October 2011
Cutting-Edge Radiation Treatment
New Research From the RTOG
By Beth W. Orenstein
Radiology Today
Vol. 12 No. 10 P. 14
The September issue of the International Journal of Radiation Oncology features the results of three Radiation Therapy Oncology Group (RTOG) trials. The lead authors of the trials, which involve brachytherapy for localized prostate cancer, prophylactic cranial irradiation for small-cell lung cancer, and the use of prognostic factors for treating low-grade glioma, spoke with Radiology Today about these studies and their significance.
Study Finds Brachytherapy Effective for Treating Localized Prostate Cancer
“Long-Term Results of a Phase II Trial of Ultrasound-Guided Radioactive Implantation of the Prostate for Definitive Management of Localized Adenocarcinoma of the Prostate (RTOG 98-05).” Lead author: Colleen A. F. Lawton, MD, FACR, FASTRO, a professor and program director of the department of radiation oncology at the Medical College of Wisconsin
The study was opened in 1998, Lawton says. The purpose was to look at whether seed implementation is a safe and effective treatment for localized prostate cancer when performed in the larger radiation community.
Numerous physicians at single institutions have published their results and have shown that brachytherapy is a safe and effective treatment for localized prostate cancer, Lawton explains. But often their results are not reproducible. “Very often, you’ll see a surgeon or radiation oncologist publish his/her results and then when we try to duplicate the results across the country, they never quite measure up to that single institution,” she says. “This study was an attempt to look at the results from a number of institutions and get a sense of how safe the procedure is and how effective it is.”
The study involved 27 institutions. By design, no institution could accrue more than eight patients, “because then it ends up being a single institution study,” Lawton says.
A total of 101 patients were enrolled, of which 94 were eligible. Patients included in the study had histologically confirmed, locally confined adenocarcinoma of the prostate clinical stage T1b, T1c, or T2a; no nodal or metastatic disease; a prostate-specific antigen level of less than or equal to 10 ng/mL; and a Gleason score of less than or equal to 6.
At the eight-year follow-up, the overall survival rate was 88%. At last follow-up, no patient had died of prostate cancer or related toxicities. Three patients had maximum late toxicities of grade 3, all of which were of the genital or urinary organs. No grade 4 or 5 toxicities were observed.
Physicians participating in the study had to pass an initial test to be part of the group, Lawton says. “However, it wasn’t difficult. We had them ‘pretend’ plan a patient to be sure that they could do the procedure the way we asked them to.”
The study results were encouraging, Lawton says, because they showed that the radioactive seed procedure, which has been around for a very long time and was resurrected in the 1980s, is very effective. “Our study shows that many, many institutions can do this work and do it well. That’s the message here as opposed to: ‘You need to go to X institution because they’re the only ones who do this procedure well.’”
Lawton says the research team did not look at procedure costs, but many others have done cost analyses and brachytherapy is looked at as one of the least expensive ways to treat localized prostate cancer. The study is encouraging, she says, because not only is radioactive seed implantation a less costly treatment compared with some, but it also is safe and effective and has relatively little in the way of toxicity.
“The take-home message from this turned out to be that this treatment is safe and the results are likely comparable to other institutions across the country,” she says. “Because brachytherapy is so well tolerated, it’s an excellent alternative. We can definitely throw it in the mix as equally effective and very well tolerated and then get patients to decide which treatment option they want.”
Study Finds Patients With Small-Cell Lung Cancer Should Be Treated With Prophylactic Radiation to the Brain—but Not at Higher Doses
“Primary Analysis of a Phase II Randomized Trial Radiation Therapy Oncology Group (RTOG) 0212: Impact of Different Total Doses and Schedules of Prophylactic Cranial Irradiation on Chronic Neurotoxicity and Quality of Life for Patients with Limited-Disease Small-Cell Lung Cancer.” Lead author: Aaron H. Wolfson, MD, a professor and the vice chairman of the department of radiation oncology at the University of Miami Miller School of Medicine
Patients with limited-disease small-cell lung cancer tend to be responsive to treatment, particularly to chemotherapy, but they often relapse at sites such as the brain because the chemotherapy has difficulty penetrating the blood-brain barrier, Wolfson says.
This study looked at whether small-cell lung cancer patients should be treated with prophylactic cranial irradiation and, if so, what the most effective dose was.
Wolfson says this area of research has been of interest to him since after training, when he joined the radiation oncology faculty at the University of Miami in 1989.
Back in the ’80s and ’90s, he explains, radiation oncologists were asking: “What’s the bang for the buck? By delivering prophylactic radiation to the brain, were you improving survival or were you creating significant damage to the brain? What if the cranial radiation made patients unable to concentrate, unable to think, unable to perform tasks? What are you doing?”
Those questions led him to a single institution study at the University of Miami of about 27 patients, the results of which he presented at the American Society of Therapeutic Radiation Oncology (ASTRO) annual meeting in 2000. At that time, he showed a survival advantage among the patients of doing radiation vs. no radiation.
Since then, he says, a number of prospective studies also showed a survival advantage from doing preventive brain radiation. “The survival advantage at three years was something like 5%, which was statistically significant for the size of the analysis,” Wolfson says.
At the same time Wolfson was completing his study, the European Organization for Research and Treatment of Cancer (EORTC), looking at the proper dosing for preventive brain treatments for patients with small-cell lung cancer. “They wanted to see whether giving a higher dose would increase survival more than the standard dose,” he says. The Europeans gave the higher dose in one treatment daily, while Wolfson looked at breaking it up into two doses per day.
When Wolfson went to the RTOG and asked it to take his trial, he was asked to work with the Europeans. “I contributed to the European study that was finished in 2005,” he says.
The study that is in the September International Journal of Radiology Oncology was presented at ASTRO in 2009. “And now the paper is out,” Wolfson says. It involved a total of 265 patients.
The study showed patients given a higher dose had lower survival rates. “We found there was no overall survival benefit, at least in a formal randomized prospective fashion, to the higher dose.” That’s why, he says, he believes “we shouldn’t push the dose up unless we have proof that it’s going to reap benefits.”
At the same time, he says, “We found that the standard dose is needed because it saves lives.”
It’s possible, Wolfson says, that the patients had neurological damage even before they were given the radiation treatment. “By the time they come to us and we do preventative brain treatment, which is later on, we don’t know all the damage that’s been done.”
Wolfson says the study shows that the standard treatment should be the standard of care and that more work is needed to evaluate patients neuropsychologically at the point of diagnosis.
As with most studies, Wolfson says, “With every question we answer, we raise more,” and more research is needed to explore ways to give higher doses effectively and to identify the brain effects from the disease prior to chemotherapy treatment.
Wolfson says he wouldn’t have been able to do the research he has over the years without the support of Roger Byhardt, MD, a radiation oncology professor in the department of radiation oncology at the Medical College of Wisconsin. “He’s been a mentor to a lot of radiation oncologists in the treatment of lung cancer,” Wolfson says. “He helped me see this to fruition and it became a reality.”
Study Finds European Clinical Prognostic Factors Help Choose Proper Treatment for Brain Cancer Patients
“Validation of EORTC Prognostic Factors for Adults with Low-Grade Glioma: A Report Using Intergroup 86-72-51.” Lead author: Paul D. Brown, MD, a professor in the department of radiation oncology in the Division of Radiation Oncology at The University of Texas MD Anderson Cancer Center
Two EORTC trials developed a clinical scoring system that helps physicians determine the chances that a patient with a low-grade glioma will survive. The scoring system is used to help determine which patients to enroll in which trials and the course of treatment.
“If, for example, a patient has a really good score—a good prognosis—after having undergone surgery, you may decide that you can just watch them at this point,” Brown says. However, if the patient’s score is unfavorable, “you probably want to treat with adjuvant radiation or chemotherapy after surgery.”
For this study, the researchers took the European scoring system and applied it to an Intergroup trial in which 203 patients with low-grade gliomas were randomized to moderate or higher radiotherapy doses.
Risk factors from the EORTC prognostic index, including histology, tumor size, neurologic deficit, age, and tumor crossing the midline, were analyzed for their prognostic value. The high-risk group was defined as patients with more than two risk factors. In addition, the Mini Mental Status Examination score, extent of surgical resection, and the chromosomal arms 1p and 19q were analyzed for prognostic value.
The researchers found that the low-risk group as defined by EORTC criteria had a superior progression-free survival and overall survival rate to the high-risk group. Analyzing by the EORTC risk groups, it found that the low-risk group had significantly better median overall survival (10.8 years vs. 3.9 years) and progression-free survival (6.2 years vs. 1.9 years) than the high-risk group.
For a small subset (66 patients), the researchers had some molecular data—1p19q—”but we did not work that into the scoring system due to small patient numbers such that it is entirely a clinical scoring system,” Brown notes.
Brown believes the clinical scoring system proved helpful primarily because of the influence of histology and tumor size.
Thus, Brown says, the researchers concluded that the EORTC clinical scoring system is a valid tool and still very useful in treating patients with low-grade gliomas, which, like all brain cancers, are on the rise.
However, Brown says, the EORTC does not use genetic markers, and he believes that the best scoring system for determining treatment and who is enrolled in which trials will be one that employs both clinical considerations and genetic markers.
“Genetic markers are proving to be some of the most significant prognostic factors,” he says. “Combining them is the answer. However, clinical prognostic factors still remain very statistically and clinically significant. We need to keep them in the scoring system, but adding genetic data is going to add additional prognostic criteria.”
If, for example, a patient had a small tumor and good neurological function after being completely resected, Brown says, “if you determine the patient’s score based on his clinical prognosis, he should have a good one. But if he had some worrisome genetic factors, that could help guide treatment decisions. That’s why you need both.”
— Beth W. Orenstein of Northampton, Pa., is a freelance medical writer and frequent contributor to Radiology Today.
