Hypofractionation for prostate cancer radiotherapy—what are the issues?

Abstract

2. 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. However, prostate tumors contain unusually small fractions of cycling cells (19), so back in 1999, Brenner and Hall (1) and Duchesne and Peters (2) reasoned that prostate tumors might not respond to changes in fractionation in the same way as other cancers. Both papers hypothesized that prostate tumors might respond to changes in fractionation more like a late-responding normal tissue. In mathematical terms, the suggestion was that the / ratio for prostate cancer might be low, comparable to that for late sequelae. If so, much of the rationale for using many fractions, or using low dose rate, would disappear for prostate radiotherapy. 3. A first estimate of / for prostate cancer was made in 1999 (1) by comparing results from external beam radiotherapy (EBRT) with those from brachytherapy (BT). Consistent with the theoretical hypotheses (see above), the estimated value of / was 1.5 Gy (95% confidence interval: 0.8–2.2 Gy), comparable to / values for late-responding normal tissues, and much smaller than those for most tumors. 4. The problem with this estimate (1) of the / value for prostate, and almost all subsequent estimates (3–11, 13– 18) is that they involve comparing or equating EBRT results with BT results. There are many pertinent differences between EBRT and BT (different dose distributions, different relative biological effectiveness, different overall times, different institutions, different PSA distributions, hypoxia), any or all of which could bias the / estimate. Much of the debate has centered around the significance of these biases, and how to take them into account. Despite these problems, there does seem to be consensus among most of the analyses that have taken this approach, that the / value for prostate cancer is indeed quite low, probably in the 1 to 4 Gy range (1, 2, 4–11, 13–16, 18), which is similar to the values for most late-responding tissues. 5. One analysis has also been performed (12) that avoided many, though not all, of the potential biases involved in comparing EBRT and BT. Here, EBRT a 2-fraction high-dose-rate (HDR) BT boost was compared with EBRT a 3-fraction HDR boost, all done with the same technique at the same institution. The resulting estimated / ratio for prostate cancer was 1.2 Gy (95% confidence interval: 0.03–4.1 Gy), again comparable with / values for late-responding normal tissues. 6. If the / value for prostate cancer is indeed similar to that for the surrounding late-responding normal tissue, one could use fewer fractions (i.e., hypofractionate) or HDR and yet, by choosing the right dose, produce