The biological basis of a comprehensive grading system for the adverse effects of cancer treatment

As described in the previous article in this issue by Trotti et al, there have been major changes in the philosophy and scope of the new National Cancer Institute comprehensive grading system for treatment-related toxicities, Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). The most prominent changes are the merging of early and late effects criteria into a single uniform document and the development of criteria that cover all treatment modalities. In this article, we briefly outline the biological support for the new grading system in the context of our current knowledge base. The clinical consequences of radiotherapy in normal tissue have been classically grouped temporally, into early and late effects, using a somewhat arbitrary dividing line, 90 days after commencement of radiotherapy. This definition was developed in an era of standard fractionation used alone or in simple sequential programs involving other modalities. However, most patients are now managed with multiple highly integrated modalities, often augmenting tissue injury and limiting our ability to ascribe any given effect to a particular modality. The use of complex concurrent or hybrid (concurrent/sequential) schedules also undermines the usefulness of a simplistic temporally defined early-late construct. Moreover, there is growing recognition that chemotherapy and surgery produce inherent long-term biologic and clinical effects as well. Our basic understanding of the roles that surgery, chemotherapy, and radiation play in normal tissue response has expanded over the last decade because of vastly improved molecular techniques. The original biologic paradigm viewing acute and late tissue injury as a continuum of response and repair has been strengthened by these additional laboratory investigations. The expression of toxicity over time has been shown to be caused by a variety of cellular, tissue, environmental, and host factors. We continue to elucidate the roles of DNA damage, cytokines, chemokines, and associated inflammation, which lead in some cases to perpetuation of the wound-healing response, progressive tissue fibrosis, and vascular compromise. The continuum model of tissue injury supports the recent changes in the common toxicity grading system. It also provides insights into potential targets and strategies for modulating response, which may in turn lead to effective interventions for altering the therapeutic ratio.