Identification of Highly Radiosensitive Patients May Lead to Side Effect-free Personalized Radiotherapy

An international group of scientists has taken the first step on the road to targeting radiotherapy dosage to individual patients by means of their genetic characteristics, a radiation oncologist told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the 15th congress of the European CanCer Organization and the 34th congress of the European Society for Medical Oncology, 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 personalized 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 characterization 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 tumor 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.

The mean radiation dose to the tumor was 45.3 ± 18.3 Gy (range 8 – 66), delivered in a mean of 21.5 ± 10.5 fractions (range 1 – 33), in a mean overall treatment time of 31.4 ± 17.6 days (range 1 – 57). The mean follow-up time after radiotherapy was 1658 ± 1048 days (range 84 – 3752).

“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 specialized 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.

Scientists already know that different types of tumors respond differently to radiotherapy; highly radiosensitive cancer cells such as leukemia 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 tumors, react differently will enable doctors in the future to target doses even more carefully, taking into account not just the radiosensitivity of the tumor 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 personalized treatment will be a major advance, allowing us to minimize both radiotherapy doses and unpleasant side effects, while treating the tumor 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 tumors.”

For more information

• Abstract no: 2007, Radiotherapy and Radiobiology session, Thursday 10.45 hrs CEST (Hall 15.3)
• Genetic Pathways for the Prediction of the Effects of Ionising Radiation: Low Dose Radiosensitivity and Risk to Normal Tissue after Radiotherapy
• GENEtic pathways for the Prediction of the effect of Irradiation-European normal an tumour tissue bank and data base

Anemic Patients With Myelodysplastic Syndromes Gain Long-Term Benefits From Erythropoietin and Myeloid Growth Factor Hormones

Myelodysplastic Syndromes (MDS), a group of blood disorders that can lead to acute myeloid leukemia (AML) in some patients, often cause severe anemia (when the body lacks a sufficient number of functional red blood cells). While certain treatments can help manage the symptoms of anemia, some studies have suggested that they may lead to complications.

Now a new study demonstrates that MDS patients with anemia may benefit from treatment with an erythropoietin (EPO)-based regimen plus supportive care without added complications as compared with those receiving supportive care alone. The study will appear in the September 17 issue of Blood, the official journal of the American Society of Hematology.

The phase III prospective, randomized trial, conducted by research teams of the Eastern Cooperative Oncology Group, was designed to evaluate the efficacy and safety of EPO with or without myeloid growth factor treatment (G-CSF, or granulocyte colony-stimulating factor) and supportive care (SC) with red blood cell transfusions for patients with early-stage MDS (n=53), in comparison to supportive care alone (n=57).

For the study, the researchers followed MDS treatment and dosing guidelines recommended by the National Comprehensive Cancer Network, which include managing anemia with erythropoiesis-stimulating agents (ESAs) such as EPO. EPO is a drug that imitates the action of the hormone erythropoietin, which stimulates the body to produce more red blood cells. Generally, therapy with G-CSF interacts with EPO treatment synergistically to improve erythroid (red blood cell) responses, especially in MDS patients that do not respond to EPO alone.

"EPO is a recommended treatment for MDS, but the combination with G-CSF and supportive care required comparative studies in this patient population," according to lead study author Peter Greenberg, MD, Professor of Medicine, Stanford University Cancer Center. "Our goal was to manage anemia while not increasing the risk of transformation to leukemia, and we undertook this study to understand if this combination might be successfully utilized in these patients."

The results of the study proved successful for this group of patients with lower-risk MDS and anemia. After the first course of therapy, 36 percent of patients in the EPO arm responded to treatment, compared with only 9.6 percent in the SC alone arm. After subsequent courses, 47 percent responded in the EPO arm. Researchers then followed both patient groups for a median of 5.8 years to determine their long-term response to treatment. Responders to EPO experienced increased survival in comparison to the non-responders (5.5 vs. 2.3 years) and significantly improved physical, emotional, and functional well-being, reduced fatigue, and improved overall quality of life.

The research team otherwise found no statistically significant differences in overall survival of patients between the EPO and SC arms (3.1 vs. 2.6 years) or the incidence of transformation to AML (7.5 vs. 10.5 percent of patients, respectively), suggesting long-term safety of the EPO treatment regimen.

The study results also indicated that the combination of EPO plus G-CSF was beneficial for patients who either did not respond initially to EPO or who experienced a delayed response. Furthermore, higher doses of EPO seemed to prove valuable for a proportion of patients who initially failed to respond. Importantly, the outcomes suggested long-term tolerance to the treatment combination, with a low overall incidence of adverse events. Specifically, the researchers found no significant treatment-related increase in incidence of either cardiovascular or thrombotic (clotting) events or transformation to AML in the patients who received EPO alone or with G-CSF, as compared with those in the SC arm.

Recently, the FDA has issued alerts regarding the use of ESAs, noting increased mortality, possible tumor promotion, and thromboembolic events that have been observed in some studies of non-MDS patients receiving ESAs. However, other studies of patients with solid tumors receiving chemotherapy did not demonstrate an adverse effect of ESAs on survival.

"We believe the data suggest that the negative effects of cytokines, like ESAs, demonstrated in some studies of other diseases may relate to biologic and clinical features or the specific treatments associated with the differing disorders studied," said Dr. Greenberg. "Findings from this study demonstrate the relative safety and efficacy of EPO plus G-CSF for treating anemic lower-risk MDS patients and may be considered as part of future treatment recommendations for the use of this class of therapies."

For Aditional Information

• Treatment of myelodysplastic syndromes patients with erythropoietin
  with or without granulocyte colony-stimulating factor: results of a
  prospective randomized phase III trial by the Eastern Cooperative
  Oncology Group (E1996), Blood First Edition Paper, prepublished online
  June 29, 2009
• American Society of Hematology/American Society of Clinical Oncology
  2007 Clinical Practice Guideline Update on the Use of Epoetin and
  Darbepoetin
• ASH Model Policy on Indications for ESA Treatment for Patients with MDS