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For other articles and previous issues click here. January 10, 2005 Enhancing
Whole Brain Radiation Therapy Efaproxiral is one agent researchers are investigating as a way to enhance radiation therapy in cancer patients with brain metastases. The spread of cancer to the brain is the most feared complication of systemic cancer. The incidence of brain metastases is rising with improved survival of cancer patients; 150,000 to 200,000 cancer patients develop brain metastases each year. Lung and breast cancer are two common sources of brain metastases, but it also occurs in patients with skin (melanoma), kidney, and colon cancer. As tumor cells multiply within the brain, they can press against, irritate, and/or destroy normal brain tissue. Symptoms associated with brain metastases include headaches, seizures, speech problems, weakness, poor vision, pain or numbness, problems moving, paralysis, nausea, or vomiting. Brain metastases can also cause problems with memory, reading, and talking. Not everyone with brain metastases gets every symptom, and roughly one-third of patients have no symptoms at all. Physicians diagnose and evaluate brain metastases with a combination of procedures, including MRI, CT, and biopsy. They need to determine the type of primary cancer and extent of its spread to begin treatment. Unfortunately, brain metastases have proven difficult to treat. Surgery is an option if the patient has only one tumor that can be easily reached, but the vast majority of patients with brain metastases have multiple lesions. Blood-Brain Barrier Since the 1950s, whole brain radiation therapy (WBRT) has been the standard treatment for patients with brain metastases. However, the effect of radiation therapy has also been limited because cancer cells are hypoxic (have low oxygen). Researchers are finding, however, that they can increase the effectiveness of WBRT when administered with oxygen and the drug efaproxiral, a radiosensitizer. Radiation therapy tends to provide better anticancer responses in tissue containing sufficient amounts of oxygen, explains John H. Suh, MD, director of the Gamma Knife Center and radiation oncologist at the Brain Tumor Institute at the Cleveland Clinic Foundation. Efaproxiral appears to aid in the delivery of oxygen from the blood to hypoxic cells, making them more sensitive to radiation therapy, he says. Efaproxiral aids the release of oxygen from hemoglobin, the oxygen-carrying protein contained within red blood cells, and increases the oxygen level in tumors. Efaproxiral, which has been in development since the mid-1990s, has not been approved by the FDA. The experimental drug is being evaluated in clinical trials worldwide. Different Approach Suh reported on the phase 3 clinical trial of the synthetic small molecule at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO) in Atlanta last October. Efaproxiral is being developed by Allis Therapeutics Inc. of Westminster, Colo., under the brand name Efaproxyn. Suh also spoke about efaproxiral as an adjunct to WBRT for patients with brain metastases at the European Society for Medical Oncology in Vienna in October 2004 and the 22nd Annual Chemotherapy Foundation Symposium in New York City in November 2004. The phase 3 study was called REACH (Radiation Enhancing Allosteric Compounds of Hypoxic Brain Metastases) and was conducted from February 2000 to August 2002. Researchers followed patients at 82 sites in 12 countries. The study was a randomized, open-label, phase 3 clinical trial designed to demonstrate the safety and efficacy of efaproxiral in treating patients with brain metastases and whose performance status was good, Suh says. Patients with radiosensitive histologies such as small-cell lung cancer, germ cell tumors, or lymphoma were excluded. Patients were allowed to have had brain surgery as long as measurable lesions remained, Suh says. The study enrolled 538 patients with brain metastases and compared the safety and efficacy of efaproxiral plus WBRT and supplemental oxygen vs. WBRT and supplemental oxygen alone. All patients were treated with oxygen and WBRT; 271 also received intravenous efaproxiral prior to WBRT. “It is given through a central venous access device 30 minutes before whole brain radiation therapy,” Suh says. Some patients already have such access from treatment of their primary cancer. The trial’s primary goal was survival, Suh says. Secondary goals of the study were response rate, cause of death, quality of life, and time to tumor progression. Breast Cancer Benefit “Our findings confirm an improvement in survival after accounting for baseline prognostic factors for patients with primary breast cancer who received Efaproxyn and WBRT with supplemental oxygen over those who received WBRT with supplemental oxygen only,” Suh says. The median survival for all patients increased from 4.4 months to 5.4 months when given WBRT and oxygen and efaproxiral. The median survival improved from 4.67 months to 8.67 months for breast cancer patients when given WBRT, oxygen, and efaproxiral. The researchers calculated that the increases in median survival with efaproxiral translated into a reduction in the risk of death of 13% for all patients treated with efaproxiral and 18% for non–small-cell lung cancer and breast cancer patients treated with efaproxiral. Further analysis of the outcomes of patients with breast cancer showed that 17% of those who received efaproxiral lived two years or more compared with none of the patients who underwent WBRT with oxygen. Breast cancer, the second most common cause of brain metastases after lung cancer, accounts for 14% to 20% of the total incidence of brain metastases. Patients in the phase 3 REACH study were given 10 treatments of WBRT over a two-week period. Normally, it takes approximately 10 minutes to deliver WBRT to a patient. The addition of efaproxiral increases the time the patient remains in the clinic, Suh says. Manageable Side Effects Roughly 18% of patients in the REACH study had grade 3 or higher adverse reactions to the drug. “That was acceptable, especially when compared to other chemotherapy agents,” Suh says. Certain drugs are known to interact with the drug’s metabolism, and for the current study, they can be reduced or withheld, Suh notes. Pulse oximeters were used to measure the percentage of the patient’s hemoglobin saturated with oxygen before, during, and after treatment. If after treatment patients had low levels of oxygen, they were given supplemental oxygen for a longer time. If the resting oxygen level was greater than 90%, they were sent home. The researchers evaluated certain factors influencing long-term survival of brain metastases patients to identify the best predictors of outcomes. The factors they evaluated included the site of the primary tumor, the patient’s age, presence of extracranial metastases, control of the primary tumor, gender, presence of liver metastases, timing of the brain metastases diagnosis, the number of brain metastases, and the patient’s Karnofsky Performance Status (KPS). KPS is a standard way of measuring the ability of cancer patients to perform ordinary tasks. The KPS scores range from 0 to 100. The higher the score, the better the patient is able to carry out daily activities. Results of their analysis indicated that KPS, prior brain tumor resection (surgery), the presence of extracranial metastases, and gender were the strongest variables in predicting outcome. Moreover, their analysis affirmed the effectiveness of efaproxiral in improving survival time across a heterogeneous patient population. The researchers also found that at least three months are needed to measure the success of WBRT and efaproxiral and predict prolonged subsequent survival in brain metastases patients. Dino B. Stea, MD, PhD, chairman of radiation oncology at the Arizona Cancer Center, who also presented at ASTRO, says some patients showed improvement after one month, but their retrospective analysis of the collect REACH data did not show a clinically significant increased ability to predict patient survival. However, the results demonstrated a statistically significant improvement in response rates at three months for patients in the efaproxiral arm vs. the control arm—28% vs. 20%. And that response rate proved to be a statistically significant predictor of survival for patients in the REACH study, one of the largest ever randomized study of patients with brain metastases, Stea says. Further Research So far, there are 37 sites in the United States and Canada enrolling patients. “Our hope is to have at 80 to 100 sites throughout the world,” Suh says. He adds that the study hopes to show at least a 40% improvement in survival. Follow-up time points of three months for MRI/CT scans were incorporated into the study design because of the results of the phase 3 REACH study, Stea says. Efaproxiral was developed by researchers looking for treatment for sickle cell anemia, a hereditary blood disorder that mostly affects people of African ancestry. Red blood cells are normally disc-shaped. In people with sickle-cell anemia, red blood cells become crescent-shaped. As a result, they function abnormally and cause small blood clots. The researchers were looking for a way to shift oxygen in the abnormal cells and realized their work could have use in oncology, Suh says. Other Research Suh, whose main area of research is brain tumors, is hopeful about the benefits of efaproxiral in breast cancer patients with brain metastases. “The main reason I was drawn to this research back in 1997 was the high morbidity and mortality rate among patients with brain metastases and very few good treatment options for the majority of them,” he says. Brain metastases are not rare, he adds. “This is clearly an unmet need in oncology.” — Beth W. Orenstein of Northampton, Pa., is a contributing writer for Radiology Today. |
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