Bone Toxicity following Pelvic Radiotherapy: understanding, predicting and preventing radiotherapy related insufficiency fractures

Context and aims and objectives of the project

Radiotherapy is used to treat about 30,000 people each year in the UK with cancers of the prostate, womb, cervix, bladder or lower bowel. Radiotherapy to the pelvis can cause long term damage in patients after their treatment. For example, cracks or breaks (fractures) may develop in the pelvic bones after treatment (radiotherapy related insufficiency fractures or "RIFFs"). This damage can cause pain, problems with moving and affect quality of life. We know that giving greater amounts of radiotherapy and having chemotherapy in addition to radiotherapy is likely to increase the risk of these RIFFs occurring. It is likely that fractures are also more common if a patient already has osteoporosis (thinning of the bone or reduced bone density) and/or a hormone deficiency although the studies looking at this are not consistent. Currently we do not know how much the radiotherapy treatment is to blame for the fractures, we don't know if we can predict which patients are likely to develop RIFFs or if there is anything that can be done to prevent the damage occurring during radiotherapy treatment. There have been no studies performed to address this.
As the type of cancer treatment given cannot be changed, we want to see if we can develop a Musculoskeletal Health Package (MHP- i.e. a package of care that can improve muscle and bone strength and function) to reduce the numbers of these fractures. This will include the following (1) screening for osteoporosis with a DXA scan to measure bone density; we can then use this, along with other risk factors to calculate a fracture risk - this is called a FRAX score (it is a risk calculator for fractures associated with osteoporosis and we do not know if it also works for patients at risk of RIFFs; this is something we are going to test), (2) checking vitamin D and looking at calcium levels in the diet, both of which are important for bone health (3) correcting any hormone deficiency if possible (4) using a bisphosphonate (a drug used to prevent bone weakness and fractures in osteoporosis) if risk of fracture is high according to our fracture prediction (5) a prehabilitation exercise program, designed as part of the Greater Manchester prehab4cancer programme, including bespoke exercise delivered by experts.
As there are a number of unanswered questions and there have been no previous studies to look at this, the first aim of this project is to perform a feasibility trial in women having pelvic radiotherapy; to understand whether a trial of the MHP is something that is feasible, that patients will want to take part in, not drop out of and find tolerable. We can also look at how much the intervention would cost in relation to improvements in quality of life.

The potential applications and benefits of the proposed research.

If the study demonstrates that the MHP is a feasible package for patients then it will lead to a larger trial to determine whether it is effective at preventing RIFFs. This will have a big impact on patient care, in terms of reduced pain and anxiety, increased mobility and quality of life after pelvic radiotherapy. The feasibility trial will be done in women who have womb or cervix cancer, and so we would need to see if the same results were seen, for example in men with prostate cancer having radiotherapy or even for patients having radiotherapy at other sites, like chest radiotherapy for breast cancer
During this feasibility trial we will also collect blood samples and other results to see if we can find any risk factors that will predict the development of RIFFs and help us to understand the mechanisms underlying the fractures, so we can target potential treatments at the right patients, personalising care and also potentially identify targets for more research and new drug development in the future.

Radiotherapy Related Insufficiency Fractures (RRIFs) are a common consequence of pelvic radiotherapy. Despite advances in radiotherapy techniques, the prevalence of these fractures is not reducing and they lead to pain, reduced mobility and anxiety. There have been no prospective, interventional or quality of life studies related to management of RIFFs. The pathogenesis of radiotherapy related bone toxicity is not well understood.

The aims of this project are (i) to address the currently unmet and large clinical need for evidence based management of RIFFs
(ii) to better understand the mechanisms underlying RIFFs, define predictive factors for their development and identify patients who are most likely to benefit from treatment.

These aims will be addressed with 3 work packages (WP 1,2,3). The objective of WP 1 is to deliver a randomised controlled clinical trial to determine the feasibility, acceptability and cost effectiveness of a "musculoskeletal health package intervention (including assessment and management of bone density and osteoporotic fracture risk, addressing known risk factors for poor bone health and a prehabilitation package of bespoke exercise provided by the GM prehab4cancer programme) in women undergoing pelvic radiotherapy and inform power calculations and an economic model for a definitive UK multicentre trial. WP1 will also allow prospective data collection on incidence of RRIFs.

WP2 will utilise blood samples taken at baseline and radiological imaging from patients in the WP1 trial to investigate potential biomarkers for the development of RIFFs, and includes innovative MS-SWATH proteomic analysis and radiomic techniques.

WP3 is designed to deepen understanding of the mechanisms of RRIFs with a longitudinal assessment of bone turnover using ELISA based proteomics during pelvic radiotherapy to determine whether bone resorption is increased initially, thus providing a potential target for anti-resorptive therapy.

Who might benefit from this research and how will they benefit?
Patients. Those randomised to the musculoskeletal health package (MHP) arm will have an assessment of osteoporotic fracture risk and appropriate management of this. They will also have the opportunity to participate in a prehabilitation exercise programme. At the end of the study, or if any fractures (osteoporotic or radiotherapy related) develop in the observational pathway (Ob) arm, fracture risk will be assessed and the patient will be treated and followed up appropriately within a metabolic bone clinic if required.
Patients, Employers and Societal benefit. The RCT in work package 1 is a feasibility study performed with the intention to power a larger UK multicentre study and therefore more patients around the UK will benefit from inclusion in this. It is well recognised that bisphosphonate therapy is cost effective for prevention of osteoporotic fractures (NICE TA 464); if bisphosphonates and/or the MHP are demonstrated to also be effective in preventing radiotherapy related insufficiency fractures (RRIF) this has direct implications for (i) improved patient quality of life, reduced anxiety, reduced hospital visits and pelvic imaging and increased well-being (ii) reduced hospital visits and improved ability to work, therefore of benefit to employers and (iii) cost effectiveness; therefore of benefit to society- the health economic modelling within this study will provide evidence base for exploring this. The findings of this research are potentially of benefit across all patients receiving radiotherapy and therefore the benefit potential widens.
Public Policy and Commissioning - influencing cultural change. NHS England Long Term Plan priorities include encouraging a culture shift in cancer care; with the focus on cancer care as a long term condition using personalised medicine and stratified follow up. The research described here aligns with these ambitions by defining pathways of care determined by risk of toxicities and targeted management and starts to provide an evidence base for their implementation, with the potential for commissioning of services and transforming aftercare. The findings from the project will be presented to the Commissioning Managers from the 10 Greater Manchester CCGs and from Eastern Cheshire, with specialist commissioning colleagues at their monthly meeting. The NHS England Long Term Plan also involves implementing an innovative quality of life metric from 2019 (Patient Reported Outcome Measures, PROMs) to track and respond to the long term impact of cancer; the intention being to show the importance of quality of life outcomes and encouraging a greater focus on enabling people living with and beyond cancer to live as well as possible. The focus in this study on developing ePROMs for pelvic radiotherapy in relation to bone toxicity and also as an evaluation tool for assessing the acceptability of novel care pathways will inform this body of work and potentially impact and improve on national QOL metrics in the future, particularly the electronic format, aligning with another NHS England priority to maximise digital potential.
Academic Stakeholders. This research will increase the research output of the Christie Living Beyond Cancer Science Centre, to the benefit of LWBC academics in Greater Manchester, supporting the LWBC theme for the BRC-2 accreditation in 2022. It will be shared in the NCRI repository of LWBC research and presented at international conferences; increasing the academic credibility of this research, benefiting UK academics and those further afield seeking research support in this area. It aligns with the recently granted RadNet funding for radiation research unit at the MCRC in Manchester and therefore this project and the academics involved will benefit, in the field of radiotherapy related research locally and further afield through sharing of results, ideas and collaboration