Cancer Management Chapter 3: Non–small-cell lung cancer

March 8, 2010

Lung cancer has been the leading cause of cancer death among men in the United States for years, and since 1988, it has become the number-one cause of cancer death among women. An estimated 219,440 new cases of lung cancer are expected in 2009, and 159,390 deaths due to this disease are expected to occur, roughly 30% of all cancer deaths. This exceeds the combined number of deaths from the leading causes of cancer (breast, prostate, and colon cancers). It accounts for 6% of all deaths in the United States.

Lung cancer has been the leading cause of cancer death among men in the United States for years, and since 1988, it has become the number-one cause of cancer death among women. An estimated 219,440 new cases of lung cancer are expected in 2009, and 159,390 deaths due to this disease are expected to occur, roughly 30% of all cancer deaths. This exceeds the combined number of deaths from the leading causes of cancer (breast, prostate, and colon cancers). It accounts for 6% of all deaths in the United States.

Lung cancer develops from pulmonary parenchymal or bronchial supportive tissues. Although multiple cell types are often found within a single lung tumor, one type usually predominates. Based on the therapeutic approach, there are two major subdivisions of lung cancer: small-cell lung cancer (SCLC), for which chemotherapy is the primary treatment, and non–small-cell lung cancer (NSCLC), which in its early stages (I and II) is treated primarily with surgery.

This chapter provides basic information on the epidemiology, etiology, screening, prevention, and signs and symptoms of lung cancer in general and then focuses specifically on the diagnosis, staging, pathology, and treatment of NSCLC and carcinoid tumors of the lungs, as well as the pulmonary evaluation of lung cancer patients and follow-up of long-term survivors.

Chapter 4 provides information on the staging, pathology and pathophysiology, and treatment of the far less common SCLC and concludes with brief discussions of mesothelioma and thymoma.

Epidemiology

Gender In the United States, the estimated number of new lung cancer cases for 2009 is 116,090 for men and 103,300 for women. Although the incidence of lung cancer had been rising in women, the rate of increase has begun to slow recently. The incidence is decreasing in men.

Age The age at which lung cancer patients are diagnosed varies widely, but the median age at diagnosis is approximately 70 years.

Race In the United States, the highest incidence of lung cancer in men and women is found in African Americans (107.6/100,000 for men and 54.9/100,000 for women) followed by Caucasians (79.3/100,000 for men and 54.9/100,000 for women).

Geography There are geographic variations in the incidence of lung cancer, with the highest rates worldwide observed in North America and Eastern Europe; in the United States, the highest rates are found in northern urban areas and along the southern coast from Texas to Florida. The state with the highest incidence of lung cancer is Kentucky, with an incidence of 136.2/100,000 in men and 76.2/100,000 in women.

Survival The overall 5-year survival rate for lung cancer is 15%, of which there has been a 1% improvement each decade for the past 30 years.

Etiology and risk factors

Cigarette smoking Approximately 87% of all cases of lung cancer are related to cigarette smoking. There is a relatively strong dose-response relationship between cigarette smoking and the development of this cancer. The greater the number of cigarettes smoked on a daily basis and the greater the number of years of smoking, the greater is the risk of lung cancer. An individual who smokes one pack of cigarettes daily has a 20-fold increased risk of lung cancer compared to a nonsmoker.

The overall incidence of cigarette smoking decreased from 1974 through 1992. Smoking cessation decreases the risk of lung cancer, but a significant decrease in risk does not occur until approximately 5 years of discontinuation, and the risk remains higher in former smokers than in nonsmokers for at least 25 years. The benefit of smoking cessation is greater if it occurs at a younger age.

Smoking cessation is difficult. Recent data have suggested that a variety of hereditary factors increase the risk of addiction to nicotine among some individuals. Nevertheless, millions of former smokers have quit successfully. Smoking cessation programs that address both physical withdrawal from nicotine and psychological dependence appear to be more effective than either of these approaches alone. In addition, continued efforts are needed to prevent adolescents and preadolescents from beginning to smoke or to encourage them to quit after a brief period of experimentation.

Several cancer centers have recently reported that more than half of their patients with newly diagnosed lung cancer are former smokers, having quit more than 1 year before diagnosis. Healthy ex-smokers represent a large group of individuals who may benefit from effective tools for early detection and/or chemoprevention of lung cancer.

Secondhand smoke Not only is smoking risky for those who smoke, but it also poses a hazard to nonsmokers who either live or work with smokers. It is estimated that approximately 3,000 lung cancer deaths per year in the United States are due to secondhand smoke. Individuals who live in a household with a smoker have a 30% increase in the incidence of lung cancer compared to nonsmokers who do not live in such an environment.

Asbestos exposure is another risk factor for lung cancer. Cigarette smokers who are exposed to asbestos develop lung cancer at an extremely high rate. There is a 90-fold increase compared with unexposed individuals. Exposure to asbestos is also a major risk factor for the development of mesothelioma (see discussion of this cancer in the following chapter).

Radioactive dust and radon exposure Uranium miners who have been exposed to radioactive dust and radon gas also have an increased incidence of lung cancer. Although there has been some controversy about the risk posed by exposure to residential radon gas, a study conducted in Sweden showed an increased incidence of lung cancer in individuals who were exposed to a high level of radon in their homes.

Screening and prevention

Screening
Currently, screening for lung cancer among asymptomatic individuals at elevated risk due to smoking history or occupational exposures is not recommended. An unfortunate result of this policy is that most patients present in advanced stage, and cure rates have improved little over the past 30 years. Only 7% of NSCLC patients are diagnosed in stage IA.

Three randomized screening trials conducted in the United States in the 1970s failed to show a reduction in lung cancer mortality among the smokers who were screened by sputum cytology and chest x-ray for lung cancer. Despite the fact that these American trials were not designed to evaluate chest x-ray as a screening tool, the results led most experts to conclude that screening for lung cancer was not worthwhile. In addition, most investigators recommended that research efforts and resources be allocated to the prevention of lung cancer. A recent, randomized, prospective trial from Czechoslovakia showed that screening with a chest x-ray increased the diagnosis of early-stage lung cancer but failed to reduce the mortality from lung cancer.

The potential to screen for lung cancer has received renewed interest due to the superior performance of low-dose helical CT compared with chest radiography in detecting small lesions. Although there is insufficient evidence to establish policy related to routine screening for lung cancer with spiral CT, there is a growing trend toward promoting screening with this new technology to individuals at increased risk for lung cancer.

Numerous studies are currently under way to evaluate chest CT scan for lung cancer screening. Several recent reports from Japan, Germany, and the United States have documented the ability of low-dose spiral CT scans to detect lung cancer at an early stage. In some recent trials, more than 80% of lung cancers detected by screening were diagnosed in stage I.

Kaneko screened male smokers > 50 years of age. Of the 15 cancers detected by CT scan, only 4 were seen on chest x-ray; 14 of the 15 cancers were stage I, with an average diameter of 1.6 cm. Ohmatsu found 35 lung cancers (0.37% detection rate) with 9,452 CT scans. Of these cancers, 27 were stage IA. These patients had a 3-year survival rate of 83%.

The I-ELCAP (http://www.ielcap.org/professionals.htm) is a single-arm prospective study that has accrued more than 35,000 study subjects from 30 sites and documented that a high percentage of lung cancers are detected in stage I, a stage in which long-term survival can reasonably be anticipated in more than 60% of patients. These studies provide early evidence to suggest that CT lung cancer population screening has the potential to reduce lung cancer mortality in the near future.

In a controversial article from I-ELCAP, Henschke et al presented the results of their low-dose CT screening trial in 31,567 high-risk participants. CT was performed every 7 to 18 months. Lung cancer was found in 484 (1.5%), of whom 412 (85%) were stage 1, with an 88% 10-year survival rate estimated in that cohort. Noncalcified pulmonary nodules were detected in 233 participants (23% [95% confidence interval (CI): 21–26]) by low-dose CT at baseline, compared with 68 (7% [95% CI: 5–9]) by chest radiography. Lung cancer was detected by CT in 27 patients (2.7% [95% CI: 1.8–3.8]) and by chest radiography in 7 patients (0.7% [95% CI: 0.3–1.3]).

Of the 27 CT-detected cancers, 26 were resectable. Stage I cancers were diagnosed in 23 of 27 patients (85%) by CT and 4 of 7 patients (57%) by chest radiography. In addition, low-dose CT detected four more nonparenchymal cases of lung cancer: two with endobronchial lesions and two in the mediastinum. These cases show an added benefit of low-dose CT over chest radiography, although the data were not included in the analysis. (The study primarily focused on malignant disease in noncalcified pulmonary nodules detected by low-dose CT or radiography.) It remains to be seen, however, whether lung cancer screening with low-dose spiral CT will reduce the lung cancer mortality of the study population or only improve the 5-year survival rate of the patients diagnosed with lung cancer.

Based on growing evidence that spiral CT may truly provide for a successful early detection strategy, the National Cancer Institute (NCI) launched the NLST (http://www.nci.nih.gov/NLST) in September 2002. NLST has accrued 50,000 current and former smokers (aged 55–74) into a prospective trial, randomizing participants to receive annual spiral CT or annual chest x-rays. Survival data will not be available for a number of years.

The efficacy of lung cancer screening is also being evaluated as part of the PLCO. Men and women were randomized to receive annual chest x-ray vs usual care. Eligibility was not based on risk of lung cancer, because given the large size of the study (> 100,000 participants), it was expected that there would be appreciable numbers of current and former smokers among the participants.

In response to the I-ELCAP results, Bach et al reviewed the collective results of three prospective concurrently run randomized screening trials in 3,246 high-risk patients. They found no reduction in lung cancer deaths or advanced cancer in the screened groups.

The increased use of CT scanning in the United States, currently more than 62 million scans per year, has significantly increased the exposure to radiation in the population and may be a future health issue. The exposure to radiation from two to three CT scans in an adult is similar to that experienced by survivors of atomic bombs dropped on Japan in 1945. The risks associated with exposure to radiation are highest in children.

Biomarkers, proteomic evaluations, and circulating endothelial cells are currently under intensive investigation within and outside the Early Detection Research Network (http://edrn.nci.nih.gov/). The lack of demonstrated benefit for the earlier radiographic screening approaches should not be misinterpreted as nihilism about the early detection of lung cancer. Individuals at risk (current and former smokers) who present with symptoms consistent with lung cancer deserve appropriate evaluation. A lack of resolution of radiographic abnormalities on a chest x-ray obtained after the completion of empiric antibiotic therapy for pneumonia should prompt further evaluation for possible lung cancer.

Chemoprevention
The concept of field carcinogenesis was originally developed for the aerodigestive tract in the early 1950s. Reducing the exposure of the epithelial mucosa to carcinogens, predominately cigarette smoke, has the greatest impact on reducing the incidence of cancer in high-risk individuals.

The Finnish Alpha-Tocopherol Beta-Carotene Study evaluated 29,133 male smokers over 5 to 8 years, and there was an 18% increased incidence of lung cancer in the group taking beta-carotene. Other chemopreventative agents studied in a phase III fashion include retinol, aspirin, retinyl palmitate, etretinate, isotretinoin, α-tocopherol, 4-hydroxyphenyl retinamide, anethole dithiolethione, and N-acetylcysteine. None of them showed any preventive benefit.

Second primary lung tumors develop at a rate of 1% to 3% annually for the first 5 years following resection of stage I NSCLC.

The intergroup randomized trial that assessed the ability of 13-cis-retinoic acid to prevent the occurrence of a second primary cancer in patients with completely resected stage I NSCLC showed no impact of treatment on the incidence of second primary tumors. Furthermore, patients who continued to smoke and who received isotretinoin had a higher risk of recurrence of the index cancer. The early findings have demonstrated a higher-than-expected recurrence rate in patients with early-stage lung cancer who received 13-cis-retinoic acid and continued to smoke. Also, there was no reduction in second primary tumors in the 13-cis-retinoic acid-treated group. Trials using cyclooxygenase-2 (COX-2) inhibition are yet to be reported in former and current smokers. Tyrosine kinase inhibition is currently being studied to reverse bronchial premalignant lesions and Ki-67 levels in the Lung Cancer Biomarkers Chemoprevention Consortium trial.

Selenium as L-selenomethionine has been shown to inhibit cell growth, induce apoptosis in vitro, and retard carcinogenesis at higher dose levels in animal models. Epidemiologic data suggest an inverse relationship between selenium intake and lung cancer.

In a study by Clark et al designed to determine the effects of selenium on the incidence of basal or squamous cell carcinomas, nutritional supplementation with this agent showed no consequences on the incidence of skin cancer; however, secondary analyses revealed that it was associated with significantly fewer cases of lung cancer.

A phase III intergroup selenium prevention trial has been designed to follow the lung cancer isotretinoin prevention trial. To reduce the incidence of second primary tumors, this double-blind design is randomizing patients by a 2:1 ratio to receive either selenomethionine (200 μg/d) vs placebo daily for 48 months. Patients are monitored for safety, development of second primary tumors, and recurrence. A total of 1,552 patients have been entered into the run-in phase, and of them, 1,375 have been enrolled in the trial. Based on enrollment to date, the projected goal of 1,960 patients should be reached by February 2011.

Educational programs Although the information from the intergroup randomized chemoprevention study is being collected, it is important to continue educational efforts to prevent adolescents from smoking cigarettes and to advocate smoking cessation in active smokers. Some experts believe that educational programs must begin during childhood, probably between the ages of 6 and 10 years. Targeting children and young adults is a significant priority of any lung cancer reduction program.

Signs and symptoms

The clinical manifestations of lung cancer depend on the location and extent of the tumor. In patients who have localized disease, the most common symptoms are related to obstruction of major airways; infiltration of lung parenchyma; and invasion of surrounding structures, including the chest wall, major blood vessels, and viscera.

Cough is a major manifestation of lung cancer and is present in nearly 80% of patients with symptomatic lung cancer. It is important to remember, however, that most lung cancer patients are current or former smokers and may have a cough related to chronic irritation of the upper and/or lower airways from cigarette smoke. Therefore, smokers should be asked whether there has been a change in their cough, such as an increase in frequency or severity.

Dyspnea and hemoptysis Increasing dyspnea and hemoptysis may be signs of lung cancer, although in the case of hemoptysis, 70% of patients bleed from nonmalignant causes, mostly infection, and more frequently, bronchitis. In patients who present with hemoptysis, are older than age 40, and have a history of smoking and chronic obstructive pulmonary disease without an abnormality on chest radiograph, lung cancer should be considered in the differential diagnosis.

Pneumonia Postobstructive pneumonia secondary to partial or complete bronchial obstruction occurs relatively frequently in association with lung cancer. It is important to obtain repeat chest x-rays in adults who have been treated for pneumonia to be certain that the radiographic abnormalities have cleared completely.

Pleural effusion Lung cancer may spread to the pleural surface or may obstruct segmental or lobar lymphatics, resulting in pleural effusion and increased dyspnea.

Chest pain Approximately 5% of lung tumors invade the chest wall. The resultant pain is a better predictor of chest wall invasion than are chest CT findings. An individual who complains of persistent chest pain should have a chest x-ray to exclude the presence of peripheral lung cancer that has invaded the chest wall.

Shoulder and arm pain Apical tumors that infiltrate surrounding structures (also called Pancoast tumors) produce shoulder and/or arm pain as a result of brachial plexus compression. Tumors in the apical lung segments may be difficult to detect on a routine chest x-ray; therefore, a person who complains of persistent shoulder pain, particularly with signs of neurologic involvement, should have a CT scan of the chest to look for an apical tumor. An MRI scan of the chest apex may be beneficial. It is also important to examine the lung apex in bone films obtained to evaluate shoulder pain.

Horner's syndrome Invasion of the sympathetic ganglion by an apical lung tumor causes Horner's syndrome (ptosis, myosis, and ipsilateral anhidrosis).

Hoarseness secondary to vocal cord paresis or paralysis occurs when tumors and lymph node metastases compress, cause dysfunction in, or invade the recurrent laryngeal nerve. This situation is more common on the left side, where the recurrent laryngeal nerve passes under the aortic arch, but it may also occur with high lesions on the right side of the mediastinum.

Other symptoms of tumor compression Lung tumors may also cause dysphagia by compression or invasion of the esophagus or superior vena cava syndrome by compression or invasion of this vascular structure.

Some tumors may result in wheezing or stridor secondary to compression or invasion of the trachea and may also cause signs of cardiac tamponade secondary to involvement of the pericardial surface and subsequent accumulation of pericardial fluid.

Signs and symptoms of metastatic disease Lung cancer can metastasize to multiple sites, most commonly to bone, liver, brain, lungs (contralateral or ipsilateral), and adrenal glands.

A lung cancer patient who has brain metastases may complain of headaches or specific neurologic symptoms, or family members may notice a decrease in the patient's mental acuity. Also, metastatic lung cancer may cause spinal cord compression, resulting in a characteristic sequence of symptoms: pain, followed by motor dysfunction, and then sensory symptoms. The patient may have any or all of these symptoms.

Patients who complain of band-like pain encircling one or both sides of the trunk may have spinal cord compression. In addition, coughing and sneezing may cause significant exacerbation of pain from spinal cord compression.

Bone x-rays and/or a bone scan are warranted in lung cancer patients who complain of persistent pain in the trunk or extremities. If performed in the evaluation of lung cancer, 18F-fluorodeoxyglucose (FDG)-PET supplants the need for a bone scan in most patients. PET appears to be more sensitive but less specific for bone metastases. If plain films are normal or equivocal for metastases, CT and/or MRI may be helpful to evaluate suspicious areas. MRI of the spine is the most effective way to evaluate suspected spinal cord compression.

Systemic paraneoplastic symptoms Lung cancer is commonly associated with systemic manifestations, including weight loss (with or without anorexia). In addition, patients frequently complain of fatigue and generalized weakness. SCLC is associated with hormone production, which causes endocrine syndromes in a subset of patients, such as SIADH (syndrome of inappropriate antidiuretic hormone secretion) and via secretion of ACTH (adrenocorticotropic hormone) hypercortisolism.

Specific neurologic syndromes, such as Lambert-Eaton syndrome (see chapter 39), cortical cerebellar degeneration, and peripheral neuropathy, may occur in lung cancer patients but are relatively rare.

Clubbing Although clubbing may occur in a variety of conditions, it is important for the clinician to evaluate a patient's hands. If clubbing is noted, obtaining a chest x-ray may result in the early diagnosis of lung cancer.

Hypertrophic pulmonary osteoarthropathy A relatively small percentage of patients with lung cancer may present with symptomatic hypertrophic osteoarthropathy. In this syndrome, periosteal inflammation results in pain in affected areas, most commonly the ankles and knees. It is frequently associated with clubbing.

Carcinoid syndrome is extremely uncommon in patients who have a bronchial carcinoid tumor. Most of these patients are asymptomatic (tumors are found by x-ray), and a few have cough from an endobronchial lesion.

TUMOR BIOLOGY

Non–small-cell tumors account for approximately 85% of all lung cancers. The three major tumor types included under this category are adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma.

Staging and prognosis

Staging

2009 changes to TNM The staging of lung cancer must be conducted in a methodical and detailed manner. The TNM staging system (Table 1) applies equally well to all histologies of NSCLC, but TNM

for SCLC is less helpful. Most patients have advanced disease at the time of presentation.

Stage is commonly reported as either clinical or pathologic, designated as c or p, respectively. Clinical stage is based on noninvasive (or minimally invasive) tests, whereas pathologic stage is based on tissue obtained during surgery (see section on “Diagnosis and staging evaluation”).

The IASLC has developed changes in the TNM system (TNM 7) based on an international collection and review of 100,809 patients. They include the following:

Change

1. T4 pleural and/or pericardial effusion and/or pleural nodules becomes M1a

2. Additional nodules in the contralateral lung are subclassified as M1a

3. Distant metastases are subclassified as M1b

Subclassify

4. T1 into T1a and T1b
a. T1a < 2 cm
b. T1b > 2 cm and < 3 cm

5. T2 into T2a and T2b
a. T2a > 3 cm and < 5 cm
b. T2b > 5 cm and < 7 cm

Reclassify

6. T2 lesions larger than 7 cm as T3

7. T4 tumors with additional nodules in the primary lobe as T3

8. M1 by additional nodules in the ipsilateral lung (different lobe) as T4

Prognostic factors
Stage
The most important prognostic factor in lung cancer is the stage of disease.

Performance status and weight loss Within a given disease stage, the next most important prognostic factors are performance status and recent, unexplained weight loss. The two scales used to define performance status are the ECOG performance status system and the Karnofsky system (see Appendix 1). Simply, patients who are ambulatory have a significantly longer survival than those who are nonambulatory. Similarly, patients who have lost > 5% of body weight during the preceding 3–6 months have a worse prognosis than patients who have not lost a significant amount of weight.

Molecular prognostic factors Several studies published over the past decade have indicated that mutations of ras proto-oncogenes, particularly KRAS, portend a poor prognosis in NSCLC, and in the case of adenocarcinomas, are more frequently found in smokers. Accordingly, selective research has focused on developing molecularly targeted therapeutic approaches to the ras proto-oncogenes, in particular, the farnesyl transferase inhibitors as well as epidermal growth factor receptor (EGFR) inhibitors and antiangiogenic approaches (see section on “Novel and promising agents”).

Of equal relevance was the completion of large studies by Pastorino et al and Kwiatowski et al evaluating the prognostic importance of immunocytochemical and molecular pathologic markers in stage I NSCLC.

In the study by Pastorino et al, gene-expression profiles were performed in 198 tumor samples to develop a predictive model for recurrence, the lung metagene model. The model was then tested in three cohorts of stage IA patients and was found to be highly accurate in predicting the likelihood of recurrence. By identifying patients who are likely to recur, adjuvant therapy is more likely to be effective. In the study by Kwiatowski et al, gene-expression profiles were performed in 185 frozen samples, and a 5-gene signature that correlated with relapse-free and overall survival was identified.

The findings of these two studies suggest that pathologic stage and completeness of surgical resection may yield the most critical prognostic information, but mutation of the KRAS oncogene and absence of expression of the HRAS p21 proto-oncogene may augment the pathologic information. Further data indicate that a molecular prognostic model differentiating patients with lung cancer may be possible using proteomics or other molecular biology techniques.

Molecular profiling has been described as a means to molecularly characterize tumors and to identify the metastatic potential and regional growth character. Other molecular markers that portend a poor prognosis include reduced expression of RASSF1A and FHIT (fragile histidine triad); reduced expression of catenins and E-cadherin; reduced ERCC1 and RRM1; reduction in tumor suppressor genes p53, retinoblastoma gene, p16INK4A, and p15INK4B; increased telomerase activity; overexpression of EGFR (c-erbB-1), matrix metalloproteinase, HER2/neu (c-erb-2), and vascular endothelial growth factor (VEGF); c-Met overexpression; overexpression of mutated p53; urokinase plasminogen activator overexpression; promoters of angiogenesis; reduced expression of nm23 gene; and low KAI1/CD82.

Potti et al used microarray techniques to study prognosis in stage I NSCLC. Their results indicate that the lung metagene model offers a potential mechanism to estimate a patient’s risk of disease recurrence and, in principle, to affect decisions regarding the use of adjuvant chemotherapy in early-stage NSCLC

(Potti A, et al: N Engl J Med 355:570–580, 2006)

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Quality of life (QOL) RTOG reanalyzed the results of RTOG 9801 to assess the added value of QOL as a prognostic factor for overall survival. On multivariate analysis, they found that the global QOL score superseded the classic predictors of survival (eg, Karnofsky performance status, stage, etc) in patients with locally advanced NSCLC. Patients with a global QOL score less than the median (66.7 of 100) had a 70% higher rate of death than patients with a QOL ≥ 66.7 (P = .002). Of note, patients who were married or had a partner had higher QOL scores than those who were not (P = .004). A clinically meaningful increase in the QOL score (of 10 points) corresponded to a decrease in the hazard of death by 10% (P = .002). This study highlights the “added value” of patient-reported outcomes and the need to incorporate QOL measures into clinical oncology trials.

Diagnosis and staging evaluation

History and physical examination
The diagnosis and preoperative staging of lung cancer begin with a good history and physical examination. When obtaining the history, the clinician should keep in mind the tendency for lung cancer to involve major airways and other central structures. Similarly, the patterns of metastatic dissemination and systemic manifestations must be considered when conducting the physical examination.

Patients should be questioned specifically about the presence of palpable masses, dysphagia, bone pain, headache, or changes in vision. Careful auscultation and percussion may suggest the presence of atelectasis or pleural effusion. Auscultation of the chest also may provide evidence of large airway obstruction and pulmonary consolidation. Rhonchi and wheezing may provide some helpful treatment planning information. An enlarged liver may indicate hepatic metastases.

Palpation of the neck and supraclavicular fossa Discovery of adenopathy of the neck and supraclavicular fossa may allow both diagnosis and staging, by needle or open biopsy.

Imaging studies
Chest x-rays
provide initial helpful information in patients with new respiratory symptoms. Posteroanterior (PA) and lateral chest x-rays are fundamental in assessing the local extent of the primary tumor and also may provide valuable information regarding metastatic disease.

The chest x-ray should be inspected for the presence of a pleural effusion or synchronous pulmonary nodules, and the bones should be examined for evidence of osseous metastases. A widened mediastinum usually indicates metastatic disease within the mediastinal lymph nodes. Comparison with previous x-rays is helpful and well worth the effort expended in their retrieval.

Chest CT from the lower neck to the mid level of the kidneys, including the entire liver and adrenal glands with 5- to 10-mm slices, is performed routinely to further define the primary tumor and to identify lymphatic or parenchymal metastases. In a review of 20 studies that assessed the value of CT scan to determine mediastinal lymph node involvement, with an average prevalence of 28%, CT had a pooled sensitivity of 57%, a specificity of 82%, and a negative predictive value (NPV) of 83%. Benign enlargement of mediastinal nodes is more common in patients with postobstructive infection. Histologic confirmation of the presence or absence of tumor within the mediastinal lymph nodes is necessary whenever this information will change treatment recommendations. In patients who are considered surgical candidates, metastatic tumor is found in approximately 15% to 20% of mediastinal lymph nodes < 1 cm in greatest diameter.

It is important to remember that patients with persistent symptoms, such as cough and dyspnea, who have a normal chest x-ray may be harboring a central lesion that is not obvious on chest x-ray but can be easily detected by chest CT. Also, as previously mentioned, apical tumors (Pancoast tumors) may be difficult to detect on a chest radiograph but are usually readily apparent on a CT scan.

PET For lung masses, FDG accumulation on PET implies a significant likelihood of malignancy.

The maximum standardized uptake value (SUV) threshold of 2.5 within the region of interest optimizes the sensitivity and specificity of PET in assessing suspicious lung lesions larger than 1 cm. An FDG-avid lesion on PET should never be assumed to be malignant, and a PET-negative lesion is not absolutely benign. Bronchioloalveolar and carcinoid are two cell types that do not readily accumulate FDG. Furthermore, higher SUV lesions do not imply a greater likelihood of cancer; the highest SUVs have been found in inflammatory lesions, such as granulomas and infections.

A review of 18 studies of the utility of PET to assess the mediastinal lymph nodes demonstrated a pooled sensitivity of 84% and a specificity of 89%, with a positive predictive value (PPV) of 79% and an NPV of 93%. Combining the results of CT and PET, the PPV and NPV were 83% to 93% and 88% to 95%, respectively. Thus, FDG-PET is superior to CT scanning in staging the mediastinal lymph nodes. An estimated 15% to 20% of patients with a known or suspected diagnosis benefit from a preoperative FDG-PET, because previously unrecognized metastatic disease will be discovered.

Several trials have evaluated the prognostic significance of FDG uptake on PET scan in NSCLC. Utilizing multivariate Cox analysis, these studies noted that SUV, particularly when > 7 to10, was an independent prognostic factor.

PET scanning may also prove a valuable tool for staging and evaluating patients undergoing radiation therapy and patients with NSCLC treated with chemoradiotherapy or irradiation. In a study by MacManus et al, the PET response after treatment was found to be a powerful predictor of survival.

Adrenal gland The adrenal gland may be the sole site of metastatic disease in as many as 10% of patients with NSCLC, though patients with adrenal masses should not be assumed to have metastatic disease and should not be denied a potentially curative surgery on the basis of a scan alone. Less than 1% of adrenal masses at least 1 cm that are negative on FDG-PET are malignant. Contrast-enhanced MRI-weighted images may assist in achieving a diagnosis. Suspicious adrenal masses should be either biopsied or resected in potentially operable patients to confirm the stage of disease.

Obtaining a tissue diagnosis
The next step is to obtain a histologic or cytologic diagnosis of the radiologically revealed lesion, although preoperative histologic diagnosis need not be obtained in a highly suspicious lung mass without evidence of distant or locoregional metastases (see below).

Central lesions Collecting sputum cytologies for 3 consecutive days provides a cytologic diagnosis for central lesions 71% of the time and for peripheral lesions 49% of the time. In clinically suspicious lung nodules/masses, a negative sputum cytology result warrants further clinical investigation. Flexible bronchoscopy is commonly required to achieve a diagnosis. For central lesions that are exophytic, at least three direct forceps biopsies should be performed to achieve a 74% sensitivity. Washings and brushings add to the sensitivity but by themselves have a sensitivity of 48% and 59%, respectively. Further improved sensitivity is obtained with bronchoscopic fluoroscopically directed transbronchial needle aspiration biopsies. For central lesions, the overall sensitivity for flexible bronchoscopy is in experienced hands 88%.

In addition, bronchoscopy may provide important staging information, such as whether the tumor involves the distal trachea or carina, and may help plan the appropriate operation (lobectomy or sleeve resection vs pneumonectomy). Determining the degree of bronchial involvement assists surgical planning. Bronchoscopy-directed biopsies should be performed to assist in determining the intended line of resection, especially when evaluating for submucosal involvement. One to two percent of patients with lung cancer will have an endobronchial synchronous primary or metastatic lesion.

Peripheral lesions Bronchoscopy is less likely to yield a diagnosis in patients with peripherally located lesions. Bronchoscopic ability to make a diagnosis of malignancy in peripheral lesions is dependent upon size; for those less than 2 cm, the sensitivity is 33%, and for lesions greater than 2 cm, it is 62%. If a bronchiole is seen traversing or extending to the mass on CT, the sensitivity is reported to be twice as high, nearly 60%. Newer image-guided bronchoscopic technologies are being investigated to improve diagnostic capabilities.

A CT-guided needle biopsy may diagnose up to 90% of peripheral lung cancers but is dependent on the quality of the CT scan and the experience of the radiologist performing the procedure. The false-negative rate is 20% to 30%. Needle biopsy is usually reserved for patients who are not candidates for an operation due to distant metastatic disease or poor health or performance status. If the patient is a candidate for surgery, resection is generally recommended for any suspicious mass, whether the result of needle biopsy is positive or nondiagnostic. Therefore, for patients with a suspicious peripheral lesion that is not associated with pleural effusion, mediastinal adenopathy, or other evidence of metastatic disease, it is reasonable to proceed directly to surgery.

Mediastinoscopy Mediastinoscopy is a time-tested technique whereby the middle (cervical mediastinoscopy) and the anterior mediastinum may be assessed for direct or metastatic lymph node involvement. In the hands of a specialist, the risk of biopsy trauma to local structures (great vessels, trachea, or esophagus), bleeding, recurrent nerve paresis, infection, or death is minimal. Whole-node biopsies may be taken, achieving a great deal of information about the location, number of nodal stations involved, number of metastatic lymph nodes within each station, degree of nodal involvement, and lymph node capsular invasion. There is no evidence that mediastinoscopic biopsy spreads tumor within the mediastinum, worsens the prognosis, or renders eventual surgical mediastinal dissection difficult.

With the advent of videoscopic technology, the video-assisted mediastinal lymphadenectomy (VAMLA) and the transcervical extended mediastinal lymphadenectomy (TEMLA) have been described, whereby extensive mediastinal evaluation and lymph node resection are performed. The additional 1 to 2 hours to perform these procedures and slightly increased patient discomfort are offset by the significant improvement in the access to the nodal stations, acquisition of lymph nodes, and improved staging and therapeutic potential.

Selective indications for mediastinoscopy are listed in Table 2. To assess response to therapy, repeat mediastinoscopy has been performed with few complications. Patients with N2 disease may potentially benefit from neoadjuvant treatment. Patients with N3 disease are considered to be stage IIIB and less likely to benefit from surgical resection. There have been a few retrospective reports that have demonstrated survival from induction therapy in patients with microscopic N3 involvement.

Endobronchial ultrasonography and endoesophageal ultrasonography staging Endobronchial ultrasonography (EBUS) is a real-time means of directly evaluating mediastinal masses and lymph nodes to direct transtracheal and transbronchial fine-needle (TTNA and TBNA) and core aspiration/biopsy. It provides access to all of the paratracheal, subcarinal, and proximal hilar lymph node stations. It appears to have a similar sensitivity to mediastinoscopy (85% to 90%) and may reduce the need for mediastinoscopy.

Real-time transesophageal biopsies by endoesophageal ultrasonography (EUS) can be performed on mediastinal tumors and the lymph nodes with similar sensitivity and accuracy to EBUS. EUS provides access to lymph node stations in the posterior mediastinum in the mid to distal periesophageal lymph nodes, involved in 10% to 15% of patients. Both are minimal-access procedures that can be performed with little risk.

Thoracentesis and thoracoscopy Individuals who have pleural effusions should undergo thoracentesis. Video-assisted thoracoscopic surgery (VATS) should be used to assess patients who have cytology-negative effusions. Sixty percent of patients with known pleural disease and effusions will have cytology-negative effusions. However, lung cancer patients with exudative cytology-negative effusions and their cytology-positive counterparts appear to have equally poor survival. VATS permits direct visualization of the pleural surface, enables direct biopsy of the pleural nodules, and also may facilitate biopsy of ipsilateral mediastinal lymph nodes. The role of VATS to assess effusions remains to be elucidated.

Measurement of serum tumor-associated antigens has no current role in the staging of NSCLC.

Diagnosis and evaluation of suspected carcinoid tumor
A carcinoid tumor of the lungs may be suspected in a patient with a slowly enlarging pulmonary mass and a prolonged history of respiratory symptoms. Patients usually have no symptoms. Most tumors are located centrally and exist endobronchially. When they occur, symptoms may include wheezing, recurrent pneumonia, dyspnea, and potentially paraneoplastic syndromes. Bronchoscopy frequently assists in diagnosing the lesion. The finding of a polypoid, pale, firm mass should not lull the bronchoscopist into taking a large-forceps biopsy. First, these masses are frequently vascular, and massive bleeding has been reported; second, the entire mass can be accidentally removed, making it difficult to identify the site of the original location of the polyp.

Given the bleeding potential, rigid bronchoscopy may be a better way to assess these lesions. Especially with cytology, carcinoid tumors may be difficult to differentiate from small-cell and atypical carcinoid tumors. Carcinoid tumor should be suspected when a small-cell tumor diagnosis by fine-needle aspiration does not respond to therapy. True carcinoids will have metastatic nodal disease in 5% to 10% of patients and have an excellent prognosis with surgical resection. Atypical carcinoid tumors are differentiated from typical tumors in that they have more than two mitotic figures per high-powered field and areas of necrosis.

Unlike its infradiaphragmatic counterpart, pulmonary carcinoid tumors rarely present with paraneoplastic syndromes, including carcinoid syndrome, acromegaly, and Cushing syndrome. Therefore, it is only necessary to measure urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion prior to surgery in symptomatic patients. Less than 3% of all patients with pulmonary carcinoid tumors have detectable urinary 5-HIAA.

Intraoperative staging

Intraoperative staging is an integral part of any operation for lung cancer. In addition to the thorough visual and tactile inspection of the lungs, diaphragm, and pleura, the ipsilateral mediastinal lymph nodes must be either completely removed or at least sampled.

The American Thoracic Society has assigned numbered levels to locations in which lymph nodes are regularly found, defined by their relation to constant anatomic structures. A complete mediastinal lymph node dissection is associated with little morbidity and lengthens the operation only slightly.

Pulmonary evaluation

To determine the volume of lung that can be removed without rendering the patient a pulmonary cripple and to identify those individuals at risk for postoperative complications, each patient may undergo pulmonary function testing, spirometry, and potentially a diffusing capacity. The results of pulmonary testing should be referenced to the normal values for ethnicity, height, age, and gender rather than the absolute value.

Forced expiratory volume in 1 second Postoperative respiratory failure rarely occurs if the postresection forced expiratory volume in 1 second (FEV1) is > 30% of predicted. Regardless of the extent of the scheduled resection (lobectomy or pneumonectomy), if the preoperative FEV1 is < 60% of predicted, a split-function perfusion scan may be obtained to determine the contribution of each lung region to overall pulmonary function. This information may be critical when an unplanned pneumonectomy is required to achieve complete tumor resection.

Other pulmonary function tests A diffusing capacity of the lung for carbon monoxide (DLCOa; a = adjusted for the patient's hemoglobin level) < 60% of the predicted value or a maximum voluntary ventilation (MVV) < 35% is associated with increased postoperative morbidity. Patients with a baseline oximetry saturation of less than 90% and those who desaturate with exercise more than 4% have a greater likelihood of postoperative complications. Arterial blood gas Pco2 > 45 mm Hg is an independent risk factor for increased operative morbidity and mortality.

In patients with borderline lung function, further physiologic testing may be required to better estimate pulmonary reserve prior to and after surgery. Quantitative pulmonary ventilation-perfusion scanning may assist in this endeavor. The perfusion portion is used to calculate the percentage of lung to be removed and the estimated postoperative percentage of normal. An additional test is exercise pulmonary function testing. Patients are monitored for heart rate, rhythm, blood pressure, and oxygen consumption. Patients who reach their target heart rate and exercise capacity and who have a maximal oxygen consumption > 15 mL/kg/min are less likely to have a postoperative complication and mortality.

Pathology

The World Health Organization and the IASLC have devised guidelines for the histologic

classification of lung cancer, which are revised as necessary (Table 3). The different cell-type classifications are performed using light microscopy and do not require electron microscopy or immunohistochemistry. There are variations in the natural history of the different cell types and potential differences in response to treatment and survival. Overall, 90% to 95% of NSCLCs are adenocarcinomas, squamous, or large cell, with 3% to 4% being mixed tumors, such as adenosquamous carcinomas. Three major types of tumors are included under the NSCLC category: adenocarcinomas, squamous cell carcinomas, and large-cell carcinomas.

Adenocarcinomas are the most common type of NSCLC, accounting for approximately 30% to 40% of cases. Of all the types of lung cancer, adenocarcinomas are most likely to occur in nonsmokers or former smokers. They are also the most common tumors in women.

Typically, adenocarcinomas present as small peripheral lesions that have a high propensity to metastasize to both regional lymph nodes and distant sites. Because of the tendency of the primary tumor to occur in peripheral locations, it frequently produces no symptoms. In contrast with their metastatic lesions, the primary adenocarcinoma tumor is histologically heterogeneous in 80% of patients, consisting of numerous histologic subtypes, and is classified as “mixed-” or “indeterminate-adenocarcinoma.”

During the past decade, it has become apparent that the incidence of bronchioloalveolar adenocarcinoma (BAC) is increasing. This tumor originates from type II pneumocytes, and it may present as a pneumonic infiltrate, as multiple nodules scattered throughout the lungs, and, occasionally, as a single nodule.

Squamous cell carcinomas comprise approximately 30% of all cases of lung cancer. These tumors tend to occur in a central location and tend to spread to regional lymph nodes; they are the most likely of all lung cancers to remain localized and to cavitate. In fact, autopsy studies have shown that about 15% to 30% of patients with squamous cell carcinoma may die of local disease without evidence of distant metastases.

Large-cell carcinomas account for approximately 10% to 15% of all lung cancers. They tend to present as relatively large peripheral lesions and, like adenocarcinomas, have a high propensity to metastasize to regional lymph nodes and distant sites.

Treatment

In operable candidates, clinically staged IA, IB, IIA, and IIB NSCLC should undergo anatomic complete surgical resection. Primarily, patients with stages IIIB and IV disease are treated nonoperatively. Although multimodality therapy is routinely recommended for stage IIIA disease, it is recommended that it be performed within a clinical trial.

SURGICAL APPROACH

The appropriate treatment of NSCLC is resection of the lobe containing the tumor. Occasionally, a bilobectomy or pneumonectomy is required. Mortality approximates 3% following lobectomy and 7% following pneumonectomy. A wedge or segmental resection has a three to five times higher incidence of local recurrence and a lower 5-year survival than a lobectomy. Therefore, if the patient can tolerate the procedure, the standard operation should be a lobectomy, rather than a wedge resection or segmentectomy. As a curative resection, segmentectomy, though, has not been sufficiently evaluated, and more recent investigation demonstrates that in selected tumors, when the bronchus and vascular supply are individually ligated with a regional node resection, survival appears to be comparable and it salvages lung parenchyma.

Evaluation of the SEER (Surveillance, Epidemiology, and End Results) database found that in stage I lung cancer, the difference in long-term survival between a wedge resection and lobectomy was negligible after 71 years of age.

A radiologic and PET evaluation has demonstrated that lesions smaller than 2 cm, peripheral ground-glass opacity with a PET maximum SUV of less than 2.5, and no evidence of metastatic disease may be considered for a more limited resection if the surgical margin is approximately the size of the lesion. A prospective randomized clinical trial (CALGB 140503) is currently accruing patients to assess whether anatomic lobectomy provides superior survival to sublobar resection in peripheral stage I NSCLC < 2 cm.

VATS Traditionally, lung cancers have been resected through a posterolateral thoracotomy incision. Muscle-sparing incisions may reduce pain. The current trend is toward an even less invasive approach: lobectomy and lymph node dissection with VATS. This approach appears to offer the same cancer operation and survival with perhaps lower morbidity.

Two VATS methods have been described: the mass hilar ligation technique and individual ligation of the vasculature and airway. Patients with peripheral tumors up to 4 to 6 cm without clinical hilar or mediastinal adenopathy appear to be good candidates for a VATS procedure. Conversion rates to open thoracotomy are 10%, and hospital stays are usually 3 to 5 days.

The results of several VATS series show lower complication rates than for reported series for thoracotomy; granted, a selection bias may have occurred. One small randomized trial showed a significant benefit favoring VATS. Patients have better shoulder function, better performance on the 6-minute walk, and less impairment of vital capacity after VATS than after thoracotomy. A VATS approach may be better tolerated than other approaches for older patients.

Patients with pathologic stage IA disease have a 70% to 80% 5-year survival rate after resection, whereas 5-year survival rates are 60% in those with stage IB disease and 40% to 50% in those with stage IIA/IIB disease. Patients found to have N2 (stage IIIA) disease located at a single nodal level have a 25% to 30% 5-year survival rate.

Mediastinal lymph node involvement The standard lung cancer operation should include sampling or dissection of mediastinal lymph nodes. The presence of metastases in any of the mediastinal lymph nodes (N2 and/or N3 disease) is indicative of advanced disease and is thought by some to represent a contraindication to surgery. Resection of mediastinal disease may have prognostic significance, implications for postoperative care, and potential therapeutic value. Some series of patients with N2 disease have shown a 5-year survival rate of 20% to 30%, but patients in these series are highly selected.

Patients with N2 disease may potentially benefit from neoadjuvant treatment. Patients with N3 disease are considered to be stage IIIB and less likely to benefit from surgical resection. A few retrospective reports have demonstrated survival from induction therapy in patients with microscopic N3 involvement. The American College of Surgeons has completed accrual to a randomized, prospective study comparing survival following mediastinal lymph node sampling vs dissection. Complications and operative mortality appear equivalent between the sampling and dissection groups. Long-term survival is under investigation. Also, clinical trials are currently testing preoperative chemotherapy and chemoradiation therapy in patients with mediastinal node involvement.

Preoperative histologic assessment of the mediastinal lymph nodes is essential if multilevel metastases are suspected, as there have been few long-term survivors among patients with metastatic disease at more than one level. Nonsurgical treatment appears preferable, or patients should be offered participation in a trial designed to assess the benefits of neoadjuvant therapy. Although patients with stage IIIB tumors are usually treated with irradiation and chemotherapy (see later discussions), the occasional patient with isolated involvement of the vena cava or atrium can undergo resection.

Carcinoid tumors Although the majority of carcinoid tumors remain localized, regional lymph node metastases are identified in 5% to 10% of patients. The surgical approach, therefore, should be similar to that used in NSCLC. If a small tumor in a proximal airway is identified and there is no histologic evidence of lymph node disease, a bronchoplastic procedure with preservation of lung tissue can sometimes be performed. Rates of survival at 10 years are > 90% for patients with stage I disease and 60% for patients with stage II disease.

ADJUVANT THERAPY

Chemotherapy
Classic postoperative adjuvant chemotherapy has been tested in three randomized trials conducted by the LCSG. For almost 20 years, the relative value of adjuvant chemotherapy for resectable NSCLC has been disputed and debated. In a randomized, prospective study involving 488 patients, Keller et al showed no benefit to adjuvant chemotherapy. The ALPI study of 1,209 patients also showed no survival benefit. In contrast, the IALT randomized 1,867 patients to receive cisplatin-based adjuvant chemotherapy or no treatment. At 5 years, the treatment arm showed a survival advantage of 4.1% (P = .003), compared with the observation arm. However, that benefit appeared to diminish with longer follow-up.

Two trials, the Canadian BR-10 and CALGB 9633, both demonstrated initial clinically significant improvement in survival, with minimal chemotherapy side effects; cisplatin and vinorelbine were used in the BR-10 trial and carboplatin and paclitaxel were used in CALGB 9633. These results, in combination with the recent positive findings of the adjuvant trial of UFT (a drug composed of tegafur and uracil mixed at the ratio of 1:4) in patients with stage IB NSCLC, increase the likelihood of adjuvant platinum-based therapy becoming the standard of treatment for patients with stages IB–IIIB NSCLC. Recent results of a prospective phase III trial from the SLCG NATCH trial compared the use of adjuvant and neoadjuvant and surgery alone in 616 patients with stages I (> 2 cm), II, and T3 N1. For those who received chemotherapy, three 3-week cycles of paclitaxel (200 mg/m²), and carboplatin (at an area under the concentration-time curve [AUC] of 6) were given. Despite an excellent safety profile, a major radiologic response at 59%, and a complete response of 9% of induction patients, there was no difference found in survival. Again, it appears that the survival advantage in the treatment arm was lost, except in those patients with larger primary tumors (> 4 cm) or more advanced disease (stage IIIA).

Based on these results from adjuvant chemotherapy trials, the initial enthusiasm has been somewhat tempered.The potential benefits are higher efficacy of chemotherapy early in the natural history of disease, facilitation of subsequent local therapy, and early eradication of distant micrometastases. Further investigation in the use of adjuvant therapy is under way to determine those patients who will benefit and the optimal treatment.

Stage I disease Currently approved chemotherapeutic regimens do not appear to provide any survival benefit in this patient population and are not advised outside of the clinical trial setting. From the subset analysis of CALGB 9335, patients with tumors > 4 cm may have some benefit, given the likelihood for recurrence. Currently under investigation is the use of tumor histology and marker evaluation to select the appropriate patient and the ideal chemotherapeutic plan with the greatest efficacy and least toxicity.

The current trend is to provide involvement in a chemopreventive clinical trial for stage IA patients. For patients with stage IB disease, platinum-based adjuvant chemotherapy (cisplatin or carboplatin combined with a taxane or vinorelbine) should be strongly considered.

Stage II/III disease In two earlier trials, postoperative adjuvant chemotherapy with 6 courses of CAP (cyclophosphamide, Adriamycin [doxorubicin], and Platinol [cisplatin]), given alone in one study and following postoperative radiation therapy in the other, resulted in a modest improvement in median survival but had no impact on long-term survival. In contrast, the IALT, ANITA, CALGB 9623, and Canadian BR-10 trials demonstrated an initial clinically significant survival advantage, justifying consideration for adjuvant chemotherapy. There does not appear to be any survival advantage to adding adjuvant mediastinal radiotherapy to chemotherapy, unless there are particularly high risk factors for local recurrence. Potential indications for postoperative radiotherapy include:

• mediastinal involvement
• multiple positive lymph nodes or lymph node stations
• extracapsular nodal extension
• bulky nodal disease
• grossly positive surgical margins
• close or microscopically positive margins

Radiation therapy
A trial conducted by the LCSG showed that in patients with squamous cell carcinoma of the lungs and resected N1/N2 disease, administration of postoperative radiation therapy reduced the risk of recurrence in the chest from 20% to 1%. Although there was no improvement in overall survival, postoperative irradiation was associated with a significant improvement in disease-free survival for patients with N2 disease. A trial by the BMRC reached similar conclusions.

A meta-analysis of nine randomized trials assessing postoperative radiation therapy in lung cancer reported a 21% increase in mortality in patients receiving this therapy. However, many of the patients in these trials had N0 disease, for whom few would advocate radiation therapy. Also, most of the patients were treated with cobalt-60 beams and technically limited treatment planning, not with modern radiation therapy techniques.

Recently, the impact of radiation therapy on survival was reanalyzed in the ANITA trial, in which postoperative radiation therapy was optional, based on each center's practice. Interestingly, in patients with N2 (mediastinal) disease, adjuvant radiation therapy improved overall survival in both arms: 21% vs 17% in the observation arms and 47% vs 34% in the adjuvant chemotherapy arms (with or without radiation therapy, respectively). Based on this descriptive analysis, radiation therapy appeared to provide a benefit in addition to adjuvant chemotherapy in patients with N2 disease (whereas the converse was true in patients with N1 disease). A randomized trial with and without postoperative radiation therapy in patients with resected N2 disease is under way in Europe.

These results created a lack of consensus about treatment recommendations, with some experts advocating the use of postoperative radiation therapy to reduce local recurrence, and others avoiding it because of the absence of an effect on survival.

At present, therefore, the appropriate role of postoperative radiation therapy remains controversial. Such therapy should be seriously considered, however, in patients at high risk for locoregional relapse. In patients who are receiving adjuvant chemotherapy, it is reasonable to administer the chemotherapy first (as it has been associated with a survival benefit) followed by radiation therapy (for enhanced local tumor control).

Moreover, in a randomized trial by Keller et al, no benefit was shown for concurrent chemoradiation therapy over radiation therapy when in the adjuvant setting for completely resected patients with stage II/IIIA NSCLC. An exception may be in patients with microscopic residual disease (ie, positive margins or extracapsular extension), for whom a delay in radiation therapy may be detrimental.

NEOADJUVANT CHEMOTHERAPY OR CHEMORADIATION THERAPY

During the past decade, numerous phase II trials showed that, in general, it is feasible to perform pulmonary resection following chemotherapy or chemoradiation therapy. Although surgery can be more difficult after preoperative treatment, morbidity and mortality are acceptable.

Stage IIIA/IIIB disease The greater effectiveness of current chemotherapeutic regimens to reduce disease bulk suggested that their use prior to surgery, either alone or in combination with radiation therapy, might increase both resectability and survival in patients with stage IIIA NSCLC. Multiple phase II trials have shown such an approach to be feasible; however, it is not clear whether such a strategy improves median or long-term survival over best nonsurgical chemoradiotherapy among patients who initially have more than minimal N2 disease.

Current recommendations In selected patients, preoperative treatment may have a favorable effect on outcome in surgically resectable stage IIIA NSCLC. Although aggressive neoadjuvant approaches may have increased treatment-associated mortality, in experienced institutions, potential benefits seem to outweigh the risks. The results of the intergroup randomized trial comparing preoperative chemoradiation therapy with definitive chemoradiation therapy (in pathologic N2 disease) showed a significant improvement in progression-free survival (but not overall survival) in the surgical arm (P = .02). This approach, however, may not be optimal if a pneumonectomy is required, as this procedure was associated with a high rate of treatment-related deaths (> 20%). However, in a subset analysis, survival was improved for patients who underwent lobectomy, but not pneumonectomy, vs chemotherapy plus radiation alone. In this trial, it is not clear whether patients with persistently positive N2 disease after neoadjuvant therapy will benefit from surgical resection. In the 2007 American College of Chest Physicians consensus guidelines, surgical treatment of stage IIIA NSCLC should be performed in the context of a clinical trial.

Stage I–IIIA disease Neoadjuvant chemotherapy may even play a role in early-stage disease. A multicenter trial from France randomized 373 patients with stage I–IIIA NSCLC to undergo either surgery alone or chemotherapy (mitomycin [6 mg/m2 on day 1], ifosfamide [1.5 g/m2 on days 1 to 3], and cisplatin [30 mg/m2 on days 1 to 3]) at 3-week intervals for 3 cycles followed by surgery. Disease-free survival was significantly longer in the patients randomized to receive neoadjuvant chemotherapy than in those treated with surgery alone (P = .02). The most striking benefit of chemotherapy was seen in patients who had minimal lymphadenopathy (either N0 or N1; P = .008). No excessive complications were seen in the chemotherapy-treated patients.

Cumulative data support a difference in treatment, but no one study is statistically significant. Pooled analyses suggest positive benefit to neoadjuvant therapy, with all individual studies showing a trend toward improved overall survival, and significant differences in disease-free survival.

Following on previous trials was a study presented by Scagliotti in which 270 patients with stage IB–IIIA NSCLC were randomized to undergo surgery and follow-up vs induction chemotherapy with cisplatin and gemcitabine (Gemzar) followed by surgery. This trial closed early due to accrual problems, after only 270 of a projected 700 patients enrolled in this study. Overall survival at 3 years favored the chemotherapy plus surgery arm with (P = .053). Overall survival at 3 years for the neoadjuvant arm was 67% vs 60% for surgery alone (P = .053).

A subset analysis suggested that for stage IIb–IIIa, 3-year overall survival was 70% vs 40% in favor of chemotherapy (P = .001), whereas there was no difference for patients with stage Ib–IIa who were treated. This continues to support data suggesting that for stage IIb–IIIa disease, chemotherapy, either in the adjuvant or neoadjuvant setting, provides a significant survival advantage.

TREATMENT OF PATIENTS WITH MEDICALLY INOPERABLE STAGE I/II DISEASE

Some patients with resectable stage I or II NSCLC are high-risk operative candidates because of poor cardiopulmonary function or other medical problems. Other patients refuse to undergo surgery despite the recommendation of their treating physicians. In such patients, an attempt should be made to optimize pulmonary function by encouraging smoking cessation and initiating vigorous treatment, such as with bronchodilators.

Radiation therapy
Several institutions have reported their experience with definitive radiation therapy for such patients. Although the results are not as good as those reported in patients selected for surgery (possibly due to differences in patient selection and between clinical vs pathologic staging), patients with medically inoperable early-stage NSCLC clearly should be offered radiation therapy, with a reasonable expectation of cure. For patients with early-stage (I/II) NSCLC, surgical resection is the standard of care. However, many patients with lung cancer are not eligible for surgery because of various comorbidities. In the past, the main treatment alternative for these medically inoperable patients has been conventional radiation therapy, typically requiring once daily treatments every weekday for approximately 7 weeks. Results with conventional radiation therapy have not been encouraging, with local tumor control rates of only 50%.

More recently, stereotactic body radiation therapy (SBRT) has evolved as another treatment option for patients with medically inoperable, peripheral stage I NSCLC. SBRT involves the delivery of high doses of highly precise radiation therapy in a hypofractionated scheme over 3 to 5 fractions, administering biologically equivalent doses (BEDs) > 100 Gy over 1 to 2 weeks, with promising local tumor control rates of 85% to 90%.

Onishi et al reported the clinical outcomes of approximately 250 patients treated in Japan with SBRT for stage I NSCLC. They reported a cumulative 5-year local tumor control rate of 84% for those treated with a BED > 100 Gy vs 37% for those receiving a BED < 100 Gy (P < .001). Interestingly, among operable patients, the 5-year overall survival rate was 72% for those treated with a BED > 100 Gy vs 50% for those receiving a BED < 100 Gy (P < .05). These promising results have led to the European ROSEL study, which is enrolling patients with early-stage NSCLC (eligible for surgery) and randomizing them to undergo surgery or SBRT to evaluate tumor control, quality of life, survival, and cost of treatment.

Timmerman et al reported the results of a phase I study of SBRT in patients with medically inoperable stage I NSCLC. SBRT was delivered in three fractions over 2 weeks, with a starting dose of 800 cGy per fraction. The dose was escalated to 2,000 cGy per fraction for 3 fractions. They reported that although this treatment was safe and effective for patients for peripheral lung lesions, there was a significantly higher rate of grade 3 toxicity in patients with central lung lesions. Other institutional studies, such as at Henry Ford Hospital, suggest that early central NSCLC lesions can be treated safely and effectively with SBRT by using smaller fraction sizes of 10 to 12 Gy per session for 3 to 4 sessions. A prospective trial, RTOG 0813, will further study this issue in a dose escalation trial.

Radiofrequency ablation
The role of radiofrequency ablation (RFA) in patients who are not operative candidates is actively being studied. Although there is considerable experience with RFA for cancer in other organs, further evaluation of RFA and cryotherapeutic techniques for lung cancer are under way to assess complications related to the therapy, local recurrence, and survival.

TREATMENT OF PATIENTS WITH STAGE IIIA/IIIB DISEASE

Radiation therapy
In the past, radiation therapy was considered the standard therapy for patients with stage IIIA or IIIB disease. Long-term survival was poor, in the range of 5%, with poor local tumor control and early development of distant metastatic disease.

RTOG 0214 studied the role of prophylactic cranial irradiation (PCI) in patients with stage III NSCLC. The study opened in September 2002 and closed due to slow accrual in August 2007. The total accrual was 356 patients (of the targeted 1,058), of whom 340 were eligible. One-year overall survival (75.6% vs 76.9%;

P

= .86) and 1-year disease-free survival (56.4% vs 51.2%;

P

= .11) for PCI vs observation, respectively, were not significantly different. However, the incidence of CNS metastases at 1 year was 7.7% for PCI vs 18% for observation (

P

= .004). Thus, PCI in stage III NSCLC significantly decreases the risk of CNS metastases, with no significant difference in overall survival or disease-free survival

(Gore EM et al: J Clin Oncol 27: abstract 7506, 2009)

.

A randomized trial compared standard daily radiation therapy (66 Gy) with a continuous hyperfractionated accelerated radiation therapy regimen (CHART) that delivered 54 Gy over 2.5 weeks. The altered fractionation schedule resulted in improved 2-year survival.

Various efforts have assessed combining altered fractionation schema with chemotherapy. Although the results of RTOG 94-10 did not favor altered fractionation (see section on “Concurrent vs sequential chemoradiation therapy”), the long-term results of another study support this strategy.

Jeremic et al compared hyperfractionated radiation therapy (bid to 69.6 Gy) and concurrent low-dose daily carboplatin/etoposide with or without weekend carboplatin/etoposide in a randomized trial of approximately 200 patients. Although investigators found no benefit with the addition of weekend carboplatin/etoposide, both arms demonstrated promising median survival times of 20 and 22 months and excellent 5-year survival rates of 20% and 23%.

Conformal radiation therapy
Hayman et al reported updated results of the Michigan phase I dose-escalation trial of three-dimensional (3D) conformal radiation therapy for NSCLC. In this study, the radiation dose was escalated based on the effective volume of irradiated lung (up to 102.9 Gy). Such doses produced acceptable toxicity and no cases of isolated failures in purposely nonirradiated, clinically uninvolved nodal regions. This strategy is now being integrated with chemotherapy.

Socinski et al reported a dose-escalation radiotherapy (from 60 Gy up to 74 Gy) trial, using 3D computer-assisted planning techniques, in patients receiving induction carboplatin and paclitaxel and concurrent weekly carboplatin/paclitaxel. Ninety-seven percent (31 of 32) of the patients completed therapy to 74 Gy, as planned. The grade 3/4 esophagitis rate overall was relatively low at only 11%. Moreover, the results found a promising median survival of 26 months and a 3-year survival of 47%.

Indeed, several analyses support the importance of radiation therapy dose escalation in stage III NSCLC. Movsas et al analyzed data from more than 1,400 patients treated in nine prospective RTOG nonoperative NSCLC studies activated during the 1990s. The analysis was stratified by the presence of chemotherapy and the accrual year. On multivariate analysis, they found that a higher BED significantly predicted for higher overall survival and higher locoregional tumor control. For an increase in BED of 10 Gy, there was a dramatic reduction in the hazard of death by 14%. Similarly, researchers at the University of Michigan found a significantly improved survival in patients treated with a higher BED. To test this important hypothesis prospectively, an RTOG/intergroup phase III trial has recently opened to compare concurrent chemoradiation therapy with either 60 Gy or 74 Gy with or without cetuximab (Erbitux).

Chemoradiation therapy
Chemoradiation therapy vs radiation therapy alone
At least 11 randomized trials have compared thoracic irradiation alone with chemoradiation therapy in patients with stage III NSCLC. Several meta-analyses have demonstrated a small, but statistically significant, improvement in survival with the combined-modality regimens.

Concurrent vs sequential chemoradiation therapy Furuse et al evaluated mitomycin, vindesine, and Platinol (cisplatin; MVP), administered either concurrently or prior to thoracic irradiation (56 Gy), in patients with unresectable stage III NSCLC. With more than 300 patients randomized, survival favored concurrent over sequential therapy (median survival, 16.5 months vs 13.3 months, and 5-year survival rates, 15.8% vs 8.9%; P = .04). Furuse et al also reported the patterns of failure, which demonstrated a benefit of concurrent chemoradiotherapy in improving the local relapse-free survival (P = .04) but not the distant relapse-free survival (P = .6).

Curran et al presented the long-term results of a larger randomized trial (> 600 patients) comparing sequential and concurrent chemoradiotherapy (RTOG 9410). The 4-year survival with concurrent cisplatin/vinblastine and once-daily irradiation was 21% vs 12% with sequential treatment (P = .04). The third treatment arm (concurrent cisplatin/oral etoposide and hyperfractionated irradiation) was intermediate, with a 4-year survival of 17%.

The role of altered radiation therapy fractionation, may deserve further study. ECOG 2597 randomized patients after induction chemotherapy (with carboplatin and paclitaxel) to receive either standard radiation therapy (64 Gy/2 Gy fraction) vs hyperfractionated accelerated radiation therapy (HART), 57.6 Gy delivered 1.5 Gy three times daily over 2.5 weeks. Although the study closed prematurely due to poor accrual (only 111 patients were eligible), the median survival in the investigational arm appeared promising (22 months).

Several randomized phase II trials also appear to support the use of concurrent chemoradiation therapy for locally advanced NSCLC. For example, Belani et al performed a randomized phase II study in 276 patients of three chemoradiation therapy regimens with paclitaxel, carboplatin, and thoracic irradiation in their locally advanced multimodality protocol (LAMP). They found that concurrent chemoradiation therapy followed by adjuvant chemotherapy appeared to have the best therapeutic outcome, with a median survival of 16.3 months, compared with either induction chemotherapy followed by concurrent chemoradiation therapy (median survival, 12.7 months) or sequential chemotherapy followed by irradiation (median survival, 13 months).

Similarly, in another randomized phase II study, Zatloukal et al studied 102 patients treated with concurrent chemoradiation therapy and sequential chemotherapy followed by irradiation. The chemotherapy consisted of 4 cycles of cisplatin and vinorelbine. The investigators reported a median survival in the concurrent arm of ~20 months, vs ~13 months in the other arm (P = .02).

Movsas et al reported the results of the first Patterns of Care Study (PCS) for lung cancer, which was conducted to determine the national patterns of radiation therapy practice in patients treated for nonmetastatic lung cancer. As supported by clinical trials, the PCS for lung cancer demonstrated that patients with clinical stage III NSCLC received chemotherapy plus radiation therapy more than radiation therapy alone (P < .0001). In clinical stage I NSCLC, though, radiation therapy alone was the primary treatment (P < .0001). Factors correlating with increased use of chemotherapy included lower age (P < .0001), histology (SCLC > NSCLC; P < .0001), increasing clinical stage (P < .0001), increasing Karnofsky performance status (P < .0001), and lack of comorbidities (P = .0002) but not academic vs nonacademic facilities (P = .81). Of all patients receiving chemotherapy, approximately three-quarters received it concurrently with radiation therapy. Only 3% of all patients were treated on Institutional Review Board–approved trials, demonstrating the need for improved accrual to clinical trials. Future PCSs will be done as part of the Quality Research in Radiation Oncology (QRRO) project.

The Hoosier Oncology Group (HOG) reported the results of the phase III trial of cisplatin plus etoposide plus concurrent chest radiation therapy with or without consolidation docetaxel (Taxotere) in patients with inoperable stage III NSCLC. In a study of 203 patients (of whom 147 were randomized to receive or not receive docetaxel) with a median follow-up of 25.6 months, they reported a median survival time in the docetaxel arm of 21.6 months vs 24.2 months in the observation arm (

P

= 0.94). They concluded that consolidation docetaxel does not further improve survival and is associated with significant toxicity (including an increased rate of hospitalization and premature deaths) and should not be used in this setting in patients with unresectable stage III NSCLC

(Hanna NH et al: J Clin Oncol 25: abstract 7512, 2007)

.

New chemotherapeutic agents plus irradiation Several phase I/II trials evaluated carboplatin and paclitaxel given concurrently with thoracic irradiation. These studies showed acceptable toxicity and relatively high response rates, and in one of the studies, the 3-year survival rate was quite high (39%).

In addition to paclitaxel and carboplatin, many other chemotherapeutic agents with activity in NSCLC have emerged, including docetaxel (Taxotere), vinorelbine, gemcitabine, UFT, and irinotecan. A trial from Japan tested induction chemotherapy with irinotecan and cisplatin followed by radiation therapy with weekly irinotecan (30 mg/m2 during radiation therapy). The study reported a response rate of 65% and a median survival rate of 16.5 months, with a grade 3/4 esophagitis rate of only 4%.

Current treatment recommendations
At present, it is reasonable to consider concurrent chemoradiation therapy (with once-daily radiation therapy) as a new treatment paradigm in stage III (inoperable) lung cancer patients with an ECOG performance status of 0/1 who have not lost more than 5% of their usual body weight. The results of a meta-analysis using individual patient data from randomized clinical trials showed that concomitant chemoradiation therapy, as compared with sequential chemotherapy and radiation therapy, improved survival of patients with locally advanced NSCLC, primarily due to a decrease in locoregional tumor progression. Overall, there was an absolute benefit in survival of 6% at 3 years.

Novel biologic agents The results of SWOG 0023 were updated. This was a randomized phase III trial of gefitinib (Iressa) vs placebo maintenance after chemoradiation therapy followed by docetaxel in patients with stage III NSCLC. With a median follow-up of 27 months in 243 randomized patients, the median survival for the gefitinib arm (n = 118) was 23 months vs 35 months for the placebo arm (n = 125; P = .013). The authors concluded that in this unselected population, gefitinib did not improve survival. The decrease in survival was likely due to cancer, not to gefitinib toxicity. A recent secondary analysis of SWOG 0023 found that V20 (which represents the percentage of total normal lung volume that received > 20 Gy of radiation) was the greatest predictor for radiation pneumonitis. This finding is consistent with other studies showing V20 to be a reliable predictor of pneumonitis in patients who are treated with radiation therapy for lung cancer. They found that patients with a V20 >35% had a higher rate of grade > 3 pneumonitis than patients with a V20 < 35% (14% vs 6%, respectively; P = .02) and a shorter median survival (11 vs 23 months, respectively; P = .0001). Of note, there was no imbalance of the V20 parameter between the two arms of this SWOG 0023. It is now considered standard for radiation oncologists to formally evaluate dose vs volume parameters in the treatment of lung cancer.

Lu et al have reported the results of a phase III study of AE-941, a shark cartilage extract with antiangiogenic properties, with induction chemotherapy and concomitant chemoradiation therapy in patients with stage III NSCLC. This was a placebo-controlled trial, and patients received AE-941 vs placebo at the start of induction chemotherapy, which was continued after chemoradiation therapy as maintenance therapy. A total of 384 patients were enrolled over more than 5 years, and then the trial was closed due to insufficient accrual. The median survival time was 14.4 months in the AE-941 arm vs 15.6 months in the placebo arm (P = .73). They concluded that shark cartilage extract in this setting did not improve survival in patients with unresectable stage III NSCLC.

Blumenschein et al combined cetuximab with paclitaxel and carboplatin with radiation therapy. This phase II RTOG trial accrued 87, with a promising median survival of 23 months. This represents an approximately 30% increase in survival from the 17 to 18 months usually observed with chemoradiation therapy alone. This novel strategy of adding cetuximab to chemoradiation therapy in locally advanced NSCLC is being tested in a 2 x 2 randomized phase III study (also investigating the role of radiation dose escalation).

TREATMENT OF PATIENTS WITH STAGE IV DISEASE

Until recently, there was considerable controversy over the value of treating stage IV NSCLC patients

with chemotherapy. Treatment with older cisplatin-containing regimens, such as cisplatin/etoposide, showed only a modest effect on survival, improving median survival by approximately 6 weeks, according to a meta-analysis, and yielding a 1-year survival rate of approximately 20% (as compared with a rate of approximately 10% for supportive care).

However, several chemotherapeutic agents have produced response rates in excess of 20% in NSCLC (Table 4). The potentially useful newer agents include the taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine, and irinotecan. Several of these drugs have unique mechanisms of action. Paclitaxel and docetaxel increase the polymerization of tubulin; gemcitabine is an antimetabolite; and irinotecan is a topoisomerase I inhibitor.

Furthermore, randomized trials demonstrated that a combination of a newer agent plus cisplatin significantly improves the response rate over cisplatin monotherapy (historically considered the most active agent for NSCLC). This increase in response rate translates into significant, although modest, improvement in survival.

Another potential strategy to improve outcomes in stage III NSCLC is to enhance the radiation therapy technique itself. One promising approach in other disease sites is particle beam therapy, which can deliver radiation in a focused area called the Bragg Peak. Recently, Komaki et al retrospectively compared toxicity in patients with locally advanced NSCLC undergoing proton beam therapy or intensity-modulated radiation therapy (IMRT). Proton beam therapy was associated with significantly less hematologic toxicity than IMRT. Of note, there were significant differences in the gross tumor volume between those treated with proton beam therapy vs IMRT (59 vs 203 mL;

P

< .001). This is a provocative analysis that merits further follow-up, given that hematologic toxicity is one of the challenges in treating patients with combined-modality therapy

(Komaki R et al: Chicago Multidisciplinary Symposium in Thoracic Oncology, Abstract 120, November 2008)

.

Optimal chemotherapy for advanced NSCLC
Until the early 1990s, regimens of cisplatin plus a vinca alkaloid or etoposide were most common. More recently, regimens that employ newer agents are more widely used. However, choosing one regimen from many options is a difficult task because there is no survival advantage documented for one regimen over another or standard regimen vs regimens containing newer agents.

Table 5 summarizes the results of selected randomized trials in which combination regimens containing a newer agent are compared with old “standard” regimens or regimens containing another newer agent. Subtle differences in the eligibility criteria (eg, inclusion of patients with stage III tumors or those with poor performance status) make it difficult to directly compare the trial results. Nevertheless, there is a trend indicating that regimens containing newer agents show higher response rates and also better survival outcomes in some series than do older regimens.

Vinorelbine plus cisplatin combination Vinorelbine was the first agent that demonstrated improved activity against NSCLC in combination with cisplatin. The European multicenter trial reported by LeChevalier showed the results favoring a cisplatin plus vinorelbine combination (vinorelbine, 30 mg/m2 weekly; cisplatin, 120 mg/m2 on days 1 and 29, then every 6 weeks) over a vindesine plus cisplatin combination (vindesine, 3 mg/m2 weekly; cisplatin, 120 mg/m2 on days 1 and 29, then every 6 weeks) and vinorelbine alone (30 mg/m2 weekly). The median survival duration of 40 weeks in the vinorelbine/cisplatin treatment arm was significantly longer than the 32 weeks in the vindesine/cisplatin arm (P = .04) and 31 weeks in the vinorelbine monotherapy arm (P < .001). This trial, however, did not confirm the role of vinorelbine in NSCLC therapy, even though it confirmed the role of cisplatin.

To address this issue, SWOG conducted a study comparing cisplatin alone (100 mg/m2 every 4 weeks) with the vinorelbine/cisplatin combination (cisplatin, 100 mg/m2 every 4 weeks; vinorelbine, 25 mg/m2 weekly × 3 every 4 weeks). Survival outcome was analyzed for 415 patients, 92% with stage IV tumors. The vinorelbine/cisplatin treatment significantly improved the disease progression-free (median, 2 months vs 4 months; P = .0001) and overall survival (median, 6 months vs 8 months; 1-year survival 20% vs 36%; P = .0018).

Comella et al reported interim analysis results of a phase III trial of the SICOG. A three-drug regimen (cisplatin, gemcitabine, and vinorelbine) was associated with a substantial survival gain over the cisplatin and vinorelbine regimen (median survival time, 51 weeks and 35 weeks, respectively).

Paclitaxel plus platinum compound A number of studies demonstrate promising results with paclitaxel in combination with cisplatin or carboplatin and other agents. Two large randomized trials compared paclitaxel plus cisplatin with standard regimens. In a three-arm, randomized trial (ECOG 5592) reported by Bonomi et al, 600 eligible patients with chemotherapy-naive stages IIIB–IV NSCLC were randomly assigned to receive a combination of cisplatin (75 mg/m2) plus etoposide (100 mg/m2 daily on days 1 to 3) vs either low-dose (135 mg/m2 over 24 hours) or high-dose (250 mg/m2 over 24 hours with growth factor) paclitaxel plus cisplatin (75 mg/m2). The response rates for the low-dose and high-dose paclitaxel arms were 26.5% and 32.1%, respectively, significantly better than the cisplatin/etoposide arm (12.0%). Superior survival was observed with the combined paclitaxel regimens (median survival time, 9.99 months; 1-year survival, 39%) compared with etoposide plus cisplatin (median survival, 8 months; 1-year survival rate, 32%; P = .048). Comparing survival rates for the two dose levels of paclitaxel revealed no significant differences.

In a European trial of similar design reported by Giaccone et al, cisplatin/paclitaxel improved the response rate and QOL parameters. There was no improvement in overall survival, however, compared with a standard regimen of cisplatin/teniposide (Vumon).

Paclitaxel/carboplatin has been the most widely favored regimen for first-line chemotherapy in all NSCLC stages among US medical oncologists, mainly due to promising phase II trial results and the ease of administration for outpatients, with manageable toxicity profiles compared with those of cisplatin-containing regimens. One of the early phase II trials, for example, reported a response rate of 62%, a median survival duration of 53 weeks, and a 1-year survival rate of 54%. However, a randomized trial sponsored by the manufacturer of paclitaxel failed to demonstrate a survival advantage over the standard cisplatin plus etoposide regimen. Nevertheless, paclitaxel plus carboplatin may remain a community standard because a SWOG trial reported results equivalent to the time-tested vinorelbine/cisplatin regimen (

).

Combination vs single-agent chemotherapy A randomized phase III study conducted by CALGB further supported the superiority of combination chemotherapy over single-agent therapy. Previous trials had indicated that a platinum plus a novel agent was superior to a platinum alone. Lilenbaum et al demonstrated that for patients with stage IIIB or IV NSCLC, carboplatin and paclitaxel are superior to paclitaxel alone, even for patients with an ECOG performance status of 2. This randomized trial showed a median survival advantage for the combination therapy.

Gemcitabine plus cisplatin Gemcitabine has also been approved by the FDA for use against NSCLC based on a series of successful phase II trials of cisplatin/gemcitabine and three major phase III trials. The Hoosier Oncology Group study, reported by Sandler et al, compared gemcitabine/cisplatin with cisplatin alone and showed a modest improvement in median and 1-year survival comparable to those seen in the vinorelbine trials. The Spanish and Italian trials, reported by Cardenal et al and Crino et al, compared gemcitabine plus cisplatin with standard-regimen cisplatin plus etoposide and mitomycin plus ifosfamide plus cisplatin, respectively. Although there was a significant improvement in overall response, these two studies failed to demonstrate a survival benefit.

Because gemcitabine is relatively well tolerated without dose-limiting myelosuppression, it is being evaluated for use as a single agent or in combination with other agents in older or medically compromised patients. Italian investigators report that gemcitabine combined with the vinorelbine regimen is associated with significantly better survival than single-agent vinorelbine in elderly patients with NSCLC.

Other combination regimens that contain cisplatin plus newer agents, such as docetaxel or irinotecan, also showed similar results when compared with other two-drug regimens of either two newer or two older agents.

Major randomized trials comparing cytotoxic regimens
To identify a better chemotherapy regimen for advanced-stage NSCLC, the US cooperative study groups conducted large phase III trials. The SWOG investigators compared paclitaxel/carboplatin with vinorelbine/cisplatin (the time-tested regimen in previous European and SWOG trials). A total of 404 evaluable patients were randomized to receive either paclitaxel (225 mg/m2 over 3 hours) plus carboplatin (at an area under the curve [AUC] of 6 mg/mL/min on day 1) every 21 days or vinorelbine (25 mg/m2 weekly) plus cisplatin (100 mg/m2 on day 1) every 28 days. Overall response rates were 27% for both groups. The median survival times were also identical (8 months), with virtually identical 1-year survival rates (35% and 33%, respectively). Although both regimens provided effective palliation for advanced NSCLC, the investigators identified paclitaxel/carboplatin for future studies because of a favorable toxicity profile and better tolerability and compliance.

The ECOG 1594 trial compared three platinum-based regimens containing new agents in the treatment of NSCLC with a control arm of cisplatin and paclitaxel. The regimens were gemcitabine (1,000 mg/m2 on days 1, 8, and 15) plus cisplatin (100 mg/m2 on day 1) every 4 weeks, docetaxel (75 mg/m2) plus cisplatin (75 mg/m2 on day 1) every 3 weeks, and paclitaxel (225 mg/m2 over 3 hours) plus carboplatin (at an AUC of 6 mg/mL/min on day 1) every 21 days; the reference regimen was paclitaxel (175 mg/m2 over 24 hours) plus cisplatin (75 mg/m2 on day 1) every 21 days.

Analysis of 1,163 eligible patients showed no statistically significant differences in overall response, median survival, and 1-year survival rates when compared with the control arm, paclitaxel and cisplatin. Gemcitabine plus cisplatin was associated with a statistically significant prolongation of time to disease progression when compared with the control arm (4.5 months vs 3.5 months; P = .002) but was also associated with a higher percentage of grade 4 thrombocytopenia, anemia, and renal toxicity.

Recent randomized trials have begun to suggest that differentiating treatment regimens by histology may be important. A phase III trial by Scagliotti et al randomized 1,725 patients to receive a combination of cisplatin and gemcitabine vs cisplatin and pemetrexed (Alimta). In patients who did not have a squamous cell histology, the combination of cisplatin and pemetrexed had a superior overall survival. On the other hand, in patients with a squamous cell histology, the combination of cisplatin and gemcitabine had a superior survival. These and other data suggest that pemetrexed and platinum appear to be superior in non-squamous cell populations. The investigators reported that this is the first prospective phase III study in NSCLC to show survival differences based on histologic type. Based on the results of this study, the FDA approved pemetrexed, in combination with cisplatin, in the first-line treatment of locally advanced and metastatic NSCLC, for patients with a nonsquamous histology.

Because all the regimens showed similar efficacy, QOL becomes a critical issue in choosing a particular regimen. The decision to use one regimen over another will depend not only on ease of administration and side effects, but also on the personal preference and experience of the treating oncologist.

Second-line chemotherapy for NSCLC
Before the new generation of more effective agents became available, few, if any, significant benefits were expected from second-line chemotherapy. As a result, reports in the literature seldom address this issue specifically or systematically. The most experience with second-line chemotherapy in NSCLC is with docetaxel, which has received FDA approval for this indication based on two randomized phase III trials confirming the promising phase II results of docetaxel monotherapy in patients with advanced NSCLC previously treated with platinum-based chemotherapy.

At ASCO 2009, Belani and colleagues presented results of the final analyses of outcomes from a phase III study that compared pemetrexed (Alimta) with placebo in 663 patients with stage IIIB/IV non–small-cell lung cancer (NSCLC), who had had no disease progression during 4 cycles of platinum-based chemotherapy. All of the patients received best supportive care in addition to pemetrexed or placebo in 21-day cycles until disease progression. Overall survival was significantly better in patients who received pemetrexed than in those who received placebo (13.4 months vs 10.6 months,

P

= .012). Pemetrexed also was associated with better progression-free survival. The survival benefits occurred primarily in patients with nonsquamous NSCLC. The incidence of drug-related grade 3/4 toxicities, including fatigue and neutropenia, was increased in the pemetrexed group, but there were no pemetrexed-related deaths, and therapy was generally well-tolerated. Fewer patients in the pemetrexed group received systemic post-discontinuation therapy. The investigators concluded that maintenance therapy with pemetrexed represents a new strategy for treating patients with advanced NSCLC who respond to initial treatment

(Belani CP et al: J Clin Oncol 27[18S]:abstract CRA8000, 2009)

. In July 2009 FDA approved Alimta for maintenance therapy in patients with advanced or metastatic NSCLC.

In a multicenter US trial reported by Fossella et al, 373 patients were randomized to receive either docetaxel (100 mg/m2 [D100] or 75 mg/m2 [D75]) or a control regimen of vinorelbine (30 mg/m2/wk) or ifosfamide (2 g/m2 × 3 days) every 3 weeks. Overall response rates were 10.8% with D100 and 6.7% with D75, each significantly higher than the 0.8% response of the control arm (P = .001 and P = .036, respectively). Although overall survival was not significantly different among the three groups, the 1-year survival was significantly higher with D75 than with the control treatment (32% vs 19%; P = .025).

In a phase III trial led by Hanna et al, 572 previously treated patients were randomized to receive pemetrexed with vitamin B12, folic acid, and dexamethasone or docetaxel with dexamethasone. The overall response rate in the pemetrexed arm was higher, 9.1% vs 8.8%. The median disease progression–free survival was 2.9 months for each arm, and the median survival favored pemetrexed (8.3 months vs 7.9 months ). The 1-year survival for each arm was 29.7%. Adverse reactions (grade 3/4) were more severe with docetaxel.

The second trial reported by Shepherd et al compared single-agent docetaxel with best supportive care. The initial docetaxel dose was 100 mg/m2, which was changed to 75 mg/m2 midway through the trial because of toxicity. A total of 204 patients were enrolled; 49 received D100, 55 received D75, and 100 received best supportive care. Treatment with docetaxel was associated with significant prolongation of survival (7.0 months vs 4.6 months; log-rank test, P = .047) and time to disease progression (10.6 weeks vs 6.7 weeks; P < .001).

Hanna et al conducted a noninferiority trial to test whether pemetrexed was equivalent to docetaxel in the second-line setting. They randomized 571 patients to receive 500 mg/m2 of pemetrexed or 75 mg/m2 of docetaxel preceded by a vitamin B12 injection every 2 cycles. The median survival on the two arms was equivalent, but the pemetrexed arm had significantly less grade 3/4 neutropenia and fewer hospitalizations overall. On the basis of this study, the FDA approved pemetrexed for second-line therapy for NSCLC.

Duration of chemotherapy
The American Society of Clinical Oncology (ASCO) has recommended that no more than 8 cycles of chemotherapy be administered to patients with stage IV NSCLC. However, therapy should be individualized depending on the quality of tumor response and the patient's tolerance.

Two trials during the past 2 years have suggested that there may be some benefit to maintenance chemotherapy in patients who have response or stable disease after front-line therapy. Fidias et al suggested that adding docetaxel as maintenance therapy after platinum-based front-line chemotherapy can delay tumor progression and lead to improvements in disease-free survival. Data by Ciuleanu et al presented at the 2008 ASCO meeting utilized maintenance pemetrexed after front-line response to chemotherapy and also showed a significant improvement in progression-free survival from 2 months for placebo to 4 months for pemetrexed. In both these trials, subpopulation analysis showed that certain groups of patients tend to benefit especially from maintenance chemotherapy. This phenomenon is currently being explored by investigators.

Novel and promising agents
Several novel agents are being developed for the treatment of solid tumors, including lung cancer. These novel agents include signal transduction inhibitors, such as tyrosine kinase inhibitors (eg, erlotinib [Tarceva], gefitinib; antiangiogenic agents, including both monoclonal antibodies, such as bevacizumab [Avastin], and small molecule tyrosine kinase inhibitors of vascular endothelial growth factor (VEGF), such as sunitinib (Sutent) and sorafenib (Nexavar); and monoclonal antibodies (C225 [antiepidermal growth factor receptor antibody] and trastuzumab [Herceptin]). Many of these novel agents are being tested in combination with chemotherapeutic agents, as their mechanisms of action suggest that they may be far more effective as chronic inhibitors of cancer progression than as classic cytotoxics.

Combinations of cetuximab with chemotherapy also appear promising. Pirker et al showed that adding cetuximab to cytotoxic chemotherapy with cisplatin and vinorelbine improved median survival from 10.1 to 11.3 months in a randomized trial of 1,125 patients with advanced and metastatic NSCLC. This statistically significant (P = .044) 1.2-month improvement in median survival was not duplicated when cetuximab was added to taxane/platinum-based chemotherapy. However, in both of these studies, adding cetuximab to chemotherapy improved response rate, and these data are currently being evaluated in their totality as physicians integrate this epidermal growth factor receptor into the therapeutic arm of NSCLC.

Gefitinib and erlotinib To date, most phase I studies of these various compounds have suffered from a difficulty in developing pharmacologically or molecularly driven endpoints that will serve as reasonable intermediate biomarkers of efficacy or even surrogates for toxicity. Further research has focused on the novel small molecule tyrosine kinase inhibitors erlotinib and gefitinib. Two phase II trials of gefitinib in the second- and third-line settings were conducted in Europe and Japan. Patients were randomized to receive either 250 or 500 mg daily. The drug was found to be active, with an 11% to 18% response rate, and there was no superiority for the higher dose. Similar data were seen for erlotinib.

Unfortunately, randomized combination trials of gefitinib at 250 and 500 mg daily with cytotoxic chemotherapy, either paclitaxel and carboplatin in one trial or gemcitabine and cisplatin in the other study vs placebo in front-line therapy, failed to demonstrate any survival advantage. These results have cast a pall over the development of tyrosine kinase inhibitors in combination with chemotherapy. Regardless, the question of whether or not to approve these new agents for third-line therapy of lung cancer in cisplatin/docetaxel-refractory patients remains open for debate.

The activity demonstrated by gefitinib and erlotinib as single agents in advanced NSCLC generated much optimism, including a recent trial indicating that erlotinib improved survival (by a median of 2 months) in the second- and third-line treatments of NSCLC, with a substantial increase in 1-year survival (P < .001). After the initial successes with chemotherapy and promising results from targeted tyrosine kinase inhibitors in stages IIIB and IV NSCLC, several large phase III trials of either gefitinib or erlotinib in combination with conventional platinum-based chemotherapy were conducted as the INTACT 1 and INTACT 2 trials or the TALENT and TRIBUTE trials.

The phase III trials of single-agent erlotinib and gefitinib, when compared with best supportive care in the second- and third-line settings, had dramatically different results. Shepherd et al conducted a randomized trial of erlotinib (150 mg daily) vs placebo in 723 patients previously treated with front- or second-line chemotherapy for NSCLC. A total of 488 patients received erlotinib and 243 received placebo.

The median overall survival significantly favored the erlotinib arm (6.7 months vs 4.7 months), with a reduction in the hazard ratio of 0.73 (P > .001), as did the 1-year survival rate (31% vs 21%; P > .01). QOL and median time to deterioration also significantly favored erlotinib. On the other hand, the phase III trial of gefitinib vs best supportive care in more than 1,600 patients was reported and showed no significant advantage to gefitinib at 250 mg daily in a patient population with a significant number of active smokers.

Bevacizumab When combined with chemotherapy, bevacizumab appears to result in a significant survival advantage for patients with advanced NSCLC. Based on promising phase II data of bevacizumab in combination with carboplatin and paclitaxel, Sandler et al randomized 878 patients to receive either bevacizumab with carboplatin and paclitaxel or carboplatin and paclitaxel alone.

There was a significant increase in the response rate for the combination (27.2%) with bevacizumab vs paclitaxel and carboplatin alone (10%; P < .0001), and both median and progression-free survival significantly favored the bevacizumab combination arm (overall survival: 12.5 months vs 10.2 months; P = .007; hazard ratio = 0.77; 95% CI = 0.65–0.93; progression-free survival: 6.4 months vs 4.5 months; P < .0001; hazard ratio = 0.62; 95% CI = 0.53–0.72). As in the phase II trial, this study reported a total of eight treatment-related deaths on the bevacizumab arm vs two on the paclitaxel and carboplatin arm. A second phase III randomized trial testing the value of adding bevacizumab to gemcitabine and cisplatin therapy showed an improvement in disease-free survival, but not overall survival.

The PASSPORT trial is designed to evaluate the safety of bevacizumab (Avastin) in the first- and second-line settings. The primary endpoint is safety based on the rate of grade 2 or greater CNS hemorrhage. A combined report presented at ASCO 2008 included patients entered onto the PASSPORT trial (n = 65) and patients on the ATLAS trial (n = 26), which was amended to include patients with treated and controlled brain metastases. PASSPORT also allowed patients treated in either the first- or second-line setting; ATLAS included only patients treated in the first-line setting. During active treatment, no grade 2 or greater CNS hemorrhagic events were reported; one grade 2 CNS hemorrhage was reported in a patient whose disease progressed following cessation of bevacizumab treatment. The PASSPORT trial has completed accrual with approximately 110 patients. This early analysis suggests bevacizumab is safe in the setting of brain metastases provided patients are treated effectively and definitively and that they retain a good performance status

(Akerley WL, et al: J Clin Oncol 26: abstract 8043, 2008)

.

Bexarotene The mechanisms of action of these new small molecules are widely divergent, and their combinations with the cytotoxics may not necessarily lead to an enhanced response rate. Khuri and colleagues demonstrated, however, that the combination of cisplatin, vinorelbine, and bexarotene (Targretin, a retinoid-X-receptor [RXR]-specific novel retinoid) resulted in substantial median and 2-year survival rates in patients with stage IIIB NSCLC with malignant pleural effusion or stage IV NSCLC. Median survival in this multicenter study was 14 months in the phase II portion; 2-year survival was 32%; and 3-year survival was 18%. The combination yielded modest response rates (25%), not markedly superior to what was expected with cisplatin and vinorelbine alone. Two phase III trials adding bexarotene to standard chemotherapy failed to show a significant overall difference in median survival. Some survival benefit was seen in those patients who developed grade 3/4 hypertriglyceridemia as a result of the bexarotene, accounting for 35% to 40% of all patients enrolled in this study.

This finding has led to an uncoupling of the requirement for higher response rates when adding cytotoxic agents to one another in the belief that doing so may lead to enhanced survival. There now appears to be a great deal of promise associated with several small molecules, either alone or combined with chemotherapy. Novel agents such as gefitinib or lonafarnib have shown promising efficacy in small trials that have included patients with NSCLC; gefitinib alone resulted in an 18% response rate in second- or third-line therapy for NSCLC in a study population recruited across several continents.

Other promising novel agents currently being investigated in lung cancer include inhibitors of the insulin-like growth factor receptor. Karp et al showed that these agents appear to be particularly promising in patients with squamous cell lung tumors, with response rates in a small study as high as 70%.

Current treatment recommendations
It is important to note that patients who have lost significant amounts of weight or who have a poor performance status are at greater risk for toxicity, including a higher likelihood of lethal toxicity, when they are treated with modest doses of chemotherapy. Based on currently available data, a reasonable approach for patients with stage IV NSCLC who have a good performance status (ECOG performance status 0/1) and have not lost a significant amount of weight (< 5% of usual weight) would be to encourage them to participate in a clinical trial. However, it would also be appropriate to treat this group of patients with etoposide plus cisplatin or with one of the newer combination regimens, such as gemcitabine/cisplatin, vinorelbine/cisplatin, paclitaxel/cisplatin, paclitaxel/carboplatin, or docetaxel/cisplatin (

and 7).

ROLE OF PHOTODYNAMIC THERAPY
Photodynamic therapy (PDT), which combines Photofrin (a hematoporphyrin derivative in which the less active porphyrin monomers have been removed) with an argon-pumped dye laser, has been explored in a variety of different tumors, with varying results. Several investigators have reported excellent results with PDT in early-stage head and neck cancers as well as intrathoracic tumors. However, initial studies have involved a limited number of patients.

Although this novel technique seems to be extremely promising, it appears to be applicable to a minority of patients with NSCLC. Nevertheless, PDT appears to be particularly useful for the treatment of early-stage lung cancer for a variety of reasons. First, it appears to preserve lung function and can be repeated as additional tumors appear-an important consideration as such patients appear to be at high risk for developing other new tumors. Second, this technique does not preclude ultimate surgical intervention

when deemed necessary.

Results in early-stage NSCLC Perhaps most striking are the results reported by Furuse et al, who treated 54 patients with 64 early-stage lung cancers using Photofrin (2.0 mg/kg) and 630-nm illumination of 100 to 200 J/cm2. Of 59 accessible tumors, 50 responded completely and 6 showed partial responses. Five of the complete responders developed recurrences 6 to 8 months after treatment.

The major predictor of response in this study was tumor length. The likelihood of achieving a complete response was 97.8% if the tumor was < 1 cm, as opposed to only 42.9% if the lesion was > 1 cm. The overall survival rate in these patients was 50% at 3 years.

A similar study by Kato et al also indicated a 96.8% complete response rate for tumors < 0.5 cm but only a 37.5% rate for tumors > 2 cm. The overall 5-year survival rate for the 75 patients treated in this study was 68.4%, which is acceptable by current standards.

Results in advanced-stage NSCLC Two prospective, randomized trials (European and US/Canadian) compared PDT with the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser for partially obstructive, advanced NSCLC. Investigators analyzed results from the two trials both individually and collectively. Collective analysis included data from 15 centers in Europe and 20 centers in the United States and Canada and involved a total of 211 patients. In the European trial, 40% of the patients had received prior therapy, whereas in the US/Canadian trial, all of the patients had received previous treatment.

Tumor response was similar for both therapies at 1 week. However, at 1 month, 61% and 42% of the patients treated with PDT in the European and US/Canadian trials, respectively, were still responding, compared with 36% and 19% of patients who underwent laser therapy in the two trials.

PDT also produced more dramatic improvements in dyspnea and cough than did Nd:YAG therapy in the European trial, but the two treatments had similar effects on these symptoms in the US/Canadian trial. Both sets of investigators concluded that PDT appears to be superior to laser therapy for the relief of dyspnea, cough, and hemoptysis. Also, the overall incidence of adverse reactions was similar with the two therapies (73% for PDT vs 64% for Nd:YAG therapy). Early-stage lung cancer, most specifically endobronchial squamous cell carcinoma smaller than 1 cm, is effectively treated with PDT, with a complete response rate of 75% and a recurrence rate of 30% over 5 years.

PALLIATION OF LOCAL AND DISTANT SYMPTOMS

Radiation therapy
Many patients with lung cancer experience distressing local symptoms at some time. They may arise from airway obstruction by the primary tumor, compression of mediastinal structures by nodal metastases, or metastatic involvement of distant organs. Radiation therapy is effective in palliating most local symptoms, as well as symptoms at common metastatic sites, such as bone and brain. For selected patients with a solitary brain metastasis and controlled disease in other sites, resection followed by irradiation appears to be superior to radiation therapy alone in improving both survival and QOL. (For more information regarding management of brain metastases, see chapter 23.)

Doses In the United States, radiation oncologists often use doses of ~30 Gy in 10 fractions for palliative thoracic treatment in lung cancer. Data from the United Kingdom suggest that similar efficacy without greater toxicity may be achieved with more abbreviated schedules, such as 17 Gy in 2 fractions 1 week apart or single fractions of 10 Gy (see

). Such schedules may facilitate the coordination of irradiation and chemotherapy and also reduce patient travel and hospitalization.

Just over 400 patients with inoperable NSCLC (stage III/IV) were randomized to receive three different fractionation regimens (8.5 Gy × 2, 2.8 Gy × 15, or 2.0 Gy × 25). Using the EORTC Quality-of-Life Questionnaire (QLQ) C-30 with the lung cancer-specific module (LC-13), Sundstrom et al found the effect of hypofractionated irradiation (17 Gy in 2 fractions) was comparable to that with longer fractionation schemes with regard to symptom relief and survival.

Endobronchial irradiation with cobalt-60 or iridium-192 has been used to palliate symptoms arising from partial airway obstruction, including cough, dyspnea, and hemoptysis. The dosimetric advantage of being able to deliver a high radiation dose to the obstructing endobronchial tumor while sparing adjacent normal structures, such as the lungs, spinal cord, and esophagus, has clear appeal, particularly in the patient whose disease has recurred following prior external-beam irradiation. Although good rates of palliation have been reported with endobronchial irradiation, significant complications, including fatal hemoptysis, are seen in 5% to 10% of patients. It remains unclear, however, how often this complication is actually due to the irradiation or the underlying disease itself.

Endobronchial irradiation should be considered as one of several approaches (including laser excision, cryotherapy, and stent placement) used in the management of patients with symptomatic airway obstruction, and management should be individualized. All of these approaches are more suitable for partial than for complete airway obstruction.

Chemotherapy
Several trials have explored the use of chemotherapy to palliate specific symptoms in patients with lung cancer. In general, these trials have found that rates of symptomatic improvement were considerably higher than objective response rates and were not dissimilar to symptomatic response rates with local radiation therapy.

Thus, although radiation therapy remains the most appropriate modality for the treatment of such problems as superior vena cava obstruction, spinal cord compression, brain metastases, or localized bone pain, patients who have more extensive disease without these local emergencies may be considered for palliative chemotherapy, which may relieve local symptoms and prolong survival.

Bisphosphonates
Approximately 30% to 65% of patients with advanced lung cancer develop bone metastases. The median survival following development of bone metastases is 6 months. Bone disease is associated with significant morbidity, including severe pain, hypercalcemia of malignancy, pathologic fracture, and spinal cord or nerve root compression. Treatment of bone metastases may include surgical intervention, radiation therapy, and chemotherapy. Bisphosphonate treatment can decrease skeleton-related complications, delay progressive disease, and relieve bone pain.

Bisphosphonates such as clodronate, pamidronate, and zoledronic acid (Zometa) exhibit strong affinity for the hydroxyapatite crystal of bone and preferentially accumulate at sites of active bone remodeling, where they prevent bone resorption. They provide effective treatment for hypercalcemia of malignancy and have been shown to delay the onset of progressive bone disease and relieve bone pain in studies largely performed in patients with metastases secondary to breast cancer, multiple myeloma, and prostate cancer. Nitrogen-containing bisphosphonates, such as pamidronate and zoledronic acid, appear to exert antitumor effects. Zoledronic acid has also been found to have pronounced antinociceptive effects, which have been absent with other bisphosphonates in preclinical studies. Zoledronic acid is the only bisphosphonate shown to be effective in reducing skeletal complications in patients with bone metastases from lung cancer and solid tumors other than breast and prostate cancers.

Follow-up of long-term survivors

At present, no standard follow-up protocol exists for patients with cured NSCLC or SCLC. However, long-term follow-up should at least include serial physical examinations once the patient has reached the 5-year mark. Controversy currently exists about the value of utilizing CT scanning or even chest x-rays for the long-term follow-up of these patients.

In this vein, retrospective reviews of the literature have revealed that patients with SCLC appear to have the highest rate of second primary tumor development-as high as 30%-over the course of their lifetime, with some studies reporting annual second primary tumor rates of 5% to 10%. Therefore, the concept of chemoprevention appears to have particular merit in these patients.

A randomized chemoprevention study of patients with stage I NSCLC showed a surprisingly high annual recurrence rate of 6.5% in patients with T1 tumors, as opposed to 11.2% in patients with T2 tumors. Whether retinoids are effective chemopreventive agents remains to be seen. Nevertheless, there is clearly a need for effective chemoprevention for both of these tumor subsets, as well as the establishment of consistent guidelines for routine long-term follow-up. Given the current controversy over lung cancer screening, however, it is unlikely that this issue will be resolved without the performance of another prospective screening trial.

References:

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Abbreviations in this chapter
ALPI = Adjuvant Lung Project Italy; ANITA = Adjuvant Navelbine International Trialist Association; BMRC = British Medical Research Council; CALGB = Cancer and Leukemia Group; B ECOG = Eastern Cooperative Oncology Group; EORTC = European Organization for Research on the Treatment of Cancer; IALT = International Adjuvant Cancer Trial; IASLC = International Association for the Study of Lung Cancer; I-ELCAP = International Early Lung Cancer Action Project; LCSG = Lung Cancer Study Group; NLST = National Lung Screening Trial; PLCO = Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; ROSEL = Radiosurgery or Surgery for Operable Stage I NSCLC; RTOG = Radiation Therapy Oncology Group; SICOG = Southern Italy Cooperative Oncology Group; SLCG = Spanish Lung Cancer Group; SWOG = Southwest Oncology Group