Clinical Projects

Chairman: Professor Alan Horwich

Most clinical radiotherapy research is described under the individual clinical units in the Radiotherapy and Cancer Therapeutic themes. The focus of this report is the research programme into novel techniques of conformal radiotherapy and intensity modulation (carried out jointly with the Joint Department of Physics and 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. The programme was reviewed at a site visit during 2003, and scored as 'Forefront' indicating that both previous research, and future proposals were regarded as internationally competitive. During the year, Michael Brada was promoted to title of Professor of Clinical Oncology. The department is well-equipped to continue research on technical advances in radiotherapy, with installation of a CT simulator, and approval of a linear accelerator replacement programme, which will include cone-beam CT verification on the treatment couches.

Present laboratory research work is focused on the biology of normal tissue reactions to radiotherapy. Cancer patients differ widely in their tolerance of radiation therapy in respect of radiation damage to normal tissues with a small minority of patients suffering a significant degree of damage. The management of these patients is clearly suboptimal and, moreover, it is their risk of treatment complications that limits the dose of radiotherapy for the whole patient group. Some of this variation in response is genetically determined and therefore potentially detectable by laboratory tests. One of the major aims of our study is to develop such tests and to evaluate them in a clinical setting.

Relevance to NHS Research and Development Programme

Technologies to support conformal radiotherapy are now available for purchase by NHS Trusts. It is important to define the indications and benefits of more sophisticated and resource-intensive techniques, and to help to disseminate methods that bring patient benefit as rapidly as possible.

CONFORMAL RADIOTHERAPY

Optimising radiotherapy involves many components, ranging from the use of new imaging techniques to define tumour volumes and assess tumour movement in multifraction treatment, to the evaluation of new technologies available for delivery of irregularly shaped or intensity modified X-ray beams. The endpoints of these studies address both tumour control and the risk of treatment toxicities. Clinical studies analyse the impact of dose and volume changes on the probability of specific toxicities and of tumour control. These will affect the optimum treatment prescription for any individual case. The major projects include:

Conformal Radiotherapy of Prostate Cancer

• In 1995, we initiated a prospective randomised trial in patients with localised prostate cancer treating all patients with neoadjuvant hormone therapy prior to radiotherapy, comparing a dose of 74Gy in 37 fractions with the conventional dose of 64Gy in 32 fractions. Following our studies, the trial was adopted by the MRC Radiotherapy Working Party as a simple dose comparison national trial now involving 15 radiotherapy centres. The trial includes quality of life and health economic assessments and there is a national quality assurance programme coordinated by The Institute/Royal Marsden. The trial has now completed recruitment at just over 800 patients. Current work involves a detailed analysis of conformal radiotherapy methodology to optimise techniques, development of intensity modulated treatments for prostate, pelvis, thorax and head and neck tumours, and adaptation of MRI and PET/SPECT for radiotherapy planning

Randomised Pilot Study of High Dose Hypofractionated Confomal Radiotherapy in Prostate Cancer

• Based on evidence that the radiation dose-response curve for prostatic cancer in linear quadratic with a low alpha/beta ratio it is rational to assess treatments based on large radiation fraction size. This trial will investigate the feasibility of studying conformally delivered large fractions for early prostate cancer, and has potential for improvements in efficacy, efficiency and patient convenience

Intensity-modulated Radiotherapy

• This novel technique permits a concave border in the high dose distribution envelope, and is being evaluated in prostate cancer to treat the primary with pelvic lymph nodes, and in head and neck cancer, to reduce the side effect of xerostomia from parotid irradiation

Phase I dose escalation study of IMRT in locally advanced cancer of the thyroid, larynx and hypopharynx

Dr Guerrero-Urbano has undertaken an MD project to evaluate IMRT applied to head and neck cancer (HNC). The application of IMRT in HNC is to reduce dose to sensitive normal doses of radiation to be delivered leading to higher cure rates. A study of inverse planning techniques is underway to minimise the radiation dose to the contralateral parotid gland and other critical structures such as the spinal cord. Studies of parotid gland NTCP (normal tissue complication probability) and TCP (tumour control probability) modelling will be performed. The project involves assisting with an international, multicentre clinical trial (PI Dr C Nutting) randomising patients between conventional radiotherapy and IMRT in patients with HNC at high risk of radiation-induced xerostomia due to irradiation of the majority of both parotid gland. Primary endpoint is grade 2 or more xerostomia at 1 year. Subsidiary aims include quantitative measurement of saliva production, QoL, patterns of relapse, intra and inter clinician variability in target definition and correlation of acute and late side effects with radiation dose. A dose escalation study of IMRT in laryngeal, hypopharyngeal and thyroid cancer, where the target volume surrounds the spinal cord will be undertaken. The primary endpoint is treatment related toxicity. Nine patients have been entered into the study. Phantom dosimetric studies showed that treatment delivery is within 0.2% of calculated dose distributions. Planning study for IMRT of other relevant head and neck cancer sites (HNC of unknown primary, middle ear, ethmoid sinus) will be undertaken.

Phase II study of high activity radioactive treatment for skeletal metastases from carcinoma of the prostate using Re-186HEDP and peripheral blood stem cell support

• This project was based around Phase I/II studies assessing tolerance and response to high activity Rhenium-186 with peripheral blood stem cell support (PBSCS) in patients with progressive hormone refractory prostate cancer metastatic to bone. The particular advantage of Rhenium-186 in this setting is its relatively short half-life. The Phase I trial involved dose escalation of rhenium-186, first without, and then with PBSCs. The Phase I trial with PBSC included 25 patients who received activities from 2500 to 5000 MBq. The dose limiting toxicity was grade 3 thrombocytopenia, lasting 8 and 9 days in 2 of the 6 patients at 5000MBqs. PSA falls by at least 50% were seen in 5 of the 25 patients. A Phase II trial has commenced and 20 patients out of a planned 47 have now received activities of 5000MBq of Rhenium-186HEDP. Associated projects included developing a prognostic nomogram for use in metastatic hormone refractory prostate cancer and an analysis of healthcare costs in the last year of life of patients with metastatic prostate cancer

Stereotactic Radiotherapy in collaboration with the Joint Department of Physics

• The Unit has implemented the full technique of fractionated conformal stereotactic radiotherapy. Studies of the effectiveness of this approach are underway in benign brain tumours including skull base meningiomas, pituitary adenomas, craniopharyngiomas and paediatric low grade gliomas. The current results show excellent tumour control and low toxicity although longer follow-up is required to confirm this together with reduction in late side effects of treatment. Further developments currently under test include evaluation of more complex means of delivery of radiation including the use of IMRT and QA

Lung Conformal Radiotherapy and IMRT

• Dr Christian investigated improvement of radiotherapy delivery for lung cancer, and included theoretical studies of sophisticated 3D planning techniques, functional imaging for target definition and strategies to compensate for tumour movements due to respiration, as an MD project. Studies have been completed of inverse planning to design radiotherapy beam arrangements in 10 patients with unresectable locally advanced lung cancer. These techniques defined the optimal beam arrangements to minimise the radiation dose to critical structures such as the lungs. Beam arrangements studied have included coplanar and non-coplanar beam. These data were presented in part at ESTRO 2002 and were submitted to UKCRO 2003. IMRT is also under evaluation. The Active Breathing Control Device (ABCD) is under investigation in clinical trial. A further trial assessing the use of SPECT lung perfusion scans in radiotherapy planning
• The Unit commenced studies of optimisation of lung radiotherapy using a newly developed inverse planning software (autoplan). Conformal multiple beam RT and IMRT will be implemented in the radical RT of lung cancer and this will be combined with the technique of active breathing control (ABC) currently under evaluation

Breast Radiotherapy Dosimetry

• This prospective randomised trial of custom-made tissue compensators versus standard tissue compensators in patients requiring breast radiotherapy after local excision of early stage breast cancer has achieved its target of 300 patients. This initiative involves a simple technique for improving breast radiation dosimetry of a test dose of radiotherapy delivered to the breast via an open tangential field and designing a 3D tissue compensator to minimise dose inhomogeneity. Patient self-assessments of quality of life and breast pain have been collected in conjunction with annual breast photographs
• The Royal Marsden Radiotherapy Fractionation Trial (1986-1994) forms the basis of the UK Standardisation of Breast Radiotherapy (START) Trial, which evaluates the safety and efficacy of radiotherapy fraction sizes greater than 2Gy. This multicentre trial was launched in January 1999 and currently has 35 centres taking part. The trial closed to recruitment in October 2002 having achieved its target accrual of 4000 patients. The trial will complete annual assessments on all patients for a minimum of 5 years. There are also associated studies of quality of life, photographic assessments, blood sampling and family history questionnaires

Modulation of Radiotherapy Complications

• Identifying genetic factors regulating normal tissue responses and modulation of tissue damage are the focus of these studies. In the clinic, we have completed accrual into an open Phase II study of hyperbaric oxygen in patients with chronic arm lymphoedema, a double blind placebo controlled randomised Phase II trial of high dose alpha tocopherol and oxpentifylline in patients with chronic arm lymphoedema and radiation fibrosis, and an open Phase II study of alpha tocopherol and oxypentifylline in patients with pelvic radiation fibrosis

OTHER CLINICAL PROJECTS

Breast

• Double blind, placebo-controlled, randomised Phase II trial of IH636 grape seed proanthocyanidin extract (GPSE) in patients with adverse effects of high dose breast radiotherapy
• This trial is testing the effects of GSPE in 72 patients who have suffered hardening of the breast due to radiotherapy normal tissue damage. Accrual has now been completed with 67 volunteers randomised into this Phase II trial. All follow up will be completed by the end of 2004 

Gastrointestinal

• Once Weekly Radiotherapy for Patients with Locally Advanced or Recurrent Rectal Cancer
  Investigation of the Role of MRI in the Staging, Radiotherapy Planning, Response, and Late Effects of Combined Chemo-radiotherapy for Carcinoma of the Anus

Gynaecology

• MRC-ASTEC- A Study of Treatment of Endometrial Cancer - a Randomised Trial of Lymphadenectomy and of Adjuvant External Beam Radiotherapy in the Treatment of Endometrial Cancer 

Head and neck

• Randomised trial of parotid-sparing IMRT (PARSPORT) in patients with head and neck cancer
• Assessment of treatment accuracy for head and neck radiotherapy using electronic portal imaging
• Study of MRI/CT co-registration in radiotherapy planning of tumours close to the base of skull
• Parotid-sparing IMRT planning study for oropharyngeal tumours
• The role of 192-Ir afterloading combined with flap cover for salvage of recurrent inoperable cervical metastases
• Outcome of 496 patients with T1/T2 larynx cancer treated with hypofractionated radical radiotherapy
• Outcome of patients with stage I-IV tonsillar cancers treated with surgery and post operative radiotherapy or radical radiotherapy
• Assessment of PET-CT as compared to CT for target volume definition in planning head and neck radiotherapy
• Analysis of hypoxia in patients with head and neck cancer: FDG-PET, DCE-MRI and immunohistological correlation
• In vivo trafficking of semi-mature dendritic cells after intratumoural injection in patients receiving chemoradiotherapy for head and neck cancer
• Acoustic, fluoroscopic and videostroboscopic analysis of the tracheoesophageal voice in patients receiving radical radiotherapy for laryngeal cancer

Lung

• Supportive Treatment in Non-small Cell Lung Cancer (NSCLC) (MRC Trial LU17)

Neuro-Oncology

• Stereotactic Radiotherapy of Brain Tumours - Recurrent Glioma, Solitary Metastases, other Non-glial Tumours, AVMs
  Determinants of Somnolence in Patients with High and Low Grade Glioma Undergoing Cranial Irradiation

Thyroid

• In Vivo Dosimetry of Radioiodine Assessed by PET or SPECT Imaging in Patients with Metastatic Differentiated Thyroid Cancer