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Non-Small Cell Lung Cancer Treatment (PDQ®)     
Last Modified: 08/01/2008
Health Professional Version
Table of Contents

Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information
The Revised International Staging System for Lung Cancer
TNM Definitions
AJCC Stage Groupings
Treatment Option Overview
Occult Non-Small Cell Lung Cancer
Current Clinical Trials
Stage 0 Non-Small Cell Lung Cancer
Current Clinical Trials
Stage I Non-Small Cell Lung Cancer
Current Clinical Trials
Stage II Non-Small Cell Lung Cancer
Current Clinical Trials
Stage IIIA Non-Small Cell Lung Cancer
Current Clinical Trials
Stage IIIB Non-Small Cell Lung Cancer
Current Clinical Trials
Stage IV Non-Small Cell Lung Cancer
Current Clinical Trials
Recurrent Non-Small Cell Lung Cancer
Current Clinical Trials
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Changes to This Summary (08/01/2008)
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Purpose of This PDQ 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. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board 1.

Information about the following is included in this summary:

  • Prognostic factors.
  • Cellular classification.
  • Staging.
  • Treatment options by cancer stage.

This summary 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.

Some of the reference citations in the 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 2 in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version 3, written in less technical language, and in Spanish 4.

General Information

Note: Separate PDQ summaries on Small Cell Lung Cancer Treatment 5; Lung Cancer Prevention 6; and Lung Cancer Screening 7 are also available.

Note: Estimated new cases and deaths from lung cancer (non-small cell and small cell combined) in the United States in 2008:[1]

  • New cases: 215,020.
  • Deaths: 161,840.

Non-small cell lung cancer (NSCLC) is a heterogeneous aggregate of histologies. The most common histologies are epidermoid or squamous carcinoma, adenocarcinoma, and large cell carcinoma. These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar. Patients with resectable disease may be cured by surgery or surgery with adjuvant 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 have long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy.

At diagnosis, patients with NSCLC can be divided into three groups that reflect both the extent of the disease and the treatment approach. The first group of patients has tumors that are surgically resectable (generally stage I, stage II, and selected stage III tumors). This group 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. Adjuvant cisplatin-based combination chemotherapy may provide a survival advantage to patients with resected stage IB, stage II, or stage IIIA NSCLC.

The second group includes patients with either locally (T3–T4) and/or regionally (N2–N3) advanced lung cancer. This group 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.

The final group includes patients with distant metastases (M1) that were found at the time of diagnosis. This group can be treated with radiation therapy or chemotherapy for palliation of symptoms from the primary tumor. Patients with good performance status (PS), 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 inhibitor.

Multiple studies have attempted to identify prognostic determinants after surgery and have yielded conflicting evidence as to the prognostic importance of a variety of clinicopathologic factors.[2-6] 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.[7-17]
  • Vascular invasion.[3,18-20]
  • Increased numbers of tumor blood vessels in the tumor specimen.

Similarly, conflicting results regarding the prognostic importance of aberrant expression of a number of proteins within lung cancers have been reported. For patients with inoperable disease, prognosis is adversely affected by poor PS 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.[21]

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 8.

References

  1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. 9 Last accessed October 1, 2008. 

  2. Albain KS, Crowley JJ, LeBlanc M, et al.: Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 9 (9): 1618-26, 1991.  [PUBMED Abstract]

  3. Macchiarini P, Fontanini G, Hardin MJ, et al.: Blood vessel invasion by tumor cells predicts recurrence in completely resected T1 N0 M0 non-small-cell lung cancer. J Thorac Cardiovasc Surg 106 (1): 80-9, 1993.  [PUBMED Abstract]

  4. Ichinose Y, Yano T, Asoh H, et al.: Prognostic factors obtained by a pathologic examination in completely resected non-small-cell lung cancer. An analysis in each pathologic stage. J Thorac Cardiovasc Surg 110 (3): 601-5, 1995.  [PUBMED Abstract]

  5. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995.  [PUBMED Abstract]

  6. Fontanini G, Bigini D, Vignati S, et al.: Microvessel count predicts metastatic disease and survival in non-small cell lung cancer. J Pathol 177 (1): 57-63, 1995.  [PUBMED Abstract]

  7. Sayar A, Turna A, Kiliçgün A, et al.: Prognostic significance of surgical-pathologic multiple-station N1 disease in non-small cell carcinoma of the lung. Eur J Cardiothorac Surg 25 (3): 434-8, 2004.  [PUBMED Abstract]

  8. Osaki T, Nagashima A, Yoshimatsu T, et al.: Survival and characteristics of lymph node involvement in patients with N1 non-small cell lung cancer. Lung Cancer 43 (2): 151-7, 2004.  [PUBMED Abstract]

  9. Ichinose Y, Kato H, Koike T, et al.: Overall survival and local recurrence of 406 completely resected stage IIIa-N2 non-small cell lung cancer patients: questionnaire survey of the Japan Clinical Oncology Group to plan for clinical trials. Lung Cancer 34 (1): 29-36, 2001.  [PUBMED Abstract]

  10. Tanaka F, Yanagihara K, Otake Y, et al.: Prognostic factors in patients with resected pathologic (p-) T1-2N1M0 non-small cell lung cancer (NSCLC). Eur J Cardiothorac Surg 19 (5): 555-61, 2001.  [PUBMED Abstract]

  11. Asamura H, Suzuki K, Kondo H, et al.: Where is the boundary between N1 and N2 stations in lung cancer? Ann Thorac Surg 70 (6): 1839-45; discussion 1845-6, 2000.  [PUBMED Abstract]

  12. Riquet M, Manac'h D, Le Pimpec-Barthes F, et al.: Prognostic significance of surgical-pathologic N1 disease in non-small cell carcinoma of the lung. Ann Thorac Surg 67 (6): 1572-6, 1999.  [PUBMED Abstract]

  13. van Velzen E, Snijder RJ, Brutel de la Rivière A, et al.: Lymph node type as a prognostic factor for survival in T2 N1 M0 non-small cell lung carcinoma. Ann Thorac Surg 63 (5): 1436-40, 1997.  [PUBMED Abstract]

  14. Vansteenkiste JF, De Leyn PR, Deneffe GJ, et al.: Survival and prognostic factors in resected N2 non-small cell lung cancer: a study of 140 cases. Leuven Lung Cancer Group. Ann Thorac Surg 63 (5): 1441-50, 1997.  [PUBMED Abstract]

  15. Izbicki JR, Passlick B, Karg O, et al.: Impact of radical systematic mediastinal lymphadenectomy on tumor staging in lung cancer. Ann Thorac Surg 59 (1): 209-14, 1995.  [PUBMED Abstract]

  16. Martini N, Burt ME, Bains MS, et al.: Survival after resection of stage II non-small cell lung cancer. Ann Thorac Surg 54 (3): 460-5; discussion 466, 1992.  [PUBMED Abstract]

  17. Naruke T, Goya T, Tsuchiya R, et al.: Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 96 (3): 440-7, 1988.  [PUBMED Abstract]

  18. Thomas P, Doddoli C, Thirion X, et al.: Stage I non-small cell lung cancer: a pragmatic approach to prognosis after complete resection. Ann Thorac Surg 73 (4): 1065-70, 2002.  [PUBMED Abstract]

  19. Macchiarini P, Fontanini G, Hardin MJ, et al.: Relation of neovascularisation to metastasis of non-small-cell lung cancer. Lancet 340 (8812): 145-6, 1992.  [PUBMED Abstract]

  20. Khan OA, Fitzgerald JJ, Field ML, et al.: Histological determinants of survival in completely resected T1-2N1M0 nonsmall cell cancer of the lung. Ann Thorac Surg 77 (4): 1173-8, 2004.  [PUBMED Abstract]

  21. Earle CC, Tsai JS, Gelber RD, et al.: Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis. J Clin Oncol 19 (4): 1064-70, 2001.  [PUBMED Abstract]

Cellular Classification

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because small cell lung cancer, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with non-small cell carcinoma.[1]

In 1999, the World Health Organization (WHO) classification of lung tumors was updated.[1] Major changes in the revised classification as compared with the previous one (WHO 1981) include the addition of two preinvasive lesions to squamous dysplasia and carcinoma in situ: atypical adenomatous hyperplasia and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Another significant change is the subclassification of adenocarcinoma: the definition of bronchioalveolar carcinoma has been restricted to noninvasive tumors. A substantial evolution of concepts in neuroendocrine lung tumor classification has occurred. Large cell neuroendocrine carcinoma (LCNEC) is now recognized as a histologically high-grade non-small cell carcinoma showing histopathological features of neuroendocrine differentiation as well as immunohistochemical neuroendocrine markers. The large-cell carcinoma class now includes several variants, including the LCNEC and the basaloid carcinoma, both with a dismal prognosis. Finally, a new class was defined called carcinoma with pleomorphic, sarcomatoid, or sarcomatous elements that are characterized by a spectrum of epithelial to mesenchymal differentiation. Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

Malignant non-small epithelial tumors of the lung are detailed in the following list.

The changes in the WHO classification are described in greater detail in the following sections.

THE NEW WHO/INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER HISTOLOGIC CLASSIFICATION OF NON-SMALL CELL LUNG CARCINOMAS (NSCLC)

  1. Squamous cell carcinoma.
    • Papillary.
    • Clear cell.
    • Small cell.
    • Basaloid.


  2. Adenocarcinoma.
    • Acinar.
    • Papillary.
    • Bronchioloalveolar carcinoma.
      • Nonmucinous.
      • Mucinous.
      • Mixed mucinous and nonmucinous or indeterminate cell type.
    • Solid adenocarcinoma with mucin.
    • Adenocarcinoma with mixed subtypes.
    • Variants.
      • Well-differentiated fetal adenocarcinoma.
      • Mucinous (colloid) adenocarcinoma.
      • Mucinous cystadenocarcinoma.
      • Signet ring adenocarcinoma.
      • Clear cell adenocarcinoma.


  3. Large cell carcinoma.
    • Variants.
      • Large-cell neuroendocrine carcinoma.
      • Combined large-cell neuroendocrine carcinoma.
      • Basaloid carcinoma.
      • Lymphoepithelioma-like carcinoma.
      • Clear cell carcinoma.
      • Large-cell carcinoma with rhabdoid phenotype.


  4. Adenosquamous carcinoma.


  5. Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.
    • Carcinomas with spindle and/or giant cells.
    • Spindle cell carcinoma.
    • Giant cell carcinoma.
    • Carcinosarcoma.
    • Pulmonary blastoma.


  6. Carcinoid tumor.
    • Typical carcinoid.
    • Atypical carcinoid.


  7. Carcinomas of salivary-gland type.
    • Mucoepidermoid carcinoma.
    • Adenoid cystic carcinoma.
    • Others.


  8. Unclassified carcinoma.


Adenocarcinoma

Adenocarcinoma is now the predominant histologic subtype in many countries, and issues relating to subclassification of adenocarcinoma are very 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/International Association for the Study of Lung Cancer (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 either a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. Several variants of adenocarcinoma are recognized in the new classification, including well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, and clear cell adenocarcinoma.

Neuroendocrine tumors

A substantial evolution of concepts of neuroendocrine lung tumor classification has occurred. 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 the high-grade SCLC and LCNEC. Neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLC that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme since 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.

Large cell carcinoma

In addition to the general category of large cell carcinoma, several uncommon variants are recognized, including LCNEC, basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, and 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.

Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements

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

References

  1. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. 

Stage Information

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.

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors (i.e., physical examination, radiology, and laboratory studies) and pathological factors (i.e., biopsy of lymph nodes, bronchoscopy, mediastinoscopy, or anterior mediastinotomy).[1] The distinction between clinical stage and pathologic stage should be considered when evaluating reports of survival outcome.

Staging procedures include history, physical examination, routine laboratory evaluations, chest x-ray, and chest computed tomography (CT) scan with infusion of contrast material. The CT scan should extend inferiorly to include the liver and adrenal glands. Magnetic resonance imaging (MRI) scans of the thorax and upper abdomen do not appear to yield advantages over CT scans.[2] 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 CT/MRI of the brain may be performed if initial assessments suggest metastases, or for patients with stage III disease who are under consideration for aggressive local and combined modality treatments. Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy. The wider availability and use of fluorodeoxyglucose positron emission tomography (FDG-PET) for staging has modified this approach to staging mediastinal lymph nodes and distant metastases.

If there is no evidence of distant metastatic disease on CT scan, FDG-PET scanning complements CT scan staging of the mediastinum. The combination of CT scanning and PET scanning has greater sensitivity and specificity than CT scanning alone.[3] Numerous nonrandomized studies of FDG-PET have evaluated mediastinal lymph nodes using surgery (i.e., mediastinoscopy and/or thoracotomy with mediastinal lymph node dissection) as the gold standard of comparison. A prospective trial studied the impact of FDG-PET on the staging of 102 patients with NSCLC and found that the sensitivity, specificity, negative predictive value and positive predictive value of FDG-PET alone for detection of mediastinal metastases were 91%, 86%, 95%, and 74%, respectively, as compared with CT scan alone, which had a sensitivity of 75% and a specificity of 66%.[4] False-negative results from FDG-PET were seen in small tumors and when FDG-PET was unable to distinguish the primary lesion from contiguous lymphadenopathy. False-positive results were often caused by the presence of benign inflammatory disease. These results have been corroborated by other studies.[5,6] For patients with clinically operable NSCLC, biopsy of mediastinal lymph nodes, found on chest CT scan to be larger than 1 cm in shortest transverse axis or positive on FDG-PET scanning, is recommended. 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 do not corroborate each other.

Numerous nonrandomized, prospective and retrospective studies have demonstrated that FDG-PET 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 is not reliable for detection of metastases in these sites.[7]

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

Patients at risk for brain metastases may be staged with CT or MRI scans. One study randomly assigned 332 patients with potentially operable NSCLC but without neurological symptoms to brain CT or MRI imaging to detect occult brain metastasis before lung surgery. MRI showed a trend toward a higher preoperative detection rate than CT (P = .069), with an overall detection rate of approximately 7% from pretreatment to 12 months after surgery.[7] Patients with stage I or stage II disease had a detection rate of 4% (i.e., 8 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.

The Revised International Staging System for 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 1997 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer.[12,13] These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging. Stage I is divided into two categories by the size of the tumor: IA (T1, N0, M0) and IB (T2, N0, M0). Stage II is divided into two categories by the size of the tumor and by the nodal status: IIA (T1, N1, M0) and IIB (T2, N1, M0). T3, N0 has been moved from stage IIIA in the 1986 version of the staging system to stage IIB in the latest version. This change reflects the slightly superior prognosis of these patients and shows that many patients with invasion of the parietal pleura or chest wall caused by pleural-based or superior sulcus tumors (T3) but with negative lymph nodes (N0) are often treated with surgery, sometimes combined with radiation therapy or chemoradiation therapy, and the results are similar to those of patients with resected stage II disease. Another change clarifies the classification of multiple tumor nodules. Satellite tumor nodules located in the same lobe as the primary lesion, which are not lymph nodes, should be classified as T4 lesions. Intrapulmonary ipsilateral metastasis in a lobe other than the lobe containing the primary lesions should be classified as an M1 lesion (stage IV).

The AJCC has designated staging by TNM classification.[13]

TNM Definitions

Primary tumor (T)

  • TX: Primary tumor cannot be assessed, or tumor is proven by the presence of malignant cells in sputum or bronchial washings but is not visualized by imaging or bronchoscopy


  • T0: No evidence of primary tumor


  • Tis: Carcinoma in situ


  • T1: A tumor that is 3 cm or smaller in greatest dimension, is surrounded by lung or visceral pleura, and is without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).  [Note: The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1.]


  • T2: A tumor with any of the following features of size or extent:
    • Larger than 3 cm in greatest dimension
    • Involves the main bronchus and is 2 cm or larger distal to the carina
    • Invades the visceral pleura
    • Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung


  • T3: A tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or, tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or, associated atelectasis or obstructive pneumonitis of the entire lung


  • T4: A tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or, separate tumor nodules in the same lobe; or, tumor with a malignant pleural effusion.  [Note: Most pleural effusions associated with lung cancer are due to tumor; however, in a few patients multiple cytopathologic examinations of pleural fluid are negative for tumor. In these cases, fluid is nonbloody and is not an exudate. Such patients may be further evaluated by videothoracoscopy and direct pleural biopsies. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element, and the patient should be staged as T1, T2, or T3.]


Regional lymph nodes (N)

  • NX: Regional lymph nodes cannot be assessed
  • N0: No regional lymph node metastasis
  • N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes including involvement by direct extension of the primary tumor
  • N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
  • N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

Distant metastasis (M)

  • MX: Distant metastasis cannot be assessed
  • M0: No distant metastasis
  • M1: Distant metastasis present.  [Note: M1 includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral).]

Specify sites according to the following notations:

Notation Key for Tumor Sites
BRA = brain EYE = eye HEP = hepatic
LYM = lymph nodes MAR = bone marrow OSS = osseous
OTH = other OVR = ovary PER = peritoneal
PLE = pleura PUL = pulmonary SKI = skin

AJCC Stage Groupings

Occult carcinoma

  • TX, N0, M0

Stage 0

  • Tis, N0, M0

Stage IA

  • T1, N0, M0

Stage IB

  • T2, N0, M0

Stage IIA

  • T1, N1, M0

Stage IIB

  • T2, N1, M0
  • T3, N0, M0

Stage IIIA

  • T1, N2, M0
  • T2, N2, M0
  • T3, N1, M0
  • T3, N2, M0

Stage IIIB

  • Any T, N3, M0
  • T4, any N, M0

Stage IV

  • Any T, any N, M1

References

  1. Pfister DG, Johnson DH, Azzoli CG, et al.: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22 (2): 330-53, 2004.  [PUBMED Abstract]

  2. Webb WR, Gatsonis C, Zerhouni EA, et al.: CT and MR imaging in staging non-small cell bronchogenic carcinoma: report of the Radiologic Diagnostic Oncology Group. Radiology 178 (3): 705-13, 1991.  [PUBMED Abstract]

  3. Vansteenkiste JF, Stroobants SG, De Leyn PR, et al.: Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol 16 (6): 2142-9, 1998.  [PUBMED Abstract]

  4. Pieterman RM, van Putten JW, Meuzelaar JJ, et al.: Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med 343 (4): 254-61, 2000.  [PUBMED Abstract]

  5. Roberts PF, Follette DM, von Haag D, et al.: Factors associated with false-positive staging of lung cancer by positron emission tomography. Ann Thorac Surg 70 (4): 1154-9; discussion 1159-60, 2000.  [PUBMED Abstract]

  6. Liewald F, Grosse S, Storck M, et al.: How useful is positron emission tomography for lymphnode staging in non-small-cell lung cancer? Thorac Cardiovasc Surg 48 (2): 93-6, 2000.  [PUBMED Abstract]

  7. Yokoi K, Kamiya N, Matsuguma H, et al.: Detection of brain metastasis in potentially operable non-small cell lung cancer: a comparison of CT and MRI. Chest 115 (3): 714-9, 1999.  [PUBMED Abstract]

  8. Dietlein M, Weber K, Gandjour A, et al.: Cost-effectiveness of FDG-PET for the management of potentially operable non-small cell lung cancer: priority for a PET-based strategy after nodal-negative CT results. Eur J Nucl Med 27 (11): 1598-609, 2000.  [PUBMED Abstract]

  9. Scott WJ, Shepherd J, Gambhir SS: Cost-effectiveness of FDG-PET for staging non-small cell lung cancer: a decision analysis. Ann Thorac Surg 66 (6): 1876-83; discussion 1883-5, 1998.  [PUBMED Abstract]

  10. Gambhir SS, Hoh CK, Phelps ME, et al.: Decision tree sensitivity analysis for cost-effectiveness of FDG-PET in the staging and management of non-small-cell lung carcinoma. J Nucl Med 37 (9): 1428-36, 1996.  [PUBMED Abstract]

  11. Viney RC, Boyer MJ, King MT, et al.: Randomized controlled trial of the role of positron emission tomography in the management of stage I and II non-small-cell lung cancer. J Clin Oncol 22 (12): 2357-62, 2004.  [PUBMED Abstract]

  12. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997.  [PUBMED Abstract]

  13. Lung. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 167-181. 

Treatment Option Overview

In non-small cell lung cancer (NSCLC), results of standard treatment are poor except for the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment. Surgery is the most potentially curative therapeutic option for this disease; radiation therapy can produce a cure in a small number of patients and can provide palliation in most patients. Adjuvant chemotherapy may provide an additional benefit to patients with resected NSCLC. In advanced-stage disease, chemotherapy offers modest improvements in median survival, though overall survival is poor.[1,2] Chemotherapy has produced short-term improvement in disease-related symptoms. 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;[3-5] however, the impact of chemotherapy on quality of life requires more study.

Current areas under evaluation include combining local treatment (surgery), regional treatment (radiation therapy), and systemic treatments (chemotherapy, immunotherapy, and targeted agents) and developing more effective systemic therapy. Several agents, including cisplatin, carboplatin, paclitaxel (Taxol), docetaxel (Taxotere), topotecan, irinotecan, vinorelbine, and gemcitabine are active in the treatment of advanced NSCLC. Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early stage lung cancer.

References

  1. Chemotherapy for non-small cell lung cancer. Non-small Cell Lung Cancer Collaborative Group. Cochrane Database Syst Rev (2): CD002139, 2000.  [PUBMED Abstract]

  2. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.  [PUBMED Abstract]

  3. Spiro SG, Rudd RM, Souhami RL, et al.: Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life. Thorax 59 (10): 828-36, 2004.  [PUBMED Abstract]

  4. Clegg A, Scott DA, Hewitson P, et al.: Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review. Thorax 57 (1): 20-8, 2002.  [PUBMED Abstract]

  5. Klastersky J, Paesmans M: Response to chemotherapy, quality of life benefits and survival in advanced non-small cell lung cancer: review of literature results. Lung Cancer 34 (Suppl 4): S95-101, 2001.  [PUBMED Abstract]

Occult Non-Small Cell Lung Cancer



Occult non-small cell lung cancer (NSCLC) is defined by the following clinical stage grouping:

  • TX, N0, M0

In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomographic 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.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with occult non-small cell lung cancer 11. 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 8.

Stage 0 Non-Small Cell Lung Cancer



Stage 0 non-small cell lung cancer (NSCLC) is defined by the following clinical stage grouping:

  • Tis, N0, M0

Stage 0 NSCLC is the same as carcinoma in situ of the lung. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, a high incidence of second primary cancers, many of which are unresectable, exists. Endoscopic phototherapy with a hematoporphyrin derivative has been described as an alternative to surgical resection in carefully selected patients.[1-3] This treatment, which is under clinical evaluation, seems to be most effective for very early central tumors that extend less than 1 cm within the bronchus.[2] Efficacy of this treatment modality in the management of early NSCLC remains to be proven.

Standard treatment options:

  1. Surgical resection using the least extensive technique possible (segmentectomy or wedge resection) to preserve maximum normal pulmonary tissue because these patients are at high risk for second lung cancers.


  2. Endoscopic photodynamic therapy.[2,3]


Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage 0 non-small cell lung cancer 12. 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 8.

References

  1. Woolner LB, Fontana RS, Cortese DA, et al.: Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period. Mayo Clin Proc 59 (7): 453-66, 1984.  [PUBMED Abstract]

  2. Furuse K, Fukuoka M, Kato H, et al.: A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. The Japan Lung Cancer Photodynamic Therapy Study Group. J Clin Oncol 11 (10): 1852-7, 1993.  [PUBMED Abstract]

  3. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992.  [PUBMED Abstract]

Stage I Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence 2 for more information.)

Stage I non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • T1, N0, M0
  • T2, N0, M0

Surgery is the treatment of choice for patients with stage I NSCLC. 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 3% mortality to 5% mortality with lobectomy can be expected.[1] Patients with impaired pulmonary function are candidates for segmental or wedge resection of the primary tumor. The Lung Cancer Study Group conducted a randomized study (LCSG-821 13) to compare lobectomy with limited resection for patients with stage I lung cancer. Results of the study showed a reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision, but the outcome showed 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 more than 3 cm but not for those with tumors less than 3 cm; however, the rate of locoregional recurrence was significantly less after lobectomy, regardless of primary tumor size.

Another study of stage I patients showed that those treated with wedge or segment resections had a local recurrence rate of 50% (i.e., 31 recurrences out of 62 patients) despite having undergone complete resections.[4] Exercise testing may aid in the selection of patients with impaired pulmonary function who can tolerate lung resection.[5] The availability of video-assisted thoracoscopic wedge resection permits limited resections in patients with poor pulmonary function who are not usually candidates for lobectomy.[6]

Patients with inoperable stage I disease and with sufficient pulmonary reserve may be candidates for radiation therapy with curative intent. In 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, survival at 5 years after radiation therapy with curative intent was comparable with an historical control group of patients of similar age who were resected with curative intent.[7] 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%.[8,9] 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.

Primary radiation therapy should consist 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.

Many patients treated surgically subsequently develop regional or distant metastases.[4] Such patients are candidates for entry into clinical trials evaluating adjuvant treatment with chemotherapy or radiation therapy following surgery. A meta-analysis of nine randomized trials evaluating postoperative radiation versus surgery alone showed a 7% reduction in OS with adjuvant radiation in patients with stage I or stage II disease.[10][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.

Patients with stage IB disease may benefit from adjuvant platinum-based combination chemotherapy, as evidenced in the INT- JBR-10 14 and the CALGB-9633 15 trials, for example.[11-15] A meta-analysis of adjuvant chemotherapy trials showed a hazard ratio (HR) for death of 0.87 for patients treated with cisplatin-based chemotherapy;[16] however, this result was not statistically significant. Four large randomized trials and an additional meta-analysis evaluating the benefit of adjuvant cisplatin combination chemotherapy have also been reported. Three of the trials and the meta-analysis have shown that adjuvant cisplatin-based chemotherapy improves OS in selected NSCLC patients.

In the largest trial, the International Adjuvant Lung Cancer Trial (IALT), 1,867 patients with resected stage I, stage II, or stage III NSCLC were randomly assigned to cisplatin combination chemotherapy or follow-up.[12] Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (5-year survival, 44.5% vs. 40.4%; HR for death = 0.86; 95% confidence interval [CI], 0.76–0.98; P < .03).[12][Level of evidence: 1iiA] Seven patients (0.8%) died of chemotherapy-induced toxic effects.

In the second trial, 482 patients with completely resected stage I (T2, N0) or stage II (excluding T3, N0) NSCLC were randomly assigned to receive four cycles of vinorelbine and cisplatin or observation.[11] OS was significantly prolonged for patients receiving chemotherapy (median survival, 94 months vs. 73 months; HR = 0.69; P = .011).[11][Level of evidence: 1iiA] Two patients died of drug-related toxicity.

In the third trial, 344 patients with stage IB (T2, N0, M0) NSCLC were randomized to four cycles of paclitaxel and carboplatin or observation.[13] There were no chemotherapy-related toxic deaths. The hazard ratio for death was significantly lower among patients receiving adjuvant chemotherapy (HR = 0.62; 95% CI, 0.41–0.95; P = .028).[13][Level of evidence: 1iiA] OS at 4 years was 71% (95% CI, 62%–81%) in the chemotherapy group and 59% (95% CI, 50%–69%) in the observation group.

In the fourth trial, the Adjuvant Lung Project Italy trial, 1,209 patients with stage I, stage II, or stage IIIA NSCLC were randomly assigned to receive mitomycin C, vindesine, and cisplatin every 3 weeks or no treatment after complete resection.[14][Level of evidence: 1iiA] After a median follow-up time of 64.5 months, there was no statistically significant difference between the two patient groups in OS (HR = 0.96; 95% CI, 0.81–1.13; P = .589) or progression-free survival (HR = 0.89; 95% CI, 0.76–1.03; P = .128).

The literature-based meta-analysis of randomized trials identified 11 trials conducted with a total of 5,716 patients. This analysis includes the IALT and ALPI trials noted above. In this analysis, HR estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR = 0.872; 95% CI, 0.805–0.944; P = .001). In a subset analysis, both cisplatin-based chemotherapy (HR = 0.891; 95% CI, 0.815–0.975; P = .012) and single-agent therapy with tegafur and uracil (UFT) (HR = 0.799; 95% CI, 0.668–0.957; P = .015) were found to yield a significant survival benefit.[15,17]

In summary, the preponderance of evidence indicates that adjuvant cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC. The optimal sequence of surgery and chemotherapy and the benefits and risks of adjuvant radiation therapy in patients with resectable NSCLC are yet to be determined.

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.[18] Others 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.[4] A randomized trial of vitamin A versus observation in patients with resected stage I disease showed a trend toward decreased second primary cancers in the vitamin A arm and no difference in OS rates;[19] however, a large randomized study of beta-carotene and retinol supplements used in the primary prevention of lung cancer showed an increase in mortality and lung cancer incidence.[20][Level of evidence: 1iA]

An intergroup trial evaluated the role of isotretinoin in the chemoprevention of second cancers in patients with resected stage I NSCLC. In the trial, 1,116 patients were randomly assigned to receive isotretinoin (30 mg/day) for 3 years or a placebo.[21][Level of evidence: 1iiA] (Refer to the PDQ summary on Lung Cancer Prevention 6 for more information.) After a median follow-up of 3.5 years, no differences existed between the arms in time to development of second primary tumors, disease recurrence, or survival.

Treatment options:

  1. Lobectomy or segmental, wedge, or sleeve resection as appropriate.


  2. Radiation therapy with curative intent (for potentially resectable tumors in patients with medical contraindications to surgery).


  3. Adjuvant chemotherapy after resection.


  4. Clinical trials of adjuvant chemoprevention , as evidenced in the ECOG-5597 16 trial, for example.


  5. Endoscopic photodynamic therapy (under clinical evaluation in highly selected patients with T1, N0, M0 tumors).[22]


Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I non-small cell lung cancer 17. 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 8.

References

  1. Ginsberg RJ, Hill LD, Eagan RT, et al.: Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 86 (5): 654-8, 1983.  [PUBMED Abstract]

  2. Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60 (3): 615-22; discussion 622-3, 1995.  [PUBMED Abstract]

  3. Warren WH, Faber LP: Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Five-year survival and patterns of intrathoracic recurrence. J Thorac Cardiovasc Surg 107 (4): 1087-93; discussion 1093-4, 1994.  [PUBMED Abstract]

  4. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995.  [PUBMED Abstract]

  5. Morice RC, Peters EJ, Ryan MB, et al.: Exercise testing in the evaluation of patients at high risk for complications from lung resection. Chest 101 (2): 356-61, 1992.  [PUBMED Abstract]

  6. Shennib HA, Landreneau R, Mulder DS, et al.: Video-assisted thoracoscopic wedge resection of T1 lung cancer in high-risk patients. Ann Surg 218 (4): 555-8; discussion 558-60, 1993.  [PUBMED Abstract]

  7. Noordijk EM, vd Poest Clement E, Hermans J, et al.: Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol 13 (2): 83-9, 1988.  [PUBMED Abstract]

  8. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992.  [PUBMED Abstract]

  9. Gauden S, Ramsay J, Tripcony L: The curative treatment by radiotherapy alone of stage I non-small cell carcinoma of the lung. Chest 108 (5): 1278-82, 1995.  [PUBMED Abstract]

  10. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 352 (9124): 257-63, 1998.  [PUBMED Abstract]

  11. Winton TL, Livingston R, Johnson D, et al.: A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage 1B and II non small cell lung cancer (NSCLC) Intergroup JBR.10. [Abstract] J Clin Oncol 22 (Suppl 14): A-7018, 621s, 2004. 

  12. Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004.  [PUBMED Abstract]

  13. Strauss GM, Herndon J, Maddaus MA, et al.: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): report of Cancer and Leukemia Group B (CALGB) protocol 9633. [Abstract] J Clin Oncol 22 (Suppl 14): A-7019, 621s, 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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  16. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.  [PUBMED Abstract]

  17. Kato H, Ichinose Y, Ohta M, et al.: A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350 (17): 1713-21, 2004.  [PUBMED Abstract]

  18. Thomas P, Rubinstein L: Cancer recurrence after resection: T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 49 (2): 242-6; discussion 246-7, 1990.  [PUBMED Abstract]

  19. Pastorino U, Infante M, Maioli M, et al.: Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 11 (7): 1216-22, 1993.  [PUBMED Abstract]

  20. Goodman GE, Thornquist MD, Balmes J, et al.: The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst 96 (23): 1743-50, 2004.  [PUBMED Abstract]

  21. Lippman SM, Lee JJ, Karp DD, et al.: Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 93 (8): 605-18, 2001.  [PUBMED Abstract]

  22. Furuse K, Fukuoka M, Kato H, et al.: A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. The Japan Lung Cancer Photodynamic Therapy Study Group. J Clin Oncol 11 (10): 1852-7, 1993.  [PUBMED Abstract]

Stage II Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence 2 for more information.)

Stage II non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • T1, N1, M0
  • T2, N1, M0
  • T3, N0, M0

Surgery is the treatment of choice for patients with stage II NSCLC. 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.

Patients with inoperable stage II disease and with sufficient pulmonary reserve are candidates for radiation therapy with curative intent.[1] Among patients with excellent performance status, a 3-year survival rate of 20% may be expected if a course of radiation therapy with curative intent can be completed. In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC, who were treated with definitive radiation therapy, achieved a 5-year overall survival (OS) rate of 10%; however, the 44 patients with T1 tumors achieved an actuarial disease-free survival rate of 60%. This retrospective study also suggested that improved disease-free survival was obtained with radiation therapy doses larger than 60 Gy.[2] Primary radiation therapy should consist 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.

After surgery, many patients develop regional or distant metastases.[3] Prospective randomized trials evaluating the role of postoperative adjuvant chemotherapy in patients with NSCLC have been performed for decades. A meta-analysis of adjuvant chemotherapy trials showed a hazard ratio (HR) for death of 0.87 for patients treated with cisplatin-based chemotherapy;[4] however, this result was not statistically significant. Four large randomized trials and an additional meta-analysis evaluating the benefit of adjuvant cisplatin combination chemotherapy have also been reported. Three of the trials and the meta-analysis have shown that adjuvant cisplatin-based chemotherapy improves OS in selected NSCLC patients.

In the largest trial, the International Adjuvant Lung Cancer Trial (IALT), 1,867 patients with resected stage I, stage II, or stage III NSCLC were randomly assigned to cisplatin combination chemotherapy or follow-up.[5] Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (5-year survival 44.5% vs. 40.4%, HR for death = 0.86; 95% confidence interval [CI], 0.76–0.98; P < .03).[5][Level of evidence: 1iiA] Seven patients (0.8%) died of chemotherapy-induced toxic effects.

In the second trial (INT- JBR-10) 14, 482 patients with completely resected stage I (T2, N0) or stage II (excluding T3, N0) NSCLC were randomly assigned to receive four cycles of vinorelbine and cisplatin or observation.[6] OS was significantly prolonged for patients receiving chemotherapy (median 94 months vs. 73 months; HR = 0.69; P = .011).[6][Level of evidence: 1iiA] Two patients died of drug-related toxic effects.

In the third trial (CALGB-9633) 15, 344 patients with stage IB (T2, N0, M0) NSCLC were randomly assigned to four cycles of paclitaxel and carboplatin or observation.[7] There were no chemotherapy-related toxic deaths. The hazard ratio for death was significantly lower among patients receiving adjuvant chemotherapy (HR = 0.62; 95% CI, 0.41–0.95; P = .028).[7][Level of evidence: 1iiA] OS at 4 years was 71% (95% CI, 62%–81%) in the chemotherapy group and 59% (95% CI, 50%–69%) in the observation group.

In the fourth trial, the Adjuvant Lung Project Italy trial, 1,209 patients with stage I, stage II, or stage IIIA NSCLC were randomly assigned to receive mitomycin C, vindesine, and cisplatin every 3 weeks, or no treatment after complete resection.[8][Level of evidence: 1iiA] After a median follow-up time of 64.5 months, there was no statistically significant difference between the two patient groups in OS (HR = 0.96; 95% CI, 0.81–1.13; P = .589) or progression-free survival (HR = 0.89; 95% CI, 0.76–1.03; P = .128).

The literature-based meta-analysis of randomized trials identified 11 trials conducted on a total of 5,716 patients. This analysis includes the IALT and ALPI trials noted above. In this analysis, HR estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR = 0.872; 95% CI, 0.805–0.944; P = .001). In a subset analysis, both cisplatin-based chemotherapy (HR = 0.891; 95% CI, 0.815–0.975; P = .012) and single-agent therapy with tegafur and uracil (UFT) (HR = 0.799; 95% CI, 0.668–0.957; P = .015) were found to yield a significant survival benefit.[9,10]

In summary, the preponderance of evidence indicates that adjuvant cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC. The optimal sequence of surgery and chemotherapy and the benefits and risks of adjuvant radiation therapy in patients with resectable NSCLC remain to be determined.

Treatment options:

  1. Lobectomy; pneumonectomy; or segmental, wedge, or sleeve resection as appropriate.


  2. Radiation therapy with curative intent (for potentially operable tumors in patients with medical contraindications to surgery).


  3. Adjuvant chemotherapy with or without other modalities after curative surgery.[5-10]


  4. Clinical trials of radiation therapy after curative surgery.[11]


Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II non-small cell lung cancer 18. 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 8.

References

  1. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985.  [PUBMED Abstract]

  2. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992.  [PUBMED Abstract]

  3. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995.  [PUBMED Abstract]

  4. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.  [PUBMED Abstract]

  5. Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004.  [PUBMED Abstract]

  6. Winton TL, Livingston R, Johnson D, et al.: A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage 1B and II non small cell lung cancer (NSCLC) Intergroup JBR.10. [Abstract] J Clin Oncol 22 (Suppl 14): A-7018, 621s, 2004. 

  7. Strauss GM, Herndon J, Maddaus MA, et al.: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): report of Cancer and Leukemia Group B (CALGB) protocol 9633. [Abstract] J Clin Oncol 22 (Suppl 14): A-7019, 621s, 2004. 

  8. Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003.  [PUBMED Abstract]

  9. Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004.  [PUBMED Abstract]

  10. Kato H, Ichinose Y, Ohta M, et al.: A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350 (17): 1713-21, 2004.  [PUBMED Abstract]

  11. Holmes EC: Adjuvant treatment in resected lung cancer. Semin Surg Oncol 6 (5): 263-7, 1990.  [PUBMED Abstract]

Stage IIIA Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence 2 for more information.)

Stage IIIA non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • T1, N2, M0
  • T2, N2, M0
  • T3, N1, M0
  • T3, N2, M0

Patients with clinical stage IIIA N2 disease have a 5-year survival rate of 10% to 15% overall; however, patients with bulky mediastinal involvement (i.e., visible on chest radiograph) 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. Although most patients do not achieve a complete response to radiation therapy, a reproducible long-term survival benefit in 5% to 10% of patients treated with standard fractionation to 60 Gy occurs, and significant palliation often results. Patients with excellent performance status (PS) and those who require a thoracotomy to prove that a surgically unresectable tumor is present are most likely to benefit from radiation therapy.[1]

Because of the poor long-term results, all patients with stage IIIA NSCLC are candidates for treatment on clinical trials. Trials examining fractionation schedules, brachytherapy, and combined modality approaches may lead to improvement in the control of this disease.[2] One prospective randomized clinical study showed that radiation therapy given as three daily fractions improved OS compared with radiation therapy given as one daily fraction.[3][Level of evidence: 1iiA]

The addition of chemotherapy to radiation therapy has been reported to improve survival in prospective clinical studies, including the RTOG-8808 19 and ECOG-4588 19 trials, for example, that have used modern cisplatin-based chemotherapy regimens.[4-7] A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[8] The optimal sequencing of modalities and schedule of drug administration is yet to be determined and is under study in ongoing clinical trials such as the RTOG-9410 20 trial, for example.

The use of preoperative (i.e., neoadjuvant) chemotherapy has been effective in two small randomized studies of a total of 120 patients with stage IIIA NSCLC.[9,10] In both studies, the 58 patients randomized to three cycles of cisplatin-based chemotherapy before surgery had a median survival more than three times as long as patients treated with surgery but no chemotherapy. Two additional single-arm studies, including SWOG-8805 21, have evaluated either two to four cycles of combination chemotherapy or combination chemotherapy plus chest radiation therapy for 211 patients with histologically confirmed N2 stage IIIA NSCLC.[11] In these studies, 65% to 75% of patients had a resection of their cancers, and 27% to 28% of patients were alive 3 years later. These results are encouraging, and combined-modality therapy with neoadjuvant chemotherapy with surgery and/or chest radiation therapy should be considered for patients with good PS who have stage IIIA NSCLC.

After surgery, many patients develop regional or distant metastases.[12] Patients with resected stage IIIA NSCLC may benefit from adjuvant cisplatin combination chemotherapy, as evidenced in the (INT- JBR-10) 22 and CALGB-9633 15 trials, for example.[13-18] Prospective randomized trials evaluating the role of postoperative adjuvant chemotherapy in patients with NSCLC have been performed for decades. A meta-analysis of adjuvant chemotherapy trials showed a hazard ratio (HR) for death of 0.87 for patients treated with cisplatin-based chemotherapy;[8] however, this result was not statistically significant. Four large randomized trials and an additional meta-analysis evaluating the benefit of adjuvant cisplatin combination chemotherapy have also been reported. Three of the trials and the meta-analysis have shown that adjuvant cisplatin-based chemotherapy improves OS in selected NSCLC patients.

In the largest trial, the International Adjuvant Lung Cancer Trial (IALT), 1,867 patients with resected stage I, stage II, or stage III NSCLC were randomly assigned to cisplatin combination chemotherapy or follow-up.[13] Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (5-year survival 44.5% vs. 40.4%, HR for death = 0.86; 95% confidence interval [CI], 0.76–0.98; P < .03).[13][Level of evidence: 1iiA] Seven patients (0.8%) died of chemotherapy-induced toxic effects.

In the second trial, 482 patients with completely resected stage I (T2, N0) or stage II (excluding T3, N0) NSCLC were randomly assigned to receive four cycles of vinorelbine and cisplatin or observation.[14] OS was significantly prolonged for patients receiving chemotherapy (median 94 months vs. 73 months; HR 0.69; P = .011).[14][Level of evidence: 1iiA] Two patients died of drug-related toxic effects.

In the third trial, 344 patients with stage IB (T2, N0, M0) NSCLC were randomly assigned to four cycles of paclitaxel and carboplatin or observation.[15] There were no chemotherapy-related toxic deaths. The hazard ratio for death was significantly lower among patients receiving adjuvant chemotherapy (HR = 0.62; 95% CI, 0.41–0.95; P = .028).[15][Level of evidence: 1iiA] OS at 4 years was 71% (95% CI, 62%–81%) in the chemotherapy group and 59% (95% CI, 50%–69%) in the observation group.

In the fourth trial, the Adjuvant Lung Project Italy (ALPI) trial, 1,209 patients with stage I, stage II, or stage IIIA NSCLC were randomly assigned to receive mitomycin C, vindesine, and cisplatin every 3 weeks or no treatment after complete resection.[16][Level of evidence: 1iiA] After a median follow-up time of 64.5 months, there was no statistically significant difference between the 2 patient groups in OS (HR = 0.96; 95% CI, 0.81–1.13; P = .589) or progression-free survival (HR = 0.89; 95% CI, 0.76–1.03; P = .128).

The literature-based meta-analysis of randomized trials identified 11 trials conducted on a total of 5,716 patients. This analysis includes the IALT and ALPI trials noted above. In this analysis, HR estimates suggested that adjuvant chemotherapy yielded a survival advantage versus surgery alone (HR = 0.872; 95% CI, 0.805–0.944; P = .001). In a subset analysis, both cisplatin-based chemotherapy (HR = 0.891; 95% CI, 0.815–0.975; P = .012) and single-agent therapy with tegafur and uracil (UFT) (HR = 0.799; 95% CI, 0.668–0.957; P =.015) were found to yield a significant survival benefit.[17,18]

In summary, the preponderance of evidence indicates that adjuvant cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC. The optimal sequence of surgery and chemotherapy and the benefits and risks of adjuvant radiation therapy in patients with resectable NSCLC are yet to be determined.

Although most retrospective studies suggest that postoperative radiation therapy can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival.[19,20] One controlled trial of patients with completely resected stage II or stage III squamous cell lung cancer failed to demonstrate a survival benefit for patients who received postoperative radiation therapy, but local recurrences were significantly reduced.[21] In one trial patients with completely resected stage I, stage II, or stage IIIA lung cancers were randomly assigned to resection alone or to resection plus postoperative radiation therapy. The addition of postoperative radiation therapy did not improve OS or local recurrence either for the whole group or for the subset of patients with stage IIIA disease.[22][Level of evidence: 1iiA] An intergroup trial comparing postoperative radiation therapy alone to postoperative radiation therapy with concurrent cisplatin and etoposide did not demonstrate either a disease-free survival or OS advantage with the combined therapy.[23][Level of evidence: 1iiA] A meta-analysis of nine randomized trials that evaluated postoperative radiation therapy versus surgery alone showed no difference in OS for the entire postoperative radiation therapy group or for the subset of N2 patients.[24][Level of evidence: 1iiA] 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.

No consistent benefit from any form of immunotherapy has been demonstrated thus far in the treatment of NSCLC.

Treatment options:

  1. Surgery alone in patients with operable tumors without bulky lymphadenopathy.[25-27]


  2. Radiation therapy alone, for patients who are not suitable for neoadjuvant chemotherapy plus surgery.[1,2,28]


  3. Chemotherapy combined with other modalities, as evidenced in the SWOG-8805 21 trial, for example.[4-6,11]


Superior sulcus tumor (T3, N0 or N1, M0)

A special approach is also merited for treatment of superior sulcus tumors. These are a locally invasive problem and usually have a reduced tendency for distant metastases; consequently, local therapy has curative potential, especially in patients with T3, N0 disease. Radiation therapy alone, radiation therapy preceded or followed by surgery, or surgery alone (in highly selected cases) may be curative in some patients, with a 5-year survival rate of more than 20% in some studies.[29] Patients with more invasive tumors of this area, or true Pancoast tumors, have a worse prognosis and generally do not benefit from primary surgical management. Follow-up surgery may be used to verify complete response in the radiation therapy field and to resect necrotic tissue. Concurrent chemotherapy and radiation therapy followed by surgery may provide the best outcome, particularly for patients with T4, N0, or N1 disease, as evidenced in the SWOG-9416 23 trial, for example.[30][Level of evidence: 3iiiDii]

Treatment options:

  1. Radiation therapy and surgery.


  2. Radiation therapy alone.


  3. Surgery alone (selected cases).


  4. Chemotherapy combined with other modalities.


  5. Clinical trials of combined modality therapy.


Chest wall tumor (T3, N0 or N1, M0)

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.

Treatment options:

  1. Surgery.[27,31]


  2. Surgery and radiation therapy.


  3. Radiation therapy alone.


  4. Chemotherapy combined with other modalities.


Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IIIA non-small cell lung cancer 24. 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 8.

References

  1. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985.  [PUBMED Abstract]

  2. Johnson DH, Einhorn LH, Bartolucci A, et al.: Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. Ann Intern Med 113 (1): 33-8, 1990.  [PUBMED Abstract]

  3. 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.  [PUBMED Abstract]

  4. Dillman RO, Seagren SL, Propert KJ, et al.: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 323 (14): 940-5, 1990.  [PUBMED Abstract]

  5. Le Chevalier T, Arriagada R, Quoix E, et al.: Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83 (6): 417-23, 1991.  [PUBMED Abstract]

  6. Schaake-Koning C, van den Bogaert W, Dalesio O, et al.: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326 (8): 524-30, 1992.  [PUBMED Abstract]

  7. Sause WT, Scott C, Taylor S, et al.: Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 87 (3): 198-205, 1995.  [PUBMED Abstract]

  8. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.  [PUBMED Abstract]

  9. Rosell R, Gómez-Codina J, Camps C, et al.: A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 330 (3): 153-8, 1994.  [PUBMED Abstract]

  10. Roth JA, Fossella F, Komaki R, et al.: A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 86 (9): 673-80, 1994.  [PUBMED Abstract]

  11. Albain KS, Rusch VW, Crowley JJ, et al.: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 13 (8): 1880-92, 1995.  [PUBMED Abstract]

  12. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  14. Winton TL, Livingston R, Johnson D, et al.: A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage 1B and II non small cell lung cancer (NSCLC) Intergroup JBR.10. [Abstract] J Clin Oncol 22 (Suppl 14): A-7018, 621s, 2004. 

  15. Strauss GM, Herndon J, Maddaus MA, et al.: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): report of Cancer and Leukemia Group B (CALGB) protocol 9633. [Abstract] J Clin Oncol 22 (Suppl 14): A-7019, 621s, 2004. 

  16. Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003.  [PUBMED Abstract]

  17. Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004.  [PUBMED Abstract]

  18. Kato H, Ichinose Y, Ohta M, et al.: A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350 (17): 1713-21, 2004.  [PUBMED Abstract]

  19. Emami B, Kaiser L, Simpson J, et al.: Postoperative radiation therapy in non-small cell lung cancer. Am J Clin Oncol 20 (5): 441-8, 1997.  [PUBMED Abstract]

  20. Sawyer TE, Bonner JA, Gould PM, et al.: Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks. Ann Thorac Surg 64 (5): 1402-7; discussion 1407-8, 1997.  [PUBMED Abstract]

  21. Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. The Lung Cancer Study Group. N Engl J Med 315 (22): 1377-81, 1986.  [PUBMED Abstract]

  22. Dautzenberg B, Arriagada R, Chammard AB, et al.: A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Groupe d'Etude et de Traitement des Cancers Bronchiques. Cancer 86 (2): 265-73, 1999.  [PUBMED Abstract]

  23. Keller SM, Adak S, Wagner H, et al.: A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med 343 (17): 1217-22, 2000.  [PUBMED Abstract]

  24. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 352 (9124): 257-63, 1998.  [PUBMED Abstract]

  25. Shields TW: The significance of ipsilateral mediastinal lymph node metastasis (N2 disease) in non-small cell carcinoma of the lung. A commentary. J Thorac Cardiovasc Surg 99 (1): 48-53, 1990.  [PUBMED Abstract]

  26. Mountain CF: The biological operability of stage III non-small cell lung cancer. Ann Thorac Surg 40 (1): 60-4, 1985.  [PUBMED Abstract]

  27. Van Raemdonck DE, Schneider A, Ginsberg RJ: Surgical treatment for higher stage non-small cell lung cancer. Ann Thorac Surg 54 (5): 999-1013, 1992.  [PUBMED Abstract]

  28. 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.  [PUBMED Abstract]

  29. Komaki R, Mountain CF, Holbert JM, et al.: Superior sulcus tumors: treatment selection and results for 85 patients without metastasis (Mo) at presentation. Int J Radiat Oncol Biol Phys 19 (1): 31-6, 1990.  [PUBMED Abstract]

  30. Rusch VW, Giroux DJ, Kraut MJ, et al.: Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 121 (3): 472-83, 2001.  [PUBMED Abstract]

  31. McCaughan BC, Martini N, Bains MS, et al.: Chest wall invasion in carcinoma of the lung. Therapeutic and prognostic implications. J Thorac Cardiovasc Surg 89 (6): 836-41, 1985.  [PUBMED Abstract]

Stage IIIB Non-Small Cell Lung Cancer

Stage IIIB non-small cell lung cancer (NSCLC) is defined by the following clinical stage groupings:

  • Any T, N3, M0
  • T4, any N, M0

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence 2 for more information.)

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 sites of tumor involvement and the performance status (PS) of the patient. Most patients with excellent PS are candidates for combined modality therapy; however, patients with malignant pleural effusion are rarely candidates for radiation therapy and should generally be treated similarly to stage IV 25 patients. Many randomized studies, including the RTOG-8808 19 and ECOG-4588 19 trials, for example, of patients with unresectable stage III NSCLC show that treatment with neoadjuvant or concurrent cisplatin-based chemotherapy and radiation therapy to the chest is associated with improved survival compared with treatment that uses radiation therapy alone.[1-5] A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[6]

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).[7][Level of evidence: 3iiiC]

T4 or N3, M0

An occasional patient with supraclavicular node involvement, who is otherwise a good candidate for radiation therapy with curative intent, will survive 3 years. Although most of these patients do not achieve a complete response to radiation therapy, significant palliation often results. Patients with excellent PS and those who are found to have advanced-stage disease at the time of resection are most likely to benefit from radiation therapy.[8] Adjuvant systemic chemotherapy with radiation therapy has been tested in randomized trials for patients with inoperable or unresectable locoregional NSCLC.[1-3,9] Some patients have shown a modest survival advantage with adjuvant chemotherapy. The addition of chemotherapy to radiation therapy has been reported to improve long-term survival in some[1,3,4] but not all[10] prospective clinical studies. A meta-analysis of patient data from 54 randomized clinical trials showed an absolute survival benefit of 4% at 2 years with the addition of cisplatin-based chemotherapy to radiation therapy.[11] The optimal sequencing of modalities is yet to be determined and is under study in clinical trials including the RTOG-9410 20 trial, for example.

Because of the poor overall results, these patients are candidates for clinical trials that examine new fractionation schedules, radiosensitizers, and combined modality approaches, which may lead to improvement in the control of disease.

Patients with NSCLC can present with superior vena cava syndrome. (Refer to the PDQ summary on Cardiopulmonary Syndromes 26 for more information.) Regardless of the clinical stage, this problem should generally be managed with radiation therapy with or without chemotherapy.

Treatment options:

  1. Radiation therapy alone.[7,12]


  2. Chemotherapy combined with radiation therapy.[1-3,9]


  3. Chemotherapy and concurrent radiation therapy followed by resection, as evidenced in the SWOG-8805 21 trial, for example.[13,14]


  4. Chemotherapy alone.


Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IIIB non-small cell lung cancer 27. 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 8.

References

  1. Le Chevalier T, Arriagada R, Quoix E, et al.: Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83 (6): 417-23, 1991.  [PUBMED Abstract]

  2. Morton RF, Jett JR, McGinnis WL, et al.: Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer. A randomized, phase III trial. Ann Intern Med 115 (9): 681-6, 1991.  [PUBMED Abstract]

  3. Dillman RO, Seagren SL, Propert KJ, et al.: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 323 (14): 940-5, 1990.  [PUBMED Abstract]

  4. Schaake-Koning C, van den Bogaert W, Dalesio O, et al.: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326 (8): 524-30, 1992.  [PUBMED Abstract]

  5. Sause WT, Scott C, Taylor S, et al.: Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 87 (3): 198-205, 1995.  [PUBMED Abstract]

  6. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995.  [PUBMED Abstract]

  7. 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.  [PUBMED Abstract]

  8. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985.  [PUBMED Abstract]

  9. Pfister DG, Johnson DH, Azzoli CG, et al.: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22 (2): 330-53, 2004.  [PUBMED Abstract]

  10. Blanke C, Ansari R, Mantravadi R, et al.: Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small-cell lung cancer: a Hoosier Oncology Group protocol. J Clin Oncol 13 (6): 1425-9, 1995.  [PUBMED Abstract]

  11. Pignon JP, Stewart LA, Souhami RL, et al.: A meta-analysis using individual patient data from randomised clinical trials (RCTS) of chemotherapy (CT) in non-small cell lung cancer (NSCLC): (2) survival in the locally advanced (LA) setting. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-1109, 334, 1994. 

  12. 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.  [PUBMED Abstract]

  13. Rusch VW, Albain KS, Crowley JJ, et al.: Surgical resection of stage IIIA and stage IIIB non-small-cell lung cancer after concurrent induction chemoradiotherapy. A Southwest Oncology Group trial. J Thorac Cardiovasc Surg 105 (1): 97-104; discussion 104-6, 1993.  [PUBMED Abstract]

  14. Albain KS, Rusch VW, Crowley JJ, et al.: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 13 (8): 1880-92, 1995.  [PUBMED Abstract]

Stage IV Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence 2 for more information.)

Stage IV non-small cell lung cancer (NSCLC) is defined by the following clinical stage grouping:

  • Any T, any N, M1

Palliative chemotherapy with a cisplatin-based or carboplatin-based regimen has been associated with objective and subjective responses for patients with metastatic NSCLC. Randomized trials have shown that cisplatin-based chemotherapy produces modest benefits in short-term survival compared with supportive care alone in patients with inoperable stage IIIB or IV disease. Although toxic effects may vary, outcomes are similar with most platinum-containing regimens. A prospective randomized trial comparing five older cisplatin-containing regimens showed no significant difference in response, duration of response, or survival among the different cisplatin-based regimens.[1][Level of evidence: 1iiA] Patients with good performance status (PS) and a limited number of sites of distant metastases have superior response and survival when given chemotherapy and compared with other patients.[2] A prospective randomized comparison of vinorelbine plus cisplatin versus vindesine plus cisplatin versus single-agent vinorelbine has reported an improved response rate of 30% and a median survival time of 40 weeks with the vinorelbine plus cisplatin regimen when compared with the other two regimens.[3][Level of evidence: 1iiA]

Reports of taxane and platinum combinations have shown relatively high response rates, significant 1-year survival, and palliation of lung cancer symptoms.[4] In a multicenter phase III study, the combination of cisplatin and paclitaxel showed a higher response rate than the older combination of cisplatin and etoposide.[5][Level of evidence: 1iiDii] Results from clinical trials indicate that platinum-doublet combinations are superior to both platinum and other single agents.[6]

Cisplatin-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care alone; however, 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. Often patients in this subgroup are not offered cytotoxic treatment because of concerns about tolerability. Several studies, including the ECOG-5592 16 trial, have demonstrated similar response rates, survival, and quality-of-life outcomes for patients 70 years or older as compared with patients younger than 70 years despite a greater frequency of leukopenia, weight loss, and neuropsychiatric toxic effects among the older population.[7,8] In a randomized trial of patients older than 70 years with NSCLC, single-agent vinorelbine resulted in superior survival when compared with supportive care alone (median survival of 28 weeks vs. 21 weeks).[9][Level of evidence: 1iiA] A multicenter Italian group conducted a randomized study of 698 older patients that compared both single-agent vinorelbine and single-agent gemcitabine with the combination of vinorelbine and gemcitabine.[10] Compared with each single drug, the combination treatment did not improve survival.[10][Level of evidence: 1iiA]. The hazard ratio of death for patients receiving the combination treatment was 1.17 (95% confidence interval [CI], 0.95–1.44) compared with single-agent vinorelbine and 1.06 (95% CI, 0.86–1.29) compared with single-agent gemcitabine. Studies to date suggest that fit elderly patients can receive the same benefit from platinum combination chemotherapy as younger patients with acceptable toxic effects.[11] In patients with contraindications to platinum compounds, no evidence indicates that nonplatinum combinations are superior to single-agent vinorelbine or single-agent gemcitabine. The use of single agent versus combination chemotherapy should be based on PS and comorbid conditions rather than age.[12]

A prospective randomized study compared four commonly used platinum-based chemotherapy regimens for patients with stage IIIB or stage IV NSCLC: cisplatin plus paclitaxel, gemcitabine plus cisplatin, cisplatin plus docetaxel, and carboplatin plus paclitaxel.[13] No regimen was found to have a significantly better response rate or survival time.[13][Level of evidence: 1iiA] The response rate for all 1,158 of the eligible patients was 19%, and the median survival time was 7.9 months (95% CI, 7.3–8.5 months). Patients with a PS of two had significantly worse toxic effects and survival compared with patients who had a PS of zero to one.[13] Another prospective randomized study compared the combination of carboplatin plus paclitaxel with vinorelbine plus cisplatin. This study also found no significant difference in efficacy between the two standard regimens.[14][Level of evidence: 1iiDii] A prospective randomized trial (E-4599 28) compared chemotherapy with carboplatin and paclitaxel with or without bevacizumab in patients with nonsquamous NSCLC. Patients with squamous cell histology were excluded because previous studies demonstrated significant bleeding complications in that group. A second planned interim analysis has been reported in abstract form.[15] Of the 842 patients entered, the response rates (10% vs. 27%, P < .001), progression-free survival (4.5 months vs. 6.4 months, P < .001), and median survival (10.2 months vs. 12.5 months, P = .075) were superior in the bevacizumab arm. The five deaths that occurred were on the bevacizumab arm and were the result of hemoptysis.

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. Appropriate patients are candidates for clinical trials that evaluate the role of platinum-based and nonplatinum-based chemotherapy. 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.

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as tracheal, esophageal, or bronchial compression; bone or brain metastases; pain; vocal cord paralysis; hemoptysis; or superior vena cava syndrome. In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[16] In the rare patient with synchronous presentation of a resectable primary tumor in the lung and a single brain metastasis, surgical resection of the solitary brain lesion is indicated with resection of the primary tumor. Appropriate postoperative chemotherapy and/or radiation therapy of the primary tumor site (and with postoperative whole-brain radiation therapy delivered in daily fractions of 1.8 Gy to 2.0 Gy) is used to avoid long-term toxic effects to normal brain tissue.[17,18]

Thoracic radiation therapy is an effective treatment modality to relieve symptoms from intrathoracic disease, either after disease progression during chemotherapy or in patients who are not candidates for or decline chemotherapy. Most of these patients will have symptoms from the primary tumor and local regional metastases, including dyspnea, cough, and hemoptysis; however, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief, [19,20] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCIC-CTG-SC15 29 trial, for example.[21] Evidence is available of a modest increase in survival in patients with better PS given high-dose radiation therapy.[19,20]

In closely observed asymptomatic patients, treatment may often be appropriately deferred until symptoms or signs of a progressive tumor develop.

Treatment options:

  1. External-beam radiation therapy, primarily for palliative relief of local symptomatic tumor growth.[19-21]


  2. Chemotherapy. The following regimens are associated with similar survival outcomes:
    • Cisplatin plus vinblastine plus mitomycin, as evidenced in the EORTC-08975 30 trial, for example.[19,22-25]
    • Cisplatin plus vinorelbine.[3,14]
    • Cisplatin plus paclitaxel.[5,13]
    • Cisplatin plus docetaxel.[13,26,27]
    • Cisplatin plus gemcitabine.[13,28]
    • Carboplatin plus paclitaxel.[13,14,29]


  3. Clinical trials evaluating the role of new chemotherapy regimens and other systemic agents. Initial results suggest newer nonplatinum-based chemotherapy regimens produce response and survival results like those produced by standard platinum-based regimens.[30] Further trials comparing platinum-based and nonplatinum-based regimens are ongoing.


  4. Endobronchial laser therapy and/or brachytherapy for obstructing lesions.[16]


Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV non-small cell lung cancer 31. 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 8.

References

  1. 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.  [PUBMED Abstract]

  2. O'Connell JP, Kris MG, Gralla RJ, et al.: Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy. J Clin Oncol 4 (11): 1604-14, 1986.  [PUBMED Abstract]

  3. Le Chevalier T, Brisgand D, Douillard JY, et al.: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 12 (2): 360-7, 1994.  [PUBMED Abstract]

  4. Johnson DH, Paul DM, Hande KR, et al.: Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol 14 (7): 2054-60, 1996.  [PUBMED Abstract]

  5. Bonomi P, Kim K, Fairclough D, et al.: Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 18 (3): 623-31, 2000.  [PUBMED Abstract]

  6. Hotta K, Matsuo K, Ueoka H, et al.: Addition of platinum compounds to a new agent in patients with advanced non-small-cell lung cancer: a literature based meta-analysis of randomised trials. Ann Oncol 15 (12): 1782-9, 2004.  [PUBMED Abstract]

  7. 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.  [PUBMED Abstract]

  8. Perrone F, Gallo C, Gridelli C: Re: 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 (13): 1029-30; discussion 1030-1, 2002.  [PUBMED Abstract]

  9. 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.  [PUBMED Abstract]

  10. Gridelli C, Perrone F, Gallo C, et al.: Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 95 (5): 362-72, 2003.  [PUBMED Abstract]

  11. 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.  [PUBMED Abstract]

  12. Maestu I, Gómez-Aldaraví L, Torregrosa MD, et al.: Gemcitabine and low dose carboplatin in the treatment of elderly patients with advanced non-small cell lung cancer. Lung Cancer 42 (3): 345-54, 2003.  [PUBMED Abstract]

  13. 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.  [PUBMED Abstract]

  14. Kelly K, Crowley J, Bunn PA Jr, et al.: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 19 (13): 3210-8, 2001.  [PUBMED Abstract]

  15. Sandler AB, Gray R, Brahmer J, et al.: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial - E4599. [Abstract] J Clin Oncol 23 (Suppl 16): A-LBA4, 2s, 2005. 

  16. 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.  [PUBMED Abstract]

  17. 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.  [PUBMED Abstract]

  18. 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.  [PUBMED Abstract]

  19. Macbeth F, Toy E, Coles B, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (3): CD002143, 2001.  [PUBMED Abstract]

  20. 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.  [PUBMED Abstract]

  21. 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.  [PUBMED Abstract]

  22. Veeder MH, Jett JR, Su JQ, et al.: A phase III trial of mitomycin C alone versus mitomycin C, vinblastine, and cisplatin for metastatic squamous cell lung carcinoma. Cancer 70 (9): 2281-7, 1992.  [PUBMED Abstract]

  23. 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.  [PUBMED Abstract]

  24. Pfister DG, Johnson DH, Azzoli CG, et al.: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22 (2): 330-53, 2004.  [PUBMED Abstract]

  25. 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.  [PUBMED Abstract]

  26. 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.  [PUBMED Abstract]

  27. 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.  [PUBMED Abstract]

  28. 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.  [PUBMED Abstract]

  29. Belani CP, Barstis J, Perry MC, et al.: Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation. J Clin Oncol 21 (15): 2933-9, 2003.  [PUBMED Abstract]

  30. Kosmidis P, Mylonakis N, Nicolaides C, et al.: Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol 20 (17): 3578-85, 2002.  [PUBMED Abstract]

Recurrent Non-Small Cell Lung Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence 2 for more information.)

Many patients with recurrent non-small cell lung cancer (NSCLC) are eligible for clinical trials. Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

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 disease-free survival with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy.[1,2] Unresectable brain metastases in this setting may be treated with radiosurgery.[3] 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.[4] Most patients who are not suitable for surgical resection should receive conventional whole-brain radiation therapy. Selected patients with good performance status (PS) and small metastases can be considered for stereotactic radiosurgery.[5]

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.[6] In those selected patients with good PS and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiosurgery.[3,6] For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[7][Level of evidence: 3iiiDiii]

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.[8,9]

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[10][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.[11,12] Informed patients with good 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. Two prospective randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;[13,14] however, criteria for the selection of appropriate patients for second-line treatment are not well defined.[15] 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, or overall survival (OS).[16][Level of evidence: 1iiA]

A phase II study of erlotinib (i.e., 150 mg orally, daily) in patients with epidermal growth factor receptor (EGFR)-expressing NSCLC previously treated with platinum-based chemotherapy reported an objective response rate of 12.3% (95% confidence interval [CI], 5.1%–23.7%).[17][Level of evidence: 3iiiDiv] Drug-related cutaneous rash and diarrhea were observed in 75% and 56% of patients, respectively. A preliminary report of a randomized, placebo-controlled trial indicated that erlotinib prolongs survival in NSCLC patients after first-line or second-line chemotherapy compared with placebo.[18] In this trial of 731 patients, the median OS was 6.7 months versus 4.7 months (hazard ratio [HR] = 0.73; 95% CI, 0.6–0.87; P = .001). The median progression-free survival was 2.23 months versus 1.84 months (HR = 0.6; 95% CI, 0.51–0.73; P < .001).[18][Level of evidence: 1iiA] When used in combination with carboplatin/paclitaxel [19] or cisplatin/gemcitabine, [20] erlotinib was not found to improve response rates, progression-free survival, or OS in previously untreated patients with advanced or metastatic NSCLC.[19,20][Level of evidence: 1iiA]

Gefitinib induces responses in 9.6% to 19% of NSCLC patients treated previously with platinum and taxane chemotherapy.[21,22][Level of evidence: 3iiiDiv] Additionally, a randomized phase III trial evaluating gefitinib versus placebo in 1,692 previously treated NSCLC patients showed that gefitinib does not improve OS (HR = 0.89; P = .11; median 5.6 vs. 5.1 months for gefitnib and placebo, respectively).[23][Level of evidence: 1iiA] In addition, in two randomized trials comparing the addition of gefitinib with standard platinum combination chemotherapy, no improvement in response rates, progression-free survival, or OS was shown.[24,25][Level of evidence: 1iiA]

Objective response rates to erlotinib and gefitinib are higher in patients who have never smoked, in females, and in patients with adenocarcinoma and bronchioloalveolar carcinoma.[26-30] Responses may be associated with mutations around the tyrosine kinase domain of the EGFR receptor [27-29] and with the absence of K-RAS mutations.[30][Level of evidence: 3iiiDiii]

Treatment options:

  1. Palliative radiation therapy.[31]


  2. Chemotherapy alone.

    For patients who have not received chemotherapy previously, the following regimens are associated with similar survival outcomes:

    • Cisplatin plus vinblastine plus mitomycin.[32]
    • Cisplatin plus vinorelbine.[33]
    • Cisplatin plus paclitaxel.[34,35]
    • Cisplatin plus gemcitabine.[35,36]
    • Carboplatin plus paclitaxel.[35,37,38]
    • Cisplatin plus docetaxel.[35,39]

    For patients who have received platinum chemotherapy previously:

    • Docetaxel.[14,16]
    • Pemetrexed.[16]
    • Erlotinib after failure of both platinum-based and docetaxel chemotherapies.[18]


  3. Surgical resection of isolated cerebral metastasis (highly selected patients).[6]


  4. Laser therapy or interstitial radiation therapy for endobronchial lesions.[40]


  5. Stereotactic radiosurgery (highly selected patients).[3,5]


Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent non-small cell lung cancer 32. 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 8.

References

  1. 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.  [PUBMED Abstract]

  2. 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.  [PUBMED Abstract]

  3. 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.  [PUBMED Abstract]

  4. 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.  [PUBMED Abstract]

  5. 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.  [PUBMED Abstract]

  6. 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.  [PUBMED Abstract]

  7. Hazuka MB, Kinzie JJ: Brain metastases: results and effects of re-irradiation. Int J Radiat Oncol Biol Phys 15 (2): 433-7, 1988.  [PUBMED Abstract]

  8. 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.  [PUBMED Abstract]

  9. Yellin A, Hill LR, Benfield JR: Bronchogenic carcinoma associated with upper aerodigestive cancers. J Thorac Cardiovasc Surg 91 (5): 674-83, 1986.  [PUBMED Abstract]

  10. 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.  [PUBMED Abstract]

  11. 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.  [PUBMED Abstract]

  12. 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. 

  13. 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.  [PUBMED Abstract]

  14. 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.  [PUBMED Abstract]

  15. 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.  [PUBMED Abstract]

  16. 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.  [PUBMED Abstract]

  17. Pérez-Soler R, Chachoua A, Hammond LA, et al.: Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer. J Clin Oncol 22 (16): 3238-47, 2004.  [PUBMED Abstract]

  18. 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. 

  19. Herbst RS, Prager D, Hermann R, et al.: TRIBUTE - A phase III trial of erlotinib HCI (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC). [Abstract] J Clin Oncol 22 (Suppl 14): A-7011, 619s, 2004. 

  20. Gatzemeier U, Pluzanska A, Szczesna A, et al.: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). [Abstract] J Clin Oncol 22 (Suppl 14): A-7010, 619s, 2004. 

  21. Kris MG, Natale RB, Herbst RS, et al.: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290 (16): 2149-58, 2003.  [PUBMED Abstract]

  22. Fukuoka M, Yano S, Giaccone G, et al.: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21 (12): 2237-46, 2003.  [PUBMED Abstract]

  23. Doctor Letter Regarding Iressa (gefitinib) ISEL Study Results. Wilmington, De: AstraZeneca, 2004. Available online. 33 Last accessed July 30, 2008. 

  24. Herbst RS, Giaccone G, Schiller JH, et al.: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol 22 (5): 785-94, 2004.  [PUBMED Abstract]

  25. Giaccone G, Herbst RS, Manegold C, et al.: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol 22 (5): 777-84, 2004.  [PUBMED Abstract]

  26. 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.  [PUBMED Abstract]

  27. 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.  [PUBMED Abstract]

  28. 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.  [PUBMED Abstract]

  29. 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.  [PUBMED Abstract]

  30. 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.  [PUBMED Abstract]

  31. 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.  [PUBMED Abstract]

  32. Veeder MH, Jett JR, Su JQ, et al.: A phase III trial of mitomycin C alone versus mitomycin C, vinblastine, and cisplatin for metastatic squamous cell lung carcinoma. Cancer 70 (9): 2281-7, 1992.  [PUBMED Abstract]

  33. Le Chevalier T, Brisgand D, Douillard JY, et al.: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 12 (2): 360-7, 1994.  [PUBMED Abstract]

  34. Bonomi P, Kim K, Fairclough D, et al.: Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 18 (3): 623-31, 2000.  [PUBMED Abstract]

  35. 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.  [PUBMED Abstract]

  36. 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.  [PUBMED Abstract]

  37. Johnson DH, Paul DM, Hande KR, et al.: Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol 14 (7): 2054-60, 1996.  [PUBMED Abstract]

  38. Belani CP, Barstis J, Perry MC, et al.: Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation. J Clin Oncol 21 (15): 2933-9, 2003.  [PUBMED Abstract]

  39. 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.  [PUBMED Abstract]

  40. 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.  [PUBMED Abstract]

Get More Information From NCI

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Search the NCI Web site

The NCI Web site 35 provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most closely related to your search term will be listed as Best Bets at the top of the list of search results.

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Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator 36. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237), TTY at 1-800-332-8615.

Changes to This Summary (08/01/2008)

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Glossary Terms

Level of evidence 1iA
Randomized, controlled, double-blinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.
Level of evidence 1iiA
Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.
Level of evidence 1iiDii
Randomized, controlled, nonblinded clinical trial with disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.
Level of evidence 3iiiC
Nonconsecutive case series with carefully assessed quality of life as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.
Level of evidence 3iiiDii
Nonconsecutive case series with total disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.
Level of evidence 3iiiDiii
Nonconsecutive case series with progression-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.
Level of evidence 3iiiDiv
Nonconsecutive case series with tumor response rate as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.


Table of Links

1http://www.cancer.gov/cancerinfo/pdq/adult-treatment-board
2http://www.cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/HealthPr
ofessional
3http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient
4http://www.cancer.gov/espanol/pdq/tratamiento/pulmon-celulas-no-pequenas/Health
Professional
5http://www.cancer.gov/cancertopics/pdq/treatment/small-cell-lung/healthprofessi
onal
6http://www.cancer.gov/cancertopics/pdq/prevention/lung/HealthProfessional
7http://www.cancer.gov/cancertopics/pdq/screening/lung/HealthProfessional
8http://www.cancer.gov/clinicaltrials
9http://www.cancer.org/downloads/STT/2008CAFFfinalsecured.pdf
10http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/HealthProf
essional/Table1
11http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=41125&tt=1&a
mp;format=2&cn=1
12http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=38941&tt=1&a
mp;format=2&cn=1
13http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=70993
14http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=63698
15http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=65095
16http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=68402
17http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=41226&tt=1&a
mp;format=2&cn=1
18http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=41327&tt=1&a
mp;format=2&cn=1
19http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=75282
20http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=63640
21http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=75231
22http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=63968
23http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=64135
24http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=38938&tt=1&a
mp;format=2&cn=1
25http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/HealthProf
essional/140.cdr#Section_140
26http://www.cancer.gov/cancertopics/pdq/supportivecare/cardiopulmonary/HealthPro
fessional
27http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=38939&tt=1&a
mp;format=2&cn=1
28http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=68744
29http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=475774
30http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=66658
31http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=38942&tt=1&a
mp;format=2&cn=1
32http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=42347&tt=1&a
mp;format=2&cn=1
33http://www.iressa-us.com/dr.pdf
34https://cissecure.nci.nih.gov/livehelp/welcome.asp
35http://cancer.gov
36https://cissecure.nci.nih.gov/ncipubs
37http://cancer.gov/cancerinfo/pdq/cancerdatabase
38http://cancer.gov/cancerinfo/pdq/adulttreatment
39http://cancer.gov/cancerinfo/pdq/pediatrictreatment
40http://cancer.gov/cancerinfo/pdq/supportivecare
41http://cancer.gov/cancerinfo/pdq/screening
42http://cancer.gov/cancerinfo/pdq/prevention
43http://cancer.gov/cancerinfo/pdq/genetics
44http://cancer.gov/cancerinfo/pdq/cam