacco product into Japan. The effect of differing assumptions, and some comparisons with the U.S.
Regul Toxicol Pharmacol. 2018; 100:92-104 [PubMed] Related Publications
We estimated, using previously described methodology, the population health impact of introducing a reduced-risk tobacco product (RRP) into Japan. Various simulations were carried out to understand the impact on the population in different situations over a 20-year period from 1990. The overall reduction in tobacco-attributable deaths from lung cancer (LC), ischemic heart disease (IHD), stroke, and chronic obstructive pulmonary disease (COPD) for men and women combined was estimated to be 269,916 over the period if tobacco use disappeared completely at baseline. In contrast, reductions ranging from 167,041 to 232,519 deaths were estimated if the RRP totally replaced smoking at baseline (assuming that switching to it had an effect equivalent to 70%-90% of the effect of quitting). If, more plausibly, the RRP were introduced at baseline, with uptake rates consistent with the known uptake of the RRP IQOS

Van Cutsem E, Karaszewska B, Kang YK, et al.
A Multicenter Phase II Study of AMG 337 in Patients with
Clin Cancer Res. 2019; 25(8):2414-2423 [PubMed] Related Publications

Tahir BA, Hughes PJC, Robinson SD, et al.
Spatial Comparison of CT-Based Surrogates of Lung Ventilation With Hyperpolarized Helium-3 and Xenon-129 Gas MRI in Patients Undergoing Radiation Therapy.
Int J Radiat Oncol Biol Phys. 2018; 102(4):1276-1286 [PubMed] Related Publications
PURPOSE: To develop and apply an image acquisition and analysis strategy for spatial comparison of computed tomography (CT)-ventilation images with hyperpolarized gas magnetic resonance imaging (MRI).
METHODS AND MATERIALS: Eleven lung cancer patients underwent xenon-129 (
RESULTS: Spatial correlation of CT-ventilation against
CONCLUSION: Comparison of ventilation-related measures from CT and registered hyperpolarized gas MRI is feasible at a voxel level using a dedicated acquisition and analysis protocol. Moderate correlation between CT-ventilation and MRI exists at a regional level. Correlation between MRI and CT is significantly less than that between

Li X, Gu G, Soliman F, et al.
The Evaluation of Durative Transfusion of Endostar Combined with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer.
Chemotherapy. 2018; 63(4):214-219 [PubMed] Related Publications
BACKGROUND: The overall survival (OS) in non-small cell lung cancer (NSCLC) is poor, with median OS of advanced NSCLC with standard systemic chemotherapy being reported at 13.6 months and the 5-year survival rate at less than 15%. Therefore, the aim of this study was to evaluate Endostar combined with chemotherapy in patients with advanced NSCLC.
METHODS: Data on 116 cases of pathologically confirmed stage IIIB-IV NSCLC were retrospectively collected. The control group was treated with chemotherapy combined with intravenous infusion of Endostar while the test group received durative transfusion of Endostar. The short-term therapeutic effects including overall response rate (ORR), disease control rate (DCR), and safety were evaluated in both groups. In the follow-up, progression-free survival (PFS) and OS were also analysed.
RESULTS: In the test group, the ORR was 53.4%, which was similar to that in the control group (44.8%) (p > 0.05). However, the DCR in the test group (86.2%) was significantly higher than that in the control group (70.7%) (p < 0.01). The median time to progression in the test group (6 months) was also significantly longer than that in the control group (4 months). Importantly, the median OS in the test group (17.5 months) was improved compared to the control group (13.5 months). The 1-year survival rate in the test and control groups was 9.7 and 15.8%, respectively. There was no significant difference in side effects (including thrombocytopenia, leucopenia, nausea, and vomiting) between the two groups.
CONCLUSIONS: Endostar durative transfusion combined with chemotherapy showed a higher DCR, longer PFS and OS time, and was well tolerated in patients with advanced NSCLC.

Kowanetz M, Zou W, Gettinger SN, et al.
Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1).
Proc Natl Acad Sci U S A. 2018; 115(43):E10119-E10126 [PubMed] Free Access to Full Article Related Publications
Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-γ-induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti-PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.

Antonia SJ, Villegas A, Daniel D, et al.
Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC.
N Engl J Med. 2018; 379(24):2342-2350 [PubMed] Related Publications
BACKGROUND: An earlier analysis in this phase 3 trial showed that durvalumab significantly prolonged progression-free survival, as compared with placebo, among patients with stage III, unresectable non-small-cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy. Here we report the results for the second primary end point of overall survival.
METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab intravenously, at a dose of 10 mg per kilogram of body weight, or matching placebo every 2 weeks for up to 12 months. Randomization occurred 1 to 42 days after the patients had received chemoradiotherapy and was stratified according to age, sex, and smoking history. The primary end points were progression-free survival (as assessed by blinded independent central review) and overall survival. Secondary end points included the time to death or distant metastasis, the time to second progression, and safety.
RESULTS: Of the 713 patients who underwent randomization, 709 received the assigned intervention (473 patients received durvalumab and 236 received placebo). As of March 22, 2018, the median follow-up was 25.2 months. The 24-month overall survival rate was 66.3% (95% confidence interval [CI], 61.7 to 70.4) in the durvalumab group, as compared with 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided P=0.005). Durvalumab significantly prolonged overall survival, as compared with placebo (stratified hazard ratio for death, 0.68; 99.73% CI, 0.47 to 0.997; P=0.0025). Updated analyses regarding progression-free survival were similar to those previously reported, with a median duration of 17.2 months in the durvalumab group and 5.6 months in the placebo group (stratified hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.63). The median time to death or distant metastasis was 28.3 months in the durvalumab group and 16.2 months in the placebo group (stratified hazard ratio, 0.53; 95% CI, 0.41 to 0.68). A total of 30.5% of the patients in the durvalumab group and 26.1% of those in the placebo group had grade 3 or 4 adverse events of any cause; 15.4% and 9.8% of the patients, respectively, discontinued the trial regimen because of adverse events.
CONCLUSIONS: Durvalumab therapy resulted in significantly longer overall survival than placebo. No new safety signals were identified. (Funded by AstraZeneca; PACIFIC number, NCT02125461 .).

Camidge DR, Kim HR, Ahn MJ, et al.
Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer.
N Engl J Med. 2018; 379(21):2027-2039 [PubMed] Related Publications
BACKGROUND: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear.
METHODS: In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred.
RESULTS: A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow-up was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted.
CONCLUSIONS: Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L number, NCT02737501 .).

Consonni D, Carugno M, De Matteis S, et al.
Outdoor particulate matter (PM10) exposure and lung cancer risk in the EAGLE study.
PLoS One. 2018; 13(9):e0203539 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Cohort studies in Europe, but not in North-America, showed an association between exposure to outdoor particulate matter with aerodynamic diameter ≤10 μm (PM10) and lung cancer risk. Only a case-control study on lung cancer and PM10 in South Korea has so far been performed. For the first time in Europe we analyzed quantitatively this association using a case-control study design in highly polluted areas in Italy.
METHODS: The Environment And Genetics in Lung cancer Etiology (EAGLE) study, a population-based case-control study performed in the period 2002-2005 in the Lombardy Region, north-west Italy, enrolled 2099 cases and 2120 controls frequency-matched for area of residence, gender, and age. For this study we selected subjects with complete active and passive smoking history living in the same municipality since 1980 until study enrollment. Fine resolution annual PM10 estimates obtained by applying land use regression modeling to satellite data calibrated with fixed site monitor measurements were used. We assigned each subject the PM10 average estimates for year 2000 based on enrollment address. We used logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (CI) adjusted for matching variables, education, smoking, and dietary and occupational variables.
RESULTS: We included 3473 subjects, 1665 cases (1318 men, 347 women) and 1808 controls (1368 men, 440 women), with PM10 individual levels ranging from 2.3 to 53.8 μg/m3 (mean: 46.3). We found increasing lung cancer risk with increasing PM10 category (P-value for trend: 0.04). The OR per 10 μg/m3 was 1.28 (95% CI: 0.95-1.72). The association appeared stronger for squamous cell carcinoma (OR 1.44, 95% CI: 0.90-2.29).
CONCLUSION: In a population living in highly polluted areas in Italy, our study added suggestive evidence of a positive association between PM10 exposure and lung cancer risk. This study emphasizes the need to strengthen policies to reduce airborne pollution.

Treue D, Bockmayr M, Stenzinger A, et al.
Proteogenomic systems analysis identifies targeted therapy resistance mechanisms in EGFR-mutated lung cancer.
Int J Cancer. 2019; 144(3):545-557 [PubMed] Related Publications
Cancer precision medicine largely relies on knowledge about genetic aberrations in tumors and next-generation-sequencing studies have shown a high mutational complexity in many cancers. Although a large number of the observed mutations is believed to be not causally linked with cancer, the functional effects of many rare mutations but also of combinations of driver mutations are often unknown. Here, we perform a systems analysis of a model of EGFR-mutated nonsmall cell lung cancer resistant to targeted therapy that integrates whole exome sequencing, global time-course discovery phosphoproteomics and computational modeling to identify functionally relevant molecular alterations. Our approach allows for a complexity reduction from over 2,000 genetic events potentially involved in mediating resistance to only 44 phosphoproteins and 35 topologically close genetic alterations. We perform single- and combination-drug testing against the predicted phosphoproteins and discovered that targeting of HSPB1, DBNL and AKT1 showed potent antiproliferative effects overcoming resistance against EGFR-inhibitory therapy. Our approach may therefore be used to complement mutational profiling to identify functionally relevant molecular aberrations and propose combination therapies across cancers.

Felley-Bosco E, MacFarlane M
Asbestos: Modern Insights for Toxicology in the Era of Engineered Nanomaterials.
Chem Res Toxicol. 2018; 31(10):994-1008 [PubMed] Related Publications
Asbestos fibers are naturally occurring silicates that have been extensively used in the past, including house construction, but because of their toxicity, their use has been banned in 63 countries. Despite this, more than one million metric tons of asbestos are still consumed annually in countries where asbestos use has not been banned. Asbestos-related disease incidence is still increasing in several countries, including those countries that banned the use of asbestos more than 30 years ago. We highlight here recent knowledge obtained in experimental models about the mechanisms leading to tumor development following asbestos exposure, including genetic and epigenetic changes. Importantly, the landscape of alterations observed experimentally in tumor samples is consistent with alterations observed in clinical tumor samples; therefore, studies performed on early/precancer stages should help inform secondary prevention, which remains crucial in the absence of an efficient primary prevention. Knowledge gathered on asbestos should also help address future challenges, especially in view of the increased production of new materials that may behave similarly to asbestos fibers.

Bibby AC, Maskell NA
Current treatments and trials in malignant pleural mesothelioma.
Clin Respir J. 2018; 12(7):2161-2169 [PubMed] Related Publications
OBJECTIVES: This article aims to review the evidence from recent clinical trials in mesothelioma, and to provide an overview of relevant clinical trials that are currently in progress.
DATA SOURCE: Ovid MEDLINE, 1946 to present.
STUDY SELECTION: Clinical trials of therapeutic interventions were considered for inclusion, regardless of phase. Of 258 papers identified in the literature search, 88 were potentially eligible based on abstract screening. Following evaluation of full-text articles, 35 were selected for inclusion in the review.
RESULTS: Since the original trial that demonstrated the efficacy of pemetrexed and cisplatin in mesothelioma, multiple trials have been conducted that have further informed management options. Anti-angiogenesis agents such as bevacizumab and nintedanib appear promising as adjuncts to first-line chemotherapy. Meanwhile, immunotherapy, anti-mesothelin agents and molecular targeted therapies are potential areas for development, with ongoing trials promising to deliver interesting results over the next few years. Current evidence does not support surgical intervention; however, investigations are ongoing as to the role of extended pleurectomy/decortication, and surgery in the context of trapped lung. Finally radiotherapy is effective as a palliative measure for pain control, but is not indicated prophylactically to prevent the development of procedure tract metastases.
CONCLUSION: A large amount of high-quality mesothelioma research has been conducted in the past decade. As a result, several new therapies are likely to become available in clinical practice in the near future. With multiple trials ongoing, the horizon for patients with mesothelioma looks brighter than ever before.

Ali J, Haiyang F, Aresu G, et al.
Uniportal Subxiphoid Video-Assisted Thoracoscopic Anatomical Segmentectomy: Technique and Results.
Ann Thorac Surg. 2018; 106(5):1519-1524 [PubMed] Related Publications
BACKGROUND: Performing sublobar resection for early stage non-small cell lung carcinoma is becoming increasingly popular, with studies suggesting equivalent outcomes to lobectomy when sufficient lymph node sampling is performed. Furthermore, there has been a move to minimally invasive thoracic surgery facilitating enhanced recovery and reduced postoperative morbidity. The subxiphoid video-assisted thoracic surgery (SVATS) approach is a novel technique that is becoming increasingly popular, with evidence of reduced postoperative pain. Here, we report experience and the technique of performing segmentectomy by the uniportal SVATS approach.
METHODS: The uniportal SVATS approach was used to perform all possible segmentectomies. Specific instruments were designed to facilitate performing surgery through this approach, and the operative technique is described and demonstrated with videos.
RESULTS: Between September 2014 and April 2017, 242 segmentectomies were performed by uniportal SVATS. Twenty-nine of the patients underwent bilateral procedures. The mean duration of surgery was 2.14 ± 0.78 hours. Lymph node stations were accessible, and a mean of 4.00 ± 1.00 lymph node stations and 10.64 ± 3.38 lymph nodes were sampled. The mean postoperative hospital length of stay was 4.67 ± 9.54 days. Only 4 cases required conversion to thoracotomy, and 3 required conversion to full lobectomy. There were no perioperative deaths, with 30-day survival of 100%.
CONCLUSIONS: This report demonstrates that the uniportal SVATS approach can be safely and effectively utilized to perform pulmonary segmentectomies. Our series demonstrates that it is possible to access and resect all segments by this novel approach to VATS.

Liu Y, Lusk CM, Cho MH, et al.
Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.
J Thorac Oncol. 2018; 13(10):1483-1495 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior.
METHODS: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls.
RESULTS: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility.
CONCLUSION: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.

Cole AJ, Veiga C, Johnson U, et al.
Toward adaptive radiotherapy for lung patients: feasibility study on deforming planning CT to CBCT to assess the impact of anatomical changes on dosimetry.
Phys Med Biol. 2018; 63(15):155014 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Changes in lung architecture during a course of radiotherapy can alter the planned dose distribution to the extent that it becomes clinically unacceptable. This study aims to validate a quantitative method of determining whether a replan is required during the course of conformal radiotherapy. The proposed method uses deformable image registration (DIR) to flexibly map planning CT (pCT) data to the anatomy of online CBCT images. The resulting deformed CT (dCT) images are used as a basis for assessing the effect of anatomical change on dose distributions. The study used retrospective data from a sample of seven replanned lung patients. The settings of an in-house, open-source DIR algorithm were first optimised for CT-to-CBCT registrations of the anatomy of the thorax. Using these optimised parameters, each patient's pCT was deformed to the CBCT acquired immediately before the replan. Registration accuracy was rigorously validated both geometrically and dosimetrically to confirm that the dCTs could reliably be used to inform replan decisions. A retrospective evaluation of the changes in dose delivered over time was then carried out for a single patient to demonstrate the clinical application of the proposed method. The geometric analysis showed good agreement between deformed structures and those same structures manually outlined on the CBCT images. Results were consistently better than those achieved with rigid-only registration. In the dosimetric analysis, dose distributions derived from the dCTs were found to match closely to the 'gold standard' replan CT (rCT) distributions across dose volume histogram and absolute dose difference measures. The retrospective analysis of serial CBCTs of a single patient produced reliable quantitative assessment of the dose delivery. Had the proposed method been available at the time of treatment, it would have enabled a more objective replan decision. DIR is a valuable clinical tool for dose recalculation in adaptive radiotherapy protocols for lung cancer patients.

Ahmed M, Flannery A, Daneshvar C, Breen D
PET and Neck Ultrasound for the Detection of Cervical Lymphadenopathy in Patients with Lung Cancer and Mediastinal Lymphadenopathy.
Respiration. 2018; 96(2):138-143 [PubMed] Related Publications
BACKGROUND: Cervical lymph nodes are frequently involved in patients with lung cancer and indicate inoperability. Some guidelines recommend neck ultrasound (NUS) in patients with bulky mediastinal lymphadenopathy. Positron emission tomography (PET) is indicated for patients with potentially curable disease.
OBJECTIVES: We aimed to assess the diagnostic yield of NUS and the diagnostic accuracy of PET for cervical lymphadenopathy in this group with a high pre-test probability of N3 disease.
METHODS: Records of all patients with lung cancer who underwent an NUS over a consecutive 5-year period were reviewed. Only patients with mediastinal lymphadenopathy on computerised tomography (CT) were included. The diagnostic accuracy of PET was assessed with NUS-guided fine needle aspiration cytology used as the reference test.
RESULTS: During the study period, 123 patients met the inclusion criteria. Malignant cervical lymphadenopathy was confirmed in 49/123 (39.8% [95% CI 31.1-49.1]). PET-CT had a specificity of 81.1%, sensitivity of 87.5%, negative predictive value of 96.8% and positive predictive value of 50% for the detection of cervical lymphadenopathy, and it contributed no additional staging information in the neck area. Overall, PET led to a change in management in only 2.2% of cases.
CONCLUSION: A significant proportion of patients with lung cancer and mediastinal lymphadenopathy have cervical lymphadenopathy detected by NUS. In this group of patients, PET offers minimal additional value in staging and management.

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