Chemoprevention entails using specific agents to suppress carcinogenesis and thereby prevent the development of primary or second primary cancers. Because the concept of chemoprevention in patients with or at risk of lung cancer is new, ongoing clinical trials are based on data from epidemiologic and preclinical research, as well as on results of chemoprevention studies in head and neck cancer. The latter studies have provided a model for such studies in lung cancer, considering the two diseases have a similar etiology and biology of field carcinogenesis. Beta-carotene, natural vitamin A, and the retinoids may be effective chemopreventive agents. However, chronic administration of such agents may be required to prevent the development of cancer. Results of chemoprevention trials in head and neck cancer have demonstrated effective inhibition of the development of second primary tumors with the synthetic retinoid 13-cis-retinoic acid; investigators are hopeful this will be repeated in patients with lung cancer. Results of ongoing phase III trials and continued advances in the epidemiologic and biologic study of lung carcinogenesis should contribute to future research in this area.

Two new technologic developments may have a significant impact on the detection and localization of early lung cancer. These two developments work together in a complementary way. The first is a solid-state microscope that can be applied in the prescreening of sputum cytology specimens. The finding that malignancy-associated changes (MACs) are present in ostensibly normal bronchial epithelial cells may be used to improve the sensitivity of sputum cytology to detect cancer. Once abnormal or MAC cells are found, a second device, a fluorescence bronchoscope, can be employed to localize the source of the abnormal cells. Fluorescence bronchoscopy is also a potentially useful tool for procuring premalignant tissue for molecular biology studies and for monitoring the progress of patients in chemoprevention studies.

The population of the United States is gradually aging. Within a generation, over 20 percent of the population will be > 65 years of age. Since cancer is a disease of older persons, the incidence of malignancies of all types is expected to increase during the coming decades. In general, since older patients appear to tolerate chemotherapy less well than their younger counterparts, strategies that lessen toxicity and yet maintain efficacy are desperately needed. Recently, the use of single-agent oral etoposide has been shown to be an effective palliative therapy for older patients with small-cell lung cancer. Future studies will need to focus on the unique requirements of older patients in order to improve therapy in these individuals.

The 12 percent five-year survival rate for patients with non-small-cell lung cancer (NSCLC) has not changed in several decades. However, four randomized trials have shown a modest increase in the mean survival time of patients with advanced NSCLC who received systemic chemotherapy vs best supportive care (BSC), and two others have demonstrated a statistically significant survival advantage (average increase, 12 weeks). Whereas the objective response rate to chemotherapy ranges from 30 to 40 percent, relief of cancer-related symptoms as well as improved performance status and weight gain typically occur in 70 percent of patients. Treatment-related adverse effects have been markedly reduced with new antiemetics. Concerns regarding costs have been lessened by the National Cancer Institute of Canada's observation that at least some chemotherapy regimens may be less costly than BSC. Direct-care costs of managing all stages of NSCLC in Canada were estimated at $102 million (1984 Canadian dollars), assuming that stage IV patients received only BSC. The average incremental cost of the most expensive chemotherapy would be $5,000 per case. If this cost were incurred by 50 percent of stage IV cases (good performance status, symptomatic patients), total care costs would be increased by about 10 percent ($10.5 million). This is less than half the cost of the introduction of neoadjuvant chemotherapy, which is rapidly being adopted as standard practice in the absence of data from randomized controlled clinical trials.

Several options are available for treatment of malignant pleural effusions in patients with non-small-cell lung cancer. Repeat thoracentesis may be appropriate for the patient with limited survival and a slowly recurrent effusion. Pleurodesis with a sclerosing agent administered via a chest tube is the most widely used therapy, though controversy exists as to which drug produces the best results. Pleuroperitoneal shunting remains an option for those patients whose lung is trapped by tumor. Video-assisted thoracoscopy is likely to change the treatment patterns of malignant pleural effusion. Thoracoscopic pleurectomy can be performed with minimal morbidity. Alternatively, sclerosing agents such as talc can be easily and uniformly introduced into the thoracic cavity under thoracoscopic control. Future therapy is likely to entail a diagnostic thoracentesis followed by a definitive thoracoscopic procedure.

Recent approaches to the treatment of limited small-cell lung cancer have combined local radiotherapy and systemic chemotherapy in an attempt to improve local control and inhibit distant metastases. Local control is a key indicator of the efficacy of radiotherapy administration in combined-modality regimens. However, even in combined-modality trials using high total radiotherapy doses, local failure rates have ranged from 30 to 50 percent. The components of radiotherapy administration--including dose, volume, fractionation, integration with chemotherapy (concurrent, alternating, or sequential), and timing (early or late administration)--are also important considerations. Hyperfractionation, or the administration of small fractions of radiation more than once daily (usually twice), and accelerated hyperfactionation, or the administration of three fourths of the standard radiation dose two to three times daily, have emerged as important concepts in radiotherapy. Although the optimal chemotherapy regimen for combined-modality treatment has not yet been established, use of cisplatin and etoposide combinations, which do not promote pulmonary, cardiac, or esophageal toxicity, have been particularly appropriate in patients with small-cell lung cancer.

This review first summarizes the potential survival outcomes for patients with the various subsets of stage III non-small-cell lung cancer. The rationale for combined-modality approaches is then reviewed, with a discussion of the possible treatment strategies using various permutations of three treatment modalities, namely, chemotherapy (CTh) radiotherapy (RT), and surgery. Conclusions that can be drawn from the published bimodality trials are discussed. The design, eligibility criteria, surgical findings, and survival data for five trimodality phase II studies of CTh plus RT followed by surgery are then presented in detail (with a focus on three larger trials). Finally, the review provides a consideration of toxicity, other caveats, and possible conclusions that can be drawn at this point from the phase II bimodality and trimodality studies involving surgery. Important questions for future study are outlined.

As we expand our knowledge of the initiators and promoters of lung cancer, early detection and intervention strategies show great potential in individuals at high risk, especially smokers and exsmokers. Documented mutations of dominant oncogenes and tumor suppressor genes in human lung cancer cells may represent important steps in the pathogenesis of invasive cancer. The precise molecular events and their sequence that lead to tumor promotion in lung cancer, however, are less well understood. Chemointervention with agents like the retinoids may halt proliferation of cancer cells prior to the development of metastatic competence. Use of anti-growth-factor therapy and peptide hormone antagonists may also have a role in intervention approaches. This paper reviews present understanding of the initiation and promotion of lung cancer, as well as preventive strategies currently proposed for patients at risk.

About 40 percent of all patients diagnosed with non-small-cell lung cancer (NSCLC) have locally advanced stage IIIA or IIIB disease. Such disease is at the borderline of anatomic resectability and associated with poor survival prospects with any present therapy. The Lung Cancer Study Group, Eastern Cooperative Oncology Group, and Radiation Therapy Oncology Group, among other North American clinical cooperative groups, have integrated radiation and chemotherapy in an attempt to prolong survival and, in some cases, cure patients with unresectable NSCLC. These two modalities have been given sequentially, concurrently, and in an alternating fashion with varying degrees of success. Trials employing cisplatin-containing chemotherapy have produced more positive results than those using other regimens, although this is not invariably so. Clearly, better treatments are needed for local and systemic disease. This paper considers possible mechanisms for combining radiation and chemotherapy, reviews the status of recent and current clinical trials, and outlines some directions for future research.

The Lung Cancer Study Group has performed a number of postoperative adjuvant trials in patients with resectable non-small-cell lung cancer (NSCLC). Adjuvant cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy was compared with immunotherapy in the treatment of 130 patients with stage II or III adenocarcinoma or large cell undifferentiated carcinoma. Careful intraoperative staging was performed in all patients. Disease-free interval was significantly prolonged in the chemotherapy group (p = 0.032). After 7.5 years of follow-up, the difference in time to recurrence and cancer deaths remains statistically significant. Another study compared CAP chemotherapy plus radiotherapy with radiotherapy alone in advanced stages II and III resected NSCLC. Again, the chemotherapy arm had significantly increased disease-free survival. In a third study, patients with high-risk stage I NSCLC were randomized after surgery to CAP chemotherapy or observation. In this study there was no difference in recurrence-free survival or overall survival.

Research on dominant oncogenes and tumor suppressor genes has characterized differences in genetic lesions between small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) and identified associations with clinical parameters. More than one half of all lung cancers contain a mutation of the p53 tumor suppressor gene. There does not appear to be an association between the presence of this mutation and survival. A ras family oncogene was found to be mutated in approximately 20 percent of tumors and tumor cell lines from patients with NSCLC in contrast to none of 45 tumors and tumor cell lines from patients with SCLC. The presence of a K-ras mutation was determined to be an adverse prognostic factor for survival in retrospective studies of patients with NSCLC. Mutations of K-ras are more common in tumors from smokers than nonsmokers and have not been detected in lung cancers resulting from occupational exposure to radon. Mutations in both the p53 gene and K-ras oncogene are most commonly G to T transversions in lung cancer vs G to A transitions in other cancers. Prospective studies of these mutations in resected tumor specimens taken from patients with accurate follow-up may continue to provide important clues about their potential clinical and biologic significance.

Diagnosis and treatment of lung cancer can significantly affect a patient's quality of life. Survival rates are dismal, but improvements have been made in dealing with common symptoms and side effects. This article reviews the nature of the problem, pertinent risk factors, and symptoms associated with nausea and vomiting, cachexia, hypercalcemia, and pain. Physicians, nurses, and other health care professionals can play a vital role in the identification and management of these complications, and thereby help to improve quality of life.

This brief review attempts to describe the present understanding of the pathogenesis of venous thrombosis in general with special reference to venous thromboembolism in spinal cord injury patients with paralysis. The component parts of Virchow's triad are examined. Most venous thrombi seem to originate in regions of slow blood flow, ie, the large venous sinuses of the calf and thigh or in valve cusp pockets. Decreased blood flow or even stasis due to lack of the pumping action of the large muscle packages in paralyzed patients is undoubtedly one of the major factors. As blood pools, activation products of the coagulation system accumulate locally leading potentially to local hypercoagulability. Activation products of clotting and fibrinolysis can induce endothelial damage which in turn leads to further activation of the hemostasis system. Endothelial damage may also result from distension of the vessel walls by the pooling blood. Blood flow is further decreased by hyperviscosity due to elevated fibrinogen levels and dehydration. Some spinal cord injury patients may sustain direct trauma to the legs; others may encounter vessel wall damage by the immobilized limbs. Shortly after injury, certain changes develop in the clotting system, especially increases in components of the von Willebrand factor macromolecular complex and increased platelet aggregability which could further contribute to hypercoagulability. Recently, an inhibition of the fibrinolytic system was suggested which also could add to a prothrombotic state. All of these interrelated processes clearly explain the high risk of venous thromboembolism in spinal cord injury patients with paralysis which has been clearly demonstrated by many investigators. It is hoped that intense thrombosis prophylaxis will reduce the incidence of this potentially devastating complication.