Boron Neutron Capture Therapy Followed by Image-Guided Intensity-Modulated Radiotherapy for Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial.

BACKGROUND: This trial investigated the efficacy and safety of salvage boron neutron capture therapy (BNCT) combined with image-guided intensity-modulated radiotherapy (IG-IMRT) for recurrent head and neck cancer after prior radiotherapy (RT). METHODS: BNCT was administered using an intravenous boronophenylalanine-fructose complex (500 mg/kg) in a single fraction; multifractionated IG-IMRT was administered 28 days after BNCT. For BNCT, the mucosa served as the dose-limiting organ. For IG-IMRT, the clinical target volume (CTV) and the planning target volume (PTV) were generated according to the post-BNCT gross tumor volume (GTV) with chosen margins. RESULTS: This trial enrolled 14 patients, and 12 patients received combined treatment. The median BNCT average dose for the GTV was 21.6 Gy-Eq, and the median IG-IMRT dose for the PTV was 46.8 Gy/26 fractions. After a median (range) follow-up period of 11.8 (3.6 to 53.2) months, five patients had a complete response and four had a partial response. One patient had grade 4 laryngeal edema; another patient had a grade 4 hemorrhage. Most tumor progression occurred within or adjacent to the CTV. The 1-year overall survival and local progression-free survival rates were 56% and 21%, respectively. CONCLUSION: Despite the high response rate (64%) of this trial, there was a high incidence of in-field and marginal failure with this approach. Future studies combining BNCT with modalities other than radiation may be tried.

NeuTHOR Station-A Novel Integrated Platform for Monitoring BNCT Clinical Treatment, Animal and Cell Irradiation Study at THOR.

(1) Background: A well-established Boron Neutron Capture Therapy (BNCT) facility includes many essential systems, which are the epithermal neutron beam system, on-line monitoring system (OMS), QA/QC (quality assurance or quality control) system, boron concentration (BC) measurement system, and treatment planning system (TPS). Accurate data transmission, monitoring, and deposition among these systems are of vital importance before, during, and after clinical, animal, and cell BNCT irradiation. This work developed a novel integrated platform NeuTHOR Station (NeuTHORS) for BNCT at Tsing Hua Open-pool Reactor (THOR). Apart from the data of the OMS and QA/QC system, the data of BC and TPS can be loaded on NeuTHORS before BNCT clinical, animal, and cell irradiation. (2) Methods: A multi-paradigm computer programming language c# (c sharp) was used to develop the integrated platform NeuTHORS. The design of NeuTHORS is based on the standard procedures of BNCT treatment or experiment at THOR. Moreover, parallel testing with OMS-BNCT (the former OMS) and QA/QC of THOR was also performed for more than 70 times to verify the validation of NeuTHORS. (3) Results: According to the comparisons of the output, NeuTHORS and OMS-BNCT and QA/QC of THOR show very good consistency. NeuTHORS is now installed on an industrial PC (IPC) and successfully performs the monitoring of BNCT Treatment at THOR. Patients' f BC and TPS data are also input into NeuTHORS and stored on IPC through an internal network from BC measurement room and TPS physicist. Therefore, the treatment data of each patient can be instantaneously established after each BNCT treatment for further study on BNCT. NeuTHORS can also be applied on data acquisition for a BNCT-related study, especially for animal or cell irradiation experiments. (4) Conclusions: A novel integrated platform NeuTHOR Station for monitoring BNCT clinical treatment and animal and cell irradiation study has been successfully established at THOR. With this platform, BNCT radiobiology investigations will be efficiently performed and a thorough data storage and analysis system of BNCT treatments or experiments can thus be systematically built up for the further investigation of BNCT at THOR.

Advances in Boron Neutron Capture Therapy (BNCT) for Recurrent Intracranial Meningioma.

Meningiomas are the most frequently diagnosed primary intracranial tumors in adults. Surgical resection is preferred if the meningioma is accessible; for those that are not suitable for surgical resection, radiotherapy should be considered to improve local tumor control. However, recurrent meningiomas are challenging to treat, as the recurrent tumor might be located in the previously irradiated area. Boron Neutron Capture Therapy (BNCT) is a highly selective radiotherapy modality in which the cytotoxic effect focuses mainly on cells with increased uptake of boron-containing drugs. In this article, we describe four patients with recurrent meningiomas treated with BNCT in Taiwan. The mean boron-containing drug tumor-to-normal tissue uptake ratio was 4.125, and the tumor mean dose was 29.414 GyE, received via BNCT. The treatment response showed two stable diseases, one partial response, and one complete response. We also introduce and support the effectiveness and safety of BNCT as an alternative salvage treatment for recurrent meningiomas.

Therapeutic Efficacy and Radiobiological Effects of Boric-Acid-Mediated BNCT in an Osteosarcoma-Bearing SD Rat Model.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignancy of the bone and is notoriously resistant to radiation therapy. High-dose cytotoxic chemotherapy and surgical resection have improved the survival rate and prognosis of patients with OS. Nonetheless, treatment challenges remain when the tumor cannot be removed by surgery. Boron neutron capture therapy (BNCT) provides high linear energy transfer (LET) radiation, and its internal targeted characteristics make BNCT a novel therapy for removing OS and reducing radiation damage to adjacent healthy tissues. METHODS: In this study, a UMR-106-grafted OS rat model was developed, and boric acid (BA) was used as the boron drug for BNCT. The pharmacokinetics of BA, following intravenous injection, were evaluated to determine the optimal time window for neutron irradiation. OS-bearing rats were irradiated by an epithermal neutron beam at Tsing Hua Open-Pool Reactor (THOR). The therapeutic efficacy of and tissue response after BNCT were evaluated by radiographic and histopathological observations. RESULTS: OS-bearing rats were irradiated by neutrons in the first hour following the intravenous injection of BA. The prescription-absorbed doses in the tumor regions were 5.8 and 11.0 Gy. BNCT reduced the body weight of the tumor-bearing rats, but they recovered after a few days. The BA-mediated BNCT effectively controlled the orthotopic OS tumor, reduced osteolysis, and induced bone healing. Autoradiography and histological analysis confirmed that the BA retention region is consistent with the calcification region in OS tissue. CONCLUSION: BA is specifically retained in OS, and the BA-mediated BNCT can significantly reduce the tumor burden and osteolysis in OS-bearing rats.

Compassionate Treatment of Brainstem Tumors with Boron Neutron Capture Therapy: A Case Series.

Brainstem tumors are heterogenous and cancerous glioma tumors arising from the midbrain, pons, and the medulla that are relatively common in children, accounting for 10% to 20% of all pediatric brain tumors. However, the prognosis of aggressive brainstem gliomas remains extremely poor despite aggressive treatment with chemotherapy and radiotherapy. That means there are many life-threatening patients who have exhausted all available treatment options and are beginning to face end-of-life stage. Therefore, the unique properties of highly selective heavy particle irradiation with boron neutron capture therapy (BNCT) may be well suited to prolong the lives of patients with end-stage brainstem gliomas. Herein, we report a case series of life-threatening patients with end-stage brainstem glioma who eligible for Emergency and Compassionate Use, in whom we performed a scheduled two fractions of salvage BNCT strategy with low treatment dosage each time. No patients experienced acute or late adverse events related to BNCT. There were 3 patients who relapsed after two fractionated BNCT treatment, characterized by younger age, lower T/N ratio, and receiving lower treatment dose. Therefore, two fractionated low-dose BNCT may be a promising treatment for end-stage brainstem tumors. For younger patients with low T/N ratios, more fractionated low-dose BNCT should be considered.

Salvage Boron Neutron Capture Therapy for Malignant Brain Tumor Patients in Compliance with Emergency and Compassionate Use: Evaluation of 34 Cases in Taiwan.

Although boron neutron capture therapy (BNCT) is a promising treatment option for malignant brain tumors, the optimal BNCT parameters for patients with immediately life-threatening, end-stage brain tumors remain unclear. We performed BNCT on 34 patients with life-threatening, end-stage brain tumors and analyzed the relationship between survival outcomes and BNCT parameters. Before BNCT, MRI and 18F-BPA-PET analyses were conducted to identify the tumor location/distribution and the tumor-to-normal tissue uptake ratio (T/N ratio) of 18F-BPA. No severe adverse events were observed (grade ≥ 3). The objective response rate and disease control rate were 50.0% and 85.3%, respectively. The mean overall survival (OS), cancer-specific survival (CSS), and relapse-free survival (RFS) times were 7.25, 7.80, and 4.18 months, respectively. Remarkably, the mean OS, CSS, and RFS of patients who achieved a complete response were 17.66, 22.5, and 7.50 months, respectively. Kaplan-Meier analysis identified the optimal BNCT parameters and tumor characteristics of these patients, including a T/N ratio ≥ 4, tumor volume < 20 mL, mean tumor dose ≥ 25 Gy-E, MIB-1 ≤ 40, and a lower recursive partitioning analysis (RPA) class. In conclusion, for malignant brain tumor patients who have exhausted all available treatment options and who are in an immediately life-threatening condition, BNCT may be considered as a therapeutic approach to prolong survival.

Suitability of boric acid as a boron drug for boron neutron capture therapy for hepatoma.

Hepatoma is the second leading cause of cancer death worldwide. Due to the poor outcomes of patients with late diagnosis, newer treatments for hepatoma are still needed. As an emerging therapy, boron neutron capture therapy (BNCT) may be an effective solution in hepatoma management. In this study, boric acid (BA) was used as the boron drug for in vivo analysis of action mechanism. The N1S1 single liver tumor-bearing rat and the VX2 multifocal liver tumor-bearing rabbit models were used to investigate the retention status of BA in the tumor regions during BNCT. The autoradiographic examination showed BA can localize specifically not only in the hepatoma cells but also in tumor blood vessels. Our findings indicate that superior hepatoma targeting could be achieved in BA-mediated BNCT, which supports BA to be a suitable boron drug for BNCT for hepatoma.

The overview and prospects of BNCT facility at Tsing Hua Open-pool reactor.

The whole picture of the BNCT facility at Tsing Hua Open-pool Reactor will be presented which consists of the following aspects: the construction project, the beam quality, routine operations including the QA program for the beam delivery, determination of boron-10 concentration in blood, T/N ratio, and the clinical affairs including the patient recruit procedure and the patient irradiation procedure. The facility is positioned to serve for conducting clinical trials, emergent (compassionate) treatments, and R&D works.

Therapeutic Efficacy and Radiobiological Effects of Boric Acid-mediated BNCT in a VX2 Multifocal Liver Tumor-bearing Rabbit Model.

BACKGROUND/AIM: Most patients with hepatocellular carcinoma (HCC) cannot be treated using traditional therapies. Boron neutron capture therapy (BNCT) may provide a new treatment for HCC. In this study, the therapeutic efficacy and radiobiological effects of boric acid (BA)-mediated BNCT in a VX2 multifocal liver tumor-bearing rabbit model are investigated. MATERIALS AND METHODS: Rabbits were irradiated with neutrons at the Tsing Hua Open Pool Reactor 35 min following an intravenous injection of BA (50 mg 10B/kg BW). The tumor size following BNCT treatment was determined by ultrasonography. The radiobiological effects were identified by histopathological examination. RESULTS: A total of 92.85% of the tumors became undetectable in the rabbits after two fractions of BNCT treatment. The tumor cells were selectively eliminated and the tumor vasculature was collapsed and destroyed after two fractions of BA-mediated BNCT, and no injury to the hepatocytes or blood vessels was observed in the adjacent normal liver regions. CONCLUSION: Liver tumors can be cured by BA-mediated BNCT in the rabbit model of a VX2 multifocal liver tumor. BA-mediated BNCT may be a breakthrough therapy for hepatocellular carcinoma.

Fractionated Boron Neutron Capture Therapy in Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial.

PURPOSE: To investigate the efficacy and safety of fractionated boron neutron capture therapy (BNCT) for recurrent head and neck (H&N) cancer after photon radiation therapy. METHODS AND MATERIALS: In this prospective phase 1/2 trial, 2-fraction BNCT with intravenous L-boronophenylalanine (L-BPA, 400 mg/kg) was administered at a 28-day interval. Before each fraction, fluorine-18-labeled-BPA-positron emission tomography was conducted to determine the tumor/normal tissue ratio of an individual tumor. The prescription dose (D80) of 20 Gy-Eq per fraction was selected to cover 80% of the gross tumor volume by using a dose volume histogram, while minimizing the volume of oral mucosa receiving >10 Gy-Eq. Tumor responses and adverse effects were assessed using the Response Evaluation Criteria in Solid Tumors v1.1 and the Common Terminology Criteria for Adverse Events v3.0, respectively. RESULTS: Seventeen patients with a previous cumulative radiation dose of 63-165 Gy were enrolled. All but 2 participants received 2 fractions of BNCT. The median tumor/normal tissue ratio was 3.4 for the first fraction and 2.5 for the second, whereas the median D80 for the first and second fraction was 19.8 and 14.6 Gy-Eq, respectively. After a median follow-up period of 19.7 months (range, 5.2-52 mo), 6 participants exhibited a complete response and 6 exhibited a partial response. Regarding acute toxicity, 5 participants showed grade 3 mucositis and 1 participant showed grade 4 laryngeal edema and carotid hemorrhage. Regarding late toxicity, 2 participants exhibited grade 3 cranial neuropathy. Four of six participants (67%) receiving total D80 > 40 Gy-Eq had a complete response. Two-year overall survival was 47%. Two-year locoregional control was 28%. CONCLUSIONS: Our results suggested that 2-fraction BNCT with adaptive dose prescription was effective and safe in locally recurrent H&N cancer. Modifications to our protocol may yield more satisfactory results in the future.

Establishment of a trimodality analytical platform for tracing, imaging and quantification of gold nanoparticles in animals by radiotracer techniques.

This study aims to establish a (198)Au-radiotracer technique for in vivo tracing, rapid quantification, and ex vivo visualization of PEGylated gold nanoparticles (GNPs) in animals, organs and tissue dissections. The advantages of GNPs lie in its superior optical property, biocompatibility and versatile conjugation chemistry, which are promising to develop diagnostic probes and drug delivery systems. (198)Au is used as a radiotracer because it simultaneously emits beta and gamma radiations with proper energy and half-life; therefore, (198)Au can be used for bioanalytical purposes. The (198)Au-tagged radioactive gold nanoparticles ((198)Au-GNPs) were prepared simply by irradiating the GNPs in a nuclear reactor through the (197)Au(n,γ)(198)Au reaction and subsequently the (198)Au-GNPs were subjected to surface modification with polyethylene glycol to form PEGylated (198)Au-GNPs. The (198)Au-GNPs retained physicochemical properties that were the same as those of GNP before neutron irradiation. Pharmacokinetic and biodisposition studies were performed by intravenously injecting three types of (198)Au-GNPs with or without PEGylation into mice; the γ radiation in blood specimens and dissected organs was then measured. The (198)Au-radiotracer technique enables rapid quantification freed from tedious sample preparation and shows more than 95% recovery of injected GNPs. Clinical gamma scintigraphy was proved feasible to explore spatial- and temporal-resolved biodisposition of (198)Au-GNPs in living animals. Moreover, autoradiography, which recorded beta particles from (198)Au, enabled visualizing the heterogeneous biodisposition of (198)Au-GNPs in different microenvironments and tissues. In this study, the (198)Au-radiotracer technique facilitated creating a trimodality analytical platform for tracing, quantifying and imaging GNPs in animals.

Fractionated BNCT for locally recurrent head and neck cancer: experience from a phase I/II clinical trial at Tsing Hua Open-Pool Reactor.

To introduce our experience of treating locally and regionally recurrent head and neck cancer patients with BNCT at Tsing Hua Open-Pool Reactor in Taiwan, 12 patients (M/F=10/2, median age 55.5 Y/O) were enrolled and 11 received two fractions of treatment. Fractionated BNCT at 30-day interval with adaptive planning according to changed T/N ratios was feasible, effective and safe for selected recurrent head and neck cancer in this trial.

Therapeutic efficacy for hepatocellular carcinoma by boric acid-mediated boron neutron capture therapy in a rat model.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. Boron neutron capture therapy (BNCT) may provide an alternative therapy for HCC. This study investigated the therapeutic efficacy of boric acid (BA)-mediated BNCT for HCC in a rat model. MATERIALS AND METHODS: The pharmacokinetic and biodistribution of BA in N1S1 tumor-bearing rats were analyzed. Rats were injected with 25 mg B/kg body weight via tail veins before neutron irradiation at the Tsing Hua Open-pool Reactor, and the efficacy of BNCT was evaluated from the tumor size, tumor blood flow, and biochemical analyses. RESULTS: HCC-bearing rats administered BNCT showed reductions in tumor size on ultrasound imaging, as well as an obvious reduction in the distribution of tumor blood flow. The lesion located in livers had disappeared on the 80th day after BNCT; a recovery of values to normal levels was also recorded. CONCLUSION: BA-mediated BNCT is a promising alternative for liver cancer therapy since the present study demonstrated the feasibility of curing a liver tumor and restoring liver function in rats. Efforts are underway to investigate the histopathological features and the detailed mechanisms of BA-mediated BNCT.

Kinetics and tissue distribution of neutron-activated zinc oxide nanoparticles and zinc nitrate in mice: effects of size and particulate nature.

Although zinc oxide nanoparticles (ZnONPs) have been applied in nanotechnology, their kinetics and tissue distribution in vivo are unknown. Here we compared the kinetics and tissue distribution of 10 nm (65)ZnONPs, 71 nm (65)ZnONPs and (65)Zn(NO(3))(2) in mice after intravenous injection. The areas under the curves and the half-lives in the second compartment of (65)Zn(NO(3))(2) were greater than those of (65)ZnONPs; the kinetic parameters were similar for both (65)ZnONPs. However, the tissue distributions for the three forms were different. ZnONPs preferentially accumulated in the liver and spleen at 24 h. At day 28, (65)Zn concentration was highest in bone and the proportion of recovered (65)Zn radioactivity was highest in the carcass; these had the same ranking, 10 nm (65)ZnONPs > 71 nm (65)ZnONPs>  (65)Zn(NO(3))(2). Although more than 80% of the 10 nm (65)ZnONPs had been excreted by day 28, greater amounts of the 10 nm (65)ZnONPs than the 71 nm (65)ZnONPs or (65)Zn(NO(3))(2) had accumulated in other organs (brain, lung, heart and kidneys). Zn ions seem to have a longer half-life in the plasma, but ZnONPs show greater tissue accumulation. Although the size of the ZnONPs had no obvious effect on the kinetics, nevertheless the smaller ZnONPs tended to accumulate preferentially in some organs.

The use of radioactive zinc oxide nanoparticles in determination of their tissue concentrations following intravenous administration in mice.

The increasing uses of zinc oxide nanoparticles (ZnONPs) in coatings, paints, personal care products and many other products increase the possibility of the body's exposure to ZnONPs. Accurate and quantitative profiling on the tissue distribution and body clearance of ZnONPs, which is an important factor to clarify the acute and chronic safety concerns of ZnONPs, is interfered by the abundance of the body's endogenous zinc moiety. In this report, radioactive zinc oxide nanoparticles (R-ZnONPs) generated from neutron activation were employed for the in vivo bio-distribution studies using mice as the animal model. Gamma-ray emitting radioactive R-ZnONPs were produced from neutron activation. Zeta potentials of the ZnONPs before and after the neutron irradiation remained about the same, and R-ZnONPs largely remained its original nano-particulate form after neutron irradiation. After intravenous administration into ICR mice, R-ZnONPs exhibited a primary retention in lung (43.6% injected dose (ID)/g tissue wet weight) for the first hour and began to be translocated to intestinal tract for feces excretion at a later stage. This type of labeling free and radioactive nanoparticles retains the surface property and can be a convenient protocol for studying bio-distribution of nanoparticles in pristine chemical form.