Phase III randomised trialDelayed rectal and urinary symptomatology in patients treated for prostate cancer by radiotherapy with or without short term neo-adjuvant androgen deprivation☆
Introduction
In a previous report in this journal from the Trans-Tasman Radiation Oncology Group's (TROG) randomised controlled 96.01 trial [11], we reported that short term (3 or 6 months duration) maximal androgen deprivation (MAD) does not alter the acute morbidity associated with prostatic radiotherapy to 66 Gy despite leading to significant reductions in radiation target volume size. In addition, it does not increase the probability of long term sexual dysfunction. We also reported that the limited inconvenience associated with its administration is partly offset by improvements in urinary function prior to radiotherapy. A further important finding to be reported was the observation that dysfunctional rectal and urinary symptom levels at the end of radiotherapy (i.e. reflecting ‘acute radiation injury’) are predicted by rectal and urinary symptom levels prior to any treatment.
Since minimum follow up time after completion of all therapy on this trial is now over four years, we have taken the opportunity to address several important additional questions in the present report:
- 1.
Does 3 or 6 months MAD prior to and during radiotherapy alter the risks of ‘delayed’ (late) dysfunctional rectal and urinary symptomatology?
- 2.
Do baseline symptom levels prior to any treatment at all also predict delayed dysfunctional symptomatology? and, if so:
- 3.
Are the associations between baseline and delayed symptoms stronger than any seen between acute and delayed symptom levels?
- 4.
Are other pre-treatment factors associated with the development of delayed symptomatology?
It is now well recognised that prevalence rates can vary greatly from actuarial probability rates [17] in normal tissues whose toxicity scales are, to a large extent, based on reported symptom levels that can fluctuate over time or even improve [18]. In this report, therefore, time to occurrence and prevalence data have been used to address our aims.
Section snippets
Study overview
Between 1996 and 2000, 818 patients with locally advanced, but non-metastatic prostate cancer were entered into a randomised clinical trial. Patients were contributed from 18 centres in Australia and New Zealand. Patients were randomised to receive either 0, 3 or 6 months of maximal androgen deprivation (MAD) prior to radiotherapy. MAD consisted of goserelin1 3.6 mg given monthly by subcutaneous injection and 250 mg flutamide2
Patient data
Out of a total of 818 patients, 802 from 18 centres across Australia and New Zealand were fully evaluable. There were no significant imbalances between the trial arms with respect to the stratification variables: age, stage, Gleason score and pre-treatment PSA level. However, significantly higher pre-treatment haemoglobin levels were recorded in the 3 month arm (Kruskal–Wallis comparison of all three arms P=0.023).
SAQ's were completed in full by 769 (95.9%) of the 802 evaluable patients prior
Morbidity rates
The high SAQ completion rates noted in our earlier publication [11] continue at least 4 years after therapy has finished. The observation that symptom levels are reported to fluctuate considerably by the majority of patients is of great relevance to the clinical interpretation of toxicity rates derived from the data. For example, the actuarial probability of grade 2 or more delayed proctopathy at 3 years following completion of therapy, is almost three times greater than the prevalence rate (28
Conclusions
Prevalence data provide more clinically meaningful estimates of risk of delayed effects in normal tissues where assessment relies substantially on reported symptom levels. In these tissues consideration of the impact of baseline symptom levels and pathologies, and greatest acute symptom levels in analyses of delayed effects appears mandatory.
Obstructive lower urinary tract symptoms improve over several years in the majority of patients treated for locally advanced prostate cancer by
Acknowledgements
The funding support of the National Health and Medical Research Council (Grant Nos 9936572 and 209802), AstraZeneca Pty Ltd and Schering-Plough Pty Ltd is gratefully acknowledged. We are also grateful for the significant clinical contribution to this trial of Drs J Jose (Auckland), G Bryant, K Gogna, G Dickie, R Allison, L Kenny (Brisbane), M Jackson, G Morgan, S Cooper, A Kneebone (Sydney), P Jeal, P Fon, M Collins (Townsville), D Byram, R Lynch (Geelong), C Johnson (Wellington), C Hamilton, P
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Trial 96.01 of the Trans-Tasman Radiation Oncology Group (TROG)