Trial Information

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.