A wide range of genetic and phenotypic abnormalities have been identified in lung cancer. However, only a few are known to have an impact on patient outcome and thus may influence choice of therapy. Biologic and molecular factors known in this regard include the epidermal growth factor family and its receptors, markers of neuroendocrine differentiation in non-small cell lung cancer, and mutations of the ras gene family. None of these factors, however, can be considered a standard for selection of patients for therapy until additional information is gleaned from ongoing prospective studies.

Better early detection strategies for lung cancer are clearly needed. About 20 years ago, cytomorphologic criteria were developed for use in staging bronchial epithelium carcinoma. Yet, when sputum cytology was added to chest radiograph in the largest early-screening-of-lung-cancer study carried out to date, the three-arm trial sponsored by the National Cancer Institute, no major outcome benefit was shown. Sputum samples of participants in one of these trials, the Johns Hopkins Lung Project, have been archived. Currently, sputum immunostaining using two monoclonal antibodies directed at a difucosylated Lewis X epitope and a 31-kilodalton protein show correlation between positive staining of these samples and eventual development of lung cancer in the sampled population. Strategies to neutralize the stimulation of growth factors like gastrin-releasing peptide, which are seen in small-cell disease, are also being explored. Development of an epithelial-directed diagnostic test is the most important goal in obtaining early detection tools for lung cancer. Several new tests await prospective trials to evaluate their utility. In developing an early detection test for lung cancer, due to the chronic nature of the risk and the vast at-risk population, cost and patient compliance are two major concerns.

It is believed that population-based screening for cancer should be advocated only when screening reduces disease-specific mortality. Four randomized controlled studies on lung cancer screening have been conducted in male cigarette smokers, and none has demonstrated reduced mortality. Accordingly, no organization that formulates screening policy advocates any specific early detection strategies for lung cancer. Yet, despite this public policy against screening, there is considerable evidence that chest x-ray screening is associated with earlier detection and improved survival. Two randomized trials, the Memorial Sloan-Kettering and Johns Hopkins Lung Projects, were specifically designed to evaluate the effectiveness of sputum cytologic study. Both evaluated the efficacy of the addition of sputum cytologic studies to annual chest radiographs, and both demonstrated that cytologic study did not favorably influence outcome. All individuals in experimental and control groups in both studies had annual chest radiographs. Because survival rates observed in both studies were about three times higher than predicted, based either on the National Cancer Institute's Surveillance Epidemiology and End Results database or based on the American Cancer Society's annual Cancer Statistics, raises the possibility that the periodic chest radiographs performed in all patients in both studies contributed to an improved outcome. In the Mayo Lung Project and in the Czechoslovak study on lung cancer screening, the experimental groups underwent a program of relatively intensive and regular rescreening with chest radiographs and sputum cytologic study, while the control groups underwent either less-frequent rescreening or no rescreening. In both studies, the screened groups achieved meaningful improvements in stage distribution, resectability, and survival. However, increases in cumulative incidence of lung cancer in the experimental group in both studies (which in the Mayo Lung Project reached statistical significance) prevented significant improvements in survival from translating into corresponding reductions in mortality. The possibility that screening may be associated with lung cancer "overdiagnosis" has been widely postulated to account for higher survival and incidence rates and equivalent mortality rates. However, analysis of autopsy information and of disease outcome in individuals with screen-detected early stage lung cancer who do not undergo surgical resection strongly supports the conclusion that screening does not lead to overdiagnosis of lung cancer. Similarly, lead-time and length bias do not adequately account for the differences in cumulative incidence observed in the Mayo and Czech studies.(ABSTRACT TRUNCATED AT 400 WORDS)

Enhancement of dose and dose intensity increases tumor response and may enhance long-term progression-free survival in patients with small cell lung cancer. Several strategies are identified to intensify therapy safely: a traditional induction/intensification mode, in which high-dose therapy with hematopoietic stem cell support is used to treat patients responding to conventional-dose therapy; and multicycle dose-intensive approaches, in which higher-dose therapy is administered over multiple cycles at initiation of therapy. This paper reviews some of the recently completed and activated trials (particularly those developed at the Dana-Farber Cancer Institute) exploring these concepts.

Chemotherapy remains the mainstay of treatment for small cell lung cancer (SCLC). For patients with limited-stage disease, the addition of thoracic radiotherapy confers a moderate improvement in local control and a modest survival benefit, but these improvements come at the cost of increased toxic reactions. The optimal method for integrating chemotherapy and thoracic radiotherapy is unresolved. Concurrent and alternating strategies are appealing because they allow uninterrupted delivery of chemotherapy, but they have not been proven to be superior to conventional sequential approaches. Based on limited data, delivery of thoracic radiation early in the treatment course may be preferable to delivery later in the course. There is evidence of a radiation dose-response effect for SCLC, and, in standard regimens, thoracic radiation doses in the range of 50 to 60 Gy are recommended. The use of limited radiation fields (to postchemotherapy tumor volumes) appears reasonable. Results for alternative thoracic radiation fractionation schedules such as accelerated hyperfractionation are promising and worthy of further investigation. The role of prophylactic cranial irradiation (PCI) is controversial and should be individualized. It should be considered for the favorable subgroup of patients with limited-stage disease who achieve a complete response to chemotherapy and thoracic radiotherapy. If given, we recommend a total dose of 30 to 36 Gy in 2-Gy fractions; PCI should not be delivered concomitantly with chemotherapy.

In the United States, small cell lung cancer (SCLC) accounts for about 20% of all cases of lung cancer. Without treatment, tumor progression in patients with SCLC is rapid, with a median survival of 2 to 4 months. Modern chemotherapy has yielded multifold increases in median survival, but only minimal improvements have occurred over the last decade. Combination chemotherapy with etoposide/cisplatin prolongs survival, especially in patients with limited disease. In patients at high risk of toxicity from standard combination chemotherapy, single-agent chemotherapy may have a viable role, but whether its efficacy is comparable to combination regimens must be established in clinical trials. Clearly, new, more effective drugs will be required for any major improvements in the treatment of SCLC. Combined-modality therapy employing chemotherapy and chest irradiation appears to produce excellent cytotoxic effects and is relatively well tolerated in patients with limited disease. A recent meta-analysis of 13 randomized trials showed a modest but significant 14% reduction in the relative mortality rate of patients receiving chemotherapy/chest irradiation vs those receiving chemotherapy alone. Surgery as sole treatment can produce cures in highly selected patients with limited disease and can reduce the rate of local recurrence. The use of surgery after definitive treatment remains experimental and should not be considered other than in controlled clinical trials.

Radiotherapy (RT) in conjunction with surgery may have a number of roles in the treatment of patients with potentially resectable esophageal carcinoma. The use of RT alone either preoperatively or postoperatively can be expected to improve resectability rates only modestly. The risk of locoregional failure, a common problem in esophageal carcinoma, has been substantially reduced with preoperative or postoperative RT in trials with a duration of follow-up of 3 or more years, although this effect has not been seen in trials with shorter follow-up. Because of the high risk of distant failure associated with these tumors and perhaps because of the inadequate doses used, most trials of RT have not shown notable improvements in overall survival rates. The risk of severe complications following preoperative or postoperative RT is small, provided that very high doses or fraction sizes are avoided. Concurrent chemotherapy and RT administration have been shown to be superior to RT alone in patients who have medically or surgically inoperable conditions; randomized trials using this combined modality in patients with resectable disease have only recently begun. In addition to evaluating the efficacy of this approach, investigators hope to establish the optimal sequencing and timing of administration of these modalities with regard to each other and to surgery.

Treatment of esophageal carcinoma with radiation alone or surgery alone has yielded unsatisfactory cure rates and has not had a major impact on survival. The failure to cure or prolong survival of patients with esophageal cancer is because of our inability to eradicate residual disease at the primary site and to early systemic dissemination of disease. Three neoadjuvant approaches involving chemotherapy have been studied in patients with apparently localized esophageal cancer: preoperative chemotherapy followed by surgery, chemotherapy and concurrent radiation therapy followed by surgery, and chemotherapy and radiation therapy without surgery. All of these approaches have shown potential in pilot trials. Large-scale trials comparing surgery alone with chemotherapy prior to operation are underway. For patients with local-regional epidermoid carcinoma who are not able to undergo or who refuse operation, chemotherapy plus concurrent radiation appears, in random assignment trials, to be superior to radiation alone.

Esophageal cancer continues to be a major health problem with an associated poor prognosis. New technology is being applied to the staging of this cancer. The new staging system requires assessment of depth of wall penetration and lymph node status prior to resection. To determine penetration and node status with a high degree of accuracy generally requires some combination of chemotherapy, magnetic resonance imaging, endoesophageal ultrasound, and/or surgical staging. Several variables need to be considered in planning the surgical approach to the patient with esophageal cancer: the intent of the surgeon to either cure or palliate, the anatomic location of the tumor, and the method of reconstruction. Surgery is optimal for localized esophageal cancer. Neoadjuvant chemoradiation has increased survival in specific subgroups. Phase 2 trials have shown the safety and efficacy of chemoradiation. Randomized multi-institutional trials are needed to verify the encouraging results of recent phase 2 trials.

The most critically ill patients in the hospital are located in the ICU. Due to intensive individualized care and monitoring, these patients often suffer from severe sleep deprivation. The amount and continuity of sleep as well as normal sleep architecture are all affected. Moreover, by impairing protein synthesis, cell division, and cellular immunity, sleep deprivation can affect the healing process and thus contribute to an increased morbidity and mortality. Reasons for sleep deprivation appear to be multifactorial and include the following: the patient's chronic underlying illness, an acute superimposed illness or surgical procedure, medications used in treatment of the primary illness, and the ICU environment itself. Therapeutic interventions need to address each of these potential causes, with an emphasis placed on providing an environment that is both diurnal and focused on the importance of uninterrupted sleep.

Recent notable developments have occurred involving radiation therapy (RT) for patients with non-small cell lung cancer (NSCLC). For patients with good performance status with unresected thoracic tumors, induction cisplatin-based chemotherapy followed by RT has resulted in a significant survival advantage over RT alone in two North American trials. However, the best sequence of administration of these two modalities in NSCLC remains to be determined. For palliation of tumor-related symptoms, efforts under way to improve control of brain metastases include the use of twice-daily cranial RT to a higher total dose, the use of focused radiation boost techniques like stereotactic radiosurgery to small metastatic deposits, and increased use of neurosurgical extirpation. For patients with NSCLC with symptomatic bone metastases, use of wider-field irradiation may benefit selected patients. Metastases to the adrenal gland, liver, and subcutaneous tissues can be palliated successfully by brief courses of RT. Intrathoracic tumor symptoms are well palliated by brief courses of thoracic RT. As adjuvant therapy following curative surgery, RT reduces the intrathoracic tumor recurrence rate among patients with metastatic tumor foci in hilar or mediastinal lymph nodes.

Laboratory investigations have begun to elucidate the regulatory molecules that control the processes of blood cell growth and differentiation. Recombinant human colony-stimulating factors are examples of biotechnology-produced molecules that have epitomized the translation of such basic scientific investigation into therapeutic advances. Small cell lung cancer, a malignancy that is overall highly sensitive to aggressive myelosuppressive chemotherapy at initial presentation, has been used as a clinical model in which the activity of human colony-stimulating factors has been tested. In this article, the clinical applications of hematopoietic growth factors are reviewed in brief. The appropriate clinical use of these agents may allow novel therapeutic strategies to be developed in a research setting. Similarly, these agents have the potential to improve supportive care and improve certain clinical outcomes in the non-research clinical care of patients. Issues of cost of treatment are raised by these agents, but the true clinical value of hematopoietic growth factors needs to be studied more rigorously, with emphasis on quality of life and redistribution of care costs outside of hospitals before definitive statements can be made.