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4. The effect of escalating the overall dose level.
(Updated 25th October 2005)

Moderation is a fatal thing. . . . Nothing succeeds like excess.
(Oscar Wilde)

SUMMARY.
The 'standard' dose in external beam radiotherapy is 70 Gy but, with 3-D conformal or intensity modulated radiotherapy, it is possible to deliver higher doses than this whilst maintaining acceptable side-effect levels. There is a significant gain in the probability of disease free survival by increasing the dose to somewhere between 76 and 80 Gy; the beneficial effect is significant for patients at all levels of risk although it is most marked for high risk patients.

With this increase in dose level coupled with concurrent and adjuvant use of hormone therapies, there should be a very significant improvement in both disease free survival and overall survival compared with external beam radiotherapy of 70Gy and neo-adjuvant hormones only.



The dilemma in using radiation as a treatment for cancer is that of walking the line between having a high enough dose to achieve good tumour control and yet not so high as to cause unacceptable adverse side effects. Additionally, there is some variability in an individual's tolerance to radiation, which further complicates the matter. In the case of prostate cancer, general practice over the last decade or so seems to have settled on a figure of about 70 Gy delivered at around 2Gy per day. However, progress in recent years with beam collimation in linear accelerators coupled with the development of mathematical techniques to optimise radiation dose profiles has enabled dose levels to be increased without increasing adverse side effects. The technique of three-dimensional conformal radiotherapy has now been further incrementally improved by beam intensity modulated techniques and dose levels as high as 86.4 Gy have been tested at the Memorial Sloan-Kettering Cancer Center (Zelefsky et al (2002)) without significant changes to acute or long-term side effects. This group has also developed nomograms for predicting the outcome of various forms of treatment for prostate cancer and these have been collated into a single Microsoft Access database that can be download from the Memorial Sloan- Kettering website (www.mskcc.org/mskcc/html/10088.cfm). For present purposes, the nomogram for predicting the outcome of external beam radiotherapy is the one that is of interest - see Kattan et al (2000). This nomogram was based on data from 1042 patients at Memorial Sloan-Kettering and then compared with a second independent set of patient data from the Cleveland Clinic, Ohio. The real value of this nomogram is not its absolute accuracy but in its prediction of trends. Although there has been a number of publications on dose escalation, this nomogram provides a compact means of looking at the influence of a variety of factors on treatment outcome. The figure below shows predictions for 5 year disease free survival as a function both of total dose with and without neoadjuvant hormones and also as a function of initial patient risk factors. Adjuvant hormones were not used in the data from which this nomogram was compiled. Failure is based on the ASTRO definition of three successive rises in PSA. The confidence intervals have not been shown to avoid cluttering up the graph.

Dose escalation

This figure shows a number of interesting trends. The first is the very strong influence of the initial risk factors on disease free survival probability. The prospects for low and intermediate risk patients are comparatively good with conventional 70Gy treatment but the outlook when PSA rises above 10 coupled with a palpable tumour and high Gleason score diminishes rapidly. The second point is that the improvement in outlook by increasing the dose from 70Gy to around 76 to 80Gy is significant and there have been a number recent reports in addition to the Zelefsky work that indicate that this increase in dose can be achieved without a significant impact on side effects provided that advanced three dimensional conformal or intensity modulated techniques are used. The third point to note is that whereas the nomogram predicts an improvement in disease free survival from the use of neo-adjuvant hormones (Sloan Kettering used goserelin), the effect is not large particularly for low and intermediate risk patients - particularly when compared to adjuvant use. This has already been discussed on the web page 3 concerned with hormone therapies used in conjunction with radiotherapy.

Recent confirmation of the value of dose escalation even for patients at a low level of risk has been provided by Zietman and colleagues (2005). They carried out a trial of 393 patients with a median PSA of 6.3 ng/ml, a predominant Gleason score of 6 or less and T-staging mainly of T1c. About half were given 70 Gy of radiation without any hormones and the other half were given 79 Gy without hormones. The five year disease free percentage was 61% and 80% for the two respective groups. Precise details of the radiation treatment are given in their paper and was a mixture of photon and proton radiation. No significant differences in early or late side-effects were noted. It should be noted that these disease free survival figures are lower than those predicted by the MSKCC nomogram which suggests that the nomogram may be rather too optimistic in its predictions.

REFERENCES.
Kattan M.W., Zelefsky, M.J., Kuperlian P.A. et al (2000) Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer.
J. of Clinical Oncology, Vol.18, No.19, pp.3352-3359.

Zelefsky M.J., Fuks Z., Hunt M. et al (2002)
High-dose inensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients.
Int.J.Radiation Oncology Biol. Phys., Vol.53, No.5, pp.1111-1116.

Zietman A.L., DeSilvio M.L., Slater, J.D. et al (2005)
Comparison of Conventional-dose vs High-Dose Conformal Radiation Therapy in Clinically Localized Adenocarcinoma of the Prostate.
JAMA, Vol.294, No. 10, pp.1233-1239.