Rationale, Conduct, and Outcome Using Hypofractionated Radiotherapy in Prostate Cancer

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Hypofractionated radiation therapy for prostate cancer has become of increasing interest with the recognition of a potential improvement in therapeutic ratio with treatments delivered in larger-sized fractions. In addition, the associated reduction in fraction number produces attractive cost and patient convenience advantages as well. A still limited but growing number of hypofractionation trials have reported acceptable short-term levels of toxicity and biochemical control, but most have insufficient follow-up to ensure the long-term safety and efficacy of this approach. This situation will improve as many currently active trials mature, particularly several high-value randomized trials. In contrast, extreme hypofractionation, with schedules delivering only on the order of 5 fractions, is truly in its infancy for prostate cancer, with extremely limited tolerance and efficacy information currently available. Several uncertainties in the radiobiology of hypofractionation mitigate for an organized, cautious investigational approach. The fractionation response (α/β ratio) of prostate cancers and, for that matter, late-responding normal tissues, has yet to be rigorously defined. Additionally, the linear-quadratic (LQ) model used in the design of hypofractionation schedules is subject to its own uncertainties, particularly with respect to the upper limit of fraction sizes for which it remains valid. Contemporary dose-escalated radiation therapy is already highly effective, making it imperative that ongoing and future studies of hypofractionation be performed in carefully designed, randomized clinical trials. Clinical validation permitting, the adaptation of hypofractionation as a standard of care could profoundly influence future management of localized prostate cancer.

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What Is the Fractionation Response of Prostate Cancer?

Conventional fractionation schemes using fraction sizes of 1.8 to 2.0 Gy are based on the premise that tumors typically are less responsive to fraction size than are late-responding normal tissues. The α/β ratio is a measure of fractionation response, with low ratios associated with late-responding normal tissues. A low α/β is consistent with a greater capacity for repair between fractions, with an accompanying greater relative sparing with small fraction sizes, than for tumors with their

The Theoretical Potential for Hypofractionation to Improve Tumor Control

Although conventional fractionation schemes using small fraction sizes of 1.8 to 2.0 Gy are based on the premise that tumors typically have high α/β ratios that make them less responsive to fraction size than are late-responding normal tissues, the situation may well be reversed for prostate cancer, favoring the use of hypofractionation. These relationships, at least over a range of fraction sizes between 1 and 6 Gy, can best be shown through the use of the linear-quadratic equation, which

How Best Can Hypofractionation Be Explored in a Clinical Setting?

Two types of hypofractionation designs could be considered that would exploit the hypothesized radiobiological advantages described earlier: (1) normal tissue de-escalation of total dose while maintaining constant predicted tumor control and (2) tumor biological dose escalation with constant predicted normal tissue late effects. These 2 hypofractionation approaches seek to achieve different desirable objectives.

What Is the Current State of Clinical Experience With Hypofractionation for Prostate Cancer?

Hypofractionated external-beam radiotherapy has actually been used clinically for a number of years, particularly in the United Kingdom.21, 22, 23 Although these treatments were generally well tolerated, overall efficacy is difficult to assess, given that these trials were performed largely in the pre-PSA era. A number of more contemporary hypofractionation trials, either published or currently in progress, are shown in Table 1. The most straightforward and intuitive way of estimating the

Extreme Hypofractionation

Even fewer fractions are beginning to be used in some clinical practices, although not always in the context of prospective trials. Called stereotactic body radiotherapy (SBRT) when only 5 total fractions are used, fraction sizes of between about 5.5 and 7 Gy are typically given, although higher-dose fractions have been used as well. Although this further reduction in fraction number might seem a logical extension of current, more modestly hypofractionated studies, there are numerous reasons

Conclusions

Results from several mostly phase I/II prostate radiotherapy studies have indicated a gain in therapeutic ratio with increases in radiation fraction size beyond the 1.8 to 2 Gy typical of standard practice. However, given that uncertainties exist in extrapolating biological effects to larger fractions and that dose-escalated radiation therapy with standard fractionation is already highly effective, it is imperative that ongoing and future studies of hypofractionation be performed in a

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