Small cell lung cancer: from the laboratory to the clinic

Radiation therapy may be made more effective for SCLC by modifying dose fractionation, based on laboratory observation that SCLC cell lines are often relatively deficient in the ability to recover from doses of 2 Gy or less. Results of this approach will be known within a year. Radiation damage to the lungs may be reduced through the use of agents like PTX which can inhibit production of TNF, a likely initial mediator of radiation-related toxicity. Chemotherapy effectiveness may be improved by building on the observation that etoposide is a schedule dependent drug for SCLC lines, now confirmed in part by clinical trials. The ability to detect low orders of contamination by SCLC cells in marrow or blood should make possible more rational evaluation of outcome in protocols that utilize highdose chemotherapy plus autologous blood products as a consolidation maneuver. The monoclonal antibodies which permit this detection may themselves be of value in "purging" unwanted tumor cells from these collections. It may soon become practical to eliminate amplified genes which are associated with drug resistance and/or confer a further growth advantage on tumor cells, through the use of agents like hydroxyurea that can selectively eliminate extrachromosomal DNA. The role of recombinant hematopoietic growth factors in SCLC treatment remains unclear at present. Applying the lessons of molecular biology, it may become possible to promote "differentiation" of SCLC, or at least to prevent its conversion to the variant phenotype associated with increased c-myc expression, with the use of trans-RA or related compounds. "Broad-spectrum" antagonists of neuropeptide function may be effective and relatively specific inhibitors of autocrine stimulation in SCLC, but toxicity is yet unknown. Finally, biologic response modification may be of use in patients who have had their initial tumor burden reduced by standard therapy, utilizing IL-2 (if it can be made less toxic) or monoclonal antibodies conjugated to a toxin or radioemitter (if they can be made more specific).