No abstract

ABSTRACT. The purpose of this study was to assess the potential of boron neutron capture therapy (BNCT), with a 6-h infusion of the boron carrier L-boronophenylalanine as a fructose preparation (BPA-f), as first-line radiotherapy for newly diagnosed glioblastoma multiforme (GBM). Patient survival data from a Phase II study using BNCT were compared with retrospective data from the two arms of a Phase III study using conventional radiotherapy (RT) in the reference arm and using RT plus concomitant and adjuvant medication with temozolomide (TMZ) in the experimental arm, and were also compared with small subgroups of these patients for whom the methylation status of the MGMT (O 6 -methylguanine-DNA methyltransferase) DNA repair gene was known. Differences in the baseline characteristics, salvage therapy after recurrence and levels of severe adverse events were also considered. The results indicate that BNCT offers a treatment that is at least as effective as conventional RT alone. For patients with an unmethylated MGMT DNA repair gene, a possible clinical advantage of BNCT over RT/ TMZ was suggested. BNCT is a single-day treatment, which is of convenience to patients, with mild side effects, which would offer an initial 6 weeks of good-quality life during the time when patients would otherwise be undergoing daily treatments with RT and TMZ. It is suggested that the use of BNCT with a 6-h infusion of BPA-f should be explored in a stratified randomised Phase II trial in which patients with the unmethylated MGMT DNA repair gene are offered BNCT in the experimental arm and RT plus TMZ in the reference arm. Boron neutron capture therapy (BNCT) is an experimental radiotherapy that, to date, has mostly been applied to treating patients with newly diagnosed glioblastoma multiforme (GBM). Several hundred GBM patients have been treated in Phase I and Phase II studies in Europe, the USA and Japan, and survival times similar to those obtained with standard radiotherapy (RT) have been reported from several of these studies [1]. No randomised trial in which BNCT is compared with standard therapies has yet been undertaken.Proper assessment of the results from these Phase II trials has been hampered by the lack of information on baseline characteristics of the patient populations, both in reports of the BNCT studies and in reports on other therapies, notably standard fractionated photon therapy (RT), to which the results from BNCT should ultimately be compared. The recursive partitioning analysis (RPA) of prognostic factors by Curran et al [2] established a method to characterise patient status prior to treatment, useful both for the planning of clinical studies and for the assessment of the significance of the results from clinical studies. The reliability and usefulness of the RPA method has been verified by Mirimanoff et al [3] by applying it to data obtained from a randomised Phase III study [4], in which RT with concomitant and adjuvant temozolomide (RT/TMZ) was offered to 287 patients with newly diagnosed GBM in the experimen...

Prolonged infusion was found to be beneficial for the efficacy of BNCT and it is suggested that 6 h infusion of BPA-f should be used in future trials of BNCT for GBM. BNCT, which is a single-day treatment with mild side effects, should be assessed in a controlled trial, as an alternative to 30 daily fractions of conventional fractionated photon therapy over a period of 6 weeks.

Objectives - To explore the use of boron neutron capture therapy (BNCT) for patients with glioblastoma multiforme (GBM), recurring after surgery and conventional radiotherapy (photon radiotherapy). Materials and Methods - Boron uptake in recurrent GBM was measured for four patients. Twelve patients were subsequently treated by BNCT with boronophenylalanine-fructose (900 mg/kg body weight), administered by intravenous infusion for 6 h. Results - Median survival time from initial diagnosis was 22.2 months. Comparison with other BNCT studies indicates a clinical advantage of the prolonged infusion. BNCT was well tolerated and quality of life remained stable until tumor progression for all 12 patients. No correlation was found between survival times and minimum tumor dose and number of radiation fields. Conclusions - Boron neutron capture therapy, with the prolonged procedure for infusion, is at least as effective as other radiation therapies for recurrent GBM and is delivered in one treatment session, with low radiation dose to the healthy brain. Survival from diagnosis compares favorably with that obtained with conventional radiotherapy plus concomitant and adjuvant temozolomide (TMZ) and survival from recurrence compares favorably with that obtained with TMZ at first relapse. The results of the present investigation are encouraging and should be confirmed in a randomized trial.

Using a novel procedure for BPA infusion, BNCT achieves local control of GBM for minimum tumor doses as low as 15 wGy, allowing treatment with very low concomitant doses to surrounding healthy tissues.