David H. Johnson,William J. Blot,
David P. Carbone,
Adriana Gonzalez,
Dennis Hallahan,
Pierre P. Massion,
Joe Bill Putnam,
Alan B. Sandler
SUMMARY OF KEY POINTS
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Non-Small Cell Lung Cancer Incidence and Epidemiology
Screening
Staging Evaluation
Primary Therapy
Small Cell Lung Cancer Incidence and Epidemiology
Staging Evaluation
Therapy
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INTRODUCTION
Although reports of pulmonary malignancies date to antiquity, lung cancer is largely a disease of modern humans. Before 1900 lung cancers were viewed as “matters of medical curiosity not known to be in any degree influenced by medicine and too rare to be of much practical importance”.[1] By the mid-twentieth century, however, lung cancer had become epidemic and firmly established as the leading cause of cancer-related death in North America and Europe.[2] It should not be forgotten that lung cancer is potentially one of the most preventable of all of the major malignancies afflicting humanity. Its primary cause is tobacco smoke.[3] King James I was among the first to chronicle the adverse health effects of tobacco smoke,[4] but it was Raymond Pearl's landmark 1938 report that conclusively established the devastating impact smoking has on longevity.[5] It would be another decade before tobacco smoking was firmly established as a causative agent of lung cancer [6] [7] and nearly 30 more years before the emergence of the U.S. Surgeon General's initial report of the ill effects of tobacco smoking. Regrettably it would be yet another 3 decades before the tobacco industry publicly acknowledged this obvious truth but only after a long, drawn-out battle of misinformation and deception[8] ironically helped along by the unwitting (perhaps) complicity of physicians.[9] With the belated recognition of the etiologic role of tobacco smoke the incidence of lung cancer started to decline in North America and parts of Europe. For the most part the decline is seen most clearly in men. Only recently has this decline become apparent in women in the United States following a similar decline among men 10 to 15 years ago.[10] In short, the story of lung cancer is replete with controversy,[11] politics,[12] pessimism,[13] and, more recently, guarded optimism.[14] This chapter focuses on our perceptions of current management of lung cancer with an emphasis on advances made over the past 5 years. We refer the reader to previous editions of Clinical Oncology for earlier works of historical importance.
EPIDEMIOLOGY
Lung cancer was an uncommon disease in the early part of the twentieth century but then began an epidemic rise to far surpass all other cancers in numbers and rates of death.[15] Indeed, lung cancer is now the second most common cause of death among American men. The increase peaked in the late 1980s among men but did not plateau until around the year 2000 among women. It is estimated that more than 170,000 individuals will be diagnosed with lung cancer in the United States in 2006.[15] Lung cancer is relatively rare in individuals younger than age 40, but rates rise steadily until age 80 and then taper off; the projected lifetime probability of developing lung cancer is estimated to be approximately 8% among males and approximately 6% among females.[16] The incidence of lung cancer varies by racial and ethnic group, with the highest age-adjusted incidence rates among African American men ( Fig. 76-1 ). The excess in age-adjusted rates among blacks occurs only among men, but examinations of recent age-specific rates show that below age 50 mortality from lung cancer is more than 25% higher among black than white women.[16] Incidence and mortality rates among Hispanic, Native, and Asian Americans are only 40% to 50% those of whites. Figure 76-2 shows trends in age-adjusted mortality rates from lung cancers in the United States since 1930.
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Figure 76-1 Lung cancer incidence in United States between 1975 and 2003. Age-adjusted to the 2000 U.S. standard population. (Data from National Center for Health Statistics, Centers for Disease Control & Prevention, 2005). |
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Figure 76-2 Tobacco use and lung cancer mortality in the United States 1900–2002. *Per 100,000, age-adjusted to the 2000 U.S. standard population. |
The trends in overall lung cancer rates mask differences in temporal patterns according to lung cancer cell type. Figure 76-3 shows changes in age-adjusted incidence rates for squamous cell carcinoma and for adenocarcinoma during 1973 to 2003 based on data from nine continuing cancer registries in the National Cancer Institute's (NCI's) SEER program of cancer registration. Among men, squamous cell cancers predominated in the first two thirds of this period. The decline in incidence of lung cancer among men was first apparent for squamous cell tumors, however, with decreases beginning in the early 1980s so that by the mid-1990s rates of squamous cell carcinoma among men had dropped below those for adenocarcinoma, which did not peak until over a decade later. Among women, adenocarcinomas have been more common than squamous cell carcinomas across the 3 decades. The adenocarcinoma excess among women has become more pronounced over time, in that rates of squamous cell cancers increased steadily through the 1980s before beginning to decline, whereas adenocarcinoma did not plateau until about a decade later. Although not shown in Figure 76-3 , rates of small cell carcinoma, the third most frequent cell type, tended to parallel those for squamous cell cancer among both sexes. Trends for other cell types of lung cancer, including large cell carcinomas and bronchioloalveolar carcinomas, tend to be intermediate between those of squamous cell carcinomas and adenocarcinomas. As discussed later in the chapter, although 5-year relative survival rates for lung cancer have improved over time, the survival rates are low, currently about 15% overall.[16] Some variation exists by sex, race, and cell type, with slightly higher survival among whites than blacks and females than males, but for no group does the overall 5-year relative survival exceed 20%.
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Figure 76-3 Age-adjusted SEER lung cancer incidence, nine registries. |
Risk Factors
The cause of the large majority (80% to 90%) of lung cancers is cigarette smoking. [17] [18] There is a massive compilation of scientific evidence from epidemiologic studies conducted around the world since the 1950s demonstrating the link between smoking and lung cancer. Epidemiologic research has also revealed that several other factors have been implicated as causes of lung cancer, though none to the extent of tobacco. [19] [20] Cigarette smokers have been shown to have large increases in the risk of lung cancer. Numerous investigations typically show 10-fold or greater increases in risk of this cancer among smokers as compared with those who have never smoked. [17] [18] One of the largest studies is the American Cancer Society's prospective cohort study of over 1 million Americans wherein a greater than 20-fold excess of lung cancer has been observed among men who were current smokers at the start of the follow-up in the early 1980s. [17] [18] In contrast, even the most prolonged and intense exposures to asbestos, perhaps the most prominent occupational cause of lung cancer, are associated with no more than about fivefold increases in lung cancer.[21]
Risks of lung cancer are lower among persons who quit smoking than among those who continue smoking. [17] [18] The reductions in risk indicate that quitting smoking is beneficial (and conversely that continuing to smoke is harmful). Risk among former smokers on average is less than one half that of those who continue to smoke. In the American Cancer Society cohort study cited discussed earlier, former smokers had a 9-fold increase in lung cancer as compared with men who had never smoked versus the 20-fold excess in those who continued to smoke. [17] [18] Such relative reductions have been consistently seen, with the size of the reduction in risk increasing the longer the time period since the person has quit smoking, although generally even long-term former smokers have higher risks of lung cancer than those who never smoked. [17] [18]
Cigarette smoking has been shown to increase risk of all the major lung cancer cell types. [17] [18] [19] [20] The magnitude of the increase varies by histologic type, however, with highest risks for squamous cell, small cell and large cell carcinomas of the lung. Some early studies tended to show only small increases in risk of adenocarcinoma among smokers, but more recent studies indicate that the excess of lung adenocarcinoma is substantial. [17] [18] [20]
Cigarette smoke has also been implicated in increasing risk of lung cancer among nonsmokers. A 2006 update of the Surgeon General's report declared that there is sufficient evidence to list passive smoking as an established cause of lung cancer and called for further control of environmental tobacco smoke (ETS) exposures.[22] The risk from ETS is far less than from active smoking, with about a 20% to 30% increase in lung cancer observed among nonsmokers married for many years to smokers, in comparison to the 2000% increase among continuing active smokers. Nevertheless, cancer control activities based on the knowledge that ETS exposure may convey an increased risk of lung cancer have helped reduce exposures in public places and have also provided additional incentive for smokers to quit the habit.
Although cigarette smoking is the dominant cause of lung cancer, several other risk factors for this cancer have been identified. [19] [20] These include occupational exposures to asbestos and some other workplace agents, some of which have been evaluated for nearly as long as cigarette smoking. Among the occupational agents considered as known lung carcinogens are arsenic, bischloromethyl ether, hexavalent chromium, mustard gas, nickel (as in certain nickel refining processes), and polycyclic aromatic hydrocarbons. [19] [20] [23] Several other occupational exposures have been associated with increased rates of lung cancer, but the causal nature of the association is not clear. Epidemiologic studies have attempted to assess the potentially synergistic interrelationship between certain workplace exposures and smoking. Risk of lung cancer among men exposed to asbestos who also smoked was originally thought to be exceptionally high (with early reports of 50-fold or greater excesses compared with unexposed nonsmokers), but recent modeling of larger data pools suggests that asbestos and tobacco combine to enhance lung cancer risk in a less than multiplicative manner.[24] Occupational observations have also provided clues to the mechanisms of lung cancer induction. Risk of lung cancer among asbestos-exposed workers, for example, is increased primarily among those with underlying asbestosis, raising the possibility that the scarring and inflammation produced by this fibrotic nonmalignant lung disease may in many cases (though probably not in all) be the trigger for asbestos-induced lung cancer.[25]
Increased risks of lung cancer have also been associated with other variables. Diet and nutrition are thought to be involved, because numerous investigations have shown somewhat higher risks of thiscancer among those with low fruit and vegetable intake during adulthood. [19] [20] The early observational studies led to hypotheses that specific nutrients, in particular retinoids and carotenoids, might have chemopreventative effects for lung cancer. Randomized clinical trials were launched, but hopes were crushed when reports from interventions involving supplementation with β-carotene in trials both in Finland and the United States found increased rather than decreased incidence of lung cancer among those supplemented. [26] [27] The current consensus regarding diet and lung cancer remains muddled, with a minor role for nutritional factors probable but difficult to assess epidemiologically. Ionizing radiation has been established as a lung carcinogen, most convincingly demonstrated from studies showing modestly increased rates of this cancer among persons exposed to the atomic bombs of Hiroshima and Nagasaki and large excesses among workers exposed to α-irradiation from radon in underground uranium mining. [19] [20] Extrapolations from the high exposures in mines to low-level radon exposures in homes, as well as direct observations from case-control studies assessing measured levels in homes, suggest that prolonged radon exposures above the recommended remedial levels might impart a risk of lung cancer equal or greater than that of ETS.[28] Prior lung diseases such as asbestosis (mentioned previously), chronic bronchitis, emphysema, and tuberculosis also have been linked to increased risks of lung cancer. Although smoking itself is a cause of the chronic obstructive pulmonary diseases (COPDs), the link between chronic bronchitis and emphysema and lung cancer persists after adjustment for smoking, with up to about a doubled smoking-adjusted cancer risk among those with COPD. [19] [20] [29] Familial clustering of lung cancer has been observed, raising the possibility of inherited traits that may increase risk among some individuals, with risk about doubled in families with prior lung cancer. [19] [20] Smoking also clusters within families, so some of the familial aggregation of lung cancer may be smoking-related. Nevertheless, there seem to be multiple genetic factors that help determine the way in which individuals metabolize, detoxify, repair, or otherwise respond to lung carcinogens, including the carcinogens in cigarette smoke, as discussed in more detail later in this chapter.
SMOKING CESSATION
Given the undeniable link between cigarette smoking and lung cancer,[3] it is incumbent upon physicians to promote tobacco abstinence and help their patients who smoke to stop smoking.[30] Smoking cessation, even well into middle age, can minimize an individual's subsequent risk of lung cancer, and stopping before middle age avoids more than 90% of the risk attributable to tobacco. [31] [32] By contrast, there is little health benefit realized by simply “cutting back”.[33] Among victims of lung cancer, smoking cessation is associated with improved survival, [34] [35] [36] [37] fewer side effects from therapy,[38] and an overall improvement in quality of life.[39] It is often forgotten that smoking alters the metabolism of many chemotherapy drugs, potentially adversely altering the toxicities and therapeutic benefits of the agents.[40] Therefore, it is important to promote smoking cessation even after the diagnosis of lung cancer is established. [41] [42] To do so requires that oncologists be well versed in the treatment of nicotine addiction.[43] Although smoking cessation is extremely difficult, patients with lung cancer tend to be highly motivated and success rates mirror that of other disease states.[44]However, the individual must want to stop smoking and must be willing to work hard to achieve the goal of smoking abstinence. Nicotine replacement therapies, bupropion and varenicline (an α4β2-nicotinic acetylcholine receptor partial agonist), are approved by the U.S. Food and Drug Administration (FDA) as first-line treatments for nicotine dependence.[45] Recently varenicline was demonstrated to be significantly more efficacious than bupropion alone for smoking cessation.[46] Furthermore, prolonged use of varenicline beyond the initial induction phase proved useful in maintaining smoking abstinence.[47] Clonidine and nortriptyline are recommended as second-line treatments.[41] A systematic review of extant smoking cessation studies indicates self-help strategies alone only marginally affect quit rates, whereas individual and combined pharmacotherapies and counseling either alone or in combination can significantly increase rates of cessation.[48]
BIOLOGY OF LUNG CANCER
The specific events that trigger malignant transformation of bronchoepithelial cells are unknown in the vast majority of cases. However, it is clear that exposure to environmental carcinogens, such as those found in tobacco smoke or asbestos fibers, induce or facilitate the transformation (extrinsic component).[49] The contribution of the extrinsic carcinogen on transformation is modulated by variations in genes (intrinsic component) that affect aspects of carcinogen metabolism, such as the conversion of procarcinogens to carcinogens and their subsequent inactivation.[50] These genetic variations occur at relatively high frequency in the population. Their contribution to an individual's lung cancer risk is generally low, but because of their population frequency, their overall impact on lung cancer risk could be high. Epidemiologic studies further suggest that a familial predisposition to lung cancer exists that is independent of tobacco smoke exposure. One study found evidence for an autosomal dominant model linked to 6q23–q25,[51] but other studies have proposed a complex multigene model for inherited risk.[52] A familial clustering of lung cancer cases has been reported with an inherited T790M mutation in the epidermal growth factor receptor (EGFR) gene.[53] The identification of individuals at particularly high risk for the development of lung cancer could justify more intense screening regimens, and the identification of the responsible chromosomal loci for lung cancer susceptibility genes could allow the development of specific chemopreventative strategies.
Environmental factors, as modified by inherited modulators, probably affect specific genes by deregulating important pathways to permit the cancer phenotype. Particularly important in lung cancer are acquired abnormalities in the genes encoding ras, Rb, p53, Akt, LKB, and BRAF.[54] However, the single most clinically significant acquired genetic abnormality in lung cancer is the recently described mutation of the EGFR. [55] [56] [57] [58] These are mutations, primarily in exons 19 (in-frame deletions of four amino acids, LREA) and 20 (L858R point mutants), that result in constitutive signaling and AKT activation,[59] and are associated with very high response rates (60% to 90%) to the specific tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib.[60] Interestingly, almost all of the mutations occur in nonsmokers and adenocarcinomas, and the frequency of mutations is much higher in Asian than Western populations (30% to 70% versus 8%). [61] [62] These responses are often dramatic and occur even in heavily pretreated patients, demonstrating that tumors with these mutations are “addicted” to the activation of this pathway. Almost all patients with these impressive responses, however, develop progressive, resistant disease, and about half of these tumors with acquired resistance to TKIs demonstrate a second T790M mutation associated with resistance. [63] [64]
Despite the incontrovertable high response rate in patients with EGFR mutations, analysis of samples from BR.21, a placebo-controlled randomized clinical trial of erlotinib in second-line nonsmall cell lung cancer (NSCLC) showed that the presence of an EGFR mutation was not associated with prolonged survival,[65] but in univariate analysis amplification of the receptor was associated with improved survival.[66] Interestingly, there was a survival benefit in the entire erlotinib arm compared with placebo, as well as every subset of patients, including smokers and patients with squamous cell cancers,[67]suggesting that variables other than mutation may contribute to clinical benefit, and that this was not necessarily related to objective response rates. Other assays, including serum proteomics, show potential for selecting patients likely to achieve clinical benefit.[68]
It is clear that the vast majority of lung cancers are not driven by single aberrant genes, however, and not all aberrancies are mutations. Complex networks of genes are finely tuned in normal cells to maintain normal growth, apoptotic responses, and differentiation. These networks can be perturbed at multiple points to deregulate key pathways in lung cancer tumors. A simple example is the mutation ofRb and the loss of p16, a regulator of Rb function; NSCLCs disrupt cell cycle control by either mutation of Rb or loss of expression of p16, but not both.
Attempts have been made to look at the genome in “comprehensive” ways so as to dissect tumors with common groups of genetic features that might provide biologic or clinical guidance beyond traditional classification by light microscopy. Single-nucleotide polymorphism arrays have been developed that are able to analyze loss or gain of genetic material at very high resolution, [69] [70] and cancer genome resequencing efforts are likely to uncover common mutations. Protein expression and therefore function is probably more often modulated by epigenetic alterations than by mutations to cause perturbations in pathway function.[71] Detection of specific promoter methylations may in fact be a useful biomarker of malignancy.[72] These sorts of pathway alterations are more likely to be detected by the analysis of gene expression, protein expression, or post-translational modification-type changes (e.g., phosphorylation) than by gene mutation analysis. High-throughput technologies have been developed for each of these, and they are beginning to be applied to lung cancer. Several studies, for example, have been able to identify prognostically distinct subgroups of lung adenocarcinomas by complementary DNA microarray analysis, [73] [74] [75] as well as likelihood of recurrence after surgical resection. [76] [77] More important than prognosis, early progress is being made in the analysis of single genes and pathways important for predicting response to targeted therapies, allowing rational individualization of therapy selection. Low expression of the DNA repair gene ERCC1 has been shown to correlate with poor prognosis in NSCLC but with improved survival after treatment with platinum drugs.[78] For the newer targeted therapies, patterns of gene expression are being developed that may identify those more likely to respond.[79] Even closer to function than gene expression, analysis of protein expression patterns [68] [80] [81] or even phosphorylation patterns[82] may hold even greater practical promise in the future.
The histologic sequence of events that leads to the various forms of lung cancer is not well understood, and it is clearly different for the various histopathologic entities. [82] [83] [84] [85] Current knowledge suggests that squamous cell carcinoma arises in an ordered progression that includes squamous metaplasia and carcinoma-in-situ (CIS). Peripheral adenocarcinomas are thought to arise from atypical adenomatous hyperplastic lesions, but this process is much more obscure largely because this type of lesion is much less accessible by bronchoscopy. Small cell carcinoma might arise from neuroendocrine hyperplasia, but evidence in support of this hypothesis is scarce.
The pathology of premalignancy will be discussed in more detail in the next section, but the molecular biology of premalignancy is of great clinical importance, not only to better understand the process of cancer development, but to provide potential therapeutic targets to intervene in this process and intermediate biomarkers to assess risk and evaluate candidate chemoprevention strategies. Premalignant lesions of the lung have been investigated for molecular alterations in NSCLC, but much less information is available for SCLC.[86] Microdissected specimens derived from normal, hyperplastic, metaplastic, dysplastic, and CIS, as well as invasive neoplastic foci of patients with lung cancer, were studied for gene mutations, promotor hypermethylation, and allele loss. Results obtained thus far suggest that allele loss on chromosome 3p is the earliest event, followed by allele loss/hypermethylation on chromosome 9p and subsequently on chromosome 8p.[85] Loss of heterozygosity at the p53 gene locus (17q13.1) is relatively rare (10%) and occurs predominantly at the dysplasia or CIS stage. Point mutations in the p53 gene[87] and the EGFR gene,[88] however, have been observed in morphologically normal bronchial epithelium obtained from the airways of patients with lung cancer. In contrast, K-ras gene mutations represent a late event, found only in CIS or invasive cancers.[89] In addition to copy number changes and mutations, alterations in the expression of the retinoic acid receptor β (RARβ) have also been used as a molecular marker for premalignancy and as an intermediate biomarker for chemoprevention trials.[90]
The fate of morphologically or molecularly abnormal areas is currently an intense area of research. One study showed that 54% of patients with high-grade dysplastic lesions developed lung cancer within 2 years, but 80% of these arise in a different part of the lung than the CIS.[91] None of the patients with low-grade dysplastic lesions progressed to cancer in this study. Of the low-grade lesions studied, 82% spontaneously regressed, 18% remained unchanged, and none progressed to CIS. Preliminary data also suggest that abnormal regions display reproducible molecular changes on repeat biopsies over time, and that these and additional abnormalities can be observed in tumors arising from these lesions.[92]
Part of the problem with the studies of preneoplasia is that we may be evaluating the microscopic appearance and molecular characteristics of the wrong population of cells. The vast majority of the respiratory epithelium (and most other tissues) is thought to be terminally differentiated and incapable of sustained replication; however, one theory holds that a small subset of the cells have unlimited, but normally tightly regulated, replicative potential. These are the pulmonary “stem cells”, [93] [94] whose biology is very poorly understood. The stem cell concept may also underlie the failure of standard medical therapies to eradicate lung cancers, even when there is a clinical complete response. The theory is that therapies have been refined to induce measurable reductions in the bulk tumor mass, while true replicative potential exists only in a small subset of “cancer stem cells” that are not effectively targeted by current therapies. Specific isolation of these cells and development of stem cell-targeted therapies may thus not cause rapid tumor regressions but instead result in significantly increased long-term survival.
Understanding of the molecular biology and discovery and validation of reliable biomarkers predictive of relapse, response to therapy, and poor outcome from lung cancer have long been pursued by investigators with the goal of guiding clinicians in selecting treatment for patients. One future approach to improve patient outcome is tailored therapy based on individualized phenotypic or genotypic tumor characteristics. We are now seeing the beginning of this with commercial EGFR mutation screening. Recent technological advances in mutation detection and quantitation of gene expression in minute clinical specimens herald the advent of clinical therapeutic decisions based on the expression of specific therapeutic targets and/or other host and/or tumor characteristics.
PATHOLOGY
The latest World Health Organization (WHO) classification of lung tumors from 2004 is essentially unchanged from the preceding classification from 1999 ( Table 76-1 ). [95] [96] The 1999 WHO classification reorganized and introduced several lesions. It defined bronchioloalveolar carcinoma (BAC) as a noninvasive tumor for the first time, and it introduced the concepts of atypical adenomatous hyperplasia and diffuse neuroendocrine hyperplasia as precursors to adenocarcinoma and neuroendocrine tumors, respectively. Since these additions, more studies have focused on evaluation of diagnostic criteria and prognosis of these preneoplastic and in situ lung lesions.
Table 76-1 -- 2004 World Health Organization Classification of Malignant Epithelial Tumors
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Squamous cell carcinoma |
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Papillary |
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Clear cell |
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Small cell |
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Basaloid |
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Small cell carcinoma |
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Combined small cell carcinoma |
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Adenocarcinoma |
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Mixed pattern |
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Acinar |
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Papillary |
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Bronchioloalveolar |
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Mucinous |
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Nonmucinous |
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Mixed |
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Solid with mucin production |
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Fetal adenocarcinoma |
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Mucinous (colloid) carcinoma |
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Mucinous cystadenocarcinoma |
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Signet ring |
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Clear cell |
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Large cell carcinoma |
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Large cell neuroendocrine carcinoma |
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Basaloid carcinoma |
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Lymphoepithelioma-like carcinoma |
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Clear cell carcinoma |
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Large cell carcinoma, rhabdoid phenotype |
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Adenosquamous carcinoma |
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Sarcomatoid carcinoma |
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Pleomorphic carcinoma |
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Spindle cell carcinoma |
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Giant cell carcinoma |
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Carcinosarcoma |
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Pulmonary blastoma |
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Carcinoid tumor |
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Typical carcinoid tumor |
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Atypical carcinoid tumor |
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Salivary gland tumors |
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Mucoepidermoid carcinoma |
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Adenoid cystic carcinoma |
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Epithelial-myoepithelial carcinoma |
Tissue and Cytologic Diagnosis of Lung Cancer
The diagnosis of lung cancer can be made on tissue specimens such as transbronchial biopsy or resected specimens, or assessment of cytologic specimens such as transbronchial or transthoracic fine-needle aspirates (FNAs), bronchial brushes, bronchial washes, bronchioloalveolar lavage, or sputum cytology. The diagnostic yield depends on several variables including location (accessibility) of the tumor, tumor size, tumor type, or technical aspects of the diagnostic procedure including the experience level of the bronchoscopist and pathologist.[97] In general, central lesions such as squamous cell carcinomas, small cell carcinoma, or endobronchial lesions such as carcinoid tumors, are more readily diagnosed by bronchoscopic examination, whereas peripheral lesions such as adenocarcinomas and large cell carcinomas are more amenable to transthoracic FNA. Diagnostic accuracy for small cell carcinoma versus nonsmall cell carcinomas for most specimens is excellent,[98] with lesser accuracy for subtypes of nonsmall cell carcinoma.[97]
Bronchoscopic specimens include bronchial brush, wash, bronchioloalveolar lavage, and transbronchial FNA. Of these, transbronchial FNA consistently demonstrates the highest sensitivity, surpassed only by the use of a combination of bronchoscopic specimens. [97] [98] [99] [100] [101] Overall sensitivity for combined use of bronchoscopic methods is approximately 80%, and together with tissue biopsy, the yield increases to 85% to 90%. [97] [98] [100] In fact, transbronchial FNA is more often diagnostic that transbronchial biopsy when the lesion of interest is submucosal. [97] [102]
Like transbronchial FNA specimens, transthoracic FNA specimens are also very good, yielding diagnostic material in 70% to 95% of cases. Sensitivity is highest for larger lesions and peripheral tumors.[103] In general, FNA specimens, whether transbronchial, transthoracic, or endoscopic ultrasound-guided, are superior to other specimen types.[104] This is primarily because of the higher percentage of lesional tumor cells with fewer confounding conditions such as obscuring inflammation and reactive nonneoplastic cells.
Sputum cytology is inexpensive and noninvasive but has a lower yield than other specimen types due to poor preservation of the cells and more variability in acquiring a good-quality specimen. The yield for sputum cytology is highest for larger and centrally located tumors such as squamous cell carcinoma and small cell carcinoma histology, although occasionally an accurate diagnosis is possible with tumors located more peripherally within the lung.[97] The specificity for sputum cytology averages close to 100%, although sensitivity is generally less than 70%. The accuracy of sputum cytology improves with increased numbers of specimens analyzed; consequently, analysis of at least three sputum specimens is recommended. Sputum cytology also has been extensively studied as a screening tool for early detection of lung cancers with varying success. Sputum cytology is not currently recommended as a routine screening tool, but recent advances in molecular diagnostic techniques may result in a resurgence of this methodology. [105] [106] [107] [108]
Precursor Lesions of the Lung
Squamous Dysplasia
The most established carcinoma sequence in lung cancer is that of preinvasive squamous lesions. In response to toxins, normal bronchial epithelium may undergo hyperplasia and squamous metaplasia, then dysplasia ( Fig. 76-4 ), leading to squamous cell carcinoma in situ ( Fig. 76-5 ) and finally to invasive squamous cell carcinoma. Although higher grade lesions such as severe dysplasia or carcinoma in situ are thought to portend a higher risk of development of invasive carcinoma, the progression through these degrees of dysplasia is not necessarily linear, and many preinvasive lesions are reversible or do not progress to invasive carcinoma. [109] [110] The 1999 and 2004 WHO classifications of preinvasive lesions detail the microscopic features defined as mild, moderate, and severe dysplasias, and carcinoma in situ. In general, these microscopic features consist of increasing epi thelial thickness, cellular crowding and disorganization, and nuclear atypia.[96] Although these changes have been shown to be reproducible among expert lung pathologists, in practice, accurate grading may be hampered by specimen size, quality, and reactive lesions that may mimic dysplasia. [111] [112] In general, molecular abnormalities increase with increasing morphologic dysplasia, but some low-grade or even normal epithelium can harbor many molecular abnormalities. In the future a combination of histology and molecular analysis might predict the lesions more likely to progress.[113]
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Figure 76-4 Schematic representation of lung neoplasia showing the transition from normal mucosa to squamous metaplasia, dysplasia, and finally to invasive carcinoma. (Adapted from Massion PP: Genomic alterations in lung cancer. In Pass HI, Carbone DP, Johnson DH [eds]: Lung Cancer Principles and Practice. Philadelphia, Lippincott Williams & Wilkins, 2005, p 89). |
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Figure 76-5 Squamous cell carcinoma in situ. A full-thickness dysplastic squamous epithelium shows disordered cells with high nuclear-to-cytoplasmic ratio and numerous mitotic figures throughout the epithelium. |
Atypical Adenomatous Hyperplasia
Atypical adenomatous hyperplasia (AAH) is a small noninvasive lesion (usually less than 5 mm) consisting of atypical cells lining the alveoli in the absence of an underlying inflammatory process ( Fig. 76-6 ). These lesions are thought be a precursor lesion to adenocarcinomas of the lung, a theory supported by the detection of molecular abnormalities within AAH similar to those found in adenocarcinomas. AAH is usually an incidental lesion, found either in lung tumor resection specimens or on radiographic imaging.[96] Because these lesions (along with bronchioloalveolar carcinoma) preserve the underlying lung architecture and alveolar spaces, they may appear as “ground-glass opacities” radiographically.[114] Although most often associated with adenocarcinomas of the lung, AAH has also been identified in conjunction with large cell carcinomas, squamous cell carcinomas, and metastatic tumors.[96]
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Figure 76-6 Atypical adenomatous hyperplasia. An area of intact alveolar walls is lined by irregularly spaced enlarged atypical alveolar cells with hyperchromatic nuclei. |
AAH differs from BAC in size and in degree of atypia. On a review of tumors identified through spiral CT screening studies performed by the Early Lung Cancer Action Project (ELCAP), a panel of expert lung cancer pathologists identified foci of AAH in roughly 25% of specimens (17 of 65). Six cases originally submitted as AAH (all less than 5 mm) were subsequently determined to be either BAC or invasive carcinoma by the ELCAP review panel based on the degree of atypia or presence of invasion.[115] Thus, it would appear that strict adherence to WHO criteria and additional experience will help to improve consistency in classification of these lesions.
Evaluation of AAH by cytology is difficult, because the atypia is less than that of carcinoma (mimicking many reactive lesions), and is similar to assessment of BAC, in that assessment of the architecture necessary for the diagnosis cannot be performed on a cytologic specimen.
Squamous Cell Carcinoma
Squamous cell carcinoma ( Fig. 76-7 ), which tends to occur centrally and is highly associated with smoking history, is defined as a malignancy showing squamous differentiation. As such, the tumor cells classically contain intercellular bridges and form keratin, although these features may be difficult to identify in poorly differentiated tumors. Histologically, the most common pattern is that of infiltrating nests of malignant squamous cells ( Fig. 76-7A ), with central necrosis, often resulting in a central cavitation. Several important variants are described, including a papillary pattern ( Fig. 76-7C ) that can present as an exophytic and endobronchial growth,[116] and a basaloid variant ( Fig. 76-7D ) that can mimic other basaloid or neuroendocrine tumors histologically.[117] On cytologic evaluation intercellular bridges are not usually identified, but keratin can be clearly seen when present. In addition, the tumor tends to consist of sheets of cells rather than the three-dimensional groups of cells characteristic of adenocarcinomas ( Fig. 76-7B ).
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Figure 76-7 Squamous cell carcinoma. A, Histologically, nests of invasive squamous cell carcinoma invade into a fibrous stroma. The tumor cells show an eosinophilic keratinized cytoplasm and intercellular bridges. B, Cytologically (Papanicolaou stain), there are malignant squamous cells in clusters with irregular nuclear shape and nuclear chromatin, and abundant “hard” (keratinized) cytoplasm. C, The papillary variant of squamous cell carcinoma is an exophytic papillary lesion composed of a malignant squamous epithelium. D, The basaloid variant of squamous cell carcinoma consists of invasive nests of basaloid cells demonstrating palisading of tumor nuclei at the periphery and keratinization toward the center of the nests. |
Squamous cell carcinomas of the lung are morphologically identical to extrapulmonary squamous cell carcinomas; moreover, immunohistochemistry does not clearly distinguish primary from metastatic tumors. Differentiating a primary from metastatic squamous cell carcinoma requires clinical correlation. In rare cases in which the invasive tumor is clearly associated with a squamous cell CIS component or squamous dysplasia, a primary tumor is highly likely. The differential diagnosis of squamous cell carcinoma of the lung includes reactive processes that may result in squamous metaplasia with reactive atypia such as that observed with infection or radiation-induced injury. In these cases, clinical correlation is also essential.
Adenocarcinoma
In North America and Japan, adenocarcinoma is the most common histologic type of lung cancer. As true of other histologies, adenocarcinomas occur predominantly in smokers, although nonsmokers are more likely to develop adenocarcinoma than other lung cancer types. Adenocarcinomas tend to occur more peripherally, but can occur almost anywhere, can be multifocal, or fill an entire lobe. Radiographically they are associated with solid opacities, ground-glass opacities, or mixed patterns, generally correlating with the amount of in situ and invasive components of the tumor. [114] [118] On tissue sections the diagnosis is made based on presence of glands (acini), papillary structures, bronchioloalveolar pattern, cellular mucin, or solid pattern if poorly differentiated[96] ( Fig. 76-8A-C ). A mixture of at least two of these patterns occurs in 80% of adenocarcinomas,[119] and many mixed adenocarcinomas (>20%) show a focal BAC pattern. [115] [120] Of these patterns, the solid and micropapillary patterns in adenocarcinomas may predict a worse prognosis. [121] [122] [123] [124] [125] [126] [127] On cytologic preparations, three-dimensional groups or glandular and papillary patterns may be identified and are diagnostic of adenocarcinoma ( Fig. 76-8D ). Variants of adenocarcinomas include signet ring, clear cell, mucinous, and fetal adenocarcinomas. The former three are primarily descriptive, whereas the latter is a distinct but rare tumor occurring in younger smoking patients in the fourth decade and is associated with a better prognosis.[128]
|
Figure 76-8 Various patterns of adenocarcinoma. A, The acinar (glandular) pattern shows malignant glandular structures invading a fibrous stroma. B, The bronchioloalveolar pattern can be pure, as seen in bronchioloalveolar carcinoma (BAC), or mixed with other patterns of adenocarcinoma. It consists of malignant epithelial cells lining alveolar walls without invasion. C, Papillary adenocarcinoma shows papillary structures with fibrovascular cores and loss of the underlying alveolar architecture. D, Adenocarcinoma by cytology (Papanicolaou stain) shows three-dimensional clusters of malignant cells with vacuolated cytoplasm. E, By cytology (H&E stain), the diagnosis of BAC is not definitive but may be suggested by flattened clusters of bland tumor cells with nuclear grooves or inclusions. |
Bronchioloalveolar Carcinoma
Only those adenocarcinomas that show a pure noninvasive bronchioloalveolar pattern are diagnostic of BAC as defined by the WHO [95] [96] ( Fig. 76-8B ). This definition arose out of studies showing that noninvasive tumors less than 3 cm resulted in a 100% 5-year patient survival;[129] in addition, tumors with limited fibrosis, smaller size, and limited invasion have a better prognosis. [129] [130] [131] [132]Minimally invasive tumors, though not defined as BAC in the strictest sense, may nonetheless experience an excellent prognosis.[114] BAC is classified as mucinous, nonmucinous (most common), or mixed. Mucinous BACs are more likely to present as multifocal tumors or a lobar consolidation[96] and to show molecular and immunohistochemical features not seen in the nonmucinous type. [133] [134]
Cytologically, bronchioloalveolar patterns may be suggested,[135] ( Fig. 76-8E ), but BAC cannot be definitively diagnosed without evaluation of the tissue architecture necessary to rule out an invasive component. The same is true for small biopsies in which a bronchioloalveolar pattern is seen. Unless the entire lesion can be evaluated for invasion, the diagnosis can only be interpreted as adenocarcinoma with BAC pattern. Because this more strict diagnosis of BAC is fairly recent,[95] pathologists are still refining their interpretation of BAC pattern lesions. Many tumors clinically consistent with BAC may contain areas of microinvasion and subtle papillary patterns that may affect prognosis. [115] [136]
The differential diagnosis of adenocarcinoma is broad and includes not only metastatic adenocarcinomas from other sites, but similar-appearing tumors such as mesothelioma. Clinical information including location of the tumor or tumors and history of prior malignancy is the most helpful in differentiating primary from metastatic tumor, but immunohistochemical stains may help narrow the differentialdiagnosis when a metastatic lesion is suspected (see the immunohistochemistry discussion that follows).
Large Cell Carcinoma
Large cell carcinomas compose fewer than 10% of lung carcinomas, tend to occur peripherally, and are defined as poorly differentiated carcinomas of the lung composed of larger malignant cells without evidence of squamous, glandular differentiation, or features of small cell carcinoma by light microscopy ( Fig. 76-9 ).[96] These tumors usually consist of sheets of large malignant cells, often with associated necrosis. Cytologically, the tumor is also arranged in syncytial groups and single cells, again without evidence of squamous, glandular, papillary, or features of small cell carcinoma. By electron microscopy, large cell carcinoma may show some evidence of glandular, squamous, or neuroendocrine differentiation, whereas others show none of these.[137] Variants of large cell carcinoma include basaloid carcinoma, which may present as an endobronchial lesion and may resemble a high-grade neuroendocrine tumor, and lymphoepithelioma-like carcinoma, which is similar to the same-named tumor of other sites and is associated with Epstein-Barr virus infection.
|
Figure 76-9 Large cell carcinoma consists of sheets of undifferentiated cells without glandular or squamous differentiation. Prominent nucleoli are seen. |
Large Cell Neuroendocrine Carcinoma
Large cell neuroendocrine carcinoma (LCNEC) is a subtype of large cell carcinoma that shows neuroendocrine differentiation by light microscopy and accounts for approximately 3% of lung cancers; it is included in the differential diagnosis of neuroendocrine lung tumors (see later discussion). LCNEC is a high-grade carcinoma showing neuroendocrine patterns (formation of rosettes, trabeculae, organoid nests, or perilobular palisading patterns), greater than 10 mitoses per 2 mm2, and positivity with neuroendocrine markers.[96] LCNEC may be difficult to diagnose cytologically and may be difficult to differentiate from a small cell carcinoma. Cytologic features include evidence of neuroendocrine differentiation (sheets or groups of cells with peripheral palisading or rosette formation, nuclear molding, or immunohistochemical staining with neuroendocrine markers), as seen in other neuroendocrine tumors, but unlike small cell carcinoma, these tumors tend to have larger cells with prominent nucleoli. [96] [138] [139] [140] LCNEC is an aggressive tumor and shares several molecular abnormalities with small cell carcinoma. The prognosis for these tumors is intermediate between other nonsmall cell carcinomas and small cell carcinoma.
Small Cell Carcinoma
Small cell carcinoma is a poorly differentiated neuroendocrine tumor that tends to occur centrally and is highly associated with smoking. Incidence rates of small cell carcinoma are higher among men than women,[16] but a higher percentage of lung cancers are of small cell origin among women than men.[141] Small cell carcinoma consists of smaller but obviously malignant cells with little cytoplasm, characteristic finely granular (“salt and pepper”) chromatin without prominent nucleoli, and greater than 10 mitoses per 2 mm2 ( Fig. 76-10A ).[96] The tumor cells may be arranged in sheets or may show neuroendocrine patterns such as rosettes, trabeculae, or peripheral palisading of cells at the periphery of nests. Often there is necrosis and crushing of tumor cells. The cells are defined as “small,” meaning fewer than 21 mm in diameter; however, variation in size is common in these tumors, and the nuclear features are the more characteristic finding,[142] including characteristic “molding” of tumor nuclei.[143] [144] The characteristic cytologic features are usually easily identified in well- preserved cytologic specimens, but they may be more difficult to differentiate from other round blue cell tumors on ThinPrep cytology[144] or on less well-preserved specimens or small specimens ( Fig. 76-10B ).[100] As with other histologic types of lung carcinoma, small cell carcinoma may occur alone or combined with other tumors. Combined small cell with LCNEC, large cell carcinoma, adenocarcinoma, and squamous cell carcinoma have all been well documented. The differential diagnosis of small cell carcinoma includes poorly differentiated nonsmall cell carcinomas and neuroendocrine carcinomas, especially poorly differentiated squamous cell carcinoma and LCNEC, as well as nonepithelial tumors such as lymphoma, small round blue cell tumors, and some sarcomas (e.g., synovial sarcoma).
|
Figure 76-10 Small cell carcinoma. A, A resected small cell carcinoma shows well-preserved tumor cells with little cytoplasm, nuclear molding, and numerous mitotic figures (arrows). Note the lack of nucleoli. B, By cytology (H&E stain) the nuclear features (“salt and pepper” chromatin pattern), scant cytoplasm, nuclear molding, and crushing of cells in this small cell carcinoma are also evident. |
Typical Carcinoid Tumor
Typical carcinoid tumor is a low-grade neuroendocrine tumor showing tumor cells arranged in organoid nests, trabeculae, or spindled patterns characteristic of neuroendocrine differentiation, but is differentiated from other tumors by its bland uniform cells, lack of necrosis, and no significant mitotic activity (fewer than 2 mitoses per 2 mm2). Typical carcinoid tumor occurs in nonsmokers, most often as an endobronchial lesion, but can occur more peripherally. Cytologic specimens show uniform low-grade cells with finely stippled (“salt and pepper”) chromatin. Although these tumors are known for their excellent prognosis, as many as 10% to 15% can have metastases at diagnosis.[96] A carcinoid tumorlet is defined as a carcinoid tumor measuring less than 5 mm. Although tumorlets are usually an incidental finding, tumorlets can be associated with other tumorlets, carcinoid tumors, or neuroendocrine hyperplasia of the bronchial epithelium.[96]
Atypical Carcinoid Tumor
Atypical carcinoid tumor shows neuroendocrine morphology similar to the typical carcinoids, but is a slightly more aggressive tumor, with mitoses in the range of 2 to 10 per 2 mm2 and higher risk of metastasis (as high as 50% lymph node metastasis at presentation).[96] Cytologically, atypical carcinoids have a similar appearance to typical carcinoids, although tumor cells may show more atypia and nuclear enlargement.[96]
Differential Diagnosis of Neuroendocrine Tumors of the Lung
Neuroendocrine tumors of the lung include a wide variety of lesions from the very bland to the most aggressive pulmonary neoplasms. The four main neuroendocrine tumors of the lung are carcinoid tumor, atypical carcinoid tumor, LCNEC (a type of large cell carcinoma), and small cell carcinoma ( Fig. 76-11 ). In general it is helpful to think of these tumors according to clinical or behavioral characteristics. Carcinoid tumor and atypical carcinoid tumors are less associated with smoking history, tend to occur in younger patients, and are less aggressive, whereas small cell carcinoma and large cell neuroendocrine carcinoma occur in smokers and behave much more aggressively. Differentiating these tumors from one another histologically is usually straightforward based on morphologic features. In some cases, however, there can be overlap in the morphologic features. The WHO classification of these tumors emphasizes mitotic count in differentiating these tumors, and in fact, these criteria are used to define these tumors ( Table 76-2 ). This approach is usually straightforward unless the tissue available is small or in the case of a cytologic specimen. Immunohistochemistry may be performed to support or verify the neuroendocrine nature of the tumor and thus differentiate neuroendocrine tumors from other nonsmall cell carcinomas.[138]
|
Figure 76-11 Neuroendocrine tumors of the lung. A, A typical carcinoid tumor shows a subtle organoid and trabecular pattern of growth. The tumor cells are uniform with round nuclei showing a neuroendocrine (“salt and pepper”) chromatin pattern. No mitoses are identified. B, An atypical carcinoid tumor is arranged in sheets with focal palisading of tumor cells, relatively bland neuroendocrine nuclei, and only a few scattered mitoses (arrows). C, A large cell neuroendocrine carcinoma is arranged in organoid nests and rosettes. Tumor cell nucleoli, necrosis, and abundant mitoses (arrows) are readily identified. D, A small cell carcinoma shows prominent molding and crushing on a transbronchial biopsy. |
Table 76-2 -- General Histologic Features of Neuroendocrine Tumors
|
Diagnosis |
Morphology |
Mitotic Count (per mm2) |
|
Typical carcinoid tumor |
Generally bland neuroendocrine morphology |
<2 |
|
Atypical carcinoid tumor |
Generally bland neuroendocrine morphology with or without focal necrosis |
2-10 |
|
Large cell neuroendocrine carcinoma |
High-grade neuroendocrine carcinoma—larger cells with nucleoli |
>10 |
|
Small cell carcinoma |
High-grade neuroendocrine carcinoma—smaller cells and few nucleoli |
>10 |
Immunohistochemistry
The diagnosis of lung cancer most often rests on the morphologic or cytologic features correlated with clinical and radiographic findings. Immunohistochemistry may be used to verify neuroendocrine differentiation within a tumor, or in differentiating primary from metastatic tumor. A summary of commonly used immunohistochemical stains is shown in Table 76-3 . [96] [117] [119] [134] [138] [145] [146] [147] [148] [149] [150] [151]
Table 76-3 -- Common Immunohistochemical Markers Used in the Diagnosis of Lung Tumors
|
Diagnosis |
Positive Immunohistochemical Markers |
|
Squamous cell carcinoma |
Cytokeratin (CK) cocktail (e.g., AE1/AE3) |
|
CK5/6 |
|
|
CK7 rare |
|
|
Adenocarcinoma including bronchioloalveolar carcinoma, nonmucinous |
CK cocktail (e.g. AE1/AE3) |
|
CK7 |
|
|
TTF-1 |
|
|
Neuroendocrine markers rare, e.g., CD56, NSE |
|
|
Bronchioloalveolar carcinoma, mucinous |
CK cocktail (e.g., AE1/AE3) |
|
CK7 |
|
|
CK20 |
|
|
TTF-1 rare |
|
|
Large cell carcinoma |
CK |
|
TTF-1 rare |
|
|
Neuroendocrine markers rare (e.g., CD56, NSE) |
|
|
Large cell neuroendocrine carcinoma |
CK cocktail (e.g., AE1/AE3) TTF-1 |
|
CD56 |
|
|
Chromogranin |
|
|
Synaptophysin |
|
|
Small cell carcinoma |
CK cocktail (tends to be patchy) |
|
TTF-1 |
|
|
CD56 |
|
|
Chromogranin |
|
|
Synaptophysin |
|
|
Carcinoid tumor |
CK cocktail (e.g., AE1/AE3) |
|
TTF-1 (weaker than high-grade neuroendocrine tumors) |
|
|
CD56 |
|
|
Chromogranin |
|
|
Synaptophysin |
|
|
Atypical carcinoid tumor |
CK cocktail (tends to be patchy) |
|
TTF-1 |
|
|
CD56 |
|
|
Chromogranin |
|
|
Synaptophysin |
|
|
Common differential diagnoses |
|
|
Colonic adenocarcinoma |
CK20+CK7- |
|
Breast, biliary, upper Gl adenocarcinoma |
CK7+CK20- |
|
Urothelial carcinoma |
CK7+CK20+ |
|
Prostatic adenocarcinoma |
CK7-CK20- |
|
Mesothelioma |
Calretinin, WT-1 |
|
Malignant melanoma |
S-100, HMB-45, Melan-A |
|
Gl, gastrointestinal. |
Neuroendocrine markers include neuron-specific enolase, CD56 or neural cell adhesion molecule, synaptophysin, chromogranin, and Leu7. Most often a combination of these stains (e.g., CD56, synaptophysin, and chromogranin) is used to establish a diagnosis.[119] These markers support neuroendocrine differentiation but do not distinguish between specific types of neuroendocrine tumors.
Immunohistochemistry is also helpful in distinguishing primary lung tumors from malignancies metastatic to the lung. This is especially true for distinguishing primary lung adenocarcinomas and metastatic adenocarcinomas. Thyroid transcription factor-1 (TTF-1), identified in tumors of thyroid and pulmonary origin, tests positive in over 70% of pulmonary adenocarcinomas.[151] When present, TTF-1 is a reliable indicator of a primary lung cancer provided a thyroid primary has been excluded. A negative test for TTF-1 does not exclude the possibility of a lung primary, however. Interestingly, TTF-1 also tests positive in neuroendocrine tumors of pulmonary and extrapulmonary origin. [138] [146] [152] [153] Thus, TTF-1 is often used in combination with other immunohistochemical stains to differentiate among various diagnostic possibilities. Individually, TTF-1 and many neuroendocrine markers can show some immunohistochemical positivity in both small cell and nonsmall cell carcinomas, and have not been shown to be prognostically significant.[154] Cytokeratins 7 and 20, used in combination, also assist in categorizing certain tumors. These stains are not specific for a particular site of origin but can narrow the differential diagnosis.
Although mesothelioma can be easily identified ultrastructurally, it has historically been difficult to differentiate from adenocarcinoma through morphology and immunohistochemical staining. Several markers in the last few years have proven to be more helpful, including CK5/6, calretinin, and Wilms’ tumor gene-1,[96] all of which show positivity in mesothelioma.
Molecular Alterations Associated with Lung Cancer Subtypes
The molecular alterations found in lung cancer are varied and not entirely specific to histologic subtype. However, there are molecular abnormalities that are more commonly associated with certain histologies. Examples of a few of the more commonly identified changes are summarized ( Table 76-4 ). [96] [148] [155] [156] [157] [158] Thus far these findings have been of limited value in diagnosis and classification of lung cancer type, but future uses may include lung cancer screening, identifying markers for chemoprevention, and predicting prognosis. [155] [157] [159] One of the more clinically significant molecular discoveries in the last few years is mutations of the EGFR gene, which were identified in adenocarcinomas of patients showing a response to treatment with TKIs. [55] [57] Response to treatment is often associated with the presence of the mutation, and EGFR mutations are associated with female gender, nonsmoking status, and adenocarcinoma histology. [57] [62] Interestingly, some responders without this mutation have also shown a response.[160] Thus far EGFR mutations have been identified in adenocarcinomas of the lung, most often of mixed type with a focal bronchioloalveolar pattern. [161] [162] [163] [164] [165] [166] [167] EGFR mutations have also been found in AAH but are rare.[167] There is some suggestion that EGFR gene amplification by fluorescence in situ hybridization (FISH) or immunohistochemistry may be predictive of response, [168] [169] and some agreement between presence of mutation and FISH copy number,[169] and FISH positivity with overexpression by immunohistochemistry. [170] [171] However, further study will be needed to determine what combination of testing will be predictive of response to TKIs or prognosis. [172] [173]
Table 76-4 -- Examples of Common Molecular Alterations in Lung Tumors
|
Diagnosis |
Common Molecular Alterations |
|
Squamous preneoplasia |
LOH: 3p, 9p21, 8p21-p23, aneuploidy, methylation |
|
Atypical adenomatous hyperplasia |
LOH: 3p, 9p |
|
Aneuploidy |
|
|
K-ras codon 12 mutation |
|
|
Adenocarcinoma |
TP53 mutation |
|
CDKN2A mutation/inactivation |
|
|
K-ras (42%) mutation; smokers more common |
|
|
EGFR overexpression (40%) |
|
|
EGFR mutation |
|
|
Her2/neu, COX-2 overexpression |
|
|
Squamous cell carcinoma |
TP53 mutation |
|
CDKN2A inactivation |
|
|
Allelic loss 3p |
|
|
EGFR overexpression (80%) |
|
|
Large cell carcinoma |
K-ras, TP53, loss CDKN2A |
|
Large cell neuroendocrine carcinoma |
P53 |
|
BCL-2 overexpression Rb mutation |
|
|
3p21, FHIT, 3p22-p24, 5q21, 9p21 |
|
|
Small cell carcinoma |
Rb mutation (>80%) |
|
TP53 mutation (50% to 80%) |
|
|
BCL-2 expression |
|
|
3p21, FHIT, 3p22-p24, 5q21, 9p21 |
|
EGFR, epidermal growth factor receptor; LOH, loss of heterozygosity; Rb, retinoblastoma. |
EARLY DETECTION AND SCREENING
Early detection is a process that involves screening tests, surveillance, and diagnosis and also implies early treatment,[174] whereas screening is defined as the systematic testing of asymptomatic individuals for preclinical disease.[175] The purpose of screening is to prevent or delay the development of advanced disease in patients with preclinical disease through early detection and treatment. Screening presumes that a test or series of tests will identify asymptomatic persons at risk for a specific disease and that a positive result leads to further testing to establish definitively the presence or absence of disease.[175] The monitoring of these subjects (surveillance) intends to detect the disease early and to treat it early. Under ideal circumstances, early intervention should change the course of the disease once the diagnosis is established, resulting in a decrease in disease-related mortality (the number of disease-specific deaths relative to the total number of persons evaluated). In addition, screening should apply to large populations that would benefit from early detection (therefore with chance of survival greater than 5 years). Finally, screening should cause no harm and be cost effective.[176]
Previous lung cancer screening efforts using periodic chest radiographs coupled with regular assessment of sputum cytology failed to demonstrate a decrease in lung cancer-related mortality. [177] [178] [179] [180] Details of these trials have been extensively reviewed elsewhere.[181] Ironically, more lung cancers were diagnosed in the screening arms of these trials. The lung cancers identified in the screened population were often found at very early stages, allowing more patients in the screened arms to go to definitive surgery. Nonetheless, there was not an improvement in lung cancer-related mortality, which is considered a requirement to validate potential screening methods.[181] Several hypotheses have been advanced to explain the findings including flawed trial design, lead-time bias, length time bias, and overdiagnosis bias. [182] [183] Briefly, these biases can be defined as follows: lead-time bias implies that earlier detection could result in longer survival from the time of diagnosis even if death is not delayed. Length time bias occurs when screening examination detects slow-growing cancers. In other words, the slower the growth of the neoplasm, the longer it is present without symptoms and the greater the likelihood of detection. Overdiagnosis bias refers to the phenomenon of detecting a lung cancer that would otherwise have remained subclinical before death from other causes. Overdiagnosis is of particular concern in lung cancer screening, because newer screening modalities can identify small nodules of unknown clinical significance. Mayo Clinic investigators found a persistence of excess lung cancer cases in the intervention arm of their original screening after an additional 16 years of follow-up,[183] providing continued support for overdiagnosis in lung cancer screening.
Thus far there is no screening procedure recommended for individuals “at risk” for lung cancer. In 2004 the U.S. Preventive Services Task Force concluded that there is insufficient evidence to recommend screening for lung cancer in asymptomatic individuals at risk for lung cancer (http://www.ahrq.gov/clinic/uspstf/uspslung.htm). Although it is assumed that the higher the risk of cancer the more useful the surveillance program, the field also lacks clear guidelines for the surveillance of “high-risk” individuals. Perhaps the greatest challenge is defining the optimal population to be screened—the population that could best benefit from lung cancer screening.[184] Entry criteria to lung cancer screening trials are still debated and no one has ever shown efficacy of surveillance program for lung cancer. Moreover, the challenges of large population screening programs are considerable and include the potential for diagnostic errors (i.e., false positives) related to pulmonary scarring from smoking or prior infection, areas of inflammation, or other noncancerous conditions as well as the anxiety experienced by the participant, the potential for unnecessary biopsy, surgery or both as well as repeated radiation exposure. Although the amount of radiation exposure engendered by a low-dose spiral CT scan is relatively modest (roughly equal to 10 chest radiographs or one tenth that experienced with a regular chest CT scan), it is not an insignificant issue. [185] [186]
High-Risk Population, a Susceptible Subgroup
As noted, a challenging problem in screening for lung cancer is the definition of a “high-risk” population—the population that could best benefit from lung cancer screening.[184] Individuals “at risk” include current and former smokers, those with specific various occupational exposures (e.g., asbestos; see section on Epidemiology), the presence of airflow obstruction, a family history of lung cancer, older individuals, and those with a prior history of a cancer of the aerodigestive tract. Individuals who smoke bathe their entire aerodigestive tract with multiple carcinogens, and it is therefore not surprising that this population experiences a high rate of second primary tumors, estimated to be between 1% and 4% per patient per year. [187] [188] [189] However, mere recognition of these features is not sufficient to identify “high-risk” individuals. For example, although smoking is an obvious risk for lung cancer—the cumulative risk of dying from lung cancer for a lifelong smoker is estimated to be approximately 16% in men and approximately 10% in women[31]—the risk of developing lung cancer varies greatly among individual current and former smokers.[190] For example, in the Carotene and Retinol Efficacy Trial, a large, randomized trial of lung cancer prevention, the 10-year cancer risk among current and former smokers ranged from less than 1% to 15%.[190] An example of an individual with a relatively low risk of developing lung cancer would be a 51-year-old woman who smoked one pack per day for 28 years and quit 9 years earlier. By contrast, a 68-year-old man who had smoked two packs per day for 50 years and continued to smoke might have a 15% risk of lung cancer.[190] Both of these individuals would be potentially eligible for screening, and yet the “payoff” would be quite different. This suggests that an accurate risk prediction model may facilitate greatly the admission of subjects in screening (or chemoprevention) trials.[190]
Cytologic atypia in sputum samples reflect the abnormalities that develop in the bronchial epithelium. Moreover, the presence of cytologic atypia has been shown to predict lung cancer risk.[191] The presence of moderate dysplasia or worse cytologic atypia is associated with a increased risk of developing lung cancer in a cohort of heavy smokers with airflow obstruction (adjusted hazards ratio of 2.8).[192] This translates into a cumulative lung cancer incidence of 10% at 3 years and 20% at 6 years. Given the limitations of cytologic evaluation of sputum samples, however, the study of molecular abnormalities in the sputum (e.g., methylation patterns of specific genes involved in lung cancer progression, cytogenetic alterations) may strengthen the assessment of risk for lung cancer in this population.
Molecular epidemiology may be used to identify patients at risk for developing lung cancer through the identification of specific genes, single-nucleotide polymorphisms, or other genetic traits associated with increased susceptibility for lung cancer.[193] Although many genotypes show increased risk (relatively low odds ratios) with lung cancer (e.g., CYP2A6, thymidylate synthase, GSTM1, XPA), their large number and low penetrance make targeted intervention extremely challenging. Assessing genetic susceptibility for lung cancer may allow the identification of susceptible subgroups most likely to represent ideal candidates for early detection. Although autosomal dominant genes have not been found in association with family history of lung cancer, there is epidemiologic evidence demonstrating a 2.5 times increased risk in patients with a family history of lung cancer after controlling for smoking.[194] A recent genomic locus on chromosome 6q23–q25 was identified as a locus of susceptibility with a maximum heterogeneity LOD score of 2.79, 3.47, and 4.26 for families with three, four, or five or more affected individuals.[51] Further complicating the picture is the role of the environment in modifying these specific genes and the interaction of genes between each other and evidence to support a genetic predisposition to smoking addiction. [195] [196] If markers of these genetic predispositions can be firmly established, intensive intervention to alter risk factors in these selected populations may alter their clinical outcome.
Imaging Approach
The last decade has witnessed a marked improvement in technology allowing for faster, higher resolution imaging of the chest. The CT scanner first became available in the 1970s but was impractical for screening because of its slow speed and radiation exposure. In the mid-1990s low-dose scanners capable of imaging the chest in less than 15 sec using radiation doses equivalent to 10 radiographs became available, opening the door to their potential use for screening.[197] Moreover, new bronchoscopic methods also demonstrate promise for the detection of preinvasive lesions. Other imaging modalities such as PET scan are able to provide metabolic information on lesions and can be combined with CT scan to give detailed resolution.
Low-Dose Spiral Computed Tomography Scan
In recent years there has been a substantial increase in the use of spiral CT scans to screen for lung cancers in former and current smokers. [174] [181] Spiral CT screening allows for a rapid and comprehensive evaluation of the lungs and is attractive because of its potential increased sensitivity, low radiation exposure, and potential cost effec tiveness.[174] Many pilot studies using spiral CT scans to screen for lung cancers have shown that this technology can identify a higher percentage of early-stage lung cancer than can conventional imaging studies. [198] [199] [200] These results are summarized inTable 76-5 and discussed in detail elsewhere. [174] [201] [202] Lung cancer prevalence rates range between 0.4% and 2.7%, depending on the population screened. In general, these prevalence rates are significantly higher than that reported using conventional imaging studies. The mean diameter of screened detected cancers ranges between 14 and 21 mm. Incidence rates based on detection of new malignancies at annual repeat screening range from 0.07% to 1.1%. [174] [203] Notably, as many as 85% of CT-screened detected lung cancers are clinical stage I lesions. By contrast, only 15% of lung cancers diagnosed through routine clinical care are found to be stage I.[204] Because stage I lung cancer is the most curable form of this disease, a high frequency of detection of stage I tumors is considered a necessary (though not sufficient) indication of a favorable screening outcome.[174] International Early Lung Cancer Action Program (IELCAP) investigators recently reported a 92% 10-year survival rate among screened detected clinical stage I lung cancer patients who underwent surgical resection within 1 month after diagnosis.[205] In a separate report, IELCAP investigators reported that the cancers identified by CT screening met standard criteria for full-fledged aggressive lung cancer.[115] Although these data are intriguing and encouraging, long-term follow-up of these patients will be very important to exclude lead-time bias (simply diagnosing the cancer earlier, but not altering its outcome) as a confounder for an improved survival and a reduced disease-related mortality.
Table 76-5 -- Results of Prevalence and Incidence Screens in Computed Tomography (CT) Screening Trials
|
Study |
Year |
No. of Patients Screened |
No. of Abnormal CT Scans |
Cancers Detected |
Stage 1 Lesions |
|
PREVALENCE CT |
|||||
|
Henschke et al[199] |
1999 |
1,000 |
233 |
27 (2.7%) |
81% |
|
Sone et al[209] |
2001 |
5,483 |
676 |
22 (0.4%) |
100% |
|
Swensen et al[210] |
2002 |
1,520 |
782 |
22(1.4%) |
59% |
|
Sobue et al[208] |
2002 |
1,611 |
186 |
14 (0.9%) |
77% |
|
Pastorino et al[200] |
2003 |
1,035 |
199 |
11 (1.1%) |
55% |
|
Henschke et al[205] |
2006 |
31,567 |
4186 |
410(1.3%) |
85% |
|
INCIDENCE CT |
|||||
|
Henschke et al[207] |
2001 |
1,184 |
63 |
7 (0.6%) |
85% |
|
Sone et al[209] |
2001 |
8,303 |
518 |
34 (0.4%) |
100% |
|
Swensen et al[210] |
2002 |
1,464 |
191 |
3 (0.2%) |
0% |
|
Sobue et al[208] |
2002 |
7,891 |
721 |
22 (0.3%) |
82% |
|
Pastorino et al[200] |
2003 |
996 |
99 |
11 (1.1%) |
100% |
|
Henschke et al[205] |
2006 |
27,456 |
1460 |
74 (0.3%) |
86% |
A major challenge confronting advocates of CT screening is the high false-positive rate.[206] On initial screening of at-risk populations, false-positive rates range between 10% and 20% but can be as high as 50%. [207] [208] [209] [210] Positive predictive values range from 2.8% to 11.6%. [207] [208] [209] [210] False positives can have a substantial impact on patients through the expense and risk of unneeded further evaluation and emotional stress. False-positive rates and positive predictive values are somewhat improved in annual follow-up CT scans, but there is still significant room for improvement. Based on extant data it seems that nodules smaller than 5 mm are unlikely to be cancerous and those 5 to 10 mm in diameter (25% to 40% of noncalcified nodules detected) are of uncertain significance.[211] The management of these patients usually consists of repetitive CT scans over time to see if the nodules grow, attempted FNAs, or surgical resection. PET has limited usefulness in detection of lesions smaller than 1 cm and has proved to be of limited value in adenocarcinoma, particularly of bronchioloalveolar subtype.[212] Each of these is costly, and some have significant morbidity. The impact of waiting to assess nodule growth on patient outcome is also not clear but can only decrease curability. Even for patients with disease that is highly suspicious for lung cancer on clinical grounds, there is a 10% to 20% incidence of “futile thoracotomies” wherein the suspicious lesion is found to be benign, and thus, the patient unnecessarily incurred the morbidity and potential mortality of a thoracotomy. [213] [214] [215]Eliminating unnecessary surgery should be one of our priorities, although this may not be feasible without the development of other strategies of early detection.
To address many of these ongoing issues, the NCI initiated the National Lung Cancer Screening Trial (NLST). The NLST is a prospective comparison of spiral CT and standard chest radiograph in 50,000 current or ex-smokers between the ages of 55 and 74 years and is designed to determine the best strategy to reduce lung cancer-related mortality. The NCI estimates that the trial may produce results that could inform policy decisions as early as 2010 (http://www.nci.nih.gov/NLST). A similar study is continuing in Europe comparing CT scanning with standard of care among 20,000 subjects with history of heavy smoking.
Finally, CT scanning has also shown promise in the detection of some preinvasive lesions. High-resolution CT has proven to be sensitive enough to detect ground-glass opacities, some of which may represent inflammatory lesions, BAC, adenocarcinomas, or AAH. AAH is a presumed precursor lesion to adenocarcinoma. [216] [217] [218] [219] Because adenocarcinoma is now the most common histologic type of lung cancer in the United States, there is some hope that CT may be able to improve survival for these patients by detecting a precursor lesion before its transformation to invasive carcinoma. Chest CT scanning, however, is not yet sensitive enough to detect preinvasive epithelial lesions of the bronchial tree with squamous differentiation, probable precursors of squamous carcinoma of the lung.
Positron Emission Tomography Scan
Many CT screening protocols now use PET scan as a method of reducing this high false-positive rate. PET scanning attempts to identify malignancy based on glucose metabolism by measuring the uptake of [18F]fluorodeoxyglucose (FDG). Lung cancers will preferentially take up FDG and appear as a “hot spot”. Thus far PET has been used mostly for staging and detection of metastases in lung cancer [220] [221] and in the diagnosis of nodules larger than 15 mm in diameter. [200] [222] In combination with another imaging modality, PET may provide information about the metabolic state of lung nodules. Combined FDG PET-CT scan has been shown to improve the accuracy of staging in lung cancer compared with visual correlation of PET and CT or either study alone.[223] The added information gained from PET and combined PET-CT may help reduce the high false-positive rates seen in trials using CT alone. A trial of low-dose CT used in combination with PET scan of 1035 patients resulted in only 6 false positives, defined as a surgical biopsy of a benign nodule, out of 27 surgical biopsies of suspicious nodules.[200] There are important limitations to this study, however. First, lung nodules of 5 mm or less in size were followed, with repeat CT in 1 year, and no other intervention. Second, PET scanning was only performed on larger nodules (7 mm or larger). Typically, PET scan has not performed well in the identification of small nodules (<15 mm), so its usefulness in intermediate lesions remains in question, in particular in areas with high prevalence of pulmonary fungal infections.[224] There is no evidence of a survival benefit using PET scan as part of a screening protocol.
Other Imaging Techniques
Fluorescence endoscopy uses differences in the autofluorescence characteristics of normal and neoplastic epithelium to localize lesions. Fluorescence bronchoscopy has been shown to be more sensitive than white-light bronchoscopy in the detection of preneoplastic lesions in many studies, including a randomized trial. [225] [226] [227] [228] The randomized trial demonstrated that the use of the laser-induced fluorescence endoscopy procedure resulted in a 46.9% absolute increase in the sensitivity of detecting moderate dysplasia in high-risk patients when compared with white light bronchoscopy, although specificity was worse.[225] Fluorescence bronchoscopy has not been proven as a validated method of early detection of lung cancer, but it is a very important research tool.
New imaging techniques are currently being developed to help improve not only the resolution of current imaging techniques but also to image lesions based on biologic activity. Both magnetic resonance and gamma camera techniques are being tested as molecular imaging tools. [229] [230] [231] Near-infrared Raman spectroscopy,[232] optical coherent tomography,[233] and confocal microscopy use optical differences within tissue to allow imaging of individual cell nuclei. This technology is being adapted for use during endoscopic examinations and may be able to provide real-time histologic evaluation of bronchial mucosa.
Blood Biomarkers for Lung Cancer
Although various serum biomarkers have been investigated in lung cancer, none has proved useful in general clinical practice, mainly because of the lack of sufficient sensitivity and specificity. For example, cytokeratin fragment antigen 21.1 (Cyfra-21.1), a marker of cytokeratin, [234] [235] [236] carcinoembryonic antigen,[235] and tissue polypeptide antigen[234] were found to have relatively poor sensitivity (31% to 64%) when specificity limits of 95% were set. In addition, most markers reach better sensitivity in advanced-disease stages as compared with stage I lung cancer. Thus, their use for early diagnosis or screening has not had an impact on patient care in the clinic. Blood-derived biomarkers used in combination with other clinical, imaging, or molecular tools might play an important role in early detection, in monitoring response to therapy, in risk assessment of recurrence, and in prognosis.
In conclusion, although no data are available from randomized trials, spiral CT of the chest and autofluorescence bronchoscopy offer excellent sensitivity to detect lung cancer at early stage, even during the preinvasive stage. The high sensitivity of these tests, however, is associated with a low specificity. Better selection of individuals at highest risk of lung cancer, using biomarkers of disease and of genetic susceptibility, may improve their positive predictive values, minimize the false-positive rates and associated unnecessary investigations or treatment, as well as reduce the cost of the early-detection process.
CLINICAL PRESENTATION AND STAGING OF LUNG CANCER
Presenting Signs and Symptoms
Symptoms, signs, and laboratory test abnormalities relating to lung cancer can be classified as those caused directly by the primary lesion, those related to intrathoracic spread or to distant metastasis, and those related to paraneoplastic syndromes. [237] [238] [239] The prototypical lung cancer patient is a current or former smoker of either gender, usually in the seventh decade of life, who presents with symptoms attributable to bulky intrathoracic disease (i.e., cough, dyspnea, chest pain, hoarseness, and/or hemoptysis) or distant metastases (e.g., bone pain, central nervous system symptoms, etc). [238] [240]Constitutional symptoms may include weakness, anorexia, weight loss, and, rarely, fever. [238] [240] Apart from the brevity of symptom duration, these parameters fail to clearly distinguish SCLC from NSCLC or even from neoplasms metastatic to the lungs.[241] Lung cancer arising in a individuals who have never smoked is more common in women and certain ethnic groups and tends to be an adenocarcinoma. [242] [243] [244] [245] Such individuals also tend to be slightly younger than their smoking counterparts at the time of diagnosis.[242] However, the clinical presentation of lung cancer in those who have never smoked tends to mirror that of current and former smokers, even though lung cancers arising in lifelong nonsmokers seem to be biologically distinct as suggested by the differing molecular abnormalities found in tumors derived from smokers and nonsmokers.[244] The prognosis of lung cancer in lifelong nonsmokers is generally better compared with cancers in current or former smokers irrespective of stage. [35] [242] [246] The reason for the improved survival is unclear.
Cough, dyspnea, and chest discomfort are the most common presenting symptoms in lung cancer ( Table 76-6 ).[237] A history of chronic cough with or without hemoptysis in a current or former smoker with COPD aged 40 years or older should prompt a thorough investigation for lung cancer even in the face of a normal chest radiogram.[237] A persistent “pneumonia” without constitutional symptoms and unresponsive to repeated courses of antibiotics also should prompt an evaluation for an underlying cause (e.g., an occult endobronchial lesion), especially if the individual is a current or former smoker. Less frequently individuals present with hemoptysis that rarely is massive and usually described as streaks of fresh or old blood in sputum. The spread of disease within the chest may result in hoarseness secondary to recurrent laryngeal nerve paralysis and less frequently phrenic nerve paralysis. The latter is associated with an elevated hemidiaphragm on standard chest radiogram. Chest wall involvement is commonly accompanied by pain that in turn may serve as a more accurate indicator of chest wall invasion than radiographic studies. Chest wall pain is usually related to either direct invasion of the pleura or chest wall by the primary tumor, or due to a rib metastasis. Tenderness may be elicited at the site of rib involvement and, rarely, a soft-tissue mass can be palpated.[237] The chest pain may have a pleuritic component if there is pleural involvement. The disappearance of pleuritic chest pain may signify the development of a pleural effusion that in turn may cause shortness of breath or worsen existing dyspnea. Venous distension of the neck and chest wall, cyanosis, facial plethora, and upper extremity edema may indicate obstruction of the superior vena cava, which today is most commonly seen with SCLC. [237] [247] Although the heart and other mediastinal structures are often involved with tumor at postmortem examination, only rarely does this involvement serve as the source of a presenting symptom.
Table 76-6 -- Presenting Sign and Symptoms of Lung Cancer
|
Symptoms and Signs |
Range of Frequency (%) |
|
Cough |
8–75 |
|
Weight loss |
0–68 |
|
Dyspnea |
3–60 |
|
Chest pain |
20–49 |
|
Hemoptysis |
6–35 |
|
Bone pain |
6–25 |
|
Clubbing |
0–20 |
|
Fever |
0–20 |
|
Weakness |
0–10 |
|
Superior vena cava obstruction |
0–4 |
|
Dysphagia |
0–2 |
|
Wheezing and stridor |
0–2 |
From Beckles MA, Spiro SG, Colice GL, Rudd RM: Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes. Chest 2003;123:97-104.
Approximately one third of patients present with symptoms as a result of distant metastases.[237] The most common sites of distant metastasis from lung cancer are the bones; liver, adrenal glands, and intra-abdominal lymph nodes; brain and spinal cord; and lymph nodes and skin. Lung cancer can metastasize to virtually any bone, with pain being the primary presenting symptom in as many as 25% of individuals at diagnosis.[237] Similarly, liver metastases are common at initial presentation in both SCLC and NSCLC. However, liver function test results are seldom abnormal until the metastases are numerous and large. Hepatic metastases most commonly produce symptoms of weakness and weight loss. Adrenal lesions, only rarely associated with adrenal insufficiency, and para-aortic lymph node metastases are most commonly seen with SCLC. Intracranial metastases at presentation are most commonly in SCLC and adenocarcinomas of the lung. Presenting symptoms may include headache, nausea and vomiting, focal neurologic symptoms or signs, seizures, confusion, and personality changes.
The stigmata of COPD in smokers may be the only findings on physical examination, or one may detect lymphadenopathy, hepatomegaly, bone tenderness, or abnormal neurologic findings. Digital clubbing and hypertrophic osteoarthropathy may be associated with any histologic subtype of lung cancer but are most frequently associated with squamous cell and adenocarcinoma and least likely to occur in a patient with small cell carcinoma. [237] [248] Digital clubbing is more common than hypertrophic osteoarthropathy, which is characterized by painful symmetric arthropathy and periosteal new bone formation of the distal limbs. Its mechanism of development is unknown. In a published series of 111 consecutive lung cancer patients, clubbing was noted in 29% with an incidence of 35% in NSCLC and only 4% in SCLC.[248] As many as 20% of patients present with palpable lymphadenopathy in the supraclavicular fossa during the course of the disease. Subcutaneous metastases while rare may serve as a source of diagnostic material.
Paraneoplastic Disorders
Although many of the symptoms of NSCLC and SCLC are attributable to mass effect and direct impingement upon vital organs, less commonly individuals with lung cancer present with symptoms related to hypercalcemia,[249] hyponatremia, [241] [250] Cushing's syndrome,[251] Lambert-Eaton syndrome, and other neurologic disorders. [252] [253] [254] These so-called paraneoplastic phenomena can be seen in any histologic type of lung cancer but are most frequently associated with SCLC. In general a majority of these paraneoplastic phenomena fall into endocrine or neurologic categories. [255] [256] [257]
Hypercalcemia
Hypercalcemia of malignancy (HCM) is the most common life-threatening metabolic complication of malignancy, affecting approximately 10% to 20% of patients with advanced cancer. Hypercalcemia may be associated with or due to production of a parathyroid hormone-related peptide.[249] The incidence of HCM varies widely by cancer type but occurs most frequently in patients with multiple myeloma and carcinomas of the lung, breast, kidney, and head and neck. With respect to lung cancer, squamous cell carcinoma is the most common histologic subtype. Clinical symptoms of HCM include nausea, vomiting, abdominal pain, constipation, polyuria and thirst, and altered mental status. HCM may lead to renal failure. The early symptoms of nausea, vomiting, and constipation may be easily confused with the initiation of narcotics for pain control. Management of HCM is covered in Chapter 48 .
Hyponatremia and the Syndrome of Inappropriate Antidiuretic Hormone
The inappropriate secretion of antidiuretic hormone, or arginine vasopressin (AVP), with its resultant euvolemic, refractory, hypo-osmolar hyponatremia, is observed in as many as 15% of individuals with SCLC. [250] [258] However, as many as one third of patients with hyponatremia have no evidence of ectopic AVP production.[259] In such cases hyponatremia may be caused by ectopic production of atrial natriuretic peptide (ANP). SCLC is the most common malignant cause of acute or chronic syndrome of inappropriate secretion of antidiuretic hormone (SIADH).[260] The presence of SIADH does not correlate with clinical stage, distribution of metastatic sites, or patient gender, nor does SIADH influence response to chemotherapy or overall survival as an independent variable.[250] As with most paraneoplastic syndromes, the best therapy for SIADH is effective treatment of the underlying SCLC. SIADH typically resolves with 1 to 4 weeks of initiating chemotherapy in the vast majority of cases.[250] While awaiting the effects of chemotherapy, serum sodium can usually be managed and maintained above 128 mEq/L via strict fluid restriction alone.[261] Demeclocycline, which blocks the action of vasopressin at the level of the renal tubule, can be a useful adjunctive measure when fluid restriction alone is insufficient to restore sodium level. [262] [263] The starting dose is 150 mg four times a day but may have to be increased to 1200 mg. Tolvaptan, an oral vasopressin V2-receptor nonpeptide antagonist, also is effective in increasing serum sodium concentrations in patients with euvolemic and hypervolemic hyponatremia.[264] Notably, patients with ectopic ANP secretion do not respond to fluid restriction.[259] In fact, fluid restriction may actually worsen hyponatremia if sodium intake is not concomitantly increased. Accordingly, if hyponatremia fails to improve or worsens after 3 to 4 days of adequate fluid restriction, plasma concentrations of AVP and ANP should be measured to determine whether inappropriate secretion of ADH or ANP is the causative syndrome.[259]
Ectopic Adrenocorticotropic Hormone Production
Cushing's syndrome may be due to ectopic secretion of adrenocorticotropic hormone from a nonpituitary tumor resulting in bilateral adrenocortical hyperplasia and hypercortisolemia.[265] Neuroendocrine lung tumors including SCLC and pulmonary carcinoids account for approximately half of the cases of ectopic tumors producing adrenocorticotropic hormone. [251] [266] Although hypercortisolemia has been documented in as many as 50% of SCLC cases, only 2% to 5% of SCLC patients have the characteristic clinical features of Cushing's syndrome.[251] Unlike Cushing's disease, the onset of symptoms in ectopic adrenocorticotropic hormone production is often abrupt because of the characteristic rapid growth of SCLC. Consequently the classical features of Cushing's disease—a buffalo hump, striae, and moon facies—are frequently absent. By contrast, hypokalemic alkalosis, hypertension, hyperglycemia, and, rarely, edema and muscle wasting are common.[251] The effect of Cushing's syndrome on survival is unclear, although some investigators hold that its onset heralds a more aggressive tumor behavior.[251] Treatment with standard medications, such as metyrapone and ketoconazole, is largely ineffective due to extremely high cortisol levels.[267] Some patients require bilateral adrenalectomy to control symptoms.[265] The most effective strategy for management of the Cushing's syndrome is effective treatment of the underlying SCLC.[251]
Neurologic Paraneoplastic Syndromes
The paraneoplastic neurologic disorders are a diverse group of diseases characterized by the presence of neurologic dysfunction in the setting of a remote cancer. [256] [257] They are often the result of production of antibodies that react with both the small cell cancer cells and with normal host tissue. Well-described syndromes include the Lambert-Eaton myasthenic syndrome, paraneoplastic encephalomyelitis and sensorimotor neuronopathy, and paraneoplastic cerebellar degeneration. [254] [268] Less frequent abnormalities include subacute sensory neuropathy, autonomic disturbances, myelopathies, progressive encephalopathy, and visual paraneoplastic syndromes. [253] [256] [269]
Lambert-Eaton myasthenic syndrome is caused by autoantibodies directed against presynaptic voltage-gated P/Q calcium channels. [254] [268] The P/Q calcium channel autoantibodies decreases calcium entry into the presynaptic terminal, which prevents binding of vesicles to the presynaptic membrane and acetylcholine release. Individuals with this disorder present with proximal muscle weakness, usually in the lower extremities, occasional autonomic dysfunction, and rarely with cranial nerve symptoms or involvement of the bulbar or respiratory muscles. Depressed deep tendon reflexes are frequently present. As contrasted to individuals with myasthenia gravis, strength improves with serial effort. The diagnosis is confirmed by electrophysiologic testing, which demonstrates small compound muscle action potentials and facilitation with exercise or 20-Hz repetitive stimulation. A serum test for voltage-gated calcium channel antibodies, estimated to occur in 5% of patients with SCLC, is commercially available. Plasma exchange and intravenous immunoglobulin can provide short-term benefit, while 3,4-diaminopyridine, which enhances the release of acetylcholine from presynaptic terminals,[270]prednisone, and azathioprine can provide limited long-term benefit.[271] Some patients who respond to chemotherapy will have resolution of the neurologic abnormalities, and this is the initial treatment of choice.
Paraneoplastic encephalomyelitis and sensory neuronopathies, cerebellar degeneration, limbic encephalitis, and brainstem encephalitis occur in SCLC in association with a variety of antineuronal antibodies such as anti-Hu, anti-CRMP5, and ANNA-3. [253] [256] [272] These antibodies have been found in as many as 25% of individuals with SCLC though not always in association with a clinically obvious neurologic disorder.[256] These disorders may predate the diagnosis of SCLC.[256] Most paraneoplastic neuropathies are sensorimotor and axonal, symmetric in distribution, and frequently disabling.[256]Limbic encephalitis is characterized by degeneration of neurons in the medial temporal lobe with clinical features that include behavioral changes, hallucinations, short-term memory loss, anosmia, ageusia, and dementia.[273] Symptoms of brainstem encephalitis include vertigo, nystagmus, oscillopsia, ataxia, diplopia, dysarthria, and dysphagia reflecting the predominant involvement of the floor of the fourth ventricle and inferior olives.[274] Some patients develop respiratory insufficiency requiring assisted ventilation. Cerebrospinal fluid studies may show pleocytosis and elevated protein levels. MRI brain scans are typically normal. As with voltage-gated calcium channel antibodies, the presence of anti-Hu antibodies does not correlate with neurologic symptoms nor with an improved prognosis. [272] [275]
Paraneoplastic cerebellar degeneration, manifesting with ataxia, dysarthria, and nystagmus, may be associated with anti-Hu, anti-Yo, or P/Q calcium channel autoantibodies. [255] [276] [277] Patients often present with loss of coordination that usually starts on one side and rapidly progresses over days to weeks to involve both sides equally.[278] Additional presenting symptoms include limb and truncal ataxia, lack of coordination, dysarthria, and nystagmus. More rarely patients experience opsoclonus, myoclonus, memory disturbances, pyramidal signs, sensory disturbances, or hyporeflexia. After progressing for a few weeks, the symptoms stabilize, leaving the person in a severely disabled state. On examination, patients may be unable to stand without assistance because of severe truncal and neck ataxia with markedly ataxic gait. Ocular findings may include horizontal or vertical nystagmus, dysconjugate gaze, ocular dysmetria, and opsoclonus.[277] Speech also can be affected severely, presenting initially as mild dysarthria and progressing to incomprehensible words in severe cases. Mild deterioration of mental status may also be seen, but marked changes in mental status are not compatible with this diagnosis.[277] Treatment may include steroids, plasmapheresis, and chemotherapy. [255] [276] However, treatment of the tumor and/or immunomodulation does not alter the course of paraneoplastic cerebellar degeneration but may improve Lambert-Eaton myasthenic syndrome symptoms. Death is frequently due to neurologic complications. Paradoxically, the tumor frequently remains localized to the chest or not detected.[277]
Diagnostic Workup and Staging
Assessment of Intrathoracic Disease
Accurate staging of lung cancer is extremely important, because treatment options and prognosis are dictated by stage.[279] The most significant dividing line is between those individuals who are candidates for surgical resection and those who are inoperable but will benefit from chemotherapy, radiation therapy, or both. Staging with regard to an individual's potential for surgical resection is most applicable to NSCLC. The basis for staging NSCLC is the TNM system ( Table 76-7 ), [280] [281] whereas for SCLC a more simplified staging classification is used (described later). Of note, the TNM system is currently undergoing revision.[280] From a practical standpoint, the involvement of disease in the mediastinum, which is reflected in the “N” designator in the system, most often determines the appropriateness of the individual for surgical resection.[279] In other words, individuals with mediastinal node involvement are usually not candidates for surgical resection, although there are selected individuals in whom surgery is appropriate as discussed later in this section. Several noninvasive imaging studies are available to aid in identifying disease both within and outside of the chest. A majority of lung cancers are detected by plain chest radiography ( Fig. 76-12 ). However, the chest radiogram is not sufficiently sensitive to accurately assess the mediastinum. Accordingly, a chest CT scan should be performed in virtually every case of suspected NSCLC. The chest CT scan provides anatomic detail that better identifies the location of the tumor, its proximity to local structures, and whether or not lymph nodes in the mediastinum are enlarged (see Fig. 76-12 ). Unfortunately, the accuracy of chest CT scanning in differentiating benign from malignant lymph nodes in the mediastinum based on node size is low. The most commonly used size criterion is a short-axis diameter of 1 cm or larger on a transverse CT scan. Whole-body PET scanning provides functional information on tissue activity and is more sensitive and specific than chest CT scanning for staging lung cancer in the mediastinum ( Fig. 76-13 ). In addition, metastatic disease can be detected by PET scan. Still, positive findings of PET scans can occur from nonmalignant etiologies (e.g., infections), so that tissue sampling to confirm the suspected malignancy is strongly recommended. [104] [279] MRI can be useful in selected circumstances such as superior sulcus tumors to rule out brachial plexus involvement but in general does not play a major role in NSCLC staging. Of course, abnormalities detected by any of the aforementioned imaging studies are not necessarily cancer. Unless overwhelming evidence of metastatic disease is present on an imaging study, in situations in which it will make a difference in treatment, all abnormal scan findings require tissue confirmation of malignancy so that individuals are not prevented from having potentially curative surgery.[279]
Table 76-7 -- TNM Staging of Lung Cancer
|
PRIMARY TUMOR (T) |
TNM STAGING |
||
|
TO |
No evidence of primary tumor |
IA |
T1N0M0 |
|
Tis |
Carcinoma in situ |
IB |
T2N0M0 |
|
T1 |
Tumor <3 cm and not involving the mainstem bronchus |
IIA |
T1N1M0 |
|
T2 |
Tumor is: >3 cm, involving mainstem bronchus >2 cm from the carina, invading visceral pleura, or associated with lobar atelectasis or obstructive pneumonitis |
IIIB |
T2N1M0 |
|
T3 |
Direct invasion of chest wall, diaphragm, mediastinal pleura, pericardium, mainstem bronchus <2 cm from carina, or associated with atelectasis or obstructive pneumonitis of entire lung |
IIIA |
T3N1M0 |
|
T4 |
Direct invasion of mediastinum, heart, great vessels, trachea, esophagus, vertebrae, carina, or associated with malignant effusion or satellite nodules in the same lobe |
T1N2M0 |
|
|
REGIONAL LYMPH NODES (N) |
T3N2M0 |
||
|
NO |
No regional nodal metastasis |
IIIB |
T4N0M0 |
|
N1 |
Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, or intrapulmonary nodes involved by direct primary tumor extension |
T4N1M0 |
|
|
N2 |
Metastasis to ipsilateral mediastinal and/or subcarinal lymph nodes |
T1N3M0 |
|
|
N3 |
Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph nodes |
T2N3M0 |
|
|
DISTANT METASTASIS (M) |
T4N3M0 |
||
|
MO |
No distant metastasis |
IV |
Any T Any N Ml |
|
Ml |
Distant metastasis present or metastatic nodules in nonprimary tumor lobe(s) |
||
|
Figure 76-12 Imaging NSCLC. (A) Posteroanterior and (B) lateral chest radiogram of patients with locally advanced disease. (C) CT imaging using lung and (D) mediastinal windows. |
|
Figure 76-13 [18F]Fluorodeoxyglucose positron emission tomography with integrated computed tomography. FDG-PET demonstrates (A) activity in left upper lobe lesion and (B) activity in the subcarinal space. Physiologic uptake is noted in the brain, bones, liver, spleen, kidney, and musculature. Increased activity is also identified at intravenous insertion site, renal collecting system and the bladder. Fused CT/PET images confirm (C) lymph node in the anteroposterior window is FDG avid and (D) mild FDG uptake in a subcarinal lymph node. |
Assessment of Extrathoracic Disease
The best predictor of metastatic disease remains a careful history and physical examination. If signs, symptoms, or findings from the physical examination suggest the presence of malignancy, then sequential imaging, starting with the most appropriate study based on the clues obtained by the clinical evaluation, should be performed. If the findings from the clinical evaluation are negative, then imaging studies such as a CT scan of the head, a bone scan, or an abdominal CT scan are unnecessary, and the search for metastatic disease is complete. Clinical findings suggestive of metastatic disease are listed in Table 76-8 .[279] Patients with abnormal clinical evaluations should undergo imaging for extrathoracic metastases. Site-specific symptoms warrant directed evaluation of that site with the most appropriate study (e.g., head CT scan, bone scan, and abdominal CT scan).[279] More controversial is how one should assess individuals with known stage III disease. Because these patients are more likely to have asymptomatic occult metastatic disease, current guidelines recommend a more extensive imaging evaluation to include a head CT scan, an abdominal CT scan, and bone imaging.[279]
Table 76-8 -- Clinical Findings Suggesting Metastatic Disease
|
Symptoms elicited in history |
Constitutional: weight loss >10 pounds |
|
Musculoskeletal: focal skeletal pain |
|
|
Neurologic: headaches, syncope, seizures, extremity weakness, recent change in mental status |
|
|
Signs found on physical examination |
Lymphadenopathy (>1 cm) |
|
Hoarseness, superior vena cava syndrome |
|
|
Bone tenderness |
|
|
Hepatomegaly (>13-cm span) |
|
|
Focal neurologic signs, papilledema |
|
|
Soft-tissue mass |
|
|
Routine laboratory tests |
Hematocrit, <40% in men; <35% in women |
|
Elevated alkaline phosphatase, GGT, SGOT, and calcium levels |
From Silvestri GA, Tanoue LT, Margolis ML, et al: The noninvasive staging of nonsmall cell lung cancer: the guidelines. Chest 2003;123(1 Suppl):147S-156S.
|
GGT, gamma-glutamyltransferase; SGOT, serum glutamic-oxaloacetic transaminase. |
Solitary Pulmonary Nodule
The approach to a patient with a pulmonary nodule is based on an estimate of the probability of cancer, determined according to the size of the nodule, the presence or absence of a history of smoking, the patient's age, and characteristics of the nodule's margins on CT imaging.[282] Mayo Clinic investigators reported that clinical charac teristics (age, cigarette smoking status, and prior cancer diagnosis 5 or more years ago) and three radiologic characteristics (diameter, spiculation, and upper lobe location) were independent predictors of malignancy.[283] An efficient algorithm for assessing these lesions is outlined in Figure 76-14 .
|
Figure 76-14 Approach to the management of solitary pulmonary nodules. Figure 76-15 Algorithm for selecting stage I NSCLC patients for postoperative adjuvant chemotherapy. CCI, Charlson Comorbidity Index; ECOG, Eastern Cooperative Oncology Group; LND, mediastinal lymph node dissection; LNS, systematic mediastinal lymph node sampling; LVI, lymphovascular invasion; PS, performance status; Rx, treatment; VPI, visceral pleural invasion. (Adapted from Ost D, Fein AM, Feinsilver SH: The solitary pulmonary nodule. N Engl J Med 2003;348:2535–2542.) |
NONSMALL CELL LUNG CANCER
The four major histologic types of lung cancer—squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell undifferentiated carcinoma—together account for more than 90% of lung cancer cases in the United States.[15] The first three are traditionally lumped together into the category of NSCLC. The incidence of NSCLC has been decreasing since the mid-1970s to 1980s among men in North America, northwestern Europe, Australia, and New Zealand, but the age-adjusted rate continues to increase among women in these countries, and among both men and women in southern and eastern Europe.[284] These trends followed changes in smoking behavior. Over time there has been a significant shift in the incidence rates of lung cancer by histologic type. Following a steadily increasing occurrence during the period 1973 to 1987, adenocarcinoma supplanted squamous cell carcinoma as the most frequent form of lung cancer.[285] Several hypotheses have been posited as to the underlying cause of this shift, but recent data suggest that changes in smoking behavior and cigarette design are major contributors.[286]
Presurgical Evaluation
Physiologic Evaluation
The physiologic evaluation must be individualized for each patient but generally emphasizes the pulmonary and cardiac function, and follows a stepwise progression. In some cases, history, physical examination, and routine spirometry are all that is required for physiologic assessment. For many patients further physiologic assessment is indicated before pulmonary resection. The assessment of an individual's ability to tolerate lung resection from a cardiopulmonary standpoint is fundamental to patient selection for surgery. Persons with advanced pulmonary disease and severe pulmonary dysfunction may have prohibitive risk in greater than one third of patients with otherwise resectable disease.[287] The most oncologically sound and perfectly executed operation for lung cancer falls far short of success in the event of a major cardiopulmonary complication or severe long-term functional detriment.
Smoking Cessation
Cigarette smoking is associated with an increase of as much as sixfold in the incidence of postoperative pulmonary complications after surgery.[288] Although there are few studies specific to pulmonary resection, there is evidence that preoperative smoking abstinence of 4 to 8 weeks’ duration is necessary to reduce the incidence of complications. [288] [289] Interestingly, higher rates of complications occur for patients who cease smoking within fewer weeks of surgery as compared with those who continue to smoke. In evaluating the current smoker with NSCLC for potential resection, the powerful addictive properties of cigarette smoking must be recognized. Individuals should be offered pharmacologic adjuncts (discussed earlier) and should be enrolled in a formal tobacco cessation program before consideration for resection. Wherever possible, smoking should cease a minimum of 4 weeks before surgery. Whether or not to offer resection to individuals with NSCLC who continue to smoke is a subject of controversy among thoracic surgeons. Whatever a particular surgeon's approach to this group, the significant deleterious effect of cigarette smoking on outcome must be recognized. Furthermore, an individual's success in preoperative tobacco cessation may reflect his or her commitment to recovery and compliance with further therapy.
Nutritional Status
Weight loss and malnutrition are very common among individuals with NSCLC. In a recent study[290] more than 40% of patients undergoing resection for NSCLC had a body mass index and skin fold thickness below the twenty-fifth percentile. Poor nutrition in surgical patients correlates with impaired wound healing and a greater propensity to postoperative infection.[291]
Impact of Age
Advanced age is an independent predictor of mortality after resection for NSCLC.[292] With recent advances in patient selection and perioperative care, however, lung resection may be performed with acceptable rates of morbidity and mortality in patients well beyond the age of 70 years. Advanced age does predict a higher incidence of perioperative cardiovascular complications, but age reflects a surrogate marker for additional comorbidities rather than an independent risk factor. [292] [293]
Spirometry and Pulmonary Diffusion Capacity
Spirometry is mandatory for patients under consideration of pulmonary resection for NSCLC and provides an objective assessment of pulmonary function. The forced expiratory volume in 1 sec (FEV1) is the historical standard to determine suitability for resection; a predicted postoperative FEV1 (ppoFEV1) can be estimated based on the planned extent of resection:
FEV1 is an independent predictor of mortality from surgery for lung cancer[294] and serves as the primary determinant of the need for further physiologic assessment before surgery for NSCLC. The criteria of ppo FEV1 of at least 0.8 L has been widely used in decisions for lung cancer resection.[295] However, an absolute value of FEV1 predicts postresection pulmonary function less accurately than FEV1expressed as a percentage of the expected value for age and size.[296] The use of absolute FEV1 measurements in patient selection may bias against older individuals, those of small stature, and females.[297]Nevertheless, patients with an absolute FEV1 of greater than 2.0 L are likely to tolerate pneumonectomy, and those with FEV1 over 1.5 L have adequate pulmonary reserve for lobectomy. [298] [299] Patients deemed unable to tolerate lobectomy from a pulmonary functional standpoint may be candidates for more limited resections, such as wedge or anatomic segmental resection, although such procedures are associated with significantly higher rates of local recurrence and a trend toward decreased survival, [300] [301] or from minimally invasive techniques and improved postoperative pain management techniques (patient-controlled analgesia, epidural anesthesia, etc.)
Pulmonary diffusing capacity for carbon monoxide (DLCO) is an adjunctive test to spirometry and lung volume measurements. DLCO provides a measurement of the lung surface area available for gas exchange and is determined by measuring expired carbon monoxide levels during controlled exhalation. Variability in the DLCO may be as much as 12% or greater. The DLCO measures the rate at which test molecules such as carbon monoxide move from the alveolar space to combine with hemoglobin in the red blood cells. The DLCO is determined by calculating the difference between inspired and expired samples of gas. DLCO levels below 50% are associated with increased perioperative risk.[302] A low DLCO reflects the presence of emphysema, fibrosis, or pulmonary vascular disease. Similar to FEV1, preoperative DLCO measurement is most useful when expressed as a percentage of predicted value [297] [299] [302] and may be used to estimate predicted postoperative DLCO (ppoDLCO).
Cardiopulmonary Exercise Testing
Cardiopulmonary exercise testing (CPET) can be extremely useful in the evaluation of marginal candidates (ppoFEV1 or ppoDLCO <40% predicted) or for patients who appear more disabled than expected from simple spirometry measurements. [303] [304] Formal CPET includes exercise electrocardiography, heart rate response to exercise, and the measurements of minute ventilation and oxygen uptake per minute. CPET allows a calculation of maximal oxygen consumption (VO2max) and provides insight into overall cardiopulmonary function (the cardiopulmonary axis) that cannot be ascertained from other objective studies. CPET may identify clinically occult cardiac disease and may provide a more accurate assessment of pulmonary function than spirometry and DLCO, which tend to overestimate functional loss after resection. [303] [304] A patient's risk of perioperative morbidity and mortality may be stratified by VO2max. Those with VO2max above 20 mL/kg/min are not at increased risk for complications or death after resection of NSCLC. A level below 15 mL/kg/min is associated with an increased risk, and VO2max less than 10 mL/kg/min indicates very high risk, generally precluding operation. [297] [305] [306] [307]
Quantitative Perfusion Study
Quantitative radionucleotide perfusion scanning involves the injection of 99mTc-radiolabeled albumin particles, followed by the visual inspection of planar images. Unlike perfusion scanning in the setting of suspected pulmonary thromboembolism, concomitant ventilation scanning is not routinely performed for preoperative assessment, because studies have demonstrated that both are usually well matched and equally effective in assessing function. Quantitative perfusion provides a measurement of the relative function of each lobe and lung, allowing a prediction of pulmonary function after lung resection:
Quantitative perfusion studies may be useful in selecting patients with marginal pulmonary reserve for resection. Like FEV1 and DLCO, quantitative perfusion studies tend to slightly underestimate actual postoperative function, erring on the side of safety in the selection of patients for resection.[308] A recent study compared quantitative perfusion studies to the segment-counting technique and reported no difference in the predictive value for the assessment of postoperative pulmonary function.[296] The study of quantitative perfusion is therefore most useful when there is clinical suspicion that the area of planned resection is not contributing homogeneously to lung function, such as in the setting of heterogeneous emphysema or an obstructive process.
Arterial Blood Gas Analysis
Arterial blood gas analysis is not a mandatory component of preoperative assessment for lung resection. It may be indicated in marginal candidates, or if there is a clinical suspicion of significant hypoxia or carbon dioxide retention.
Informal Exercise Assessment
Observed performance during stair climbing has historically been practiced in the preoperative assessment of patients with lung cancer. Stair-climbing ability has some correlation with values on spirometry[297] [309] but perhaps is most correlated with a person's global cardio pulmonary status and determination,[309] both of which are fundamental to a successful outcome after surgery. This modality has not been standardized in duration, extent, or technique, and studies thus far represent limited single-institutional experiences. Given the wide availability of more objective and standardized noninvasive tests for cardiopulmonary function, stair-climbing performance should not be used as the sole criterion to determine physiologic suitability for lung cancer resection.
Cardiovascular Status
Cardiovascular evaluation should conform to American College of Cardiology and American Heart Association guidelines for noncardiac surgery.[310] Patients with greater than one major risk factor for coronary artery disease, those with prior cardiac interventions, and those whose functional limitations preclude adequate assessment for angina should be evaluated further. Preoperative electrocardiography should be performed in all patients, and echocardiography is indicated in all patients with a heart murmur, clinical features suggestive of congestive heart failure, or unexplained dyspnea. Echocardiography is also a useful initial evaluation for clinically suspected pulmonary hypertension, which represents a contraindication to lung resection. Pulmonary resection for NSCLC should generally not be undertaken within 6 weeks of an acute myocardial infarction. Patients with a prior history of cerebrovascular events and those with cervical bruits on physical examination should be assessed by carotid Doppler studies and referred for vascular consultation as appropriate.
Effects of Induction Chemotherapy
Patients who have received chemotherapy for NSCLC before surgery typically have more advanced-stage disease and may require greater extent of resection than early-stage disease. There seems to be no significant difference for stage-matched patients who receive induction chemotherapy followed by resection compared to those with resection alone.[311] Malnutrition and current cigarette smoking must be recognized as potentially reversible risk factors for complications after resection and should be modified where possible. It is unclear whether deferral of surgery for any prescribed interval after the completion of chemotherapy may offset some of these deleterious effects. Although induction therapy is not the current standard for NSCLC, many institutions have adopted its use in selected patients with stage IIIA disease. The thoracic surgeon must be aware of the increased attendant perioperative risk, which should be part of the global assessment of a patient's fitness to undergo surgery.
In summary, every person with potentially resectable NSCLC must be carefully assessed by the thoracic surgeon for his or her physiologic fitness to undergo surgery, because patients with severe cardiopulmonary deficiency are at a predictably increased risk for major complications and death after resection. All patients should be assessed for cardiovascular risk using American College of Cardiology and American Heart Association guidelines. Spirometry allows a determination of ppoFEV1, and DLCO should be liberally used as an adjunct to spirometry measurements. Patients with a ppoFEV1 or ppoDLCO below 40% of expected values should be further evaluated with CPET. At institutions where CPET is not available, supervised stair-climbing assessment may be an acceptable alternative means for assessment. Quantitative perfusion scanning should be considered in patients with marginal ppoFEV1 or ppoDLCO, particularly where heterogeneous pulmonary function is clinically suspected. There are several studies reporting acceptable outcomes for lung resection in patients with preoperative measurements well below accepted standards, [312] [313] and no single test result should be viewed as an absolute contraindication to surgical resection for NSCLC. Although the physiologic assessment of a patient with normal spirometry and minimal comorbidity is fairly straightforward, patients with marginal preoperative indices must be considered on an individual basis. Surgical decision making in this patient population should incorporate input from the pulmonologist and medical oncologist. The decision whether to pursue lobectomy, limited resection, or primary nonoperative treatment of NSCLC is made best under the guidance of this multidisciplinary team.
Surgical Management of Non-Small Cell Lung Cancer
Since the introduction of the pneumonectomy for extirpation of lung cancer, surgeons and surgical resection have played a pivotal role in the management of early-stage NSCLC.[314] However, in the last 2 decades the management of NSCLC has become a multidisciplinary process involving not only surgeons but also pulmonologists, pathologists, radiologists, radiation oncologists, and medical oncologists. Notably, however, thoracic surgeons retain a key role in the management of all stages of lung cancer from premalignant lesions to the management of selected individuals with advanced stage IV disease.
Surgical management of NSCLC is multifaceted and entails the invasive staging for optimal therapeutic decisions, extirpation of the local disease with mechanical and other physical strategies, alone or in combination with chemotherapy or radiation therapy, and management of the physical sequelae of progressive neoplastic growth with dyspnea from airway compromise, pleural effusion, or other consequences. Fundamentals of surgical management of NSCLC include complete resection of the tumor with negative margins, systematic mediastinal lymph node dissection, and integration of the multidisciplinary team in all but the most early or late stages of disease (i.e., clinical stage IA or metastatic disease, respectively). Ideally NSCLC should be managed by a thoracic surgeon trained in the management of thoracic neoplasms and their sequelae. Both the skill of the surgeon and the volume of procedures performed at a particular facility significantly influence survival following lung cancer surgery. [315] [316] Experienced thoracic surgeons working in facilities that perform a high volume of procedures invariably have better outcomes than nonthoracic surgeons and/or thoracic surgeons and nonthoracic surgeons operating in facilities that perform a low volume of lung cancer operations. [315] [316] The thoracic surgeon cannot eliminate perioperative risk but can manage it by optimizing patient selection, and various parameters for patient preparation, intraoperative care, and convalescence. Resection of lung cancer can be done with low mortality by experienced thoracic surgeons (i.e., <1.5% mortality rates), as demonstrated in a recently completed multi-institutional prospective randomized trial of over 1000 patients evaluating mediastinal lymph node dissection versus node sampling.[315]
Although the extant International Staging System is undergoing revision, the current iteration has served surgeons well since its publication in the late 1990s (see Table 76-7 ).[280] Clear survival differences are demonstrable by stage as determined by differences in tumor size and location, characteristics of hilar, mediastinal, or other nodal groups, and presence or absence of metastatic disease. Patients are selected for a specific treatment on the basis of the clinical stage as determined by the clinician's best and final estimate of the extent of the NSCLC based on all available data before the initiation of definitive therapy. Consequently treatment decisions require accurate and complete staging as an integral component of pulmonary resection for lung cancer. For postoperative treatment decisions, mediastinal lymphadenectomy determines pathologic stage and provides information about potential survival and the need for postresection therapy. The pathologic stage of the tumor most accurately defines the overall and disease-free survival.
Without question, surgical resection of NSCLC provides the best opportunity for cure and offers the greatest potential for prolonged survival.[314] Historically, a pneumonectomy was considered the only procedure that reliably achieved complete resection. However, with the advent of more detailed staging as outlined previously, coupled with more specific survival data, less aggressive surgical resections have been performed for early-stage NSCLC, with improvements in postoperative morbidity and mortality. Currently, patients with stages I, II, and select IIIA (T3N1) NSCLC, as determined by preoperative imaging and staging strategies, are candidates for attempting pulmonary resection in the absence of other contraindications to surgery. In some parts of the world individuals with known mediastinal nodal involvement (i.e., N2 disease) also are treated with resection. However, in North America and much of Europe, individuals with known N2 disease are typically treated without primary surgical intervention, although selected patients may undergo surgery as part of a multidisciplinary approach. [314] [317] The surgical procedure of choice is a thoracotomy and complete resection to obtain negative surgical margins via lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy depending on tumor burden and location.[314] Moreover, recent data demonstrate that postoperative chemotherapy is beneficial in selected patients with completely resected stages II and IIIA disease and very possibly in some patents with stage IB disease. The subject of adjuvant and neoadjuvant therapies is covered in greater detail immediately after the following brief overview of the surgical management of some of the more common and not so common presentations of NSCLC.
Occult Lung Cancer
Screening for second aerodigestive malignancies can result in identification of CIS or microinvasive tumor by flexible bronchoscopy. These occult lung cancers (Tx-TisN0M0) occur without symptoms or other radiographic finding and may be treated with endoluminal therapy. However, most patients would be considered for resection with segmentectomy or lobectomy. The choice of anatomic resection must be carefully considered, because field cancerization may exist with many involved areas present. Mucosal ablating techniques include photodynamic therapy, brachytherapy, electrocautery, cryotherapy, and neodymium-yttrium-garnet (Nd-Yag) laser therapy.[318]
Stage I Lung Cancer
Stage I NSCLC includes individuals with a T1 or T2 primary tumor designation and no evidence of hilar or mediastinal nodal disease (N0) or metastatic spread (M0). Medically fit persons with stage I disease should be considered for aggressive local therapy, and curative treatment is possible with 5-year survival rates ranging from 45% to 70% in most series depending in large part on tumor size and whether or not pleural invasion is found. [314] [319] Surgical resection is the accepted treatment for individuals with stage I disease. [314] [320] [321] Only rarely is a pneumonectomy necessary in stage I NSCLC. Lobectomy is usually sufficient to achieve negative surgical margins and is considered the surgical preferred approach, although lesser resections (wedge, segmentectomy, etc.) have advantages in persons with limited pulmonary reserve. [322] [323] Compared with a lobectomy, a segmental resection tends to spare pulmonary reserve without significant impairment of survival, although additional local control measures are needed. [324] [325] Iodine-125 brachytherapy mesh applied to the suture line may be helpful in decreasing local recurrence. [326] [327] Notably, video-assisted thoracic surgery (VATS) techniques have advanced to a common level commensurate with safe anatomic resection of parenchymal neoplasms and lymph node sampling. [328] [329] Anatomic resection (open or VATS) is preferred to a wedge resection of NSCLC, because the latter is associated with increased rates of local recurrence.[325] In experienced hands, VATS is associated with low morbidity and mortality, and the risk of intraoperative bleeding or recurrence in an incision is minimal.[328] Moreover, VATS is associated with less postoperative immunosuppression compared with the thoracotomy approach.[330] However, the clinical relevance of better preserved cellular immunity in the early postoperative period is unclear. There are insufficient data to suggest that one method of resection (open thoracotomy, minimally invasive techniques) is superior to another.
Accurate pathologic staging in stage I disease requires adequate segmental, hilar, and mediastinal lymph node dissection. [331] [332] The performance of a systematic sampling or full mediastinal lymph node dissection may improve pathologic staging but is unproven therapeutically.[321] Mediastinal lymph node dissection provides for a significantly larger amount of material, which can refine pathologic (nodal) stage determination. On the right side, mediastinal stations 2R, 4R, 7, 8R, and 9R should be dissected; on the left side, stations 5, 6, 7, 8L, and 9L should be dissected. Hilar lymph nodes are typically resected and sent with the specimen, although it is helpful to specifically dissect and label level 10 lymph nodes when possible. On the left side, level 2 and sometimes level 4 lymph nodes are generally obscured by the aorta. Mediastinal lymph node dissection optimizes the accuracy of the pathologic stage and provides information to the clinician as to potential survival and the need for postresection therapy. [331] [332] Although the therapeutic benefit of nodal dissection versus nodal sampling remains controversial, in a recent pooled analysis of three trials, 4-year survival was superior in individuals undergoing resection with stage I through IIIA NSCLC who had complete mediastinal lymph node dissection compared with lymph node sampling (hazard ratio [HR] 0.78; 95% confidence interval [CI], 0.65 to 0.93).[333] Moreover, a complete mediastinal lymphadenectomy adds little morbidity to a pulmonary resection for lung cancer.[315] Thus, the recommendation is that patients should have a complete mediastinal node dissection.
Although the cost effectiveness of surveillance is not well established, many surgeons choose to follow patients with resected stage I NSCLC for the development of a second primary tumor. [334] [335]About 5% of stage I NSCLC patients will develop a second primary cancer (incidence = 1.99/100 patient-years), [336] [337] and surgical intervention in such cases may prove beneficial.[338]
Stage II Lung Cancer
Clinically stage II patients are often misclassified as stage I disease. Stage II NSCLC is a heterogeneous classification covering patients with T1–2N1 or T3N0 tumors. Stage II composes only 5% of all NSCLC based on clinical assessment alone.[339] By definition, patients with tumor invading the chest wall apex, mediastinum, diaphragm, pericardium, phrenic nerve, azygos vein, or right or left pulmonary artery or even the mainstem bronchus have T3 tumors. [339] [340] Stage II patients with N1 metastases may require more aggressive surgical strategies to remove all evidence of tumor. For example, one recent retrospective series of 124 patients with T1N1 or T2N1 disease suggested a survival advantage with pneumonectomy compared with a lobectomy in patients with hilar (level 10) lymph node involvement,[341] a finding supported by a lower local recurrence rate in the pneumonectomy patients. The risks of pneumonectomy must be considered for these individuals, because nodal metastasis at level 10 often portends occult distant metastases more so than inadequate local control. The relatively poorer survival as compared with stage I disease had prompted several clinical trials specifically for this subgroup of patients.
Mainstem Bronchus Tumor Less Than 2 Cm from the Carina
Even when the NSCLC lesion is located in the proximal airway a complete resection is feasible in some cases. Although pneumonectomy can be performed, specific techniques that spare noninvolved lung parenchyma are preferred. [314] [342] These parenchymal sparing procedures include sleeve resection, bronchoplasty, pulmonary artery sleeve resection, pulmonary arterioplasty, and tracheal resection/reconstruction. Candidates for these procedures must be carefully staged by contrasted CT and bronchoscopy so as to permit surgical airway reconstruction.[314] Bronchial sleeve resection with or without pulmonary artery resection and reconstruction can be accomplished with excellent results and good long-term survival. [343] [344] [345] Morbidity, mortality, and functional data suggest that such reconstructions are comparable to lobectomy in terms of pulmonary function. Parenenchymal sparing techniques are infrequently required; however, they may be critical in individuals with marginal pulmonary reserve, and highly desirable in all others. Persons with N2 metastasis should not undergo thoracotomy. Five-year survival with complete resection is approximately 50%. [343] [344] [345]
Superior Sulcus Tumors
Superior sulcus tumors are apical masses that often extend to involve the chest wall, upper ribs, vertebral body, brachial plexus, stellate ganglion, or subclavian vascular structures.[346] These tumors account for roughly 3% of all NSCLC and always should be considered for surgery to improve function and relieve pain. Extension of apical tumors into the thoracic inlet may be accompanied by shoulder and/or arm pain, Horner syndrome, and occasionally paresthesias in the ulnar nerve distribution of the hand (fourth and fifth fingers). Patients with all these characteristics may be classified as having Pancoast syndrome. [346] [347] Pain arises from involvement of the C8 and T1 nerve roots, whereas Horner syndrome (miosis, ptosis, anhidrosis, and enophthalmos) is caused by sympathetic nerve involvement. Frequently the first, second, and third ribs are involved, requiring resection.[347] Reconstruction of the defect is not required because the scapula and arm protect the defect. CT and MRI are used to assess treatment options. Reportedly, the complete resection (50%) and the 5-year survival (30%) rates for superior sulcus tumors have not changed for over 4 decades.[348] Historically superior sulcus tumors were treated with external beam irradiation (30 Gy) to the primary tumor before resection. However, no prospective trial has proven the benefit of this therapy over surgery alone, and several disadvantages may occur. The usual dose of irradiation is inadequate to completely control most tumors, and accelerated repopulation may occur. If negative surgical margins are not achieved, subsequent attempts to obtain local control via further irradiation can prove problematic. Resection of tumors abutting or invading the brachial plexus after radiation therapy also can be challenging. Finally, definitive postresection radiation therapy can be performed easily. In one retrospective review of 143 superior sulcus tumors, overall 5-year survival was 47% for stage IIB, 14% for stage IIIA, and 16% for stage IIIB superior sulcus tumors. Individuals without gross residual disease after surgical resection who received postoperative radiation therapy with total doses of 55 to 64 Gy had a 5-year survival rate of 82% as compared with the 5-year survival rate of 56% in persons who received 50 to 54 Gy.[349]
Because combined-modality therapy has improved outcome in other subsets of locally advanced NSCLC the North American Intergroup tested the feasibility of induction chemoradiation and surgical resection in superior sulcus tumors with the ultimate aim of improving resectability and survival.[348] Individuals with mediastinoscopy-negative superior sulcus tumors received two cycles of cisplatin and etoposide with concurrent irradiation (45 Gy), followed by resection 3 to 5 weeks later. More than 90% of patients had a complete resection, and postoperative mortality was 2.4%. A complete pathologic response or microscopic residual disease only was noted in 65% of all resected specimens. Two-year survival was 55% for all patients and 70% for patients with an R0 resection. Local failure rates are improved with this strategy. Systemic failure, mostly cerebral metastases, occurs in about 25% of patients. Although this approach has not been compared to surgical intervention with or without postoperative irradiation, it has become the default standard of care for patients meeting the eligibility criteria of this study. Accordingly we believe a multidisciplinary approach is warranted in all cases of superior sulcus tumors with attention to the need for preoperative induction therapy and the use of alternatives to surgery (e.g., definitive chemotherapy and radiation therapy) for medically inoperable patients.
Mediastinal Involvement
Mediastinal involvement is generally identified at the time of operation with tangential involvement of the mediastinal pleura, pericardium, phrenic nerve, or mediastinal fat. Complete resection of the primary tumor en bloc with the mediastinal structure is recommended in an otherwise suitable patient. Unilateral phrenic nerve resection is appropriate if negative margins can be achieved.
Chest Wall Invasion
In the absence of other contraindications to surgery, tumors invading the chest wall should be considered for complete resection. Reconstruction of the chest wall with a muscle flap or patch may also be performed.[350] In the case of pleural invasion and chest wall involvement, en bloc resection is advised over extrapleural resection, because of significantly more favorable survival rates. [350] [351] Long-term survival is stage and sex dependent. The best survival is observed in women who have T3N0M0 disease.[351] Persons found to have N2 disease should be managed with multimodality therapy as outlined later in this chapter. Adjuvant irradiation is not recommended for patients with complete resection of T3 chest wall NSCLC but may be considered for local control in patients with positive resection margins.
Stage IIIA Locally Advanced Lung Cancer
Stage IIIA NSCLC constitutes roughly 30% of all NSCLC patients at diagnosis.[317] It is an extraordinary heterogeneous category of patients with metastatic disease to the ipsilateral mediastinal (N2) lymph nodes and also includes T3N1 patients. Approximately one third of stage IIIA patients present with ipsilateral N2 lymph node metastases. Presentations of disease can range from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky multistation nodal disease. It is the latter group that constitutes one of the more therapeutically challenging and controversial subsets of NSCLC, with a published 5-year survival of only 23%. Accordingly, the management of IIIA NSCLC patients challenges the surgeon and the multidisciplinary team given the heterogeneity of the local disease and the variable, yet common, occult systemic metastasis.
Clinical staging of stage IIIA typically involves both diagnostic imaging and invasive staging. Invasive staging with pathology examination of lymph node or other tissues further describes the extent of the disease needed to optimally determine treatment decisions. Pathologic staging occurs after resection and typically reveals a spectrum of disease extent. Patients with enlarged mediastinal lymph nodes must undergo mediastinoscopy as node size alone does not predict pathologic findings. Patients with positive N2 nodes determined preoperatively should be referred for definitive chemotherapy and radiation therapy, or entry into a prospective clinical trial (which may or may not evaluate resection as a therapeutic intervention; see later discussion). Resection following chemotherapy and radiation therapy, so-called trimodality therapy, should not routinely take place outside of a clinical trial or without a multidisciplinary plan to include resection established before initiation of therapy.
In each situation a spectrum extends from occult, unrecognized IIIA disease (typically identified after resection such as T3 with N1 nodal involvement, or microscopic N2 disease in the mediastinal lymph node dissection specimen) and single-station N2 disease identified by mediastinoscopy or guided by FDG-PET, to multistation and/or bulky mediastinal N2 disease identified by CT, FDG-PET, or mediastinoscopy. If the surgeon finds involved but resectable mediastinal nodal disease at the time of operation, a complete anatomic resection and mediastinal lymph node dissection is recommended. If the individual has many involved N2 stations, or bulky mediastinal disease, then the decision to proceed with resection must balance risk and benefit (e.g., improved local control). If the patient is at high medical risk for resection (advanced disease with poor predicted survival), then the operation should be aborted and concurrent chemoradiation therapy initiated.
“Incidental” N2 Disease
Despite a careful preoperative staging evaluation, as many as a quarter of patients will be found to have metastases to N2 nodes at the time of thoracotomy. [352] [353] [354] Frequently occult N2 disease is identified only at the time of final pathologic examination of the surgical specimen. In other individuals, metastases will be found on intraoperative frozen-section examination of mediastinal nodes. For individuals with an occult, single-station mediastinal node metastasis recognized at thoracotomy in which a complete resection of the nodes and primary tumor is technically possible, most thoracic surgeons proceed with the planned lung resection and a mediastinal lymphadenectomy. If a complete resection is not possible or there is multistation or bulky nodal disease or extracapsular nodal disease, then the planned lung resection should be aborted. These patients can then be considered for multimodality therapy as described later in this chapter. Although incomplete resection rarely results in long-term survival, collected results indicate that surgery alone in stage IIIA disease (N2 disease) is associated with a 14% to 30% 5-year survival. The best survival is seen in cases with minimal N2 disease and complete resection.[354]
“Clinically Evident” N2 Disease
Individuals with stage IIIA clinically evident N2 disease present more of a problem. Induction chemotherapy (±preoperative radiation therapy) has the theoretical attraction of improving the “resectability” of patients with “bulky” N2 disease stage IIIA (N2) disease based on the premise that improved resection rates would translate into improved overall survival. Both small single-institution studies and multi-institutional trials support this possibility. [355] [356] [357] However, such trials are usually inadequately powered to provide definitive proof. Concern vis-à-vis perioperative morbidity has limited this approach to a large extent.[358] More recently data have emerged that suggest induction therapy does not increase the risk of survival complications compared to surgery alone based on a clinical and pathologic stage-specific analysis.[311]
In an important but as yet unpublished North American Intergroup study (INT-0139), individuals with clinical stage IIIA-N2 (T1–3pN2M0) NSCLC, a good performance status (PS) (Eastern Cooperative Oncology Group [ECOG] PS: 0–1) and considered technically resectable at initial evaluation were randomized to induction chemotherapy–radiation therapy followed by surgical resection or chemotherapy–radiation therapy alone.[359] Progression-free survival but not overall survival was improved with resection after induction chemotherapy–radiation therapy. As found in other trials of induction therapy, pN0 status was associated with prolonged survival. Pneumonectomy accounted for 14/15 postoperative deaths and may have compromised overall survival. Thus, the trimodality approach used in this study cannot be considered standard of care for persons with positive N2 disease determined preoperatively. These individuals should be managed with combined chemoradiation therapy as outlined later if they are otherwise physically fit.
A multicenter European trial (EORTC 08941) was designed to determine the optimal local-regional treatment for NSCLC patients with positive N2 involvement.[360] Selected individuals with NSCLC with histologically or cytologically proven stage IIIA (N2) disease were initially treated with three cycles of platinum-based induction chemotherapy. Those individuals who responded to induction chemotherapy were then randomized to a radical resection with lymph node dissection and optional postoperative radiation therapy or thoracic radiation therapy (TRT) alone to a minimal dose of 40 Gy in 2-Gy daily fractions to the mediastinum, with a boost to at least 60 Gy on the involved field. With a median follow-up of 72 months, median (16.4 vs.17.5 months) and 5-year survival rates (16% vs. 13%) were not significantly different between the two arms (HR 0.95, 95% CI 0.75–1.19; P = 0.6).
The downstaging of pN2 to pN0 that may occur with induction therapy seems to be important in identifying patients with improved chances for survival. In a phase II trial conducted by the Southwest Oncology Group (SWOG 8805) persons with clinical stages IIIA or IIIB disease received induction chemotherapy–radiation therapy followed by resection. This strategy provided a pathologic complete response in 22% and an overall 3-year survival rate of 27%. Notably, individuals with no residual mediastinal lymph node involvement had a median survival of 30 months compared with 10 months for those with with residual disease (P = 0.0005).[361] Whether or not patients without pathologic downstaging of N2 disease should undergo surgery is controversial. In a subset analysis of the aforementioned EORTC study 08941, it was determined that failure to downstage to pN0 after induction chemotherapy portended a worse outcome that may be improved with the application of postoperative radiation therapy. However, surgical resection in this subset of patients was not apparently beneficial.[362] These data warrant prospective validation.
Pulmonary resection after induction chemotherapy–radiation therapy presents several technical challenges. For example, patients who have received in excess of 50 Gy during their neoadjuvant treatment have a higher rate of serious complications such as bronchopleural fistula, prolonged air leak with empyema, and prolonged postoperative ventilation; therefore, the dose should be limited to 45 Gy. The sequelae of chemotherapy–radiation therapy include dense fibrous tissue in the hilum and mediastinum, and tissue planes are often obliterated.
Outside of a clinical trial, individuals with bulky or multistation N2 disease should not be considered for trimodality therapy. These individuals are usually treated with alternatives to resection such as chemoradiation (see later discussion). Trimodality therapy should be used only in rare circumstances. Even if mediastinal nodes are downstaged to pN0 the usefulness of surgical resection remains highly questionable.[363] Moreover, although repeat cervical mediastinoscopy can be performed, the risks of this repeat operation after mediastinal chemoradiation therapy are greater than standard mediastinoscopy. Alternatives to the initial mediastinal staging include esophageal ultrasound and transbronchial ultrasound.[364] Without question, resection should be avoided after induction therapy in persons who have biopsy-proven residual tumor in the mediastinal nodes.
Unresectable N2 Disease
In general, individuals with histologically involved lymph nodes larger than 2 cm in short-axis diameter measured by CT, who have extranodal involvement or multistation disease along with groups of multiple involved smaller lymph nodes, are considered to have bulky, unresectable disease. These individuals are referred for protocols involving chemoradiation as described later in this chapter if they are functionally fit to tolerate the therapy.
Stage IIIB Locally Advanced Lung Cancer
Stage IIIB includes individuals with T4, any N, M0, and any T, N3, M0[365] (e.g., tumor invading into the trachea, carina, esophagus, vertebrae, aorta, vena cava, great vessels, or atrium/cardiac structures; any N3 nodal description; malignant pleural effusion; or more than one nodule in one lobe). Resection with or without neoadjuvant chemotherapy or chemotherapy–radiation therapy is typically reserved for those persons with clinical T4-N0-M0 status in whom the tumor can be removed with negative margins (R0 resection). Survival may approach 25% to 30 % at 5 years for selected patients. Individuals with N3 lymph node involvement are not considered as surgical candidates. For those with unresectable disease, good performance score, and minimal weight loss, treatment with combined chemotherapy and radiation therapy has resulted in better survival than treatment with radiation therapy alone. Multiple daily fractions of radiation therapy have not resulted in improved survival compared to standard fractionation once daily.[365] Concurrent chemotherapy–radiation therapy seems to be associated with improved survival compared with sequential chemotherapy and radiation therapy (see later discussion).[365]
Carinal Resection
Tracheal resection and reconstruction for NSCLC is infrequently performed. More commonly, the extent of the disease requires a nonsurgical approach to include radiation therapy, or chemotherapy and radiation therapy. Palliative techniques include mechanical fulguration, laser ablation, or placement of expandable metal stents. Resection is reserved for localized endobronchial disease of the carina or very distal trachea but is contraindicated in the presence of N2 or N3 disease.[366] Resection of the carina with or without right pneumonectomy is performed with anastomosis between the trachea and the left mainstem bronchus. Mediastinoscopy is required and reserved until the operation itself is planned so as to avoid any disruption of blood supply and to facilitate mobilization anteriorly. Consistent success requires excellent surgical technique and meticulous attention to detail. Gentle handling of tissue, avoiding disruption of the tracheal blood supply, anastomosis under no tension, and complete resection of the neoplasm with negative margins are necessary. [343] [366] [367]
Other Mediastinal Structures
Various mediastinal structures may be involved with tumor and may be resected and reconstructed as necessary.[368] The superior vena cava may be resected en bloc with the tumor and reconstructed with primary repair, patch venoplasty, or reconstruction with vascular graft. Limited resection of the left atrium or esophagus for tangential invasion would be appropriate if such resection would provide an R0 resection. The esophageal musculature can be removed, leaving the mucosa intact. Preoperative endoscopy is required for tumors that may abut the esophagus. Resection of the aorta with reconstruction is rarely performed. Individuals with involvement of the vertebral body would require en bloc resection of the tumor and anatomic portion of the lung, with the involved portion of the chest wall and vertebrae.[347] A multispecialty surgical team with thoracic surgery and either neurosurgery or orthopedic surgery, and stabilization of the vertebral column would be needed. Superior sulcus tumors with vertebral invasion can be treated with success.[369] Most patients resected in this small study had received external beam radiation therapy. The absence of perioperative mortality and a 2-year actuarial survival of 54% suggest that benefit can accrue to patients. Tumors that invade the vertebral column can undergo resection with posterior-lateral thoracotomy, lobectomy with en bloc chest wall resection, laminectomy, vertebrectomy, and anterior spinal column reconstruction with methylmethacrylate and spinal instrumentation. [347] [369] Additional studies have examined the outcomes of superior sulcus tumors with a T3 or T4 status.[348] Five-year survival was 46% for stage IIB, 0% for stage IIIA, and 13% for stage IIIB.
Other T4 Presentations
Various other clinical presentations are included in stage IIIB NSCLC. These include satellite nodules, and extrathoracic or contralateral nodal metastasis (N3). A satellite nodule is a separate NSCLC of identical histology contained within the same lobe as the primary tumor. These are resectable with good survival. A satellite nodule is a secondary tumor nodule in the same lobe as the primary cancer having histology identical to that of the primary tumor. These are resectable with 5-year survival of 33%.[370] Such individuals should be carefully staged for occult nodal or distant metastasis. Even with treatment, persons with extranodal or contralateral nodal disease typically have poor survival (15% 5-year survival).[371] Although bilateral nodal dissection has been advocated by some Japanese surgeons, the presence of contralateral mediastinal disease or supraclavicular disease suggests a more widely advanced tumor that would be treated with chemotherapy and radiation therapy. [365] [372]
Malignant Pleural Effusions
Patients with malignant pleural effusions frequently present with dyspnea, cough, and loss of function.[373] Symptomatic treatment is initially achieved via simple and complete drainage by thoracentesis. Those with a good performance status are subsequently managed like individuals with stage IV disease as described later in this chapter. However, many patients have recurrent effusions in which case treatment options may be much more varied. Treatment for individuals with initial or recurrent malignant pleural effusions should focus on relief of symptoms of dyspnea and restoration of normal activity.[373] The traditional practice of arbitrarily requiring pleural symphysis (obliteration of the pleural space), achieved by in-hospital drainage of the effusion followed by sclerosis with chemical or other agents, may subject the individual to a prolonged hospitalization or other interventions that may significantly reduce quality of life and remaining survival time outside the hospital. Persons with cancer frequently develop recurrent malignant pleural effusions secondary to their disease. In 25% of patients with cancer, malignant cells may not be identified by pathologic examination of the fluid. Median life expectancy in cancer patients with malignant pleural effusion ranges from 3 to 9 months depending upon the histologic subtype of the primary tumor. In one prospective randomized study, the median survival time for all persons with malignant pleural effusions was 90 days.[374]
Treatment options for malignant pleural effusion include thoracentesis or repeat thoracentesis; tube thoracostomy, drainage, and sclerotherapy using talc, bleomycin, or other material; placement of a chronic indwelling pleural catheter [374] [375]; and thoracoscopy with drainage and talc insufflation. In the past, successful treatment of malignant pleural effusions required hospitalization for chest tube drainage, sclerosis, and, hopefully, pleural symphysis followed by removal of the drainage catheters. If pleural symphysis could not be achieved during the individual's hospitalization the treatment was considered “failed,” and the patient was then treated with the best available means. Pleurodesis was required for discharge. In contrast, today's patient-centered treatment focuses on relief of the patient's symptoms and restoration of normal function. Pleurodesis is not necessarily required to accomplish these goals.[373]
Stage IV Non-Small Cell Lung Cancer
In individuals with metastatic NSCLC, surgery is reserved for palliation of symptoms or resection of metastases with significant local manifestations (e.g., brain metastasis and seizures).[376] Persons with two synchronous nodules of NSCLC with identical histology in different lobes have M1 disease by the current staging system, although it is impossible to exclude synchronous stage I NSCLC by clinical means alone. When doubt exists, the benefit of resection should be considered in selected physiologically fit individuals. Appropriate staging with CT and PET scanning and cervical mediastinoscopy is required. If there is no evidence of nodal or other metastatic disease, and the nodules are completely resectable with an appropriate risk-to-benefit ratio, then resection could be considered. [377] [378]
Brain metastases are often seen in individuals with NSCLC, and although they are frequently multiple, a subset of patients with a solitary brain metastasis (with controlled primary tumor) is occasionally encountered in clinical practice. Patients with isolated brain metastases may do well with resection of the symptomatic lesion. [379] [380] Although treatment of a solitary brain metastasis is usually surgical whenever possible, the development of new stereotactic techniques of radiation therapy using a linear accelerator or the gamma knife provides new potential treatment options.[381] Before resection all patients should have additional staging to include CT and PET scans. In those considered as candidates for resection, cervical mediastinoscopy should also be performed even if the preoperative CT reveals no enlarged nodes, and the PET demonstrates no FDG-avid lesions. The primary lung tumor is then treated according to T and N stage. [379] [380] Survival may range between 20% and 40% at 5 years.
Hematogenous metastases to the adrenal gland and elsewhere, in general, portend a poor survival, and although isolated reports of resection have occurred, this treatment strategy is not uniformly successful. [376] [382] [383] [384] Resection of metastatic lung cancer with curative intent is not recommended, because adrenal and other extrathoracic metastases represent systemic metastases.[382] The curious survival advantage seen in some patients may be related to overdiagnosis bias in individuals with early primary-stage disease.
Experimental Surgical Techniques
Experimental techniques for treatment of parenchymal NSCLC in medically inoperable individuals include radiofrequency ablation and stereotactic thoracic radiation. [385] [386]
Second Primary Tumors or Metastasis
Recurrent tumors may be resected safely and with good survival. Generally, lung cancer that recurs with identical histology within 2 years is considered a metastasis; lung cancer that recurs after 2 years is considered a second primary. Patients with resection of second (metachronous) primary lung cancers can have up to 5-year survival of 40% after resection that is based on the T and N status of the second primary. [336] [338] [387] A completion pneumonectomy, if required, can be performed safely, with good local control achieved, and as much as a 25% 5-year survival.
In summary, the thoracic surgeon must balance the risks from mechanical extirpation of lung cancer (local disease control, pain relief, improved survival) and the benefits of improvement in survival and quality of life. Typically, when the risks are high, resection is not considered; however, in some high-risk patients risk may be successfully managed with good local control and survival.[314] Resection of NSCLC can be performed safely in most individuals who meet certain minimal physiologic thresholds. Consistency of approach, application of proven intraoperative and perioperative techniques, completeness of resection, and adequacy of mediastinal lymph node dissection all benefit the patient in optimizing local control and subsequent therapeutic decisions. Selection of optimal surgical treatment for individuals with NSCLC requires excellent pretreatment staging and clinical evaluation with discussion of all therapeutic possibilities by the integrated multidisciplinary care team: thoracic surgeon, pathologist, pulmonologist, radiation oncologist, medical oncologist, and allied specialties. Individuals with advanced-stage lung cancer (i.e., stage IIIA or greater, biopsy-proven N2, etc.) inconsistently benefit from resection alone, because the risks of resection frequently do not exceed the benefits.[314] In selected individuals resection of advanced-stage lung cancer may be desirable for local tumor control (alone or as part of a multidisciplinary treatment plan), palliation of symptoms, improved quality of life, and the potential for improved survival. Few prospective multi-institutional clinical trials have specifically addressed surgery compared to other therapies for early-stage disease. Future clinical trials should consider accurate and noninvasive measures of local control and recurrence, specific measures of response, quality-of-life measures, as well as overall and disease-free survival.
Adjuvant Chemotherapy
Until recently convincing evidence supporting the routine use of postoperative adjuvant chemotherapy in resected NSCLC was lacking. Notably, an evaluation of adjuvant studies completed before 31 December 1991 was included in a landmark 1995 meta-analysis of 52 randomized chemotherapy trials in NSCLC.[388] Globally no improvement in overall survival was identified following postoperative chemotherapy. However, when the data were analyzed by composition of the adjuvant chemotherapy regimen, there was a nonsignificant 13% reduction in the risk of death observed with platinum-based regimens that translated into an absolute survival benefit of 5% at 5 years (P = 0.08).[388] The magnitude of the survival benefit was similar to that observed with adjuvant chemotherapy in early-stage breast cancer,[389] prompting several groups to initiate a new series of adjuvant trials in NSCLC using a newer and more efficacious generation of platinum-based chemotherapy regimens. [390] [391] [392] [393] [394] [395] [396] A few of the recent studies also permitted the use of postoperative radiation therapy. Meta-analyses of these data estimate a relative risk reduction in mortality of 11% to 13% at 5 years. [397] [398] [399] Collectively the results of these trials clearly support the use of postoperative therapy in individuals with good performance status with stage II or IIIA NSCLC ( Table 76-9 ). [400] [401] [402]
Table 76-9 -- Results of Recent Postoperative Adjuvant Trials in Non-Small Cell Lung Cancer
|
Trial |
Stage |
Treatment |
No. of Patients |
5-Yr Survival (%) |
HR |
P Value |
|
ALPI[390] |
I–III |
Surgery |
540 |
45 |
0.96 |
0.59 |
|
MVP |
548 |
50 |
||||
|
IALT[391] |
I–III |
Surgery |
935 |
40.4 |
0.86 |
<0.03 |
|
CDDP-based |
932 |
44.5 |
||||
|
ANITA[394] |
IB–IIIA |
Surgery |
433 |
42.6 |
0.80 |
0.017 |
|
CDDP + VNB |
407 |
51.2 |
||||
|
BLT[396] |
I–IIIA |
Surgery |
189 |
58[†] |
1.02 |
0.90 |
|
CDDP-based |
192 |
60[†] |
||||
|
NCI-C[393] |
IB–II |
Surgery |
240 |
54 |
0.60 |
0.03 |
|
CDDP + VNB |
242 |
69 |
||||
|
CALGB[395] |
IB |
Surgery |
171 |
57 |
0.80 |
0.10 |
|
CBDCA + Pac |
173 |
59 |
||||
|
JLCRG[392] |
IA–B[*] |
Surgery |
488 |
85 |
0.71 |
0.047 |
|
UFT |
491 |
88 |
||||
|
Roselli et al[406] |
IB |
Surgery |
70 |
42 |
NR |
0.02 |
|
CDDP + E |
70 |
62 |
|
CDDP + E, cisplatin + etoposide; CDDP + VNB, cisplatin + vinorelbine; CBDCA + Pac, carboplatin + paclitaxel; MVP, mitomycin, vinblastine, cisplatin; UFT, uracil-tegafur. |
|
* |
Adenocarcinomas only. |
|
† |
2-year survival. |
Much less clear and far more controversial is the role adjuvant chemotherapy plays in the management of individuals with resected stage I NSCLC. [401] [402] [403] The controversy stems in part from subgroup analyses of recently completed adjuvant trials data that suggest stage I patients do not obtain a meaningful survival improvement following postoperative chemotherapy. [393] [394] This is somewhat surprising, in that extrathoracic metastases are the most common site of recurrence in resected individuals with stage I disease,[404] and one would predict a favorable effect with systemic therapy. Nonetheless, the verisimilitude of the subgroup analyses was bolstered by the negative results of a Cancer and Leukemia Group B (CALGB 9633) phase III trial that specifically addressed the utility of adjuvant chemotherapy in stage IB NSCLC. [395] [405] Although the initial report of the CALGB study indicated that postoperative carboplatin and paclitaxel imparted a significant survival advantage compared with no adjuvant therapy,[405] the survival benefit was no longer apparent upon longer follow-up.[395] Five of the adjuvant chemotherapy trials listed in Table 76-9 were included in a recent meta-analysis [390] [391] [393] [394] [396]—the so-called Lung Adjuvant Cisplatin Evaluation (LACE) analysis.[398] Despite the increased statistical power, there was not a survival benefit among individuals with stage I NSCLC. In fact, there was a trend toward detriment with treatment in persons with stage IA disease. The effect of adjuvant chemotherapy in stage IB disease seemed to be neutral.
Three of the post-1995 meta-analysis adjuvant trials specifically addressed the question of postoperative chemotherapy in resected stage I NSCLC, [392] [395] [406] whereas a fourth study was limited to persons with stages IB and II disease.[393] None of the stage I-only adjuvant trials was included in the LACE meta-analysis.[398] Two of these trials demonstrated a statistically significant improvement in survival in stage I individuals given adjuvant chemotherapy. [392] [406] Only the CALGB 9633 proved negative for a survival improvement, although interestingly disease-free survival was statistically significantly improved with chemotherapy.[395] Collectively the data derived from studies confined to stage I NSCLC suggest there may be some patients with stage I disease who benefit from adjuvant chemotherapy. This is not too surprising, because stage I NSCLC is a heterogeneous disease that in some circumstances carries a prognosis that rivals that of stage II or stage IIIA disease (e.g., large primary lesions >5 cm; visceral pleural involvement). [407] [408] Adjuvant therapy may be appropriate for such individuals, provided he or she understands the risks of treatment. Our approach to resected stage I NSCLC is outlined in the accompanying algorithm ( Fig. 76-15 ).
|
Figure 76-15 Algorithm for selecting stage I NSCLC patients for postoperative adjuvant chemotherapy. CCI, Charlson Comorbidity Index; ECOG, Eastern Cooperative Oncology Group; LND, mediastinal lymph node dissection; LNS, systematic mediastinal lymph node sampling; LVI, lymphovascular invasion; PS, performance status; Rx, treatment; VPI, visceral pleural invasion. |
There are several promising technologies on the horizon that may soon permit oncologists to prospectively assign persons with NSCLC into “good” or “bad” survival categories and help guide treatment decisions. [76] [78] [81] However, until these newer technologies are proved to be reliable predictors of treatment response and survival, clinical judgment is still required when making a decision to offer adjuvantchemotherapy to individuals with resected NSCLC. Most experts agree that adjuvant therapy should be limited to those with a good performance status (i.e., ECOG PS = 1), few comorbidities, and a relatively short postoperative recovery period (i.e., <8 weeks). [400] [401] [402]
Adjuvant Radiation Therapy
Individuals with resected node-negative lung cancer do not benefit from adjuvant radiation therapy. [4] [409] [410] [411] Likewise, randomized trials studying the efficacy of adjuvant radiation therapy after surgical resection of persons with N2 disease have shown no improvement in survival. [411] [412] A recent clinical trial studied overall survival, progression-free survival, and toxicity associated with concurrent paclitaxel plus carboplatin and TRT for patients with completely resected stage II and IIIA NSCLC.[413] Eighty-eight eligible individuals had surgical resection for pathologic stage II or IIIA disease and received postoperative paclitaxel and carboplatin. Concurrent TRT at 50.4 Gy in 28 fractions for 6 weeks was given. A boost of 10.8 Gy in six fractions was given for extracapsular nodal extension or T3 lesions. The median overall survival time was 56.3 months, with 1-, 2-, and 3-year survival rates of 86%, 70%, and 61%, respectively. Local failure was a component of first failure in 15% of these individuals. Our current practice is to consider postoperative radiation therapy when surgical resection is incomplete (positive surgical margins), surgical margins are close (≤1 mm), or when there is extracapsular extension from lymph node metastases.
Neoadjuvant Chemotherapy
Neoadjuvant or induction chemotherapy offers several potential advantages compared with adjuvant chemotherapy, such as improved compliance and drug delivery, early control of micrometastases, and reduction of the primary tumor size before surgery, thus allowing for more conservative and possibly complete resection of the tumor. [414] [415] [416] Several phase II clinical trials have shown that induction chemotherapy is safe and feasible, with no significant increase in surgical complications, and results in favorable survival rates in persons with resectable NSCLC (see reviews [414] [415] [416]). Improved survival is seemingly greatest in individuals in whom a complete pathologic response is achieved.[417] Randomized neoadjuvant chemotherapy trials, however, have revealed conflicting results. [418] [419]
Initial enthusiasm for neoadjuvant chemotherapy originated in part with the publication of two small randomized trials conducted exclusively in persons with N2-positive stage IIIA NSCLC. [356] [357]Although these trials closed prematurely as a result of accrual problems, both studies yielded a positive survival advantage with neoadjuvant therapy. Subsequently, two larger phase III trials were undertaken in an attempt to validate these results and extend the observation with earlier stage, resectable NSCLC. [355] [420] The first of these was conducted by the French Thoracic Cooperative Group in which individuals with stage I through IIIA NSCLC were randomized to surgery or surgery combined with two cycles of neoadjuvant mitomycin, ifosfamide, and cisplatin.[355] Two cycles of postoperative mitomycin, ifosfamide, and cisplatin were administered to responding individuals. In addition, persons with pathologic T3 or N2 disease or incomplete resection received postoperative radiation therapy. There was a statistically nonsignificant 3.8% (95% CI, 1.3% to 25.1%) improvement in 1-year survival increasing to 8.6% (95% CI, 2.64% to 24.4%) survival benefit at 4 years in persons treated with preoperative chemotherapy. This benefit, however, was seemingly limited to persons with N0 and N1 disease (relative risk [RR], 0.68, 95% confidence interval [CI], 0.49–0.96, P = 0.027).[355] Neoadjuvant chemotherapy was associated with nonsignificant higher perioperative mortality (9% vs. 5%), a problem not reported by others. [311] [356] [357] Complicating the interpretation of these data were potentially important differences in the patient characteristics and treatment of the two arms. For example, almost twice as many patients in the chemotherapy arm had N2 disease (40% vs. 28%), whereas almost twice as many patients in the surgery-alone arm received postoperative radiation therapy (48% vs. 28%). These differences may or may not have contributed to the overall outcomes.
A U.S. Intergroup study (S9900) enrolled individuals with clinical stages IB through IIIA NSCLC (T2N0, T1–2N1, and T3N0–1) into a randomized study of surgery alone or surgery preceded by three cycles of paclitaxel and carboplatin.[420] Individuals with superior sulcus tumors were excluded. The study was closed prematurely with the recognition that postoperative adjuvant chemotherapy imparted a survival benefit in this group of individuals with NSCLC (discussed earlier). Neoadjuvant paclitaxel and carboplatin yielded an objective response of 40%. Although progression-free and overall survival tended to favor the neoadjuvant chemotherapy arm, these differences were not statistically significant (median and 2-year survivals were 42 months and 68% with neoadjuvant chemotherapy vs. 37 months and 64% with surgery alone; P = 0.47). There were six treatment-related deaths within 30 days of surgery in the neoadjuvant arm compared with three deaths in the surgery-alone arm.
A recent literature-based meta-analysis examined the role of induction chemotherapy in early-stage NSCLC.[419] The analysis involved all randomized studies conducted between 1965 and 2004 published in English or French. The overall hazard ratio was 0.66 (95% CI, 0.48–0.93) in favor of the addition of induction chemotherapy to a standard surgical procedure. Although the trend was in favor of neoadjuvant chemotherapy in stage III disease (HR = 0.65; 95% CI, 0.41–1.04), it was not statistically significant. By contrast, a second meta-analysis evaluating trials published between 1994 and 2004 failed to note a survival advantage for persons with resectable NSCLC who had preoperative chemotherapy.[421]
At the present time the role of induction chemotherapy remains ill-defined. Similar to other solid tumors (e.g., breast cancer), neoadjuvant chemotherapy may ultimately prove useful in rendering a marginally resectable lesion more amenable to definitive resection but without imparting a positive survival benefit. Only prospective trials will answer this question. However, defining the optimal candidate for preoperative versus postoperative chemotherapy comparative trials will prove challenging. Our approach has been to treat individuals with clinical stage I and II disease with surgery and to administer postoperative adjuvant chemotherapy to those who are appropriate candidates as described previously. Individuals with so-called marginally resectable lesions are assessed on a case-by-case basis. We are more inclined to administer neoadjuvant chemotherapy to those with minimal involvement of N2 lymph nodes. Persons with multiple positive N2 disease are not thought to be candidates for surgery and are treated with concurrent chemotherapy–radiation therapy as discussed later.
Neoadjuvant Chemotherapy–Radiation Therapy
The addition of TRT to preoperative chemotherapy further increases the frequency of pathologic clearance of mediastinal lymph nodes, suggesting that trimodality therapy (i.e., neoadjuvant chemotherapy–radiation therapy followed by surgery) might be superior to a bimodality approach.[416] To address this possibility several investigators have conducted trials combining induction chemotherapy with radiation given either sequentially or concurrently before surgery for individuals with stage III NSCLC (see review[416]). A variety of cisplatin-based chemotherapy regimens have been administered in combination with various total doses of TRT (typically 30–45 Gy) given once or twice daily, and some trials even included stage IIIB patients (excluding pleural effusions). For example, SWOG investigators administered concurrent TRT (45 Gy) with two cycles of induction cisplatin plus etoposide to 126 patients with biopsy-proven stage IIIA (N2) or IIIB NSCLC.[361] Persons who experienced an objective response or stable disease were taken to definitive resection. The objective response rate to induction was 59%, and 29% had stable disease. Resectability was 85% for the IIIA group and 80% for the IIIB group. Although 13 treatment-related deaths (10%) were observed, 3-year survival rates were 27% and 24%, respectively, for stage IIIA (N2) and IIIB disease. As noted by others, the strongest predictor of long-term survival after thoracotomy was absence of tumor in the mediastinal nodes at surgery (3-year survival: 44% vs. 18%; P = 0.0005).
The phase II trials of preoperative chemoradiation yielded results that were similar to the induction chemotherapy-alone trials in terms of response, resection, and survival rates.[416] The need for surgery also in the treatment of individuals with N2-positive stage IIIA NSCLC has not been fully determined. Intergroup trial 0139 was designed to address this controversy and prospectively compared preoperative concurrent chemotherapy–radiation therapy to concurrent chemotherapy–radiation therapy alone.[359] Eligible patients had a good performance status (0–1) and proven involvement of N2 nodes with no evidence of metastatic disease. All study participants received cisplatin and etoposide with concomitant TRT to 45 Gy starting day 1. The trimodality group went to a resection if there was no evidence of disease progression with induction therapy and then received two additional cycles of etoposide and cisplatin (EP). The bimodality group continued with TRT to a total dose of 61 Gy with EP for two additional cycles. Although progression-free survival was superior following trimodality therapy, this did not translate into an improvement in 5-year survival (27.7% vs. 20.3%; P = 0.10). There were 16 treatment-related deaths in the trimodality arm (10 within 30 days of surgery) and 4 treatment-related deaths in the bimodality arm. Postoperative mortality was particularly high in those requiring simple or complex pneumonectomy. Improved long-term survival was observed in persons with downstaging from positive to N2 to N0 disease at surgery (5-year survival: pN0 = 41%; pN1–3 = 24%; no surgery = 8%; P < 0.0001). This is similar to several smaller studies that have highlighted the importance of N0 disease at the time of resection following neoadjuvant chemotherapy–radiation therapy. [416] [417]
Although these data are intriguing, there remain no data that definitively prove that radiation therapy improves outcome over chemotherapy and surgery, or that surgery adds to the therapeutic efficacy of chemotherapy and radiation therapy.[416] The subsets for which trimodality treatment is preferred include patients with T4N0–1 disease and superior sulcus tumors. Cancers located in the superior sulcus are difficult to resect and frequently have residual disease after resection. For these reasons, neoadjuvant chemotherapy–radiation therapy is indicated before thoracotomy.[348] Our current practice is to only use neoadjuvant chemotherapy and radiation therapy when this therapy is needed to facilitate resection of locally extensive tumors such as superior sulcus tumors. Moreover, a strong statement can be made that patients who will require a pneumonectomy should NOT be considered for a trimodality approach and should be treated with concurrent chemotherapy–radiation therapy.
Treatment of Locally Advanced Unresectable Non-Small Cell Lung Cancer
Locally advanced NSCLC consists of stages IIIA (T3N1M0 or T1–3N2M0) and IIIB (T4NanyM0 or TanyN3M0) and is considered unresectable in all but the most unusual of cases. [317] [365] [372]Nonetheless, with the exception of the subset of persons with malignant pleural effusion, individuals with stage III lung cancer are treated with curative intent. [317] [365] Individuals with malignant pleural effusion preferentially are treated with chemotherapy (see later discussion; metastatic disease). Until the 1980s radiation therapy alone had been the standard of care for locally advanced NSCLC despite dismal survival results. [422] [423] [424] Using standard traditional radiation doses and technique, survival rates of 40%, 15%, and 5% were achieved at 1, 2, and 5 years respectively. [422] [423] [424] During the early 1990s, however, results of many randomized phase III studies shifted the standard toward concurrent chemoradiation therapy.[424] The key trials that led to the evolution in treatment of locally advanced NSCLC are described later. In addition, recent technologic advances in radiation therapy and novel chemotherapeutic approaches have provided pre liminary data for further improving clinical outcome while minimizing the morbidity associated with the therapy.[423]
Sequential Chemoradiation versus Radiation Alone
With sequential chemoradiation, full doses of both modalities can be delivered without compromise of either. The rationale behind the sequential combination of chemotherapy and radiation therapy is based on the premise that radiation therapy addresses the local-regional disease whereas chemotherapy acts systemically to eradicate micrometastases. The first large-scale trial to demonstrate a survival benefit with sequential chemoradiation therapy compared to standard radiation therapy alone was conducted by the Cancer and Leukemia Group B (CALGB); ( Table 76-10 ).[425] These investigators administered cisplatin and vinblastine before standard TRT (i.e., 60 Gy over 6 weeks) and observed an improvement in median and long-term survival (23% vs. 11% at 3 years). These findings were later validated by a North American Intergroup trial (Radiation Therapy Oncology Group [RTOG] 88–08) in which persons with unresectable NSCLC were randomized to one of two radiation-alone arms (daily to 60 Gy or twice daily to 69.6 Gy), or to a third arm of induction chemotherapy with cisplatin and vinblastine followed by daily radiation therapy to 60 Gy. [426] [427] Similar to the CALGB trial, there was a statistically significant improvement in median survival with sequential chemoradiation therapy, compared with those of the two arms using radiation therapy alone (see Table 76-10 ). These in addition to other landmark trials consistently demonstrate a significant survival benefit with the addition of induction chemotherapy over conventional or hyperfractionated irradiation alone. Induction chemotherapy seems to reduce the number of distant relapses, which translates into a modest benefit in survival. As a result of these studies, sequential chemoradiation became the basis for comparisons in clinical trials of the 1990s.
Table 76-10 -- Multicenter Phase III Trials Comparing Sequential Chemoradiation versus Radiation Alone
|
Study |
CT-RT Sequence |
No. of Patients |
RT Dose (Gy) |
CT |
MST |
5 Yr (%) |
Acute Grade ≥3 Toxicity (%) |
|
CALGB 8433 [425] [440] |
Daily RT |
77 |
60 |
N/A |
9.6 mo |
6 |
7 |
|
CT ➙ daily RT |
78 |
60 |
PVbl |
13.7 mo |
17 |
3 |
|
|
RTOG 8808 [426] [427] |
Daily RT |
152 |
60 |
N/A |
11.4 mo |
5 |
1 |
|
CT ➙ daily RT |
152 |
60 |
PVbl |
13.8 mo |
8 |
1 |
|
|
Twice daily RT |
154 |
69.9 |
N/A |
12.3 mo |
6 |
3 |
|
|
CEBI 138[661] |
Daily RT |
167 |
65 |
N/A |
10 mo |
3 |
3 |
|
CT ➙ daily RT |
165 |
65 |
VCPC |
12 mo |
6 |
5 |
|
CT, chemotherapy; MST, median survival time; P, cisplatin; RT, radiotherapy; Vbl, vinblastine; VCPC, vindesine, cyclophosphamide, cisplatin, and lomustine. |
Sequential versus Concurrent Chemoradiation Therapy
The mechanism of chemotherapeutic radiosensitization is thought to be direct inhibition of repair of radiation-induced damage; elimination of radioresistant, chemosensitive clones; and/or suppression of interfraction tumor repopulation.[428] Concurrent chemoradiation addresses both distant and local-regional disease simultaneously. The two modalities should act synergistically on tumor clonogens susceptible to both modalities and in a complementary fashion on local-regional clonogens that are susceptible to only one of the modalities. The superiority of concurrent chemotherapy with radiation therapy compared with sequential chemotherapy followed by irradiation was conclusively demonstrated in large multicenter trials. [429] [430] [431] In the first of these trials, Japanese investigators randomized individuals with locally advanced NSCLC to receive either concurrent or sequential chemoradiation therapy.[431] Chemotherapy consisted of mitomycin (8 mg/m2 days 1 and 29), vindesine (3 mg/m2 days 1, 8, 29, and 36), and cisplatin (80 mg/m2 days 1 and 29). TRT (56 Gy) was administered as a split course in the concurrent arm but was given continuously in the sequential arm. Overall response rate and survival were statistically significantly improved with concurrent chemotherapy–radiation therapy ( Table 76-11 ). The survival benefit seemed to be due primarily to improved local tumor control based on a marked improvement in local failure-free survival (30 vs. 11 months), whereas distant failure rates were similar at approximately 50%. These findings recapitulate earlier reports of improved local tumor control without improvement in the rate of distant metastasis when cisplatin is administered with split-course radiation therapy.[432]
Table 76-11 -- Multicenter Phase III Trials Comparing Concurrent with Sequential Chemoradiotherapy
|
Study |
Sequence |
No. of Patients |
RT Dose (Gy) |
CT |
MST |
3 Yr (%) |
5 Yr (%) |
Gr ≥3 Esophagitis (%) |
|
West Japan Lung |
CT ➙ daily RT |
158 |
56 |
MVP |
13.3 mo |
15 |
9 |
2 |
|
Cancer Group[431] |
CT +daily RT |
156 |
56[*] |
MVP |
16.5 mo |
22 |
16 |
3 |
|
RTOG 9410 [429] [433] |
CT ➙ daily RT |
201 |
60 |
PVbl |
14.6 mo |
n.r. |
10 |
4 |
|
CT +daily RT |
201 |
60 |
PVbl |
17 mo |
n.r. |
16 |
23 |
|
|
CT + twice daily RT |
193 |
69.6 |
PE |
15.1 mo |
n.r. |
13 |
46 |
|
|
GLOT-GFPC NPC |
CT ➙ daily RT |
101 |
66 |
PVbl |
14.5 mo |
19 |
14[†] |
3 |
|
95-01[430] |
CT +daily RT➙CT |
100 |
66 |
PE ➙ PVin |
16.3 mo |
25 |
21[†] |
32 |
|
Czech study[434] |
CT ➙ daily RT |
50 |
60 |
PVbl |
12.9 mo |
9.5 |
n.r. |
4 |
|
CT +daily RT |
52 |
60 |
PVbl |
16.6 mo |
18.6 |
n.r. |
18 |
|
CT, chemotherapy; E, etoposide; MST, median survival time; MVP, mitomycin, vindesine, cisplatin; P, cisplatin; RT, radiotherapy; Vbl, vinblastine; Vin, vinorelbine; n.r., not reported. |
|
* |
Split course RT |
|
† |
4-yr survival. |
The RTOG addressed the question of sequential versus concurrent chemotherapy–radiation therapy in study 9410. [429] [433] The trial also included a third arm designed to assess the value of twice-daily irradiation in conjunction with chemotherapy. Chemotherapy consisted of cisplatin and vinblastine. The twice-daily radiation therapy arm demonstrated improved local control without improving survival, whereas the concurrent chemotherapy–radiation therapy arm was superior to the sequential treatment in terms of local control, median survival (17.0 vs. 14.6 months; P = 0.0038), and 4-year survival rate (21% vs. 12%; P = 0.046; see Table 76-10 ). Acute grade 3 to 5 toxicities were more frequent in the two concurrent chemotherapy–radiation therapy arms. However, the differences in late effects were not statistically significant.
French investigators also compared sequential and concurrent chemotherapy–radiation therapy in individuals with unresectable stage III NSCLC.[430] Sequential therapy consisted of three cycles of cisplatin (120 mg/m2) every 3 weeks and weekly vinorelbine (30 mg/m2 per week) followed by TRT (66 Gy in 33 fractions), whereas the concurrent arm used the same radiation therapy with simultaneous initiation of daily cisplatin (20 mg/m2 daily) and etoposide (50 mg/m2 per day) on days 1 to 5 and 29 to 33. The concurrent arm then received two courses of consolidation therapy with cisplatin (80 mg/m2) and vinorelbine (30 mg/m2 per week). Treatment-related deaths (10 vs. 3) and WHO grade 3 to 4 esophageal toxicity (32% vs. 3%; P < 0.0001) were significantly more frequent in the concurrent arm than in the sequential arm. Median survival (16.3 vs. 14.5 months) and 4-year survival rates (21% vs. 14%) were not statistically significantly different; this result the investigators attributed to insufficient powering of the trial (see Table 76-11 ). However, an alternative explanation might be the excess of toxic deaths in the concurrent arm, which in turn may be attributable to the dose and scheduling of cisplatin and vinorelbine. Less life-threatening toxicity has been observed with different doses and scheduling of these agents without an apparent compromise in overall efficacy.[424]
These and similar trials[434] consistently demonstrate a survival advantage for the concurrent chemotherapy–radiation therapy as opposed to the sequential use of chemotherapy followed by TRT but always with an increase in host toxicity—most specifically with respect to an increase in treatment-related esophagitis. Of concern is the modest but clinically meaningful increase in treatment-related deaths accompanying concurrent chemotherapy–radiation therapy in some of the aforementioned trials. Nonetheless, the results from these trials established concurrent chemoradiation therapy as the current standard for locally advanced NSCLC in good-performance-status patients with limited comorbidities.
Concurrent Chemoradiation Therapy with Consolidation or Induction Chemotherapy
Building on the survival benefits achieved with concurrent chemotherapy–radiation therapy in locally advanced NSCLC, SWOG investigators conducted a series of sequential phase II trials designed to assess the benefit of consolidation therapies in locally advanced NSCLC ( Table 76-12 ). The first of these trials, S9019, assessed the feasibility and impact on long-term survival of full-dose cisplatin and etoposide given during and after full-dose TRT (61 Gy).[371] The study enrolled only individuals with pathologically confirmed stage IIIB NSCLC and yielded a median survival time of 15 months and 5-year survival of 17%. In a follow-up study (S9504), 83 individuals with pathologic stage IIIB NSCLC were treated with the same regimen of cisplatin and etoposide with concurrent TRT followed by docetaxel. [435] [436] With a median follow-up of 71 months, median survival time was 26 months, and the 5-year survival rate was 29%. Long-term survival compared favorably with the data from the SWOG S9019 study. Despite a lack of phase III confirmatory data, this regimen became the reference arm for a third SWOG trial (S0023) in which patients were randomized to gefitinib, an inhibitor of the EGFR tyrosine kinase, or a placebo.[437] Notably, the median survival of patients randomized to gefitinib was dramatically lower than that of patients given a placebo (19 vs. 29 months; P = 0.09). This trial was closed early, because gefitinib was deemed unlikely to improve overall survival. At the same time SWOG S0023 was under way, the Hoosier Oncology Group (HOG) undertook a phase III trial (LUN-01–24) designed to confirm the results of SWOG trial S9504 (i.e., to evaluate the role of consolidation docetaxel in individuals with unresectable stage III disease).[438] In the HOG study, persons with stage III NSCLC and no evidence of local disease progression or distant metastases were randomized to receive docetaxel or observation after completing concurrent cisplatin and etoposide with TRT. The HOG trial recently closed on the recommendation of a Data and Safety Monitoring Committee as a consequence of a statistical improbability that the docetaxel arm would yield an increase in overall survival. (Overall median survival = 21.15 months; median survival for those taking docetaxel = 21.6 months vs. 24.2 months for those in the observation arm; P = 0.94.)[439]
Table 76-12 -- Phase II Trials Comparing Induction or Consolidation Chemotherapy with Concurrent Chemoradiotherapy
|
Study |
Sequence |
No. of Patients |
RT Dose (Gy) |
CT |
MST |
3 Yr (%) |
Gr>3 Esophagitis (%) |
|
SWOGS9019[371] |
CT +daily RT➙CT |
50 |
61 |
PE➙PE |
15 mo |
17 |
20 |
|
SWOG S9504 [435] [436] |
CT +daily RT➙CT |
83 |
61 |
PE➙D |
26 mo |
40 |
n.r. |
|
CALGB39801[440] |
CT ➙CT + daily RT |
184 |
66 |
CbT |
14 mo |
54[*] |
n.r. |
|
CT +daily RT |
182 |
66 |
CbT |
11.4 mo |
48[*] |
n.r. |
|
|
LAMP[442] |
CT ➙ daily RT |
91 |
63 |
CbT |
13 mo |
17 |
3 |
|
CT ➙CT + daily RT |
74 |
63 |
CbT ➙ low-dose CbT |
12.7 mo |
15 |
19 |
|
|
CT +daily RT➙CT |
92 |
63 |
low-dose CbT ➙ CbT |
16.3 mo |
17 |
28 |
|
CbT, carboplatin/paclitaxel; CT, chemotherapy; D, docetaxel; MST, median survival time; PE, cisplatin/etoposide; RT, radiotherapy; n.r., not reported. |
|
* |
1-year survival. |
In contrast to SWOG, CALGB investigators opted to evaluate the role of induction chemotherapy with concurrent chemotherapy–radiation therapy based on their long-standing interest in the use of induction chemotherapy.[440] In CALGB 39801 individuals with unresectable stage III NSCLC were randomized to immediate concurrent chemotherapy–radiation therapy (i.e., carboplatin AUC = 2 and paclitaxel 50 mg/m2 each given weekly during 66 Gy TRT; 182 patients) or two cycles of induction carboplatin (AUC 6) and paclitaxel (200 mg/m2) followed by concurrent chemotherapy–radiation therapy.[441] There were no differences in survival outcomes (median and 1-year survival of 11.4 and 14.6 months and 48% to 58% respectively; P = 0.154), although follow-up is short (see Table 76-12 ). Curiously, the results of both arms were somewhat inferior to historical controls and the results in the control arms of the studies listed in the preceding section. Nonetheless, the results of this study suggest that induction chemotherapy before concurrent chemoradiation is not beneficial.
The American College of Radiology conducted a randomized phase II study designed to determine the optimal sequencing and integration of chemotherapy with standard daily TRT in individuals with locally advanced unresectable stages IIIA and IIIB NSCLC.[442] This trial, better known as the Locally Advanced Multimodality Protocol (LAMP) study, randomized patients to induction chemotherapy followed by irradiation (arm A), induction chemotherapy followed by concurrent chemoradiation (arm B), or chemoradiation followed by consolidation chemotherapy (arm C; see Table 76-12 ). Participants received full systemic doses of carboplatin and paclitaxel as induction or consolidation therapy and weekly low doses of carboplatin and paclitaxel during concurrent chemotherapy–radiation therapy. All patients received TRT to 63 Gy. The LAMP trial suffered from poor accrual and was terminated before enrolling the target number of patients. Nonetheless, LAMP is the only large trial directly comparing induction and consolidation chemotherapy in the setting of concurrent chemoradiation. With a median follow-up time of more than 3.5 years, median overall survival was virtually identical in the induction arms (arm A 13.1; arm B 12.7 months) and longest with the concurrent chemotherapy–radiation therapy–consolidation approach (16.3 months). Toxicity, however, was greater in the latter arm. The results of the LAMP trial suggest a benefit of consolidation chemotherapy following concurrent chemotherapy–radiation therapy,[442] although these results can hardly be considered definitive because of inadequacies in the study design and imbalances in prognostic factors among the three arms.[424] Likewise, the role of consolidative docetaxel after full-dose EP and concomitant chemoradiation therapy is not supported by phase III data.[438] Neither docetaxel nor gefitinib is recommended as consolidation therapy following concurrent chemotherapy–radiation therapy for locally advanced NSCLC given the lack of a survival advantage and an increase in toxicity. Further studies are necessary to fully define the optimal administration of concurrent chemotherapy–radiation therapy with or without induction or consolidation chemotherapy.
Optimal Chemotherapy Regimen in Stage III Non-Small Cell Lung Cancer
There is a paucity of data comparing different chemotherapy regimens in the setting of locally advanced NSCLC. For many theoretical reasons a regimen that includes cisplatin may be superior to a non-platinum-containing regimen. However, questions remain as to whether a low-dose platinum regimen is actually equivalent to a full-dose cisplatin-based regimen given concurrently with radiation therapy. One regimen that has consistently stood the test of time consists of that first used in SWOG trial S9019.[371] The SWOG approach consists of two cycles of induction EP administered concurrently with once-daily TRT (45 Gy). In the absence of progressive disease, radiation therapy is continued to a total dose of 61 Gy after which two additional cycles of EP are delivered. An alternative approach is to use the LAMP regimen of concurrent low-dose weekly carboplatin plus paclitaxel with radiation therapy followed by two additional cycles of full-dose consolidation carboplatin plus paclitaxel chemotherapy.[442] The decision to use one particular regimen over others is often made on the basis of secondary factors such as cost, logistical convenience, ease of administration, toxicity profile, patient preference, and physician experience.
Modulation of Concurrent Chemoradiation Therapy Toxicity
Although concurrent chemoradiation provides a significant survival benefit in locally advanced NSCLC, it comes at the cost of increased toxicity. [443] [444] [445] Radioprotectors are an attractive way to reduce the morbidity associated with combined-modality therapy and thereby may allow radiation therapy dose escalation to improve local control and survival. Amifostine is a candidate drug and acts primarily by scavenging free radicals released during the interaction of ionizing radiation and water. It theoretically protects normal tissue preferentially, thus increasing the therapeutic window. Thus far four randomized studies have been performed with amifostine in the setting of lung cancer with divergent results. [446] [447] [448] [449] The largest of these trials was conducted by RTOG (RTOG 98–01).[449]All patients enrolled in the RTOG study received induction and concurrent carboplatin and paclitaxel with hyperfractionated radiation therapy (69.6 Gy) with or without amifostine. The primary endpoint was the frequency of grade 3 or higher esophagitis, a common toxicity of concurrent chemoradiation administration. However, no difference in the rate of grade 3 or higher esophagitis was detected, and there was a significant increase in the rate of nausea and vomiting, cardiovascular toxicity, and infection and febrile neutropenia with amifostine. Individuals given amifostine reported subjective improvement in swallowing and improved pain control, but quality-of-life measures were not statistically different nor was there an improvement in treatment compliance or survival. These data coupled with negative results achieved in other settings in which concurrent chemoradiation therapy is used[450] suggest that further study of this approach using amifostine is unlikely to be productive. However, some experts believe improved schedules of amifostine administration (such as more frequent dosing closer to the treatment time) could yield improved results. [446] [447] The cost-to-benefit ratio of such frequent, strict dosing of this expensive drug in routine clinical practice has not been adequately studied, and thus we believe there is no compelling reason to use amifostine in this setting.
Molecular-Targeted Combined Modality Therapy
Molecular-targeted therapy is a novel strategy evolving from our increasing understanding of the underlying pathways and key molecules involved in tumor growth and progression. Theoretically, the specificity of molecular-targeted therapy should improve the therapeutic window by affecting the tumor cells and sparing normal cells. EGFR is an important mediator of growth factor signaling pathways that affect normal cell proliferation, motility, adhesion, and survival, as well as angiogenesis. EGFR is highly expressed in many solid tumors, and there have been reports correlating overexpression of EGFR with poor prognosis. Gefitinib, an inhibitor of EGFR tyrosine kinase activity, was the first targeted agent to be approved for the treatment of third-line NSCLC. As noted previously, SWOG investigators evaluated the potential benefit of maintenance therapy with gefitinib in locally advanced NSCLC in trial S0023.[437] An interim analysis prompted study closure when it showed that the gefitinib arm had no possibility of improving overall survival or progression-free survival compared with placebo. University of Chicago investigators are conducting a randomized phase II trial evaluating another EGFR-TKI, erlotinib, in a concurrent fashion with chemoradiation therapy consisting of either EP and radiation therapy followed by consolidation docetaxel for three cycles or induction chemotherapy with paclitaxel and carboplatin followed by concurrent chemoradiation consisting of weekly paclitaxel, carboplatin, with daily erlotinib.[451]
Another promising targeted agent is cetuximab, a chimeric antibody to IgG1 subclass with fivefold greater affinity than the murine monoclonal antibody. It works by blocking the binding of ligand to EGFR and suppressing the downstream activity. In individuals with squamous cell carcinoma of head and neck cetuximab combined with radiation therapy improved overall survival,[452] prompting similar studies in locally advanced NSCLC. In a recently completed RTOG phase II trial (RTOG-0324) cetuximab was combined with carboplatin and paclitaxel and daily fractionated radiation therapy.[453] The study has completed planned accrual and is awaiting maturation.
Metastatic Non-Small Cell Lung Cancer
Before the widespread use of chemotherapy, individuals with metastatic NSCLC experienced a median survival of 4 to 5 months and 1-year survival rates of approximately 10% when managed with supportive care alone. [454] [455] Moreover, with rare exception, clinical trials conducted during the 1970s and 1980s comparing chemotherapy to best supportive care failed to provide definitive evidence supporting the use of chemotherapy for individuals with advanced NSCLC. The failure to demonstrate a survival benefit was attributed to a lack of effective treatment and to the intolerable side effects of the agents available. However, the statistical power of these studies was inadequate to detect a modest improvement in survival. To remedy this shortcoming a landmark meta-analysis of the extant data was undertaken.[388] No survival benefit was observed with chemotherapy regimens composed of alkylating drugs or vinca alkaloids. However, the meta-analysis also included eight trials involving nearly 800 patients who received cisplatin-based chemotherapy versus supportive care alone. In these trials the hazard ratio for death was 0.73 in favor of cisplatin-based chemotherapy (P < 0.0001), corresponding to a 1.5-month increase in median survival time and a 10% increase in survival at 1 year. For most oncologists these data firmly established the survival benefits of platinum-based chemotherapy. Numerous subsequent studies confirmed this survival advantage and also convincingly demonstrated an improvement in quality of life compared with supportive care alone and the cost effectiveness of chemotherapy as well. [456] [457]
Platinum-based chemotherapy assessed in the aforementioned meta-analysis mainly consisted of drug combinations consisting of older or second-generation cytotoxic agents (e.g., etoposide or vinca). These older drugs were associated with significant side effects that may have contributed to a less than optimal outcome. Beginning in the 1990s newer and less toxic chemotherapy drugs such as gemcitabine, vinorelbine, paclitaxel, and docetaxel were shown to possess good single-agent activity against advanced NSCLC and, in some instances, to impart a survival benefit compared with supportive care alone. [458] [459] Subsequently these third-generation drugs were compared as single agents to older platinum-based combinations containing second-generation drugs (e.g., etoposide, vindesine, etc.) and platinum-based doublets containing third-generation drugs (see reviews [460] [461]). For the most part third-generation agents used alone seemed to perform as well as the older platinum-based doublets in terms of overall survival but proved inferior to platinum-based doublets containing the newer third-generation drugs. [460] [461] This observation was later borne out in a meta-analysis of studies conducted between 1994 and 2003 involving third-generation drugs as single agents or in combination with platinum.[462] Platinum-based doublets using third-generation agents produced a twofold higher overall response rate than the new agent alone (OR = 2.32; 1.68–3.20) and a 13% prolongation of survival (HR = 0.87; 0.80–0.94, P < 0.001). Despite significant increases in the frequencies of various toxic effects in patients receiving newer platinum-based doublets, no significant difference in treatment-related mortality was observed.
Newer versus Older Platinum-Based Doublet Drug Combinations
As the newer third-generation drug combinations emerged they naturally led to randomized phase III trials aimed at defining an optimal platinum-based doublet therapy regimen in advanced NSCLC. Several of these important trials are listed in Table 76-13 . For example, the ECOG conducted a landmark phase III trial in which chemotherapy-naive individuals with advanced NSCLC were randomized to receive cisplatin plus paclitaxel as the reference standard based on earlier work from an earlier ECOG study[463] or to one of three experimental arms: cisplatin plus gemcitabine, cisplatin plus docetaxel, or carboplatin plus paclitaxel.[464] Overall response rates and survival, however, did not differ significantly between the reference regimen of cisplatin plus paclitaxel and the three investigational arms. Similar results have been reported by other groups. [465] [466] Although response rates and survival times differ slightly among these trials, the differences are relatively minor and mainly attributable to subtle but important differences in the characteristics of the various study populations.[467] For example, in the TAX-326 study, approximately one third of the participants had stage III disease, compared with fewer than 20% stage III disease in the other large trials.[468] Because individuals with stage III disease tend to live longer, this difference introduces a potential bias and makes it difficult to compare across trials (although within the trials the balance of stages was similar between the randomized arms). Collectively these data indicate platinum-based doublets using third-generation agents represent the standard of care in individuals with advanced NSCLC. [454] [469] No clinically significant differences among the common regimens have emerged.
Table 76-13 -- Phase III Trials with Third-Generation Drugs in Advanced Non-Small Cell Lung Cancer
|
|
|
|
|
SURVIVAL |
|
|
Group |
CT |
No. of Patients |
RR (%) |
Median (mo.) |
1 Yr (%) |
|
ECOG[464] |
Paclitaxel/cisplatin |
288 |
21 |
7.8 |
31 |
|
Gemcitabine/cisplatin |
288 |
22 |
8.1 |
36 |
|
|
Docetaxel/cisplatin |
289 |
17 |
7.4 |
31 |
|
|
Paclitaxel/carboplatin |
290 |
17 |
8.1 |
34 |
|
|
EORTC[480] |
Paclitaxel/cisplatin |
159 |
31 |
8.1 |
35 |
|
Gemcitabine/cisplatin |
160 |
36 |
8.8 |
31 |
|
|
Gemcitabine/paclitaxel |
161 |
27 |
6.9 |
26 |
|
|
ILCP[662] |
Vinorelbine/cisplatin |
201 |
30 |
9.5 |
37 |
|
Gemcitabine/cisplatin |
205 |
30 |
9.8 |
37 |
|
|
Paclitaxel/carboplatin |
201 |
32 |
9.9 |
43 |
|
|
SWOG[465] |
Paclitaxel/carboplatin |
206 |
25 |
8.0 |
38 |
|
Vinorelbine/cisplatin |
202 |
28 |
8.0 |
36 |
|
|
TAX-326[468] |
Cisplatin/vinorelbine |
394 |
25 |
10.1 |
41 |
|
Cisplatin/docetaxel |
406 |
32 |
11.3 |
46 |
|
|
Carboplatin/docetaxel |
404 |
24 |
9.4 |
38 |
|
|
RR, response rate. |