NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Lung cancer is the leading cause of cancer death in the United States. An estimated 226,200 new cases (116,500 in men and 109,700 in women) of lung and bronchial cancer will be diagnosed in 2012, and 160,300 deaths (87,700 in men and 72,600 in women) are estimated to occur from the disease.1 Only 15.9% of all patients are alive 5 years or more after lung cancer diagnosis (seer.cancer.gov/statfacts/html/lungb.html). Common symptoms of lung cancer include cough, dyspnea, weight loss, and chest pain; symptomatic patients are more likely to have chronic obstructive pulmonary disease.
These guidelines only include information about stage IV non–small cell lung cancer (NSCLC). The complete version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC is available on the NCCN Web site (NCCN.org).
Currently, most patients with NSCLC are diagnosed with advanced cancer at presentation. Symptoms of metastatic cancer include weight loss, bone pain, headaches, anemia, and paraneoplastic syndromes.2 A preliminary diagnosis of metastatic disease is established using symptoms, signs, and laboratory tests,2 and is aided by imaging (eg, PET/CT scan, MRI).3,4 Patients with widespread metastatic disease (stage IV) are usually candidates for systemic therapy (consisting of chemotherapy, targeted therapy, or a combination), clinical trials, and/or palliative treatment. The goal is to identify patients with metastatic disease before initiating aggressive treatment (eg, combined modality therapy), thus sparing these patients from unnecessary futile treatment. If metastatic disease is discovered during surgery, then extensive surgery is often aborted. Decisions regarding treatment should be based on multidisciplinary discussion.
Risk Factors
The primary risk factor for lung cancer is smoking tobacco, which accounts for more than 85% to 90% of all lung cancer–related deaths (www.surgeongeneral.gov/library/smokingconsequences/).5–7 Cigarette smoke contains many carcinogenic chemicals (eg, nitrosamines, benzo[a]pyrene diol epoxide).6,8 The risk for lung cancer increases with the number of cigarettes packs smoked per day and with the number of years spent smoking (ie, pack-years of smoking history). Exposed nonsmokers also have an increased risk (relative risk [RR], 1.24) of developing lung cancer from “secondhand smoke” (www.surgeongeneral.gov/library/secondhandsmoke/report/executivesummary.pdf).8–11 Other risk factors for lung cancer (eg, asbestos, radon, family history) are discussed in the NCCN Guidelines for Lung Cancer Screening (to view the most recent version of these guidelines, visit NCCN.org).
NCCN Clinical Practice Guidelines in Oncology: Non–Small Cell Lung Cancer, Version 3.2012
Version 3.2012, 04-11-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 10; 10.6004/jnccn.2012.0130
NCCN Clinical Practice Guidelines in Oncology: Non–Small Cell Lung Cancer, Version 3.2012
Version 3.2012, 04-11-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 10; 10.6004/jnccn.2012.0130
NCCN Clinical Practice Guidelines in Oncology: Non–Small Cell Lung Cancer, Version 3.2012
Version 3.2012, 04-11-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 10; 10.6004/jnccn.2012.0130
NCCN Clinical Practice Guidelines in Oncology: Non–Small Cell Lung Cancer, Version 3.2012
Version 3.2012, 04-11-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 10; 10.6004/jnccn.2012.0130
NCCN Clinical Practice Guidelines in Oncology: Non–Small Cell Lung Cancer, Version 3.2012
Version 3.2012, 04-11-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 10; 10.6004/jnccn.2012.0130
NCCN Clinical Practice Guidelines in Oncology: Non–Small Cell Lung Cancer, Version 3.2012
Version 3.2012, 04-11-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 10; 10.6004/jnccn.2012.0130
Prevention and Screening
Approximately 85% to 90% of lung cancer cases are caused by cigarette smoking.5 Active smoking and secondhand smoke both cause lung cancer (see Reports from the Surgeon General, the next 2 links). A causal relationship exists between active smoking and lung cancer, in addition to other cancers (eg, esophageal, oral cavity, laryngeal, pharyngeal, bladder, pancreatic, gastric, kidney, ovarian, colorectal, and cervical cancers) and other diseases and conditions (www.cdc.gov/tobacco/data_statistics/sgr/2004/pdfs/executivesummary.pdf).
Smoking harms nearly every organ in the body. People who live with someone who smokes have a 20% to 30% increased risk for lung cancer (www.surgeongeneral.gov/library/secondhandsmoke/report/executivesummary.pdf). Further complicating this problem, cigarettes also contain nicotine, which is a highly addictive substance.
Oncologists should encourage smoking cessation, especially in patients with cancer (www.smoke-free.gov). Persistent smoking is associated with second primary cancers, treatment complications, and decreased survival. Programs using behavioral counseling combined with medications that promote smoking cessation (approved by the FDA) can be very useful (see Treating Tobacco Use and Dependence: 2008 Update, available at www.ahrq.gov/clinic/tobacco/tobaqrg.htm#Findings).
Agents that can be used to promote smoking cessation include nicotine replacement (eg, gum, inhaler, lozenge, nasal spray, patch), sustained-release bupropion, and varenicline. Studies have shown that varenicline is better than bupropion or a nicotine patch for smoking cessation.12–14 However, almost 30% of patients experienced nausea while using varenicline.15 The effectiveness of varenicline for preventing relapse has not been clearly established,16 and the FDA has issued an alert regarding neuropsychiatric symptoms (www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106540.htm). Varenicline has also been associated with other disorders (eg, visual disturbances, movement disorders, unconsciousness, cardiovascular disorders), and therefore its use is banned in truck and bus drivers, pilots, and air traffic controllers.17 Bupropion is also associated with serious adverse events (www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm169986.htm). Nicotine replacement has fewer adverse effects than varenicline or bupropion.18 However, despite their potential adverse effects, using agents to promote smoking cessation is probably more beneficial for motivated patients.18
Lung cancer is still the leading cause of cancer death worldwide, and late diagnosis is a fundamental obstacle to improving outcomes.19,20 Because localized cancer can be managed curatively, and survival in other solid tumors (eg, breast, cervix, colon, and prostate) seems to be increased through screening and early detection, lung cancer would be an appropriate candidate for a population-based screening approach. Pilot trials of spiral (helical) low-dose CT in lung cancer screening were promising, with stage I detectable lung cancer found in more than 80% of newly diagnosed cases.21–23
The National Lung Screening Trial (NLST; ACRIN protocol A6654) was a randomized, controlled trial involving more than 53,000 current or former heavy smokers that assessed the risks and benefits of low-dose helical CT scans compared with chest radiographs in detecting lung cancer.24 Recent published results from the NLST show that screening high-risk patients with low-dose helical CT decreases the mortality rate from lung cancer by 20% compared with chest radiograph.25 High-risk patients were either current or former smokers with a 30-pack year smoking history (former smokers had quit 15 years ago), were aged 55 to 74 years, and had no evidence of lung cancer.24,26 Additional information on NLST can be found at www.cancer.gov/nlst. The new NCCN Guidelines for Lung Cancer Screening were published in JNCCN in March 2012,27 and are available on the NCCN Web site (NCCN.org).
The International Early Lung Cancer Action Program (I-ELCAP) is assessing whether annual screening with low-dose helical CT scan increases the detection of early stage lung cancer in patients at risk for cancer. Data from I-ELCAP showed that stage I lung cancer can be detected using annual low-dose CT screening. The 10-year survival rate was 92% for patients with stage I disease whose cancers were promptly removed; however, all patients who chose not to be treated died within 5 years.28 Additional information on I-ELCAP can be found at www.ielcap.org/index.htm. Screening can increase the diagnosis of early-stage lung cancers. Recent data from the NLST show that screening decreases the mortality rate.25
Classification and Prognostic Factors
The WHO divides lung cancer into 2 major classes based on its biology, therapy, and prognosis: NSCLC and small cell lung cancer (SCLC; see the NCCN Guidelines for Small Cell Lung Cancer, available at NCCN.org). NSCLC accounts for more than 85% of all lung cancer cases and includes 2 major types: nonsquamous carcinoma (including adenocarcinoma, large-cell carcinoma, and other cell types) and squamous cell (epidermoid) carcinoma. Adenocarcinoma is the most common type of lung cancer found in the United States and is the most frequently occurring cell type in nonsmokers. An international panel recently revised the classification of lung adenocarcinoma (see next section on “Pathologic Evaluation of Lung Cancer”).29
Certain prognostic factors are predictive of survival in patients with NSCLC. Good prognostic factors include early-stage disease at diagnosis, good performance status (PS; ECOG 0, 1, or 2), no significant weight loss (not > 5%), and female sex.30
Pathologic Evaluation of Lung Cancer
Pathologic evaluation is performed to classify the histologic type of the lung cancer, determine the extent of invasion, and determine whether it is primary lung cancer or metastatic cancer, and molecular diagnostic studies are performed to determine whether certain gene mutations are present (eg, epidermal growth factor receptor [EGFR] mutations) (see pages 1245–1247). Data show that targeted therapy is potentially very effective in patients with specific gene mutations or rearrangements (see “EGFR Mutations” and “EML4-ALK Gene Rearrangements” on pages 1253 and 1254, respectively).31–35 Evaluations include examination of the following: bronchial brushings, bronchial washings, fine-needle aspiration (FNA) biopsy, core needle biopsy, endobronchial biopsy, and transbronchial biopsy. Also, the mediastinal lymph nodes are systematically sampled (if appropriate) to assess the staging and therapeutic options. However, if it is obvious that the patient has widespread metastatic disease, then extensive evaluation of the mediastinal lymph nodes is not necessary.
Evaluation provides the pathologic characteristics necessary for classification of tumor type, staging, and prognostic factors. The surgical pathology report should include the histologic classification published by the WHO for carcinomas of the lung.36 However, an international panel recently revised the classification for lung adenocarcinoma (see next section)29 to require immunohistochemical, histochemical, and molecular studies (see pages 1245–1247). The revised classification also recommends that use of general categories (eg, NSCLC) should be minimized, because more effective treatment can be selected when the histology is known.
Adenocarcinoma
Recently, the classification for adenocarcinoma was revised; the categories of bronchioloalveolar carcinoma (BAC) or mixed subtype adenocarcinoma are no longer used.29 If necessary, the term former BAC is used. The new categories include 1) adenocarcinoma in situ (AIS; formerly BAC), which is a preinvasive lesion; 2) minimally invasive adenocarcinoma (MIA); 3) invasive adenocarcinoma (includes formerly nonmucinous BAC); and 4) variants of invasive adenocarcinoma (includes formerly mucinous BAC). The international panel and NCCN recommend that all patients with adenocarcinoma be tested for the EGFR mutation; the NCCN panel also recommends that these patients be tested for the ALK gene rearrangement.
Immunohistochemical Staining
Immunostains are used to differentiate primary pulmonary adenocarcinoma from metastatic adenocarcinoma of the lung (eg, breast, prostate, colorectal), distinguish adenocarcinoma from malignant mesothelioma, and determine the neuroendocrine status of tumors. Immunohistochemical staining is described in the algorithm (see pages 1245–1247). Although cytology can be used to distinguish adenocarcinomas from squamous cell carcinomas, immunohistochemistry is also useful for poorly differentiated NSCLC in small biopsy and/or cytology specimens.29,37 Squamous cell carcinomas are often thyroid transcription factor -1 (TTF-1)–negative, p63-positive, and cytokeratin 5/6–positive, whereas adenocarcinomas are usually TTF-1–positive. Thus, a panel of these 3 markers may be sufficient to distinguish adenocarcinomas from squamous cell carcinomas.37 Other markers (eg, high-molecular-weight cytokeratin [34ßE12], napsin A, mucicarmine) may also be useful in distinguishing adenocarcinoma from squamous cell carcinoma.38,39
Immunohistochemistry is most valuable in distinguishing between malignant mesothelioma and lung adenocarcinoma.40 Stains that are positive for adenocarcinoma but negative for mesothelioma include carcinoembryonic antigen (CEA), B72.3, Ber-EP4, MOC31, and TTF-1.41 Stains that are sensitive and specific for mesothelioma include WT-1, calretinin, D2-40 (podoplanin),42 and cytokeratin 5/6.40 A panel of 4 markers are used to distinguish mesothelioma from adenocarcinoma; 2 are positive in mesothelioma and 2 are positive in adenocarcinoma but negative in mesothelioma, and include calretinin, cytokeratin 5/6 (or WT-1), CEA, and MOC-31 (or B72.3, Ber-EP4, or BG-8).40,43
TTF-1 is a transcription factor that regulates tissue-specific expression of surfactant apoprotein A, surfactant apoprotein B, surfactant apoprotein C, Clara cell antigen, and T1α. TTF-1 is very important in distinguishing primary from metastatic adenocarcinoma, because most primary carcinomas are TTF-1–positive; TTF-1 is typically negative for squamous cell carcinoma.37 However, TTF-1 is positive in tumors from patients with thyroid cancer.44 In addition, thyroglobulin is present in tumors from patients with thyroid cancer, whereas it is absent in lung cancer tumors. Pulmonary adenocarcinoma of the lung is usually CK7+ and CK20–, whereas metastatic adenocarcinoma of the colorectum is usually CK7– and CK20+. CDX-2 is a marker for metastatic gastrointestinal malignancies that can be used to differentiate between primary lung tumors. All typical and atypical carcinoid tumors are positive for chromogranin and synaptophysin, whereas small cell lung carcinoma is negative in 25% of cases.
Although the cytologic diagnosis of NSCLC is generally reliable, it is more difficult to diagnose SCLC.45 However, many patients with SCLC have characteristic CT and clinical findings (eg, massive lymphadenectomy, mediastinal invasion). Most SCLCs are immunoreactive for TTF-1 and are typically negative for CK34βE12 and p63.46,47 Many SCLCs also stain positively for markers of neuroendocrine differentiation, including chromogranin A, neuron-specific enolase, neural cell adhesion molecule (NCAM), and synaptophysin. However, these markers alone cannot be used to distinguish SCLC from NSCLC, because approximately 10% of NSCLCs are immunoreactive for at least 1 of these neuroendocrine markers.48 Recent data suggest that microRNA (miRNA) expression can be used to distinguish SCLC from NSCLC.49
Staging
The international staging system for lung cancer has been revised and adopted by the AJCC and by the Union Internationale Contre le Cancer.50–53 Recently, the lung cancer staging system was revised by the International Association of the Study of Lung Cancer (IASLC)54,55 and is available from the AJCC (7th edition). These NCCN Guidelines use the revised AJCC (7th edition) staging.56 The revised stage grouping and descriptors of the TNM classification scheme are shown in the staging tables for lung cancer (available online, in these guidelines, at NCCN.org).
The TNM staging revisions (AJCC 7th edition) became effective for all new cases diagnosed after January 1, 2010.56 With the revised staging, locally advanced disease is now stage III and advanced disease is now stage IV. The revised AJCC staging for 2010 includes upstaging and downstaging; for example, wet IIIB (ie, malignant pleural effusions) is upstaged to stage IV.57,58 These changes reflect the prognosis of patients with these different tumors. Pathologic staging uses both clinical staging information, which is noninvasive and includes medical history, physical examination, and imaging, and other invasive staging procedures, such as examination of lymph nodes using mediastinoscopy.50
For 2005 through 2009, the overall 5-year relative survival rate for lung cancer was 15.9% (from 17 SEER geographic areas in the United States). Of lung and bronchial cancer cases, 15% were diagnosed while the cancer was still confined to the primary site (localized stage); 22% were diagnosed after the cancer had spread to regional lymph nodes or directly beyond the primary site; 56% were diagnosed after the cancer had already metastasized (distant stage); and the staging information was unknown for the remaining 6%. The corresponding 5-year relative survival rates were 52% for localized, 25% for regional, 3.7% for distant, and 7.9% for unstaged (seer.cancer.gov/statfacts/html/lungb.html). However, these data include SCLC, which has a poorer prognosis.
Prognostic and Predictive Biomarkers
Several biomarkers have emerged as prognostic and predictive markers for NSCLC, including EGFR and the EML4-ALK fusion oncogene (fusion between echinoderm microtubule-associated protein-like 4 [EML4] and anaplastic lymphoma kinase [ALK]). A prognostic biomarker is a biomolecule that indicates patient survival independent of the treatment received; that is, the biomolecule is an indicator of innate tumor aggressiveness. A predictive biomarker is a biomolecule that indicates therapeutic efficacy; that is, an interaction between the biomolecule and therapy predicts patient outcome. A more extensive discussion of biomarkers (eg, K-ras) is available in the complete version of the NCCN Guidelines for NSCLC (available at NCCN.org).
The presence of the EGFR exon 19 deletion (LREA) or exon 21 L858R mutation does not seem to be prognostic of survival for patients with NSCLC, independent of therapy.59 However, the presence of the EGFR exon 19 deletion or exon 21 L858R mutation is predictive of treatment benefit with EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy.60,61 The EML4-ALK fusion oncogene (ie, ALK gene rearrangement) is a new predictive biomarker that has been identified in a small subset of patients with NSCLC (see “EML4-ALK Gene Rearrangements” on page 1254, and pages 1245–1247 of the algorithm).
Testing for EGFR mutations and ALK gene rearrangements is recommended for select patients (eg, those with adenocarcinoma) so those with these genetic abnormalities can receive effective treatment (eg, erlotinib, crizotinib). Patients with adenocarcinoma may have other genetic abnormalities.62,63 Mutation screening assays for detecting multiple biomarkers (eg, SNaPshot Multiplex System) have been developed that can detect more than 100 point mutations, including EGFR (www.mycancergenome.org/molecular-pathology/).64 However, these systems do not detect ALK gene rearrangements, because they are not point mutations. ALK gene rearrangements are detected using fluorescence in situ hybridization (FISH; see “EML4-ALK Gene Rearrangements” on page 1254). Ongoing research is assessing whether other biomarkers (eg, BRAF) may be useful therapeutic targets.65
EGFR Mutations
EGFR is a transmembrane receptor that is detectable in approximately 80% to 85% of patients with NSCLC, and the levels of expression vary widely on a continual scale. The most commonly found EGFR mutations in patients with NSCLC are deletions in exon 19 (E19del [LREA deletion] in 45% of patients) and a mutation in exon 21 (L858R in 40%). Both mutations result in activation of the tyrosine kinase domain and are associated with sensitivity to the small-molecule TKIs (eg, erlotinib, gefitinib). These drug-sensitive mutations are found in approximately 10% of Caucasian patients with NSCLC and up to 50% of Asian patients.66 Other drug-sensitive mutations include point mutations at exon 21 (L861Q) and 18 (G719X).6 The T790M mutation is associated with resistance to TKI therapy and has been reported in approximately 50% of patients with disease progression.68–70
DNA mutational analysis is the preferred method to assess for EGFR status, although FISH (to determine gene copy number) and immunohistochemistry (to determine level of expression) have been used.71–73 Various DNA mutation detection assays can be used to determine the EGFR mutation status in tumor cells. Direct sequencing of DNA corresponding to exons 18 to 21 (or just testing for exons 19 and 21) is a reasonable approach; however, more-sensitive methods are available.66,72,74–76 The multiplex mutation screening assay, SNaPshot Multiplex System, can detect more than 100 point mutations, including EGFR.64 EGFR mutation status may be better to assess on the primary tumor before therapy and not on the metastasis, although no consensus has been reached.
The prognostic effect of the drug-sensitive EGFR mutations—E19del (LREA deletion) and L858R—is not clear, whereas the predictive effects of these mutations are well defined. Patients with these mutations have a significantly better response to erlotinib or gefitinib. Initial retrospective reports suggested that approximately 90% of patients with a tumor response to these drugs had mutations, whereas unresponsive patients did not.77,78 Subsequent retrospective studies have demonstrated an objective response rate of approximately 80%, with a median progression-free survival of 13 months to single-agent therapy in patients with a bronchioloalveolar variant of adenocarcinoma and an EGFR mutation.60 A prospective study showed that the objective response rate in North American patients with nonsquamous cell histology and EGFR mutations (53% E19del [LREA deletion], 26% L858R, 21% other mutations) is 55%, with a median progression-free survival of 9.2 months.61 In patients treated with first-line chemotherapy with or without erlotinib, EGFR mutations were predictive of a better response in those receiving erlotinib (53% with mutations vs. 18% without).33 The response rates in the group of patients receiving only chemotherapy were 21% for those with mutations and 27% for those without.
In contrast, recent data suggest that erlotinib alone should be used as first-line systemic therapy in patients with proven EGFR mutations before use of standard first-line chemotherapy.79–83 Data show an improved progression-free survival with use of TKI inhibitors in patients with EGFR mutations when compared with standard chemotherapy, although overall survival is not statistically different.
EML4-ALK Gene Rearrangements
An estimated 2% to 7% of patients (approximately 10,000) have EML4-ALK gene rearrangements in the United States.35 These patients are resistant to EGFR TKIs but are similar to those with EGFR mutations (eg, those with adenocarcinoma, nonsmokers, or light smokers) except that they are often younger and male.63 In addition, ALK rearrangements are found in patients with adenocarcinoma but are not usually found in squamous cell or large cell carcinoma.63 ALK rearrangement testing is not routinely recommended for those with squamous cell carcinoma.
In these selected populations, estimates are that approximately 30% of patients will have EML4-ALK rearrangements.63 EGFR mutations and EML4-ALK rearrangements are generally mutually exclusive.84 Thus, erlotinib (or gefitinib) may not be effective as second-line therapy in patients with ALK rearrangements who experience relapse on crizotinib.62,63 Recently, a molecular diagnostic test (using FISH) was FDA-approved for detecting ALK. A FISH probe set (for ALK-rearranged anaplastic large cell lymphomas) seems to be better than immunohistochemistry tests for detecting EML4-ALK rearrangements.85–87
Crizotinib (an inhibitor of ALK and MET tyrosine kinases) was recently approved by the FDA for patients with locally advanced or metastatic NSCLC who have the ALK gene rearrangement (www.accessdata.fda.gov/drugsatfda_docs/label/2012/202570s003lbl.pdf).88–90 Recently, crizotinib was shown to yield very high response rates (> 80%) and improve survival when used in patients with advanced NSCLC who have EML4-ALK rearrangements and have experienced disease progression on previous therapy.35,91 Crizotinib is orally active with few side effects (eg, elevations in aminotransferases). However, a few patients have had life-threatening pneumonitis, and administration of crizotinib was stopped.88 Patients have responded rapidly to crizotinib, although many have developed resistance after approximately 1 year.92 However, other EMLK4-ALK inhibitors are in development.93–96 A randomized phase III trial (PROFILE-1007) is comparing crizotinib with standard second-line chemotherapy.
Treatment Approaches
History and physical, standard laboratory testing, and imaging (eg, brain MRI, PET/CT scan) are used to assess whether a patient has metastatic disease. For example, patients may have clinical stage II–III disease that is later found to be stage IV disease (more information is available in these guidelines at NCCN.org). Pathologic evaluation of the mediastinal nodes (eg, mediastinoscopy) is recommended for many patients with stages I–III NSCLC. It is not necessary, however, for patients with NSCLC whose disease is clearly metastatic, because lymph node status (eg, N2 vs. N3) will not change treatment. If metastatic disease is suspected, less-invasive staging procedures may be useful (eg, transesophageal endoscopic ultrasound–guided FNA [EUS-FNA], endobronchial ultrasound–guided transbronchial needle aspiration [EBUS-TBNA]).
Systemic therapy (consisting of chemotherapy, targeted therapy, or a combination), clinical trials, and/or palliative treatment are commonly used to treat patients with metastatic NSCLC; these patients are not candidates for aggressive treatment (eg, combined modality treatment).97 The goal is to identify patients with metastatic disease before administering aggressive treatment (eg, chemoradiation, pneumonectomy) and thus spare them unnecessary futile (and potentially toxic) treatment. Radiation therapy (RT) is appropriate in select patients with stage IV disease; surgery is rarely performed in these patients (see “Surgery,” next section, and “Radiation Therapy,” on page 1257).
For patients with stage IV disease who have a good PS, platinum-based chemotherapy is beneficial.98–100 Despite the development of new chemotherapy regimens, the prognosis for advanced inoperable lung cancer remains poor. Recent data show that early palliative care combined with standard care improves quality of life, mood, and survival in patients with metastatic NSCLC, even though these patients received less-aggressive therapy than those receiving standard care alone.101
Surgery
Typically, surgery (eg, pneumonectomy) is not appropriate for patients with metastatic disease. If surgery is planned (eg, clinical stage III), it may be aborted if metastatic disease is found during surgical evaluation. Surgical resection of a solitary brain metastasis may improve survival in select patients with stage IV disease and is recommended in the NCCN Guidelines (see page 1239 and the NCCN Guidelines for Central Nervous System Cancers, available at NCCN.org).102 Surgical resection of a solitary metastasis located in sites other than the brain remains controversial; however, stereotactic radiosurgery (SRS) or stereotactic ablative radiotherapy (SABR) may be useful in these settings (see page 1239).
Systemic Therapy
Chemotherapy: Patients with stage IV disease who have a good PS benefit from chemotherapy, usually with a platinum-based regimen.98–100 Many drugs are useful for stage IV NSCLC (see “Treatment of Recurrences and Distant Metastases” on page 1260, and pages 1248–1249 of the algorithm).99,100,103,104 These drugs include platinum agents (cisplatin, carboplatin), taxanes (paclitaxel, docetaxel), vinorelbine, vinblastine, etoposide, pemetrexed, and gemcitabine. Combinations using many of these drugs produce 1-year survival rates of 30% to 40% and are superior to single agents. Regimens include carboplatin/paclitaxel, cisplatin/paclitaxel, cisplatin/vinorelbine, gemcitabine/cisplatin, cisplatin/pemetrexed, and docetaxel/cisplatin.105–109 Phase III randomized trials have shown that many of the platinum-doublet combinations have similar objective response rates and survival.110,111 Platinum-doublet regimens differ slightly for toxicity, convenience, and cost; thus, clinicians can individualize therapy for patients. Other carboplatin-based regimens include gemcitabine/carboplatin, docetaxel/carboplatin, and pemetrexed/carboplatin106,112–114; gemcitabine/vinorelbine and gemcitabine/docetaxel are also options.115–117
Note that albumin-bound paclitaxel can be substituted for paclitaxel or docetaxel in patients who have experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despite premedication, or those for whom the standard premedications (ie, dexamethasone, H2 and H1 blockers) to prevent hypersensitivity are contraindicated.118,119
Targeted Therapies: Specific targeted therapies have been developed for the treatment of advanced lung cancer.120,121 Bevacizumab is a recombinant monoclonal antibody that blocks the vascular endothelial growth factor (VEGF). Erlotinib is a small molecule inhibitor of EGFR; crizotinib is a small molecule inhibitor that targets ALK and MET. Cetuximab is a monoclonal antibody that targets EGFR.
In 2006, the FDA approved bevacizumab for patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC. The ECOG recommends bevacizumab in combination with paclitaxel and carboplatin for select patients with advanced nonsquamous NSCLC based on the results of phase II/III clinical trials (ECOG 4599).122 To undergo treatment with bevacizumab and chemotherapy, patients must have nonsquamous NSCLC and no recent history of hemoptysis. Any regimen with a high risk for thrombocytopenia, and therefore possible bleeding, should be used with caution when combined with bevacizumab. For patients with nonsquamous NSCLC and PS 0 or 1 who are EGFR mutation–negative or unknown, bevacizumab in combination with chemotherapy is one of the recommended options (see page 1242).
Erlotinib was approved by the FDA in 2004 for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. However, erlotinib is also recommended as first-line therapy in patients with advanced, recurrent, or metastatic nonsquamous NSCLC who have a known active EGFR mutation or gene amplification, regardless of PS (see page 1241).33,123–125 This recommendation is based on the results of a phase III randomized trial (Iressa Pan-Asia study [IPASS]) in which patients with EGFR mutations who received gefitinib had increased progression-free survival (24.9% vs. 6.7%), response rates (71.2% vs. 47.3%), and quality of life with fewer side effects (eg, neutropenia) compared with those receiving chemotherapy (carboplatin/paclitaxel).124 Gefitinib is not readily available in the United States, and therefore erlotinib is often used. Erlotinib is an orally active agent that is very well tolerated by most patients.
An analysis of 5 clinical trials in predominantly Western populations (N = 223) with advanced NSCLC (stage IIIB or IV) found that patients with EGFR mutations who received TKIs had a 67% response rate and an overall survival of approximately 24 months.126 The recent TORCH trial suggests that EGFR mutation testing should be performed in patients with advanced nonsquamous NSCLC.127 Survival was increased in patients with wild-type EGFR who received first-line chemotherapy compared with those who received erlotinib followed by second-line chemotherapy (10.8 vs. 7.7 months). The recent OPTIMAL trial found that progression-free survival was increased in patients with EGFR mutations receiving erlotinib.81,82 ASCO recommends that patients be tested for an EGFR mutation.128 However, NCCN and the European Society for Medical Oncology (ESMO) guidelines specify that only patients with nonsquamous histology (eg, adenocarcinoma) be assessed for EGFR mutations.129 Patients with squamous cell carcinoma are unlikely to have these mutations.
Crizotinib was recently FDA-approved for patients with locally advanced or metastatic NSCLC who are positive for the ALK gene rearrangement. The approval was based on an ongoing phase II trial that showed dramatic response rates (> 80%) in patients whose disease had previously progressed.88,89 Patients receiving crizotinib reported clinically significant improvements in pain, dyspnea, and cough.
A large phase III randomized trial (FLEX) assessed cisplatin/vinorelbine with or without cetuximab for patients with advanced NSCLC (most had stage IV disease).130 Adding cetuximab slightly increased overall survival (11.3 vs. 10.1 months; P = .04). Cetuximab/cisplatin/vinorelbine is an option for patients with advanced NSCLC, regardless of histology (see page 1242). However, the cetuximab/cisplatin/vinorelbine regimen has a category 2B recommendation in these guidelines because the benefits are very slight, it is a difficult regimen to administer, and patients have a poor tolerance for this regimen compared with other regimens (eg, almost 40% experienced grade 4 neutropenia). Patients may also have comorbid conditions that prevent them from receiving cisplatin (eg, poor kidney function). Although the FLEX trial results were statistically significant, some clinicians believe they were not clinically significant.
Maintenance Therapy: Maintenance therapy refers to systemic therapy that may be given to patients with advanced NSCLC after 4 to 6 cycles of first-line chemotherapy. However, patients are only candidates for maintenance therapy if they experienced response to their previous treatment (ie, tumor response) or have stable disease and have no disease progression. Continuation maintenance therapy refers to the use of at least one of the agents given in the first-line regimen. Switch maintenance therapy refers to the initiation of a different agent not included as part of the first-line regimen. Selection of appropriate maintenance therapy depends on several factors (eg, histologic type, PS).
For continuation maintenance therapy, targeted agents (initially given in combination with conventional chemotherapy) may be continued until evidence of disease progression or unacceptable toxicity, as per the design of the clinical trials that led to FDA approval. Bevacizumab (category 1) may be continued beyond 4 to 6 cycles of initial therapy (ie, platinum-doublet chemotherapy given with bevacizumab) in patients with nonsquamous histology.122,131,132 Pemetrexed may also be given as continuation maintenance therapy in patients with nonsquamous histology (who are EGFR mutation–negative or unknown).131 A recent phase III randomized trial (PARAMOUNT) found that continuation therapy with pemetrexed slightly increased progression-free survival compared with placebo (4.1 vs. 2.8 months); overall survival data are not yet available.133 Cetuximab (category 1) may be continued beyond 4 to 6 cycles of initial therapy (ie, cisplatin, vinorelbine, and cetuximab therapy) in patients with nonsquamous histology (who are EGFR mutation–negative or unknown) or those with squamous histology.130
Use of continuation maintenance therapy depends on several factors, such as whether the patient had minimal toxicity during treatment. A drug “vacation” may be more appropriate for some patients. Some clinicians believe that continuation maintenance therapy is only appropriate for select patients, because it has not been shown to improve overall survival or quality of life.134–136 In addition, maintenance therapy has not been shown to be superior to second-line therapy, which is initiated at disease progression. No randomized trials support the continuation maintenance of conventional cytotoxic agents beyond 4 to 6 cycles of therapy.134 However, some clinicians believe that the cytotoxic chemotherapy should be continued if patients experience response.
A recent phase III randomized trial compared maintenance therapy with either gemcitabine or erlotinib after first-line therapy with cisplatin/gemcitabine. Data show that continuation maintenance therapy with gemcitabine increased progression-free survival to a greater extent (3.8 months) than switch maintenance therapy with erlotinib (2.9 months) when compared with observation (1.9 months).137 Another phase III randomized trial assessed continuation maintenance therapy with gemcitabine versus best supportive care after an initial regimen of cisplatin/gemcitabine.138 The data showed a slight difference in progression-free survival but no difference in overall survival. Thus, these guidelines recommend using gemcitabine as continuation maintenance therapy.
For switch maintenance therapy, 2 recent phase III randomized trials have shown a benefit in progression-free and overall survival with the initiation of pemetrexed or erlotinib after first-line chemotherapy (4–6 cycles) in patients without disease progression.139,140 Switch maintenance therapy with pemetrexed may be initiated in patients with histologies other than squamous cell carcinoma who are EGFR mutation–negative (or with unknown mutation status).140 The FDA has approved maintenance therapy with pemetrexed (www.accessdata.fda.gov/drugsatfda_docs/label/2011/021462s029s030s032lbl.pdf).141 Likewise, switch maintenance therapy with erlotinib may be initiated in patients with or without EGFR mutations, or with squamous cell carcinoma.137,139 Both erlotinib and pemetrexed have a category 2A recommendation for switch maintenance (see page 1242). A phase III trial assessed switch maintenance therapy with docetaxel given either immediately after chemotherapy or delayed until progression.142 However, switch maintenance therapy with docetaxel is a category 2B recommendation because many patients in the delayed chemotherapy arm did not receive docetaxel.
Recently, an updated study (CALGB 30406) compared erlotinib alone versus erlotinib/carboplatin/paclitaxel in patients (mainly Caucasian) with advanced NSCLC.143 The data showed that in patients with EGFR mutations, erlotinib alone was associated with fewer side effects than erlotinib and chemotherapy. Thus, switching to maintenance therapy with erlotinib is appropriate in patients found to have EGFR mutations during chemotherapy (see page 1241). The FDA has approved maintenance therapy with erlotinib (www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf).144
Radiation Therapy
In patients with advanced lung cancer (stage IV), RT is recommended for 1) palliative care, 2) prevention of symptoms, 3) whole-brain RT and/or SRS for brain metastases (see page 1239), and 4) SABR, traditionally known as stereotactic body RT (SBRT) for lung lesions. In patients with extensive metastases, palliative RT can be used for primary or distant sites. Treatment of brain metastases is described in the NCCN Guidelines for Central Nervous System Cancers (to view the most recent version of these guidelines, visit NCCN.org).
The complete version of the NCCN Guidelines for NSCLC (available at NCCN.org) contains a “Principles of RT” section, which includes 1) general principles for advanced lung cancer; 2) target volumes, prescription doses, and normal tissue dose constraints for advanced lung cancer; and 3) radiation simulation, planning, and delivery.145–150 Whole-brain RT and SRS for brain metastases and the abbreviations for RT are also described in this complete version.
External-beam RT is recommended for local palliation or for prevention of symptoms (ie, pain, bleeding, and obstruction; see page 1240 and NSCL-B, 8 of 8 [available online, in these guidelines, at NCCN.org]). The dose and fractionation of palliative RT should be individualized based on goals of care, symptoms, PS, and logistical considerations to maximize quality of life. Shorter courses of RT provide similar pain relief as longer courses and are favored for patients with poor PS and/or shorter life expectancy.151–154 However, shorter courses of RT have a higher potential for retreatment. When higher doses (> 30 Gy) are warranted, 3D conformal RT should be used to reduce normal tissue irradiation.
Definitive local therapy to isolated or limited metastatic sites (oligometastases), including brain, lung, and adrenal gland, achieves prolonged survival in a small proportion of well-selected patients with good PS who have also received radical therapy to the intrathoracic disease. Definitive RT to oligometastases, particularly SABR, is an appropriate option in these cases if it can be safely delivered to the involved site.155–157
SABR: SABR (traditionally known as SBRT) uses short courses of very high RT doses delivered precisely to the target.158–160 SABR can be used for patients with limited lung metastases and for palliative therapy.161,162 Studies also suggest that SABR can be used for bone, liver, and brain metastases.158 SABR is discussed more fully in the “Principles of RT” section of the full NCCN Guidelines for NSCLC (available at NCCN. org), including fractionation regimens, normal tissue constraints,163–171 and dose recommendations. Decisions regarding whether to recommend SABR should be based on multidisciplinary discussion.
Whole-Brain RT and SRS: Many patients with NSCLC have brain metastases (30%–50%), which substantially affect their quality of life.172 Surgery followed by whole-brain RT is recommended (category 1) for select patients (those with good PS) with a single brain metastasis (see page 1239 and the NCCN Guidelines for Central Nervous System Cancers, available at NCCN.org).173–176 SRS is another option after surgical resection, although only a few retrospective case series support this option.173 Patients with a single brain metastasis who cannot tolerate or refuse surgery may be treated with SRS with or without whole-brain RT.172, 177, 178 Recent data suggest that erlotinib may be useful for managing brain metastases.179,180
Decisions regarding whether to recommend surgery, whole-brain RT, SRS, or combined modality therapy for brain metastases should be based on multidisciplinary discussion, weighing the potential benefit against the risks for each individual patient.173,181 Treatment should be individualized for patients with recurrent or progressive brain lesions.182
Some concern exists that whole-brain RT adversely affects neurocognition. However, a study in 208 patients with brain metastases found that those who experienced response (with tumor shrinkage) after whole-brain RT had improved neurocognitive function, and that tumor progression affects neurocognition more than whole-brain RT.183 Survival was similar among 132 patients with 1 to 4 brain metastases who received SRS with or without whole-brain RT.178 In a subset of 92 of these patients, controlling the brain tumor with combined therapy was more important for stabilizing neurocognitive function.184 However, a study in 58 patients found that those who received SRS and whole-brain RT had fewer central nervous system recurrences but experienced worse neurocognition than patients receiving SRS alone.185 Some investigators have suggested that using resection with SRS (vs. resection with whole-brain RT) will decrease neurocognitive problems.186
Prophylactic Cranial Irradiation: Prophylactic cranial irradiation (PCI) does not appear to improve survival in patients with NSCLC; however, it may be considered in individual patients. Although it closed early because of poor accrual, a randomized phase III trial (RTOG 0214) in patients with stage III NSCLC showed that the incidence of brain metastases was lower in those who received PCI (18% vs. 7.7%), but overall survival was not improved187 and impaired memory (immediate and delayed recall) was reported.188
Initial Clinical Evaluation
These guidelines begin with a patient who has already been given a pathologic diagnosis of NSCLC. The clinical stage is initially determined from disease history (ie, cough, dyspnea, chest pain, weight loss) and physical examination together with a limited battery of tests (see page 1238). The panel also recommends that smoking cessation counseling be made available (www.smokefree.gov/). Based on initial evaluation, the clinical stage is determined and the patient is assigned to one of the pathways defined by the stage, specific subdivision of the particular stage, and tumor location.
Additional Pretreatment Evaluation
Other Imaging Studies: PET scans have been used to help evaluate the extent of disease and to provide more accurate staging. The NCCN NSCLC Panel reviewed the diagnostic performance of CT and PET scans. Because they detect tumor physiology as opposed to anatomy, PET scans may be more sensitive than CT scans, and therefore the panel believes that PET scans can play a role in the evaluation and more accurate staging of NSCLC, such as in identifying stage IV disease.189,190 However, PET/CT is even more sensitive and is recommended by NCCN.191–193 Positive PET/CT scan findings require pathologic or other radiologic confirmation (eg, MRI of bone).
EUS-FNA and EBUS-TBNA have proven useful in staging patients or diagnosing mediastinal lesions; these techniques can be used instead of invasive staging procedures in select patients.194 Compared with CT and PET, EBUS-TBNA has a high sensitivity and specificity for staging mediastinal and hilar lymph nodes in patients with lung cancer.195 In patients with positive nodes on CT or PET, EBUS-TNBA can be used to clarify the results.196,197 However, in patients with negative findings on EBUS-TNBA, conventional mediastinoscopy can be performed to confirm the results.197,198
The routine use of bone scans (to exclude bone metastases) is not recommended. Brain MRI is recommended for patients with stage IV disease.199
Initial Therapy for Metastatic Disease
Recommended therapy for metastatic disease is described in this section, the sections on “Systemic Therapy” and “Treatment of Recurrences and Distant Metastases” (pages 1255 and 1260, respectively), and the algorithm (see 1248–1249).
Lung Metastases
When a lung metastasis is present, it usually occurs in patients with other systemic metastases, and the prognosis is poor. Therefore, many of these patients are not candidates for surgery; however, systemic therapy is recommended. Although uncommon, patients with lung metastases but without systemic metastases have a better prognosis and are candidates for surgery.200 Intrapulmonary metastases have been downstaged in the recent TNM revised staging (ie, AJCC 7th edition).58,201,202
Pleural or Pericardial Effusion
Pleural or pericardial effusion is a criterion for stage IV, M1a disease. Note that with the revised AJCC staging (7th edition), T4 with effusion has been reclassified as stage IV, M1a (see staging tables, available online, in these guidelines, at NCCN.org).58 Although pleural effusions are malignant in 90% to 95% of patients, they may be related to obstructive pneumonitis, atelectasis, lymphatic or venous obstruction, or a pulmonary embolus. Therefore, pathologic confirmation of a malignant effusion through thoracentesis or pericardiocentesis is recommended (see page 1239). In certain cases in which thoracentesis is inconclusive, thoracoscopy may be performed. In the absence of nonmalignant causes (eg, obstructive pneumonia), an exudate or sanguinous effusion is considered malignant regardless of the results of cytologic examination. If the pleural effusion is considered negative, the algorithm tracks back to the confirmed T and N stage (in the complete version of these guidelines, available online at NCCN.org). However, all pleural effusions, malignant or not, are associated with unresectable disease in 95% of cases.203 In patients with effusions positive for malignancy, the tumor is treated as for M1a, with local therapy (eg, ambulatory small catheter drainage, pleurodesis, and pericardial window), and as for stage IV disease (see pages 1239 and 1241).
Solitary Distant Metastasis
The algorithm for patients with distant metastases (ie, stage IV, M1b) depends on the location of the metastases—a solitary nodule in the brain or adrenal gland—which is determined by PET/CT scan, brain MRI, mediastinoscopy, and bronchoscopy (see page 1239). The increased sensitivity of PET/CT scans compared with other imaging methods may identify additional metastases and spare some patients from unnecessary surgery. However, positive PET/CT scan findings require pathologic or other radiologic confirmation.
Patients with solitary brain metastases may benefit from surgical resection and/or RT (see page 1239, “Whole-Brain RT and SRS” on page 1258, and the NCCN Guidelines for Central Nervous System Cancers, available at NCCN.org).172,173 The 5-year survival rates associated with this approach range from 10% to 20%120,204; median survival is approximately 40 weeks.176 Follow-up whole-brain RT (category 1) or SRS may be used.174,183,205 SRS alone or followed by whole-brain RT are additional treatment options.177,178 This therapy can be effective in patients who have surgically inaccessible brain metastases and in those with multiple lesions.206 After the brain lesions are treated, further treatment options for these patients with T1–2,N0–1 NSCLC or for those with T3,N0 include 1) surgical resection of the lung lesion followed by chemotherapy (category 2B for chemotherapy), 2) SABR of the lung lesion (category 2B), or 3) additional chemotherapy followed by surgical resection of the lung lesion (category 2B). Systemic therapy is an option after surgery for patients with higher-stage NSCLC.
Adrenal metastases from lung cancer are common, found in approximately 33% of patients at autopsy. In patients with otherwise resectable primary tumors, however, many solitary adrenal masses are not malignant. Any adrenal mass found on a preoperative CT scan in a patient with lung cancer should be biopsied to rule out benign adenoma. If an adrenal metastasis is found and the lung lesion is curable, resection has produced some long-term survivors (category 2B; see page 1239).207,208 However, some panel members believe that resection of adrenal metastases only makes sense if the synchronous lung disease is stage I or maybe stage II (ie, resectable). Systemic therapy is another treatment option for adrenal metastasis.
Surveillance
The surveillance guidelines are described on page 1240. A helical chest CT scan with or without contrast is recommended every 6 to 12 months postoperatively for 2 years (category 2B); a non–contrast-enhanced chest CT is recommended annually thereafter (category 2B), although the panel disagreed about the recommendations for helical chest CT scans.21 Information about smoking cessation (eg, advice, counseling, therapy) should be provided to aid the treatment of lung cancer and improve the patients’ quality of life (www.smokefree.gov/). Recent data show that low-dose CT screening of select patients at high risk for lung cancer (ie, 30 pack years of smoking) increases survival.25 However, use of low-dose CT for surveillance is not currently recommended for those who have previously undergone treatment for lung cancer.
Treatment of Recurrences and Distant Metastases
Recurrences are subdivided into locoregional recurrences and distant metastases. Management of locoregional recurrences (eg, endobronchial obstruction, mediastinal lymph node recurrence, superior vena cava obstructions, severe hemoptysis) is described on page 1240. For patients with endobronchial obstruction, relieving airway obstruction may increase survival, especially in those who are severely compromised, and may improve quality of life.209 After treatment for the locoregional recurrence, observation or systemic chemotherapy (category 2B for chemotherapy) is recommended if disseminated disease is not evident. However, for observed disseminated disease, systemic chemotherapy or best supportive care is recommended. The type of systemic therapy depends on the histologic type, EGFR mutation status, and PS (see page 1241).
Management of distant metastases (eg, localized symptoms; diffuse brain, bone, solitary, or disseminated metastases) is described on page 1240. For distant metastases with localized symptoms, diffuse brain metastases, or bony metastasis, external-beam RT can be used for palliation of symptoms.151 Bisphosphonate therapy or denosumab can be considered in patients with bone metastasis.210–212 Note that denosumab can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk for hypocalcemia. The FDA has approved the use of zoledronic acid in patients with bone metastases from solid tumors.213
For patients with recurrent and metastatic disease, these guidelines now recommend that the histologic subtype should be determined before therapy so that the best treatment can be selected (see page 1241).109 EGFR mutation testing is recommended in patients with nonsquamous NSCLC (ie., adenocarcinoma, large cell) or in NSCLC not otherwise specified, because erlotinib is recommended in patients who are EGFR mutation–positive (see “EGFR Mutations” on page 1253).33,80,124,214 Recent recommendations from an international panel suggest that general categories be avoided (eg, NSCLC), because more effective treatment can be selected when the histology is known.29 However, very few patients with squamous cell carcinoma have EGFR mutations (< 4%), and therefore routine testing is not recommended in these patients.215,216
Treatment recommendations and eligibility criteria for those with nonsquamous NSCLC who are EGFR mutation–negative (or with unknown mutation status) are described in the algorithm on page 1242. Treatment recommendations and eligibility criteria for those with squamous histology are described on page 1243. These recommendations are also briefly summarized in the following paragraph. Data supporting these recommendations are described in the next section on “Trial Data.”
Cisplatin/pemetrexed is recommended (category 1) for patients with nonsquamous NSCLC who are EGFR mutation–negative (or with unknown mutation status) if eligibility criteria are met109; bevacizumab/chemotherapy is another option.217 Patients with brain metastases were previously excluded from receiving bevacizumab because of concerns regarding central nervous system hemorrhage; however, data suggest that bevacizumab can be used in those with treated central nervous system metastases.218 Other chemotherapy options are also recommended, although some regimens may be more appropriate for certain patients, depending on PS and other factors (see next section on “Trial Data”). Panel members disagreed (category 2B) regarding the use of cetuximab with cisplatin and vinorelbine, because data only showed a slight improvement in survival with the addition of cetuximab (11.3 vs. 10.1 months; P = .04); additionally, this regimen is not generally used in the United States because of concerns regarding toxicity with cisplatin.130
For patients with squamous cell carcinoma, cisplatin/gemcitabine is an option.109 Another option is cetuximab with cisplatin and vinorelbine, although this is a category 2B recommendation.130
Trial Data
In a phase II/III trial (ECOG 4599), 878 patients were randomly assigned to either bevacizumab in combination with paclitaxel and carboplatin, or paclitaxel and carboplatin alone.122,219 Both regimens were well tolerated, with selected toxicities. Patients receiving bevacizumab/paclitaxel/carboplatin showed an improved median survival (12.3 vs. 10.3 months; P = .003) compared with paclitaxel and carboplatin alone.122 Overall 1- and 2-year survival rates were 51% versus 44% and 23% versus 15%, respectively, in favor of the bevacizumab/paclitaxel/carboplatin arm.122 However, more significant toxicities were observed with bevacizumab/paclitaxel/carboplatin than with paclitaxel and carboplatin alone (grade 4 neutropenia: 25.5% vs. 16.8%; grade 5 hemoptysis: 1.2% vs. 0%; grade 3 hypertension: 6.8% vs. 0.5%), and treatment-related deaths were more common with bevacizumab/paclitaxel/carboplatin (15 vs. 2 patients; P = .001).
A recent analysis of ECOG 4599 found that adenocarcinoma histology was associated with improved survival in patients receiving bevacizumab/paclitaxel/carboplatin compared with chemotherapy alone (14.2 vs. 10.3 months).217 However, a trial (AVAil) comparing cisplatin/gemcitabine with or without bevacizumab did not show an increase in survival with the addition of bevacizumab.220,221
A noninferiority trial in 1725 patients with advanced NSCLC (either stage IIIB or IV; most were stage IV) compared cisplatin plus gemcitabine versus cisplatin plus pemetrexed.109 Patients with either adenocarcinoma or large cell histology (ie, nonsquamous) had improved survival with cisplatin/pemetrexed (adenocarcinoma: 12.6 vs. 10.9 months). Patients with squamous cell histology had improved survival with cisplatin/gemcitabine (10.8 vs. 9.4 months). The cisplatin/pemetrexed regimen had significantly lower rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001). Treatment-related deaths were similar for both regimens (cisplatin/pemetrexed, 9 patients [1.0%]; cisplatin/gemcitabine, 6 patients [0.7%]). A recent analysis of 3 phase III trials confirmed that pemetrexed improves survival for patients with nonsquamous NSCLC when used in first-line, second-line, and maintenance therapy.222
In the FLEX trial, 1125 patients with advanced NSCLC (either stage IIIB or IV; most were stage IV) were randomly assigned to either cetuximab in combination with vinorelbine and cisplatin, or vinorelbine and cisplatin alone.130 The response rate was increased with cetuximab (36% vs. 29%; P = .012), and no difference was seen in progression-free survival. Overall survival was slightly better in patients receiving cetuximab (11.3 vs. 10.1 months; P = .04). However, patients receiving cetuximab experienced increased grade 3 or 4 febrile neutropenia (22% vs. 15%; P < .05) and grade 2 acne-like rash. Treatment-related deaths were similar in both groups (3% vs. 2%).
Data show that platinum-based combination therapy is superior to best supportive care for patients with advanced incurable disease. Cisplatin or carboplatin have been proven effective in combination with any of the following agents: docetaxel, etoposide, gemcitabine, paclitaxel, pemetrexed, vinblastine, and vinorelbine.105–109,112,113 Non–platinum-based regimens are reasonable alternatives if available data show activity and tolerable toxicity (eg, gemcitabine/docetaxel, gemcitabine/vinorelbine).115–117
Maintenance Therapy
Patients receiving therapy should be evaluated for tumor response with a CT scan. Approximately 25% of patients show disease progression after the initial cycle of chemotherapy. Patients with responsive or stable disease can continue to receive a total of 4 to 6 cycles of chemotherapy223 or until disease progression. A meta-analysis suggests that continuing the initial regimen beyond 4 to 6 cycles is associated with increased progression-free survival; however, patients have more adverse events.224 Another review suggests that continuing chemotherapy beyond 4 to 6 cycles confers no benefit; however, many patients assigned to a longer duration of therapy did not receive the planned number of cycles.134
For patients with nonsquamous NSCLC who are EGFR mutation–negative (or unknown mutation status), continuation maintenance therapy regimens include bevacizumab (category 1), cetuximab (category 1), pemetrexed, or gemcitabine (see page 1242).122,130,133,137 Switch maintenance therapy regimens for these patients include pemetrexed or erlotinib.137,139,140 Observation is another option.
For patients with squamous cell histology, cetuximab (category 1) or gemcitabine can be used as a continuation maintenance therapy regimen (see page 1243).137,139 Switch maintenance therapy for these patients includes erlotinib or docetaxel (category 2B). Observation is another option. A phase III trial assessed switch maintenance therapy with docetaxel either given immediately after chemotherapy or delayed until progression.142 However, switch maintenance therapy with docetaxel is a category 2B recommendation in these guidelines, because many patients in the delayed chemotherapy arm did not receive docetaxel.
A phase III randomized trial (n = 663) assessed the effect of best supportive care with or without maintenance pemetrexed in patients with advanced NSCLC who had received platinum-based chemotherapy but whose disease had not progressed.140 In patients with nonsquamous NSCLC, overall survival was increased with pemetrexed compared with placebo (15.5 vs. 10.3 months; P = .002).
Continuation of Erlotinib or Gefitinib After Progression: Has Its Time Come?
Patients may continue to derive benefit from erlotinib or gefitinib after disease progression, and discontinuation of erlotinib or gefitinib leads to more rapid disease progression (symptoms, tumor size, and FDG-avidity on PET scan).225 This strategy mirrors the experience in other oncogene-addicted cancers, particularly HER2-amplified breast cancer. In women with HER2-amplified breast cancer who experience disease progression on trastuzumab, improved radiographic response rate, time to progression, and overall survival are observed when conventional chemotherapy is added to trastuzumab.226 Data support the continued use of erlotinib or gefitinib in patients with lung adenocarcinoma with EGFR mutations after development of acquired resistance to erlotinib or gefitinib when conventional chemotherapy is initiated.
Data are accumulating regarding how cancers become resistant to EGFR inhibitors. The most common known mechanism is the acquisition of a secondary mutation in EGFR, T790M, that renders the kinase resistant to erlotinib and gefitinib.227,228 Amplification of the MET oncogene is another validated resistance mechanism. Activation of the insulin-like growth factor 1 receptor (IGF-1R) pathway has been observed in laboratory models. To overcome all 3 types of resistance, EGFR must still be inhibited. In the case of MET amplification and IGF-IR activation, new inhibitors must be added to the EGFR inhibitor; however, EGFR inhibition is still required to induce remission. Furthermore, data by Riely et al225 show that when cancers once sensitive to EGFR inhibitors begin to progress, discontinuation of the EGFR-TKI can lead to a much more accelerated cancer progression. In total, it is likely that continuing EGFR-TKIs is beneficial in many patients even after they develop resistance to EGFR-TKIs.
Second- and Third-Line Chemotherapy
Although many new active drugs are available for lung cancer, the reported response rates to second-line chemotherapy have generally been less than 10%. Docetaxel, pemetrexed, erlotinib, or platinum doublet (with or without bevacizumab) are recommended as second-line chemotherapy regimens for patients with a PS of 0 to 2 who experience disease progression during or after first-line therapy (see page 1244).229–232 Docetaxel has proven superior to best supportive care, vinorelbine, or ifosfamide, with improved survival and quality of life; docetaxel may be used for third-line therapy.229,230 When compared with docetaxel, pemetrexed has similar median survival but less toxicity.231,233 Pemetrexed is recommended in patients with adenocarcinoma or large cell histology (ie, nonsquamous NSCLC) for second- and third-line therapy.140 Erlotinib has proven superior to best supportive care, with significantly improved survival and delayed time to symptom deterioration.232 Erlotinib is recommended for second- or third-line therapy for progressive disease in patients with a PS of 3 or 4 who have the EGFR mutation (see page 1244). A platinum doublet with or without bevacizumab is an option for those with nonsquamous NSCLC (ie, adenocarcinoma, large cell, NSCLC not otherwise specified) whose disease has progressed after first-line therapy with erlotinib or crizotinib.122
In a randomized, placebo-controlled, double-blind trial (NCIC CTG trial), 731 patients (stage IIIB or IV, PS 0–3) were randomly assigned (2:1) to receive either erlotinib or placebo after failure of first- or second-line chemotherapy.232 Patients treated with erlotinib showed an overall survival of 6.7 versus 4.7 months for placebo (hazard ratio, 0.70; P < .001). Progression-free survival was 2.2 months for the erlotinib group versus 1.8 months for placebo (hazard ratio, 0.61, adjusted for stratification categories; P < .001). However, 5% of patients discontinued erlotinib because of toxic side effects. This trial confirms that erlotinib can prolong survival in patients after failure of first- or second-line chemotherapy. A randomized phase III trial in 829 patients found that oral topotecan was not inferior to docetaxel.234
If disease progression occurs after third-line chemotherapy, patients with a PS of 0 to 2 may be enrolled in a clinical trial or treated with best supportive care (see the NCCN Guidelines for Palliative Care; to view the most recent version of these guidelines, visit NCCN.org).
Individual Disclosures for the NCCN Non–Small Cell Lung Cancer Panel Members
References
- 2↑
Spiro SG, Gould MK, Colice GL. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007;132:149S–160S.
- 3↑
Silvestri GA, Gould MK, Margolis ML et al.. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007;132:178S–201S.
- 4↑
De Wever W, Vankan Y, Stroobants S, Verschakelen J. Detection of extrapulmonary lesions with integrated PET/CT in the staging of lung cancer. Eur Respir J 2007;29:995–1002.
- 5↑
The Health Consequences of Smoking: A Report of the Surgeon General. (ed 2010/07/30). Atlanta, GA: U.S. Department of Health and Human Services. Centers for Disease Control and Prevention (US); 2004.
- 6↑
Secretan B, Straif K, Baan R et al.. A review of human carcinogens—Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 2009;10:1033–1034.
- 7↑
Doll R, Peto R. Mortality in relation to smoking: 20 years’ observations on male British doctors. Br Med J 1976;2:1525–1536.
- 8↑
Taylor R, Najafi F, Dobson A. Meta-analysis of studies of passive smoking and lung cancer: effects of study type and continent. Int J Epidemiol 2007;36:1048–1059.
- 9
The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. (ed 2010/07/30). Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2006.
- 10
Hackshaw AK, Law MR, Wald NJ. The accumulated evidence on lung cancer and environmental tobacco smoke. BMJ 1997;315:980–988.
- 11↑
Wald NJ, Nanchahal K, Thompson SG, Cuckle HS. Does breathing other people’s tobacco smoke cause lung cancer? Br Med J (Clin Res Ed) 1986;293:1217–1222.
- 12↑
Aubin HJ, Bobak A, Britton JR et al.. Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial. Thorax 2008;63:717–724.
- 13
Jorenby DE, Hays JT, Rigotti NA et al.. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006;296:56–63.
- 14↑
Gonzales D, Rennard SI, Nides M et al.. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 2006;296:47–55.
- 15↑
Garrison GD, Dugan SE. Varenicline: a first-line treatment option for smoking cessation. Clin Ther 2009;31:463–491.
- 16↑
Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2011:CD006103.
- 17↑
Xi ZX. Preclinical pharmacology, efficacy and safety of varenicline in smoking cessation and clinical utility in high risk patients. Drug Healthc Patient Saf 2010;2010:39–48.
- 18↑
Hays JT, Ebbert JO. Adverse effects and tolerability of medications for the treatment of tobacco use and dependence. Drugs 2010;70:2357–2372.
- 20↑
Chute JP, Chen T, Feigal E et al.. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol 1999;17:1794–1801.
- 21↑
Henschke CI, McCauley DI, Yankelevitz DF et al.. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99–105.
- 22
Henschke CI, Naidich DP, Yankelevitz DF et al.. Early Lung Cancer Action Project: initial findings on repeat screenings. Cancer 2001;92:153–159.
- 23↑
Kaneko M, Kusumoto M, Kobayashi T et al.. Computed tomography screening for lung carcinoma in Japan. Cancer 2000;89:2485–2488.
- 25↑
Aberle DR, Adams AM, Berg CD et al.. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409.
- 26↑
Aberle DR, Adams AM, Berg CD et al.. Baseline characteristics of participants in the randomized national lung screening trial. J Natl Cancer Inst 2010;102:1771–1779.
- 28↑
Henschke CI, Yankelevitz DF, Libby DM et al.. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355:1763–1771.
- 29↑
Travis WD, Brambilla E, Noguchi M et al.. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244–285.
- 30↑
Finkelstein DM, Ettinger DS, Ruckdeschel JC. Long-term survivors in metastatic non-small-cell lung cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1986;4:702–709.
- 31↑
Cooper WA, O’Toole S, Boyer M et al.. What’s new in non-small cell lung cancer for pathologists: the importance of accurate subtyping, EGFR mutations and ALK rearrangements. Pathology 2011;43:103–115.
- 32
Fossella FV, Putnam JB, Komaki R, eds. Lung Cancer. M.D. Anderson Cancer Care Series. New York: Springer; 2003.
- 33↑
Eberhard DA, Johnson BE, Amler LC et al.. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23:5900–5909.
- 34
Cappuzzo F, Ligorio C, Toschi L et al.. EGFR and HER2 gene copy number and response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Thorac Oncol 2007;2:423–429.
- 35↑
Kwak EL, Bang YJ, Camidge DR et al.. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693–1703.
- 36↑
Travis WD. Pathology and genetics of tumours of the lung, pleura, thymus and heart Lyon: IARC Press; 2004.
- 37↑
Rekhtman N, Ang DC, Sima CS et al.. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol 2011;24:1348–1359.
- 38↑
Mukhopadhyay S, Katzenstein AL. Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: Utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5/6. Am J Surg Pathol 2011;35:15–25.
- 39↑
Terry J, Leung S, Laskin J et al.. Optimal immunohistochemical markers for distinguishing lung adenocarcinomas from squamous cell carcinomas in small tumor samples. Am J Surg Pathol 2010;34:1805–1811.
- 40↑
Husain AN, Colby TV, Ordonez NG et al.. Guidelines for pathologic diagnosis of malignant mesothelioma: a consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med 2009;133:1317–1331.
- 41↑
King JE, Thatcher N, Pickering CA, Hasleton PS. Sensitivity and specificity of immunohistochemical markers used in the diagnosis of epithelioid mesothelioma: a detailed systematic analysis using published data. Histopathology 2006;48:223–232.
- 42↑
Ordonez NG. D2-40 and podoplanin are highly specific and sensitive immunohistochemical markers of epithelioid malignant mesothelioma. Hum Pathol 2005;36:372–380.
- 43↑
Ordonez NG. The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma. Am J Surg Pathol 2003;27:1031–1051.
- 44↑
Ordonez NG. Thyroid transcription factor-1 is a marker of lung and thyroid carcinomas. Adv Anat Pathol 2000;7:123–127.
- 45↑
Rivera MP, Mehta AC. Initial diagnosis of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132:131S–148S.
- 46↑
Tan D, Zander DS. Immunohistochemistry for assessment of pulmonary and pleural neoplasms: a review and update. Int J Clin Exp Pathol 2008;1:19–31.
- 47↑
Zhang H, Liu J, Cagle PT et al.. Distinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: an immunohistochemical approach. Mod Pathol 2005;18:111–118.
- 48↑
Guinee DG Jr, Fishback NF, Koss MN et al.. The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies. Am J Clin Pathol 1994;102:406–414.
- 49↑
Du L, Schageman JJ, Irnov et al.. MicroRNA expression distinguishes SCLC from NSCLC lung tumor cells and suggests a possible pathological relationship between SCLCs and NSCLCs. J Exp Clin Cancer Res 2010;29:75.
- 50↑
Greene FL, Page DL, Fleming ID et al.. AJCC Cancer Staging Manual, 6th ed. New York: Springer-Verlag; 2002.
- 51
Mountain CF. A new international staging system for lung cancer. Chest 1986;89:225S–233S.
- 52
Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710–1717.
- 53↑
Mountain CF. Staging classification of lung cancer. A critical evaluation. Clin Chest Med 2002;23:103–121.
- 54↑
Goldstraw P, Crowley J, Chansky K et al.. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007;2:706–714.
- 56↑
Edge SB, Byrd DR, Compton CC et al.. AJCC Cancer Staging Manual, 7th ed. New York: Springer; 2010.
- 57↑
Rami-Porta R, Bolejack V, Goldstraw P. The new tumor, node, and metastasis staging system. Semin Respir Crit Care Med 2011;32:44–51.
- 58↑
Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009;15:4–9.
- 59↑
Tsao MS, Sakurada A, Cutz JC et al.. Erlotinib in lung cancer–molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–144.
- 60↑
Miller VA, Riely GJ, Zakowski MF et al.. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol 2008;26:1472–1478.
- 61↑
Sequist LV, Martins RG, Spigel D et al.. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008;26:2442–2449.
- 62↑
Shaw AT, Forcione DG, Digumarthy SR, Iafrate AJ. Case records of the Massachusetts General Hospital. Case 21-2011. A 31-year-old man with ALK-positive adenocarcinoma of the lung. N Engl J Med 2011;365:158–167.
- 63↑
Shaw AT, Yeap BY, Mino-Kenudson M et al.. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:4247–4253.
- 64↑
Dias-Santagata D, Akhavanfard S, David SS et al.. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med 2010;2:146–158.
- 65↑
Paik PK, Arcila ME, Fara M et al.. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 2011;29:2046–2051.
- 66↑
Hirsch FR, Bunn PA Jr. EGFR testing in lung cancer is ready for prime time. Lancet Oncol 2009;10:432–433.
- 67
Riely GJ, Politi KA, Miller VA, Pao W. Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res 2006;12:7232–7241.
- 68↑
Pao W, Miller VA, Politi KA et al.. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.
- 69
Kosaka T, Yatabe Y, Endoh H et al.. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res 2006;12:5764–5769.
- 70↑
Onitsuka T, Uramoto H, Nose N et al.. Acquired resistance to gefitinib: the contribution of mechanisms other than the T790M, MET, and HGF status. Lung Cancer 2010;68:198–203.
- 71↑
Han SW, Kim TY, Jeon YK et al.. Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res 2006;12:2538–2544.
- 73↑
Sholl LM, Xiao Y, Joshi V et al.. EGFR mutation is a better predictor of response to tyrosine kinase inhibitors in non-small cell lung carcinoma than FISH, CISH, and immunohistochemistry. Am J Clin Pathol 2010;133:922–934.
- 74↑
Eberhard DA, Giaccone G, Johnson BE. Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. J Clin Oncol 2008;26:983–994.
- 75
Pao W, Ladanyi M. Epidermal growth factor receptor mutation testing in lung cancer: searching for the ideal method. Clin Cancer Res 2007;13:4954–4955.
- 76↑
Shepherd FA, Tsao MS. Epidermal growth factor receptor biomarkers in non-small-cell lung cancer: a riddle, wrapped in a mystery, inside an enigma. J Clin Oncol 2010;28:903–905.
- 77↑
Lynch TJ, Bell DW, Sordella R et al.. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.
- 78↑
Paez JG, Janne PA, Lee JC et al.. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.
- 79↑
Mitsudomi T, Morita S, Yatabe Y et al.. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121–128.
- 80↑
Maemondo M, Inoue A, Kobayashi K et al.. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380–2388.
- 81↑
Zhou C, Wu YL, Chen G et al.. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735–742.
- 82↑
Zhou C, Wu YL, Chen G et al.. Updated efficacy and quality-of-life (QoL) analyses in OPTIMAL, a phase III, randomized, open-label study of first-line erlotinib versus gemcitabine/carboplatin in patients with EGFR-activating mutation-positive (EGFR Act Mut+) advanced non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2011;29(Suppl 15):Abstract 7520.
- 83↑
Rosell R, Gervais R, Vergnenegre A et al.. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial [abstract]. J Clin Oncol 2011;29(Suppl 15):Abstract 7503.
- 84↑
Takahashi T, Sonobe M, Kobayashi M et al.. Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol 2010;17:889–897.
- 85↑
Kim H, Yoo SB, Choe JY et al.. Detection of ALK gene rearrangement in non-small cell lung cancer: a comparison of fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression. J Thorac Oncol 2011;6:1359–1366.
- 86
Rodig SJ, Mino-Kenudson M, Dacic S et al.. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 2009;15:5216–5223.
- 87↑
Mino-Kenudson M, Chirieac LR, Law K et al.. A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res 2010;16:1561–1571.
- 88↑
Crino L, Kim D, Riely GJ et al.. Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005 [abstract]. J Clin Oncol 2011;29(Suppl 15):Abstract 7514.
- 89↑
Camidge DR, Bang Y, Kwak EL et al.. Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2011;29(Suppl 15):Abstract 2501.
- 90↑
Rodig SJ, Shapiro GI. Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases. Curr Opin Investig Drugs 2010;11:1477–1490.
- 91↑
Shaw AT, Yeap BY, Solomon BJ et al.. Impact of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls [abstract]. J Clin Oncol 2011;29(Suppl 15):Abstract 7507.
- 92↑
Choi YL, Soda M, Yamashita Y et al.. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 2010;363:1734–1739.
- 93↑
Katayama R, Khan TM, Benes C et al.. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A 2011;108:7535–7540.
- 94
Sequist LV, Gettinger S, Senzer NN et al.. Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol 2010;28:4953–4960. A
- 95
Zhang S, Wang F, Keats F. AP26113, a potent ALK inhibitor, overcomes mutations in EML4-ALK that confer resistance to PF-02341066 (PF1066) [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; April 17–21, 2010; Washington, DC. Abstract LB-298.
- 96↑
Cheng M, Ott GR. Anaplastic lymphoma kinase as a therapeutic target in anaplastic large cell lymphoma, non-small cell lung cancer and neuroblastoma. Anticancer Agents Med Chem 2010;10:236–249.
- 97↑
Socinski MA, Crowell R, Hensing TE et al.. Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132:277S–289S.
- 98↑
Azzoli CG, Baker S Jr, Temin S et al.. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009:27:6251–6266.
- 99↑
NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 2008;26:4617–4625.
- 100↑
Souquet PJ, Chauvin F, Boissel JP et al.. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 1993;342:19–21.
- 101↑
Temel JS, Greer JA, Muzikansky A et al.. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363:733–742.
- 102↑
Magilligan DJ Jr, Duvernoy C, Malik G et al.. Surgical approach to lung cancer with solitary cerebral metastasis: twenty-five years’ experience. Ann Thorac Surg 1986;42:360–364.
- 103↑
Azzoli CG, Temin S, Aliff T et al.. 2011 Focused update of 2009 American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2011;29:3825–3831.
- 104↑
Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995;311:899–909.
- 105↑
Ohe Y, Ohashi Y, Kubota K et al.. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007;18:317–323.
- 106↑
Fossella F, Pereira JR, von Pawel J et al.. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21:3016–3024.
- 107
Smit EF, van Meerbeeck JP, Lianes P et al.. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group—EORTC 08975. J Clin Oncol 2003;21:3909–3917.
- 108
Zatloukal P, Petruzelka L, Zemanova M et al.. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 2004;46:87–98.
- 109↑
Scagliotti GV, Parikh P, von Pawel J et al.. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543–3551. A
- 110↑
Kelly K, Crowley J, Bunn PA Jr et al.. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non–small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001;19:3210–3218.
- 111↑
Schiller JH, Harrington D, Belani CP et al.. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–98.
- 112↑
Danson S, Middleton MR, O’Byrne KJ et al.. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer 2003;98:542–553.
- 113↑
Booton R, Lorigan P, Anderson H et al.. A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1). Ann Oncol 2006;17:1111–1119.
- 114↑
Gronberg BH, Bremnes RM, Flotten O et al.. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2009;27:3217–3224.
- 115↑
Greco FA, Spigel DR, Kuzur ME et al.. Paclitaxel/carboplatin/gemcitabine versus gemcitabine/vinorelbine in advanced non-small-cell lung cancer: a phase II/III study of the Minnie Pearl Cancer Research Network. Clin Lung Cancer 2007;8:483–487.
- 116
Herbst RS, Khuri FR, Lu C et al.. The novel and effective nonplatinum, nontaxane combination of gemcitabine and vinorelbine in advanced nonsmall cell lung carcinoma: potential for decreased toxicity and combination with biological therapy. Cancer 2002;95:340–353.
- 117↑
Pujol JL, Breton JL, Gervais R et al.. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin. Ann Oncol 2005;16:602–610.
- 118↑
Rizvi NA, Riely GJ, Azzoli CG et al.. Phase I/II trial of weekly intravenous 130-nm albumin-bound paclitaxel as initial chemotherapy in patients with stage IV non-small-cell lung cancer. J Clin Oncol 2008;26:639–643.
- 119↑
Green MR, Manikhas GM, Orlov S et al.. Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol 2006;17:1263–1268.
- 120↑
Sandler AB, Johnson DH, Herbst RS. Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. Clin Cancer Res 2004;10:4258s–4262s.
- 121↑
Giaccone G. Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol 2005;23:3235–3242.
- 122↑
Sandler A, Gray R, Perry MC et al.. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–2550.
- 123↑
Sequist LV, Joshi VA, Janne PA et al.. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist 2007;12:90–98.
- 124↑
Mok TS, Wu YL, Thongprasert S et al.. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–957.
- 125↑
Inoue A, Kobayashi K, Usui K et al.. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol 2009;27:1394–1400.
- 126↑
Jackman DM, Miller VA, Cioffredi LA et al.. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res 2009;15:5267–5273.
- 127↑
Gridelli C, Ciardiello F, Feld R et al.. International multicenter randomized phase III study of first-line erlotinib (E) followed by second-line cisplatin plus gemcitabine (CG) versus first-line CG followed by second-line E in advanced non-small cell lung cancer (aNSCLC): the TORCH trial [abstract]. J Clin Oncol 2010;28(Suppl 15):Abstract 7508.
- 128↑
Keedy VL, Temin S, Somerfield MR et al.. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol 2011;29:2121–2127.
- 129↑
Felip E, Gridelli C, Baas P et al.. Metastatic non-small-cell lung cancer: consensus on pathology and molecular tests, first-line, second-line, and third-line therapy: 1st ESMO Consensus Conference in Lung Cancer; Lugano 2010. Ann Oncol 2011;22:1507–1519.
- 130↑
Pirker R, Pereira JR, Szczesna A et al.. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009;373:1525–1531.
- 131↑
Patel JD, Hensing TA, Rademaker A et al.. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. J Clin Oncol 2009;27:3284–3289.
- 132↑
Nadler E, Yu E, Ravelo A et al.. Bevacizumab treatment to progression after chemotherapy: outcomes from a U.S. community practice network. Oncologist 2011;16:486–496.
- 133↑
Paz-Ares LG, De Marinis F, Dediu M et al.. PARAMOUNT: Phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo plus BSC immediately following induction treatment with pem plus cisplatin for advanced nonsquamous non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2011;29(Suppl 18):Abstract CRA7510.
- 134↑
Fidias P, Novello S. Strategies for prolonged therapy in patients with advanced non-small-cell lung cancer. J Clin Oncol 2010;28:5116–5123.
- 135
Stinchcombe TE, Socinski MA. Treatment paradigms for advanced stage non-small cell lung cancer in the era of multiple lines of therapy. J Thorac Oncol 2009;4:243–250.
- 136↑
Fidias P, Novello S. Strategies for prolonged therapy in patients with advanced non-small-cell lung cancer. J Clin Oncol 2010;28:5116–5123.
- 137↑
Perol M, Chouaid C, Milleron BJ et al.. Maintenance with either gemcitabine or erlotinib versus observation with predefined second-line treatment after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC: IFCT-GFPC 0502 phase III study [abstract]. J Clin Oncol 2010;28(Suppl 15):Abstract 7507.
- 138↑
Brodowicz T, Krzakowski M, Zwitter M et al.. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer 2006;52:155–163.
- 139↑
Cappuzzo F, Ciuleanu T, Stelmakh L et al.. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11:521–529.
- 140↑
Ciuleanu T, Brodowicz T, Zielinski C et al.. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009;374:1432–1440.
- 141↑
Cohen MH, Cortazar P, Justice R, Pazdur R. Approval summary: pemetrexed maintenance therapy of advanced/metastatic nonsquamous, non-small cell lung cancer (NSCLC). Oncologist 2010;15:1352–1358.
- 142↑
Fidias PM, Dakhil SR, Lyss AP et al.. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2009;27:591–598.
- 143↑
Janne PA, Wang XF, Socinski MA et al.. Randomized phase II trial of erlotinib (E) alone or in combination with carboplatin/paclitaxel (CP) in never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 [abstract]. J Clin Oncol 2010;28(Suppl 15):Abstract 7503.
- 144↑
Cohen MH, Johnson JR, Chattopadhyay S et al.. Approval summary: erlotinib maintenance therapy of advanced/metastatic non-small cell lung cancer (NSCLC). Oncologist 2010;15:1344–1351.
- 145↑
Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. The Lung Cancer Study Group. N Engl J Med 1986;315:1377–1381.
- 146
Keller SM, Adak S, Wagner H et al.. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med 2000;343:1217–1222.
- 147
Douillard JY, Rosell R, De Lena M et al.. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys 2008;72:695–701.
- 148
Bradley JD, Paulus R, Graham MV et al.. Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA non-small-cell lung cancer: promising long-term results of the Radiation Therapy Oncology Group—RTOG 9705. J Clin Oncol 2005;23:3480–3487.
- 149
Feigenberg SJ, Hanlon AL, Langer C et al.. A phase II study of concurrent carboplatin and paclitaxel and thoracic radiotherapy for completely resected stage II and IIIA non-small cell lung cancer. J Thorac Oncol 2007;2:287–292.
- 150↑
Jaklitsch MT, Herndon JE 2nd, DeCamp MM Jr et al.. Nodal downstaging predicts survival following induction chemotherapy for stage IIIA (N2) non-small cell lung cancer in CALGB protocol #8935. J Surg Oncol 2006;94:599–606.
- 151↑
Chow E, Harris K, Fan G et al.. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 2007;25:1423–1436.
- 152
Lutz S, Berk L, Chang E et al.. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys 2011;79:965–976.
- 153
Cross CK, Berman S, Buswell L et al.. Prospective study of palliative hypofractionated radiotherapy (8.5 Gy x 2) for patients with symptomatic non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;58:1098–1105.
- 154↑
A Medical Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small-cell lung cancer (NSCLC) and poor performance status. Medical Research Council Lung Cancer Working Party. Br J Cancer 1992;65:934–941.
- 155↑
Milano MT, Katz AW, Okunieff P. Patterns of recurrence after curative-intent radiation for oligometastases confined to one organ. Am J Clin Oncol 2010;33:157–163.
- 156
Rusthoven KE, Kavanagh BD, Burri SH et al.. Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases. J Clin Oncol 2009;27:1579–1584.
- 157↑
Salama JK, Chmura SJ, Mehta N et al.. An initial report of a radiation dose-escalation trial in patients with one to five sites of metastatic disease. Clin Cancer Res 2008;14:5255–5259.
- 158↑
Dahele M, Senan S. The role of stereotactic ablative radiotherapy for early-stage and oligometastatic non-small cell lung cancer: evidence for changing paradigms. Cancer Res Treat 2011;43:75–82.
- 159
Heinzerling JH, Kavanagh B, Timmerman RD. Stereotactic ablative radiation therapy for primary lung tumors. Cancer J 2011;17:28–32.
- 160↑
Potters L, Kavanagh B, Galvin JM et al.. American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the performance of stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2010;76:326–332.
- 161↑
Salazar OM, Sandhu TS, Lattin PB et al.. Once-weekly, high-dose stereotactic body radiotherapy for lung cancer: 6-year analysis of 60 early-stage, 42 locally advanced, and 7 metastatic lung cancers. Int J Radiat Oncol Biol Phys 2008;72:707–715.
- 162↑
Guckenberger M, Wulf J, Mueller G et al.. Dose-response relationship for image-guided stereotactic body radiotherapy of pulmonary tumors: relevance of 4D dose calculation. Int J Radiat Oncol Biol Phys 2009;74:47–54.
- 163↑
Hadziahmetovic M, Loo BW, Timmerman RD et al.. Stereotactic body radiation therapy (stereotactic ablative radiotherapy) for stage I non-small cell lung cancer—updates of radiobiology, techniques, and clinical outcomes. Discov Med 2010;9:411–417.
- 164
Hara R, Itami J, Kondo T et al.. Clinical outcomes of single-fraction stereotactic radiation therapy of lung tumors. Cancer 2006;106:1347–1352.
- 165
Baumann P, Nyman J, Hoyer M et al.. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 2009;27:3290–3296.
- 166
Fakiris AJ, McGarry RC, Yiannoutsos CT et al.. Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys 2009;75:677–682.
- 167
Chang JY, Balter PA, Dong L et al.. Stereotactic body radiation therapy in centrally and superiorly located stage I or isolated recurrent non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;72:967–971.
- 168
Takeda A, Sanuki N, Kunieda E et al.. Stereotactic body radiotherapy for primary lung cancer at a dose of 50 Gy total in five fractions to the periphery of the planning target volume calculated using a superposition algorithm. Int J Radiat Oncol Biol Phys 2009;73:442–448.
- 169
Stephans KL, Djemil T, Reddy CA et al.. A comparison of two stereotactic body radiation fractionation schedules for medically inoperable stage I non-small cell lung cancer: the Cleveland Clinic experience. J Thorac Oncol 2009;4:976–982.
- 170
Jin JY, Kong FM, Chetty IJ et al.. Impact of fraction size on lung radiation toxicity: hypofractionation may be beneficial in dose escalation of radiotherapy for lung cancers. Int J Radiat Oncol Biol Phys 2010;76:782–788.
- 171↑
Onishi H, Shirato H, Nagata Y et al.. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol 2007;2:S94–100.
- 172↑
Hu C, Chang EL, Hassenbusch SJ 3rd et al.. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer 2006;106:1998–2004.
- 173↑
Kalkanis SN, Kondziolka D, Gaspar LE et al.. The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:33–43.
- 174↑
Gaspar LE, Mehta MP, Patchell RA et al.. The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:17–32.
- 175
Mintz A, Perry J, Spithoff K et al.. Management of single brain metastasis: a practice guideline. Curr Oncol 2007;14:131–143.
- 176↑
Patchell RA, Tibbs PA, Walsh JW et al.. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494–500.
- 177↑
Linskey ME, Andrews DW, Asher AL et al.. The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:45–68.
- 178↑
Aoyama H, Shirato H, Tago M et al.. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006;295:2483–2491.
- 179↑
Kim JE, Lee DH, Choi Y et al.. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer 2009;65:351–354.
- 180↑
Olson JJ, Paleologos NA, Gaspar LE et al.. The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics. J Neurooncol 2010;96:115–142.
- 181↑
Mehta MP, Paleologos NA, Mikkelsen T et al.. The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:71–83.
- 182↑
Ammirati M, Cobbs CS, Linskey ME et al.. The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010;96:85–96.
- 183↑
Li J, Bentzen SM, Renschler M, Mehta MP. Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol 2007;25:1260–1266.
- 184↑
Aoyama H, Tago M, Kato N et al.. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys 2007;68:1388–1395.
- 185↑
Chang EL, Wefel JS, Hess KR et al.. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009;10:1037–1044.
- 186↑
Marsh JC, Gielda BT, Herskovic AM, Abrams RA. Cognitive sparing during the administration of whole brain radiotherapy and prophylactic cranial irradiation: current concepts and approaches. J Oncol 2010;2010:198208.
- 187↑
Gore EM, Bae K, Wong SJ et al.. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J Clin Oncol 2011;29:272–278.
- 188↑
Sun A, Bae K, Gore EM et al.. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol 2011;29:279–286.
- 189↑
Pieterman RM, van Putten JW, Meuzelaar JJ et al.. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med 2000;343:254–261.
- 190↑
Manente P, Vicario G, Piazza F et al.. Does PET/CT modify the therapeutic approach in medical oncology [abstract]? J Clin Oncol 2008;26(Suppl 15):Abstract 17525.
- 191↑
Maziak DE, Darling GE, Inculet RI et al.. Positron emission tomography in staging early lung cancer: a randomized trial. Ann Intern Med 2009;151:221–228, W-248.
- 192
Fischer B, Lassen U, Mortensen J et al.. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med 2009;361:32–39.
- 193↑
De Wever W, Stroobants S, Coolen J, Verschakelen JA. Integrated PET/CT in the staging of nonsmall cell lung cancer: technical aspects and clinical integration. Eur Respir J 2009;33:201–212.
- 194↑
Vilmann P, Krasnik M, Larsen SS et al.. Transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy: a combined approach in the evaluation of mediastinal lesions. Endoscopy 2005;37:833–839.
- 195↑
Yasufuku K, Nakajima T, Motoori K et al.. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer. Chest 2006;130:710–718.
- 196↑
Ernst A, Eberhardt R, Krasnik M, Herth FJ. Efficacy of endobronchial ultrasound-guided transbronchial needle aspiration of hilar lymph nodes for diagnosing and staging cancer. J Thorac Oncol 2009;4:947–950.
- 197↑
Rintoul RC, Tournoy KG, El Daly H et al.. EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes-an international multi-centre experience. J Thorac Oncol 2009;4:44–48.
- 198↑
Medford AR, Bennett JA, Free CM, Agrawal S. Mediastinal staging procedures in lung cancer: EBUS, TBNA and mediastinoscopy. Curr Opin Pulm Med 2009;15:334–342.
- 199↑
Mayr NA, Hussey DH, Yuh WT. Cost-effectiveness of high-contrast-dose MR screening of asymptomatic brain metastasis. AJNR Am J Neuroradiol 1995;16:215–217.
- 200↑
Nakagawa T, Okumura N, Miyoshi K et al.. Prognostic factors in patients with ipsilateral pulmonary metastasis from non-small cell lung cancer. Eur J Cardiothorac Surg 2005;28:635–639.
- 201↑
Lee JG, Lee CY, Kim DJ et al.. Non-small cell lung cancer with ipsilateral pulmonary metastases: prognosis analysis and staging assessment. Eur J Cardiothorac Surg 2008;33:480–484.
- 202↑
Oliaro A, Filosso PL, Cavallo A et al.. The significance of intrapulmonary metastasis in non-small cell lung cancer: upstaging or downstaging? A re-appraisal for the next TNM staging system. Eur J Cardiothorac Surg 2008;34:438–443; discussion 443.
- 203↑
Decker DA, Dines DE, Payne WS et al.. The significance of a cytologically negative pleural effusion in bronchogenic carcinoma. Chest 1978;74:640–642.
- 204↑
Burt M, Wronski M, Arbit E, Galicich JH. Resection of brain metastases from non-small-cell lung carcinoma. Results of therapy. Memorial Sloan-Kettering Cancer Center Thoracic Surgical Staff. J Thorac Cardiovasc Surg 1992;103:399–410; discussion 410–391.
- 205↑
Mehta MP, Tsao MN, Whelan TJ et al.. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 2005;63:37–46.
- 206↑
Alexander E 3rd, Moriarty TM, Davis RB et al.. Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 1995;87:34–40.
- 207↑
Raviv G, Klein E, Yellin A et al.. Surgical treatment of solitary adrenal metastases from lung carcinoma. J Surg Oncol 1990;43:123–124.
- 208↑
Reyes L, Parvez Z, Nemoto T et al.. Adrenalectomy for adrenal metastasis from lung carcinoma. J Surg Oncol 1990;44:32–34.
- 209↑
Gelb AF, Tashkin DP, Epstein JD et al.. Physiologic characteristics of malignant unilateral main-stem bronchial obstruction. Diagnosis and Nd-YAG laser treatment. Am Rev Respir Dis 1988;138:1382–1385.
- 210↑
Henry DH, Costa L, Goldwasser F et al.. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29:1125–1132.
- 211
Rosen LS, Gordon D, Tchekmedyian NS et al.. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer 2004;100:2613–2621.
- 212↑
Henry DH, von Moos R, Hungria V et al.. Delaying skeletal-related events in a randomized phase III study of denosumab versus zoledronic acid in patients with advanced cancer [abstract]. J Clin Oncol 2010;28(Suppl 15):Abstract 9133.
- 213↑
Ibrahim A, Scher N, Williams G et al.. Approval summary for zoledronic acid for treatment of multiple myeloma and cancer bone metastases. Clin Cancer Res 2003;9:2394–2399.
- 214↑
Sakuma Y, Matsukuma S, Yoshihara M et al.. Distinctive evaluation of nonmucinous and mucinous subtypes of bronchioloalveolar carcinomas in EGFR and K-ras gene-mutation analyses for Japanese lung adenocarcinomas: confirmation of the correlations with histologic subtypes and gene mutations. Am J Clin Pathol 2007;128:100–108.
- 215↑
Forbes SA, Bhamra G, Bamford S et al.. The catalogue of somatic mutations in cancer (COSMIC). Curr Protoc Hum Genet 2008;Chapter 10:Unit 10.11.
- 216↑
Lee SY, Kim MJ, Jin G et al.. Somatic mutations in epidermal growth factor receptor signaling pathway genes in non-small cell lung cancers. J Thorac Oncol 2010;5:1734–1740.
- 217↑
Sandler A, Yi J, Dahlberg S et al.. Treatment outcomes by tumor histology in Eastern Cooperative Group Study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer. J Thorac Oncol 2010;5:1416–1423.
- 218↑
Socinski MA, Langer CJ, Huang JE et al.. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol 2009;27:5255–5261.
- 219↑
Johnson DH, Fehrenbacher L, Novotny WF et al.. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22:2184–2191.
- 220↑
Reck M, von Pawel J, Zatloukal P et al.. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009;27:1227–1234.
- 221↑
Mezger J, von Pawel J, Reck M. Bevacizumab (Bv) single-agent maintenance following Bv-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): results from an exploratory analysis of the AVAiL study [abstract]. J Clin Oncol 2009;27(Suppl 15):Abstract e19001.
- 222↑
Scagliotti G, Brodowicz T, Shepherd FA et al.. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol 2011;6:64–70.
- 223↑
Socinski MA, Schell MJ, Peterman A et al.. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 2002;20:1335–1343.
- 224↑
Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol 2009;27:3277–3283.
- 225↑
Riely GJ, Kris MG, Zhao B et al.. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res 2007;13:5150–5155.
- 226↑
von Minckwitz G, du Bois A, Schmidt M et al.. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol 2009;27:1999–2006.
- 227↑
Nguyen KS, Kobayashi S, Costa DB. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer 2009;10:281–289.
- 228↑
Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009;28 Suppl 1:S24–31.
- 229↑
Fossella FV, DeVore R, Kerr RN et al.. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354–2362.