Title: Development and optimisation of a patient specific radionuclide dosimetry protocol for calculation of the radiation dose to bone marrow and normal organs in patients prior to bone marrow transplant.
Funder: Department of Health and Social Care

Abstract: Background Around 2000 patients per year need a bone marrow transplant during their treatment for blood cancers such as Leukaemia. Before a bone marrow transplant, patients must undergo chemotherapy and/or total body radiotherapy to remove their diseased bone marrow. Current treatment regimes have significant side effects. Attempts have been made to reduce the rate of relapse and side effects experienced but these have not been successful.Radionuclide therapy has the potential to replace radiotherapy and uses an injected radioisotope bound to a vector which locates to the bone marrow. Dosimetry is the method of calculating radiation dose to the bone marrow, which is affected by the bone marrow cellularity. Cellularity is the percentage of red marrow in the bone marrow, which is patient specific. This is currently calculated by visual interpretation of histological slides, which has known inter and intra-operator variability. Current dosimetry models also assume homogeneous bone marrow which is not clinically accurate, and increases the inaccuracy. At present treatment is based on patient weight, as it is not possible to treat by targeted radiation dose to the bone marrow.AimThe aim of this project is to develop and optimise a dosimetry protocol to take into account the cellularity and homogeneity of bone marrow. Methods The study will use retrospective patient datasets from several clinical trials. Each dataset includes a bone marrow sample, imaging data and patient outcome. The bone marrow samples will be scanned using a microCT scanner. Phase 1A method will be developed to automatically calculate bone marrow cellularity and homogeneity from microCT scans. Cellularity and homogeneity will be calculated for the patient samples.Phase 2 The current dosimetry model will be optimised to include cellularity and homogeneity of the bone marrow and produce patient specific values for the radiation dose received by the bone marrow. A protocol to allow others to calculate bone marrow dosimetry in the same way will be produced.Phase 3A retrospective analysis of the absorbed dose to bone marrow in comparison to patient outcome and side effects will be carried out to validate the protocol.Timelines for delivery 2019 October: Start PhD and start developing and validating model to calculate cellularity and homogeneity2020 June: Complete validation of cellularity method December: Complete validation of homogeneity method2021 April: Start developing dosimetry model2022 October: Start retrospective analysis of patient data2023 April: Complete retrospective analysis of patient data and start writing thesis September: Finish PhDAnticipated impact and dissemination It is anticipated that the models developed will lead to treatment by targeted absorbed dose to the bone marrow which should: Improve patient prognosis Reduce side effects of treatment, improving quality of life and reducing long term costs to the NHS. Allow radioimmunotherapy to be used with groups of patients who undergo bone marrow transplant for other conditions. The research will be disseminated through: Open access journal publications Presentations at scientific conferences and NHS user groups Participation in events for the general public Plain English blog posts for charity website

Lay abstract: Background to the research Around 2000 patients per year need a bone marrow transplant as part of their treatment for blood cancers such as Leukaemia. At Great Ormond Street Hospital, the one year survival rate for patients who have a bone marrow transplant as part of their treatment for blood cancer is 79%.Before a bone marrow transplant, patients must have their unhealthy bone marrow eliminated from the body by a treatment programme so that they can receive healthy donor bone marrow. The treatment programme uses medicines and radiation using high energy x-rays. If a patient receives x-ray treatment, they receive a known radiation dose to the bone marrow. However, many other organs also receive a radiation dose and this causes significant side effects for the patient, which may last for the rest of their lifeRadioimmunotherapy is a new technique which could replace high energy x-rays. It uses a radioactive medicine which can be injected into the patient and goes to the bone marrow. Currently it is possible to check that other organs in the body will not receive too much radiation but it is not possible to accurately calculate the radiation dose to the bone marrow. Developing a method to accurately calculate the radiation dose to bone marrow would allow clinicians to treat patients with a personalised dose to give patients the best outcome possible and reduce side effects, improving their quality of life.Aim(s) of the research My research aims to develop a method to accurately calculate the radiation dose to the bone marrow. I will develop my method using existing patient bone marrow samples and test it against patient outcome results. I will publish a protocol to allow other hospitals to use the method. Design and methods usedI will develop my method to calculate the radiation dose to the bone marrow using bone marrow biopsy samples scanned using a microCT scanner, which is a new technique that can provide clear 3D images of very small samples. I will develop an automatic computer-based method which can outline the different parts of the bone marrow and calculate what percentage of the volume is each type of tissue. These percentages will be used to produce patient-specific values for the radiation dose received by the bone marrow from radiation in the body. I will test these results against patient outcome after their treatment. I will publish the protocol to allow other hospitals to use it with their patients. I will use bone marrow samples from patients on previous clinical trials. This means patient outcome data has already been collected and no patients will need to undergo any additional procedures.Patient and Public involvementDuring the development of the project, I have presented my project to the Young Person's Advisory Group at Great Ormond Street Children's Hospital, where they reviewed the planned research and provided feedback, as well as advice on the plain English summary. I will return to present to the group the results of my project and to discuss the direction of future work to ensure the experiments I have planned are acceptable. I will ask them for advice on how to explain my project to children and adults.Dissemination I will inform other researchers, clinical staff members, patients and the public by: Publishing papers in scientific journals Presenting at international scientific conferences and NHS clinical meetings Presenting at science events for the general public Participating in charity events Blogging in plain English

Research activity codes: 6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE