Toxicities in RTOG combined-modality trials for inoperable non-small-cell lung cancer

Inoperable non-small-cell lung cancer has become the domain of combined-modality treatment based on several recent, large, phase III studies. Results of Radiation Therapy Oncology Group (RTOG) phase II studies have suggested improvements in response and short-term survival, using a strategy of intensification of dosing and scheduling of cisplatin-based regimens and either standard or hyperfractionated radiation therapy. However, some trials also have shown higher rates of severe acute toxicity and more frequent severe late toxicity. There appears to be an institutional learning curve in administering these more complex, intense regimens and in effective management of the acute toxicities. As the RTOG institution accrued more cases onto the intensified regimen studies, toxicity management improved, treatment was given with fewer interruptions or dosage reductions, and survival rates improved. Quality-adjusted survival analysis, in which survival time is reduced by the amount of time spent with severe toxicity, shows that the survival gains observed with some concurrent regimens may be negated by time spent with toxicity. Future attempts to optimize combined-modality therapy must take account of toxicity issues in the study design by incorporating less toxic chemotherapy agents, normal tissue protectors, tumor-targeting sensitizing agents, normal tissue-sparing radiation therapy techniques (e.g., three-dimensional conformal), and proactive, aggressive management of toxicity.