Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version

General Information About Non-Small Cell Lung Cancer (NSCLC)

NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histological variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who never smoked.

As a class, NSCLC is usually less sensitive to chemotherapy and radiation therapy than SCLC. Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy. Local control can be achieved with radiation therapy in many patients with unresectable disease, but cure is seen in relatively few patients. Patients with locally advanced unresectable disease may achieve long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy, targeted agents, and other supportive measures.

Incidence and Mortality

Estimated new cases and deaths from lung cancer (NSCLC and SCLC combined) in the United States in 2024:[1]

Lung cancer is the leading cause of cancer-related mortality in the United States. The 5-year relative survival rate from 2013 to 2019 for patients with lung cancer was 25%. The 5-year relative survival rate varies markedly for patients diagnosed at local stage (63%), regional stage (35%), or distant stage (8%).[1]

Anatomy

NSCLC arises from the epithelial cells of the lung of the central bronchi to terminal alveoli. The histological type of NSCLC correlates with site of origin, reflecting the variation in respiratory tract epithelium of the bronchi to alveoli. Squamous cell carcinoma usually starts near a central bronchus. Adenocarcinoma and bronchioloalveolar carcinoma usually originate in peripheral lung tissue.

Respiratory system anatomy; drawing shows the right lung with the upper, middle, and lower lobes, the left lung with the upper and lower lobes, and the trachea, bronchi, lymph nodes, and diaphragm. An inset shows the bronchioles, alveoli, artery, and vein.

Pathogenesis

Smoking-related lung carcinogenesis is a multistep process. Squamous cell carcinoma and adenocarcinoma have defined premalignant precursor lesions. Before becoming invasive, lung epithelium may undergo morphological changes that include:

Dysplasia and carcinoma in situ are considered the principal premalignant lesions because they are more likely to progress to invasive cancer and less likely to spontaneously regress.

Risk Factors

Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include the following:

The single most important risk factor for the development of lung cancer is smoking. For a smoker, the risk of lung cancer is, on average, tenfold higher than in a lifetime nonsmoker (defined as a person who has smoked

Smoking cessation results in a decrease in precancerous lesions and a reduction in lung cancer risk. Former smokers continue to have an elevated risk of lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on lung cancer risk.[17]

In addition, after resection of a lung cancer, there is a 1% to 2% risk per patient per year that a second lung cancer will occur.[18]

A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers.[19] Other studies have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers.[20]

Because of the persistent risk of developing second lung cancers in former smokers, various chemoprevention strategies have been evaluated in randomized control trials. None of the phase III trials using the agents beta carotene, retinol, 13-cis-retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results.[16,21-24][Level of evidence A1] Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early-stage lung cancer.

Screening

In patients considered at high risk of developing lung cancer, the only screening modality for early detection that has been shown to alter mortality is low-dose helical CT scanning.[25] Studies have failed to demonstrate that screening with chest radiography and sputum cytology lowers lung cancer mortality rates.

For more information, see the Screening by low-dose computed tomography: benefit section in Lung Cancer Screening.

Clinical Presentation

Lung cancer may present with symptoms or be found incidentally on chest imaging. The most common symptoms at presentation include:

Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck.

Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases. Infrequently, patients may present with symptoms and signs of paraneoplastic diseases such as hypertrophic osteoarthropathy with digital clubbing or hypercalcemia from parathyroid hormone-related protein.

Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease or pulmonary fibrosis.

Diagnosis

Investigations of patients with suspected NSCLC focus on confirming the diagnosis and determining the extent of the disease. Treatment options are determined by histology, stage, and general health and comorbidities of the patient.

The procedures used to determine the presence of cancer include:

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathological material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[26] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

For more information on tests and procedures used for staging, see the General Staging Evaluation section.

Prognostic Factors

Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathological factors.[20,27-30] Factors that have correlated with adverse prognosis include:

For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%. These patients have been excluded from clinical trials evaluating aggressive multimodality interventions.

In multiple retrospective analyses of clinical trial data, advanced age alone has not been shown to influence response or survival with therapy.[45]

Because treatment is not satisfactory for almost all patients with NSCLC, eligible patients should consider clinical trials. Information about ongoing clinical trials is available from the NCI website.

References
  1. American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024. Available online. Last accessed June 21, 2024.
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  8. Berrington de González A, Kim KP, Berg CD: Low-dose lung computed tomography screening before age 55: estimates of the mortality reduction required to outweigh the radiation-induced cancer risk. J Med Screen 15 (3): 153-8, 2008. [PUBMED Abstract]
  9. Shimizu Y, Kato H, Schull WJ: Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 2. Cancer mortality based on the recently revised doses (DS86). Radiat Res 121 (2): 120-41, 1990. [PUBMED Abstract]
  10. Katanoda K, Sobue T, Satoh H, et al.: An association between long-term exposure to ambient air pollution and mortality from lung cancer and respiratory diseases in Japan. J Epidemiol 21 (2): 132-43, 2011. [PUBMED Abstract]
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  16. Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334 (18): 1150-5, 1996. [PUBMED Abstract]
  17. Wingo PA, Ries LA, Giovino GA, et al.: Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 91 (8): 675-90, 1999. [PUBMED Abstract]
  18. Johnson BE: Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 90 (18): 1335-45, 1998. [PUBMED Abstract]
  19. Thomas P, Rubinstein L: Cancer recurrence after resection: T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 49 (2): 242-6; discussion 246-7, 1990. [PUBMED Abstract]
  20. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995. [PUBMED Abstract]
  21. van Boxem AJ, Westerga J, Venmans BJ, et al.: Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose? Lung Cancer 31 (1): 31-6, 2001. [PUBMED Abstract]
  22. Blumberg J, Block G: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finland. Nutr Rev 52 (7): 242-5, 1994. [PUBMED Abstract]
  23. Lippman SM, Lee JJ, Karp DD, et al.: Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 93 (8): 605-18, 2001. [PUBMED Abstract]
  24. van Zandwijk N, Dalesio O, Pastorino U, et al.: EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 92 (12): 977-86, 2000. [PUBMED Abstract]
  25. Aberle DR, Adams AM, Berg CD, et al.: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365 (5): 395-409, 2011. [PUBMED Abstract]
  26. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Springer-Verlag, 1999.
  27. Albain KS, Crowley JJ, LeBlanc M, et al.: Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 9 (9): 1618-26, 1991. [PUBMED Abstract]
  28. Macchiarini P, Fontanini G, Hardin MJ, et al.: Blood vessel invasion by tumor cells predicts recurrence in completely resected T1 N0 M0 non-small-cell lung cancer. J Thorac Cardiovasc Surg 106 (1): 80-9, 1993. [PUBMED Abstract]
  29. Ichinose Y, Yano T, Asoh H, et al.: Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer. An analysis in each pathologic stage. J Thorac Cardiovasc Surg 110 (3): 601-5, 1995. [PUBMED Abstract]
  30. Fontanini G, Bigini D, Vignati S, et al.: Microvessel count predicts metastatic disease and survival in non-small cell lung cancer. J Pathol 177 (1): 57-63, 1995. [PUBMED Abstract]
  31. Sayar A, Turna A, Kiliçgün A, et al.: Prognostic significance of surgical-pathologic multiple-station N1 disease in non-small cell carcinoma of the lung. Eur J Cardiothorac Surg 25 (3): 434-8, 2004. [PUBMED Abstract]
  32. Osaki T, Nagashima A, Yoshimatsu T, et al.: Survival and characteristics of lymph node involvement in patients with N1 non-small cell lung cancer. Lung Cancer 43 (2): 151-7, 2004. [PUBMED Abstract]
  33. Ichinose Y, Kato H, Koike T, et al.: Overall survival and local recurrence of 406 completely resected stage IIIa-N2 non-small cell lung cancer patients: questionnaire survey of the Japan Clinical Oncology Group to plan for clinical trials. Lung Cancer 34 (1): 29-36, 2001. [PUBMED Abstract]
  34. Tanaka F, Yanagihara K, Otake Y, et al.: Prognostic factors in patients with resected pathologic (p-) T1-2N1M0 non-small cell lung cancer (NSCLC). Eur J Cardiothorac Surg 19 (5): 555-61, 2001. [PUBMED Abstract]
  35. Asamura H, Suzuki K, Kondo H, et al.: Where is the boundary between N1 and N2 stations in lung cancer? Ann Thorac Surg 70 (6): 1839-45; discussion 1845-6, 2000. [PUBMED Abstract]
  36. Riquet M, Manac'h D, Le Pimpec-Barthes F, et al.: Prognostic significance of surgical-pathologic N1 disease in non-small cell carcinoma of the lung. Ann Thorac Surg 67 (6): 1572-6, 1999. [PUBMED Abstract]
  37. van Velzen E, Snijder RJ, Brutel de la Rivière A, et al.: Lymph node type as a prognostic factor for survival in T2 N1 M0 non-small cell lung carcinoma. Ann Thorac Surg 63 (5): 1436-40, 1997. [PUBMED Abstract]
  38. Vansteenkiste JF, De Leyn PR, Deneffe GJ, et al.: Survival and prognostic factors in resected N2 non-small cell lung cancer: a study of 140 cases. Leuven Lung Cancer Group. Ann Thorac Surg 63 (5): 1441-50, 1997. [PUBMED Abstract]
  39. Izbicki JR, Passlick B, Karg O, et al.: Impact of radical systematic mediastinal lymphadenectomy on tumor staging in lung cancer. Ann Thorac Surg 59 (1): 209-14, 1995. [PUBMED Abstract]
  40. Martini N, Burt ME, Bains MS, et al.: Survival after resection of stage II non-small cell lung cancer. Ann Thorac Surg 54 (3): 460-5; discussion 466, 1992. [PUBMED Abstract]
  41. Naruke T, Goya T, Tsuchiya R, et al.: Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 96 (3): 440-7, 1988. [PUBMED Abstract]
  42. Thomas P, Doddoli C, Thirion X, et al.: Stage I non-small cell lung cancer: a pragmatic approach to prognosis after complete resection. Ann Thorac Surg 73 (4): 1065-70, 2002. [PUBMED Abstract]
  43. Macchiarini P, Fontanini G, Hardin MJ, et al.: Relation of neovascularisation to metastasis of non-small-cell lung cancer. Lancet 340 (8812): 145-6, 1992. [PUBMED Abstract]
  44. Khan OA, Fitzgerald JJ, Field ML, et al.: Histological determinants of survival in completely resected T1-2N1M0 nonsmall cell cancer of the lung. Ann Thorac Surg 77 (4): 1173-8, 2004. [PUBMED Abstract]
  45. Earle CC, Tsai JS, Gelber RD, et al.: Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis. J Clin Oncol 19 (4): 1064-70, 2001. [PUBMED Abstract]

Cellular and Molecular Classification of NSCLC

Malignant non-small cell epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). The three main subtypes of non-small cell lung cancer (NSCLC) include:

Additional types include adenosquamous carcinoma, sarcomatoid carcinomas, salivary gland type tumors, carcinoid tumors, and other unclassified carcinomas. There are many subtypes in these categories.[1]

Tumor Types

Squamous cell carcinoma

Most squamous cell carcinomas of the lung are located centrally, in the larger bronchi of the lung. Squamous cell carcinomas are linked more strongly with smoking than other forms of NSCLC. The incidence of squamous cell carcinoma of the lung has been decreasing in recent years.

Adenocarcinoma

Adenocarcinoma is now the most common histological subtype in many countries, and subclassification of adenocarcinoma is important. One of the biggest problems with lung adenocarcinomas is the frequent histological heterogeneity. Mixtures of adenocarcinoma histological subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation.

Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/IASLC definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors.

If stromal, vascular, or pleural invasion are identified in an adenocarcinoma that has an extensive bronchioloalveolar carcinoma component, the classification would be an adenocarcinoma of mixed subtype with predominant bronchioloalveolar pattern and a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. However, the future of bronchioloalveolar carcinoma as a distinct clinical entity is unclear; a multidisciplinary expert panel representing the IASLC, the American Thoracic Society, and the European Respiratory Society proposed a major revision of the classification of adenocarcinomas in 2011 that entails a reclassification of what was called bronchioloalveolar carcinoma into newly defined histological subgroups.

The following variants of adenocarcinoma are recognized in the WHO/IASLC classification:

Large cell carcinoma

In addition to the general category of large cell carcinoma, several uncommon variants are recognized in the WHO/IASLC classification, including:

Basaloid carcinoma is also recognized as a variant of squamous cell carcinoma, and rarely, adenocarcinomas may have a basaloid pattern; however, in tumors without either of these features, they are regarded as a variant of large cell carcinoma.

Neuroendocrine tumors

LCNEC is recognized as a histologically high-grade non-small cell carcinoma. It has a very poor prognosis similar to that of small cell lung cancer (SCLC). Atypical carcinoid is recognized as an intermediate-grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and high-grade SCLC and LCNEC.

Neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLCs that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme because the clinical and therapeutic significance of neuroendocrine differentiation in NSCLC is not firmly established. These tumors are referred to collectively as NSCLC with neuroendocrine differentiation.

Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements

This is a group of rare tumors. Spindle cell carcinomas and giant cell carcinomas comprise only 0.4% of all lung malignancies, and carcinosarcomas comprise only 0.1% of all lung malignancies. In addition, this group of tumors reflects a continuum in histological heterogeneity, as well as epithelial and mesenchymal differentiation. On the basis of clinical and molecular data, biphasic pulmonary blastoma is regarded as part of the spectrum of carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.

Molecular Features

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[2] In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. Genomic alterations that can be targeted with approved therapies or for which treatments are under development include:

EGFR and ALK mutations predominate in adenocarcinomas that develop in nonsmokers, and KRAS and BRAF mutations are more common in smokers or former smokers. EGFR mutations strongly predict the improved response rate and progression-free survival of patients who take EGFR inhibitors. In a set of 2,142 lung adenocarcinoma specimens from patients treated at Memorial Sloan Kettering Cancer Center, EGFR exon 19 deletions and L858R were found in 15% of tumors from former smokers (181 of 1,218; 95% confidence interval [CI], 13%–17%), 6% from current smokers (20 of 344; 95% CI, 4%–9%), and 52% from never-smokers (302 of 580; 95% CI, 48%–56%; P < .001 for ever- vs. never-smokers).[3]

Fusions of ALK with EML4 genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. Sensitizing fusions of ALK with other genes have also been reported.

References
  1. Travis WD, Brambilla E, Nicholson AG, et al.: The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol 10 (9): 1243-1260, 2015. [PUBMED Abstract]
  2. Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011. [PUBMED Abstract]
  3. D'Angelo SP, Pietanza MC, Johnson ML, et al.: Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol 29 (15): 2066-70, 2011. [PUBMED Abstract]

Stage Information for NSCLC

General Staging Evaluation

In non-small cell lung cancer (NSCLC), the determination of stage has important therapeutic and prognostic implications. Careful initial diagnostic evaluation to define the location and to determine the extent of primary and metastatic tumor involvement is critical for the appropriate care of patients.

In general, symptoms, physical signs, laboratory findings, and perceived risk of distant metastasis lead to an evaluation for distant metastatic disease. Additional tests such as bone scans and computed tomography (CT)/magnetic resonance imaging (MRI) of the brain may be performed if initial assessments suggest metastases or if patients with stage III disease are being evaluated for aggressive local and combined modality treatments.

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors and pathological factors.[1] The distinction between clinical stage and pathological stage should be considered when evaluating reports of survival outcome.

Procedures used to determine stage include:

Procedures used to obtain tissue samples include bronchoscopy, mediastinoscopy, or anterior mediastinotomy.

Pathological staging of NSCLC requires examination of the tumor, knowledge of resection margins, and determination of lymph node status.

At diagnosis, patients with NSCLC can be divided into the following three groups that reflect both the extent of the disease and the treatment approach:

  1. Surgically resectable disease (generally stage I, stage II, and selected stage III tumors).

Evaluation of mediastinal lymph node metastasis

Surgical evaluation

Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy.

Accurate staging of the mediastinal lymph nodes provides important prognostic information.

Evidence (nodal status):

  1. The association between survival and the number of examined lymph nodes during surgery for patients with stage I NSCLC treated with definitive surgical resection was assessed from the population-based Surveillance, Epidemiology, and End Results (SEER) Program database for the period from 1990 to 2000.[2] A total of 16,800 patients were included in the study.
  1. The overall survival analysis for patients without radiation therapy was done by comparing the reference group (one to four lymph nodes) with the following groups:

The corresponding results for lung cancer–specific mortality and for patients who received radiation therapy were not substantially different.

CT imaging

CT scanning is primarily used for determining the size of the tumor. The CT scan should extend inferiorly to include the liver and adrenal glands. MRI scans of the thorax and upper abdomen do not appear to yield advantages over CT scans.[3]

Evidence (CT scan):

  1. A systematic review of the medical literature relating to the accuracy of CT scanning for noninvasive staging of the mediastinum in patients with lung cancer was conducted. In the 35 studies published between 1991 and June 2006, 5,111 evaluable patients were identified. Almost all studies specified that CT scanning was performed following the administration of intravenous contrast material and that a positive test result was defined as the presence of one or more lymph nodes that measured larger than 1 cm on the short-axis diameter.[4]
18F-FDG PET scanning

The wider availability and use of 18F-FDG PET scanning for staging has modified the approach to staging mediastinal lymph nodes and distant metastases.

Randomized trials evaluating the utility of 18F-FDG PET scanning in potentially resectable NSCLC patients reported conflicting results in terms of the relative reduction in the number of noncurative thoracotomies.

Although the current evidence is conflicting, 18F-FDG PET scanning may improve results of early-stage lung cancer by identifying patients who have evidence of metastatic disease that is beyond the scope of surgical resection and that is not evident by standard preoperative staging procedures.

Evidence (18F-FDG PET scan):

  1. A systematic review, an expansion of a health technology assessment conducted in 2001 by the Institute for Clinical and Evaluative Sciences, evaluated the accuracy and utility of 18F-FDG PET scanning in the diagnosis and staging of lung cancer.[7] Through a systematic search of the literature, 12 evidence summary reports and 15 prospective studies of the diagnostic accuracy of 18F-FDG PET scanning were identified.

Decision analyses demonstrate that 18F-FDG PET scanning may reduce the overall costs of medical care by identifying patients with falsely negative CT scans in the mediastinum or otherwise undetected sites of metastases.[8-10] Studies concluded that the money saved by forgoing mediastinoscopy in 18F-FDG PET-positive mediastinal lesions was not justified because of the unacceptably high number of false-positive results.[8-10] A randomized study found that the addition of 18F-FDG PET scanning to conventional staging was associated with significantly fewer thoracotomies.[11] A second randomized trial evaluating the impact of 18F-FDG PET scanning on clinical management found that 18F-FDG PET scanning provided additional information regarding appropriate stage but did not lead to significantly fewer thoracotomies.[12]

Combination of CT imaging and 18F-FDG PET scanning

The combination of CT imaging and 18F-FDG PET scanning has greater sensitivity and specificity than CT imaging alone.[13]

Evidence (CT/18F-FDG PET scan):

  1. If there is no evidence of distant metastatic disease on CT scan, 18F-FDG PET scanning complements CT scan staging of the mediastinum. Numerous nonrandomized studies of 18F-FDG PET scanning have evaluated mediastinal lymph nodes using surgery (i.e., mediastinoscopy and/or thoracotomy with mediastinal lymph node dissection) as the gold standard of comparison.
  2. A meta-analysis evaluated the conditional test performance of 18F-FDG PET scanning and CT scanning.

For patients with clinically operable NSCLC, the evidence supports performing a biopsy of mediastinal lymph nodes that are found to be larger than 1 cm in shortest transverse axis on chest CT scan or are found to be positive on 18F-FDG PET scan. Negative 18F-FDG PET scanning does not preclude biopsy of radiographically enlarged mediastinal lymph nodes. Mediastinoscopy is necessary for the detection of cancer in mediastinal lymph nodes when the results of the CT scan and 18F-FDG PET scan do not corroborate each other.

Evaluation of brain metastasis

Patients at risk of brain metastases may be staged with CT or MRI scans.

Evidence (staging with CT or MRI):

  1. One study randomly assigned 332 patients with potentially operable NSCLC and no neurological symptoms to brain CT or MRI imaging to detect occult brain metastasis before lung surgery.[16]

Whether the improved detection rate of MRI translates into improved outcome remains unknown. Not all patients are able to tolerate MRI, and for these patients contrast-enhanced CT scan is a reasonable substitute.

Evaluation of distant metastasis to sites other than the brain

Numerous nonrandomized, prospective, and retrospective studies have demonstrated that 18F-FDG PET scanning offers diagnostic advantages over conventional imaging in staging distant metastatic disease; however, standard 18F-FDG PET scans have limitations. 18F-FDG PET scans may not extend below the pelvis and may not detect bone metastases in the long bones of the lower extremities. Because the metabolic tracer used in 18F-FDG PET scanning accumulates in the brain and urinary tract, 18F-FDG PET scanning is not reliable for detection of metastases in these sites.[16]

The Revised International System for Staging Lung Cancer

The Revised International System for Staging Lung Cancer, based on information from a clinical database of more than 5,000 patients, was adopted in 2010 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer.[17,18] These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging.

AJCC Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define NSCLC.[18]

Table 1. Definitions of Primary Tumor (T) for Lung Cancer a
T CategoryT Criteria
a Reprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56.
TXPrimary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.
T0No evidence of primary tumor.
TisCarcinoma in situ; SCIS =Squamous cell carcinoma in situ; AIS: Adenocarcinoma in situ; Adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension.
T1Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).
T1miMinimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension.
T1aTumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.
T1bTumor >1 cm but ≤2 cm in greatest dimension.
T1cTumor >2 cm but ≤3 cm in greatest dimension.
T2Tumor >3 cm but ≤5 cm or having any of the following features: involves the main bronchus regardless of distance to the carina, but without involvement of the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung. T2 tumors with these features are classified as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.
T2aTumor >3 cm but ≤4 cm in greatest dimension.
T2bTumor >4 cm but ≤5 cm in greatest dimension.
T3Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary.
T4Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary.
Table 2. Definitions of Regional Lymph Node (N) for Lung Cancer a
N CategoryN Criteria
a Reprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56.
NXRegional lymph nodes cannot be assessed.
N0No regional lymph node metastasis.
N1Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
N2Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
N3Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
Table 3. Definitions of Distant Metastasis (M) for Lung Cancer a
M CategoryM Criteria
a Reprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56.
M0No distant metastasis.
M1Distant metastasis.
M1aSeparate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
M1bSingle extrathoracic metastases in a single organ (including involvement of a single nonregional node).
M1cMultiple extrathoracic metastases in a single organ or in multiple organs.
Table 4. AJCC Prognostic Stage Groups for Lung Cancer a
StageTNM ClassificationIllustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted with permission from AJCC: Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 431–56.
Occult carcinomaTX, N0, M0
0Tis, N0, M0
IA1T1mi, N0, M0Stage IA lung cancer; drawing shows a tumor (3 cm or smaller) in the right lung. Also shown are the lymph nodes, trachea, pleura, and diaphragm.
T1a, N0, M0
IA2T1b, N0, M0
IA3T1c, N0, M0
IBT2a, N0, M0Two-panel drawing of stage IB lung cancer; the panel on the left shows a tumor (larger than 3 cm but not larger than 4 cm) in the right lung. Also shown are the pleura and diaphragm. The panel on the right shows a primary tumor (4 cm or smaller) in the left lung and cancer in (a) the left main bronchus and (b) the inner membrane covering the lung (inset). Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina and a rib (inset) are also shown.
IIAT2b, N0, M0Stage IIA lung cancer; drawing shows a primary tumor (larger than 4 cm but not larger than 5 cm) in the left lung and cancer in (a) the left main bronchus and (b) the inner membrane covering the lung (inset). Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina, pleura, and a rib (inset) are also shown.
IIBT1a, N1, M0Stage IIB lung cancer (1); drawing shows a primary tumor (5 cm or smaller) in the right lung and cancer in lymph nodes in the same lung as the primary tumor. Also shown are the trachea, main bronchus, pleura, and diaphragm.Stage IIB lung cancer (2); drawing shows (a) a primary tumor (larger than 5 cm but not larger than 7 cm) in the left lung (top inset) and (b) a separate tumor in the same lobe of the lung as the primary tumor. Also shown is cancer that has spread to (c) the chest wall and the membranes covering the lung and chest wall (middle inset); (d) the nerve that controls the diaphragm; and (e) the sac around the heart (bottom inset). The pleura, diaphragm, heart, and a rib (middle inset) are also shown.
T1b, N1, M0
T1c, N1, M0
T2a, N1, M0
T2b, N1, M0
T3, N0, M0
IIIAT1a, N2, M0Stage IIIA lung cancer (1); drawing shows a primary tumor (5 cm or smaller) in the left lung (top inset) and cancer in lymph nodes around the trachea. Also shown is cancer that has spread to (a) the left main bronchus and (b) the membrane covering the lung (bottom inset). Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina, pleura, and a rib (bottom inset) are also shown.Stage IIIA lung cancer (2); drawing shows (a) a primary tumor (larger than 5 cm but not larger than 7 cm) in the left lung and cancer in lymph nodes in the lung or near the bronchus on the same side of the chest as the primary tumor. Also shown is (b) separate tumors in the same lobe of the lung as the primary tumor and cancer that has spread to (c) the chest wall and the membranes covering the lung and chest wall (top right inset); (d) the nerve that controls the diaphragm; and (e) the sac around the heart (bottom right inset). The trachea, left main bronchus, diaphragm, heart, and a rib (top right inset) are also shown.Stage IIIA lung cancer (3); drawing shows (a) a primary tumor (larger than 7 cm) in the left lung and (b) separate tumors in a different lobe of the lung with the primary tumor. Also shown is cancer that has spread to the (c) trachea, (d) carina, (e) esophagus, (f) breastbone, (g) diaphragm, (h) heart, and (i) the aorta and vena cava.
T1b, N2, M0
T1c, N2, M0
T2a, N2, M0
T2b, N2, M0
T3, N1, M0
T4, N0, M0
T4, N1, M0
IIIBT1a, N3, M0Stage IIIB lung cancer (1); drawing shows a primary tumor (5 cm or smaller) in the left lung and cancer in lymph nodes above the collarbone on the same side of the chest as the primary tumor and in lymph nodes on the opposite side of the chest as the primary tumor. Also shown is cancer that has spread to (a) the left main bronchus and (b) the membrane covering the lung. Also shown is (c) part or all of the lung has collapsed or has pneumonitis (inflammation). The carina, pleura, and a rib (inset) are also shown.Stage IIIB lung cancer (2); drawing shows a primary tumor in the left lung and (a) a separate tumor in a different lobe of the lung with the primary tumor. Also shown is cancer in lymph nodes on the same side of the chest as the primary tumor. The lymph nodes with cancer are around the trachea or where the trachea divides into the bronchi. Also shown is (b) cancer that has spread to the following: the chest wall and the lining of the chest wall and lung, the nerve that controls the voice box, the trachea, the carina, the esophagus, the breastbone, the diaphragm, the nerve that controls the diaphragm, the aorta and vena cava, the heart, and the sac around the heart.
T1b, N3, M0
T1c, N3, M0
T2a, N3, M0
T2b, N3, M0
T3, N2, M0
T4, N2, M0
IIICT3, N3, M0Stage IIIC lung cancer; drawing shows a primary tumor in the left lung and (a) separate tumors in the same lobe of the lung with the primary tumor. Also shown is cancer in lymph nodes above the collarbone on the same side and opposite side of the chest as the primary tumor. Also shown is (b) cancer that has spread to the following: the chest wall and the lining of the chest wall and lung, the nerve that controls the voice box, the trachea, the carina, the esophagus, the breastbone, the diaphragm, the nerve that controls the diaphragm, the heart, the aorta and vena cava, and the sac around the heart.
T4, N3, M0
IVAny T, Any N, M1
IVAAny T, Any N, M1aStage IVA lung cancer; drawing shows a primary tumor in the right lung and (a) a tumor in the left lung. Also shown is (b) fluid or cancer nodules around the lungs or heart (inset), and (c) other organs or tissues where lung cancer may spread, including the brain, adrenal gland, kidney, liver, bone, and distant lymph nodes.
Any T, Any N, M1b
IVBAny T, Any N, M1cStage IVB lung cancer; drawing shows a primary cancer in the right lung and other parts of the body where lung cancer may spread, including the brain, adrenal gland, kidney, liver, distant lymph nodes, and bone. An inset shows cancer cells spreading from the lung, through the blood and lymph system, to another part of the body where metastatic cancer has formed.
References
  1. Pfister DG, Johnson DH, Azzoli CG, et al.: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22 (2): 330-53, 2004. [PUBMED Abstract]
  2. Ludwig MS, Goodman M, Miller DL, et al.: Postoperative survival and the number of lymph nodes sampled during resection of node-negative non-small cell lung cancer. Chest 128 (3): 1545-50, 2005. [PUBMED Abstract]
  3. Webb WR, Gatsonis C, Zerhouni EA, et al.: CT and MR imaging in staging non-small cell bronchogenic carcinoma: report of the Radiologic Diagnostic Oncology Group. Radiology 178 (3): 705-13, 1991. [PUBMED Abstract]
  4. Toloza EM, Harpole L, McCrory DC: Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Chest 123 (1 Suppl): 137S-146S, 2003. [PUBMED Abstract]
  5. Gould MK, Kuschner WG, Rydzak CE, et al.: Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann Intern Med 139 (11): 879-92, 2003. [PUBMED Abstract]
  6. Dwamena BA, Sonnad SS, Angobaldo JO, et al.: Metastases from non-small cell lung cancer: mediastinal staging in the 1990s--meta-analytic comparison of PET and CT. Radiology 213 (2): 530-6, 1999. [PUBMED Abstract]
  7. Ung YC, Maziak DE, Vanderveen JA, et al.: 18Fluorodeoxyglucose positron emission tomography in the diagnosis and staging of lung cancer: a systematic review. J Natl Cancer Inst 99 (23): 1753-67, 2007. [PUBMED Abstract]
  8. Dietlein M, Weber K, Gandjour A, et al.: Cost-effectiveness of FDG-PET for the management of potentially operable non-small cell lung cancer: priority for a PET-based strategy after nodal-negative CT results. Eur J Nucl Med 27 (11): 1598-609, 2000. [PUBMED Abstract]
  9. Scott WJ, Shepherd J, Gambhir SS: Cost-effectiveness of FDG-PET for staging non-small cell lung cancer: a decision analysis. Ann Thorac Surg 66 (6): 1876-83; discussion 1883-5, 1998. [PUBMED Abstract]
  10. Gambhir SS, Hoh CK, Phelps ME, et al.: Decision tree sensitivity analysis for cost-effectiveness of FDG-PET in the staging and management of non-small-cell lung carcinoma. J Nucl Med 37 (9): 1428-36, 1996. [PUBMED Abstract]
  11. van Tinteren H, Hoekstra OS, Smit EF, et al.: Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet 359 (9315): 1388-93, 2002. [PUBMED Abstract]
  12. Viney RC, Boyer MJ, King MT, et al.: Randomized controlled trial of the role of positron emission tomography in the management of stage I and II non-small-cell lung cancer. J Clin Oncol 22 (12): 2357-62, 2004. [PUBMED Abstract]
  13. Vansteenkiste JF, Stroobants SG, De Leyn PR, et al.: Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol 16 (6): 2142-9, 1998. [PUBMED Abstract]
  14. Roberts PF, Follette DM, von Haag D, et al.: Factors associated with false-positive staging of lung cancer by positron emission tomography. Ann Thorac Surg 70 (4): 1154-9; discussion 1159-60, 2000. [PUBMED Abstract]
  15. Liewald F, Grosse S, Storck M, et al.: How useful is positron emission tomography for lymphnode staging in non-small-cell lung cancer? Thorac Cardiovasc Surg 48 (2): 93-6, 2000. [PUBMED Abstract]
  16. Yokoi K, Kamiya N, Matsuguma H, et al.: Detection of brain metastasis in potentially operable non-small cell lung cancer: a comparison of CT and MRI. Chest 115 (3): 714-9, 1999. [PUBMED Abstract]
  17. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997. [PUBMED Abstract]
  18. Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 431–56.

Treatment Option Overview for NSCLC

In non-small cell lung cancer (NSCLC), results of standard treatment are poor except for the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment.

Treatment decisions are based on some of the following factors:

Surgery is potentially the most curative therapeutic option for this disease. Postoperative chemotherapy may provide an additional benefit to patients with resected NSCLC. Radiation therapy combined with chemotherapy can produce a cure in a small number of patients and can provide palliation in most patients. Prophylactic cranial irradiation may reduce the incidence of brain metastases, but there is no evidence of a survival benefit and the effect of prophylactic cranial irradiation on quality of life is not known.[1,2] In patients with advanced-stage disease, chemotherapy or epidermal growth factor receptor (EGFR) kinase inhibitors offer modest improvements in median survival, although overall survival is poor.[3,4]

Chemotherapy has produced short-term improvement in disease-related symptoms in patients with advanced NSCLC. Several clinical trials have attempted to assess the impact of chemotherapy on tumor-related symptoms and quality of life. In total, these studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life;[5,6] however, the impact of chemotherapy on quality of life requires more study. In general, medically eligible older patients with good performance status obtain the same benefits from treatment as younger patients.

The identification of gene mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[7] In particular, genetic abnormalities in EGFR, MAPK, and PI3K signaling pathways in subsets of NSCLC may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. EGFR mutations strongly predict the improved response rate and progression-free survival of inhibitors of EGFR. Fusions of ALK with EML4 and other genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as alectinib. The MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors. Recurrent fusions involving the ROS1 gene are observed in up to 2% of NSCLCs and are responsive to treatment with crizotinib and entrectinib. NTRK gene fusions can occur in up to 1% of NSCLCs and can be treated with the TRK inhibitors, larotrectinib and entrectinib. For more information, see the Molecular Features section.

The treatment options for each stage of NSCLC are presented in Table 5.

Table 5. Treatment Options for NSCLC
Stage (TNM Definitions)Treatment Options
ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; HER2 = human epidermal growth factor receptor 2; mTOR = mammalian target of rapamycin; NSCLC = non-small cell lung cancer; NTRK = neurotrophic tyrosine kinase; TKIs = tyrosine kinase inhibitors; TNM = tumor, node, metastasis.
Occult NSCLCSurgery
Stage 0 NSCLCSurgery
Endobronchial therapies
Stages IA and IB NSCLC Surgery
Adjuvant therapy
Radiation therapy
Stages IIA and IIB NSCLCSurgery with or without adjuvant and/or neoadjuvant therapy
Radiation therapy
Stage IIIA NSCLCResected or resectable diseaseSurgery with neoadjuvant and/or adjuvant therapy
Neoadjuvant therapy
Perioperative (neoadjuvant and adjuvant) immunotherapy with chemotherapy
Adjuvant therapy
Unresectable diseaseChemoradiation therapy
Radiation therapy
Superior sulcus tumorsSurgery
Chemoradiation therapy followed by surgery
Radiation therapy alone
Tumors that invade the chest wallSurgery
Surgery and radiation therapy
Radiation therapy alone
Chemotherapy combined with radiation therapy and/or surgery
Stages IIIB and IIIC NSCLCSequential or concurrent chemotherapy and radiation therapy
Radiation therapy alone
Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLCCytotoxic combination chemotherapy
Combination chemotherapy with monoclonal antibodies
Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)
EGFR TKIs with or without chemotherapy (for patients with EGFR mutations)
EGFR-directed therapy (for patients with EGFR exon 20 insertion mutations)
ALK inhibitors (for patients with ALK translocations)
BRAF V600E and MEK inhibitors (for patients with BRAF V600E mutations)
ROS1 inhibitors (for patients with ROS1 rearrangements)
NTRK inhibitors (for patients with NTRK fusions)
RET inhibitors (for patients with RET fusions)
MET inhibitors (for patients with MET exon 14 skipping mutations)
Immune checkpoint inhibitors with or without chemotherapy
mTOR inhibitors (for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors)
Local therapies and special considerations
Progressive Stage IV, Relapsed, and Recurrent NSCLCChemotherapy
EGFR-directed therapy
ALK-directed TKIs
BRAF V600E and MEK inhibitors (for patients with BRAF V600E mutations)
ROS1-directed therapy
NTRK inhibitors (for patients with NTRK fusions)
RET inhibitors (for patients with RET fusions)
MET inhibitors (for patients with MET exon 14 skipping mutations)
KRAS G12C inhibitors (for patients with KRAS G12C mutations)
HER2-targeted therapy (for patients with HER2 mutations)
Immunotherapy
mTOR inhibitors (for patients with unresectable, locally advanced or metastatic, progressive, well-differentiated, nonfunctional, neuroendocrine tumors)

In addition to the treatment options presented in Table 5, treatment options under clinical evaluation include:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Lester JF, MacBeth FR, Coles B: Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small-cell lung cancer: a Cochrane Review. Int J Radiat Oncol Biol Phys 63 (3): 690-4, 2005. [PUBMED Abstract]
  2. Pöttgen C, Eberhardt W, Grannass A, et al.: Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. J Clin Oncol 25 (31): 4987-92, 2007. [PUBMED Abstract]
  3. Chemotherapy for non-small cell lung cancer. Non-small Cell Lung Cancer Collaborative Group. Cochrane Database Syst Rev (2): CD002139, 2000. [PUBMED Abstract]
  4. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995. [PUBMED Abstract]
  5. Spiro SG, Rudd RM, Souhami RL, et al.: Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life. Thorax 59 (10): 828-36, 2004. [PUBMED Abstract]
  6. Clegg A, Scott DA, Hewitson P, et al.: Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review. Thorax 57 (1): 20-8, 2002. [PUBMED Abstract]
  7. Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011. [PUBMED Abstract]

Treatment of Occult NSCLC

In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomography scan), when needed, to define the site and nature of the primary tumor; tumors discovered in this fashion are generally early stage and curable by surgery.

After discovery of the primary tumor, treatment involves establishing the stage of the tumor. Therapy is identical to that recommended for other non-small cell lung cancer (NSCLC) patients with similar-stage disease.

Treatment Options for Occult NSCLC

Treatment options for occult NSCLC include:

  1. Surgery.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of Stage 0 NSCLC

Stage 0 non-small cell lung cancer (NSCLC) frequently progresses to invasive cancer.[1-3] Patients may be offered surveillance bronchoscopies and, if lesions are detected, potentially curative therapies.

Treatment Options for Stage 0 NSCLC

Treatment options for stage 0 NSCLC include:

  1. Surgery.
  2. Endobronchial therapies, including photodynamic therapy, electrocautery, cryotherapy, and neodymium-doped yttrium aluminum garnet (Nd-YAG) laser therapy.

Surgery

Segmentectomy or wedge resection are used to preserve maximum normal pulmonary tissue because patients with stage 0 NSCLC are at a high risk of second lung cancers. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, such lesions, when identified, are often centrally located and may require a lobectomy.

Endobronchial therapies

Patients with central lesions may be candidates for curative endobronchial therapy. Endobronchial therapies that preserve lung function include photodynamic therapy, electrocautery, cryotherapy, and Nd-YAG laser therapy.[3-6]

Evidence (endobronchial therapies):

  1. Small case series have reported high complete response rates and long-term survival in selected patients.[7,8][Level of evidence C2]

Efficacy of these treatment modalities in the management of patients with early NSCLC remains to be proven in definitive randomized controlled trials.

A high incidence of second primary cancers develop in these patients.[1,2]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Woolner LB, Fontana RS, Cortese DA, et al.: Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period. Mayo Clin Proc 59 (7): 453-66, 1984. [PUBMED Abstract]
  2. Venmans BJ, van Boxem TJ, Smit EF, et al.: Outcome of bronchial carcinoma in situ. Chest 117 (6): 1572-6, 2000. [PUBMED Abstract]
  3. Jeremy George P, Banerjee AK, Read CA, et al.: Surveillance for the detection of early lung cancer in patients with bronchial dysplasia. Thorax 62 (1): 43-50, 2007. [PUBMED Abstract]
  4. Kennedy TC, McWilliams A, Edell E, et al.: Bronchial intraepithelial neoplasia/early central airways lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 221S-233S, 2007. [PUBMED Abstract]
  5. Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007. [PUBMED Abstract]
  6. Deygas N, Froudarakis M, Ozenne G, et al.: Cryotherapy in early superficial bronchogenic carcinoma. Chest 120 (1): 26-31, 2001. [PUBMED Abstract]
  7. van Boxem TJ, Venmans BJ, Schramel FM, et al.: Radiographically occult lung cancer treated with fibreoptic bronchoscopic electrocautery: a pilot study of a simple and inexpensive technique. Eur Respir J 11 (1): 169-72, 1998. [PUBMED Abstract]
  8. van Boxem AJ, Westerga J, Venmans BJ, et al.: Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose? Lung Cancer 31 (1): 31-6, 2001. [PUBMED Abstract]

Treatment of Stages IA and IB NSCLC

Treatment Options for Stages IA and IB NSCLC

Chemotherapy and radiation therapy have not been shown to improve survival in patients with stage I NSCLC that has been completely resected.

Surgery

Surgery is the treatment of choice for patients with stage I NSCLC. A lobectomy or segmental, wedge, or sleeve resection may be performed as appropriate. Patients with impaired pulmonary function are candidates for segmental or wedge resection of the primary tumor. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age related, but a 3% to 5% mortality rate with lobectomy can be expected.[1]

  1. The Lung Cancer Study Group conducted a randomized study (LCSG-821) that compared lobectomy with limited resection for patients with stage I lung cancer. Results of the study showed:[2]

These results suggest that sublobar resection by anatomical segmentectomy or wedge resection is effective for management of clinical stage T1a, N0 NSCLC when intraoperative sampling of hilar and mediastinal lymph nodes is negative.

Current evidence suggests that lung cancer resection combined with CMLND is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.[8][Level of evidence A1]

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and the potential methodological weaknesses of the trials.

Adjuvant therapy

Many patients who have surgery subsequently develop regional or distant metastases.[9] Such patients are candidates for entry into clinical trials evaluating postoperative treatment with chemotherapy or radiation therapy following surgery. At present, neither chemotherapy nor radiation therapy has been found to improve survival in patients with stage I NSCLC that has been completely resected.

Adjuvant chemotherapy

Based on a meta-analysis, postoperative chemotherapy is not recommended outside of a clinical trial for patients with completely resected stage I NSCLC.[10] However, there may be some benefit of adjuvant chemotherapy in patients with stage IB tumors that are larger than 4 cm.

Evidence (adjuvant chemotherapy for patients with stage IB NSCLC):

  1. The Cancer and Leukemia Group B study (CALGB-9633 [NCT00002852]) addressed the results of adjuvant carboplatin and paclitaxel versus observation for OS in 344 patients with resected stage IB (i.e., pathological T2, N0) NSCLC. Within 4 to 8 weeks of resection, patients were randomly assigned to postoperative chemotherapy or observation.[11]

Given the magnitude of observed survival differences, CALGB-9633 may have been underpowered to detect small but clinically meaningful improvements in survival. In addition, the use of a carboplatin versus a cisplatin combination might have affected the results. At present, there is no reliable evidence that postoperative chemotherapy improves survival of patients with stage IB NSCLC.[11][Level of evidence A1]

Adjuvant targeted therapy (for patients with stage IB NSCLC with EGFR mutations)

Adjuvant targeted therapy with osimertinib for patients with EGFR-mutated NSCLC and resected stage IB to IIIA NSCLC was studied in a phase III clinical trial and showed improved OS.

Evidence (adjuvant targeted therapy with osimertinib for patients with stage IB EGFR-mutated NSCLC):

  1. The ADAURA (NCT02511106) phase III, double-blind, placebo-controlled trial randomly assigned 682 patients with surgically resected stage IB to stage IIIA NSCLC with EGFR-sensitizing mutations (centrally determined, deletion in exon 19 or L858R mutation in exon 21) to receive either osimertinib 80 mg by mouth daily or a placebo for 3 years. Standard postoperative adjuvant chemotherapy was allowed but not mandatory; decisions regarding adjuvant chemotherapy were made by the physician and patient before trial enrollment. There were 399 patients who received osimertinib and 342 patients who received placebo.[12][Level of evidence A1]

The U.S. Food and Drug Administration (FDA) approved osimertinib as adjuvant therapy for patients with stage IB to IIIA NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.

Adjuvant immunotherapy

Evidence (adjuvant immunotherapy with pembrolizumab for patients with stage IB tumors >4 cm):

  1. The phase III, multicenter, open-label PEARLS/KEYNOTE-091 trial (NCT02504372) randomly assigned 1,177 patients with completely resected stage IB (tumor >4 cm) to stage IIIA NSCLC to receive pembrolizumab (200 mg every 3 weeks) or placebo for up to 18 cycles, or until disease progression or unacceptable toxicity. Patients started study treatment after resection or, if indicated, after adjuvant chemotherapy (maximum of four cycles). The dual primary end points were DFS in the overall study population and DFS in patients with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 50% or greater, as determined using the PD-L1 IHC 22C3 pharmDx assay. These end points were reported in a prespecified interim analysis after a median follow-up of 35.6 months (interquartile range, 27.1–45.5).[13][Level of evidence B1]

The FDA approved pembrolizumab as a single agent for adjuvant treatment following resection and platinum-based chemotherapy for patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Of note, the FDA label specifies that pembrolizumab can be used as adjuvant therapy after platinum-based chemotherapy. However, chemotherapy was not required in the overall study patient population evaluated in KEYNOTE-091.

Adjuvant external radiation therapy

The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated and has not been found to improve the outcome of patients with completely resected stage I NSCLC.[14]

Adjuvant brachytherapy

The value of intraoperative (adjuvant) brachytherapy applied to the suture line has been evaluated in patients undergoing sublobar resections for stage I NSCLC to improve local control; it has not been found to improve outcomes.

Evidence (adjuvant brachytherapy):

  1. A phase III trial that randomly assigned 222 patients to undergo sublobar resection with or without suture line brachytherapy reported the following:[15]

Radiation therapy

A substantial number of patients are ineligible for standard surgical resection because of comorbid conditions that are associated with unacceptably high perioperative risk. Patients with potentially resectable tumors with medical contraindications to surgery or those with inoperable stage I disease and with sufficient pulmonary reserve may be candidates for radiation therapy with curative intent.[16-18] Nonrandomized observational studies comparing treatment outcomes associated with resection, radiation therapy, and observation have demonstrated shorter survival times and higher mortality for patients who undergo observation only.[16,19]

Conventional radiation therapy

Historically, conventional primary radiation therapy consisted of approximately 60 Gy to 70 Gy delivered with megavoltage equipment to the midplane of the known tumor volume using conventional fractionation (1.8–2.0 Gy per day).

Improvements in radiation techniques include planning techniques to account for tumor motion, more conformal planning techniques (e.g., 3-D conformal radiation therapy and intensity-modulated radiation therapy), and image guidance during treatment. Modern approaches to delivery of external-beam radiation therapy (EBRT) include hypofractionated radiation therapy and stereotactic body radiation therapy (SBRT). However, there are limited reliable data from comparative trials to determine which approaches yield superior outcomes.[17,18]

Evidence (conventional radiation therapy):

  1. In the largest retrospective conventional radiation therapy series, patients with inoperable disease were treated with definitive radiation therapy.[20-22]
Hypofractionated radiation therapy

Hypofractionated radiation therapy involves the delivery of a slightly higher dose of radiation therapy per day (e.g., 2.4–4.0 Gy) over a shorter period of time compared with conventionally fractionated radiation therapy. Multiple prospective phase I/II trials have demonstrated that hypofractionated radiation therapy to a dose of 60 Gy to 70 Gy delivered over 3 to 4 weeks with 2.4 Gy to 4.0 Gy per day resulted in a low incidence of moderate to severe toxicity, 2-year OS rates of 50% to 60%, and 2-year tumor local control of 80% to 90%.[26-28][Level of evidence C1]

Stereotactic body radiation therapy (SBRT)

SBRT involves the delivery of highly conformal, high-dose radiation therapy over an extremely hypofractionated course (e.g., one to five treatments) delivered over 1 to 2 weeks. Commonly used regimens include 18 Gy × 3, 12 Gy to 12.5 Gy × 4, and 10 Gy to 12 Gy × 5, and deliver a substantially higher biologically effective dose compared with historic conventional radiation therapy regimens.

Multiple prospective phase I/II trials and institutional series have demonstrated that SBRT results in a low incidence of pulmonary toxicity (

  1. Early phase I/II trials from Indiana University identified the maximum tolerated dose of three-fraction SBRT at 18 Gy × 3 for T1 tumors.

A randomized trial of hypofractionated radiation therapy versus SBRT (LUSTRE [NCT01968941]) is ongoing to determine the optimal radiation therapy regimen, but SBRT has been widely adopted for patients with medically inoperable stage I NSCLC.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Ginsberg RJ, Hill LD, Eagan RT, et al.: Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 86 (5): 654-8, 1983. [PUBMED Abstract]
  2. Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60 (3): 615-22; discussion 622-3, 1995. [PUBMED Abstract]
  3. Warren WH, Faber LP: Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Five-year survival and patterns of intrathoracic recurrence. J Thorac Cardiovasc Surg 107 (4): 1087-93; discussion 1093-4, 1994. [PUBMED Abstract]
  4. Mantz CA, Dosoretz DE, Rubenstein JH, et al.: Endobronchial brachytherapy and optimization of local disease control in medically inoperable non-small cell lung carcinoma: a matched-pair analysis. Brachytherapy 3 (4): 183-90, 2004. [PUBMED Abstract]
  5. Altorki N, Wang X, Kozono D, et al.: Lobar or Sublobar Resection for Peripheral Stage IA Non-Small-Cell Lung Cancer. N Engl J Med 388 (6): 489-498, 2023. [PUBMED Abstract]
  6. Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005. [PUBMED Abstract]
  7. Allen MS, Darling GE, Pechet TT, et al.: Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81 (3): 1013-9; discussion 1019-20, 2006. [PUBMED Abstract]
  8. Darling GE, Allen MS, Decker PA, et al.: Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 141 (3): 662-70, 2011. [PUBMED Abstract]
  9. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995. [PUBMED Abstract]
  10. Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008. [PUBMED Abstract]
  11. Strauss GM, Herndon 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 26 (31): 5043-51, 2008. [PUBMED Abstract]
  12. Tsuboi M, Herbst RS, John T, et al.: Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med 389 (2): 137-147, 2023. [PUBMED Abstract]
  13. O'Brien M, Paz-Ares L, Marreaud S, et al.: Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 23 (10): 1274-1286, 2022. [PUBMED Abstract]
  14. PORT Meta-analysis Trialists Group: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005. [PUBMED Abstract]
  15. Fernando HC, Landreneau RJ, Mandrekar SJ, et al.: Impact of brachytherapy on local recurrence rates after sublobar resection: results from ACOSOG Z4032 (Alliance), a phase III randomized trial for high-risk operable non-small-cell lung cancer. J Clin Oncol 32 (23): 2456-62, 2014. [PUBMED Abstract]
  16. McGarry RC, Song G, des Rosiers P, et al.: Observation-only management of early stage, medically inoperable lung cancer: poor outcome. Chest 121 (4): 1155-8, 2002. [PUBMED Abstract]
  17. Lanni TB, Grills IS, Kestin LL, et al.: Stereotactic radiotherapy reduces treatment cost while improving overall survival and local control over standard fractionated radiation therapy for medically inoperable non-small-cell lung cancer. Am J Clin Oncol 34 (5): 494-8, 2011. [PUBMED Abstract]
  18. Grutters JP, Kessels AG, 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 95 (1): 32-40, 2010. [PUBMED Abstract]
  19. Raz DJ, Zell JA, Ou SH, et al.: Natural history of stage I non-small cell lung cancer: implications for early detection. Chest 132 (1): 193-9, 2007. [PUBMED Abstract]
  20. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992. [PUBMED Abstract]
  21. Gauden S, Ramsay J, Tripcony L: The curative treatment by radiotherapy alone of stage I non-small cell carcinoma of the lung. Chest 108 (5): 1278-82, 1995. [PUBMED Abstract]
  22. Sibley GS, Jamieson TA, Marks LB, et al.: Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience. Int J Radiat Oncol Biol Phys 40 (1): 149-54, 1998. [PUBMED Abstract]
  23. Noordijk EM, vd Poest Clement E, Hermans J, et al.: Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol 13 (2): 83-9, 1988. [PUBMED Abstract]
  24. Dosoretz DE, Galmarini D, Rubenstein JH, et al.: Local control in medically inoperable lung cancer: an analysis of its importance in outcome and factors determining the probability of tumor eradication. Int J Radiat Oncol Biol Phys 27 (3): 507-16, 1993. [PUBMED Abstract]
  25. Kaskowitz L, Graham MV, Emami B, et al.: Radiation therapy alone for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 27 (3): 517-23, 1993. [PUBMED Abstract]
  26. Bradley J, Graham MV, Winter K, et al.: Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 61 (2): 318-28, 2005. [PUBMED Abstract]
  27. Bogart JA, Hodgson L, Seagren SL, et al.: Phase I study of accelerated conformal radiotherapy for stage I non-small-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904. J Clin Oncol 28 (2): 202-6, 2010. [PUBMED Abstract]
  28. Cheung P, Faria S, Ahmed S, et al.: Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25. J Natl Cancer Inst 106 (8): , 2014. [PUBMED Abstract]
  29. Timmerman R, Papiez L, McGarry R, et al.: Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 124 (5): 1946-55, 2003. [PUBMED Abstract]
  30. Timmerman 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 24 (30): 4833-9, 2006. [PUBMED Abstract]
  31. Lagerwaard FJ, Haasbeek CJ, Smit EF, et al.: Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 70 (3): 685-92, 2008. [PUBMED Abstract]
  32. Baumann P, Nyman J, Hoyer M, et al.: Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 27 (20): 3290-6, 2009. [PUBMED Abstract]
  33. Fakiris AJ, McGarry RC, Yiannoutsos CT, et al.: Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys 75 (3): 677-82, 2009. [PUBMED Abstract]
  34. Timmerman R, Paulus R, Galvin J, et al.: Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303 (11): 1070-6, 2010. [PUBMED Abstract]
  35. Senthi S, Lagerwaard FJ, Haasbeek CJ, et al.: Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. Lancet Oncol 13 (8): 802-9, 2012. [PUBMED Abstract]
  36. Senthi S, Haasbeek CJ, Slotman BJ, et al.: Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review. Radiother Oncol 106 (3): 276-82, 2013. [PUBMED Abstract]

Treatment of Stages IIA and IIB NSCLC

Treatment Options for Stages IIA and IIB NSCLC

  1. Surgery alone.
  2. Adjuvant chemotherapy.
  3. Adjuvant targeted therapy (for patients with EGFR mutations).
  4. Adjuvant immunotherapy.
  5. Adjuvant radiation therapy.
  6. Neoadjuvant chemotherapy.
  7. Neoadjuvant immunotherapy with chemotherapy.

Adjuvant radiation therapy has not been shown to improve outcomes in patients with stage II NSCLC.

Surgery with or without adjuvant or neoadjuvant therapy

Surgery alone

Surgery is the treatment of choice for patients with stage II NSCLC. A lobectomy, pneumonectomy, segmental resection, wedge resection, or sleeve resection may be performed as appropriate. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. In addition to the immediate and age-related postoperative mortality rate, a 5% to 8% mortality rate with pneumonectomy or a 3% to 5% mortality rate with lobectomy can be expected.

  1. The Cochrane Collaboration reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.[1] A pooled analysis of three trials reported the following:

Evidence suggests that lung cancer resection combined with CMLND is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.[3][Level of evidence A1]

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied and potential methodological weaknesses of the trials.

Adjuvant chemotherapy

The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected stage II NSCLC. Preoperative chemotherapy may also provide survival benefit. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC remain to be determined.

After surgery, many patients develop regional or distant metastases.[4] Several randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.[5-11]

Evidence (adjuvant chemotherapy):

  1. Data on individual patient outcomes were collected and pooled into a meta-analysis from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in patients with completely resected NSCLC that were conducted after 1995.[7]
  1. Superior OS for the trial population and patients with stage II disease was reported for the Lung Adjuvant Cisplatin Evaluation (LACE) pooled analysis (pooled HR, 0.83; 95% CI, 0.73–0.95); the Adjuvant Navelbine International Trialist Association (ANITA) trial (HR, 0.71; 95% CI, 0.49–1.03); and the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial (HR, 0.59; 95% CI, 0.42–0.85).
  2. Chemotherapy effect was higher in patients with better performance status.
  3. There was no interaction between chemotherapy effect and any of the following:

Based on these data, patients with completely resected stage II lung cancer may benefit from postoperative cisplatin-based chemotherapy.[13][Level of evidence A1]

Adjuvant targeted therapy (for patients with EGFR mutations)

Adjuvant targeted therapy with osimertinib for patients with EGFR-mutated NSCLC and resected stage IB to IIIA NSCLC was studied in a phase III clinical trial and showed improved OS.

Evidence (adjuvant targeted therapy with osimertinib for patients with stages IIA and IIB EGFR-mutated NSCLC):

  1. The ADAURA (NCT02511106) phase III, double-blind, placebo-controlled trial randomly assigned 682 patients with surgically resected stage IB to stage IIIA NSCLC with EGFR-sensitizing mutations (centrally determined, deletion in exon 19 or L858R mutation in exon 21) to receive osimertinib 80 mg by mouth daily or a placebo for 3 years. Standard postoperative adjuvant chemotherapy was allowed but not mandatory; decisions regarding adjuvant chemotherapy were made by the physician and patient before trial enrollment. There were 399 patients who received osimertinib and 342 patients who received placebo.[14][Level of evidence A1]

The U.S. Food and Drug Administration (FDA) approved osimertinib as adjuvant therapy for patients with stage IB to IIIA NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.

Adjuvant immunotherapy

Adjuvant immunotherapy for patients with resected stage IB to IIIA NSCLC has been found to significantly increase DFS.[15,16]

Evidence (adjuvant immunotherapy with pembrolizumab for patients with stage IIA and IIB tumors >4 cm):

  1. The phase III, multicenter, open-label PEARLS/KEYNOTE-091 trial (NCT02504372) randomly assigned 1,177 patients with completely resected stage IB (tumor >4 cm) to stage IIIA NSCLC to receive pembrolizumab (200 mg every 3 weeks) or placebo for up to 18 cycles, or until disease progression or unacceptable toxicity. Patients started study treatment after resection or, if indicated, after adjuvant chemotherapy (maximum of four cycles). The dual primary end points were DFS in the overall study population and DFS in patients with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 50% or greater, as determined using the PD-L1 IHC 22C3 pharmDx assay. These end points were reported in a prespecified interim analysis after a median follow-up of 35.6 months (interquartile range [IQR], 27.1–45.5).[15][Level of evidence B1]

The FDA approved pembrolizumab as a single agent for adjuvant treatment following resection and platinum-based chemotherapy for patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Of note, the FDA label specifies that pembrolizumab can be used as adjuvant therapy after platinum-based chemotherapy. However, chemotherapy was not required in the overall study patient population evaluated in KEYNOTE-091.

Evidence (adjuvant immunotherapy with atezolizumab for patients with stages IIA and IIB NSCLC):

  1. IMpower010 (NCT02486718) was a phase III, multicenter, open-label trial that randomly assigned 1,005 patients with surgically resected stage IB (tumor >4 cm) to stage IIIA NSCLC. Patients received atezolizumab (1,200 mg every 21 days intravenously) or best supportive care for 16 cycles or 1 year after standard adjuvant platinum-based chemotherapy. Patients were enrolled after resection if they were eligible for cisplatin-based chemotherapy and were randomized after completion of chemotherapy if they remained eligible and did not experience disease progression. The primary end point was investigator-assessed DFS.[16]

The FDA approved atezolizumab for adjuvant treatment of patients with stage II to IIIA NSCLC whose tumors express PD-L1 on at least 1% of tumor cells.

Adjuvant radiation therapy

The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated.[17]

Evidence (adjuvant radiation therapy):

  1. A meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported the following:[17]

Further analysis is needed to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

Neoadjuvant chemotherapy

The role of chemotherapy before surgery was tested in clinical trials. The proposed benefits of preoperative chemotherapy include:

Preoperative chemotherapy may, however, delay potentially curative surgery.

Evidence (neoadjuvant chemotherapy):

  1. The Cochrane Collaboration reported a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and evaluated the addition of preoperative chemotherapy to surgery versus surgery alone. These trials evaluated patients with stages I, II, and IIIA NSCLC.[18]
Neoadjuvant immunotherapy with chemotherapy
Nivolumab plus platinum-based chemotherapy

The CheckMate 816 trial evaluated the combination of nivolumab (an anti-programmed death 1 antibody) and platinum-based chemotherapy as neoadjuvant therapy in patients with resectable (≥4 cm or node positive) NSCLC. Nivolumab therapy improved event-free survival (EFS) and pathological complete response rates compared with chemotherapy alone.

Evidence (nivolumab plus platinum-based chemotherapy):

  1. CheckMate 816 (NCT02998528) was a phase III open-label trial that enrolled 358 patients with resectable stage IB to stage IIIA NSCLC. Notably, patients with stage IB disease had tumors measuring at least 4 cm and were classified according to the AJCC 7th edition staging criteria used for this trial; these tumors are now classified as stage IIA according to the AJCC 8th edition staging criteria. Patients were randomly assigned to receive nivolumab (360 mg) in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy alone every 3 weeks for three cycles before undergoing definitive surgery. The primary end points were EFS (defined as the time from randomization to any progression of disease precluding surgery, progression or recurrence of disease after surgery, progression of disease in the absence of surgery, or death from any cause) and pathological complete response (defined as 0% residual viable tumor cells in the primary tumor and sampled lymph nodes) according to blinded independent central review.[20][Level of evidence B1]

The FDA approved nivolumab in combination with platinum-doublet chemotherapy for neoadjuvant treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC.

Perioperative (neoadjuvant and adjuvant) immunotherapy with chemotherapy

Several immune checkpoint inhibitors have been approved by the FDA for select patient populations with potentially resectable NSCLC, either in the neoadjuvant setting (nivolumab) or adjuvant setting (atezolizumab, durvalumab, or pembrolizumab). Ongoing phase III trials are evaluating the role of perioperative immune checkpoint inhibitors. These regimens for patients with potentially resectable stages II to III NSCLC include neoadjuvant immune checkpoint inhibitors with chemotherapy followed by surgery and adjuvant immune checkpoint inhibitors. Compared with neoadjuvant chemotherapy alone, early results from studies of perioperative immune checkpoint inhibitor regimens have shown improvements in several key outcomes including EFS, major pathological response, pathological complete response, and OS.

Perioperative pembrolizumab plus platinum-based chemotherapy

Evidence (neoadjuvant pembrolizumab plus chemotherapy and adjuvant pembrolizumab):

  1. The phase III double-blind KEYNOTE-671 (NCT03425643) trial randomly assigned 797 patients with untreated stage II, IIIA, or IIIB (≥1 ipsilateral mediastinal node or subcarinal node) NSCLC. Patients received neoadjuvant pembrolizumab (200 mg every 3 weeks) or placebo with cisplatin-based chemotherapy for four cycles, followed by surgery and adjuvant pembrolizumab or placebo for up to 13 cycles, or until disease progression or unacceptable toxicity. The dual primary end points were EFS (defined as the time from randomization to local progression precluding surgery, unresectable tumor, progression or recurrence, or death) and OS. These end points were reported in a prespecified interim analysis after a median follow-up of 25.2 months (range, 7.5–50.6).[21][Level of evidence B1]
  1. The estimated 24-month EFS rate was 62.4% (95% CI, 56.8%–67.5%) for patients in the pembrolizumab group and 40.6% (95% CI, 34.8%–46.3%) for patients in the placebo group. Median EFS was not reached in the pembrolizumab group (95% CI, 34.1–NR) and was 17.0 months (95% CI, 14.3–22.0) in the placebo group (HRprogression, recurrence, or death, 0.58; 95% CI, 0.46–0.72; P< .001).
Perioperative durvalumab plus platinum-based chemotherapy

Evidence (durvalumab plus platinum-based chemotherapy):

  1. The phase III AEGEAN trial (NCT03800134) investigated perioperative durvalumab plus neoadjuvant chemotherapy compared with neoadjuvant chemotherapy alone in patients with resectable (stage II to IIIB [N2]) NSCLC. Patients received four cycles of treatment every 3 weeks before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. The modified intention-to-treat population (740 patients) included all patients who were randomly assigned, excluding patients with documented EGFR or ALK alterations. The first planned interim analysis occurred with 31.9% data maturity and at a median follow-up of 1 year. The primary end points were EFS and pathological complete response.[22][Level of evidence B1]
Perioperative nivolumab plus platinum-based chemotherapy

Evidence (neoadjuvant nivolumab plus chemotherapy and adjuvant nivolumab):

  1. The phase III randomized CheckMate 77T (NCT04025879) trial, published in abstract form, compared neoadjuvant chemotherapy and nivolumab followed by surgery and adjuvant nivolumab versus neoadjuvant chemotherapy alone in patients with untreated EGFR/ALK wild-type, resectable stage IIA (>4 cm)–IIIB (N2) NSCLC. Patients were stratified by tumor histology, PD-L1 expression, and disease stage. A total of 461 patients were randomly assigned 1:1 to receive either neoadjuvant nivolumab plus platinum-doublet chemotherapy for four cycles, surgery, and adjuvant nivolumab for 12 months or neoadjuvant platinum-doublet chemotherapy alone followed by surgery. The primary end point was EFS, and secondary end points were pathological complete response, major pathological response, OS, and safety.[23]
Perioperative toripalimab plus platinum-based chemotherapy

Evidence (toripalimab plus platinum-based chemotherapy):

The FDA has not approved this drug for patients with lung cancer.

Radiation therapy

Patients with potentially operable tumors with medical contraindications to surgery or those with inoperable stage II disease and with sufficient pulmonary reserve are candidates for radiation therapy with curative intent.[25] Primary radiation therapy often consists of approximately 60 Gy delivered with megavoltage equipment to the midplane of the volume of the known tumor using conventional fractionation. A boost to the cone down field of the primary tumor is frequently used to enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures, to the extent possible, is needed for optimal results; this requires the use of a simulator.

Among patients with excellent performance status, a 3-year survival rate of 20% may be expected if a course of radiation therapy with curative intent can be completed.

Evidence (radiation therapy):

  1. In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC were treated with definitive radiation therapy. The study reported the following:[26]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005. [PUBMED Abstract]
  2. Allen MS, Darling GE, Pechet TT, et al.: Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81 (3): 1013-9; discussion 1019-20, 2006. [PUBMED Abstract]
  3. Darling GE, Allen MS, Decker PA, et al.: Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 141 (3): 662-70, 2011. [PUBMED Abstract]
  4. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995. [PUBMED Abstract]
  5. Winton T, Livingston R, Johnson D, et al.: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352 (25): 2589-97, 2005. [PUBMED Abstract]
  6. Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004. [PUBMED Abstract]
  7. Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008. [PUBMED Abstract]
  8. Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003. [PUBMED Abstract]
  9. Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004. [PUBMED Abstract]
  10. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992. [PUBMED Abstract]
  11. Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007. [PUBMED Abstract]
  12. Douillard 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 7 (9): 719-27, 2006. [PUBMED Abstract]
  13. Pepe C, Hasan B, Winton TL, et al.: Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol 25 (12): 1553-61, 2007. [PUBMED Abstract]
  14. Tsuboi M, Herbst RS, John T, et al.: Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med 389 (2): 137-147, 2023. [PUBMED Abstract]
  15. O'Brien M, Paz-Ares L, Marreaud S, et al.: Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 23 (10): 1274-1286, 2022. [PUBMED Abstract]
  16. Felip E, Altorki N, Zhou C, et al.: Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 398 (10308): 1344-1357, 2021. [PUBMED Abstract]
  17. PORT Meta-analysis Trialists Group: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005. [PUBMED Abstract]
  18. Burdett SS, Stewart LA, Rydzewska L: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev (3): CD006157, 2007. [PUBMED Abstract]
  19. Gilligan D, Nicolson M, Smith I, et al.: Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 369 (9577): 1929-37, 2007. [PUBMED Abstract]
  20. Forde PM, Spicer J, Lu S, et al.: Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 386 (21): 1973-1985, 2022. [PUBMED Abstract]
  21. Wakelee H, Liberman M, Kato T, et al.: Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med 389 (6): 491-503, 2023. [PUBMED Abstract]
  22. Heymach JV, Harpole D, Mitsudomi T, et al.: Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med 389 (18): 1672-1684, 2023. [PUBMED Abstract]
  23. Cascone T, Awad MM, Spicer JD, et al.: CheckMate 77T: Phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC. [Abstract] Ann Oncol 34 (Suppl 2): A-LBA1, S1295, 2023.
  24. Lu S, Zhang W, Wu L, et al.: Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial. JAMA 331 (3): 201-211, 2024. [PUBMED Abstract]
  25. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985. [PUBMED Abstract]
  26. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992. [PUBMED Abstract]

Treatment of Stage IIIA NSCLC

Patients with stage IIIA non-small cell lung cancer (NSCLC) are a heterogenous group. Patients may have metastases to ipsilateral mediastinal nodes, potentially resectable T3 tumors invading the chest wall, or mediastinal involvement with metastases to peribronchial or hilar lymph nodes (N1). Presentations of disease range from resectable tumors with microscopic metastases to lymph nodes to unresectable, bulky disease involving multiple nodal stations.

Patients with clinical stage IIIA N2 disease have a 5-year overall survival (OS) rate of 10% to 15%; however, patients with bulky mediastinal involvement (i.e., visible on chest radiography) have a 5-year survival rate of 2% to 5%. Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage IIIA NSCLC are radiation therapy, chemotherapy, surgery, and combinations of these modalities.

Treatment options vary according to the location of the tumor and whether it is resectable.

Treatment Options for Resected/Resectable Stage IIIA NSCLC

Treatment options for resected/resectable disease include:

  1. Surgery with neoadjuvant or adjuvant therapy.
  2. Neoadjuvant therapy.
  1. Neoadjuvant chemotherapy.
  2. Neoadjuvant chemoradiation therapy.
  3. Neoadjuvant immunotherapy with chemotherapy.
  1. Perioperative pembrolizumab plus platinum-based chemotherapy.
  2. Perioperative durvalumab plus platinum-based chemotherapy.
  3. Perioperative nivolumab plus platinum-based chemotherapy.
  4. Perioperative toripalimab plus platinum-based chemotherapy.
  1. Adjuvant chemotherapy.
  2. Adjuvant targeted therapy (for patients with EGFR mutations).
  3. Adjuvant immunotherapy.
  4. Adjuvant chemoradiation therapy.
  5. Adjuvant radiation therapy.

Despite careful preoperative staging, some patients will be found to have metastases to mediastinal N2 lymph nodes at thoracotomy.

The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC with occult N2 disease discovered at surgery. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC are yet to be determined.

Surgery

If complete resection of tumor and lymph nodes is possible, such patients may benefit from surgery followed by postoperative chemotherapy. Current evidence suggests that lung cancer resection combined with complete ipsilateral mediastinal lymph node dissection (CMLND) is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.[1][Level of evidence A1]

The addition of surgery to chemoradiation therapy for patients with stage IIIA NSCLC did not result in improved OS in a phase III trial but did improve progression-free survival (PFS) and local control.[2][Level of evidence B1]

  1. The Cochrane Collaboration reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.[3] A pooled analysis of three trials reported the following:

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and by the potential methodological weaknesses of the trials.

Neoadjuvant therapy

Neoadjuvant chemotherapy

The role of chemotherapy before surgery in patients with stage IIIA NSCLC has been extensively tested in clinical trials. The proposed benefits of preoperative (neoadjuvant) chemotherapy include:

Evidence (neoadjuvant chemotherapy):

  1. The Cochrane Collaboration provided a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and evaluated the addition of preoperative chemotherapy to surgery versus surgery alone.[5] These trials evaluated patients with stages I, II, and IIIA NSCLC.
Neoadjuvant chemoradiation therapy

Administering concurrent neoadjuvant chemotherapy and radiation therapy before surgery may intensify treatment and increase the likelihood of downstaging the tumor burden. Commonly used regimens that have been tested in the phase II setting include cisplatin/etoposide (EP5050) and weekly carboplatin/paclitaxel.[8,9] In a randomized trial of neoadjuvant chemoradiation therapy and surgery versus concurrent chemoradiation therapy alone, there was no difference in OS, but surgery improved PFS and local control.[2][Level of evidence B1]

Evidence (neoadjuvant chemoradiation therapy):

  1. The Intergroup-0139 trial (NCT00002550) compared chemoradiation therapy alone with neoadjuvant chemoradiation followed by surgery in 396 patients with stage IIIA (N2) NSCLC.[2]

A direct comparison of neoadjuvant chemotherapy versus neoadjuvant chemoradiation therapy using modern treatment regimens has not been performed to date; the optimal neoadjuvant approach remains unclear.

Neoadjuvant immunotherapy with chemotherapy
Nivolumab plus platinum-based chemotherapy

The CheckMate 816 trial evaluated the combination of nivolumab (an anti-programmed death 1 antibody) and platinum-based chemotherapy as neoadjuvant therapy in patients with resectable (≥4 cm or node positive) NSCLC. Nivolumab therapy improved event-free survival (EFS) and pathological complete response rates compared with chemotherapy alone.

Evidence (nivolumab plus platinum-based chemotherapy):

  1. CheckMate 816 (NCT02998528) was a phase III open-label trial that enrolled 358 patients with resectable stage IB to stage IIIA NSCLC. Notably, patients with stage IB disease had tumors measuring at least 4 cm and were classified according to the AJCC 7th edition staging criteria used for this trial; these tumors are now classified as stage IIA according to the AJCC 8th edition staging criteria. Patients were randomly assigned to receive nivolumab (360 mg) in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy alone every 3 weeks for three cycles before undergoing definitive surgery. The primary end points were EFS (defined as the time from randomization to any progression of disease precluding surgery, progression or recurrence of disease after surgery, progression of disease in the absence of surgery, or death from any cause) and pathological complete response (defined as 0% residual viable tumor cells in the primary tumor and sampled lymph nodes) according to blinded independent central review.[10][Level of evidence B1]

The U.S. Food and Drug Administration (FDA) approved nivolumab in combination with platinum-doublet chemotherapy for neoadjuvant treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC.

Perioperative (neoadjuvant and adjuvant) immunotherapy with chemotherapy

Several immune checkpoint inhibitors have been approved by the FDA for select patient populations with potentially resectable NSCLC, either in the neoadjuvant setting (nivolumab) or adjuvant setting (atezolizumab, durvalumab, or pembrolizumab). Ongoing phase III trials are evaluating the role of perioperative immune checkpoint inhibitors. These regimens for patients with potentially resectable stages II to III NSCLC include neoadjuvant immune checkpoint inhibitors with chemotherapy followed by surgery and adjuvant immune checkpoint inhibitors. Compared with neoadjuvant chemotherapy alone, early results from studies of perioperative immune checkpoint inhibitor regimens have shown improvements in several key outcomes including EFS, major pathological response, pathological complete response, and OS.

Perioperative pembrolizumab plus platinum-based chemotherapy

Evidence (neoadjuvant pembrolizumab plus chemotherapy and adjuvant pembrolizumab):

  1. The phase III double-blind KEYNOTE-671 (NCT03425643) trial randomly assigned 797 patients with untreated stage II, IIIA, or IIIB (≥1 ipsilateral mediastinal node or subcarinal node) NSCLC. Patients received neoadjuvant pembrolizumab (200 mg every 3 weeks) or placebo with cisplatin-based chemotherapy for four cycles, followed by surgery and adjuvant pembrolizumab or placebo for up to 13 cycles, or until disease progression or unacceptable toxicity. The dual primary end points were EFS (defined as the time from randomization to local progression precluding surgery, unresectable tumor, progression or recurrence, or death) and OS. These end points were reported in a prespecified interim analysis after a median follow-up of 25.2 months (range, 7.5–50.6).[12][Level of evidence B1]
  1. The estimated 24-month EFS rate was 62.4% (95% CI, 56.8%–67.5%) for patients in the pembrolizumab group and 40.6% (95% CI, 34.8%–46.3%) for patients in the placebo group. Median EFS was not reached in the pembrolizumab group (95% CI, 34.1–NR) and was 17.0 months (95% CI, 14.3–22.0) in the placebo group (HRprogression, recurrence, or death, 0.58; 95% CI, 0.46–0.72; P< .001).
Perioperative durvalumab plus platinum-based chemotherapy

Evidence (durvalumab plus platinum-based chemotherapy):

  1. The phase III AEGEAN trial (NCT03800134) investigated perioperative durvalumab plus neoadjuvant chemotherapy compared with neoadjuvant chemotherapy alone in patients with resectable (stage II to IIIB [N2]) NSCLC. Patients received four cycles of treatment every 3 weeks before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. The modified intention-to-treat population (740 patients) included all patients who were randomly assigned, excluding patients with documented EGFR or ALK alterations. The first planned interim analysis occurred with 31.9% data maturity and at a median follow-up of 1 year. The primary end points were EFS and pathological complete response.[13][Level of evidence B1]
Perioperative nivolumab plus platinum-based chemotherapy

Evidence (neoadjuvant nivolumab plus chemotherapy and adjuvant nivolumab):

  1. The phase III randomized CheckMate 77T (NCT04025879) trial, published in abstract form, compared neoadjuvant chemotherapy and nivolumab followed by surgery and adjuvant nivolumab versus neoadjuvant chemotherapy alone in patients with untreated EGFR/ALK wild-type, resectable stage IIA (>4 cm)–IIIB (N2) NSCLC. Patients were stratified by tumor histology, PD-L1 expression, and disease stage. A total of 461 patients were randomly assigned 1:1 to receive either neoadjuvant nivolumab plus platinum-doublet chemotherapy for four cycles, surgery, and adjuvant nivolumab for 12 months or neoadjuvant platinum-doublet chemotherapy alone followed by surgery. The primary end point was EFS, and secondary end points were pathological complete response, major pathological response, OS, and safety.[14]
Perioperative toripalimab plus platinum-based chemotherapy

Evidence (toripalimab plus platinum-based chemotherapy):

The FDA has not approved this drug for patients with lung cancer.

Adjuvant therapy

Adjuvant chemotherapy

Patients with completely resected stage IIIA NSCLC may benefit from postoperative cisplatin-based chemotherapy.[16][Level of evidence A1]

Evidence (adjuvant chemotherapy):

Evidence from randomized controlled clinical trials indicates that when stage IIIA NSCLC is encountered unexpectedly at surgery, chemotherapy given after complete resection improves survival.

Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.[16-22]

  1. Data on individual patient outcomes from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC were collected and pooled into a meta-analysis.[16]
  1. For the subgroup of stage IIIA patients in the ANITA trial (n = 325), the HR was 0.69 (95% CI, 0.53–0.90), and the result for the FRE-IALT trial (n = 728) was HR, 0.79 (95% CI, 0.66–0.95).
  2. The chemotherapy effect was higher in patients with a better performance status.
  3. There was no interaction between the chemotherapy effect and any of the following:
Adjuvant targeted therapy (for patients with EGFR mutations)

Adjuvant targeted therapy with osimertinib for patients with EGFR-mutated NSCLC and resected stage IB to IIIA NSCLC was studied in a phase III clinical trial and showed improved OS.

Evidence (adjuvant targeted therapy with osimertinib for patients with stage IIIA EGFR-mutated NSCLC):

  1. The ADAURA (NCT02511106) phase III, double-blind, placebo-controlled trial randomly assigned 682 patients with surgically resected stage IB to stage IIIA NSCLC with EGFR-sensitizing mutations (centrally determined, deletion in exon 19 or L858R mutation in exon 21) to osimertinib 80 mg by mouth daily or a placebo for 3 years. Standard postoperative adjuvant chemotherapy was allowed but not mandatory; decisions regarding adjuvant chemotherapy were made by the physician and patient before trial enrollment. There were 399 patients who received osimertinib and 342 patients who received placebo.[24][Level of evidence A1]

The FDA approved osimertinib as adjuvant therapy for patients with stage IB to IIIA NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.

Adjuvant immunotherapy

Adjuvant immunotherapy for patients with resected stage IB to IIIA NSCLC has been found to significantly increase DFS.[25,26]

Evidence (adjuvant immunotherapy with pembrolizumab for patients with stage IIIA NSCLC):

  1. The phase III, multicenter, open-label PEARLS/KEYNOTE-091 trial (NCT02504372) randomly assigned 1,177 patients with completely resected stage IB (tumor >4 cm) to stage IIIA NSCLC to receive pembrolizumab (200 mg every 3 weeks) or placebo for up to 18 cycles, or until disease progression, or unacceptable toxicity. Patients started study treatment after resection or, if indicated, after adjuvant chemotherapy (maximum of four cycles). The dual primary end points were DFS in the overall study population and DFS in patients with a PD-L1 tumor proportion score (TPS) of 50% or greater, as determined using the PD-L1 IHC 22C3 pharmDx assay. These end points were reported in a prespecified interim analysis after a median follow-up of 35.6 months (interquartile range, 27.1–45.5).[25][Level of evidence B1]

The FDA approved pembrolizumab as a single agent for adjuvant treatment following resection and platinum-based chemotherapy for patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Of note, the FDA label specifies that pembrolizumab can be used as adjuvant therapy after platinum-based chemotherapy. However, chemotherapy was not required in the overall study patient population evaluated in KEYNOTE-091.

Evidence (adjuvant immunotherapy with atezolizumab for patients with resected stage IIIA NSCLC):

  1. IMpower010 (NCT02486718) was a phase III, multicenter, open-label trial that randomly assigned 1,005 patients with surgically resected stage IB (tumor >4 cm) to stage IIIA NSCLC. Patients received atezolizumab (1,200 mg every 21 days intravenously) or best supportive care for 16 cycles or 1 year after standard adjuvant platinum-based chemotherapy. Patients were enrolled after resection if they were eligible for cisplatin-based chemotherapy and were randomized after completion of chemotherapy if they remained eligible and did not experience disease progression. The primary end point was investigator-assessed DFS.[26]

The FDA approved atezolizumab for adjuvant treatment of patients with stage II to IIIA NSCLC whose tumors express PD-L1 on at least 1% of tumor cells.

Adjuvant chemoradiation therapy

Combination chemotherapy and radiation therapy administered before or following surgery should be viewed as investigational and requiring evaluation in future clinical trials.

Evidence (adjuvant chemoradiation therapy):

  1. Five randomized trials have assessed the value of postoperative combination chemoradiation therapy versus radiation therapy following surgical resection.[5,7,27-29][Level of evidence A1]
  1. In the largest series (EORTC-08941), 579 patients with histologically- or cytologically-proven stage IIIA (N2) NSCLC were given three cycles of platinum-based induction chemotherapy.[31] The 333 responding patients were subsequently randomly assigned to surgical resection or radiation therapy. Of the 154 patients (92%) who underwent surgery, 50% had a radical resection, 42% had a pathological downstaging, and 5% had a pathological complete response; 4% died after surgery. Postoperative (adjuvant) radiation therapy (PORT) was administered to 62 patients (40%) in the surgery arm. Among the 154 patients (93%) who received radiation therapy, overall compliance to the radiation therapy prescription was 55%, and grade 3 to 4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7% of patients; one patient died of radiation pneumonitis.
Adjuvant radiation therapy

The value of PORT has been assessed.[27] Although some studies suggest that PORT can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival. The optimal dose of thoracic PORT is not known at this time. Most studies cited used doses ranging from 30 Gy to 60 Gy, typically provided in 2 Gy to 2.5 Gy fractions.[27]

As referred to in the National Cancer Institute of Canada (NCIC) Clinical Trials Group JBR.10 study (NCT00002583), PORT may be considered in selected patients to reduce the risk of local recurrence, if any of the following are present:[23]

Evidence (adjuvant radiation therapy):

Evidence from one large meta-analysis, subset analyses of randomized trials, and one large population study suggest that PORT may reduce local recurrence. Results from these studies on the effect of PORT on OS are conflicting.

  1. A meta-analysis of ten randomized trials that evaluated PORT versus surgery alone showed the following:

There is benefit of PORT in stage IIIA (N2) disease, and the role of PORT in early stages of NSCLC should be clarified in ongoing phase III trials. Further analysis is needed to determine whether these outcomes can be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.[18]

Treatment Options for Unresectable Stage IIIA NSCLC

Treatment options for patients with unresectable stage IIIA NSCLC include:

  1. Chemoradiation therapy.
  2. Radiation therapy.

Chemoradiation therapy

The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials and meta-analyses. Overall, concurrent treatment may provide the greatest benefit in survival with an increase in toxic effects.

Concomitant platinum-based radiation chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.[32]

Evidence (chemoradiation therapy):

  1. A meta-analysis of patient data from 11 randomized clinical trials showed the following:[33]
Concurrent versus sequential chemoradiation therapy

The results from two randomized trials (including RTOG-9410 [NCT01134861]) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy may provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.[35-37][Level of evidence A1]

Evidence (concurrent vs. sequential chemoradiation therapy):

  1. In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared with chemotherapy followed by continuous daily radiation therapy to 56 Gy.[35]
Radiation therapy dose escalation for concurrent chemoradiation

With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.[39-41] However, a phase III trial of a conventional dose of 60 Gy versus dose escalation to 74 Gy with concurrent weekly carboplatin/paclitaxel did not demonstrate improved local control or PFS, and OS was worse with dose escalation (HR, 1.38; 95% CI, 1.09–1.76; P = .004). There was a nonsignificant increase in grade 5 events with dose escalation (10% vs. 2%) and higher incidence of grade 3 esophagitis (21% vs. 7%; P = .0003). Thus, there is no clear benefit in radiation dose escalation beyond 60 Gy for stage III NSCLC.[42][Level of evidence A1]

Consolidation therapy following concurrent chemoradiation

Evidence (consolidation therapy following concurrent chemoradiation):

  1. The randomized phase III PROCLAIM study [NCT00686959] enrolled 598 patients with newly diagnosed, stage IIIA/B, unresectable, nonsquamous NSCLC.[43] Patients were randomly assigned on a 1:1 ratio to either of two arms:

The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS HR of 0.74 with a type 1 error of .05. This study randomly assigned 598 patients (arm A, 301; arm B, 297) and treated 555 patients (arm A, 283; arm B, 272).

Consolidation immunotherapy
Durvalumab

Durvalumab is a selective human IgG1 monoclonal antibody that blocks PD-L1 binding to programmed death 1 (PD-1) and CD80, allowing T cells to recognize and kill tumor cells.[44]

Evidence (durvalumab following concurrent chemoradiation):

  1. The phase III PACIFIC trial (NCT02125461) enrolled 713 patients with stage III NSCLC whose disease had not progressed after two or more cycles of platinum-based chemoradiation therapy. Patients were randomly assigned in a 2:1 ratio to receive durvalumab (10 mg/kg intravenously) or placebo (every 2 weeks for up to 12 months).[44]
Osimertinib (for patients with EGFR mutations)

Evidence (osimertinib following concurrent chemoradiation therapy):

  1. The phase III, double-blind, placebo-controlled LAURA trial (NCT03521154) included patients with unresectable EGFR-mutated stage III NSCLC who had not progressed during or after definitive chemoradiation therapy. A total of 216 patients who had undergone chemoradiation therapy were randomly assigned to receive either osimertinib (n = 143) or placebo (n = 73). The primary end point was PFS as assessed by blinded independent central review.[46]
Other systemic consolidation therapies

The addition of induction chemotherapy before concurrent chemotherapy and radiation therapy has not been shown to improve survival.[47][Level of evidence A1]

Randomized trials of other consolidation systemic therapies, including docetaxel,[48] gefitinib,[49] and tecemotide (MUC1 antigen-specific immunotherapy) [50] have not shown an improvement in OS.[Level of evidence A1]

Radiation therapy

Locally advanced unresectable tumors

Radiation therapy alone may provide benefit to patients with locally advanced unresectable stage IIIA NSCLC.

Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[51]

Evidence (radiation therapy for locally advanced unresectable tumor):

  1. One prospective randomized clinical study showed the following:[52]

Although patients with unresectable stage IIIA disease may benefit from radiation therapy, long-term outcomes have generally been poor because of local and systemic relapse.

Palliative treatment

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as:

In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[53]

Evidence (radiation therapy for palliative treatment):

  1. A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[54]

Treatment Options for Superior Sulcus Tumors

Treatment options for superior sulcus tumors include:

  1. Surgery.
  2. Chemoradiation therapy followed by surgery.
  3. Radiation therapy alone.

NSCLC of the superior sulcus, frequently termed Pancoast tumors, occurs in less than 5% of patients.[61,62] Superior sulcus tumors usually arise from the apex of the lung and are challenging to treat because of their proximity to structures at the thoracic inlet. At this location, tumors may invade the parietal pleura, chest wall, brachial plexus, subclavian vessels, stellate ganglion, and adjacent vertebral bodies. However, Pancoast tumors are amenable to curative treatment, especially in patients with T3, N0 disease.

Adverse prognostic factors include the presence of mediastinal nodal metastases (N2 disease), spine or subclavian-vessel involvement (T4 disease), and limited resection (R1 or R2).

Surgery

  1. Retrospective case series have reported that complete resection was achieved in only 64% of T3, N0 tumors and 39% of T4, N0 tumors.[63]

Chemoradiation therapy followed by surgery

Evidence (chemoradiation therapy):

  1. Two large, prospective, multicenter phase II trials have evaluated induction chemoradiation therapy followed by resection.[64,65]
  1. In the first trial (NCT00002642), 110 eligible patients were enrolled with mediastinoscopy negative, clinical T3–4, N0–1 tumors of the superior sulcus.[65] Induction treatment was two cycles of etoposide and cisplatin with 45 Gy of concurrent radiation therapy.
Radiation therapy dose escalation for concurrent chemoradiation

With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.[39-41] However, a phase III trial of a conventional dose of 60 Gy versus dose escalation to 74 Gy with concurrent weekly carboplatin/paclitaxel did not demonstrate improved local control or PFS, and OS was worse with dose escalation (HR, 1.38 [1.09–1.76]; P = .004). There was a nonsignificant increase in grade 5 events with dose escalation (10% vs. 2%) and higher incidence of grade 3 esophagitis (21% vs. 7%; P = .0003). Thus, there is no clear benefit in radiation dose escalation beyond 60 Gy for stage III NSCLC.[42][Level of evidence A1]

Radiation therapy alone

While radiation therapy is an integral part of the treatment of Pancoast tumors, variations in dose, treatment technique, and staging that were used in various published series make it difficult to determine its effectiveness.[61,62]

Small, retrospective series of radiation therapy in patients who were only clinically staged have reported 5-year survival rates of 0% to 40%, depending on T stage, total radiation dose, and other prognostic factors. Induction radiation therapy and en bloc resection was shown to be potentially curative.

Evidence (radiation therapy):

  1. In the preoperative setting, a dose of 45 Gy over 5 weeks is generally recommended, while a dose of approximately 61 Gy is required when using definitive radiation therapy as the primary modality.[61,62]

Treatment Options for Tumors That Invade the Chest Wall

Treatment options for tumors that invade the chest wall include:

  1. Surgery.
  2. Surgery and radiation therapy.
  3. Radiation therapy alone.
  4. Chemotherapy combined with radiation therapy and/or surgery.

Selected patients with bulky primary tumors that directly invade the chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected.

Evidence (radical surgery):

  1. In a small case series of 97 patients, the 5-year survival rate of patients who had completely resected T3, N0, M0 disease was 44.2%. For patients with completely resected T3, N1, M0 disease, the 5-year survival rate was 40.0%. In patients with completely resected T3, N2, M0 disease, the 5-year survival rate was 6.2%.[66][Level of evidence C2]
  2. In a small case series of 104 patients, the 5-year survival rate of patients who had completely resected T3, N0, M0 disease was 67.3%. For patients with completely resected T3, N1, M0 disease, the 5-year survival rate was 100.0%. In patients with completely resected T3, N2, M0 disease, the 5-year survival rate was 17.9%.[67][Level of evidence C2]
  3. In a case series of 309 patients treated at three centers, patients who underwent en bloc resection had superior outcomes compared with patients who underwent extrapleural resections (60.3% vs. 39.1%; P = .03).[68][Level of evidence C2]

Adjuvant chemotherapy is recommended, and radiation therapy is reserved for cases with unclear resection margins. Survival rates were lower in patients who underwent incomplete resection and had mediastinal lymph node involvement. Combined-modality approaches have been evaluated to improve ability to achieve complete resection.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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Treatment of Stages IIIB and IIIC NSCLC

On the basis of the Surveillance, Epidemiology, and End Results (SEER) Program registry, the estimated incidence of stage IIIB non-small cell lung cancer (NSCLC) is 17.6%.[1] The anticipated 5-year survival rate for most patients who present with clinical stage IIIB NSCLC is 3% to 7%.[2] In small case series, selected patients with T4, N0–1 disease, solely as the result of satellite tumor nodule(s) within the primary lobe, had 5-year survival rates of 20%.[3,4][Level of evidence C1]

Treatment Options for Stages IIIB and IIIC NSCLC

Treatment options for stages IIIB NSCLC and IIIC NSCLC include:

  1. Radiation therapy dose escalation for concurrent chemoradiation.
  2. Systemic consolidation therapy before or after concurrent chemoradiation therapy.