On the Road to Personalizing Radiation Therapy

Developing targeted pharmacotherapies to personalize cancer care has become the mantra in oncology, and now a team of scientists from The Netherlands, Belgium, Germany, and Canada has taken the first step toward targeting radiotherapy dosages to individual patients by assessing the genetic characteristics of individuals with hypersensitivity to radiation therapy. Dirk de Ruysscher, MD, of Maastricht University Medical Center, Maastricht, The Netherlands, who presented the findings at the ECCO 15 — ESMO 34 Joint Congress, noted that his team’s work may eventually allow physicians to select optimal radiation doses for patients using a simple blood test, which would minimize, and potentially eliminate, untoward side effects from radiation therapy.

A tissue bank containing skin fibroblasts, whole blood, lymphocytes, plasma and lymphoblastoid cell lines from patients who were clinically hypersensitive to radiation was established in Europe and Canada. Patients were classified as hypersensitive if they developed CTCAE 3.0 severe acute side effects of grade 2 or higher at very low radiation doses where such side effects are unexpected; suffered from grade 3 or 4 effects lasting more than 4 weeks after the end of radiotherapy or requiring surgical intervention at any time; or had severe late side effects of grade 3 or 4 occurring or persisting more than 90 days after the end of radiotherapy. Overreacting individuals had to exhibit severe acute or late side effects after radiotherapy without concurrent chemotherapy, biologicals, targeted drugs, or radio-protectors at doses where side effects are reported to occur in less than 1 in 500 patients. The control group consisted of patients who did not exhibit abnormal reactions to radiotherapy, and this group was pulled from the GENEPI I (Genetic Pathways for the Prediction of the Effect of Irradiation I) study, which integrated biological material with patient data and treatment specifications.

Through their analysis, the scientists identified 33 hypersensitive individuals, of whom 10 were males and 23 were females. Eleven of these patients (2 males and 9 females) were found to be really hypersensitive to radiation. The patients’ mean age was 61.6 ± 8.5 years (range, 49-74 years), and there were numerous cancer types, including breast (n = 15), prostate (n = 5), cervix (n = 4), head and neck (n = 3), lymphoma (n = 3), endometrial (n = 1), lung (n = 1), and medulloblastoma (n = 1). The radiation dose was 49.3 ± 17.6 Gy (15—90), which fell within the usual parameters.

On average, patients developed severe side effects 675 ± 40.3 days (0—2705) after radiotherapy. Eight of the hypersensitive patients (28.6%) experienced severe acute side effects and the remainder had late damage. “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,” he noted.

“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 characterization of molecular pathways related to radiosensitivity,” 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 tumor control.”

Scientists already know that different tumors have different responses to radiotherapy (eg, leukemia cells are highly radiosensitive and can be destroyed by low radiation doses whereas melanomas require high doses). The finding that individuals, and not just tumors, react differently to radiation 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.

ECCO/ESMO Abstract 2007