Background

Lung cancer was a rare entity in the early 1900s but has since become far more prevalent. The prevalence of lung cancer is second only to that of prostate cancer in men and breast cancer in women. By the end of the 1900s, lung cancer had become the leading cause of preventable death in the United tates,!"# and recently, it surpassed heart disease as the leading cause of smo$ing% related mortality. Lung cancers are generally divided into " main categories& small cell lung cancer ' (L() and non%small cell lung cancer '* (L(). * (L( accounts for appro+imately ,-. of all lung cancers. * (L( is divided further into adenocarcinoma, s/uamous cell carcinoma ' ((), and large cell carcinoma histologies. ' ee 0athophysiology.) Lung cancer is the leading cause of cancer%related mortality in both men and women not only in the United tates but also throughout the world. 1n "002, the disease caused more than 1-,,000 deaths in the United tates3more than colorectal, breast, and prostate cancers combined.!4# The type of lung cancer in the United tates, as well as in many other countries, have also changed in the past few decades& the fre/uency of adenocarcinoma has risen, and that of (( has declined. ' ee 5pidemiology.) 6ost lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis. The need to diagnose lung cancer at an early and potentially curable stage is thus obvious. ' ee 0rognosis.) 1n addition, most patients who develop lung cancer have been smo$ers and have smo$ing%related damage to the heart and lungs, ma$ing aggressive surgical or multimodality therapies less viable options. Lung cancer is often insidious, and it may produce no symptoms until the disease is well advanced. 7ppro+imately 8%10. of patients with lung cancer are asymptomatic, and their cancers are diagnosed incidentally after a chest radiograph performed for other reasons. ystemic findings may include une+plained weight loss and low%grade fever. *umerous signs may be associated with * (L(. ' ee (linical 0resentation.) Because of the importance of stage on the therapeutic decision%ma$ing process, all patients with non%small cell lung cancer '* (L() must be staged ade/uately. 7 complete staging wor$up for * (L( should be carried out to evaluate the e+tent of disease. ' ee 9or$up.) Treatment primarily involves surgery, chemotherapy, or radiation therapy. Because most lung cancers cannot be cured with currently available therapeutic modalities, the appropriate application of s$illed palliative care is an important part of the treatment of patients with * (L(. ' ee Treatment and 6anagement.)

Pathophysiology
Both e+posure 'environmental or occupational) to particular agents and an individual:s susceptibility to these agents are thought to contribute to one:s ris$ of developing lung cancer. 1n

the United tates, active smo$ing is responsible for 90. of lung cancer cases. ;ccupational e+posures to carcinogens account for appro+imately 9%1-. of lung cancer cases.
Exposure to carcinogens

Tobacco smo$e contains more than 400 harmful substances with at least <0 $nown potent carcinogens. 0oly%aromatic hydrocarbons and the nitrosamine%**= are $nown to cause >*7 damage by forming >*7 adducts in animal models. Ben?o%7%pyrine also appears to induce molecular signaling such as 7=T, as well as inducing mutations in p53 and other tumor suppressor genes. The most common occupational ris$ factor for lung cancer is e+posure to asbestos. tudies have shown radon e+posure to be associated with 10. of lung cancer cases, while outdoor air pollution accounts for perhaps 1%"..!<# 1n addition, pree+isting nonmalignant lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and tuberculosis have all been shown to be associated with increased lung cancer rates. The current multiple hit theory suggests that a series of to+ic cellular insults disrupts orderly genetic reproduction. ymptoms ultimately develop from the uncontrolled disorgani?ed growth that interferes with local or distant anatomy or physiologic processes.!<# 7 study by 1to et al assessed the shift in histologic types of lung cancer in @apan and the United tates in relation to the shift from nonfiltered to filtered cigarettes.!-# The study determined that the shift in cigarette types only altered the most fre/uent type of lung cancer, shifting from (( to adenocarcinoma.
Genetic susceptibility

Aecently, advanced molecular techni/ues have identified amplification of oncogenes and inactivation of tumor suppressor genes in * (L(. The most important abnormalities detected are mutations involving the ras family of oncogenes. The ras oncogene family has 4 members& B%ras, =%ras, and *%ras. These genes encode a protein on the inner surface of the cell membrane with CT0ase activity and may be involved in signal transduction. tudies performed on mice suggest the involvement of ras mutations in the molecular pathogenesis of * (L(. tudies in humans suggest that ras activation contributes to tumor progression in persons with lung cancer. The ras gene mutations occur almost e+clusively in adenocarcinoma and are found in 40. of such cases. These mutations were not identified in adenocarcinomas that developed in persons who do not smo$e. The =%ras mutation appears to be an independent prognostic factor. tudies are ongoing to develop management plans according to the presence or absence of ras gene mutations. ;ther molecular abnormalities found in * (L( include mutations in c-myc and c-raf among oncogenes and retinoblastoma 'Rb) and p53 among tumor suppressor genes.

Classification of lung cancer

Lung cancers are generally divided into " main categories& (L( and * (L(. * (L( accounts for appro+imately ,-. of all lung cancers. * (L( is divided further into adenocarcinoma, ((, and large cell carcinoma histologies. 7ll share similar treatment approaches and prognoses but have distinct histologic and clinical characteristics. 7denocarcinoma, arising from the bronchial mucosal glands, is the most fre/uent non%small cell lung cancer in the United tates, representing 4-%<0. of all lung cancers. 1t usually occurs in a peripheral location within the lung. 7denocarcinoma is the most common histologic subtype, and may manifest as a Dscar carcinoma.E This is the subtype observed most commonly in persons who do not smo$e. This type may manifest as multifocal tumors in a bronchoalveolar form. Bronchoalveolar carcinoma is a distinct subtype of adenocarcinoma with a classic manifestation as an interstitial lung disease on chest radiograph. Bronchoalveolar carcinoma arises from type 11 pneumocytes and grows along alveolar septa. This subtype may manifest as a solitary peripheral nodule, multifocal disease, or a rapidly progressing pneumonic form. 7 characteristic finding in persons with advanced disease is voluminous watery sputum. (( accounts for "-%40. of all lung cancers. 9hereas adenocarcinoma tumors are peripheral in origin, (( is found in the central parts of the lung 'see the image below). The classic manifestation is a cavitary lesion in a pro+imal bronchus. This type is characteri?ed histologically by the presence of $eratin pearls and can be detected with cytologic studies because it has a tendency to e+foliate. 1t is the type most often associated with hypercalcemia.

Nonsmall cell lung cancer. A cavitating right lower lobe squamous cell carcinoma.

Large cell carcinoma accounts for 10%1-. of lung cancers, typically manifesting as a large peripheral mass on chest radiographF it appears to be decreasing in incidence because of improved diagnostic techni/ues.!2# Bistologically, this type has sheets of highly atypical cells with focal necrosis, with no evidence of $eratini?ation 'typical of (() or gland formation 'typical of adenocarcinomas). 1mproved histopathologic procedures and the use of electron microscopy allow for most large cell tumors to be identified as undifferentiated adenocarcinomas and less fre/uently as ((s.

Large cell undifferentiated cancers have the same prognosis as do adenocarcinomas and are combined with them in clinical trials. (L( is also divided into several types, including pure small cell, mi+ed small cell, and combined small cell. (L( is usually more aggressive than * (L( and presents as a central lesion with hilar and mediastinal invasion along with regional adenopathy. 1t is not uncommon for patients with (L( to already have metastatic disease at initial diagnosis. The most common sites of metastasis of lung cancer are the bones, liver, adrenal glands, pericardium, brain, and spinal cord.!8#

Etiology
(auses of lung cancer include the following&

Smoking (78% in men, 9 % in women! Asbestos e"#osure $a%on e"#osure &alogen ether e"#osure 'hronic interstitial #neumonitis (norganic arsenic e"#osure $a%ioisoto#e e"#osure, ioni)ing ra%iation Atmos#heric #ollution 'hromium, nickel e"#osure *in+l chlori%e

Unli$e many other malignancies, whose causes are largely un$nown, lung cancer is $nown to be caused by tobacco smo$ing in as many as 90. of patients. Because not all smo$ers develop lung cancer and not all lung cancer patients have a history of smo$ing, other factors 'eg, genetic susceptibility see 0athophysiology, arsenic e+posure, radiation e+posure, and other environmental carcinogens!,# ) also play a causative role, either independently or in conGunction with smo$ing. Cenetic factors probably contribute in all populations, but the contribution of other factors is population%specific. 7 study by Bagnardi et al determined that alcohol is not an independent factor in the etiology of lung cancer.!9#

Smoking

mo$ing prevalence in the United tates has gradually declined over last < decades. 1n "00,, there were an estimated <2 million active smo$ers in the United tates, with highest prevalence among *ative 7mericans and lowest prevalence among Bispanic and 7sian 7mericans. ;verall, the prevalence was highest in adults aged "- years or older with low educational attainment.!10# 9orldwide, the incidence of smo$ing in developing countries is on the rise, with almost 4"0 million smo$ers in (hina alone. The development of lung cancer is directly related to number of cigarettes smo$ed, length of smo$ing history, and the tar and nicotine content of the cigarettes. Ais$ is highest among current smo$ers and lowest among nonsmo$ers. 7 large trial showed that persistent smo$ers had a 12% fold elevated lung cancer ris$, which was further doubled in those who started smo$ing when younger than 12 years.!11# The age%adGusted incidence rates range from <.,%"0., per 100,000 among nonsmo$ers to 1<0%42" among active smo$ers. 7lthough tobacco smo$ing is the maGor cause of lung cancer, it is now believed that males and females may differ in their susceptibility to carcinogenic effects of tobacco smo$e. This difference may be due to differences in >*7 repair mechanisms. 7lthough still considered controversial, it is well $nown that women are more li$ely to develop adenocarcinomas and that, stage for stage, women live longer. 1n addition, differences in response to certain biologic therapies 'eg, epidermal growth factor !5CH# inhibitors) and antiangiogenic agents have been observed between se+es. The ris$ of lung cancer declines slowly after smo$ing cessation. Long%term follow%up studies show that the relative ris$ remains high in the first 10 years after cessation and gradually declines to "%fold appro+imately 40 years after cessation. This long%term ris$ e+plains the development of almost -0. of United tates lung cancer cases in past smo$ers. 7 minority of lung cancers develop in those who have never smo$ed. These lung cancers are genetically distinct from smo$ing%related * (L(, and this distinction may have therapeutic implications. The observed genetic differences include a lower fre/uency of K-ras and a higher fre/uency of mutations in 5CH receptor and li$ely are responsible for the higher efficacy of 5CH receptor inhibitors in this patient population. (igarette smo$e containing the carcinogenic N %nitrosamines and aromatic polycyclic hydrocarbons can be inhaled passively by nonsmo$ers 'secondhand smo$e)F urinary levels of these carcinogens are 1%-. of those found in active smo$ers. 7s many as "-. of the lung cancers in persons who do not smo$e are believed to be caused by secondhand smo$e.!1"# The U 5nvironmental 0rotection 7gency has recogni?ed passive smo$ing as a potential carcinogen. 7bout 4000 cases of lung cancer appear to be related to passive e+posure. This awareness has led to local ordinances restricting smo$ing in enclosed public places, including restaurants and government buildings.

Asbestos exposure

The silicate type of asbestos fiber is an important carcinogen. 7sbestos e+posure has been shown to be strongly associated with the causation of lung cancer, malignant pleural mesothelioma, and pulmonary fibrosis. 1t increases the ris$ of developing lung cancer by as much as - times. Tobacco smo$e and asbestos e+posure act synergistically, and the ris$ of developing lung cancer for persons who currently smo$e tobacco and have a history of asbestos e+posure approaches ,0% 90 times that of control populations.
Radon exposure

Aadon is an inert gas produced as a result of uranium decay. Aadon e+posure is a well% established ris$ factor for lung cancer in uranium miners. 7ppro+imately "%4. of lung cancers annually are estimated to be caused by radon e+posure. Bousehold e+posure to radon, however, has never been clearly shown to cause lung cancer. The U *ational Aesearch (ouncil:s report of the i+th (ommittee on Biological 5ffects of 1oni?ing Aadiation has estimated that radon e+posure causes "100 new lung cancers each year, while it contributes to lung cancer causation in appro+imately 9100 persons who smo$e.
HIV infection

7 recent report from the tate of Te+as Bealth >epartment suggested a 2.-%fold increase in lung cancer in patients infected with B1I.!14# ;ther large series do not support an increased prevalence of lung cancers in subGects with B1I infection.!1<#
Ot er en!ironmental agents

Beryllium, nic$el, copper, chromium, and cadmium have all been implicated in causing lung cancer. >ietary fiber and vegetables have been suggested as protective from lung cancer. 7lthough diets rich in fruits and vegetables appear to be associated with lower rates of lung cancer, trials of supplemental beta%carotene, alone or in combination with vitamin 5 or retinyl palmitate, in persons at high ris$ for lung cancer found that this supplementation actually increased the incidence of lung cancers.

Epidemiology
"nited States statistics

1n the United tates, lung cancer is the second most common cancer in women, and it is second only to prostate cancer in men. 1n "00,, "1-,000 lung cancer cases occurred and 121,000 deaths were e+pected.!1-# The 7merican (ancer ociety proGected that "19,<<0 cancers of the lung and

bronchus would be diagnosed in the United tates in "009, with 112,090 cases in males and 104,4-0 cases in females.!12# Hrom 1991%"00-, the incidence of lung cancer in men has decreased each year by 1.,.F however, the incidence has increased by 0.-. per year for women over that same period. Lung cancer death rates for U women are among the highest in the world. 7lthough in the United tates death rates among males are higher than among females, rates for U men are still lower than rates among men in several other countries.!18# These trends in U death rates parallel trends in smo$ing prevalence over the past -0 years. ;verall, the prevalence of smo$ing is appro+imately "1.2. in the United tates and has remained unchanged over the past 1- years.
International statistics

Lung cancer is the most commonly diagnosed cancer worldwide,!1,# and its incidence continues to grow. 1n "008, an estimated 1.- million new cases of lung cancer were diagnosed globally, accounting for appro+imately 1". of the global cancer burden. 7n estimated 1.4- million lung cancer deaths occurred in "008. 7mong all cancers, lung cancer now has the highest mortality rate in most countries, with industriali?ed regions such as *orth 7merica and 5urope having the highest rates. everal differences e+ist in lung cancer incidence according to geographic area. The highest incidence occurs in the United =ingdom and 0oland 'J100 cases per 100,000 population per year). The lowest incidence rate occurs in enegal and *igeria 'K 1 case per 100,000 population per year). 9ith increased smo$ing in developing countries, the incidence is e+pected to increase in the ne+t few years, notably in (hina and 1ndia. Cenerally, global lung cancer trends have followed the trends in smo$ing, with a lag time of several decades. Lung cancer incidence has been declining in several countries, including the United tates, (anada, the United =ingdom, and 7ustralia, following the decreasing rate of smo$ing. Lung cancer incidence among women, however, continues to increase in several parts of the globe, although it has begun to plateau in the United tates. *otably, despite a very low rate of smo$ing, (hinese females have a higher incidence of lung cancer than 5uropean females.
Age distribution for #SC$C

Lung cancer occurs predominately in persons aged -0%80 years. The probability of developing lung cancer remains very low until age 49 years in both se+es. 1t then slowly starts to rise and pea$s among those older than 80 years. The ris$ of developing lung cancer remains higher among men in all age groups after age <0 years.
Sex distribution for #SC$C

Lung cancer is more common in men than in women. 1n the United tates, *orthern 5urope, and 9estern 5urope, the prevalence of lung cancer has been decreasing in men. 1n 5astern and

outhern 5uropean countries, the incidence of lung cancer has been rapidly increasing. 6ost 9estern countries have encountered a disturbing trend of increasing prevalence in women and younger patients. 9omen have a higher incidence of locali?ed disease at presentation and of adenocarcinoma and typically are younger when they present with symptoms. 1n the United tates, the probability of developing lung cancer remains e/ual in both se+es until age 49 years '0.04. or appro+imately 1 in 4,000). 1t then starts to increase among men compared with women, reaching a ma+imum in those older than 80 years '2.8<. vs <.21. or 1 in 1- vs 1 in "", among men and women respectively).
%re!alence of #SC$C by race

9hereas lung cancer incidence rates are similar among 7frican 7merican and white women, lung cancer occurrence is appro+imately <-. higher among 7frican 7merican men than among white men.!18# This increased incidence has been attributed to differences in smo$ing habitsF however, recent evidence suggests a slight difference in susceptibility. Hrom 199-%"001, the -%year relative survival rate was 14. lower in 7frican 7mericans compared with white individuals.!18# This racial gap persisted within each stage at diagnosis for both men and women. Trends in -%year survival rates in lung cancer from 198-%"004 revealed that while modest gains occurred in -%year survival rates among whites, survival rates remained unchanged in the 7frican 7merican population. (urrent -%year survival rates are estimated to be 12. among whites and 14. among non%whites.

Prognosis
Lung cancer is highly lethal. >ata compiled by the 7merican (ancer ociety show lung cancer to be, by far, the most common fatal cancer in men '41.) and in women '"2.). The 7merican (ancer ociety proGected that deaths related to lung cancer would total 1-9,490 ',,,900 in males and 80,<90 in females) in the United tates in "009, accounting for ",. of all cancer%related deaths.!4# 9orldwide, an estimated 1,4-1,000 deaths due to lung cancer occurred in "008 '98-,000 in men and 482,000 in females). 1n 5urope, the -%year overall survival rate is ,., similar to that of the developing world. The highest recorded -%year patient survival rates are observed in the United tates. U data collected from 199-%"001 indicate that the -%year relative survival rate for lung cancer was 1-.8., reflecting a steady but slow improvement from 1".-. in 198-.!18# Bowever, the -%year relative survival rate varies mar$edly, depending on how advanced the disease is at diagnosis&

<9. for local disease 12. for regional disease ". for distant stage disease

5stimated -%year survival rates for specific stages of disease are as follows&

tage 17 % 8-. tage 1B % --. tage 117 % -0. tage 11B % <0. tage 1117 % 10%4-. tage 111B % Less than -. tage 1I % Less than -.

0rognostic factors for * (L( are summari?ed in the image below.

*onLsmall cell lung cancer. 0rognostic factors for lung cancer. 7 retrospective urveillance, 5pidemiology, and 5nd Aesults ' 55A) data analysis suggests that the number of nodes with cancer may be predictive of survival.!19# 0atients with in situ and stage 1 lung cancer may respond to surgery. Their prognosis is far better than that of patients with more advanced disease. 1n patients with radiologically occult lung neoplasms, the -%year survival rate is "<%"2.F in those with abnormal chest radiographic

findings, the rate is 1".. 1f the cancer is nonresectable, the prognosis is poor, with a mean survival rate of ,%1< months. 6ostert? et al found that in some patient populations, the oncogenic pathway activation profile of the tumor can have prognostic significance.!"0# Aetrospective analysis of 8,8 patients with predominantly early%stage * (L(, using gene e+pression profiling, showed the following&

1n patients younger than 80 years, high%ris$ patients, with the shortest recurrence%free survival, demonstrated increased activation of the rc and tumor necrosis factor 'T*H) pathways. 1n women, high%ris$ patients demonstrated increased activation of the invasiveness and signal transducer and activator of transcription 4 ' T7T4) pathways. 6ultivariate analyses confirmed the independent clinical relevance of the pathway%based subphenotypes in women and patients younger than 80 years.

7 meta%analysis by 0arsons et al suggests that smo$ing cessation after diagnosis of early%stage lung cancer may improve prognosis, probably by reducing cancer progression. Life table modelling on the basis of data from 9 studies gave an estimated -%year survival rate of 44. in 2-%year%old patients with early%stage * (L( who continued to smo$e compared with 80. in those who /uit smo$ing.!"1# 1n an analysis of data on <"00 patients who participated in the *ational (omprehensive (ancer *etwor$Ms * (L( >atabase 0roGect, patients who were current smo$ers at the time of diagnosis had worse survival compared with patients who never smo$ed, and among younger patients with stage 1I disease, current smo$ers had worse survival compared with former smo$ers who /uit smo$ing more than 1" months before being diagnosed.!""# econdary analyses of the 9omen:s Bealth 1nitiative '9B1) randomi?ed, placebo%controlled trial, performed on patients ta$ing daily conGugated e/uine estrogen '(55, 0.2"- mg) plus medro+yprogesterone acetate '607, ".- mg), found that women diagnosed with * (L( who ta$e estrogen%progestin had an increased mortality compared with women who have * (L( and do not ta$e hormone therapy.!"4# The analyses included 12,20, multiethnic postmenopausal women aged -0%89 years and assessed the association of hormone therapy on lung cancer incidence and mortality. (onfirmation of lung cancers was completed by medical record review. Aesults showed that the use of (55 plus 607 for more than - years increased a woman:s ris$ for * (L(. This area deserves more attention and study to determine the ris$s and benefits of hormone therapy for postmenopausal women who smo$e. 7 review of , trials by Aothwell et al found that allocation to aspirin reduced death caused by cancer. 1ndividual patient data were available from 8 of the , trials. Benefit was apparent after years of follow%up. The "0%year ris$ of cancer death was also lower in the aspirin group for all solid cancers. 7 latent period of - years was observed before ris$ of death was decreased for esophageal, pancreatic, brain, and lung cancers. 7 more delayed latent period was observed for stomach, colorectal, and prostate cancer.

Benefit was only seen for adenocarcinomas in lung and esophageal cancers. The overall effect on "0%year ris$ of cancer death was greatest for adenocarcinomas.!"<# 7 study by Bouchardy et al found that patients who had received antiestrogen treatment for breast cancer had a lower lung cancer mortality rate.!"-# 1n a "01" retrospective review of 1<0" consecutive stage 1%111 '*0%*1) * (L( patients who underwent complete resection without adGuvant radiation therapy, significant ris$ factors for local recurrence included surgical procedure 'singleNmultiple wedges O segmentectomy versus lobectomy O bilobectomy O pneumonectomy), visceral pleural invasion, and tumor si?e J".8 cm, and significant ris$ factors for regional recurrence included pathologic *1 stage, lymphovascular space invasion, and visceral pleural invasion.!"2#

Patient Education
7dvise patients that, among all measures, smo$ing cessation is most important. mo$ing cessation by others who share the patient:s home, car, or both is also important. 7ccording to published data, the use of nicotine alternatives 'eg, gum, patch, spray) instead of cigarettes reduces the incidence of lung cancer. Bowever, it does not affect the incidence of ischemic heart disease. 7dvise the patient to avoid asbestos e+posure. (onsider prophylactic administration of retinoids, such as beta%carotene.

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