当前位置:首页 >> 临床医学 >>

2014版NCCN非小细胞肺癌指南英文版


NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines?)

Non-Small Cell Lung Cancer
Version 3.2014 NCCN.org
NCCN Guidelines for Patients? available at www.nccn.org/patients

Continue

Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Panel Members Non-Small Cell Lung Cancer
* David S. Ettinger, MD/Chair ? The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Douglas E. Wood, MD/Vice Chair ? Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Wallace Akerley, MD ? Huntsman Cancer Institute at the University of Utah Lyudmila A. Bazhenova, MD ? ? UC San Diego Moores Cancer Center Hossein Borghaei, DO, MS ? ? Fox Chase Cancer Center D. Ross Camidge, MD, PhD ? University of Colorado Cancer Center Andrew C. Chang, MD ? University of Michigan Comprehensive Cancer Center Richard T. Cheney, MD ≠ Roswell Park Cancer Institute Lucian R. Chirieac, MD ≠ Dana-Farber/Brigham and Women’s Cancer Center Thomas A. D’Amico, MD ? Duke Cancer Institute Todd L. Demmy, MD ? Roswell Park Cancer Institute Ramaswamy Govindan, MD ? Siteman Cancer Center at BarnesJewish Hospital and Washington University School of Medicine Frederic W. Grannis, Jr., MD ? City of Hope Comprehensive Cancer Center Stefan C. Grant, MD, JD ? ? University of Alabama at Birmingham Comprehensive Cancer Center Leora Horn, MD, MSc ? Vanderbilt-Ingram Cancer Center Thierry M. Jahan, MD ? ? UCSF Helen Diller Family Comprehensive Cancer Center Ritsuko Komaki, MD § The University of Texas MD Anderson Cancer Center Mark G. Kris, MD ? Memorial Sloan-Kettering Cancer Center Lee M. Krug, MD ? Memorial Sloan-Kettering Cancer Center Rudy P. Lackner, MD Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center Inga T. Lennes, MD ? Massachusetts General Hospital Cancer Center Jules Lin, MD ? University of Michigan Comprehensive Cancer Center Billy W. Loo, Jr., MD, PhD § Stanford Cancer Institute Renato Martins, MD, MPH ? Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance Gregory A. Otterson, MD ? The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

NCCN Guidelines Index NSCLC Table of Contents Discussion

Jyoti D. Patel, MD ? Robert H. Lurie Comprehensive Cancer Center of Northwestern University Mary C. Pinder-Schenck, MD ? Moffitt Cancer Center Katherine M. Pisters, MD ? The University of Texas MD Anderson Cancer Center Karen Reckamp, MD, MS ? ? City of Hope Comprehensive Cancer Center Gregory J. Riely, MD, PhD ? Memorial Sloan-Kettering Cancer Center Eric Rohren, MD, PhD ф The University of Texas MD Anderson Cancer Center Theresa A. Shapiro, MD, PhD ? The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Scott J. Swanson, MD ? Dana-Farber/Brigham and Women’s Cancer Center Kurt Tauer, MD University of Tennessee Health Science Center Stephen C. Yang, MD ? The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

NCCN Kristina Gregory, RN, MSN Miranda Hughes, PhD
? Medical oncology ? Surgery/Surgical oncology § Radiation oncology/Radiotherapy ≠ Pathology ? Hematology/Hematology oncology ф Diagnostic/Interventional radiology ? Patient advocate *Writing committee member

Continue
NCCN Guidelines Panel Disclosures

Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Table of Contents Non-Small Cell Lung Cancer
NCCN Non-Small Cell Lung Cancer Panel Members
Summary of Guidelines Updates Lung Cancer Prevention and Screening (PREV-1) Clinical Presentation and Risk Assessment (DIAG-1) Initial Evaluation and Clinical Stage (NSCL-1) Evaluation and Treatment: ? Stage I (T1ab-2a, N0), Stage II (T1ab-2ab, N1; T2b, N0), and Stage IIB (T3, N0) (NSCL-2) ? Stage IIB (T3 invasion, N0) and Stage IIIA (T4 extension, N0-1; T3, N1) (NSCL-4) ? Stage IIIA (T1-3, N2) and Separate Pulmonary Nodules (Stage IIB, IIIA, IV) (NSCL-7) ? Multiple Lung Cancers (NSCL-10) ? Stage IIIB (T1-3, N3) (NSCL-11) ? Stage IIIB (T4 extension, N2-3) and Stage IV (M1a) (pleural or pericardial effusion) (NSCL-12) ? Stage IV (M1b: solitary site) (NSCL-13) Surveillance (NSCL-14) Therapy for Recurrence and Metastasis (NSCL-15) Systemic Therapy for Metastatic Disease (NSCL-16) Principles of Pathologic Review (NSCL-A) Principles of Surgical Therapy (NSCL-B) Principles of Radiation Therapy (NSCL-C) Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D) Chemotherapy Regimens Used with Radiation Therapy (NSCL-E) Systemic Therapy for Advanced or Metastatic Disease (NSCL-F) Cancer Survivorship Care (NSCL-G) Targeted Agents for Patients with Other Genetic Alterations (NSCL-H) Staging (ST-1)

NCCN Guidelines Index NSCLC Table of Contents Discussion

Clinical Trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at NCCN member institutions, click here: nccn.org/clinical_trials/physician.html. NCCN Categories of Evidence and Consensus: All recommendations are Category 2A unless otherwise specified. See NCCN Categories of Evidence and Consensus.

The NCCN Guidelines? are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network? (NCCN?) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network?. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ?2014.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Updates Non-Small Cell Lung Cancer
Updates in the 3.2014 version of the Guidelines for Non-Small Cell Lung Cancer from the 2.2014 version include: MS-1 - The Discussion section updated to reflect the changes in the algorithm. Updates in the 2.2014 version of the Guidelines for Non-Small Cell Lung Cancer from the 1.2014 version include:

NCCN Guidelines Index NSCLC Table of Contents Discussion

NSCL-3 ? Stage IB, IIA, margins negative: adjuvant chemotherapy recommendation changed from a category 2B to a category 2A for high risk patients. Updates in the 1.2014 version of the Guidelines for Non-Small Cell Lung Cancer from the 2.2013 version include: DIAG-2 ? >10 mm non-solid or part-solid nodule, options modified after LDCT: increase in size or increase in solid component. NSCL-1 ? Initial evaluation: “Supportive care” changed to “Integrate palliative care.” A link to the NCCN Guidelines for Palliative Care added. NSCL-2 ? Stage IA, medically inoperable treatment recommendation modified: Definitive RT including SABR. ? Stage IB, I, II, IIB, medically inoperable treatment recommendations modified. Nodal status added N0 is recommended to receive definitive RT including SABR, followed by adjuvant chemotherapy (category 2B) for high-risk stages IB-II. N1 is recommended to receive definitive chemoradiation. High-risk footnote added from NSCL-3: Examples of high-risk factors may include poorly differentiated tumors (including lung neuroendocrine tumors [excluding well-differentiated neuroendocrine tumors]), vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement, and incomplete lymph node sampling (Nx). These factors independently may not be an indication and may be considered when determining treatment with adjuvant chemotherapy. NSCL-3 ? Adjuvant treatment recommendations for Stage IIA, IIB, margins positive modified. R1 resection separated out with the following recommendations: reresection + chemotherapy or chemoradiation (sequential or concurrent). R2 resection separated out with the following recommendations: reresection + chemotherapy or concurrent chemoradiation. ? Adjuvant treatment recommendations for Stage IIIA modified. R0 resection clarified as chemotherapy (category 1) or sequential chemotherapy + RT (N2 only). R1 resection separated out with the following recommendations: chemoradiation (sequential or concurrent). R2 resection separated out with the following recommendations: concurrent chemoradiation. ? Previous footnote “j” deleted: Patients likely to receive adjuvant chemotherapy may be treated with induction chemotherapy as an alternative. ? Footnote “l” modified: Examples of high-risk patients factors may include are defined by poorly differentiated tumors (including lung neuroendocrine tumors [excluding well-differentiated neuroendocrine tumors]), vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement, and incomplete lymph node sampling (Nx). These factors independently may not be an indication and may be considered when determining treatment with adjuvant chemotherapy. ? Previous footnote “p” deleted: The panel recommends concurrent chemoradiation for R2 resections and sequential chemoradiation for R1 resections. This information is now delineated in the algorithm. (also applies to NSCL-5, NSCL-6, NSCL-8, NSCL-9) NSCL-5 ? Superior sulcus tumor (T4 extension, N0-1): marginally resectable changed to possibly resectable. ? Footnote “q” modified: If full-dose chemotherapy is not given concurrently with RT as initial treatment, give additional 42 cycles of full-dose chemotherapy. (also applies to NSCL-6, NSCL-12) UPDATES Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Updates Non-Small Cell Lung Cancer
Updates in the 1.2014 version of the Guidelines for Non-Small Cell Lung Cancer from the 2.2013 version include:

NCCN Guidelines Index NSCLC Table of Contents Discussion

NSCL-6 ? Chest wall, proximal airway, or mediastinum: T4 clarified as “resectable.” ? Surgery as initial treatment, margins positive: R1 resection separated out with the following recommendations: resection + chemotherapy or chemoradiation (sequential or concurrent). R2 resection separated out with the following recommendations: resection + chemotherapy or concurrent chemoradiation. NSCL-8 ? T1-3, N0-1: unresectable changed to medically inoperable. ? Surgery as initial treatment, margins positive: R1 resection separated out with the following recommendations: chemoradiation (sequential or concurrent). R2 resection separated out with the following recommendations: concurrent chemoradiation. ? Footnote “s” is new to the page: Patients likely to receive adjuvant chemotherapy may be treated with induction chemotherapy as an alternative. NSCL-9 ? Surgery as initial treatment, margins positive: R1 resection separated out with the following recommendations: chemoradiation (sequential or concurrent). R2 resection separated out with the following recommendations: concurrent chemoradiation. NSCL-10 ? Footnote “v” modified: Lesions at low risk of becoming symptomatic can be observed (eg, small subsolid nodules with slow growth). However, if the lesion(s) becomes symptomatic or becomes high risk for producing symptoms (eg, subsolid nodules with accelerating growth or increasing solid component or increasing FDG uptake, even while small), treatment should be considered. NSCL-13 ? T1-2, N0-1; T3, N0: SABR of the lung lesion added as a treatment option after chemotherapy. NSCL-14 ? H&P and chest CT recommendations in surveillance changed from a category 2B to a category 2A. NSCL-15 ? Mediastinal lymph node recurrence: treatment recommendations listed according to prior treatment with RT. If patients received prior RT, the recommendation of systemic chemotherapy added. NSCL-16 ? Establish histologic subtype with adequate tissue for molecular testing: “consider rebiopsy if appropriate” added. ? “Integrate palliative care” added with footnote “b”. A link to the NCCN Guidelines for Palliative Care added. ? Adenocarcinoma, large cell, NSCLC NOS; the following added: Category 1 added to ALK testing. EGFR ± ALK testing should be conducted as part of a multiplex/next-generation sequencing. ? Squamous cell carcinoma; the following modified/added: Consider EGFR mutation and ALK testing are not routinely recommended except especially in never smokers and or small biopsy specimens, or mixed histology. EGFR ± ALK testing should be conducted as part of a multiplex/next-generation sequencing. ? Footnote “cc” added with direction to a new page, Targeted Agents for Patients with Other Genetic Alterations (NSCL-H). ? EGFR mutation and ALK negative: “or unknown” added.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

UPDATES

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Updates Non-Small Cell Lung Cancer
Updates in the 1.2014 version of the Guidelines for Non-Small Cell Lung Cancer from the 2.2013 version include:

NCCN Guidelines Index NSCLC Table of Contents Discussion

NSCL-16 ? Footnote “dd” modified: In patients with squamous cell carcinoma, the observed incidence of EGFR mutations is 2.7% with a confidence that the true incidence of mutations is less than 3.6% in patients with squamous cell carcinoma. This frequency of EGFR mutations does not justify routine testing of all tumor specimens. Forbes SA, Bharma G, Bamford S, et al. The catalogue of somatic mutations in cancer (COSMIS). Curr Protoc Hum Genet 2008;chapter 10:unit 10.11. ? Footnote “ff” modified: Consider ROS1 testing, if positive If ROS1 mutation status is known and positive, may treat with crizotinib. http:// www.nccn.org/disclosures/panel_list.asp?ID=40 Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-870. (also applies to NSCL-18) NSCL-17 ? First-line therapy, EGFR mutation discovered prior to first-line chemotherapy: afatinib added as a category 1 recommendation. ? First-line therapy, EGFR mutation discovered during first-line chemotherapy: recommended treatment options modified to “Interrupt or complete planned chemotherapy, start erlotinib or afatinib or May add erlotinib or afatinib to current chemotherapy (category 2B)” ? Second-line therapy: afatinib added as a treatment option. ? Second-line therapy, symptomatic brain: footnote “ll” added: Consider pulse erlotinib for carcinomatosis meningitis. ? Second-line therapy, systemic multiple lesions: Consider systemic therapy changed to Consider platinum doublet ± bevacizumab ± erlotinib. ? Footnote “mm” added: Afatinib appears to have some efficacy in patients who progressed on EGFR therapy. Miller VA, Hirsh V, Cadrenal J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012;13:528-38. NSCL-18 ? Treatment recommendations for ALK positive modified to be consistent with EGFR-positive mutations. NSCL-19 ? First-line therapy: the combination regimen cisplatin/pemetrexed was deleted from this page, as it is included in doublet chemotherapy. ? Maintenance therapy: Continuation of current regimen until disease progression removed as an option. Continuation maintenance with gemcitabine changed from a category 2A recommendation to a category 2B recommendation. Switch maintenance with pemetrexed or erlotinib changed from a category 2A recommendation to a category 2B recommendation. ? Footnote “nn” added: Consider additional mutational testing if only EGFR and ALK were performed. See Targeted Agents for Patients with Other Genetic Alterations (NSCL-H). ? Previous footnote “ii” removed: There is evidence of superior efficacy and reduced toxicity for cisplatin/pemetrexed in patients who do not have squamous histology, in comparison to cisplatin/gemcitabine. 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 NSCLC. J Clin Oncol 2008;26:3543-3551. ? Previous footnote “jj” removed: Pirker R, Periera JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-smallcell lung cancer (FLEX): an open label randomised phase III trial. Lancet 2009;373:1525-1531. (also applies to NSCL-20) ? Previous footnote “ll” removed: Pérol M, Chouaid C, Pérol D, et al. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced nonsmall-cell lung cancer. J Clin Oncol 2012;30:3516-3524. (also applies to NSCL-20) ? Second-line therapy The qualifying statement “if not already given” added. Gemcitabine added as a treatment option. UPDATES Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Updates Non-Small Cell Lung Cancer
Updates in the 1.2014 version of the Guidelines for Non-Small Cell Lung Cancer from the 2.2013 version include:

NCCN Guidelines Index NSCLC Table of Contents Discussion

NSCL-20 ? Maintenance therapy: “Continuation of current regimen until disease progression” removed as an option. Continuation maintenance with gemcitabine changed from a category 2A recommendation to a category 2B recommendation. Switch maintenance with docetaxel or erlotinib changed from a category 2A recommendation to a category 2B recommendation. ? Second-line therapy The qualifying statement “if not already given” added. Gemcitabine added as a treatment option. NSCL-21 ? Third-line therapy: Gemcitabine added as an option. ? Footnote “ss” is new to the page: Pemetrexed, docetaxel, and gemcitabine are category 2B if patient did not receive erlotinib or crizotinib in first- or second-line therapy. NSCL-A (1 of 4) ? Previous bullet 5 removed: Although formalin?fixed paraffin?embedded tumor may be used for most molecular analyses, acquisition of fresh cryopreserved tumor tissue for advanced molecular studies should be considered. ? Current bullet 5 modified: Limited use of IHC studies in small tissue samples is strongly recommended, thereby preserving critical tumor tissue for molecular studies, particularly in patients with advanced-stage disease. A limited panel of one squamous cell carcinoma marker (eg, p63) and one adenocarcinoma marker (eg, TTF-1) should suffice for most diagnostic problems. NSCL-A (3 of 4) ? EGFR and KRAS, sub-bullets 2 and 7 modified: L861 added to exon 21 and G719 added to exon 18. Primary resistance to TKI therapy is associated with KRAS mutation. Acquired resistance is associated with second-site mutations within the EGFR kinase domain (such as T790M), amplification of alternative kinases (such as MET), histologic transformation from NSCLC to SCLC, and epithelial to mesenchymal transition (EMT). ? ALK, sub-bullets 2 and 3 modified: ALK NSCLC occurs most commonly in a unique subgroup of NSCLC patients who share many of the clinical features of NSCLC patients likely to harbor EGFR mutations. However, for the most part, ALK translocations and EGFR mutations are mutually exclusive. ALK translocations tend to occur in younger patients and in those with more advanced NSCLC, though this relationship has not been reported for EGFR mutant NSCLC. The current standard method for detecting ALK NSCLC is fluorescence in situ hybridization (FISH), although other methods are currently being evaluated, including polymerase chain reaction (PCR) and IHC. A big advantage of FISH is that a commercially available probe set, developed for the diagnosis of ALK?rearranged anaplastic large cell lymphomas (ALCL), is applicable for the diagnosis of ALK?rearranged lung adenocarcinomas. The IHC tests used to diagnose ALK?rearranged ALCLs in clinical laboratories worldwide are inadequate for the detection of most ALK?rearranged lung adenocarcinomascancer. This inadequacy is because of the lower level of ALK expression in ALK?rearranged NSCLCs compared with ALK?rearranged ALCLs. A molecular diagnostic test that uses FISH was recently approved by the FDA to determine which patients with lung adenocarcinoma are have ALK-positive lung cancer.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

UPDATES

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Updates Non-Small Cell Lung Cancer
Updates in the 1.2014 version of the Guidelines for Non-Small Cell Lung Cancer from the 2.2013 version include:

NCCN Guidelines Index NSCLC Table of Contents Discussion

NSCL-B (1 of 4) ? Evaluation Previous bullet 6 removed: In current smokers who stop smoking, consider waiting 4 weeks before surgery to maximize outcomes after surgery. ? Resection Bullet 5 modified: VATS or minimally invasive surgery should be strongly considered is a reasonable and acceptable approach for patients with no anatomic or surgical contraindications, as long as there is no compromise of standard oncologic and dissection principles of thoracic surgery. NSCL-C (1 of 9) ? Early-stage NSCLC (Stage I) Bullet 2 modified with the removal of the following sentence: A prospective randomized cooperative group trial of sublobar resection versus SABR is ongoing. NSCL-C (3 of 9) ? Locally advanced stage/conventionally fractionated RT Bullet 2 modified: The final results from RTOG 0617, comparing 60 versus 74 Gy with concurrent chemotherapy are pending, but preliminarily, 74 Gy was not associated with improved overall survival at 1 yeardoes not improve overall survival. A meta-analysis demonstrated improved survival with accelerated fractionation RT regimens, and individualized accelerated RT dose intensification is now being evaluated in a randomized trial (RTOG 1106). NSCL-E ? Concurrent chemotherapy/RT followed by chemotherapy: Weekly paclitaxel/carboplatin regimen changed from a category 2B to a category 2A recommendation. ? Previous footnote “*” removed: There are data that support full dose cisplatin over carboplatin-based regimens. Carboplatin regimens have not been adequately tested. NSCL-F (1 of 3) ? First-line therapy Bullet 3 modified: Erlotinib is recommended as a first-line therapy in patients with sensitizing EGFR mutations and should not be given as first-line therapy to patients negative for these EGFR mutations or with unknown EGFR status. Bullet 4 added: Afatinib is indicated for select patients with sensitizing EGFR mutations. NSCL-F (2 of 3) ? Maintenance therapy: category 2B added to continuation maintenance with gemcitabine and switch maintenance with erlotinib or pemetrexed. ? Second-line therapy: Sub-bullet 4 added: Afatinib is indicated for select patients with sensitizing EGFR mutations. ? Third-line therapy: “Erlotinib is superior to best supportive care” replaced with “If not already given, options for PS 0-2 include docetaxel, pemetrexed (nonsquamous), erlotinib, or gemcitabine (category 2B for all options).” NSCL-F (3 of 3) ? Afatinib added to systemic therapy options with reference. NSCL-G ? Link to NCCN Guidelines for Cervical Cancer Screening removed. NSCL-H ? New page added listing targeted agents for patients with genetic alterations.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

UPDATES

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
LUNG CANCER PREVENTION AND SCREENING

NCCN Guidelines Index NSCLC Table of Contents Discussion

? Lung cancer is a unique disease in that the major etiologic agent is an addictive product that is made and promoted by an industry. Approximately 85% to 90% of cases are caused by voluntary or involuntary (second-hand) cigarette smoking. Reduction of lung cancer mortality will require effective public health policies to prevent initiation of smoking, U.S. Food and Drug Administration (FDA) oversight of tobacco products, and other tobacco control measures. ? Persistent smoking is associated with second primary cancers, treatment complications, drug interactions, other tobacco-related medical conditions, diminished quality of life, and reduced survival. ? Reports from the Surgeon General on both active smoking (http://www.cdc.gov/tobacco/data_statistics/sgr/2004/pdfs/executivesummary.pdf) and second-hand smoke show that both cause lung cancer. The evidence shows a 20% to 30% increase in the risk of lung cancer from second-hand smoke exposure associated with living with a smoker (http://surgeongeneral.gov/library/reports/smokeexposure/fullreport.pdf). Every person should be informed of the health consequences, addictive nature, and mortal threat posed by tobacco consumption and exposure to tobacco smoke, and effective legislative, executive, administrative, or other measures should be contemplated at the appropriate governmental level to protect all persons from exposure to tobacco smoke (www.who.int/tobacco/framework/final_text/en/). ? Further complicating this problem, the delivery system of lung carcinogens also contains the highly addictive substance, nicotine. Reduction of lung cancer mortality will require widespread implementation of Agency for Healthcare Research & Quality (AHRQ) Guidelines (www.ahrq.gov/path/tobacco.htm#Clinic) to identify, counsel, and treat patients with nicotine habituation. ? Patients who are current or former smokers have significant risk for the development of lung cancer; chemoprevention agents are not yet established for these patients. When possible, these patients should be encouraged to enroll in chemoprevention trials. ? Lung cancer screening using low-dose CT (LDCT) is recommended in select high-risk smokers and former smokers (see the NCCN Guidelines for Lung Cancer Screening).

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

PREV-1

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CLINICAL PRESENTATION RISK ASSESSMENTb

NCCN Guidelines Index NSCLC Table of Contents Discussion

Nodule suspicious for lung cancer

? Multidisciplinary evaluationa ? Smoking cessation counseling

Patient factors ? Age ? Smoking history ? Previous cancer history ? Family history ? Occupational exposures ? Other lung disease (chronic obstructive pulmonary disease [COPD], pulmonary fibrosis) ? Exposure to infectious agents (eg, endemic areas of fungal infections, tuberculosis) or risk factors or history suggestive of infection (eg, immune suppression, aspiration, infectious respiratory symptoms) Radiologic factorsc ? Size, shape, and density of the pulmonary nodule ? Associated parenchymal abnormalities (eg, scarring or suspicion of inflammatory changes) ? Fluorodeoxyglucose (FDG) avidity on PET imaging

See Findings and Follow-up (DIAG-2)

aMultidisciplinary

evaluation including thoracic surgeons, thoracic radiologists, and pulmonologists to determine the likelihood of a cancer diagnosis and the optimal diagnostic or follow-up strategy. bRisk calculators can be used to quantify individual patient and radiologic factors but do not replace evaluation by a multidisciplinary diagnostic team with substantial experience in the diagnosis of lung cancer. cSee Principles of Diagnostic Evaluation (DIAG-A 1 of 2).
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

DIAG-1

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
FINDINGS <8 mm pulmonary nodule FOLLOW-UPc Radiologic surveillance See NCCN Guidelines for Lung Cancer Screening Low suspicion of lung cancer Suspicion of lung cancere LDCT at 3 mo Biopsyf,g or Surgical excisionf,g

NCCN Guidelines Index NSCLC Table of Contents Discussion

>8 mm solid noncalcified nodule

Consider PET-CT scana,b,d

See NCCN Guidelines for Lung Cancer Screening No cancer Cancer confirmed See NCCN Guidelines for Lung Cancer Screening See NSCL-1 or appropriate NCCN Guidelines

≤10 mm non-solid or part-solid nodule

Radiologic surveillance See NCCN Guidelines for Lung Cancer Screening LDCT in 6-12 mo? or Biopsyf,g or Consider surgical excisionf,g Surgical excisiong

See NCCN Guidelines for Lung Cancer Screening No cancer Cancer confirmed See NCCN Guidelines for Lung Cancer Screening See NSCL-1 or appropriate NCCN Guidelines

>10 mm non-solid or part-solid nodule
aMultidisciplinary

Stable LDCT in 3-6 mo Increase in size or increase in solid component

evaluation including thoracic surgeons, thoracic radiologists, and pulmonologists to determine the likelihood of a cancer diagnosis and the optimal diagnostic or follow-up strategy. bRisk calculators can be used to quantify individual patient and radiologic factors but do not replace evaluation by a multidisciplinary diagnostic team with substantial experience in the diagnosis of lung cancer. cSee Principles of Diagnostic Evaluation (DIAG-A 1 of 2). dA positive PET result is defined as a standardized uptake value (SUV) in the lung nodule greater than the baseline mediastinal blood pool. A positive PET scan finding can be caused by infection or inflammation, including absence of lung cancer with localized infection, presence of lung cancer with associated (eg, postobstructive) infection, and presence of lung cancer with related inflammation (nodal, parenchymal, pleural). A false-negative PET scan can be caused by a small nodule, low cellular density (nonsolid nodule or ground-glass opacity [GGO]), or low tumor avidity for FDG (eg, adenocarcinoma in situ [previously known as bronchoalveolar carcinoma], carcinoid tumor). ePatients with a suspicion of lung cancer after PET-CT require histologic confirmation before any nonsurgical therapy. fThe choice of biopsy or surgical excision should be based on the clinical suspicion of lung cancer, location of lesion (feasibility for surgical identification and resection by minimally invasive video-assisted thoracic surgery [VATS]), and patient preferences. gPatients with a strong clinical suspicion of stage I or II lung cancer (based on risk factors and radiologic appearance) do not require a biopsy before surgery.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

DIAG-2

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF DIAGNOSTIC EVALUATION

NCCN Guidelines Index NSCLC Table of Contents Discussion

? Patients with a strong clinical suspicion of stage I or II lung cancer (based on risk factors and radiologic appearance) do not require a biopsy before surgery. A biopsy adds time, costs, and procedural risk and may not be needed for treatment decisions. A preoperative biopsy may be appropriate if a non-lung cancer diagnosis is strongly suspected that can be diagnosed by FNA. A preoperative biopsy may be appropriate if an intraoperative diagnosis appears difficult or very risky. If a preoperative tissue diagnosis has not been obtained, then an intraoperative diagnosis (ie, wedge resection or needle biopsy) is necessary before lobectomy, bilobectomy, or pneumonectomy. ? Bronchoscopy should preferably be performed during the planned surgical resection, rather than as a separate procedure. Bronchoscopy is required before surgical resection (see NSCL-2). A separate bronchoscopy may not be needed for treatment decisions before the time of surgery and adds time, costs, and procedural risk. A preoperative bronchoscopy may be appropriate if a central tumor requires pre-resection evaluation for biopsy, surgical planning (eg, potential sleeve resection), or preoperative airway preparation (eg, coring out an obstructive lesion). ? Invasive mediastinal staging is recommended before surgical resection for most patients with clinical stage I or II lung cancer (see NSCL-2). Patients should preferably undergo invasive mediastinal staging as the initial step before the planned resection (during the same anesthetic procedure), rather than as a separate procedure. A separate staging procedure adds time, costs, coordination of care, inconvenience, and an additional anesthetic risk. Preoperative invasive mediastinal staging may be appropriate for a strong clinical suspicion of N2 or N3 nodal disease or when intraoperative cytology or frozen section analysis is not available. ? In patients with suspected NSCLC, many techniques are available for tissue diagnosis. Diagnostic tools that should be routinely available include: ??Sputum cytology ??Bronchoscopy with biopsy and transbronchial needle aspiration (TBNA) ??Image-guided transthoracic needle aspiration (TTNA) ??Thoracentesis ??Mediastinoscopy ??Video-assisted thoracic surgery (VATS) and open surgical biopsy Diagnostic tools that provide important additional strategies for biopsy include: ??Endobronchial ultrasound (EBUS)–guided biopsy ??Navigational bronchoscopy

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

DIAG-A 1 of 2

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF DIAGNOSTIC EVALUATION

NCCN Guidelines Index NSCLC Table of Contents Discussion

? The preferred diagnostic strategy for an individual patient depends on the size and location of the tumor, the presence of mediastinal or distant disease, patient characteristics (such as pulmonary pathology and/or other significant comorbidities), and local experience and expertise. Factors to be considered in choosing the optimal diagnostic step include: ??Anticipated diagnostic yield (sensitivity) ??Diagnostic accuracy including specificity and particularly the reliability of a negative diagnostic study (ie, true negative) ??Adequate volume of tissue specimen for diagnosis and molecular testing ??Invasiveness and risk of procedure ??Efficiency of evaluation ––Access and timeliness of procedure ––Concomitant staging is beneficial, because it avoids additional biopsies or procedures. It is preferable to biopsy the pathology that would confer the highest stage (ie, to biopsy a suspected metastasis or mediastinal lymph node rather than the pulmonary lesion). ??Technologies and expertise available Decisions about the optimal diagnostic steps for suspected stage I to III lung cancer should be made by thoracic radiologists, interventional radiologists, and board-certified thoracic surgeons who devote a significant portion of their practice to thoracic oncology. Multidisciplinary evaluation may also benefit from involvement of a pulmonologist with experience in advanced bronchoscopic techniques for diagnosis, depending on local expertise. The least invasive biopsy with the highest yield is preferred as the first diagnostic study. ??Patients with central masses and suspected endobronchial involvement should undergo bronchoscopy. ??Patients with peripheral (outer one-third) nodules should have navigational bronchoscopy, radial EBUS, or TTNA. ??Patients with suspected nodal disease should be biopsied by EBUS, navigational bronchoscopy, or mediastinoscopy. ––Esophageal ultrasound (EUS)–guided biopsy provides additional access to station 5, 7, 8, and 9 lymph nodes if these are clinically suspicious. ––TTNA and anterior mediastinotomy (ie, Chamberlain procedure) provide additional access to anterior mediastinal (station 5 and 6) lymph nodes if these are clinically suspicious. ??Lung cancer patients with an associated pleural effusion should undergo thoracentesis and cytology. A negative cytology result on initial thoracentesis does not exclude pleural involvement. An additional thoracentesis and/or thoracoscopic evaluation of the pleura should be considered before starting curative intent therapy. ??Patients suspected of having a solitary site of metastatic disease should preferably have tissue confirmation of that site if feasible. ??Patients suspected of having metastatic disease should have confirmation from one of the metastatic sites if feasible. ??Patients who may have multiple sites of metastatic disease—based on a strong clinical suspicion—should have biopsy of the primary lung lesion or mediastinal lymph nodes if it is technically difficult or very risky to biopsy a metastatic site.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

DIAG-A 2 of 2

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PATHOLOGIC DIAGNOSIS OF NSCLC INITIAL EVALUATION CLINICAL STAGE Stage IA, peripheralc (T1ab, N0) Mediastinal CT negative (lymph nodes <1 cm) Stage I, peripheralc (T2a, N0); centralc (T1ab-T2a, N0); Stage II (T1ab-T2ab, N1; T2b, N0); stage IIB (T3, N0)d Mediastinal CT negative (lymph nodes <1 cm) Stage IIBe (T3 invasion, N0); Stage IIIAe (T4 extension, N0-1; T3, N1) Stage IIIAe (T1-3, N2) Separate pulmonary nodule(s) (Stage IIB, IIIA, IV) Multiple lung cancers Stage IIIBe (T1-3, N3) mediastinal CT positive Contralateral (lymph nodes ≥1 cm) or palpable supraclavicular lymph nodes Stage IIIBe (T4 extension, N2-3) on CT Stage IV (M1a)b (pleural or pericardial effusion) Stage IV (M1b)b Solitary metastasis with resectable lung lesion Stage IV (M1b)b disseminated metastases

NCCN Guidelines Index NSCLC Table of Contents Discussion

See Pretreatment Evaluation (NSCL-2) See Pretreatment Evaluation (NSCL-2) See Pretreatment Evaluation (NSCL-4) See Pretreatment Evaluation (NSCL-7) See Pretreatment Evaluation (NSCL-7) See Pretreatment Evaluation (NSCL-9) See Pretreatment Evaluation (NSCL-11) See Pretreatment Evaluation (NSCL-12) See Pretreatment Evaluation (NSCL-12) See Pretreatment Evaluation (NSCL-13) See Systemic Therapy (NSCL-16)

Non-Small Cell Lung Cancer (NSCLC)

? Pathology reviewa ? H&P (include performance status + weight loss) ? CT chest and upper abdomen, including adrenals ? CBC, platelets ? Chemistry profile ? Smoking cessation advice, counseling, and pharmacotherapy Use the 5 A’s Framework: Ask, Advise, Assess, Assist, Arrange http://www.ahrq.gov/clinic/ tobacco/5steps.htm ? Integrate palliative careb (See NCCN Guidelines for Palliative Care)

aSee Principles of Pathologic Review (NSCL-A). bTemel 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. cBased on the CT of the chest: Peripheral = outer third of lung. Central = inner two thirds of lung. dT3, N0 related to size or satellite nodules. eFor patients considered to have stage IIB and stage III tumors, where more than one treatment modality (surgery, radiation therapy, or chemotherapy) is

considered, a multidisciplinary evaluation should be performed.

usually

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-1

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CLINICAL ASSESSMENT PRETREATMENT EVALUATIONf ? PFTs (if not previously done) ? Bronchoscopy (intraoperative preferred) ? Pathologic mediastinal lymph node evaluationg (category 2B) ? PET/CT scanh (if not previously done) ? PFTs (if not previously done) ? Bronchoscopy ? Pathologic mediastinal lymph node evaluationg ? PET/CT scanh (if not previously done) ? Brain MRI (Stage II, Stage IB [category 2B]) Operable Medically inoperable INITIAL TREATMENT

NCCN Guidelines Index NSCLC Table of Contents Discussion

Stage IA (peripheral T1ab, N0)

Negative mediastinal nodes Positive mediastinal nodes

Surgical exploration and resectioni + mediastinal lymph node dissection or systematic lymph node sampling

See Adjuvant Treatment (NSCL-3)

Definitive RT including stereotactic ablative radiotherapyj (SABR) See Stage IIIA (NSCL-8) or Stage IIIB (NSCL-11)

Operable Negative mediastinal nodes Medically inoperable

Stage IB (peripheral T2a, N0) Stage I (central T1ab–T2a, N0) Stage II (T1ab–2ab, N1; T2b, N0) Stage IIB (T3, N0)d

Surgical exploration and resectioni + mediastinal lymph See Adjuvant node dissection or systematic Treatment (NSCL-3) lymph node sampling Consider adjuvant Definitive RT chemotherapyk N0 including SABRj (category 2B) for high-risk stages IB-IIl N1 Definitive chemoradiationj,m

Positive mediastinal nodes

See Stage IIIA (NSCL-8) or Stage IIIB (NSCL-11)

dT3, N0 related to size or satellite nodules. fTesting is not listed in order of priority and is

dependent upon clinical circumstances, institutional processes, and judicious use of resources. gMethods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. hPositive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. iSee Principles of Surgical Therapy (NSCL-B).

jSee Principles of Radiation Therapy (NSCL-C). kSee Chemotherapy Regimens for Neoadjuvant lExamples of high-risk factors may include poorly

and Adjuvant Therapy (NSCL-D). differentiated tumors (including lung neuroendocrine tumors [excluding well-differentiated neuroendocrine tumors]), vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement, and incomplete lymph node sampling (Nx). These factors independently may not be an indication and may be considered when determining treatment with adjuvant chemotherapy. mSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E).

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-2

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
FINDINGS AT SURGERY Margins negative Stage IA (T1ab, N0) (R0)n ADJUVANT TREATMENT Observe Reresection (preferred) or RTj (category 2B)

NCCN Guidelines Index NSCLC Table of Contents Discussion

Margins positive (R1, R2)n Margins negative (R0)n

Stage IB (T2a, N0); Stage IIA (T2b, N0)

Margins positive (R1, R2)n Margins negative (R0)n

Observe or Chemotherapyk for high-risk patientsl Reresection (preferred) ± chemotherapyk,o or RTj ± chemotherapyk (chemotherapy for stage IIA) Chemotherapyk (category 1) Reresection + chemotherapyk or Chemoradiationj,m (sequential or concurrent) Reresection + chemotherapyk or Concurrent chemoradiationj,m Chemotherapyk (category 1) or Sequential chemotherapym + RTj (N2 only) Chemoradiationj,m (sequential or concurrent) Concurrent chemoradiationj,m
mSee Chemotherapy Regimens Used with Radiation Therapy nR0 = no residual tumor, R1 = microscopic residual tumor, R2 oIncreasing

Stage IIA (T1ab-T2a, N1) Stage IIB (T3, N0; T2b, N1) Margins positive

R1n R2n Margins negative (R0)n

Surveillance (NSCL-14)

Stage IIIA (T1-3, N2; T3, N1) Margins positive
jSee Principles of Radiation Therapy (NSCL-C). kSee Chemotherapy Regimens for Neoadjuvant lExamples of high-risk factors may include poorly

R1n R2n

and Adjuvant Therapy (NSCL-D). differentiated tumors (including lung neuroendocrine tumors [excluding well-differentiated neuroendocrine tumors]), vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement, and incomplete lymph node sampling (Nx). These factors independently may not be an indication and may be considered when determining treatment with adjuvant chemotherapy.

residual tumor. size is an important variable when evaluating the need for adjuvant chemotherapy.

(NSCL-E). = macroscopic

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-3

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CLINICAL ASSESSMENT PRETREATMENT EVALUATION CLINICAL EVALUATION

NCCN Guidelines Index NSCLC Table of Contents Discussion

Superior sulcus tumor

See Treatment (NSCL-5)

Stage IIB (T3 invasion, N0) Stage IIIA (T4 extension, N0-1; T3, N1)

? PFTs (if not previously done) ? Bronchoscopy ? Pathologic mediastinal lymph node evaluationg ? Brain MRI ? MRI of spine + thoracic inlet for superior sulcus lesions abutting the spine or subclavian vessels ? PET/CT scanh (if not previously done)

Chest wall

See Treatment (NSCL-6)

Proximal airway or mediastinum

See Treatment (NSCL-6)

Unresectable disease

See Treatment (NSCL-6)

Metastatic disease

See Treatment for Metastasis solitary site (NSCL-13) or distant disease (NSCL-15)

gMethods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. hPositive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT

needs pathologic confirmation.

scan is positive in the mediastinum, lymph node status

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-4

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CLINICAL PRESENTATION Superior sulcus tumor (T3 invasion, N0-1) INITIAL TREATMENT Preoperative concurrent chemoradiationj,m

NCCN Guidelines Index NSCLC Table of Contents Discussion ADJUVANT TREATMENT Surgeryi + chemotherapyk Surveillance (NSCL-14)

Possibly resectablei Superior sulcus tumor (T4 extension, N0-1) Unresectablei

Preoperative concurrent chemoradiationj,m

Resectable Surgical reevaluationp Unresectable

Surgeryi + chemotherapyk Complete definitive RTj + chemotherapym

Surveillance (NSCL-14) Surveillance (NSCL-14)

Definitive concurrent chemoradiationj,m,p,q

Surveillance (NSCL-14)

iSee Principles of Surgical Therapy (NSCL-B). jSee Principles of Radiation Therapy (NSCL-C). kSee Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D). mSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E).

pRT should continue to definitive dose without interruption if patient is not a surgical qIf full-dose chemotherapy is not given concurrently with RT as initial treatment, give

candidate.

additional 2 cycles of full-dose chemotherapy.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-5

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CLINICAL PRESENTATION INITIAL TREATMENT Margins negative (R0)n Surgeryi (preferred) Margins positive R1n ADJUVANT TREATMENT Chemotherapyk

NCCN Guidelines Index NSCLC Table of Contents Discussion

Reresection + chemotherapyk or Chemoradiationj,m (sequential or concurrent) Reresection + chemotherapyk or Concurrent chemoradiationj,m Observe

Surveillance (NSCL-14) Surveillance (NSCL-14)

Chest wall, proximal airway, or mediastinum (T3 invasion, N0-1 Resectable T4 extension, N0-1)

or

R2n

Surveillance (NSCL-14) Surveillance (NSCL-14)

Concurrent chemoradiationj,m or Chemotherapyk

Margins negative (R0)n Surgeryi Margins positive (R1, R2)n

Reresectionr

Surveillance (NSCL-14) Surveillance (NSCL-14)

Stage IIIA (T4, N0-1) Unresectable

Definitive concurrent chemoradiationj,m,p,q (category 1)

iSee Principles of Surgical Therapy (NSCL-B). jSee Principles of Radiation Therapy (NSCL-C). kSee Chemotherapy Regimens for Neoadjuvant and Adjuvant mSee Chemotherapy Regimens Used with Radiation Therapy nR0 = no residual tumor, R1 = microscopic residual tumor, R2

pRT

residual tumor.

Therapy (NSCL-D). (NSCL-E). = macroscopic

should continue to definitive dose without interruption if patient is not a surgical candidate. qIf full-dose chemotherapy is not given concurrently with RT as initial treatment, give additional 2 cycles of full-dose chemotherapy. rConsider RT boost if chemoradiation is given as initial treatment.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-6

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CLINICAL ASSESSMENT PRETREATMENT EVALUATION MEDIASTINAL BIOPSY FINDINGS AND RESECTABILITY N2, N3 nodes negative ? PFTs (if not previously done) ? Bronchoscopy ? Pathologic mediastinal lymph node evaluationg ? PET/CT scanh (if not previously done) ? Brain MRI N2 nodes positive N3 nodes positive Metastatic disease

NCCN Guidelines Index NSCLC Table of Contents Discussion

See Treatment T 1-3, N0-1 (NSCL-8) See Treatment (NSCL-8) See Stage IIIB (NSCL-11) See Treatment for Metastasis solitary site (NSCL-13) or distant disease (NSCL-15)

Stage IIIA (T1–3, N2)

Separate pulmonary nodule(s) (Stage IIB, IIIA, IV)

? PFTs (if not previously done) ? Bronchoscopy ? Pathologic mediastinal lymph node evaluationg ? Brain MRI ? PET/CT scanh (if not previously done)

Separate pulmonary nodule(s), same lobe (T3, N0) or ipsilateral non-primary lobe (T4, N0) Stage IV (N0, M1a): Contralateral lung (solitary nodule) Extrathoracic metastatic disease

See Treatment (NSCL-9)

See Treatment (NSCL-9)

See Treatment for Metastasis solitary site (NSCL-13) or distant disease (NSCL-15)

gMethods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. hPositive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT

needs pathologic confirmation.

scan is positive in the mediastinum, lymph node status

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-7

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
MEDIASTINAL BIOPSY FINDINGS T1-3, N0-1 (including T3 with multiple nodules in same lobe) Resectable Surgeryi,s Medically inoperable INITIAL TREATMENT Surgical resectioni + mediastinal lymph node dissection or systematic lymph node sampling See Treatment according to clinical stage (NSCL-2) Definitive concurrent chemoradiationj,m (category 1) or Induction chemotherapyk ± RTj N0–1 Margins negative (R0)n N2 Margins positiven R1n R2n See NSCL-3

NCCN Guidelines Index NSCLC Table of Contents Discussion ADJUVANT TREATMENT Sequential chemotherapyk (category 1) + RTj Chemoradiationj (sequentialk or concurrentm) Concurrent chemoradiationj,m Surveillance (NSCL-14) Surveillance (NSCL-14) Surveillance (NSCL-14)

T1-2, T3 (≥7 cm), N2 nodes positivei

? Brain MRI ? PET/CT scan,h if not previously done ? Brain MRI ? PET/CT scan,h if not previously done

Negative for M1 disease

No apparent progression Local Progression Systemic

Surgeryi ± chemotherapyk (category 2B) ± RTj (if not given) RTj (if not given) ± chemotherapyk See Treatment for Metastasis solitary site (NSCL-13) or distant disease (NSCL-15)

Positive Negative for M1 disease Positive

See Treatment for Metastasis solitary site (NSCL-13) or distant disease (NSCL-15) Definitive concurrent chemoradiationj,m See Treatment for Metastasis solitary site (NSCL-13) or distant disease (NSCL-15)

T3 (invasion), N2 nodes positive

hPositive

PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. iSee Principles of Surgical Therapy (NSCL-B). jSee Principles of Radiation Therapy (NSCL-C). kSee Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D).

mSee Chemotherapy Regimens Used with Radiation Therapy nR0 = no residual tumor, R1 = microscopic residual tumor, R2 sPatients

residual tumor. likely to receive adjuvant chemotherapy may be treated with induction chemotherapy as an alternative.

(NSCL-E). = macroscopic

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-8

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CLINICAL PRESENTATION Separate pulmonary nodule(s), same lobe (T3, N0), or ipsilateral non-primary lobe (T4, N0) N0–1 Surgeryi N2 Margins positiven Stage IV (N0, M1a): Contralateral lung (solitary nodule) Suspected multiple lung cancers (based on the presence of biopsyproven synchronous lesions or history of lung cancer)t,u Margins negative (R0)n R1n R2n ADJUVANT TREATMENT Chemotherapyk Sequential chemotherapyk (category 1) + RTj

NCCN Guidelines Index NSCLC Table of Contents Discussion Surveillance (NSCL-14) Surveillance (NSCL-14) Surveillance (NSCL-14) Surveillance (NSCL-14)

Chemoradiationj (sequentialk or concurrentm) Concurrent chemoradiationj,m

Treat as two primary lung tumors if both curable ? Chest CT with contrast ? PET-CT scan (if not previously done)h ? Brain MRI Disease outside of chest No disease outside of chest

See Evaluation (NSCL-1)

See Systemic Therapy for Metastatic Disease (NSCL-16) N2-3 See Systemic Therapy for Metastatic Disease (NSCL-16) See Initial Treatment (NSCL-10)

Pathologic mediastinal lymph node evaluationg

N0-1

gMethods

for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. hPositive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. iSee Principles of Surgical Therapy (NSCL-B). jSee Principles of Radiation Therapy (NSCL-C). kSee Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy (NSCL-D). mSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E).

nR0

= no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic residual tumor. tLesions with different cell types (eg, squamous cell carcinoma, adenocarcinoma) may be different primary tumors. This analysis may be limited by small biopsy samples. However, lesions of the same cell type are not necessarily metastases. uFor guidance regarding the evaluation, workup, and management of subsolid pulmonary nodules, please see the diagnostic evaluation of a nodule suspicious for lung cancer (DIAG-1).

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 2.2014, 11/04/13 ? National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-9

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CLINICAL PRESENTATION Low risk of becoming symptomaticv Multiple lesions High risk of becoming symptomaticv Solitary lesion (metachronous disease) Definitive local therapy not possible Definitive local therapy possible INITIAL TREATMENT

NCCN Guidelines Index NSCLC Table of Contents Discussion

Observation

Surveillance (NSCL-14)

Asymptomatic

Parenchymal sparing resection (preferred)i,w or Radiationj or Ablation

Multiple lung cancers

Symptomatic

Consider palliative chemotherapy ± local palliative therapy

See Systemic Therapy for Metastatic Disease (NSCL-16)
iSee Principles of Surgical Therapy (NSCL-B). jSee Principles of Radiation Therapy (NSCL-C). vLesions at low risk of becoming symptomatic can

be observed (eg, small subsolid nodules with slow growth). However, if the lesion(s) becomes symptomatic or becomes high risk for producing symptoms (eg, subsolid nodules with accelerating growth or increasing solid component or increasing FDG uptake, even while small), treatment should be considered. wLung-sparing resection is preferred, but tumor distribution and institutional expertise should guide individual treatment planning.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-10

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CLINICAL ASSESSMENT PRETREATMENT EVALUATION INITIAL TREATMENT

NCCN Guidelines Index NSCLC Table of Contents Discussion

Stage IIIB (T1–3, N3)

? PFTs (if not previously done) ? PET/CT scanh (if not previously done)?? ? Brain MRI ? Pathologic confirmation of N3 disease by either: Mediastinoscopy Supraclavicular lymph node biopsy Thoracoscopy Needle biopsy Mediastinotomy EUS biopsy EBUS biopsy

N3 negative

See Initial treatment for stage I–IIIA (NSCL-8)

N3 positive

Definitive concurrent chemoradiationj,m,q (category 1) See Treatment for Metastasis solitary site (NSCL-13) or distant disease (NSCL-15)

Metastatic disease

hPositive

PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT scan positive in the mediastinum, lymph node status needs pathologic confirmation. jSee Principles of Radiation Therapy (NSCL-C). mSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E). qIf full-dose chemotherapy is not given concurrently with RT as initial treatment, give additional 2 cycles of full-dose chemotherapy.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-11

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CLINICAL ASSESSMENT PRETREATMENT EVALUATION Ipsilateral mediastinal node negative (T4, N0-1) Ipsilateral mediastinal node positive (T4, N2)

NCCN Guidelines Index NSCLC Table of Contents Discussion INITIAL TREATMENT See Treatment for Stage IIIA (NSCL-8)

Stage IIIB (T4 extension, N2–3)

? PET/CT scanh (if not previously done) ? Brain MRI ? Pathologic confirmation of N2–3 disease by either: Mediastinoscopy Supraclavicular lymph node biopsy Thoracoscopy Needle biopsy Mediastinotomy EUS biopsy EBUS biopsy

Contralateral mediastinal node negative

Definitive concurrent chemoradiationj,m,q (category 1) Definitive concurrent chemoradiationj,m,q (category 1)

Contralateral mediastinal node positive (T4, N3)

Metastatic disease Negativex

See Treatment for Metastasis solitary site (NSCL-13) or distant disease (NSCL-15) See Treatment according to TNM stage (NSCL-8) Local therapy if necessary (eg, pleurodesis, ambulatory small catheter drainage, pericardial window) + treatment for stage IV disease solitary site (NSCL-13) or distant disease (NSCL-15)

Stage IV, M1a: pleural or pericardial effusion

Thoracentesis or pericardiocentesis ± thoracoscopy if thoracentesis indeterminate

Positivex

hPositive PET/CT scan findings for distant disease need pathologic or other

radiologic confirmation. If PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. jSee Principles of Radiation Therapy (NSCL-C). mSee Chemotherapy Regimens Used with Radiation Therapy (NSCL-E). qIf full-dose chemotherapy is not given concurrently with RT as initial treatment, give additional 2 cycles of full-dose chemotherapy.

xWhile most pleural effusions associated with lung cancer are due to tumor, there

are a few patients in whom multiple cytopathologic examinations of pleural fluid are negative for tumor and fluid is non-bloody and not an exudate. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element. Pericardial effusion is classified using the same criteria.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-12

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CLINICAL ASSESSMENT PRETREATMENT EVALUATION INITIAL TREATMENT

NCCN Guidelines Index NSCLC Table of Contents Discussion

Brainy Stage IV, M1b: solitary site ? Pathologic mediastinal lymph node evaluationg ? Bronchoscopy ? Brain MRI ? PET/CT scanh (if not previously done) Adrenal

Surgical resection,i followed by whole brain RTj (WBRT) (category 1) or stereotactic radiosurgeryj (SRS) or SRS + WBRTj (category 1 for one metastasis) or SRSj alone Pathologic diagnosis by needle or resection Local therapy for adrenal lesionz (if lung lesion curable, based on T and N stage) (category 2B)aa or See Systemic Therapy for Metastatic Disease (NSCL-16)

T1-2, N0-1; T3, N0

Surgical resection of lung lesioni or Stereotactic ablative radiotherapyj (SABR) of lung lesion or Chemotherapybb

Chemotherapybb

Surgical resection of lung lesioni or SABR of lung lesion

T1-2, N2; T3, N1-2; Any T, N3; T4, Any N

See Systemic Therapy for Metastatic Disease (NSCL-16)

gMethods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. hPositive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If PET/CT

needs pathologic confirmation. iSee Principles of Surgical Therapy (NSCL-B). jSee Principles of Radiation Therapy (NSCL-C). ySee NCCN Guidelines for Central Nervous System Cancers. zMay include adrenalectomy or RT (including SABR). aaPatients with N2 disease have a poor prognosis and systemic therapy should be considered. bbSee Systemic Therapy for Advanced or Metastatic Disease (NSCL-F).

scan is positive in the mediastinum, lymph node status

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-13

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
SURVEILLANCE

NCCN Guidelines Index NSCLC Table of Contents Discussion

Locoregional recurrence No evidence of clinical/radiographic disease, stages I-IV: ? H&P and chest CT ± contrast every 6-12 mo for 2 y, then H&P and a non-contrast-enhanced chest CT annually ? Smoking cessation advice, counseling, and pharmacotherapy ? PET or brain MRI is not indicated ? See Cancer Survivorship Care (NSCL-G). Distant metastases

See Therapy for Recurrence and Metastasis (NSCL-15)

See Therapy for Recurrence and Metastasis (NSCL-15)

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-14

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
THERAPY FOR RECURRENCE AND METASTASIS Endobronchial obstruction Resectable recurrence Locoregional recurrence Mediastinal lymph node recurrence Superior vena cava (SVC) obstruction No prior RT Prior RT ? Laser/stent/other surgeryi ? External-beam RT or brachytherapyj ? Photodynamic therapy ? Reresection (preferred)i ? External-beam RT or SABRj Concurrent chemoradiation Systemic chemotherapybb ? Concurrent chemoradiationm (if not previously given) ? External-beam RTj ? SVC stent ? External-beam RT or brachytherapyi ? Laser or photodynamic therapy or embolization ? Surgery Palliative external-beam RTj Palliative external-beam RTj,y ? Palliative external-beam RTj + orthopedic stabilization, if risk of fracture ? Consider bisphosphonate therapy or denosumab See pathway for Stage IV, M1b, solitary site (NSCL-13) See Systemic Therapy for Metastatic Disease (NSCL-16)

NCCN Guidelines Index NSCLC Table of Contents Discussion

No evidence of disseminated disease Evidence of disseminated disease

Observation or Systemic chemotherapybb (category 2B) See Systemic Therapy for Metastatic Disease (NSCL-16)

Severe hemoptysis

Localized symptoms Diffuse brain metastases Distant metastases Bone metastasis Solitary metastasis Disseminated metastases
iSee Principles of Surgical Therapy (NSCL-B). jSee Principles of Radiation Therapy (NSCL-C). mSee Chemotherapy Regimens Used with Radiation

See Systemic Therapy for Metastatic Disease (NSCL-16)

Therapy (NSCL-E).

ySee NCCN Guidelines for Central Nervous System Cancers. bbSee Systemic Therapy for Advanced or Metastatic Disease (NSCL-F).

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-15

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
SYSTEMIC THERAPY FOR METASTATIC DISEASE HISTOLOGIC SUBTYPE Sensitizing EGFR mutation positive ? Adenocarcinoma ? Large Cell ? NSCLC not otherwise specified (NOS) ? EGFR mutation testinga (category 1)a ? ALK testing (category 1)a ? EGFR ± ALK testing should be conducted as part of multiplex/next-generation sequencingcc

NCCN Guidelines Index NSCLC Table of Contents Discussion

See First-Line Therapy (NSCL-17)

Metastatic Disease

? Establish histologic subtypea with adequate tissue for molecular testing (consider rebiopsy if appropriate) ? Smoking cessation counseling ? Integrate palliative careb (See NCCN Guidelines for Palliative Care)

ALK positive

See First-Line Therapy (NSCL-18)

Sensitizing EGFR mutation and ALK negative or unknownff

See First-Line Therapy (NSCL-19)

Squamous cell carcinoma

? Consider EGFR mutation and ALK testingdd especially in never smokers or small biopsy specimens, or mixed histologyee ? EGFR ± ALK testing should be conducted as part of multiplex/nextgeneration sequencingcc

See First-Line Therapy (NSCL-20)

aSee Principles of Pathologic Review (NSCL-A). bTemel 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. ccSee Targeted Agents for Patients with Other Genetic Alterations (NSCL-H). ddIn patients with squamous cell carcinoma, the observed incidence of EGFR mutations is 2.7% with a confidence that the true incidence of mutations is

less than 3.6%. This frequency of EGFR mutations does not justify routine testing of all tumor specimens. Forbes SA, Bharma G, Bamford S, et al. The catalogue of somatic mutations in cancer (COSMIS). Curr Protoc Hum Genet 2008;chapter 10:unit 10.11. eePaik PK, Varghese AM, Sima CS, et al. Response to erlotinib in patients with EGFR mutant advanced non-small cell lung cancers with a squamous or squamous-like component. Mol Cancer Ther 2012;11:2535-2540. ffConsider ROS1 testing; if positive, may treat with crizotinib. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-870.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-16

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
ADENOCARCINOMA, LARGE CELL, NSCLC NOS: SENSITIZING EGFR MUTATION POSITIVEa FIRST-LINE THERAPYbb Isolated lesion Brainll Multiple lesions Isolated lesion Systemic Multiple lesions Asymptomatic

NCCN Guidelines Index NSCLC Table of Contents Discussion

SECOND-LINE THERAPYbb,mm Consider local therapy and continue erlotinibhh or afatinib Consider WBRT and continue erlotinibhh or afatinib Consider local therapy and continue erlotinibhh or afatinib Consider platinum doublet ± bevacizumabbb ± erlotinibhh Continue erlotinibhh or afatinib Progression, See third-line therapy (NSCL-21)

EGFR mutation discovered prior to first-line chemotherapy Sensitizing EGFR mutation positive

Erlotinibgg,hh (category 1) or Afatinib (category 1) Interrupt or complete planned chemotherapy, start Progressionjj,kk erlotinibhh or afatinib or May add erlotinibhh,ii or afatinib to current chemotherapy (category 2B)

Symptomatic

EGFR mutation discovered during first-line chemotherapy

aSee Principles of Pathologic Review (NSCL-A). bbSee Systemic Therapy for Advanced or Metastatic Disease (NSCL-F). ggFor performance status 0-4. hhIn areas of the world where gefitinib is available, it may be used in place

jjBiopsy

of erlotinib. iiJanne PA, Wang X, Socinski MA, et al. Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who are never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. J Clin Oncol 2012;30:2063-2069.

on progression to determine mechanism of acquired resistance, because proportion of patients will transform to SCLC at progression. kkBeware of flare phenomenon in subset of patients who discontinue EGFR TKI. If disease flare occurs, restart EGFR TKI. llConsider pulse erlotinib for carcinomatosis meningitis. mmAfatinib appears to have some efficacy in patients who progressed on EGFR therapy. Miller VA, Hirsh V, Cadrenal J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012;13:528-38.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-17

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
ADENOCARCINOMA, LARGE CELL, NSCLC NOS: ALK POSITIVEa FIRST-LINE THERAPYbb Isolated lesion Brain ALK rearrangement discovered prior to first-line chemotherapy ALK positive ALK rearrangement discovered during first-line chemotherapy Interrupt or complete planned chemotherapy, start crizotinib Multiple lesions Crizotinibff Symptomatic Isolated lesion Progression Systemic Multiple lesions Asymptomatic

NCCN Guidelines Index NSCLC Table of Contents Discussion

SECOND-LINE THERAPYbb Consider local therapy and continue crizotinib Consider WBRT and continue crizotinib Progression, See third-line Consider local therapy therapy and continue crizotinib (NSCL-21) Consider platinum doublet ± bevacizumab Continue crizotinib

aSee Principles of Pathologic Review (NSCL-A). bbSee Systemic Therapy for Advanced or Metastatic Disease (NSCL-F). ffConsider ROS1 testing; if positive, may treat with crizotinib. Bergethon K,

cancers. J Clin Oncol 2012;30:863-870.

Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-18

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
ADENOCARCINOMA, LARGE CELL, NSCLC NOS: EGFR MUTATION AND ALK NEGATIVE OR UNKNOWNnn FIRST-LINE THERAPY

NCCN Guidelines Index NSCLC Table of Contents Discussion

SECOND-LINE THERAPYbb If not already given: Docetaxel or Pemetrexed or Erlotinibhh or Gemcitabine Progression, see Third-line therapy (NSCL-21)

PS 0-1

Doublet chemotherapybb (category 1) or Bevacizumab + chemotherapybb,oo,pp (if criteria met)qq or Cetuximab/vinorelbine/ cisplatin (category 2B) Chemotherapybb

PS 0-2 Progression Tumor response evaluation Response or stable disease 4-6 cycles (total) PS 3-4

Best supportive care See NCCN Guidelines for Palliative Care Progression See Second-line therapy, above Continuation maintenancebb ? bevacizumab (category 1) ? cetuximab (category 1) ? pemetrexed (category 1) ? bevacizumab + pemetrexedrr ? gemcitabine (category 2B) or ? Switch maintenancebb (category 2B) ? pemetrexed or erlotinib or Close observation

PS 2

Tumor response evaluation Response or stable disease

PS 3-4

Best supportive care See NCCN Guidelines for Palliative Care

Progression, see Secondline therapy, above

bbSee Systemic Therapy for Advanced or Metastatic Disease (NSCL-F). hhIn areas of the world where gefitinib is available, it may be used in place nnConsider

additional mutational testing if only EGFR and ALK were performed. See Targeted Agents for Patients with Other Genetic Alterations (NSCL-H). ooBevacizumab should be given until progression.

erlotinib.

of

ppAny

regimen with a high risk of thrombocytopenia and the potential risk of bleeding should be used with caution in combination with bevacizumab. qqCriteria for treatment with bevacizumab + chemotherapy: non-squamous NSCLC, and no recent history of hemoptysis. Bevacizumab should not be given as a single agent, unless as maintenance if initially used with chemotherapy. rrIf bevacizumab was used with a first-line pemetrexed/platinum chemotherapy regimen.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-19

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
SQUAMOUS CELL CARCINOMA FIRST-LINE THERAPY

NCCN Guidelines Index NSCLC Table of Contents Discussion

SECOND-LINE THERAPYbb If not already given: Docetaxel or Erlotinibhh or Gemcitabine Progression, see Third-line therapy (NSCL-21)

PS 0-2 Doublet chemotherapybb (category 1) or Cetuximab/vinorelbine/ cisplatin (category 2B) Chemotherapybb Progression Tumor response evaluation Response or stable disease 4-6 cycles (total) PS 3-4 Progression Tumor response evaluation Response or stable disease

PS 0-1

Best supportive care See NCCN Guidelines for Palliative Care See Second-line therapy, above

PS 2

PS 3-4

Best supportive care See NCCN Guidelines for Palliative Care

Continuation maintenancebb ? cetuximab (category 1) ? gemcitabine (category 2B) or Switch maintenancebb (category 2B) ? erlotinib or docetaxel or Close observation

Progression, see Secondline therapy, above

bbSee Systemic Therapy for Advanced or Metastatic Disease (NSCL-F). hhIn areas of the world where gefitinib is available, it may be used in place

of erlotinib.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-20

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
ADENOCARCINOMA, LARGE CELL, NSCLC NOS, or SQUAMOUS CELL CARCINOMA THIRD-LINE THERAPY If not already given: Docetaxelbb,ss or Pemetrexedbb,ss (nonsquamous) or Erlotinibbb,hh or Gemcitabiness Best supportive care See NCCN Guidelines for Palliative Care or Clinical trial

NCCN Guidelines Index NSCLC Table of Contents Discussion

PS 0-2

PS 0-2

Progression Best supportive care See NCCN Guidelines for Palliative Care

Progression

PS 3-4

PS 3-4

Erlotinibbb,hh,tt or Best supportive care See NCCN Guidelines for Palliative Care

bbSee Systemic Therapy for Advanced or Metastatic Disease (NSCL-F). hhIn areas of the world where gefitinib is available, it may be used in place of erlotinib. ssPemetrexed, docetaxel, and gemcitabine are category 2B if patient did not receive erlotinib ttErlotinib may be considered for PS 3 and 4 patients with EGFR mutation.

or crizotinib in first- or second-line therapy.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-21

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF PATHOLOGIC REVIEW (1 of 4)

NCCN Guidelines Index NSCLC Table of Contents Discussion

Pathologic Evaluation ? The purpose of pathologic evaluation is to classify the histologic type of lung cancer and to determine all staging parameters as recommended by the AJCC,1 including tumor size, the extent of invasion (pleural and bronchial), adequacy of surgical margins, and presence or absence of lymph node metastasis.2,3 Further, determination of the specific molecular abnormalities of the tumor is critical for predicting sensitivity or resistance to an increasing number of drugable targets, primarily tyrosine kinase inhibitors (TKIs) (see Molecular Diagnostic Studies in this section).4,5 ? The WHO tumor classification system has historically provided the foundation for the classification of lung tumors, including histologic types, clinical features, staging considerations, and the molecular, genetic, and epidemiologic aspects of lung cancer.6,7 ? The pathology diagnostic report should include the histologic classification as described by the WHO for carcinomas of the lung with squamous morphology, neuroendocrine differentiation, and other variant carcinomas. The recently published classification of adenocarcinoma should be used for this tumor subtype in resection specimens and small biopsies.8 Use of bronchioloalveolar carcinoma (BAC) terminology is strongly discouraged. ? The generic term “non-small cell lung cancer (NSCLC)” should be avoided as a single diagnostic term. In small biopsies of poorly differentiated carcinomas where immunohistochemistry (IHC) is used, the following terms are acceptable: “NSCLC favor adenocarcinoma” or “NSCLC favor squamous cell carcinoma.”8 Mutational testing (eg, epidermal growth factor receptor [EGFR]) should be performed in this setting. ? Although formalin-fixed paraffin-embedded tumor may be used for most molecular analyses, acquisition of fresh cryopreserved tumor tissue for advanced molecular studies should be considered. ? Limited use of IHC studies in small tissue samples is strongly recommended, thereby preserving critical tumor tissue for molecular studies, particularly in patients with advanced-stage disease. A limited panel of one squamous cell carcinoma marker (eg, p63) and one adenocarcinoma marker (eg, TTF-1) should suffice for most diagnostic problems.8 Adenocarcinoma Classification8 ? Adenocarcinoma in situ (AIS; formerly BAC): ≤3 cm nodule, lepidic growth, mucinous, non-mucinous, or mixed mucinous/non-mucinous types. ? Minimally invasive adenocarcinoma (MIA): ≤3 cm nodule with ≤5 mm of invasion, lepidic growth, mucinous, non-mucinous, or mixed mucinous/non-mucinous types. ? Invasive adenocarcinoma, predominant growth pattern: lepidic >5 mm of invasion, acinar, papillary, micropapillary, or solid with mucin. ? Invasive adenocarcinoma variants: mucinous adenocarcinoma, colloid, fetal, and enteric morphologies.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-A 1 of 4

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF PATHOLOGIC REVIEW (2 of 4)

NCCN Guidelines Index NSCLC Table of Contents Discussion

Immunohistochemical Staining ? Although the concordance is generally good between the histologic subtype and the immunophenotype seen in small biopsies compared with surgical resection specimens, caution is advised in attempting to subtype small biopsies with limited material or cases with an ambiguous immunophenotype. ? IHC should be used to differentiate primary pulmonary adenocarcinoma from the following—squamous cell carcinoma, large cell carcinoma, metastatic carcinoma, and malignant mesothelioma—and to determine whether neuroendocrine differentiation is present.9-11 ? Primary pulmonary adenocarcinoma An appropriate panel of immunohistochemical stains is recommended to exclude metastatic carcinoma to the lung.12 TTF-1 is a homeodomain-containing nuclear transcription protein of the Nkx2 gene family that is expressed in epithelial cells of the embryonal and mature lung and thyroid. TTF-1 immunoreactivity is seen in primary pulmonary adenocarcinoma in the majority (70%-100%) of non-mucinous adenocarcinomas subtypes.13 Metastatic adenocarcinoma to the lung is virtually always negative for TTF-1 except in metastatic thyroid malignancies, in which case thyroglobulin is also positive. Napsin A—an aspartic proteinase expressed in normal type II pneumocytes and in proximal and distal renal tubules—appears to be expressed in >80% of lung adenocarcinomas and may be a useful adjunct to TTF-1.12 The panel of TTF-1 and p63 (or alternatively p40) may be useful in refining the diagnosis to either adenocarcinoma or squamous cell carcinoma in small biopsy specimens previously classified as NSCLC, not otherwise specified (NOS).8 ? Neuroendocrine differentiation CD56, chromogranin, and synaptophysin are used to identify neuroendocrine tumors. ? Malignant mesothelioma versus pulmonary adenocarcinoma The distinction between pulmonary adenocarcinoma and malignant mesothelioma (epithelial type) is made by using a panel of markers, including 2 with known immunopositivity in mesothelioma (but negative in adenocarcinoma) and 2 with known positivity in adenocarcinoma (but negative in mesothelioma).11 ??Immunostains relatively sensitive and specific for mesothelioma include WT-1, calretinin, D2-40, HMBE-1, and cytokeratin 5/6 (negative in adenocarcinoma).14,15 Antibodies immunoreactive in adenocarcinoma include CEA, B72.3, Ber-EP4, MOC31, CD15, and TTF-1 (negative in mesothelioma).8,11

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-A 2 of 4

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF PATHOLOGIC REVIEW (3 of 4)

NCCN Guidelines Index NSCLC Table of Contents Discussion

Molecular Diagnostic Studies in Lung Cancer ? EGFR and KRAS EGFR is normally found on the surface of epithelial cells and is often overexpressed in a variety of human malignancies. Presence of EGFR-activating mutations represents a critical biological determinant for proper therapy selection in patients with lung cancer. There is a significant association between EGFR mutations—especially exon 19 deletion and exon 21 (L858R, L861) and exon 18 (G719X, G719) mutations—and sensitivity to TKIs.16-19 The exon 20 insertion mutation may predict resistance to clinically achievable levels of TKIs.20,21 EGFR and KRAS mutations are mutually exclusive in patients with lung cancer.22 KRAS mutations are associated with intrinsic TKI resistance, and KRAS gene sequencing could be useful for the selection of patients as candidates for TKI therapy.23 The prevalence of EGFR mutations in adenocarcinomas is 10% of Western and up to 50% of Asian patients, with higher EGFR mutation frequency in non-smokers, women, and non-mucinous cancers. KRAS mutations are most common in non-Asians, smokers, and in mucinous adenocarcinoma.24 The most common EGFR mutations result in an arginine for leucine substitution at amino acid 858 in exon 21 (L858R) and in frame deletions at exon 19. Mutations are more common in non-mucinous lung adenocarcinoma with lepidic pattern (former BAC pattern) and in lung adenocarcinoma with papillary (and or micropapillary) pattern. Primary resistance to TKI therapy is associated with KRAS mutation. Acquired resistance is associated with second-site mutations within the EGFR kinase domain (such as T790M), amplification of alternative kinases (such as MET), histologic transformation from NSCLC to SCLC, and epithelial to mesenchymal transition (EMT). ? ALK Anaplastic lymphoma kinase (ALK) gene rearrangements represent the fusion between ALK and various partner genes, including echinoderm microtubule-associated protein-like 4 (EML4).25 ALK fusions have been identified in a subset of patients with NSCLC and represent a unique subset of NSCLC patients for whom ALK inhibitors may represent a very effective therapeutic strategy.26 Crizotinib is an oral ALK inhibitor that is approved by the FDA for patients with locally advanced or metastatic NSCLC who have the ALK gene rearrangement (ie, ALK positive). ALK NSCLC occurs most commonly in a unique subgroup of NSCLC patients who share many of the clinical features of NSCLC patients likely to harbor EGFR mutations.27,28 However, for the most part, ALK translocations and EGFR mutations are mutually exclusive.27, 29-31 The current standard method for detecting ALK NSCLC is fluorescence in situ hybridization (FISH), although other methods are currently being evaluated, including polymerase chain reaction (PCR) and IHC. A big advantage of FISH is that a commercially available probe set, developed for the diagnosis of ALK-rearranged anaplastic large cell lymphomas (ALCL), is applicable for the diagnosis of ALK-rearranged lung adenocarcinomas. The IHC tests used to diagnose ALK-rearranged ALCLs in clinical laboratories worldwide are inadequate for the detection of most ALK-rearranged lung cancer.32,33 This inadequacy is because of the lower level of ALK expression in ALK-rearranged NSCLCs compared with ALK-rearranged ALCLs. A molecular diagnostic test that uses FISH was recently approved by the FDA to determine which patients have ALK-positive lung cancer.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-A 3 of 4

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF PATHOLOGIC REVIEW (4 of 4) - References
1Edge

NCCN Guidelines Index NSCLC Table of Contents Discussion

SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual, 7th ed. New York: Springer; 2010. 2Fossella FV, Putnam JB, Komaki R, eds. Lung Cancer. M.D. Anderson Cancer Care Series. New York: Springer; 2003:316. 3Schrump DS, Carter D, Kelsey CR, et al. Non-small cell lung cancer. In: DeVita Jr. VT, Lawrence TS, Rosenberg SA, et al., eds. DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins; 2011. 4Cappuzzo 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. 5Eberhard 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-smallcell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23:5900-5909. 6Travis WD. Pathology and genetics of tumours of the lung, pleura, thymus and heart Lyon: IARC Press; 2004. 7Brambilla E, Travis WD, Colby TV, et al. The new World Health Organization classification of lung tumours. Eur Respir J 2001;18:1059-1068. 8Travis 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. 9Rekhtman N, Ang DC, Sima CS, et al. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of wholetissue sections with validation in small specimens. Mod Pathol 2011;24:1348-1359. 10Mukhopadhyay 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. 11Husain AN, Colby T, Ordonez N, et al. Guidelines for Pathologic Diagnosis of Malignant Mesothelioma: 2012 Update of the Consensus Statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med 2012 Aug 28. [Epub ahead of print] 12Jagirdar J. Application of immunohistochemistry to the diagnosis of primary and metastatic carcinoma to the lung. Arch Pathol Lab Med 2008;132:384-396. 13Goldstein NS, Thomas M. Mucinous and nonmucinous bronchioloalveolar adenocarcinomas have distinct staining patterns with thyroid transcription factor and cytokeratin 20 antibodies. Am J Clin Pathol 2001;116:319-325. 14Ordonez NG. D2-40 and podoplanin are highly specific and sensitive immunohistochemical markers of epithelioid malignant mesothelioma. Hum Pathol 2005;36:372-380. 15Chirieac LR, Pinkus GS, Pinkus JL, et al. The immunohistochemical characterization of sarcomatoid malignant mesothelioma of the pleura. Am J Cancer Res 2011;1:14-24. 16Cappuzzo F, Finocchiaro G, Metro G, et al. Clinical experience with gefitinib: an update. Crit Rev Oncol Hematol 2006;58:31-45. 17Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500.

18Sequist

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. 19Ji H, Li D, Chen L, et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 2006;9:485495. 20Lund-Iverson M, Kleinber L, Fjellbirkeland L, Helland A, et al. Clinicopathological characteristics of 11 NSCLC patients with EGFR-exon 20 mutations. J Thorac Oncol 2012;7:1471-1413. 21Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small cell lung cancer: preclinical data and clinical implications. Lancet Oncol 2012;13:e23-31. 22Riely 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. 23Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006;118:257-262. 24Finberg KE, Sequist LV, Joshi VA, et al. Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. J Mol Diagn 2007;9:320-326. 25Cataldo KA, Jalal SM, Law ME, et al. Detection of t(2;5) in anaplastic large cell lymphoma: comparison of immunohistochemical studies, FISH, and RT-PCR in paraffin-embedded tissue. Am J Surg Pathol 1999;23:1386-1392. 26Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-smallcell lung cancer. N Engl J Med 2010;363:1693-1703. 27Shaw 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. 28Koivunen JP, Kim J, Lee J, et al. Mutations in the LKB1 tumour suppressor are frequently detected in tumours from Caucasian but not Asian lung cancer patients. Br J Cancer 2008;99:245-252. 29Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008;14:4275-4283. 30Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A 2008;105:19893-19897. 31Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol 2009;22:508-515. 32Rodig 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. 33Mino-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.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-A 4 of 4

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF SURGICAL THERAPY (1 of 4)

NCCN Guidelines Index NSCLC Table of Contents Discussion

Evaluation ? Determination of resectability, surgical staging, and pulmonary resection should be performed by board-certified thoracic surgeons who perform lung cancer surgery as a prominent part of their practice. ? CT and PET used for staging should be within 60 days before proceeding with surgical evaluation. ? Resection is the preferred local treatment modality (other modalities include radiofrequency ablation, cryotherapy, and SABR). Thoracic surgical oncology consultation should be part of the evaluation of any patient being considered for curative local therapy. In cases where SABR is considered for high-risk patients, a multidisciplinary evaluation (including a radiation oncologist) is recommended. ? The overall plan of treatment as well as needed imaging studies should be determined before any non-emergency treatment is initiated. ? Thoracic surgeons should actively participate in multidisciplinary discussions and meetings regarding lung cancer patients (eg, multidisciplinary clinic and/or tumor board). Resection ? Anatomic pulmonary resection is preferred for the majority of patients with NSCLC. ? Sublobar resection - Segmentectomy and wedge resection should achieve parenchymal resection margins ≥2 cm or ≥ the size of the nodule. ? Sublobar resection should also sample appropriate N1 and N2 lymph node stations unless not technically feasible without substantially increasing the surgical risk. ? Segmentectomy (preferred) or wedge resection is appropriate in selected patients for the following reasons: Poor pulmonary reserve or other major comorbidity that contraindicates lobectomy Peripheral nodule1 ≤2 cm with at least one of the following: ??Pure AIS histology ??Nodule has ≥50% ground-glass appearance on CT ??Radiologic surveillance confirms a long doubling time (≥400 days) ? VATS or minimally invasive surgery should be strongly considered for patients with no anatomic or surgical contraindications, as long as there is no compromise of standard oncologic and dissection principles of thoracic surgery. ? In high-volume centers with significant VATS experience, VATS lobectomy in selected patients results in improved early outcomes (ie, decreased pain, reduced hospital length of stay, more rapid return to function, fewer complications) without compromise of cancer outcomes. ? Lung-sparing anatomic resection (sleeve lobectomy) is preferred over pneumonectomy, if anatomically appropriate and margin-negative resection is achieved. ? T3 (invasion) and T4 local extension tumors require en-bloc resection of the involved structure with negative margins. If a surgeon or center is uncertain about potential complete resection, consider obtaining an additional surgical opinion from a high-volume specialized center.
1Peripheral

Margins and Nodal Assessment (see NSCL-B 2 of 4)
is defined as the outer one third of the lung parenchyma.

The Role of Surgery in Patients With Stage IIIA (N2) NSCLC (see NSCL-B 2 of 4 through NSCL-B 4 of 4) NSCL-B 1 of 4

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 2.2014, 11/04/13 ? National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF SURGICAL THERAPY (2 of 4)

NCCN Guidelines Index NSCLC Table of Contents Discussion

Margins and Nodal Assessment ? Surgical pathologic correlation is critical to assess apparent close or positive margins, as these may not represent true margins or may not truly represent areas of risk for local recurrence (eg, medial surface of mainstem or bronchus intermedius when separate subcarinal lymph node dissection has been performed, or pleural margin adjacent to aorta when no attachment to aorta is present). ? N1 and N2 node resection and mapping should be a routine component of lung cancer resections—a minimum of three N2 stations sampled or complete lymph node dissection. ? Formal ipsilateral mediastinal lymph node dissection is indicated for patients undergoing resection for stage IIIA (N2) disease. ? Complete resection requires free resection margins, systematic node dissection or sampling, and the highest mediastinal node negative for tumor. The resection is defined as incomplete whenever there is involvement of resection margins, unremoved positive lymph nodes, or positive pleural or pericardial effusions. A complete resection is referred to as R0, microscopically positive resection as R1, and macroscopic residual tumor as R2. ? Patients with pathologic stage II or greater should be referred to medical oncology for evaluation. ? Consider referral to a radiation oncologist for resected stage IIIA. The Role of Surgery in Patients With Stage IIIA (N2) NSCLC The role of surgery in patients with pathologically documented N2 disease remains controversial.1 Two randomized trials evaluated the role of surgery in this population, but neither showed an overall survival benefit with the use of surgery.2,3 However, this population is heterogeneous and the panel believes that these trials did not sufficiently evaluate the nuances present with the heterogeneity of N2 disease and the likely oncologic benefit of surgery in specific clinical situations. ? The presence or absence of N2 disease should be vigorously determined by both radiologic and invasive staging prior to the initiation of therapy since the presence of mediastinal nodal disease has a profound impact on prognosis and treatment decisions. (NSCL-1, NSCL-2, and NSCL-6) ? Patients with occult-positive N2 nodes discovered at the time of pulmonary resection should continue with the planned resection along with formal mediastinal lymph node dissection. If N2 disease is noted in patients undergoing VATS, the surgeon may consider stopping the procedure so that induction therapy can be administered before surgery; however, continuing the procedure is also an option. ? The determination of the role of surgery in a patient with N2-positive lymph nodes should be made prior to the initiation of any therapy by a multidisciplinary team, including a board-certified thoracic surgeon who has a major part of his/her practice dedicated to thoracic oncology.4 ? The presence of N2-positive lymph nodes substantially increases the likelihood of positive N3 lymph nodes. Pathologic evaluation of the mediastinum must include evaluation of the subcarinal station and contralateral lymph nodes. EBUS +/- EUS are additional techniques for minimally invasive pathologic mediastinal staging that are complementary to mediastinoscopy. Even when these modalities are employed it is important to have an adequate evaluation of the number of stations involved and biopsy and documentation of negative contralateral lymph node involvement prior to a final treatment decision. The Role of Surgery in Patients With Stage IIIA (N2) NSCLC is continued on NSCL-B 3 of 4 through NSCL-B 4 of 4
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-B 2 of 4

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF SURGICAL THERAPY (3 of 4)

NCCN Guidelines Index NSCLC Table of Contents Discussion

The Role of Surgery in Patients With Stage IIIA (N2) NSCLC ? Repeat mediastinoscopy, while possible, is technically difficult and has a lower accuracy compared to primary mediastinoscopy. One possible strategy is to perform EBUS (± EUS) in the initial pretreatment evaluation and reserve mediastinoscopy for nodal restaging after neoadjuvant therapy.5 ? Patients with a single lymph node smaller than 3 cm can be considered for a multimodality approach that includes surgical resection.1,6,7 ? Restaging after induction therapy is difficult to interpret, but CT +/- PET should be performed to exclude disease progression or interval development of metastatic disease. ? Patients with negative mediastinum after neoadjuvant therapy have a better prognosis.7,8 ? Neoadjuvant chemoradiotherapy is used in 50% of the NCCN Member Institutions, while neoadjuvant chemotherapy is used in the other 50%. Overall survival appears similar provided RT is given postoperatively, if not given preoperatively.5,9 Neoadjuvant chemoradiotherapy is associated with higher rates of pathologic complete response and negative mediastinal lymph nodes.10 However, that is achieved at the expense of higher rates of acute toxicity and increased cost. ? When neoadjuvant chemoradiotherapy is used with doses lower than those used for standard definitive therapy, all efforts should be made to minimize any possible breaks in radiotherapy for surgical evaluation. Treatment breaks of more than 1 week are considered unacceptable. ? When timely surgical evaluation is not available, the strategy of neoadjuvant chemoradiotherapy should not be used. Another option in individual cases, and with the agreement of the thoracic surgeon, is to complete definitive chemoradiotherapy prior to re-evaluation and consideration for surgery.11,12 If a surgeon or center is uncertain about the feasibility or safety of resection after definitive doses of radiation, consider obtaining an additional surgical opinion from a high-volume specialized center. These operations may also benefit from additional considerations of soft tissue flap coverage in the radiation field resection. ? Data from a large multi-institutional trial indicate that pneumonectomy after neoadjuvant chemoradiotherapy has unacceptable morbidity and mortality.2 However, it is not clear if this is also true with neoadjuvant chemotherapy alone. Further, many groups have challenged that cooperative group finding with single-institution experiences demonstrating safety of pneumonectomy after induction therapy.13-16 In addition, there is no evidence that adding RT to induction regimens for patients with operable stage IIIA (N2) disease improves outcomes compared to induction chemotherapy.17 A questionnaire was submitted to the NCCN Member Institutions in 2010 regarding their approach to patients with N2 disease. Their responses indicate the patterns of practice when approaching this difficult clinical problem. a) Would consider surgery in patients with one N2 lymph node station involved by a lymph node smaller than 3 cm: (90.5%) b) Would consider surgery with more than one N2 lymph node station involved, as long as no lymph node was bigger than 3 cm: (47.6%) c) Uses EBUS (+/- EUS) in the initial evaluation of the mediastinum: (80%) d) Uses pathologic evaluation of the mediastinum, after neoadjuvant therapy, to make a final decision before surgery: (40.5%) e)  Would consider neoadjuvant therapy followed by surgery when a patient is likely, based on initial evaluation, to require a pneumonectomy: (54.8%)
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-B 3 of 4

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF SURGICAL THERAPY (4 of 4) The Role of Surgery in Patients With Stage IIIA (N2) NSCLC - References
1Martins

NCCN Guidelines Index NSCLC Table of Contents Discussion

RG, D'Amico TA, Loo BW Jr, et al. The management of patients with stage IIIA non-small cell lung cancer with N2 mediastinal node involvement. J Natl Compr Canc Netw 2012;10:599-613. 2Albain K, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomized controlled trial. Lancet 2009;374:379-386. 3van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 nonsmall-cell lung cancer. J Natl Cancer Inst 2007;99:442-450. 4Farjah F, Flum DR, Varghese TK Jr, et al. Surgeon specialty and long-term survival after pulmonary resection for lung cancer. Ann Thorac Surg 2009;87:995-1006. 5Thomas M, Rübe C, Hoffknecht P, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol. 2008;9:607-608. 6Andre F, Grunenwald D, Pignon J, et al. Survival of patients with resected N2 non–small-cell lung Cancer: Evidence for a subclassification and implications. J Clin Oncol 2000;18:2981-2989. 7Decaluwé H, De Leyn P, Vansteenkiste J, et al. Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothorac Surg 2009;36:433-439. 8Bueno R, Richards WG, Swanson SJ, et al. Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg 2000;70:18261831. 9Higgins K, Chino JP, Marks LB, et al. Preoperative chemotherapy versus preoperative chemoradiotherapy for stage III (N2) non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2009;75:1462-1467. 10de Cabanyes Candela S, Detterbeck FC. A systematic review of restaging after induction therapy for stage IIIa lung cancer: prediction of pathologic stage. J Thorac Oncol 2010;5:389-398. 11Bauman JE, Mulligan MS, Martins RG, et al. Salvage Lung Resection After Definitive Radiation (>59 Gy) for Non-Small Cell Lung Cancer: Surgical and Oncologic Outcomes. Ann Thorac Surg 2008;86:1632-1639. 12Sonett JR, Suntharalingam M, Edelman MJ, et al. Pulmonary Resection After Curative Intent Radiotherapy (>59 Gy) and Concurrent Chemotherapy in Non–Small-Cell Lung Cancer. Ann Thorac Surg 2004;78:1200-1205. 13Evans NR 3rd, Li S, Wright CD, et al. The impact of induction therapy on morbidity and operative mortality after resection of primary lung cancer. J Thorac Cardiovasc Surg 2010;139:991-996. 14Gaissert HA, Keum DY, Wright CD, et al. POINT: Operative risk of pneumonectomy—Influence of preoperative induction therapy. J Thorac Cardiovasc Surg 2009;138:289-294. 15Mansour Z, Kochetkova EA, Ducrocq X, et al. Induction chemotherapy does not increase the operative risk of pneumonectomy! Eur J Cardiothorac Surg 2007;31:181185. 16Weder W, Collaud S, Eberhardt WEE, et al. Pneumonectomy is a valuable treatment option after neoadjuvant therapy for stage III non–small-cell lung cancer. J Thorac Cardiovasc Surg 2010;139:1424-1430. 17Shah AA, Berry M, Tzao C, et al. Induction chemoradiotherapy is not superior to induction chemotherapy alone in stage IIIA lung cancer: a systematic review and meta-analysis. Ann Thorac Surg 2012;93:1807-1812.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-B 4 of 4

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF RADIATION THERAPY (1 of 9)

NCCN Guidelines Index NSCLC Table of Contents Discussion

General Principles (see Table 1. Commonly Used Abbreviations in Radiation Therapy) ? Determination of the appropriateness of radiation therapy (RT) should be made by board-certified radiation oncologists who perform lung cancer RT as a prominent part of their practice. ? RT has a potential role in all stages of NSCLC, as either definitive or palliative therapy. Radiation oncology input as part of a multidisciplinary evaluation or discussion should be provided for all patients with NSCLC. ? The critical goals of modern RT are to maximize tumor control and to minimize treatment toxicity. A minimum technologic standard is CTplanned 3D-CRT.1 ? More advanced technologies are appropriate when needed to deliver curative RT safely. These technologies include (but are not limited to) 4D-CT and/or PET-CT simulation, IMRT/VMAT, IGRT, motion management, and proton therapy. Nonrandomized comparisons of using advanced technologies versus older techniques demonstrate reduced toxicity and improved survival.2-4 ? Centers using advanced technologies should implement and document modality-specific quality assurance measures. The ideal is external credentialing of both treatment planning and delivery such as required for participation in RTOG clinical trials employing advanced technologies. Useful references include the ACR-ASTRO Practice Guidelines for Radiation Oncology (http://www.acr.org/~/media/ACR/Documents/PGTS/toc.pdf). Early-Stage NSCLC (Stage I) ? SABR (also known as SBRT) is recommended for patients who are medically inoperable and who refuse to have surgery after thoracic surgery evaluation. SABR has achieved primary tumor control rates and overall survival, comparable to lobectomy and higher than 3D-CRT in nonrandomized and population-based comparisons in medically inoperable or older patients.5-10 ? SABR is also an appropriate option for patients with high surgical risk (able to tolerate sublobar resection but not lobectomy, eg, ≥ age 75 years, poor lung function). SABR and sublobar resection achieve comparable cancer-specific survival and primary tumor control.10-12 ? For institutions without an established SABR program, more modestly hypofractionated or dose-intensified conventionally fractionated 3D-CRT regimens are alternatives.13-14? ? In patients treated with surgery, postoperative radiotherapy (PORT) is not recommended unless there are positive margins or upstaging to N2 (see Locally Advanced NSCLC below). Locally Advanced NSCLC (Stagew II-III) ? The standard of care for patients with inoperable stage II and stage III is concurrent chemoRT.15-17 (http://www.acr.org/~/media/ACR/Documents/AppCriteria/Oncology/NonsurgicalTreatmentForNSCLCGoodPerformanceStatusDefinitiveIntent. pdf) RT interruptions and dose reductions for manageable acute toxicities should be avoided by employing supportive care. ? Sequential chemoRT or RT alone is appropriate for frail patients unable to tolerate concurrent therapy.18,19 (http://www.acr.org/~/media/ACR/Documents/AppCriteria/OncologyNonsurgicalTreatmentForNSCLCPoorPerformanceStatusOrPalliativeIntent. pdf)
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-C 1 of 9

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF RADIATION THERAPY (2 of 9)

NCCN Guidelines Index NSCLC Table of Contents Discussion

Locally Advanced NSCLC (Stage II-III) (continued) ? Accelerated RT regimens may be beneficial, particularly if not concurrent with chemotherapy (ie, in a sequential or RT-only approach).20,21 ? RT has a role before or after surgery. http://www.acr.org/~/media/ACR/Documents/AppCriteria/Oncology/InductionAndAdjuvantTherapyForN2NSCLC.pdf Preoperative concurrent chemoRT is an option for patients with resectable stage IIIA (minimal N2 and treatable with lobectomy)22 and is recommended for resectable superior sulcus tumors.23-24 Preoperative chemotherapy and postoperative RT is an alternative for patients with resectable stage IIIA.25,26 The determination of resectability in trimodality therapy should be made prior to initiation of all treatment. In patients with clinical stage I/II upstaged surgically to N2+, PORT appears to improve survival significantly as an adjunct to postoperative chemotherapy in non-randomized analyses.27,28 Although the optimal sequence is not established, PORT is generally administered after postoperative chemotherapy. PORT with concurrent chemotherapy can be administered safely in medically fit patients29-31 and is recommended for positive resection margins. PORT is not recommended for patients with pathologic stage N0-1 disease, because it has been associated with increased mortality, at least when using older RT techniques.32 Advanced/Metastatic NSCLC (Stage IV) ? RT is recommended for local palliation or prevention of symptoms (such as pain, bleeding, or obstruction). ? Definitive local therapy to isolated or limited metastatic sites (oligometastases) (including but not limited to brain, lung, and adrenal gland) achieves prolonged survival in a small proportion of well-selected patients with good performance status who have also received radical therapy to the intrathoracic disease. Definitive RT to oligometastases, particularly SABR, is an appropriate option in such cases if it can be delivered safely to the involved sites.33-35 ? See the NCCN Guidelines for Central Nervous System Cancers regarding RT for brain metastases. Target Volumes, Prescription Doses, and Normal Tissue Dose Constraints (See Tables 2-5 on NSCL-C 6 of 9 and NSCL-C 7 of 9) ? ICRU Reports 62 and 83 detail the current definitions of target volumes for 3D-RT and IMRT. GTV comprises the known extent of disease (primary and nodal) on imaging and pathologic assessment, CTV includes regions of presumed microscopic extent or dissemination, and PTV comprises the ITV (which includes margin for target motion) plus a setup margin for positioning and mechanical variability. http://www.rtog.org/CoreLab/ContouringAtlases/LungAtlas.aspx ? PTV margin can be decreased by immobilization, motion management, and IGRT techniques. ? Consistent delineation of normal structures is critical for evaluating plans for safety. The RTOG consensus lung-contouring atlas is a useful resource. http://www.rtog.org/CoreLab/ContouringAtlases/LungAtlas.aspx ? Commonly used prescription doses and normal tissue dose constraints are summarized in Tables 2-5. These are based on published experience, ongoing trials, historical data, modeling, and empirical judgment.37,38 Useful references include the recent reviews of normal organ dose responses from the QUANTEC project.39-43
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-C 2 of 9

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF RADIATION THERAPY (3 of 9)

NCCN Guidelines Index NSCLC Table of Contents Discussion

Node-Negative Early-Stage SABR ? The high-dose intensity and conformity of SABR require minimizing the PTV. ? For SABR, intensive regimens of BED ≥100 Gy are associated with significantly better local control and survival than less intensive regimens.44 In the United States, only regimens of ≤5 fractions meet the arbitrary billing code definition of SBRT, but slightly more protracted regimens are appropriate as well.44,45 For centrally located tumors (defined as within 2 cm of the proximal bronchial tree), 4 to 10 fraction riskadapted SABR regimens appear to be effective and safe,45,46 while 54 to 60 Gy in 3 fractions is unsafe and should be avoided.47 The dose for 5-fraction regimens is being studied prospectively in RTOG 0813. ? SABR is most commonly used for tumors up to 5 cm in size, though selected larger isolated tumors can be treated safely if normal tissue constraints are respected.48 ? Prescription doses incompletely describe the actual delivered doses, which also depend strongly on how the dose is prescribed (to the isocenter vs. an isodose volume covering a proportion of the PTV), the degree of dose heterogeneity, whether tissue density heterogeneity corrections are used, and the type of dose calculation algorithm.49,50 All of these must be considered when interpreting or emulating regimens from prior studies. Locally Advanced Stage/Conventionally Fractionated RT ? IFI omitting ENI allows tumor dose escalation and is associated with a low risk of isolated nodal relapse, particularly in PET-CT–staged patients.51-55 One randomized trial found improved survival for IFI versus ENI, possibly because it enabled dose escalation.56?IFI is reasonable in order to optimize definitive dosing to the tumor. ? The most commonly prescribed doses for definitive RT are 60 to 70 Gy in 2 Gy fractions. Doses of at least 60 Gy should be given.57 Dose escalation in RT alone,58 sequential chemoRT,59 or concurrent chemoRT60 is associated with better survival in non-randomized comparisons. Doses of up to 74 Gy with concurrent chemotherapy can be delivered safely when normal tissue dose constraints are respected.61-64 The final results from RTOG 0617, comparing 60 versus 74 Gy with concurrent chemotherapy are pending, but preliminarily, 74 Gy does not improve overall survival.65 A meta-analysis demonstrated improved survival with accelerated fractionation RT regimens,66 and individualized accelerated RT dose intensification is now being evaluated in a randomized trial (RTOG 1106). ? Doses of 45 to 50 Gy in 1.8 to 2 Gy fractions are standard preoperative doses. Definitive RT doses delivered as preoperative chemoRT can safely be administered and achieve promising nodal clearance and survival rates,67-70 but require experience in thoracic surgical techniques to minimize the risk of surgical complications after high-dose RT. ? In PORT, the CTV includes the bronchial stump and high-risk draining lymph node stations.71 Standard doses after complete resection are 50 to 54 Gy in 1.8 to 2 Gy fractions, but a boost may be administered to high-risk regions including areas of nodal extracapsular extension or microscopic positive margins.29,30 Lung dose constraints should be more conservative as tolerance appears to be reduced after surgery. The ongoing European LungART trial provides useful guidelines for PORT technique.72

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-C 3 of 9

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF RADIATION THERAPY (4 of 9)

NCCN Guidelines Index NSCLC Table of Contents Discussion

Advanced Stage/Palliative RT ? The dose and fractionation of palliative RT should be individualized based on goals of care, symptoms, performance status, and logistical considerations. Shorter courses of RT provide similar pain relief as longer courses, but with a higher potential need for retreatment,73-76 and are preferred for patients with poor performance status and/or shorter life expectancy. When higher doses (>30 Gy) are warranted, 3D-CRT should be used to reduce normal tissue irradiation. Radiation Therapy Simulation, Planning, and Delivery ? Simulation should be performed using CT scans obtained in the RT treatment position with appropriate immobilization devices. IV contrast with or without oral contrast is recommended for better target/organ delineation whenever possible in patients with central tumors or nodal disease. Because IV contrast can affect tissue heterogeneity correction calculations, density masking or use of a pre-contrast scan may be needed when intense enhancement is present. ? PET/CT significantly improves targeting accuracy,77 especially for patients with significant atelectasis and when IV CT contrast is contraindicated. A randomized trial of PET/CT versus CT-only RT planning demonstrated improved preemption of futile radical RT, decreased recurrences, and a trend toward improved overall survival with PET/CT RT planning.77 Given the potential for rapid progression of NSCLC,79,80 PET/CT should be obtained preferably within 4 weeks before treatment. It is ideal to obtain PET/CT in the treatment position. ? Tumor and organ motion, especially owing to breathing, should be assessed or accounted for at simulation. Options include fluoroscopy, inhale/exhale or slow scan CT, or, ideally, 4D-CT. ? Photon beam energy should be individualized based on the anatomic location of the tumors and beam paths. In general, photon energies between 4 to 10 MV are recommended for beams passing through low-density lung tissue before entering the tumor. When there is no air gap before the beam enters the tumor (such as for some large mediastinal tumors or tumors attached to chest wall), higher energies may improve the dose distribution, especially when using a smaller number of fixed beam angles. ? Tissue heterogeneity correction and accurate dose calculation algorithms that account for buildup and lateral electron scatter effects in heterogeneous density tissues are recommended. Heterogeneity correction with simple pencil beam algorithms is not recommended.50 ? Respiratory motion should be managed when motion is excessive. This includes (but is not limited to) forced shallow breathing with abdominal compression, accelerator beam gating with the respiratory cycle, dynamic tumor tracking, active breathing control (ABC), or coaching/biofeedback techniques. If motion is minimal or the ITV is small, motion-encompassing targeting is appropriate. A useful resource for implementation of respiratory motion management is the report of AAPM Task Group 76.81 ? IGRT—including (but not limited to) orthogonal pair planar imaging and volumetric imaging (such as CBCT or CT on rails)—is recommended when using SABR and 3D-CRT/IMRT with steep dose gradients around the target, when OARs are in close proximity to high-dose regions, and when using complex motion management techniques.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-C 4 of 9

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF RADIATION THERAPY (5 of 9) Table 1. Commonly Used Abbreviations in Radiation Therapy RT 2D-RT 4D-CT AAPM ABC ACR ASTRO BED CBCT CTV* DVH ENI GTV* ICRU Radiation Therapy or Radiotherapy 2-Dimensional RT  -Dimensional Computed 4 Tomography  merican Association of Physicists A in Medicine Active Breathing Control American College of Radiology  merican Society for Radiation A Oncology Biologically Effective Dose Cone-Beam CT Clinical Target Volume Dose-Volume Histogram Elective Nodal Irradiation Gross Tumor Volume nternational Commission on I Radiation Units and Measurements IFI IGRT IMRT ITV* MLD OAR OBI PORT PTV* Involved Field Irradiation Image-Guided RT Intensity-Modulated RT Internal Target Volume Mean Lung Dose Organ at Risk On-Board Imaging Postoperative RT Planning Target Volume

NCCN Guidelines Index NSCLC Table of Contents Discussion

3D-CRT 3-Dimensional Conformal RT

QUANTEC Q  uantitative Analysis of Normal Tissue Effects in the Clinic RTOG SABR V20 VMAT Radiation Therapy Oncology Group  tereotactic Ablative RT, also known as S Stereotactic Body RT (SBRT) % Volume of an OAR receiving ≥20 Gy Volumetric Modulated Arc Therapy

*Refer to ICRU Report 83 for detailed definitions.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-C 5 of 9

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF RADIATION THERAPY (6 of 9) Table 2. Commonly Used Doses for SABR Total Dose 25-34 Gy # Fractions Example Indications 1  eripheral, small (<2 cm) P tumors, esp. >1 cm from chest wall Peripheral tumors and >1 cm from chest wall  entral or peripheral tumors C <4-5 cm, especially <1 cm from chest wall  entral or peripheral tumors, C especially <1 cm from chest wall Central tumors Table 3. Maximum Dose Constraints for SABR* OAR/Regimen 1 Fraction Spinal Cord Esophagus Brachial Plexus Heart/ Pericardium Great Vessels Trachea & Proximal Bronchi Rib Skin Stomach 14 Gy 15.4 Gy 17.5 Gy 22 Gy 37 Gy 20.2 Gy 3 Fractions 18 Gy (6 Gy/fx) 30 Gy (10 Gy/fx) 21 Gy (7 Gy/fx) 30 Gy (10 Gy/fx) 39 Gy (13 Gy/fx) 30 Gy (10 Gy/fx) 30 Gy (10 Gy/fx) 30 Gy (10 Gy/fx) 27 Gy (9 Gy/fx)

NCCN Guidelines Index NSCLC Table of Contents Discussion

4 Fractions 26 Gy (6.5 Gy/fx) 30 Gy (7.5 Gy/fx) 27.2 Gy (6.8 Gy/fx) 34 Gy (8.5 Gy/fx) 49 Gy (12.25 Gy/fx) 34.8 Gy (8.7 Gy/fx) 30 Gy (7.5 Gy/fx) 36 Gy (9 Gy/fx) 30 Gy (7.5 Gy/fx)

5 Fractions 30 Gy (6 Gy/fx) 32.5 Gy (6.5 Gy/fx) 30 Gy (6 Gy/fx) 35 Gy (7 Gy/fx) 55 Gy (11 Gy/fx) 32.5 Gy (6.5 Gy/fx) 32.5 Gy (6.5 Gy/fx) 40 Gy (8 Gy/fx) 35 Gy (7 Gy/fx)

45-60 Gy 48-50 Gy

3 4

50-55 Gy

5

60-70 Gy

8-10

30 Gy 26 Gy 12.4 Gy

*Based on constraints used in recent and ongoing RTOG SABR trials (RTOG 0618, 0813, & 0915).
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-C 6 of 9

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF RADIATION THERAPY (7 of 9) Table 4. Commonly Used Doses for Conventionally Fractionated and Palliative RT Treatment Type Definitive RT with or without chemotherapy Preoperative RT Postoperative RT ? Negative margins ? Extracapsular nodal extension or microscopic positive margins ? Gross residual tumor Palliative RT ? Obstructive disease (SVC syndrome or obstructive pneumonia) ? Bone metastases with soft tissue mass ? Bone metastases without soft tissue mass ? Brain metastases ? Symptomatic chest disease in patients with poor PS ? Any metastasis in patients with poor PS Total Dose 60-74 Gy 45-50 Gy 50-54 Gy 54-60 Gy 60-70 Gy 30-45 Gy 20-30 Gy 8-30 Gy CNS GLs 17 Gy 8-20 Gy Fraction Size 2 Gy 1.8-2 Gy 1.8-2 Gy 1.8-2 Gy 2 Gy 3 Gy 4-3 Gy 8-3 Gy CNS GLs 8.5 Gy 8-4 Gy Treatment Duration 6-7.5 weeks 5 weeks 5-6 weeks 6 weeks 6-7 weeks 2-3 weeks 1-2 weeks 1 day-2 weeks CNS GLs 1-2 weeks 1 day-1 week

NCCN Guidelines Index NSCLC Table of Contents Discussion

Table 5. Normal Tissue Dose-Volume Constraints for Conventionally Fractionated RT OAR Spinal cord Lung Heart Esophagus Constraints in 30-35 Fractions Max ≤50 Gy V20 ≤35%; V5 ≤65%; MLD ≤20 Gy V40 ≤80%; V45 ≤60%; V60 ≤30%; Mean ≤35 Gy Mean ≤34 Gy; Max ≤105% of prescription dose

Brachial plexus Max ≤66 Gy
Vxx = % of the whole OAR receiving ≥xx Gy.

Figure 1. ICRU Report 62 Schema of Target Volume Definitions
T he arrow illustrates the influence of the organs at risk on delineation of the PTV (thick, full line)

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-C 7 of 9

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF RADIATION THERAPY - References (8 of 9)
1Chen AB, Neville BA, Sher DJ, et al. Survival outcomes after radiation therapy for stage III non-small-cell lung

NCCN Guidelines Index NSCLC Table of Contents Discussion

cancer after adoption of computed tomography-based simulation. J Clin Oncol 2011;29:2305-2311. 2Liao ZX, Komaki RR, Thames HD, et al. Influence of Technologic Advances on Outcomes in Patients With Unresectable, Locally Advanced Non-Small-Cell Lung Cancer Receiving Concomitant Chemoradiotherapy. Int J Radiat Oncol Biol Phys 2010; 76:775-781. 3Sejpal S, Komaki R, Tsao A, et al. Early findings on toxicity of proton beam therapy with concurrent chemotherapy for nonsmall cell lung cancer. Cancer 2011; 117:3004-3013. 4Chang JY, Komaki R, Lu C, et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer. Cancer 2011;117:4707-4713. 5Timmerman R, Paulus R, Galvin J, et al. Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer. JAMA 2010; 303:1070-1076. 6Baumann P, Nyman J, Hoyer M, et al. Outcome in a prospective phase II trial of medically inoperable stage I nonsmall-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 2009; 27:3290-3296. 7Onishi H, Shirato H, Nagata Y, et al. Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery? Int J Radiat Oncol Biol Phys 2011;81:1352-1358. 8Grutters JPC, Kessels AGH, Pijls-Johannesma M, et al. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis. Radiother Oncol 2010; 95:32-40. 9Palma D, Visser O, Lagerwaard FJ, et al. Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non-small-cell lung cancer: a population-based time-trend analysis. J Clin Oncol 2010; 28:5153-5159. 10Shirvani SM, Jiang J, Chang JY, et al. Comparative effectiveness of 5 treatment strategies for early-stage nonsmall cell lung cancer in the elderly. Int J Radiat Oncol Biol Phys 2012;84:1060-1070. 11Grills IS, Mangona VS, Welsh R, et al. Outcomes After Stereotactic Lung Radiotherapy or Wedge Resection for Stage I Non-Small-Cell Lung Cancer. J Clin Oncol 2010;28:928-935. 12Crabtree TD, Denlinger CE, Meyers BF, et al. Stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 2010; 140:377-386. 13Bogart JA, Hodgson L, Seagren SL, et al. Phase I study of accelerated conformal radiotherapy for stage I nonsmall-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904. J Clin Oncol 2010; 28:202-206. 14Zhao L, West BT, Hayman JA, et al. High radiation dose may reduce the negative effect of large gross tumor volume in patients with medically inoperable early-stage non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2007; 68:103-110. 15Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010; 28:2181-2190. 16O'Rourke N, Roqué I Figuls M, Farré Bernadó N, Macbeth F. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010:CD002140. 17Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 2011;103:1452-1460. 18Sause W, Kolesar P, Taylor S IV, et al. Final results of phase III trial in regionally advanced unresectable nonsmall cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 2000; 117:358-364. 19Dillman RO, Herndon J, Seagren SL, et al. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996; 88:1210-1215. 20Baumann M, Herrmann T, Koch R, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol 2011;100:76-85. 21Mauguen A, Le Péchoux C, Saunders MI, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol 2012;30:2788-2797. 22Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009; 374:379-386. 23Kunitoh H, Kato H, Tsuboi M, et al. Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806. J Clin Oncol 2008; 26:644-649.

24Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small25Thomas M, Rube C, Hoffknecht P, et al. Effect of preoperative chemoradiation in addition to preoperative

cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007; 25:313-318. chemotherapy: a randomized trial in stage III non-small-cell lung cancer. Lancet Oncol 2008;9:607-608.

26Higgins K, Chino JP, Marks LB, et al. Preoperative chemotherapy versus preoperative chemoradiotherapy for stage III 27Douillard J-Y, Rosell R, De Lena M, et al. Impact of postoperative radiation therapy on survival in patients with complete 28Lally BE, Zelterman D, Colasanto JM, et al. Postoperative radiotherapy for stage II or III non-small-cell lung cancer 29Feigenberg SJ, Hanlon AL, Langer C, et al. A phase II study of concurrent carboplatin and paclitaxel and thoracic

(N2) non-small-cell lung cancer. Int J Radiat Biol Phys 2009;75:1462-1467.

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. using the surveillance, epidemiology, and end results database. J Clin Oncol 2006; 24:2998-3006.

30Bradley JD, Paulus R, Graham MV, et al. Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic 31Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant therapy in patients with completely 32Burdett S, Stewart L, Group PM-a. Postoperative radiotherapy in non-small-cell lung cancer: update of an individual 33Milano MT, Katz AW, Okunieff P. Patterns of recurrence after curative-intent radiation for oligometastases confined to 34Rusthoven KE, Kavanagh BD, Burri SH, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for 35Salama JK, Chmura SJ, Mehta N, et al. An initial report of a radiation dose-escalation trial in patients with one to five 36Kong FM, Ritter T, Quint DJ, et al. Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, 37Kong FM, Pan C, Eisbruch A, Ten Haken RK. Physical models and simpler dosimetric descriptors of radiation late 38Timmerman RD. An overview of hypofractionation and introduction to this issue of seminars in radiation oncology. 39Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue complication probability models in the clinic. Int J Radiat 40Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys 2010; 41Werner-Wasik M, Yorke E, Deasy J, et al. Radiation dose-volume effects in the esophagus. Int J Radiat Oncol Biol Phys 42Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys 43Kirkpatrick JP, van der Kogel AJ, Schultheiss TE. Radiation dose-volume effects in the spinal cord. Int J Radiat Oncol 44Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell 45Lagerwaard FJ, Haasbeek CJA, Smit EF, et al. Outcomes of risk-adapted fractionated stereotactic radiotherapy for

radiotherapy for completely resected stage II and IIIA non-small cell lung cancer. J Thorac Oncol 2007; 2:287-292. 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.

resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med 2000; 343:1217-1222. patient data meta-analysis. Lung Cancer 2005; 47:81-83.

one organ. Am J Clin Oncol 2010; 33:157-163.

lung metastases. J Clin Oncol 2009; 27:1579-1584.

sites of metastatic disease. Clin Cancer Res 2008; 14:5255-5259.

proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus. Int J Radiat Oncol Biol Phys 2011;81:14421457. toxicity. Semin Radiat Oncol 2007; 17:108-120. Semin Radiat Oncol 2008; 18:215-222.

Oncol Biol Phys 2010; 76:S10-19.

76:S70-76.

2010; 76:S86-93.

2010; 76:S77-85.

Biol Phys 2010; 76:S42-49.

lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol 2007; 2:S94-100. stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008; 70:685-692.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-C 8 of 9

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
PRINCIPLES OF RADIATION THERAPY - References (9 of 9)
46Chang JY, Balter PA, Dong L, et al. Stereotactic body radiation therapy in centrally and superiorly located stage I

NCCN Guidelines Index NSCLC Table of Contents Discussion

or isolated recurrent non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008; 72:967-971. 47Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 2006; 24:4833-4839. 48Fakiris 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. 49Xiao Y, Papiez L, Paulus R, et al. Dosimetric evaluation of heterogeneity corrections for RTOG 0236: stereotactic body radiotherapy of inoperable stage I-II non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2009; 73:1235-1242. 50Liu MB, Eclov NC, Trakul N, et al. Clinical impact of dose overestimation by effective path length calculation in stereotactic ablative radiation therapy of lung tumors. Practical Radiation Oncology 2012 In press. 51Belderbos JS, Kepka L, Kong FM, et al. Report from the International Atomic Energy Agency (IAEA) consultants’ meeting on elective nodal irradiation in lung cancer: non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 2008;72:335-342.. 52Bradley J, Bae K, Choi N, et al. A phase II comparative study of gross tumor volume definition with or without PET/CT fusion in dosimetric planning for non-small-cell lung cancer (NSCLC): primary analysis of radiation therapy oncology group (RTOG) 0515. Int J Radiat Oncol Biol Phys 2012;82:435-441. 53Sanuki-Fujimoto N, Sumi M, Ito Y, et al. Relation between elective nodal failure and irradiated volume in non-smallcell lung cancer (NSCLC) treated with radiotherapy using conventional fields and doses. Radiother Oncol 2009; 91:433-437. 54Sulman EP, Komaki R, Klopp AH, et al. Exclusion of elective nodal irradiation is associated with minimal elective nodal failure in non-small cell lung cancer. Radiat Oncol 2009; 4:5-11. 55Rosenzweig KE, Sura S, Jackson A, Yorke E. Involved-field radiation therapy for inoperable non small-cell lung cancer. J Clin Oncol 2007; 25:5557-5561. 56Yuan S, Sun X, Li M, et al. A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer. Am J Clin Oncol 2007; 30:239-244. 57Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Report by the Radiation Therapy Oncology Group. Cancer 1987; 59:1874-1881. 58Kong FM, Ten Haken RK, Schipper MJ, et al. High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys 2005; 63:324-333. 59Rengan R, Rosenzweig KE, Venkatraman E, et al. Improved local control with higher doses of radiation in largevolume stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004; 60:741-747. 60Machtay M, Bae K, Movsas B, et al. Higher biologically effective dose of radiotherapy is associated with improved Outcomes for Locally Advanced Non-Small Cell Lung Carcinoma Treated with Chemoradiation: An Analysis of the radiation therapy oncology group. Int J Radiat Oncol Biol Phys 2012;82:425-434. 61Schild SE, McGinnis WL, Graham D, et al. Results of a Phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2006; 65:1106-1111. 62Socinski MA, Blackstock AW, Bogart JA, et al. Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol 2008; 26:2457-2463. 63Stinchcombe TE, Lee CB, Moore DT, et al. Long-term follow-up of a phase I/II trial of dose escalating threedimensional conformal thoracic radiation therapy with induction and concurrent carboplatin and paclitaxel in unresectable stage IIIA/B non-small cell lung cancer. J Thorac Oncol 2008; 3:1279-1285.

64Bradley JD, Bae K, Graham MV, et al. Primary analysis of the phase II component of a phase I/II dose intensification 65Bradley JD, Paulus R, Komaki R, et al. A randomized phase III comparison of standard-dose (60 Gy) versus high66Maugen A, Le Pechoux C, Saunders M, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an

study using three-dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117. J Clin Oncol 2010; 28:2475-2480.

dose (74 Gy) conformal chemoradiotherapy +/- cetuximab for stage III non-small cell lung cancer: results on radiation dose in RTOG 0617. J Clin Oncol 2013;31(suppl; abstr 7501). individual patient data meta-analysis. J Clin Oncol 2012;30:2788-2797.

67Cerfolio RJ, Bryant AS, Jones VL, Cerfolio RM. Pulmonary resection after concurrent chemotherapy and high dose 68Kwong KF, Edelman MJ, Suntharalingam M, et al. High-dose radiotherapy in trimodality treatment of Pancoast

(60Gy) radiation for non-small cell lung cancer is safe and may provide increased survival. Eur J Cardiothorac Surg 2009; 35:718-723; discussion 723. tumors results in high pathologic complete response rates and excellent long-term survival. J Thorac Cardiovasc Surg 2005; 129:1250-1257. and concurrent chemotherapy in non-small-cell lung cancer. Ann Thorac Surg 2004; 78:1200-1205.

69Sonett JR, Suntharalingam M, Edelman MJ, et al. Pulmonary resection after curative intent radiotherapy (>59 Gy) 70Suntharalingam M, Paulus R, Edelman MJ, et al. Radiation therapy oncology group protocol 02-29: a phase II

trial of neoadjuvant therapy with concurrent chemotherapy and full-dose radiation therapy followed by surgical resection and consolidative therapy for locally advanced non-small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 2012;84:456-463. 71Kelsey CR, Light KL, Marks LB. Patterns of failure after resection of non-small-cell lung cancer: implications for postoperative radiation therapy volumes. Int J Radiat Oncol Biol Phys 2006; 65:1097-1105. 72Spoelstra FOB, Senan S, Le Péchoux C, et al. Variations in target volume definition for postoperative radiotherapy in stage III non-small-cell lung cancer: analysis of an international contouring study. Int J Radiat Oncol Biol Phys 2010; 76:1106-1113. 73Chow E, Harris K, Fan G, et al. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 2007; 25:1423-1436. 74Lutz 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. 75Cross 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. 76Medical Research Council Lung Cancer Working Party. 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 Canc 1992; 65:934-941. 77MacManus M, Nestle U, Rosenzweig KE, et al. Use of PET and PET/CT for radiation therapy planning: IAEA expert report 2006-2007. Radiother Oncol 2009; 91:85-94. 78Ung YC, Gu C-S, Cline K, et al. An Ontario Clinical Oncology Group (OCOG) randomized trial (PET START) of FDG PET/CT in patients with stage 3 non-small cell lung cancer (NSCLC): impact of PET on radiation treatment volumes [Abstract]. J Thorac Oncol 2011; 6:S428. 79Everitt S, Herschtal A, Callahan J, et al. High rates of tumor growth and disease progression detected on serial pretreatment fluorodeoxyglucose-positron emission tomography/computed tomography scans in radical radiotherapy candidates with nonsmall cell lung cancer. Cancer 2010;116:5030-5037. 80Mohammed N, Kestin LL, Grills IS, et al. Rapid disease progression with delay in treatment of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011; 79:466-472. 81Keall PJ, Mageras GS, Balter JM, et al. The management of respiratory motion in radiation oncology report of AAPM Task Group 76. Med Phys 2006;33:3874-3900.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-C 9 of 9

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CHEMOTHERAPY REGIMENS FOR NEOADJUVANT AND ADJUVANT THERAPY

NCCN Guidelines Index NSCLC Table of Contents Discussion

? Cisplatin 50 mg/m2 days 1 and 8; vinorelbine 25 mg/m2 days 1, 8, 15, 22, every 28 days for 4 cyclesa ? Cisplatin 100 mg/m2 day 1; vinorelbine 30 mg/m2 days 1, 8, 15, 22; every 28 days for 4 cyclesb,c ? Cisplatin 75-80 mg/m2 day 1; vinorelbine 25-30 mg/m2 days 1 + 8, every 21 days for 4 cycles ? Cisplatin 100 mg/m2 day 1; etoposide 100 mg/m2 days 1-3, every 28 days for 4 cyclesb ? Cisplatin 80 mg/m2 days 1, 22, 43, 64; vinblastine 4 mg/m2 days 1, 8, 15, 22, 29 then every 2 wks after day 43, every 21 days for 4 cyclesb ? Cisplatin 75 mg/m2 day 1; gemcitabine 1250 mg/m2 days 1, 8, every 21 days for 4 cycles ? Cisplatin 75 mg/m2 day 1; docetaxel 75 mg/m2 day 1 every 21 days for 4 cyclesd ? Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1 for adenocarcinoma and large cell carcinoma and NSCLC NOS (without specific histologic subtype) every 21 days for 4 cycles Chemotherapy Regimens for patients with comorbidities or patients not able to tolerate cisplatin Paclitaxel 200 mg/m2 day 1, carboplatin AUC 6 day 1, every 21 dayse

aWinton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-lung cancer. N Engl J Med 2005;352:2589-2597. bArriagada R, Bergman B, Dunant A, et al. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients

with completely resected non-small cell lung cancer. N Engl J Med 2004;350:351-360. cDouillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006;7:719-727. dFossella 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. eStrauss GM, Herndon III JE, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008;26:50435051.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-D

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CHEMOTHERAPY REGIMENS USED WITH RADIATION THERAPY

NCCN Guidelines Index NSCLC Table of Contents Discussion

Concurrent Chemotherapy/RT Regimens ? Cisplatin 50 mg/m2 on days 1, 8, 29, and 36; etoposide 50 mg/m2 days 1-5, 29-33; concurrent thoracic RTa (preferred)* ? Cisplatin 100 mg/m2 days 1 and 29; vinblastine 5 mg/m2/weekly x 5; concurrent thoracic RTb (preferred) ? Carboplatin AUC 5 on day 1, pemetrexed 500 mg/m2 on day 1 every 21 days for 4 cycles; concurrent thoracic RTc (nonsquamous) ? Cisplatin 75 mg/m2 on day 1, pemetrexed 500 mg/m2 on day 1 every 21 days for 3 cycles; concurrent thoracic RTd (nonsquamous) Sequential Chemotherapy/RT Regimens ? Cisplatin 100 mg/m2 on days 1 and 29; vinblastine 5 mg/m2/weekly on days 1, 8, 15, 22, and 29; followed by RTb ? Paclitaxel 200 mg/m2 over 3 hours on day 1; carboplatin AUC 6 over 60 minutes on day 1 every 3 weeks for 2 cycles followed by thoracic RTe Concurrent Chemotherapy/RT Followed by Chemotherapy ? Paclitaxel 45-50 mg/m2 weekly; carboplatin AUC 2, concurrent thoracic RT followed by 2 cycles of paclitaxel 200 mg/m2 and carboplatin AUC 6e ? Cisplatin 50 mg/m2 on days 1, 8, 29, and 36; etoposide 50 mg/m2 days 1-5, 29-33; concurrent thoracic RT followed by cisplatin 50 mg/m2 and etoposide 50 mg/m2 x 2 additional cycles (category 2B)a

* This regimen can be used as neoadjuvant chemoradiotherapy. Cisplatin and etoposide is the preferred regimen. If weekly carboplatin and paclitaxel is used because the patient is not able to tolerate concurrent full-dose cisplatin and radiotherapy, the treating physician should consider 2 cycles of full-dose platinum therapy after local treatment is completed.
aAlbain

KS, Crowley JJ, Turrisi AT III, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: A Southwest Oncology Group Phase II Study, SWOG 9019. J Clin Oncol 2002;20:3454-3460. bCurran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103:1452-1460. cGovindan R, Bogart J, Stinchcombe T, et al. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol 2011;29:3120-3125. dVokes EE, Senan S, Treat JA, Iscoe NA. PROCLAIM: A phase III study of pemetrexed, cisplatin, and radiation therapy followed by consolidation pemetrexed versus etoposide, cisplatin, and radiation therapy followed by consolidation cytotoxic chemotherapy of choice in locally advanced stage III non-small-cell lung cancer of other than predominantly squamous cell histology. Clin Lung Cancer 2009;10:193-198. eBelani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005;23:5883-5891.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-E

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE (1 OF 3)

NCCN Guidelines Index NSCLC Table of Contents Discussion

ADVANCED DISEASE: ? The drug regimen with the highest likelihood of benefit with toxicity deemed acceptable to both the physician and the patient should be given as initial therapy for advanced lung cancer. ? Stage, weight loss, performance status, and gender predict survival. ? Platinum-based chemotherapy prolongs survival, improves symptom control, and yields superior quality of life compared to best supportive care. ? Histology of NSCLC is important in the selection of systemic therapy. ? New agent/platinum combinations have generated a plateau in overall response rate (≈ 25%-35%), time to progression (4-6 mo), median survival (8-10 mo), 1-year survival rate (30%-40%), and 2-year survival rate (10%-15%) in fit patients. ? Unfit of any age (performance status 3-4) do not benefit from cytotoxic treatment, except erlotinib for EGFR mutation-positive patients. First-line therapy ? Bevacizumab + chemotherapy or chemotherapy alone is indicated in PS 0-1 patients with advanced or recurrent NSCLC. Bevacizumab should be given until disease progression. ? Cetuximab + vinorelbine/cisplatin is an option for patients with performance status 0-1 (category 2B). ? Erlotinib is recommended as a first-line therapy in patients with sensitizing EGFR mutations and should not be given as first-line therapy to patients negative for these EGFR mutations or with unknown EGFR status. ? Afatinib is indicated for select patients with sensitizing EGFR mutations. ? Crizotinib is indicated for select patients with ALK rearrangements. ? There is superior efficacy and reduced toxicity for cisplatin/pemetrexed in patients with nonsquamous histology, in comparison to cisplatin/gemcitabine. ? There is superior efficacy for cisplatin/gemcitabine in patients with squamous histology, in comparison to cisplatin/pemetrexed. ? Two drug regimens are preferred; a third cytotoxic drug increases response rate but not survival. ? Single-agent therapy or platinum-based combinations are a reasonable alternative in PS 2 patients or the elderly. ? Cisplatin or carboplatin have been proven effective in combination with any of the following agents: paclitaxel, docetaxel, gemcitabine, etoposide, vinblastine, vinorelbine, pemetrexed, or albumin-bound paclitaxel. ? New agent/non-platinum combinations are reasonable alternatives if available data show activity and tolerable toxicity (eg, gemcitabine/docetaxel, gemcitabine/vinorelbine).

See Maintenance Chemotherapy, Second- and Third-line therapy NSCL-F (2 of 3)
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-F 1 of 3

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE (2 OF 3)

NCCN Guidelines Index NSCLC Table of Contents Discussion

Maintenance Therapy Continuation maintenance refers to the use of at least one of the agents given in first line, beyond 4-6 cycles, in the absence of disease progression. Switch maintenance refers to the initiation of a different agent, not included as part of the first-line regimen, in the absence of disease progression, after 4-6 cycles of initial therapy. ? Continuation Maintenance: Bevacizumab and cetuximab given in combination with chemotherapy should be continued until evidence of disease progression or unacceptable toxicity, as per the design of the clinical trials supporting their use. Continuation of bevacizumab after 4-6 cycles of platinum-doublet chemotherapy and bevacizumab (category 1). Continuation of cetuximab after 4-6 cycles of cisplatin, vinorelbine, and cetuximab (category 1). Continuation of pemetrexed after 4-6 cycles of cisplatin and pemetrexed chemotherapy, for patients with histologies other than squamous cell carcinoma (category 1). Continuation of bevacizumab + pemetrexed after 4 to 6 cycles of bevacizumab, pemetrexed, cisplatin/carboplatin, for patients with histologies other than squamous cell carcinoma. Continuation of gemcitabine after 4-6 cycles of platinum-doublet chemotherapy (category 2B). ? Switch Maintenance: Two studies have shown a benefit in progression-free and overall survival with the initiation of pemetrexed or erlotinib after first-line chemotherapy, in patients without disease progression after 4-6 cycles of therapy. Initiation of pemetrexed after 4-6 cycles of first-line platinum-doublet chemotherapy, for patients with histologies other than squamous cell carcinoma (category 2B). Initiation of erlotinib after 4-6 cycles of first-line platinum-doublet chemotherapy (category 2B). Initiation of docetaxel after 4-6 cycles of first-line platinum-doublet chemotherapy in patients with squamous cell carcinoma (category 2B). ? Close surveillance of patients without therapy is a reasonable alternative to maintenance. Second-line therapy ? In patients who have experienced disease progression either during or after first-line therapy, single-agent docetaxel, pemetrexed, or erlotinib are established second-line agents. Docetaxel is superior to vinorelbine or ifosfamide. Pemetrexed is considered equivalent to docetaxel with less toxicity in patients with adenocarcinoma and large cell carcinoma. Erlotinib is superior to best supportive care. Afatinib is indicated for select patients with sensitizing EGFR mutations. Third-line therapy ? If not already given, options for PS 0-2 include docetaxel, pemetrexed (nonsquamous), erlotinib, or gemcitabine (category 2B for all options). Continuation After Disease Progression ? With the exception of targeted agents (erlotinib, gefitinib, afatinib, crizotinib) in patients with EGFR sensitizing mutations or ALK rearrangements who have experienced objective regressions with targeted therapy, no agent should be continued after disease progression has been documented except in selected situations. (refer to discussion section) See Specific Systemic Agents on page NSCL-F (3 of 3)
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-F 2 of 3

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer

NCCN Guidelines Index NSCLC Table of Contents Discussion

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE (3 OF 3) Agents listed below are used in the treatment of patients with NSCLC. Most are used in combination, while others are used as monotherapy (eg, maintenance or second-line therapy). ? Cisplatin1-9 ? Carboplatin4,6-11 ? Paclitaxel1,4,6,8-11 ? Docetaxel5,7,8,12,13 ? Vinorelbine7,9,10
1Bonomi

? Gemcitabine3,5,6,8,9,13 ? Etoposide4 ? Irinotecan9 ? Vinblastine ? Mitomycin

? Ifosfamide12 ? Pemetrexed14,15 ? Erlotinib16 ? Bevacizumab17 ? Cetuximab18
13Pujol

? Albumin-bound paclitaxel19-21 ? ? Crizotinib22 ? Afatinib23

P, Kim K, Fairclough D, et al. Comparison of survival and quality of life in advanced non-small cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin:results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000;18:623-631. 2Wozniak AJ, Crowley JJ, Balcerzak SP, et al. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small cell lung cancer: A Southwest Oncology Group Study. J Clin Oncol 1998;16:2459-2465. 3Cardenal F, Lopez-Cabrerizo MP, Anton A, et al. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 1999;17:12-18. 4Belani CP, Lee JS, Socinski MA, et al. Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer. Ann Oncol 2005;16:10691075. 5Sandler AB, Nemunaitis J, Denham C, et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 2000;18:122-130. 6Smit 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. 7Fossella F, Periera 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(16):3016-3024. 8Schiller 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. 9Ohe 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 nonsmall-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007;18:317-323. 10Kelly K, Crowley J, Bunn PA, 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. 11Belani CP, Ramalingam S, Perry MC, et al. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol 2008;26:468-473. 12Fossella 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 platinumcontaining chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354-2362.

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. 14Hanna NH, Sheperd FA, Fossella FV, et al. Randomized phase III study of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589-1597. 15Scagliotti 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 NSCLC. J Clin Oncol 2008;26:3543-3551. 16Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32. 17Sandler AB, 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. 18Pirker R, Periera JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced nonsmall-cell lung cancer (FLEX): an open label randomised phase III trial. Lancet 2009;373:1525-1531. 19Green M, Manikhas G, 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;17:12631268. 20Rizvi N, Riely G, Azzoli, C, 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. 21Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small cell lung cancer: final results of a phase III trial. J Clin Oncol 2012:30:2055-2062. 22Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 2011;12:1004-1012. 23Sequist LV, Yang JC-H, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;published ahead of print on July 1, 2013. ?Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in patients who have experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despite premedication, or for patients where the standard premedications (dexamethasone, H2 blockers, H1 blockers) are contraindicated.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
? ?

NSCL-F 3 of 3

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Cell Lung Cancer
CANCER SURVIVORSHIP CARE NSCLC Long-term Follow-up Care ? Cancer Surveillance H&P and a chest CT scan ± contrast every 6-12 months for 2 years, then H&P and a non-contrast-enhanced chest CT scan annually Smoking status assessment at each visit; counseling and referral for cessation as needed. ? Immunizations Annual influenza vaccination, herpes zoster vaccine Pneumococcal vaccination with revaccination as appropriate Counseling Regarding Health Promotion and Wellness1 ? Maintain a healthy weight ? Adopt a physically active lifestyle (Regular physical activity: 30 minutes of moderate-intensity physical activity on most days of the week) ? Consume a healthy diet with emphasis on plant sources ? Limit consumption of alcohol if one consumes alcoholic beverages

NCCN Guidelines Index NSCLC Table of Contents Discussion

Additional Health Monitoring ? Routine blood pressure, cholesterol, and glucose monitoring ? Bone health: Bone density testing as appropriate ? Dental health: Routine dental examinations ? Routine sun protection Resources ? National Cancer Institute Facing Forward: Life After Cancer Treatment http://www.cancer.gov/cancertopics/life-after-treatment/allpages Cancer Screening Recommendations2,3 These recommendations are for average-risk individuals and high-risk patients should be individualized. ? Colorectal Cancer: See NCCN Guidelines for Colorectal Cancer Screening ? Prostate Cancer: See NCCN Guidelines for Prostate Cancer Early Detection ? Breast Cancer: See NCCN Guidelines for Breast Cancer Screening

1ACS

Guidelines on Nutrition and Physical Activity for Cancer Prevention: http://www.cancer.org/docroot/PED/content/PED_3_2X_Diet_and_Activity_Factors_That_Affect_Risks.asp?sitearea=PED (Accessed November 30, 2012) 2Memorial Sloan-Kettering Cancer Center Screening Guidelines: http://www.mskcc.org/mskcc/html/65279.cfm (Accessed November 30, 2012) 3American Cancer Society Guidelines for Early Detection of Cancer: http://www.cancer.org/docroot/PED/content/PED_2_3X_ACS_Cancer_Detection_Guidelines_36.asp?sitearea=PED (Accessed November 30, 2012)
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2014, 1/24/14 ? National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines? and this illustration may not be reproduced in any form without the express written permission of NCCN?.

NSCL-G

Printed by jiang long on 3/5/2014 3:31:37 AM. For personal use only. Not approved for distribution. Copyright ? 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 3.2014 Non-Small Ce

赞助商链接
相关文章:
NCCN指南解读非小细胞肺癌2016更新汇总
2016 年第 3 版 NCCN 非小细胞肺癌指南 (V3. 2016) 在 V2.2016 基础 上主要进行了以下部分的更新: ALK 阳性肿瘤药物新药获批 ?NSLC-18: ? ALK 阳性肺癌...
NCCN指南:非小细胞肺癌的全身治疗(2015第六版)
NCCN指南:非小细胞肺癌的全身治疗(2015第六版)_临床医学_医药卫生_专业资料。NCCN 指南:非小细胞肺癌的全身治疗(2015 第六版)医脉通 2015-05-12 发表评论 医...
《NCCN非小细胞肺癌临床实践指南》解析 Microsoft Word...
NCCN)2011 版《非小细胞肺癌(NSCLC)临床实践指 南》(简称《指南》)发布,中国专家组也在今年 4 月召开第 4 届 NCCN 亚洲学术会 议上对《指南》(中国版...
《NCCN非小细胞肺癌临床实践指南》解析
非小细胞肺癌临床实践指南》 《NCCN 非小细胞肺癌临床实践指南》解析随着美国国立综合癌症网络(NCCN)2011 版《非小细胞肺癌(NSCLC)临床实 践指南》(简称《指南》)...
非小细胞肺癌NCCN指南更新解读
非小细胞肺癌NCCN指南更新解读_临床医学_医药卫生_专业资料。非小细胞肺癌 NCCN 指南更新解读 ? ? ? ? 发布日期: 2012-06-06 出处: 作者: 首都医科大学宣武医...
《NCCN非小细胞肺癌临床实践指南》更新
NCCN非小细胞肺癌临床实践指南》更新_临床医学_医药卫生_专业资料。《NCCN非小...九妖笑话 2014年笑话大全之让你笑个够 儿童笑话大全爆笑 爆笑笑话精选文档...
NCCN非小细胞肺癌临床实践指南主笔者David S.Ettinger简介
标题中译: 《聚焦非小细胞肺癌EGFR基因表达对实体肿瘤进展的临床意义》 标题英文...文档贡献者 wrpxsav6 贡献于2014-08-15 1/2 相关文档推荐 NCCN临床实践指南...
【NCCN2014】非小细胞肺癌治疗值得关注的四部分
NCCN2014非小细胞肺癌治疗值得关注的四部分医脉通 2014-07-11 发表评论 分享 在第19届 NCCN 年会上, Leora Horn 强调了2014NCCN NSCLC 指南中的几个...
解析2010版《NCCN非小细胞肺癌临床实践指南》
解析2010 版《NCCN 非小细胞肺癌临床实践指南》美国国立综合癌症网络(NCCN)制定临床实践指南是目前我国肿瘤诊疗 主要参考指南。随着最新非小细胞肺癌(NSCLC)循...
解析2010版《NCCN非小细胞肺癌临床实践指南》
随着最新非小细胞肺癌( 国肿瘤诊疗主要参考指南。随着最新非小细胞肺癌(NSCLC) ) 循证医学证据公布, 《NCCN 非小细胞肺癌临床实践指南(2010 非小细胞...
更多相关标签: