Prognostic assessment of 18F-boronophenylalanine positron emission tomography (BPA-PET) in salvage boron neutron capture therapy for malignant brain tumors.

Background: Boron neutron capture therapy (BNCT) stands out as a propitious anti-cancer modality. 18F-boronophenylalanine positron emission tomography (BPA-PET) holds the potential to ascertain the concentration of BPA within the tumor, enabling meticulous treatment planning and outcome evaluation. However, no studies have been conducted on comparing the outcomes of those treated with BNCT to those who did not undergo this therapy. This study endeavors to analyze the correlation between BPA-PET and BNCT in the context of malignant brain tumors, and assess the survival outcomes following BNCT. Methods: A cohort study was performed on patients who underwent BPA-PET between February 2017 and April 2022 in our hospital. Patients were stratified into two groups: those subjected to BNCT (Group 1) and those not (Group 2). The tumor to normal tissue (T/N) ratio derived from BPA-PET was set at 2.5. The findings were scrutinized based on clinical follow-up. Student's t-test and Chi-squared test were employed to discern differences between the groups. A cumulative survival curve was constructed employing the Kaplan-Meier method. Differences were considered statistically significant at P<0.05. Results: In total, 116 patients with T/N ratios obtained from BPA-PET were enrolled. BNCT was administered to 58 patients, while mortality was observed in 100 patients. The median overall survival (OS) for the two groups was 8.5 and 6.0 months, respectively. The cumulative OS exhibited no significant discrepancy between the two groups, nor in their T/N ratios. Within Group 1, 44 out of 58 (75.9%) patients exhibited T/N ratios exceeding 2.5. Excluding 3 patients who expired within 3 months, 55 out of 58 patients were evaluated for response after BNCT. The objective response rate (ORR) was 30.9%. Patients achieving ORR displayed substantially higher survival rates compared to those without (median OS 13.5 vs. 8.3 months, P=0.0021), particularly when T/N ratio exceeded 2.5 (median OS 14.8 vs. 9.0 months, P=0.0199). Conclusions: BNCT does not appear indispensable for prolonging the survival of patients afflicted with malignant brain tumors. Nevertheless, it proves advantageous when ORR is attained, a condition closely linked to the values of T/N ratio derived from BPA-PET.

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.

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.

Correction: Visual light perceptions caused by medical linear accelerator: Findings of machine-learning algorithms in a prospective questionnaire-based case-control study.

[This corrects the article DOI: 10.1371/journal.pone.0247597.].

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.

Visual light perceptions caused by medical linear accelerator: Findings of machine-learning algorithms in a prospective questionnaire-based case-control study.

This study aimed to investigate the possible incidence of visual light perceptions (VLPs) during radiation therapy (RT). We analyzed whether VLPs could be affected by differences in the radiation energy, prescription doses, age, sex, or RT locations, and whether all VLPs were caused by radiation. From November 2016 to August 2018, a total of 101 patients who underwent head-and-neck or brain RT were screened. After receiving RT, questionnaires were completed, and the subjects were interviewed. Random forests (RF), a tree-based machine learning algorithm, and logistic regression (LR) analyses were compared by the area under the curve (AUC), and the algorithm that achieved the highest AUC was selected. The dataset sample was based on treatment with non-human units, and a total of 293 treatment fields from 78 patients were analyzed. VLPs were detected only in 122 of the 293 exposure portals (40.16%). The dataset was randomly divided into 80% and 20% as the training set and test set, respectively. In the test set, RF achieved an AUC of 0.888, whereas LR achieved an AUC of 0.773. In this study, the retina fraction dose was the most important continuous variable and had a positive effect on VLP. Age was the most important categorical variable. In conclusion, the visual light perception phenomenon by the human body during RT is induced by radiation rather than being a self-suggested hallucination or induced by phosphenes.

The importance of optimal ROIs delineation for FBPA-PET before BNCT.

One of the eligible criteria for patients to receive boron neutron capture therapy (BNCT) is based on the tumour-to-normal ratio (T/N) measured by FBPA-PET. However, there is no standard protocol for normal region-of-interested delineation. With comparison of contralateral cerebrum, our study revealed the consistency (p < 0.05) and high feasibility using the cerebellum as an alternative normal tissue baseline because of its homogeneous uptake. Following RECIST version 1.1, the standard-operating-procedure (SOP) for the BNCT fulfilled the expected tumour response and tumour shrinkage rate (p < 0.05). Our modified procedure can provide more precise information for BNCT within a reasonable time.

Using salvage Boron Neutron Capture Therapy (BNCT) for recurrent malignant brain tumors in Taiwan.

Radiation therapy has an irreplaceable role in modern oncologic therapy, thanks to the advanced radiation techniques developed in recent decades. However, photon-resistant cases are sometimes encountered. Boron Neutron Capture Therapy (BNCT) is a highly selective radiotherapy technique due to the high tumor to tissue ratio of boronophenylalanine (BPA), the unique medication used for the BNCT treatment reaction. In this study, we report on three special patients with malignant brain tumors treated with BNCT.

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.

A comparison of dose distributions in gross tumor volume between boron neutron capture therapy alone and combined boron neutron capture therapy plus intensity modulation radiation therapy for head and neck cancer.

Nine patients with recurrent head and neck (H&N) cancer received boron neutron capture therapy (BNCT) in one fraction at the Tsing-Hua Open pool reactor (THOR) utilizing the THORplan treatment planning system (TPS). The aims of the present study were to evaluate the use of intensity modulated radiation therapy (IMRT) of 45 Gy in 20 fractions to compensate for the dose heterogeneity in gross tumor volume observed with single-fraction BNCT with mean prescription dose 19 Gy (w), and to evaluate planning quality indices of simulated BNCT+IMRT versus single-fraction BNCT alone. All IMRT plans were generated using the Eclipse TPS which employs the analytical anisotropic algorithm. The conformity index for the gross tumor volume (GTV) was better for the BNCT+IMRT plan than for the BNCT-alone plan (p = 0.003). In addition, the BNCT+IMRT plan provided significantly better homogeneity in the GTV (p = 0.03). The cold spots in inhomogeneous dose distribution in the BNCT plan may be a key factor for H&N cancer recurrence. Our results suggest that single-fraction BNCT combined with compensated multi-fraction IMRT improves treatment homogeneity and conformity than single-fraction BNCT alone, especially for tumor volumes >100 cm3, and possibly increases local tumor control.

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.

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy.

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting.

Total body irradiation with step translation and dynamic field matching.

The purpose of this study is to develop a total body irradiation technique that does not require additional devices or sophisticated processes to overcome the space limitation of a small treatment room. The technique aims to deliver a uniform dose to the entire body while keeping the lung dose within the tolerance level. The technique treats the patient lying on the floor anteriorly and posteriorly. For each AP/PA treatment, two complementary fields with dynamic field edges are matched over an overlapped region defined by the marks on the body surface. A compensator, a spoiler, and lung shielding blocks were used during the treatment. Moreover, electron beams were used to further boost the chest wall around the lungs. The technique was validated in a RANDO phantom using GAFCHROMIC films. Dose ratios at different body sites along the midline ranged from 0.945 to 1.076. The dose variation in the AP direction ranged from 96.0% to 104.6%. The dose distribution in the overlapped region ranged from 98.5% to 102.8%. Lateral dose profiles at abdomen and head revealed 109.8% and 111.7% high doses, respectively, at the body edges. The results confirmed that the technique is capable of delivering a uniform dose distribution to the midline of the body in a small treatment room while keeping the lung dose within the tolerance level.