Combining radiotherapy with chemotherapy and immunotherapy

Radiotherapy has been used for more than 100 years in cancer treatment and it remains one of the most effective ways to treat the disease, currently accounting for 40% of cancer cures. However, suggests Professor Sharma, this figure could be increased if more attention was given to combining radiotherapy with new drug treatments.

Such combinations could enhance treatment success in two ways. First, prior drug treatment could sensitise tumours to radiotherapy. For example, agents that act by damaging DNA could synergise with the DNA-damaging effects of radiation. But radiotherapy could also enhance the impact of immunotherapy, by promoting tumour antigen release and take up by immune cells, thereby boosting anti-cancer immune responses.

Part of a global suite of trials evaluating chemotherapy-radiotherapy combinations, the international multicentre FOXFIRE trial led by Professor Sharma examined use of adding radiotherapy to oxaliplatin-based chemotherapy to treat advanced metastatic colorectal cancer in the liver (the main organ affected by metastasis in colorectal cancer, and the main cause of death). Metastatic cancer can be cured by surgery, but only 20% of patients are suitable for such treatment. The addition of radiotherapy reduced the burden of liver disease and improved the control of the cancer in the liver, but unfortunately did not translate into improved overall survival compared to chemotherapy on its own [1].

Nevertheless, the studies demonstrated that large-scale combination trials could be done to test new combination therapies, and further work could identify how the biological benefits seen could be translated into improvements in survival.

Professor Sharma is also leading a second major international study, the EPOCH trial [2], which is evaluating combined use of other chemotherapies with innovative glass microspheres loaded with radioactive yttrium-90 delivered directly into patient tumours. The combination is being evaluated as a second-line treatment for patients with metastatic colorectal cancer in the liver who have progressed following first-line chemotherapy.

Until recently, limited progress had been made on clinical evaluation of radiotherapy-based combinations. Key obstacles included a poorly defined pathway for regulatory approvals and a focus in industry on individual therapeutics.

Alongside work on these major clinical trials, Professor Sharma has also been leading an international initiative to promote the development and clinical evaluation of radiotherapy-chemotherapy combinations. A Joint Working Group chaired by Professor Sharma, set up by the National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) and the Cancer Research UK Combinations Alliance, brought together representatives from academia, industry, patient groups and regulatory bodies to identify barriers to the development of radiotherapy-based combinations and how they might be overcome.

The group developed consensus statements incorporating eight recommendations covering areas such as choice of endpoints and routes to registration [3]. Its work has led to a growing portfolio of combination trials, and a greater integration in industry of radiotherapy applications in product development plans.

Looking further ahead, to exploit the potential of radiotherapy-immunotherapy combinations, Professor Sharma is going back to basics, systematically examining sequencing and dosing in pre-clinical models as a prelude to more rationally based combination strategies for use in patients. His research group's focus is on liver, bowel and lung cancers, where immunotherapies are emerging and radiotherapy stands a good chance of boosting immune responses.

1. Wasan HS et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017;18(9):1159-1171.
2. https://clinicaltrials.gov/ct2/show/NCT01483027
3. Sharma RA et al. Clinical development of new drug-radiotherapy combinations. Nat Rev Clin Oncol. 2016;13(10):627-42.