Primary Care Physicians and the Fight Against Lung Cancer
January 1, 2007 54 minutes read
Primary Care Physicians and the Fight Against Lung Cancer
Authors: Yolanda L. Colson, MD, PhD, Women's Lung Surgery Program, Gretchen and Edward Fish Center for Women's Health, and Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA; Jason Sanders, Women's Lung Surgery Program, Gretchen and Edward Fish Center for Women's Health, and Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA; Laura Nason, Division of Thoracic Imaging, Department of Radiology, Brigham and Women's Hospital, Boston, MA; and Francine Jacobson, MD, MPH, Division of Thoracic Imaging, Department of Radiology, Brigham and Women's Hospital, Boston, MA.
Peer Reviewer: Hemant M. Shah, MD, FACP, FCCP, Associate Professor of Medicine, Wright State University, Dayton, OH; Director, Coronary Care Unit, Kettering Medical Center, Kettering, OH.
In 1912, the distinguished pathologist Isaac Adler questioned, "Is it worthwhile to write a monograph on the subject of primary malignant lung tumors? There is nearly complete consensus that primary malignant neoplasms of the lung are among the rarest forms of disease."1 Unfortunately, this fact no longer represents the truth today. This year, lung cancer will kill more men than prostate, colon, rectal, and pancreatic cancers combined, and more women than the total from breast, uterine, and ovarian cancers. While it represents only 12.5% of cancer diagnoses, lung and bronchus cancers will account for 28.8% of cancer deaths. Only 15% of patients diagnosed with this disease will be alive five years after diagnosis.2
Although it is known that cigarette smoking is the most prevalent risk factor for lung cancer, other risk factors are important. It is notable that 10% of men and 20% of women with lung cancer never smoked, and that nearly half of patients are former smokers.3,4 Subsequently, when a patient presents with symptoms or incidental radiographic findings that are consistent with lung cancer, it is important to identify the patient's individual risk factors and radiographic features that may warrant further evaluation. Ultimately, a tissue diagnosis and staging studies will be required to determine the best treatment for most patients. Prompt referral for early diagnosis and treatment by pulmonologists, thoracic surgeons, and medical and radiation oncologists may give patients the best chance of survival and improved quality of life. Throughout the disease process, primary care physicians (PCPs) play a critical role in prevention, smoking cessation, proper referral, and coordination of care between specialists, ancillary services, and patients themselves. Facilitating these patient-centered interactions will lead to more favorable outcomes by saving lives, increasing survival, and maximizing quality of life for the individual patient.
By identifying the risk factors, prevention strategies, and common and uncommon risk factors for lung cancer, this article will help PCPs become more attuned to the prevention and early recognition of potential cases. This should enable PCPs to hasten referral and treatment to maximize the chance of a cure. Indications for referral, current diagnostic procedures, and treatment strategies are well outlined, empowering PCPs to become key players in the diagnosis, management, and support of lung cancer patients. By providing better medical, psychosocial, and supplementary services for these patients, survival and quality of life may be significantly improved, allowing patients to combat the stigma of lung cancer that currently halts progress in treatment of this disease.
—The Editor
Epidemiology
Incidence, Mortality, Gender, and Race. There will be an estimated 174,470 cases (92,700 male and 81,770 female) of cancer within the lung and bronchus diagnosed in the United States this year. Only prostate cancer in men and breast cancer in women will be diagnosed more often, however, none will be more lethal. While lung and bronchus cancers, collectively known as lung cancer, will account for 12.5% of cancers diagnosed in 2006, lung cancer will account for 28.8% (162,460) of cancer deaths, far exceeding deaths due to any other cancer. Lung cancer will claim more men than colon, rectal, prostate and pancreatic cancers combined, and more women than the combination of breast, uterine, and ovarian cancers.2
Gender differences in incidence and mortality trends are marked. The incidence in men was relatively stable around 100/100,000 during the 1980s, but declined to 90.1 between 1998 and 2002. In contrast, the incidence of lung cancer continued to rise in women, reaching 54.6 in 2002.2,5 Alarmingly the incidence of lung cancer in women rose more than 600% from 1950-1997,6 and it is estimated that this rise will continue until 2010.7 Of the five leading cancers in women, lung cancer is the sole cancer whose mortality has risen appreciably in the past 50 years.
Incidence and mortality of lung cancer vary by race as well. (See Table 1.) While white and African American women have similar rates of disease, those of Asian American/Pacific Islanders, American Indian/Alaskan Natives, and Hispanic/Latino women are lower. African American and white men have the first and second highest incidence rates, respectively, of any racial group, and Hispanics have the lowest rates.2 Although rates in American Indians/Alaskan Natives are low overall, they vary widely geographically, with high rates in Alaska and low rates in New Mexico.8
| Table 1. Lung and Bronchus Cancer Age-Standardized Incidence and Death Rates in the United States 1998-2002* |
|
Survival is influenced by multiple factors and has increased over time. Between 1975 and 2000, the overall 1- and 5-year survival rates for lung cancer at all stages rose from 37% to 42% and 12% to 15%, respectively.2,9 Of all major cancers, lung cancer had the lowest 5-year survival (1995-2001) at 15.3%. This is likely reflective of the late stage of disease found at diagnosis in the majority of patients rather than a specific characteristic of lung cancer. As will be discussed in more detail under treatment, 10-year survival for early stage disease ranges from 92%-47% depending on size and other histologic factors.10,11 Unfortunately, more than two-thirds of lung cancers are diagnosed as regional or distant disease where the 5-year survival is 16.2% and 2.1% respectively.12 Gender differences also play a role in survival as women have better survival at every stage compared with men.13 Although Caucasians exhibit better overall survival than African American patients (16% vs. 13%),2 the cause of this disparity is unclear. It is likely a combination of differential access to care14 and differences in treatment.15
Histology
Lung cancer is divided into two main categories based on histology: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). (See Table 2.) NSCLC is subdivided into large cell carcinoma (LCC), adenocarcinoma (AC), or squamous cell carcinoma (SCC). Bronchoalveolar carcinoma (BAC) can occur in a "pure" form or in the setting of adenocarcimona and is also included within NSCLC. Small and large cell carcinoma are diagnosed equally often in both genders (20% and 11%, respectively). Men develop squamous cancers (36.3%) slightly more often than adenocarcinoma (33.2%), while women are diagnosed with AC more than twice as often as SCC (44.7% vs. 21.4%). SCC was the most prevalent type of lung cancer for decades and was most strongly associated with smoking, whereas AC has recently become the most prevalent type. The incidence of AC has risen over the past 25 years while that of all other types has fallen.13 Bronchoalveolar carcinoma has become an increasingly prevalent diagnosis, notable due to its overall better survival rate16 and response to new targeted chemotherapy.17,18
| Table 2. Lung Cancer Histologic Types |
|
Risk Factors
Tobacco Smoke. The greatest risk factor for lung cancer is smoking. The relative risk (RR) of lung cancer from smoking has regularly been shown to be in excess of 20.19 Although both active and passive exposure to cigarette smoke is the greatest risk factor for developing lung cancer, it is crucial to realize that 10% of male and 20% of female patients diagnosed with lung cancer are non-smokers and do not have any known exposure.7 Approximately 27% of lung cancer cases in non-smokers are attributable to environmental tobacco smoke (ETS), notably from occupational environments or spousal smoking habits.9 Multiple pooled and meta-analyses conclude that ETS elevates lung cancer risk by 25%20-22 depending on location of exposure and gender.23,24 Many service occupations, which employ a greater number of women, expose individuals to greater than normal amounts of ETS. Restaurant and drinking establishment employees encounter 1.5 to 6.1 times more ETS than the general population,25 while flight attendants were previously exposed to 14 times more ETS.26 Surprisingly, a RR of 2.4 has been reported for non-smoking women with > 22 years of household exposure.27 Although risk of lung cancer does not appear to be elevated in children exposed during pregnancy.28 in utero and newborn exposure to ETS is positively associated with low birth weight, asthma, otitis media, respiratory tract infections, decreased lung growth, and sudden infant death syndrome.29-31
It is important to realize that approximately 50% of patients with lung cancer are former smokers, having quit smoking prior to diagnosis.4 This is significant because smoking cessation at any point is beneficial, and cessation of more than 16 years can reduce risk by 5- to 10-fold depending on previous smoking history.32 Patients must know that their risk decreases immediately following cessation and continues to fall over time, although their risk will never be as low as that of a person who never smoked. Any smoking history still poses a risk, warranting high clinical suspicion for the development of lung cancer in any former smoker.
Asbestos and Radon. Asbestos exposure has been associated with an increased risk of lung cancer for more than 50 years.33 Risk is greatest 30-35 years after initial exposure,34 although the magnitude of risk varies with length and severity of exposure, and increases given a history of smoking.35 Radon is a ubiquitous, naturally occurring gas and an acknowledged carcinogen due to its production of radioactive compounds upon decomposition.36 As with asbestos, radon exhibits a dose-response relationship and increases risk synergistically with smoking.37 It is thought that radon may pose particular risk to women given their traditional work in the home, which often involves washing clothes in less well ventilated areas (such as the basement) where radon levels are higher.
Metals and Chemicals. Arsenic exposure from mining, non-ferrous smelting, fur handling, manufacturing of sheep-dip compounds and pesticides, and vineyard-related jobs also increases risk.38,39 Occupational exposure to chromium from chromate production, zinc chromate pigment, chromium electroplating, and ferrochromium alloy products elevates lung cancer risk,40 as does contact with oxidic and sulfidic nickel compounds during industrial production.41 Individuals, particularly smokers, with significant occupational exposures to these materials should be monitored for the development of lung cancer and other cancers due to the broad carcinogenicity of these compounds.
Bis chloromethyl ethers (BCME) are used industrially as chemical intermediates during organic chemical production. Workers exposed to BCMEs have high rates of lung cancer, possibly due to the ease with which BCME vapor mixes with air.40 Similarly, there has been concern that exposure to polycyclic aromatic hydrocarbons (PAHs) modulates risk for lung cancer due to their widespread production as byproducts of incomplete combustion. Excess risk of lung cancers in certain occupational cohorts due to PAHs has been noted but not proven.40
Other Lung Diseases. Chronic obstructive pulmonary disease (COPD) increases risk for lung cancer by approximately 4-fold.42 Prior bronchitis, asthma, emphysema, hay fever, and pneumonia may modulate risk, although studies are inconclusive due to confounding and multiple sources of bias.43-46 Repeated challenge from tobacco smoke and respiratory disease could act synergistically to augment lung carcinogenesis.47
Prior Breast Cancer. Prior cancer treatments can also affect the risk of lung cancer. Patients who have been treated for prior breast cancer, predominantly women, are at increased risk for lung cancer. This risk increases slightly over time following breast cancer diagnosis48 and also varies with age at the time of breast cancer diagnosis, such that women diagnosed with breast cancer before age 50 are about twice as likely to be subsequently diagnosed with lung cancer at a later date than women diagnosed after age 50 or those without breast cancer.48,49 Increased risk of lung cancer following a breast cancer diagnosis has been attributed to radiation exposure during treatment, predisposing genetic factors, or environmental or behavioral risks held in common between breast and lung cancers. Studies have shown that prior radiation treatment for breast cancer increases the risk for lung cancer by 62% within 10-14 years following breast cancer treatment and 49% within 15 or more years.50 The dose responsiveness of this risk was validated with the observation that patients receiving lower doses of radiation (following lumpectomy) were at less elevated risk for lung cancer than patients receiving higher doses of radiation (following mastectomy).51 Additionally, the risk of a fatal lung cancer following radiotherapy is 42% higher in the lung ipsilateral to the prior breast cancer than in the contralateral lung. It is for this reason that an isolated lung nodule identified in patients with a prior history of breast cancer cannot be assumed to be metastatic breast cancer, especially if in the ispilateral lung, and a tissue biopsy for diagnosis should be considered.52
Dietary Factors. Micronutrient studies show protective effects from isothiocyanates and carotenoids in the form of fruits and vegetables,53,54 but there is significant debate over the effects of retinoids. Although large cohort studies such as the Physician's Health Study and Women's Health Study show no effect,55,56 phase III trials including the Beta-Carotene and Retinol Efficacy Trial (CARET), the Alpha-Tocopherol, Beta-Carotene (ATBC) Prevention Trial, and the Intergroup Lung Study have all pointed to a deleterious effect of retinoids in smokers but a protective effect in nonsmokers.57-59 The verdict on retinoid involvement in lung cancer is complicated by discussion over proper dosage, duration of the trials, and the isomeric form used,60 and thus retinoids currently are not recommended.
Gender and Hormones. Although gender differences in histology and disease outcomes are well established, the role of exogenous hormones in lung cancer is unknown, partly due to bias and poor control of confounding variables in published studies. One study demonstrated a potentially protective effect of oral contraceptives or hormone replacement therapy (HRT) but only in female smokers,61 whereas other studies have documented a slight or no association between HRT and lung cancer.62,63 Still others argue that HRT may decrease survival in patients who have already developed lung cancer,64 or that risk modification depends on the form or mode of exposure.44
Similarly, the impact of endogenous hormones status (i.e., menopause) is unknown. While initially believed that women with menopause before age 40 had a 70% decreased risk for developing adenocarcinoma,65 more recent studies have demonstrated that age at menopause or menarche, duration of the menstrual cycle, and the number of births had no association with the development of lung cancer.61 In contrast, however, pre-menopausal women with lung cancer do have a survival advantage compared to post-menopausal women, and post-menopausal women exhibit better survival than men of similar age. Of interest, despite their better survival, pre-menopausal women presented with more advanced disease and required more extensive surgical resection, suggesting that hormonal status may play a role in disease progression and response to treatment. It is also important to consider the population bias that may be present because pre-menopausal women would be expected to have fewer comorbidities, and since clinical suspicion would be low,66 would most likely be diagnosed late, only after symptoms developed.
Family History, Genetic, and Molecular Risks. Not all smokers develop lung cancer even when controlling for smoking exposure, suggesting that individual genetic differences in carcinogen metabolism, DNA repair capacity, and cell cycle control play a significant role in the susceptibility to lung cancer.67,68 A primary example is the difference in DNA repair capacity exhibited by women and the possible increased susceptibility to lung cancer despite similar exposure to tobacco smoke.69-71 Similarly, the clustering of lung cancer cases in some families has lead to the discovery of chromosomal susceptibility loci,72 and numerous genes have been associated with increased risk for the development of lung cancer, propensity for metastasis, and other processes along the pathophysiologic pathway.73 In addition to quantifying risk more accurately, modern genomic techniques hold the promise of early cancer detection, individualized tumor classification, and prediction of endpoints, such as metastasis, recurrence, response to therapy, and survival time.73-78
Prevention and Smoking Cessation
Primary care physicians are uniquely poised in the fight against lung cancer as a result of their long-term, close contact with patients that allows for regular, personalized education and risk assessment. Recommendations leading to behavior modification can decrease lung cancer risk and save lives. Primary prevention focuses on smoking cessation and maintenance of a smoke-free lifestyle, including advocating a smoke-free home for non-smoking spouses of smokers. Smokers unwilling to quit should be repeatedly informed of the immediate cardiac, vascular, and pulmonary benefits of cessation to both themselves and their families. Continued refusal to stop smoking should be met with robust motivational strategies that include identification of defined barriers to successful cessation and their solutions. Often the highest rates of permanent cessation occur when the patient, family member, or close friend has been diagnosed with lung cancer. This opportunity should be utilized to promote smoking cessation. When a smoker indicates willingness to stop smoking, physicians should provide the highest level of support possible: i.e., choose a date to quit, prescribe cessation medications and therapies such as nicotine gum, transdermal patches, nasal spray, mouth inhaler, lozenges, sublingual tablets, or bupropion, in concert with physician encouragement and behavioral modification techniques to prevent relapse. It is also important to keep abreast of new cessation therapies as a recent clinical trial demonstrated varenicline was more effective than bupropion and placebo in producing sustained abstinence from smoking.79
Primary care physicians play a unique and crucial role in winning the battle against lung cancer through their interaction with adolescents as well. Physicians can underscore "teen sensitive" anti-smoking messages such as the negative impacts of tobacco on appearance, premature aging and discoloration of skin, teeth, and finger nails, bad breath, chronic cough and wheezing, personal finances, and athletic abilities. For both adult and adolescent smokers, offering multiple smoking cessation methods is important. Frequent office visits with inquiry into smoking status and accountability are powerful tools to help with cessation. Continued praise for patients who have quit and regular assessment of their need to maintain a smoke-free lifestyle are essential.
Smoking cessation methods have proven to be successful. Greater than six-month quit rates vary by intervention, but all show improvements vs. control.80,81 Twelve-month cessation rates can be as high as 35.5% for the nicotine patch plus bupropion, 30.3% for bupropion alone, and 16.4% for the patch alone.82 It is crucial to note that versus no clinician intervention, 5-month cessation rates rose by 10% with self-help intervention, 70% with non-clinician intervention, and 120% with physician intervention,83 illustrating the value of physician involvement in smoking cessation. An often-overlooked resource is smoking quit-lines, whose cessation rates are only slightly less than those of nicotine replacement therapy.84
Given the established success of multiple smoking cessation interventions, physicians perform inadequately when noting smoking status, advising and providing counseling, and prescribing cessation medications.85 A disparity in physician attitudes toward women and elderly tobacco users continues as well: both groups are far less likely to receive prescriptions for cessation medications.86 This is particularly worrisome if recent reports are true regarding women's increased susceptibility to tobacco smoke.
Limiting exposure to other risk factors is also important. For smokers and others concerned about lung cancer, discussion about personal risk from prior breast cancer treatment or occupational exposures is warranted, as is explaining that any association between lung cancer and HRT, diet, and other risk modifiers is not fully understood. Stressing healthy diet and lifestyle is a given and will yield benefits above and beyond reduction of lung cancer risk. Patients interested in their own risk can be referred to risk calculators available through the Internet, such as the Memorial Sloane Kettering Lung Cancer Risk Assessment Tool87 or the Your Disease Risk calculator from the Harvard Center for Cancer Prevention.88
Secondary prevention has focused on screening using non-invasive diagnostics (discussed in more detail later). There is currently no official recommendation for population screening for lung cancer; however, the results from the International Early Lung Cancer Action Program (I-ELCAP) modeling study are promising, illustrating a projected 92% 10-year survival following resection of screen-detected early lung cancers.11 However, the I-ELCAP study model does not address the issue of disease specific mortality benefit from lung cancer screening with computed tomography (CT). The National Lung Screening Trial (NLST) currently being undertaken by the National Cancer Institute (NCI) and the American College of Radiology Imaging Network (ACRIN) is following more than 53,000 high-risk individuals (minimum 30 pack-years history) aged 55-74 years to answer this question. NLST participants were randomized into two groups to receive low-dose CT of chest or chest radiograph as their primary screening modality for baseline prevalence, followed by two annual incidence screens and biospecimen collection. In addition to analyzing mortality, the NLST will describe cost and psychosocial factors associated with screening, key issues in the consideration of implementing screening guidelines, and aid in the search for lung cancer biomarkers.
Until the data from the NLST are available, the decision to be screened for lung cancer with CT is up to the individual in consultation with his or her physician. Patients must be prepared to assume a significant portion of the responsibility for their decision and financial responsibility for the test because it often is not reimbursed by third-party payers. Patients interested in the study should be referred to an imaging center with extensive experience in performing "screening CT" examinations and risk assessment.
Pathophysiology and Clinical Presentation
The clinical presentation of lung cancer varies widely and can include seemingly unrelated symptoms. (See Table 3.) Patients with early disease are often initially asymptomatic, developing symptoms only as the disease grows to involve local airways, extends into nearby structures, or metastasizes. Unfortunately, the majority of patients present with advanced disease, and common symptoms include cough, hoarseness, dyspnea, fatigue, hemoptysis, or chest, shoulder, or rib pain. Notably, nearly half of patients note a cough, and 20-30% of patients have greater than a 10% weight loss at presentation.89 Many patients will have persistent cervical or supraclavicular lymphadenopathy on exam.90,91 Approximately one-third of patients show clinical manifestations of metastatic disease, consistent with the fact that 40% of NSCLC patients are diagnosed at Stage IV. Asymptomatic patients comprise 2-15% of NSCLC cases.92-94 Alternatively, they may develop a paraneoplastic syndrome. There are a myriad of paraneoplastic conditions associated with lung cancer, although they occur in fewer than 2% of cases, most of which are SCLC. Paraneoplastic symptoms typically develop before diagnosis but usuallyare associated with advanced disease. Identification and proper interpretation of these syndromes can result in earlier diagnosis and allow for more effective treatment to be administered at an earlier stage.
| Table 3. Potential Symptoms of Lung Cancer |
|
When assessing a patient whose differential diagnosis includes the possibility of lung cancer, a physician cannot be overly cautious. Prompt referral of a patient with potentially resectable disease to a thoracic surgeon can result in diagnosis and treatment an average of two months earlier, a critical fact given the direct link between stage at diagnosis and survival. As the first medical professional with the opportunity to suspect lung cancer, the PCP has a direct effect on patient outcome. A PCP failing to consider a diagnosis of lung cancer or unknowingly dismissing the need for further diagnostic tests can lead to litigation and cost the patient valuable time and perhaps his or her life.
Definition of Lung Cancer Staging. PCPs should be familiar with the International System for Staging Lung Cancer to facilitate ease of communication with patients and specialists. The system utilizes the TNM staging classifications based on the size of the tumor (T), involvement of lymph nodes (N), and presence or absence of distant metastases (M). The TNM stages can be correlated to conventional Stages I-IV in NSCLC. (See Table 4.) The majority of NSCLC patients present with advanced disease (35% Stage IV and 40% Stage III), while only 25% present with early localized disease (Stage I or II).95
| Table 4. The International System for Staging Lung Cancer, TNM Classifications |
|
SCLC is classified as either limited or extensive disease. Limited disease involves the ipsilateral hemithorax within a single radiation port. In contrast, extensive disease involves tumor extension beyond these margins, and metastases are always considered evidence of extensive disease. Sixty percent of SCLC patients present with extensive disease, since SCLC has commonly metastasized at the time of presentation. It is for this reason that SCLC is usually not considered a surgically resectable disease.95
Radiographic Assessment. Lung cancer is visualized on diagnostic scans either as an incidental finding or as the focus of radiographic assessment. The probability of malignancy for an incidental mass will determine whether further diagnostic work-up is necessary, while extent and location determines which invasive diagnostic method or treatment modality will be used. Generally, radiographic assessment of lung cancer involves the identification of a solitary pulmonary nodule (SPN), commonly in asymptomatic patients, or a detailed imaging of a more extensive mass and perhaps associated lesions in symptomatic patients. For most patients diagnosed with lung cancer, the disease is recognized only after they have developed symptoms. In patients complaining of cough, the clinician must determine whether there are other explanations for this symptom and whether the cough is persistent. Patients with chronic cough may describe a change in the quality of their cough that relates to a new lung cancer. Imaging evaluation should be considered in those with cough that is unexplained, new, changed, or persistent. In any symptomatic patient, it is essential to assess the possibility of lung cancer with more sensitive and specific diagnostic scans. In patients presenting with dyspnea, chest pain or hemoptysis, it is appropriate to obtain a chest x-ray (CXR) initially. However, hemoptysis can be a sign of a small, potentially curable cancer that often is missed on CXR, and thus further work-up with a chest CT scan and bronchoscopy is warranted.91
Lung Nodules Identified on Chest Radiograph. When a pulmonary nodule or mass is detected incidentally on a chest radiograph, the probability of malignancy must be assessed. Clinicians should consider a number of factors that affect the likelihood of malignancy, including the radiographic appearance of the nodule, the patient's risk factors, and any associated symptoms. Lung lesions that measure > 3 cm in diameter are defined as lung masses and have a very high rate of malignancy. Solitary pulmonary nodules (SPNs), which are identified in up to 1 in 500 chest radiographs, are a much greater diagnostic challenge .96 SPNs are intraparenchymal lesions < 3 cm in diameter that are not associated with atelectasis, lymphadenopathy, or pneumonia. The differential diagnosis of an SPN is broad and includes neoplastic, infectious, inflammatory, vascular, traumatic, and congenital lesions. The percentage of nodules that ultimately prove to be malignant varies between studies and is dependent upon the patient population. Reports have shown that 35% of nodules < 1 cm represent a primary malignancy, while 23% are solitary metastases.97,98
The diagnosis of lung cancer by CXR is very difficult to make in many cases. Most SPNs are not visible on radiographs until they are at least 9 mm in diameter.99 Even larger nodules can be missed easily, especially when there are no prior chest x-rays available for comparison or when they are obscured by overlying structures. An error rate of 20-50% in the diagnosis of early lung cancer from chest radiographs is common.100 Failure to recognize a SPN on chest x-ray can lead to a substantial delay in diagnosis of a malignancy,101 possibly with tragic results when a cancer progresses to a more advanced stage where cure or long-term survival is unlikely. For this reason, it is imperative that chest radiographs are reviewed using a systematic search pattern and always compared to previous imaging if available, since SPNs often are identified solely because of changes compared to prior radiographs.
Evaluation with Computed Tomography. Chest CT scans offer significantly greater detail about SPNs and lung masses, help in the assessment of relative risk of benign vs. malignant lesions, identify involved structures and extent of disease, and also may identify associated nodules, adenopathy, or pleural or pericardial effusions. The chest CT scan is critical in the assessment of surgically resectable lesions. There are several characteristics that classically are associated with benign vs. malignant nodules. (See Table 5.) Information regarding nodule size, attenuation, edge characteristics and the presence of calcification, fat, or cavitation is best described using thin-section CT.
| Table 5. General Characteristics of Benign and Malignant Nodules Identified on Chest Readiographs or Computed Tomography |
|
A benign pattern of calcification, such as central, diffuse, laminar, or popcorn pattern, indicates an exceedingly low chance of malignancy, however not all benign lesions exhibit such calcification.102,103 Other patterns of calcification, such as eccentric or stippled patterns, may be seen in both benign and malignant lesions and should be considered indeterminate findings. Although studies have shown that calcification is present in approximately 10% of lung cancers, it is uncommon in cancers < 3 cm in diameter.104 Importantly, a nodule may falsely appear to contain calcification on a chest x-ray and therefore, CT imaging should be used to confirm the presence and pattern of calcification.
The absence of growth of a lung nodule over a two-year period traditionally has been another reliable predictor of benign disease.105 The majority of malignant lesions have doubling times between 1 month and 12 months, while benign lesions typically have doubling times that are less than 1 month or longer than 16 months.96,105 Recent studies have shown, however, that there may be a wider range in the doubling times of malignancies than originally thought as cases have been reported in which malignancies were found with doubling times ranging from 1 month to virtually no detected growth over a prolonged period of time.106,107 In addition, it is important to note that radiographs are not as sensitive to increases in nodule size as CT. Though a nodule may increase in diameter by only a few millimeters, the volume may have doubled, and this is best assessed using CT.
Air bronchograms and irregular, spiculated, or lobulated edges are more common in malignant than in benign lesions.96,103,105,108,109 Cavitation may occur in both malignant and benign lesions, however, wall thickness and appearance may aid in the differentiation. The majority of nodules with cavitation and wall thickness > 15 mm are malignant while the majority with wall thickness < 5 mm are benign.110 Partly solid nodules are more likely to be malignant than are nonsolid nodules, and solid nodules are the least likely to be malignant. However, since the vast majority of all nodules are solid, most lung cancers are found in a solid nodule.96 The presence of fat in a nodule is generally reassuring, especially if there is no prior history of malignancy, since fat is highly suggestive of benign lesions such as hamartomas, although one must remember that metastases from liposarcoma also may contain fat.96,105
Despite the association of specific characteristics with benign lesions, these characteristics cannot be followed dogmatically. Figure 1 demonstrates that lung cancers come in many shapes and appearances. Even in the setting of benign characteristics, the index of suspicion for any SPN or lesion must remain high. If symptoms, increased growth, or significant risk factors also are present, referral to a thoracic surgeon should be considered seriously.
| Figure 1. CT Scans Demonstrating Spectrum of Findings in Early Lung Cancer |
|
| Images from CT scans demonstrating spectrum of findings in early lung cancer. A: Smoothly marginated small soft-tissue nodule. B: Well-demarcated ground glass opacity without solid component, also called non-solid nodule. C: Small soft-tissue nodule accompanied by ground glass opacity, also called part-solid nodule. D: Soft-tissue nodule with small cysts and spiculated margins; the peripheral portion of this opacity may include post-obstructive pneumonia. |
In addition to chest radiograph and CT, the imaging evaluation of an SPN may include positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG). FDG is taken up by cells in glycolysis and increased activity is demonstrated in cells with high metabolic rates, as is seen in tumors or infectious/inflammatory lesions. One meta-analysis estimated the sensitivity of PET to be approximately 96.8% and the specificity to be approximately 77.8% for detecting malignancy.20 Given this high sensitivity, PET and combined PET/CT may be useful in patients with a relatively low pretest likelihood of malignancy. In these patients, a negative PET evaluation may make radiographic follow-up a reasonable option in an otherwise benign appearing lesion. However in patients at high risk or in a lesion with a high likelihood of cancer, a negative PET should not change management, and these patients likely still will need a tissue diagnosis. PET should be included in a patient's workup only if the findings may change patient management and are used to assess for evidence of metastatic disease. Limitations of PET include poor resolution for SPNs < 1 cm, a high false-negative rate in carcinoid or bronchoalveolar tumors and a high false positive rate in inflammatory conditions such as sarcoidosis or TB, etc.111
Referral to Pulmonologist, Thoracic Surgeon and/or Medical Oncologist
Referral to a specialist is warranted for further evaluation using invasive or non-invasive diagnostic tests whenever there is a suspicion of lung cancer. (See Table 6.) In general, pulmonologists are particularly helpful with diagnosis of endobronchial lesions, management of underlying lung disease, and multiple small pulmonary nodules that often are present in conditions such as prior granulomatous infections or sarcoidosis. In contrast, patients with a suspicious SPN (see Table 6), especially with recent changes in size or character, are usually better served with direct referral to a thoracic surgeon (if available), whereas medical and radiation oncologists commonly treat more advanced malignant disease or disease deemed inoperable by a thoracic surgeon. Although the index of suspicion is significantly higher in patients with a smoking history, radiographically suspicious or progressive lesions in non-smokers must also be aggressively pursued, particularly if there is significant environmental tobacco smoke exposure. The Fleischner Society has previously published guidelines for the initial follow-up of incidentally identified SPNs.112 (See Table 7.)
| Table 6. Indications for Referral to a Specialist |
| • Spiculated lesions • History of malignancy • Recurrent hemoptysis • Puckering or invasive mass • Masses associated with adenopathy • A solid or partly solid solitary pulmonary nodule • New or progressive findings on subsequent radiographic studies • Unresolved abnormality after antibiotics or directed therapy • Persistent unexplained cough • Radiographic findings consistent with pneumonia in an asymptomatic, non-immunocompromised patient Consider referral: • > 6 mm nodule in a high-risk patient (current or former smoker significant past or family history, etc.) • > 6 mm nodule in any patient with "suspicious" features, symptoms, or growth • > 8 mm nodule in any patient |
| Table 7. Fleischner Society Guidelines for Follow-up and Management of SPNs23 |
|
The radiologic perspective of the guidelines must be augmented with a thorough risk assessment and a surgical perspective since earlier, aggressive resection recently has been demonstrated in a large clinical study to result in improved long-term survival.11 It is reasonable for a PCP to consider follow-up of an SPN with a chest CT alone if a lung nodule is less than 4 mm and the PCP is comfortable in the assessment of the patient's risk. Nodules up to 6 mm also may be followed with chest CT, although early referral to a thoracic surgeon for further invasive or non-invasive work-up should be made in high-risk patients, growing lesions, or if there is question of the nodule's potential for malignancy, since small peripheral nodules often are resectable via minimally invasive thoracoscopy near the 6 mm size. Serious consideration of prompt referral to a thoracic surgeon should be considered for lesions larger than 8 mm, especially in patients with an increased risk of malignancy. Early involvement of the thoracic surgeon in high-risk patients, or for suspicious or growing lesions can significantly decrease the time until surgical resection. This is a critical point, since recent studies show that surgical resection of early stage lung cancer shortly after identification can achieve 10-year projected survival rates as high as 92%.11
A diagnosis of lung cancer is not required for referral since the approach to biopsy varies dramatically with stage of the disease, resectability, location of the lesion, patient comorbidities, and areas of expertise at any given institution. Since surgical resection offers the best possible chance for cure, patients with suspicious lesions in the setting of significant risk factors should be evaluated by a thoracic surgeon for possible surgical resection, unless a tissue diagnosis of widely metastatic lung cancer has been obtained. Similarly, patients with multiple sites of disease and/or late stage disease should be evaluated by a medical oncologist and possibly a radiation oncologist after a tissue diagnosis has been obtained by a surgeon, pulmonologist, or with a needle biopsy. The use of surgery, chemotherapy, or radiation will depend on the symptoms, prognosis, extent of disease, response to therapy, and treatment options available to a particular patient given their comorbidities. Unlike locally resectable disease where surgical oncologists (surgeons) traditionally coordinate care, treatment for more extensive disease is coordinated by the medical oncologist, since chemotherapy is more commonly utilized in these patients. Treatment of extensive metastatic disease focuses on palliation of symptoms rather than cure. Primary care physicians play a vital role throughout this process from the initial identification of the lesion to appropriate and timely referral and provision of support for the patient after diagnosis. PCPs are particularly valuable to a patient with a poor prognosis by offering guidance to the patient, family, and specialty physicians during palliative and end-of-life care.113
Obtaining a Diagnosis
There are many diagnostic modalities available for obtaining a tissue diagnosis and staging patients, which are discussed below from least to most invasive. The least invasive technique is chosen that will provide adequate and definite results. If results are inconclusive, a more invasive technique is employed until a diagnosis is obtained. Because stage will determine therapy, it is prudent to seek the least invasive approach to obtaining a diagnosis of the lesion that is also indicative of the most advance stage rather than to biopsy all sites of disease. For example, both the diagnosis of lung cancer and metastatic (stage IV) disease can be determined by a single needle biopsy of a suspicious adrenal or bone lesion rather than performing a biopsy of a lung lesion to get the diagnosis of lung cancer, and subsequent lymph node, adrenal, and/or bone biopsies to establish widespread stage IV metastatic disease.
Fine Needle Aspiration (FNA). Also referred to as transthoracic needle aspiration biopsy, FNA uses fluoroscopy or CT guidance under local anesthesia to obtain a biopsy of a pulmonary, adrenal, or bone mass suspected of harboring cancer. Pneumothorax requiring a chest tube occurs in 10% of FNA cases.95 Sensitivity for diagnosis is very dependent on the characteristics of the lesion; although it can be as high as 90%, it is commonly lower. False positives occur in only 1% of cases, however false negatives occur in 25% of cases and are particularly high in cavitary and necrotic lesions where tumor cells are primarily within the thin wall. Abundant necrosis within tumors and ill-defined opacities with inflammatory cells in the surrounding parenchyma complicate the accurate identification of malignancy on FNA cytology.95 Because false negatives can be high, one cannot assume that failure to see malignant cells on FNA means that a malignancy is not present. An indeterminate result requires more in-depth investigation using a more invasive approach.94 Therefore, if a lesion warrants resection for a positive FNA but due to risk factors or radiographic appearance would also warrant a surgical biopsy even if the FNA is indeterminant, or if the likelihood of a diagnostic FNA is low, proceeding directly to a more invasive, yet more definitive and perhaps therapeutic approach, may be more appropriate and may expedite treatment.
Bronchoscopy. Bronchoscopy involves the visual inspection of the airway, bronchi, and bronchioles using an endoscope inserted through the nose or mouth. The procedure can be performed with the patient awake, under sedation, or fully anesthetized, depending on the patient's condition, risk of procedural morbidity, and planned extent of the procedure. Bronchoscopy is useful in the diagnosis, staging, and opening the bronchial tree when tumor is present. Various forms of bronchoscopic techniques can be used in combination to obtain a diagnosis, such as direct biopsy, transbronchial needle aspiration (TBNA), brushing, saline lavage, fluoroscopically guided biopsy, brushing, needle aspiration and endobronchial ultrasound for lymph node sampling.94 Not surprisingly, the ability to obtain a diagnosis via bronchoscopy is largely dependent on the location of the lesion in relation to the airway. The sensitivity of bronchoscopy for detecting central, large peripheral, and small peripheral (< 2 cm) lesions is 85%, 70%, and < 33%, respectively.95
Mediastinoscopy. Mediastinoscopy is utilized to access the middle mediastinum and, through a lighted scope, permits biopsy of ipsilateral and contralateral mediastinal lymph nodes associated with the lung lesion. This outpatient procedure is performed under general anesthesia. Mediastinoscopy can provide a histologic diagnosis if the lymph nodes exhibit tumor. Proper staging of localized or advanced disease is possible because tumor involvement in mediastinal nodes (N2 or N3) is indicative of stage III disease. Stage differentiation is important as early stage disease is potentially operable and shows better survival, while treatment for advanced disease utilizes adjuvant chemotherapy and radiation therapy with surgery playing a role in only select patients.94
Thoracoscopy. Excision of a suspected tumor is the most reliable means for diagnosis due to complete removal of the suspected nodule. Video assisted thoracoscopic surgery (VATS) or thoracoscopy is performed under general anesthesia utilizing single lung ventilation. Thoracoscopy is less invasive than a formal thoracotomy and can reliably diagnose and stage lung cancer. The tumor is most likely to be accessible via VATS if it is less than 3 cm in diameter and contained within the outer third of the lung, since VATS excision requires that a wedge of non-involved lung parenchyma surrounding the tumor be removed intact with the tumor.114 VATS also is useful for sampling ipsilateral mediastinal lymph nodes, assessing pleural effusions or disease, and in the biopsy of other intrathoracic masses that could be primary lesions or metastases from other tumors.94 Thoracoscopy is associated with very low mortality (< 1%), and acceptable morbidity (4-22% with minor complications). The length of hospital stay is generally two to four days. The majority of patients will resume their regular activities within one to two weeks, although recovery may be delayed by bleeding, prolonged air leak from the resection site, and post-operative complications such as pneumonia or respiratory compromise in patients with severe end-stage lung disease.115 Given that VATS resection of a lung lesion is also therapeutic, thoracoscopy with removal of the lesion is often the first choice for diagnosis if the lesion is small and there is no other evidence of disease.
Thoracotomy. Although 95% of patients with suspected lung cancer are diagnosed and staged without thoracotomy, it is nonetheless necessary for those patients in which diagnosis and/or staging cannot be determined using other procedures. Confirmation of unresectable T4 disease due to mediastinal invasion commonly calls for surgical exploration before deeming the patient non-operable. FNA core, open, or wedge biopsy can be achieved under direct vision with avoidance of vital structures to provide rapid pathologic diagnosis. If lung cancer is positively identified and the lesion is resectable, mediastinal lymph node sampling or total lymphadenectomy are necessary for decisive staging and prognosis.94
All surgical procedures require an assessment of risk both for general anesthesia and the ramifications of the planned procedure. The approach to diagnosis in a given patient often is dictated by risk of an operative intervention. The pre-operative evaluation required is dependent on the magnitude of the operation planned, but commonly involves some degree of cardiac risk assessment and pulmonary function testing. Such assessment involves close communication between PCP, pulmonologist, and surgeon, as the morbidity and mortality can differ widely between thoracoscopy with a wedge resection and a thoracotomy with a more aggressive lobe resection.
Treatment
Treatment depends on the stage and type of lung cancer identified, as well as patient characteristics such as co-morbidities, pulmonary reserve, and preconceived attitudes about lung cancer and cancer treatments. Treatments outlined herein follow guidelines and recommendations published by the American College of Chest Physicians (ACCP).116
Early Stage and Stage I NSCLC. Early stage lung cancer refers to limited non-invasive lesions within the airway. The ACCP defines early stage disease as a radiographically occult squamous cell carcinoma that is < 2 cm in surface area, appears superficial on endoscopy, has clearly visible margins, and has no invasion beyond the bronchial cartilage after pathologic assessment or non-invasive (CT) imagery. Early stage lung cancer can be treated using photodynamic therapy (PDT), brachytherapy, electrocautery, cryotherapy, and Nd-YAG laser therapy. These therapies typically have been used in the treatment of late and end stage cancer, they have emerged as options for very early stage endobronchial malignancies, particularly if surgical resection is not an option.117
Stage I lung cancer is more invasive and is classified as a T1 or T2 tumor in the lung parenchyma without nodal involvement. The primary tumor must not involve the chest wall or parietal pleura.118 (See Table 4 for tumor staging criteria.) Stage I NSCLC, therefore, potentially is amenable to surgical resection. All patients with stage I NSCLC should be evaluated for possible surgical resection because Stage I (A and B) NSCLC patients achieve the best survival and best chance of cure with aggressive surgical therapy. The extent of resection required depends on location, tumor size, and the ability of the patient to tolerate the "optimal" pulmonary resection, either due to cardiac co-morbidities or limited pulmonary reserve. When pulmonary function is adequate, a lobectomy or, if needed for complete resection, a pneumonectomy, is favored over a limited resection such as a wedge resection or segmentectomy since local recurrence rates are increased in the latter. Five-year survival following complete surgical resection varies from 54-92% for T1 tumors, and 38-68% for T2 tumors.71,119 Survival benefits of chemotherapy in the setting of surgically resected stage I disease have not been proven and use of these agents should be limited to within clinical trials.118,120 Limited resection in patients with poor pulmonary function and significant co-morbidities still offers improved survival over other treatment options and can avoid the potential complications of chemotherapy and radiation therapy or death from progressive disease. Proper pathologic staging in stage I disease requires surgical evaluation of hilar and mediastinal lymph nodes to rule out evidence of occult metastatic disease and the need for adjuvant therapy. Patients unable or unwilling to undergo surgical resection should be assessed for treatment via radiofrequency ablation, chemotherapy and/or radiation therapy after a tissue diagnosis and extent of disease has been determined.
Stage II NSCLC. Stage II NSCLCs include T1 or T2 tumors with N1 (hilar) nodal involvement or T3 tumors with negative lymph nodes (T3N0). No distant metastases are present. Therapy for stage II NSCLC follows much of the same guidelines as that for stage I disease, but stage II disease represents spread of disease to the nearby hilar lymph nodes. Again, the larger anatomic resection via lobectomy or pneumonectomy offers better survival, but five-year survival remains inferior to stage I disease, ranging from 39% for T2N1 disease to 52% for T1N1 disease.95 Most surgeons advocate the addition of a mediastinal lymphadenectomy or nodal sampling to improve surgical staging of mediastinal lymph nodes (and detect occult stage III disease), as well as radical lymphadenectomy to potentially decrease recurrence in these nodal stations. Adjuvant radiation for stage II N1 disease is acceptable in an attempt to prevent early recurrence, but risk vs. benefit should be discussed between the radiation oncologist and surgeon before proceeding.121 The American Society of Clinical Oncology (ASCO) reported results in 2005 from the National Cancer Institute of Canada Clinical Trials Group and the U.S. National Cancer Institute Intergroup Trial evaluating adjuvant chemotherapy in early stage NSCLC, concluding that adjuvant chemotherapies such as vinorelbine and cisplatin can significantly increase survival following surgery.122
Advanced NSCLC. Stage III and IV NSCLC is indicative of tumor extension beyond the immediate area of the ipsilateral lung to involve either more distal lymph nodes, vital structures, or, in stage IV disease, distant non-thoracic sites. In general, surgical resection alone does not result in prolonged survival and primary treatment is focused on chemotherapy and radiation therapy, with surgical resection utilized for post-treatment stage III salvage or palliative purposes.
Stage IIIA NSCLC. Stage IIIA NSCLC encompasses an assorted group of patients with ipsilateral N2 mediastinal lymph node metastases or T3N1 disease. Given the poor survival with surgical resection alone, these patients often are offered chemoradiation therapy as initial treatment, referred to as neoadjuvant or induction therapy. Patients who respond to combination chemoradiation therapy by reverting to negative lymph node status can undergo complete surgical resection, including lymphadenectomy, with significantly increased survival.123,124 Several randomized phase II and phase III trials including stage IIIA patients have suggested that induction therapy followed by surgery is of benefit, achieving overall two- and five-year survival rates of 42% and 28%, respectively.125-127 Patients with persistent N2 disease do not exhibit the same degree of benefit from surgery and may not be offered resection. Rather, patients with unresectable disease achieve the best results with combined chemotherapy and radiotherapy.128
Stage IIIB NSCLC. Stage IIIB represents T4 disease with any N, or any T with N3 disease. Patients with malignant pleural effusions secondary to NSCLC tumor implants along the pleura are included as T4 disease. No extrathoracic metastatic disease is present. Approximately 10-15% of patients are believed to be stage IIIB at the time of diagnosis. Surgery is usually not considered to be beneficial in this group of patients and is primarily reserved for select T4N0M0 patients for which resection may be achieved with or without adjuvant therapy. Surgical resection can significantly improve survival and result in cure in this T4N0 subset of patients. Five-year survival rates have been reported as high as 26-46% with completely resected vertebral SVG or carinal involvement.129 Patients with good performance status (0 or 1) should undergo concurrent chemo-radiotherapy for best survival. Although sequential therapy is less likely to produce acute esophagitis, it is associated with worse survival compared with concurrent therapy and thus combined chemoradiation therapy usually is instituted in good performance patients.130 Two-year and five-year survival can be achieved in 26% and 14% of patients, respectively, despite their initial advanced disease.131
Stage IV NSCLC. The presence of metastases in distant organs or another lobe of the lung confers a diagnosis of stage IV disease. Given the impact of this diagnosis, it is critical to document that the suspicious lesion is a metastatic lesion and not a benign lesion or concurrent second primary lung cancer elsewhere in the lung, or a benign or primary malignant lesion in another organ (i.e., adrenal adenoma). Platinum-based chemotherapy is the primary option for patients with good performance status who would benefit from therapy over the best supportive care, although there are no recommendations for specific types of chemotherapy either alone or in combination.132 Recently it has been noted that the addition of the angiogenesis inhibitor bevacizumab to combination chemotherapy (carboplatin and paclitaxel) significantly increased survival compared to combination chemotherapy alone in histologically confirmed stage IIIB (with pleural effusion), stage IV, or recurrent NSCLC patients.133 The new epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib are also options for patients with tumors found to contain specific EGFR mutations. Significant responses have been seen most often in those patient subsets that are more likely to exhibit responder-type gene mutations in the EGFR-TK domain (women, non-smokers and Asian).18 Overall, care for patients with Stage IV NSCLC should concentrate on minimization of pain and maximization of quality of life.
Small Cell Lung Cancer (SCLC). SCLC typically is more aggressive than NSCLC. Despite therapy, median survival for limited disease is 16-24 months, and for extensive disease is 6-12 months. Proper staging includes a CT of the chest and abdomen, CT or MRI of the brain, bone scan, blood work including CBC, LFTs, LDH, and potentially a bone marrow biopsy. SCLC is treated non-surgically unless the tumor is completely localized with no nodal involvement, but this is a rare and often unexpected finding following surgical resection of a solitary pulmonary nodule. Medical and radiation oncologists are the primary team for treatment planning as treatment traditionally is based on a combination chemotherapy regimen, which can include etoposide, cisplatin, cyclophosphamide, doxorubicin, vincristine, ifosfamide, paclitaxel, carboplatin, or topotecan, among others. Patients who achieve complete response are usually given prophylactic cranial irradiation. The five-year survival for limited stage patients is approximately 20%, although 50% of patients survive who have isolated SCLC treated primarily with surgery.134,135 Extensive disease is treated with platinum-based chemotherapy and palliative care.134
Survivorship-Issues Following Therapy
Despite complete surgical resection, the risk of recurrent disease or new primary lung cancers is high in this patient population. Therefore, following surgical resection patients should be followed regularly by the thoracic surgeon and/or medical oncologist and their primary care physician and/or pulmonologist. Established guidelines by various organizations recommend visits with radiographic imaging approximately every 3 months within the first two years of treatment. Less frequent visits three to five years after treatment eventually are transitioned to annual visits. The majority of oncologists will utilize CT scans for follow-up to detect lesions early in their course and to assess the surrounding lung for other changes as well.
The most common post-treatment morbidities are decreased lung function and chronic pain. Patients who continue to smoke following treatment must be encouraged to quit in an effort to decrease lung cancer risk and preserve pulmonary function. Primary care physicians, pulmonologists, and medical and radiation oncologists all must work together to provide support and multiple smoking cessation treatment options. While clinicians help ensure physical well-being, psychosocial support is equally crucial. A patient's psychological state should be assessed at each visit. Psychosocial studies of lung cancer patients show that physician support helps abate feelings of helplessness and hopelessness, and positively correlates with a "fighting spirit," especially in female patients.136 These improvements beneficially impact quality of life and survival following curative resection.136
Although the standard of care for most serious illnesses lacks comprehensive psychosocial support, this fault is even more damaging to lung cancer patients, and must be corrected. Compared with other cancer patients, lung cancer patients report more unmet needs and are more likely to suffer depression.137 Even non-smokers often hide their diagnosis due to the social stigma of lung cancer, leaving them with feelings of shame and isolation. A recent national study of graduating primary care residents revealed that many of these physicians felt unprepared to counsel patients on prevention and psychosocial issues regardless of time spent in ambulatory care settings.138 This is particularly concerning for patients with lung cancer since primary care physicians often possess more intimate knowledge of their patients' habits, medical history, and medical care directives. Primary care physicians should feel confident in leveraging these connections to meet psychosocial needs and serve as a supportive resource for patients during follow-up. This can be accomplished through direct care and education or by offering ancillary contacts for medical, psychosocial, behavioral, and pastoral care. In effect, the PCP becomes a much-needed anchor about which a lung cancer patient's care revolves.
Palliative and End-of-Life Care
There are numerous interventional modalities that can be used to achieve symptom relief. Rigid and flexible bronchoscopy, Nd-YAG and APC lasers, cryotherapy, PDT, and electrocautery can be utilized to remove tumors obstructing the airway. Endobronchial stents can help keep airways open and HDR brachytherapy can be used for targeted radiation therapy while minimizing scatter to surrounding structures. Similarly, recurrent pleural effusions despite chemotherapy, can be managed via thoracentesis, thoracoscopy, chest tube placement and pleurodesis or placement of Pleurx catheters with significant improvement in pulmonary status.
High-quality pain management is essential for patients with lung cancer. Patients should be allowed and encouraged to report their own pain levels rather than relying on a proxy. Perception of pain by family caregivers is often in accord with a patient's true level of pain, but there is great variability. Incongruity can develop due to high caregiver stress or high patient psychological distress. Physicians should be cognizant that caregivers can overestimate patient pain if a strained relationship exists between patient and caregiver, or if caregiver stress and patient symptoms are high.139
For effective pain therapy, administration of pain medication should be tailored to the patient's needs, be non-invasive when possible, and be available at all hours of the day or night. Patients should be encouraged to maintain as much care over themselves as possible, and a patient-directed pain management plan should be written in collaboration with physicians and caregivers. Acetaminophen and NSAIDs are first-line treatment for low to moderate pain, and opioid analgesics should be used for more severe pain. Tricyclic antidepressants, anticonvulsants, and neuroleptic medications can be used as adjuvant therapy when necessary, and constipation should be questioned and prophylactically treated. Pain due to metastases can be treated with palliative radiation and occasionally surgery. Because pain and psychological function are intimately tied, psychosocial needs should be considered and treated throughout the course of pain management.140
Most patients present with end stage disease such that overall 5-year survival for lung cancer patients is 15%. Subsequently, end-of-life care will be a reality for the majority of patients with this disease. The American College of Chest Physicians has recognized that end of life care is not only necessary, but often not well supported. Their guidelines stress the importance of a deeper regard and understanding of a patient's wishes and personal values by every member of the multidisciplinary care team.113 The primary care physician is particularly important in this setting. At the foundation of these recommendations is the belief in effective and informed communication with the patient, including medical, psychosocial, religious, cultural, and other personal interests important to the patient. Physicians often do not communicate adequately with cancer patients during end-of-life care, and the result commonly is unwanted treatment. The multicenter analysis entitled Study to Understand Prognosis and Preferences for Risk of Treatment (SUPPORT) found that doctor-patient communication about treatment preferences was severely lacking, and despite a two-year intervention whereby nurses noted and reported patient preferences to physicians, patient preferences were discussed in only 15% of cases.141 Physicians should actively discuss their patient's wishes and respond promptly and appropriately to those wishes.
Additionally, end-of-life care is not a specialist-directed enterprise. Rather, surgeons, pulmonologists, and oncologists must coordinate with primary care physicians, hospice services, and others to provide comprehensive, compassionate care. The American Society of Clinical Oncology Task Force on Cancer Care at the End of Life outlined several recommendations for physicians caring for terminally ill cancer patients. At the forefront of their guidelines was the respect for and utilization of established longitudinal relationships between patients and their primary care physicians. This multidisciplinary care team should continually recognize and reevaluate a patient's and family's wishes, including physical, mental, psychosocial, and spiritual requests. Fragmentation of care amongst many caregivers, trained and untrained, hinders high-quality end-of-life care.142 In contrast, longstanding ties between a patient and his or her physician can be the thread that holds a multidisciplinary care team together, especially when the primary care physician can provide ancillary resources such as pharmacists, chaplains, nurses, psychologists, and social workers.113
Moving Past the Public Stigma
Due to its association with smoking, lung cancer has been improperly branded as a wholly "patient-responsible" disease, despite the fact that the majority of patients quit smoking and that 10% of male and 20% of female patients never smoked.4,7 Patients with lung cancer are shunned by society as smokers who knowingly "gave themselves cancer." One of the most common responses to "I have lung cancer" is not one of support and sympathy but of blame. Patients are accusingly asked, "Did you smoke?" rather than being offered help and sympathy. Although this patient population deserves the medical and public attention that all patients with a devastating, emotionally charged illness deserve, lung cancer patients, regardless of their smoking status, often will not disclose their ailment to extended family or the community for fear of condemnation. Evaluation of lung cancer patients in the United Kingdom found that both smoking and non-smoking patients felt more stigmatized than patients with other types of cancer. Stigmatization affected interaction with family, friends, and doctors. Most patient felt unjustly blamed for their illness, especially those who had quit smoking years before diagnosis. Interpersonal communication was weakened when patients concealed their illness, resulting in unfavorable financial consequences and decreased social support.143
Early diagnosis, access to care, and lung cancer research are all adversely affected by the stigma of smoking and tragically result in increased numbers of deaths. Although overall survival for lung cancer is poor, diagnosis of early stage disease coupled with effective therapy can yield survival rates as high as 92%. Patients must have enough will and self-esteem to fight lung cancer, and for smokers this can be very difficult without the proper support. Breast cancer patients thrive on national support and open discourse that fosters hope and leads to new forms of research aimed at early diagnosis, better treatment, and improved prevention. Lung cancer mortality surpassed that of breast cancer in 1987, yet in 2006 the federal government invested almost thirteen-fold more dollars per breast cancer death than lung cancer death.2,4 Unfortunately, lung cancer patients lack the political power of other cancer patients. Support groups are rare due to the aggressiveness of the disease, high mortality, and shame. By encouraging survivors to share their stories, it is possible to show that lung cancer is not always fatal. Primary care physicians can help patients to help themselves by collectively providing support and acceptance to victims of an often self-inflicted disease. Support will lead to increased funding for lung cancer and, in time, lung cancer patients can hope for more effective prevention methods and therapy, as well as comprehensive treatment programs incorporating medical, psychosocial, and behavioral care.
References
1. Adler I. Primary malignant growths of the lungs and bronchi. A pathological and clinical study. Longmans, Green and Co, New York.1912.
2. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106-130.
3. Doddoli C, Aragon A, Barlesi F, et al. Does the extent of lymph node dissection influence outcome in patients with stage I non-small-cell lung cancer? Eur J Cardiothorac Surg 2005;27:680-685.
4. Lung Cancer Alliance. The Facts About Lung Cancer, 2006, http://www.lungcanceralliance.org/pdf_docs/lungcancer_factsheet.pdf.
5. Edwards BK, Brown ML, Wingo PA, et al. Annual report to the nation on the status of cancer, 1975-2002, featuring population-based trends in cancer treatment. J Natl Cancer Inst 2005;97:1407-1427.
6. Baldini EH, Strauss GM. Women and lung cancer: Waiting to exhale. Chest 1997;112:229S-234S.
7. Thomas L, Doyle LA, Edelman MJ. Lung cancer in women: Emerging differences in epidemiology, biology, and therapy. Chest 2005;128:370-381.
8. Wingo PA, Ries LA, Giovino GA, et al. Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 1999;91:675-690.
9. American Cancer Society. Cancer Facts and Figures, 2006. American Cancer Society, Atlanta, GA; 2006.
10. Martini N, Bains MS, Burt ME, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995;109:120-129.
11. Henschke CI, Yankelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355:1763-1771.
12. Bulzebruck H, Bopp R, Drings,P, et al. New aspects in the staging of lung cancer. Prospective validation of the International Union Against Cancer TNM classification. Cancer 1992;70:1102-1110.
13. Fu J. Lung Cancer in women, Analysis of the national surveillance, epidemiology, and end results database. Chest 2005;127.
14. Mulligan CR, Meram AD, Proctor CD, et al. Unlimited access to care: effect on racial disparity and prognostic factors in lung cancer. Cancer Epidemiol Biomarkers Prev 2006;15:25-31.
15. Bach PB, Cramer LD, Warren JL, et al. Racial differences in the treatment of early-stage lung cancer. N Engl J Med 1999;341:1198-1205.
16. Travis WD, Travis LB, Devesa SS. Lung cancer. Cancer 1995;75:191-202.
17. Sonobe M, Manabe T, Wada H, et al. Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer 2005;93:355-363.
18. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
19. U.S. Department of Health and Human Services. The Health Benefits of Smoking Cessation. A Report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health 1990;DHHS Publication No. (CDC) 90-8416.
20. Pershagen G. Passive Smoking and Lung Cancer. In: J. Samet, ed. Epidemiology of Lung Cancer. Marcel Dekker, Inc.: New York; 1994:109-130.
21. Law MR, Morris JK, Wald NJ. Environmental tobacco smoke exposure and ischaemic heart disease: An evaluation of the evidence. BMJ 1997;315:973-980.
22. Taylor RJ, Mamoon HA, Morrell SL, et al. Cervical screening by socio-economic status in Australia. Aust N Z J Public Health 2001;25:256-260.
23. Hackshaw AK, Law MR, Wald NJ. The accumulated evidence on lung cancer and environmental tobacco smoke. BMJ 1997;315:980-988.
24. Boffetta P. Involuntary smoking and lung cancer. Scand J Work Environ Health 2002;28 Suppl 2:30-40.
25. Siegel M. Involuntary smoking in the restaurant workplace. A review of employee exposure and health effects. JAMA 1993;270:490-493.
26. Repace J. Flying the smoky skies: secondhand smoke exposure of flight attendants. Tob Control 2004;13 Suppl 1:18-19.
27. Stockwell HG, Goldman AL, Lyman GH, et al. Environmental tobacco smoke and lung cancer risk in nonsmoking women. J Natl Cancer Inst 1992;84:1417-1422.
28. Boffetta P, Tredaniel J, Greco A. Risk of childhood cancer and adult lung cancer after childhood exposure to passive smoke: A meta-analysis. Environ Health Perspect 2000;108:73-82.
29. National Cancer Institute. Health Effects of Exposure to Environmental Tobacco Smoke: The Report of the California Environmental Protection Agency. US Dept of Health and Human Services; Bethesda, MD 1999.
30. Environmental tobacco smoke: A hazard to children. American Academy of Pediatrics Committee on Environmental Health. Pediatrics 1997;99:639-642.
31. Gold DR, Wang X, Wypij D, et al. Effects of cigarette smoking on lung function in adolescent boys and girls. N Engl J Med 1996;335:931-937.
32. Humphrey EW, et al. The ACS Textbook of Clinical Oncology. 1995:220-235.
33. Doll R. Mortality from lung cancer in asbestos workers. Br J Ind Med 1955;12:81-86.
34. Selikoff IJ, Hammond EC, Seidman H. Latency of asbestos disease among insulation workers in the United States and Canada. Cancer 1980;46:2736-2740.
35. Saracci R. The interactions of tobacco smoking and other agents in cancer etiology. Epidemiol Rev 1987;9:175-193.
36. Man-made mineral fibres. IARC Monogr Eval Carcinog Risks Hum 1988;43:39-171.
37. Darby S, Samet J. Radon. In: J. Samet, ed. Epidemiology of Lung Cancer. Marcel Dekker, Inc.: New York; 1994:219-244.
38. Overall evaluations of carcinogenicity: An updating of IARC Monographs volumes 1-42. IARC monogr Eval Carcinog Risks Hum Suppl 1987;7:1-440.
39. Hayes RB. The carcinogenicity of metals in humans. Cancer Causes Control 1997;8:371-385.
40. Coultas DB. Other occupational carcinogens. In: Samet JM, ed. Epidemiology of Lung Cancer. Marcel Dekker, Inc.: New York; 1994.
41. Report of the International Committee on Nickel Carcinogenesis in Man. Scand J Work Environ Health 1990;16:1-82.
42. Rivera MP, Loomis DP. Epidemiology and Classification of Lung Cancer. In: Diagnosis and Treatment of Lung Cancer: An Evidence Based Guide for the Practicing Clinician. W. Saunders: Philadelphia, PA; 2001: 45-72.
43. Talbot-Smith A, Fritschi L, Divitini ML, et al. Allergy, atopy, and cancer: A prospective study of the 1981 Busselton cohort. Am J Epidemiol 2003;157:606-612.
44. Schabath MB, Delclos GL, Martynowicz MM, et al. Opposing effects of emphysema, hay fever, and select genetic variants on lung cancer risk. Am J Epidemiol 2005;161:412-422.
45. Santillan AA, Camargo CA, Jr., Colditz GA. A meta-analysis of asthma and risk of lung cancer (United States). Cancer Causes Control 2003;14:327-334.
46. Turner MC, Chen Y, Krewski D, et al. An overview of the association between allergy and cancer. Int J Cancer 2006;118:3124-3132.
47. Fitzpatrick FA. Inflammation, carcinogenesis and cancer. Int Immunopharmacol 2001;1:1651-1667.
48. Mellemkjaer L, Friis S, Olsen JH, et al. Risk of second cancer among women with breast cancer. Int J Cancer 2006;118:2285-2292.
49. Evans HS, Lewis CM, Robinson D, et al. Incidence of multiple primary cancers in a cohort of women diagnosed with breast cancer in southeast England. Br J Cancer 2001;84:435-440.
50. Roychoudhuri R, Evans H, Robinson D, et al. Radiation-induced malignancies following radiotherapy for breast cancer. Br J Cancer 2004;91:868-872.
51. Deutsch M, Land SR, Begovic M, et al. The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy. Results of National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials B-04 and B-06. Cancer 2003;98:1362-1368.
52. Darby SC, McGale P, Taylor CW, et al. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: Prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 2005;6:557-565.
53. Verhoeven DT, Goldbohm RA, van Poppel G, et al. Epidemiological studies on brassica vegetables and cancer risk. Cancer Epidemiol Biomarkers Prev 1996;5:733-748.
54. Holick CN, Michaud DS, Stolzenberg-Solomon R, et al. Dietary carotenoids, serum beta-carotene, and retinol and risk of lung cancer in the alpha-tocopherol, beta-carotene cohort study. Am J Epidemiol 2002;156:536-547.
55. Cook NR, Le IM, Manson JE, et al. Effects of beta-carotene supplementation on cancer incidence by baseline characteristics in the Physicians' Health Study (United States). Cancer Causes Control 2000;11:617-626.
56. Lee IM, Cook NR, Manson JE, et al. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: The Women's Health Study. J Natl Cancer Inst 1999;91:2102-2106.
57. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029-1035.
58. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-1155.
59. Lippman SM, Lee JJ, Karp DD, et al. Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 2001;93:605-618.
60. Greenwald P. Beta-carotene and lung cancer: a lesson for future chemoprevention investigations? J Natl Cancer Inst 2003;95:E1.
61. Kreuzer M, Gerken M, Heinrich J, et al. Hormonal factors and risk of lung cancer among women? Int J Epidemiol 2003;32:263-271.
62. Blackman JA, Coogan PF, Rosenberg L, et al. Estrogen replacement therapy and risk of lung cancer. Pharmacoepidemiol Drug Saf 2002;11:561-567.
63. Schabath MB, Wu X, Vassilopoulou-Sellin R, et al. Hormone replacement therapy and lung cancer risk: A case-control analysis. Clin Cancer Res 2004;10:113-123.
64. Ganti AK, Sahmoun AE, Panwalkar AW, et al. Hormone replacement therapy is associated with decreased survival in women with lung cancer. J Clin Oncol 2006;24:59-63.
65. Taioli E, Wynder EL. Re: Endocrine factors and adenocarcinoma of the lung in women. J Natl Cancer Inst 1994;86:869-870.
66. Moore KA, Mery CM, Jaklitsch MT, et al. Menopausal effects on presentation, treatment, and survival of women with non-small cell lung cancer. Ann Thorac Surg 2003;76:1789-1795.
67. Zhou W, Liu G, Miller DP, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk. Cancer Epidemiol Biomarkers Prev 2003;12:359-365.
68. Nelson HH, Christiani DC, Mark EJ, et al. Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. J Natl Cancer Inst 1999;91:2032-2038.
69. Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996;88:183-192.
70. Risch HA, Howe GR, Jain M, et al. Are female smokers at higher risk for lung cancer than male smokers? A case-control analysis by histologic type. Am J Epidemiol 1993;138:281-293.
71. Henschke CI, Yip R, Miettinen OS. Women's susceptibility to tobacco carcinogens and survival after diagnosis of lung cancer. JAMA 2006;296:180-184.
72. Bailey-Wilson JE, Amos CI, Pinney SM, et al. A major lung cancer susceptibility locus maps to chromosome 6q23-25. Am J Hum Genet 2004;75:460-474.
73. Xi L, Luketich JD, Raja S, et al. Molecular staging of lymph nodes from patients with esophageal adenocarcinoma. Clin Cancer Res 2005;11:1099-1109.
74. Gordon GJ, Jensen RV, Hsiao LL, et al. Translation of microarray data into clinically relevant cancer diagnostic tests using gene expression ratios in lung cancer and mesothelioma. Cancer Res 2002;62:4963-4967.
75. Garber ME, Troyanskaya OG, Schluens K, et al. Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci U S A 2001;98:13784-13789.
76. Beer DG, Kardia SL, Huang CC, et al. Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med 2002;8:816-824.
77. Kikuchi T, Daigo Y, Katagiri T, et al. Expression profiles of non-small cell lung cancers on cDNA microarrays: identification of genes for prediction of lymph-node metastasis and sensitivity to anti-cancer drugs. Oncogene 2003;22:2192-2205.
78. Herbst RS, Yano S, Kuniyasu H, et al. Differential expression of E-cadherin and type IV collagenase genes predicts outcome in patients with stage I non-small cell lung carcinoma. Clin Cancer Res 2000;6:790-797.
79. Gonzales D, Rennard SI, Nides M, et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs. sustained-release bupropion and placebo for smoking cessation: A randomized controlled trial. JAMA 2006;296:47-55.
80. Silagy C. Physician advice for smoking cessation. Cochrane Database Syst Rev 2000:CD000165.
81. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2000:CD000031.
82. Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340:685-691.
83. Fiore MC, Cohen SF. Treating Tobacco Use and Dependence: Clinical Practice Guideline. Rockville, MD: 2000.
84. Stead LF, Perera R, Lancaster T. Telephone counselling for smoking cessation. Cochrane Database Syst Rev 2006;3:CD002850.
85. Schnoll RA, Rukstalis M, Wileyto EP, et al. Smoking cessation treatment by primary care physicians: An update and call for training. Am J Prev Med 2006;31:233-239.
86. Steinberg MB, Akincigil A, Delnevo CD, et al. Gender and age disparities for smoking-cessation treatment. Am J Prev Med 2006;30:405-412.
87. Memorial Sloane Kettering Lung Cancer Risk Assessment Tool, http://www.mskcc.org/mskcc/html/12463.cfm.
88. Harvard Center for Cancer Prevention, http://www.yourdiseaserisk.harvard.edu/.
89. Detterbeck F, Rivera MP. Clinical Presentation and Diagnosis. Diagnosis and Treatment of Lung Cancer: An Evidence Based Guide for the Practicing Clinician. W. Saunders, ed: Philadelphia, PA; 2001:45-72.
90. Hamilton W, Peters TJ, Round A, et al. What are the clinical features of lung cancer before the diagnosis is made? A population based case-control study. Thorax 2005;60:1059-1065.
91. Hamilton W, Sharp D. Diagnosis of lung cancer in primary care: A structured review. Fam Pract 2004;21:605-611.
92. Chute CG, Greenberg ER, Baron J, et al. Presenting conditions of 1539 population-based lung cancer patients by cell type and stage in New Hampshire and Vermont. Cancer 1985;56:2107-2111.
93. Huhti E, Sutinen S, Reinila A, et al. Lung cancer in a defined geographical area: History and histological types. Thorax 1980;35:660-667.
94. Maddaus MA, GR. Clinical Features, Diagnosis, and Staging of Lung Cancer. In: P. GF, ed. Thoracic Surgery. Churchill Livingstone: New York, NY; 2002.
95. Detterbeck F, Egan T. Surgery for Stage II Non-Small Cell Lung Cancer. Diagnosis and Treatment of Lung Cancer: An Evidence-Bases Guide for the Practicing Clinician. 2001;12:191-197.
96. Winer-Muram HT. The solitary pulmonary nodule. Radiology 2006;239:34-49.
97. Munden RF, Pugatch RD, Liptay MJ, et al. Small pulmonary lesions detected at CT: Clinical importance. Radiology 1997;202:105-110.
98. Swanson SJ, Jaklitsch MT, Mentzer SJ, et al. Management of the solitary pulmonary nodule: role of thoracoscopy in diagnosis and therapy. Chest 1999;116:523S-524S.
99. Kundel HL. Predictive value and threshold detectability of lung tumors. Radiology 1981;139:25-29.
100. Guiss LW, Kuenstler P. A retrospective view of survey photofluorograms of persons with lung cancer. Cancer 1960;13:91-95.
101. Quekel LG, Kessels AG, Goei R, et al. Miss rate of lung cancer on the chest radiograph in clinical practice. Chest 1999;115:720-724.
102. Siegelman SS, Khouri NF, Leo FP, et al. Solitary pulmonary nodules: CT assessment. Radiology 1986;160:307-312.
103. Zerhouni EA, Stitik FP, Siegelman SS, et al. CT of the pulmonary nodule: A cooperative study. Radiology 1986;160:319-327.
104. Grewal RG, Austin JH. CT demonstration of calcification in carcinoma of the lung. J Comput Assist Tomogr 1994;18:867-871.
105. Tan BB, Flaherty KR, Kazerooni EA, et al. The solitary pulmonary nodule. Chest 2003;123:89S-96S.
106. Winer-Muram HT, Jennings SG, Tarver RD, et al. Volumetric growth rate of stage I lung cancer prior to treatment: serial CT scanning. Radiology 2002;223:798-805.
107. Hasegawa M, Sone S, Takashima S, et al. Growth rate of small lung cancers detected on mass CT screening. Br J Radiol 2000;73:1252-1259.
108. Kui M, Templeton PA, White CS, et al. Evaluation of the air bronchogram sign on CT in solitary pulmonary lesions. J Comput Assist Tomogr 1996;20:983-986.
109. Gurney JW, Lyddon DM, McKay JA. Determining the likelihood of malignancy in solitary pulmonary nodules with Bayesian analysis. Part II. Application. Radiology 1993;186:415-422.
110. Woodring JH, Fried AM. Significance of wall thickness in solitary cavities of the lung: A follow-up study. AJR Am J Roentgenol 1983;140:473-474.
111. Goldsmith SJ, Kostakoglu L. Nuclear medicine imaging of lung cancer. Radiol Clin North Am 2000;38:511-524.
112. MacMahon H, Austin JH, Gamsu G, et al. Guidelines for management of small pulmonary nodules detected on CT scans: A statement from the Fleischner Society. Radiology 2005;237:395-400.
113. Griffin JP, Nelson JE, Koch KA, et al. End-of-life care in patients with lung cancer. Chest 2003;123:312S-331S.
114. Landreneau RJ, Mack MJ, Hazelrigg SR, et al. Video-assisted thoracic surgery: Basic technical concepts and intercostal approach strategies. Ann Thorac Surg 1992;54:800-807.
115. Hazelrigg SR, Magee MJ, Cetindag IB. Video-assisted thoracic surgery for diagnosis of the solitary lung nodule. Chest Surg Clin N Am 1998;8:763-774, vii.
116. American College of Chest Physicians. Diagnosis and Management of Lung Cancer: ACCP Evidence Based Guidelines. Chest 2003;123:1S-337S.
117. Mathur PN, Edell E, Sutedja T, et al. Treatment of early stage non-small cell lung cancer. Chest 2003;123:176S-180S.
118. Smythe WR. Treatment of stage I non-small cell lung carcinoma. Chest 2003;123:181S-187S.
119. Jones D, Detterbeck F. Surgery for Stage I Non-Small Cell Lung Cancer. Diagnosis and Treatment of Lung Cancer, An Evidence-Based Guide for the Practicing Clinician 2001;11:177-190.
120. Wakelee HA, Schiller JH, Gandara DR. Current status of adjuvant chemotherapy for stage IB non-small-cell lung cancer: Implications for the New Intergroup Trial. Clin Lung Cancer 2006;8:18-21.
121. Scott WJ, Howington J, Movsas B. Treatment of stage II non-small cell lung cancer. Chest 2003;123:188S-201S.
122. Herbst RS, Bajorin DF, Bleiberg H, et al. Clinical Cancer Advances 2005: Major research advances in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology. J Clin Oncol 2006;24:190-205.
123. Jaklitsch MT, Herndon JE, 2nd, Decamp MM, Jr., et al. Nodal downstaging predicts survival following induction chemotherapy for stage IIIA (N2) non-small cell lung cancer in CALGB protocol #8935. J Surg Oncol 2006;94:599-606.
124. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: Mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880-1892.
125. Depierre A, MB. Phase III trial of neo-adjuvant chemotherapy (NCT) in resectable stage I (except T1N0), II, IIIa non-small cell lung cancer (NSCLC): The French Experience. In Proc ASCO, 1999;18:465a.
126. Rosell R, Gomez-Codina J, Camps C, et al. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: A 7-year assessment of a randomized controlled trial. Lung Cancer 1999;26:7-14.
127. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 1994;86:673-680.
128. Robinson LA, Wagner H, Jr., Ruckdeschel JC. Treatment of stage IIIA non-small cell lung cancer. Chest 2003;123:202S-220S.
129. Detterbeck F, Jones DR. Surgery for Stage IIIB Non-Small Cell Lung Cancer. In: Diagnosis and Treatment of Lung Cancer: An Evidence-Based Guide for the Practicing Clinician. W. Saunders, ed, Philadelphia, 2001:283-289.
130. Jett JR, Scott WJ, Rivera MP, et al. Guidelines on treatment of stage IIIB non-small cell lung cancer. Chest 2003;123:221S-225S.
131. Hensing TA, HJaSM. Chemoradiotherapy for Stage IIIA,B Non-Small Cell Lung Cancer. In: Diagnosis and Treatment of Lung Cancer: An Evidence Based Guide for the Practicing Clinician. W. Saunders, ed, Philadelphia, PA;2001:291-303.
132. Socinski MA, Morris DE, Masters GA, et al. Chemotherapeutic management of stage IV non-small cell lung cancer. Chest 2003;123:226S-243S.
133. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22:2184-2191.
134. Simon GR, Wagner H. Small cell lung cancer. Chest 2003;123:259S-271S.
135. Morris DE, SMaDF. Limited Stage Small Cell Lung Cancer. In: Diagnosis and Treatment of Lung Cancer: An Evidence Based Guide for the Practicing Clinician. W. Saunders, ed, Philadelphia, PA; 2001: 341-359.
136. Uchitomi Y, Mikami I, Kugaya A, et al. Physician support and patient psychologic responses after surgery for nonsmall cell lung carcinoma: a prospective observational study. Cancer 2001;92:1926-1935.
137. Li J, Girgis A. Supportive care needs: Are patients with lung cancer a neglected population? Psychooncology 2006;15:509-516.
138. Park ER, Wolfe TJ, Gokhale M, et al. Perceived preparedness to provide preventive counseling: Reports of graduating primary care residents at academic health centers. J Gen Intern Med 2005;20:386-391.
139. Porter LS, Keefe FJ, McBride CM, et al. Perceptions of patients' self-efficacy for managing pain and lung cancer symptoms: correspondence between patients and family caregivers. Pain 2002;98:169-178.
140. Kvale PA, Simoff M, Prakash UB. Lung cancer. Palliative care. Chest 2003;123:284S-311S.
141. A controlled trial to improve care for seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). The SUPPORT Principal Investigators. JAMA 1995;274:1591-1598.
142. Cancer care during the last phase of life. J Clin Oncol 1998;16:1986-1996.
143. Chapple A, Ziebland S, McPherson A. Stigma, shame, and blame experienced by patients with lung cancer: Qualitative study. BMJ 2004;328:1470.
Although it is known that cigarette smoking is the most prevalent risk factor for lung cancer, other risk factors are important. It is notable that 10% of men and 20% of women with lung cancer never smoked, and that nearly half of patients are former smokers.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content