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.

A study on out-of-field leakage of an accelerator-based neutron beam for boron neutron capture therapy.

More and more accelerator-based boron neutron capture therapy (AB-BNCT) facilities are under the construction or commissioning stage, and the neutron beam characteristic measurements at each facility will start soon. In addition to the in-field neutron beam properties, the leakage of neutron beam is also important, which is related to the side effects of the patient. In the Virtual Technical Meeting on Advances in Boron Neutron Capture Therapy held by International Atomic Energy Agency (IAEA) in July 2020, the issue of the out-of-field leakage in BNCT was addressed. Heron Neutron Medical Corporation has been working on the beam design for China Medical University Hsinchu Hospital AB-BNCT research center. To evaluate the out-of-field leakage, both beam profile analysis and whole-body dose calculation are performed. An Oak Ridge National Laboratory (ORNL) Medical Internal Radiation Dose (MIRD) mathematical phantom is used to calculate the whole-body dose. For the estimated irradiation time which is set to be the time required for 80% of tumor dose to reach 20 Gy-w, the relative biological effectiveness weighted dose of abdomen region is less than 40 mGy-w and the whole-body dose is 104 mSv. The beam profile calculational result shows that the neutron ambient dose equivalent at 15 cm from the field edge is 11 mSv/Gy-w and drops to 5 mSv/Gy-w at 26 cm from the field edge. The gamma ray ambient dose equivalent is less than 1 mSv/Gy-w starting from 10 cm from the field edge. Although the neutron out-of-field leakage of the beam design is higher than that of the initially proposed guideline by IAEA in 2020, the whole-body dose, however, is reasonably low. Both the whole-body dose evaluation and the beam profile analysis are useful in the beam design consideration. The whole-body dose calculation together with the beam profile analysis can also be helpful in reaching an acceptable recommendation for the out-of-field leakage for BNCT neutron beam, a job wished to be accomplished in the near future as proposed in the 2023 IAEA's report on Advances in Boron Neutron Capture Therapy.

Development of a tumor control probability model for boron neutron capture therapy of head and neck cancer.

The tumor control probability (TCP) model has been used for estimating the response of the radiation (photon) therapy for a given treatment dose (distribution). In Taiwan, boron neutron capture therapy (BNCT) is still at the stage of the clinical trials without standard dose prescription. In this study, universal survival curve (USC) model was selected as the TCP model for BNCT. The tumor response and dose distribution from protocol I of the clinical trial of the recurrent head and neck (H&N) cancer conducted by Taipei Veterans General Hospital and National Tsing Hua University were used to verify the TCP model established in this study. The results showed that, using the USC model as a biological model of dose conversion, the TCP calculated by the generalized Equivalent Uniform Dose (gEUD)-based TCP model can be used to well correlate the relationship between the tumor response and dose distribution of the patients of recurrent H&N cancer. The result shows that 25% and 60% of TCP correspond to partial response and complete response of H&N cancer, respectively. This study also indicated that, when BNCT was used to treat recurrent H&N cancer, the minimum dose was an important factor on the efficacy of the treatment. Minimum dose of 18 Gy-w corresponds to at least 60% of TCP.

Electrosprayed chitosan/alginate/polyvinyl alcohol nanoparticles as boric acid carriers for 10Boron neutron capture therapy.

Aim: To improve the killing efficacy of head and neck squamous cells (SAS) by boric acid-mediated boron neutron capture therapy (BNCT). Materials & methods: Boric acid-containing chitosan/alginate/polyvinyl alcohol nanoparticles (B-capNPs) were manufactured using the nano-electrospray process. Results: Less than 10% of the boric acid leaked from the B-capNPs over 2 days. The B-capNPs killed up to 2.8-fold more SAS cells and reduced cytotoxicity tenfold when compared with pure boric acid alone. B-capNPs show selective uptake in tumor cells with tumor/normal ratios of SAS to normal (NIH 3T3) and macrophage (RAW 264.7) cells of 4.0 and 3.5, respectively, which are greater than the minimum acceptable tumor/normal ratio for BNCT of 2.5. Conclusion: These findings illustrate that B-capNPs may be more superior as BNCT drugs than pure boric acid.

Clinical trials for treating recurrent head and neck cancer with boron neutron capture therapy using the Tsing-Hua Open Pool Reactor.

Head and neck (HN) cancer is an endemic disease in Taiwan, China. Locally recurrent HN cancer after full-dose irradiation poses a therapeutic challenge, and boron neutron capture therapy (BNCT) may be a solution that could provide durable local control with tolerable toxicity. The Tsing-Hua Open Pool Reactor (THOR) at National Tsing-Hua University in Hsin-Chu, provides a high-quality epithermal neutron source for basic and clinical BNCT research. Our first clinical trial, entitled "A phase I/II trial of boron neutron capture therapy for recurrent head and neck cancer at THOR", was carried out between 2010 and 2013. A total of 17 patients with 23 recurrent HN tumors who had received high-dose photon irradiation were enrolled in the study. The fructose complex of L-boronophenylalanine was used as a boron carrier, and a two-fraction BNCT treatment regimen at 28-day intervals was used for each patient. Toxicity was acceptable, and although the response rate was high (12/17), re-recurrence within or near the radiation site was common. To obtain better local control, another clinical trial entitled "A phase I/II trial of boron neutron capture therapy combined with image-guided intensity-modulated radiotherapy (IG-IMRT) for locally recurrent HN cancer" was initiated in 2014. The first administration of BNCT was performed according to our previous protocol, and IG-IMRT was initiated 28 days after BNCT. As of May 2017, seven patients have been treated with this combination. The treatment-related toxicity was similar to that previously observed with two BNCT applications. Three patients had a complete response, but locoregional recurrence was the major cause of failure despite initially good responses. Future clinical trials combining BNCT with other local or systemic treatments will be carried out for recurrent HN cancer patients at THOR.

A volume-equivalent spherical necrosis-tumor-normal liver model for estimating absorbed dose in yttrium-90 microsphere therapy.

PURPOSE: Primary hepatocellular carcinoma and metastatic liver tumors are highly malignant tumors in Asia. The incidence of fatal liver cancer is also increasing in the United States. The aim of this study was to establish a spherical tumor model and determine its accuracy in predicting the absorbed dose in yttrium-90 (Y-90) microsphere therapy for liver cancer. METHODS: Liver morphology can be approximated by a spherical model comprising three concentric regions representing necrotic, tumor, and normal liver tissues. The volumes of these three regions represent those in the actual liver. A spherical tumor model was proposed to calculate the absorbed fractions in the spherical tumor, necrotic, and normal tissue regions. The THORplan treatment planning system and Monte Carlo N-particle extended codes were used for this spherical tumor model. Using the volume-equivalent method, a spherical tumor model was created to calculate the total absorbed fraction [under different tumor-to-healthy-liver ratios (TLRs)]. The patient-specific model (THORplan) results were used to verify the spherical tumor model results. RESULTS: The results for both the Y-90 spectrum and the Y-90 mean energy indicated that the absorbed fraction was a function of the tumor radius and mass. The absorbed fraction increased with tumor radius. The total absorbed fractions calculated using the spherical tumor model for necrotic, liver tumor, and normal liver tissues were in good agreement with the THORplan results, with differences of less than 3% for TLRs of 2-5. The results for the effect of TLR indicate that for the same tumor configuration, the total absorbed fraction decreased with increasing TLR; for the same shell tumor thickness and TLR, the total absorbed fraction was approximately constant; and for tumors with the same radius, the total fraction absorbed by the tumor increased with the shell thickness. CONCLUSIONS: The results from spherical tumor models with different tumor-to-healthy-liver ratios were highly consistent with the reference results (THORplan). These findings indicate that a spherical tumor model can provide good estimates of Y-90 doses in microsphere therapy and can be considered a first approximation for dose estimation in Y-90 microsphere therapy.

BNCT treatment planning for superficial and deep-seated tumors: Experience from clinical trial of recurrent head and neck cancer at THOR.

Under the collaboration between National Tsing Hua University and Taipei Veterans General Hospital, clinical trial of recurrent head-and-neck cancer by Boron neutron capture therapy at Tsing Hua open-pool reactor started on August 11, 2010. Up to January 2014, 17 patients were treated. Based on the treatment planning experiences of clinical trials using in-house designed THORplan, different setups should be used for superficial and deep-seated tumors. Superficial tumor treatment gains benefits from the use of patient collimator, while direct irradiation is a better choice for deep-seated tumor.

Influence of metal of the applicator on the dose distribution during brachytherapy.

This study explores how the metal materials of the applicator influence the dose distribution when performing brachytherapy for cervical cancer. A pinpoint ionization chamber, Monte Carlo code MCNPX, and treatment planning system are used to evaluate the dose distribution for a single Ir-192 source positioned in the tandem and ovoid. For dose distribution in water with the presence of the tandem, differences among measurement, MCNPX calculation and treatment planning system results are <5%. For dose distribution in water with the presence of the ovoid, the MCNPX result agrees with the measurement. But the doses calculated from treatment planning system are overestimated by up to a factor of 4. This is due to the shielding effect of the metal materials in the applicator not being considered in the treatment planning system. This result suggests that the treatment planning system should take into account corrections for the metal materials of the applicator in order to improve the accuracy of the radiation dose delivered.

Performance evaluation of the source description of the THOR BNCT epithermal neutron beam.

This paper aims to evaluate the performance of the source description of the THOR BNCT beam via different measurement techniques in different phantoms. The measurement included (1) the absolute reaction rate measurement of a set of triple activation foils, (2) the neutron and gamma-ray dose rates measured using the paired ionization chamber method, and (3) the relative reaction rate distributions obtained using the indirect neutron radiography. Three source descriptions, THOR-Y09, surface source file RSSA, and THOR-50C, were tested. The comparison results concluded that THOR-Y09 is a well-tested source description not only for neutron components, but also for gamma-ray component.

Development and verification of THORplan--a BNCT treatment planning system for THOR.

THORplan is a treatment planning system under continuous development and refinement at Tsing Hua University, Taiwan, for BNCT purpose. New features developed for homogeneous model calculation include material grouping model, and voxel data reconstruction model. Material grouping model is a two-step grouping method, tissue-volume-percent grouping method followed by atom-gram-density grouping method. The root mean square difference of neutron flux due to material grouping is <0.8%. In the voxel data reconstruction model, voxel neutron dose is calculated based on the material composition and dose of individual atom of each voxel, which is calculated by linear interpolation from the dose of individual atom of neighboring cells tallied in MCNP calculation. The detailed voxel model is used to benchmark the accuracy of the new features developed for the homogeneous model calculation. The maximum error of the neutron flux and dose of voxels using the homogeneous cell model is 5% and 7%, respectively. Big improvement of accuracy of voxel dose over the original dose calculation model based on F6 tally is observed at locations containing very heterogeneous compositions.

BNCT treatment planning of recurrent head-and-neck cancer using THORplan.

A cooperation program on Boron Neutron Capture Therapy (BNCT) between National Tsing Hua University (NTHU) and Taipei Veterans General Hospital (TPEVGH) was established in 2008. Clinical trial of recurrent head-and-neck cancer is the goal of the program. In this study, treatment plannings of two head-and-neck cancer cases are performed using treatment planning system THORplan developed at NTHU of Taiwan. The patients are assumed to be irradiated under current THOR epithermal neutron beam. The prescription dose is 20 Gy-Eq for at least 80% of tumor volume. The irradiation time to reach the target tumor dose can be kept within 1h. The skin dose is within the limiting dose of 11 Gy-Eq. The spinal cord dose is well within the limiting dose of 10 Gy-Eq. The use of an extension collimator for easier patient positioning is helpful in reducing the dose of eye lens to within the dose limit of 5 Gy-Eq. The irradiation time, however, will increase slightly due to the increase of source-to-tumor distance. The CPU time for treatment planning calculation is ~10 h. With the use of user friendly treatment planning system THORplan, dose planning for BNCT at THOR can be easily performed.