Lung cancer killed an estimated 156,940 men and women in the United States in 2011, more than colon, breast, prostate, and pancreatic cancer combined.¹ More than 80% of these cases were caused by habitual or environmental exposure to tobacco smoke.² This clear-cut origin makes lung cancer a disease better suited to prevention than treatment. Non–tobacco-associated lung cancer (NTLC) is not a rare disease, however, with about 40,000 cases per year in the United States and an even greater percentage of total lung cancer cases in Asia. NTLC differs at a molecular level from tobacco-associated NSCLC, and these differences have clinical and therapeutic implications.

The reduction of lung cancer deaths in white American men over the past two decades has resulted more from the decrease in cigarette smoking after the publication of the U.S. Surgeon General’s report in 1964 than the real but modest advances in the effectiveness of therapy.

Although the results of current therapy are frustrating, they must not be met with nihilism. Small improvements in therapy help many individuals, comparable in years of life saved to the modest benefit seen with adjuvant therapy for patients with other common tumors, such as breast or colon cancer. Although avoiding tobacco use is the most efficient strategy for reducing lung cancer deaths, it is clearly worthwhile to optimize current therapeutic modalities of surgery, irradiation, and chemotherapy. Even if all current smokers quit smoking now, their previous carcinogen exposure would lead to another million or more cases of lung cancer. The need for effective treatment will continue in the foreseeable future.

Advances in multiple disciplines include tumor biology techniques that enable both identification and selective treatment of particular molecular entities within the broad spectrum of diseases termed lung cancer, imaging and treatment delivery technologies that better identify where to put the dose and deliver it there accurately and reproducibly (or adaptively to a target size and shape that is changing over time), and a growing willingness of specialists of all modalities to work collaboratively for their patients’ benefit.³ The development of interventions to facilitate such continuity of care and communication to patients is gaining attention.⁴ The key to improving treatment is the integration of diagnostic and treatment modalities by a team whose members are interested in lung cancer and its treatment, well versed in the application of the appropriate modalities, and able to combine them without undue bias.^5,⁶ The development of advocacy groups such as the Lung Cancer Alliance and their endorsement by groups such as the American Academy of Chest Physicians should hasten this becoming the standard of practice, as happened for patients with breast and prostate cancers.

Etiology and Epidemiology

More than 80% of cases of lung cancer can be attributed to carcinogens in tobacco smoke. Habitual and environmental exposures are clearly linked to lung cancer at levels ranging from descriptive epidemiology, characteristic patterns of oncogene and tumor suppressor gene mutations, and measurement of tobacco-associated carcinogens in the urine of individuals exposed to second-hand smoke.⁷^–¹⁰ Hecht and associates^11,¹² showed that nonsmokers, when exposed to side-stream smoke in concentrations comparable to those found in a smoky bar, excreted metabolites of tobacco-specific carcinogens in their urine. Pipe and cigar smokers have lower lung cancer rates than cigarette smokers, but these habits are far from innocuous, particularly in former cigarette smokers, who often continue to inhale.

The risk of lung cancer is related to the amount smoked daily and the duration of smoking, leading to the term pack-years as a measure of smoking exposure. When individuals quit smoking, their risk of lung cancer declines over at least a decade but remains higher than that of those who have never smoked.¹³^–¹⁵ Lung cancer incidence and death rates typically reflect smoking behavior from two to three decades previous. Examination of the respiratory epithelium of former smokers years after quitting shows persistence of telltale patterns of genetic and epigenetic change.^16,¹⁷ Once initiated, the process of lung carcinogenesis can proceed without continued smoke exposure.

Current epidemiologic efforts are devoted to better understanding the molecular determinants of risk distal to smoke exposure, including metabolic activation of procarcinogens, degradation and excretion of carcinogens, accurate repair of damaged DNA (or apoptotic execution of cells harboring DNA damage), and other less well understood mechanisms that result in the development of lung cancer in some but not all heavy smokers.¹⁸^–²⁰ Although no single genetic abnormality has been clearly implicated in causing lung cancer, there is considerable epidemiologic evidence for an inherited component of risk, particularly for cases of lung cancer diagnosed in younger individuals.²¹ Polymorphisms in a variety of enzymes involved in the metabolism of potential carcinogens, their detoxification, and in DNA repair enzymes have been associated with risk of lung cancer in a number of small studies of both smokers and nonsmokers but no clear risk pattern has been replicated in large populations.

Several recent studies have reported that a polymorphism in the nicotinic receptor gene cluster in the chromosome 15q24-25 region is strongly associated both with nicotine dependence and the development of chronic obstructive pulmonary disease (COPD) and lung cancer.²² Such associations have been seen in European, African, and Asian populations. Whether this locus is directly involved in tobacco carcinogenesis or indirectly mediated through strength of nicotine dependence is not yet clear.

In addition to tobacco smoke, many other substances have been implicated in causing lung cancer. Several industrial chemicals, particularly the chloromethyl ethers, have been associated with lung cancer. Exposure to asbestos and tobacco smoke produces lung cancer more frequently than either exposure alone. Exposure to inhaled radioactive substances by uranium miners or by individuals living in areas with high endogenous radon levels also increases risk.

Smokers with significant COPD are at significantly higher risk for lung cancer than individuals with similar smoke exposure without COPD.^23,²⁴ It is not known whether this reflects a common behavioral cause (e.g., deeper smoke inhalation, longer smoke retention) in these individuals or if there are differences in metabolism of components of tobacco smoke that increase the risk for COPD and lung cancer. Chronic inflammation has also been implicated in the pathogenesis of a variety of cancers.

Lung cancer has been reported in a number of patients with human immunodeficiency virus (HIV) infection, but there is no good evidence for a direct causative role. Lung cancer is not particularly common in individuals otherwise immunosuppressed, such as after organ transplantation. HIV-positive individuals with lung cancer tend to be younger than other patients, almost always have a history of heavy tobacco use, tend to present with advanced-stage disease (80% stage III and IV), show a predominance of adenocarcinomas, and have a poorer prognosis, even for those presenting with early-stage disease. The tolerance of these patients to treatment, particularly to aggressive chemoradiation may be compromised by limited hematologic reserve and development of severe mucositis during and after RT. Care must be taken to balance therapeutic aggressiveness and tolerance.

Human papillomavirus (HPV) infection, particularly with serotypes 16 and 18, has been associated with head and neck squamous cell carcinoma in humans, often without significant tobacco exposure.²⁵ Such tumors are biologically distinct from the typical tobacco-associated head and neck cancers and have a better outcome when treated with chemoradiation. Several studies have investigated the association of HPV with lung cancer and have found HPV in about 25% of lung cancers studied, with considerable geographic variation (about 15% in Europe and the Americas, about 35% in Asia, and as high as 80% in parts of Japan and Taiwan²⁶). It is not clear that the HPV virus is truly causative of lung cancer rather than associated with it, and this remains an area of active investigation. The therapeutic responsiveness and natural history of HPV-associated lung cancers has not been well characterized.

Although lung cancer used to be a predominately male disease, its incidence and death rates in women began to rise in the United States in the 1960s and the death rate from lung cancer in women has exceeded that of breast cancer since 1987.²⁷ In the United States, the incidence of lung cancer in men increased through the 20th century until leveling off and then starting to decline in the 1980s. In women, the incidence rose steadily through the latter part of the century but may now be starting to level off in the United States and Europe.

Although most cases of lung cancer occur in individuals with a history of tobacco use, lung cancer in those who have never smoked or in minimal smokers is far from a rare disease. It represents 15% to 20% of lung cancer seen in North America and Europe and up to 40% in parts of Asia. In the United States, deaths from non–tobacco-associated lung cancer amount to about 20,000 per year, ranking in the top five causes of cancer death. There are clear data that the clinical and molecular characteristics of lung cancer arising in persons who have never smoked or in minimal smokers are quite distinct from those of tobacco-associated lung cancer and warrant separate therapeutic strategies.28,29

Molecular Biology of Lung Cancer

Multiple genetic changes have been identified in lung cancers and cell lines derived from them and several distinct pathways of oncogenic development, both for squamous cell and several distinct varieties of adenocarcinoma, have been proposed.30,31 The morphologic and clinical differences between the various types of NSCLC are reflected in decidedly different patterns of oncogene and tumor suppressor genes modifications in these disease families. Although there are no absolute differences or characteristic mutations for either type in the way that the BCR-ABL translocation is relatively pathognomonic of chronic myeloid leukemia, some molecular abnormalities frequent in one histologic type are rare in another, and vice versa.

RAS

The RAS oncogene family contains three members, HRAS, KRAS, and NRAS, which encode membrane-associated proteins involved in mediation of signals arising from binding of ligands to cell membrane receptors such as epidermal growth factor receptors (EGFRs) to nuclear transcription factors.³² Mutation in several specific sites, including codons 12, 13, and 61, lead to constitutive activation of these signaling pathways.³³ In lung cancer, mutations are most commonly seen in KRAS.³⁴ They are most frequently seen in adenocarcinoma but are also seen in other NSCLC histologies.³⁵ They are seen almost exclusively in smokers and rarely if ever in those who have never smoked whose tumors contain EGFR mutations. Patients whose lung cancers contain mutated KRAS almost never respond to EGFR tyrosine kinase inhibition (EGFR-TKI), but it is not clear that they are resistant to cetuximab as is the situation in colorectal cancer.³⁶ The presence of mutated RAS genes has been an adverse prognostic factor in resected and advanced lung cancer in most series in which this has been assessed.³⁷ RAS mutations are rare in SCLC, and, when detected, they may represent an admixture of NSCLC elements or the development of an intermediate SCLC line.³⁸

MYC

The MYC gene products are nuclear transcription factors. Structural mutations are not reported in lung cancer, but amplification of copy number and overexpression are common in SCLC and uncommon in NSCLC with the exception of large cell neuroendocrine tumors. Amplification has been more commonly reported in cell lines from patients with clinically resistant tumors after chemotherapy, but the role of MYC amplification in de novo drug resistance is uncertain.³⁹^–⁴³

TP53

Abnormalities in TP53 function through deletion or mutation of the gene or overexpression of MDM2 leading to aberrant TP53 inactivation are among the most common genetically induced changes in human malignancies.⁴⁴ Mutations are reported in a high frequency in lung cancer, about 50% of NSCLCs, and 90% of SCLCs.^45,⁴⁶ Different patterns of mutation (e.g., ratio of transitions to transversions) are seen in smokers and in persons who have never smoked, suggesting different mutagens. Normal TP53 plays several key roles in determining cellular response to genetic damage, particularly whether cells enter growth arrest or apoptosis. There have been conflicting reports about the prognostic implications of abnormal TP53 function in lung cancer. For a number of chemotherapeutic agents and ionizing radiation, cells lacking normal TP53 function are resistant to apoptotic cell death, although the effect on overall cell survival is controversial.^47,⁴⁸

RB1

The RB1 gene–encoded product (RB) is a nuclear protein that undergoes cyclic phosphorylation and dephosphorylation during the cell cycle under the control of G₁ cyclins.^49,⁵⁰ RB regulates E2F1 transcription factor activation. Absence of normal function occurs in most SCLCs but only in about 10% of NSCLC lines examined.⁵¹^–⁵³

CDKN2A

Normally, CDKN2A (previously designated p16) regulates transcription through phosphorylation of the RB1 protein. Abnormalities of CDKN2A function are reported in a reciprocal fashion to those of RB1; they are common in NSCLC and rare in SCLC. Because either of these abnormalities can allow uncontrolled transcriptional activation through E2F, it is not surprising that they are not commonly found together.⁵⁴ Although mutations in either are common in lung cancer, these mutations have not been correlated with prognosis.

Growth Factors

Abnormalities in normal growth factor signaling pathways have been proposed as a common mechanism for the dysregulated cell growth in cancer. In lung cancer, several clear examples of this have been demonstrated to exist and have become targets for possible therapeutic intervention.

Epidermal Growth Factor Receptor

EGFR mediates a number of signaling pathways critical for cell growth, survival, and response to cytotoxins, including ionizing radiation and several chemotherapeutic agents. It is overexpressed in a variety of malignancies, and overexpression has been correlated with poorer clinical outcome and resistance to radiation. Clinical attempts to target this pathway have included monoclonal antibodies targeted to the extracellular domain of the receptor (C225, ABX) and low-molecular-weight compounds that bind the adenosine triphosphate (ATP) site and inhibit the tyrosine kinase activity of the receptor. About 10% of patients with NSCLC have mutations involving the ATP-binding pocket of the EGFR, which gives rise to more prolonged signaling activity in response to ligands such as epidermal growth factor (EGF) or transforming growth factor–beta and causes them to bind these inhibitors more tightly.⁵⁵^–⁵⁷ Such activation mutations are seen primarily in individuals with no or minimal smoking history and in Asian women and are more common in adenocarcinomas than squamous cell carcinoma. Patients whose tumors have these mutations are likely to have significant objective responses to treatment with these compounds, but it is postulated that patients with wild-type, overexpressed EGFR are more likely to show a response of growth restraint but not regression. The relative importance of mutation and overexpression of EGFR in predicting outcome of treatment with EGFR-TKI such as erlotinib is a subject of controversy and active research.^58,59,60

ERBB2

Overexpression of ERBB2 (formally HER2) is reported in NSCLC, particularly adenocarcinoma, and it is correlated with decreased survival of patients with resected disease.^61,⁶² The degree of overexpression is typically much less than seen in cancer of the breast, with few lung cancer patients showing 3+ staining. Trials of monoclonal antibodies directed against ERBB2 in unselected NSCLC patients have shown relatively little activity whether used alone or in combination with cytotoxic chemotherapy.⁶³

In addition to overexpression of wild-type ERBB2, activating point mutations have been described in a number of patients with NSCLC.⁶⁴ These patients, about 5% of all with NSCLC or 15% of those with adenocarcinoma, may be more sensitive to therapies directed against ERBB2-mediated signaling and warrant further study with these agents, as may also be appropriate for patients with unmutated but highly overexpressed (3+ by immunohistochemical staining) ERBB2.⁵⁹

Recently, fusion genes that produce atypically activated transcription factors or kinases, long known in leukemias and sarcomas, have been described in a number of solid tumors.⁶⁵ Fusion of EML4 and ALK has been described in a subset of patients with NSCLC.⁶⁶ Patients with EML4-ALK are typically young and light smokers or persons who have never smoked with adenocarcinoma. Because these clinical features also are more commonly seen in patients with EGFR mutations but patients with EML4-ALK mutations are not sensitive to TKI targeting EGFRs such as gefitinib or erlotinib, it becomes increasingly important to select targeted therapies on the basis of molecular profiling of individual tumors rather than population statistics.⁶⁷ Inhibitors of the ALK kinase have shown significant activity in vitro and in early clinical trials and are entering trials comparing them with conventional cytotoxic agents in patients with EML4-ALK mutations.⁶⁸

Early Detection and Prevention

Fewer than 20% of lung cancer patients in the United States are diagnosed with localized (stage I) disease. The poor survival of patients with symptomatic lung cancer prompted efforts to diagnose the disease in asymptomatic individuals. The U.S. National Cancer Institute (NCI) sponsored several trials in the 1970s comparing active screening using annual chest radiography and sputum cytology with “routine” medical care.^69,⁷⁰ These studies showed increased detection of localized disease in the screened populations, with higher rates of resectability but no decrease in mortality. This led to recommendations from the American Cancer Society to abandon routine screening for lung cancer by the methods used and in the populations studied (warranted by the data) and to an unwarranted pessimism about early diagnosis in general.

Since these trials, important demographic and technologic changes have occurred. Lung cancer is increasingly a disease of women.⁷¹ Lung cancer has also increasingly become a disease of former smokers. Several large centers have reported that more than one half of their lung cancer patients are former (i.e., more than 1 year since cessation) rather than current smokers.⁷² This change has key implications for therapeutic interventions and in the possibility of enlisting this population, who have already demonstrated a high degree of motivation by quitting smoking, in studies of early detection and chemoprevention.

Silvestri and associates ⁷³ have reviewed the current status of screening for lung cancer in the light of this changing demography and proposed 10 essential criteria for a successful screening program: “The disease must have serious consequences and be readily detectable in the preclinical phase. The test should have a high accuracy, detect the disease before a critical point, cause little morbidity, be available and affordable, and result in little overdiagnosis. Finally, treatment for the disease must exist, and it must be effective before symptoms occur, with little risk or morbidity.”

Computed Tomography–Based Screening Studies

The availability of fast high-resolution computed tomography (CT) has prompted a new round of screening trials.⁷⁴ CT is more sensitive in detecting pulmonary nodules in asymptomatic individuals than chest radiography. The percentage of detected nodules ultimately proved to be cancerous has varied considerably between different series, in part owing to the background frequency of conditions such as endemic fungal infections that may give rise to benign pulmonary nodules. Most series have shown a shift to earlier stage at diagnosis for screened patients compared with historical controls, which is potentially a marker for improved survival. However, others have argued that tumors detected through screening are likely to have a different and more indolent biology than other tumors and that only prospective trials can determine whether CT screening reduces overall or tumor-specific mortality. Several large trials of screening CT have been completed in recent years to determine whether there is a reduction in overall mortality. Results are pending, and the current National Comprehensive Cancer Network (NCCN) and American College of Chest Physicians (ACCP) recommendations do not advocate screening for any groups.⁷⁵

Cytologic and Molecular Screening

Advances in molecular technology offer the promise of detecting malignant changes in exfoliated cells well before morphologic changes appear. Tockman and associates ⁷⁶ have shown that with monoclonal antibody staining using sera developed against SCLC and NSCLC lines, sputum cells showing atypia could predict which patients were going to develop frank malignancy with a lead time of about 2 years. This technique is being studied further in a prospective trial of patients who have undergone resection of a stage I NSCLC and are at high risk for local recurrence and development of a second primary lung cancer. Mao and co-workers⁷⁷ reported similar findings using probes for mutations of KRAS and TP53 genes. Mills and colleagues⁷⁸ also reported detection of KRAS mutations in fluid obtained at bronchioalveolar lavage. Others have reported the ability to detect EGFR mutations in circulating tumor cells or DNA fragments.^79,80 These findings, reported initially in retrospective pilot trials, are being validated in large, prospective trials seeking to detect second malignancies in patients curatively resected for their first lung cancers. Examination of the bronchial epithelium reveals multiple areas of dysplasia and carcinoma in many of these patients at the time of their initial diagnosis, and the risk of a second invasive malignancy is about 3% per year.

Autofluorescence bronchoscopy has been used to examine the tracheobronchial tree and look for early neoplastic or preneoplastic lesions.⁸¹ This approach complements CT screening, which primarily detects peripheral lesions and has poor sensitivity for small endobronchial lesions.⁸²

One reasonable interpretation of the results of the NCI-sponsored early-detection trials is that although they were successful in detecting disease earlier than would have been done without screening, this “early” disease was still quite advanced in terms of the natural history of the disease. Key events such as the ability of tumor cells to metastasize, induce angiogenesis, and develop resistance to chemotherapeutic agents were likely to have occurred earlier in their history. Recognition of the long promotion period in the development of lung cancer suggests that a more fruitful approach would be to detect intermediate points in this process, to screen for carcinogenesis instead of cancer.⁸³

Screening is not innocuous. In addition to the small but finite radiation hazard from CT scans, patients undergoing screening are at risk for complications of further testing and intervention associated with false-positive screen findings. Patients should be made aware of these potential downsides of screening before making decisions to be screened outside the context of a clinical trial.

At present the techniques available for detection of early lung cancer are undergoing rapid development and may lead to the development of effective screening techniques, but no regimen (target population, tests, frequency) has been shown to improve overall mortality of the screened population. Until this has been shown, the recommendation of the ACCP that “individuals undergo screening only when it is administered as a component of a well designed clinical trial with appropriate human subjects’ protection” seems quite appropriate.⁷⁵

Chemoprevention

Several classes of compounds have been investigated as candidate agents for lung cancer prevention.⁸⁴ Epidemiologic data show a higher incidence of lung cancer in populations with low dietary intake of retinoids and carotenoids. Deficiencies of these agents can lead to squamous metaplasia in animal models. Provision of exogenous vitamin A to animals that have developed metaplasia or atypia can lead to morphologic normalization of the epithelium.

Several trials of retinoids have been conducted in patients at high risk for lung cancer. Hong and associates ^85,⁸⁶ randomized patients with treated cancers of the head and neck to 13-cis-retinoic acid or placebo and found that although the recurrence rates of the initial lesion were unchanged, the treated group had a significantly reduced incidence of second primary tumors, particularly of the head, neck, lung, and esophagus. Pastorino and associates⁸⁷ conducted a similar trial in resected lung cancer patients using retinoyl palmitate and observed fewer second primary tumors and a borderline improvement in OS. However, larger, prospective, confirmatory trials testing isotretinoin or retinyl palmitate and N-acetylcysteine^88,⁸⁹ have failed to confirm the initial promise of earlier trials. To further complicate matters, several trials of β-carotene as a chemopreventive agent⁹⁰ have observed increased rates of cancer in populations of individuals who continue to smoke.

The epidemiologic correlation between reduced consumption of foods rich in carotenoids and an increased risk of lung cancer in smokers and the laboratory data showing a protective effect of β-carotene against lung carcinogenesis led to two large chemoprevention trials.⁹¹^–⁹⁴ In Finland, a trial of placebo versus β-carotene or α-tocopherol (i.e., vitamin E), or both,⁹⁵ showed increased rates of and death from lung cancer in subjects receiving β-carotene. Participants in this trial were predominantly actively smoking males. In the United States, a trial of β-carotene (CARET) was closed prematurely when interim analysis also showed an increased incidence of lung cancer in the treated arm of the study.⁹⁶ The increased risk of lung cancer incidence and death of lung cancer persisted even after further administration of β-carotene was discontinued.^97,⁹⁸ Although the popular interpretation of these trials has been negative, they offer clear proof of the principle that human lung carcinogenesis is a dynamic process amenable to pharmacologic manipulation. They also reinforce the basic principle that clever ideas must be tested in careful trials before becoming standard of practice. No agent has yet been recognized and confirmed as an effective chemopreventive agent for lung, head, or neck cancers, and an untreated control group remains appropriate and essential for future trials.

Selenium is a trace mineral whose presence in the soil varies considerably with geography. Selenium deficiency in animals can produce premalignant changes. Epidemiologic studies have suggested correlation between low dietary intake and cancer of a number of sites. With these considerations in mind, Clark and colleagues ⁹⁹ performed a trial of selenium supplementation versus placebo in subjects with a history of multiple skin cancers, with a reduction in subsequent skin cancers as the designed trial outcome. Such a reduction was not seen, but the number of cases of lung cancer in the treated group was one half of that in the control group. Because multiple secondary comparisons were made in the trial, this observation might reflect chance, and a confirmatory trial to compare selenium with placebo in patients with resected stage I NSCLC has been conducted in North America, with results pending.

One limitation of the chemoprevention trials is that the candidate agents were administered systemically with the attendant toxicities associated with this approach. An approach of delivering agents directly to the bronchial epithelium, where the smoke went and where carcinogenesis occurs, is appealing and is being explored with the development of agents deliverable by aerosol.¹⁰⁰

At present no agent or combination of agents has been proven to delay or prevent the development of lung cancer of any histology in an at-risk population of current or former smokers. Although a number of the candidate agents (e.g., selenium) are of relatively low toxicity, the surprising result of increased lung cancer incidence in some retinoid trials as well as the increased risk of diabetes in patients taking selenium in a prostate cancer chemoprevention trial suggest caution rather than therapeutic adventurism in this area.¹⁰¹ The ACCP currently recommends that no agent be used for lung cancer chemoprevention outside of a clinical trial.¹⁰²

Pathology and Pathways of Spread

The respiratory epithelium has a total surface area about the size of a tennis court. It may be divided functionally and pathologically into three zones. From the trachea through the major bronchi the normal lining is made of squamous cells with interspersed neuroendocrine cells, which appear most commonly at airway bifurcations. Terminal alveoli are lined predominantly with type I and type II pneumocytes. Intermediate bronchi and bronchioles show a transition between squamous and adenomatous lining cells and a corresponding mixture of tumor types. The exposure of this large organ to a common set of inhaled toxins sets in process a widespread set of molecular and subsequent morphologic changes. Slaughter and associates,¹⁰³ who first observed this phenomenon in patients with multiple primary tumors of the head and neck, referred to it as field cancerization. Auerbach and colleagues¹⁰⁴ described similar widespread changes in the lungs of smokers with lung cancer, and Saccomano and colleagues¹⁰⁵ described a pattern of progressive degrees of cytologic atypia leading to frankly invasive carcinoma. The practical consequence of this is that patients who develop one neoplasm of the upper aerodigestive tract (i.e., head, neck, lung, and esophagus), if treated successfully, remain at substantial risk for developing a second or subsequent primary tumor. For patients with resected stage I NSCLC, this risk is on the order of 2% to 3% per year for at least 10 years after treatment of the first cancer.^88,^106,¹⁰⁷ It can sometimes be difficult to distinguish second primary tumors from local recurrences or metastases; differences in histology location, and presence of adjacent mucosal abnormalities have been proposed as criteria. Molecular markers may allow for fingerprinting by characteristic mutations at such sites as KRAS or TP53 (which are known to have different mutational spectra in different parts of the aerodigestive tract), although it still sometimes may be difficult to distinguish between separate primary tumors and clonal variation of a metastasis and most cells in its primary tumor. Recent data have suggested, however, that multifocal lung cancers may share a common clonal origin.^108,109

Lung cancer is divided into two major histologic subgroups: SCLC and the combination of squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma considered collectively as NSCLC. In the past, SCLC and NSCLC were viewed as quite different diseases, but there is increasing convergence in modern therapeutic approaches with the understanding that both are usually disseminated diseases that manifest as substantial bulk disease in the chest, for which successful treatment requires systemic and locoregional therapies.

In addition to cell type and anatomic stage, a variety of molecular prognostic factors have been proposed to provide further prognostic or predictive information in lung cancer (Table 42-1). These include measures of cell proliferation (e.g., S-phase fraction, proliferating-cell nuclear antigen [PCNA], Ki-67, potential doubling time [T_pot]), mutated or overexpressed oncogenes and/or tumor suppressor genes (e.g., KRAS, TP53, ERBB2, BCL2), cell surface antigens (i.e., blood type antigens and their precursors), and induction of angiogenesis. Most of these have been proposed on the basis of small series of patients treated in a nonuniform fashion, and they often are based on univariate rather than multivariate analysis. Proper validation of these will require prospective study in large series of patients staged, treated, and observed in a uniform fashion.¹¹⁰ It is likely that patterns of expression of multiple markers as assessed by genomic or proteomic analysis will more successfully predict prognosis, as has been shown for breast cancer and intermediate-grade lymphomas. Small series have reported the success of such profiling in lung adenocarcinomas, but large validation series in uniformly treated patient groups are awaited.¹¹¹ Such profiling may also be useful in determining those patients at greatest risk for specific patterns of metastatic spread, such as to the brain, for whom particular targeted adjuvant therapies such as prophylactic cranial irradiation may be more appropriate than in an unselected population.

TABLE 42-1 Proposed Prognostic and Predictive Factors for Non–Small Cell Lung Cancer

Factor	Comment
Tumor volume	Partially incorporated into new TNM classification
Number of nodal sites	—
Clinically evident nodal involvement	Identified preoperatively as distinct from microscopic nodal involvement
Extranodal extension	May be prognostic for local recurrence and predictive of impact of postoperative radiation therapy on survival
IHC detection of nodal metastases	Nodes negative by H&E but positive by IHC
Histology	Predictive of response and toxicity with some agents
Ploidy	—
Proliferative rate (labeling index, Ki-67, T_POT	—
KRAS mutation	Predictive of resistance to EGFR-TKI
3p deletion	—
TP53 mutation or overexpression	—
Angiogenesis (microvessel density)	—
Vascular endothelial growth factor (VEGF) overexpression	—
Epidermal growth factor receptor (EGFR) overexpression and/or mutation	Mutation predictive for response to EGFR-TKI
ERBB2 (HER/neu) oncogene expression and/or mutation	Possibly predictive for response to trastuzumab
EML4-ALK	Possibly predictive for response to ALK-TKI

H&E, hematoxylin-eosin; IHC, immunohistochemical; TKI, tyrosine kinase inhibition.

Adapted from Wagner H, Bonomi P: Preoperative and postoperative therapy for non–small cell lung cancer. In Roth JA, Ruckdeschel JC, Weisenburger TH (eds): Thoracic Oncology. Philadelphia, WB Saunders, 1995, pp 147-163.

The outcome of an individual case of lung cancer is a function of the histology and stage of the disease and the status of the host. Host factors reflect both tumor burden not yet demonstrable by imaging techniques and the individual’s ability to withstand the morbidity of treatment. In many patients with lung cancer, physiologic function is impaired, in part owing to the advanced age of many patients (median age of diagnosis is in the seventh decade) and the frequency of other illnesses, such as COPD and cardiac disease, which are also smoking related.

Lung cancer spreads through regional lymphatic vessels within the lung to the hilar and paratracheal nodes, which drain to the supraclavicular fossae and, to a lesser degree, the upper abdomen (Fig. 42-1). The patterns of nodal spread are partially predictable on the basis of tumor size, histology, and proximity to central airways. Involvement most often begins with intrapulmonary nodes, extends centrally to the hilum, and then extends to the mediastinum. However, noncontiguous “skip” metastases are well described. Although nodal involvement can usually be detected by preoperative CT, even for T1 primary tumors, the incidence of clinically unsuspected nodal metastases can be as high as 15% to 20% for peripheral adenocarcinomas.^112,¹¹³

Figure 42-1 Map of intrathoracic lymph node stations. Single-digit stations (1 to 9) are N2 nodes; double-digit stations (10 to 14) are N1 nodes.

From Mountain C: Revisions in the international system for staging lung cancer. Chest 111:1710-1717, 1997.

Hematogenous dissemination is common and usually is associated with nodal involvement, although about 20% of patients with resected T1N0 lesions will experience relapse in distant sites. Nodes that appear normal on routine histology, when examined by immunohistochemical staining for epithelial antigens, contain tumor cells in 15% to 25% of cases.¹¹² Occult bone marrow metastases in resected rib at the time of thoracotomy are also found by this method, including patients without any evidence of nodal disease.¹¹⁴ It appears that nodal and hematogenous spread, which usually is associated, may occur independently. Routine histologic examination of nodes underestimates the true frequency of metastatic involvement.¹¹⁵

Although nodal drainage is primarily to the ipsilateral mediastinum, the left upper lobe drains commonly to contralateral paratracheal nodes as well as to nodes in the anterior mediastinum.¹¹⁶ Direct involvement of visceral and parietal pleura by peripheral tumors puts the pleural space at risk for involvement. The true frequency of this is not well known, nor is its clinical significance or appropriate therapeutic response. Several series have reported that intraoperative pleural lavage detects tumor cells in about 10% of patients and that their survival is markedly worse than that of patients with tumors of otherwise similar stage with cytologically negative lavage.^117,¹¹⁸

Extrathoracic spread differs somewhat among the major histologic types of NSCLC. Early extrathoracic dissemination, particularly to the central nervous system (CNS), is seen more frequently with adenocarcinoma and large cell carcinoma than with squamous cell carcinoma.¹¹⁹ However, all histologic types are prone to early and widespread extrathoracic metastases, with brain, bone, liver, adrenal, and lung the most commonly involved sites.

Clinical Manifestations, Patient Evaluation, and Staging

Most patients diagnosed with lung cancer present with symptoms that may be due to the primary tumor, its nodal and systemic metastases, or to paraneoplastic syndromes.

Central endobronchial tumors may cause partial or complete airway obstructions, with cough, hemoptysis, postobstructive pneumonia, or dyspnea. Peripheral tumors are often asymptomatic unless they involve the chest wall and produce pain from involvement of intercostal nerves. Tumors that involve the superior pulmonary sulcus may directly involve branches of the brachial plexus with pain and weakness in the shoulder and arm or involve the sympathetic trunk, producing Horner’s syndrome with ipsilateral ptosis, miosis, and anhidrosis.

Regional lymph node metastases may compress adjacent structures. Although complete obstruction of main bronchi by extrinsic compression is uncommon, this occurs more readily in more distal airways. The superior vena cava is a relatively thin-walled, low-pressure system, and it is vulnerable to compression with significant clinical consequences. The intrathoracic course of the recurrent laryngeal and phrenic nerves is vulnerable to compression by nodal metastases. Patients presenting with hoarseness or who have a fixed elevated hemidiaphragm should be suspected of having such nodal involvement.

Lung cancer can metastasize to a wide variety of extrathoracic sites and produce diverse symptoms. The most frequent symptoms of distant metastatic disease are bone pain and neurologic symptoms from brain metastases. These are not, however, absolute indicators of metastatic disease. Pulmonary hypertrophic osteoarthropathy typically presents as bilateral pain and tenderness in the legs, which are often most tender over the tibias. Bone scintigraphy or CT/PET will show diffuse uptake in these areas, and plain films usually show a characteristic elevation of the periosteum without involvement of cortical bone.

Although focal neurologic symptoms most commonly result from brain metastases, CNS symptoms may also be caused by paraneoplastic cerebellar degeneration or to metabolic disturbances such as hyponatremia (most commonly seen in SCLC) or hypercalcemia (most commonly seen in squamous cell carcinoma). Nonspecific decreases in cognitive function compared with age- and gender-matched controls have also been reported in patients with lung cancer before any treatment, particularly in SCLC.¹²⁰

Liver metastases are common but usually asymptomatic unless advanced. Abnormalities in liver function studies are uncommon unless there has been extensive destruction of liver parenchyma, although alkaline phosphatase and bilirubin levels may be elevated by small-volume hepatic or nodal disease blocking the common hepatic or common bile duct. Elevation of the lactate dehydrogenase level is a poor prognostic sign, but it probably reflects overall tumor burden more than specifically hepatic disease. Adrenal metastases are common, particularly at autopsy, but rarely symptomatic unless large and painful. Symptomatic adrenal hypofunction has been described but is infrequent.

Radiographic Procedures in Staging

As with any other medical test, radiographic staging procedures should be used primarily when their results will lead to a change in choice of therapy. A secondary role is in defining homogeneous groups of patients for clinical research. When used in this manner, the possibility of differences between groups so staged and the more general population of patients must be kept in mind.

Appropriate radiographic procedures for patients with suspected or newly diagnosed lung cancer depend in part on the histologic type of cancer and on the therapeutic options. The otherwise healthy individual who presents for an elective orthopedic procedure and is found to have a 2-cm peripheral lung nodule without any other abnormalities on chest radiography, combined PET/CT of the chest, and routine laboratory studies (e.g., complete blood cell count, chemistry profile including electrolytes, renal, and hepatic function) is unlikely to have any useful information found with further testing. At the other end of the spectrum, the patient who presents with limiting cardiopulmonary disease, substantial recent weight loss, poor performance status, new bone pain, and a large hilar mass requires only an efficient choice of the least invasive means of obtaining a tissue diagnosis and choice of appropriate palliative therapy. Delineation of all sites of metastatic disease in such a setting is an expensive and wasteful application of resources that does not often lead to changes in care.

Evaluation of the primary tumor is generally best accomplished by CT enhanced with intravenous administration of a contrast agent.¹²¹ The parameters of contrast enhancement (dose, infusion rate, and site of infusion [left side preferred to visualize vessels crossing in the anterior mediastinum]) can make a large difference in the quality of information obtained. It is important to examine the chest using both lung and mediastinal window settings.

Staging of the Mediastinum

Combined PET/CT is the radiographic method of choice for evaluation of the mediastinum.122,123 The false-positive and false-negative rates are about 20%, however, and this should be considered when planning therapy. In most cases, histologic confirmation of suspected nodal involvement should be done before making decisions regarding potentially curative treatment. The accessibility of mediastinal nodes to biopsy under guidance of CT or of endoesophageal or endobronchial ultrasonography makes this a simple, minimally invasive procedure for most patients, with the use of the more invasive procedures of mediastinoscopy or anterior sternotomy (i.e., Chamberlain procedure) reserved for a minority of patients.^124,¹²⁵ It is important to recognize that diagnostic radiologists are neither uniform nor necessarily precise in their description of the appearance and nature of mediastinal nodes. In some cases, a patient is said to have “mediastinal adenopathy” with the implication of unresectable N2 disease, although what has been shown by CT is the presence of several 1-cm nodes. The distribution of size of mediastinal nodes in normal individuals easily includes this range; and of nodes 1.5 cm in the greatest dimension, about 20% will be histologically benign. The percentage of such false-positive results is even higher among patients with obstructing endobronchial lesions or extrinsic bronchial obstruction from hilar nodes and postobstructive infection. When normal-size nodes are histologically positive, disease is usually intranodal and technically resectable. It remains unresolved whether these patients are better served by initial resection and postoperative adjuvant therapy or by detection of these N2 nodes by preoperative mediastinoscopy or mediastinotomy and treatment with neoadjuvant therapy before resection.

Although there was initially hope that magnetic resonance imaging (MRI) might be superior to CT in differentiating benignly enlarged from malignant mediastinal nodes, this has not been the case. CT, with its better spatial resolution and greater freedom from motion artifact, is the superior modality for imaging of the mediastinum. MRI does have a role in evaluation of lesions that involve the lung apex (and possibly the brachial plexus) and medial lesions that abut the vertebrae and may invade the neural foramina. Such involvement may preclude resection and poses a risk for spinal cord compression, and its delineation has important implications for planning treatment.

FDG-PET may have good sensitivity and specificity in detecting mediastinal nodal involvement and diseases in extrathoracic metastatic sites.¹²⁶^–¹³² PET has greater sensitivity and specificity than CT, but it is still imperfect. Nodes that appear involved by PET or CT should be sampled for confirmation of their status when such information will lead to alterations in clinical management, particularly when deciding whether to consider resection. If a negative PET scan is being considered to avoid performing mediastinoscopy, it is important to require that the primary tumor show good uptake (often not the case for bronchioalveolar carcinoma), that there not be a central primary tumor whose uptake could obscure small nodes, and that a dedicated PET/CT scanner be used.¹³³ FDG-PET has also been studied for evaluating the response to preoperative chemotherapy or chemoradiation and for distinguishing between viable tumor and fibrosis in patients who have received RT or chemotherapy, or both, in assessing local disease control in patients treated nonoperatively.^128,¹³⁴^–¹⁴¹

Evaluation for Extrathoracic Metastases

The liver and adrenals are common sites of metastasis for SCLC and NSCLC and are well imaged by CT and PET. Although metastases to the adrenals are common, so are adenomas, and the distinction between these may require biopsy in the patient who is otherwise a good candidate for curative treatment. Routine bone scintiscans are of limited value. Many patients have abnormal results of bone scintigraphy, owing to benign degenerative diseases. The likelihood of detecting occult metastatic disease in patients without focal symptoms or elevation in alkaline phosphatase levels is low.

The use of total-body PET has been advocated as a cost-effective replacement for CT of the liver and adrenals and radionuclide bone scanning and may well be a reasonable replacement for these.¹²² Because the typical PET does not image the brain, it will not replace MRI for this purpose. The typical PET or fused PET/CT does not image the entire skeleton, typically omitting the calvaria and the distal extremities.

Clinically occult involvement of the CNS, especially in patients with SCLC, adenocarcinoma, and large cell carcinoma, is more common, especially in patients with involvement of mediastinal nodes. Although scanning of the brain is not indicated for patients with stage IA disease, for which the probability of involvement is about 5%, for patients with N2 disease it is in the range of 15% to 20% with high-resolution gadolinium-enhanced MRI.¹²² For patients being considered for aggressive chemoradiation with or without surgery, the finding of CNS metastases will lead to major changes in therapy, and scanning is warranted. Routine scanning is not done in patients with extrathoracic metastatic disease to look for CNS disease in the absence of symptoms, but the patient is instead asked about early symptoms and a scan is done at that time.

The role of CNS imaging in the patient with stage IB to II disease is controversial. Although the false-positive rate of CT and MRI is low and few patients would wrongly be excluded from surgery, the true-positive rate is also low, making this an uninformative test for most patients. However, in some series, 10% of patients with stage I to II NSCLC without neurologic symptoms had metastases demonstrated on enhanced CT.¹⁴² Such a frequency of involvement probably warrants more common CNS imaging as part of routine staging, particularly considering the cost and morbidity of a thoracotomy, which would most likely be futile in the presence of brain metastases.

Tumor-Node-Metastasis Stage Grouping

NSCLC is staged according to the principles of the tumor-node-metastasis (TNM) system. The International Staging System as outlined by Mountain in 1986 ¹⁴³ has been the standard for reporting treatment results since that time. The broad outlines of this system are clearly valid. However, several areas emerged that indicated the need for modification of this system, and several revisions were implemented in 1997 and again in 2009.¹⁴⁴

The TNM staging system generally is used for patients with NSCLC, and it is reasonably predictive of outcome, particularly for patients treated surgically (Tables 42-2 and 42-3). This system does not deal so well with anatomic prognostic factors important for nonsurgical treatment.

TABLE 42-2 International Staging System: TNM Classification (2009)

Category	Definition
Tx	Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	A tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without radiographic or bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)
T1a	Tumor 2 cm or less in greatest dimension*
T1b	Tumor more than 2 cm but not more than 3 cm in greatest dimension
T2	Tumor more than 3 cm but not more than 7 cm; or tumor with any of the following features†: • Involves main bronchus, 2 cm or more distal to the carina • Invades visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

T2a Tumor more than 3 cm but not more than 5 cm in greatest dimension T2b Tumor more than 5 cm but not more than 7 cm in greatest dimension T3 Tumor more than 7 cm or one that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe as the primary tumor T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s) in a different ipsilateral lobe to that of the primary tumor NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastases in ipsilateral peribronchial and/or hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2 Metastases in ipsilateral mediastinal and/or subcarinal lymph node(s) N3 Metastases in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) M0 No distant metastases M1 Distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural or pericardial effusion‡ M1b Distant metastasis

* The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified T1a.

† T2 tumors with these features are classified T2a if 5 cm or less or if size cannot be determined and T2b if greater than 5 cm but not larger than 7 cm.

‡ Most pleural (pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor and the fluid is nonbloody and is not an exudate. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient’s disease should be classified as M0.

From Goldstraw P: Staging Manual in Thoracic Oncology. Orange Park, Fla., Editorial Rx Press, 2009.

TABLE 42-3 Stage Grouping and TNM Categories

Stage	TNM Categories
Occult carcinoma	TXN0M0
Stage 0	TisN0M0
Stage IA	T1a,bN0M0
Stage IB	T2aN0M0
Stage IIA	T1N1M0
Stage IIB	T2bN1M0
Stage IIB	T3N0M0
Stage IIIA	T1a,bT2a,bN2M0
	T3N1-2M0
	T4N0-1M0
Stage IIIB	T4N0-2M0
Stage IIIB	Any T, N3M0
Stage IV	Any T, any N, M1

From Goldstraw P: Staging Manual in Thoracic Oncology. Orange Park, Fla., Editorial Rx Press, 2009.

The distinction between T2 and T3 lesions based on their proximity to the carina is of little importance in radiotherapeutic treatment. Although bulky central mediastinal disease may be difficult to treat while adequately protecting the esophagus and spinal cord, this is more commonly caused by nodal disease than tumor extending proximally along the main-stem bronchus.

Tumor volume is not considered an independent prognostic factor except by the proxy of unidimensional measurements. A 1-cm lesion involving the visceral pleura is T2, and a 2.9-cm lesion surrounded by lung parenchyma is T1. It might be expected that the smaller T2 lesion would be more readily controlled by RT than the larger T1 lesion, and available data are in agreement with this expectation. Data from several institutions support the hypothesis that tumor volume, independent of stage, is prognostic for local control and survival of patients with NSCLC treated with RT or chemoradiation.145,146–149 Such volumetric measurements can be performed using commercially available RT planning software, although standardization of technique is important to reduce interobserver variability.¹⁵⁰

There are several reports that size is an important predictor of prognosis within the clinical T1N0 group, with particular importance in predicting microscopic involvement of hilar and mediastinal lymph nodes.¹⁵¹ This is relevant to treatment strategies that try to reduce the extent of resection or limit the radiation target volume by eliminating elective nodal irradiation (ENI) in these patients. Data suggest that only patients with lesions smaller than 1 cm in diameter have a risk of nodal involvement below 10%.

Several of the old TNM stage groups have considerable heterogeneity in outcome.¹⁵⁴ This is true to some degree for patients with stage I disease, where the survival of patients with T1N0M0 disease (∼80%) is strikingly better than that of patients with T2N0M0 disease (∼60%). It is in the current stage group III that the heterogeneity and need for subgrouping is greatest. This was partially recognized by Mountain,¹⁴³ who divided the grouping into IIIA (i.e., no invasion of the mediastinum or involvement of contralateral mediastinal or supraclavicular nodes, no pleural effusion) and IIIB (i.e., with one or more of the previous characteristics). In retrospect, this has separated a group of patients (IIIA), some of whom are treated surgically, who can undergo complete resection and have a reasonably favorable prognosis (especially T3N1M0), from those who have unresectable disease and are often treated palliatively. If patients with stage IIIA and IIIB NSCLC who are treated nonsurgically with radical RT or chemoradiation are considered, the survival differences are much less striking.¹⁵²

Several other groups have proposed different revisions to the current staging system. Based on the European Lung Cancer Working Party data on patients receiving chemoradiation, Berghmans and associates ¹⁵³ proposed separating patients with stage T3 to T4, N3, and M0 disease from other factors that better predicted survival than the usual stage IIIA versus IIIB distinction. Andre,¹⁵⁴ looking at patients with resected stage III NSCLC, some of whom had received induction chemotherapy, found that the number of lymph node levels and clinically detectable nodal metastases (cN2) were adverse prognostic factors.

Although the 2009 modifications introduced to the staging system are steps in the right direction, they do not deal adequately with a number of the issues that pertain to surgical and nonsurgical therapy. The number of lymph node stations involved, as well as whether their involvement is microscopic or macroscopic, has also been found to be of prognostic significance in patients with resected stage IIIA disease. One difficulty including this, as well as a number of the important molecular prognostic factors, is their inconstant evaluation from institution to institution.

Practical treatment decisions for patients with stage IIIA and IIIB NSCLC are often made along the following lines ¹⁵⁵:

GROUP A (old T1-3N2aM0): Involvement of a single mediastinal nodal station found at mediastinoscopy or mediastinotomy or at thoracotomy. The nodal capsule is not breached. In some institutions, these patients have disease resected and then are given adjuvant postoperative therapy; others are given preoperative therapy.

GROUP B (old T1-3N2bM0): Involvement of multiple mediastinal nodal stations with potentially resectable disease. Current trials compare chemoradiation or chemotherapy as preoperative regimens.

GROUP C (old T1-3N2cM0): Bulky involvement of mediastinal nodes (e.g., seen on a chest radiograph), possibly with superior vena caval compression. Disease is unlikely to be resectable, even with preoperative therapy, but the patient is a candidate for definitive chemoradiation.

GROUP D (old T4aNXM0): Central T4 or N3 disease that can all be encompassed within a reasonable RT portal, limited by lung and spinal cord dose. These patients should be considered for definitive chemoradiation.

GROUP E (old T4bNXM0, now stage IVa): Disease extent includes malignant pleural effusion. Because all known disease cannot be irradiated to a tumoricidal dose, these patients should be treated as patients with stage IV disease using primary chemotherapy, with irradiation to treat or prevent local symptoms.

Medical Considerations for Surgical Resection: Cardiopulmonary Evaluation

Before undergoing surgery, patients must undergo appropriate cardiopulmonary evaluation to determine their ability to tolerate the operative procedure and the expected reduction in lung function after resection.156,159 Patients with a history of cardiac artery disease should be assessed typically including a stress test along with stress radionuclide angiography. Patients in whom coronary artery calcification can be seen on CT should be similarly evaluated.

Pulmonary function evaluation should include determination of lung volumes and flow rates and of diffusing capacity and arterial blood gas analysis. A recommended preoperative workup is outlined in Table 42-4. Some patients with poor baseline pulmonary function due to extensive bullous disease and poor lung compliance may have improvement in function after combined resection of the tumor and pulmonary dead space.

TABLE 42-4 Preoperative Evaluation of Pulmonary Function

Test	Desirable Value	Comment
FEV₁	>1.5 L lobectomy >2 L pneumonectomy >80% predicted	Should obtain regional ventilation and perfusion scans and calculate predicted postoperative FEV₁ in borderline cases
PCO₂	<45 mm Hg	Recent studies suggest that this may not be an independent risk factor
SaO₂	>90%	Further testing indicated if <90%
DLCO	>80% of predicted	Further testing indicated if <80%
	10 mL/kg/min	Values ≥15 mL/kg/min predict low surgical morbidity. Those >10 but <15 are borderline, and the patient’s overall clinical status needs to be considered carefully.

DLCO, diffusing capacity of the lung for carbon dioxide; FEV₁, forced expiratory volume in 1 second; PCO₂, partial pressure of carbon dioxide; , maximum oxygen consumption.

Data from Colice GL, Shafazand S, Griffin R, et al: Physiologic evaluation of the patients with lung cancer being considered for resectional surgery. Chest 132(Suppl):161S-177S, 2007.

Patients not meeting criteria for lobectomy should be considered for lesser resections (i.e., wedge or segmental resection) if these appear capable of obtaining negative margins. The Lung Cancer Study Group (LCSG) trial,¹⁵⁷ which randomized patients with stage T1N0M0 NSCLC between lobectomy and more conservative resection, showed significantly better local control for lobectomy and an emergent difference in survival. The role of limited excision followed by RT to the tumor bed, either by external beam or intraoperatively placed brachytherapy mesh, is not known and is being studied by the Cancer and Leukemia Group B (CALGB) and by the American College of Surgeons Oncology Group (ACOSOG). These patients may well be better treated by stereotactic body radiation therapy (SBRT) delivering very high radiation doses to restricted volumes (see later).

Sometimes, a patient referred to the radiation oncologist for definitive RT appears to be a borderline surgical candidate. Such situations require an honest but tactful discussion of the issues with the patient and the referring physician and occasionally the suggestion of referral to another surgeon, preferably a cardiothoracic surgeon with particular expertise and interest in lung cancer, for a second opinion. In this setting the difference in experience between a surgeon who specializes in treating thoracic malignancies and a general thoracic surgeon may be significant, and the best interests of the patient must be kept in view.

Primary Therapy

Early-Stage Disease

Surgery is the most effective treatment for patients with technically resectable NSCLC of stage IA through IIB. The role of surgery for patients with IIIA (N2) disease is controversial. Several points arise from consideration of the survival of patients with surgically resected disease and the patterns of failure for those with disease that recurs:

• Five-year OS for the most favorable patients, those with small stage T1N0M0 lesions, approaches 80%, not far from what is seen for women with early-stage breast cancer.¹⁵⁸ This refutes the common impression of lung cancer as an intrinsically incurable disease and more correctly focuses attention on early detection.

• Most treatment failures are systemic rather than local (Table 42-5).

• Many patients with compromised pulmonary function can be managed surgically, if they undergo careful perioperative care.¹⁵⁹

• Complication rates depend on patient (age, physiologic status), disease (e.g., extent of required resection), and technical (e.g., surgical expertise) factors.¹⁶⁰

TABLE 42-5 Selected Reports of Stereotactic Radioablation of Lung Tumors: Primary Lung Cancers and Metastatic Lesions

Definitive Radiation Therapy

Single-institution reports of results of definitive RT for patients with stage I or II NSCLC who refuse surgery or are deemed inoperable for medical reasons vary in patient selection, RT technique, and outcome (Table 42-6). Some of this variation comes from different definitions of “medical unresectability,” with institutions that consider borderline disease to be unresectable in many patients, improving the apparent results of both their surgical and RT series by the Will Rogers effect (i.e., stage migration).¹⁶¹ However, several general conclusions may be drawn from these series:

1 Some patients with locally confined disease are cured with definitive RT. “Unresectable” is not synonymous with “incurable.”

2 Survival of clinically staged patients treated with radical RT is inferior to that of surgically staged patients treated surgically.

3 Survival of these patients decreases with increasing T stage, tumor size (within T stage), and clinical involvement of hilar lymph nodes.

4 Even for patients with the most favorable disease status, local control has historically been poor and inferior to that seen with surgery.

5 Even for patients with favorable disease status, distant metastases are a common cause of death.

TABLE 42-6 Radical Radiation Therapy for Patients with Medically Inoperable Non–Small Cell Lung Cancer

These observations suggest several strategies to improve treatment outcome. Combining RT with systemic chemotherapy in an attempt to reduce distant relapse or to improve local control is a logical approach to explore, particularly as the toxicity of current chemotherapeutic regimens has decreased. RT parameters are another fertile ground for clinical trials. Sibley ¹⁶² reviewed 10 reports of definitive RT for patients with medically inoperable stage I NSCLC. About 15% of patients were long-term survivors, 25% died of intercurrent disease, 30% died of distant metastases, and 30% died of local failure. Neither time to local failure nor OS correlated with the treatment volume (i.e., primary tumor volume alone or prophylactic nodal irradiation), whereas the total tumor dose, in the range of 55 to 70 Gy, did correlate with outcome. This suggests that escalation of the biologic effective dose (by increasing the total dose or decreasing overall time with an increased fraction size or multiple fractions per day) to a small target volume, typically that of the primary tumor with margins, is a logical approach to improve the RT management of these patients. Such an approach would not preclude combination with systemic treatment, although caution should be taken because of a possible increase in pneumonitis with concurrent chemoradiation.^163,¹⁶⁴

Stereotactic Body Radiation Therapy

A number of investigators have explored the use of hypofractionated SBRT for these patients (see Table 42-5). Both frame-based and frameless systems have been used, with daily tumor localization by orthogonal images, cone-beam CT, and real-time tracking of implanted fiducial markers. Motion due to respiration presents a complicating factor not encountered in intracranial stereotactic treatment. Such motion is present in conventional large-field RT, but it is often accommodated by increasing field margins at the expense of treating increasing volumes of normal lung tissue. This is unacceptable for stereotactic large-fraction treatment. A number of approaches have been developed for minimizing respiratory motion through breath-hold and abdominal compression techniques, gating the beam-on time to a particular phase of the respiratory cycle, or tracking the tumor or radiopaque fiducial markers implanted in it and adapting the target volume to the real-time position of the tumor. These approaches are evolving, but the reported results are highly promising and suggest that, at least for T1 tumors, the results of SBRT may rival those of surgery for local control and survival (see Table 42-5). Until recently, the experience with such stereotactic approaches had been limited to single institutions, but the Radiation Therapy Oncology Group (RTOG) has conducted a phase I/II trial of fractionated SBRT for patients with medically inoperable stage I NSCLC using a regimen of three treatment fractions. Results from this and multi-institutional trials in Japan and Europe indicate local control rates of about 90% when tumors are treated to a biologically effective dose of 100BED or greater.¹⁶⁵ A number of different fractionation schemes have been employed, ranging from a single fraction of 34 Gy to three- to five-fraction regimens over 1 to 2 weeks. At present, the optimal dose and fractionation, as well as the optimal dose homogeneity in the target volume (i.e., is a 30% hot spot at the center of the planning target volume a good thing for local control or a bad thing for complications?) remain to be clarified. Dose calculations for the multiple small fields used and tissue heterogeneities are also highly dependent on the calculation model used.¹⁶⁶ There also have been reports of substantial toxicity, particularly with regimens using smaller numbers of fractions, when the high-dose volume includes central vascular or airway structures or the chest wall.^167,¹⁶⁸ Implementation of a program of SBRT requires careful attention to details of patient positioning, treatment planning, and dose calculation to be safe and effective, but this approach, when properly executed, appears to challenge the primacy of surgery in treating patients with early-stage lung cancer.

Another therapeutic option that has been explored for medically inoperable patients with early stage NSCLC is radiofrequency ablation (RFA). In this modality, a needle electrode is placed percutaneously under CT guidance and the tumor then heated with radiofrequency energy. Treatment is typically given in a single session. Local control rates of 50% or more seem achievable for tumors less than 3 cm, although most series are small and include a mixture of primary and metastatic tumors. Prospective trials are being conducted to better define the role of this therapy.¹⁶⁹

Adjuvant Therapy for Early-Stage Disease

Discussing the risks and benefits of adjuvant treatment with patients is difficult. Telling a patient who is recovering from a major surgical procedure that he or she is at high risk for recurrence despite having had a complete resection, that adjuvant therapy designed to reduce this risk is of only modest benefit (typically making a difference in long-term survival for about 5% of patients), can be a daunting task. The statistical nuances of disease-free and OS curves escape many patients (Table 42-7). The format in which data are presented (i.e., whether the effect of an adjuvant treatment is expressed as a hazard ratio, a relative survival difference, or an absolute survival difference) can greatly affect their acceptance by patients.^170,¹⁷¹

TABLE 42-7 Rates and Patterns of Relapse after Resection of Non–Small Cell Lung Cancer

Postoperative Radiation Therapy

Several retrospective series published in the 1960s claimed that postoperative irradiation of mediastinal and hilar nodes improved survival of patients with resected NSCLC, particularly if they had nodal metastases.¹⁷²^–¹⁷⁵ This issue has been investigated in several prospective trials that, although methodologically flawed, provide a consensus answer that survival is minimally if at all improved but local failure is probably reduced with such treatment.

A meta-analysis of 2128 patients treated in nine randomized trials of postoperative radiation therapy (PORT) concluded that this treatment was associated with a highly significant increase in the risk of death ¹⁷⁶ (Fig. 42-2). Overall, the risk ratio was 1.21 (p = .001). The authors concluded that PORT as used in these studies was detrimental and should not be used, at least for the time being. There are several significant differences between the treatment administered in several of the trials included in this meta-analysis and current practice patterns in the United States. One fourth of the patients had stage I disease. There has never been a strong case favoring PORT for these patients and little suggestion from their patterns of failure after surgery that such treatment would be beneficial (see Table 42-7). Details of treatment, including preoperative staging, surgical technique, and radiation dose and dose delivery, differed substantially from current practice. Several of the trials required or allowed daily fraction sizes in excess of 2.0 Gy, with the Medical Research Council (MRC) trial using 2.6 Gy/day and the Slovenian trial using 3.0 Gy/day. Larger fraction sizes would be expected to produce an increase in acute and late complications compared with slower fractionation. Seven of the nine trials also allowed the use of cobalt-60 (⁶⁰Co) treatment beams, with their poorer depth-dose characteristics than higher energy accelerator beams, and only one study included CT-based treatment planning. Compared with current practice, PORT as used in these trials probably caused excess deaths from cardiac and pulmonary damage. It is notable that in this meta-analysis the increase in risk of death was most marked in those patients with stage I disease and was not significant for patients with N2 disease. This is consistent with, but does not prove, a potential benefit for properly delivered irradiation for patients with resected N2 disease.

Figure 42-2 A, The OS curves for all patients analyzed show a significant deleterious effect of postoperative radiation therapy (PORT) on survival. B, This deleterious effect varies strongly with extent of local disease (expressed as stage group or N stage), with the hazard function not overlapping with unity for patients with stage groups 1 or N0 disease.

From Burdett S, Stewart L: Postoperative radiotherapy in non–small-cell lung cancer. Update of an individual patient data meta-analysis. Lung Cancer 47:81-83, 2005.

The PORT Meta-analysis Group updated their analysis with the inclusion of one additional trial.¹⁷⁷ The overall conclusions that PORT was detrimental for patients with stage I or II NSCLC and that there was no clear evidence for benefit or detriment for patients with stage III N2 disease were not altered. However, results and updates of several other recent trials were not included in this analysis.¹⁷⁸^–¹⁸⁰

Phlips and colleagues ¹⁸¹ reported results of postoperative therapy given over two time periods, one with ⁶⁰Co therapy and a later one with high-energy photons. For comparable patient groups, 5-year survival was 8% for those treated with ⁶⁰Co but 30% for those treated on linear accelerators with CT-based treatment planning. Less cardiac and pulmonary toxicity was reported in the more recent patient group. Schraube and associates¹⁸² reported calculated complication probabilities for patients receiving postpneumonectomy RT delivered using two-dimensional (2D) or three-dimensional (3D) treatment planning. For equivalent physical doses to the mediastinal nodal target volume, the biologic mean dose to lung and heart and the associated normal tissue complication probabilities were considerably lower with 3D treatment planning. Machtay and colleagues¹⁸³ compared the rates of death from intercurrent disease (DID) for patients who had received adjuvant PORT. They observed a 4-year actuarial risk of 13.5%, which was minimally but not significantly greater than the 10% expected. The total radiation dose was strongly associated with the risk of DID: 2% for doses less than 54 Gy and 17% for 54 Gy and higher doses. Wakelee and colleagues^184,¹⁸⁵ performed a retrospective analysis of DID in the INT 0115 trial, which compared PORT (50.4 Gy if no extracapsular extension, 59.4 Gy if this was documented) with or without concurrent chemotherapy with cisplatin and etoposide against that expected based on U.S. vital statistics. The actuarial rates of DID at 4 years were 12.3% for irradiation and 13.7% for irradiation plus chemotherapy (not significant) and no higher than expected given the age and smoking status of the treated patients.

Selection of patients at highest risk for mediastinal recurrence after R0 resection cannot at present be done as accurately as desired. Although the presence of metastases in resected N2 nodes clearly predicts for remaining disease in unresected nodes, the role of extracapsular extension has not been well investigated. One surgical study reported that it predicted for overall relapse in patients treated with surgery alone,¹⁸⁵ whereas in another retrospective review¹⁸⁶ it was found that postoperative mediastinal irradiation appeared to improve OS in patients with resected N2 disease without but not with extracapsular extension. Evidence from several institutions¹⁸⁷^–¹⁹⁰ indicates that locoregional failure is increasingly common with a higher number of involved N2 nodes and that induction chemotherapy followed by surgery gives inadequate control of mediastinal disease.

If the PORT meta-analysis failed to demonstrate a survival benefit for patients with N2 disease because this benefit was counterbalanced by excess deaths due to complications of the RT as given and modern RT is less toxic as the described studies suggest, a trial conducted now might well show a survival benefit. Because even with nontoxic therapy this benefit would be relatively small (on the order of a 5% to 10% gain in absolute survival), any trial attempting to demonstrate a difference will require a large number of patients (approximately 2000) to minimize the risk of type 2 error.

The CALGB initiated a phase III trial of PORT in patients with resected N2 disease in an attempt to answer this question.¹⁹¹ Patients received four cycles of adjuvant chemotherapy with carboplatin plus paclitaxel and then were randomly assigned to observation or mediastinal irradiation. Accrual to the trial was slow, and it was closed with only 40 patients. Median failure-free survival time was 15.6 months for the nonirradiated patients and 25.9 months for those receiving mediastinal irradiation. Failure-free and OS at 1 year were 60% and 70%, respectively, on the observation arm and 56% and 72% on the irradiation arm. None of these differences reached statistical significance. The closure of this trial made it underpowered to detect a small but clinically worthwhile benefit.

Several recent nonrandomized analyses may shed some further light on the question of PORT for patients with N2 disease. Lally and associates ¹⁹² analyzed data from the U.S. Surveillance, Epidemiology, and End Results (SEER) database and found that although survival for patients with resected NSCLC was not generally improved by the addition of PORT, it was significantly improved for patients with N2 disease. Douillard and colleagues¹⁹³ reviewed the results of the ANITA trial in which patients with resected NSCLC, stages I through IIIA, were randomized as to whether they received adjuvant chemotherapy but received PORT or not based on institutional preference. While the numbers were small and not protected by randomization to PORT, the results were provocative. PORT was not beneficial for patients with N0 or N1 disease. But for patients with N2 disease, PORT improved both local control and survival whether or not patients received adjuvant chemotherapy, and did not significantly increase the risk of death from intercurrent disease.

A difficult clinical situation is the question of PORT for a patient without proven mediastinal lymph node involvement but whose surgery did not adequately sample or dissect the mediastinum. CT scans done postoperatively may show one or more somewhat enlarged mediastinal nodes, but this may reflect tumor or postoperative infection or inflammation. The use of PET in this setting has been explored by Roberts and colleagues, who suggested that it might be helpful in directing when to give and when to withhold further therapy.¹³⁹ However positive nodes in this setting are not specific and should be considered for biopsy by endoscopic ultrasonography or endobronchial ultrasonography.

At present adjuvant PORT cannot be recommended on the basis of demonstrably improved survival but should be considered in selected patients at high risk of local recurrence, particularly when there is involvement of multiple nodal stations or extracapsular tumor spread. Its use in conjunction with adjuvant chemotherapy is discussed in the next section. For patients with microscopically positive margins after resection the situation is quite different, and they should receive concurrent chemoradiation for their residual microscopic disease.

Prophylactic cranial irradiation has been less well evaluated in patients with NSCLC than in SCLC. Three reported randomized trials of prophylactic cranial irradiation in patients with NSCLC failed to show any survival benefit, but none of them included patients with early-stage, resected disease or even patients thought to be in complete remission after definitive RT (with or without chemotherapy).¹⁹⁴^–¹⁹⁶ One retrospective series reported benefit in CNS failure rates for prophylactic cranial irradiation in patients with stage III NSCLC treated with an aggressive chemoradiation regimen. The earlier group of patients who did not receive prophylactic cranial irradiation had a CNS failure rate of 46% (13 of 28) compared with 9% (4 of 47) of a subsequent group who received prophylactic cranial irradiation.¹⁹⁷ Others have also reported high CNS relapse rates for aggressively treated patients with stage IIIA/B NSCLC (Table 42-8). The RTOG conducted a phase III trial¹⁹⁸ of prophylactic cranial irradiation in patients with stage IIIA/B NSCLC who had completed all other planned therapy, which included various combinations of surgery, RT, and chemotherapy, and had stable disease or better. The trial had planned to accrue 1058 patients to evaluate a potential 20% improvement in OS as its primary endpoint but was closed after accrual of 356 patients because of slow accrual. Neither overall nor disease-free survival is significantly different between the two arms, but the incidence of brain relapse at 1 year was 7.7% in the prophylactic cranial irradiation arm and 18% in the observation arm. As control of local and extrathoracic metastatic tumor improve, the potential benefit of prophylactic cranial irradiation will increase, but it cannot be considered standard at this time. As is the case for patients with SCLC, attention to details of prophylactic cranial irradiation dose and fractionation, as well as timing relative to chemotherapy, may be important in limiting neurologic toxicity.^199,²⁰⁰

TABLE 42-8 Central Nervous System Relapse in Patients with Locally Advanced Non–Small Cell Lung Cancer

Postoperative Chemotherapy

Early trials of postoperative chemotherapy for patients with resected NSCLC failed to show significant benefit. Many of these were conducted with agents with minimal antitumor activity in this disease, and all were underpowered to detect a modest but clinically worthwhile improvement in survival on the order of 5%. A meta-analysis of all published randomized trials comparing observation with adjuvant chemotherapy showed no overall benefit, but the results differed by type of chemotherapy regimen.²⁰¹ Older alkylating agent–based regimens significantly worsened survival by 5%, whereas cisplatin-based regimens gave a 5-year survival improvement of 5%, which approached statistical significance (p = .08). Although there was considerable heterogeneity of stage, surgical procedure, and planned and delivered chemotherapy, this result suggested that chemotherapy with modest activity for metastatic disease could improve survival in the adjuvant setting, as had been previously demonstrated in breast and colorectal cancers.

Several large trials of adjuvant chemotherapy have been reported in full or abstract since publication of the meta-analysis (Table 42-9). The North American Intergroup conducted a large trial designed to test the efficacy of postoperative chemotherapy in patients with completely resected N1 and N2 NSCLC.²⁰² After extensive discussion of trial design, a two-arm comparison of PORT with or without concurrent chemotherapy (cisplatin and etoposide) was adopted. The use of PORT in both arms was designed to optimize local control, potentially increasing the ability to detect an effect of chemotherapy on systemic metastases. It was also thought that a comparison of two adjuvant regimens rather than treatment versus observation would be more acceptable to both patients and physicians. This trial (INT 0115), which enrolled 488 patients, showed no trend or significant difference in survival for the two arms, regardless of whether all 488 entered patients or 368 eligible and evaluable patients were considered. Multivariate analysis showed no benefit of the chemotherapy used in this study (i.e., four cycles of cisplatin and etoposide beginning concurrently with the start of irradiation) for any clinical subset of patients. Concurrent chemoradiation also failed to improve local mediastinal control, compared with RT alone.

TABLE 42-9 Adjuvant Chemotherapy Trials

The Adjuvant Lung Project Italy (ALPI) enrolled 1209 patients with resected stage IA-IIIA NSCLC to a randomization between observation and chemotherapy with mitomycin, vindesine, and cisplatin.²⁰³ Forty-three percent of patients also received PORT (after chemotherapy if this was given). There was a survival trend favoring the chemotherapy study arm that did not reach statistical significance.

The International Adjuvant Lung Cancer Trial (IALT) is the largest trial of adjuvant chemotherapy in lung cancer that has been conducted.²⁰⁴ The trial was planned to study 3000 patients, but it closed after enrolling 1867 patients because of declining accrual and evidence of a significant difference between the arms of the trial on interim analysis. Patients were randomized between observation and adjuvant chemotherapy that used cisplatin and an institutional choice of second agents (i.e., etoposide, vindesine, vinblastine, or vinorelbine). RT could be given (by institutional policy) after chemotherapy. There was an overall absolute improvement in the 5-year survival rate of 4% (44.4% vs. 40.4%), which was highly significant, was present for all stage groups, and was seen whether patients also received postoperative mediastinal irradiation (not a randomized variable in this trial but done according to institutional preference). Although this trial showed a clear benefit in survival for adjuvant chemotherapy, it did not provide information on patterns of failure. To facilitate rapid accrual of a large number of patients to the trial, which was key in demonstrating the primary survival endpoint, the amount of data collected on patients was limited. Restricting the amount of information collected at randomization and during follow-up facilitated enrollment, as in previous trials.

Two other trials have demonstrated the strong, positive effects of adjuvant chemotherapy. The National Cancer Institute of Canada Cancer Treatment Group (NCIC-CTG) randomized patients with resected stage IB-IIIA NSCLC to observation or adjuvant chemotherapy with cisplatin and vinorelbine ²⁰⁵ They found a rather large and significant improvement in OS: 69% versus 54%. Despite the availability of effective antiemetic regimens, compliance with this adjuvant chemotherapy regimen was not very good; only about 50% of patients completed all four cycles of this regimen, with variations by age, gender, extent of surgery, and nationality.²⁰⁶ That this was a randomized trial with a no-treatment option may have contributed to the poor compliance, with patients making the choice between known toxicity and possible benefit. With survival benefits for adjuvant chemotherapy now reasonably well established, patients may find the same regimens that were difficult to tolerate when their benefits were uncertain, much more tolerable. The CALGB randomized patients with resected stage T2N0M0 NSCLC to observation or adjuvant therapy with carboplatin plus paclitaxel. The result of this trial was initially positive, with 71% versus 59% survival at 4 years, but the difference became nonsignificant with longer follow-up.²⁰⁷

Hotta and associates ²⁰⁸ published a meta-analysis of trials of adjuvant chemotherapy limited to those trials reported after the Collaborative Group meta-analysis published in 1995. Eleven trials and 5716 patients were analyzed. These investigators excluded trials in which the randomization was between PORT and chemoradiation (e.g., INT 0115). With the exception of several Japanese trials using only tegafur and uracil (UFT), the chemotherapy was cisplatin plus a variety of other agents, mostly Vinca alkaloids or etoposide. A significant survival improvement (hazard ratio = 0.872; p = .001) was seen overall, and in subset analysis this held for the cisplatin-containing chemotherapy and for UFT. The latter results are not well understood in view of the rather low response rates (6.3%) seen with UFT in the setting of metastatic disease.²⁰⁹ Hamada and associates²¹⁰ also analyzed six published Japanese trials of UFT adjuvant chemotherapy with a highly significant improvement in 5-year OS (absolute magnitude of 5%; p = .01).

A meta-analysis of these recent trials, the Lung Adjuvant Cisplatin Evaluation (LACE) has confirmed an OS benefit for cisplatin-containing adjuvant chemotherapy for node-positive patients. There is no clear signal for patients with node-negative tumors, but there is a suggestion of benefit for patients with larger lesions. Several recent publications with longer follow-up of some of the adjuvant trials have reported conflicting results as to the durability of the benefit of adjuvant chemotherapy. The IALT trial showed survival benefit for the first 5 years but not with longer follow-up, similar to results seen by the CALGB using carboplatin and paclitaxel for earlier stage disease. But the Canadian trial using cisplatin/vinorelbine reported continued benefit beyond 5 years.

A reasonable take-home message and off-study clinical policy at the present would recognize the following:

1 Cisplatin containing doublets has shown modest but statistically significant survival benefit in a number of trials of patients with resected NSCLC and should be considered for most patients.

2 The benefits are most clearly seen in patients with node-positive tumors and possibly with larger (>4 cm) node-negative tumors.

3 Substitution of carboplatin for cisplatin is not supported by the available data but may be considered for patients with contraindications to cisplatin.

4 The role of molecular selection of patients for adjuvant therapy, for example by ERCC1 expression, is suggested in some analyses but awaits wider confirmation and the availability of readily available assays.

5 The role of molecular targeted agents (including cetuximab and bevacizumab) and EGFR-TKI (e.g., gefitinib and erlotinib) is currently under active investigation but is not established.

Although there are sufficient data to establish adjuvant chemotherapy as standard for most patients with resected NSCLC, with the exception of patients with stage T1N0M0 disease, there are few data on the ability of this therapy to reduce the high rates of local recurrence seen in some patient subgroups. With the failure of CALGB 9734 to accrue adequate numbers of patients, the question of adjuvant RT in combination with or after adjuvant chemotherapy for patients with N2 disease remains unresolved. At present there is one trial coordinated by the French Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) that is accruing patients with resected stage N2 NSCLC who have received either preoperative or postoperative adjuvant chemotherapy and randomizing them to mediastinal irradiation or observation (LungART trial).

Potentially Resectable Disease: Stages IIIA and IIIB

Preoperative Treatment for Patients with Resectable Non–Small Cell Lung Cancer

Several trials conducted in the 1960s ²¹¹^–²¹³ showed that for patients with initially resectable lung cancers, preoperative RT did not improve survival, and for those with initially unresectable disease, it improved resectability with no effect on survival. Surgical complications, particularly bronchopleural fistulas, were increased. The approach was largely discarded until recently, when the flurry of trials of preoperative chemotherapy or chemoradiation prompted renewed interest in preoperative RT. Unlike the trials of the 1960s, these trials have used strict criteria for resectability, surgical staging of the mediastinal nodes, and modern attention to RT planning.

Two small, randomized, phase II trials have been reported from the CALGB and the LCSG.^214,²¹⁵ Both studies randomized patients with unresectable stage IIIA/B NSCLC between preoperative RT followed by surgery or preoperative chemotherapy followed by surgery. Postoperative treatment was not specified in the LCSG trial but included RT to varying doses depending on tumor status at time of resection in the CALGB trial. Table 42-10 shows the results of these two trials, as well as those of several other randomized trials that compared immediate resection to induction chemotherapy followed by surgery for patients with stage IIIA NSCLC.²¹⁶^–²¹⁹ Results of the trials reported by Roth and Rosell were significantly positive, and the trials were closed early because of survival differences seen on interim analysis, but the LCSG, Japan Clinical Oncology Group (JCOG), and CALGB trials failed to show any difference in survival or resectability between preoperative RT, a strategy that might improve local but not systemic control, and preoperative chemotherapy. The trial by Depierre included patients with stages IB through IIIB; and although it demonstrated a survival benefit for patients with stage IB and IIA/B disease, it did not show a significant difference for patients with stage IIIA disease. Because all of these studies were small there is no clear consensus on the optimal management of patients with operable stage IIIA NSCLC. In the United States, many centers advocate the use of preoperative treatment with chemotherapy or chemoradiation, but whether this is superior to resection and postoperative therapy remains unclear, although a number of theoretical considerations ranging from better patient tolerance to earlier treatment of occult systemic disease favor the preoperative approach.

TABLE 42-10 Randomized Phase II and Phase III Trials of Neoadjuvant Therapy in Patients with Stage IIIA/IIIB Non–Small Cell Lung Cancer

The Bimodality Lung Oncology Team (BLOT) investigated preoperative therapy in patients with clearly resectable stage IB and II NSCLC using carboplatin and paclitaxel for two or three cycles. Despite a low overall pathologic complete response rate of only 5%, 2- and 3-year survival rates compared favorably with those of historical controls. The data were sufficiently encouraging to warrant a prospective trial coordinated by the Southwest Oncology Group (SWOG, S9900) comparing surgery alone to induction chemotherapy for patients with stage IB through IIIA disease. Unlike the original BLOT trial, pathologic assessment of the mediastinum was not required. The accrual goal of this trial was over 600 patients, and it was closed early in 2004 because of declining accrual. Since it opened, the positive results of the Depierre trial for preoperative chemotherapy (at least for patients with stage IB and II disease) and the positive IALT trial for adjuvant postoperative chemotherapy for all stages made the randomization on S9900 unappealing. Preliminary reports of the patients entered on the trial suggested modest benefits in progression-free and OS for the induction chemotherapy arm, but these did not reach statistical significance, perhaps because of the smaller than planned accrual.

A Spanish trial that compared surgery alone to either preoperative or postoperative chemotherapy (the NATCH trial) failed to show a progression-free survival benefit for either timing of chemotherapy, and a meta-analysis of trials of preoperative or postoperative chemotherapy for patients with resectable NSCLC did not find any difference between these strategies in OS.²²⁰ An indirect comparison meta-analysis of trials of either preoperative or postoperative chemotherapy compared with surgery alone failed to show differences in the hazard ratios for either disease-free or OS between the preoperative and postoperative approaches.²²¹

It is unlikely that it will be possible in the United States to conduct a large, multicenter, prospective trial of neoadjuvant chemotherapy in a well-staged group of patients, and we may be left without a scientifically rigorous answer to this question. For patients with resectable stage I and II NSCLC, preoperative RT should not be considered standard treatment. Patients with more extensive stage IIIA and IIIB disease, who are at the border of technical resectability, should be considered for entry on trials investigating the role of surgery after induction treatment with chemotherapy alone or chemoradiation.

The role of surgery in patients with stage IIIA and IIIB disease remains controversial. A small RTOG/Eastern Cooperative Oncology Group (ECOG) trial of induction chemotherapy followed by RT or surgery found no difference but was inadequately powered.²²² The North American Intergroup Trial INT 0139 that randomized patients with pathologic N2 disease to definitive chemoradiation (cisplatin/etoposide concurrent with 61 Gy) or concurrent preoperative chemoradiation to 45 Gy showed better disease-free but not OS with the inclusion of surgery, but an unplanned subset analysis of patients who underwent lobectomy compared with patients who were thought to be candidates for lobectomy had they been randomized to surgery did show a survival benefit.²²³ Advocates of surgery argue that better exclusion of patients at poor risk for surgery would have shown an OS benefit, whereas partisans of nonsurgical treatment will point out that there have been significant improvements in radiographic staging (e.g., PET/CT) and RT planning and delivery since this trial was conducted (1994-2001).

In the European Organization for Research in Cancer Therapy (EORTC) trial 08941 patients with stage IIIA (N2) NSCLC received induction chemotherapy with cisplatin/etoposide and responders were randomized between RT and surgery. There was no difference in median or 5-year survival between these approaches.

Neither of these trials, which are the largest published ones addressing the role of surgery for patients with stage IIIA (N2) disease, showed it to have clear benefit. They do differ somewhat in design, and neither meets current standards for staging or treatment delivery. Strong advocates of either surgical or nonsurgical approaches to these patients are unlikely to be convinced by their results.

A German Lung Cancer Group trial of preoperative CT or CT plus RT showed no progression-free or OS benefit to the irradiation-containing arm of this study.²²⁴ However, PORT was given to the patients in the study arm not receiving preoperative treatment. The overall resectability rate in the trial was low, only about 50%, in a population that was composed of about two thirds of patients with stage IIIB disease. By including RT in both arms of the trial, the issue becomes one of timing rather than amount of treatment, and the similarity in overall outcome is perhaps not surprising.

Betticher and colleagues ²²⁵ reported 90 patients with stage IIIA N2 NSCLC given induction chemotherapy with cisplatin and docetaxel, of whom 75 underwent resection, with 59 R0 resections (i.e., microscopically negative margins). The overall median survival was 27.6 months and 33 months for resected patients. Among patients with resected disease, 38 had experienced relapse (10 local, 10 local plus distant, and 18 distant only). An RTOG neoadjuvant trial took the Betticher regimen and added RT in one arm to determine whether preoperative RT in this setting improves local control, but this trial closed prematurely due to low accrual.

Several trials have found that those patients faring best after preoperative treatment with chemotherapy or chemoradiation were those with pathologic sterilization of mediastinal nodes, but not necessarily of the primary tumor. This has prompted trials of higher preoperative radiation doses, with demonstration by the RTOG that 60 Gy concurrent with weekly carboplatin and paclitaxel could be delivered with acceptable toxicity and a high resectability rate.

If sterilization of mediastinal lymph nodes is a useful criterion in selecting patients for surgery, how can this best be assessed preoperatively? CT is not particularly helpful, and it is not clear that early PET, done to allow resection within 4 to 6 weeks after neoadjuvant therapy, can discriminate between dead or dying cells or radiation-induced inflammatory changes at this early point. PET with other agents imaging cell proliferation (thymidine) or apoptosis might be of value.

Unresectable Stage IIIA/IIIB Disease

There are few good prospective data on the dependence of local control and survival of patients with NSCLC on radiation dose. In the 1980s it was believed by many authorities that local control could be achieved in about one half of patients treated to doses to 60 Gy given in 30 fractions over 6 weeks. However, the data on which that assumption was based (RTOG 73-01) indicated failure of progression rather than long-term control.²²⁶ Patients were randomized to 40, 50, or 60 Gy given as a continuous course with 2 Gy/day and to a fourth arm of 40 Gy given by split course (i.e., 20 Gy in five fractions, a 2-week break, repeated dosage). The 50- and 60-Gy arms showed modest improvement in local control and survival compared with the 40-Gy split or continuous arms, but this advantage was lost after 2 years. The lack of durable benefit for the higher doses may be because local control was poor with even the highest doses, to the lack of CT treatment planning, and the use of posterior spinal cord blocks that shielded mediastinal lymph nodes. Patterns of failure in this trial were reported in terms of crude risk of clinically detected local failure: 33% with 60 Gy and 44% to 49% with 40 Gy. It is incorrect to assume that local control is achieved in 67% of patients with 60 Gy. Le Chevalier and colleagues²²⁷^–²²⁹ reported actuarial local control, assessed radiographically and bronchoscopically for patients treated with definitive RT to a dose of 65 Gy in 26 fractions in 6.5 weeks) alone or preceded and followed by chemotherapy with cyclophosphamide, cisplatin, lomustine, and vindesine, of only 17% to 20% at 1 year and falling to about 10% at 4 years. In addition to its necessity for cure, local control is also important for quality of life, because even patients dying of systemic disease are benefited if they can avoid the complications of local disease progression (e.g., airway obstruction with dyspnea or postobstructive infection, hemoptysis, compression of mediastinal structures such as the superior vena cava and phrenic or recurrent laryngeal nerves, or pain from chest wall invasion.

Several strategies have been investigated to improve local control. One approach uses chemotherapeutic agents or biologic response modifiers in conjunction with irradiation, and several of these appear to be effective. Another involves surgery after induction therapy with chemotherapy, RT, or both, a strategy that is being investigated in the phase III trials discussed in the preceding section. Strategies involving modification of radiation time dose and fractionation have also been explored, falling into the general categories of accelerated hyperfractionation and classic hyperfractionation.

Combining Radiation Therapy and Chemotherapy

One risk of multimodality therapy of lung cancer is the potential for extending the time from initial presentation to start of treatment. Several reports have shown inconsistent effects of time to treatment on average and long-term survival of lung cancer patients. This may in part stem from starting patients with a disease with a poor prognosis on simple palliative treatment quickly, with more delay for both thorough staging and planning of more complex treatment for patients treated with curative intent. In the study by Wang and co-workers,²³⁰ no benefit in average survival was seen but there was a significant association between short time to treatment and survival for patients who lived more than 5 years, who comprised about 10% of the entire population.

Chemotherapy and RT can be combined in several ways. One can try to achieve additive cytotoxicity by treating the known local disease with RT and the local and systemic disease with chemotherapy. Such an approach is epitomized by the use of induction chemotherapy before local treatment with RT or surgery. This strategy may allow greater sparing of normal tissue by virtue of smaller RT target volumes or lesser resections performed of the postchemotherapy tumor volume. Another approach is to administer RT and chemotherapy concurrently in the hope of shortening the overall time of treatment and avoid delay of starting either modality. Both approaches were superior to RT alone in prospective trials conducted in the 1980s. Concurrent therapy has more acute toxicity (myelosuppression and esophagitis), but its superiority to sequential therapy has been demonstrated. At least six randomized trials comparing the sequential and concurrent use of chemotherapy and RT for patients with stage IIIA/B NSCLC have been reported (Table 42-11). Although all trials addressed the same general question of sequencing, they differed in many details. In some, different chemotherapy regimens were used in the two arms. The number of cycles of induction chemotherapy used before RT ranged from two to four. It is not clear in all trials whether the prechemotherapy or postchemotherapy tumor volume was taken as the gross tumor volume or whether, if the prechemotherapy volume was to be used, the treatment planning was completed before the start of chemotherapy.

TABLE 42-11 Chemoradiation Sequencing in Non–Small Cell Lung Cancer: Randomized Trials

The overall tendency confirmed in a meta-analysis of individual patient data, although not reaching statistical significance in most of these small trials, is for better results with concurrent rather than sequential combination of irradiation and chemotherapy.²³¹ An alternate interpretation is that the overall treatment time is key and that this is shorter in concurrent regimens. With protraction of the overall treatment time, accelerated repopulation of the tumor, which may have begun during chemotherapy, may outpace the ability of daily fractionated radiation to kill remaining tumor clonogens. Data from the U.K. Continuous Hyperfractionated Accelerated Radiation Therapy (CHART) trial and ECOG 2597 are consistent with this hypothesis. The median survival for the ECOG sequential chemotherapy followed by accelerated irradiation arm was 20.3 months compared with 14 months for patients receiving conventional irradiation after chemotherapy.²³²

The CALGB has reported a trial comparing induction chemotherapy with carboplatin and paclitaxel followed by concurrent chemoradiation with initial concurrent therapy. Unlike the Locally Advanced Multimodality Protocol (LAMP) trial, this was planned as a phase III comparison. This large cooperative group trial failed to confirm the earlier phase II results, with somewhat disappointing median survival times of 11.4 months for the initial concurrent regimen and 14 months for induction followed by concurrent therapy (p = .154).²³³

The SWOG conducted a phase II trial of consolidation with docetaxel rather than additional cycles of cisplatin plus etoposide after concurrent irradiation with cisplatin plus etoposide. Median survival was 26 months, and the 3-year survival rate was 37%. In the prior trial with cisplatin plus etoposide, consolidation values were 15 months and 17%.²³⁴ This is a striking difference, but it does represent two studies done at different times, with potentially different staging, patient allocation, and treatment planning. The Hoosier Oncology Group (HOG) attempted to confirm the SWOG results in a phase II trial: this showed no survival benefit for consolidation therapy with docetaxel but a significant increase in toxicity and hospitalization.

Prior to the results of the HOG trial the SWOG incorporated consolidation docetaxel as part of their standard treatment regimen in a trial testing the role of maintenance gefitinib. This trial showed significantly poorer disease specific and OS in the patients receiving gefitinib, for reasons that are not fully understood. Possible explanations include the development of more aggressive phenotypes (e.g., MET mutation) with the selective pressure of gefitinib. In any case there is not, at present, an established role for additional chemotherapy after concurrent chemoradiation for patients with stage IIIA and IIIB NSCLC, although it is common to deliver one or two cycles of full-dose chemotherapy after completion of concurrent RT, a strategy that has not been prospectively compared with stopping chemotherapy after the concurrent phase).

Integration of Molecular Targeted Agents with Radiation Therapy

Identification of radioresistant cells in human tumors has led to several approaches to sensitize them while not altering the radiation response of normal tissues. Tumor cells may be resistant for reasons of local environment (e.g., hypoxia) or because of genetic changes (e.g., mutations in TP53 or KRAS). Past strategies have looked largely to reverse environmental hypoxia without great success, but some newer agents show promise. Several approaches that exploit specific tumor genetic changes are being explored.^235,²³⁶

Epidermal Growth Factor Receptor Inhibitors

Exposure of cells to ionizing radiation induces phosphorylation of EGFR and activation of its kinase activity in much the same fashion as binding of ligands such as EGF or transforming growth factor-α. This leads to activation of several signaling cascades with resultant increased cellular proliferation, decreased apoptosis, and effects on angiogenesis and DNA repair.237,238–240 Inhibition of these processes through anti-EGFR monoclonal antibodies, expression of a dominant-negative truncated version of EGFR, or low-molecular-weight compounds that bind to the ATP site of EGFR and block its kinase activity result in significant radiosensitization of a number of cell lines in vitro and in vivo.^241,²⁴² A completed phase III trial comparing RT with or without the anti-EGFR antibody C225 in patients with squamous cell carcinoma of the head and neck, which commonly overexpresses EGFR, has demonstrated clinically significant improvements in local control and survival.²⁴³ Similar trials in NSCLC using monoclonal antibodies and the low-molecular-weight tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib are being conducted. Although several groups have shown that objective regressions of NSCLC in response to treatment with these TKIs occur almost exclusively in patients with specific point mutations in the ATP-binding region, which are present in only a minority of patients, it is not clear that such mutations are required for response to monoclonal antibodies that target the extracellular domain of the receptor or for radiosensitization by TKIs. The RTOG conducted a phase II trial investigating the combination of cetuximab with concurrent weekly carboplatin and paclitaxel with irradiation to 63 Gy that showed acceptable toxicity and an encouraging median survival of about 22 months.

The incremental activity of bevacizumab in combination with chemotherapy in patients with metastatic NSCLC and theoretical considerations and demonstration in colorectal cancer or increased tumor perfusion after bevacizumab treatment prompted interest in its combination with chemoradiation for patients with stage III NSCLC and limited SCLC. Several small trials have been conducted using concurrent treatment, with disturbing reports of formation of tracheobronchial fistulas, prompting early trial closure.²⁴⁴ Such combinations, and by extrapolation other strategies combining RT or chemoradiation with antivascular agents, should be approached with caution and only in the context of a clinical trial.

Radiation Dose and Fractionation

In North America, dose and fractionation for curative treatment of patients with unresectable NSCLC has generally been 1.8 to 2.0 Gy per fraction, with one fraction per day, 5 days per week, to a total dose of 60 to 65 Gy. Such a low total dose has been recognized as unlikely to achieve a high rate of local control, but simple dose escalation was limited by acute and late toxicity to normal tissues. Several series have challenged this assumption by using conformal treatment planning and quantitative evaluation of doses to various normal tissues. Retrospective data from the University of Michigan found a relation between radiation dose and survival for patients with stage III NSCLC, which was seen both for patients receiving irradiation as a single modality as well as those having concurrent or sequential chemoradiation.²⁴⁵ Some of these trials have also limited the target volume by eliminating ENI.^147,246 Others have treated more traditional elective volumes, at least to doses of 50 Gy or so for possible microscopic disease.²⁴⁷ These trials have clearly demonstrated the feasibility of dose escalation substantially above what had been previously believed limiting, to at least 74 to 78 Gy. Retrospective review suggests improvement in clinical outcome, particularly in patients with bulky disease, with such higher doses.²⁴⁸ Whether such doses will truly result in better local control and survival when used as a component of combined-modality therapy remains to be evaluated in prospective trials. The RTOG is currently randomizing patients with stage IIIA/B NSCLC to doses of 60 Gy or 74 Gy in combination with concurrent and consolidation chemotherapy (± cetuximab in a second randomization) to address the dose question. In both trial arms only gross disease is targeted; there is no ENI.

The use of altered fractionation schedules is an attempt to exploit differences between tumor and normal tissues in the fraction-size dependence of their radiation sensitivity.²⁴⁹ Several variations on standard fractionation have been proposed and evaluated:

• Hyperfractionation: The use of small fractions (e.g., 100 to 120 cGy) given two or more times each day to allow a higher total dose to be delivered within the tolerance of late effects to normal tissues.

• Accelerated fractionation: Reduction of the overall treatment time to decrease tumor cell proliferation during RT, increasing the probability of local control for a given dose.

• Concomitant boost: Another approach to reduce proliferation during treatment is to begin with conventional fractionation but accelerate with twice-daily treatment during the last 2 or 3 weeks of treatment.

• Continuous hyperfractionated accelerated RT: In a combination of the previous two methods, fraction size is decreased but overall time significantly shortened, typically by treating with three fractions per day.

In addition to these regimens, many other variations have been proposed and tested. Some regimens have given accelerated fractionation in two courses with an intervening treatment break. Although the dose rate during the weeks of treatment is increased, when the break is taken into account, the overall rate of dose delivery is often only minimally greater than with conventional fractionation.

Hyperfractionation

The RTOG conducted a series of trials exploring the use of altered fractionation in NSCLC.^250,²⁵¹ The first group-wide trial (RTOG 81-08) evaluated acute toxicity of several radiation dose levels using fractions of 1.2 Gy given 4 to 6 hours apart. Dose to the initial large volume encompassing known and electively treated tissues was always 50.4 Gy, whereas the dose to known disease was increased from 50.4 to 60, 69.6, and 74.4 Gy. This was a dose-seeking and toxicity study, but comparison of the group of patients treated to 69.6 Gy with contemporaneous controls from other trials (RTOG 78-11 and 79-17) suggested a late survival benefit (8.3 ± 4.0% vs. 5.6 ± 1.5% survival at 5 years). After this, in RTOG 83-11 the total dose was increased in two sequential randomizations from 60 to 79.2 Gy.²⁵² Late toxicities were similar in all trial arms, and OS did not differ among arms. However, when a favorable subset of patients, identified retrospectively by the CALGB criteria of good performance status and minimal weight loss, was analyzed, the 69.6-Gy arm appeared superior to other arms and to patients treated to 60 Gy in 6 weeks on other RTOG trials (13 months on median survival time [MST], with 1- and 2-year survival rates of 56% and 29%, compared with 9 months on RTOG 83-21, with rates of 35% and 10%, respectively). The higher-dose arms did not show this benefit, nor were they associated with greater toxicity, which might have offset a better therapeutic effect.

An Intergroup RTOG/ECOG trial made two comparisons: conventional RT alone or preceded by induction chemotherapy (as in CALGB 8433) and, as a third arm, the 69.6-Gy, twice-daily regimen, which had been the most favorable dose level in prior RTOG trials. It confirmed the CALGB demonstration of benefit for induction chemotherapy, with a statistically significant difference between this and standard RT alone.^253,²⁵⁴ The twice-daily arm was numerically superior to daily fractionation, but the differences did not reach statistical significance.

The North Central Cancer Treatment Group conducted a trial of similar design. Instead of using a continuous twice-daily regimen, they used a split-course regimen of 1.5 Gy given twice daily for 20 fractions over 2 weeks, a 2-week break, and another 1.5 Gy given in 20 fractions.²⁵⁵ The total dose was 60 Gy in 20 fractions, but the overall time was no shorter than with conventional fractionation. This was compared with standard fractionation of 60 Gy in 30 fractions over 6 weeks. A third arm combined the twice-daily split-course regimen with concomitant cisplatin plus etoposide chemotherapy. Accrual to this trial was slow, and it was closed short of the planned sample size. The results trend toward favoring the twice-daily arm (with or without chemotherapy) for freedom from progression and survival. For patients with nonsquamous histology, survival was significantly improved (p = .02). In the North Central Cancer Treatment Group (NCCTG) trial, freedom from local progression was better for the twice-daily regimen with or without concomitant chemotherapy, although this did not quite reach statistical significance (p = .06).

Fu and associates ²⁵⁶ reported a trial in which 109 patients with stage I-IIIB NSCLC were randomized between a standard daily regimen of 63.9 Gy and a twice-daily regimen of 69.6 Gy. Although survival in the two arms did not differ for the entire group, in a subgroup of patients with stage I to IIIA disease (number not specified), there were significant benefits for local control and survival for the twice-daily arm (2-year survival, 32% vs. 6%; local control, 28% vs. 13%).

In RTOG 83-01,²⁵⁷ 11% of patients had significant treatment interruptions. When compared with those completing treatment in the planned time, survival at 2 and 5 years was significantly less for those with treatment interruption (24% vs. 13% at 2 years; 10% vs. 3% at 5 years). However, the length of treatment was not determined randomly and may reflect other prognostic factors. Survival differences, like the benefit for hyperfractionation, were seen only for the subset of patients with good performance status and minimal weight loss.

Accelerated Fractionation: Chart, Hart, and Chartwel Regimens

Saunders and colleagues ^258,²⁵⁹ compared an accelerated regimen called continuous hyperfractionated accelerated radiation therapy (CHART) with a conventional regimen of 60 Gy in 30 fractions in a mixed group of patients who had locally advanced (stage IIIA/IIIB) or medically unresectable (stage I or II) disease. The CHART regimen consisted of 54 Gy given in 36 fractions over 12 consecutive days (weekends included). The interfraction interval was 6 hours. Results showed a survival advantage (30% vs. 20% at 2 years; p <.001) for the CHART regimen, with local control also significantly improved. Modifications of this regimen that increased total dose, shortened interfraction interval to 4 hours, and omitted weekend treatments (HART in the United States²⁶⁰ and CHARTWEL in the United Kingdom²⁶¹) have reported similar encouraging results in phase II trials.

ECOG conducted a trial of HART compared with standard daily fractionation in patients with stage IIIA and IIIB NSCLC.²³² Patients received two cycles of induction chemotherapy with carboplatin and paclitaxel and were then randomized to conventional RT or HART. The study was designed to look for an improvement in median survival from 14 to 21 months, but it was closed early because of slow patient entry. The results, a median survival of 21 months on the HART arm and 13 months on the standard arm, are provocative, but the difference did not reach statistical significance.