Side Effects of Radiotherapy may be Reduced by Identifying Highly Radiosensitive Patients

The first step on the road to targeting radiotherapy dosage to individual patients by means of their genetic characteristics has been accomplished by an international team of scientists. This was revealed by a radiation oncologist at Europe's largest cancer congress, ECCO 15 – ESMO 34 [1], in Berlin today.

Professor Dirk de Ruysscher, from Maastricht University Medical Centre, Maastricht, The Netherlands, said that his team's work might provide the basis for personalised radiotherapy in which, with a simple blood test, doctors may be able to select the optimal radiation dose for a particular patient.

The team of scientists from The Netherlands, Belgium, Germany, and Canada studied a group of patients with hypersensitivity to radiation therapy, drawn from the largest world-wide database available – the European Union-funded Genetic pathways for the prediction of the effect of irradiation (GENEPI) study, which integrates biological material with patient data and treatment specifications. The database included information from more than 8000 European patients.

"Part of this project is the establishment of a sub-database in which very rare patient characteristics are brought together with the hypothesis that their genetic traits will enable the characterisation of molecular pathways related to radio-sensitivity," explained Professor de Ruysscher. "A major problem for radiation oncologists at present is that we are bound by the need to avoid damage to normal tissues. This means that the dose of radiation generally used is governed by the response of the most radiosensitive patients, and this may lead to many patients receiving lower than optimal doses, hence affecting the ability to deliver a higher dose that may result in better local tumour control."

A tissue bank including skin fibroblasts (the structural framework of skin cells), whole blood, lymphocytes (white blood cells involved in the immune system), plasma, and lymphoblastic (immature lymphocyte) cell lines from patients who were known to be hypersensitive to radiation was established from patients in Europe and Canada.

When compared with a control group, also drawn from the GENEPI study, the hypersensitive patients showed either severe side effects occurring at very low radiation levels, or severe side effects lasting for more than four weeks after the end of radiotherapy and/or requiring surgery, or severe late side effects occurring or persisting more than 90 days after the end of radiotherapy.

The scientists identified 33 such patients, 10 males and 23 females, of whom 11 (two males and nine females) ultimately proved to be really hypersensitive to radiation, underlining the rarity of this condition. Their mean age was 61.6  8.5 years (range 49 – 74). One patient had non-small cell lung cancer, six breast cancer, two head and neck cancer and one lymphoma. The radiation doses, the overall treatment times, and the follow-up times all fell within the usual parameters.

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"The severe side effects included acute skin reactions, extreme skin thickening or fibrosis, lung tissue inflammation and blindness due to optical nerve damage," said Professor de Ruysscher. "Although radiotherapy is a highly effective way of treating cancer, it is important that we are able to identify the patients who will react badly to it and adjust their dosage accordingly."

Radiotherapy works by causing DNA damage in cells in a particular area so that they destroy themselves. Because cancer cells reproduce more and are undifferentiated (lacking the ability to become a more specialised cell type), they are less able to repair the damage caused by radiotherapy than are differentiated, normal cells which can usually repair themselves. However, some of the normal cells surrounding the treatment site may also be damaged during radiotherapy, and it is this damage that leads to side effects.

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Scientists already know that different types of tumours respond differently to radiotherapy; highly radiosensitive cancer cells such as leukaemias can be killed by quite low radiation doses, whereas melanomas need such a high dose that it would be unsafe to use radiation therapy in this case. The finding that individuals, as well as tumours, react differently will enable doctors in the future to target doses even more carefully, taking into account not just the radiosensitivity of the tumour type but also the potential reaction of the particular patient to treatment.

"We hope that the EU will fund a successor project to elucidate genetic pathways in combination with other patient data so that we can make predictive models that can be implemented in standard clinical practice," said Professor de Ruysscher. "We believe that, if we can understand what it is going on at a molecular level, we may be able to develop a blood test that will allow us to know precisely how an individual patient will react to radiotherapy, and to target the dose accordingly. Such personalised treatment will be a major advance, allowing us to minimise both radiotherapy doses and unpleasant side effects, while treating the tumour in the most effective way possible. Perhaps even more importantly, it will enable us to give higher doses to many patients and hence improve control of their tumours."



Source-Eurekalert
RAS