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CHEST SupplementDIAGNOSIS AND MANAGEMENT OF LUNG CANCER, 3RD ED: ACCP GUIDELINES

journal.publications.chestnet.org CHEST / 143 / 5 / MAY 2013 SUPPLEMENT 7S

Lung cancer causes as many deaths as the next fourleading causes of cancer deaths combined.1In the

developing world, which has seen a dramatic increasein the rate of smoking, the impending number ofdeaths from this disease is staggering. Although theincidence and death rate in the United States hasbeen declining since around 2000, lung cancer is pro-

jected to remain by far the leading cause of cancerdeaths for many decades.

For many years, lung cancer was a relatively neglecteddisease, shrouded in pessimism and with little researchfunding. However, many advances have occurred,

and it is now a vibrant field with a rapid pace ofnew information. The explosion of literature makesit difficult for anyone to stay current. With more

insight comes the identification of many nuancesthat are important to correctly understand new stud-ies and choose the optimal treatments for patients.Lung cancer has evolved to where it takes a team ofindividuals, each with lung cancer expertise withintheir specialty, to be able to provide the necessaryup-to-date knowledge base. The crucial aspect hereis not to simply have multiple specialties but todevelop a forum for ongoing interaction, so that theindividuals think and function as a team, makingdecisions collectively. Such integration and collab-oration allow collective knowledge and judgment to

be brought to bear on caring for patients. Even forsuch a team, however, staying abreast of advances ischallenging.

Evidence-based guidelines are intended to makethe process of providing up-to-date care easier. Thethird edition of the American College of Chest Physi-cians (ACCP) Lung Cancer Guidelines (LC III) is asystematic, extensive, comprehensive review of theliterature, a structured interpretation of the data, andpractical patient management recommendations. TheLC III panelists were selected based on expertise and

volunteered an astounding number of hours to care-

fully and systematically provide the basis for and,finally, produce the guidelines. The result is a prod-uct that can be accessed superficially to quickly findguideline statements relevant to a particular clinicalissue or more in depth by reviewing the data tablesand reading the individual articles. The organizedprocess to produce the guidelines helps to ensurethat it is not biased and is representative of the cur-rent state of knowledge. The LC III documents rep-resent a distillation of thousands of hours to make theinsights more easily accessible to the clinicians on thefront lines.

Abbreviations:ACCP5American College of Chest Physicians;

AFB5autofluorescence bronchoscopy; APW5AortopulmonaryWindow; BSC5 best supportive care; CIS5 carcinoma in situ;CPET5cardiopulmonary exercise test; CXR5chest radiograph;Dlco5diffusing capacity for carbon monoxide; EBUS5endo-bronchial ultrasound; ECOG5Eastern Cooperative OncologyGroup; EGFR5epidermal growth factor receptor; ES5exten-sive stage; FA5fine needle aspiration; GGO5ground glass opacity;IASLC5 International Association for the Study of Lung Can-cer; LC III53rd edition of the ACCP Lung Cancer Guidelines;LDCT5 low-dose CT; LS5 limited stage; LUL5 left upper lobe;LVRS5 lung volume reduction surgery; MFLC5multifocal lungcancer; MPE5malignant pleural effusion; NA5needle aspira-tion; NLST5National Lung Cancer Screening Trial; NRS5numer-ical rating scale; NSAID5 nonsteroidal antiinflammatory drug;

NSCLC5non-small cell lung cancer; PET5positron emissiontomography; PPO5predicted postoperative; PS5performancestatus; QOL5quality of life; RCT5 randomized controlled trial;RT5 radiotherapy; SBRT5 stereotactic body radiation ther-apy; SCLC5 small cell lung cancer; SVC5 superior vena cava;SWT5shuttle walk test; TBNA5transbronchial needle aspiration;TRT5 thoracic radiotherapy; TTNA5 transthoracic needle aspi-ration; VAS5visual analog scale; VATS5video-assisted thoracicsurgery; VEGF5vascular endothelial growth factor; o2max5max-imal oxygen consumption; WHO5World Health Organization;

WLB5white light bronchosopy

Executive Summary

Diagnosis and Management of Lung Cancer,3rd ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines

Frank C. Detterbeck, MD, FCCP; Sandra Zelman Lewis, PhD; Rebecca Diekemper, MPH;Doreen J. Addrizzo-Harris, MD, FCCP; and W. Michael Alberts, MD, MBA, FCCP

CHEST 2013; 143(5)(Suppl):7S37S

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8S Executive Summary

possible in that setting. The LC III guidelines weredesigned to provide enough details to facilitatesuch local adaptation in an efficient manner. Thisexecutive summary provides a brief synopsis of eacharticle, highlights the major points, and lists therecommendations.

2.0Methodology for Developmentof Guidelines for Lung Cancer

There have been major advances in the clinical sci-ence of lung cancer. There have also been majoradvances in methodologic science. The ACCP hasbeen at the forefront of these advances and is com-mitted to continuing to evolve the process of litera-ture review, data extraction, and guideline development.

With the advancement of methodologic techniques,content experts and methodologists must work handin hand to bring the best each has to offer to bear on

the process. Because resources are not unlimited, andpractical aspects and logistics present challenges, howto achieve this collaboration was a process that con-tinued to evolve during the development of LC IIIguidelines. We were fortunate to have the participa-tion of a small but growing number of individuals

who have content expertise as well as formal method-ology training. For each article, a methodologist wasassigned and involved during the process of researchand guideline development.

3.0Epidemiology of Lung Cancer

The epidemiology of lung cancer is an active field.Researchers in the area of molecular epidemiologyare making advances in the identification of bio-markers of risk and for early detection, although theseare not yet mature enough for clinical application.

Cigarette smoking remains the predominant riskfactor for lung cancer. A dramatic increase in deathsfrom lung cancer is anticipated in the developing

world, given the current high rate of smoking in theseregions. This will have significant social and economic

impact.Although smoking is the major risk factor, a better

understanding of the risk of developing lung canceris needed, particularly with the advent of screening

with low-dose CT (LDCT) scanning. This article dis-cusses the risk models that have been developed.Further validation of these models is needed to allowprediction of risk for individual patients. Further-more, a better understanding of other factors is needed,for example, to address the substantial number ofpatients who develop lung cancer despite being life-long nonsmokers.

Nevertheless, implementation of the guidelinesrequires some effort. They cannot provide a simplerecipe for treatment. Clinical judgment is neededto assess and balance the many factors that go intoclinical decision-making. How well do the patientsfrom whom the data are derived match the patientfor whom a management plan is being developed?How strong and consistent are the data, and how

heavily should other factors or patient preferencesinfluence the plan? The essence of clinical judg-ment is being able to weigh the strength of themany factors that each patient brings to decision-making. The LC III guidelines are designed to impartinsight into these matters to enhance clinical deci-sion making and not merely present a relatively rigidalgorithm.

A difficulty in developing guidelines is that imple-mentation must also be tailored to the local setting.In some countries or institutions, certain tests or pro-cedures may not be available. On a more subtle level,

although a test may sometimes be available, one cannotassume that the results in every clinical setting matchthose of the published literature. The best way toimplement guidelines is to thoughtfully tailor themto the local setting. This requires assembling the localteam of specialists and critically reviewing the majorguideline recommendations and the local strengthsand challenges. This allows the development of alocally adapted system of care that can significantlystreamline the process of care and ensure that patientsare receiving thoughtful care to the highest degree

Manuscript received September 24, 2012; revision acceptedNovember 30, 2012.Affiliations: From the Department of Thoracic Surgery(Dr Detterbeck), Yale University School of Medicine, New Haven,CT; the American College of Chest Physicians (Dr Lewis andMs Diekemper), Northbrook, IL; the Pulmonary Division(Dr Addrizzo-Harris), New York University School of Medicine,New York, NY; and the H. Lee Moffitt Cancer Center (Dr Alberts),Tampa, FL.Funding/Sponsors: The development of this guideline wassupported primarily by the American College of Chest Physicians.The lung cancer guidelines conference was supported in part bya grant from the Lung Cancer Research Foundation. The publica-tion and dissemination of the guidelines was supported in part bya 2009 independent educational grant from Boehringer IngelheimPharmaceuticals, Inc.

COI grids reflecting the conflicts of interest that were current asof the date of the conference and voting are posted in the onlinesupplementary materials.Disclaimer:American College of Chest Physician guidelines areintended for general information only, are not medical advice,and do not replace professional medical care and physician advice,

which always should be sought for any medical condition. Thecomplete disclaimer for this guideline can be accessed at http://dx.doi.org/10.1378/chest.1435S1.Correspondence to:Frank C. Detterbeck, MD, FCCP, YaleUniversity School of Medicine, 330 Cedar St, PO Box 208062,New Haven, CT 06520-8062; e-mail: [email protected] 2013 American College of Chest Physicians. Reproductionof this article is prohibited without written permission from theAmerican College of Chest Physicians. See online for more details.DOI: 10.1378/chest.12-2377


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3.3.1.2. Among lung cancer patients with depres-sive symptoms, we suggest cessation pharmaco-therapy with bupropion as a method to improveabstinence rates, depressive symptoms, andquality of life(Grade 2B).

3.3.1.3. Among lung cancer patients for whompharmacotherapeutic support is either contrain-

dicated or refused, we suggest cessation coun-seling alone as a method to improve abstinencerates(Grade 2C).

3.4.1.1. Among lung cancer patients undergoingradiotherapy, we recommend cessation inter-ventions that include counseling and pharmaco-therapy(Grade 1C).

7.0Screening for Lung Cancer

Major progress has been made in defining the roleof screening for lung cancer. The results of a majorRCT evaluating chest radiographs is consistent withearlier RCTs, showing that this is not a useful screen-ing test. There are several RCTs evaluating the roleof LDCT scanning. The largest of these is the NationalLung Cancer Screening Trial (NLST), which hasreported a reduction in lung cancer deaths amongscreened individuals. This involved patients with asignificant risk of lung cancer due to age and smok-ing history. Two smaller studies have also reportedmortality data; although they did not demonstrate a

mortality benefit, they are probably best viewed asneither supporting nor refuting the NLST results.The average risk of lung cancer of individuals partici-pating in these smaller trials appears to be slightlyless.

LDCT scanning identifies small nodules in 10% to50% of those screened, the vast majority of which arebenign. The rate of nodule detection varies and is notreadily explained (eg, size criteria, scanner parame-ters, population risk, and so forth). All of the con-trolled LDCT scanning trials have had an organizedprocess in place for evaluation of findings, and this

has resulted in relatively few patients undergoinginvasive biopsies. Nevertheless, the rate of biopsy forbenign lesions is highly variable and averages around30%. The reason for the variation is poorly under-stood. Although harms have been relatively few, thereis a risk from radiation exposure, and there have beencomplications and even rare deaths in patients under-going investigation of what turned out to be a benign,screen-detected nodule.

These results indicate that screening is a complexinterplay of baseline risk, the screening test, test inter-pretation, and management of the findings. There is

an up-to-date, sophisticated evidence-based treatmentprogram for treatment of tobacco use.

Summary of Recommendations: Treatment ofTobacco Use

3.1.1.1. We recommend that current smokersundergoing low-dose CT screening be provided

with cessation interventions that include coun-seling and pharmacotherapy(Grade 1B).

Remark:The act of screening alone is insufficient topromote smoking cessation.

Remark:The use of self-help materials is insufficientfor achieving an increased rate of smoking abstinence.

3.1.1.2. Among current smokers with demon-strated smoking related pulmonary disease werecommend providing intensive cessation inter-ventions(Grade 1B).

3.2.1.1. Among lung cancer patients undergoingsurgery, we recommend perioperative cessationpharmacotherapy as a method for improvingabstinence rates(Grade 1B).

3.2.1.2. Among lung cancer patients undergoingsurgery for whom pharmacotherapeutic sup-port is either contraindicated or refused, wesuggest cessation counseling alone during theperioperative period(Grade 2C).

3.2.1.3. Among lung cancer patients undergoingsurgery, the timing of cessation does not appearto increase the risk of post-operative complica-tions; we suggest that cessation interventions beinitiated in the pre-operative period (Grade 2C).

Remark:Small observed effect sizes and limitationsin experimental design do not justify delaying surgicalprocedures in favor of longer abstinence duration.

3.2.1.4. For lung cancer patients attemptingcessation in conjunction with surgical interven-tions, we recommend initiating counseling andpharmacotherapy at the outset of surgical inter-vention(Grade 1B).

Remark:There is substantial evidence suggestingthat reliance on short, low intensity cessation inter-

ventions such as advice to quit does not improveabstinence outcomes.

3.3.1.1. Among lung cancer patients undergoingchemotherapy, we recommend cessation inter-ventions that include counseling and pharmaco-therapy to improve abstinence rates(Grade 1B).


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could help enhance the benefits and minimize theharm for individuals who undergo screening.

Remark:Screening for lung cancer is not a substi-tute for stopping smoking. The most important thingpatients can do to prevent lung cancer is not smoke.

Remark:The most effective duration or frequency ofscreening is not known.

3.4.2. For individuals who have accumulated fewerthan 30 pack-years of smoking or are eitheryounger than age 55 or older than 74, or indi-viduals who quit smoking more than 15 yearsago, and for individuals with severe comorbidi-ties that would preclude potentially curativetreatment and/or limit life expectancy, we sug-gest that CT screening should not be performed(Grade 2C).

8.0 Evaluation of Individuals WithPulmonary Nodules: When

Is It Lung Cancer?

The management of a solitary pulmonary nodulehas been addressed extensively, yet most pulmonolo-gists and thoracic surgeons use an approach that isnot closely grounded in solid evidence. The manage-ment of these patients is somewhat complex and isinfluenced by many considerations (eg, the risk ofmalignancy based on the patients history and fea-tures of the lesion), patient characteristics (eg, lung

function), patient values and preferences, and thereliability of various tests.

This article does a superb job of integrating a largeamount of data in a complex field into an evidence-based approach. It is extensively researched and wellsummarized, but the real value is the structure thatis provided, which organizes the various factors andconsiderations (see Fig 2 in Gould et al2in LC III). Auseful starting point is to assess the risk of lung can-cer as well as the patients risk for an invasive proce-dure. Larger masses must be approached differentlythan subcentimeter lesions or ground-glass opacities.

Careful observation is reasonable in some settings. Ifa bronchoscopic or needle-based biopsy is selected,the possibility of a false-negative result must be keptin mind.

Summary of Recommendations: Evaluationof Pulmonary Nodules

General Approach

2.3.1. In the individual with an indeterminatenodule that is visible on chest radiography and/or

a large potential for benefit, but implementation ofLDCT screening is made difficult by the lack of dataabout the impact that various selection, structural,and technical aspects of the screening process haveon outcomes. Furthermore, many RCTs of LDCTscanning are still ongoing. The recommendation atthis time is to implement screening in settings andpatients that match those of the NLST while further

data are acquired.

Summary of Recommendations: Screeningfor Lung Cancer

3.2.1. In patients at risk for developing lung can-cer, screening for lung cancer with chest radio-graph (CXR) once or at regular intervals is notrecommended(Grade 1A).

Remark:These results should not be interpreted asdiminishing the role of CXR in evaluating patients

with pulmonary symptoms (an entirely different situ-ation than screening asymptomatic individuals).

3.2.2. In patients at risk for developing lungcancer, screening for lung cancer with sputumcytology at regular intervals is not suggested(Grade 2B).

3.4.1. For smokers and former smokers whoare age 55 to 74 and who have smoked for30 pack-years or more and either continue tosmoke or have quit within the past 15 years, wesuggest that annual screening with low-dose

CT (LDCT) should be offered over both annualscreening with CXR or no screening, but only insettings that can deliver the comprehensivecare provided to National Lung Screening Trialparticipants(Grade 2B).

Remark:Counseling should include a complete descrip-tion of potential benefits and harms, so the individualcan decide whether to undergo LDCT screening.

Remark:Screening should be conducted in a centersimilar to those where the National Lung ScreeningTrial was conducted, with multidisciplinary coordi-nated care and a comprehensive process for screening,image interpretation, management of findings, andevaluation and treatment of potential cancers.

Remark: A number of important questions aboutscreening could be addressed if individuals who arescreened for lung cancer are entered into a registrythat captures data on follow-up testing, radiationexposure, patient experience, and smoking behavior.

Remark:Quality metrics should be developed suchas those in use for mammography screening, which


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When the clinical probability of malignancyis very low (,5%)

When clinical probability is low (,30% to40%) and the results of a functional imag-ing test are negative (ie, the lesion is nothypermetabolic by PET or does not enhance.15 Hounsfield units on dynamic contrast CT),resulting in a very-low posttest probability

of malignancy When needle biopsy is nondiagnostic and

the lesion is not hypermetabolic by PET When a fully informed patient prefers this

nonaggressive management approach.

Remark: CT surveillance of solid nodules 8 mmshould use low-dose, noncontrast techniques.

4.5.1.2. In the individual with a solid, indeter-minate nodule that measures .8 mm in diam-eter who undergoes surveillance, we suggestthat serial CT scans should be performed at 3 to6, 9 to 12, and 18 to 24 months, using thin sec-tions and noncontrast, low-dose techniques(Grade 2C).

Remark:Serial CT scans should be compared with allavailable prior studies, especially the initial (index)CT scan.

Remark:Where available, manual and/or computer-assisted measurements of area, volume, and/or massmay facilitate early detection of growth.

4.5.1.3. In the individual with a solid, indetermi-nate nodule that shows clear evidence of malig-nant growth on serial imaging, we recommendnonsurgical biopsy and/or surgical resectionunless specifically contraindicated(Grade 1C).

Remark:Solid nodules that decrease in size but donot disappear completely should be followed to reso-lution or lack of growth over 2 years.

4.6.2.1.1. In the individual with a solid, inde-terminate nodule that measures .8 mm indiameter, we suggest nonsurgical biopsy in the

following circumstances(Grade 2C):

When clinical pretest probability and find-ings on imaging tests are discordant

When the probability of malignancy is lowto moderate (~ 10% to 60%)

When a benign diagnosis requiring specificmedical treatment is suspected

When a fully informed patient desires proofof a malignant diagnosis prior to surgery,especially when the risk of surgical compli-cations is high.

chest CT, we recommend that prior imagingtests should be reviewed(Grade 1C).

2.3.2. In the individual with a solid, indetermi-nate nodule that has been stable for at least2 years, we suggest that no additional diagnosticevaluation need be performed(Grade 2C).

Remark: This recommendation applies only to solidnodules. For guidance about follow-up of subsolidnodules, see Recommendations 6.5.1. to 6.5.4.

2.3.3. In the individual with an indeterminatenodule that is identified by chest radiography,

we recommend that CT of the chest should beperformed (preferably with thin sections throughthe nodule) to help characterize the nodule(Grade 1C).

Solid Nodules.8 mm

4.1.1.1. In the individual with a solid, indetermi-nate nodule that measures .8 mm in diameter,

we suggest that clinicians estimate the pretestprobability of malignancy either qualitativelyby using their clinical judgment and/or quanti-tatively by using a validated model(Grade 2C).

4.2.4.1. In the individual with a solid, indeter-minate nodule that measures.8 mm in diameterand low to moderate pretest probability of malig-nancy (5%-65%), we suggest that functional imag-ing, preferably with PET, should be performedto characterize the nodule(Grade 2C).

4.2.4.2. In the individual with a solid, indeter-minate nodule that measures .8 mm in diam-eter and a high pretest probability of malignancy(.65%), we suggest that functional imagingshould not be performed to characterize thenodule(Grade 2C).

Remark: PET may be indicated for pretreatmentstaging among those patients with nodules in whommalignancy is strongly suspected or confirmed.

4.4.1.1. In the individual with a solid, indetermi-nate nodule that measures .8 mm in diameter,

we recommend that clinicians discuss the risksand benefits of alternative management strat-egies and elicit patient preferences for manage-ment(Grade 1C).

4.5.1.1. In the individual with a solid, indeter-minate nodule that measures .8 mm in diam-eter, we suggest surveillance with serial CT scansin the following circumstances(Grade 2C):


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5.3.2. In the individual with a solid nodule thatmeasures 8 mm in diameter who has one ormore risk factors for lung cancer, we suggestthat the frequency and duration of CT surveil-lance be chosen according to the size of thenodule(Grade 2C):

Nodules measuring 4 mm in diameter

should be reevaluated at 12 months with-out the need for additional follow-up ifunchanged

Nodules measuring .4 mm to 6 mmshould be followed sometime between 6 and12 months and then again between 18 and24 months if unchanged

Nodules measuring.6 mm to 8 mm shouldbe followed initially sometime between 3and 6 months, then subsequently between 9and 12 months, and again at 24 months ifunchanged.

Remark:For the individual with multiple small, solidnodules, the frequency and duration of follow-upshould be based on the size of the largest nodule.

Remark: CT surveillance of solid nodules 8 mmshould use low-dose, noncontrast techniques.

Nonsolid (Pure Ground Glass) Nodules

6.5.1. In the individual with a nonsolid (pureground glass) nodule measuring 5 mm in diam-eter, we suggest no further evaluation(Grade 2C).

6.5.2. In the individual with a nonsolid (pureground glass) nodule measuring .5 mm in diam-eter, we suggest annual surveillance with chestCT for at least 3 years(Grade 2C).

Remark:CT surveillance of nonsolid nodules shoulduse noncontrast techniques with thin sections throughthe nodule of interest.

Remark: Nonsolid nodules that grow or develop asolid component are often malignant, prompting fur-ther evaluation and/or consideration of resection.

Remark: Early follow-up at 3 months may be indi-cated for nonsolid nodules measuring .10 mm (fol-lowed by nonsurgical biopsy and/or surgical resectionfor nodules that persist).

Remark: Limited duration or no follow-up may bepreferred by individuals with life-limiting comor-bidities in whom a low-grade malignancy would beof little consequence or by others who place a high

value on avoiding treatment of possibly indolent lungcancer.

Remark:The type of biopsy should be selected basedon nodule size, location, and relation to a patent air-

way; the risk of complications in the individual patient;and available expertise.

4.6.3.1.1. In the individual with a solid, indetermi-nate nodule that measures .8 mm in diameter,

we suggest surgical diagnosis in the following

circumstances(Grade 2C):

When the clinical probability of malignancyis high (.65%)

When the nodule is intensely hypermeta-bolic by PET or markedly positive by anotherfunctional imaging test

When nonsurgical biopsy is suspicious formalignancy

When a fully informed patient prefers under-going a definitive diagnostic procedure.

4.6.3.1.2. In the individual with a solid, indeter-minate nodule measuring .8 mm in diameter

who chooses surgical diagnosis, we recommendthoracoscopy to obtain a diagnostic wedge resec-tion(Grade 1C).

Remark:Use of advanced localization techniques oropen thoracotomy may be necessary when resectingsmall or deep nodules.

Solid Nodules8 mm

5.3.1. In the individual with a solid nodule thatmeasures 8 mm in diameter and no risk factorsfor lung cancer, we suggest that the frequencyand duration of CT surveillance be chosenaccording to the size of the nodule(Grade 2C):

Nodules measuring 4 mm in diameterneed not be followed, but the patient shouldbe informed about the potential benefitsand harms of this approach

Nodules measuring.4 mm to 6 mm shouldbe reevaluated at 12 months without the

need for additional follow-up if unchanged Nodules measuring .6 mm to 8 mm

should be followed sometime between 6 and12 months, and then again at between 18 and24 months if unchanged.

Remark:For the individual with multiple small, solidnodules, the frequency and duration of follow-upshould be based on the size of the largest nodule.

Remark:CT surveillance of solid nodules 8 mmshould use low-dose, noncontrast techniques.


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9.0Clinical and OrganizationalFactors in the Initial Evaluation

of Patients With Lung Cancer

Patients with lung cancer may present with nosymptoms, symptoms related to the primary tumor,or symptoms related to distant metastases. A numberof paraneoplastic effects are also seen. The evalua-tion starts with a careful history and physical exam-ination. The tasks of the initial evaluation, namely toestablish a diagnosis and clinical stage and developa treatment plan, proceed in an overlapping, notsequential manner. Involving a multidisciplinary teamearly during these processes can make the evaluationproceed more quickly with fewer unnecessary tests.However, quantifying the value of multidisciplinaryevaluation or more timely care is difficult.

Summary of Recommendations: Initial

Evaluation of Patients With Lung Cancer4.4.1. For patients with known or suspectedlung cancer, we suggest that the delivery of carebe timely and efficient(Grade 2C).

Remark:Interventions to improve timeliness shouldbe developed locally by addressing barriers to pro-

viding timely care that are specific to the localsetting.

Remark:Efforts to improve timeliness should be bal-anced with the need to attend to other dimensions of

health-care quality (such as safety, effectiveness, effi-ciency, equality, and consistency with patient valuesand preferences).

5.1.1. For patients with lung cancer who requiremultimodality therapy, we suggest using a mul-tidisciplinary team approach(Grade 2C).

Remark:We suggest that multidisciplinary teamshave representatives from pulmonary medicine, tho-racic surgery, medical oncology, radiation oncology,palliative care, radiology, and pathology.

10.0Establishing the Diagnosisof Lung Cancer

In most patients, the diagnosis of lung cancer isbest established in a way that simultaneously con-firms the stage of disease. If there is a pleural effu-sion, this represents an obvious target; however, thereis a substantial false-negative rate to thoracentesisand cytology. Biopsy of distant sites or mediastinalnodes may be indicated but is covered elsewhere.

Part-Solid (.50% Ground Glass) Nodules

6.5.3. In the individual with a part-solid nodulemeasuring 8 mm in diameter, we suggestCT surveillance at approximately 3, 12, and24 months, followed by annual CT surveillancefor an additional 1 to 3 years(Grade 2C).

Remark:CT surveillance of part-solid nodules should

use noncontrast techniques with thin sections throughthe nodule of interest.

Remark: Part-solid nodules that grow or develop asolid component are often malignant, prompting fur-ther evaluation and/or consideration of resection.

Remark: Limited duration or no follow-up may bepreferred by individuals with life-limiting comor-bidities in whom a low-grade malignancy would beof little consequence or by others who place a high

value on avoiding treatment of possibly indolent lung

cancer.6.5.4. In the individual with a part-solid nodulemeasuring .8 mm in diameter, we suggestrepeat chest CT at 3 months followed by fur-ther evaluation with PET, nonsurgical biopsy,and/or surgical resection for nodules that per-sist(Grade 2C).

Remark:PET should not be used to characterizepart-solid lesions in which the solid componentmeasures8 mm.

Remark:Nonsurgical biopsy can be used to establishthe diagnosis and/or be combined with wire, radioac-tive seed, or dye localization to facilitate subsequentresection. A nondiagnostic biopsy result does notexclude the possibility of malignancy.

Remark: Part-solid nodules measuring .15 mm indiameter should proceed directly to further evalua-tion with PET, nonsurgical biopsy, and/or surgicalresection.

One or More Additional NodulesDetected During Nodule Evaluation

7.1.1. In the individual with a dominant noduleand one or more additional small nodules, wesuggest that each nodule be evaluated indi-vidually and curative treatment not be deniedunless there is histopathological confirmationof metastasis(Grade 2C).

Remark:The classification and appropriate treatmentof patients with more than one pulmonary focus oflung cancer is difficult and requires multidisciplinaryconsideration.


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thoracentesis is recommended to diagnose thecause of the pleural effusion(Grade 1C).

Remark: Ultrasound-guided thoracentesis improvesthe success rate and decreases the rate of pneumo-thorax and therefore ultrasound is recommended forperforming diagnostic thoracentesis.

2.3.6. In patients suspected of having lung can-cer who have an accessible pleural effusion, ifpleural fluid cytology is negative, pleural biopsy(via image-guided pleural biopsy, medical orsurgical thoracoscopy) is recommended as thenext step(Grade 1C).

Remark: If the CT scan of the chest shows pleuralthickening or pleural nodules/masses, image-guidedneedle biopsy may be considered as the first step toobtain a biopsy of the pleura.

Remark:If pleural cytology is negative after the first

thoracentesis, a second thoracentesis has been shownto increase the diagnostic yield of pleural fluid cytology.Depending on preferences and values (a simpler andless invasive test vs a more definitive test) a secondthoracentesis may be considered before proceedingto biopsy of the pleura.

Diagnosis of the Primary Tumor

3.1.2.1. In patients suspected of having lungcancer, if sputum cytology is done but is nega-tive for carcinoma, it is recommended that fur-

ther testing be performed(Grade 1C).Remark:Sputum cytology is an acceptable method ofestablishing the diagnosis. However, the sensitivity orsputum cytology varies by location of the lung cancer,and with the frequency and processing of the sputumat the center.

3.2.2.1. In patients suspected of having lung can-cer, who have a central lesion, bronchoscopy isrecommended to confirm the diagnosis. However,it is recommended that further testing be per-formed if bronchoscopy results are non-diagnosticand suspicion of lung cancer remains(Grade 1B).

Remark:In recent years a number of complementarytools including radial endobronchial ultrasound andelectromagnetic navigation have been added to flex-ible bronchoscopy to aid in the diagnosis of periph-eral lung lesions.

3.3.2.1. In patients suspected of having lungcancer, who have a peripheral lung nodule, anda tissue diagnosis is required due to uncertaintyof diagnosis or poor surgical candidacy, radial

Many techniques are available to diagnose the pri-mary tumor. This article extensively reviews the datafor these, parsed out for specific situations. This helpsguide the selection of which test to perform as well ashow to interpret the results (ie, how to proceed if thetest does not show cancer in a patient suspected oflung cancer). Bronchoscopy is ideal for central lesionsbut has low sensitivity and a high false-negative rate

for peripheral lesions. Newer navigational techniqueshave improved sensitivity for peripheral lesions and alower rate of pneumothorax compared with transtho-racic needle aspiration, but all methods have a sub-stantial false-negative rate.

Summary of Recommendations: Establishingthe Diagnosis of Lung Cancer

General Approach to Diagnosis

2.3.1. In patients suspected of having small celllung cancer (SCLC) based on the radiographic

and clinical findings, it is recommended thatthe diagnosis be confirmed by the least invasivemethod (sputum cytology, thoracentesis, fineneedle aspiration [FNA], bronchoscopy includingtransbronchial needle aspiration [TBNA]), asdictated by the patients presentation(Grade 1C).

2.3.2. In patients suspected of having lung can-cer, who have extensive infiltration of the medi-astinum based on radiographic studies and noevidence of extrathoracic metastatic disease(negative PET scan), it is recommended that the

diagnosis of lung cancer be established by theleast invasive and safest method (bronchoscopywith TBNA, endobronchial ultrasound-guided nee-dle aspiration [EBUS-NA], endoscopic ultrasound-guided needle aspiration [EUS-NA], transthoracicneedle aspiration[TTNA], or mediastinoscopy)(Grade 1C).

2.3.3. In patients suspected of having lung can-cer who have a solitary extrathoracic site suspi-cious of a metastasis, it is recommended thattissue confirmation of the metastatic site beobtained if a FNA or biopsy of the site is feasible(Grade 1C).

2.3.4. In patients suspected of having lung can-cer, who have lesions in multiple distant sitessuspected of metastases but in whom biopsy of ametastatic site would be technically difficult, itis recommended that diagnosis of the primarylung lesion be obtained by the least invasivemethod(Grade 1C).

2.3.5. In patients suspected of having lung can-cer who have an accessible pleural effusion,


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testing be performed to establish a definitivecell type(Grade 1B).

11.0Physiologic Evaluation of thePatient With Lung Cancer Being

Considered for Resectional Surgery

Surgery remains the mainstay of treatment of early-stage lung cancer, and assessment of a patients abilityto tolerate a resection is important. Patients shouldundergo a simple cardiac risk assessment, with fur-ther investigation (ie, cardiopulmonary exercise testing)if this suggests potential complications. Assessmentof pulmonary reserve should include both spirometryand diffusion capacity, calculated as a predicted post-operative value (taking into account the intendedresection) and expressed as a percent of normal (thustaking into account variations in body size). Patients

with moderate impairment should undergo a simpleexercise test, such as stair climbing; if performance islimited (stair climb of,22 m), formal cardiopulmonaryexercise testing is indicated (see Fig 2 in Brunelli et al3in LC III).

An important aspect of physiologic evaluation is thatthere is a continuum of risk and benefit that is not

well served by simple dichotomization into a yes/nocategorization of candidacy for pulmonary resection.Furthermore, the available data primarily pertain toopen thoracotomy; thoracoscopic resection is clearlybetter tolerated, although the criteria for preopera-tive assessment are not well defined. The decision toundertake surgery must take into account aspectssuch as the possibility of sublobar resection, thoraco-scopic resection, alternative (nonsurgical) treatments,and beneficial effects of smoking cessation and pre-operative pulmonary rehabilitation.

The available data primarily define outcomes rela-tive to acute morbidity and mortality; the effect onlong-term functional status is less well understood.Patients with worse preoperative lung function oftenlose less function. The evaluation of marginal patientsrequires multidisciplinary management.

Summary of Recommendations: PhysiologicEvaluation Prior to Resectional Surgery

2.6.1. In patients with lung cancer who arepotential candidates for curative surgical resec-tion, it is recommended that they be assessedby a multidisciplinary team, which includes athoracic surgeon specializing in lung cancer,medical oncologist, radiation oncologist andpulmonologist(Grade 1C).

2.6.2. In elderly patients with lung cancer whoare potential candidates for curative surgical

EBUS is recommended as an adjunct imagingmodality(Grade 1C).

Remark: Radial EBUS can confirm in real time theideal location of bronchoscopic sampling and increasethe diagnostic yield over conventional bronchoscopyfor peripheral nodules.

3.4.2.1. In patients with peripheral lung lesionsdifficult to reach with conventional bronchos-copy, electromagnetic navigation guidance isrecommended if the equipment and the exper-tise are available(Grade 1C).

Remark: The procedure can be performed with orwithout fluoroscopic guidance and it has been foundcomplementary to radial probe ultrasound

Remark: If electromagnetic navigation is not avail-able, TTNA is recommended.

3.5.2.1. In patients suspected of having lungcancer who have a peripheral lesion, and whorequire tissue diagnosis before further manage-ment can be planned, TTNA is a diagnosticoption. However, it is recommended that fur-ther testing be performed if TTNA results arenon-diagnostic and suspicion of lung cancerremains(Grade 1B).

3.6.2.1. In patients suspected of having lungcancer, the diagnosis of non-small cell lung can-cer made on cytology (sputum, TTNA, broncho-

scopic specimens, or pleural fluid) is reliable.However, it is recommended that adequatetissue be obtained to accurately define the his-tologic type and to perform molecular analysis

when applicable(Grade 1B).

Remark:It is critical to obtain adequate tissue to char-acterize a lung cancer. Within an institution, effec-tive communication between those obtaining thebiopsies, those interpreting them, and those deliv-ering the treatment must be in place so that collec-tively, the members of various subspecialties involved

in the care of the lung cancer patient can decide howbest to obtain and optimally use the tissue. If speci-mens are not adequate for histologic and molecularcharacterization then obtaining a second biopsy isacceptable given the importance of accurate tumorcharacterization.

3.6.2.2. The possibility of an erroneous diagno-sis of SCLC on a cytology specimen must bekept in mind if the clinical presentation or clin-ical course is not consistent with that of SCLC.In such a case, it is recommended that further


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resection it is recommended that they be fullyevaluated regardless of age(Grade 1C).

2.6.3. In patients with lung cancer being consid-ered for surgery who have increased periopera-tive cardiovascular risk, a preoperative cardiologicevaluation is recommended, with further man-agement according to existing cardiologic guide-

lines for non cardiac surgery(Grade 1C).3.1.1.1. In patients with lung cancer being con-sidered for surgery, it is recommended thatboth FEV1 and diffusing capacity for carbonmonoxide (DLCO) be measured in all patientsand that both predicted postoperative (PPO)FEV1and PPO DLCOare calculated(Grade 1B).

3.2.1.1. In patients with lung cancer being con-sidered for surgery, if both PPO FEV1and PPODLCOare.60% predicted, no further tests arerecommended(Grade 1C).

Remark: Values of both PPO FEV1 and PPODlco.60% indicate low risk for perioperative deathand cardiopulmonary complications following resec-tion including pneumonectomy.

3.2.1.2. In patients with lung cancer being con-sidered for surgery, if either the PPO FEV1orPPO DLCO are,60% predicted and both areabove 30% predicted, it is recommended that alow technology exercise test (stair climb orshuttle walk test [SWT]) is performed(Grade 1C).

3.2.1.3. In patients with lung cancer being con-sidered for surgery, with either a PPO FEV1,30%predicted or a PPO DLCO,30% predicted per-formance of a formal cardiopulmonary exer-cise test (CPET) with measurement of maximaloxygen consumption ( O2max) is recommended(Grade 1B).

Remark: Either a PPO FEV1,30% predicted or aPPO Dlco,30% predicted indicate an increasedrisk for perioperative death and cardiopulmonarycomplications with anatomic lung resection.

3.9.1. In patients with lung cancer being consid-ered for surgery who walk,25 shuttles (or,400m)on the SWT or climb,22m at symptom limitedstair climbing test, performance of a formalCPET with measurement of O2max is recom-mended(Grade 1C).

Remark:Walking,25 shuttles (or,400m) on the SWTor climbing,22m at symptom limited stair climbingtest suggests an increased risk for perioperative deathand cardiopulmonary complications with anatomiclung resection.

3.9.2. In patients with lung cancer being con-sidered for surgery and a O2max,10mL/kg/min or,35% predicted it is recommendedthat they are counseled about minimally inva-sive surgery, sublobar resections or nonoper-ative treatment options for their lung cancer(Grade 1C).

Remark:ao

2max,10mL/kg/min or,35% predictedindicates a high risk for perioperative death and car-diopulmonary complications with major anatomiclung resection through thoracotomy.

Remark:For values of o2max in the range of 10 to15 mL/kg/min an increased risk of mortality is expected.However, data are less definitive for making deci-sions based solely on those values without taking intoaccount other factors like PPO FEV1and Dlcoas

well as patient comorbidities.

6.1.1. In patients with lung cancer being con-

sidered for surgery who undergo neoadjuvanttherapy, it is suggested that repeat pulmonaryfunction testing with diffusion capacity be per-formed after completion of neoadjuvant therapy(Grade 2C).

7.4.1. In patients with lung cancer in an area ofupper lobe emphysema who are candidates forlung volume reduction surgery (LVRS), com-bined LVRS and lung cancer resection is sug-gested(Grade 2C).

7.4.2. In all patients with lung cancer being con-sidered for surgery who are actively smoking,tobacco dependence treatment is recommended(Grade 1C).

Remark:Smoking cessation is associated with short-term perioperative and long-term survival benefits(see also specific recommendations in chapter 6,3.1.1, 3.1.2, 3.1.3).

7.4.3. In patients with lung cancer being con-sidered for surgery and deemed at high risk(as defined by the proposed functional algo-

rithm, ie, PPO FEV1or PPO DLCO,60% andO2max,10 mL/kg/min or,35%), preopera-

tive or postoperative pulmonary rehabilitationis recommended(Grade 1C).

12.0The Stage Classificationof Lung Cancer

Having a consistent nomenclature is crucial tobeing able to communicate and compare data fromdifferent studies and centers. The official worldwide


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Remark: If PET scan is unavailable for staging, theCT of the chest should be extended to include theliver and adrenal glands to assess for metastatic disease.

2.1.2. For patients with either a known or sus-pected lung cancer, it is recommended that athorough clinical evaluation be performed toprovide an initial definition of tumor stage

(Grade 1B).2.1.3. In patients with either a known or sus-pected lung cancer who have an abnormal clin-ical evaluation and no suspicious extrathoracicabnormalities on chest CT, additional imagingfor metastases is recommended(Grade 1B).

Remark:Site specific symptoms warrant directed eval-uation of that site with the most appropriate study.

Extrathoracic Staging

3.1.1. In patients with a normal clinical evaluationand no suspicious extrathoracic abnormalitieson chest CT being considered for curative-intent treatment, PET imaging (where available)is recommended to evaluate for metastases(except the brain)(Grade 1B).

Remark:Ground glass opacities and an otherwisenormal chest CT do not require a PET scan for staging.

Remark:In patients with peripheral stage cIA tumorsa PET scan is not required.

Remark: If PET is unavailable, bone scan and abdom-inal CT are reasonable alternatives to evaluate forextrathoracic disease.

3.1.2. In patients with an imaging finding (eg, byPET) suggestive of a metastasis, further evalua-tion of the abnormality with tissue sampling topathologically confirm the clinical stage is recom-mended prior to choosing treatment(Grade 1B).

Remark:Tissue sampling of the abnormal site is imper-ative so that the patient is not excluded from poten-

tially curative treatment.Remark:Tissue sampling of a distant metastatic site isnot necessary if there is overwhelming radiographicevidence of metastatic disease in multiple sites.

Remark: Tissue sampling of the mediastinal lymphnodes does not necessarily need to be performed ifthere is overwhelming radiographic evidence of met-astatic disease in multiple distant sites.

3.4.1. In patients with clinical stage III or IV non-small cell lung cancer(NSCLC) it is suggested

stage classification system (seventh edition) is basedon an unprecedented initiative of the InternationalAssociation for the Study of Lung Cancer involving adatabase of .100,000 patients diagnosed between1990 and 2000. This system is the basis for the nomen-clature used in the third edition of the ACCP LungCancer Guidelines. This article discusses the basicsas well as the many details of the system. An Internet-

accessible tool to navigate the stage classification isalso available at www.staginglungcancer.org.

As with any detailed and complex system, there areareas that are confusing and ambiguous (eg, measure-ment of ground-glass opacities; the use of clinical andpathologic stage for individual T, N, and M descrip-tors; and classification of synchronous primary can-cers, additional pulmonary nodules, and multifocallung cancer). This article also provides some guidanceabout how to deal with these issues.

13.0Methods of Staging forNon-small Cell Lung Cancer

Accurately defining the anatomic extent of diseaseis critical to selecting the appropriate therapy forpatients with lung cancer. Many studies have pro-

vided additional data regarding how best to achievethis. PET imaging has assumed a prominent role, butit is important to confirm positive PET findings witha biopsy in most situations. The clinical setting andthe extent of additional staging tests influences theimpact of PETthe benefit being most marked inpatients at greater risk of distant metastases (weight

loss, mediastinal node enlargement) and those whodo not undergo extensive imaging for distant metas-tases or invasive mediastinal staging in addition toPET imaging.

Invasive mediastinal staging is important for mostpatients who do not have distant metastases. The roleof endobronchial ultrasound has become well founded,

with many studies being available. It is important tonote, however, that details of how a procedure is per-formed likely influence how well the test functions inpractice. Data from reported studies often involvea thorough sampling. In general practice, node sam-

pling during mediastinoscopy has been more limited;whether this will be true of endobronchial ultrasoundwith wider application is yet to be determined.

Summary of Recommendations: Methods ofStaging for Non-small Cell Lung Cancer

General Approach

2.1.1. For patients with either a known or sus-pected lung cancer who are eligible for treat-ment, a CT scan of the chest with contrast isrecommended(Grade 1B).


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4.4.6.2. In patients with an intermediate suspi-cion of N2,3 involvement, ie, a radiographicallynormal mediastinum (by CT and PET) and acentral tumor or N1 lymph node enlargement(and no distant metastases), a needle technique(EBUS-NA, EUS-NA or combined EBUS/EUS-NA)is suggested over surgical staging as a best firsttest(Grade 2B).

Remark:This recommendation is based on the avail-ability of these technologies (EBUS-NA, EUS-NAor combined EBUS/EUS-NA) and the appropriateexperience and skill of the operator.

Remark: In cases where the clinical suspicion ofmediastinal node involvement remains high after anegative result using a needle technique, surgicalstaging (eg, mediastinoscopy, VATS, etc) should beperformed.

Remark: The reliability of mediastinal staging maybe more dependent on the thoroughness with whichthe procedure is performed than by which test isused.

4.4.8.1. For patients with a peripheral clinicalstage IA tumor (negative nodal involvement byCT and PET), it is suggested that invasive pre-operative evaluation of the mediastinal nodes isnot required(Grade 2B).

4.4.10.1. For the patients with a left upper lobe

(LUL) cancer in whom invasive mediastinalstaging is indicated as defined by the previousrecommendations, it is suggested that invasiveassessment of the Aortopulmonary Window (APW)nodes be performed (via Chamberlain, VATS,or extended cervical mediastinoscopy) if othermediastinal node stations are found to be unin-volved(Grade 2B).

14.0Diagnostic SurgicalPathology in Lung Cancer

Details of the pathologic assessment of lung cancerhave become more important. Definition of the his-tologic subtype of NSCLC is crucial in selection ofchemotherapy regimens. Further subtyping of ade-nocarcinoma may be important in determining bio-logic behavior and the extent of local therapy. Thisarticle provides a framework for the pathologist inassessment of lung cancers with immunohistochem-ical and genetic tests. Reporting is ideally done in astandardized form, but communication with clini-cians to discuss nuances remains important.

that routine imaging of the brain with head MRI(or CT if MRI is not available) should be per-formed, even if they have a negative clinicalevaluation(Grade 2C).

Mediastinal Staging

4.4.2.1. For patients with extensive mediastinal

infiltration of tumor and no distant metastases,it is suggested that radiographic (CT) assess-ment of the mediastinal stage is usually suffi-cient without invasive confirmation(Grade 2C).

4.4.4.1. In patients with discrete mediastinallymph node enlargement (and no distant metas-tases) with or without PET uptake in medias-tinal nodes, invasive staging of the mediastinumis recommended over staging by imaging alone(Grade 1C).

4.4.4.2. In patients with PET activity in a medi-astinal lymph node and normal appearing nodesby CT (and no distant metastases), invasive stag-ing of the mediastinum is recommended overstaging by imaging alone(Grade 1C).

4.4.4.3. In patients with high suspicion of N2,3involvement, either by discrete mediastinal lymphnode enlargement or PET uptake (and no dis-tant metastases), a needle technique (endobron-chial ultrasound[EBUS]-needle aspiration[NA],EUS-NA or combined EBUS/EUS-NA) is recom-mended over surgical staging as a best first test

(Grade 1B).

Remark:This recommendation is based on the avail-ability of these technologies (EBUS-NA, EUS-NAor combined EBUS/EUS-NA) and the appropriateexperience and skill of the operator.

Remark:In cases where the clinical suspicion of medi-astinal node involvement remains high after a nega-tive result using a needle technique, surgical staging(eg, mediastinoscopy, video-assisted thoracic surgery[VATS], etc) should be performed.

Remark:The reliability of mediastinal staging may bemore dependent on the thoroughness with which theprocedure is performed than by which test is used.

4.4.6.1. In patients with an intermediate suspi-cion of N2,3 involvement, ie, a radiographicallynormal mediastinum (by CT and PET) and acentral tumor or N1 lymph node enlargement(and no distant metastases), invasive staging ofthe mediastinum is recommended over stagingby imaging alone(Grade 1C).


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15.0Diagnosis and Treatment of BronchialIntraepithelial Neoplasia and Early

Lung Cancer of the Central Airways

A small number of patients present with a superfi-cial neoplastic lesion of the central airways (ie, high-grade dysplasia, carcinoma in situ, and small foci ofinvasive cancer). Autofluorescence bronchoscopy ismore sensitive at detecting such lesions. A numberof endobronchial treatments have been tried, mostprominently photodynamic therapy. However, thenatural history of these precancerous lesions is poorlydefined, and many appear to regress over time. There-fore the impact of detection and treatment is some-

what unclear. At this time standard white lightbronchoscopy remains the diagnostic tool of greatestclinical relevance.

Summary of Recommendations:

Bronchial Intraepithelial Neoplasia3.1.1.1. In patients with severe dysplasia or car-cinoma in situ (CIS) in sputum cytology who havechest imaging studies showing no localizingabnormality, standard white light bronchoscopy(WLB) is suggested to exclude an endobronchiallesion(Grade 2C).

Remark:Autofluorescence bronchoscopy (AFB) maybe used as an adjunct to WLB when available.

3.2.1.1. For patients with known severe dys-

plasia or CIS in the central airways on biopsy,follow-up WLB is suggested(Grade 2C).

Remark:AFB may be used when available. The timingand duration of follow-up are unknown.

Remark:Physicians and patients should discuss poten-tial risk and benefits of follow-up bronchoscopy.

3.3.3.1. For patients with early lung cancerundergoing resection, WLB is suggested for thedelineation of tumor margins and the assess-ment of synchronous lesions(Grade 2C).

Remark: AFB or narrow band imaging may be usedwhen available.

3.4.1.1. For patients being considered for cura-tive endobronchial therapy to treat CIS or earlycentral lung cancer, WLB is suggested over rou-tine use of AFB(Grade 2C).

4.6.1. For patients with superficial limited mucosallung cancer in the central airway who are notcandidates for surgical resection, endobronchial

Summary of Recommendations: DiagnosticSurgical Pathology in Lung Cancer

2.1.1. When pathologically diagnosing patientswith lung cancer, the synoptic reporting of his-tologic type, tumor size and location, tumorgrade (if appropriate), lymphovascular invasion,pleural involvement, surgical margins, and statusand location of lymph nodes by station is recom-mended(Grade 1B).

3.1.1. In individuals with pleural-based tumors,a designated limited panel of histochemical andimmunohistochemical assays or ultrastructuralanalysis is recommended to distinguish betweenpleural adenocarcinoma and malignant meso-thelioma in order to increase diagnostic accu-racy(Grade 1B).

4.1.1. In individuals with parenchymal-based

tumors, distinguishing between small cell car-cinoma and non-small cell carcinoma of thelung is recommended. For challenging cases, adiagnostic panel of immunohistochemical assaysor ultrastructural analysis is recommended toincrease the diagnostic accuracy(Grade 1B).

5.1.1. For individuals with glandular producingtumors, distinguishing adenocarcinoma in situand minimally invasive adenocarcinomas frominvasive adenocarcinomas is recommended(Grade 1C).

Remark: Pathologic discrimination among these diag-nostic entities are made on complete review of thetumor and not on needle biopsies.

6.1.1. In individuals with pathologically diag-nosed non-small cell lung cancer, additionaldiscrimination between adenocarcinoma andsquamous cell carcinoma, even on cytologic mate-rial or small tissue samples, is recommended(Grade 1B).

Remark: The precise subclassification is achieved inmost cases by conventional histo- and cytomorphol-ogy. Immunohistochemical assays are recommendedin cases where routine histopathologic differentiationis difficult to ascertain.

7.1.1. For individuals with lung tumors whosedifferential includes primary lung carcinomavs metastatic carcinoma, a directed panel ofimmunohistochemical assays is recommendedto increase the diagnostic accuracy(Grade 1C).


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plinary team even if the patients are consideredfor nonsurgical therapies such as percutaneousablation or stereotactic body radiation therapy(Grade 2C).

Remark:At a minimum, we suggest that multidisci-plinary teams have representatives from pulmonarymedicine, thoracic surgery, medical oncology, radia-

tion oncology, radiology, and pathology.2.2.4.1. For patients with clinical stage I or IINSCLC and who are medically fit, it is recom-mended that they be treated by a board certi-fied thoracic surgeon with a focus on lung cancer(Grade 1B).

Remark:Ideally general thoracic surgical procedureswould constitute.75% of the thoracic surgeonsclinical practice, and involve an average of4 ana-tomic surgical resections performed per month at thecenter to maintain the experience and smooth func-

tion of the care teams.

Lobectomy: Surgical Issues

3.2.1. For patients with clinical stage I NSCLC,a minimally invasive approach such as video-assisted thoracic surgery (thoracoscopy) is pre-ferred over a thoracotomy for anatomic pulmonaryresection and is suggested in experienced cen-ters (Grade 2C).

3.3.4.1. For patients with clinical stage I and

II NSCLC, systematic mediastinal lymph nodesampling or dissection at the time of anatomicresection is recommended over selective orno sampling for accurate pathologic staging(Grade 1B).

3.3.4.2. For patients with clinical stage I NSCLCundergoing anatomic resection who have under-gone systematic hilar and mediastinal lymphnode staging showing intraoperative N0 status,the addition of a mediastinal lymph node dis-section does not provide a survival benefit andis not suggested(Grade 2A).

3.3.4.3. For patients with clinical stage IINSCLC undergoing anatomic resection, medi-astinal lymph node dissection may provide addi-tional survival benefit over mediastinal lymphnode sampling and is suggested(Grade 2B).

3.5.1. For patients with clinical stage I or IIcentral NSCLC in whom a complete resectioncan be achieved, a sleeve or bronchoplasticresection is suggested over a pneumonectomy(Grade 2C).

treatment with photodynamic therapy, brachyther-apy, cryotherapy, or electrocautery is recom-mended(Grade 1C).

16.0Treatment of Stage I and IINon-small Cell Lung Cancer

Although the mainstay of treatment of stage I or IINSCLC remains surgical resection, significant advancesin understanding nuances have occurred. An exten-sive body of data demonstrates better outcomes whenresection is performed by surgeons with specialtytraining, or when done in a higher-volume center orin a teaching facility. However, the understanding islacking of exactly what processes lead to these out-comes, making it difficult to disseminate successfulpractices to improve outcomes more broadly. Datahave accumulated regarding video-assisted tho-racic surgery resection, making a minimally invasive

approach to resection the preferred technique, whichshould include at least a systematic lymph node sam-pling. Lobectomy remains the procedure of choice;sublobar resection is reserved for patients unable totolerate lobectomy, those with major competing causesof death, or those with a predominantly ground-glassopacity,2 cm in diameter. Details of the sublobarresection are probably important but are incompletelydefined. A margin of .2 cm, or, for smaller tumors,larger than the diameter of the tumor, appears to beimportant. Anatomic sublobar resection (ie, segmen-tectomy) appears to result in better outcomes than a

wedge resection. A sublobar resection is recommendedover nonsurgical therapy in patients able to toleratethis, but nonsurgical ablative treatment is preferredover no therapy in those who cannot.

The role of adjuvant chemotherapy is firmly estab-lished for patients with stage II NSCLC. Evaluationof the long-term results of RCTs does not support theuse of adjuvant chemotherapy for stage I NSCLC.Adjuvant radiotherapy (RT) is not beneficial for com-pletely resected stage I,II NSCLC.

Summary of Recommendations: Stage I

and II Non-small Cell Lung Cancer

General Approach

2.1.1. For patients with clinical stage I and IInon-small cell lung cancer (NSCLC) and nomedical contraindications to operative inter-vention, surgical resection is recommended(Grade 1B).

2.1.2. For patients with clinical stage I and IINSCLC, it is suggested that they be evaluatedby a thoracic surgical oncologist or a multidisci-


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and surgical wedge resection are suggested overno therapy(Grade 2C).

Remark:Surgical resection has the potential benefitof definitive histologic analysis (eg, adenocarcinomasubtype) and pathologic nodal information. In com-promised patients for whom such information wouldnot change management SBRT is a preferred option.

Also, SBRT is favored in patients for whom an adequatemargin in unlikely with a surgical wedge resection.

Remark: Radiofrequency ablation may also be con-sidered for peripheral tumors,3 cm in inoperablepatients.

Adjuvant Therapy

6.1.5.1. For patients with completely resectedpathologic stage IA,B NSCLC, it is recommendedthat postoperative chemotherapy not be used(outside of a clinical trial)(Grade 1B).

6.1.5.2. For patients with completely resectedpathologic stage IIA,B(N1) NSCLC and goodperformance status, postoperative platinum-based chemotherapy is recommended(Grade 1A).

Remark:No clear recommendation is possible regard-ing adjuvant chemotherapy for larger tumors withoutlymph node involvement.

6.2.5.1. For patients with completely resectedpathologic stage I NSCLC, it is recommendedthat postoperative radiation therapy should notbe used(Grade 1A).

6.2.5.2. For patients with completely resectedpathologic stage II NSCLC, it is suggested thatpostoperative radiation therapy should not beused(Grade 2A).

6.2.5.3. For patients with stage I and II NSCLCand a positive bronchial margin (R1 resection),postoperative radiation therapy is suggested(Grade 2C).

17.0Treatment of Stage IIINon-small Cell Lung Cancer

The management of stage III NSCLC is amongthe most confusing and controversial areas, despitethe many papers published on the subject. In part,this stems from the fact that stage III involves a broadspectrum of disease burden, from patients with exten-sive mediastinal infiltration, others with discrete medi-astinal node involvement, and those only found to havea small focus of nodal involvement after resection

Sublobar Resection

4.3.1. For patients with clinical stage I and IINSCLC who are medically fit for surgical resec-tion, a lobectomy rather than sublobar resec-tion is recommended(Grade1B).

4.8.1. For patients with clinical stage I NSCLCwho may tolerate operative intervention but not

a lobar resection due to decreased pulmonaryfunction or comorbid disease, sublobar resec-tion is recommended over nonsurgical therapy(Grade 1B).

Remark: Regardless of whether patients undergowedge or segmentectomy, adequate margins should beachieved.

Remark: Sublobar resection should involve an ana-tomic segmentectomy whenever possible.

4.8.2. During sublobar resection of solid tumorsin compromised patients, it is recommendedthat margins greater than the maximal tumordiameter for lesions less than 2 cm should beachieved; for tumors larger than 2 cm at least2 cm gross margins should be sought to mini-mize the likelihood of a positive margin and/orlocal recurrence(Grade 1C).

Remark: The data regarding the appropriate grossmargin necessary to achieve a pathologically negativemargin or minimize local recurrence in larger tumors

(.2 cm) is less well established. It may be that largermargins for larger tumors are required.

Remark: In patients undergoing resection of solidstage cI NSCLC in whom the ability to achieve anadequate margin is compromised, the addition ofbrachytherapy mesh to sublobar resection may improvelocal control.

4.10.1. In patients with major increased risk ofperioperative mortality or competing causes ofdeath (due to age related or other co-morbidities),an anatomic sublobar resection (segmentectomy)over a lobectomy is suggested(Grade 2C).

4.12.1. For patients with a clinical stage Ipredominantly ground glass opacity (GGO)lesion2 cm, a sublobar resection with negativemargins is suggested over lobectomy(Grade 2C).

Nonresectional Treatment Approaches

5.3.1. For patients with clinical stage I NSCLCwho cannot tolerate a lobectomy or segmentec-tomy, stereotactic body radiation therapy(SBRT)


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Summary of Recommendations: Stage III NSCLC

Infiltrative Stage III (N2,3) Non-small Cell Lung Cancer

2.3.1. In patients with infiltrative stage III (N2,3)non-small cell lung cancer (NSCLC) and perfor-mance status 0-1 being considered for curative-intent treatment, radiotherapy alone is notrecommended (Grade 1A).

2.3.2. In patients with infiltrative stage III (N2,3)NSCLC and performance status 0-1 being con-sidered for curative-intent treatment, com-bination platinum-based chemotherapy andradiotherapy (60-66 Gy) are recommended(Grade 1A).

Remark:Dose escalation of radiotherapy is not rec-ommended (except in a clinical trial).

Remark: For patients with stage III NSCLC, once

daily thoracic radiotherapy plus platinum-based dou-blet chemotherapy is recommended.

2.3.3. In patients with infiltrative stage III (N2,3)NSCLC, performance status 0-1, and minimal

weight loss being considered for curative-intenttreatment, concurrent chemoradiotherapy isrecommended over sequential chemoradiother-apy (Grade 1A).

Remark: We cannot currently recommend for oragainst induction chemotherapy (ie, before) concurrentchemoradiotherapy, and patients should be referredfor clinical trials to answer this question.

Remark: We cannot currently recommend for oragainst consolidation chemotherapy (ie, after) con-current chemoradiotherapy, and patients should bereferred to clinical trials to answer this question.

2.3.4. In patients with infiltrative stage III (N2,3)NSCLC with a complete response after treat-ment with concurrent chemoradiotherapy, wesuggest that prophylactic cranial irradiationshould not be given (outside of a clinical trial)

(Grade 2C).

2.3.5. In patients with infiltrative stage III (N2,3)NSCLC and performance status 0-1 being con-sidered for curative-intent treatment, treatment

with neoadjuvant (induction) chemotherapy orchemoradiotherapy followed by surgery is notrecommended (Grade 1C).

2.3.6. In patients with infiltrative stage III (N2,3)NSCLC and performance status 2 or those withsubstantial weight loss (.10%), concurrent

despite negative preoperative invasive mediastinalstaging. For some questions there are clear data fromRCTs; in other areas the data are more limited anddifficult to interpret because of many confoundingfactors. This article of the ACCP Lung Cancer Guide-lines does a good job of summarizing the data inareas of clarity as well as providing a structure thatmore clearly demonstrates the factors at play in the

more confusing areas to allow a more clear interpre-tation of what we know and what we can only specu-late about.

Extensive data from RCTs demonstrate that for themajority of patients with N2,3 node involvement(who have a good performance status [PS] and min-imal weight loss), aggressive curative-intent treatmentis indicated using a combination of chemotherapyand RT, delivered concurrently. The role of inductionor consolidation chemotherapy or targeted therapybefore or following definitive chemoradiation forstage III NSCLC is unclear and requires further study.

The RT should involve once-daily fractionation anda total dose of 60 to 66 Gy; further dose escalationor prophylactic cranial irradiation is not supported bythe data. Details of treatment and management oftoxicities are important and best addressed in a mul-tidisciplinary team setting. Tailoring the aggressive-ness and the intent of treatment (curative or palliative)in patients with comorbidities, weight loss, or impairedPS requires judgment and consideration of patients

values and preferences.For patients with discrete N2 node involvement,

data from RCTs show similar outcomes with either

chemotherapy and RT or neoadjuvant (preoperative)treatment followed by resection. Arguments that par-ticular subgroups of patients benefit from a trimodal-ity approach are confounded and not supported bythe available data. Various markers with prognostic

value have been identified (eg, response to neoadju-vant therapy), but there are no data that demonstratethese have predictive value of a benefit from surgicalresection (see Fig 8 in Ramnath et al,4in LC III).Patient values and preferences should play a role indecision-making. Management of toxicities, particularlyperioperative mortality, is critical, and a trimodality

approach should be undertaken by an experiencedteam that tracks and manages its outcomes. Trimo-dality treatment should be planned at the outset bya multidisciplinary team.

For N2 involvement discovered during or after pri-mary surgical resection for clinical stage I,II NSCLC,the key prognostic factor is the diligence with whichpreoperative staging was conducted. If preoperativestaging was thorough, resection should be completed(provided an R0 resection is possible). RCT data sup-port the use of adjuvant chemotherapy; the role oradjuvant RT is unclear.


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Remark: All multimodality therapy should be per-formed in centers with experienced multidisciplinaryteams that track their relevant clinical outcomes andare capable of minimizing and managing the toxicityand complications involved.

Remark:Further identification of patients more likelyto benefit from surgical resection after induction ther-

apy is not possible based upon pretreatment charac-teristics. Decisions to pursue surgical resection afterinduction therapy should be made prior to initiationof any therapy.

3.5.3. In patients with discrete N2 involvementby NSCLC identified preoperatively (IIIA), pri-mary surgical resection followed by adjuvanttherapy is not recommended (except as part ofa clinical trial) (Grade 1C).

Occult N2 Involvement Discovered at ResectionDespite Thorough Preoperative Staging (Stage IIIA)

Surgical Considerations

4.5.1. In patients with NSCLC undergoing sur-gical resection, systematic mediastinal lymphnode sampling or complete mediastinal lymphnode dissection is recommended (Grade 1B).

Remark: At least a systematic sampling is needed toaccurately assess the pathologic stage; this is criticalto direct adjuvant therapy.

Remark: It is unclear whether lymphadenectomy

offers a survival benefit over systematic sampling, butin general, lymphadenectomy is suggested if thereis evidence of N2 node involvement.

4.5.2. In patients with NSCLC who have inci-dental (occult) N2 disease (IIIA) found at sur-gical resection despite thorough preoperativestaging and in whom complete resection of thelymph nodes and primary tumor is technicallypossible, completion of the planned lung resec-tion and mediastinal lymphadenectomy is sug-gested (Grade 2C).

Remark:This recommendation assumes that stagingfor distant disease and invasive preoperative medias-tinal staging according to guidelines have been car-ried out.

Remark:In a patient who has not received preop-erative staging despite clinical suspicion of N2 nodeinvolvement (ie, enlarged on CT, uptake on PET, ornegative CT and PET but with a central tumor orN1 involvement), the operation should be abortedand staging completed if N2 disease is identifiedintraoperatively.

chemoradiotherapy is suggested but with care-ful consideration of the potential risks and ben-efits (Grade 2C).

Remark: Patient-related and tumor-related factorscan influence the balance of risks vs benefits; patientpreferences should also play a significant role.

2.3.7. In patients with infiltrative stage III (N2,3)NSCLC, performance status 0-1, and minimal

weight loss being considered for curative-intenttreatment, a platinum-based doublet chemo-therapy is suggested (Grade 2C).

Remark: An optimal agent to be combined with plat-inum cannot be defined; one should choose a regimen

with an acceptable toxicity profile for the individualpatient among several combinations that have dem-onstrated activity when used concurrently with radia-tion in stage III NSCLC.

2.3.8. In patients with symptomatic infiltrativestage III (N2,3) NSCLC and either performancestatus 3-4, comorbidities, or disease too exten-sive to treat with curative intent, palliative radio-therapy is recommended. The fractionationpattern should be chosen based on the physi-cians judgment and patients needs (Grade 1C).

Discrete Mediastinal Node Involvement

3.5.1. In patients with discrete N2 involvementby NSCLC identified preoperatively (IIIA), werecommend the treatment plan should be made

with the input from a multidisciplinary team(Grade 1C).

Remark:The multidisciplinary team should includeat a minimum a thoracic surgeon, medical oncologist,and radiation oncologist.

Remark:The decision should be made collaborativelyby the entire team so as to reflect collective judgment.

Remark:The plan should include the entire proposedtreatment, including plans contingent on the results

of reevaluations (ie, initial treatment response ornonresponse), not simply a first step.

3.5.2. In patients with discrete N2 involvementby NSCLC identified preoperatively (IIIA), eitherdefinitive chemoradiation therapy or inductiontherapy followed by surgery is recommendedover either surgery or radiation alone (Grade 1A).

Remark: As the data do not permit the selection ofone option or the other as superior, patient valuesand preferences should factor significantly in thedecision.


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to potentially be at greater risk for toxicity. The valueof second-line chemotherapy has been further strength-ened. Finally, patient groups believed to be poorcandidates for more aggressive treatment based onage, PS, or other criteria have been shown to benefitfrom doublet chemotherapy without undue toxicityin some situations.

Summary of Recommendations: Stage IV NSCLC

General Approach

2.1.1. In patients with a good performancestatus (PS) (ie, Eastern Cooperative OncologyGroup[ECOG] level 0 or 1) and stage IV non-small cell lung cancer (NSCLC), a platinum-based chemotherapy regimen is recommendedbased on the survival advantage and improve-ment in quality of life (QOL) over best suppor-tive care (BSC). (Grade 1A).

Remark:Patients may be treated with several chemo-therapy regimens (carboplatin and cisplatin are accept-able, and can be combined with paclitaxel, docetaxel,gemcitabine, pemetrexed or vinorelbine)

2.2.2. In patients with stage IV NSCLC and agood PS, two-drug combination chemotherapyis recommended. The addition of a third cyto-toxic chemotherapeutic agent is not recom-mended because it provides no survival benefitand may be harmful.(Grade 1A).

First Line Treatment

3.1.1.1. In patients receiving palliative chemo-therapy for stage IV NSCLC, it is recommendedthat the choice of chemotherapy is guided bythe histologic type of NSCLC(Grade 1B).

Remark:The use of pemetrexed (either alone or incombination) should be limited to patients with non-squamous NSCLC.

Remark:Squamous histology has not been identifiedas predictive of better response to any particular che-motherapy agent.

3.2.1.1. In patients with known epidermalgrowth factor receptor(EGFR) mutations andstage IV NSCLC, first-line therapy with anEGFR tyrosine kinase inhibitor (gefitinib orerlotinib) is recommended based on superiorresponse rates, progression-free survival andtoxicity profiles compared with platinum-baseddoublets(Grade 1A).

3.3.1.1. Bevacizumab improves survival combinedwith carboplatin and paclitaxel in a clinically

Adjuvant Therapy

4.5.3. In patients with resected NSCLC (R0)who were found to have incidental (occult)N2 disease (IIIA) despite thorough preopera-tive staging and who have good performancestatus, adjuvant platinum-based chemotherapyis recommended (Grade 1A).

Remark: We suggest this should typically involve adoublet regimen for 3 to 4 cycles initiated within12 weeks.

4.5.4. In patients with R0 resected NSCLC whowere found to have incidental (occult) N2 dis-ease (IIIA) despite thorough preoperative staging,sequential adjuvant radiotherapy is suggested

when concern for a local recurrence is high(Grade 2C).

Remark: Adjuvant postoperative radiotherapy reduces

the incidence of local recurrence, but it is unclearwhether it improves survival.

Remark:Adjuvant chemotherapy should be used ini-tially followed by radiotherapy; concurrent chemo-radiotherapy is not recommended (except in a clinicaltrial).

4.5.5. In patients with NSCLC who were foundto have incidental (occult) N2 disease (IIIA)despite thorough preoperative staging and wereincompletely resected (R1,2), combined postop-erative concurrent chemotherapy and radio-

therapy is suggested (Grade 2C).

18.0Treatment of Stage IV NSCLC

Significant advances continue to be made in thetreatment of stage IV NSCLC; although cure is notpossible, significant palliation in terms of improvedquality of life (QOL) and duration of survival can beaccomplished. Significant clarity has been achievedin terms of which agents to use in very specific sit-uations. The choice of chemotherapy is directed to a

large extent by the histologic type of NSCLC, makingit all the more important to have adequate materialfor a detailed diagnosis. Furthermore, targeted therapyis the first-line treatment of choice for patients withan epidermal growth factor receptor mutation.

Maintenance chemotherapy has been establishedto be useful in many situations, with the details of

which agents being determined by the histologic typeand the choice of the initial regimen. Furthermore,the safety and efficacy of chemotherapy have beenextended. Vascular endothelial growth factor inhibi-tors are safe and useful in patients initially believed


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with erlotinib improves survival compared withBSC and is recommended(Grade 1B).

Remark:No recommendation can be given about theoptimal chemotherapeutic strategy in patients withstage IV NSCLC who have received three prior regi-mens for advanced disease.

Special Patient Populations and Considerations5.1.1. In elderly patients (age7079 years)

with stage IV NSCLC who have good PS andlimited co-morbidities, treatment with the twodrug combination of monthly carboplatin and

weekly paclitaxel is recommended(Grade 1A).

Remark:In patients with stage IV NSCLC who are80 years or over, the benefit of chemotherapy isunclear and should be decided based on individualcircumstances.

6.2.1. For patients with stage IV NSCLC with aPS of 2 in whom the PS is caused by the canceritself, double agent chemotherapy is suggestedover single agent chemotherapy(Grade 2B).

6.2.2. In patients with stage IV NSCLC who arean ECOG PS of 2 or greater, it is suggested notto add bevacizumab to chemotherapy outside ofa clinical trial(Grade 2B).

7.1.1. In patients with stage IV NSCLC earlyinitiation of palliative care is suggested to

improve both QOL and duration of survival(Grade 2B).

19.0Special Treatment Issues in NSCLC

There are several relatively unusual presentationsof NSCLC for which the anatomic and biologic issuesdictate a different approach. This includes patients

with Pancoast tumors, T4N0,1M0 central tumors,chest wall involvement, additional pulmonary tumornodules, synchronous and metachronous second pri-

mary lung cancers, multifocal lung cancer, and solitarymetastases.

Patients with Pancoast tumors appear to have thebest outcomes after preoperative chemoradiotherapyand surgical resection, although preoperative RT is areasonable alternative. Advances in surgical tech-niques allow a complete resection to be achieved inspecialized centers in situations traditionally con-sidered unresectable. Similarly, good results can beachieved in the relatively small number of patients

with a T4 (due to local invasion) N0,1M0 tumor bysurgical resection in specialized centers.

selected subset of patients with stage IV NSCLCand good PS (nonsquamous histology, lack ofbrain metastases, and no hemoptysis). In thesepatients, addition of bevacizumab to carbopla-tin and paclitaxel is recommended(Grade 1A).

3.3.1.2. In patients with stage IV non-squamousNSCLC and treated, stable brain metastases,

who are otherwise candidates for bevacizumabtherapy, the addition of bevacizumab to first-line, platinum-based chemotherapy is a safetherapeutic option(Grade 2B).

Remark: No recommendation can be given about theuse of bevacizumab in patients receiving therapeuticanticoagulation or with an ECOG PS of 2.

Maintenance Therapy

3.4.4.1. In patients with stage IV non-squamousNSCLC who do not experience disease progres-

sion after 4 cycles of platinum-based therapy(which does not include pemetrexed), treatmentwith switch maintenance pemetrexed is sug-gested(Grade 2B).

3.4.4.2. In patients with stage IV NSCLC, switchmaintenance therapy with chemotherapy agentsother than pemetrexed has not demonstratedan improvement in overall survival and is notrecommended(Grade 1B).

3.4.4.3. In patients with stage IV non-squamousNSCLC who do not experience disease pro-

gression after 4 cycles of platinum-pemetrexedtherapy, continuation pemetrexed maintenancetherapy is suggested(Grade 2B).

3.4.4.4. In patients with stage IV NSCLC whodo not experience disease progression after4 cycles of platinum-based double agent chemo-therapy, maintenance therapy with erlotinib issuggested(Grade 2B).

3.5.1.1. In patients with stage IV NSCLC theaddition of cetuximab in combination with che-motherapy is suggested not to be used outsideof a clinical trial(Grade 2B).

Second and Third Line Treatment

4.1.1. In patients with stage IV NSCLC whohave good PS (ECOG 0-2), second-line treat-ment with erlotinib or docetaxel (or equivalentsingle-agent such as pemetrexed) is recom-mended(Grade 1A).

4.1.2. In patients with stage IV NSCLC whohave good PS (ECOG 0-2), third-line treatment


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2.4.

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