NEUTRON RADIOTHERAPY FOR HIGH GRADE GLIOMAS: THE SEARCH FOR THE ELUSIVE THERAPEUTIC WINDOW

High grade gliomas of the brain are an intriguing but frustrating tumor system for the radiation oncologist. These tumors tend to be deeply infiltrating and because of proximity to critical areas oft he brain, total surgical extripation is exceedingly rare. As noted by Kolker et al. (8), postoperative photon radiation has been shown to improve survival provided that doses approaching the tolerance of normal brain tissues are given. Nevertheless, tumor regrowth almost invariably occurs and causes the patient’s ultimate demise. Since distant metastases are rare, complete eradication of the residual local tumor could well lead to greatly improved survival. The problem is how to accomplish this without unacceptable damage to the normal brain tissue. At one time, fast neutron radiotherapy was thought by many to have the potential for revolutionizing the treatment of this disease. Early reports from the University of Washington ( 10, 14) and the Hammersmith ( 1,2) neutron facilities showed tumor eradication in the majority of neutron patients who went to autopsy but considerable white matter damage and demyelinization were also noted in the normal brain tissue. The patients exhibited no improvement in survival compared to historical photon controls at the respective institutions. Subsequent surgical attempts to remove the post-treatment necrotic tissue did not yield increased survival or improved quality of life. These early trials were conducted prior to the routine use of CT scans for tumor localization, and the entire brain was irradiated with neutrons. A logical next step was to reduce the overa. volume of the brain receiving fast neutron radiotherapy. This was done in the context of a Radiation Therapy Oncology Group (RTOG) randomized trial (RTOG 76-l 1) (5). Patients in this study received 50 Gy whole brain photon irradiation, and then were randomized to either a photon boost or a neutron boost to the primary tumor volume as determined on contrast-enhanced CT scans. The neutron doses were adjusted for each treatment facility according to a relative biological equivalence (RBE) factor determined from radiobiological data. The neutron dose was made equivalent (according to the best information available at that time) to the 15 Gy given in the photon boost arm with the actual neutron doses ranging from 4.5-4.8 Gy,,. This study documented the prognostic importance of the new classification schema for gliomas proposed by Nelson et al. (12). In the RTOG 76-l 1 study, patients with glioblastoma multiforme (GBM) had a median survival of 8.5 months on the photon boost arm and 9.6 months on the neutron boost arm, whereas patients with atypical anaplastic astrocytomas (AAF) had a median survival of 26.3 months on the photon boost arm but only 15.8 months on the neutron boost arm. Although disconcerting, there were only 17 patients with AAF tumors treated on this study, and so the difference in median survivals was not statistically significant. A total of 24 patients went to autopsy-12 on the photon boost arm and 12 on the neutron boost arm. All 12 patients treated with the photon boost showed proliferating, viable tumor masses while 9/ 12 patients treated with the neutron boost exhibited no viable tumor on the autopsy specimens. The concern was that late radiation effects were the cause of the reduced survival of the AAF patients treated with the neutron boost, but this could not be either proven or disproven from the data. Another phase III trial was conducted by Duncan et al. (3) at Edinburgh. This study did not use the Nelson schema (12) but rather was open to patients with grades 3 and 4 astrocytomas using the older Kernohan grading schema (7). The data analysis was not segregated by histology, and median survival was 8 months for the photon group and 4 months for the group treated with a combination of neutrons and photons (mixed beam). Autopsies were performed on four mixed beam patients and one photon patient; all showed evidence of frank tumor progression and none showed any significant deleterious side effects caused by treatment.