Title: Using PET Imaging to improve survival and reduce side-effects of treatment for patients with cancer
Funder: Department of Health and Social Care

Abstract: Background: Positron Emission Tomography (PET) scans show functional changes in cancer at the molecular level. PET can enable earlier and more accurate treatment monitoring than CT and MR with the potential for earlier modification of cancer treatment to minimise toxicity and optimise effectiveness, using a personalised approach. Escalation of treatment may involve more aggressive chemotherapy or boosting radiotherapy dose. New techniques using intensity modulated radiotherapy (IMRT) permit dose-painting', to areas that PET suggests may be more resistant to treatment. My proposed research: Will use PET to optimize patients' ongoing treatment based on individual response and risk to side-effects. Maximise the benefit of new radiotherapy treatments, using PET to target the right areas. Will develop quantitative techniques for PET reading to improve on the use of the naked eye. Research will focus on haematological and head and neck cancers but have wider application.Aim 1We hypothesise that PET can guide treatment to reduce toxicity and/or increase cure in trials: a) in early stage Hodgkin Lymphoma (HL) Patients will receive 3 drugs - doxorubicin, vinblastine, darcarbazine and either bleomycin [standard] or brentuximab vedotin (BV) [experimental] as the 4th drug. BV may be more effective with less toxicity. Patients with early complete metabolic response (CMR) on PET which is the primary endpoint will not receive radiotherapy [1042 patients]. b) in Follicular Lymphoma (FL) Patients with PET-CMR after induction will be randomised to receive rituximab for 2 years or no further treatment. Potential cost savings are ~50 million annually for the NHS if no further treatment is not inferior. Patients without CMR will receive treatment with rituximab and lenalidomide which may prolong progression free survival. [840 patients]. c) in patients > 60 years with HL or co-morbidities that limit standard treatment. BV and Bendamustine will be compared with standard treatment with CMR as the primary endpoint [120 patients].We will also explore whether pre-treatment PET predicts patient outcomes, to enable PET-guided treatment from the start. Baseline features including metabolic tumour volume will be tested in cohorts with HL, Diffuse large B cell lymphoma and FL. The combination of imaging and non-imaging biomarkers including gene expression profiling and circulating tumour markers will be evaluated in collaboration with the Precision Medicine for Aggressive Lymphoma Consortium. Aim 2 We hypothesise that PET can be used to response-adapt radiotherapy We will use methodology established by our group using PET-CT and currently being evaluated in PET-MR in a planned multicentre trial. Patients with head and neck cancer will be randomised to receive standard or adaptive intensity-modulated radiotherapy, boosting radiotherapy dose to areas of poor response on PET. We will evaluate PET tracers that image hypoxia with nested studies to explore observer variability in target volume delineation to derive a standard approach for PET-guided radiotherapy. We will explore practicalities of using PET with targeted radiotherapy techniques in lymphoma patients to spare normal tissues, using radiobiological modelling to estimate risk reduction.Aim 3 To evaluate techniques to improve the interpretation of PET response Semi-quantitative analysis will be tested in lymphoma datasets to determine if this reduces observer variation and provides a continuous scale with incremental value. PET has been reported to show false positive' uptake with new immunomodulatory agents effective against solid tumours. We will assess PET as an exploratory endpoint in 2 UK trials of novel agents in lymphoma to develop criteria for future response-adapted trials.Benefits include using PET-guided treatment to reduce toxicity and improve survival for patients with cancer cost savings by reducing ineffective therapy translation of new imaging guided RT techniques into clinical practice. This is timely with a 130million NHS investment in IMRT.

Lay abstract: Cancer cells are very active. They need energy and take up lots of sugar. In a PET scan, a tiny amount of radioactive sugar is injected into a vein. The sugar is taken up by cancer cells which show up on the scan. When cancer is successfully killed by treatment the PET scan becomes clear'. This usually happens before the cancer shrinks on CT and MR scans. PET scans are combined with CT scans however to give a clearer picture of exactly which body areas are affected.We aim to use PET to monitor patients' response to cancer treatment to decide which patients need more treatment and which patients need less. This will help to cure more patients with fewer side-effects.Research Plan We will test PET in clinical trials for patients with lymphoma. Trial 1: Patients with Hodgkin lymphoma will be treated with chemotherapy - doxorubicin, vinblastine, darcarbazine and either bleomycin or a new drug brentuximab vedotin (BV). Research suggests BV may be more effective and better tolerated than bleomycin, which can damage the lungs. If a PET scan after 3 months' treatment becomes clear, patients will have 3 instead of 4 months' chemotherapy and no radiotherapy. We expect using BV and PET to guide treatment will cure more patients, cause fewer side-effects and mean fewer people need radiotherapy. Trial 2: Patients with follicular lymphoma will receive chemotherapy for 4-6 months and the antibody treatment, rituximab. Current practice is for patients to continue taking rituximab as maintenance' treatment for 2 years. This aims to prolong remission (no evidence of lymphoma) but can cause side-effects such as more infections. We will do a PET scan after chemotherapy. In patients with a clear scan, half will have rituximab maintenance, half no further treatment. If rituximab makes no difference, patients with clear scans could avoid the side-effects that come with rituximab. If the scan is abnormal, patients would have either rituximab or rituximab and lenalidomide. This part of the trial will test whether giving 2 drugs makes the remission last longer. Trial 3: Patients with heart or lung disease often cannot have the usual treatment for Hodgkin lymphoma. This trial will test if BV and bendamustine can be given instead. We will use PET to see how many patients have a clear scan using this combination instead of usual treatment. In other studies, we will look at PET scans before treatment. Research suggests treatment may be less effective in patients with large amounts of cancer at the start. We will combine PET results with tests on biopsy and blood samples. This is to see if genetic changes in these samples and PET scans together can forecast better if treatment will work. We will test PET with new ways to give radiotherapy PET can identify cancerous areas that may be difficult to treat with radiotherapy. Newer radiotherapy machines can boost the radiotherapy dose to these areas. We will design a trial where half the patients with head and neck cancer will receive a boost to areas with poor response to treatment on PET scans. The other half will receive the usual radiotherapy dose. This will test whether using PET can improve cure rates. We will try out ways to reduce radiotherapy dose as well, e.g. using deep breathing techniques in patients with lymphoma. This may reduce the dose to normal breast and heart.In a small number of patients, we will test a PET tracer that measures low oxygen levels in cancers. Radiotherapy works less well with low oxygen levels. We aim to find the best way to measure this. We will improve reading of PET scans We will test if automatic methods can improve on reading the scans by eye'. We will also see if PET can be used to measure response in 2 trials of new drugs that work on the immune system. We don't know if PET will be as accurate measuring response with these drugs. Patient and Public Involvement is important to guide our research. Patients from the National Cancer Research Institute, Bloodwise and the Lymphoma Association helped design and will help manage our lymphoma trials. Patients from the Guise and Dolls support group have helped plan and will manage our radiotherapy research. Results will be presented through medical meetings, journals and websites. We will write guidelines how to use PET and radiotherapy techniques for the NHS. We will inform patients through charities and social media and share results in newspapers, on TV and radio.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS