The Concept of Therapeutic Ratio

Shortly after the turn of the last century, radiation therapy began as a new modality for cancer treatment based on the discovery of X-rays by Roentgen and radium by the Curies. The pioneering use of X-rays and radium in the first two decades of the 20th century involved the use of large single doses of radiation therapy delivered in short treatment intervals, which, although resulting in a reduction of the tumor mass, was also associated with severe acute and late normal tissue toxicities. The concept of radiation dose fractionation (i.e., the use of smaller radiation doses given in multiple, typically daily, fractions) over several weeks evolved from an in vivo experiment in the 1920s using the testes of a rabbit as a model system for tumor proliferation.1 These early French radiobiologists found that multiple radiation treatments compared to a large single dose of radiation resulted in sterility (the desired effect) without producing severe injury to the surrounding scrotum. The initial clinical use of radiation dose fractionation was then applied to patients with head and neck cancers as early as the 1930s, with improved tumor responses and reduced acute and late normal tissue toxicities.2,3 Thus, the concept of a therapeutic ratio or index for radiation therapy was initially recognized more than 75 years ago.

The concept of the therapeutic ratio for radiation therapy, which compares the radiation dose-response curves for both tumor control rates and normal tissue(s) complication rates, is illustrated in three separate panels in Figure 3.1. The upper panel represents a theoretical optimal therapeutic ratio, where the tumor control curve lies always to the left of the normal tissue complication curve, whereas the middle panel shows an unacceptable therapeutic ratio in which the tumor control and normal tissue complication curves are reversed. Obviously, it would be easy to recommend the clinical use of radiation therapy for this idealized situation depicted in the upper panel. Conversely, in the middle panel, the radiation oncologist would need to carefully weight the type (acute, late) and grade (severity) of expected normal tissue(s) complications before recommending radiation therapy. Indeed, as illustrated in the section on radiation treatment planning (later in this chapter), the current use of three-dimensional conformal radiation treatment (3-D CRT), intensity-modulated radiation treatment (IMRT) planning, and image guided radiation therapy (IGRT) allows the radiation oncologist to quantitate the dose-volume histograms for each normal tissue included in the treatment volume so as to change an unacceptable therapeutic ratio (middle panel) to the bottom panel in Figure 3.1, which is the most realistic graph of tumor control and normal tissue injury as a function of radiation dose as found in many clinical settings. In actuality, for most common solid cancers the curves are not parallel, and the tumor control curve for most solid tumors is less steep than the normal tissue injury curves. Actual dose-response curves derived from in vivo experimental data or from clinical trials in humans are often more variable than the illustration in the bottom panel of Figure 3.1, particularly depending on the tumor type. Indeed, as is presented in other chapters on specific tumor types throughout this textbook, it is only by carefully designed and controlled clinical trials that the concept of a therapeutic ratio for radiation therapy can be quantitated for a specific tumor type.

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