CA CANCER I CLIN 201161:91-112 Lung Cancer:New Biological Insights and Recent Therapeutic Advances Suresh S.Ramalingam,MD';Taofeek K.Owonikoko,MD,PhD Fadlo R.Khuri,MD Abstract Approximately 1.6 million new cases of lung cancer are diagnosed each vear throughout the world.In many coun cure rates in both re unresectable patient groups.For swith advanced stage disease,modes but real improve and qu t of en a ieved markers for patient selection.Patients with non-small cell lung cancer with mutations in the epidermal growth fac to receptor(EGFR)tyrosine kinase domain achieve response rates of greater than 70%and superior progression-free survival when treated with an EGFR tyrosine kinase inhibitor compared with standard chemotherapy.This has now subset or patients with a mutation in exons e use of an anapla hoa4asea22 Finally,a paradigm shift in favor of maintenance therapy for patients with advanced stage disease has gained strength from recent data.All of these advances have been made possible by developing a greater understanding of the biology,the discovery of novel anticancer agents,and improved supportive care measures.This article reviews ne major strides made in the treatment of lung cancer in the recent past.CA Cancer J Clin 2011;61:91-112. 2011An nerican Cancer Society,Inc Introduction Lnging caue of emortalityrwide with death the year,apprc imately 0aredi 2 There the en ough omen this trend has only been noted very recently in the Unite tes.I ncontrast,in many parts of the worl the number of cases and deaths related to lung cancer is on the rise.' tis also increasingly becoming a disease c the elderly,with a median age at diagnosis of approximately 70 years.Lung cancer is diagnosed at an advanced stage in a majority of patients,which is the primary reason behind the high mortality rate associated with this disease.Early detection continues to be an elusive goal,and substantial numbers of patients diagnosed with local- ized disease are often unsuitable for curative surgical procedures due to concomitant medical illness. Non-small cell lung cancer (NSCLC),which includes adenocarcinoma,squamous cell carcinoma,large cell carcinoma,and bronchioloalveolar carcinoma,accounts for nearly 85%of all cases of lung cancer.Cigarette smoking is the most common etiological factor,accounting for nearly 85%of patients with lung cancer. Associate Professor.De and The Winship Cancer Institute.Emory Unive y and ueta Dis n .epartment of Hem atology and Medical Oncology.Emory Univ ersity School of Medicine.1365 Clifton Road NE 11American Cancer Society,Inc.doi:10.332/c0102. Available online at htto://cajournalong and http://cacancerjoumalorg OLUME 61 NUMBER 2 MARCH/APRIL 201 91
Lung Cancer: New Biological Insights and Recent Therapeutic Advances Suresh S. Ramalingam, MD1 ; Taofeek K. Owonikoko, MD, PhD2 ; Fadlo R. Khuri, MD3 Abstract Approximately 1.6 million new cases of lung cancer are diagnosed each year throughout the world. In many countries, the mortality related to lung cancer continues to rise. The outcomes for patients with all stages of lung cancer have improved in recent years. The use of systemic therapy in conjunction with local therapy has led to improved cure rates in both resectable and unresectable patient groups. For patients with advanced stage disease, modest but real improvements in overall survival and quality of life have been achieved with systemic chemotherapy. A major focus of research has been the development of molecularly targeted agents and the identification of biomarkers for patient selection. Patients with non-small cell lung cancer with mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain achieve response rates of greater than 70% and superior progression-free survival when treated with an EGFR tyrosine kinase inhibitor compared with standard chemotherapy. This has now emerged as the preferred therapeutic approach for the subset of patients with a mutation in exons 19 or 21 of the EGFR. Another promising targeted approach involves the use of an anaplastic lymphoma kinase (ALK) inhibitor in patients with a translocation involving the echinoderm microtubule-associated protein-like 4 (EML4) and -ALK genes. Finally, a paradigm shift in favor of maintenance therapy for patients with advanced stage disease has gained strength from recent data. All of these advances have been made possible by developing a greater understanding of the biology, the discovery of novel anticancer agents, and improved supportive care measures. This article reviews the major strides made in the treatment of lung cancer in the recent past. CA Cancer J Clin 2011;61:91–112. VC 2011 American Cancer Society, Inc. Introduction Lung cancer is the leading cause of cancer-related mortality worldwide, with nearly 1.4 million deaths each year. 1 Of the 1.6 million new cases of lung cancer diagnosed each year, approximately 220,000 are diagnosed in the United States.2 There has been an overall decrease in the incidence of lung cancer in men, although in women this trend has only been noted very recently in the United States. In contrast, in many parts of the world the number of cases and deaths related to lung cancer is on the rise.1 It is also increasingly becoming a disease of the elderly, with a median age at diagnosis of approximately 70 years.3 Lung cancer is diagnosed at an advanced stage in a majority of patients, which is the primary reason behind the high mortality rate associated with this disease. Early detection continues to be an elusive goal, and substantial numbers of patients diagnosed with localized disease are often unsuitable for curative surgical procedures due to concomitant medical illness. Non-small cell lung cancer (NSCLC), which includes adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and bronchioloalveolar carcinoma, accounts for nearly 85% of all cases of lung cancer. Cigarette smoking is the most common etiological factor, accounting for nearly 85% of patients with lung cancer. 1 Associate Professor, Department of Hematology and Medical Oncology and The Winship Cancer Institute, Emory University, Atlanta, GA; 2 Assistant Professor, Department of Hematology and Medical Oncology and The Winship Cancer Institute, Emory University, Atlanta, GA; 3 Professor and Chair of Hematology and Medical Oncology, Roberto C. Goizueta Distinguished Chair in Translational Cancer Research, Department of Hematology and Medical Oncology and The Winship Cancer Institute, Emory University, Atlanta, GA. Corresponding author: Fadlo R. Khuri, MD, Department of Hematology and Medical Oncology, Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, GA 30322; fkhuri@emory.edu DISCLOSURES: Supported by National Cancer Institute grant 1PO1 CA116676 and the Distinguished Cancer Clinical Scholar Award by the Georgia Cancer Coalition to all the coauthors. Dr. Ramalingam has served on Ad Hoc Advisory Board for Lilly, Genentech, OSI Pharmaceuticals, Astellas, GlaxoSmithKline, and ImClone. Dr. Khuri serves as a consultant for Pfizer. VC 2011 American Cancer Society, Inc. doi:10.3322/caac.20102. Available online at http://cajournal.org and http://cacancerjournal.org VOLUME 61 _ NUMBER 2 _ MARCH/APRIL 2011 91 CA CANCER J CLIN 2011;61:91–112
Lung Cancer Revie Nonetheless,the number of cases of lung ca agn sed in nokers has recent time nd of Mib diseas presence or ce o 1 tion in sm population,I extrathoracic lignant pleural effusion that lung cancer will continue to be a has been upstaged to Mla based on its poorer prog major health problem for the next 40 to 50 years. nosis compared with the rest of the T4 descriptors Small cell lung cancer(SCLC)incidence relative to from the older system.The other major change NSCLC has decreased in recent years,although it involves the categorization of additional nodules in continues to be a lethal disease for the majority of the same lobe and other ipsilateral lobes as T3 and patients. T4,respectively.Although the overall treatment In the past few decades,lung cancer has gone guidelines are not likely to be affected,this new stage from an untreatable disease with dismal outcomes to categorization will lead to improved prognostic one that has a number of novel therapeutic options determination and better stratification of patients on and more recently,to a disease for which individual- tandomized clinical trials. ized treatment options have become available.There has been a tre ndous in Biology of Lung Cancer targets.In d the ionaldinilc be made ba tech lung cance ed on bio earch ha mor,at least for a subset a molecularly diverse set of tumor types whoseon There is a greater emphasis on identifying dominan commonality is their origination in the lung. molecular pathways that drive an individual patient's Lung cancer classification is far more complex thar tumor.This has paved the way for the evaluation of the simplistic grouping into small cell and non-small novel strategies to modulate such molecular targets cell variants that was once thought to represent a ho for the treatment of NSCLC.In addition to molec- ularly targeted approaches,newer chemotherapeuti ume when aiom agents with a favorable therapeutic index have also well accepted that the histologic subdivision of lung been developed.This has enhanced the ability to ancer based on light micros opy uses only one of make refinements to well-established systemic ther many phenotypic manifestatio s of the e methods to char ge control.This article eviews the curately nts in the t nt of appearance oted with the clinically that h ave contribu ted to improved pat ng can ent outcome f a pu to an in ive lung ade alignan Staging of Lung Cancer a nchymal Under the epithelial-m a hallmark of national Association for the Study of Lung Cancer More important to the understanding and manage (IASLC),an updated staging manual for lung cance ment of lung cancer,however,is the crystallization (American Joint Committee on Cancer,seventh edi of the theory that,similar to other cancer types,lung tion)was published and adopted for general use in cancer development is a result of a stepwise progres early 2010.The new staging system incorporates sion of malignant transformation of normal respira- major changes that allow for an improved ability to tory epithelium.5 This transformation is driven by determine overall prognosis.The "T status of the cumulative effect of genetic alterations induced tumors is now categorized into less than 2 cm,2 cm to 3 cm,3 cm to 5 cm,5 cm to 7 cm,and greater smoke,an implicated etiologic factor in more than than 7 cm.The lymph node descriptors remain 85%of all cases of lung cancer diagnosed in the 92
Nonetheless, the number of cases of lung cancer diagnosed in never-smokers has also increased in recent times.4 Despite the positive trend of a reduction in smoking habits in the general population, it is estimated that lung cancer will continue to be a major health problem for the next 40 to 50 years. Small cell lung cancer (SCLC) incidence relative to NSCLC has decreased in recent years, although it continues to be a lethal disease for the majority of patients.5 In the past few decades, lung cancer has gone from an untreatable disease with dismal outcomes to one that has a number of novel therapeutic options, and more recently, to a disease for which individualized treatment options have become available. There has been a tremendous increase in the understanding of the biological mechanisms that underlie lung cancer development, which has led to the identification of novel therapeutic targets. In addition to conventional clinical factors, treatment decisions can now be made based on biological factors related to the tumor, at least for a subset of patients with NSCLC. There is a greater emphasis on identifying dominant molecular pathways that drive an individual patient’s tumor. This has paved the way for the evaluation of novel strategies to modulate such molecular targets for the treatment of NSCLC. In addition to molecularly targeted approaches, newer chemotherapeutic agents with a favorable therapeutic index have also been developed. This has enhanced the ability to make refinements to well-established systemic therapy strategies and to develop newer methods to achieve disease control. This article reviews the recent developments in the treatment of lung cancer that have contributed to improved patient outcomes. Staging of Lung Cancer Under the leadership and coordination of the International Association for the Study of Lung Cancer (IASLC), an updated staging manual for lung cancer (American Joint Committee on Cancer, seventh edition) was published and adopted for general use in early 2010. The new staging system incorporates major changes that allow for an improved ability to determine overall prognosis.6 The ‘‘T’’ status of tumors is now categorized into less than 2 cm, 2 cm to 3 cm, 3 cm to 5 cm, 5 cm to 7 cm, and greater than 7 cm.6 The lymph node descriptors remain unchanged in the new staging system.7 Metastatic disease has been further divided into M1a disease or M1b disease based on the presence or absence of extrathoracic disease.8 Malignant pleural effusion has been upstaged to M1a based on its poorer prognosis compared with the rest of the T4 descriptors from the older system. The other major change involves the categorization of additional nodules in the same lobe and other ipsilateral lobes as T3 and T4, respectively. Although the overall treatment guidelines are not likely to be affected, this new stage categorization will lead to improved prognostic determination and better stratification of patients on randomized clinical trials. Biology of Lung Cancer Advanced molecular biology techniques have greatly accelerated the understanding of cancer biology. The application of such technology to lung cancer research has led to the recognition of lung cancer as a molecularly diverse set of tumor types whose only commonality is their origination in the lung.9-11 Lung cancer classification is far more complex than the simplistic grouping into small cell and non-small cell variants that was once thought to represent a homogenous tumor population with a comparable outcome when treated in a similar fashion.12 It is now well accepted that the histologic subdivision of lung cancer based on light microscopy uses only one of many phenotypic manifestations of the genetic changes that underlie lung cancer development. Histologic appearance may accurately predict biologic behavior as noted with the clinically indolent course of a pure bronchioloalveolar-type carcinoma relative to an invasive lung adenocarcinoma or the malignant course of a sarcomatoid variant of NSCLC, now known to represent epithelial-mesenchymal transition, a hallmark of cancer dedifferentiation.13,14 More important to the understanding and management of lung cancer, however, is the crystallization of the theory that, similar to other cancer types, lung cancer development is a result of a stepwise progression of malignant transformation of normal respiratory epithelium.15 This transformation is driven by the cumulative effect of genetic alterations induced predominantly by inhaled carcinogens from tobacco smoke, an implicated etiologic factor in more than 85% of all cases of lung cancer diagnosed in the Lung Cancer Review 92 CA: A Cancer Journal for Clinicians
CA CANCER J CLIN 2011:61:91-112 Western world.16.17 The Noguchi classification of (FHIT),epidermal growth factor receptor (EGFR), lung adenocarcinoma is a pioneering effort to relate vclin-der ndent kinase 2a (CDKN2),LKBI,reti- noblastoma (RB),and Mw g mishaps such as chr om of atypical aden hor equer subtypes noma thre ough a progressive transformation into the tages More recently,inversion translocation of type A,B,and C adenocarcinomas with lepidic the echinoderm microtubule-associated protein-like4 growth (referring to growth along alveolar struc- (EML4)and anaplastic lymphoma kinase (LK)genes tures)characterized by an increasing component of on chromosome 2(2p21 and 2p23)was shown to char invasive carcinoma but showing excellent surviva cinealanholbgcPpoiC"7hheanaitng acterize a small subset of NS( outcome,and the type D,E,and F solid-type The discovery of adenocarcinomas with a well-recognized poor prog other molecularly defined lung cancer subsets is likely to nosis.1 Well-designed molecular biology investi be hastened by this finding. gations over the last decade have also led to the Epigenetic modulation leading to changes in the recognition that genetic and molecular alterations in level of DNA methylation or histone acetylation the host as well as in the lung cancer cells drive the The role of biology of These t im netic change in b an t footprints and P can be g prognosis pons dic p16(TP16 ng car ce. for gets of the in refor e rly mole signatures of the dis Pro nyper hylation of between several prognostic markers that have been herin 13(CDH13),TP16,RASSFIA,and APC i patients with early stage NSCLC correlated with arly disease recurrence. Given the regulatory role been described in lung cancer.Genome-Wide Associ of chromatin structure in gene expression and the ation studies revealed a strong association between implication of chromatin structural alteration in can lung cancer risk and a single-nucleotide poly orphism cer development and progression,markers of epige variant in the region of chromosome 15925.1,which netic changes provide early warning signs of cancer contains the nicotinic acetylcholine receptor genes and may also predict the benefit of ep genetic ther (CHRNA5 CHRNA3 and CHrnrA thereby The increasi g number of viding a genetic basis for variation in susceptibility to the addic oducts the for eristic of lung cancer hasno ren into a fo mult Fi .These es will h that on the develc ovative treatmen s for one The NexGer M3 [GSTM3],glutathione ta inf [GSTP1],and glutathione S-transferase theta- [GSTT1D),may predispose toward lung cancer devel gration of genomic information into cancer manage- effect of tobacco carcinogens. The most frequently described acquired genetic (TCGA)is a gargantuan collaborative project built aberrations within the tumor involve the tumor pro- on these technological advancements.It is sponsored tein p53 (TP53),KRAS,fragile histidine triad by the National Cancer Institute (NCI)and the 93
Western world.16,17 The Noguchi classification of lung adenocarcinoma is a pioneering effort to relate tumor histology with clinical and radiologic characteristics.12,15 This has resulted in the identification of atypical adenomatous hyperplasia and adenocarcinoma in situ as preinvasive neoplastic lung lesions that serve as precursors to invasive lung adenocarcinoma through a progressive transformation into the type A, B, and C adenocarcinomas with lepidic growth (referring to growth along alveolar structures) characterized by an increasing component of invasive carcinoma but showing excellent survival outcome, and the type D, E, and F solid-type adenocarcinomas with a well-recognized poor prognosis.12,15 Well-designed molecular biology investigations over the last decade have also led to the recognition that genetic and molecular alterations in the host as well as in the lung cancer cells drive the biology of the tumor. These changes represent important footprints of biologic drivers and can be used for tumor classification,9-11,18-20 response prediction,19 and assigning prognosis,18,21-23 or even as targets of therapy. Molecular prognostic models of lung cancer have been developed that are based on genomic signatures of the disease,18-22 or based on the interplay between several prognostic markers that have been determined to be individually important in prognosis.24 A very diverse range of genetic abnormalities has been described in lung cancer. Genome-Wide Association Studies revealed a strong association between lung cancer risk and a single-nucleotide polymorphism variant in the region of chromosome 15q25.1, which contains the nicotinic acetylcholine receptor genes (CHRNA5, CHRNA3, and CHRNB4), thereby providing a genetic basis for variation in susceptibility to the addictive potential of tobacco products, the foremost etiology of lung cancer.25-28 Further support for an important role for host biology in lung cancer came from the observation that polymorphisms in genes encoding detoxifying enzymes, glutathione S-transferases (glutathione S-transferase Mu 1 [GSTM1], glutathione S-transferase M3 [GSTM3], glutathione S-transferase P [GSTP1], and glutathione S-transferase theta-1 [GSTT1]), may predispose toward lung cancer development because of an increased susceptibility to the effect of tobacco carcinogens.29-31 The most frequently described acquired genetic aberrations within the tumor involve the tumor protein p53 (TP53), KRAS, fragile histidine triad (FHIT), epidermal growth factor receptor (EGFR), cyclin-dependent kinase 2a (CDKN2), LKB1, retinoblastoma (RB), and Myc genes.32-34 Larger genomic mishaps such as chromosomal deletions involving the short arms of chromosomes 1, 3, and 9 (del 1p36, del 3p, and del 9p, respectively) are also frequently observed in different lung cancer histologic subtypes and stages.35-38 More recently, inversion translocation of the echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes on chromosome 2 (2p21 and 2p23) was shown to characterize a small subset of NSCLC with a characteristic clinical and histologic profile.39-41 The discovery of other molecularly defined lung cancer subsets is likely to be hastened by this finding. Epigenetic modulation leading to changes in the level of DNA methylation or histone acetylation may result in aberrant gene function. The role of epigenetic changes in lung cancer biology is underscored by the finding that aberrant tumor protein p16 (TP16) gene promoter methylation in sputum precedes the detection of lung cancer for up to 3 years in smokers and may therefore represent an early molecular event in the biology of this disease.42 Furthermore, promoter hypermethylation of cadherin 13 (CDH13), TP16, RASSFIA, and APC in patients with early stage NSCLC correlated with early disease recurrence.43 Given the regulatory role of chromatin structure in gene expression and the implication of chromatin structural alteration in cancer development and progression, markers of epigenetic changes provide early warning signs of cancer and may also predict the benefit of epigenetic therapy in lung cancer.44-47 The increasing number of molecular, genetic, and histologic alterations characteristic of lung cancer has now been woven into a multistep carcinogenesis model for this cancer type (Fig. 1).15 These biologic advances will have a major impact on the development of innovative treatment options for lung cancer in the years to come. The development of high-throughput NexGen sequencing capability and advanced data information management systems have further advanced the integration of genomic information into cancer management from a mere promise to a realistic possibility in the very near future.48 The Cancer Genome Atlas (TCGA) is a gargantuan collaborative project built on these technological advancements. It is sponsored by the National Cancer Institute (NCI) and the CA CANCER J CLIN 2011;61:91–112 VOLUME 61 _ NUMBER 2 _ MARCH/APRIL 2011 93
EGFR (ype C) 53%) (yP) D21L0H60 13a13L0H53% 7e1879 FIGURE 1.scher tation of Mok o of No r29ReC Cancer National Human Genome Research Institute of the patients with stage I,II,and certain subsets of stage National Institutes of Health to establish genomic IIIA NSCLC.Among patients with early stage changes in the 20 most common cancer types with NSCLC,approximately 40%are not candidates for the goal of facilitating the understanding and ability to urgery due to the presence of medical comorbid illness exploit genomic changes in cancer for dia Removal of an entire lobe of the lung or,in some instances,the entire lung is the recommended approach with ovarian cancer and glioblastoma with plans to for patients with surgically resectable disease.Sublobar cancer ections are associated with a higher incidence Another high-impact res ch endeavor is the Lung nce.In recent tudies have bee Cancer Mutation which ioeloeu uld focused screer ng for driv A .1 d e su on i morbid lung cancer TCGA,it has set specific goals achievabl e in the shor Until the earlier part of this decade,surgery alone to medium term leading to a better understanding of remained the standard of care for patients with early the complex biology of lung cancer and the identifica- stage NSCLC.The use of postoperative radiotherapy tion of predictive,prognostic markers as well as poten- was noted to be detrimental to survival in a meta tial new treatment targets. analysishaled studies cducted in the past 3 decades The included time period included the Early Stage NSCLC era in which older radiation techniques and larger radiation ports were in common use in the absence CuC of prospective studies to address the role of radiation in the postoperative setting,it is not recommended resection is considered the standard therapy for the routine care of patients who underwent a
National Human Genome Research Institute of the National Institutes of Health to establish genomic changes in the 20 most common cancer types with the goal of facilitating the understanding and ability to exploit genomic changes in cancer for diagnostic, prognostic, and therapeutic endpoints. The TCGA began with ovarian cancer and glioblastoma with plans to expand to other tumor types including lung cancer. Another high-impact research endeavor is the Lung Cancer Mutation Consortium study, which was designed to perform focused screening for driver oncogenic mutations in 1000 patients with stage IIIB/IV NSCLC (ClinicalTrials.gov identifier NCT01014286). Although this is a much more modest effort than the TCGA, it has set specific goals achievable in the short to medium term leading to a better understanding of the complex biology of lung cancer and the identification of predictive, prognostic markers as well as potential new treatment targets. Early Stage NSCLC Approximately one-third of the patients with NSCLC present with early stage disease. Surgical resection is considered the standard therapy for patients with stage I, II, and certain subsets of stage IIIA NSCLC. Among patients with early stage NSCLC, approximately 40% are not candidates for surgery due to the presence of medical comorbid illness. Removal of an entire lobe of the lung or, in some instances, the entire lung is the recommended approach for patients with surgically resectable disease. Sublobar resections are associated with a higher incidence of local recurrence. In recent years, studies have been undertaken to define the subset of patients that could be optimally treated with sublobar resection. Advances in surgical techniques including minimally invasive surgery have led to a reduction in the morbidity and mortality associated with surgery for lung cancer.49-51 Until the earlier part of this decade, surgery alone remained the standard of care for patients with early stage NSCLC. The use of postoperative radiotherapy was noted to be detrimental to survival in a metaanalysis that analyzed studies conducted in the past 3 decades.52,53 The included time period included the era in which older radiation techniques and larger radiation ports were in common use. In the absence of prospective studies to address the role of radiation in the postoperative setting, it is not recommended for the routine care of patients who underwent a FIGURE 1. Schematic Representation of Molecular Aberrations Implicated in the Multistage Neoplastic Progression of Non-Small Cell Lung Cancer. EGFR indicates epidermal growth factor receptor; LOH, loss of heterozygosity. Reprinted with kind permission from Springer Science 1 Business Media from Noguchi M. Stepwise progression of pulmonary adenocarcinoma–clinical and molecular implications. Cancer Metastasis Rev. 2010;29:15-21. Lung Cancer Review 94 CA: A Cancer Journal for Clinicians
CA CANCER J CLIN 2011:61:91-112 TABLE 1.Randomized trials of Adiuvant chemotherapy for Early stage NSCLc STUDY REGIMEN MEDIAN OR PFS MEDIAN OR S-YEAR OS Adjuvant Lung Project Italy 7839m0佩08995% The Big Lung Trial (BLT) 册 cioo2tug 识6吸9赋9% 5%00g26 a060gP08195% 95320302R26%4 CALGB 96335 pd 盟08说P民8%90% 8品e00 aeoreom sandnmorebne 65700339g00 egafur-uradil vs observation 77.4%s73.6%(P=.25) 8a8%牌05% PFS.progre ee survival:OS. erall survival:HR.hazard ratio:95%Cl,95%confidence interval:CALGB,Car complete surgery.Nonetheless,subset analysis sug in addition to local therapy,the need for ed a ative radiother he rasis has b with fo initial effor with py a high rate of local and systemic failure not su are treated with postoperative systemic Th rapy and radiotherapy. e treatment option for a For patients with early stage NSCLC who are not NSCLC led to studies in patients with early stage candidates for surgery due to medical comorbid ill disease. A meta-analysis reported in 1995 demon ness,palliative external beam radiation is used for strated a modest 14%reduction in the risk of death local tumor treatment and control.Recently,stereo tactic body radiotherapy (SBrT)has emerged as a this was not statistically significant. highly promising therapeutic option for these a number of large clinical trials with adequate power patients.a recent phase 2 study for medically unre to detect modest improvements in outcome have been conducted.Tthe international adiuvant lung safety of using SBRT for patients with tumorsp mal to the c ently under a cisnlatin-hased 2 tion The ults in with gery or ohe ion (Table 1).56-61 Th ectable NSCLC have absolute the 5-year survival ized study in Eu rope that compar SBRT with 49% ith djuvant stage other phase apy udy tha ncy ablation RF is also use da15% solute imp ment n 5-yea patients with early stage NS CLC wh wit he combination c cispla are not candidates for surgical resection.RFA is used patients with stages IB ndha and II NSCLC. A meta-analysis of all recent trials with adjuvant cisplatin-based chemotherapy demor strated a 5%improvement in overall survival with Systemic Chemotherapy adiuvant chemotherapy.These results have led to Nearly two-thirds of recurrences after surgery for the use of adjuvant chemotherapy as the new stand- early stage disease occur at distant sites.Therefore, ard of care for patients with early stage NSCLC. 95
complete surgery. Nonetheless, subset analysis suggested a potential benefit of postoperative radiotherapy in patients with positive surgical margins and those with mediastinal lymph node-positive NSCLC52 that experience a high rate of local and systemic failure and are therefore treated with postoperative systemic therapy and radiotherapy. For patients with early stage NSCLC who are not candidates for surgery due to medical comorbid illness, palliative external beam radiation is used for local tumor treatment and control. Recently, stereotactic body radiotherapy (SBRT) has emerged as a highly promising therapeutic option for these patients. A recent phase 2 study for medically unresectable patients demonstrated a 3-year primary tumor control rate of 97% with SBRT.54 The efficacy and safety of using SBRT for patients with tumors proximal to the central airway is currently under investigation. The promising results in patients with medically unresectable NSCLC have already led to a randomized study in Europe that compares SBRT with surgical resection in patients with early stage NSCLC. Radiofrequency ablation (RFA) is also used for the treatment of patients with early stage NSCLC who are not candidates for surgical resection. RFA is used for the treatment of smaller peripheral tumors and has been associated with high local control rates.55 Systemic Chemotherapy Nearly two-thirds of recurrences after surgery for early stage disease occur at distant sites. Therefore, in addition to local therapy, the need for systemic therapy to eradicate micrometastasis has been recognized for a long time. Despite this, initial efforts to evaluate chemotherapy in the postoperative setting for patients with early stage NSCLC were not successful. The emergence of platinum-based chemotherapy as an effective treatment option for advanced NSCLC led to studies in patients with early stage disease. A meta-analysis reported in 1995 demonstrated a modest 14% reduction in the risk of death with the use of cisplatin-based chemotherapy, but this was not statistically significant.53 Subsequently, a number of large clinical trials with adequate power to detect modest improvements in outcome have been conducted. The International Adjuvant Lung Cancer Trial (IALT) included approximately 1800 patients with stages I, II, or III NSCLC who were randomized after surgery to a cisplatin-based, 2- drug regimen or observation (Table 1).56-61 There was an absolute improvement in the 5-year survival rate of 4% with adjuvant chemotherapy. These results were confirmed in another phase 3 study that demonstrated a 15% absolute improvement in 5-year survival with the combination of cisplatin and vinorelbine over observation in patients with stages IB and II NSCLC.58 A meta-analysis of all recent trials with adjuvant cisplatin-based chemotherapy demonstrated a 5% improvement in overall survival with adjuvant chemotherapy.62 These results have led to the use of adjuvant chemotherapy as the new standard of care for patients with early stage NSCLC. TABLE 1. Randomized Trials of Adjuvant Chemotherapy for Early Stage NSCLC STUDY REGIMEN MEDIAN OR PFS MEDIAN OR 5-YEAR OS Adjuvant Lung Project Italy Mitomycin, vindesine, and cisplatin vs observation 36.5 mo vs 28.9 mo (HR, 0.89; 95% CI, 0.76-1.03 [P ¼ .128]) 55.2 mo vs 48 mo (HR, 0.96; 95% CI, 0.81-1.13 [P ¼ .589]) The Big Lung Trial (BLT)57 Cisplatin-based doublet vs observation 27.0 mo vs 24.7 mo (HR, 0.97; 95% CI, 0.74–1.26 [P ¼ .81]) 33.9 mo vs 32.6 mo (HR, 1.02; 95% CI, 0.77–1.35 [P ¼ .90]) International Adjuvant Lung Cancer Trial (IALT)56 Cisplatin-based doublet vs observation 39.4% vs 34.3% (HR, 0.83; 95% CI, 0.74-0.94 [P < .003]) 44.5% vs 40.4% (HR, 0.86; 95% CI, 0.76-0.98 [P < .03]) JBR1058 Cisplatin and vinorelbine vs observation 61% vs 49% (HR, 0.60; 95% CI, 0.45-0.79 [P < .001]) 94 mo vs 73 mo (HR, 0.69; 95% CI, 0.52-0.91 [P ¼ .04]) CALGB 963359 Carboplatin and paclitaxel vs observation 89 mo vs 56 mo (HR, 0.80; 90% CI, 0.62-1.02 [P ¼ .065]) 95 mo vs 78 mo (HR, 0.83; 90% CI, 0.64-1.08 [P ¼ .125]) Adjuvant Navelbine International Trialist Association (ANITA) Trial60 Cisplatin and vinorelbine vs observation 36.3 mo vs 20.7 mo (HR, 0.76; 95% CI, 0.64–0.91 [P ¼ .002]) 65.7 mo vs 43.7 mo (HR, 0.80; 95% CI, 0.66–0.96 [P ¼ .017]) Japan Lung Cancer Research Group (JLCRG): adjuvant trial61 Tegafur-uracil vs observation 77.4% vs 73.6% (P ¼ .25) 88% vs 85% (HR, 0.71; 95% CI, 0.52-0.98 [P ¼ .04]) NSCLC indicates non-small cell lung cancer; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; 95% CI, 95% confidence interval; CALGB, Cancer and Leukemia Group B. CA CANCER J CLIN 2011;61:91–112 VOLUME 61 _ NUMBER 2 _ MARCH/APRIL 2011 95