Leena Kankaanranta

Boron neutron capture therapy of brain tumors: clinical trials at the Finnish facility using boronophenylalanine

SummaryTwo clinical trials are currently running at the Finnish dedicated boron neutron capture therapy (BNCT) facility. Between May 1999 and December 2001, 18 patients with supratentorial glioblastoma were treated with boronophenylalanine (BPA)-based BNCT within a context of a prospective clinical trial (protocol P-01). All patients underwent prior surgery, but none had received conventional radiotherapy or cancer chemotherapy before BNCT. BPA-fructose was given as 2-h infusion at BPA-dosages ranging from 290 to 400 mg/kg prior to neutron beam irradiation, which was given as a single fraction from two fields. The average planning target volume dose ranged from 30 to 61 Gy (W), and the average normal brain dose from 3 to 6 Gy (W). The treatment was generally well tolerated, and none of the patients have died during the first months following BNCT. The estimated 1-year overall survival is 61%. In another trial (protocol P-03), three patients with recurring or progressing glioblastoma following surgery and conventional cranial radiotherapy to 50–60 Gy, were treated with BPA-based BNCT using the BPA dosage of 290 mg/kg. The average planning target dose in these patients was 25–29 Gy (W), and the average whole brain dose 2–3 Gy (W). All three patients tolerated brain reirradiation with BNCT, and none died during the first three months following BNCT. We conclude that BPA-based BNCT has been relatively well tolerated both in previously irradiated and unirradiated glioblastoma patients. Efficacy comparisons with conventional photo radiation are difficult due to patient selection and confounding factors such as other treatments given, but the results support continuation of clinical research on BPA-based BNCT.

Boron Neutron Capture Therapy in the Treatment of Locally Recurred Head-and-Neck Cancer: Final Analysis of a Phase I/II Trial

PURPOSE To investigate the efficacy and safety of boron neutron capture therapy (BNCT) in the treatment of inoperable head-and-neck cancers that recur locally after conventional photon radiation therapy. METHODS AND MATERIALS In this prospective, single-center Phase I/II study, 30 patients with inoperable, locally recurred head-and-neck cancer (29 carcinomas and 1 sarcoma) were treated with BNCT. Prior treatments consisted of surgery and conventionally fractionated photon irradiation to a cumulative dose of 50 to 98 Gy administered with or without concomitant chemotherapy. Tumor responses were assessed by use of the RECIST (Response Evaluation Criteria in Solid Tumors) and adverse effects by use of the National Cancer Institute common terminology criteria version 3.0. Intravenously administered L-boronophenylalanine-fructose (400 mg/kg) was administered as the boron carrier. Each patient was scheduled to be treated twice with BNCT. RESULTS Twenty-six patients received BNCT twice; four were treated once. Of the 29 evaluable patients, 22 (76%) responded to BNCT, 6 (21%) had tumor growth stabilization for 5.1 and 20.3 months, and 1 (3%) progressed. The median progression-free survival time was 7.5 months (95% confidence interval, 5.4-9.6 months). Two-year progression-free survival and overall survival were 20% and 30%, respectively, and 27% of the patients survived for 2 years without locoregional recurrence. The most common acute Grade 3 adverse effects were mucositis (54% of patients), oral pain (54%), and fatigue (32%). Three patients were diagnosed with osteoradionecrosis (each Grade 3) and one patient with soft-tissue necrosis (Grade 4). Late Grade 3 xerostomia was present in 3 of the 15 evaluable patients (20%). CONCLUSIONS Most patients who have inoperable, locally advanced head-and-neck carcinoma that has recurred at a previously irradiated site respond to boronophenylalanine-mediated BNCT, but cancer recurrence after BNCT remains frequent. Toxicity was acceptable. Further research on novel modifications of the method is warranted.

L-BORONOPHENYLALANINE-MEDIATED BORON NEUTRON CAPTURE THERAPY FOR MALIGNANT GLIOMA PROGRESSING AFTER EXTERNAL BEAM RADIATION THERAPY: A PHASE I STUDY

PURPOSE To investigate the safety of boronophenylalanine-mediated boron neutron capture therapy (BNCT) in the treatment of malignant gliomas that progress after surgery and conventional external beam radiation therapy. METHODS AND MATERIALS Adult patients who had histologically confirmed malignant glioma that had progressed after surgery and external beam radiotherapy were eligible for this Phase I study, provided that >6 months had elapsed from the last date of radiation therapy. The first 10 patients received a fixed dose, 290 mg/kg, of L-boronophenylalanine-fructose (L-BPA-F) as a 2-hour infusion before neutron irradiation, and the remaining patients were treated with escalating doses of L-BPA-F, either 350 mg/kg, 400 mg/kg, or 450 mg/kg, using 3 patients on each dose level. Adverse effects were assessed using National Cancer Institute Common Toxicity Criteria version 2.0. RESULTS Twenty-two patients entered the study. Twenty subjects had glioblastoma, and 2 patients had anaplastic astrocytoma, and the median cumulative dose of prior external beam radiotherapy was 59.4 Gy. The maximally tolerated L-BPA-F dose was reached at the 450 mg/kg level, where 4 of 6 patients treated had a grade 3 adverse event. Patients who were given >290 mg/kg of L-BPA-F received a higher estimated average planning target volume dose than those who received 290 mg/kg (median, 36 vs. 31 Gy [W, i.e., a weighted dose]; p = 0.018). The median survival time following BNCT was 7 months. CONCLUSIONS BNCT administered with an l-BPA-F dose of up to 400 mg/kg as a 2-hour infusion is feasible in the treatment of malignant gliomas that recur after conventional radiation therapy.

Effect of overall treatment time on local control in radical radiotherapy for squamous cell carcinoma of esophagus.

PURPOSE To analyze the effect of overall treatment time on local control in radical radiotherapy for squamous cell carcinoma of esophagus. METHODS AND MATERIALS Three hundred and fifty-three patients with inoperable esophageal cancer (tumor length < or = 10 cm in all cases) treated during 1963-1988 by radical radiotherapy alone either as continuous or split-course therapy. The overall treatment time varied from 35 to 55 days and the total dosage from 50 to 71 Gy in the continuous therapy group (n = 138), and in the split-course group (n = 215) with a planned 3-week rest interval in the middle of the treatment from 56 to 70 days and from 55 to 70 Gy, respectively. The logit method of the linear-quadratic formula for local control at 1 year was used to examine the effect of treatment time on local control. All patients were pooled to obtain a wide range of overall treatment times. RESULTS The 1-, 2-, and 5-year actuarial survival rates according to the T-stage in the continuous therapy group from the first day of the radiotherapy were: 57%, 32%, and 10% for the T1 tumors and 23%, 8%, and 5% for the T2 tumors. The corresponding figures for the split-course group were: 50%, 19%, and 4% for the T1 tumors and 17%, 6%, and 3% for the T2 tumors. The 1-year local control rate was 56% for the T1 tumors and 15% for the T2 tumors in the continuous therapy group and 48% for the T1 tumors and 10% for the T2 tumors in the split-course group. The results of the logit method did not fit well with the T1 tumors. For the T2 tumors, they showed Dprolif to be about 0.24 Gy/day for local control at 1 year. As a consequence, protraction of overall time by 1 week should be compensated by increasing the total dose by 1.8 Gy for 1 year local control. CONCLUSIONS More attention should be focused on repopulation. Shortening of overall treatment time might be beneficial for the treatment of squamous cell carcinoma of esophagus.

Boron neutron capture therapy (BNCT) followed by intensity modulated chemoradiotherapy as primary treatment of large head and neck cancer with intracranial involvement.

To the Editor, Boron neutron capture therapy (BNCT) is an effective treatment for inoperable, locally recurrent head and neck cancer, and most patients respond to BNCT despite prior irradiation with photons [1]. BNCT is based on the neutron capture reaction that occurs when non-radioactive boron is irradiated with neutrons of low energy, which results in a nuclear decay yielding densely ionizing particles that deposit most radiation effect in the tumour provided that the tumour accumulates more boron relative to normal tissues. This can be achieved using tumour-seeking boron carriers, such as L-boronophenylalanine (L-BPA) [2]. To our knowledge, only recurrent head and neck cancers have been treated with BNCT thus far [3–6]. We administered BNCT followed by chemoradiation as first-line therapy of a patient diagnosed with large, inoperable head and neck carcinoma, since the tumour was adjacent to both optic nerves making it challenging to achieve a cure at a low risk of severe organ damage with conventional radiotherapy. BNCT increases relatively little the dose to the optic nerves, since they accumulate little L-BPA. A 53-year-old woman presented with an obstructed nose and headache, and a biopsy from an intranasal mass showed poorly differentiated carcinoma. Computed tomography (CT) and MRI revealed a 7.4 6.7 4.4 cm tumour that filled the intranasal cavities and ethmoid sinuses, and grew into both orbits, intracranially, and onto both optic nerves causing exopthalmos and diplopia (Fig. 1). No distant metastases were present. The tumour accumulated 5.6 times more F-L-BPA compared to adjacent normal tissues in a PET scan. BNCT, given on March 4, 2010, consisted of 400 mg/kg of L-BPAfructose infused intravenously followed by neutron irradiation [7]. The estimated average gross tumour volume (GTV) dose was 31 Gy (W), and the average planning target volume dose was 28 Gy (W). The dose to the optic chiasm was 4 Gy (W). The tumour had decreased in size in a CT performed on March 18, and once mucositis had subsided, IMRT was administered between April 6 and May 10

1H MRS of a boron neutron capture therapy 10B-carrier, L-p-boronophenylalanine-fructose complex, BPA-F: phantom studies at 1.5 and 3.0 T.

The quantification of a BNCT 10B-carrier, L-p-boronophenylalanine-fructose complex (BPA-F), was evaluated using 1H magnetic resonance spectroscopy (1H MRS) with phantoms at 1.5 and 3.0 T. For proper quantification, relaxation times T1 and T2 are needed. While T1 is relatively easy to determine, the determination of T2 of a coupled spin system of aromatic protons of BPA is not straightforward with standard MRS sequences. In addition, an uncoupled concentration reference for aromatic protons of BPA must be used with caution. In order to determine T2, the response of an aromatic proton spin system to the MRS sequence PRESS with various echo times was calculated and the product of the response curve with exponential decay was fitted to the measured intensities. Furthermore, the response curve can be used to correct the intensities, when an uncoupled resonance is used as a concentration reference. BPA was quantified using both phantom replacement and internal water referencing methods with accuracies of +/- 5% and +/- 15%. Our phantom results suggest that in vivo studies on BPA concentration determination will be feasible.

Dose planning with comparison to in vivo dosimetry for epithermal neutron irradiation of the dog brain.

Boron neutron capture therapy (BNCT) is an experimental type of radiotherapy, presently being used to treat glioblastoma and melanoma. To improve patient safety and to determine the radiobiological characteristics of the epithermal neutron beam of Finnish BNCT facility (FiR 1) dose-response studies were carried on the brain of dogs before starting the clinical trials. A dose planning procedure was developed and uncertainties of the epithermal neutron-induced doses were estimated. The accuracy of the method of computing physical doses was assessed by comparing with in vivo dosimetry. Individual radiation dose plans were computed using magnetic resonance images of the heads of 15 Beagle dogs and the computational model of the FiR 1 epithermal neutron beam. For in vivo dosimetry, the thermal neutron fluences were measured using Mn activation foils and the gamma-ray doses with MCP-7s type thermoluminescent detectors placed both on the skin surface of the head and in the oral cavity. The degree of uncertainty of the reference doses at the thermal neutron maximum was estimated using a dose-planning program. The estimated uncertainty (+/-1 standard deviation) in the total physical reference dose was +/-8.9%. The calculated and the measured dose values agreed within the uncertainties at the point of beam entry. The conclusion is that the dose delivery to the tissue can be verified in a practical and reliable fashion by placing an activation dosimeter and a TL detector at the beam entry point on the skin surface with homogeneous tissues below. However, the point doses cannot be calculated correctly in the inhomogeneous area near air cavities of the head model with this type of dose-planning program. This calls for attention in dose planning in human clinical trials in the corresponding areas.

Epithermal Neutron Beam Interference with Cardiac Pacemakers

In this paper, a phantom study was performed to evaluate the effect of an epithermal neutron beam irradiation on the cardiac pacemaker function. Severe malfunction occurred in the pacemakers after substantially lower dose from epithermal neutron irradiation than reported in the fast neutron or photon beams at the same dose rate level. In addition the pacemakers got activated, resulting in nuclides with half-lives from 25 min to 115 d. We suggest that BNCT should be administrated only after removal of the pacemaker from the vicinity of the tumor.

Comparative study of dose calculations with SERA and JCDS treatment planning systems.

Three treatment planning systems developed for clinical boron neutron capture therapy (BNCT) use are SERA developed by INL/Montana State University, NCTPlan developed by the Harvard-MIT and the CNEA group and JAEA computational dosimetry system (JCDS) developed by Japan Atomic Energy Agency (JAEA) in Japan. Previously, performance of the SERA and NCTPlan has been compared in various studies. In this preliminary study, the dose calculations performed with SERA and JCDS systems were compared in single brain cancer patient case with the FiR 1 epithermal neutron beam. A two-field brain cancer treatment plan was performed with the both codes. The dose components to normal brain, tumor and planning target volume (PTV) were calculated and compared in case of one radiation field and combined two fields. The depth dose distributions and the maximum doses in regions of interest were compared. Calculations with the treatment planning systems for the thermal neutron induced ((10)B and nitrogen) dose components and photon dose were in good agreement. Higher discrepancy in the fast neutron dose calculations was found. In case of combined two-field treatment plan, overall discrepancy of the maximum weighted dose was approximately 3% for normal brain and PTV and approximately 4% for tumor dose.

At the Threshold of Clinical Trials

The aim of the Finnish BNCT-project is to start BNC-treatments of malignant brain tumors. The first clinical trial is planned to start in early 1999 at the treatment facility of the 250kW FiR 1 TRIGA research reactor. Excellent patient treatment facilities have been built at the reactor which is located only 5 km from the Helsinki University Central Hospital making the treatment facility very easy to reach.