Non-Small-Cell Lung Cancer

April 2, 2005

Lung cancer has long been the leading cause of cancer-related mortality in men, and beginning in the late 1980s, lung cancer exceeded breast cancer as the leading cause of cancer-related mortality in women. Lung cancer is responsible for one of three cancer-related deaths in men and one of four cancer-related deaths in women

EpidemiologyRisk Factors/EtiologyHistologyMolecular BiologyClinical PresentationDiagnosisStagingTreatmentConclusionsReferences

Lung cancer has long been the leading cause of cancer-related mortality in men, and beginning in the late 1980s, lung cancer exceeded breast cancer as the leading cause of cancer-related mortality in women. Lung cancer is responsible for one of three cancer-related deaths in men and one of four cancer-related deaths in women (Table 1).

All agesUnder 1515-3435-5455-7475+
All cancer 272,380All cancer 982All cancer 3,699All cancer 27,529All cancer 142,089All cancer 98,607
Lung 91,690Leukemia 350Leukemia 661Lung 8,741Lung 55,890Lung 26,896
Prostate 33,564Brain & CNS 252Non-Hodgkin's lymphomas 501Colon & rectum 2,393Colon & rectum 13,888Prostate 20,909
Colon & rectum 28,178Endocrine 111Brain & CNS 414Non-Hodgkin's lymphomas 1,726Prostate 12,306Colon & rectum 11,686
Pancreas 12,375Non-Hodgkin's lymphomas 64Skin 298Brain & CNS 1,577Pancreas 6,730Pancreas 4,299
Leukemia 10,194Connective tissue 46Hodgkin's disease 233Pancreas 1,298Esophagus 4,600Bladder 3,698
All agesUnder 1515-3435-5455-7475+
All cancer 242,277All cancer 727All cancer 3,434All cancer 29,302All cancer 111,419All cancer 97,388
Lung 52,068Leukemia 260Breast 660Breast 9,188Lung 30,154Lung 16,400
Breast 43,583Brain & CNS 220Leukemia 432Lung 5,372Breast 19,900Colon & rectum 15,727
Colon & rectum 29,017Endocrine 69Uterus 343Colon & rectum 1,999Colon & rectum 11,117Breast 13,834
Ovary 13,247Connective tissue 33Brain & CNS 328Uterus 1,978Ovary 6,720Pancreas 6,637
Pancreas 13,161Bone 28Non-Hodgkin's lymphomas 209Ovary 1,779Pancreas 5,669Ovary 4,601

An estimated 169,900 new cases of lung cancer will be diagnosed in the United States in 1995 [1]. Of these new cases, approximately 80% will be non-small-cell lung cancer (NSCLC). The great majority of cases will occur in current or former cigarette smokers. Over 70% of patients will present with advanced disease at diagnosis, and fewer than 5% of those with metastatic disease will be alive at 5 years. In the United States, 1 of every 14 deaths from any cause is due to lung cancer (Table 2) [1].

RankCause of deathNumber of deathsDeath rate per 100,000 populationªPercent of total deaths
 All causes2,169,518691.8100.0
1Heart diseases
720, 862219.8
2Cancer
514,657173.4
3Cerebrovascular diseases
4Chronic obstructive lung diseases
5Accidents
6Pneumonia & influenza
7Diabetes
8Suicide
9HIV infection
10Homicide
11Cirrhosis of liver
12Diseases of arteries
13Nephritis
14Septicemia
15Atherosclerosis
 Other & ill-defined

Epidemiologic studies have demonstrated a clear correlation between environmental factors-in particular, tobacco exposure-and the development of lung cancer [2]. Increases in lung cancer risk following exposure to carcinogens such as asbestos and radon have also been reported and have an effect independent of cigarette smoking. Other studies have suggested a dietary influence in the development of lung cancer, which has led to investigation of the role of chemoprevention in this disease. Molecular biology studies of lung cancer may give insight into both the pathophysiology and the treatment of this troublesome cancer.

In recent years, several novel chemotherapeutic agents have been identified that have shown activity against NSCLC. Despite this, chemotherapy has had little impact on patients with metastatic disease. Combination chemotherapy has an established role in the combined-modality treatment of patients with locally advanced disease [3]. Surgery remains the treatment of choice for patients with early-stage disease.

Epidemiology

Lung, colorectal, and prostate cancers are the most common cancers in developed countries, whereas cancers of the cervix, liver, and head and neck are the most common cancers in developing countries. Nonetheless, the incidence of lung cancer is beginning to fall in developed countries-which may reflect the efficacy of antismoking campaigns-and rise in developing countries-which may reflect industrialization and the increasing use of tobacco products. Worldwide, lung cancer is the most common cancer in males, accounting for 17.6% of all cancers in men, and the fifth most common cancer in women. The worldwide mortality rate associated with lung cancer is 86%. This rate is exceeded only by the mortality rates of primary tumors of the pancreas, liver, and esophagus [4].

The incidence of lung cancer has changed over the past four decades. Lung cancer was not common prior to the 1930s. Following the large increase in cigarette smoking during the 1940s, the incidence of lung cancer in men increased dramatically, from 11 per 100,000 in 1940 to 75 per 100,000 in 1985. Over the last decade, the incidence of lung cancer in men has leveled off somewhat, to approximately 70 per 100,000. However, there has been a sharp rise in the incidence of lung cancer in women, from 6 per 100,000 in 1960 to 28 per 100,000 in 1987 [5].

The majority of lung cancer patients are between 35 and 75 years old, with a peak incidence between the ages of 55 and 65 (Table 3)[1].

Birth to 39 years40 to 59 years60 to 79 yearsEver (birth to death
All sitesMale1.72 (1 in 58)7.74 (1 in 13)34.30 (1 in 3)44.84 (1 in 2)
Female1.92 ( 1 in 52)9.33 (1 in 11)23.22 (1 in 4)39.26 (1 in 3)
BreastFemale0.46 (1 in 217)3.83 (1 in 26)6.77 (1 in 15)12.30 (1 in 8)
Colon and rectumMale0.06 (1 in 1,667)0.93 (1 in 108)4.39 (1 in 23)6.14 (1 in 16)
Female0.05 (1 in 2,000)0.73 (1 in 137)3.32 (1 in 30)5.92 (1 in 17)
ProstateMaleLess than 1 in 10,0000.97 (1 in 103)1.84 (1 in 8)15.44 (1 in 6)
LungMale0.04 (1 in 2,500)1.55 (1 in 65)6.71 (1 in 15)8.49 (1 in 12)
Female0.03 (1 in 3,333)1.07 (1 in 93)3.62 (1 in 28)5.17 (1 in 19)

Black males have a 40% higher incidence of lung cancer than do white males; however, the incidence is leveling off in both black and white males in connection with a decrease in cigarette smoking [6]. In addition, the decline in lung cancer is most pronounced in individuals of higher education and appears to correlate with the marked decrease in cigarette consumption among individuals with a college education [5]. While changes in the incidence of lung cancer correlate most closely with changes in the incidence of smoking, there are several other risk factors that appear to contribute to the development of lung cancer (Table 4).

Risk factorRelative riskReference
Cigarette smoking in males1704Garfinkel and Silverberg [20]
Cigarette smoking in females10.8Garfinkel and Silverberg [5]
Passive smoking1.5Wald et al [12]
Asbestos1.4-2.6Hodgson and Jones [15]
Mining3-8 (lifetime)Harley et al [18]
Radon (residential, > 8 pCi/yr)2 (lifetime)Nero et al [20]

Risk Factors/Etiology

Cigarette Smoking

The most important risk factor for the development of NSCLC is cigarette smoking. Epidemiologic data on smoking and lung cancer demonstrate a causal association. Changes in lung cancer incidence and mortality have paralleled changes in the prevalence of cigarette smoking. The relative risk for lung cancer in current smokers, compared to those who have never smoked, is 13.3. There is also evidence for a dose-response relationship between smoking and lung cancer [7]. In addition, smoking cessation leads to a decrease in lung cancer risk over time.

Chemistry of Carcinogenesis

The N-nitrosamines and polycyclic aromatic hydrocarbons are the two major classes of tobacco-related inhaled carcinogens. N-Nitrosamines are formed during tobacco processing and pyrosynthesis. They originate from nicotine and the alkaloid arecoline [8]. Chemicals derived from tobacco smoke cause lung tumors in experimental animals. The main nitrosation products of nicotine are NNK (nicotine-derived nitrosamino ketone) and NNN (N´-nitrosonornicotine). They are considered very strong lung carcinogens [9].

The nitrosamines are activated through hydroxylation by the P450 enzyme system and then exert their action through the formation of DNA adducts. The formation of DNA adducts is directly related to the amount of cigarette consumption [10]. DNA adducts can remain in the system for as long as 5 years without significant change, and in heavy smokers, they may be responsible for as many as 100 mutations per cell genome.

The polycyclic aromatic hydrocarbons benzo[a]pyrene and dimethylbenz[a]anthracene are also significant chemical mutagenic/carcinogenic substances that lead to the formation of DNA adducts [11].

Passive Smoking

The National Research Council has estimated that the risk of developing lung cancer in nonsmokers exposed to cigarette smoke is approximately 1.35 times the risk of unexposed nonsmokers [12], although the risk is difficult to estimate. Moreover, according to risk analysis, as many as 40% of lung cancer deaths in nonsmokers may be caused by passive smoking [13]. Indeed, passive smoking has recently been declared a carcinogen by the Environmental Protection Agency on the basis of the correlation between passive exposure to cigarette smoke and the development of lung cancer.

Asbestos

Asbestos exists in many natural forms. The silicate fiber has been implicated in carcinogenesis, is chemically inert, and can remain in a person's lungs for a lifetime. Epidemiologic studies have confirmed the association between asbestos exposure and certain lung diseases such as pulmonary fibrosis, mesothelioma, and lung cancer [14]. Most asbestos exposure occurs in the workplace, for example, among shipyard workers or plumbers. In a study of British asbestos workers, the relative risk of lung cancer was 1.4 to 2.6 [15].

Most likely, asbestos acts as a tumor promoter [16]. As smoking is known to impair bronchial clearance, it is reasonable to assume that smoking prolongs the presence of asbestos in the pulmonary epithelium. When smoking is combined with asbestos exposure, the relative risk of lung cancer is strikingly increased, to 28.8 [17].

Radon

Radon is a naturally occurring, chemically inert gas that is a decay product of uranium. Radon decays to products that emit heavy ionizing alpha particles. Radon exposure increases the risk of developing lung cancer as much as 10 times [18], and lung cancer caused by radon exposure is usually the small-cell type [19].

Among uranium miners who smoke, the risk of developing lung cancer is 10 times that of their nonsmoking colleagues. Another study estimated that 1,000,000 homes in the United States may be exposed to levels of radon greater than 8 pCi per year, which is similar to or in excess of the level of exposure in uranium miners [20]. Other studies have estimated that as many as 25% of all cases of lung cancer among nonsmokers may be related to radon exposure [21].

Diet

Diet may also be a risk factor for lung cancer [22]. Of 15 retrospective studies, 14 found an association between increased beta-carotene intake and decreased risk of lung cancer.

A decrease in lung cancer risk was also associated with increased vitamin C intake in four of these studies and with increased fiber intake in two studies. Five of six prospective studies found a decreased risk of lung cancer to be associated with an increased intake of carotenoids. In addition, several studies have demonstrated an inverse correlation between serum beta-carotene levels and the incidence of lung cancer. However, other studies have failed to confirm this correlation.

A recent review of these data suggests that if the general public increased its fruit and vegetable consumption to levels characteristic of the highest 30% of individuals in these studies, the risk of lung cancer in the community might be decreased by 15% to 31%. While the exact agents in the diet that result in a decreased incidence of lung cancer remain unknown, a large body of epidemiologic evidence suggests that increased fruit and vegetable consumption decreases the risk of lung cancer. These data, combined with data on other tumor types, led to the National Cancer Institute's recommendation for the consumption of five or more servings of fruits and vegetables daily.

A surprising result, however, came recently from a randomized, double-blind, placebo-controlled primary prevention trial. The Cancer Prevention Study Group [23] enrolled 29,133 male smokers aged 50 to 69 years, and randomly assigned them to one of four regimens: alpha-tocopherol, 50 mg/d; beta-carotene, 20 mg/d; both alpha-tocopherol and beta-carotene; or placebo. Patients were followed up for 5 to 8 years. A total of 876 new cases of lung cancer were diagnosed during the trial, and no reduction in the incidence of lung cancer was observed among the men receiving alpha-tocopherol. Patients receiving beta-carotene had a higher incidence of lung cancer and 8% higher mortality from lung cancer and heart disease than did patients not receiving beta-carotene. The investigators concluded that there was no reduction in the incidence of lung cancer among male smokers after 5 years of dietary supplementation with beta-carotene or alpha-tocopherol and that such supplementation might do as much harm as good.

Genetic Predisposition

It has been estimated that cigarette smoking is responsible for 90% of lung cancers occurring in the United States [24]. However, only a fraction of smokers develop a bronchial malignancy. Passive smoking and occupational exposure to substances such as asbestos, radon, arsenic, nickel, and polycyclic aromatic hydrocarbons are risk factors for lung cancer, but only a portion of individuals exposed to these substances develop cancer. These facts suggest that cancer susceptibility differs among individuals and may have a genetic basis.

Several findings seem to support genetic susceptibility. First, the risk of lung cancer appears to be increased in individuals with chronic obstructive pulmonary disease, even when the degree of cigarette consumption is taken into account. The development of chronic ostructive pulmonary disease appears to have a familial association. Therefore, the increased risk of lung cancer may also involve a genetic risk [25]. Second, recent data have suggested that the predisposition to developing lung cancer at an early age is inherited in a Mendelian codominant fashion [26].

Third, increased metabolism of the antihypertensive drug debrisoquine has been associated with an increased risk of lung cancer. It has been hypothesized that interindividual variations in the ability to metabolically oxidize substances via the cytochrome P450 system may account, in part, for differences in the susceptibility to cancer. Individuals with increased oxidative activity may be at increased risk of developing cancer because of their increased level of activated carcinogens. Furthermore, the ability to metabolize debrisoquine segregates individuals into different phenotypes. In support of the association between debrisoquine metabolism and lung cancer, individuals with the ability to extensively metabolize debrisoquine showed an increased incidence of lung cancer [27]. This association was further confirmed by a 1990 case-control study, which found that individuals who could extensively metabolize debrisoquine had an increased risk of lung cancer, with an odds ratio of 6.1 [28].

Familial aggregation of lung cancer has been studied by Tokuhata et al [29], who conducted a case-control study that examined the frequency of lung cancer among parents and siblings of 270 lung cancer patients. The incidence of lung cancer was twice as great as expected among smokers and four times as great as expected among nonsmokers. Another case-control study conducted by Ooi et al [30] reviewed a population of 336 deceased lung cancer patients from Louisiana. Lung cancer was seen much more commonly in first-degree relatives than in spouses of patients.

Thus, although the genetic risk factors associated with lung cancer are poorly defined, increasing data suggest the existence of a genetic predisposition to the development of lung cancer.

Histology

The distinction between non-small-cell lung cancer and small-cell lung cancer is of major clinical import, as it significantly alters treatment options. The histologic types of lung cancer defined by the World Health Organization are listed in Table 5. While specific subtypes of NSCLC do not alter treatment plans overall, certain clinical patterns are associated with specific subtypes, eg, adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma.

IEpidermoid carcinoma
IISmall-cell carcinoma
IIIAdenocarcinoma
IVLarge-cell carcinoma
VCombined epidermoid and adenocarcinomas
VICarcinoid tumors
VIIBronchial gland tumors
VIIIPapillary tumors of the surface epithelium
IX"Mixed" tumors and carcinosarcomas
XSarcomas
XIUnclassified
XIIMelanoma

The frequency of the histologic subtypes has changed over the past 20 years. Squamous-cell carcinoma was formerly the most frequent subtype of NSCLC. Recently, however, the incidence of this subtype has decreased while the incidence of adenocarcinoma has increased.

Adenocarcinoma

Adenocarcinoma is the most common subtype of NSCLC in North America and constitutes about 50% of all NSCLC cases in some series. Although adenocarcinoma is associated with smoking, it is especially predominant among women and nonsmokers. Most of these tumors are peripheral and arise from surface epithelium or bronchial mucosal glands and as peripheral scar carcinomas. On histologic examination, adenocarcinoma demonstrates gland formation, papillary structures, or mucin production; on immunohistochemical examination, the tumors stain positive for keratin as well as carcinoembryonic antigen (CEA).

Patients with adenocarcinoma frequently present with metastatic disease prior to the development of symptoms secondary to local disease. Pulmonary adenocarcinoma is associated with hypertrophic osteoarthropathy, Trousseau's syndrome, and cerebellar ataxia. The bronchioalveolar subtype of adenocarcinoma appears to be a distinct clinicopathologic entity. It may present as a solitary peripheral nodule, as multicentric disease, or with rapidly progressing pneumonic involvement. It may occur as early as the second decade of life, and the characteristic clinical presentation is that of multiple pulmonary nodules.

Squamous-Cell Carcinoma

Squamous-cell, or epidermoid, carcinoma, formerly the most common subtype of NSCLC, is now the second most frequent, accounting for roughly 30% of such cancers. This tumor arises most frequently in the proximal bronchi. Because of its central location and the tendency of these cells to exfoliate, squamous-cell carcinoma can be detected on cytologic examination at an early stage. With time, these tumors tend to cause bronchial obstruction and atelectasis or pneumonia. They also tend to remain localized and cavitate.

Of all the subtypes of NSCLC, the squamous-cell variety has the strongest association with smoking. Pathologically, it is characterized by visible keratinization with prominent desmosomes and intercellular bridges. Increased secretion of a parathyroid-like hormone in squamous-cell carcinoma has led to this subtype's association with hypercalcemia.

Large-Cell Carcinoma

The least common subtype of NSCLC, large-cell carcinoma, accounts for approximately 20% of all NSCLC. Refinements in histopathologic techniques have led to the diagnosis of adenocarcinoma or squamous-cell carcinoma in cases previously diagnosed as undifferentiated large-cell carcinoma.

In some cases, the exact histologic subtype of NSCLC cannot be determined; however, as long as NSCLC can be clearly documented, therapeutic plans can proceed [31].

Molecular Biology

Advances in our understanding of the biology of lung cancer may lead to progress in the therapy for or prevention of lung cancer. Carcinogenesis of lung cancer appears to evolve through a multiple-step process involving changes in many suppressor genes and oncogenes [32]. Cytogenetic studies of lung cancer have revealed a large number of chromosomal abnormalities, several of which have been found to be nonrandom (Table 6) [33,34].

The most commonly identified deletion involves the short arm of chromosome 3. This event is more frequent in small-cell lung cancer, but has been seen in NSCLC, as well. Mutations in the tumor-suppressor genes p53 and retinoblastoma (Rb) have been associated with the development of NSCLC. The p53 gene is responsible for the production of a nuclear phosphoprotein that is considered extremely important in DNA repair, growth regulation, cell division, and programmed cell death (apoptosis) [35].

Under normal conditions, the production of p53 protein is increased when DNA damage occurs. Increased amounts of p53 induce G1 arrest, thereby allowing time for DNA repair. Once repair has occurred, the cell is released from the cell-cycle block and proceeds to S-phase and cell division. If the DNA cannot be repaired, the cell is diverted toward programmed death [36]. When a mutation or deletion has occurred in the p53 gene, G1 arrest cannot be achieved. The abnormal cell is allowed to proceed to S-phase, where it divides and further propagates the genetic damage, which may lead to cancer.

Inherited lesions of p53 have been found in the Li-Fraumeni syndrome, which is associated with an increased incidence of brain cancer, breast cancer, and soft-tissue sarcomas. Lung cancer also is frequently found in families with this syndrome. Although mutations of the p53 gene have been found in about 50% of NSCLC [37], correlation of p53 mutations with prior smoking, tumor histology, and survival has not been elucidated.

The Rb gene codes for a nuclear phosphoprotein that appears to be involved in the cell cycle. Mutations of the Rb gene are very common in patients with small-cell lung cancer. However, only 20% of tumor specimens from NSCLC contain an Rb mutation [38].

The dominant oncogene ras codes for a 21-kDa protein that has structural homology to the G proteins and mediates signal transduction pathways between cell-surface receptors and intracellular molecules. Transfection of a mutated ras gene into small-cell lung cancer cell lines results in a phenotype consistent with NSCLC [39]. Mutations of codon 12 of the K-ras gene are commonly found in NSCLC adenocarcinomas [39]. The presence of the K-ras codon-12 mutation is an adverse prognostic factor for survival in patients with resected adenocarcinoma of the lung and may be associated with early metastatic disease [41]. The myc oncogene family appears to play a role in the pathogenesis of small-cell lung cancer.

The cell surface expresses a variety of molecules that play a role in cell-cell and cell-matrix communication. It has been found that various human cancers lose the cell-surface expression of blood-group determinants [42]. In NSCLC, patients whose tumors do not express ABO blood group antigen have shorter survival than do patients whose tumors maintain blood group antigen A and AB expression [43]. Enhanced expression of H/Ley/Leb antigens, which is associated with the absence of A and B group antigens, is also associated with decreased survival [44].

Autocrine production of peptides and inappropriate production of hormones or hormone-like substances have been associated with tumor growth in many malignancies. In NSCLC, epidermal growth factor binds to the epidermal growth factor receptor and stimulates the growth of the tumor [45]. This receptor is present in approximately two thirds of NSCLC [46]. Monoclonal antibodies blocking the action of epidermal growth factor are being tested in clinical trials [47].

Activation of opioid receptors on the surface of human lung cancer cells results in inhibition of tumor growth. Nicotine has been found to reverse this inhibition [48]. Methadone in low doses is able to inhibit the growth of lung cancer cells, presumably through diversion of the cells to programmed cell death [49].

Advances in the understanding of the molecular biology of lung cancer may improve the diagnosis, staging, and even treatment of patients with this disease. In addition, understanding of molecular markers may allow identification of individuals at increased risk for the development or recurrence of lung cancer and selection of those individuals for chemoprevention or adjuvant therapy studies.

Clinical Presentation

The signs and symptoms of lung cancer are related to the location of the disease and the occurrence of paraneoplastic syndromes [31,50]. Many patients present asymptomatically with a coin lesion discovered on a routine chest roentgenogram. The symptoms of centrally located lesions include cough, hemoptysis, wheezing, stridor, dyspnea, and postobstructive pneumonia. Peripheral lesions may result in pain from pleural or chest wall invasion, cough, or restrictive dyspnea.

A lesion involving the intrathoracic nerves may result in one of several syndromes. Pancoast's syndrome, which is characterized by shoulder pain radiating to the arm in an ulnar distribution, is caused by tumor invasion of the eighth cervical and first thoracic nerves in the superior sulcus. Horner's syndrome, which consists of enophthalmos, ptosis, meiosis, and ipsilateral dyshidrosis, may be caused by extension of the tumor into the paravertebral sympathetic nerves. Because the left recurrent laryngeal nerve passes through the aortic pulmonary window, it is susceptible to injury secondary to mediastinal node involvement. Such injury causes vocal cord paralysis with subsequent hoarseness. Elevation of the hemidiaphragm secondary to phrenic nerve paralysis may be caused by tumor invasion into the mediastinum. Other symptoms also occur commonly with mediastinal involvement. For instance, malignant pleural effusions may result in dyspnea. Cardiac symptoms may result from malignant pericardial effusions secondary to pericardial invasion. Superior vena cava syndrome may result from either right-sided tumors or mediastinal nodal involvement. Dysphagia may result from compression of the esophagus.

Non-small-cell lung cancer is frequently metastatic, and symptoms secondary to the site of metastases are common. The most common sites of metastases in descending order of frequency are listed in Table 7. Bone metastases may be associated with pain, pathologic fractures, or spinal cord compression. Liver metastases may be associated with pain. Central nervous system metastasis may be indicated by seizures, headache, nausea, vomiting, altered mental status, or focal neurologic signs.

Finally, the clinical observation of weight loss and tumor related cachexia has been found to be an independent adverse prognostic factor.

Paraneoplastic Syndromes

The production of ectopic hormones or hormone-like substances is not uncommon in lung cancer and results in paraneoplastic syndromes, which have been described most commonly with small-cell carcinoma. Nonetheless, a significant number of patients with NSCLC develop a paraneoplastic syndrome during the course of the disease.

Hypercalcemia, caused by bone metastases or ectopic production of a parathyroid hormone-related peptide, is the most frequent paraneoplastic syndrome in NSCLC. Hypercalcemia is most commonly associated with the squamous-cell subtype.

Hypertrophic pulmonary osteoarthropathy characterized by painful periostitis of the long bones and clubbing of the fingers and toes is usually seen with adenocarcinoma. Radionuclide bone scans and plain roentgenograms are usually helpful in establishing this diagnosis. Trousseau's syndrome or migratory thrombophlebitis, leukocytosis, and thrombocytosis have also been observed in lung cancer patients.

Diagnosis

Obtaining a pathologic diagnosis is essential to the management of lung cancer, because NSCLC is managed differently than small-cell lung cancer. A complete history, physical examination, and chest roentgenograms may reveal sites of disease, such as cervical or supraclavicular lymph nodes, skin nodules, or pleural effusions. This initial survey may establish whether the tumor is operable.

Sputum cytology is an appropriate first diagnostic study, especially in the case of a central lesion, since this will allow for a noninvasive diagnosis in some patients. If an easily biopsied lesion is not found and the sputum cytology is negative, the next step is usually flexible fiberoptic bronchoscopy. For lesions that can be visualized endoscopically, diagnoses are made in 97% of tumors with the combination of biopsies, bronchial washings, and bronchial brushings [51]. Only 55% of cases can be diagnosed with bronchial brushings and washings when the lesion is peripheral and cannot be visualized [31].

In the absence of a histologic diagnosis following broncoscopy, the clinical setting will dictate the next appropriate step. Percutaneous transthoracic fine-needle aspiration of pulmonary nodules can be useful in some clinical settings. It is usually performed under fluoroscopic or computed tomographic (CT) guidance. Negative results on fine-needle aspiration biopsy are frequent and must be considered indeterminate until the diagnosis is established by another method. Supraclavicular adenopathy, pleural effusions, or metastasis to liver, bone, or adrenal glands may be confirmed using the fine-needle aspiration technique. Finally, if a diagnosis still cannot be established using the above studies, mediastinoscopy with biopsy may be used. If the mediastinal nodes are negative, resection of the nodule will lead to a definitive diagnosis.

Solitary Pulmonary Nodule

The solitary pulmonary nodule represents a unique diagnostic dilemma. A solitary pulmonary nodule is a single mass, usually found incidentally on chest x-ray examination, that is surrounded by lung, is well circumscribed, and does not show evidence of mediastinal or hilar adenopathy. A review of an old chest x-ray film is the single most important step in evaluating a solitary pulmonary nodule. Age less than 40 years, nonsmoker status, a history of exposure to tuberculosis, or residence in an area endemic for histoplasmosis are other factors suggestive of a benign lesion.

If old chest x-ray films are not available and the patient has none of the risk factors described above, surgical resection for diagnosis and therapy is indicated following a staging workup. Radiologic evaluation may also be useful in the presence of factors such as distinct margins, certain calcification patterns (diffuse, central core bull's eye [granuloma], “popcorn ball” [hamartoma], or concentric layers) or high density on CT scans, all of which suggest a benign lesion. However, radiologic tests alone are not sufficient to conclusively rule out malignancy [31].

Staging

Once the histologic diagnosis of NSCLC has been established, the extent of disease must be evaluated to guide appropriate therapy. A complete history and physical examination often suggests sites of extrathoracic spread, which should be confirmed with appropriate imaging studies. A laboratory evaluation, including a complete blood count and routine electrolyte and blood chemistry tests (with liver enzyme studies), should be performed. Any patient who is being considered for surgery should have pulmonary function tests.

A CT scan of the chest and upper abdomen (to include the adrenal glands) is done in the vast majority of patients treated in the United States because the liver and adrenal glands are frequent sites of metastatic involvement. This test permits evaluation of the mediastinum and the contralateral lung and can detect pleural effusions. Patients with abnormal biochemistry values, including elevations in serum calcium or alkaline phosphatase, and patients with pain should have radionuclide bone scans performed to document metastatic disease. The routine use of CT scanning or magnetic resonance imaging of the brain in asymptomatic patients remains controversial, but it is probably not cost effective. Mediastinoscopy can reveal the occasional patient with unsuspected mediastinal lymph-node spread and, thereby, avoid unnecessary thoracotomy and resection. Its routine use in patients with normal imaging of the mediastinum on CT scanning is controversial.

Clinical staging often underestimates the true disease extent. To most accurately predict prognosis, surgical/pathologic staging should be considered. Following the completion of a staging workup, the disease is assigned a TNM stage (outlined in Tables 8 and 9) [52].

StageCharacteristics
TXTumor proven by the presence of malignant cells in bronchopulmonary secretions but not visualized roentgenographically or bronchoscopically, or any tumor that cannot be assessed (as in a pretreatment staging)
T0No evidence of primary tumor
TisCarcinoma in situ
T1Tumor = 3.0 cm or less in greatest dimension surrounded by lung or visceral pleura and without evidence of invasion proximal to a lobar bronchus at bronchoscopyª
T2Tumor > 3.0 cm in greatest dimension, or a tumor of any size that either invades the visceral pleura or has associated atelectasis or obstructive pneumonitis extending to the hilar region; at bronchoscopy, the proximal extent of demonstrable tumor must be within a lobar bronchus or at least 2.0 cm distal to the carina; any assoicated atelectasis or obstructive pneumonitis must involve less than an entire lung
T3Tumor of any size with direct extension into the chest wall (including superior sulcus tumors), diaphragm, or the mediastinal pleura or pericardium without involving the heart, great vessels, trachea, esophagus, or vertebral body; or a tumor in the main bronchus within 2 cm of the carina without involving the carina
T4Tumor of any size with invasion of the mediastinum or involving the heart, great vessels, trachea, esophagus, vertebral body, or carina, or presence of malignant pleural effusion*
N0No demonstrable metastasis to regional lymph nodes
N1Metastasis to lymph nodes in the peribronchial and/or ipsilateral hilar region, including direct extension.
N2Metastasis to ipsilateral mediastinal and subcarinal lymph nodes
N3Metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes, ipsilateral or contralateral scalene or supraclavicular lymph nodes
M0No (known) distant metastasis
M1Distant metastasis present (specify site[s])

 

Stage groupingTNM
Occult carcinomaTXN0M0
Stage 0TisCarcinoma in situ
Stage IT1 T2N0 N0M0 M0
Stage IIT1 T2N1 N1M0 M0
Stage IIIaT3 T3 T1-3N0 N1 N2M0 M0 M0
Stage IIIbAny T T4N3 Any NM0 M0
Stage IVAny TAny NM1

Schematic interpretation of the TNM system is given in Figures 1 to 9 [53].

Treatment

Stages I and II Disease

Patients with stage I or II lung cancer should undergo surgical resection if possible. Despite thorough investigation prior to surgery, many patients are found to have more extensive disease at thoracotomy. The 5-year survival rate for those who have pathologically proven stage I disease (T1-2N0) is 65% [54]. For the subset of patients with completely resected T1N0M0 disease, the 5-year survival rate approaches 75%. For patients with pathologically proven stage II disease (T1N1 or T2N1)-about 10% of all NSCLC patients-the overall 5-year disease-free survival rate is 39% [55].

Surgery is the standard treatment for stages I and II disease, and radiotherapy is indicated for patients who cannot undergo surgery. Several studies have reported 5-year survival rates of 15% to 20% when potentially curative radiotherapy is used in patients with inoperable disease. The decreased survival is probably due, in part, to the lack of pathologic staging in this population as well as to concomitant medical illnesses [56].

The major causes of mortality in patients with stage I and II disease are distant metastatic disease [57] and second primary tumors. In a trial by the Lung Cancer Study Group, the rate of second cancers (not lung primaries) was 1.8% per year, and the rate of new lung cancers was 1.6% per year [58]. A series of nearly 600 stage I NSCLC patients with mature follow-up from Memorial Sloan-Kettering Cancer Center revealed an overall incidence of recurrence of 27% (local or regional, 7%; systemic, 20%) and an incidence of second primary tumors of 34% [59]. This has led to current studies aimed at identifying prognostic factors that may indicate those patients at risk for relapse and to trials of chemoprophylaxis. An ongoing intergroup clinical trial is evaluating the role of 13-cis-retinoic acid as a chemopreventive agent for patients who have undergone resection of stage I disease [60].

Adjuvant chemotherapy has been explored in early-stage NSCLC, and the results have been mixed. Most studies have not documented a survival benefit. A recently reported study of combination chemotherapy with cyclophosphamide (Cytoxan, Neosar), doxorubicin (Adriamycin, Rubex), and cisplatin (Platinol) as adjuvant treatment vs no further therapy was conducted in patients with completely resected stage I NSCLC. No differences in time to recurrence or overall survival were found [61]. In contrast, a study from Finland did find improvements in disease-free survival among patients randomly assigned to receive postresection chemotherapy [62]. At present, adjuvant chemotherapy or radiotherapy in patients with stage I or II NSCLC should be administered only within the context of a well-designed clinical trial. As these patients are at increased risk for second primary tumors and recurrence of their disease, close follow-up is indicated [63].

Stage III Disease

The use of combined-modality therapy in stage III NSCLC is an area of considerable investigation [64]. Intensive research has led, in turn, to the subdivision of stage III disease into stage IIIa (potentially resectable) and stage IIIb (not resectable) based on the difference in outcomes following surgical resection. Stage IIIa patients have a 5-year survival rate approaching 15% with surgery, whereas stage IIIb patients have a 5-year survival rate of less than 5% [55]. However, as the current staging system has been in place only since 1986, much of the literature classifies all locally advanced disease into one category. In addition, under the old staging system in use prior to 1986, distant metastasis was included in the stage III category. Therefore, interpretation of much of the past literature is difficult [64].

Surgery: The efficacy of surgery varies with the subset of stage III disease. For instance, patients with T3N0 disease have a favorable outcome. A 5-year survival rate of 54% was reported from the Mayo Clinic [65] in T3N0M0 patients whose T3 designation was based on chest wall involvement. Patients whose stage III classification is based on N2 disease have a less favorable outcome.

In a large series of patients at Memorial Sloan-Kettering Cancer Center [66], the 5-year survival rate for patients with N2 disease was 30%. The majority of survivors, however, were patients whose disease was clinically defined as N0 or N1 and were found to have N2 disease at surgery. Among those patients with clinically evident N2 disease, the 5-year survival rate was 9%. Because the majority of these patients were evaluated between 1974 and 1984, it is unlikely that CT scans of the chest were done routinely.

At present, surgery in stage III disease should be reserved for patients with certain clinical presentations of stage IIIa disease and should not be considered as primary therapy for patients with stage IIIb disease.

Radiotherapy: Radiotherapy has been considered a routine measure for patients with inoperable, locally advanced disease. The standard therapy is 50 to 60 Gy in 200-Gy fractions five times weekly for 5 to 6 weeks. This regimen is based on a Radiation Therapy Oncology Group (RTOG) trial [67] that found improved local control and a nonsignificant trend toward improved survival at 2 years in patients receiving 50 to 60 Gy vs 40 Gy (19% survival vs 11% survival).

To study the relationship between radiotherapy and survival in detail, a study performed by the Southeastern Oncology Group [68] randomly assigned patients with locally advanced, unresectable NSCLC to one of three treatments: (1) 60 Gy of radiotherapy over 6 weeks; (2) vindesine, 3 mg/m²; or (3) a combination of radiotherapy and vindesine. Median survival durations with the three treatment regimens were 8.6, 10.1, and 9.4 months, respectively. The study concluded that radiotherapy did not improve survival in patients with locally advanced NSCLC.

There are two major criticisms of this study. First, treatment with the single agent vindesine at 3 mg/m² is currently considered suboptimal chemotherapy and would not be expected to have a significant impact on survival. Thus, as the response rate was only 11%, this arm represents more a control arm than a chemotherapy arm. Second, the vindesine-only patients were crossed over to radiotherapy if they became symptomatic, which occurred in 37% of patients initially assigned to vindesine only. Therefore, a conclusion of this study may be that early radiotherapy has no benefit over late thoracic radiotherapy.

In a recent retrospective analysis [69] of a randomized phase I/II trial of 120 cGy twice daily escalating to 60 to 79.2 Gy, the RTOG reported that in a subset of patients with locally advanced, unresectable stage III disease who had good performance status, no supraclavicular lymph-node involvement, and less than 6% weight loss, survival increased with increased radiation dose. Patients in this subset who received 69.6 Gy or more had a median survival of 13 months, with 29% of patients alive at 2 years. In contrast, similar patients receiving 60.0 Gy had a median survival of 10 months and a 2-year survival rate of 18% (P = .02). The improved median survival seen with high doses of radiotherapy may demonstrate that improved survival in locally advanced disease is possible with improvements in local therapy. Because the overall survival of stage III patients remains poor after radiotherapy or surgery alone, the role of multimodality therapy has become an area of intensive investigation.

Adjuvant Chemotherapy: The role of adjuvant chemotherapy in NSCLC is unclear. The Lung Cancer Study Group [70] randomly assigned patients with stage II or III adenocarcinoma or large-cell carcinoma to receive either cyclophosphamide, doxorubicin, and cisplatin (CAP) or a regimen of bacillus Calmette-Gurin (BCG) and levamisole (Ergamisol). Disease-free survival was increased by 7 months (P < .05) in the group receiving chemotherapy, and overall survival increased by 7 months.

Furthermore, in another Lung Cancer Study Group trial of squamous-cell carcinoma patients with positive margins or involved high paratracheal nodes [71], patients who received concurrent chemotherapy (CAP) and radiotherapy showed improved disease-free survival compared with those who received radiotherapy alone (14 vs 8 months, P £ .004). However, overall survival was not significantly improved. Concerns about these studies include the use of doxorubicin and cyclophosphamide, which do not have major single-agent activity in NSCLC, and the very low dose of cisplatin.

Memorial Sloan-Kettering Cancer Center conducted a prospective, randomized study of adjuvant radiation with or without vindesine and cisplatin in stage III (T1-3N2M0) NSCLC patients. No difference in time to progression or overall survival was found [72]. A similar study conducted in Japan randomly assigned stage III patients whose disease had been completely resected to receive no further treatment or adjuvant vindesine and cisplatin chemotherapy. Again, no difference in disease-free or overall survival was found [73]. In summary, cisplatin-based postoperative chemotherapy for stage III NSCLC has not resulted in significantly prolonged survival. The use of such therapy should not be recommended outside the context of a clinical trial.

Neoadjuvant Chemotherapy: The use of chemotherapy prior to surgery in patients with stage IIIa disease has been extensively investigated. Several studies have demonstrated response rates of 50% to 70% and long-term disease-free survival rates of 20% to 30% in patients treated with neoadjuvant chemotherapy. Two randomized trials have confirmed these results (Table 10).

ReferenceNumber of patientsChemotherapyScheduleMedian survival (months)Survival rate
Roth et al [75]28Etoposide, 100 mg/m² × 3 + cyclophosphamide, 500 mg/m² + cisplatin, 100 mg/m²Chemotherapy for 3 cycles preoperatively642 yr/60%
32NoneSurgery alone112 yr/25%
Rosell et al [74]30Mitomycin, 6 mg/m² + ifosfamide, 3 mg/m² + cisplatin, 50 mg/m²Surgery alone261 yr/75%
30NoneSurgery alone81 yr/20%

In one study, 60 patients with stage IIIa NSCLC were randomly assigned to receive either surgery alone or three courses of mitomycin (Mutamycin), ifosfamide (Ifex), and cisplatin given at 3-week intervals followed by surgery [74]. Mediastinal radiotherapy was given to all patients after surgery. The median overall and disease-free survivals were 26 and 20 months, respectively, for the chemotherapy-plus-surgery group vs 8 and 5 months, respectively, for the surgery-only group.

A second study conducted at the University of Texas M.D. Anderson Cancer Center [75] randomly assigned 60 patients with previously untreated, potentially operable stage IIIa disease to six cycles of perioperative chemotherapy (cyclophosphamide, etoposide [VePesid], and cisplatin) and surgery or surgery alone. The major response rate to the preoperative chemotherapy was 35%. Patients treated with perioperative chemotherapy and surgery had an estimated median survival of 64 months, compared with 11 months for patients who had surgery alone. The estimated 2- and 3-year survival rates, respectively, were 60% and 56% for the perioperative chemotherapy patients and 25% and 15% for those who had surgery alone.

Adjuvant Radiotherapy: Several retrospective trials of radiotherapy following resection of stage II or III lung cancer have demonstrated an improvement in overall survival [76-78]. However, a large randomized trial conducted by the Lung Cancer Study Group [79] failed to confirm an overall survival benefit of postoperative radiotherapy in patients with resected stage II or III squamous-cell lung carcinoma. A significant decrease in local recurrence was found, however, and in patients with N2 disease, the overall recurrence rate was decreased, though survival was not improved.

Preoperative Radiotherapy for stage III disease has been investigated in two large randomized trials [80,81], neither of which showed a benefit of this approach. However, both trials included patients with small-cell lung carcinoma, and neither provided adequate preoperative staging by current protocol standards. The use of CT scans, now standard practice, would likely have revealed metastatic disease in some of these patients.

Superior sulcus tumors may represent a unique subset of stage III tumors. Some small uncontrolled series [82,83] demonstrated improved survival in patients with superior sulcus tumors who received preoperative radiotherapy, compared with historical controls. Randomized trials, however, will be necessary to confirm this finding.

Chemoradiotherapy: The combination of chemotherapy and radiotherapy in the treatment of locally advanced, surgically unresectable NSCLC is an active area of research. Of the large randomized trials performed to date, trials conducted by four groups-Dillman et al [84], LeChevalier et al [85,86], Schaake-Koning et al [87], and more recently, the RTOG (RTOG 88-08) and Eastern Cooperative Oncology Group (ECOG 4588) [88]-have shown improvement in survival, albeit modest, in patients receiving chemotherapy plus radiotherapy. However, these trials have used two different approaches to the combination of chemotherapy and radiotherapy: sequential and concurrent.

The sequential chemoradiotherapy and radiotherapy trials listed in Table 11 used systemic doses of chemotherapy prior to and sometimes following radiotherapy. Mattson et al [89] found no benefit of chemotherapy alternating with radiotherapy vs radiotherapy alone; however, the chemotherapy was given during the interval between two courses of radiotherapy. The presence of a gap during radiotherapy may be considered to be suboptimal in radiotherapy-only trials but has not been found to result in decreased survival in phase III trials. In addition, if only the M0 patients are evaluated, a strong trend toward improved survival is found in the chemotherapy-plus-radiotherapy arm. Morton et al [90] also failed to demonstrate a benefit for chemotherapy, but cisplatin was not included in the chemotherapy arm.

ReferenceNumber of patientsRadiation dose (Gy)ChemotherapyScheduleSurvival, 1 yr/2 yr (median in months)
Morton et al [87]5660Methotrexate + doxorubicin + cyclophosphamide + lomustineChemotherapy × 2, radiotherapy46%/21% (10.5)
5860NoneRadiotherapy45%/16% (10.5)
Mattson et al [86]11955Cyclophosphamide + doxorubicin + cisplatinChemotherapy × 2, radiotherapy, chemotherapy × 642%/19% (10.5)
11955NoneRadiotherapy41%/17% (9)
LeChevalier et al [82,83]17665Cisplatin + cyclophosphamide + vindesine + lomustineChemotherapy × 3, radiotherapy50%/21% (12)
17765None
Dillman et al [81]7860Cisplatin + vinblastineChemotherapy × 2, radiotherapy55%/26% (13.8)
7760NoneRadiotherapy40%/13% (9.7)
van Houtte et al [88]2755Cisplatin + etoposide + vindesineChemotherapy × 3, radiotherapy40%/18% (11)
3255NoneRadiotherapy42%/7% (11)
Mira et al [89]10958Cisplatin + cyclophosphamide + doxorubicin + fluorouracil + vincristine + mitomycinChemotherapy, radiotherapy + chemotherapy(9.1)
11758NoneRadiotherapy(9.2)
Trovo et al [93]6245Cyclophosphamide + doxorubicin + methotrexateRadiotherapy, chemotherapy × 12(11.7)
4945NoneRadiotherapy(10.0)
Sause et al [85]15160Cisplatin + vinblastineChemotherapy × 1, radiotherapy60%/13.8
15269.6NoneHyperfractionated radiotherapy51% (12.3)
14960NoneRadiotherapy46% (11.4)

The studies reported by Le Chevalier et al [85,86] and Dillman et al [84] both involved cisplatin-based chemotherapy (three and two cycles, respectively) prior to radiotherapy. In both of these trials, the patients receiving chemotherapy had a significant survival advantage. Of particular interest, Le Chevalier et al [85,86] found significantly fewer failures secondary to metastatic disease in patients given chemotherapy. Dillman et al [84] found no difference in the pattern of relapse, but formal staging was not performed at the time of failure. Furthermore, a higher number of unexpected deaths than expected [90] were found among the patients who received radiotherapy only, compared with only four deaths in the chemoradiotherapy group.

In the study by Van Houtte et al, [91] there was no distinction between stages IIIa and IIIb, which could have led to bias. The study failed to show an advantage in median survival with a cisplatin-containing combination. However, this trial involved far fewer patients than did the other studies. Also, a trend toward a survival advantage was identified at 2 years.

Mira et al [92] and Trovo et al [93] also failed to demonstrate improved survival with chemotherapy, although both trials used suboptimal chemotherapy. Furthermore, Trovo et al [93] utilized suboptimal radiation therapy, with only 45 Gy in both treatment arms. Finally, the RTOG and ECOG study [88] confirmed that cisplatin-based induction chemotherapy followed by radiotherapy was superior to hyperfractionated radiotherapy or standard radiotherapy alone in terms of 1-year survival rates and median survival durations (60% and 13.8 months; 51% and 12.3 months; and 46% and 11.4 months, respectively). The patients in this study had stages II, IIIa, and IIIb disease, had good performance status, and were considered clinically to have unresectable disease.

Another group of studies, summarized in Table 12, involved the use of concurrent chemoradiotherapy to take advantage of the radiosensitizing effects of cisplatin in patients with inoperable tumors. Soresi et al [94] found a trend toward improved survival in a group of patients receiving cisplatin, 15 mg m²/wk, in addition to radiotherapy. A significant decrease in the rate of intrathoracic relapses was noted in the chemoradiotherapy arm, compared with the radiotherapy-only arm (48% vs 59%).

ReferenceNumber of patientsRadiation dose (Gy)ChemotherapyScheduleSurvival, 1 yr/2 yr
Soresi et al [91]4550.4CisplatinChemotherapy weekly + radiotherapy75%/40%ª
5050.4NoneRadiotherapy70%/30%ª
Schaake-Koning et al [93]11055CisplatinChemotherapy weekly + radiotherapy44%/19%
10755CisplatinChemotherapy daily + radiotherapy54%/26%
11455NoneRadiotherapy46%/13%
Ansari et al [92]9060CisplatinChemotherapy every 3rd week + radiotherapy35%/15%
9360NoneRadiotherapy40%/9%
Trovo et al [93]8745CisplatinChemotherapy daily + radiotherapy-/17%
8945NoneRadiotherapy-/20%

A second study of radiotherapy vs concurrent chemoradiotherapy for inoperable patients by Schaake-Koning et al [87] revealed a statistically significant survival advantage for the groups receiving daily cisplatin (6 mg/m²) plus radiotherapy, compared with the patients who received radiotherapy alone. Daily cisplatin appeared to have an advantage over weekly cisplatin, but not a statistically significant one. As in the trial by Soresi et al [94], this study showed a decrease in local recurrence with the combination of chemotherapy and radiotherapy. A major criticism of both of these studies is that they gave relatively low doses of split-course radiotherapy.

In a third large randomized trial by Ansari et al [95], reported in abstract form only, patients with inoperable stage III disease received 60 Gy of radiotherapy without interruption or the same radiation dose with cisplatin (70 mg/m² every 3 weeks). The survival rate at 2 years was slightly better in patients who received chemotherapy plus radiotherapy, but the difference between the two groups did not approach statistical significance. Data on patterns of failure were not included. The failure to demonstrate a benefit from the addition of cisplatin may be due to the lack of radiosensitization resulting from the infrequent cisplatin administration.

While these three studies together suggest a benefit for the addition of chemotherapy to radiotherapy, the combination should not be considered standard therapy for stage III NSCLC at present. Finally, an abstract published by Trovo et al [96] reported no survival advantage for daily cisplatin combined with radiotherapy, compared with radiotherapy alone. However, one fourth of the patients in this study could not be evaluated, and only 45 Gy was administered, both to patients receiving radiotherapy and chemotherapy and to those receiving radiotherapy alone.

Stage IV Disease

Chemotherapy: The presence of metastatic spread (ie, stage IV disease) is an ominous finding in NSCLC. While many trials have been performed using various chemotherapy regimens to combat metastases, it has been difficult to determine whether patients receiving chemotherapy have improved survival. The most active single agents are listed in Table 13. No single agent has been demonstrated to significantly prolong survival. The combination of active agents has been shown to increase response rates to as high as 50% in phase II trials. Unfortunately, it has been difficult to demonstrate significant improvements in survival with such combinations in randomized trials.

Cisplatin
Ifosfamide
Mitomycin
Vinblastine
Vindesine
Vinorelbine
Paclitaxel
Oral etoposide

Edatrexate
Gemcitabine
Docetaxel
CPT-11

As cisplatin appears to be one of the most active and best studied single agents, multiple trials have attempted to demonstrate that combinations containing cisplatin are superior to regimens that do not include this agent. Despite improved response rates for cisplatin-based combinations in most of the major trials [55], only one of six trials comparing cisplatin-containing regimens with regimens not containing cisplatin has demonstrated a significant survival advantage for cisplatin-based therapy [97]. This is not unexpected, as these regimens rarely result in major response rates exceeding 30%. Further attempts have been made to improve response rates by giving cisplatin in escalated doses, but this has resulted in an increase in toxicity with no increase in the response rate [98].

In view of the finding that NSCLC is not sensitive to chemotherapy, the appropriateness of using chemotherapy for NSCLC has been questioned. Five large randomized trials, summarized in Table 14 [99-103], have compared best supportive care with cisplatin-based chemotherapy. All five trials demonstrated an improved median survival in patients receiving chemotherapy; however, this difference attained statistical significance in only two studies [100,103]. In a study by Rapp et al [100], chemotherapy was found to be cost-effective and to improve quality of life, compared with best supportive care.

ReferenceNumber of patientsChemotherapyMedian survival
Cellerino et al [96]62Cyclophosphamide + epirubicin + cisplatin34.3 wk
61None21.1 wk
Rapp et al [97]44Vindesine + cisplatin32.6 wk
43Cyclophosphamide + doxorubicin + cisplatin24.7 wk
50None17.0 wk
Woods et al [98]97Vindesine + cisplatin6 mo
91None4 mo
Ganz et al [99]31Vinblastine + cispatin4.8 mo
32None3.2 mo
Quoix et al [100]24Vindesine + cisplatin199 d
22None73 d

A study conducted at Memorial Sloan-Kettering Cancer Center [104] attempted to identify prechemotherapy characteristics of NSCLC patients that are important prognostic factors and predictive of chemotherapy response. According to this study, pretreatment characteristics associated with a good response to cisplatin-based chemotherapy were Karnofsky performance status greater than or equal to 80, no bone or liver metastases, normal lactate dehydrogenase levels, female gender, less than one site of metastasis, no prior chemotherapy, and weight loss of less than 5%.

Investigational Agents: Several new agents are currently being evaluated in phase II trials. Oral etoposide, paclitaxel (Taxol), and vinorelbine (Navelbine) are relatively recent additions to the list of active chemotherapy agents for the treatment of NSCLC.

Etoposide, when given orally as a single agent over short intervals (less than 5 days), produces responses in approximately 15% of patients, but prolonged (14 to 21 days), low-dose oral administration has produced response rates in excess of 20% [102].

Paclitaxel has also been found to have a response rate in excess of 20% in phase II trials [106,107]. Further studies exploring paclixatel in combination with cisplatin and carboplatin (Paraplatin) are ongoing.

Vinorelbine is a semisynthetic vinca alkaloid recently approved by the Food and Drug Administration for the treatment of inoperable NSCLC. Phase II trials of vinorelbine have been conducted mainly in Europe in patients with NSCLC, breast cancer, ovarian cancer, and Hodgkin's disease. The biologic effect is exerted by inhibition of the microtubule assembly, which results in mitosis blockade. A randomized trial comparing single-agent vinorelbine with the combination of fluorouracil and leucovorin was conducted in NSCLC patients. The median survival was significantly improved for patients receiving vinorelbine (30 vs 22 weeks)[108]. Another study conducted in France compared vinorelbine with vinorelbine plus cisplatin in patients with advanced NSCLC [109]. This trial found the vinorelbine-cisplatin combination to be superior to the other treatment regimens in terms of response rates and overall survival. Further trials exploring the role of vinorelbine in the treatment of NSCLC are currently under way in several cancer centers.

Docetaxel (Taxotere) is a semisynthetic taxoid compound related to paclitaxel that has been evaluated in phase II studies. Response rates of 33% to 38% have been reported in previously untreated NSCLC patients [110,111].

Edatrexate has been shown to be active in phase II trials [112,113]. Kris et al explored a combination of edatrexate, mitomycin, and vinblastine in patients with stage III or IV NSCLC. In this study, the major response rate was 58% and median survival time, 13.6 months [114]. Based on these results, a large phase III trial enrolling over 600 patients was performed comparing the three-drug regimen of edatrexate, mitomycin, and vinblastine with the combination of mitomycin plus vinblastine. No significant improvement in survival was found [115]. Although the use of second-line chemotherapy was not reported, it is noteworty that median survival was 8 months in both arms in this multi-institutional study.

Gemcitabine, a new antimetabolite with an excellent toxicity profile [116] that has been evaluated in both phase I and phase II studies, has produced single-agent response rates of approximately 20% [117].

Topoisomerase inhibitors are currently being investigated. One such agent, CPT-11, was associated with a response rate exceeding 30% in one phase II trial [118]. Topotecan, another drug in this class, is also being studied.

Other Therapies: Although chemotherapy may be used in most patients with metastatic disease, radiotherapy and surgery may be helpful in managing disease in selected patients with stage IV NSCLC. Radiotherapy is indicated for palliation of symptomatic lesions in this population. Radiotherapy to the chest may help relieve pain, hemoptysis, or obstructive symptoms. Furthermore, radiotherapy of bone metastases may help prevent pathologic fractures and relieve pain.

Surgery may be helpful in selected patients with metastatic disease, even though surgical debulking of the primary tumor has not been found to benefit patients with stage IV disease. In patients with a metachronous solitary brain metastasis, surgical resection of the metastatic lesion may improve survival in those patients whose primary lesion is adequately controlled [119].

Finally, proximal bronchial obstructive lesions may be relieved with bronchoscopic Rd/YAG laser treatment or with brachytherapy, both of which are highly effective as short-term (2 to 4 months) palliative measures, even in patients who have had previous radiotherapy [120].

Screening and Prevention: Because advanced-stage NSCLC has a poor prognosis, two strategies-screening and chemoprevention-have been studied for their potential benefits before or early in the course of the disease. Unfortunately, however, large randomized trials conducted over the past 20 years suggest that screening strategies have had little impact.

Whether screening for lung cancer could alter survival in men who smoked heavily was examined in three large studies (Table 15) [121]. A study performed at the Mayo Clinic compared sputum cytology and chest x-ray films vs no scheduled screening. Although the screened population was found to have twice as many pathologic stage I tumors as the unscreened group, there was no difference in overall lung cancer mortality. The other two trials were primarily tests of the screening capabilities of sputum cytologies, as both the control and test groups were followed with chest x-ray films. Neither study showed a reduction in rates of lung cancer mortality among patients who underwent routine sputum cytologies.

TrialNumber of patientsScreening procedureLung cancer mortality per year
Mayo Clinic9,211Chest x-ray + sputum cytology3.2/1,000
None3.0/1,000
Johns Hopkins10,386Chest x-ray + sputum cytology3.4/1,000
Annual chest x-ray3.8/1,000
Memorial Sloan-Kettering10,040Chest x-ray + sputum cytologyNo difference

Current efforts at developing effective screening programs are based on the development of molecular markers of the early onset of lung cancer. For example, the use of monoclonal antibodies to screen sputum specimens preserved from the Johns Hopkins screening trial was very effective in detecting patients destined to develop lung cancer [122].

The second approach to early intervention is chemoprevention. Several lines of evidence suggest that such intervention may be effective. First, NSCLC is a multistep process characterized by premalignant changes, such as bronchial metaplasia and dysplasia, in heavy smokers. These changes may permit identification of high-risk individuals who are candidates for early intervention.

Second, dietary evidence presented earlier in this review suggests that substances such as beta-carotene or retinoids may help prevent lung cancer [22]. Several studies have been undertaken to demonstrate the benefits of various retinoids in preventing lung cancer. In a randomized trial of patients who had undergone resection of primary head and neck cancers (a group at very high risk for lung cancer)[123], patients randomized to receive 13-cis-retinoic acid had a significantly lower incidence of second primary tumors than did a placebo group. In addition, no lung cancers developed in the cis-retinoic acid group, whereas three lung cancers developed in the placebo group.

A large intergroup trial is currently being planned to determine whether 13-cis-retinoic acid can prevent second primary tumors in patients with pathologic stage I disease. In view of the continued lack of effective therapy for advanced NSCLC, ongoing efforts to determine effective screening and chemoprevention programs have assumed the utmost importance.

Conclusions

Non-small-cell lung cancer remains one of the most devastating illnesses in the United States in terms of the number of patients and overall mortality. Surgery offers the potential for significant long-term survival in those patients who have pathologically staged early, local disease. Unfortunately, 70% of all NSCLC patients have regional, nodal, or metastatic involvement at the time of presentation.

Although current efforts to develop multimodality therapies may offer some hope of improved survival for the patient with locally advanced disease, current therapies are simply ineffective for patients with metastatic disease. Therefore, one of the oncologist's most important roles must be to promote primary prevention, with an emphasis on advising patients to stop smoking, as this will affect lung cancer mortality. In addition, further attempts to improve screening strategies and to develop effective chemoprevention regimens are essential.

References:

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