In 2010, an estimated 222,520 new cases of lung cancer were diagnosed in the United States.¹ Lung cancer is the second most frequently diagnosed cancer in men and women (prostate and breast cancers are most frequent in men and women) (Figure 28-1). The incidence of lung cancer peaked in men in 1984 (86.5 per 100,000 men) and has since been declining (69.1 per 100,000 in 1997). In women, the incidence increased during the 1990s, with a leveling off toward the end of the decade (43.1 per 100,000 women). These trends parallel the smoking patterns of men and women.¹ The World Health Organization estimates that there are 2 million cases of lung cancer worldwide each year.

Deaths

Lung cancer is the leading cause of cancer-related mortality in men and women; it surpassed colon cancer in the early 1950s in men and breast cancer in the late 1980s in women. Mortality rates in men declined significantly in the 1990s, whereas a slow increase occurred in women. These rates parallel the smoking patterns of men and women (Figures 28-2 and 28-3). In 2010 in the United States, an estimated 157,300 deaths were due to lung cancer. In men, lung cancer is the leading cause of cancer-related mortality from age 40 on. In women, lung cancer surpasses breast cancer in the age group of 60 and older.¹

Lung Cancer Classification

Lung cancers are divided into two major groups—small cell carcinoma and non–small cell carcinoma—based on pathologic features that are visible under light microscopy. The evaluation and management of a patient are guided by the category and stage (see later) of lung cancer. The non–small cell cancer category consists of adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and variants (Figure 28-4). Table 28-1 presents the pathologic and epidemiologic features of the four most common types of lung cancer: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and small cell carcinoma.

Pathophysiology

The pathophysiology of lung cancer development is complex and incompletely understood. Damage to genetic material in lung cells is the result of exposure to chemical carcinogens such as the carcinogens contained in tobacco smoke.²⁰ People who develop lung cancer may have a genetic predisposition to the effects of these carcinogens. The genes influenced in the pathogenesis of lung cancer produce proteins involved in cell growth and differentiation, cell cycle processes, apoptosis (programmed cell death), angiogenesis (production of new blood vessels), tumor progression, and immune regulation. If enough of these pathways have been affected, the uncontrolled growth of cells that defines cancer occurs. If the mechanisms that lead to genetic damage can be identified and the means by which the pathways involved are controlled, novel means of risk stratification, prevention, early detection, and therapy should be able to be developed.

Clinical Features

The clinical features of lung cancer result from the effects of local growth of the tumor, regional growth or spread through the lymphatic system, hematogenous (blood-borne) distant metastatic spread, and remote paraneoplastic effects from tumor products or immune cross reaction with tumor antigens (Box 28-2). Some manifestations occur more commonly with a particular cell type. Despite modern imaging advances, only approximately 15% of patients with a diagnosis of lung cancer do not have symptoms at the time of presentation. Some of the initial symptoms may be related to accompanying illnesses because these patients are at risk for other medical problems in addition to lung cancer (e.g., COPD, heart disease).

Local growth in a central location (e.g., in a main stem bronchus) can cause cough, hemoptysis, or features of large airway obstruction. Squamous cell carcinoma and small cell carcinoma are more likely to grow in a central location than other cell types. Peripheral growth may also cause cough and dyspnea. If the pleura or chest wall is involved, pain may occur. Adenocarcinoma and large cell carcinoma occur more commonly in the periphery of the lung.

Regional growth may lead to esophageal compression (dysphagia), recurrent laryngeal nerve paralysis (hoarseness), phrenic nerve paralysis with an elevated hemidiaphragm (dyspnea), and sympathetic nerve paralysis leading to Horner syndrome (ptosis [droopy eyelid], miosis [small pupils], anhidrosis [lack of facial sweating], and enophthalmos [sunken eye]). Apical growth may lead to Pancoast syndrome, with shoulder pain radiating in an ulnar distribution as a result of involvement of the brachial plexus. The superior vena cava can become obstructed, resulting in swelling of the face, neck, and upper chest; plethora; and dilation of superficial veins over these areas; this is called the superior vena cava syndrome. Lung cancer can grow to involve the heart and pericardium. Lymphatic obstruction and spread can lead to dyspnea, hypoxemia, and pleural effusions.

Distant metastatic disease can affect most organs; the brain, bones, liver, and adrenal glands are most commonly involved. Neurologic symptoms such as headaches, vision changes, and seizures may suggest brain metastases. Back pain and changes in strength or sensation in an extremity may indicate spinal cord compression. Bone pain could indicate bone metastases. Laboratory abnormalities may point to bone marrow or liver involvement. Imaging may detect adrenal involvement.

When symptoms develop that are the result of the presence of cancer but are not related to the growth or spread of the cancer, these symptoms constitute a paraneoplastic syndrome. Paraneoplastic syndromes can result from the effects of proteins produced by the tumor that circulate through the body to have their effects on distant organs or result from the immune response of the body to a tumor antigen that is similar to antigens in other parts of the body, causing immune injury to the distant organ. Paraneoplastic syndromes may occur before the primary tumor appears and be the first sign of disease or an indication of tumor recurrence. Examples include production of excess glucocorticoids (ectopic Cushing syndrome), parathyroid hormone (hypercalcemia of malignancy), and antidiuretic hormone (syndrome of inappropriate antidiuretic hormone [SIADH]). Paraneoplastic neurologic syndromes can affect all parts of the neurologic system resulting in emotional lability (limbic encephalitis), loss of balance (cerebellar degeneration), and muscle weakness with a characteristic recruitment of strength on electrical stimulation (Lambert-Eaton syndrome). Other paraneoplastic syndromes include skeletal and connective tissue syndromes (clubbing, hypertrophic pulmonary osteoarthropathy), coagulation and hematologic disorders, cutaneous and renal manifestations, and systemic symptoms (anorexia, cachexia, and weight loss).²¹

Diagnosis

Approximately 85% of patients with lung cancer present with one or more of the previously described symptoms. In the remainder, lung cancer is detected by radiographic evaluation performed for an unrelated problem. This proportion may change in the future if computed tomography (CT) screening programs become widespread. Most patients have a chest radiograph and CT scan of the chest performed in their initial evaluation. These studies show a small spot (<3 cm in diameter) termed a nodule in the lungs or a larger spot (>3 cm in diameter) termed a mass. Other findings on imaging include enlarged lymph nodes in the hila (where the bronchi and central blood vessels emerge from the mediastinum into the lung) or mediastinum or a pleural effusion. An individual patient’s clinical and radiographic presentation dictates further evaluation.

The symptoms of lung cancer are nonspecific. There are many reasons that someone could have a cough or be short of breath. Similarly, an abnormality such as a lung nodule can be present on chest imaging for various reasons. Certain clinical and radiographic features make it more likely that the presentation represents lung cancer. Clinical features to consider include age, smoking history, history of other cancers, and presence of key symptoms. The older the patient is and the more he or she has smoked over time, the more likely the chest finding is lung cancer. Also, individuals with prior cancers are more likely to have lung cancer. Hemoptysis increases concern about cancer.

Radiographic features are also used to determine the probability of cancer. The larger the lung abnormality, the more likely it is to be cancer. When the abnormality has reached the size of a mass (3 cm), it needs to be considered a cancer until proven otherwise. The rate of growth of the lesion is also helpful. If a nodule grows rapidly (doubles in size in <1 month) or grows very slowly or not at all over a couple of years, it is unlikely to be due to cancer. If the nodule appears to be heavily calcified on imaging, it has likely been present for quite some time and is unlikely to represent cancer. If the abnormality has an irregular border, is lobulated, or is spiculated, it is more likely to be a cancer than if the border is smooth and rounded. Finally, if the lesion is cavitary, the thickness of the wall of the cavity can suggest cancer. A wall thickness of 14 mm or greater is likely to represent a cancer.²²

After the clinical and standard imaging features are reviewed, a probability of malignancy can be determined. If the probability is very high, the potential cancer does not seem to have spread, and the individual is fit, proceeding directly to surgery would be reasonable. If the previously mentioned features suggest a very low probability of malignancy, the clinician and patient might choose to follow along with serial chest imaging over time to assess for further growth. When the probability falls between these extremes, adjunctive imaging and invasive procedures can be used to help alter the probability. The most commonly used additional imaging technique is positron emission tomography (PET) with fluorodeoxyglucose (FDG-PET). Because malignant cells are metabolically very active, they take up the glucose analogue more avidly than nonmalignant cells. The attached radioactive tracer becomes trapped in the cells, allowing it to be imaged. When this test is used to help predict the presence of lung cancer, it has a sensitivity of 97% and a specificity of 78%.²³ PET imaging can produce false-positive results in other metabolically active conditions such as infections. It can be falsely negative if the lesion is too small (<10 mm) or if the tumor is slow growing and not very metabolically active (e.g., some adenocarcinomas, carcinoid tumor). Single photon emission computed tomography (SPECT) and lung nodule enhancement with contrast-enhanced CT are other imaging techniques that have been studied but are not being used clinically.²²

Ultimately, tissue is obtained to confirm the diagnosis of lung cancer. Flexible bronchoscopy and transthoracic needle biopsy are invasive, nonsurgical approaches used to obtain tissue. If these procedures fail or are deemed unnecessary, a surgical approach is used.

Flexible bronchoscopy is a procedure in which a long, thin, flexible camera is passed through a patient’s nostril or mouth into the lungs. The camera can be extended into the branches of the lung as far as the branches are large enough to admit it. The camera has a small channel through which very thin biopsy instruments can be passed out deeper into the lung to take samples from concerning areas. Flexible bronchoscopy has a high diagnostic yield for lesions that are endoscopically visible within the larger airways. Samples are collected by washing saline over the lesion, sending a small brush through the camera to collect cells on its bristles, and taking biopsy samples with a forceps or needle.

Addition of needle aspiration to the conventional sampling techniques (washing, brushing, and forceps biopsy) improves the yield. The diagnostic yield from lesions in the periphery of the lung, beyond where the camera is able to see, is lower. Conventional sampling techniques and peripheral transbronchial needle aspiration complement each other. Factors that influence the diagnostic yield of flexible bronchoscopy for peripheral lesions include the size of the lesion, its location, and the presence of a “bronchus sign” on CT (an airway leading directly into the lesion). Smaller, more peripheral lesions, without a visible bronchus within or leading directly to them, are unlikely to be diagnosed by flexible bronchoscopy.²² More recent technologic advances, such as multiplanar imaging, electromagnetic navigation of the bronchoscopy instruments, and peripheral endobronchial ultrasound, have been able to improve the yield of flexible bronchoscopy for these small peripheral lesions.²⁴ Endobronchial ultrasound can also be used to guide biopsies of hilar and mediastinal lymph nodes.^25–26

Transthoracic needle biopsy, using fluoroscopic or CT guidance, can also be used to obtain tissue. With this procedure, an aspirating needle is passed through the skin into the lung lesion under the guidance of chest imaging. The positive predictive value of this procedure is high, the negative predictive value is modest, and the rate of establishing a specific benign diagnosis is low. Smaller nodules in central locations have lower diagnostic rates. A higher rate of pneumothorax occurs with transthoracic needle biopsy.²⁴ The choice of which procedure to use is guided by the size and location of the lesion and by the local expertise with each technique.

Staging

A major factor that determines the prognosis of lung cancer and guides the selection of appropriate treatment is the extent to which the cancer has spread in the lungs and throughout the body. The extent of cancer spread is termed the stage of the cancer. Non–small cell lung cancer is staged using the TNM staging system (T for extent of primary tumor, N for regional lymph node involvement, and M for metastases).

The T component of the staging system is divided into T1 through T4 lesions, as follows:

The N component of the staging system is determined by which lymph nodes, if any, are involved with tumor, as follows:

The M part of the staging system represents the absence (M0) or presence (M1) of metastases outside of the chest. M1a refers to metastasis of separate tumor nodules in the contralateral lung or malignant pleural involvement (including a malignant pleural or pericardial effusion). M1b refers to distant metastatic spread, such as liver, bone, or brain lesions.

The most recent revision²⁷ to this staging system occurred in 2009 (Table 28-2 and Figure 28-5). The stages are labeled from stage IA to stage IV based on the combination of T, N, and M features.

For patients with small cell lung cancer, the TNM staging system was previously thought to be less useful. Instead, small cell lung cancer has been staged as limited or extensive disease. Limited stage disease is present when the tumor is confined to a hemithorax (including ipsilateral mediastinal and supraclavicular lymph nodes) and can be contained within a radiotherapy port. Extensive stage disease is present when the tumor extends beyond these boundaries. The recent lung cancer staging revision recognized a benefit to applying the TNM staging system used for non–small cell cancer to small cell cancer as well.27,29

The proper use of testing to stage a patient with lung cancer is addressed in a more recent set of guidelines.³⁰ The history and physical examination are important in guiding testing. The extent of spread is best evaluated using CT of the chest extending to the upper abdomen to include the liver and adrenal glands; this should be ordered in all patients. Magnetic resonance imaging (MRI) has not proved to be more accurate except in the setting of a Pancoast tumor. The sensitivity and specificity of CT for the evaluation of regional lymph node involvement are modest, commonly noted to be 60% and rarely greater than 75%. Imaging with FDG-PET scanning seems to have better test characteristics for staging mediastinal nodes, with sensitivity and specificity greater than 90%.³¹ Integrated PET/CT scanning seems to have better test characteristics than PET and CT used alone or together.³²

Because noninvasive tests can have false-positive results, tissue confirmation is necessary. Bronchoscopy with transbronchial needle aspiration is useful to stage the mediastinum. The addition of endobronchial and endoscopic ultrasound has increased the yield of nonsurgical mediastinal staging.26,33 If such staging is negative, mediastinoscopy, mediastinotomy, or thoracoscopy can confirm the nodal status. Despite the advances in imaging technology and sampling techniques, definitive staging with surgical resection and mediastinal dissection remains the “gold standard” in a patient with resectable disease. The assigned clinical stage (determined by the previously listed testing, including mediastinoscopy) can be lower than the pathologic staging (assigned after surgery).

The evaluation of metastatic disease also takes into consideration the history, physical examination, laboratory results (electrolytes, calcium, alkaline phosphatase, liver profile, and creatinine), and pathology results. All patients should have the chest CT scan extended through the adrenal glands because metastatic disease to the adrenal glands is usually asymptomatic, and frequently no alterations are seen in routine laboratory tests. Contrast-enhanced CT, ultrasound, or MRI of the liver should be performed if the chest CT scan, laboratory results, or clinical evaluation suggests metastatic liver disease.

Per guidelines, a head CT or MRI scan should be performed if symptoms or signs of metastatic disease are present or when evaluating what appears to be stage IIIA through IV disease. Although there is no proven survival benefit from CT versus MRI, many clinicians prefer to use MRI of the brain because it has greater sensitivity to detect metastatic disease.30,34 Bone scanning was previously performed if symptoms or signs suggest bone involvement, if the patient has an elevated calcium or alkaline phosphatase level, or if the patient is in stage IIIA/B disease. This scan has been largely replaced by PET. PET has been used to stage all but brain metastases. The rate of detecting distant metastases using PET appears to be higher than using non-PET approaches.³⁵

Along with evaluating the anatomic extent of disease, a patient’s performance status is important in determining his or her prognosis and ability to tolerate any proposed treatment. The two most commonly used scales of performance status are the Zubrod scale and the Karnofsky scale. Although their definitions differ, the general principles of the two scales are the same, with ratings based on activity level, independence in daily activities, and severity of symptoms.

Further evaluation of performance status may be necessary in patients for whom surgical resection is indicated. To determine if a patient would tolerate lung resection, reports of activity tolerance and pulmonary function testing are used. Although no one pulmonary function study or absolute cutoff has proved to be ideal, FEV₁ and diffusing capacity for carbon monoxide (DLCO) are the most frequently used measures. Traditional preoperative cutoff values are being replaced by percent predicted postoperative values. Percent predicted postoperative values of FEV₁ and DLCO can be calculated by multiplying the percent predicted preoperative value by the fraction of the total number of lung segments that will remain postoperatively. Alternatively, quantitative perfusion imaging can be used to guide the calculation. If the percent predicted postoperative FEV₁ and DLCO are greater than 40%, the patient should be able to tolerate surgery. As would be expected, a pneumonectomy requires better preoperative lung function than a lobectomy. When doubt remains or when measured values and predictions seem discordant with an individual’s reported activity tolerance, a cardiopulmonary exercise test should be performed. If the maximum oxygen consumption is greater than 15 ml/kg/min, a lobectomy should be reasonably well tolerated. If the maximum oxygen consumption is less than 10 ml/kg/min, conventional surgery should not be performed. Patients with a maximum oxygen consumption value between these two limits should be considered on a case-by-case basis.³⁶

Screening For Lung Cancer

Given the poor prognosis for advanced stage lung cancer and the high proportion of patients who present in an advanced stage, there has been great interest in screening for lung cancer. The earliest efforts at radiographic screening involved the analysis of mass chest radiograph screenings from the population of an individual city. Subsequently in the 1970s, there were large efforts to use chest radiograph, sputum, or a combination of the two as screening tools. Despite considerable ongoing debate about the design and analysis of these randomized studies, they have been interpreted as not showing that screening with plain chest radiograph or sputum examination has a beneficial effect on mortality from lung cancer.³⁷

Given the disappointing overall results from studies of chest radiograph as a screening technique, efforts have centered on the use of low-dose CT imaging as a screening tool. Important highlights of several available CT cohort studies include the ability to find many early stage lung cancers and the long survival times of patients whose lung cancer is diagnosed at an early stage. Limitations of CT and the trial designs that have been identified in these studies are an inability to comment on lung cancer–specific mortality, numerous benign nodules being identified (5% to 50% of participants on the initial scan), intense testing protocols required to follow the identified nodules to ensure they are not cancer, invasive procedures performed on some benign nodules, and questionable cost-effectiveness.38–45

These limitations have prompted the performance of a few large-scale randomized screening trials of CT imaging as the screening tool. One trial, the National Lung Screening Trial, reported a 20% reduction in lung cancer–specific mortality in subjects with very high risk. This finding may change the standard recommendations for lung cancer screening. Remaining issues include identifying individuals at high risk for developing lung cancer, the appropriate management of the numerous small lung nodules identified on CT, the potential harms of radiation from the CT scan, and the cost-effectiveness of the screening program.⁴⁶

To address these issues, researchers are attempting to develop other tests, including safe and noninvasive tests of the blood and breath. Autoantibodies directed at tumor-associated antigens have been identified in the blood of some patients with primary lung cancer. A positive blood test such as this may be an early indicator of lung cancer before a tumor appears in the lungs and could be a potential tool in selecting patients for screening programs.⁴⁷ Studies are under way to determine how these blood tests may best be used clinically. In addition, the analysis of exhaled human breath has become an area of interest in lung cancer. Compounds within patients’ exhaled breath form unique chemical signatures. These signatures have shown measurable, specific patterns in lung cancer compared with controls. As research continues in breath analysis, we may see its use in the screening, diagnosis, and treatment monitoring of lung cancer.⁴⁸

Treatment And Outcomes

Although the RT would not be administering the treatments for lung cancer, and the therapies change with advances over time, a brief discussion to familiarize the RT with the approach to treatment and the types of available therapy is important.

Future Scenario

The prospect of major advances in the prevention, detection, and treatment of lung cancer is strong. An attainable vision for 2031 could be as follows: Primary prevention campaigns have successfully minimized the number of individuals who are smoking, legislation has passed broadly to prevent exposure to tobacco smoke in public places, progress has been made in occupational exposure avoidance, and successful measures have been enacted to clean the air. Individuals are now identified who have changes in lung cells that suggest lung cancer could develop and are being treated with medication to prevent it from developing. Individuals at risk for developing lung cancer are part of a screening program that detects early stage lung cancer with a test that is inexpensive and acceptable to all. Technology has improved diagnostic abilities by making imaging more specific and biopsies more accurate. Noninvasive diagnostics have expanded with advances in blood and breath testing.47,48,64,65 In addition to tumor appearance, researchers are identifying characteristics of tumor biology that allow more selection in choosing treatments.^66,67 The best form of local control for a given tumor (resection, radiation) is known, and means have been developed to minimize the effect of these interventions on the quality of life. Novel agents have been developed that can reach and kill tumor cells, while avoiding injury to healthy tissue. As evidence of successes to date, lung cancer is no longer the leading cause of cancer-related mortality in the United States.

Role Of The Respiratory Therapist In Managing Patients With Lung Cancer

RTs perform many important roles in the evaluation and management of patients with lung cancer. Many patients in the care of the RT are smokers, and the RT has the opportunity to educate these individuals on the dangers of smoking and on the means available to help one quit. Because many of these patients also have smoking-related lung disorders (e.g., COPD), RTs can offer guidance on the proper use of inhaled medications, the use of supplemental oxygen, and the role of pulmonary rehabilitation before and after treatment. Also, many RTs assist with diagnostic tests such as bronchoscopy and the measurement of pulmonary function. Finally, in the context that the RT may spend substantial time with the patient with lung cancer, the RT may be an important source of psychologic support and help. Taken together, these various diagnostic and treatment roles establish that the RT plays a crucial role in helping to manage patients with lung cancer.