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3. The interaction between external beam radiotherapy and hormone therapies.
(Contents updated - 13th November 2005)

The whole is greater than the sum of the parts.

SUMMARY
The outcome of external beam radiotherapy is significantly enhanced if the radiotherapy is given in conjunction with hormone therapy. The addition of hormone therapy benefits both disease free survival and overall survival. These drugs are usually given for a period of two or three months before the start of radiation therapy and continued during and after the radiation treatment. Drugs given before the radiotherapy seem to have little impact on disease free survival but those taken during and after radiotherapy have a significant effect. The period of drug treatment after the end of radiotherapy may only need to be a few months for men at a low or intermediate level of risk but a conservative approach would be to continue them for, say, six months to a year. For high risk patients, the period may need to be longer. Most of the data on hormone therapies relate to the use of LHRH agonists like Zoladex and although the less toxic anti-androgen Casodex seems to have a similar effect on disease free survival, it doesn't appear from data published so far to confer any overall survival benefit. This is not the case with Zoladex. At the end of this web page, there are some conjectural comments on the use of Casodex.


The use of hormone therapy in conjunction with external beam radiotherapy is emerging as an important contributor to improving the overall efficacy of radiation treatment. The two principal types of hormone therapy in use are goserelin (trade name of Zoladex) and bicalutamide (trade name of Casodex). However, the action of the two drugs and their side-effects are quite different. Goserelin is known as an LHRH agonist and its action is effectively to chemically castrate the patient and cause the testosterone level in the blood to fall to a low value. Bicalutamide is known as an anti-androgen and is a drug that has similarities to testosterone and it locks into the receptors on those cells that require testosterone and thus prevents testosterone reaching the cells. The effect of both drugs is similar in that they slow the rate of replication of prostate cells that are sensitive to testosterone and they also reduce the size of the prostate gland.

Before discussing the interaction between hormones and radiotherapy, three common terms need to be defined. Neo-adjuvant hormone use means taking the hormones before the start of radiotherapy. Concurrent hormone use is taking the hormones during radiotherapy and adjuvant hormone use is taking the hormones following radiotherapy. Most of the detailed results on the interaction of hormones with radiotherapy have been using goserelin (Zoladex) and the comments below apply to that hormone only. The effect of concurrent and adjuvant use of hormones will be discussed first because their effects seem to be the most significant.

CONCURRENT AND ADJUVANT HORMONE USE FOR MEN AT A LOW OR INTERMEDIATE LEVEL OF RISK.
Contrary to earlier ideas, neo-adjuvant hormones seem to have little impact on treatment efficacy and it is concurrent and adjuvant use that seems to have a major effect both on disease free survival and overall survival.It is difficult often to compare the results of trials on hormones and radiotherapy because they are carried out on dissimilar patient groups but work by Bolla and colleagues (2002) and D'Amico and colleagues (2004) are sufficiently similar in this respect that the results can be compared. In the case of the D'Amico trial, the average pre-treatment PSA was 11 ng/ml with the majority of the patients having a Gleason score of 7 and a t-staging of T1c to T2a. This is similar to the group defined by Bolla as being at an intermediate stage of risk. In both cases, the trial consisted of several hundred patients split into two groups. One of the groups received just external beam radiotherapy with a total dose of 70 Gy delivered in daily fractions either equal to or close to 2 Gy per day. The other group received the same radiotherapy dose but were also treated with hormones in the form of LHRH agonists (mainly Zoladex). However, whereas Bolla's group continued the hormone therapy for three years after the radiation treatment, D'Amico continued hormone therapy for only two months after the end of the radiotherapy. The table below summarises the differences in the hormone treatments.


Trial size
Neo-adjuvant.
(Before ebrt)
Concurrent
(During ebrt)
Adjuvant
(After ebrt)
D'Amico et al (2004)
415
Yes - 2 months
Yes - 2 months
Yes - 2 months
Bolla et al (2002)
195
No
Yes - 2 months
Yes - 3 years

The graph below shows the effects of hormones combined with radiotherapy on disease free survival as compared with radiotherapy alone. Failure of treatment was defined slightly differently in the two trials. In Bolla's case, it was taken as a PSA greater than 1.5 ng/ml and two consecutive increases in PSA. In D'Amico's case, it was taken to be a PSA of greater than 1.0 ng/ml and two consecutive increases of more than 0.2 ng/ml. However, these differences in definition of failure will not alter significantly the general conclusions that can be drawn from the results shown in the figure. The first and most important point is that the probability of disease free survival is very significantly improved by the use of concurrent and adjuvant hormones. The second and even more surprising result is that there does not seem to be too much difference between the results when adjuvant hormones were taken for three years after treatment and just two months after treatment. Since Zoladex leads to a significant loss of quality of life, this is a significant finding. If Zoladex had only to be taken for even, say, six months after the end of ebrt, many would be able to accept this more stoically than taking it for three years.

Hormones and ebrt interaction

Whilst there are different definitions of treatment failure, there are no uncertainties about death in overall survival data. The figure below shows the D'Amico trial data for overall survival and it again demonstrates the favourable influence of combining concurrent and adjuvant hormones with external beam radiotherapy. The actual survival figures are interesting too. There were 103 men in the radiotherapy only group. In the six year period, 6 died from prostate cancer whilst 17 died from other causes (heart disease being the most common). In the radiotherapy with hormones group, there were 98 men and none of these died from prostate cancer in the six year period but there were 12 deaths from other causes (heart disease again being the most common).

Overall survival D'Amico

The figure below shows the overall survival data from the Bolla trial. It is important to note that whereas Bolla gave disease free survival data for intermediate risk patients, his overall survival data contained all patient groups including those at a high risk. This is almost certainly why the survival data are more unfavourable than the result from the D'Amico trial. Nevertheless, it once again shows that concurrent and adjuvant hormones combine with radiotherapy to produce better treatment outcome than radiotherapy alone.

Overall survival Bolla


REFERENCES.
Bolla, M., Collette L., Blank L., et al (2002)
Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial.
The Lancet Vol.360, pp.103-108.

D'Amico A.V., Manola, J., Loffredo, M. et al (2004)
6-month androgen suppression plus radiation therapy versus radiation therapy alone for patients with clinically localised prostate cancer.
JAMA, Vol.292, No.7 pp.821-827.


CONCURRENT AND ADJUVANT HORMONE USE FOR MEN AT A HIGHER LEVEL OF RISK.
A trial of 945 men has also been carried out in the US on patients at a higher level of risk with palpable tumours at a T3 stage and/or evidence of spread to the lymph nodes. This trial was conducted by the Radiation Therapy Oncology Group and was called trial 85-31 (Pilepich and colleagues(2005)). The men received typically 65 Gy of radiation in 1.8 to 2 Gy fractions. About half the group were given adjuvant Zoladex started during the last week of radiotherapy and continued indefinitely thereafter. The other half only received hormone therapy when they showed signs of disease relapse.The figure below shows a clear survival benefit for those receiving hormone therapy as an immediate adjuvant to the radiotherapy. It is important to emphasise that the majority of the deaths in both arms of the trial were from causes other than prostate cancer. From the data in the original paper, 477 men were in the group who had Zoladex immediately after the radiotherapy and, of these, 269 had died at ten years but only 82 from prostate cancer. The figures for the other group are 468 men of whom 306 had died at ten years with 113 dying from prostate cancer.

Overall survival RTOG

In view of the result of D'Amico and Bolla, it is possible that the same benefit might have arisen even if the adjuvant hormones were given for a period of just a year or two. Evidence in support of this can be found in an analysis of about 300 patients treated in Canada with radiotherapy with a dose ranging from 66 to 72 Gys. The average pre-treatment PSA for the whole group was about 33 ng/ml so that these men were within a high risk group. About half the men had hormone therapies whose average duration was about 6 months (i.e.the less than 12 months group) whereas the other half had hormone therapies extending for an average of about 33 months. Precise details of the hormone therapies are given in the paper (Berthelet and colleagues(2005)) but, in the short period group, the hormones were mainly either neo-adjuvant or neo-adjuvant and concurrent. In the longer period group, it was neo-adjuvant, concurrent and adjuvant use. The figure below shows the overall survival data for the two groups and shows a survival benefit from the longer period of hormone therapy.

Overall survival Berthelet
It seems clear that it is the adjuvant use of hormone therapy that brings the main benefits and there seems to be some synergy between the hormone therapies and the radiation treatment. As to the optimum length of adjuvant use, it may be that this is a function of the patient pre-treatment parameters and that low risk patients may get most of the benefit from just a few months of adjuvant therapy whereas longer periods may be appropriate for men at a higher level of risk.

REFERENCES.
Pilepich M.V., Winter K., Lawton C.A., et al (2005)
Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma - long-term results of phase III RTOG 85-31.
Int.J.Radiation Oncology Biol. Phys., Vol.61, No.5, pp.1285-1290.

Berthelet E., Pickles T., Won Jae Lee K., et al (2005)
Long-term androgen deprivation therapy improves survival in prostate cancer patients presenting with prostate-specific antigen levels > 20ng/ml.
Int.J.Radiation Oncology Biol. Phys., Vol.63, No.3, pp.781-787.

NEO-ADJUVANT HORMONE USE.
In terms of a long term improvement in either the probability of overall survival or the probability of disease recurrence, the influence of neo-adjuvant hormones seems at best to be weak. In fact, in the case of permanent seed brachytherapy, there is even a suggestion that it diminishes long term survival - Beyer and colleagues (2005). However, in the case of EBRT, there may still be an advantage in using neo-adjuvant hormones particularly for men with large prostates because they shrink the gland and so make it a more compact target which, in turn, may reduce the degree to which the rectum and bladder are subject to a high dose of radiation. From Canadian work (Crook and colleagues (2004)), it seems that three months of neo-adjuvant Zoladex reduces the prostate volume to about 70% of its original volume. The linear dimensions of the prostate will be reduced by about 10%.The sketch shows a cross-section through the body with the prostate and rectum roughly to scale. The effect of reducing the volume to around 70% is shown. Whilst this reduction may seem small, it will affect the extent of the rectum that is exposed to high levels of radiation although by what percentage is difficult to estimate until the beam angles and beam geometries are specified - but see Zelefsky and Harrison (1997) for an example of possible reductions.

Prostate sketch


The same Canadian work also included results from 8 months of neo-adjuvant hormones and although this resulted in a greater prostate volume reduction to about 50%, no long term benefit over 3 months use was found in disease free survival.

With men whose prostates are of normal size or less, it is arguable that there is little benefit in delaying the start of radiotherapy by three months for neo-adjuvant hormone use.

REFERENCES.
Beyer D.C., McKeough T., Thomas T (2005)
Impact of short course hormonal therapy on overall and cancer specific survival after permanent prostate brachytherapy.
Int.J.Radiation Oncology Biol. Phys., Vol.61, No.5, pp.1299-1305

Crook J., Ludgate C., Malone S., et al (2004)
Report of a multicenter Canadian phase III randomized trial of 3 months versus 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer.
Int.J.Radiation Oncology Biol. Phys., Vol.60, No.1, pp.15-23.

Zelefsky M.J., Harrison A. (1997)
Neoadjuvant androgen ablation prior to radiotherapy for prostate cancer - reducing the potential morbidity of therapy.
Urology. Vol.49(3A Suppl)pp.38-45.

THE USE OF CASODEX RATHER THAN ZOLADEX AS THE PRIMARY ADJUVANT HORMONE.
The side effects from the anti-androgen Casodex are not as unpleasant as those of LHRH agonists like Zoladex so it is an attractive alternative hormone therapy. However, detailed data on its use with external beam radiotherapy have not yet been published although a very large trial (See et al(2002)) on the general use of Casodex has been carried out which contained 1370 patient who received Casodex at 150mg per day as the primary adjuvant hormone used in conjunction with external beam radiotherapy. A later report (Wirth et al (2005)) on one of the trial groups with an inital average PSA of 11.7 ng/ml (trial 24) showed that whereas the use of Casodex improved disease free survival, it did not increase overall survival. Although fewer died of prostate cancer in the Casodex group compared with the placebo control group, there was an increase of non-prostate cancer deaths in the Casodex group so that the overall mortality was statistically the same. The problem with the trial is that most of the patients were treated either by radical prostatectomy or watchful waiting and the results for those treated by radiotherapy were not reported separately. It is just possible that the effect of Casodex on overall survival might be treatment specific but until the data for radiotherapy is reported separately, a question mark must hang over the effect of Casodex on overall survival. This does not seem to be the case with Zoladex where there seems to be a clear survival benefit.

It should also be noted that Casodex was taken for a period of five years in the trial. In view of the results of the Zoladex trials shown earlier, it is possible that the beneficial effects of Casodex on disease free survival might have been achieved with a shorter period of use and, with this shorter period, the increase in non-prostate cancer deaths might have been reduced. The use of Casodex clearly requires further study in order to optimise its potential benefits.

One final point should be made. Whereas Casodex taken over five years led to an increase in non-prostate cancer deaths in trial 24 in the Worth et al (2005) paper, there is a hint in the results shown earlier on this web page on the adjuvant use of Zoladex that this drug not only reduces prostate cancer deaths but it may reduce also the non-prostate cancer deaths. This can be seen in both the D'Amico trial results and the RTOG 85-31 trial results. A proper statistical analysis would be necessary to check on the significance of the actual numbers. With Zoladex, blood testosterone levels are reduced to castration levels whereas, with Casodex, blood testosterone levels apparently increase slightly. It is impossible not to conjecture that this most obvious of differences may be responsible for the differences in non-prostate cancer deaths behaviour.

REFERENCES.
See W.A., Wirth M.P., McLeod D.G. et al (2002).
Bicalutamide as immediate therapy either alone or as an adjuvant to standard care of patients with localised or locally advanced prostate cancer: first analysis of the early prostate cancer program.
J. of Urology, Vol. 168, pp.429-435.

Wirth M., Tyrell C., Delaere K. et al (2005)
Bicalutamide ('Casodex') 150mg in addition to standard care in patients with non-metastatic prostate cancer: updated results from a randomised double-blind phase III study (median follow-up 5.1 y) in the early prostate cancer programme.
Prostate Cancer and Prostatic Disease, Vol.8, No.2, pp.194-200.