PURPOSE: The primary objective was to determine clinical practice guidelines for the diagnostic evaluation, treatment, and follow-up care of patients with surgically unresectable stage III and IV non-small-cell lung cancer (NSCLC). These guidelines are intended for use by oncologists in the care of patients outside of clinical trials. METHODS: An expert multidisciplinary Panel reviewed pertinent information from the published literature through April 1997; certain investigators were contacted for more recent and, in some cases, unpublished information. A computerized search was performed of MEDLINE data; directed searches based on the bibliographies of primary articles were also performed. Values for levels/grades of evidence were assigned by expert reviewers and approved by the Panel. Expert consensus was used for issues in which published data were insufficient. The options considered included the appropriate diagnostic evaluation of patients; the role of chemotherapy, radiation, and surgery; and strategies for follow-up care and lifestyle changes. The significant health outcomes considered in making the clinical practice guidelines included survival (disease-free and overall), quality of life, toxicity (both short- and long-term), and cost-effectiveness. An intervention or strategy was assigned benefit if it led to favorable changes in the outcomes listed. Harms considered were inappropriate disease management and excess cost without definable benefit. Costs were considered but were never the sole determinant for a recommendation. The guidelines underwent external review by selected physicians and a cancer quality-of-life expert, by Health Services Research Committee members, and by the American Society of Clinical Oncology (ASCO) Board of Directors. RESULTS AND CONCLUSIONS: In patients without evidence of extrathoracic cancer, a chest x-ray and chest computed axial tomography (CAT) scan are recommended to stage locoregional disease, with biopsy of mediastinal lymph nodes found on CAT scan to be greater than 1 cm in shortest transverse diameter. Pretreatment bone scan and head CAT scan are recommended only when signs or symptoms of disease are present. If a patient is otherwise potentially resectable, a biopsy should be performed of a radiographically documented isolated adrenal or hepatic mass to rule out metastatic disease. Chemotherapy, ideally a platinum-based regimen, is appropriate for selected patients who have a good performance status with both unresectable, locally advanced, and metastatic NSCLC. A detrimental effect on survival was observed with older alkylating agent-based regimens. In patients with unresectable stage III NSCLC, two or more cycles of cisplatin-based chemotherapy with or followed by radiation has been proven to enhance survival; ongoing maintenance chemotherapy is of unproven benefit. Chemotherapy should be administered for no more than eight cycles in patients with stage III or IV NSCLC. Initial treatment with an investigational agent is appropriate, provided a standard regimen is then given if the disease does not respond after two cycles. Delaying chemotherapy until symptoms develop may negate the survival benefits of treatment. There is no current evidence that either confirms or refutes that second-line chemotherapy improves survival in patients with nonresponding or progressive NSCLC. NSCLC histologic type is not an important prognostic factor in these patients, and the role of newer prognostic factors (eg, p53 mutation) in clinical decision-making is investigational. Radiation should be included as part of the standard treatment for selected patients with unresectable stage III NSCLC, whose performance status and pulmonary function are adequate. Definitive-dose thoracic radiotherapy should be no less than 60 Gy in 1.8- to 2-Gy fractions. Local symptoms from primary or metastatic NSCLC can be relieved by judicious use of radiotherapy. (ABSTRACT TRUNCATED)