Head of Unit: Professor David P Dearnaley MA MD FRCP FRCR

This multidisciplinary Unit focuses on the management of, and research involving, patients with testicular, prostate, bladder and renal cancers. Urological surgery is based in Chelsea and the associated specialised ward also co-ordinates stoma care. The chemotherapy of testicular and bladder cancers is undertaken predominantly in Sutton with clinical research data co-ordinated by the Bob Champion Cancer Trust Research Unit. The problems of urological tumours are extremely diverse. For example, although uncommon, testicular cancers are the most frequent malignancy occurring in young adult males and are increasing in incidence.

However, they are a model for chemo-sensitive cancer and the majority of men are cured. Prostate cancer is now the most common cancer in more elderly men. Treatment of localised disease is highly controversial and progressive advanced disease is often associated with widespread incurable bone metastases.

Over the last decade The Institute and Royal Marsden teams have developed an extensive portfolio of clinical and laboratory research in urological cancers. The national importance (and previous neglect) of prostate cancer has been the development of the National Prostate Cancer Programme and establishment of two national 'Centres of Excellence' for prostate cancer research. As a result of our previous track record and current research proposals, The Institute and Royal Marsden teams were invited to form the core of one of these with colleagues from Brunel and Liverpool Universities. This Cancer Collaborative, led by Professor Colin Cooper has won major support from the Cancer Research Funders' Forum to develop a 5-year programme in translational research including:

• Molecular pathology of prostate cancer
• Novel therapies for prostate cancer
• Aetiology of prostate cancer

Relevance to the NHS Research and Development Programme

The Unit has large referral practices for prostate and testicular tumours as well as for bladder and renal cancer. The Unit is particularly fortunate to be able to take advantage of a broad range of clinical specialists excellently supported by specialised pathology and radiology services. Our research programme makes significant contributions to many areas of the NHS R&D priorities in cancer, including the study of the genetics of testicular and prostate cancer, conformal radiotherapy, high dose chemotherapy and peripheral blood stem cell support for testicular cancer. Also our studies on neoadjuvant treatments in prostate cancer, extending nursing roles, and psycho-social intervention in males with cancers are areas which qualify as of very high or high importance to the NHS.

Recent Highlights

Recent personal achievements include the conferment of title of Reader in Cancer Genetics to Dr Ros Eeles and of Professor of Uro-Oncology to David Dearnaley. Dr Johann de Bono has been appointed Senior Lecturer in the Department of Medicine and will work on Phase I and II clinical trials within the Urology Unit particularly developing new targets in prostate cancer. Dr Vincent Khoo has been appointed Consultant Clinical Oncologist and will lead the non-surgical oncology team in in Chelsea. Dr Chris Parker and Professor Colin Cooper have become members of the Prostate Cancer Advisory Group where Dr Parker chairs the Committee developing decision tools for the management of localised prostate cancer. The Unit's genetics (lead Dr Ros Eeles) and clinical studies in prostate cancer have made leading contributions to the recruitment of patients through the National Cancer Research Network portfolio of trials in urological cancer research both nationally and in the South West Thames Cancer Network. The Academic Unit Quinquennial CR-UK programme grant (lead Professor Alan Horwich) gained 'Forefront/Outstanding' ratings. Development of conformal and intensity modulated radiotherapy programmes have been supported by a Department of Health grant to support a Phase III trial of hypofractionated treatment (PI Professor David Dearnaley). Major laboratory research publications include the identification of a gene called E2F3 in the development of bladder cancer (Professor Colin Cooper), confirmation that BRCA2 is a susceptibility gene for prostate cancer (Dr Ros Eeles) and identification of over-expressed sequences in chromosome 12p in testicular cancer (Dr Janet Shipley). Major published clinical studies include the evaluation of intensive induction chemotherapy in testicular cancer and identification of cardiovascular disease as a long term treatment complication in germ cell tumours (Dr Robert Huddart and colleagues) and the first Phase III trial evaluating bisphosphonate drugs in prostate cancer (Professor Dearnaley).

Future Aims

The Male Cancer Research Centre, 'Centre of Excellence' Collaborative Grant and Everyman Campaign provide unique opportunities to develop public awareness of male cancers and to translate high quality laboratory research into clinical benefit for patients. In prostate cancer we aim to develop genetic markers to determine the natural history of disease on an individual basis, so as to select appropriate management policies. Genetic studies will continue in both testicular and prostate cancer with the aim of identifying the gene(s) responsible for familial cancers. The Unit is ideally placed, because of its strong links with the Joint Department of Physics and large prostate cancer referral practice, to continue its national role in developing and assessing the use of conformal and intensity modulated radiotherapy in localised prostate cancer. The new impetus for clinical trials given by the development of the National Cancer Research Institute's Study Groups (Prostate Cancer Chair: D Dearnaley, Renal Cancer Chair: M Gore, Testis Cancer Chair: R Huddart) and National Cancer Research Network brings the responsibility for developing a portfolio of national trials for these urological cancers. The Active Surveillance Programme led by Dr C Parker will give new insights into disease behaviour and correlating predictive factors including tissue hypoxia and proteomics with disease progression and lead to opportunities for novel interventions. New targets will be evaluated in Phase I and II studies in collaboration with Dr de Bono.

TESTICULAR TUMOURS

Many patients referred to the Unit take part in prospective randomised trials co-ordinated by the MRC/EORTC. Major studies completed in 2003 include an assessment of intensive induction chemotherapy schedule CBOP-BEP for men with poor prognosis metastatic germ cell tumours. 5-year survivorship of 88% has been seen which compares very favourably with standard chemotherapy schedules (Christian et al, J Clin Oncol 21.871.2003). Further analysis of patient cohorts who have undergone prolonged follow up has identified cardiovascular disease to be a long-term complication of testicular cancer treatment emphasising the need to minimise therapy in good risk patients (Huddart et al, J Clin Oncol. 21.1513.2003). In the laboratory Janet Shipley's team have identified the over-expressed sequences of genes from chromosome 12p which are candidate genes for the development of testicular cancer (Rodriquez et al, Oncogene 22. 1880. 2003).

Projects in progress or recently completed

• Adjuvant Radiotherapy Treatment of Stage I Seminoma (MRC TE18)
• A Phase II Trial of C-BOP/BEP Intensive Induction Chemotherapy for Intermediate and Poor Prognosis Metastatic Germ Cell Tumours (EORTC 30948)
• Testicular Tumour Late Effects Study Comparison of Radiotherapy and Single Agent Carboplatin in Stage I Seminoma (MRC TE19)
• The Evaluation of Risk Adopted Strategy for the Salvage of Relapsed/Refractory Germ Cell Tumour Stage I Testicular Tumour - CT Scan Frequency (MRC TE08)
• Phase II Study of TIP Chemotherapy in Relapsed Germ Cell Tumours High Dose Salvage Chemotherapy for Germ Cell Tumours (IT94)
• The Role of Surgery in Primary Treatment and Salvage Therapy of Germ Cell Tumours [Treatment Development]
• Familial Predisposition to Germ Cell Tumours
• A Randomised Prospective Double-blind Placebo Controlled Trial of Oral Prophylactic Levofloxacin following Chemotherapy for Lymphoma and Solid Tumours - The Significant Trial
• MRC TER2 Risk of Testis Cancer in the Families of Patients with Bilateral Germ Cell Malignancy
• EORTC 30983 - Taxol-BEP versus BEP in Intermediate Prognosis Germ Cell Tumours
• A Phase I Dose Finding Study (OX-BOP-BEP)
• PET Scanning in Patients with Stage I Non-seminomatous Germ Cell Tumours
• Phase II study of Glivec in Refractory Germ Cell Tumours, 'STIGER' Study
• HERV K Antibody Study
• Prospective analysis of the sensitivity of MRI scanning in the diagnosis of testicular germ cell tumours
• cKIT mutations in bilateral testicular germ cell tumours
• Risk factors of testicular cancer in patients with testicular cancer and their relatives

PROSTATE CANCER

Localised Disease
A programme of active surveillance (lead Dr C Parker) has rapidly recruited patients and has generated considerable interest and support both from within our Cancer Network and nationally. Opportunities to develop 'tertiary' prevention strategies will be explored. Clinical studies of the use of MRI in the development of new radiotherapy strategies has been supported by a Department of Health New and Emerging Applications of Technology (NEAT) grant. Localisation studies using ultrasound and implantable gold grain seeds are underway to improve the accuracy of radiotherapy using conformal or intensity modulated radiotherapy techniques. The Phase III trial of high dose hypofractionated radiotherapy testing the hypothesis that prostate cancer may have a low alpha-beta ratio is underway and has been supported by a Department of Health grant to the Prostate Cancer Collaborate to develop into a multicentre trial.

Metastatic Disease
Studies continue into the use of second- and third-line treatment approaches using hormones, chemotherapy, bisphosphonate drugs, novel agents such as the endothelin antagonist Atrasentan and bispecific antibody omnitarg as well as high dose isotope therapy in a compendium of national, institutional and commercially supported studies. Publication of the MRC PR05 study has documented the potential role of using the biphosphonate Clodronate as an adjuvant in metastatic disease which may prolong both disease free and overall survival (Dearnaley et al, JNCI 17.1300.2003).

Cancer Genetics and Laboratory Programme
UK studies into the genetic predisposition of prostate cancer, undertaken in collaboration with Cancer Research UK and the British Prostate Group, involve over 200 collaborating centres nationwide. The studies have expanded internationally. We lead a consortium (ACTANE) involved in the analysis of DNA samples from prostate cancer families in the UK (Anglo), Canada, Texas, Australia, Norway and European Union to find high-risk genes. We have confirmed that 2% of men with early onset prostate cancer harbour germ line mutations in the BRCA2 gene (Edwards et al Am.J. Hum.Genet 72(1).1.2003) but failed to show any relationship between leptin receptor polymorphisms and risk of young onset prostate cancer (Kote Jarai et al, BJU Int 92.109.2003). Epidemiological studies have started to try to identify interactions of genetic make up and environment. New techniques processing prostatectomy and transrectal guided biopsies are being developed to construct tissue microarrays. These will be used to assess putative markers of prostate cancer behaviour.

Projects in progress or recently completed

• Prospective Randomised Trial of Dose Escalation using Radical Conformal Radiotherapy for Localised Prostate Cancer
  following Neoadjuvant Androgen Deprivation
• Randomised Trial of High Dose Therapy in Localised Cancer of the Prostate using Conformal Radiotherapy Techniques (MRC
  RT01 Trial)
• Phase II Study of Stilboestrol 3mg/day in Hormone Refractory Prostate Cancer [Treatment Development]
• MRC Randomised Trial of Oral Sodium Clodronate in Patients with Locally Advanced Prostatic Adenocarcinoma (PR04)
• MRC Randomised Trial of Adjuvant Sodium Clodronate in Patients Commencing or Responding to Hormone Therapy for Metastatic Prostatic Adenocarcinoma (PR05)
• A Multicentre, Double-blind, Randomised, Placebo-controlled, Phase III Study to Determine if Strontium-89 Chloride Can Delay
• Pain Due to Bone Metastases in Pain-free Prostate Cancer Patients with Biochemical Evidence (Rising PSA Levels) of Escape from Hormonal Control
• Genetic Predisposition of Prostate Cancer
• Gene Environment Interactions in Prostate Cancer
• A Randomised Trial of Hormone Therapy Plus Radical Radiotherapy versus Hormone Therapy Alone in Non-Metastatic Prostate Cancer (MRC PR07)
• Characterisation of Human Prostate Cancer - Phenotypic/Genotypic Analysis
• Pilot Screening Study for Familial Prostate Cancer
• Psychosocial Impact of Pilot Screening Study
  Pelvic IMRT for Prostate Cancer
• Time Course of Recovery of Serum Testosterone following Neoadjuvant LHRH Analogue Administration and Radical Radiotherapy
• Long Term Effects of Neoadjuvant LHRH Analogue Administration and Radical Radiotherapy on Male Hormonal Profile
• Evaluation of the Precision of Digitally Reconstructed Radiographs (DRRs) Compared to Simulation Films to Determine Set-up Errors
• RE 186 HEDP Treatment of Prostate Cancer Bone Metastases
• A Study to Assess the Safety and Effectiveness of Atrasentan in Men with Metastatic Prostate Cancer
• A Study to Assess the Safety and Effectiveness of Atrasentan in Men with Non-metastatic Prostate Cancer
• A Study of the Clinical Value of the Flare Phenomenon on Bone Scan in Patients with Prostate Cancer Being Treated with Hormone Therapy
• A Phase III Randomised Trial Comparing Intermittent Versus Continuous Androgen Suppression for Patients with Prostate-specific-antigen Progression in the Clinical Absence of Distant Metastases following Radiotherapy in Prostate Cancer (Intercontinental)
• Extension Study to Determine the Safety of Atrasentan in Men With Hormone Refractory Prostate Cancer
• A Study of Tumour Micro Environment in Localised Prostate Cancer Managed by Surveillance
• Tissue Collection at Prostate Biopsy
• Oxygenation of the Prostate Gland
• Tissue Collection at Radical Prostatectomy
• Active Surveillance of Early Prostate Cancer
• Treatment Patterns for Metastatic Hormone Refractory Prostate Cancer
• Hypofractionated Radiotherapy for Prostate Cancer
• Prostate Markers for Radiotherapy Treatment Verification
• Markers of Tumour Hypoxia
• Information needs of men with prostate cancer and their family/carers
• Correlation of dynamic contrast enhanced MRI findings with histological specimens in patients undergoing radical prostatectomy
• Comparison between CT and distortion corrected MRI for prostate cancer radiotherapy planning
• Assessment of ferumoxtran lymph node visulatisation in prostate radiotherapy planning
• Phase II study of pertruzamab in patients with hormone refractory prostate cancer
• A study of the accuracy of prostate gland localisation with the BAT-Sxi ultrasound compared to CT
• Assessing the quality of life of patients with prostate cancer, EORTC

CLINICAL RESEARCH PROJECTS
Most clinical radiotherapy research is described under the individual Clinical Units in the Radiotherapy, Therapeutics, Breast and Haemato-oncology themes. We include here a description of the major research programme into novel techniques of conformal radiotherapy and intensity modulation (which are carried out jointly with the Department of Physics and are supported by a programme grant from Cancer Research UK). The more precise delivery of radiotherapy permits studies either to reduce radiation side-effects, or dose escalation to increase tumour control.