Non-Small Cell Lung Cancer

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of non-small cell lung cancer.


Non-Small Cell Lung Cancer

General Information

Note: Separate PDQ summaries on Small Cell Lung Cancer Treatment; Prevention of Lung Cancer; and Screening for Lung Cancer are also available.

Note: Estimated new cases and deaths from lung cancer (non-small cell and small cell combined) in the United States in 2007:1,

  • New cases: 213,380.
  • Deaths: 160,390.

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.2,3,4,5,6 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.7,8,9,10,11,12,13,14,15,16,17,
  • Vascular invasion.3,18,19,20,
  • 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.



1 American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed March 5, 2007.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.



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.8,9,10 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.8,9,10 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). 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. 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. 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 = brainEYE = eyeHEP = hepaticLYM = lymph nodes MAR = bone marrowOSS = osseousOTH = otherOVR = ovaryPER = peritonealPLE = pleura PUL = pulmonarySKI = 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


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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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;3,4,5 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.

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.



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

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.

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.

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.

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.

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.

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.1,2,3 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,


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

2 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.

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.

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 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 2 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).3 Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy.4 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.5 Exercise testing may aid in the selection of patients with impaired pulmonary function who can tolerate lung resection.6 The availability of video-assisted thoracoscopic wedge resection permits limited resections in patients with poor pulmonary function who are not usually candidates for lobectomy.7,

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.8 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%.9,10 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.5 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.11,[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.12,13,14,15,16 A meta-analysis of adjuvant chemotherapy trials showed a hazard ratio (HR) for death of 0.87 for patients treated with cisplatin-based chemotherapy;17 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 randomized to receive four cycles of vinorelbine and cisplatin or observation.12 OS was significantly prolonged for patients receiving chemotherapy (median survival, 94 months vs. 73 months; HR = 0.69; P = .011).12,[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.14 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).14,[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.15,[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 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.16,18,

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.

A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers.19 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.5 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;20 however, a large randomized study of β-carotene and retinol supplements used in the primary prevention of lung cancer showed an increase in mortality and lung cancer incidence.21,[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.22,[Level of evidence: 1iiA] (Refer to the PDQ summary on Prevention of Lung Cancer 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.23,
  5. Endoscopic photodynamic therapy (under clinical evaluation in highly selected patients with T1, N0, M0 tumors).24,

Information about ongoing clinical trials is available from the NCI Web site.



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

2 Ginsberg RJ, Lung Cancer Study Group: Phase III Randomized Comparison of Lobectomy vs Limited Pulmonary Resection for T1 N0 non-Small Cell Lung Carcinoma (Summary Last Modified 11/88), LCSG-821, Clinical trial, Closed.

3 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.

4 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.

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.

6 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.

7 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.

8 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.

9 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.

10 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.

11 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.

12 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.

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

14 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.

15 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.

16 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.

17 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.

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.

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

20 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.

21 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.

22 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.

23 Karp DD, Eastern Cooperative Oncology Group: Phase III Randomized Chemoprevention Study of Selenium in Participants With Previously Resected Stage I Non-Small Cell Lung Cancer, ECOG-5597, Clinical trial, Active.

24 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.

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 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 underwent randomization 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, 482 patients with completely resected stage I (T2, N0) or stage II (excluding T3, N0) NSCLC were randomized 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, 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 (ALPI), 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 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 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.5,6,7,8,9,10
  4. Clinical trials of radiation therapy after curative surgery.11,

Information about ongoing clinical trials is available from the NCI Web site.



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.

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.

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.

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

5 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.

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.

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.

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.

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

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