Hypofractionated Adaptive Image-Guided Radiation Therapy for Localized Adenocarcinoma of the Prostate

Radiation therapy is an effective and frequently utilized modality for the treatment of clinically localized prostate cancer. Traditionally, external beam radiation has been delivered in a fractionated manner using daily doses of 1.8-2.0 Gy. This daily dose was derived from early animal experiments and clinical experience, supported by mathematical models of normal tissue and tumor response to fraction size. The most widely used of these models is the linear-quadratic formula, which predicts responses to different fraction sizes based on the alpha/beta ratio of any given tissue.

One of the main motivations for delivering a treatment at low dose rate or with many fractions is that late-responding normal tissue are generally more sensitive than early-responding tissues (i.e. tumor) to increases in fraction size. So increasing the number of fractions generally spares late-responding tissues more than the tumor. This can be quantified in terms of the alpha/beta ratio:

Small alpha/beta ratio (2-4 Gy), typical of late sequelae, means high sensitivity to fractionation changes.
Large alpha/beta ratio (>8 Gy), typical of tumor control, means low sensitivity to fractionation changes.

It is generally assumed that the mechanistic basis for the different fractionation response of tumors and late-responding normal tissues relates to the larger proportion of cycling cells in tumors. But prostate tumors contain unusually small fractions of cycling cells. Brenner and Hall as well as Duchesne and Peters have reasoned that prostate tumors might not respond to changes in fractionation in the same way as other cancers; both papers hypothesize that prostate tumors might respond to changes in fractionation or dose rate more like a late-responding normal tissue. , In mathematical terms, the suggestion is that the alpha/beta ratio for prostate cancer might be low, comparable to that for late-responding tissues or even lower. Previous estimates of alpha/beta ratios of normal tissue and tumor tissue have generally been 3 and 10, respectively. Recent evidence has estimated the alpha/beta ratio of prostate cancer to be as low as 1.5. If these hypotheses are true, then the optimal therapeutic ratio for prostate cancer would be achieved using daily doses higher than 2 Gy.

Several preliminary clinical reports have found reasonable PSA control rates and no increase in late toxicity using doses of 2.5 to 3 Gy. Kupelian from the Mayo Clinic found PSA-free survival rates of 97%, 88%, and 70% in low-, intermediate-, and high-risk patients, respectively. The dose regimen used was 70 Gy in 2.5 Gy daily fractions. Both acute and late toxicity were not higher than seen with typical dose regimens. A group from Christie Hospital reported 82%, 56%, and 39% 5-year biochemical disease free survival rates (low, intermediate, and high risk, respectively) in patients treated with 50 Gy in 16 fractions (3.125 Gy per fraction), with acceptable bowel and bladder toxicity.

These results, although promising, require further validation. If the hypothesis that prostate cancer alpha/beta ratio is lower than normal tissue is correct, then the optimal fractional dose is likely to be even higher than the doses tested thus far, but if incorrect, the result may be increased normal tissue toxicity.