Site-Specific Cancer Series: Lung Cancer

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Chapter 1. Overview

Nancy G. Houlihan, RN, MA, AOCN^®

Introduction

Lung cancer represents one of the most challenging health threats in the United States and around the world. Despite progress over the last decade in the control or cure of many cancers, lung cancer continues to occur at high rates and kill most of its victims. This is true for many reasons, including ineffective prevention programs, lack of a good population-based screening test, and controversy over the most effective treatment strategies. In addition, research funding for lung cancer has lagged behind that appropriated for other diseases, possibly because of its association with tobacco products and the related political and financial implications (Kennedy, Miller, & Prindiville, 2000). Despite the persistent poor statistics, the 1990s marked the beginning of a shift in the lung cancer paradigm. Technological advances with low-dose computed tomography (CT) scans offer hope for earlier diagnosis and treatment. Clinical research has identified more effective treatments with improved survival and quality of life for patients at every stage of disease. Greater understanding of the genetic alterations in lung cancer has led to investigations into novel approaches and advances in early diagnostic and treatment strategies. In addition, national legislation, education on prevention, and availability of effective smoking cessation interventions have led to changes in the tobacco usage trends in the United States. Although lung cancer persists as the most deadly cancer, there is hope that the future will bring improvements in outcomes.

Nursing care of those with lung cancer also has advanced during this time as a result of the development of more effective, research-based interventions for managing symptoms. Care of patients with lung cancer incorporates all aspects of oncology nursing, including direct care delivery, patient education and counseling, treatment side effect management, and palliation. This book will review the current knowledge related to the disease and its properties, including prevention, screening, diagnosis, clinical manifestations, treatment and research, and nursing management.

Lung Cancer Overview

Lung cancer is the third most commonly occurring cancer in the United States, with an estimated 173,770 new cases developing in 2004. Cancers of the breast and prostate occur more frequently, with estimates of 217,440 and 230,110 cases, respectively. However, lung cancer also is associated with the highest cancer-related mortality, with an estimated 160,440 deaths occurring in 2004. This far outweighs deaths from breast (40,580) and prostate cancers (29,900) (Jemal et al., 2004).

Overall five-year survival from lung cancer is approximately 14%. Treatment of early-stage disease can produce cures, with five-year survival from treated stage I lung cancers as high as 70%. Unfortunately, less than 15% of lung cancers are localized at the time of diagnosis. Most lung cancers are diagnosed in advanced stages, and five-year survival in patients with locally advanced and metastatic disease is less than 10% (Jemal et al., 2004). Late diagnosis is attributed to multiple factors. First, there is no proven tool or recommendation for screening or early detection in high-risk individuals. Although most patients present with symptoms, symptoms such as cough and exertional dyspnea often can be subtle and attributed to chronic symptoms of smoking. These topics will be explored further in this publication.

According to data gathered by the National Cancer Institute Surveillance, Epidemiology, and End Results Program (n.d.), the age-adjusted rate for lung cancer for all race and sex groups combined has risen sharply since 1950. From 1969 to 1991, the overall incidence almost doubled, with rates diminishing over the last decade. Lung cancer rates for African American and White men peaked and began to decrease around 1984. Although incidence for women of both races continues to rise, the rate at which it occurs is diminishing, as well (Travis, Linder, & Mackay, 2000).

Lung cancer was thought to be a disease of elderly men until the last half of the 20th century, when incidence in women rose sharply. Women now represent almost half of all new cases, with 2004 estimates of 93,110 for men versus 80,660 for women (Jemal et al., 2004). In addition, lung cancer surpassed breast cancer in 1987 as the leading cause of cancer-related deaths in women and currently accounts for more deaths than breast and all gynecologic cancers (i.e., ovarian, vulvar, vaginal, uterine) combined and breast and colorectal cancer, the other leading causes of death, combined. Lung cancer is expected to account for 25% of all female cancer deaths in 2003 (Jemal et al.) (see Table 1-1).

Most lung cancers are attributed to tobacco exposure. At least 79% of lung cancer cases in women are related to smoking. Although smoking rates have declined since the 1960s, the current prevalence of smoking among U.S. women is still high—estimated at 26%—and smoking rates are highest among teenage girls (Baldini & Strauss, 1997). Whether the association between smoking and lung cancer is stronger for women than men is unclear. Many epidemiologic studies have provided evidence that women are more susceptible than men to the adverse effects of tobacco smoke, whereas other studies suggest that estrogen plays a role in lung carcinogenesis. The presence of estrogen receptors on lung cancer cells has been documented, with evidence that estrogen induces cell proliferation and stimulates growth factors in the lung (Stabile et al., 2002).

The magnitude of the effect of smoking on lung cancer risk may not differ across the genders, but smoking appears to have an impact on the type of lung cancer that develops in each gender. Women smokers have a greater risk of developing small cell lung cancer (SCLC) than men smokers. Also, women are more likely to develop adenocarcinoma than men, and evidence suggests that this may be related to the role of estrogen (Baldini & Strauss, 1997). The inclusion of women in lung cancer screening and treatment trials has not been adequate in the past. Active recruitment of women for trials with specific reference to gender is needed to investigate this phenomenon further (Baldini & Strauss).

Male African Americans experience higher lung cancer incidence and mortality rates than all other male racial groupings, including Whites, Asian/Pacific Islanders, American Indians/Alaska Natives, and Latinos. This is not true for women, who demonstrate similar incidence and death rates among Whites and African Americans. Incidence and mortality in the other female ethnic groups is half of that for Whites and African Americans (Jemal et al., 2004).

Histologic Classification

The World Health Organization classification of lung cancer includes four major histologic types: squamous cell carcinoma, adenocarcinoma, small cell lung carcinoma, and large cell carcinoma. These classes are further subdivided more specifically, and there are other, less common, lung tumors, such as carcinoid. For clinical purposes, the histologic classes are grouped into two main categories of lung cancer: SCLC and non-small cell lung cancer (NSCLC). SCLC includes a category called combined small cell carcinoma. NSCLC includes squamous cell carcinoma (SCC), large cell carcinoma, and adenocarcinoma (Travis et al., 2000) (see Table 1-2).

Non-Small Cell Lung Cancer

Approximately 75%-80% of all lung cancers in the United States are NSCLC. Although the subtypes may differ in incidence according to sex, race, and age, they are grouped because of similarities in course and response to treatment. SCC arises most frequently in the proximal segmental bronchi and is associated with squamous metaplasia. Tumors are composed of sheets of epithelial cells, which may be poorly or well differentiated. At one time, SCC was the most frequently occurring lung cancer in North America, but its incidence is decreasing and has been surpassed by adenocarcinoma for reasons that are thought to be related to changes in tobacco use (Ginsberg, Vokes, & Rosenzwieg, 2001). SCC can be detected by cytologic examination of exfoliated cells in its earliest form, carcinoma in situ, where stratified squamous epithelium is replaced with malignant squamous cells. Unchecked, the tumor eventually invades and obstructs the bronchial lumen. SCC tends to be slow growing and can take three to four years to develop from a carcinoma in situ to a clinically evident tumor (Ginsberg et al.).

Adenocarcinoma is the most common form of lung cancer in North America, accounting for almost 40% of all lung cancers. It presents as a peripheral tumor, arising from the alveolar surface epithelium or the bronchial mucosal glands. Tumors also can arise from areas of previous infections or scars. Adenocarcinoma tumors are mucin-producing and form glands. Other than very early stage tumors, adenocarcinoma appears to have a worse prognosis than SCC. Bronchoalveolar carcinoma (BAC) is a subclassification of adenocarcinoma that appears to have distinct clinical and pathologic properties (Ginsberg et al., 2001).

Large cell lung carcinoma (LCLC) is the least common of all NSCLC tumors, representing about 15% of all lung tumors. As diagnostic techniques have improved, tumors originally thought to be LCLC have been more appropriately diagnosed as poorly differentiated adenocarcinoma or SCC (Ginsberg et al., 2001). The prognosis of LCLC appears to be the same as for adenocarcinoma except for those with neuroendocrine features. These tumors appear to have a worse prognosis, and their relation to SCLC is still undefined (Ginsberg et al.).

Small Cell Lung Cancer

SCLC is less common than NSCLC, representing fewer than 20% of all lung cancers or approximately 30,000 cases per year in the United States. The latest World Health Organization classification of SCLC includes a variant known as combined small cell carcinoma, which is defined as a small cell carcinoma with a component of any histologic subtype of NSCLC (Travis et al., 2000). SCLC is a neuroendocrine tumor that routinely occurs in the central airways. Among the subtypes of lung cancer, the highest association between the extent of tobacco exposure and risk occurs in SCLC and SCC. SCLC also has a higher incidence in women than men (Murren, Glatstein, & Pass, 2000).

Although SCLC officially is staged according to the International System for Staging Lung Cancer, a more common clinical staging introduced by the Veterans Administration Lung Study Group generally is used. SCLC is staged as either limited or extensive disease. Nearly one-third of patients present with limited-stage disease, which is defined as disease that is confined to one hemithorax, without pericardial or pleural effusion, and encompassable by a single radiotherapy port (Kristjansen & Hansen, 1990). Extensive is the term applied to all other presentations of the disease. SCLC is an aggressive disease, in which limited stage is more curable than extensive-stage disease. Prior to the use of chemotherapy, patients diagnosed with limited-stage disease survived about three months. Median survival with chemotherapy is 10-14 months, with a five-year survival of 2%-8% (Murren et al., 2000). SCLC exhibits a high degree of neuroendocrine differentiation with expression of a wide variety of neuropeptides and neuropeptide receptors. Several of these neuropeptides have mitogenetic potential and have been shown to be mediators of SCLC proliferation.

Staging of Lung Cancer

Staging is a major indicator of prognosis and treatment for lung cancer. The International System for Staging Lung Cancer was adopted by the American Joint Committee on Cancer and the International Union Against Cancer in 1986 as a means of unifying variations in definitions and providing consistent meaning and interpretation among clinicians and scientists throughout the world. The system was revised in 1996 to improve the rules for TNM subsets and incorporate a new schema for regional lymph node mapping (Mountain, 1997).

The primary tumor is subdivided into four categories (T1-T4) and reflects size, site, and local involvement. Lymph node spread is subdivided into bronchopulmonary (N1), ipsilateral mediastinal (N2), and contralateral or supraclavicular disease (N3). Metastatic spread is either absent (M0) or present (M1) (Ginsberg et al., 2001). The purpose of clinical stage classification is to facilitate the accurate, concise description of the extent of disease in a way that can be communicated and replicated (the TNM classification) and to facilitate comparison of differing therapeutic approaches by combining patients with certain common attributes (TNM subsets) into groups or stages with generally similar prognoses and treatment options (Mountain, 2000). Four stages of lung cancer have been identified depending on the presentation at diagnosis, and treatment is prescribed accordingly. The accuracy of the system in predicting survival has been confirmed by many investigators (Ginsberg et al.).

The International System for Staging Lung Cancer is relevant for classifying the major types of lung cancer. Even though SCLC stages commonly are designated as either "limited" or "extensive" diseases, the TNM system can be useful and often is required for participation in multimodality programs or clinical trials (Mountain, 1997).

Prognostic Factors

Clinical stage is the most important prognostic indicator for lung cancer survival. The size and location of the tumor at the time of diagnosis is tied directly to the ability to achieve cure. Other factors have been known to affect survival. Male gender and age greater than 60 years have been found to adversely affect survival. Numerous studies have shown that women generally survive longer than men (Baldini & Strauss, 1997). Tumor expression of mucin, seen in adenocarcinoma, has been identified as an adverse factor in early-stage disease because mucin may facilitate formation of metastases. In those with advanced stages at diagnosis, performance status, weight loss, and elevated serum lactate dehydrogenase have been associated with poor outcomes, whereas histologic subtype is of no prognostic importance (Ginsberg et al., 2001).

The significance of specific metastatic sites is unclear, although presence of liver and bone metastases is reported to be associated with shorter survival. Total number of metastatic sites or degree of tumor burden does seem to be associated with survival. This is most clearly evident in the longer duration of survival associated with a single site of metastasis (Ginsberg et al., 2001).

Advances in molecular testing have produced a variety of novel potentially useful prognostic factors. The connection between activated oncogenes and loss of tumor suppressor gene function offers targets for determining prognostic outcomes. These targets include the significance of the presence of epidermal growth factor receptors on lung cancer cells, neuroendocrine markers, blood group antigen, and genetic markers such as K-ras mutations, p53 mutations, bcl-2 expression, Fas expression, and angiogenic indicators, to name a few (Ginsberg et al., 2001).

Histogenesis

More than 90% of primary lung cancers begin with an epithelial stem cell in the bronchial epithelium (Elpern, 1993) (see Figure 1-1). This stem cell normally differentiates to those cells found in the tracheobronchial tree, including pseudostratified reserved cells, ciliated goblet columnar cells, neuroendocrine cells, and pneumocytes lining the alveoli (Ginsberg et al., 2001). The columnar epithelial cells line the area from the trachea to the terminal bronchioles resting on a basement membrane. Some of these cells are ciliated, and some are mucin producing (goblet cells). Between the columnar cells and the bronchial lumen are the smaller, shorter basal cells, some of which differentiate to become columnar cells. Others contain secretory granules and are thought to have a neurosecretory or endocrine function (Elpern)

Normal bronchial epithelial cells function as a lining and offer protection to the tracheobronchial tree. As a protective layer, the bronchial epithelium is continually damaged, shed, and replaced. Cellular abnormalities occur as the epithelium is chronically exposed to irritating inhaled substances, as most commonly is seen with tobacco smoke (see Figure 1-2). Exposure of the cell results in various combined genetic mutations that contribute to malignant transformation, taking a normal cell through the morphologic evolution of hyperplasia; metaplasia; mild, moderate, and severe dysplasia; carcinoma in situ; and invasive carcinoma (Ginsberg et al., 2001).

Short-term exposure to irritants changes ciliary structure and function and leads to mucous cell hyperplasia and hypersecretion of mucus. With continued exposure, ciliated cells are repeatedly damaged and shed from the basement membrane, leading to basal cell hyperplasia. Repeated insult causes the rapidly proliferating basal cells to become less able to differentiate, leading to squamous cell metaplasia. The protective ciliated and mucus-producing cells are replaced by these dysplastic cells, allowing even greater exposure to irritants and carcinogens. Even at the point of squamous metaplasia, injury is reversible if the cause is removed. With continued exposure, atypia of the cell progresses, leading to intraepithelial carcinomas in both bronchi that do not invade the basement membrane (carcinoma in situ). Although not all of these cells progress to become invasive tumors, over time, many invade through the basement membrane with downgrowth of the tumor. Continued replication of mutant cells results in progression through carcinogenesis with further proliferation, angiogenesis, metastasis, and resistance (Sekido, Fong, & Minna, 2001).

Transformation of the bronchial epithelium occurs over extended periods of time, usually several decades, and depends on the duration and degree of exposure to lung irritants and carcinogens (Elpern, 1993). However, only 5%-10% of heavy smokers develop lung cancer, implying a genetic susceptibility (Deveraux, Taylor, & Barrett, 1996). Genetic susceptibility may involve individual variability in genes that encode proteins that are responsible for activation and detoxification of environmental carcinogens. An inherited variability also may exist in the tumor suppressor genes and oncogenes, which also influence a person's susceptibility to developing lung cancer (Deveraux et al.). Chapter 2 will further discuss the genetic development of lung cancer.

References

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