Hanna Koivunoro

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.

Boron neutron capture therapy (BNCT) in Finland: Technological and physical prospects after 20 years of experiences

Boron Neutron Capture Therapy (BNCT) is a binary radiotherapy method developed to treat patients with certain malignant tumours. To date, over 300 treatments have been carried out at the Finnish BNCT facility in various on-going and past clinical trials. In this technical review, we discuss our research work in the field of medical physics to form the groundwork for the Finnish BNCT patient treatments, as well as the possibilities to further develop and optimize the method in the future. Accordingly, the following aspects are described: neutron sources, beam dosimetry, treatment planning, boron imaging and determination, and finally the possibilities to detect the efficacy and effects of BNCT on patients.

Computational study of the required dimensions for standard sized phantoms in boron neutron capture therapy dosimetry

The minimum size of a water phantom used for calibration of an epithermal neutron beam of the boron neutron capture therapy (BNCT) facility at the VTT FiR 1 research reactor is studied by Monte Carlo simulations. The criteria for the size of the phantom were established relative to the neutron and photon radiation fields present at the thermal neutron fluence maximum in the central beam axis (considered as the reference point). At the reference point, for the most commonly used beam aperture size at FiR 1 (14 cm diameter), less than 1% disturbance of the neutron and gamma radiation fields in a phantom were achieved with a minimum a 30 cm x 30 cm cross section of the phantom. For the largest 20 cm diameter beam aperture size, a minimum 40 cm x 40 cm cross-section of the phantom and depth of 20 cm was required to achieve undisturbed radiation field. This size can be considered as the minimum requirement for a reference phantom for dosimetry at FiR 1. The secondary objective was to determine the phantom dimensions for full characterization of the FiR 1 beam in a rectangular water phantom. In the water scanning phantom, isodoses down to the 5% level are measured for the verifications of the beam model in the dosimetric and treatment planning calculations. The dose distribution results without effects caused by the limited phantom size were achieved for the maximum aperture diameter (20 cm) with a 56 cm x 56 cm x 28 cm rectangular phantom. A similar approach to study the required minimum dimensions of the reference and water scanning phantoms can be used for epithermal neutron beams at the other BNCT facilities.

Boron Neutron Capture Therapy in the Treatment of Recurrent Laryngeal Cancer.

PURPOSE To investigate the safety and efficacy of boron neutron capture therapy (BNCT) as a larynx-preserving treatment option for patients with recurrent laryngeal cancer. METHODS AND MATERIALS Six patients with locally recurrent squamous cell laryngeal carcinoma and 3 patients with persistent laryngeal cancer after prior treatment were treated with BNCT at the FiR1 facility (Espoo, Finland) in 2006 to 2012. The patients had received prior radiation therapy with or without concomitant chemotherapy to a cumulative median dose of 66 Gy. The median tumor diameter was 2.9 cm (range, 1.4-10.9 cm) before BNCT. Boron neutron capture therapy was offered on a compassionate basis to patients who either refused laryngectomy (n=7) or had an inoperable tumor (n=2). Boronophenylalanine-fructose (400 mg/kg) was used as the boron carrier and was infused over 2 hours intravenously before neutron irradiation. RESULTS Six patients received BNCT once and 3 twice. The estimated average gross tumor volume dose ranged from 22 to 38 Gy (W) (mean; 29 Gy [W]). Six of the 8 evaluable patients responded to BNCT; 2 achieved complete and 4 partial response. One patient died early and was not evaluable for response. Most common side effects were stomatitis, fatigue, and oral pain. No life-threatening or grade 4 toxicity was observed. The median time to progression within the target volume was 6.6 months, and the median overall survival time 13.3 months after BNCT. One patient with complete response is alive and disease-free with a functioning larynx 60 months after BNCT. CONCLUSIONS Boron neutron capture therapy given after prior external beam radiation therapy is well tolerated. Most patients responded to BNCT, but long-term survival with larynx preservation was infrequent owing to cancer progression. Selected patients with recurrent laryngeal cancer may benefit from BNCT.

Validation of dose planning calculations for boron neutron capture therapy using cylindrical and anthropomorphic phantoms

In this paper, the accuracy of dose planning calculations for boron neutron capture therapy (BNCT) of brain and head and neck cancer was studied at the FiR 1 epithermal neutron beam. A cylindrical water phantom and an anthropomorphic head phantom were applied with two beam aperture-to-surface distances (ASD). The calculations using the simulation environment for radiation application (SERA) treatment planning system were compared to neutron activation measurements with Au and Mn foils, photon dose measurements with an ionization chamber and the reference simulations with the MCNP5 code. Photon dose calculations using SERA differ from the ionization chamber measurements by 2-13% (disagreement increased along the depth in the phantom), but are in agreement with the MCNP5 calculations within 2%. The (55)Mn(n,gamma) and (197)Au(n,gamma) reaction rates calculated using SERA agree within 10% and 8%, respectively, with the measurements and within 5% with the MCNP5 calculations at depths >0.5 cm from the phantom surface. The (55)Mn(n,gamma) reaction rate represents the nitrogen and boron depth dose within 1%. Discrepancy in the SERA fast neutron dose calculation (of up to 37%) is corrected if the biased fast neutron dose calculation option is not applied. Reduced voxel cell size (<or=0.5 cm) improves the SERA calculation accuracy on the phantom surface. Despite the slight overestimation of the epithermal neutrons and underestimation of the thermal neutrons in the beam model, neutron calculation accuracy with the SERA system is sufficient for reliable BNCT treatment planning with the two studied treatment distances. The discrepancy between measured and calculated photon dose remains unsatisfactorily high for depths >6 cm from the phantom surface. Increasing discrepancy along the phantom depth is expected to be caused by the inaccurately determined effective point of the ionization chamber.

Prompt gamma and neutron detection in BNCT utilizing a CdTe detector

In this work, a novel sensor technology based on CdTe detectors was tested for prompt gamma and neutron detection using boronated targets in (epi)thermal neutron beam at FiR1 research reactor in Espoo, Finland. Dedicated neutron filter structures were omitted to enable simultaneous measurement of both gamma and neutron radiation at low reactor power (2.5 kW). Spectra were collected and analyzed in four different setups in order to study the feasibility of the detector to measure 478 keV prompt gamma photons released from the neutron capture reaction of boron-10. The detector proved to have the required sensitivity to detect and separate the signals from both boron neutron and cadmium neutron capture reactions, which makes it a promising candidate for monitoring the spatial and temporal development of in vivo boron distribution in boron neutron capture therapy.

Biokinetic analysis of tissue boron (10B) concentrations of glioma patients treated with BNCT in Finland

A total of 98 patients with glioma were treated with BPA-F-mediated boron neutron capture therapy (BNCT) in Finland from 1999 to 2011. Thirty-nine (40%) had undergone surgery for newly diagnosed glioblastoma and 59 (60%) had malignant glioma recurrence after surgery. In this study we applied a closed 3-compartment model based on dynamic (18)F-BPA-PET studies to estimate the BPA-F concentrations in the tumor and the normal brain with time. Altogether 22 patients with recurrent glioma, treated within the context of a clinical trial, were evaluated using their individual measured whole blood (10)B concentrations as an input to the model. The delivered radiation doses to tumor and the normal brain were recalculated based on the modeled (10)B concentrations in the tissues during neutron irradiation. The model predicts from -7% to +29% (average, +11%) change in the average tumor doses as compared with the previously estimated doses, and from 17% to 61% (average, 36%) higher average normal brain doses than previously estimated due to the non-constant tumor-to-blood concentration ratios and considerably higher estimated (10)B concentrations in the brain at the time of neutron irradiation.

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.

Photon iso-effective dose for cancer treatment with mixed field radiation based on dose–response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer

Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearsons correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r  >  0.87 and p-values  >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy.