Radiotherapy combinations

Programme stream(s): Treatment
Programme session type(s): Specialist session

Chair: Maria Hawkins, CRUK MRC Oxford Institute for Radiation Oncology, UK
Speaker: Alan Melcher, The Institute of Cancer Research, UK
Speaker: Kaye Williams, The University of Manchester, UK
Speaker: Susan Short, University of Leeds, UK

14:00-16:00

Room: M1

There is an unmet need for rational approaches to drugradiotherapy combinations on the basis of our molecular understanding of radiobiology. There are several agents in development and testing that target different biological effects of radiation (DNA damage repair inhibitors, metabolic inhibitors, IGF signal transduction, immune modulators). Understanding tumour specific effects and how normal tissues are react are both key for preclinical and clinical work. The paradigm shift that radiation has more than a cytotoxic effect and causes immunogenic cell death of cancer cells, modulates antigen presentation by cancer cells, and alters the microenvironment within the irradiated field has gained traction in the last years. Understanding how, when and which combination would benefit specific tumour situations is still under evaluation. An area of increasing importance will be the development of suitable biomarkers that will be able to reliably assess the effect on target, immune effector stimulation for example. Such profile of biomarkers will aid in searching for an optimal combination of radiotherapy and novel agents and will allow patient selection and response prediction.

Tumour microenvironment and radiation - friend or foe?
Speaker: Kaye Williams
Affiliation: University of Manchester

Abstract:

The tumour microenvironment is complex and heterogeneous in terms of cellular composition, pathophysiology and structure. It is also dynamic, changing in response to physical and chemical stimuli, including therapy. Gaining a greater understanding of how microenvironmental components within a tumour change in response to therapy can give rise to key therapeutic opportunities. A classical example here is that tumours reoxygenate during fractionated radiotherapy, increasing the proportion of the tumour readily killed by radiation treatment. For a molecular targeted therapy example, vascular endothelial cells activate signalling pathways making them more sensitive to small molecule inhibitors of the vascular endothelial growth factor receptor.  An overriding pathophysiological condition in tumours likely to impact on all aspects of the microenvironment is hypoxia. From a radiation perspective, hypoxia directly causes tumour cell radioresistance but will further influence overall response as hypoxia mediated changes in protein expression influence complex interactions between tumour and host cells within the microenvironment. This “foe” can be targeted in many ways. Of interest is whether we are coincidentally manipulating other aspects of the tumour microenvironment towards a more opportunistic state for additional therapies, and if so, which ones.

Intra-operative Electron beam radiotherapy for advanced and recurrent abdominopelvic malignancies in the UK: Development, implementation, and medium term results
Speaker: Alan Melcher
Affiliation: Institute of Cancer Research

Abstract:

Intra-operative electron beam radiotherapy (IOERT) is an intensive form of radiotherapy delivered to a targeted zone during surgery. IOERT is most applied for advanced or recurrent malignancies with a high rate of local control failure and positive or close margins at surgery and has become incorporated into national guidelines in North America and some EU countries. To date this modality has not been developed or studied in the UK within an NHS setting. Here we present the challenges in the development and implementation of the first UK IOERT unit and describe the safety and early results from its delivery in the setting of a challenging group of advanced or recurrent abdomino-pelvic malignancies.

DNA damage repair inhibitors and radiation- are normal tissues spared?
Speaker: Susan Short
Affiliation: University of Leeds

Abstract:

DNA repair inhibitors – are normal tissues spared?New classes of DNA repair inhibitors are entering clinical studies with the promise of significant enhancement of delivered dose. Highly conformal radiotherapy permits normal tissue and organ at risk sparing to high dose treatments providing spatial specificity, however this is not absolute as surrounding tissue is often exposed to low doses, sometimes to relatively large volumes. In view of the fact that some repair inhibitors may result in enhancement ratios of 4-5 It is therefore important to understand the effect of repair inhibitors on normal tissue. This is generally less well described than the effects on tumour; the relevant target cell population(s) are not well defined and the relationship between DNA damage, repair and expression of toxicity at organ level is complex. There are also intriguing data suggesting that some repair inhibitors, including PARP inhibitors may spare normal tissues in some circumstances although this is tissue and damage specific. Equally, the effects of repair protein deficiency in knockout models such as ATM deficient mice have suggested radio-protection of some cell populations, including neurons, but it is not clear whether pharmacologic inhibition has the same effect. These findings highlight the importance of developing pre-clinical models to explore effects on normal tissue as well as careful design of clinical studies to address short and long-term toxicities.