Elsevier

Clinical Oncology

Volume 19, Issue 5, June 2007, Pages 289-301
Clinical Oncology

Overview
Is the α/β Value for Prostate Tumours Low Enough to be Safely Used in Clinical Trials?

https://doi.org/10.1016/j.clon.2007.02.007Get rights and content

Abstract

There has been an intense debate over the past several years on the relevant α/β value that could be used to describe the fractionation response of prostate tumours. Previously it has been assumed that prostate tumours have high α/β values, similar to most other tumours and the early reacting normal tissues. However, the proliferation behaviour of the prostate tumours is more like that of the late reacting tissues, with slow doubling times and low α/β values. The analyses of clinical results carried out in the past few years have indeed suggested that the α/β value that characterises the fractionation response of the prostate is low, possibly even below the 3 Gy commonly assumed for most late complications, and hence that hypofractionation of the radiation treatment might improve the therapeutic ratio (better control at the same or lower complication rate). However, hypofractionation might also increase the complication rates in the surrounding late responding tissues and if their α/β value is not larger that of prostate tumours it could even lead to a decrease in the therapeutic ratio. Therefore, the important question is whether the α/β value for the prostate is lower than the α/β values of the surrounding late responding tissues at risk. This paper reviews the clinical and experimental data regarding the radiobiological differential that might exist between prostate tumours and the late normal tissues around them. Several prospective hypofractionated trials that have been initiated recently in order to determine the α/β value or the range of values that describe the fractionation response of prostate tumours are also reviewed. In spite of several confounding factors that interfere with the derivation of a precise value, it seems that most data support a trend towards lower α/β values for prostate tumours than for rectum or bladder.

Introduction

There is increased interest in the clinically relevant α/β value for prostate tumours in light of the potential advantages of hypofractionated treatments. Such treatment, with a few large radiation fractions, will lead to fewer treatment sessions, which might be convenient from the point of view of both the patient (who will face a shorter treatment) and the economy of the radiotherapy department (which might be able to treat more patients in the same time period and therefore shorten the waiting lists). Furthermore, hypofractionated treatments of prostate carcinomas might also have the potential of an increased therapeutic ratio if it is confirmed that these tumours do have a smaller α/β value than the late responding normal tissues at risk. This paper will critically review the published clinical and experimental data regarding the radiobiological differential that might or might not exist between prostate tumours and the late normal tissues around them. Relevant publications reporting the derivation of the α/β value for prostate tumours or the outcome of radiotherapy in patients with prostate carcinoma were retrieved using standardised queries (e.g. ‘prostate alpha/beta’, ‘prostate radiotherapy’, ‘prostate hypofractionation’, etc.). These were supplemented with references from the relevant papers, as well as by additional papers identified in the personal database of the author.

Section snippets

Radiobiological Analysis of Clinical and Experimental Data

An α/β value as low as 1.5 Gy (95% confidence interval 0.8–2.2 Gy) was first presented in detail by Brenner and Hall [1], based on a review of 367 patients from two centres, some being treated at a low dose rate with I-125 and the others with high dose rate external beams at 1.8 or 2.0 Gy per fraction. This first report was disputed 2, 3 and was the starting point for many discussions about the prospects of hypofractionation for the treatment of prostate tumours 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

Clinical Studies of Hypofractionated External Beam Radiation Therapy

Hypofractionation has been used for several years, but on a small scale compared with conventional fractionation, due to the risk of an increase rate of unacceptable late effects [41]. This is why there are relatively few studies that have reported clinical results of hypofractionated treatments for prostate carcinoma with external beam irradiation (Table 2).

Highly hypofractionated treatments of the prostate with either 55 Gy in 12 fractions (BED3 = 139 Gy3) or 36 Gy in six fractions (BED3 = 108 Gy3)

Clinical Hypofractionation with High Dose Rate Brachytherapy

Analyses have also been carried out on the results reported from clinical treatments delivering a part or the entire therapeutic dose with high dose rate brachytherapy (Table 3). Borghede et al. [59] presented the results of 50 patients treated with a combination of 50 Gy of external beam radiotherapy and 2 × 10 Gy of brachytherapy (BED3 = 170 Gy3) showing high control rates (84% biochemical and 96% clinical) and minimal toxicity after 4 years. Mate et al. [60] reported on a group of 104 patients

Normal Tissue Radiobiology

Turning from low α/β values in tumours to the relative values for late rectal reactions (usually assumed to be 3 Gy), it seems that almost all the radiobiological aspects that have been taken into consideration point towards an α/β value for prostate tumours that is lower than the α/β value for late rectal complications. Indeed, the review by Fowler et al. [15] suggests α/β values for the rectal response between 4 and 6 Gy (with confidence intervals ranging from 2 to 8 Gy), which are higher than

Discussion

Most of the clinical studies available now seem to support the idea of a low α/β value for the prostate tumours that may favour hypofractionated regimens, which could be beneficial for both the patient and the radiotherapy department. However, such regimens might seem unsettling, especially in light of the many clinical examples of other body sites where the use of a few large fractions has resulted in an unacceptable rate of late effects [41]. The clinical data available now do not justify the

Conclusions

There is now quite a broad range of clinical data, both retrospective analyses and clinical trials, that suggest that the α/β values for prostate carcinomas are small, possibly even lower than the α/β values for the late responding normal tissues at risk. This opens up the prospect of a potential increase in the therapeutic ratio for these cancers through the use of hypofractionated treatments. However, there are many other radiobiological factors that have to be taken carefully into

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