The challenge for modern day radiotherapy is to harness the major technological and computational advances in radiotherapy planning and delivery with the development of targeted treatment agents for use in combination with radiotherapy. Novel imaging methodologies for treatment planning and response assessment need to be integrated together with molecular markers to guide treatment selection. Study of these different aspects of treatment modification may initially proceed in isolation, but need to be brought together to give the best opportunities for cancer control keeping treatment-related side effects as low as possible.
Radiotherapy dose-distributions can now be achieved with complex target volumes as a consequence of the research on 3D and 4D planning embodied as conformal and intensity modulated delivery techniques. Improved imaging for verification and development of methods of radiotherapy tracking with tighter margins offer the potential for reduced doses to adjacent normal tissues and opportunities to lessen the risk of chronic injury and to improve tumour control by dose escalation.
Important problems remain to be addressed if these gains are to be realised including; How to increase the precision of tumour and target volume definition? Can dose-distributions be tailored to sites of tumour resistance or normal tissue sensitivity based on functional imaging? How to predict tolerance of different dose-distributions within an organ? How to respond to movement of the target during treatment? How can radiation response be modulated by small molecules and vaccines? How can we select optimal radiotherapy schedules?
Prostate cancer is the most common cancer in men in the UK, USA and Western Europe with 37,000 men diagnosed in the UK and an estimated 913,000 cases worldwide in 2008 (CRUK). Following the introduction of prostate specific antigen (PSA) testing the considerable majority of men diagnosed have localised disease.
Management options include external beam radiotherapy, brachytherapy, radical prostatectomy, active surveillance for men with low risk disease or watchful waiting for those unsuitable for radical curative treatment. External beam radiotherapy may be most appropriate for men with intermediate or high risk features and is associated with long term disease control in the majority of men. It is estimated that more than 10,000 men receive radical prostate radiotherapy in the UK each year.
At present, curative treatment for all cases remains a standard approach. Active surveillance of early prostate cancer is a policy designed to reduce over-treatment, in which curative treatment is targeted to men with evidence of disease progression during a period of close monitoring.
Considerable technological advances over the past decade have improved the ability to sculpt dose distributions to the prostate target and improve treatment accuracy. Several phase III randomised control trials (RCTs) have demonstrated the benefit of dose escalation.
The trial addresses the fraction sensitivity of prostate cancer comparing standard treatment (2Gy daily fractions) to a total dose of 74Gy in 37 fractions over seven weeks or experimental hypofractionated treatment schedules (3Gy daily fractions) to total doses of 57Gy in 19 fractions over 3.8 weeks and 60Gy in 20 fractions over four weeks.
The role of pelvic lymph-node irradiation in prostate cancer remains controversial particularly following the recent results of two phase III trials. Nevertheless it is argued that for ‘high-risk’ disease standard therapy should remain prostate and pelvic radiotherapy with three years of androgen suppression, as this has been the treatment used in phase III trials assessing the duration of hormonal therapy.
Radiation therapy for prostate cancer currently treats the whole gland to a uniform dose, but technological advances allow accurate matching of dose to tumour target. Functional MR methods significantly improve the localisation of tumour tissue and the Cancer Research UK MR Unit (Dr DeSouza, Professor Leach) is evaluating dynamic contrast-enhanced pharmacokinetic data, diffusion weighted images, R2* BOLD mapping and spectroscopic data using an endorectal receiver coil at 3T. Tumour localisation will be validated by comparison with specially prepared whole-mount histopathology using methodology developed in the ICR.
Spinal cord compression (SCC) is a devastating complication of skeletal metastases. Our studies show this is common, and that spinal MR may be used to detect subclinical SCC in prostate cancer. We are developing a national phase III trial of spinal MR in asymptomatic men with castrate resistant prostate cancer and bone metastases treating subclinical SCC with immediate radiotherapy with the aim of reducing the clinical incidence of SCC.
An important part of our programme is to support the analysis of the physical data arising from clinical trials aiming to produce robust validated normal tissue constraints to embed in national treatment guidelines. The limitations of physician-based scoring systems of toxicity (usually RTOG) are well-known.
We aim in collaborative studies to assess the genetic component of radiosensitivity in prostate cancer patients treated in radiotherapy trials and link findings with DVH data in prostate cancer.
We have demonstrated the feasibility of evaluating candidate tissue biomarkers using a novel biopsy tissue micro array (TMA) technique developed at the ICR. TMAs have been constructed from 200 patients from the active surveillance study and we will evaluate expression of a range of candidate biomarkers (eg. Ki 67, Bcl2, VEGF, HIF-1alpha, E cadherin, SPINK1) with respect to disease progression.