1. Sherry, Victoria DNP, MSN, CRNP-BC, AOCNP

Article Content

Lung cancer is the leading cause of oncology-related deaths in both men and women worldwide, claiming over 1.6 million lives annually.1 This death estimate is higher than colon, prostate, and breast cancers combined. The high mortality connected to lung cancer is due to the majority of patients being diagnosed late in the disease trajectory. Despite novel therapeutic advances coupled with personalized medicine, the 5-year survival rate remains dismal at only 17%.2


Lung cancer is more common in men than in women, higher in Blacks, and is a disease of older adults, with 80% of cases diagnosed in individuals over age 65.2-,3,4 Cigarette smoking remains the leading risk factor, accounting for 80% of all lung cancer cases.2 Although the relationship between cigarette smoking and lung cancer is well established, a surprising one-half of lung cancer cases diagnosed each year are never-smokers or former-smokers.5 "Never-smokers" is defined as individuals who have smoked fewer than 100 cigarettes in their lifetime.6


In addition to cigarette smoking, other risk factors (in both smokers and nonsmokers) include secondhand smoke, radon, occupational human carcinogens (asbestos, arsenic, and diesel dust), prior radiation to the chest, use of beta carotene supplements, and a family history of lung cancer.2,7


The signs and symptoms of lung cancer depend on the location of the tumor and the extent of the disease. Some patients are asymptomatic and diagnosed incidentally on a routine chest X-ray (CXR). However, the majority of patients with lung cancer are diagnosed late in the disease trajectory and therefore exhibit signs and symptoms indicative of advanced disease. Presenting symptoms may be related to the cancer (cough, shortness of breath, wheezing, hemoptysis, chest pain, weight loss, hoarseness, fatigue), metastasis (blurred vision, headaches, pain), or a paraneoplastic syndrome (hypercalcemia, syndrome of inappropriate antidiuretic hormone). Prompt identification of these symptoms can lead to a timely diagnosis and improved quality of life.


Prior to 2011, recommendations for early detection screening for lung cancer did not exist. The National Lung Screening Trial (NLST) revealed that annual screening for lung cancer with low-dose computed tomography (LDCT), when compared with standard CXRs, lowered the risk of dying from lung cancer by 15% to 20%.8


Based on these results, the National Comprehensive Cancer Network (NCCN) and United States Preventive Services Task Force (USPSTF) developed evidence-based screening guidelines recommending annual screening for lung cancer with LDCT. Both guidelines agree that individuals who have a 30-pack-per-year smoking history and currently smoke or have quit within the past 15 years should be screened. However, the NCCN recommends screening for ages 55 to 74; the USPSTF recommends screening for ages 55 to 80.9,10 It is essential to obtain a comprehensive health history including tobacco use, occupational history, comorbidities, weight loss, performance status, and physical exam to identify high-risk patients.


Case study

Mr. W, a 67-year-old White male, presents to his primary care clinic with complaints of a persistent dry cough over the past 2 months. He does not have fever, chest pain, dyspnea, night sweats, heartburn, sore throat, or rhinorrhea. Mr. W notes an unintentional 10-lb weight loss over the past 3 months, and his medical history is unremarkable. He is married and has two grown children. He recently retired from his job as a computer programmer, has smoked a pack of cigarettes per day for 45 years, drinks 8 to 16 oz of wine on the weekends, and has no history of illicit drugs.


Mr. W's father is deceased from prostate cancer, his mother is deceased from heart disease, his brother has hypertension and hypercholesterolemia, and both his children are alive and healthy. His physical exam is significant for decreased breath sounds and dullness to percussion in the right lower lobe as well as scattered inspiratory wheezes. Mr. W's vital signs are stable and he is afebrile. He is seen in the clinic by an NP who plans to treat him with antibiotics and corticosteroids for a possible upper respiratory infection.


Diagnostic testing

As in Mr. W's case, patients not yet diagnosed with lung cancer often present to their primary care provider's office with respiratory symptoms (fever, cough, hemoptysis, dyspnea, shortness of breath, chest pain, and fatigue) that are mistaken for pneumonia, bronchitis, a chronic obstructive pulmonary disease flare, or a pneumothorax. Patients often have recurrent respiratory infections and often receive several rounds of antibiotics before any diagnostic test is performed. A CXR, chest computed tomography (CT) scan, positron emission tomography (PET) scan, and brain magnetic resonance imaging (MRI) are critical to completing a lung cancer workup.


A CXR is a quick and affordable way to grossly identify a lung mass. However, it is unable to detect subcentimeter nodules and mediastinal lymph nodes that are frequently concealed by the heart and large blood vessels. A chest CT scan is considered the cornerstone of imaging studies and can identify much smaller nodules than a CXR.11 Even though a chest CT provides invaluable information on the extent of the disease, it has limited ability to discern benign and malignant lesions in an organ or in lymph nodes.12 If an abnormal finding is seen on a CT scan or a pathologic diagnosis is confirmed, a PET scan should be ordered. A PET scan evaluates the level of metabolic activity and has a higher sensitivity and specificity than a chest CT for assessment of mediastinal lymph nodes and distant sites of disease.13 The PET scan report includes the tumor standardized uptake value (SUV) and a value of 2.5 or greater suggest a tumor may be malignant.14


MRI of the chest is not routinely used due to chest movement during inspiration and expiration, making interpretation difficult; however, it is an invaluable tool for evaluating cardiac, bone, brain, liver, and adrenal metastasis. Regardless of the stage of lung cancer, all patients should have a brain MRI to rule out brain metastases in order to complete the diagnostic workup. A brain MRI is the most sensitive diagnostic tool for detecting brain metastases; however, if contraindicated due to a pacemaker, other metallic implants, or metal foreign body, a head CT should be performed.15


A CXR is ordered for Mr. W and shows a 5 cm mass in the right lower lobe. The NP notifies Mr. W of the results and that he needs additional tests to check for a possible lung carcinoma. He is given a prescription for a CT scan of the chest in order to further characterize the mass. The CT shows a 5.4 cm spiculated mass in the right lower lobe as well as several ipsilateral and contralateral mediastinal lymph nodes. The NP suspects a lung carcinoma and understands that it is essential to confirm a pathologic diagnosis and promptly refers Mr. W. to a pulmonologist for a biopsy.


There are a variety of approaches to collect tissue to confirm a diagnosis of a suspected lung carcinoma. The type of procedure utilized largely depends on the location and size of the tumor. While sputum cytology is a quick and noninvasive method for diagnosing lung cancer, it is more sensitive for central lesions (squamous cell carcinomas) and is limited by scant material for immunohistochemical and molecular analysis, and is therefore not used frequently.16


For a large number of suspected lesions, use of a flexible bronchoscopy is a common way to achieve a diagnosis. Recent advances in ultrasound and navigational technology have improved the diagnostic yield of flexible bronchoscopy.



There are two types of endobronchial ultrasound (EBUS): a curvilinear endobronchial ultrasound (which is directly incorporated on the bronchoscope and allows for transbronchial needle aspiration [EBUS-TBNA]) and peripheral radial EBUS probes (which can access as far as the pleural surface). The EBUS-TBNA bronchoscope uses an ultrasound probe to visualize the target lesion and surrounding structures and allows for simultaneous tissue sampling of the target lesion under direct sonographic guidance.17 The peripheral radial EBUS probes can be threaded through a standard white light flexible bronchoscopy to allow peripheral nodules to be identified for biopsy.


In addition to the peripheral radial EBUS probes, the development of navigational bronchoscopy, which uses a CT scan to create a virtual bronchoscopic path to the lesion of interest, can improve identification of parenchymal nodules.2 If a lesion is not accessible to bronchoscopy, a CT-guided transthoracic needle aspiration or fine needle aspiration are also excellent for detecting more peripheral malignancies in the chest, but they are associated with a high rate of pneumothorax.16,18 A mediastinoscopy, where a surgeon makes a small incision above the suprasternal notch to pass a scope down through the mediastinum to biopsy lymph nodes, was the procedure of choice for staging patients with potentially operable lung cancer.19,20 However, recent evidence has found that EBUS-TBNA is a safe, less invasive, and cost-effective way to evaluate the mediastinum prior to surgery due to its high diagnostic accuracy.19,21,22


If EBUS-TBNA is not available, mediastinoscopy is an effective way to sample mediastinal lymph nodes. One goal of any diagnostic evaluation for possible lung cancer should be to obtain the most information from the least invasive procedures. Often, patients with possible lung cancer will present with a pleural effusion where a thoracentesis can be performed to not only confirm the diagnosis, but to stage the cancer with one bedside procedure. Regardless of what procedure is used to confirm a diagnosis, in today's era of differential tumor responses based on tumor subtype and targeted therapeutics, it is paramount to obtain adequate tissue to test for histologic and molecular characterization.16


Additional tests and staging

An EBUS-TBNA of Mr. W's mediastinal lymph nodes is performed and reveals a diagnosis of non-small cell lung adenocarcinoma, stage IV (T2bN3M1b). Once a pathologic diagnosis is confirmed, the NP orders a PET scan and brain MRI to complete the staging process. A PET scan confirms hypermetabolic activity in the right lower lobe (SUV 10) and mediastinal lymph nodes (SUV 9) as well as metastatic lesions to the left 5th rib, thoracic 5, and lumbar 3 (SUV 11). A brain MRI is performed, which is negative for metastases. Mr. W is informed of his diagnosis and referred to a medical oncology team for further management.


Non-small cell lung cancer (NSCLC) is staged according to the 7th edition of the American Joint Committee on Cancer tumor, node, metastasis (TNM) staging system.23 Prognosis is highly dependent on the stage of disease, with stage IV representing the poorest 5-year survival (see Five-year observed survival rate for NSCLC). NSCLC staging is not only a valuable predictor of survival, but also determines appropriate treatment options.24 Lung cancer is divided into two types: small cell and NSCLC, which is the most common, accounting for 83% of all lung cancers.2,25 There are three primary histologic subtypes of NSCLC: squamous cell, adenocarcinoma, and large cell.2 Adenocarcinoma is the leading subtype of lung cancer, accounting for 40% of lung cancers.2 Differentiating lung adenocarcinoma from other tumor types can be difficult. Thyroid transcription factor-1 (TTF-1) is expressed in approximately 75% of lung adenocarcinomas, making it an important marker in diagnosis.26


Other pulmonary tumors, such as neuroendocrine tumors, share expression of TTF-1; however, it is rarely expressed in any other organ, making it a very sensitive predictor of lung adenocarcinoma. This subtype of lung cancer is primarily associated with smoking, but approximately 10% to 40% of patients diagnosed are never-smokers.27 It is critical to establish histologic subtyping of all NSCLCs because therapy differs for each subtype.

Table Five-year obse... - Click to enlarge in new windowTable Five-year observed survival rate for NSCLC

After histology is confirmed, molecular testing should be performed to identify genetic alterations that will help guide treatment decisions and personalize treatment. Personalizing treatment for NSCLC adenocarcinoma includes understanding tumor histology and molecular abnormalities as well as considering the age, performance status, and comorbidities of the patient.13 A subset of patients with metastatic NSCLC adenocarcinoma harbor genetic alterations associated with higher response rates, longer progression free survival, and improved quality of life.13


The epidermal growth factor receptor (EGFR) mutation and echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) translocation are two genetic alterations that are treated with molecularly targeted therapy. Both genetic alterations are generally exclusive to adenocarcinoma, although there have been a few case reports in squamous cell and other histologies. The EGFR mutation is found in 10% to 15% of patients with adenocarcinoma and EML4-ALK translocation is present in 2% to 7% of patients with adenocarcinoma.28,29


The results from these molecular tests can take from several days to weeks, which can be detrimental to a patient who is very symptomatic and needs urgent treatment. In an age of personalized medicine, genetic alterations provide an individualistic approach to treating lung cancer. The therapies used to target these two genetic alterations are oral formulations, making treatment more convenient and less invasive. However, these therapies can be costly to individuals who do not have insurance or have suboptimal coverage.


Treatment options

Mr. W inquires about treatment options for his stage IV lung adenocarcinoma diagnosis. He is informed that his tumor does not harbor any genetic alterations and he is offered treatment with standard chemotherapy.


If a tumor does not harbor a genetic alteration, as in Mr. W's case, first-line therapy (according to the NCCN guidelines) consists of a platinum doublet (cisplatin or carboplatin) in combination with pemetrexed, a taxane (paclitaxel or docetaxel), gemcitabine, vinorelbine, or etoposide with or without bevacizumab (an angiogenesis inhibitor).30,31 Bevacizumab is contraindicated in patients with a history of a thromboembolic event, hemoptysis, or untreated brain metastases.32 Patients with no tumor progression after 4 to 6 cycles of first-line chemotherapy will receive continuation maintenance therapy with pemetrexed with or without bevacizumab or switch maintenance (using agents that are different from those used in first-line therapy) with pemetrexed or erlotinib until disease progression or toxicity that affects quality of life.30


These chemotherapeutic agents have an array of adverse reactions, such as fatigue, nausea, vomiting, peripheral neuropathy, neutropenia, thrombocytopenia, anemia, and hypersensitivity reactions. Bevacizumab has its own unique adverse reactions, including hypertension, proteinuria, and epistaxis.26 These reactions can be minimized with continual patient education coupled with aggressive management.


Patients with metastatic lung cancer have a high symptom burden and elevated levels of distress related to their disease.33 Because stage IV lung adenocarcinoma is not curable, goals of care are focused on extending the patient's time to live balanced with a good quality of life. Initiation of early palliative care is key to achieving this goal. Palliative care is a patient- and family-centered approach that focuses on pain management and distress that is brought on by symptoms of their cancer treatment as well as psychosocial and spiritual care.34 A landmark study by Temel and colleagues demonstrated that patients with metastatic lung cancer who received early palliative care had a survival advantage despite receiving less aggressive care at the end of life.35


It is also critical to address a patient's cigarette smoking. Patients who continue to smoke tobacco after being diagnosed with lung cancer experience decreased efficacy of chemotherapy, increased radiation therapy complications, and a decreased quality of life; therefore, it is never too late for patients with lung cancer to stop smoking.36,37 Immediate positive benefits include improved oxygenation and breathing, lowered BP, enhanced smell and taste, higher energy, and improved immune response.36


Clinical practice guidelines for treating tobacco dependence includes evidence-based pharmacotherapy, behavior therapy, and close follow-up.36,38 The most successful treatment is a combination of counseling and pharmacotherapy (varenicline and nicotine replacement therapy).36


Improving outcomes

This case study demonstrates how diagnosing a patient with lung cancer can be prolonged, challenging, and labor intensive. Patients often present to their primary care team with complaints of a cough or other symptom suggestive of an infection; lung cancer should always be considered as a differential diagnosis. NPs in primary care play a key role in improving patient outcomes through identifying and screening patients at high risk for lung cancer, promoting smoking cessation at every visit, recognizing the signs and symptoms of lung cancer (regardless of smoking status), and expediting the initial workup through appropriate diagnostic tests and referrals.


Once a lung cancer diagnosis is established, primary care NPs continue to work collaboratively with the oncology and palliative care team to educate the patient and manage toxicities they are experiencing from cancer treatment. Primary care NP involvement in a patient with lung cancer is essential and does not end after a patient is diagnosed with lung cancer but expands throughout the entire cancer care continuum.




1. World Health Organization. Cancer fact sheet. 2015. [Context Link]


2. American Cancer Society. Cancer Facts and Figures 2016. Atlanta, GA: American Cancer Society; 2016. [Context Link]


3. Centers for Disease Control and Prevention. National Center for Health Statistics. 2014. CDC WONDER On-line Database, compiled from Compressed Mortality File 1999-2012 Series 20 No. 2R. [Context Link]


4. National Cancer Institute. 2016. SEER Cancer Statistics Review, 1975-2013. [Context Link]


5. Yang P. Lung cancer in never smokers. Semin Respir Crit Care Med. 2011;32(1):10-21. [Context Link]


6. Centers for Disease Control and Prevention. Adult tobacco use information. 2015. [Context Link]


7. National Cancer Institute. Non-small cell lung cancer treatment. 2015. [Context Link]


8. Kramer BS, Berg CD, Aberle DR, Prorok PC. Lung cancer screening with low-dose helical CT: results from the National Lung Screening Trial (NLST). J Med Screen. 2011;18(3):109-111. [Context Link]


9. U.S. Preventive Services Task Force. Lung cancer screening. 2013. [Context Link]


10. National Comprehensive Cancer Network. NCCN guidelines version 2.2014 updates: lung cancer screening. 2014. [Context Link]


11. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. [Context Link]


12. Liao S, Penney BC, Wroblewski K, et al. Prognostic value of metabolic tumor burden on 18F-FDG PET in nonsurgical patients with non-small cell lung cancer. Eur J Nucl Med Mol Imaging. 2012;39(1):27-38. [Context Link]


13. Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E. Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(suppl 7):vii56-vii64. [Context Link]


14. Kinahan PE, Fletcher JW. Positron emission tomography-computed tomography standardized uptake values in clinical practice and assessing response to therapy. Semin Ultrasound CT MR. 2010;31(6):496-505. [Context Link]


15. Serres S, Soto MS, Hamilton A, et al. Molecular MRI enables early and sensitive detection of brain metastases. Proc Natl Acad Sci U S A. 2012;109(17):6674-6679. [Context Link]


16. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 suppl):e142S-e165S. [Context Link]


17. Khazai L, Kundu UR, Jacob B, et al. Endobronchial ultrasound-guided transbronchial needle aspiration biopsy is useful evaluating mediastinal lymphadenopathy in a cancer center. CytoJournal. 2011;8:10. [Context Link]


18. Bugalho A, Ferreira D, Eberhardt R, et al. Diagnostic value of endobronchial and endoscopic ultrasound-guided fine needle aspiration for accessible lung cancer lesions after non-diagnostic conventional techniques: a prospective study. BMC Cancer. 2013;13:130. [Context Link]


19. Clementsen PF, Skov BG, Vilmann P, Krasnik M. Endobronchial ultrasound-guided biopsy performed under optimal conditions in patients with known or suspected lung cancer may render mediastinoscopy unnecessary. J Bronchology Interv Pulmonol. 2014;21(1):21-25. [Context Link]


20. De Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014;45(5):787-798. [Context Link]


21. Tan S, Sharma K, Tham K, et al. Comparing performance and cost of EBUS-TBNA versus other methods for diagnosis and staging of non-small cell lung cancer (NSCLC). Eur Resp J. 2014;44(58):340. [Context Link]


22. Yasufuku K, Pierre A, Darling G, et al. A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer. J Thorac Cardiovasc Surg. 2011;142(6):1393-1400. [Context Link]


23. American Joint Committee on Cancer. Lung. In: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:253-266. [Context Link]


24. Mirsadraee S, Oswal D, Alizadeh Y, Caulo A, van Beek E Jr. The 7th lung cancer TNM classification and staging system: review of the changes and implications. World J Radiol. 2012;4(4):128-134. [Context Link]


25. Goldenberg MM. Pharmaceutical approval update. P T. 2014;39(7):481-520. [Context Link]


26. Bishop JA, Sharma R, Illei PB. Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. Hum Pathol. 2010;41(1):20-25. [Context Link]


27. Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012;150(6):1121-1134. [Context Link]


28. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189-1197. [Context Link]


29. Shim H, Lee H, Park E, Kim S. Histopathologic characteristics of lung adenocarcinomas with epidermal growth factor receptor mutations in the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification. Arch Pathol Lab Med. 2014;135(10):1329-1334. [Context Link]


30. National Comprehensive Cancer Network. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology Non-Small Cell Lung Cancer version 7. 2015. [Context Link]


31. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551. [Context Link]


32. Genentech, Inc. Avastin Prescribing Information. 2014. [Context Link]


33. Molassiotis A, Lowe M, Blackhall F, Lorigan P. A qualitative exploration of a respiratory distress symptom cluster in lung cancer: cough, breathlessness and fatigue. Lung Cancer. 2011;71(1):94-102. [Context Link]


34. National Comprehensive Cancer Network. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Palliative Care version 2. 2015. [Context Link]


35. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742. [Context Link]


36. National Comprehensive Cancer Network. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology Smoking Cessation version 1. 2015. [Context Link]


37. Cataldo JK, Dubey S, Prochaska JJ. Smoking cessation: an integral part of lung cancer treatment. Oncology. 2010;78(5-6):289-301. [Context Link]


38. Fiore M, Jaen C, Baker TB. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: US Department of Health and Human Services; 2008. [Context Link]