An estimated 142,000 men and women died of lung cancer in 1990. The majority of patients present with locally advanced, unresectable disease for whom the 5 year survival is 5-7%. New strategies are urgently needed to improve the therapeutic ratio. Frequently, advanced non-small cell (NSC) lung cancer will produce endobronchial obstruction. High dose rate (HDR) brachytherapy combined with external beam irradiation has the advantage of providing improved localization so that the portion of the tumor most responsible for the obstruction receives the highest dose, while sparing the normal surrounding lung tissue. The lung is one of the most sensitive structures to irradiation and is a major dose-limiting organ to the delivery of optimal therapy. The acute and late effects of radiation therapy, pneumonitis and pulmonary fibrosis, are of particular concern and the ability to predict for these side effects could allow early intervention and thus, reduce the morbidity of lung cancer therapy. We propose to identify the optimal dose schedule for concurrent external radiation therapy and HDR brachytherapy in terms of symptom relief and local disease response in patients with locally advanced NSC lung cancer. Because HDR brachytherapy requires bronchoscopy, it provides a unique opportunity, via bronchoalveolar lavage (BAL), to study the effects of irradiation in vivo, and to correlate laboratory findings to date in several animal models with clinical outcome in humans. Serial BAL will provide cellular material to: identify and quantify the production of specific growth factors for fibroblasts by alveolar macrophages induced by radiation; measure production of extra cellular matrix (ECM) proteins and expression of ECM mRNA in vitro by fibroblasts in response to specific growth and inhibitory factors produced by alveolar macrophages; identify changes in cellular responses outside the radiation volume due to the release of biochemical messages from within the irradiated volume. Serum samples will be analyzed to measure the release of biochemical messages into the vascular system after irradiation as monitors/predictors of radiation injury. These laboratory findings will be correlated with each patient's clinical outcome. The information obtained could contribute significantly to our understanding of the pneumonitic and fibrotic processes secondary to lung irradiation in humans. This could enable the development of early interventions and would impact on our ability to lower the morbidity in future clinical trials for all disease sites where the lungs may be irradiated.
