Lung Cancer

Jayne M. Camporeale, MS, RN, OCN, APN-C Susan Roberts, MS, RD, lD, cNsD INTRODUCTION

One of the most difficult and challenging areas of oncology involves the treatment of lung cancer, which is largely a disease of the twentieth century. Before 1930, there were few reported cases. In the 1930s, however, a sharp rise in mortality from lung cancer was noted. By the mid-1950s, lung cancer had become the leading cause of cancer mortality in men—a dubious distinction that it maintains today. Eventually women caught up to men, with 1986 being the first year that more women died from lung cancer than breast cancer.1 Today, lung cancer remains the leading cause of cancer mortality in men and women in the United States. Death rates from this cause for 2008 are estimated to be 161,840.2 Worldwide, in 1990, lung cancer was the most frequently diagnosed cancer in terms of both incidence and mortality, with 1.04 million new cases being identified, accounting for 12.8% of all cancer cases.3

Every area of oncology has its own challenges in advancing treatment. Unfortunately, research funding for optimal treatments in lung cancer lags behind other cancer research areas, perhaps because lung cancer is most often attributed to smoking and, therefore, is considered a preventable cancer. As yet, researchers have not found a low-cost, effective screening tool for lung cancer, which poses yet another barrier to research in this area. The disease is usually asymptomatic in the early stages, so most patients are diagnosed at an advanced stage of disease. Fewer than 15% of lung cancers are localized when diagnosed, and only 20% of patients present with lung cancer that makes them candidates for curative treatment.4 The one-year relative survival rate for lung cancer is 41%, which is 7% higher than the corresponding rate in the 1970s. This improvement is probably related to improved surgical techniques and the use of combined therapies to treat lung cancer.2 Unfortunately, the five-year survival rate for individuals diagnosed with all stages combined remains a paltry 15%.

Ideally, clinical advances made during the last 20 years will lead to improved outcomes in lung cancer. In the 1990s, the development of low-dose computerized tomography (CT) scanning advanced the treatment of lung cancer.5 The advent of positron emission tomography/computerized tomography (PET/CT) scanning in the 2000s has further improved lung cancer treatment planning and increased diagnostic accuracy. Finally, a better understanding of the genetic alterations involved in the development of lung cancer is emerging and may result in development of a variety of treatment options.

Background

As the number of lung cancer cases began to increase in the 1930s, speculation about the source of this disease was directed toward two suspected culprits: air pollution and smoking.6 By 1950, the first definitive epidemiologic studies on smoking and lung cancer were published. These case-controlled studies associated smoking with lung cancer. These studies compared lung cancer patients who smoked with smokers who did not have lung cancer.6, 7

In 1964, the office of the U.S. Surgeon General released its landmark report on smoking and health, which concluded that smoking is causally related to lung cancer in men and (despite the availability of fewer data at the time) probably women, too.8 Since the release of this report, epidemiologic research on lung cancer has been conducted with increased frequency. Although cigarette smoking has remained a central theme in these studies, other causes have been evaluated. After nearly 60 years of research, numerous environmental causes of lung cancer have been identified. Genetics may also play a key role in determining a particular individual’s susceptibility to these carcinogens, but the full genomic picture has yet to be identified, and the interplay between genetics and smoking has yet to be fully elucidated.6

Incidence of Lung Cancer

Worldwide, lung cancer is the most common and deadly form of cancer, accounting for 1.35 million of the 10.9 million cancer cases expected to be diagnosed in 2008. In 2008, the number of newly diagnosed cancer cases involving the respiratory system, which includes cancers of the larynx, lung, bronchus, and other respiratory organs, was expected to be approximately 232,270 in the United States. Of these new cases, 127,880 were predicted to affect men and 104,390 were predicted to affect women.2 In the United States, more people die from lung cancer than from prostate, breast, and colorectal cancer combined.4

Although the rate of lung cancer has peaked and is now on the decline in both the United States and the United Kingdom, lung cancer tends to be more common in developed countries. The lowest and highest rates of lung cancer in the United States are found in Utah and Kentucky, respectively, where the lowest and highest smoking prevalence rates are also found.9 Globally, people in developing countries such as those in East Asia—and especially China—are consuming an increasing proportion of the world’s tobacco; by 2010, people in these areas are expected to account for 71% of world tobacco consumption. Two-thirds of all adult Chinese men are smokers by age 25, accounting for one-third of all smokers worldwide.2, 10 The risk of developing lung cancer is 23 times higher in male smokers and 13 times higher in female smokers compared to lifelong nonsmokers.2

Types of Lung Cancer

Lung cancer occurs when normal gene expression goes awry, leading to mutation of an epithelial cell in response to exposure to a carcinogen. The bronchial epithelium of the smoker progresses from squamous metaplasia, to dysplasia, to invasive carcinoma and progressive genomic instability.1 Many of the genetic defects seen in lung neoplasms are acquired during adult life and are related to exposures to environmental carcinogens. Other genetic events are inherited. Interactions of genes and outside agents likely reflect the activity of environmental agents that alter expression of genes involved in cell cycle regulation, intercellular signaling, cell-cycle arrest, and apoptosis. Susceptible individuals may be at increased risk of lung cancer when they are exposed to even low-dose levels of tobacco smoke or other mutagens.1 The genetic alterations that occur most commonly are p53 mutations and deletions on chromosomes 3p, 5q, 9p, 11p, and 17p.4

The lungs are divided into right and left sides; the right lung is divided into three lobes and the left lung has two lobes. The right and left bronchus arise from the trachea and ultimately branch into smaller airways. A rich network of lymphatic vessels weaves throughout the loose interstitial connective tissues of the lungs, ultimately draining into various lymph node stations (Figure 11.1). This network of lymph vessels, while designed for prevention of illness, makes it possible for lung cancer to metastasize elsewhere, as the lymph drainage may transport the cancer to other body sites.11 Common sites of metastases in lung cancer include the brain, bones, adrenal glands, and liver.12

Figure 11.1 Lung Anatomy and Lymphatic Network Four major histologic types of lung cancer are distinguished: squamous cell cancer, adenocarcinoma, and large-cell carcinoma—which are collectively termed non-small-cell lung cancer (NSCLC)—plus small-cell undifferentiated carcinoma, which is also known as small-cell lung cancer (SCLC). Other less commonly occurring lung cancers include undifferentiated cancers, carcinoids, and bronchial gland tumors.4

Squamous cell carcinoma is closely correlated with smoking and is more common in men. This type of tumor generally occurs in the larger, more central bronchi, tends to spread locally, and metastasizes later than other patterns.11 Its pathologic hallmark is the presence of keratin pearls produced by tumor cells with intercellular bridges.11

Adenocarcinoma is the most common type of lung cancer in women, young adults, and nonsmokers. Pathologically, intracytoplasmic mucin production is seen with this type of cancer.11 Adenocarcinoma accounts for the largest subset of NSCLC cases in Western countries and Japan. These lesions are usually more peripheral, smaller, and more slowly growing than squamous cell cancers. Bronchoalveolar carcinoma (BAC) is a subtype of adenocarcinoma whose pattern of neoplastic growth occurs along preexisting alveolar structures without evidence of stromal, vascular, or pleural invasion.11

Large-cell carcinomas probably represent squamous cell carcinomas that are so undifferentiated they can no longer be recognized. These tumors are usually found as large peripheral masses with necrosis. On pathology, sheets of round to polygonal cells with prominent nucleoli and pale-staining cytoplasm without differentiating features are seen.11

Small-cell carcinoma—the classic oat-cell cancer—is strongly correlated with cigarette smoking, occurring most often in the hilar or central chest, and metastasizing widely.11 Small-cell cancer pathologically reveals populations of small cells with variable amounts of cytoplasm.11

The incidence rates for lung cancer histology have changed over time. Today, NSCLC is the most common lung cancer, accounting for 85-90% of all lung cancers in the United States. Adenocarcinoma accounts for 49% of all NSCLC cases,4, 7 13 likely related to changes in smoking habits. The introduction of low-tar cigarettes has been correlated with the increase in adenocarcinoma incidence. It is speculated that filter-cigarette users take larger puffs and retain smoke longer to compensate for the lower nicotine yield. Low-tar cigarettes also enhance the delivery of smoke to the peripheral regions of the lung, where adenocarcinoma is most often found. Additionally, many non-filter-cigarette users who switch to lower-tar cigarettes with filters actually increase their daily cigarette consumption.14 Filter cigarettes also have a higher nitrate content, and nitrate has been proven to produce adenocarcinoma in lab studies.4

SCLC accounts for 15% of all lung cancer cases diagnosed.15 It is staged in one of two ways: as limited or extensive disease. Only 25% of all SCLC patients will have disease that is truly limited. The World Health Organization classifies SCLC into three cell types: pure or classic, variant cell, or mixed. The subtypes do not have any notable differences in terms of outcome, however. Indeed, the most important prognostic factor for SCLC is stage of disease at time of diagnosis.4

Etiology of Lung Cancer

Cigarette Smoke

Trends in population prevalence of cigarette smoking strongly predict lung cancer incidence and mortality. Worldwide, smoking is the main cause of lung cancer.6 During the period 1997-2001, cigarette smoking and exposure to tobacco smoke resulted in approximately 438,000 premature deaths in the United States and led to $92 billion in productivity losses annually.16 Multiple economic, political, and social factors impede progress toward elimination of smoking. Smoking dates back to the ancient Mayan civilization. Tobacco’s medicinal qualities, addictive properties, and use throughout the years in rituals and ceremonies have made acceptance of its harmful properties more difficult.17

In the United States, cigarette smoking decreased in males from 1964, when the U.S. Surgeon General’s report was published, until 1990, when the prevalence leveled at 25%; female prevalence reached a plateau shortly after male prevalence entered a steady state.7 An estimated 45 million Americans currently smoke cigarettes.2

The historic smoking trends in the United States offer an explanation for past trends in lung cancer rates and current rates, while also providing predictions for future occurrence. Mortality rates are expected to decrease until 2020, assuming a 30-year lag between population patterns and subsequent incidence, and then to remain constant. By 2030, lung cancer incidence is predicted to be divided equally between males and females.7 However, smoking does not explain the whole picture of lung cancer: Not all persons who smoke get lung cancer, and 10% of lung cancer cases occur in people who have never smoked.

Other Sources of Nicotine

Second-hand smoke (SHS), also known as environmental tobacco smoke (ETS), is a mixture of sidestream smoke—the smoke given off by the burning end of a tobacco product—and mainstream smoke—the smoke exhaled by smokers.18 It is primarily emitted from cigarettes, with smaller amounts being given off by pipes and cigars, and contains more than carcinogens.18 More than 126 million nonsmoking Americans are believed to be exposed to SHS in homes, vehicles, workplaces, and public areas.2 The U.S. Surgeon General’s report entitled The Health Consequences of Involuntary Exposure, to Tobacco Smoke reported that 3,000 people, or 1.6% of all nonsmoking adults, die annually from breathing SHS.18 The carcinogens most commonly found in ETS include arsenic, cadmium, benzopyrenes, nitrosamines, and vinyl chloride.19

Multiple epidemiologic studies have been conducted on ETS and the development of lung cancer in nonsmokers, mostly involving women.19 For example, Asomaning and colleagues20 focused on the effects of SHS exposure relevant to lung development from birth to age 25. This case-controlled study involved 1,669 participants and 1,263 controls at Massachusetts General Hospital. The study participants were required to be age 18 or older and to have a diagnosis of primary lung cancer. The control cases were friends or spouses of other patients visiting Massachusetts General Hospital. The study concluded that individuals who were first exposed to SHS before age 25 have a higher risk of lung cancer development than do persons who were older when first exposed to SHS. While there are some flaws in this study with respect to SHS exposure, it appears that, if anything, exposures to environmental tobacco smoke are underreported.20

Environmental Factors

Radon Radon is a colorless, odorless, inert, radioactive gas found in soil, water, and air. Radon is known to cause lung cancer in humans through the inhalation of radon decay products, which emit alpha particles that damage the respiratory epithelium.21, 22 Radon and smoking are also known to act synergistically, so there is an absolute increased risk for lung cancer due to radon exposure for a smoker versus a never-smoker.22

Radon and its effects were first discovered in underground uranium miners. The miners who worked where concentrations of radon were higher because of confined air space were found to have higher rates of lung can-cer.21, 23 Indoor radon was first recognized as a danger several decades ago, when initial measurements were made and revealed that levels in some homes were as high as those in the uranium mines.23 Multiple case-controlled studies were then performed, and their results supported the introduction of radon monitoring in homes.21

Air Pollution Outdoor air pollution is a complex mixture of different gaseous and particulate components, whose composition varies both by locality and by time.22 The biologic rationale for the carcinogenic potential of air pollution focuses on the numerous components of air pollution, which may include benzopyrene, benzene, fine particles, metals, and possibly ozone.22 Overall, the evidence for an increased risk of lung cancer from exposure to air pollution is strong.22, 24

Indoor air pollution may also play a role in lung cancer development. Very high rates of lung cancer have been discovered in some regions in China among women who spend much time at home. Exposure to combustion-based sources of heating and cooking as well as oil vapors from some styles of cooking have been studied.22 Although the results of many studies have been inconclusive, a persistent, significant increase in risk of lung cancer has been associated with air pollution from combustion or cooking oil vapors, which merits further research.22

Asbestos Another contributor to the current burden of lung cancer is widespread asbestos exposure, which occurred in the United States from the 1940s to the 1960s. Asbestos and asbestiform fibers are naturally occurring fibrous silicates with commercial use in thermal insulation and acoustics. They are classified into two types: chrysotile and amphiboles. Chrysotile is the most widely used type of asbestos.22 All commercial forms of asbestos are carcinogenic in mice, rats, hamsters, and rabbits.25 In humans, occupational exposure to chrysotile, amosite, anthophyllite, and mixed fibers containing crocidolite has resulted in a high incidence of lung cancer.25 Owing to this link with cancer, use of asbestos has been restricted or banned in many countries.22

Few studies have examined the health effects of household and residential exposure to asbestos. Household sources include installation, degradation, removal, and repair of asbestos-containing products. Cigarette smoking and asbestos exposure, when present together, act in a synergistic fashion to increase lung cancer incidence.25

Nonenvironmental Factors

Socioeconomics In the United States and many other countries, smoking rates—and thus incidence of lung cancer—are higher in individuals of lower socioeconomic status. Socioeconomic status is an important determinant of health and is associated with many interacting lung cancer risk factors, such as smoking, diet, and exposure to inhaled carcinogens at work and in the environment.7

For women, poorer females are more likely affected by these risk factors than their wealthier counterparts.16 The Norwegian Women and Cancer Study included 96,638 women and evaluated cancer risk and educational level. The study concluded the risk of lung cancer was strongly related to education, explained mostly by differences in smoking habits.26

Gender Women appear to be overrepresented in terms of lung cancer patients who are nonsmokers. At the same time, women have better relative survival rates compared to men for each disease stage.1326 Women who develop lung cancer are more likely to have never smoked than men. However, women who do smoke tend to have less education, start smoking earlier, and have a higher number of packs per year consumption.26 Hormones—specifically estrogen— may promote bronchial cell proliferation, which may play a role in lung cancer by influencing the metabolism of carcinogens or precipitating the development of lung disease.27

Race and Ethnicity Lung cancer incidence is much higher among African American men than among white American men, whereas the rates are similar for African American and white American women.7 African American men are diagnosed at a 37% higher rate and die at a 43% higher rate than white men.2 The risk of lung cancer is significantly lower among white smokers than among African American smokers who smoke no more than 10 cigarettes per day and among those who smoke 11-20 cigarettes per day.

The Multi Ethnic Cohort Study enrolled 215,000 men and women from 5 self-reported racial and ethnic classes (Japanese American, African American, white, Native Hawaiian, and Latino) who were living in Hawaii and California from 1993 to 1996. Among both men and women in this study, the mean age of smoking initiation was similar among African Americans, Latinos, and Native Hawaiians. In an age-adjusted analysis, African American males and Native Hawaiian males had the highest incidence of lung cancer.28 It is unknown why these differences exist, but variations in the metabolism of nicotine among different ethnic and racial populations may underlie the differences in the uptake of carcinogens.28

Genetics Our understanding of the role played by genetic mutations in lung cancer is evolving. If a gene modifies lung cancer susceptibility, it must do so by inhibiting or facilitating tumorigenesis.19 Tobacco-smoke-induced tumorige-nesis is believed to occur when tobacco-smoke carcinogens bind to epithelial cells in lung DNA to form DNA adducts. Adduct formation initiates tumorigenesis through DNA repair processes that may lead to mutations in genes that start or aid tumor growth.19

A number of genetic mutations and molecular alterations have been studied, such as those involving p53, K-ras proto-oncogene mutations, and chromosomal abnormalities, such as loss or inactivation of material on the short arm of chromosome 3.19 The K-ras gene is the most often mutated gene in lung cancer, representing approximately 90% of the mutations identified as linked to this disease.29 K-ras mutation is particularly common in patients with an extensive smoking history and is found in 20% of all lung cancer tumors.29

Other Risk Factors

Other carcinogens known to be involved in the pathogenesis of lung cancer are inorganic arsenic, chromium VI compounds, and silica and polycyclic aromatic hydrocarbons, which are formed during incomplete combustion of inorganic material. These substances have a very widespread distribution, being found in tobacco smoke, engine exhaust, and diesel exhaust.22 Additionally, individuals with a previous history of radiation therapy to the chest, as might be administered in the setting of breast cancer and Hodgkin’s disease, have an increased risk of developing lung cancer.

Prevention of Lung Cancer

Non-nutritional Factors

Most lung cancers could be prevented by the elimination of smoking. Smoking remains the leading preventable cause of premature death.30 Clearly, not starting smoking is the best way to avoid lung cancer. For those individuals who do smoke, identifying effective mechanisms for smoking cessation is essential. Smoking cessation has clearly been shown to reduce the likelihood of future morbidity.30 Also, for those persons who do not smoke, it is imperative to avoid exposure to SHS. The American Cancer Society’s collaborative effort with national groups on tobacco control focuses on achieving reductions in advertising of tobacco, increasing funding for research, reducing SHS by support of clean indoor air laws, providing access to smoking-cessation programs, increasing tobacco taxes, and supporting global partnerships to reduce tobacco-related deaths.2

Nutritional Factors

Epidemiologic studies have yielded insight into the nature of dietary deficiencies that influence the risk of lung cancer. Consistently, research has demonstrated increased consumption of fresh vegetables and fruits lower the risk in both men and women, in both current and former smokers, and among never-smokers, for all lung cancer histologies.1 A major focus has been on the pro-vitamin A carotenoids, particularly beta-carotene. Collectively, the Alpha-Tocopherol, Beta Carotene (ATBC) cancer prevention study, the Beta-Carotene and Retinol Efficacy Trial (CARET), and the Physicians’ Health Study have studied more than 69,000 persons. These studies, in which the beta-carotene dose ranged from 20 mg per day to 50 mg every other day, have all found that supplementation with beta-carotene is not effective in preventing lung cancer and, in fact, may increase the risk.31-34 Smokers should be cautioned against taking vitamin supplements containing large doses (similar to the amounts used in the randomized trials mentioned earlier) of beta-carotene, as this practice appears to increase their risk of developing lung cancer. By contrast, beta-carotene from food sources is not linked to an increase in risk, and foods containing carotenoids are actually thought to be protective against lung cancer.35 Research has also failed to find to a beneficial effect with alpha-tocopherol (vitamin E) supplementation at 50 mg/day on the incidence or mortality of lung cancer.34

An increased risk of lung cancer has been associated with high dietary intake of foods rich in fat and cholesterol, or with elevated indices of abdominal adiposity. However, the positive association between dietary cholesterol and lung cancer risk has not been reflected in studies of serum cholesterol. Lung cancer risk is also not associated with increasing body mass.1

A 2007 study by Galeone and colleagues studied dietary intake of vegetables and fruits in northeast China, where one of the leading causes of death in both sexes is lung cancer. An inverse relationship was found between vegetable and fruit intake and lung cancer risk. The most protective foods were Chinese cabbage, chives, carrots, and celery. This study, while not population or histologically based, provides some credence to the fact that increased consumption of fruits and vegetables is inversely associated with lung cancer incidence.36

Selenium has also been suggested to be a chemopreventive agent for lung cancer. Selenium is a trace element that may assist in the repair and prevention of oxidative damage. Thus far, studies are inconclusive on selenium’s effects. If there is any benefit to supplementation for lung cancer prevention, it may occur only in those persons with initially low selenium levels.37, 38

Table 11.1 summarizes the current evidence for nutrients that do or may influence lung cancer risk.35

Strength of Evidence

Associated with Increased Risk

Associated with Decreased Risk

Convincing

Beta-carotene supplements

Probable

Fruits

Foods containing carotenoids (e.g., carrots, apricots, mangoes, squash, sweet potatoes, spinach, kale, collard greens, tomatoes, grapefruit)

Limited (suggestive)

Red and processed meats

Butter

Retinol supplements

Non-starchy vegetables

Selenium and foods containing selenium (e.g., nuts, fish, shellfish, poultry)

Foods containing quercetin (e.g., citrus fruits, apples, onions, parsley, green and black tea, red wine, olive oil, dark cherries, blueberries)

Limited (no conclusion)

Grains, fiber, legumes, poultry, fish, eggs, milk and dairy products, animal and total fats

Vitamins A, C, and E, the B vitamins, multivitamins, calcium, copper, iron, zinc, pro-vitamin carotenoids, lycopene, flavonoids

Source: World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC: American Institute for Cancer Research; 2007.

Symptoms and Therapy of Lung Cancer

Lung cancer is commonly diagnosed when the disease is at a more advanced stage and symptoms have appeared.4 Symptoms may include persistent coughing, hemoptysis, shortness of breath, wheezing, hoarseness, recurring pneumonia or bronchitis, weakness, and anorexia.

The stage of lung cancer at diagnosis is determined by the Tumor, lymph Node, Metastasis (TNM) classification system and directs the care that will be rendered. The TNM classification system is the accepted system for staging many cancers, including lung cancer (see Table 11.2). It was adopted by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer in 1986 as a means of unifying variations in definitions

Stage Grouping

Occult carcinoma

TX

N0

M0

Stage 0

Tis

N0

M0

Stage IA

T1

N0

M0

Stage IB

T2

N0

M0

Stage IIA

T1

N1

M0

Stage IIB

T2

N1

M0

T3

N0

M0

Stage IIIA

T1

N2

M0

T2

N2

M0

T3

N1

M0

T3

N2

M0

Stage IIIB

Any T

N3

M0

T4

Any N

M0

Stage IV

Any T

Any N

M1

Definition of TNM

Primary Tumor (T)

TX: Primary tumor cannot be assessed, or

tumor proven by the presence of malignant

cells in sputum or bronchial washings but not visualized by imaging

or bronchoscopy

T0: No evidence of primary tumor

Tis: Carcinoma in situ

T1: Tumor 3 cm or less in

greatest dimension, surrounded by lung or

visceral pleura,

without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e.,

not in the main bronchus)

T2: Tumor with any of the following features of size or extent:

More than 3 cm in greatest dimension

Involves main bronchus, 2 cm or more distal to the carina

Invades the visceral pleura

Associated with atelectasis or obstructive pneumonitis that extends to the hilar region

Does not involve the entire lung T3: Tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung

(continues)

Table 11.2 Staging of Lung Cancer, Continued Definition of TNM Primary Tumor (T), continued T4: Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; separate tumor nodule(s) in the same lobe; or tumor with a malignant pleural effusion Regional Lymph Nodes (N)

All regional lymph nodes are above the diaphragm. They include the intrathoracic, scalene, and supraclavicular nodes.

NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes including involvement by direct extension of the primary tumor N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)

N3: Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node(s)

Distant Metastasis (M)

MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis present; this includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral)

Source: Reprinted with permission from Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer; 2002.

and providing consistent meaning and interpretation among clinicians and scientists throughout the world.4

In the staging process, the treating professional will also take into account comorbid diseases and general patient condition. In addition to stage, the most important prognostic indicators affecting survival are performance status and weight loss.4 Patients who have never smoked and patients with a remote smoking history have an increased probability of partial response to chemotherapy compared to patients with a recent smoking history.39 Patients who cease smoking do gain an advantage in time to progression and survival over those who continue to smoke.39

Generally, treatment options include surgery, radiation, and chemotherapy. Depending on the stage of disease at diagnosis, two or more modalities may be recommended.

Sputum cytology is the only noninvasive method available to evaluate patients with suspected lung cancer and determine pathologic classification. Sputum cytology has a positive predictive value near 100% but sensitivity of only 10—15%.4 Other more common and standard evaluation techniques include fiber-optic bronchoscopy, which can determine the endobronchial extent of disease, identify occult lesions, and measure tumor distance to the carina,4 and CT-guided percutaneous fine-needle aspiration, which can be used to sample areas that are poorly accessible in the lung and mediastinum. Mediastinoscopy is best for evaluating upper, middle paratracheal and sub-carinal lymph nodes. Video-assisted thorascopy (VATS) is usually performed as an adjunct to mediastinoscopy.

Once the invasive procedure is performed and the sample is obtained, the tumor is measured for size, lymph nodes are studied, and other staging studies are performed. PET/CT or CT of the chest, abdomen, and adrenal glands and PET scan will be performed to determine the extent of disease and subsequent treatment.9 Four stages of NSCLC are distinguished, with the various subdivisions within each stage being based on tumor size and nodal involvement. By comparison, SCLC is staged as limited or extensive only.

Non-Small-Cell Lung Cancer

Surgical Treatment For many years, surgery has been the standard mode of treatment in patients with stage I—IIIA NSCLC.39 Surgery is the most consistent and successful option for patients, but a cure by this means is possible only when the cancer is completely resectable and the patient is able to tolerate the extent of resection.9 Only 20% of patients presenting with lung cancer are candidates for curative surgery.4 Unfortunately, even with complete resection, relapse often occurs at distant sites.39

Surgical procedures that may be performed include pneumonectomy, lobectomy, or limited resection, usually called wedge resection. Lobectomy is the standard of care for surgical management.9 The local recurrence rate is three times higher in patients who undergo wedge resection over lobectomy; thus lobectomy is recommended for most patients who are able to tolerate the surgery.4 Minimal-access surgical procedures are gaining ground, and video-assisted lobectomy is being offered more often because it represents a less invasive method to accomplish the same resection as lobectomy.9

The average 5-year survival rate following surgery for NSCLC ranges from 23% to 65% for stage IA—IIIA disease.40 Adjuvant chemotherapy is not recommended for patients with completely resected stage IA NSCLC. Postoperative thoracic radiation is also not recommended for patients with completely resected stage I or II NSCLC.39 Only 5% of all patients will present with stage II disease, which is further subdivided into stages IIA and IIB. The average 5-year survival rate for stage II disease is 41.2%.4 In patients with completely resected stage IIIA NSCLC, postoperative radiation is controversial and not routinely recommended due to the lack of randomized clinical trial data evaluating its efficacy.39

Chemotherapy and Radiation Chemotherapy for NSCLC generally consists of platinum-based agents; carboplatin and paclitaxel are the most frequently used chemotherapeutic drugs. Platinum-based chemotherapy prolongs survival, improves symptom control, and yields superior quality of life compared to supportive care.4 Adjuvant cisplatin-based chemotherapy is often recommended for patients with completely resected stage II-IIIA NSCLC, but is under active investigation for patients with stage IB-IIIA NSCLC who have undergone complete resection. The preferred timing, regimen, and patient selection for use of this therapy has yet to be determined.41 In patients with unresectable stage III NSCLC, 2 to 8 cycles of platinum-based chemotherapy in association with definitive thoracic irradiation is considered appropriate treatment.42

Chemotherapy with concurrent radiation improves local control by sensitizing the tumor to radiation and treating systemic disease.42 Approximately 25-40% of patients with NSCLC have stage III disease, which is further subdivided into stages IIIA and IIIB. Stage IIIB disease is generally not resectable.4 Currently, the role of surgery following induction chemotherapy or chemoradiotherapy for patients with initially unresectable cancer is being explored; the 5-year survival rate is 9-15%.4, 41

Chemotherapy is also appropriate for selected patients with stage IV NSCLC and good performance status, as this type of treatment prolongs survival. The chemotherapy plan should include a 2-drug combination regimen, and non-platinum-based chemotherapy may be used as an alternative to platinum-based agents.41 Initial treatment with investigational agents or regimens is appropriate for selected patients with stage IV NSCLC, provided they are crossed over to an active treatment regimen if they do not respond after two cycles of chemotherapy.42 With best supportive care, the 1-year survival rate for stage IV lung cancer is 10%. Platinum-based chemotherapy can improve this rate to 30-35%.43

Docetaxol is recommended as second-line therapy for patients with locally advanced or metastatic NSCLC, adequate performance status, and progressive disease after first-line platinum-based therapy. Gefitinib, an orally active inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, was the first targeted therapy to be approved for use in lung cancer and was originally recommended for the treatment of patients with locally advanced or metastatic NSCLC after failure of both platinum-based and doc-etaxol chemotherapy.41 Unfortunately, a Southwest Oncology Group phase III randomized trial in patients with stage IIIB lung cancer showed no survival benefit with its use.9 Erlotinib, another EGFR tyrosine kinase inhibitor (TKI), has shown some promise and is approved for second- or third-line treatment of NSCLC in patients who have not responded to one previous round of therapy.9 Furthermore, cetuximab, another EGFR inhibitor, has demonstrated the ability to extend survival when combined with platinum-based chemotherapy.

Studies have also focused on cancer angiogenesis, which is induced by vascular endothelial growth factor (VEGF). Bevacizumab, a monoclonal antibody against VEGF, has been found to offer a survival benefit when added to a paclitaxel-carboplatin regimen. This agent is associated with a small but significant risk of serious bleeding, so it is not used in patients with squamous cell histology, brain metastases, or hemoptysis, or in those patients who are receiving anticoagulation therapy.9

Small-Cell Lung Cancer

SCLC accounts for 15% of all diagnosed lung cancers in the United States. At presentation, two-thirds of patients will have extensive disease.15 SCLC is defined as limited disease when the tumor is confined to one hemithorax and its regional lymph nodes. Extensive disease means the tumor is more widespread.44 For patients with stage I SCLC, complete resection via lobectomy with mediastinal nodal dissection or sampling is considered if the disease is very limited. Nevertheless, a mediastinoscopy should be performed prior to surgery to rule out occult disease in the lymph nodes.4 If nodes are found to be positive after resection, postoperative chemotherapy and radiation should be offered.

SCLC is highly chemosensitive; therefore, combination chemotherapy is the cornerstone of treatment for most patients. Unfortunately, median survival despite treatment is only 9-11 months.15 In the 1970s, a survival benefit of combination chemotherapy over single-agent therapy was discovered. As in NSCLC, platinum-based chemotherapy is used. In SCLC, cisplatin is combined with etoposide—a standard of care that has been in place for the last 2 decades. Many physicians substitute carboplatin for cisplatin due to the former agent’s equally efficacious but more favorable toxicity profile. Other trials continue to study chemotherapy agents for the treatment of SCLC. Some success has been achieved with irinotecan and cisplatin in terms of response rate and median survival. Adding radiation therapy to chemotherapy for treating limited-stage SCLC improves median survival to

14-18 months.45

The risk of brain metastases in SCLC is correlated with length of survival. Given this relationship, prophylactic cranial irradiation (PCI) is often offered for complete responders as they face a 50—60% risk of developing brain metastases within 2-3 years after diagnosis.445

Complementary and Alternative Therapies

The use of complementary and alternative medicine (CAM) by persons with lung cancer is relatively common.46, 47 One study, which included 189 women with NSCLC in the United States, found that 44% of these patients used CAM.46 Women with a younger age, those with more symptoms, and those living in the western or southern regions of the United States were more likely to implement CAM therapies. CAM options included prayer, meditation, tea, herbs, massage and acupuncture. More frequent symptoms—such as pain, dyspnea, and fatigue—led to increased use of CAM.46 Prayer was practiced more frequently than any other therapy.

Another study examined CAM use in 111 lung cancer patients from 8 European countries.47 Approximately 24% of those studied used some type of CAM; herbal medicine, teas, homeopathy, animal extracts, and spiritual therapies were the most popular options. In this study, CAM users were more likely to be younger and to have a higher education level than non-users.

Jatoi and colleagues reported that 63% of 1,129 patients with NSCLC were users of multivitamins or other individual vitamin or mineral supplements.48 As this and the other studies illustrate, because of the prevalence of CAM in lung cancer patients, clinicians must query patients about CAM use and be aware of potential interactions between conventional therapies and CAM.

Several investigators have studied the use of CAM’s effectiveness, along with other conventional treatments, against lung cancer. Two studies (one in patients with NSCLC and the other in patients with SCLC), conducted by Jatoi and colleagues,48, 49 evaluated the association between patient-directed vitamin and mineral supplementation and quality of life and survival. Study participants were classified as users or non-users based on a mailed questionnaire. After adjustments for other prognostic factors, including tumor stage, vitamin/mineral supplementation was associated with improved survival in both studies, and with improved quality of life in the NSCLC cohort. Nevertheless, because of the study methodology and potential confounding reasons for the survival benefit, the investigators do not advise clinicians to recommend vitamin/mineral supplements to patients until prospective clinical trials are conducted.

Astragalus, a Chinese herbal medicine, has been combined with platinum-based chemotherapy to treat NSCLC. Astragalus’s proposed immune-enhancing actions include promotion of macrophage and natural-killer cell activity and inhibition of T-helper cell type 2 cytokines. McCulloch and associates performed a meta-analysis of 34 randomized trials evaluating outcomes (survival, tumor response, performance status, chemotherapy toxicity) with Astragalus plus platinum-based chemotherapy versus platinum-based chemotherapy alone. The combination of Astragalus and platinum-based chemotherapy lowered the risk of death at 1 year in 12 studies and increased tumor response in 30 studies. However, the studies located for the meta-analysis were of poor quality, such that further investigation with high-quality prospective, randomized trials is needed to confirm Astragulus’s role (combined with chemotherapy) in the treatment of in lung cancer.50

Hydrazine sulfate (HS) has been, and still is, promoted as being able to improve survival when combined with standard chemotherapy regimens and treat symptoms associated with cancer cachexia.51 However, several randomized trials have demonstrated that HS, when combined with chemotherapy, does not improve tumor response, survival, quality of life, or nutritional sta-tus.52-54 Therefore, HS cannot be recommended in lung cancer patients.

Clearly, more research is needed to confirm the claims that specific CAM therapies can assist in treatment of lung cancer. Refer to Chapter 16 for more detailed information on CAM therapies.

Nutritional Implications of Lung Cancer

The nutritional status of patients with lung cancer is affected by a multitude of factors, including adequacy of nutrient intake, weight loss, presence of treatment-related symptoms, and cancer-related cachexia. Nutritional status at diagnosis and during management of lung cancer has been shown to affect outcomes.

Weight Loss and Outcomes

Studies conducted prior to 2000 strongly support the idea that weight loss and nutritional status play key roles in outcomes for patients with lung cancer. An early study by Lanzotti and colleagues evaluated the use of a regression analysis model to determine clinical factors influencing survival in patients with inoperable lung cancer.55 The study evaluated 129 patients with limited disease and 187 with extensive disease. Survival was 36 weeks in patients with limited disease and 14 weeks in those with extensive disease. In patients with limited disease, the proposed model found weight loss to be the major factor for prediction of survival, followed by symptom status, supraclavicular metastases, and age.55

Dewys and colleagues reported on the prognostic effect of weight loss before initiation of chemotherapy in a variety of cancer diagnoses, including lung cancer.56 More than 1,000 patients with SCLC and NSCLC were included in the analysis. The percentages of patients who lost weight—defined as more than 10%, 5-10%, 0-5%, or 0% of body weight—in the previous 6 months in the lung cancer group were approximately 15%, 20%, 24%, and 40%, respectively. The effect of weight loss on survival in the lung cancer patients was significant. SCLC patients with no weight loss survived a median of 34 weeks versus 27 weeks for those patients with weight loss (p < 0.05). NSCLC patients with no weight loss survived a median of 20 weeks, whereas patients with weight loss had a median survival of 14 weeks (p < 0.01).56

A third study, by Espinosa and colleagues, also found a relationship between weight loss and survival in advanced nonoperable NSCLC patients undergoing chemotherapy treatment.57 Those without weight loss (69%) survived a median of 2 more months compared to patients with weight loss (31%). This study also reported a normal serum albumin (more than 4 g/dL) was associated with better response to chemotherapy and survival.57

More recent studies provide a less consistent picture of the incidence of weight loss and the effect of nutritional status and weight loss on outcomes. Jagoe and colleagues published two studies in 2001 that included lung cancer patients referred for lung cancer surgery.58- 59 One study focused on the nutritional status of patients undergoing surgery for lung cancer; the other examined the role of nutritional status on complications after surgery.

In the first study, Jagoe et al. assessed a variety of nutritional indices in 60 patients, including BMI, percent weight loss, albumin, prealbumin, energy and protein intake for 5 days prior to hospital admission, and Subjective Global Assessment (SGA) score.58 The mean BMI was 25.4; 8 patients (13.3%) had BMI < 20 and 9 patients (15%) were obese (BMI > 30). Fourteen patients (23%) reported weight loss of more than 5% of total body weight; of these, only 3 patients experienced weight loss more than 10% of total body weight. The mean serum albumin level was 44.7 g/dL and the mean prealbumin was 0.28 g/dL; 2 patients had low albumin levels and 7 had low prealbumin levels. The majority of patients were able to consume adequate calories and protein intake (70% and 87%, respectively). The SGA scored 29 patients as mildly to moderately depleted and 1 patient as severely depleted. Therefore, a minority of patients in this study population were nutritionally deficient upon presentation for surgical intervention.

In the second study, Jagoe et al. evaluated essentially the same cohort of patients (n = 52) to determine how nutritional status affected the incidence of surgical complications.59 A univariate analysis found patients with a lower BMI, percent usual body weight, and fat-free mass index to be more likely to die or to require reventilation. A multivariate analysis also found BMI and percent usual body weight to be significant factors for predicting surgical complications. Overall, this series of patients was less nutritionally depleted than those in earlier studies and generally had a less advanced disease stage. Even so, the investigators do conclude nutritional status may be a prognostic indicator of postoperative outcomes.

Ross and colleagues evaluated whether patients with weight loss who undergo chemotherapy experience worse outcomes.60 Approximately 700 patients with SCLC and NSCLC were included in this study, and some 58% of patients experienced weight loss. Patients with weight loss had a significantly shorter survival time. Patients with SCLC and weight loss survived 8 months compared to 11 months in those without weight loss. NSCLC patients with weight loss lived an average of 6 months versus 9 months for patients without weight loss.

Win and others investigated the incidence and impact of BMI on outcomes in 109 patients with operable lung cancer.61 In this cohort, the mean BMI was

25.7, and 7 patients had BMI > 19. Most study participants were either at ideal body weight (44 patients) or overweight (58 patients). This study found no association between BMI and postoperative deaths or other surgical outcomes. These same investigators found that both diabetes and a low serum albumin level are predictors of survival.62

Tewari and colleagues analyzed the relationship between nutritional status and long-term survival in 642 patients with lung cancer who underwent lobectomy. Twenty-eight percent of patients were classified as having poor nutritional status (BMI < 18.5, preoperative albumin < 30 g/dL, or history of weight loss). Twenty-four percent experienced weight loss, 9% had BMI < 18.5, and 21% presented with an albumin level of less than 30 g/dL. Nutritional status did not affect short-term outcomes but did influence long-term survival. Those patients with a depleted nutritional status had a median survival of 36 months, whereas those with a normal nutritional status had median survival of 58 months.63

Overall, the evidence supports paying close attention to the nutritional status of patients with lung cancer at the time of diagnosis and/or when planning surgical intervention.

Nutritional Assessment and Interventions

Patients with lung cancer should undergo nutritional screening by a healthcare professional to determine if weight loss, underweight status, low serum albumin, or gastrointestinal symptoms are present. If any of these conditions are present, it is optimal to refer the patient for further assessment to a registered dietitian (RD) with experience in the field of oncology nutrition. Refer to Chapter 2 for more detailed information related to nutrition screening and assessment in the oncology patient.

Like other cancer patients, patients with lung cancer often experience cancer cachexia.6465 (See Chapters 1 and 15 for more details about cancer cachexia and its treatment.) Cachexia has been defined by Morley et al. as the combination of the following in the setting of ongoing disease: unintentional weight loss (> 5% of total body weight); BMI < 20 in patients younger than 65 years or < 22 in patients 65 years or older; albumin < 3.5 g/dL; low fat-free mass (lowest 10 percentile); and evidence of cytokine excess (elevated C-reactive protein).66 Nutrition therapy alone is usually not sufficient or effective in treating cancer-related cachexia.

A small 8-week study, which included both pancreatic and NSCLC patients, utilized weekly counseling by a dietitian along with an oral nutritional supplement to treat cachexia.67 The patients’ protein and energy intake increased significantly (p < 0.02) over the 8-week period. Weight and lean body mass also increased by 2.5 kg and 1 kg, respectively, although these gains were not statistically significant. In addition, significant improvements were seen in SGA nutritional score, Karnofsky performance status, and quality of life. While this study is limited by its small sample size, it does suggest that intensive nutritional intervention can affect important outcomes in a very difficult-to-treat patient population.

Vitamin D has been promoted as a significant nutrient in cancer prevention. Notably, according to recent research in patients with lung cancer, vitamin D status may also be an important factor in their outcomes. Zhou and colleagues studied the effect of circulating 25-hydroxyvitamin D—25(OH) vitamin D—levels and vitamin D intake on overall survival and recurrence-free survival in 447 patients with NSCL.68 The data suggest that patients with both a high 25(OH) vitamin D level and high vitamin D intake have improved overall survival and recurrence-free survival, and that this effect is most pronounced in stage IB-IIB patients compared to stage IA patients.68 In the future, nutrition assessment may routinely include evaluation of vitamin D status. For now, however, the authors recommend further observational studies and randomized trials to confirm vitamin D’s role in improving outcomes in patients with lung cancer.

Limited study results are available on the use of nutrition support in patients with lung cancer. Overall, their findings have not shown any nutritional or clinical benefit from the use of adjuvant parenteral nutrition support in this population.69, 70 Nevertheless, if a patient is responding well to therapy and has a good prognosis but is unable to maintain adequate intake through nutritional counseling, oral diet, and nutritional supplements, enteral nutrition should be considered. Also, if enteral nutrition cannot be tolerated because of prolonged gastrointestinal side effects related to oncologic therapies, parenteral nutrition is an option. The use of parenteral nutrition in cancer patients continues to be controversial, however, and clinicians must weigh all the pros and cons carefully before initiating this therapy. See Chapter 3 for more detailed information related to nutrition support in oncology patients.

Future Novel Options

The research focusing on lung cancer continues to evolve, especially in the area of lung cancer detection. A large number of potential molecular markers are being identified, and this line of research could eventually enhance the scientist’s ability to predict relapse and chemosensitivity for treatment. For example, biomarkers in the epithelium of the cheek are currently under investigation. Thus molecular events in higher-risk patients may be monitored for development of changes that are usually evident only via bronchoscopy. Additionally, blood RNA is being studied to detect lung cancer.

In the past, screening attempts for lung cancer with sputum cytology and, to a smaller extent, chest x-ray have failed to demonstrate a reduction in lung cancer mortality. The newest hope for lung cancer screening, low-dose CT, is now under evaluation. As yet, no prospective data have been published regarding how CT might affect long-term outcomes. While the CT may be able to detect earlier-stage lung cancers, it is unknown whether its use would improve mortality.

Celecoxib, a cyclooxygenase 2 (COX-2) inhibitor, is also being studied for its chemoprevention potential. This drug appears to reduce Ki-67, a protein that promotes cell proliferation in premalignant lesions in bronchial epithelia.

SUMMARY Lung cancer remains a devastating disease that leaves few long-term survivors. Despite research that is aimed toward elucidating the roles played by racial disparities, socioeconomics, and air pollution as factors in its incidence, one cannot escape the fact that lung cancer was virtually nonexistent two centuries ago. Improving the health of the general population through smoking cessation would be a major accomplishment throughout the world. Healthcare expenditures would be markedly decreased and general health status improved. Healthcare professionals are the voice of those who have no voice. It is our job to be role models for our patients by adopting healthy lifestyles and advocating for tighter smoking laws on second-hand smoke. It is also our job to educate our patients on the dangers of smoking and to offer smoking-cessation strategies for our smoking patients who wish to quit.

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