Accelerator-based boron neutron capture therapy facility at the Helsinki University Hospital

Background

Boron neutron capture therapy (BNCT) is a unique type of radiation therapy that enables biological targeting of cancer at the cellular level. BNCT has been used to treat cancer with a two-step process. First, the patient receives a tumor-seeking drug containing a non-radioactive enriched boron (¹⁰B). Secondly, the target is exposed to low energy neutrons, which are captured by the ¹⁰B atoms. Due to the higher boron carrier accumulation in tumor cells, BNCT causes large dose gradients between cancerous and normal tissue. BNCT can be used to treat tissues that have previously been irradiated with conventional radiotherapy, and tumors that are located next to sensitive organs, like the eyes, the brain stem or the spinal cord [1].

Boron neutron capture therapy (BNCT)

BNCT is based on the nuclear capture and fission reaction that occurs when ¹⁰B nuclei are irradiated with low energy neutrons. The neutron capture reaction ¹⁰B(n,α)⁷Li causes fission of the ¹⁰B atoms to α particles and ⁷Li nuclei. These high linear energy transfer (high-LET) particles travel short distances (<10 µm) in tissue, producing damage to DNA within the ¹⁰B containing cells [2,3]. Since BNCT is a high-LET radiotherapy modality, it is often delivered in a single treatment session or in two sessions [3,4].

BNCT was initially evaluated clinically in the 1950s, and since then significant progress has been made through a wide range of clinical and non-clinical research efforts. Over 1,500 patients have been treated with BNCT globally so far, with a variety of diseases including glioblastoma multiforme [5], meningioma, head and neck cancer [6,7], lung cancer, breast cancer, hepatocellular carcinoma, sarcoma, melanoma, and a few other malignancies [8]. Approximately half of the treated patients had brain cancer, and one third had head and neck cancer. Despite the potential, BNCT has not become a standard method for radiotherapy yet [8]. Until recently, the conduct of clinical BNCT studies required use of a modified nuclear reactor. In the past, more than 10 reactors were used for clinical BNCT worldwide, but there are currently only one reactor in Taiwan that treat patients [9]. For this reason, an emerging trend is to consider an accelerator-based neutron system for clinical BNCT [10,11]. The first clinical trials with accelerator-based BNCT have already been completed [12,13].

BNCT treatments in Finland

BNCT has been actively investigated in Finland since 1992. Research reactor FiR 1 located in Otaniemi (Espoo, Finland) was constructed as a dedicated BNCT facility [14], and the clinical trials started in May 1999 with primary glioblastoma patients [15]. Over 200 patients with malignant brain tumor or head and neck cancer were treated at the facility [1]. Boronated phenylalanine (BPA)-fructose was used as the boron carrier [16]. In case of head and neck cancer, BNCT was given twice 3 to 5 weeks apart, most typically with 2 oblique treatment fields. The total neutron irradiation time was on average about 40 min. From various clinical trials carried out at the FiR 1 reactor BNCT facility, the results indicate clinical efficacy and safety of BNCT [17–20]. In addition, the Finnish BNCT team participated in international projects where uniform practices for BNCT dosimetry were developed [21,22]. Unfortunately, FiR 1 reactor was closed in 2012 for financial reasons.

Materials and methods

Helsinki BNCT facility

Helsinki University Hospital and Neutron Therapeutics Inc. formed a joint project to install a compact accelerator-based neutron source at the Helsinki University Hospital campus area. The facility was designed and constructed under the oversight of the appropriate regulatory authorities and international recommendations [22,23].

The layout of the Helsinki BNCT facility is presented in Figure 1. The facility is connected to the other hospital buildings with a service tunnel and has 2 floors. The accelerator room, treatment room, control room, and patient preparation room are located on the ground floor, and the supporting laboratories are located on the upper floor. Since the facility is located within hospital campus area, hospital resources and infrastructure are available for patient care.

Figure 1. Upper panel: General layout of the Helsinki BNCT facility. The accelerator, neutron source system and treatment room are located at the ground floor. Laboratory rooms and office rooms are located at the upper floor where only personnel can enter. Lower panel: nuBeam compact accelerator-based neutron source system. From left to right: (A) proton accelerator, (B) proton beam optics, (C) beam shaping assembly (BSA), (D) robotic couch, and (E) rail mounted CT.

Neutron source system

The neutron source system nuBeam by Neutron Therapeutics Inc. is an accelerator-based, in-hospital neutron source to replace the previously required nuclear reactor. The system, presented in Figure 1 is composed of a single ended 2.6 MeV/30 mA electrostatic proton accelerator, a beam transport system, an on-line proton beam monitoring system, a rotating solid lithium target for neutron generation with the reaction ⁷Li(p,n)⁷Be, a beam shaping assembly (BSA) and an on-line neutron beam monitoring system. Circular beam delimiter sizes vary from 8 cm to 20 cm, with the nominal size being 14 cm in diameter.

The on-line neutron beam monitoring detectors are placed inside the BSA embedded in the beam delimiter material so that they view the epithermal beam. Treatment doses are controlled by automatically terminating irradiation based on the neutron fluence reported by the beam monitors. This provides a more direct measurement of the delivered dose than relying on calibrated proton current data.

Treatment room and patient care

The patient treatment room meets applicable standards for medical facilities, including patient monitoring and temperature, ventilation, and aseptic conditions. Since the beam is stationary, a robotic patient positioning and image-guiding system, Exacure, manufactured by BEC GmbH (Reutlingen, Germany), was installed in the treatment room. In-room imaging is performed with a rail mounted Siemens Healthineers Somatom Confidence® CT scanner.

A patient preparation room, located next to the treatment room is used for physical examination, boron infusion and blood sampling. A pneumatic transport tube is installed for a fast transport of the blood samples to the boron laboratory.

Radiation safety

The Finnish Radiation and Nuclear Safety Authority (STUK) has approved the usage of the facility at each stage of operation. To minimize residual activity, interior surfaces are covered with lithiated or boronated plastic that absorb efficiently neutrons. Walls are built of heavy concrete to absorb secondary gamma radiation. Treatment room ventilation is designed to remove activated argon (⁴¹Ar) from the room air. A continuous-action gamma dose rate monitor is installed in the treatment room and, a red light outside of the room indicates when the residual dose rate is high. Typically, the cooling time after a beam operation lasts only for a few minutes.

For radiation safety, the accelerator room and the treatment room have been classified as controlled areas, the control room and the patient preparation room as supervised areas, and the personnel working in the facility is considered as Class A radiation workers.

Dosimetry

No uniform international dosimetry guidance exists for BNCT. The European project for a Code of Practice for BNCT dosimetry and International Atomic Energy Agency (IAEA) has published recommendations for BNCT dosimetry and treatments [22–24].

Dosimetry at the Helsinki BNCT facility

Based on the recommendations, Helsinki BNCT facility uses the neutron activation method for neutron flux dosimetry and the paired-ionization chamber method for neutron and gamma radiation measurements. The measurements are performed in air within a cylindrical PMMA phantom of 20 cm diameter and in a large water phantom (PTW MP3-PL Hi-Tech 3 D Water Phantom, Freiburg, Germany). In addition, end-to-end tests will be performed in a small cubic 20 cm wide water phantom to enable 3D measurements of all dose components and imaging of the phantom during system commissioning.

Since methods to determine the tumor ¹⁰B content directly are currently unavailable for clinical use [25], tumor boron content is estimated from the blood boron concentration, and tissue-to-blood concentration ratios are based on the recommended values from biodistribution studies [3]. ¹⁸F labeled BPA will be available at the Helsinki University Hospital allowing making macroscopic estimates of tumor boron content with a PET scanner.

Activation foil gamma spectrometry

Neutron activation is a widely used method for the neutron fluence rate determination. At the Helsinki BNCT facility, neutron beam characterization and daily quality assurance is performed with diluted Al-Au and Al-Mn (1% weight Au/Mn) activation foils and wires Al-Mn (2.6% weight Mn), obtained from Goodfellow Cambridge (Huntington, UK).

Activity of the foils or wires is measured with a high-purity gamma spectrometer ORTEC HPGe Gamma-Ray Detector (Atlanta, USA) located at the BNCT facility. It has an integrated Cryo-cooling System, DSPEC-50 multi-channel analyzer, and an analysis software LVis provided by ORTEC. The gamma energy range is set from 40 keV to 2,000 keV. Small samples are measured using a Hidex (Turku, Finland) automatic sample changer. Larger samples are measured using an opening in the top of the lead shield, and a gamma spectrometer can also be used to identify unknown activated isotopes.

Paired ionization chamber method

The paired ionization chamber method is recommended as the reference method for estimating the neutron and gamma ray dose absorbed to the reference tissue [22]. At the Helsinki BNCT facility, a methane-based tissue-equivalent (TE) gas filled A-150 plastic walled Exradin T2 chamber (Middleton, USA) is used together with an extra pure argon filled magnesium walled Exradin M2 chamber.

Blood boron concentration measurement

Blood boron concentrations are measured using inductively coupled plasma-atomic emission spectrometry (ICP-OES) [26]. An Agilent 5110 ICP-OES instrument (Santa Clara, USA) is equipped with a Meinhard-type nebulizer and a double pass glass cyclonic spray chamber. Quantification of boron was optimized using the software parameters of the instrument. A typical blood sample weight is approximately 500 mg, and the analysis is performed duplicated.

Treatment planning

Treatment planning for HUS BNCT treatments is based on full Monte Carlo (MC) simulation with material assignment deduced from DICOM (CT, MRI and PET) images of the patient. The dose engine for patient dose calculation has been developed by Neutron Therapeutics Inc. on top of the GEANT4 MC toolkit [27]. The dose engine is used through the RayStation treatment planning system (Stockholm, Sweden) [28] that is used to define the target volumes, organs at risk, and their tissue compositions. In addition, Raystation is used for reporting of the doses.

Results

The Finnish Radiation and Nuclear Safety Authority (STUK) has inspected and approved the usage of the facility for neutron beam commissioning. Residual radioactivity inside the treatment room has found to be low, and it is possible to enter the room shortly after the end of neutron irradiation. The gamma spectrometer system for neutron activation analysis and the boron laboratory equipment for blood boron concentration measurements have been calibrated and are ready for usage.

The neutron beam energy spectrum in air has been characterized, and the beam profile and the depth dose curves have been measured in phantoms using both neutron activation analysis and the paired ionization chamber technique. The properties of the beam are in line with modeling and fulfill the recommendations of the TECDOC [23]. The neutron beam was designed similar to the FiR 1 reactor-based neutron source beam aiming at high epithermal neutron flux, and low fast neutron, thermal neutron, and gamma dose levels [29]. The beam parameters are presented in Table 1.

Table 1. BNCT beam parameters for nominal beam size.

	Φepi(cm^2/s)	Ḋf/Φepi(Gy*cm^2)	Φthermal/Φepi	Ḋγ/Φepi(Gy*cm^2)	J/Φ
IAEA TECDOC recommendations	≥1 × 10^9	≤2 × 10^−13	≤0.05	≤2 × 10^−13	≥0.7
nuBeam (MCNP6) 14 cm beam, 30 mA, 100% neutron yield	1.5 × 10^9	1.9 × 10^−13	0.012	4.0 × 10^−14	0.73
FiR 1 (measured) [29]	1.1 × 10^9	2.3 × 10^−13	0.0673	5.0 × 10^−14	0.77 (estimated in [29])

IAEA TECDOC recommended beam parameters [23], nuBeam (MCNP6 model), and FiR 1 (measured): Epithermal neutron flux (Φ_epi), the fast neutron dose contamination (Ḋ_f/Φ_epi)_, the ratio between the thermal flux and the epithermal flux (Φ_thermal/Φ_epi), the gamma dose contamination (Ḋ_γ/Φ_epi), and the ratio between the total neutron current and the total neutron flux (J/ϕ).

Discussion

The accelerator-based BNCT facility is under commissioning at the Helsinki University Hospital. The Finnish Radiation and Nuclear Safety Authority (STUK) will review the final test results, and a license for the facility clinical use will be applied prior to treating patients. A comprehensive verification and validation testing of the system will be conducted prior to its use in the clinical studies.

We aim to treat first patients who have inoperable, locally recurrent head and neck cancer at the HUS BNCT facility, because good responses of locally recurred head and neck cancers were achieved in our earlier studies at the FiR 1 reactor-based BNCT facility [18,30], and responses of head and neck cancer are generally easier to evaluate with imaging than those of glioblastomas. This approach may also allow us to compare the results obtained with accelerator-based BNCT to those we obtained at the FiR 1 reactor-based BNCT facility [4,18], although comparisons with historical controls need to be viewed with caution. In the first study protocol, we intend to administer BPA-F in an identical manner as at the FiR 1 facility, and treat the patients with an identical irradiation protocol. Ideally, up to 4 treatment sessions can be performed daily at the facility.

An interim safety analysis and an early efficacy analysis will be carried out after the first patients, with an aim to obtain a clinical CE mark for the system. Once the safety of accelerator-based BNCT with BPA as the boron carrier has been confirmed, we aim to expand the study patient populations beyond head and neck cancer to other solid tumors, such as gliomas, meningioma, melanoma, and sarcoma, and to treat patients from Finland and abroad. We also plan to devote a part of the beam time for preclinical radiation research, particularly for testing of novel boron carrier compounds.

Disclosure statement

P. Eide, H. Koivunoro, N. Smick and T. Smick are employed by Neutron Therapeutics Inc. H. Joensuu is the Chairman of the Scientific Advisory Board of Neutron Therapeutics Inc. No further potential conflict of interest was reported by the author(s).