Lung Cancer

Author(s): Ashish Khanna, MD, Zachary Fallon, MD, Tanya DiFrancesco, MD, Mohammad Aalai, MD

Originally published:January 6, 2020

Last updated:January 6, 2020

1. DISEASE/DISORDER:

Definition

Lung cancer is a malignant tumor of the lungs or bronchus. Its origin is either a primary pulmonary carcinoma or metastasis from distant malignancy. Primary lung carcinoma is a heterogeneous group of tumor subtypes with the most important distinction being small cell or non-small cell carcinoma.

Etiology

While cancer, in general, arises from mutated genes, lung cancer can particularly be attributed to cigarette smoke as a leading cause, contributing to 90% of lung cancer cases.1 Radon is the second leading cause of lung cancer at 10%, followed by occupational exposures to carcinogens and air pollution.2

Epidemiology including risk factors and primary prevention

Lung cancer is the second most common cancer, with American Cancer Society estimating 228,150 new cases in 2019.3 However, lung cancer is the leading cause of cancer death in both men and women, with ACS estimating 142,670 deaths in 2019 from lung cancer alone.3,4 National Cancer Institute estimates a 19.4% survival rate of 5 years for lung cancer survivors; although patients diagnosed with localized lung cancer could expect a significantly improved 5 year survival rate, at 57.4%.4 As of 2016, approximately 538,243 Americans carry this diagnosis with median age of 70 at time of diagnosis.4

Risk factors: cigarette smoking, age, radon exposure, gender, environmental pollution occupational exposures, race, and pre-existing lung disease.5

Patho-anatomy/physiology

Lung cancers are carcinomas, meaning they are malignancies that arise from epithelial cells. They are classified histopathologically as one of two subtypes: small cell lung carcinoma (SCLC) or non-small cell lung carcinomas (NSCLC). SCLC are about 10-15% of all lung cancers. The other 80% are NSCLC, which are of multiple subtypes. The most prevalent are adenocarcinoma (40%), squamous cell carcinoma (30%), large cell carcinoma (10%).

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

SCLC and NSCLC are staged using the TNM classification, the descriptors of which are used to assign stages. These are staged 0 to IV and help determine treatment and prognosis.

The lung cancer five-year survival rate of nearly 20% is lower than most common cancers.

Only 15% are diagnosed at an early stage, giving the best prognosis of a five-year survival rate of 57.4%.4 Once metastasized the five-year survival rate is only 4%.4 Median survival after diagnosis was 13 months for non-metastatic and five months for metastatic lung cancer.6

Specific secondary or associated conditions and complications

Pulmonary complications result in significant morbidity and mortality. Many of these issues are the result of cancer treatments themselves as the treatment of isolated lung nodules offers mixed results. Multiple surgical resections are poorly tolerated and the lungs have poor resilience to radiation, resulting in significant side effects.

One such side effect is radiation pneumonitis, which presents with dyspnea 2-3 months following high-dose external beam radiation in up to 15% of irradiated patients.7 Exudation of fluid into the alveoli causes decreased compliance and gas exchange, then eventual restrictive lung disease. Chemotherapy pneumonitis results in pulmonary fibrosis; it may be reversible if the offending agent is stopped. Offending drugs include Methotrexate, Bleomycin, and Mitomycin-C.

Radiation fibrosis is an associated condition secondary to radiation treatment. Three phases of radiation fibrosis have been described.8

  1. The prefibrotic phase: usually asymptomatic and characterized by endothelial cell dysfunction. Local inflammation, increased vascular permeability and edema may result in necrosis of the microvasculature and subsequent local ischemia.
  2. The constitutive organized phase: symptoms may appear. The radiated tissue contains a patchwork of activated fibroblasts (myofibroblasts) and senescent fibroblasts (fibrocytes) in a densely sclerotic (fibrotic) matrix. Together, the endothelial and connective tissue cell damage, along with the action of cytokines results in an irreversible fibrotic process.
  3. The late fibroatrophic phase: successive remodeling of the extracellular matrix leads to progressively dense radiated tissue. This stage may develop and progress years or decades following RT, resulting in tissue that is poorly vascularized, friable and fragile.9

Side effects of systemic chemotherapy have the potential to severely impact patient’s quality of life during treatment. Common side effects include:

  • Chemotherapy induced nausea and vomiting
  • Hematologic toxicity, particularly anemia and neutropenia
  • Nephrotoxicity
  • Neurotoxicity (especially with cisplatin and taxanes)
  • Fatigue
  • Anorexia and weight loss

The role of the physiatrist is to minimize side effects through symptomatic treatments while maintaining the patient’s functionality to best preserve quality of life during and after cancer treatments have taken place.

2. ESSENTIALS OF ASSESSMENT

History

Diagnosis of lung cancer involves a thorough review of systems including cough, hemoptysis, dyspnea, chest pain, fever, night sweats, weight loss, smoking history, family history and prior malignancy or other risk factors. Environmental exposure is also a critical piece of information.  Paraneoplastic syndromes should also be suspected (SIADH, Hypercalcemia, LEMS).10

Physical examination

Examination should begin with vital signs, including orthostatic blood pressure, pulse oximetry and respiratory rate. Basic techniques including inspection for chest excursion, asymmetry, cyanosis, hypertrophic pulmonary osteoarthropathy (finger clubbing, diffuse joint pain, bone and muscle tenderness), superior vena cava syndrome (venous distension of neck, facial edema, plethora), muscle atrophy, soft tissue fibrosis and contractures affecting range of motion, lymphedema and scapular winging. Palpation, percussion and auscultation to detect masses, effusion and consolidation are also critical.

Motor strength is evaluated for localized or generalized weakness. Sensation including light touch, pinprick, temperature, proprioception and vibration should be assessed. Reflexes, tone, balance and gait must also be examined. Speech, swallow, visual, auditory and cognitive assessment will assist in rehabilitation planning.10

New symptoms that may indicate metastatic disease:11

  • Bone pain, notably in the hips and spine
  • Brain metastases may manifest as headaches, weakness, numbness, dizziness, balance problems and seizures
  • Jaundice may be a sign of metastases to the liver
  • Lymphadenopathy as an indicator of regional metastatic spread

Clinical functional assessment: mobility, self care cognition/behavior/affective state

Observing the patient ambulating, transferring, and performing ADLs is the easiest way to characterize the patient’s deficits and their impact on function and quality of life. Other functional-based tests give insight into how the patient may tolerate real-life scenarios and measure cardiorespiratory performance as well as describe functional capacity, response to therapy, and prognosis. Examples include the shuttle walk test and the 6-minute walk test.12 Distances less than 350m in the shuttle walk test are associated with increased mortality. The Functional Reach Test, the distance forward beyond arm’s length reached with a fixed base of support, has been tied to falls risk. Timed Up and Go Test involves rising from an armchair, walking 3 meters, turning, walking back, and sitting.13 This has been shown to predict the patient’s ability to go outside alone safely.13

Additionally, if specialized equipment is available, various pulmonary function tests provide thorough quantitative insight into the functional reserve and endurance capacity of the patient.14 An example is cardiopulmonary exercise testing, which measures respiratory oxygen uptake, carbon dioxide production, and ventilatory measures during a symptom‐limited exercise test.

Laboratory studies

Studies should include basic blood tests such as hemoglobin, electrolyte levels, albumin/prealbumin for nutritional status, kidney/liver function tests and alkaline phosphate, and lab tests reflecting specific sequelae of lung cancer including glucose, hypercalcemia due to Parathyroid related protein (PTHrp), hyponatremia due to SIADH, leukocytosis due to granulocyte colony stimulating factor (GCSF), thrombocytosis, eosinophilia, and ACTH levels in the setting of Cushing’s syndrome.15 Tumor markers may also be drawn such as Carcinoembryonic antigen, squamous cell carcinoma antigen, neuron-specific enolase, cytokeratin 19 fragment and pro-gastrin-releasing peptide.16

Imaging

An A/P chest x-ray is used for initial evaluation of symptoms of lung cancer.17 However, optimal evaluation should utilize CT imaging. Secondary to technological advances and the low rate of early disease detection, the US Preventative Services Task Force recommends annual screening for lung cancer with low-dose computed tomography (LDCT) in adults 55-80 years of age with a smoking history of 30 pack-years and currently smoke or have quit within the past 15 years.18, 19 With approximately 20% less radiation than traditional CT screening, LDCT is safer for patients who may need serial imaging for management.20 For investigating metastases, PET scans can be helpful.

Supplemental assessment tools

Throughout followup, if concerned about the possibility of new metastasis or a recurrence of lung cancer, additional imaging may be warranted. While the histologic type and staging of lung cancer will guide the likelihood of recurrence21, having a low threshold for imaging and consulting an oncologic colleague is suitable. If recurrent tumor is to be ruled out, a PET scan to distinguish between persistent or recurrent tumor from post-treatment scarring or fibrosis may be indicated.22 If bone metastasis is expected, a CT scan will provide insight regarding osteolytic and osteosclerotic metastases.22 An MRI may be indicated to examine for metastatic spread in soft tissue, bone marrow cavity, or suspected cord compression secondary to pathologic vertebral compression fractures.23 Skeletal scintigraphy (bone scan) is commonly used to detect skeletal metastasis, with the added benefit that whole body scan can be performed.24

Early predictions of outcomes

TNM staging influences treatment and predicts survival. Poor performance status and/or weight loss have been associated with shortened survival. Staging of SCLC usually uses the Veterans Administration Lung Study Group designations of limited (one hemithorax) or extensive (beyond one hemithorax) disease.25 Poorly differentiated tumors and lymphatic invasion have a worse prognosis. A tumor’s metabolic activity can be measured using the standardized uptake value (SUV) to assess the tumor uptake of fluorodeoxyglucose (FDG); high SUV was associated with a poor prognosis, and a lower FDG uptake was associated with a better prognosis.26 PET (or PET-CT) may also be useful in predicting response to chemotherapy.

Environmental

Smoking is the primary risk factor, however other factors include exposure to asbestos, radon, metals (arsenic, chromium and nickel), ionizing radiation and polycyclic aromatic hydrocarbons.27 Dietary factors may reduce the risk of lung cancer, these include antioxidants, cruciferous vegetables and phytoestrogens.

Social role and social support system

Screening for depression, anxiety and adjustment disorder are important. Cancer survivors have specific cancer related impairments which alter their role in families, communities and work.28 End of life care involves minimizing complications associated with debility (pressure ulcers, contractures), appropriate pain management and providing emotional support to the patient and family.

Professional Issues

Lung cancer survivors are 2-3 times more likely to be unemployed and have the strongest decline in earnings, when compared to other cancer groups, due to a higher median duration of sickness as compared with other cancer survivors.29 Involving a vocational therapist early in treatment will help patients navigate occupational options.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Pulmonary rehabilitation is the mainstay of therapy to address the complications of lung cancer. The goal is to design a comprehensive intervention to optimize functional status and manage symptoms of dyspnea and fatigue in order to increase quality of life. These goals are achieved through exercise training, patient education, and behavioral interventions.

All prescriptions for pulmonary rehabilitation should be based on results from the various assessment tools described above. A prescription should be defined in terms of intensity, duration, frequency, type (interval or continuous), mode (e.g. walking, cycling, arm exercise), and progression.

Home oxygen may be indicated if:

  1. arterial oxygen tension (PaO2) is less than or equal to 55 mmHg or a pulse oxygen saturation (SpO2) less than or equal to 88%, or,
  2. PaO2 less than or equal to 59 mmHg or a SpO2 less than or equal to 89% and there is evidence of cor pulmonale, right heart failure, or erythrocytosis.30

In addition, if there is dyspnea or ventilatory abnormalities during exercise, supplemental O2 may be given during exercise without evidence of desaturation demonstrated by a decrease in SpO2.

At different disease stages

In the acute phase of cancer treatment deconditioning, anxiety, and weakness are common contributors to disability. Dyspnea is highly prevalent as well, which may have been present premorbidly due to COPD since the vast majority of lung cancer patients have a history of smoking. This compounds the symptoms burden.

The majority (>75%) of cancer patients experience cancer-related fatigue, which can occur at any point along the cancer continuum and for years after.31 Paraneoplastic phenomena can occur at any time as well. Treatments include addressing the underlying malignancy, immunosuppression, and correction of electrolyte and hormonal derangements as indicated.

Chemotherapeutic agent Bleomycin is a known cause of pulmonary fibrosis. Any patient treated with this agent at any time should not be exposed to supplemental oxygen. Oxygen is a mainstay of pulmonary rehabilitation but if provided to these patients it may trigger acute-onset pulmonary edema, even decades later.

Coordination of care

A quality comprehensive intervention would necessitate coordination among physicians, nurses, physical and occupational therapists, respiratory therapists, and social workers. Efficient coordination is key to integrating the expertise of all these providers into a cohesive program individually tailored to each patient.

Patient & family education

Educational topics should include breathing retraining and techniques (diaphragmatic, pursed-lip, etc), and appropriate use of bronchodilators. Educational goals should include smoking cessation, awareness of disease process, promotion of self-management skills, and recognition of when to seek medical care.

Measurement of Treatment Outcomes including those that are impairment-based, activity participation-based and environmentally-based

Measures of ADLs or quality of life (QoL) are important to quantify treatment outcomes. One such measure is the Chronic Respiratory Disease Questionnaire, a QoL measurement designed specifically for COPD but can be used for any disease process that results in chronic airflow limitations. Severity is measured through a 20-item inventory across four dimensions – dyspnea, fatigue, emotional function and mastery. The St. George’s Questionnaire is a self-reported QoL instrument. It is designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. The Borg Rating of Perceived Exertion (RPE) Scale measures perceived exertion during exercise.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Pulmonary rehabilitation in the lung cancer patient often requires modification of standard practices to adhere to the individual’s unique disease process.  This may be dependent on where in the cancer continuum the patient lies. A knowledge of the cancer type, severity, and prognosis is required. Just as important is a frank discussion about the patient’s individual needs and functional limitations. The physiatrist must also be mindful of safety constraints such as bone metastasis. A thorough baseline evaluation is important prior to starting any program.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Liquid biopsy has become an important, minimally invasive diagnostic and evaluative technique in the therapeutic management of NSCLC.32 For example, its use analyzing circulating tumor DNA, (ctDNA) has allowed insight into mechanisms of acquired resistance in patients with lung cancer who have been treated with EGFR-targeted therapies.33 Identification of tumor suppressor gene and oncogene mutations has shown promise in the development of targeted therapy for NSCLC.34,35 Investigations into less invasive surgical procedures including, sublobar resection and single-port video-assisted thoracoscopic surgery (VATS) for NSCLC are promising.36

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

  • Neo-adjuvant treatment prior to surgery in the management patients with stage III 37
  • Prophylactic cranial irradiation (PCI) in the management of small cell lung cancer (SCLC).38
  • Identifying and incorporating coexisting chronic illness into decision-making and patient selection for lung cancer screening.39

REFERENCES

  1. The Health Consequences of Smoking — 50 Years of progress: A Report of the Surgeon General. (2014). PsycEXTRA Dataset. doi:10.1037/e510072014-001
  2. American Lung Association. URL: https://www.lung.org/lung-health-and-diseases/lung-disease-lookup/lung-cancer/resource-library/lung-cancer-fact-sheet.html. Accessed August 3, 2019.
  3. American Cancer Society. URL: https://cancerstatisticscenter.cancer.org/#!/. Accessed August 3, 2019.
  4. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2016, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, posted to the SEER web site, April 2019.
  5. Groot, P. D., & Munden, R. F. (2012). Lung Cancer Epidemiology, Risk Factors, and Prevention. Radiologic Clinics of North America, 50(5), 863-876. doi:10.1016/j.rcl.2012.06.006
  6. Riihimäki, M., Hemminki, A., Fallah, M., Thomsen, H., Sundquist, K., Sundquist, J., & Hemminki, K. (2014). Metastatic sites and survival in lung cancer. Lung Cancer, 86(1), 78-84. doi:10.1016/j.lungcan.2014.07.020
  7. Stubblefield, M. (2018). Cancer Rehabilitation 2E: Principles and Practice. Demos Medical.
  8. Pradat PF, Delanian S. Late radiation injury to peripheral nerves. Handbook Clin Neurol 2013;115:743–58.
  9. DiFrancesco T, Khanna A, Stubblefield M. Clinical Evaluation and Management of Cancer Survivor with Radiation Fibrosis Syndrome. PM&R issue of Seminars of Oncology Nursing- Medical Clinics (Elsevier) for publication Jan/Feb 2020.
  10. Ost DE, Yeung SC, Tanoue LT, Gould MK. Clinical and organizational factors in the initial evaluation of patients with lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e121S-41S.
  11. Lung Cancer Signs & Symptoms: Common Symptoms of Lung Cancer. (2019, October 1). Retrieved from https://www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/signs-symptoms.html#references.
  12. Rasekaba T, Lee AL, Naughton MT, Williams TJ, Holland AE. The six-minute walk test: a useful metric for the cardiopulmonary patient. Intern Med J. 2009 Aug;39(8):495-501.
  13. Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991 Feb;39(2):142-8.
  14. Bradley A, Marshall A, Stonehewer L, Reaper L, Parker K, Bevan-Smith E, Jordan C, Gillies J, Agostini P, Bishay E, Kalkat M, Steyn R, Rajesh P, Dunn J, Naidu B. Pulmonary rehabilitation programme for patients undergoing curative lung cancer surgery. Eur J Cardiothorac Surg. 2013 Oct;44(4):e266-71.
  15. Patz EF Jr, Campa MJ, Gottlin EB, Kusmartseva I, Guan XR, Herndon JE 2nd. Panel of serum biomarkers for the diagnosis of lung cancer. J Clin Oncol. 2007. Dec 10;25(35):5578-83.
  16. Niho S, Shinkai T. [Tumor markers in lung cancer]. Gan To Kagaku Ryoho. 2001. Dec;28(13):2089-93. Review. Japanese. PubMed PMID: 11791391.
  17. Purandare NC, Rangarajan V. Imaging of lung cancer: Implications on staging and management. Indian J Radiol Imaging. 2015;25(2):109–120.
  18. Smith, S. R., Khanna, A. and Wisotzky, E. M. (2017), An Evolving Role for Cancer Rehabilitation in the Era of Low‐Dose Lung Computed Tomography Screening. PM&R, 9: S407-S414.
  19. Moyer VA. Screening for lung cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med 2014;160:330-338.
  20. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409.
  21. Bogot, N. R. (2004). Imaging of recurrent lung cancer. Cancer Imaging4(2), 61–67. doi: 10.1102/1470-7330.2004.0002.
  22. O’Sullivan, G. J. (2015). Imaging of bone metastasis: An update. World Journal of Radiology7(8), 202. doi: 10.4329/wjr.v7.i8.202.
  23. Bäuerle, T., & Semmler, W. (2009). Imaging response to systemic therapy for bone metastases. European Radiology19(10), 2495–2507. doi: 10.1007/s00330-009-1443-1.
  24. Cuccurullo, V., Cascini, G. L., Tamburrini, O., Rotondo, A., & Mansi, L. (2013). Bone Metastases Radiopharmaceuticals: An Overview. Current Radiopharmaceuticals6(1), 41–47. doi: 10.2174/1874471011306010007.
  25. Argirls A, Murren JR. Staging and clinical prognostic factors for small-cell lung cancer. Cancer J. 2001. Sep-Oct; 7(5): 437-47.
  26. Paesmans M, Berghmans T, Dusart M, et al. Primary tumor standardized uptake value measured on fluorodeoxyglucose positron emission tomography is of prognostic value for survival in non-small cell lung cancer: update of a systematic review and meta-analysis by the European Lung Cancer Working Party for the International Association for the Study of Lung Cancer Staging Project. J Thorac Oncol 2010; 5:612.
  27. Field, R. W., & Withers, B. L. (2012). Occupational and Environmental Causes of Lung Cancer. Clinics in Chest Medicine, 33(4), 681-703. doi:10.1016/j.ccm.2012.07.001
  28. Cristian, A. (2019). Central nervous system cancer rehabilitation. St. Louis, MO: Elsevier.
  29. Vayr, F., Savall, F., Bigay-Game, L., Soulat, J., Chouaid, C., & Herin, F. (2019). Lung cancer survivors and employment: A systematic review. Lung Cancer, 131, 31-39. doi:10.1016/j.lungcan.2019.03.010
  30. Lacasse , Y., Tan, A. M., Maltais , F., & Krishnan , J. A. (2018). Home Oxygen in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med197(10).
  31. Jacobsen PB. Assessment of fatigue in cancer patients. J Natl Cancer Inst Monogr. 2004(32):93‐97.
  32. Li BT. Translating liquid biopsy technology into clinical practice. Presented at: Physicians’ Education Resource®, LLC, 2nd Annual Precision Medicine in Plasma: Using Liquid Biopsies in Contemporary Oncology Care. December 9, 2018. New York, NY. gotoper.com/conferences/ pmlb/meetings/2nd-annual-precision-medicine-through-plasma-using-liquid-biopsies-in-contemporary-oncology-care/agenda.
  33. Offin M, Chabon JJ, Razavi P, et al. Capturing genomic evolution of lung cancers through liquid biopsy for circulating tumor DNA. J Oncol. 2017;2017:4517834. doi: 10.1155/2017/4517834
  34. Shojaee S, Nana-Sinkam P. Recent advances in the management of non-small cell lung cancer. F1000Res. 2017;6:2110. Published 2017 Dec 7.
  35. Marissa Mayor, Neng Yang, Daniel Sterman, David R. Jones, Prasad S. Adusumilli, Immunotherapy for non-small cell lung cancer: current concepts and clinical trials, European Journal of Cardio-Thoracic Surgery, Volume 49, Issue 5, May 2016, Pages 1324–1333
  36. Hsu PK, Lin WC, Chang YC, et al. : Multiinstitutional analysis of single-port video-assisted thoracoscopic anatomical resection for primary lung cancer. Ann Thorac Surg. 2015;99(5):1739–44. 10.1016/j.athoracsur.2015.01.041
  37. Lewis Jennifer, Gillaspie Erin A., Osmundson Evan C., Horn Leora Before or After: Evolving Neoadjuvant Approaches to Locally Advanced Non-Small Cell Lung Cancer. Frontiers in Oncology. Vol. 8, 2018. https://www.frontiersin.org/article/10.3389/fonc.2018.00005
  38. Varlotto JM, Veronesi G. Editorial: Controversies in the Local Management of Lung Cancer. Front Oncol. 2018;8:233. Published 2018 Jun 18. doi:10.3389/fonc.2018.00233
  39. Rivera MP et al. Incorporating Coexisting Chronic Illness into Decisions about Patient Selection for Lung Cancer Screening. An Official American Thoracic Society Research Statement. Am J Respir Crit Care Med. 2018 Jul 15;198(2):e3-e13.

Author Disclosures

Ashish Khanna, MD
Nothing to Disclose

Zachary Fallon, MD
Nothing to Disclose

Tanya DiFrancesco, MD
Nothing to Disclose

Mohammad Aalai, MD
Nothing to Disclose

Related Articles