Title: Minimising radiotherapy toxicities in soft tissue sarcoma of the extremities by developing radiotherapy planning dose-volume constraints for limb normal tissue structures
Funder: Health Education England

Abstract: Background: Soft tissue sarcomas of the extremities (STSE) are uncommon, representing 1% of cancers diagnosed in adults. Localized disease is curable, with 5-year survival rates of 50%. Radiotherapy improves local control rates, however STSE survivors often develop significant side-effects (defined as grade 2 RTOG; grade 2+), which can impact heavily on their quality-of-life. The CRUK VorteX trial, comparing standard against reduced post-operative radiotherapy target volumes, has recently reported grade 2+ toxicity rates of about 50%, including subcutaneous (47% in standard arm and 41% in the experimental arm), bone (11% versus 15%) and joint (18% for both arms) toxicities. A radiotherapy plan is calculated on a computed tomography scan, ensuring that the target volume (either the tumour or the tumour bed) receives a therapeutic radiation dose, while limiting the volume of neighbouring healthy (defined as normal tissue) tissues receiving significant doses to minimise side-effects. These radiation dose limits, called dose-volume constraints, allow clinicians to predict the likelihood of a given patient developing severe side-effects. Dose-volume constraints for STSE are currently unknown. Pre-defined dose-volume constraints for prostate and head and neck cancers have been shown to mitigate the incidence and severity (grade) of side-effects. My research hypothesis is that dose-volume constraints will allow better prediction of toxicity for STSE. Research question: Will radiation dose-volume constraints of normal tissue structures help predict the frequency and intensity of side-effects caused by radiotherapy for STSE? Objectives: The primary objective is to identify specific dose-volume constraints for anatomical regions of interest within the normal limb tissues lying outside the target volume predicting for the frequency and intensity of side-effects induced by radiotherapy for STSE. Secondary objectives are: identification of anatomical regions of interest within normal limb tissues where delivery of high dose radiotherapy may result in specific toxicities such as fibrosis and lymphoedema; quantification of differences in the frequency and intensity of side-effects between 3D-conformal radiotherapy and intensity-modulated radiotherapy (IMRT).Methods:A statistical model predicting radiotherapy side-effects will be generated using prospectively collected radiotherapy specific normal tissue dose volume histograms and patient and clinician-reported toxicity data from CRUK VorteX and IMRiS, two of the largest radiotherapy datasets for STSE. VorteX has completed accrual and outcomes presented recently, and IMRiS will have mature data for analysis in 2019. Permission has been obtained to use radiotherapy dose-volume and toxicity data. I will then test the validity of this model in an observational study, using a prospectively recruited cohort of patients with STSE. Timelines for delivery:5 years Anticipated impact and dissemination: On completion, I will describe pre-defined anatomical regions of normal tissue structures and dose-volume constraints to use in STSE radiotherapy planning. This will improve the quality of radiotherapy planning and hopefully reduce radiation dose to critical regions without compromising treatment of the tumour volume. It is anticipated this will translate into a reduced incidence of side-effects and improved limb function and quality-of-life. These recommendations will be published in the form of guidelines in a peer-reviewed journal.

Lay abstract: Limb soft-tissue sarcomas are rare cancers, which originate in the muscles, nerves, cartilage and fatty tissues. The use of radiotherapy combined with surgery to remove these tumours improves the chances of curing patients. However, this can be at the cost of experiencing long-term permanent side-effects caused by radiotherapy, such as limb swelling, scar tissue formation, joint stiffness, all of which can lead to a deterioration of limb function and have a significant impact on a patient's quality-of-life. This research study aims to predict a specific frequency and intensity of radiotherapy-related side-effects for patients with limb sarcoma. When radiotherapy is given to any tumour, the neighbouring healthy tissue will receive an incidental radiation dose. As a result, a proportion of patients may develop side-effects. A radiotherapy plan is made before treatment, to ensure that the tumour is adequately treated with radiation and also measuring the amount of radiation given to healthy tissues. Treatment planning aims to keep the dose of radiation to the healthy tissues within safe limits; this involves using dose limits called dose-volume constraints. Unlike for tumours such as prostate or head and neck cancer, these constraints have not been well defined for limb sarcoma because of the rarity of the tumour type, and the lack of previous research in this area. Robust evidence that is based on recent clinical trials collating radiotherapy planning and side effect data is necessary to predict side-effects for limb sarcoma. This research study provides a unique opportunity to analyse and evaluate the clinical and radiotherapy data from two radiotherapy clinical trials for limb sarcomas; the CRUK VorteX and the IMRiS trials. VorteX closed recruitment in 2013 and investigated whether a reduction in the volume of tissue at risk of developing local recurrence treated with post-operative radiation would improve limb function. IMRiS studied a new radiotherapy technique; intensity modulated radiotherapy (IMRT) in limb sarcomas and investigated whether a reduced dose to healthy tissues could reduce side-effects. IMRiS completed recruitment in 2017 and has maturing data which will be ready for analysis in 2019. These trials enrolled 216 and 168 patients, respectively. Presented VorteX trial results reported that there was no difference in incidence of side-effects in patients who received treatment to smaller radiation volumes compared to conventional larger volumes. The data collected in the study is therefore extremely valuable to inform the limits of dose that can be given to healthy tissue without causing significant side-effects. IMRiS provides the opportunity to research the limits of radiation in patients treated with IMRT. A statistical model will be produced from the VorteX and IMRiS datasets relating the radiotherapy dose delivered with the side-effect data. As a result, I will describe the radiation doses to healthy tissues that, when exceeded, are expected to cause side-effects. Subsequently, the model will be validated in a new cohort of patients, recruited to an observational study at The Royal Marsden and at the University College of London Hospitals. Patient data will be collected with the intention of validating the dose-volume limits. The main outcome of this research will be to define radiation dose-volume limits for the healthy tissues surrounding the tumour. Ultimately, it will result in more effective radiotherapy planning and treatment, which will hopefully reduce long-term side-effects, improve patients' limb function and quality-of-life. Upon completion of the study, a set of recommendations that doctors and radiotherapy planning staff can use to plan limb sarcoma radiotherapy will be made available and published in specialist journals and presented at national and international conferences. The results will be shared with patients and the public through communications from the patient charity, Sarcoma UK.

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS