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5. Increasing the daily dose fraction above 2 Gray.
The dose rate effect and hypofractionation.

A win/win situation?

SUMMARY.
Cells are sensitive not only to the overall dose of radiation but also to the rate at which it is given. There is evidence that prostate cells are more sensitive to this rate effect than the rectum and bladder and there is therefore a potential advantage in delivering the dose at a greater rate than 2 Gray per day. This is still the subject of controversy but a conservative approach would be to replace the existing 70 Gray in 2 Gray fractions with 63 Gray in 3 Gray fractions. Such a change potentially would improve the treatment effectiveness without increasing side effects and it would save both the patient and the hospital money because of the reduction in treatment days from 35 to 21 days.


The effect of radiation on cells is not dependent just on the overall dose of radiation but it also depends on the rate at which the radiation is delivered - the so-called dose-rate effect. Some cells are more sensitive to dose rate than others. In particular, work started by Brenner and Hall (1999) suggests that prostate cells are more sensitive to the rate at which radiation is delivered than the surrounding organs like the rectum and bladder. The evidence about this is still the subject of discussion in the literature but, if it is correct, the effectiveness of external beam radiation therapy can be further improved by replacing the current daily fraction of 2 Gray by a larger daily fraction like 3 or 4 Gray. Moreover, by increasing the daily fraction, the overall dose necessary to have the same effect as 70 Gy given in 2 Gy fractions is reduced. It is unfortunately not possible to describe easily how these equivalent doses are calculated so that, for present purposes, only the results will be presented. A second review paper (web page 11) can be downloaded from this site as an Adobe Acrobat document and this gives more complete information and references on this subject.

Calculations about the equivalence of different radiation doses depend on theoretical models of how radiation interacts with cells and there are a number of such theories. However, they are not substantially different from one another and one of the simplest theoretical models is called the linear-quadratic model - abbreviated to the LQ model. For external beam radiotherapy delivered in acute fractions, there is one important parameter in this model called the alpha-beta ratio and it is this parameter that determines the equivalence of doses delivered at different rates. The units of this parameter are Grays and the lower the value of this parameter, the more sensitive the cells are to the dose rate effect. According to Brenner and Hall, the value of this parameter for prostate cells is about 1.5 Gy whereas the value for rectal tissue that causes long term side effects is thought to be nearer 6 Gy. The graph below shows the ratio of the overall dose at different daily fractions compared to the overall dose with a 2Gy per day fraction. The equivalent doses have been calculated for both an alpha-beta ratio of 1.5 Gy and for an alpha-beta ratio of 6 Gy.

Iso-effect dose ratios

As an example of the potential advantage of increasing the daily dose fraction, consider the red curve with an alpha-beta ratio of 6.0 that is representative of rectal tissue. Suppose that the daily fraction is increased from 2 Gy per day to 4Gy per day. The iso-effect dose ratio is 0.8 which means that if we wished to have the same effect on the rectal tissue as 70 Gy dose delivered at 2 Gy per day, we would now only need a dose of 0.8 x 70 =56 Gy. Since this dose is delivered now in 4 Gy fractions, the number of treatment days would only be 14. However, the really important point now arises when we consider what this dose means in terms of the prostate cells having an alpha-beta ratio of 1.5. The iso-effect dose ratio for these cells at 4 Gy per day is 0.64 and this means that the 56 Gy dose in 4 Gy fractions would be equivalent to 56/0.64 = 87.5 Gy delivered in 2 Gy fractions. By reference to the graph shown in web page 4, this would increase the probability of being disease free for, say, an intermediate risk patient, from around 75% for radiation treatment alone up to nearer 90% but without increasing the extent of damage to the rectum. This is a very significant improvement in the effectiveness of the treatment and it seems like an unusually propitious win/win situation. The patient only has to attend for 14 treatment days rather than the present 35 days and this will save money for both the patient and the hospital; additionally, treatment outcome will be improved!

At this point, it would be reasonable to ask why there hasn't been a rush towards changing the 'standard' protocol to this new type of regime - which is called hypofractionation on the basis that the number of treatment days is reduced (hypo meaning below normal). At least part of the answer is that the precise values of the alpha-beta ratio for the prostate and the rectum are the subject of controversy and uncertainty so that this necessitates some caution in making what is a comparatively radical change in treatment procedure. However, it is possible to adopt a cautious approach that carries very little risk to it by considering a more modest change in the daily fraction from 2 Gy to 3 Gy. In this case, the iso-effect dose ratio for an alpha-beta ratio of 6 is 0.89 and for an alpha-beta ratio of 1.5, it is 0.78. Keeping the effect on the rectum the same as 70 Gy in 2 Gy fractions now leads to an overall dose of 0.89 x 70 = 62 Gy. Delivered in 3 Gy fractions, this rounds up to 21 days of treatment (i.e.63 Gy). For the prostate, this dose would be the equivalent of 63/0.78 = 81 Gy in 2 Gy fractions. This would still result in a significant improvement in the probability of disease free progression and carries very little risk of worsening side effects.


It is worth noting that a trial was carried out at the Christie Hospital NHS trust between 1995 and 1998 in which 705 men were treated with daily fractions of 3.13 Gy over 16 days amounting to a total dose of 50 Gy. From the above graph for an alpha-beta ratio of 1.5, this would have amounted to a dose of 65 Gy delivered in 2 Gy fractions. They reported similar tumour control and side effects to a 2 Gy per day protocol and they then reported that they were now treating patients with 60 Gy in 3 Gy fractions over 20 days - Livesey and colleagues (2003). This is just one day less than than the 63 Gy in 3 Gy fractions referred to as a reasonably conservative protocol in the previous paragraph.

In recent times, more trials with hypofractionation are being carried out both in the UK and in the US and whilst it is unlikely that a consultant would change his treatment routine to a hypofractionated one for an individual patient, it would be worth asking about such trials and whether or not one was eligible to take part in them.

REFERENCES.
Brenner, D.J., Hall E.J.(1999)
Fractionation and protraction for radiotherapy of prostate carcinoma.
Int.J.Radiation Oncology Biol. Phys., Vol.43, No.5, pp.1095-1101.

Wang J.Z., Guerrero, M., Allen, X (2003)
How low is the alpha-beta ratio for prostate cancer.
Int.J.Radiation Oncology Biol. Phys., Vol.55, No.1, pp.194-203.

Livesey J.E., Cowan R.A., Wylie J.P. et al (2003)
Hypofractionated conformal radiotherapy in carcinoma of the prostate: five-year outcome analysis.
Int.J.Radiation Oncology Biol. Phys., Vol.57, No.5, pp.1254-1259.