Fong-In Chou

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

To introduce our preliminary experience of treating locally and regionally recurrent Head and Neck cancer patients at Tsing Hua Open-Pool Reactor in Taiwan, four patients (M/F=3/1, median age 68 Y/O) were enrolled. BNCT with BPA (400 mg/kg) injected in 2 phases and prescription dose of 12-35 Gy (Eq.)/fraction for 2 fractions at 30 day interval can be given with sustained blood boron concentration and tolerable early toxicities for recurrent H & N cancer.

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 bodys 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 bodys 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.

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.

Biodistribution of phenylboric acid derivative entrapped lipiodol and 4-borono-2-18F-fluoro-l-phenylalanine-fructose in GP7TB liver tumor bearing rats for BNCT

A new phenylboric acid derivative entrapped lipiodol (PBAD-lipiodol) was developed as a boron carrier for the boron neutron capture therapy (BNCT) of hepatoma in Taiwan. The biodistribution of both PBAD-lipiodol and BPA-fructose was assayed in GP7TB hepatoma-bearing rat model. The highest uptake of PBAD-lipiodol was found at 2h post injection. The application of BNCT for the hepatoma treatment in tumor-bearing rats is suggested to be 2-4h post PBAD-lipiodol injection.

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.

Potential of using boric acid as a boron drug for boron neutron capture therapy for osteosarcoma.

Osteosarcoma is a malignant tumor commonly found in human and animals. The ability of boric acid (BA) to accumulate in osteosarcoma due to the mechanism of the bone formation of cancer cells would make boron neutron capture therapy (BNCT) an alternative therapy for osteosarcoma. This study evaluated the feasibility of using BA as the boron drug for BNCT of bone cancer. The cytotoxicity of BA to L929 cells exceeded that of UMR-106 cells. With 25 μg (10)B/mL medium of BA treatment, the boron concentration in UMR-106 cells was higher than that in L929 cells. The biodistribution and pharmacokinetics of BA in Sprague-Dawley (SD) rats were studied by administrating 25 mg (10)B/kg body weight to SD rats. Blood boron level decreased rapidly within one hour after BA injection. Boron concentration in the long bone was 4-6 time higher than that of blood. Results of this study suggest that BA may be a potential drug for BNCT for osteosarcoma.

Assessment of dose rate scaling factors used in NCTPlan treatment planning code for the BNCT beam of THOR

Tsing Hua open-pool reactor (THOR) at Tsing Hua University in Taiwan has been used to investigate the feasibility and to enhance the technology of boron neutron capture therapy (BNCT) for years. A rebuilt epithermal beam port for BNCT at THOR was finished in the summer of 2004, and then researches and experiments were performed to hasten the first clinical treatment case of BNCT in Taiwan in the near future. NCTPlan, a Monte Carlo-based clinical treatment planning code, was used to calculate the dose-rate distributions of BNCT in this work. A self-made Snyder head phantom with a servo-motor control system was irradiated in front of the THOR BNCT beam exit. The phantom was made from a 3mm shell of quartz wool impregnated with acrylic casting resin mounted on an acrylic base, and was filled with water. Gold foils (bare and cadmium-covered) and paired ion chambers (one with graphite wall and filled with CO(2) gas, another with A-150 plastic tissue equivalent wall and filled with tissue equivalent gas) were placed inside the Snyder phantom to measure and estimate the depth-dose distributions in the central axis of the beam. Dose components include the contribution of thermal neutrons, fast neutrons, photons and emitted alpha particles from (10)B(n,alpha)(7)Li reaction. Comparison and analysis between computed and measured results of depth-dose distributions were made in this work. Dose rate scaling factors (DRSFs) were defined as normalization factors derived individually for each dose component in the BNCT in-phantom radiation field that provide the best agreement between measured and computed data. This paper reports the in-phantom calculated and experimental dosimetry and the determined DRSFs used in NCTPlan code for the BNCT beam of THOR.

Microdosimetry study of THOR BNCT beam using tissue equivalent proportional counter

Boron neutron capture therapy (BNCT) is a cancer treatment modality using a nuclear reactor and a boron compound drug. In Taiwan, Tsing Hua open-pool reactor (THOR) has been modulated for the basic research of BNCT for years. A new BNCT beam port was built in 2004 and used to prepare the first clinical trial in the near future. This work reports the microdosimetry study of the THOR BNCT beam by means of the tissue equivalent proportional counter (TEPC). Two self-fabricated TEPCs (the boron-doped versus the boron-free counter wall) were introduced. These dual TEPCs were applied to measure the lineal energy distributions in air and water phantom irradiated by the THOR BNCT mixed radiation field. Dose contributions from component radiations of different linear energy transfers (LETs) were analyzed. Applying a lineal energy dependent biological weighting function, r(y), to the total and individual lineal energy distributions, the effective relative biological effectiveness (RBE), neutron RBE, photon RBE, and boron capture RBE (BNC RBE) were all determined at various depths of the water phantom. Minimum and maximum values of the effective RBE were 1.68 and 2.93, respectively. The maximum effective RBE occurred at 2cm depth in the phantom. The average neutron RBE, photon RBE, and BNC RBE values were 3.160+/-0.020, 1.018+/-0.001, and 1.570+/-0.270, respectively, for the THOR BNCT beam.

The Dosimetric Impact of Shifts in Patient Positioning during Boron Neutron Capture Therapy for Brain Tumors

Unlike conventional photon radiotherapy, sophisticated patient positioning tools are not available for boron neutron capture therapy (BNCT). Thus, BNCT remains vulnerable to setup errors and intra-fractional patient motion. The aim of this study was to estimate the impact of deviations in positioning on the dose administered by BNCT for brain tumors at the Tsing Hua open-pool reactor (THOR). For these studies, a simulated head model was generated based on computed tomography (CT) images of a patient with a brain tumor. A cylindrical brain tumor 3 cm in diameter and 5 cm in length was modeled at distances of 6.5 cm and 2.5 cm from the posterior scalp of this head model (T6.5 cm and T2.5 cm, respectively). Radiation doses associated with positioning errors were evaluated for each distance, including left and right shifts, superior and inferior shifts, shifts from the central axis of the beam aperture, and outward shifts from the surface of the beam aperture. Rotational and tilting effects were also evaluated. The dose prescription was 20 Gray-equivalent (Gy-Eq) to 80 % of the tumor. The treatment planning system, NCTPlan, was used to perform dose calculations. The average decreases in mean tumor dose for T6.5 cm for the 1 cm, 2 cm, and 3 cm lateral shifts composed by left, right, superior, and inferior sides, were approximately 1 %, 6 %, and 11 %, respectively, compared to the dose administered to the initial tumor position. The decreases in mean tumor dose for T6.5 cm were approximately 5 %, 11 %, and 15 % for the 1 cm, 2 cm, and 3 cm outward shifts, respectively. For a superficial tumor at T2.5cm, no significant decrease in average mean tumor dose was observed following lateral shifts of 1 cm. Rotational and tilting up to 15° did not result in significant difference to the tumor dose. Dose differences to the normal tissues as a result of the shifts in positioning were also minimal. Taken together, these data demonstrate that the mean dose administered to tumors at greater depths is potentially more vulnerable to deviations in positioning, and greater shift distances resulted in reduced mean tumor doses at the THOR. Moreover, these data provide an estimation of dose differences that are caused by setup error or intra-fractional motion during BNCT, and these may facilitate more accurate predictions of actual patient dose in future treatments.