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Non-Small Cell Lung Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Non-Small Cell Lung Cancer Treatment

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 histologic variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who have never smoked. As a class, NSCLCs are relatively insensitive to chemotherapy and radiation therapy compared with SCLC. Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy. Local control can be achieved with radiation therapy in a large number of patients with unresectable disease, but cure is seen only in a small number of 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 2013:[1]

  • New cases: 228,190.
  • Deaths: 159,480.

Lung cancer is the leading cause of cancer-related mortality in the United States.[1] The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate varies markedly depending on the stage at diagnosis, from 49% to 16% to 2% for patients with local, regional, and distant stage disease, respectively.[2]

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 anatomy; drawing shows right lung with upper, middle, and lower lobes; left lung with upper and lower lobes; and the trachea, bronchi, lymph nodes, and diaphragm. Inset shows bronchioles, alveoli, artery, and vein.
Anatomy of the respiratory system.

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 the following:

  • Hyperplasia.
  • Metaplasia.
  • Dysplasia.
  • Carcinoma in situ.

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.

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.[3]

Pathology

NSCLC is a heterogeneous aggregate of histologies. The most common histologies include the following:

  • Epidermoid or squamous cell carcinoma.
  • Adenocarcinoma.
  • Large cell carcinoma.

These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar.

Risk Factors

Several risk factors contribute to the development of lung cancer. These risk factors may include the following:

  • Cigarette, pipe, or cigar smoking.
  • Exposure to second-hand smoke, radon, arsenic, asbestos, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons, radon progeny, other agents, and air pollution.[4]
  • Radiation therapy to the breast or chest.

The single most important risk factor for the development of lung cancer is smoking. For smokers, the risk for lung cancer is on average tenfold higher than in lifetime nonsmokers (defined as a person who has smoked <100 cigarettes in his or her lifetime). The risk increases with the quantity of cigarettes, duration of smoking, and starting age.

Smoking cessation results in a decrease in precancerous lesions and a reduction in the risk of developing lung cancer. Former smokers continue to have an elevated risk for lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on the lung cancer risk.[4]

Prevention

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.[5] 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.[6]

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 with the agents beta carotene, retinol, 13-cis-retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results.[7,8,9,10,11][Level of evidence: 1iiA] Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early-stage lung cancer.

Refer to the PDQ summaries on Lung Cancer Prevention and Smoking in Cancer Care for more information.

Screening

In patients considered at high risk for developing lung cancer, the only screening modality for early detection that has been shown to alter mortality is low-dose helical CT scanning.[12] Studies of lung cancer screening with chest radiography and sputum cytology have failed to demonstrate that screening lowers lung cancer mortality rates.

(Refer to the Screening by low-dose helical computed tomography subsection in the PDQ summary on Lung Cancer Screening for more information.)

Clinical Features

Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough or chest pain. Other presenting symptoms include the following:

  • Hemoptysis.
  • Malaise.
  • Weight loss.
  • Dyspnea.
  • Hoarseness.

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

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

The procedures used to determine the presence of cancer include the following:

  • History.
  • Physical examination.
  • Routine laboratory evaluations.
  • Chest x-ray.
  • Chest CT scan with infusion of contrast material.
  • Biopsy.

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic 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.[13] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

(Refer to the Staging Evaluation section of this summary for more information on tests and procedures used for staging.)

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.[14] 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.

Other genetic abnormalities of potential relevance to treatment decisions include translocations involving the anaplastic lymphoma kinase (ALK)-tyrosine kinase receptor, which are sensitive to ALK inhibitors, and amplification of MET (mesenchymal epithelial transition factor), which encodes the hepatocyte growth factor receptor. MET amplification has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

Prognostic Factors

Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathologic factors.[6,15,16,17,18] Factors that have correlated with adverse prognosis include the following:

  • Presence of pulmonary symptoms.
  • Large tumor size (>3 cm).
  • Nonsquamous histology.
  • Metastases to multiple lymph nodes within a TNM-defined nodal station.[19,20,21,22,23,24,25,26,27,28,29] (Refer to the Evaluation of Mediastinal Lymph Node Metastasis section of this summary for more information.)
  • Vascular invasion.[16,30,31,32]

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.[33]

Refer to the separate treatment sections for each stage of NSCLC in this summary for more information about prognosis.

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

Related Summaries

Other PDQ summaries containing information related to lung cancer include the following:

  • Lung Cancer Prevention
  • Lung Cancer Screening
  • Small Cell Lung Cancer Treatment
  • Smoking in Cancer Care

References:

1. American Cancer Society.: Cancer Facts and Figures 2013. Atlanta, Ga: American Cancer Society, 2013. Available online. Last accessed September 5, 2013.
2. Ries L, Eisner M, Kosary C, et al., eds.: Cancer Statistics Review, 1975-2002. Bethesda, Md: National Cancer Institute, 2005. Available online. Last accessed May 30, 2013.
3. Johnson BE: Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 90 (18): 1335-45, 1998.
4. 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.
5. 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.
6. 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.
7. 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.
8. Blumberg J, Block G: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finland. Nutr Rev 52 (7): 242-5, 1994.
9. 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.
10. 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.
11. 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.
12. 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.
13. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999.
14. Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.

Cellular 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). There are three main subtypes of non-small cell lung cancer (NSCLC), including the following:

  • Squamous cell carcinoma (25% of lung cancers).
  • Adenocarcinoma (40% of lung cancers).
  • Large cell carcinoma (10% of lung cancers).

There are numerous additional subtypes of decreasing frequency.[1]

WHO/IASLC Histologic Classification of NSCLC

1. Squamous cell carcinoma.
1. Papillary.
2. Clear cell.
3. Small cell.
4. Basaloid.
2. Adenocarcinoma.
1. Acinar.
2. Papillary.
3. Bronchioloalveolar carcinoma.
1. Nonmucinous.
2. Mucinous.
3. Mixed mucinous and nonmucinous or indeterminate cell type.
4. Solid adenocarcinoma with mucin.
5. Adenocarcinoma with mixed subtypes.
6. Variants.
1. Well-differentiated fetal adenocarcinoma.
2. Mucinous (colloid) adenocarcinoma.
3. Mucinous cystadenocarcinoma.
4. Signet ring adenocarcinoma.
5. Clear cell adenocarcinoma.
3. Large cell carcinoma.
1. Variants.
1. Large cell neuroendocrine carcinoma (LCNEC).
2. Combined LCNEC.
3. Basaloid carcinoma.
4. Lymphoepithelioma-like carcinoma.
5. Clear cell carcinoma.
6. Large cell carcinoma with rhabdoid phenotype.
4. Adenosquamous carcinoma.
5. Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.
1. Carcinomas with spindle and/or giant cells.
2. Spindle cell carcinoma.
3. Giant cell carcinoma.
4. Carcinosarcoma.
5. Pulmonary blastoma.
6. Carcinoid tumor.
1. Typical carcinoid.
2. Atypical carcinoid.
7. Carcinomas of salivary gland type.
1. Mucoepidermoid carcinoma.
2. Adenoid cystic carcinoma.
3. Others.
8. Unclassified carcinoma.

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 histologic subtype in many countries, and subclassification of adenocarcinoma is important. One of the biggest problems with lung adenocarcinomas is the frequent histologic heterogeneity. In fact, mixtures of adenocarcinoma histologic 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 histologic subgroups.

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

  • Well-differentiated fetal adenocarcinoma.
  • Mucinous (colloid) adenocarcinoma.
  • Mucinous cystadenocarcinoma.
  • Signet ring adenocarcinoma.
  • Clear cell adenocarcinoma.

Large cell carcinoma

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

  • LCNEC.
  • Basaloid carcinoma.
  • Lymphoepithelioma-like carcinoma.
  • Clear cell carcinoma.
  • Large cell carcinoma with rhabdoid phenotype.

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 histologic 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. Other mutations of potential relevance to treatment decisions include:

  • Kirsten rat sarcoma viral oncogene (KRAS).
  • Anaplastic lymphoma kinase receptor (ALK).
  • Human epidermal growth factor receptor 2 (HER2).
  • V-raf murine sarcoma viral oncogene homolog B1 (BRAF).
  • PIK3 catalytic protein alpha (PI3KCA).
  • AKT1.
  • MAPK kinase 1 (MAP2K1 or MEK1).
  • MET, which encodes the hepatocyte growth factor receptor (HGFR).

These mutations are mutually exclusive, except for those in PIK3CA and EGFR mutations and ALK translocations.[3]

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 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% 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).[4]

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. Other mutations that occur in less than 5% of NSCLC tumors include:

  • HER2, present in 2% of tumors.
  • PI3KCA, present in 2% of tumors.
  • AKT1, present in 1% of tumors.
  • BRAF mutations, present in 1% to 3% of tumors.

BRAF mutations are mutually exclusive of EGFR and KRAS mutations. Somatic mutations in MAP2K1 (also known as MEK) have been identified in 1% of NSCLC. MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

References:

1. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999.
2. Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011.
3. Tiseo M, Gelsomino F, Boggiani D, et al.: EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer 71 (2): 241-3, 2011.
4. 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.

Stage Information for NSCLC

Background

In NSCLC, the determination of stage is important in terms of 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, or 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 under consideration 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 staging include the following:

  • History.
  • Physical examination.
  • Routine laboratory evaluations.
  • Chest x-ray.
  • Chest CT scan with infusion of contrast material.
  • Fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning.

Procedures used to obtain tissue samples include bronchoscopy, mediastinoscopy, or anterior mediastinotomy. Pathological staging of NSCLC requires the following:

  • Examination of the tumor.
  • Resection margins.
  • Lymph nodes.

Prognostic and treatment decisions are based on some of the following factors:

  • Knowledge of histologic type.
  • Tumor size and location.
  • Involvement of pleura.
  • Surgical margins.
  • Status and location of lymph nodes by station.
  • Tumor grade.
  • Lymphovascular invasion.

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).
  • Has the best prognosis, which depends on a variety of tumor and host factors.
  • Patients with resectable disease who have medical contraindications to surgery are candidates for curative radiation therapy.
  • Postoperative cisplatin-based combination chemotherapy may provide a survival advantage to patients with resected stage II or stage IIIA NSCLC.
2. Locally (T3–T4) and/or regionally (N2–N3) advanced disease.
  • Has a diverse natural history.
  • Selected patients with locally advanced tumors may benefit from combined modality treatments.
  • Patients with unresectable or N2-N3 disease are treated with radiation therapy in combination with chemotherapy.
  • Selected patients with T3 or N2 disease can be treated effectively with surgical resection and either preoperative or postoperative chemotherapy or chemoradiation therapy.
3. Distant metastatic disease (includes distant metastases [M1] that were found at the time of diagnosis).
  • May be treated with radiation therapy or chemotherapy for palliation of symptoms from the primary tumor.
  • Patients with good performance status, women, and patients with distant metastases confined to a single site live longer than others.[2]
  • Platinum-based chemotherapy has been associated with short-term palliation of symptoms and with a survival advantage.
  • Currently, no single chemotherapy regimen can be recommended for routine use.
  • Patients previously treated with platinum combination chemotherapy may derive symptom control and survival benefit from docetaxel, pemetrexed, or epidermal growth factor receptor inhibitors.

Staging Evaluation

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 database for the period from 1990 to 2000.[3] A total of 16,800 patients were included in the study.
  • The overall survival (OS) analysis for patients without radiation therapy demonstrated that in comparison to the reference group (one to four lymph nodes), patients with five to eight lymph nodes examined during surgery had a modest but statistically significant increase in survival, with a proportionate hazard ratio (HR) of 0.90 (95% confidence interval [CI], 0.84–0.97). For patients with 9 to 12 lymph nodes and 13 to 16 lymph nodes examined, HRs were 0.86 (95% CI, 0.79–0.95) and 0.78 (95% CI, 0.68–0.90), respectively. There appeared to be no incremental improvement after evaluating more than 16 lymph nodes. The corresponding results for lung cancer–specific mortality and for patients receiving radiation therapy were not substantially different.
  • These results indicate that patient survival following resection for NSCLC is associated with the number of lymph nodes evaluated during surgery. Because this is most likely the result of a reduction-of-staging error, namely, a decreased likelihood of missing positive lymph nodes with an increasing number of lymph nodes sampled, it suggests that an evaluation of nodal status should include 11 to 16 lymph nodes.

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.[4]

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 has been 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 IV 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.[5]
  • The median prevalence of mediastinal metastasis was 28% (range, 18%–56%).
  • The pooled sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were 51% (95% CI, 47%–54%) and 86% (95% CI, 84%–88%), respectively. The corresponding positive and negative likelihood ratios were 3.4 and 0.6, respectively.
2. The results from the systematic review are similar to those of a large meta-analysis that reported the median sensitivity and specificity of CT scanning for identifying malignant mediastinal nodes as 61% and 79%, respectively.[6]
3. An earlier meta-analysis reported average sensitivity and specificity of 64% and 74%, respectively.[7]

FDG-PET scanning

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

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

Although the current evidence is conflicting, 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 (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 FDG-PET scanning in the diagnosis and staging of lung cancer.[8] Through a systematic search of the literature, 12 evidence summary reports and 15 prospective studies of the diagnostic accuracy of FDG-PET scanning were identified. FDG-PET scanning appears to be superior to CT imaging for mediastinal staging in NSCLC. FDG-PET scanning also appears to have high sensitivity and reasonable specificity for differentiating benign from malignant lesions as small as 1 cm.
2. A systematic review of the medical literature relating to the accuracy of FDG-PET scanning for noninvasive staging of the mediastinum in patients with lung cancer identified 44 studies published between 1994 and 2006 with 2,865 evaluable patients.[5] The median prevalence of mediastinal metastases was 29% (range, 5%–64%). Pooled estimates of sensitivity and specificity for identifying mediastinal metastasis were 74% (95% CI, 69%–79%) and 85% (95% CI, 82%–88%), respectively. Corresponding positive and negative likelihood ratios for mediastinal staging with FDG-PET scanning were 4.9 and 0.3, respectively. These findings demonstrate that FDG-PET scanning is more accurate than CT scanning for staging of the mediastinum in patients with lung cancer.

Cost effectiveness of FDG-PET scanning

Decision analyses demonstrate that 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.[9,10,11] Studies concluded that the money saved by forgoing mediastinoscopy in FDG-PET-positive mediastinal lesions was not justified because of the unacceptably high number of false-positive results.[9,10,11] A randomized study found that the addition of FDG-PET scanning to conventional staging was associated with significantly fewer thoracotomies.[12] A second randomized trial evaluating the impact of FDG-PET scanning on clinical management found that FDG-PET scanning provided additional information regarding appropriate stage but did not lead to significantly fewer thoracotomies.[13]

Combination of CT imaging and FDG-PET scanning

The combination of CT imaging and FDG-PET scanning has greater sensitivity and specificity than CT imaging alone.[14]

Evidence (CT/FDG-PET scan):

1. If there is no evidence of distant metastatic disease on CT scan, FDG-PET scanning complements CT scan staging of the mediastinum. Numerous nonrandomized studies of 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. In a meta-analysis evaluating the conditional test performance of FDG-PET scanning and CT scanning, the median sensitivity and specificity of FDG-PET scans were reported as 100% and 78%, respectively, in patients with enlarged lymph nodes.[6] FDG-PET scanning is considered very accurate in identifying malignant nodal involvement when nodes are enlarged. However, FDG-PET scanning will falsely identify a malignancy in approximately one-fourth of patients with nodes that are enlarged for other reasons, usually as a result of inflammation or infection.[15,16]
3. The median sensitivity and specificity of FDG-PET scanning in patients with normal-sized mediastinal lymph nodes were 82% and 93%, respectively.[6] These data indicate that nearly 20% of patients with normal-sized nodes but with malignant involvement had falsely negative FDG-PET scan findings.

For patients with clinically operable NSCLC, the recommendation is for a biopsy of mediastinal lymph nodes that were found to be larger than 1 cm in shortest transverse axis on chest CT scan or were found to be positive on FDG-PET scan. Negative 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 FDG-PET scan do not corroborate each other.

Evaluation of brain metastasis

Patients at risk for brain metastases may be staged with CT or MRI scans. 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. MRI showed a trend towards a higher preoperative detection rate than CT scan (P = .069), with an overall detection rate of approximately 7% from pretreatment to 12 months after surgery.[17] Patients with stage I or stage II disease had a detection rate of 4% (i.e., eight detections out of 200 patients); however, individuals with stage III disease had a detection rate of 11.4% (i.e., 15 detections out of 132 patients). The mean maximal diameter of the brain metastases was significantly smaller in the MRI group. 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 other than the brain

Numerous nonrandomized, prospective, and retrospective studies have demonstrated that FDG-PET scanning seems to offer diagnostic advantages over conventional imaging in staging distant metastatic disease; however, standard FDG-PET scans have limitations. 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 FDG-PET scanning accumulates in the brain and urinary tract, FDG-PET scanning is not reliable for detection of metastases in these sites.[17]

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.[18,19] These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging.

Summary of Changes

This staging system is now recommended for the classification of both NSCLC and small cell lung carcinomas and for carcinoid tumors of the lung.[19]

The T (primary tumor) classifications have been redefined as follows:[19]

  • T1 has been subclassified into T1a (≤2 cm in size) and T1b (>2–3 cm in size).
  • T2 has been subclassified into T2a (>3–5 cm in size) and T2b (>5–7 cm in size).
  • T2 (>7 cm in size) has been reclassified as T3.
  • Multiple tumor nodules in the same lobe have been reclassified from T4 to T3.
  • Multiple tumor nodules in the same lung but a different lobe have been reclassified from M1 to T4.

No changes have been made to the N (regional lymph nodes) classification. However, a new international lymph node map defining the anatomical boundaries for lymph node stations has been developed.

The M (distant metastasis) classifications have been redefined as follows:

  • M1 has been subdivided into M1a and M1b.
  • Malignant pleural and pericardial effusions have been reclassified from T4 to M1a.
  • Separate tumor nodules in the contralateral lung are considered M1a.
  • M1b designates distant metastasis.

Table 1. Stage Grouping Comparisons: Sixth Edition Versus Seventh Edition Descriptors, T and M Categories, and Stage Groupingsa,b

Sixth Edition T/M Descriptor (cm) Seventh Edition T/M N0 N1 N2 N3
T = primary tumor; N0 = no regional lymph node metastasis; N1 = metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension; N2 = metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s); N3 = metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s); M = distant metastasis.
a Cells in bold indicate a change from the sixth edition for a particular TNM category.
b Reprinted with permission from Goldstraw P, Crowley J, Chansky K, et al.: The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours.J. Thorac Oncol 2:706-14, 2007.
T1 (≤2) T1a IA IIA IIIA IIIB
T1 (>2–3) T1b IA IIA IIIA IIIB
T2 (≤5) T2a IB IIA IIIA IIIB
T2 (>5–7) T2b IIA IIB IIIA IIIB
T2 (>7) T3 IIB IIIA IIIA IIIB
T3 invasion T3 IIB IIIA IIIA IIIB
T4 (same lobe nodules) T3 IIB IIIA IIIA IIIB
T4 (extension) T4 IIIA IIIA IIIB IIIB
M1 (ipsilateral lung) T4 IIIA IIIA IIIB IIIB
T4 (pleural effusion) M1a IV IV IV IV
M1 (contralateral lung) M1a IV IV IV IV
M1 (distant) M1b IV IV IV IV

AJCC Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM classification to define NSCLC.[19]

Table 2. Definitions of TNM Occult Carcinomaa

Stage TNM Description
a Reprinted with permission from AJCC: Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70.
Occult carcinoma TX, N0, M0 TX = Primary 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.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.

Table 3. Definitions of TNM Stage 0a

Stage TNM Description
a Reprinted with permission from AJCC: Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70.
0 Tis, N0, M0 Tis = Carcinomain situ.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.

Table 4. Definitions of TNM Stage IAa

Stage TNM Description Illustration
a Reprinted with permission from AJCC: Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70.
b The uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.
IA
T1a, N0, M0
T1a = Tumor ≤2 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).b

Two-panel drawing of stage I non-small cell lung cancer. First panel shows stage IA with cancer (3 cm or less) in the right lung; also shown are the right main bronchus, trachea, lymph nodes, bronchioles, and diaphragm. Second panel shows stage IB with cancer (more than 3 cm but not more than 5 cm) in the left lung and in the left main bronchus; the carina is also shown. Inset shows cancer that has spread from the lung into the innermost layer of the lung lining; a rib is also shown.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T1b, N0, M0 T1b = Tumor >2 cm but ≤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).b
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.

Table 5. Definitions of TNM Stage IBa

Stage TNM Description Illustration
a Reprinted with permission from AJCC: Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70.
b The uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.
IB
T2a, N0, M0
T2a = Tumor >3 cm but ≤5 cm in greatest dimension,or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2);or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

Two-panel drawing of stage I non-small cell lung cancer. First panel shows stage IA with cancer (3 cm or less) in the right lung; also shown are the right main bronchus, trachea, lymph nodes, bronchioles, and diaphragm. Second panel shows stage IB with cancer (more than 3 cm but not more than 5 cm) in the left lung and in the left main bronchus; the carina is also shown. Inset shows cancer that has spread from the lung into the innermost layer of the lung lining; a rib is also shown.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.

Table 6. Definitions of TNM Stage IIAa

Stage TNM Description Illustration
a Reprinted with permission from AJCC: Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70.
b The uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.
IIA
T2b, N0, M0
T2b = Tumor >5 cm but ≤7 cm or less in greatest dimension,or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2);or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

Two-panel drawing of stage IIA non-small cell lung cancer. First panel shows cancer (5 cm or less), and cancer in the right main bronchus and lymph nodes; also shown are the trachea, bronchioles, and diaphragm. Second panel shows cancer (more than 5 cm but not more than 7 cm), and cancer in the left main bronchus; also shown are the trachea, lymph nodes, bronchioles, and diaphragm. Insets show cancer that has spread from the lung into the innermost layer of the lung lining; a rib is also shown.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T1a, N1, M0 T1a = Tumor ≤2 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).b
N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
M0 = No distant metastasis.
T1b, N1, M0 T1b = Tumor >2 cm but ≤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).b
N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
M0 = No distant metastasis.
T2a, N1, M0 T2a = Tumor >3 cm but ≤5 cm in greatest dimension,or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2);or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.
N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
M0 = No distant metastasis.

Table 7. Definitions of TNM Stage IIBa

Stage TNM Description Illustration
a Reprinted with permission from AJCC: Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70.
b The uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.
IIB
T2b, N1, M0
T2b = Tumor >5 cm but ≤7 cm in greatest dimension,or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2);or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

Two-panel drawing of stage IIB non-small cell lung cancer. First panel shows cancer (more than 5 cm but not more than 7 cm), and cancer in the right main bronchus and lymph nodes; also shown are the trachea, bronchioles, and diaphragm. Inset shows cancer that has spread from the lung to the innermost layer of the lung lining; a rib is also shown. Second panel shows cancer (more than 7 cm), and cancer in the left main bronchus; also shown are the trachea, lymph nodes, bronchioles, and diaphragm. Top inset shows cancer that has spread from the lung through the lung lining and chest wall lining into the chest wall; a rib is also shown. Bottom inset shows the heart and cancer that has spread from the lung into the membrane around the heart.
N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
M0 = No distant metastasis.
T3, N0, M0 T3 = Tumor >7 cmor one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardiumor tumor in the main bronchus (<2 cm distal to the carinab but without involvement of the carina)or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.b
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.

Table 8. Definitions of TNM Stage IIIAa

Stage TNM Description Illustration
a Reprinted with permission from AJCC: Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70.
b The uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.
IIIA
T1a, N2, M0
T1a = Tumor ≤2 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).b

Stage IIIA non-small cell lung cancer (1). Drawing shows cancer in lymph nodes, left main bronchus, and diaphragm; there may be separate tumors in the same lung; the trachea is also shown. Top inset shows cancer that has spread from the lung through the lung lining and chest wall lining into the chest wall; a rib is also shown. Bottom inset shows the heart and cancer that has spread from the lung into the membrane around the heart.

Stage IIIA lung cancer (2). Drawing shows cancer in the lymph nodes, trachea, carina, left main bronchus, esophagus, sternum, diaphragm, and major blood vessels that lead to or from the heart; there may be separate tumors in the same lung. Top inset shows cancer that has spread from the lung through the lung lining and chest wall lining into the chest wall; a rib is also shown. Bottom inset shows cancer that has spread from the lung, through the membrane around the heart, into the heart.

Stage IIIA non-small cell lung cancer (3). Drawing shows cancer in the heart, major blood vessels that lead to or from the heart, the trachea, esophagus, sternum, and carina; the diaphragm is also shown. Inset shows cancer that has spread from the lung, through the membrane around the heart, into the heart.
N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
M0 = No distant metastasis.
T1b, N2, M0 T1b = Tumor >2 cm but ≤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).b
N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
M0 = No distant metastasis.
T2a, N2, M0 T2a = Tumor >3 cm but ≤5 cm in greatest dimension,or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2);or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.
N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
M0 = No distant metastasis.
T2b, N2, M0 T2b = Tumor >5 cm but ≤7 cm in greatest dimension,or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2);or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.
N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
M0 = No distant metastasis.
T3, N1, M0 T3 = Tumor >7 cmor one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardiumor tumor in the main bronchus (<2 cm distal to the carinab but without involvement of the carina)or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.
N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
M0 = No distant metastasis.
T3, N2, M0 T3 = Tumor >7 cmor one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardiumor tumor in the main bronchus (<2 cm distal to the carinab but without involvement of the carina)or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.
N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
M0 = No distant metastasis.
T4, N0, M0 T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T4, N1, M0 T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe.
N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
M0 = No distant metastasis.

Table 9. Definitions of TNM Stage IIIBa

Stage TNM Description Illustration
a Reprinted with permission from AJCC: Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70.
b The uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.
IIIB
T1a, N3, M0
T1a = Tumor ≤2 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).b

Stage IIIB non-small cell lung cancer (1). Drawing shows cancer in lymph nodes above the collarbone on the opposite side of the chest as the primary tumor, and in the trachea, carina, left main bronchus, esophagus, sternum, diaphragm, and major blood vessels that lead to or from the heart; there may be separate tumors in the same lung. Top inset shows cancer that has spread from the lung, through the lung lining and chest wall lining, into the chest wall; a rib is also shown. Bottom inset shows cancer that has spread from the lung, through the membrane around the heart, into the heart.

Stage IIIB non-small cell lung cancer (2). Drawing shows cancer in lymph nodes on the same side of the chest as the primary tumor, in the heart, major blood vessels that lead to or from the heart, the trachea, esophagus, sternum, carina, and in separate tumors in different lobes of the same lung; the diaphragm is also shown. Inset shows cancer that has spread from the lung, through the membrane around the heart, into the heart.
N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
M0 = No distant metastasis.
T1b, N3, M0 T1b = Tumor >2 cm but ≤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).b
N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
M0 = No distant metastasis.
T2a, N3, M0 T2a = Tumor >3 cm but ≤5 cm or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2);or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.
N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
M0 = No distant metastasis.
T2b, N3, M0 T2b = Tumor >5 cm but ≤7 cmor tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2);or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.
N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
M0 = No distant metastasis.
T3, N3, M0 T3 = Tumor >7 cmor one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardiumor tumor in the main bronchus (<2 cm distal to the carinab but without involvement of the carina)or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.
N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
M0 = No distant metastasis.
T4, N2, M0 T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe.
N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
M0 = No distant metastasis.
T4, N3, M0 T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe.
N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
M0 = No distant metastasis.

Table 10. Definitions of TNM Stage IVa

Stage TNM Description Illustration
a Reprinted with permission from AJCC: Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70.
b The uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.
c Most pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element, and the patient should be classified as M0.
IV
Any T, Any N, M1aOR Any T, Any N, M1b
TX = Primary 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.

Stage IV non-small cell lung cancer. Drawing shows other parts of the body where lung cancer may spread, including the other lung, the brain, lymph nodes, adrenal gland, kidney, liver, and bone. Inset shows cancer spreading through the blood and lymph nodes to other parts of the body.
T0 = No evidence of primary tumor.
Tis = Carcinomain situ.
T1 = Tumor ≤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).b
T2 = Tumor >3 cm but ≤7 cm in greatest dimension,or tumor with any of the following features (T2 tumors with these features are classified T2a if ≤5 cm): involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2);or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.
T3 = Tumor >7 cmor one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardiumor tumor in the main bronchus (<2 cm distal to the carinab but without involvement of the carina)or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.
T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.
N2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).
N3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
M0 = No distant metastasis.
M1 = Distant metastasis.
M1a = Separate tumor nodule(s) in a contralateral lobe tumor with pleural nodules or malignant pleural (or pericardial) effusion.c
M1b = Distant metastasis (in extrathoracic organs).

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4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997.
19. Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70.

Treatment Option Overview for NSCLC

In 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.

Surgery is the most potentially 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 (PCI) may reduce the incidence of brain metastases, but there is no evidence of a survival benefit and the effect of PCI 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, though 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 fit elderly patients with good performance status obtain the same benefits from treatment as younger patients.

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.[7] In particular, genetic abnormalities in EGFR, MAPK, 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 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. MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

The standard treatment options for each stage of NSCLC are presented in Table 11.

Table 11. Standard Treatment Options for NSCLC

Stage (TNM Staging Criteria) Standard Treatment Options
Occult NSCLC Surgery
Stage 0 NSCLC Surgery
Endobronchial therapies
Stages IA and IB NSCLC Surgery
Radiation therapy
Stages IIA and IIB NSCLC Surgery
Neoadjuvant chemotherapy
Adjuvant chemotherapy
Radiation therapy
Stage IIIA NSCLC Resected or resectable disease Surgery
Neoadjuvant therapy
Adjuvant therapy
Unresectable disease Radiation therapy
Chemoradiation therapy
Superior sulcus tumors Radiation therapy alone
Radiation therapy and surgery
Concurrent chemotherapy with radiation therapy and surgery
Surgery alone (for selected patients)
Tumors that invade the chest wall Surgery
Surgery and radiation therapy
Radiation therapy alone
Chemotherapy combined with radiation therapy and/or surgery
Stage IIIB NSCLC Sequential or concurrent chemotherapy and radiation therapy
Chemotherapy followed by surgery (for selected patients)
Radiation therapy alone
Stage IV NSCLC Cytotoxic combination chemotherapy (first line)
Combination chemotherapy with bevacizumab or cetuximab
EGFR tyrosine kinase inhibitors (first line)
EML4-ALK inhibitors in patients with EML-ALK translocations
Maintenance therapy following first-line chemotherapy
Endobronchial laser therapy and/or brachytherapy (for obstructing lesions)
External-beam radiation therapy (primarily for palliation of local symptomatic tumor growth)
Recurrent NSCLC Radiation therapy (for palliation)
Chemotherapy or kinase inhibitors alone
EGFR inhibitors in patients with/without EGFR mutations
EML4-ALK inhibitors in patients with EML-ALK translocations
Surgical resection of isolated cerebral metastasis (for highly selected patients)
Laser therapy or interstitial radiation therapy (for endobronchial lesions)
Stereotactic radiation surgery (for highly selected patients)

In addition to the standard treatment options presented in Table 11, treatment options under clinical evaluation include the following:

  • Combining local treatment (surgery).
  • Regional treatment (radiation therapy).
  • Systemic treatments (chemotherapy, immunotherapy, and targeted agents).
  • Developing more effective systemic therapy.

Follow-Up

Several small series have reported that reduction in fluorodeoxyglucose-positron emission tomography (FDG-PET) after chemotherapy, radiation therapy, or chemoradiation therapy correlates with pathological complete response and favorable prognosis.[8,9,10,11,12,13,14,15] Studies have used different timing of assessments, FDG-PET parameters, and cutpoints to define FDG-PET response. Reduction in maximum standardized uptake value (SUV) of more than 80% predicted for complete pathological response with a sensitivity of 90%, specificity of 100%, and accuracy of 96%.[16] Median survival after resection was greater for patients with tumor SUV values of less than 4 (56 mo vs. 19 mo).[15] Patients with complete metabolic response following radiation therapy were reported to have median survivals of 31 months versus 11 months.[17]

FDG-PET may be more sensitive and specific than computed tomography scan in assessing response to induction therapy. Optimal timing imaging remains to be defined; however, one study suggests that greater sensitivity and specificity of FDG-PET is achieved if repeat imaging is delayed until 30 days after radiation therapy.[16]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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.
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.
3. Chemotherapy for non-small cell lung cancer. Non-small Cell Lung Cancer Collaborative Group. Cochrane Database Syst Rev (2): CD002139, 2000.
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.
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.
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.
7. Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011.
8. Curran WJ, Scott CB, Langer CJ, et al.: Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III nsclc: RTOG 9410. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-2499, 2003.
9. Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005.
10. Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004.
11. Rowell NP, O'rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004.
12. Cerfolio RJ, Bryant AS, Winokur TS, et al.: Repeat FDG-PET after neoadjuvant therapy is a predictor of pathologic response in patients with non-small cell lung cancer. Ann Thorac Surg 78 (6): 1903-9; discussion 1909, 2004.
13. Pöttgen C, Levegrün S, Theegarten D, et al.: Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res 12 (1): 97-106, 2006.
14. Eschmann SM, Friedel G, Paulsen F, et al.: 18F-FDG PET for assessment of therapy response and preoperative re-evaluation after neoadjuvant radio-chemotherapy in stage III non-small cell lung cancer. Eur J Nucl Med Mol Imaging 34 (4): 463-71, 2007.
15. Hellwig D, Graeter TP, Ukena D, et al.: Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma. J Thorac Cardiovasc Surg 128 (6): 892-9, 2004.
16. Cerfolio RJ, Bryant AS: When is it best to repeat a 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan on patients with non-small cell lung cancer who have received neoadjuvant chemoradiotherapy? Ann Thorac Surg 84 (4): 1092-7, 2007.
17. Mac Manus MP, Hicks RJ, Matthews JP, et al.: Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 21 (7): 1285-92, 2003.

Occult NSCLC Treatment

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 NSCLC patients with similar stage disease.

Standard Treatment Options for Occult NSCLC

Standard treatment options for occult NSCLC include the following:

1. Surgery.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with occult non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage 0 NSCLC Treatment

Stage 0 NSCLC frequently progresses to invasive cancer.[1,2,3] Patients may be offered surveillance bronchoscopies and, if lesions are detected, potentially curative therapies.

Standard Treatment Options for Stage 0 NSCLC

Standard treatment options for stage 0 NSCLC include the following:

1. Surgery.
2. Endobronchial therapies, including photodynamic therapy, electrocautery, cryotherapy, and Nd-YAG laser therapy.

Surgery

Segmentectomy or wedge resection are used to preserve maximum normal pulmonary tissue since patients with stage 0 NSCLC are at a high risk for 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.[3,4,5,6]

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: 3iiiDiii]

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

There is a high incidence of second primary cancers developing.[1,2]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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.
2. Venmans BJ, van Boxem TJ, Smit EF, et al.: Outcome of bronchial carcinoma in situ. Chest 117 (6): 1572-6, 2000.
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.
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.
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.
6. Deygas N, Froudarakis M, Ozenne G, et al.: Cryotherapy in early superficial bronchogenic carcinoma. Chest 120 (1): 26-31, 2001.
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.
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.

Stages IA and IB NSCLC Treatment

Standard Treatment Options for Stages IA and IB NSCLC

Standard treatment options for stage IA NSCLC and IB NSCLC include the following:

1. Surgery.
2. Radiation therapy.

Chemotherapy and radiation therapy have not been shown to improve outcomes in 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]

Evidence (surgery):

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 the following:[2]
  • A reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision.
  • No significant difference in overall survival (OS).
2. Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy.[3]
  • A survival advantage was noted with lobectomy for patients with tumors larger than 3 cm but not for those with tumors smaller than 3 cm.
  • The rate of locoregional recurrence was significantly less after lobectomy, regardless of primary tumor size.
3. A study of stage I patients showed the following:[4]
  • Those treated with wedge or segmental resections had a local recurrence rate of 50% (i.e., 31 recurrences out of 62 patients) despite having undergone complete resections.[4]
4. The Cochrane Collaboration group reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.[5] A pooled analysis of three trials reported the following:
  • Four-year survival was superior in patients with resectable stage I, II, or IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND), compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93, P = .005).[5][Level of evidence: 1iiA]
  • There was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR], 0.79; 95% CI, 0.66–0.95; P = .01) that appeared mainly because of a reduction in the number of distant recurrences (RR, 0.78; 95% CI, 0.61–1.00; P = .05).
  • There was no difference in operative mortality.
  • Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR, 2.94; 95% CI, 1.01–8.54; P = .05).
5. Current evidence suggests that lung cancer resection combined with CMLND is associated with a small-to-modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I, II, or IIIA NSCLC.[5][Level of evidence: 1iiA]
6. CMLND versus lymph node sampling was evaluated in a large randomized phase III trial (ACOSOG-Z0030).[6]
  • Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[6]

Limitations of evidence (surgery):

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 treated surgically subsequently develop regional or distant metastases.[7] 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 the outcome of patients with stage I NSCLC that has been completely resected.

Adjuvant 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.[8]

Evidence (adjuvant radiation therapy):

1. A meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported the following:[8]
  • An 18% relative increase in the risk of death for patients who received PORT compared with surgery alone (HR, 1.18; P = .002). This is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2–9), reducing OS from 58% to 52%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0-N1 disease, whereas for patients with stage III, N2 disease, there was no clear evidence of an adverse effect.
  • Results for local (HR, 1.13; P = .02), distant (HR, 1.14; P = .02), and overall (HR, 1.10; P = .06) recurrence-free survival similarly showed a detriment of PORT.[8][Level of evidence: 1iiA]

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.

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.[9,10][Level of evidence: 1iiA]

Evidence (adjuvant chemotherapy for stage I NSCLC):

1. Data on individual patient outcomes were collected and pooled into a meta-analysis from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[11]
1. With a median follow-up time of 5.2 years, the overall HRof death was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.
2. The benefit varied with stage (test for trend, P = .04; HR for stage IA, 1.40; 95% CI, 0.95–2.06; HR for stage IB, 0.93; 95% CI, 0.78–1.10; HR for stage II, 0.83; 95% CI, 0.73–0.95; and HR for stage III, 0.83; 95% CI, 0.72–0.94).
3. The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR, 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR, 0.92; 95% CI, 0.80–1.07), or other drugs (HR, 0.97; 95% CI, 0.84–1.13).
4. The apparent greater benefit seen with vinorelbine should be interpreted cautiously as vinorelbine and cisplatin combinations generally required that a higher dose of cisplatin be given. Chemotherapy effect was higher in patients with a better performance status.
5. There was no interaction between chemotherapy effect and any of the following:
  • Sex.
  • Age.
  • Histology.
  • Type of surgery.
  • Planned radiation therapy.
  • Planned total dose of cisplatin.
2. Several other randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.[11,12,13,14,15,16,17]

Although there is sufficient evidence that postoperative chemotherapy is effective in patients with stage II or stage IIIA NSCLC, its usefulness in patients with stage IB NSCLC is less clear.

Evidence (adjuvant chemotherapy for stage IB NSCLC):

1. The Cancer and Leukemia Group B study (CALGB-9633) 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.[18]
  • Survival was not significantly different (HR, 0.83; CI, 0.64–1.08; P = .12) at a median follow-up of 74 months.
  • Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths.
  • A post-hoc exploratory analysis demonstrated a significant survival difference in favor of postoperative chemotherapy for patients who had tumors 4 cm or greater in diameter (HR, 0.69; CI, 0.48–0.99; P = .043).

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.[18] [Level of evidence: 1iiA]

Radiation therapy

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. Primary radiation therapy often consists of approximately 60 Gy delivered with megavoltage equipment to the midplane of the known tumor volume 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.

Prognosis:

In the two largest retrospective radiation therapy series, patients with inoperable disease treated with definitive radiation therapy achieved 5-year survival rates of 10% and 27%.[19,20] Both series found that patients with T1, N0 tumors had better outcomes, and 5-year survival rates of 60% and 32% were found in this subgroup.

Evidence (radiation therapy):

1. A single report of patients older than 70 years who had resectable lesions smaller than 4 cm but who had medically inoperable disease or who refused surgery reported the following:[21]
  • Survival at 5 years after radiation therapy with curative intent was comparable with a historical control group of patients of similar age who were resected with curative intent.
2. A small case series using matched controls reported the following:[4]
  • The addition of endobronchial brachytherapy improved local disease control compared with external-beam radiation therapy.[4][Level of evidence: 3iiiDiii]

A substantial number of patients are ineligible for standard surgical resection because of comorbid conditions that are associated with unacceptably high perioperative risk. Observation and radiation therapy may be considered for these patients.[22,23,24] Nonrandomized observation studies comparing treatment outcomes associated with resection, radiation therapy, and observation have demonstrated shorter survival times and higher mortality for patients treated with observation only.[22] There are a number of approaches to delivery of radiation therapy, including conventional external-beam radiation therapy, stereotactic total-body radiation therapy, and others, and limited reliable data from comparative trials to determine which yield superior outcomes.[23,24]

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

1. Clinical trials of postoperative chemoprevention (as evidenced in the ECOG-5597 trial, for example).
2. Endobronchial therapies, including photodynamic therapy, for highly selected patients with T1, N0, M0 tumors.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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.
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.
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.
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.
5. Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005.
6. 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.
7. 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.
8. PORT Meta-analysis Trialists Group.: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.
9. Deygas N, Froudarakis M, Ozenne G, et al.: Cryotherapy in early superficial bronchogenic carcinoma. Chest 120 (1): 26-31, 2001.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. Strauss GM, Herndon JE 2nd, 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. Lanni TB Jr, 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.
24. 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.

Stages IIA and IIB NSCLC Treatment

Standard Treatment Options for Stages IIA and IIB NSCLC

Standard treatment options for stages IIA NSCLC and IIB NSCLC include the following:

1. Surgery.
2. Neoadjuvant chemotherapy.
3. Adjuvant chemotherapy.
4. Radiation therapy.

Adjuvant radiation therapy has not been show to improve outcomes in patients with stages II NSCLC.

Surgery

Surgery is the treatment of choice for patients with stage II NSCLC. A lobectomy, pneumonectomy, or 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. Despite 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.

Evidence (surgery):

1. The Cochrane Collaboration group 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:
  • Four-year survival was superior in patients with resectable stage I, II, or IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND), compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93; P = .005).[1][Level of evidence: 1iiA]
  • There was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR], 0.79; 95% CI, 0.66–0.95; P = .01) that appeared mainly as the result of a reduction in the number of distant recurrences (RR, 0.78; 95% CI, 0.61–1.00; P = .05).
  • There was no difference in operative mortality.
  • Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR, 2.94; 95% CI, 1.01–8.54; P = .05).
2. Current evidence suggests that lung cancer resection combined with CMLND is associated with a small-to-modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I, II, or IIIA NSCLC.[1][Level of evidence: 1iiA]
3. CMLND versus lymph node sampling was evaluated in a large randomized phase III trial (ACOSOG-Z0030).[2]
  • Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[2]

Limitations of evidence (surgery):

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 potential methodological weaknesses of the trials.

Neoadjuvant chemotherapy

The role of chemotherapy prior to surgery was tested in clinical trials. The proposed benefits of preoperative chemotherapy include the following:

  • A reduction in tumor size that may facilitate surgical resection.
  • Early eradication of micrometastases.
  • Better tolerability.

Preoperative chemotherapy may, however, delay potentially curative surgery.

Evidence (neoadjuvant chemotherapy):

1. The Cochrane Collaboration Review group 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.[3]
  • Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease, from 14% to 20% at 5 years (HR, 0.82; 95% CI, 0.69–0.97; P = .022).[3][Level of evidence: 1iiA]
  • This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.
2. In the largest trial reported to date, 519 patients were randomly assigned to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery. Most patients (61%) had clinical stage I disease; 31% had stage II disease; and 7% had stage III disease.[4]
  • No survival advantage was seen.[4]
  • Postoperative complications were similar between groups, and no impairment of quality of life was observed.
  • There was no evidence of a benefit in terms of overall survival (OS) (HR, 1.02; 95% CI, 0.80–1.31; P = .86).
  • Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant (preoperative) chemotherapy (1,507 patients; HR, 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.

Adjuvant radiation therapy

The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated.[5]

Evidence (adjuvant radiation therapy):

1. A meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported the following:[5]
  • An 18% relative increase in the risk of death for patients who received PORT compared with surgery alone (HR, 1.18; P = .002). This is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2%–9%), reducing OS from 58% to 52%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0–N1 disease, whereas for patients with stage III, N2 disease there was no clear evidence of an adverse effect.
  • Results for local (HR, 1.13; P = .02), distant (HR, 1.14; P = .02), and overall (HR, 1.10; P = .06) recurrence-free survival similarly showed a detriment of PORT.[5][Level of evidence: 1iiA]

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.

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.[6] Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.[7,8,9,10,11,12,13]

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) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[9]
1. With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.
2. The benefit varied with stage (test for trend, P = .04; HR for stage IA, 1.40; 95% CI, 0.95–2.06; HR for stage IB, 0.93; 95% CI, 0.78–1.10; HR for stage II, 0.83; 95% CI, 0.73–0.95; and HR for stage III, 0.83; 95% CI, 0.72–0.94).
3. The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR, 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR, 0.92; 95% CI, 0.80–1.07), or other drugs (HR, 0.97; 95% CI, 0.84–1.13).
4. The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted cautiously as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine.
2. The meta-analysis as well as the individual studies [7,14] support the administration of postoperative cisplatin-based chemotherapy in combination with vinorelbine.
1. The LACE pooled analysis (NCT00576914), ANITA trial, and NCIC-CTG JBR.10 trial (NCT00002583) all reported superior OS for the trial population as well as for the patients with stage II disease (pooled HR, 0.83; 95% CI, 0.73–0.95; HR, 0.71; 95% CI, 0.49–1.03; HR, 0.59; 95% CI, 0.42–0.85, respectively).
2. Chemotherapy effect was higher in patients with better performance status (PS).
3. There was no interaction between chemotherapy effect and any of the following:
  • Sex.
  • Age.
  • Histology.
  • Type of surgery.
  • Planned radiation therapy.
  • Planned total dose of cisplatin.
3. In a retrospective analysis of a phase III trial of postoperative cisplatin and vinorelbine, patients older than 65 years were found to benefit from treatment.[15]
  • Chemotherapy significantly prolonged OS for elderly patients (HR, 0.61; 95% CI, 0.38–0.98; P = .04).
  • There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group, although elderly patients received less treatment.[15]
4. Several other randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.[7,8,9,10,11,12,13]

Based on these data, patients with completely resected stage II lung cancer may benefit from postoperative cisplatin-based chemotherapy.[15][Level of evidence: 1iiA]

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.[16] 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.

Prognosis:

Among patients with excellent PS, 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:[17]
  • A 5-year OS rate of 10%.
  • Forty-four patients with T1 tumors achieved an actuarial disease-free survival (DFS) rate of 60%.
  • This retrospective study also suggested that improved DFS was obtained with radiation therapy doses greater than 60 Gy.[17]

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

1. Clinical trials of radiation therapy after curative surgery.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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.
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.
3. 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.
4. 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.
5. PORT Meta-analysis Trialists Group.: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.

Stage IIIA NSCLC Treatment

Patients with stage IIIA NSCLC are a heterogenous group. Patients may have metastases to ipsilateral mediastinal nodes, potentially resectable T3 tumors invading 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.

Prognosis:

Patients with clinical stage IIIA-N2 disease have a 5-year overall survival 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.

Standard Treatment Options for Resected/Resectable Stage IIIA N2 NSCLC

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

Standard treatment options for resected/resectable disease include the following:

1. Surgery.
2. Neoadjuvant therapy.
  • Neoadjuvant chemotherapy.
3. Adjuvant therapy.
  • Adjuvant chemotherapy.
  • Adjuvant chemoradiation therapy.
  • Adjuvant radiation therapy.

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 associated with a small-to-modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I, II, or IIIA NSCLC.[1][Level of evidence: 1iiA]

Evidence (surgery):

1. The Cochrane Collaboration group 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:
  • Four-year survival was superior in patients with resectable stage I, II, or IIIA NSCLC who underwent resection and CMLND, compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93; P = .005).[1][Level of evidence: 1iiA]
2. CMLND versus lymph node sampling was evaluated in a large randomized phase III trial (ACOSOG-Z0030). Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[2]

Limitations of evidence (surgery):

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 prior to surgery in patients with stage III-N2 NSCLC has been extensively tested in clinical trials. The proposed benefits of preoperative (neoadjuvant) chemotherapy include the following:

  • A reduction in tumor size that may facilitate surgical resection.
  • Early eradication of micrometastases.
  • Better tolerability.

Evidence (neoadjuvant chemotherapy):

1. The Cochrane Collaboration group 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.[3] These trials evaluated patients with stages I, II, and IIIA NSCLC.
  • Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease, from 14% to 20% at 5 years (HR, 0.82; 95% CI, 0.69–0.97; P = .022).[3][Level of evidence: 1iiA]
  • This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.[4]
2. In the largest trial reported to date, 519 patients were randomly assigned to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery.[5] Most patients (61%) had clinical stage I disease, 31% had stage II disease, and 7% had stage III disease.
  • Postoperative complications were similar between groups, and no impairment of quality of life was observed.
  • There was no evidence of a benefit in terms of overall survival (OS) (HR, 1.02; 95% CI, 0.80–1.31; P = .86)
  • Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of preoperative chemotherapy (1,507 patients, HR, 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.[5]

Adjuvant therapy

Adjuvant chemotherapy

Patients with completely resected stage IIIA NSCLC may benefit from postoperative cisplatin-based chemotherapy.[6][Level of evidence: 1iiA]

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 stage I, II, and IIIA NSCLC.[6,7,8,9,10,11,12]

1. Data on individual patient outcomes were collected and pooled into a meta-analysis from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[6]
1. With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.
2. The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR, 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR, 0.92; 95% CI, 0.80–1.07), or other drugs (HR, 0.97; 95% CI, 0.84–1.13).
3. The benefit varied with stage (HR for stage IIIA, 0.83; 95% CI, 0.72–0.94).
4. The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted with caution as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine.
2. Two trials (FRE-IALT and ANITA) reported significant OS benefits associated with postoperative chemotherapy in stage IIIA disease.[4,8]
1. For the subgroup of stage IIIA patients in ANITA (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. Chemotherapy effect was higher in patients with a better performance status (PS).
3. There was no interaction between the chemotherapy effect and any of the following:
  • Sex.
  • Age.
  • Histology.
  • Type of surgery.
  • Planned radiation therapy.
  • Planned total dose of cisplatin.
3. In a retrospective analysis of a phase III trial of postoperative cisplatin and vinorelbine, patients older than 65 years were found to benefit from treatment.[13]
1. Chemotherapy significantly prolonged OS for elderly patients (HR, 0.61; 95% CI, 0.38–0.98; P = .04).
2. There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group, although elderly patients received less treatment.

Adjuvant chemoradiation therapy

Combination chemotherapy and radiation 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 following surgical resection.[3,5,14,15,16][Level of evidence: 1iiA]
1. Only one trial reported improved disease-free survival (DFS) and no trial reported improved OS.
2. Three trials have evaluated platinum-based combination chemotherapy followed by surgery versus combined platinum-based combination chemoradiation therapy (60 Gy–69.6 Gy) alone to determine which local treatment modality (surgery or radiation therapy) was most efficacious.[16,17,18] Although studies were small, enrolling 73, 107, and 333 patients with stage IIIA-N2 disease, respectively, no trial reported a difference in local control or survival.[16,17,18][Level of evidence: 1iiA]
1. In the largest series (EORTC-08941), 579 patients with histologic- or cytologic-proven stage IIIA-N2 NSCLC were given three cycles of platinum-based induction chemotherapy.[18] 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 pathologic downstaging, and 5% had a pathologic 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 3-4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7% of patients; one patient died of radiation pneumonitis.
  • Median and 5-year OS for patients randomly assigned to resection versus radiation therapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (HR, 1.06; 95% CI, 0.84–1.35).[18]
  • Rates of progression-free survival were also similar in both groups. In view of its low morbidity and mortality, it was concluded that radiation therapy should be considered the preferred locoregional treatment for these patients.[18]

Adjuvant radiation therapy

The value of PORT has been assessed.[14] 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. The majority of studies cited used doses ranging from 30 Gy to 60 Gy, typically provided in 2 Gy to 2.5 Gy fractions.[14]

As referred to in the National Cancer Institute of Canada and Intergroup Study 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:[13]

  • Involvement of multiple nodal stations.
  • Extracapsular tumor spread.
  • Close or microscopically positive resection margins.

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:
  • No difference in OS for the entire PORT group or for the subset of N2 patients.[8][Level of evidence: 1iiA]
2. Results from a nonrandomized subanalysis of the ANITA trial, comparing 5-year OS in N2 patients who did or did not receive PORT, found the following:[4]
  • Higher survival rates in patients receiving radiation therapy in both the observation and chemotherapy arms (21% vs. 17% and 47% vs. 34%, respectively [statistical tests of comparison were not conducted]).[4]
3. Results from the Surveillance, Epidemiology, and End Results (SEER) [15] suggest the following:
  • The large SEER retrospective study (N = 7,465) found superior survival rates associated with radiation therapy in N2 disease (HR, 0.855; 95% CI, 0.762–0.959).

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.[8]

Standard Treatment Options for Unresectable Stage IIIA N2 NSCLC

Standard treatment options for patients with unresectable NSCLC include the following:

1. Radiation therapy.
  • For treatment of locally advanced unresectable tumor in patients who are not candidates for chemoradiation therapy.
  • For patients requiring palliative treatment.
2. Chemoradiation therapy.

Radiation therapy

For treatment of locally advanced unresectable tumor

Radiation therapy alone, administered sequentially with chemotherapy and concurrently with chemotherapy, may provide benefit to patients with locally advanced unresectable stage III NSCLC.

Prognosis:

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.[19]

Evidence (radiation therapy for locally advanced unresectable tumor):

1. One prospective randomized clinical study showed the following:[20]
  • Radiation therapy given continuously (including weekends) as three daily fractions (CHART) improved OS compared with radiation therapy given as one daily fraction.[20][Level of evidence: 1iiA]
  • Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

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.

For palliative treatment

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

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[21]

Evidence (radiation therapy for palliative treatment):

1. A systematic review identified six randomized trials of high-dose rate brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[22]
  • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[22][Level of evidence: 1iiC]
  • Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used.
  • For EBRT, different multifraction regimens appear to provide similar symptom relief;[23,24,25,26,27,28] however, single-fraction radiation therapy may be insufficient for symptom relief compared with hypofractionated or standard regimens, as seen in the NCIC Clinical Trials' Group trial (NCT00003685).[25][Level of evidence: 1iiC]
  • Evidence of a modest increase in survival in patients with better PS given high-dose EBRT is available.[23,24][Level of evidence: 1iiA]
  • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

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 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.[29]

Evidence (chemoradiation therapy):

1. A meta-analysis of patient data from 11 randomized clinical trials showed the following:[30]
  • Cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[30][Level of evidence: 1iiA]
2. A meta-analysis of 13 trials (based on 2,214 evaluable patients) showed the following:[31]
  • The addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (relative risk [RR], 0.93; 95% CI, 0.88–0.98; P = .01).
  • For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99; P = .02).[31]
3. A meta-analysis of individual data from 1,764 patients was based on nine trials and showed the following:[29]
  • The HR of death among patients treated with radiation therapy and chemotherapy compared with radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02), corresponding to an absolute benefit of chemotherapy of 4% at 2 years.
  • The combination of platinum with etoposide seemed more effective than platinum alone.

Concurrent versus sequential chemoradiation therapy

The results from two randomized trials (including RTOG-9410) 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.[32,33,34,35][Level of evidence: 1iiA]

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.[32]
  • Five-year OS favored concurrent therapy (27% vs. 9%).
  • Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[32]
2. In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiation therapy, concurrent chemotherapy, or concurrent chemotherapy with cisplatin and vinblastine with twice-daily radiation therapy.[33]
  • Median and 4-year survival were superior in the concurrent chemotherapy with daily radiation therapy arm (17 mo vs. 14.6 mo and 21% vs. 12% for sequential regimen [P = .046]).[33]
3. Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[34,36][Level of evidence: 1iiA]
4. A meta-analysis of three trials evaluated concurrent versus sequential treatment (711 patients).[31]
  • The analysis indicated a significant benefit of concurrent over sequential treatment (RR, 0.86; 95% CI, 0.78–0.95; P = .003). All studies used cisplatin-based regimens and once-daily radiation therapy.[31]
  • More deaths (3% OS rate) were reported in the concurrent arm, but this did not reach statistical significance (RR, 1.60; CI, 0.75–3.44; P = .2).
  • There was more acute esophagitis (grade 3 or worse) with concurrent treatment (range = 17%–26%) compared with sequential treatment (range = 0%–4%; RR, 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.

Standard Treatment Options for Superior Sulcus Tumors (T3, N0 or N1, M0)

Standard treatment options for superior sulcus tumors include the following:

1. Radiation therapy alone.
2. Radiation therapy and surgery.
3. Concurrent chemotherapy with radiation therapy and surgery.
4. Surgery alone (for selected patients).

NSCLC of the superior sulcus, frequently termed Pancoast tumors, occurs in less than 5% of patients.[37,38] 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).

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.[37,38]

Prognosis:

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.[37,38]

Surgery

Evidence (surgery):

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

Chemoradiation therapy

Evidence (chemoradiation therapy):

1. Two large, prospective, multicenter phase II trials have evaluated induction chemoradiation therapy followed by resection.[40,41]
1. In the first trial (NCT00002642), 110 eligible patients were enrolled with mediastinoscopy negative, clinical T3–4, N0–1 tumors of the superior sulcus.[41] Induction treatment was two cycles of etoposide and cisplatin with 45 Gy of concurrent radiation therapy.
  • The induction regimen was well tolerated, and only five participants had grade 3 or higher toxic effects.
  • Induction chemoradiation therapy could sterilize the primary lesion. Induction therapy was completed by 104 patients (95%). Of the 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resections.
  • Pathologic complete response or minimal microscopic disease was seen in 61 (56%) resection specimens. Pathologic complete response led to better survival than when any residual disease was present (P = .02).
  • Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Disease progression occurred mainly in distant sites.
2. In the second trial, 75 patients were enrolled and treated with induction therapy with mitomycin C, vindesine, and cisplatin combined with 45 Gy of radiation therapy.[40] Fifty-seven patients (76%) underwent surgical resection, and complete resection was achieved in 51 patients (68%).
  • There were 12 patients with pathologic complete response.
  • Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding, was observed in eight patients. There were three treatment-related deaths.
  • The disease-free and OS rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively.[40][Level of evidence: 3iiiDi]

Standard Treatment Options for Tumors That Invade the Chest Wall (T3, N0 or N1, M0)

Standard treatment options for tumors that invade the chest wall include the following:

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. Radical surgery, including chest wall resection, may result in a 5-year survival rate of up to 50%.

Evidence (radical surgery):

1. In two small case series of 97 and 104 patients, respectively, the 5-year survival rates of patients who had completely resected T3, N0, M0 disease were 44.2% and 67.3%; for T3, N1, M0 disease 5-year rates were 40.0%, and T3; and for N2, M0 disease 5-year rates were 6.2% and 17.9%.[42,43][Level of evidence: 3iiiDi]
2. 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).[44][Level of evidence: 3iiiDi]

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.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

1. Combined modality therapy, including chemotherapy, radiation therapy, and surgery in various combinations.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIA non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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.
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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
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.
14. PORT Meta-analysis Trialists Group.: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.
15. Lally BE, Zelterman D, Colasanto JM, et al.: Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 24 (19): 2998-3006, 2006.
16. Johnstone DW, Byhardt RW, Ettinger D, et al.: Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 54 (2): 365-9, 2002.
17. Taylor NA, Liao ZX, Cox JD, et al.: Equivalent outcome of patients with clinical Stage IIIA non-small-cell lung cancer treated with concurrent chemoradiation compared with induction chemotherapy followed by surgical resection. Int J Radiat Oncol Biol Phys 58 (1): 204-12, 2004.
18. van Meerbeeck JP, Kramer GW, Van Schil PE, et al.: Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 99 (6): 442-50, 2007.
19. 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.
20. Saunders M, Dische S, Barrett A, et al.: Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet 350 (9072): 161-5, 1997.
21. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.
22. Ung YC, Yu E, Falkson C, et al.: The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review. Brachytherapy 5 (3): 189-202, 2006 Jul-Sep.
23. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004.
24. Lester JF, Macbeth FR, Toy E, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002143, 2006.
25. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002.
26. Erridge SC, Gaze MN, Price A, et al.: Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules. Clin Oncol (R Coll Radiol) 17 (1): 61-7, 2005.
27. Kramer GW, Wanders SL, Noordijk EM, et al.: Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol 23 (13): 2962-70, 2005.
28. Senkus-Konefka E, Dziadziuszko R, Bednaruk-Młyński E, et al.: A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC). Br J Cancer 92 (6): 1038-45, 2005.
29. Aupérin A, Le Péchoux C, Pignon JP, et al.: Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 17 (3): 473-83, 2006.
30. 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.
31. Rowell NP, O'rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004.
32. Furuse K, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17 (9): 2692-9, 1999.
33. Curran WJ, Scott CB, Langer CJ, et al.: Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III nsclc: RTOG 9410. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-2499, 2003.
34. Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005.
35. Curran WJ Jr, Paulus R, Langer CJ, et al.: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103 (19): 1452-60, 2011.
36. Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004.
37. Rusch VW: Management of Pancoast tumours. Lancet Oncol 7 (12): 997-1005, 2006.
38. Narayan S, Thomas CR Jr: Multimodality therapy for Pancoast tumor. Nat Clin Pract Oncol 3 (9): 484-91, 2006.
39. Rusch VW, Parekh KR, Leon L, et al.: Factors determining outcome after surgical resection of T3 and T4 lung cancers of the superior sulcus. J Thorac Cardiovasc Surg 119 (6): 1147-53, 2000.
40. Kunitoh H, Kato H, Tsuboi M, et al.: Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806. J Clin Oncol 26 (4): 644-9, 2008.
41. Rusch VW, Giroux DJ, Kraut MJ, et al.: Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 25 (3): 313-8, 2007.
42. Matsuoka H, Nishio W, Okada M, et al.: Resection of chest wall invasion in patients with non-small cell lung cancer. Eur J Cardiothorac Surg 26 (6): 1200-4, 2004.
43. Facciolo F, Cardillo G, Lopergolo M, et al.: Chest wall invasion in non-small cell lung carcinoma: a rationale for en bloc resection. J Thorac Cardiovasc Surg 121 (4): 649-56, 2001.
44. Doddoli C, D'Journo B, Le Pimpec-Barthes F, et al.: Lung cancer invading the chest wall: a plea for en-bloc resection but the need for new treatment strategies. Ann Thorac Surg 80 (6): 2032-40, 2005.

Stage IIIB NSCLC Treatment

Based on the Surveillance, Epidemiology, and End Registry, the estimated incidence of stage IIIB NSCLC is 17.6%.[1] The anticipated 5-year survival for the vast majority of 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, have been reported to have 5-year survival rates of 20%.[3,4][Level of evidence: 3iiiA]

Standard Treatment Options for Stage IIIB NSCLC

Standard treatment options for stage IIIB NSCLC include the following:

1. Sequential or concurrent chemotherapy and radiation therapy.
2. Chemotherapy followed by surgery (for selected patients).
3. Radiation therapy alone.
  • For treatment of locally advanced unresectable tumor in patients who are not candidates for chemotherapy.
  • For patients requiring palliative treatment.

In general, patients with stage IIIB NSCLC do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on the following:

  • Sites of tumor involvement.
  • The patient's performance status (PS).

Most patients with excellent PS are candidates for combined modality chemotherapy and radiation therapy with the following exceptions:

  • Selected patients with T4, N0 disease may be treated with combined modality therapy and surgery similar to patients with superior sulcus tumors.

Sequential or concurrent chemotherapy and radiation therapy

Many randomized studies of patients with unresectable stage III NSCLC show that treatment with preoperative or concurrent cisplatin-based chemotherapy and radiation therapy to the chest is associated with improved survival compared with treatment that uses radiation therapy alone. Although patients with unresectable stage IIIB disease may benefit from radiation therapy, long-term outcomes have generally been poor, often the result of local and systemic relapse. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials.

Evidence (sequential or concurrent chemotherapy and radiation therapy):

1. A meta-analysis of patient data from 11 randomized clinical trials showed the following:[5]
1. Cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[5][Level of evidence: 1iiA]
2. A meta-analysis of 13 trials (based on 2,214 evaluable patients) showed the following:[6]
1. The addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (relative risk [RR], 0.93; 95% confidence interval [CI], 0.88–0.98; P = .01).
2. For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99; P = .02).[6]
3. A meta-analysis of individual data from 1,764 patients evaluated nine trials.[7]
1. The hazard ratio of death among patients treated with radiation therapy and chemotherapy compared with radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years.
2. The combination of platinum with etoposide seemed more effective than platinum alone. Concomitant platinum-based chemotherapy and radiation therapy 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.[7]
4. The results from two randomized trials (including RTOG-9410) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.[8,9,10][Level of evidence: 1iiA]
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.[8]
  • Five-year overall survival (OS) favored concurrent therapy (27% vs. 9%).
  • Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[8]
2. In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiation therapy, concurrent chemotherapy, or concurrent chemotherapy with cisplatin and vinblastine with twice-daily radiation therapy.[10]
  • Median and 4-year survival were superior in the concurrent chemotherapy with daily radiation therapy arm (17 mo vs. 14.6 mo and 21% vs. 12% for sequential regimen [P = .046]).
3. Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[10][Level of evidence: 1iiA][11]
5. A meta-analysis of three trials evaluated concurrent versus sequential treatment (711 patients).[6]
1. The analysis indicated a significant benefit of concurrent versus sequential treatment (RR, 0.86; 95% CI, 0.78–0.95; P = .003). All used cisplatin-based regimens and once-daily radiation therapy.[6]
2. More deaths (3% overall) were reported in the concurrent arm, but this did not reach statistical significance (RR, 1.60; CI, 0.75–3.44; P = .2).
3. There was more acute esophagitis (grade 3 or worse) with concurrent treatment (range = 17%–26%) compared with sequential treatment (range = 0%–4%; RR, 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.

Radiation therapy alone

For treatment of locally advanced unresectable tumor

Radiation therapy alone, administered sequentially or concurrently with chemotherapy, may provide benefit to patients with locally advanced unresectable stage III NSCLC. However, combination chemoradiation therapy delivered concurrently provides the greatest benefit in survival with increase in toxic effects.

Prognosis:

Radiation therapy with traditional dose and fractionation schedules (1.8 Gy–2.0 Gy per fraction per day to 60 Gy–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[12]

Evidence (radiation therapy for locally advanced unresectable tumor):

1. One prospective randomized clinical study showed the following:
  • Radiation therapy given as three daily fractions improved OS compared with radiation therapy given as one daily fraction.[13][Level of evidence: 1iiA]
  • Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

For palliative treatment

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

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[14]

Evidence (radiation therapy for palliative treatment):

1. A systematic review identified six randomized trials of high-dose rate brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[15]
  • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[15][Level of evidence: 1iiC]
  • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.
  • Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used.
  • Although different multifraction regimens appear to provide similar symptom relief,[16,17,18,19,20,21] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as shown in the NCIC Clinical Trials' Group trial (NCT00003685).[18][Level of evidence: 1iiC]
  • Evidence of a modest increase in survival in patients with better PS given high-dose radiation therapy is available.[16,17][Level of evidence: 1iiA]

Patients with stage IIIB disease with poor PS are candidates for chest radiation therapy to palliate pulmonary symptoms (e.g., cough, shortness of breath, hemoptysis, or pain).[12][Level of evidence: 3iiiC] (Refer to the PDQ summaries on Cardiopulmonary Syndromes and Pain for more information.)

Treatment Options Under Clinical Evaluation

Because of the poor overall results, patients with stage IIIB NSCLC are candidates for clinical trials, which may lead to improvement in the control of disease.

Treatment options under clinical evaluation include the following:

1. New fractionation schedules.
2. Radiosensitizers.
3. Combined modality approaches.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIB non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Wisnivesky JP, Yankelevitz D, Henschke CI: Stage of lung cancer in relation to its size: part 2. Evidence. Chest 127 (4): 1136-9, 2005.
2. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997.
3. Deslauriers J, Brisson J, Cartier R, et al.: Carcinoma of the lung. Evaluation of satellite nodules as a factor influencing prognosis after resection. J Thorac Cardiovasc Surg 97 (4): 504-12, 1989.
4. Urschel JD, Urschel DM, Anderson TM, et al.: Prognostic implications of pulmonary satellite nodules: are the 1997 staging revisions appropriate? Lung Cancer 21 (2): 83-7; discussion 89-91, 1998.
5. 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.
6. Rowell NP, O'rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004.
7. Aupérin A, Le Péchoux C, Pignon JP, et al.: Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 17 (3): 473-83, 2006.
8. Furuse K, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17 (9): 2692-9, 1999.
9. Curran WJ, Scott CB, Langer CJ, et al.: Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III nsclc: RTOG 9410. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-2499, 2003.
10. Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005.
11. Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004.
12. Langendijk JA, ten Velde GP, Aaronson NK, et al.: Quality of life after palliative radiotherapy in non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys 47 (1): 149-55, 2000.
13. 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.
14. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.
15. Ung YC, Yu E, Falkson C, et al.: The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review. Brachytherapy 5 (3): 189-202, 2006 Jul-Sep.
16. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004.
17. Lester JF, Macbeth FR, Toy E, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002143, 2006.
18. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002.
19. Erridge SC, Gaze MN, Price A, et al.: Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules. Clin Oncol (R Coll Radiol) 17 (1): 61-7, 2005.
20. Kramer GW, Wanders SL, Noordijk EM, et al.: Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol 23 (13): 2962-70, 2005.
21. Senkus-Konefka E, Dziadziuszko R, Bednaruk-Młyński E, et al.: A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC). Br J Cancer 92 (6): 1038-45, 2005.

Stage IV NSCLC Treatment

Forty percent of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage IV disease. Treatment goals are to prolong survival and control disease-related symptoms. Treatment options include cytotoxic chemotherapy and targeted agents. Factors influencing treatment selection include comorbidity, performance status (PS), histology, and molecular genetic features of the cancer. Radiation therapy and surgery are generally used in selective cases for symptom palliation.

Standard Treatment Options for Stage IV NSCLC

Standard treatment options for stage IV NSCLC include the following:

1. Cytotoxic combination chemotherapy (first line) with platinum (cisplatin or carboplatin) and paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, and pemetrexed.
1. Factors influencing treatment.
  • Histology.
  • Age versus comorbidity.
  • PS.
2. Combination chemotherapy with bevacizumab or cetuximab.
3. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (first line) (for patients with EGFR mutations).
4. EML4-ALK inhibitors in patients with EML-ALK translocations.
5. Maintenance therapy following first-line chemotherapy (for patients with stable or responding disease following four cycles of non–pemetrexed-platinum combination chemotherapy).
6. Endobronchial laser therapy and/or brachytherapy (for obstructing lesions).[1]
7. External-beam radiation therapy (EBRT) (primarily for palliation of local symptomatic tumor growth).[2,3,4]

Randomized controlled trials of patients with stage IV disease and good PS have shown that cisplatin-based chemotherapy improves survival and palliates disease-related symptoms.[5][Level of evidence: 1iiA] Patients with nonsquamous cell histology, good PS, no history of hemoptysis or other bleeding, or recent history of cardiovascular events may benefit from the addition of bevacizumab to paclitaxel and carboplatin. Patients with tumors harboring mutations in EGFR, particularly those from East Asia, never smokers, and those with adenocarcinoma may benefit from EGFR tyrosine kinase inhibitors as an alternative to first- or second-line chemotherapy. Second-line chemotherapy with docetaxel, pemetrexed, or erlotinib also improves survival in patients with good PS.[5][Level of evidence: 1iiA] The role of chemotherapy in patients with poor PS was less certain.

Cytotoxic combination chemotherapy (first line)

The type and number of chemotherapy drugs to be used for the treatment of patients with advanced NSCLC has been extensively evaluated in randomized controlled trials and meta-analyses.

Several randomized trials have evaluated various drugs combined with either cisplatin or carboplatinum in previously untreated patients with advanced NSCLC. Based on meta-analyses of the trials, the following conclusions can be drawn:

  • Certain three-drug combinations that add so-called targeted agents may result in superior survival.
  • EGFR inhibitors may benefit selected patients with EGFR mutations.
  • Maintenance chemotherapy following four cycles of platinum combination chemotherapy may improve progression-free survival (PFS).
  • Platinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, and pemetrexed yield similar improvements in survival. Types and frequencies of toxic effects differ, and these may determine the preferred regimen for an individual patient. Patients with adenocarcinoma may benefit from pemetrexed.
  • Cisplatin and carboplatinum yield similar improvements in outcome with different toxic effects. Some, but not all, trials and meta-analyses of trials suggest that outcomes with cisplatin may be superior, although with a higher risk of certain toxicities such as nausea and vomiting.
  • Nonplatinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority.
  • Three-drug combinations of the commonly used chemotherapy drugs do not result in superior survival and are more toxic than two-drug combinations.

Evidence (combination chemotherapy):

1. The Cochrane Collaboration group reviewed data from all randomized controlled trials published between January 1980 and June 2006, comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.[6] Sixty-five trials (13,601 patients) were identified.
1. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.37– 0.47; P < .001) and 1-year survival (OR, 0.80; 95% CI, 0.70–0.91; P < .001) in favor of the doublet regimen. The absolute benefit in 1-year survival was 5%, which corresponds to an increase in 1-year survival from 30% with a single-agent regimen to 35% with a doublet regimen. The rates of grades 3 and 4 toxic effects caused by doublet regimens were statistically increased compared with rates following single-agent therapy, with ORs ranging from 1.2 to 6.2. There was no increase in infection rates in doublet regimens.
2. There was no increase in 1-year survival (OR, 1.01; 95% CI, 0.85–1.21; P = .88) for triplet regimens versus doublet regimens. The median survival ratio was 1.00 (95% CI, 0.94–1.06; P = .97).
2. Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior with variable results.[7,8,9] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[7]
1. The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% vs. 24%, respectively; OR, 1.37; 95% CI, 1.16–1.61; P < .001).
2. Carboplatin treatment was associated with a non–statistically significant increase in the hazard of mortality relative to treatment with cisplatin (hazard ratio [HR], 1.07; 95% CI, 0.99–1.15; P = .100).
3. In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR, 1.12; 95% CI, 1.01–1.23 and HR, 1.11; 95% CI, 1.01–1.21, respectively).
4. Treatment-related toxic effects were also assessed in the meta-analysis. More thrombocytopenia was seen with carboplatin than with cisplatin (12% vs. 6%; OR, 2.27; 95% CI, 1.71–3.01; P < .001), while cisplatin caused more nausea and vomiting (8% vs. 18%; OR, 0.42; 95% CI, 0.33–0.53; P < .001) and renal toxic effects (0.5% vs. 1.5%; OR, 0.37; 95% CI, 0.15–0.88; P = .018).
5. The authors concluded that treatment with cisplatin was not associated with a substantial increase in the overall risk of severe toxic effects. This comprehensive individual-patient meta-analysis is consistent with the conclusions of other meta-analyses, which were based on essentially the same clinical trials but which used only published data.
3. Three literature-based meta-analyses have trials comparing platinum with nonplatinum combinations.[10,11,12]
1. The first meta-analysis identified 37 assessable trials that included 7,633 patients.[10]
  • A 62% increase in the OR for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46–1.8; P < .001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% vs. 29%; OR, 1.21; 95% CI, 1.09–1.35; P = .003).
  • No statistically significant increase in 1-year survival was found when platinum therapies were compared with third-generation-based combination regimens (OR, 1.11; 95% CI, 0.96–1.28; P = .17).
  • The toxic effects of platinum-based regimens was significantly higher for hematologic toxic effects, nephrotoxic effects, and nausea and vomiting but not for neurologic toxic effects, febrile neutropenia rate, or toxic death rate. These results are consistent with the second literature-based meta-analysis.
2. The second meta-analysis identified 17 trials that included 4,920 patients.[11]
  • The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (relative risk [RR], 1.08; 95% CI, 1.01%–1.16%; P = .03) and a better partial response (RR, 1.11; 95% CI, 1.02–1.21; P = .02), with a higher risk of anemia, nausea, and neurologic toxic effects.
  • In subanalyses, cisplatin-based doublet regimens improved survival at 1 year (RR, 1.16%; 95% CI, 1.06–1.27; P = .001), complete response (RR, 2.29; 95% CI, 1.08–4.88; P = .03), and partial response (RR, 1.19; 95% CI, 1.07–1.32; P = .002), with an increased risk of anemia, neutropenia, neurologic toxic effects, and nausea.
  • Conversely, carboplatin-based doublet regimens did not increase survival at 1 year (RR, 0.95; 95% CI, 0.85–1.07; P = .43).
3. The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.[12] Experimental arms were gemcitabine and vinorelbine (n = 4), gemcitabine and taxane (n = 7), gemcitabine and epirubicin (n = 1), paclitaxel and vinorelbine (n = 1), and gemcitabine and ifosfamide (n = 1). This meta-analysis was limited to the set of 11 phase III studies that used a platinum-based doublet (2,298 and 2,304 patients in platinum-based and nonplatinum arms, respectively).
  • Patients treated with a platinum-based regimen benefited from a statistically significant reduction in the risk of death at 1 year (OR, 0.88; 95% CI, 0.78–0.99; P = .044) and a lower risk of being refractory to chemotherapy (OR, 0.87; CI, 0.73–0.99; P = .049).
  • Forty-four (1.9%) and 29 (1.3%) toxic-related deaths were reported for platinum-based and nonplatinum regimens, respectively (OR, 1.53; CI, 0.96–2.49; P = 0.08). An increased risk of grade 3-4 gastrointestinal and hematologic toxic effects for patients treated with platinum-based chemotherapy was statistically demonstrated. There was no statistically significant increase in risk of febrile neutropenia (OR, 1.23; CI, 0.94–1.60; P = .063).

Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made, with the exception of pemetrexed for patients with adenocarcinoma.

Evidence (drug and dose schedule):

1. There has been one meta-analysis of seven trials that included 2,867 patients to assess the benefit of docetaxel versus vinorelbine.[13] Docetaxel was administered with a platinum agent in three trials, with gemcitabine in two trials, or as monotherapy in two trials. Vinca alkaloid (vinorelbine in six trials and vindesine in one trial) was administered with cisplatin in six trials or alone in one trial.
  • The pooled estimate for overall survival (OS) showed an 11% improvement in favor of docetaxel (HR, 0.89; 95% CI, 0.82–0.96; P = .004). Sensitivity analyses that considered only vinorelbine as a comparator or only the doublet regimens showed similar improvements.
  • Grade 3 to 4 neutropenia and grade 3 to 4 serious adverse events were less frequent with docetaxel-based regimens versus vinca alkaloid-based regimens (OR, 0.59; 95% CI, 0.38–0.89; P = .013 and OR, 0.68; 95% CI, 0.55–0.84; P < .001, respectively).
2. There have been two randomized trials comparing weekly versus every 3 weeks' dosing of paclitaxel and carboplatin, which reported no significant difference in efficacy and better tolerability for weekly administration.[14,15] Although meta-analyses of randomized controlled trials suggest that cisplatin combinations may be superior to carboplatin or nonplatinum combinations, the clinical relevance of the differences in efficacy must be balanced against the anticipated tolerability, logistics of administration, and familiarity of the medical staff for treatment decisions for individual patients.
3. A large, noninferiority, phase III randomized study compared the OS in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and a PS of 0 to 1.[16] Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles.
  • OS for cisplatin and pemetrexed was noninferior to cisplatin and gemcitabine (median survival, 10.3 mo vs. 10.3 mo, respectively; HR, 0.94; 95% CI, 0.84%–1.05%).
  • OS was statistically superior for cisplatin and pemetrexed versus cisplatin and gemcitabine in patients with adenocarcinoma (n = 847; 12.6 mo vs. 10.9 mo, respectively) and large cell carcinoma histology (n = 153; 10.4 mo vs. 6.7 mo, respectively).
  • In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin and gemcitabine versus cisplatin and pemetrexed (n = 473; 10.8 mo vs. 9.4 mo, respectively). For cisplatin and pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.
  • This study suggests that cisplatin and pemetrexed are another alternative doublet for first-line chemotherapy for advanced NSCLC and also suggests that there may be differences in outcome depending on histology.

Factors influencing treatment

Histology

Patients with adenocarcinoma may benefit from pemetrexed,[16] EGFR inhibitors, and bevacizumab.

Age versus comorbidity

Evidence supports that elderly patients with good PS and limited comorbidity may benefit from combination chemotherapy. Age alone should not dictate treatment-related decisions in patients with advanced NSCLC. Elderly patients with a good PS enjoy longer survival and a better quality of life when treated with chemotherapy compared with supportive care alone. Caution should be exercised when extrapolating data for elderly patients (aged 70–79 years) to patients aged 80 years or older because only a very small number of patients aged 80 years or older have been enrolled on clinical trials, and the benefit in this group is uncertain.[17,18]

Evidence (age vs. comorbidity):

1. Platinum-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care or single-agent therapy; however, such treatment may be contraindicated in some older patients because of the age-related reduction in the functional reserve of many organs and/or comorbid conditions. Approximately two-thirds of patients with NSCLC are aged 65 years or older and approximately 40% are aged 70 years or older.[19] Surveillance, Epidemiology, and End Results (SEER) data suggest that the percentage of patients aged older than 70 years is closer to 50%.
2. A review of the SEER Medicare data from 1994 to 1999 found a much lower rate of chemotherapy use than expected for the overall population.[20] It also suggested that elderly patients may have more comorbidities or a higher rate of functional compromise that would make study participation difficult, if not contraindicated, and lack of clinical trial data may influence decisions to treat individual patients with standard chemotherapy.
3. Single-agent chemotherapy and combination chemotherapy clearly benefit at least some elderly patients. In the Elderly Lung Cancer Vinorelbine Italian Study, 154 patients who were older than 70 years were randomly assigned to vinorelbine or supportive care.[21]
  • Patients who were treated with vinorelbine had a 1-year survival rate of 32%, compared with 14% for those who were treated with supportive care alone. Quality-of-life parameters were also significantly improved in the chemotherapy arm, and toxic effects were acceptable.
4. A more recent trial from Japan compared single-agent docetaxel with vinorelbine in 180 elderly patients with good PS.[22]
  • Response rates and PFS were significantly better with docetaxel (22% vs. 10%; 5.4 mo vs. 3.1 mo, respectively), whereas median and 1-year survival rates did not reach statistical significance (14.3 mo vs. 9.9 mo; 59% vs. 37%, respectively).
5. Retrospective data analyzing and comparing younger (age <70 years) patients with older (age ≥70 years) patients who participated in large, randomized trials of doublet combinations have also shown that elderly patients may derive the same survival benefit, although with a higher risk of toxic effects in the bone marrow.[17,18,23,24,25,26]

Performance status (PS)

PS is among the most important prognostic factors for survival of patients with NSCLC.[27] The benefit of therapy for this group of patients has been evaluated through retrospective analyses as well as through prospective clinical trials.

The results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced NSCLC; however, the efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Outside of a clinical trial setting, chemotherapy should be given only to patients with good PS and evaluable tumor lesions, who desire such treatment after being fully informed of its anticipated risks and limited benefits.

Evidence (performance status):

1. The Cancer and Leukemia Group B trial (CLB-9730), which compared carboplatin and paclitaxel with single-agent paclitaxel, enrolled 99 patients with a PS of 2 (18% of the study's population).[25]
  • When compared with patients with a PS of 0 to 1, who had a median survival of 8.8 months and a 1-year survival of 38%, the corresponding figures for patients with a performance status of 2 were 3.0 months and 14%, respectively; this demonstrates the poor prognosis conferred by a lower PS. These differences were statistically significant.
  • When patients with a PS of 2 were analyzed by treatment arm, those who received combination chemotherapy had a significantly higher response rate (24% vs. 10%), longer median survival (4.7 mo vs. 2.4 mo), and superior 1-year survival (18% vs. 10%), compared with those who were treated with single-agent paclitaxel.[25]
2. A subset analysis of 68 patients with a PS of 2 from a trial that randomly assigned more than 1,200 patients to four platinum-based regimens has been published.
  • Despite a high incidence of adverse events, including five deaths, the final analysis showed that the overall toxic effects experienced by patients with a PS of 2 was not significantly different from that experienced by patients with a PS of 0 to 1.
  • An efficacy analysis demonstrated an overall response rate of 14%, median survival time of 4.1 months, and a 1-year survival rate of 19%; all were substantially inferior to the patients with PS of 0 to 1.
3. A phase II randomized trial (E-1599) of attenuated dosages of cisplatin plus gemcitabine and carboplatin plus paclitaxel included 102 patients with a PS of 2.[28]
  • Response rates were 25% and 16%, median survival times were 6.8 months and 6.1 months, and 1-year survival rates were 25% and 19%, respectively. None of these differences was statistically significant, but the survival figures were longer than expected on the basis of historical controls.
4. Results from two trials suggest that patients with a PS of 2 may experience symptom improvement.[29,30]

Combination chemotherapy with bevacizumab or cetuximab

Evidence (combination chemotherapy with bevacizumab or cetuximab):

1. Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy.
1. In a randomized study of 878 patients with recurrent or advanced stage IIIB or stage IV NSCLC, 444 patients received paclitaxel and carboplatin alone, and 434 patients received paclitaxel and carboplatin plus bevacizumab.[31] Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or PS (ECOG PS >1) were excluded.
  • The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (HR for death, 0.79; P = .003).
  • The median PFS in the two groups was 6.2 months and 4.5 months, respectively (HR for disease progression, 0.66; P < .001), with corresponding response rates of 35% and 15%, respectively (P < .001).
  • Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P < .001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including five from pulmonary hemorrhage.
  • For this subgroup of patients with NSCLC, the addition of bevacizumab to paclitaxel and carboplatin may provide survival benefit.[31][Level of evidence: 1iiA]
2. Another randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine plus bevacizumab.[32] Patients were randomly assigned to receive cisplatin (80 mg/m2) and gemcitabine (1,250 mg/m2) for up to six cycles, plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The primary endpoint was amended from OS to PFS during the course of the study. A total of 1,043 patients were accrued (placebo group, n = 347; low-dose group, n = 345; high-dose group, n = 351).
  • PFS was significantly prolonged; the HRs for PFS were 0.75 (median PFS, 6.7 mo vs. 6.1 mo for placebo group; P = .03) in the low-dose group and 0.82 (median PFS, 6.5 mo vs. 6.1 mo for placebo group; P = .03) in the high-dose group compared with the placebo group.[32][Level of evidence: 1iiB]
  • Objective response rates were also improved with the addition of bevacizumab, and they were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus cisplatin/gemcitabine, respectively.
  • Incidence of grade 3 or greater adverse events was similar across arms.
  • Grade 3 or greater pulmonary hemorrhage rates were 1.5% or less for all arms, despite 9% of patients receiving therapeutic anticoagulation.
  • These results support the addition of bevacizumab to platinum-containing chemotherapy, but the results are far less impressive than when the carboplatin-paclitaxel combination was used.
  • Furthermore, no significant difference in survival was shown in this study, as reported in abstract form.
  • Altogether, these findings may suggest that the backbone of chemotherapy may be important when bevacizumab is added.
2. Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[33,34]
1. In the first trial, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC, without restrictions by histology or EGFR expression, received cetuximab with taxane (paclitaxel or docetaxel with carboplatin) or combination chemotherapy.[33]
  • The addition of cetuximab did not result in a statistically significant improvement in PFS, the primary study endpoint, or OS.
  • Median PFS was 4.40 months with cetuximab/chemotherapy versus 4.24 months with taxane/carboplatin (HR, 0.902; 95% CI, 0.761–1.069; P = .236).
  • Median OS was 9.69 months with cetuximab/chemotherapy versus 8.38 months with chemotherapy (HR, 0.890; 95% CI, 0.754–1.051; P = .169).
  • No significant associations were found between EGFR expression, EGFR mutation, EGFR copy number, or KRAS mutations and PFS, OS, and response in the treatment-specific analyses.[35]
2. The second trial was composed of 1,125 chemotherapy-naïve patients with advanced EGFR-expressing stage IIIB or stage IV NSCLC treated with cisplatin/vinorelbine chemotherapy plus cetuximab or chemotherapy alone.[34]
  • The primary study endpoint, OS, was longer for patients treated with cetuximab and chemotherapy (median 11.3 months vs. 10.1 months; HR for death, 0.871; 95% CI, 0.762–0.996; P = .044).
  • A survival benefit was seen in all histological subgroups; however, survival benefit was not seen in non-white or Asian patients. Only the interaction between the treatment and the ethnic origin was significant (P = .011).
  • The main cetuximab-related adverse event was acne-like rash (10%, grade 3).
3. It is not clear whether the differences in outcome in these two studies are the result of differences in the study populations, tumor characterization for EGFR expression, or chemotherapy regimens.

EGFR tyrosine kinase inhibitors (first line)

Selective patients may benefit from single-agent EGFR tyrosine kinase inhibitors. Randomized controlled trials of patients with chemotherapy-naïve NSCLC and EGFR mutations have shown that EGFR inhibitors improved PFS but not OS and have favorable toxicity profiles compared with combination chemotherapy.

Evidence (EGFR tyrosine kinase inhibitors):

1. A phase III, multicenter, randomized trial compared gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients in East Asia who had advanced adenocarcinoma of the lung and had never smoked or were former light smokers.[36]
1. The study met its primary objective of demonstrating the superiority of gefitinib as compared with the carboplatin-paclitaxel combination for PFS (HR for progression or death, 0.74; 95% CI, 0.65–0.85; P < .001).
2. The median PFS was 5.7 months in the gefitinib group and 5.8 months in the carboplatin-paclitaxel group.[36][Level of evidence: 1iDiii]
3. Following the time that chemotherapy was discontinued and while gefitinib was continued, the PFS curves clearly separated and favored gefitinib.
  • The 12-month PFS rates were 24.9% with the gefitinib group and 6.7% with the carboplatin-paclitaxel group.
4. More than 90% of the patients in the trial with mutations had either del19 or exon 21 L858R mutations, which have been shown to be sensitive to EGFR inhibitors. In the subgroup of patients with a mutation, PFS was significantly longer among those who received gefitinib (HR, 0.48; 95% CI, 0.36–0.64; P < .001), whereas, in the subgroup of patients who were negative for a mutation, PFS was significantly longer in those who received the carboplatin-paclitaxel combination (HR with gefitinib, 2.85; 95% CI, 2.05–3.98; P < .001). There was a significant interaction between treatment and EGFR mutation with respect to PFS (P < .001).[36]
5. OS was similar for gefitinib and carboplatin/paclitaxel, with no significant difference between treatments overall (HR, 0.90; 95% CI, 0.79–1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76– 1.33; P = .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86–1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34–0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09–7.09).
2. Two phase III trials from Japan prospectively confirmed that patients with NSCLC and EGFR mutations have improved PFS but not OS when treated with gefitinib.[37,38]
1. In the first trial, 230 chemotherapy-naïve patients with metastatic, NSCLC, and EGFR mutations were randomly assigned to receive gefitinib or carboplatin-paclitaxel.[37]
  • In the planned interim analysis of data for the first 200 patients, PFS was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P < .001), resulting in early termination of the study.
  • The gefitinib group had a significantly longer median PFS (10.8 months vs. 5.4 months in the chemotherapy group; HR, 0.30; 95% CI, 0.22–0.41; P < .001).[37][Level of evidence: 1iiDiii] The median OS was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P = .31).
2. In the second trial, the West Japanese Oncology Group conducted a phase 3 study (WJTOG3405) in 177 chemotherapy-naïve patients aged 75 years or younger and diagnosed with stage IIIB/IV NSCLC or postoperative recurrence harboring EGFR mutations (either the exon 19 deletion or L858R point mutation).[38]
  • Patients were randomly assigned to receive either gefitinib or cisplatin plus docetaxel (administered every 21 days for three to six cycles). The primary endpoint was PFS.
  • The gefitinib group had significantly longer PFS compared with the cisplatin plus docetaxel group, with a median PFS time of 9.2 months (95% CI, 8.0–13.9) versus 6.3 months (5.8–7.8; HR, 0.489; 95% CI, 0.336–0.710, log-rank, P < .0001).[38][Level of evidence: 1iiDiii]
3. Similar benefit may be achieved with erlotinib.
1. In an open-label, randomized, phase III trial (NCT00874419) from China, 165 patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until they experienced disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin.[39]
  • Median PFS was significantly longer in erlotinib-treated patients than in those treated with chemotherapy (13.1 [95% CI, 10.58–16.53] vs. 4.6 [4.21–5.42] months; HR, 0.16; 95% CI, 0.10–0.26; P < .0001).[39][Level of evidence: 1iiDiii]

The above trials demonstrated that EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib are superior to the platinum combination chemotherapy as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. It is likely that these results are applicable to non-Asian populations.

1. In a European study (EURTAC), 1,227 patients with advanced NSCLC were screened for EGFR mutations. Of these, 174 patients with EGFR mutations were randomly assigned to receive erlotinib or platinum-based chemotherapy.[40] The primary endpoint was PFS.
  • In an interim analysis of the first 153 patients, PFS in the chemotherapy arm was 5.2 months (95% CI, 4.5–5.8) compared to 9.7 months (95% CI, 8.4–12.3) in the erlotinib arm (HR, 0.37; P < .0001). Median survival was 19.3 months in the chemotherapy arm and 19.5 months in the erlotinib arm (HR, 0.80; P = .42).[41][Level of evidence: 1iiDiii]

Maintenance therapy following first-line chemotherapy

One treatment strategy that has been investigated extensively in NSCLC is maintenance therapy following initial response to chemotherapy. Options for maintenance therapy that have been investigated include the following:

  • Continuing the initial combination chemotherapy regimen.
  • Continuing only single-agent chemotherapy.
  • Introducing a new agent as "maintenance."

Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.

Evidence (maintenance therapy following first-line chemotherapy):

1. None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles.
2. Three trials found statistically significantly improved PFS or time to progression with additional chemotherapy.[42,43,44]
3. No consistent improvement in quality of life was reported.[43,45,46]
4. Chemotherapy-related toxicities were greater with prolonged chemotherapy.[45,46]

These data suggest that PFS, but not OS, may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events from additional cytotoxic chemotherapy and no consistent improvement in quality of life. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy prior to disease progression. Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it can be administered for no more than six cycles.[42,43,45,46]

Evidence (first-line platinum-based combination chemotherapy followed by pemetrexed):

1. The findings of two randomized trials (NCT00102804 and NCT00789373) have shown outcomes with the addition of pemetrexed following standard first-line platinum-based combination chemotherapy.[44,47]
1. In the first trial, 663 patients with stage IIIB or stage IV disease who had not progressed on four cycles of nonpemetrexed platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
  • Both the primary endpoint of PFS and the secondary endpoint of OS were statistically significantly prolonged with the addition of maintenance pemetrexed (median PFS, 4.3 months vs. 2.6 months; HR, 0.50; 95% CI, 0.42–0.61; P < .0001; median OS, 13.4 months vs. 10.6 months; HR, 0.79; 95% CI, 0.65–0.95; P = .012).
  • Benefit was not seen in patients with squamous histology.
  • Higher than grade 3 toxicity and treatment discontinuations resulting from drug-related toxic effects were higher in the pemetrexed group than in the placebo group.
  • No pemetrexed-related deaths occurred.
  • Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs. 149 [67%]; P = .0001).
  • Quality of life during maintenance therapy with pemetrexed was similar to placebo, except for a small increase in loss of appetite and significantly delayed worsening of pain and hemoptysis as assessed using the Lung Cancer Symptom Scale.[48] The quality-of-life results should be evaluated with caution as there was a high degree of censoring (> 50%) for the primary quality-of-life endpoint of time to worsening of symptoms.
  • Trials have not evaluated maintenance pemetrexed versus pemetrexed at progression.
2. In the second trial, 539 patients with NSCLC with nonprogression following treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.[44]
  • There was a statistically significant improvement in the primary endpoint of PFS (4.1 months vs. 2.8 months (HR, 0.62; 95% CI, 0.49–0.79) but no improvement in OS.[44][Level of evidence: 1iDiii]

Evidence (maintenance erlotinib following platinum-based doublet chemotherapy):

1. One trial (NCT00556712) reported favorable outcomes with maintenance erlotinib after four cycles of platinum-based doublet chemotherapy in patients with stable disease.[49]
1. In this trial, 889 patients with NSCLC but without progressive disease were randomly assigned to receive erlotinib (150 mg/day) or placebo until they experienced progressive disease or unacceptable toxicity.[49]
  • Median PFS was significantly longer with erlotinib than with placebo: 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for those in the placebo group (HR, 0.71; 95% CI, 0.62–0.82; P < .0001).
  • In the overall population, patients whose tumors had activating EGFR mutations derived the greatest PFS benefit from maintenance erlotinib treatment (n = 49; HR, 0.10; P < .0001).
  • Patients whose tumors with wild-type EGFR also obtained significant PFS and OS improvements (HR, 0.78 and 0.77, respectively).
  • In the subgroup of patients with stable disease whose tumors did not have activating EGFR mutations (n = 217), both PFS and OS were significantly prolonged with erlotinib (HR, 0.72; 95% CI, 0.54–0.96; P = .0231 and HR, 0.65; 95% CI, 0.48–0.87; P = .0041, respectively).
  • In patients whose tumors had activating EGFR mutations (n = 30), OS was also improved with erlotinib (HR, 0.48; 95% CI, 0.14–1.62) but was not statistically significant in this analysis.[50]
  • EGFR IHC [immunohistochemistry], EGFR FISH [fluorescence in situ hybridization], KRAS mutation, and EGFR CA-SSR1 [simple sequence repeat 1] repeat length status were not predictive for erlotinib efficacy.[51]KRAS mutation status was a significant, negative prognostic factor for PFS.[51][Level of evidence: 1iDiii]

Radiation therapy

Radiation therapy may be effective in palliating symptomatic patients with local involvement of NSCLC with any of the following:

  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy have been used to alleviate proximal obstructing lesions.[1]

Although EBRT is frequently prescribed for symptom palliation, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief,[52,53,54,55,56,57] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCT00003685 trial.[2][Level of evidence: 1iiC] Evidence of a modest increase in survival in patients with a better PS given high-dose radiation therapy is available.[4,58][Level of evidence: 1iiA] In closely observed asymptomatic patients, treatment may often be appropriately deferred until symptoms or signs of a progressive tumor develop.

Evidence (radiation therapy):

1. A systematic review identified six randomized trials of high-dose rate brachytherapy (HDREB) alone or with EBRT or laser therapy.[59]
  • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[59][Level of evidence: 1iiC]
  • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

1. New chemotherapy regimens.
2. Other systemic agents.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.
2. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002.
3. Macbeth F, Toy E, Coles B, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (3): CD002143, 2001.
4. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004.
5. Weick JK, Crowley J, Natale RB, et al.: A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol 9 (7): 1157-62, 1991.
6. Delbaldo C, Michiels S, Rolland E, et al.: Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease. Cochrane Database Syst Rev (4): CD004569, 2007.
7. Ardizzoni A, Boni L, Tiseo M, et al.: Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst 99 (11): 847-57, 2007.
8. Jiang J, Liang X, Zhou X, et al.: A meta-analysis of randomized controlled trials comparing carboplatin-based to cisplatin-based chemotherapy in advanced non-small cell lung cancer. Lung Cancer 57 (3): 348-58, 2007.
9. Hotta K, Matsuo K, Ueoka H, et al.: Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 22 (19): 3852-9, 2004.
10. D'Addario G, Pintilie M, Leighl NB, et al.: Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 23 (13): 2926-36, 2005.
11. Rajeswaran A, Trojan A, Burnand B, et al.: Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: a systematic review of randomized controlled trials. Lung Cancer 59 (1): 1-11, 2008.
12. Pujol JL, Barlesi F, Daurès JP: Should chemotherapy combinations for advanced non-small cell lung cancer be platinum-based? A meta-analysis of phase III randomized trials. Lung Cancer 51 (3): 335-45, 2006.
13. Douillard JY, Laporte S, Fossella F, et al.: Comparison of docetaxel- and vinca alkaloid-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer: a meta-analysis of seven randomized clinical trials. J Thorac Oncol 2 (10): 939-46, 2007.
14. Belani CP, Ramalingam S, Perry MC, et al.: Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol 26 (3): 468-73, 2008.
15. Schuette W, Blankenburg T, Guschall W, et al.: Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer 7 (5): 338-43, 2006.
16. Scagliotti GV, Parikh P, von Pawel J, et al.: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26 (21): 3543-51, 2008.
17. Langer CJ, Vangel M, Schiller J, et al.: Age-specific subanalysis of ECOG 1594: fit elderly patients (70-80 YRS) with NSCLC do as well as younger pts (<70). [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-2571, 2003.
18. Langer CJ, Manola J, Bernardo P, et al.: Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 94 (3): 173-81, 2002.
19. Ries LA: Influence of extent of disease, histology, and demographic factors on lung cancer survival in the SEER population-based data. Semin Surg Oncol 10 (1): 21-30, 1994 Jan-Feb.
20. Ramsey SD, Howlader N, Etzioni RD, et al.: Chemotherapy use, outcomes, and costs for older persons with advanced non-small-cell lung cancer: evidence from surveillance, epidemiology and end results-Medicare. J Clin Oncol 22 (24): 4971-8, 2004.
21. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 91 (1): 66-72, 1999.
22. Takeda K, Kudoh S, Nakagawa K, et al.: Randomized phase III study of docetaxel (D) versus vinorelbine (V) for elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): Results of a West Japan Thoracic Oncology Group trial (WJTOG9904). [Abstract] J Clin Oncol 23 (Suppl 16): A-7009, 2005.
23. Schiller JH, Harrington D, Belani CP, et al.: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346 (2): 92-8, 2002.
24. Belani CP, Fossella F: Elderly subgroup analysis of a randomized phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for first-line treatment of advanced nonsmall cell lung carcinoma (TAX 326). Cancer 104 (12): 2766-74, 2005.
25. Lilenbaum RC, Herndon JE 2nd, List MA, et al.: Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol 23 (1): 190-6, 2005.
26. Hensing TA, Peterman AH, Schell MJ, et al.: The impact of age on toxicity, response rate, quality of life, and survival in patients with advanced, Stage IIIB or IV nonsmall cell lung carcinoma treated with carboplatin and paclitaxel. Cancer 98 (4): 779-88, 2003.
27. Sweeney CJ, Zhu J, Sandler AB, et al.: Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma . Cancer 92 (10): 2639-47, 2001.
28. Tester WJ, Stephenson P, Langer CJ, et al.: ECOG 1599: randomized phase II study of paclitaxel/carboplatin or gemcitabine/cisplatin in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC). [Abstract] J Clin Oncol 22 (Suppl 14): A-7055, 630s, 2004.
29. Vansteenkiste JF, Vandebroek JE, Nackaerts KL, et al.: Clinical-benefit response in advanced non-small-cell lung cancer: A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine. Ann Oncol 12 (9): 1221-30, 2001.
30. Hickish TF, Smith IE, O'Brien ME, et al.: Clinical benefit from palliative chemotherapy in non-small-cell lung cancer extends to the elderly and those with poor prognostic factors. Br J Cancer 78 (1): 28-33, 1998.
31. Sandler A, Gray R, Perry MC, et al.: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355 (24): 2542-50, 2006.
32. Reck M, von Pawel J, Zatloukal P, et al.: Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 27 (8): 1227-34, 2009.
33. Lynch TJ, Patel T, Dreisbach L, et al.: Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 28 (6): 911-7, 2010.
34. Pirker R, Pereira JR, Szczesna A, et al.: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 373 (9674): 1525-31, 2009.
35. Khambata-Ford S, Harbison CT, Hart LL, et al.: Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 28 (6): 918-27, 2010.
36. Mok TS, Wu YL, Thongprasert S, et al.: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361 (10): 947-57, 2009.
37. Maemondo M, Inoue A, Kobayashi K, et al.: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362 (25): 2380-8, 2010.
38. Mitsudomi T, Morita S, Yatabe Y, et al.: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11 (2): 121-8, 2010.
39. Zhou C, Wu YL, Chen G, et al.: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12 (8): 735-42, 2011.
40. Rosell R, Gervais R, Vergnenegre A, et al.: Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. [Abstract] J Clin Oncol 29 (Suppl 15): A-7503, 2011.
41. Rosell R, Carcereny E, Gervais R, et al.: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13 (3): 239-46, 2012.
42. Brodowicz T, Krzakowski M, Zwitter M, et al.: Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer 52 (2): 155-63, 2006.
43. Park JO, Kim SW, Ahn JS, et al.: Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol 25 (33): 5233-9, 2007.
44. Paz-Ares L, de Marinis F, Dediu M, et al.: Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 13 (3): 247-55, 2012.
45. Socinski MA, Schell MJ, Peterman A, et al.: Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 20 (5): 1335-43, 2002.
46. von Plessen C, Bergman B, Andresen O, et al.: Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer. Br J Cancer 95 (8): 966-73, 2006.
47. Ciuleanu T, Brodowicz T, Zielinski C, et al.: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 374 (9699): 1432-40, 2009.
48. Belani CP, Brodowicz T, Ciuleanu TE, et al.: Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study. Lancet Oncol 13 (3): 292-9, 2012.
49. Cappuzzo F, Ciuleanu T, Stelmakh L, et al.: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11 (6): 521-9, 2010.
50. Coudert B, Ciuleanu T, Park K, et al.: Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy. Ann Oncol 23 (2): 388-94, 2012.
51. Brugger W, Triller N, Blasinska-Morawiec M, et al.: Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 29 (31): 4113-20, 2011.
52. Danson S, Middleton MR, O'Byrne KJ, et al.: Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer 98 (3): 542-53, 2003.
53. 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.
54. Smit EF, van Meerbeeck JP, Lianes P, et al.: Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group--EORTC 08975. J Clin Oncol 21 (21): 3909-17, 2003.
55. Kubota K, Watanabe K, Kunitoh H, et al.: Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol 22 (2): 254-61, 2004.
56. Georgoulias V, Ardavanis A, Agelidou A, et al.: Docetaxel versus docetaxel plus cisplatin as front-line treatment of patients with advanced non-small-cell lung cancer: a randomized, multicenter phase III trial. J Clin Oncol 22 (13): 2602-9, 2004.
57. Sandler AB, Nemunaitis J, Denham C, et al.: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 18 (1): 122-30, 2000.
58. Lester JF, Macbeth FR, Toy E, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002143, 2006.
59. Ung YC, Yu E, Falkson C, et al.: The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review. Brachytherapy 5 (3): 189-202, 2006 Jul-Sep.

Recurrent NSCLC Treatment

Standard Treatment Options for Recurrent NSCLC

Standard treatment options for recurrent NSCLC include the following:

1. Radiation therapy (for palliation).[1]
2. Chemotherapy or kinase inhibitors alone, including the following for patients who have previously received platinum chemotherapy:
  • Docetaxel.[2,3]
  • Pemetrexed.[3]
  • Erlotinib after failure of both platinum-based and docetaxel chemotherapies.[4]
  • Gefitinib.[5]
  • Crizotinib for EML4-ALK translocations.[6,7]
3. EGFR inhibitors in patients with or without EGFR mutations.
4. EML4-ALK inhibitors in patients with EML-ALK translocations.
5. Surgical resection of isolated cerebral metastasis (for highly selected patients).[8]
6. Laser therapy or interstitial radiation therapy (for endobronchial lesions).[9]
7. Stereotactic radiation surgery (for highly selected patients).[10,11]

Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[12][Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.[13,14] Informed patients with good performance status (PS) and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered.

Evidence (chemotherapy and targeted therapy):

1. Two prospective, randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;[2,15] however, criteria for the selection of appropriate patients for second-line treatment are not well defined.[16]
2. A meta-analysis of five trials of 865 patients assessing the efficacy and safety of docetaxel administered weekly or every 3 weeks has been reported.[17] In that analysis the following was shown:
1. Median survival was 27.4 weeks for patients treated every 3 weeks and 26.1 weeks for patients treated weekly (P = .24, log-rank test).
2. Significantly less-severe neutropenia and febrile neutropenia were reported with weekly docetaxel (P < .001 for both), whereas no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxic effects.
3. A randomized, phase III trial of 571 patients designed to demonstrate the noninferiority of pemetrexed compared with docetaxel showed no difference in response rates, progression-free survival (PFS), or overall survival (OS).[3][Level of evidence: 1iiA] Of note, patients with squamous histology benefited from docetaxel and those with nonsquamous histologies appeared to benefit more from pemetrexed.[18]
4. Two randomized, placebo-controlled trials indicated that erlotinib prolongs survival and time to deterioration in symptoms in patients with NSCLC after first-line or second-line chemotherapy compared to placebo [19,20] but does not improve survival compared to standard second-line chemotherapy with docetaxel or pemetrexed.[21]
1. The trial of erlotinib versus best supportive care included 731 patients; 49% had received two prior chemotherapy regimens and 93% had received platinum-based chemotherapy.
  • OS was 6.7 months among those who had received two prior chemotherapy regimens and 4.7 months among those who had received platinum-based chemotherapy. The HR was 0.70 (P < .001) in favor of erlotinib.[19][Level of evidence: 1iiA]
2. In the trial (NCT00556322), which was designed to show the superiority of erlotinib versus standard second-line chemotherapy following progression on first-line platinum combination therapy, 424 patients were randomly assigned.
  • There was no difference in the primary endpoint of OS (median OS survival, 5.3 months vs. 5.5 months; HR, 0.96; 95% CI, 0.78–1.19).[21][Level of evidence: 1iiA]
5. A randomized phase III trial evaluating gefitinib versus placebo in 1,692 previously treated NSCLC patients showed the following:
  • Gefitinib does not improve OS.
  • Median survival did not differ significantly between the groups in the overall population (5.6 mo for gefitinib and 5.1 mo for placebo; HR, 0.89; 95% CI, 0.77–1.02; P = .087) or among the 812 patients with adenocarcinoma (6.3 mo vs. 5.4 mo; HR, 0.84; CI, 0.68–1.03; P = .089).
  • Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than in the placebo group for never-smokers (n = 375; 95% CI, 0.67 [0.49–0.92]; P = .012; median survival 8.9 mo vs. 6.1 mo) and for patients of Asian origin (n = 342; 95% CI, 0.66 [0.48–0.91]; P = .01; median survival 9.5 mo vs. 5.5 mo).[22][Level of evidence: 1iiA]
6. In a large, randomized trial, gefitinib was compared with docetaxel in patients with locally advanced or metastatic NSCLC who had been pretreated with platinum-based chemotherapy.[5] The primary objective was to compare OS between the groups with coprimary analyses to assess noninferiority in the overall population and superiority in patients with high epidermal growth factor receptor (EGFR) gene copy number in the intention-to-treat population. The 1,466 patients were randomly assigned to receive gefitinib (250 mg per day orally; n = 733) or docetaxel (75 mg/m2 intravenously every 3 weeks; n = 733).
  • Noninferiority of gefitinib compared with docetaxel was confirmed for OS (HR, 1.020; 95% CI, 0.905–1.150). However, superiority of gefitinib in patients with high EGFR gene copy number (85 patients vs. 89 patients) was not proven (HR, 1.09; 95% CI, 0.78–1.51; P = .62).
  • In the gefitinib group, the most common adverse events were rash or acne (49% vs. 10%) and diarrhea (35% vs. 25%). In the docetaxel group, neutropenia (5% vs. 74%), asthenia (25% vs. 47%), and alopecia (3% vs. 36%) were most common.
  • This trial established noninferior survival of patients treated with gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced NSCLC.
7. A study (NCT00585195) that screened 1,500 patients with NSCLC for ALK rearrangements identified 82 patients with advanced ALK-positive disease who were enrolled in a clinical trial that was an expanded cohort study instituted after phase I dose escalation had established a recommended dose of crizotinib dual MET and ALK inhibitor of 250 mg twice daily in 28-day cycles.[6] Most of the patients had received previous treatment.
  • At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses, and 1 confirmed complete response); 27 patients (33%) had stable disease.[6][Level of evidence: 3iiiD]
  • The estimated probability of 6-month PFS was 72%.
  • 1-year OS was 74% (95% CI, 63–82), and 2-year OS was 54% (40–66).
  • Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls identified from a different cohort given any second-line therapy (median OS not reached [95% CI, 14 months–not reached] vs. 6 months [CI 4–17], 1-year OS, 70% [95% CI, 50–83] vs. 44% [23–64], and 2-year OS 55% [33–72] vs. 12% [2–30]; HR, 0.36; 95% CI, 0.17–0.75; P = .004).[7][Level of evidence: 3iiiD]
  • Common toxicities were grade 1 or 2 (mild) gastrointestinal side effects.
  • Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas.

Objective response rates to erlotinib and gefitinib are higher in patients who have never smoked, in females, in East Asians, and in patients with adenocarcinoma and bronchioloalveolar carcinoma.[23,24,25,26,27,28,29] Responses may be associated with sensitizing mutations in the tyrosine kinase domain of the EGFR [24,25,26,28,29] and with the absence of K-RAS mutations.[27,28,29][Level of evidence: 3iiiDiii] Survival benefit may be greater in patients with EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by fluorescence in situ hybridization studies,[28,29] although the clinical utility of EGFR testing by immunohistochemistry has been questioned.[30]

Treatment of second primary tumor

A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Whether the new lesion is a new primary cancer or a metastasis may be difficult to determine. Studies have indicated that in most patients the new lesion is a second primary tumor, and after its resection, some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected, if possible.[31,32]

Treatment of brain metastases

Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged DFS with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy (WBRT).[33,34] Unresectable brain metastases in this setting may be treated with radiation surgery.[10]

Because of the small potential for long-term survival, radiation therapy should be delivered by conventional methods in daily doses of 1.8 Gy to 2.0 Gy. Because of the high risk of toxic effects observed with such treatments, higher daily doses over a shorter period of time (i.e., hypofractionated schemes) should be avoided.[35] Most patients who are not suitable for surgical resection should receive conventional WBRT.

Approximately 50% of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment.[8] In those selected patients with good PS and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiation surgery.[8,10] For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[36][Level of evidence: 3iiiDiii]

Treatment Options Under Clinical Evaluation

  • Many patients with recurrent NSCLC are eligible for clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004.
2. Shepherd FA, Dancey J, Ramlau R, et al.: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18 (10): 2095-103, 2000.
3. Hanna N, Shepherd FA, Fossella FV, et al.: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22 (9): 1589-97, 2004.
4. Shepherd FA, Pereira J, Ciuleanu TE, et al.: A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. [Abstract] J Clin Oncol 22 (Suppl 14): A-7022, 622s, 2004.
5. Kim ES, Hirsh V, Mok T, et al.: Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372 (9652): 1809-18, 2008.
6. Kwak EL, Bang YJ, Camidge DR, et al.: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363 (18): 1693-703, 2010.
7. Shaw AT, Yeap BY, Solomon BJ, et al.: Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12 (11): 1004-12, 2011.
8. Arbit E, Wroński M, Burt M, et al.: The treatment of patients with recurrent brain metastases. A retrospective analysis of 109 patients with nonsmall cell lung cancer. Cancer 76 (5): 765-73, 1995.
9. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.
10. Loeffler JS, Kooy HM, Wen PY, et al.: The treatment of recurrent brain metastases with stereotactic radiosurgery. J Clin Oncol 8 (4): 576-82, 1990.
11. Alexander E 3rd, Moriarty TM, Davis RB, et al.: Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 87 (1): 34-40, 1995.
12. Souquet PJ, Chauvin F, Boissel JP, et al.: Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 342 (8862): 19-21, 1993.
13. Ellis PA, Smith IE, Hardy JR, et al.: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 71 (2): 366-70, 1995.
14. Girling DJ, et al.: Randomized trial of etoposide cyclophosphamide methotrexate and vincristine versus etoposide and vincristine in the palliative treatment of patients with small-cell lung cancer and poor prognosis. Br J Cancer 67 (Suppl 20): A-4;2, 14, 1993.
15. Fossella FV, DeVore R, Kerr RN, et al.: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18 (12): 2354-62, 2000.
16. Huisman C, Smit EF, Giaccone G, et al.: Second-line chemotherapy in relapsing or refractory non-small-cell lung cancer: a review. J Clin Oncol 18 (21): 3722-30, 2000.
17. Di Maio M, Perrone F, Chiodini P, et al.: Individual patient data meta-analysis of docetaxel administered once every 3 weeks compared with once every week second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 25 (11): 1377-82, 2007.
18. Scagliotti G, Hanna N, Fossella F, et al.: The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist 14 (3): 253-63, 2009.
19. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al.: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353 (2): 123-32, 2005.
20. Bezjak A, Tu D, Seymour L, et al.: Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 24 (24): 3831-7, 2006.
21. Ciuleanu T, Stelmakh L, Cicenas S, et al.: Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol 13 (3): 300-8, 2012.
22. Thatcher N, Chang A, Parikh P, et al.: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366 (9496): 1527-37, 2005 Oct 29-Nov 4.
23. Miller VA, Kris MG, Shah N, et al.: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22 (6): 1103-9, 2004.
24. Paez JG, Jänne PA, Lee JC, et al.: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304 (5676): 1497-500, 2004.
25. Lynch TJ, Bell DW, Sordella R, et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350 (21): 2129-39, 2004.
26. Pao W, Miller V, Zakowski M, et al.: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101 (36): 13306-11, 2004.
27. Pao W, Wang TY, Riely GJ, et al.: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2 (1): e17, 2005.
28. Tsao MS, Sakurada A, Cutz JC, et al.: Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 353 (2): 133-44, 2005.
29. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al.: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24 (31): 5034-42, 2006.
30. Clark GM, Zborowski DM, Culbertson JL, et al.: Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol 1 (8): 837-46, 2006.
31. Salerno TA, Munro DD, Blundell PE, et al.: Second primary bronchogenic carcinoma: life-table analysis of surgical treatment. Ann Thorac Surg 27 (1): 3-6, 1979.
32. Yellin A, Hill LR, Benfield JR: Bronchogenic carcinoma associated with upper aerodigestive cancers. J Thorac Cardiovasc Surg 91 (5): 674-83, 1986.
33. Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322 (8): 494-500, 1990.
34. Mandell L, Hilaris B, Sullivan M, et al.: The treatment of single brain metastasis from non-oat cell lung carcinoma. Surgery and radiation versus radiation therapy alone. Cancer 58 (3): 641-9, 1986.
35. DeAngelis LM, Mandell LR, Thaler HT, et al.: The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 24 (6): 798-805, 1989.
36. Hazuka MB, Kinzie JJ: Brain metastases: results and effects of re-irradiation. Int J Radiat Oncol Biol Phys 15 (2): 433-7, 1988.

Changes to This Summary (05 / 30 / 2013)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Stages IA and IB NSCLC Treatment

Added text to state that a substantial number of patients are ineligible for standard surgical resection because of comorbid conditions that are associated with unacceptably high perioperative risk; observation and radiation therapy may be considered for these patients (cited McGarry et al., Lanni et al., and Grutterset al. as reference 22, reference 23, and reference 24, respectively). Also added text to state that nonrandomized observation studies comparing treatment outcomes associated with resection, radiation therapy, and observation have demonstrated shorter survival times and higher mortality for patients treated with observation only, there are a number of approaches to delivery of radiation therapy, and there are limited reliable data from comparative trials to determine which yield superior outcomes.

Stage IIIA NSCLC Treatment

Added Curran et al as reference 35.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of non-small cell lung cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Non-Small Cell Lung Cancer Treatment are:

  • Janet Dancey, MD, FRCPC (Ontario Institute for Cancer Research & NCIC Clinical Trials Group)
  • Giuseppe Giaccone, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Non-Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2013-05-30

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