Targeted Alpha Therapy for Glioblastoma: Review on In Vitro, In Vivo and Clinical Trials.

Glioblastoma (GB), a prevalent and highly malignant primary brain tumour with a very high mortality rate due to its resistance to conventional therapies and invasive nature, resulting in 5-year survival rates of only 4-17%. Despite recent advancements in cancer management, the survival rates for GB patients have not significantly improved over the last 10-20 years. Consequently, there exists a critical unmet need for innovative therapies. One promising approach for GB is Targeted Alpha Therapy (TAT), which aims to selectively deliver potentially therapeutic radiation doses to malignant cells and the tumour microenvironment while minimising radiation exposure to surrounding normal tissue with or without conventional external beam radiation. This approach has shown promise in both pre-clinical and clinical settings. A review was conducted following PRISMA 2020 guidelines across Medline, SCOPUS, and Embase, identifying 34 relevant studies out of 526 initially found. In pre-clinical studies, TAT demonstrated high binding specificity to targeted GB cells, with affinity rates between 60.0% and 84.2%, and minimal binding to non-targeted cells (4.0-5.6%). This specificity significantly enhanced cytotoxic effects and improved biodistribution when delivered intratumorally. Mice treated with TAT showed markedly higher median survival rates compared to control groups. In clinical trials, TAT applied to recurrent GB (rGB) displayed varying success rates in extending overall survival (OS) and progression-free survival. Particularly effective when integrated into treatment regimens for both newly diagnosed and recurrent cases, TAT increased the median OS by 16.1% in newly diagnosed GB and by 36.4% in rGB, compared to current standard therapies. Furthermore, it was generally well tolerated with minimal adverse effects. These findings underscore the potential of TAT as a viable therapeutic option in the management of GB.

An Integrated Monte Carlo Model for Heterogeneous Glioblastoma Treated with Boron Neutron Capture Therapy.

BACKGROUND: Glioblastomas (GBMs) are notorious for their aggressive features, e.g., intrinsic radioresistance, extensive heterogeneity, hypoxia, and highly infiltrative behaviours. The prognosis has remained poor despite recent advances in systemic and modern X-ray radiotherapy. Boron neutron capture therapy (BNCT) represents an alternative radiotherapy technique for GBM. Previously, a Geant4 BNCT modelling framework was developed for a simplified model of GBM. PURPOSE: The current work expands on the previous model by applying a more realistic in silico GBM model with heterogeneous radiosensitivity and anisotropic microscopic extensions (ME). METHODS: Each cell within the GBM model was assigned an α/ß value associated with different GBM cell lines and a 10B concentration. Dosimetry matrices corresponding to various MEs were calculated and combined to evaluate cell survival fractions (SF) using clinical target volume (CTV) margins of 2.0 & 2.5 cm. SFs for the BNCT simulation were compared with external X-ray radiotherapy (EBRT) SFs. RESULTS: The SFs within the beam region decreased by more than two times compared to EBRT. It was demonstrated that BNCT results in markedly reduced SFs for both CTV margins compared to EBRT. However, the SF reduction as a result of the CTV margin extension using BNCT was significantly lower than using X-ray EBRT for one MEP distribution, while it remained similar for the other two MEP models. CONCLUSIONS: Although the efficiency of BNCT in terms of cell kill is superior to EBRT, the extension of the CTV margin by 0.5 cm may not increase the BNCT treatment outcome significantly.

Cannot Target What Cannot Be Seen: Molecular Imaging of Cancer Stem Cells.

Cancer stem cells are known to play a key role in tumour development, proliferation, and metastases. Their unique properties confer resistance to therapy, often leading to treatment failure. It is believed that research into the identification, targeting, and eradication of these cells can revolutionise oncological treatment. Based on the principle that what cannot be seen, cannot be targeted, a primary step in cancer management is the identification of these cells. The current review aims to encompass the state-of-the-art functional imaging techniques that enable the identification of cancer stem cells via various pathways and mechanisms. The paper presents in vivo molecular techniques that are currently available or await clinical implementation. Challenges and future prospects are highlighted to open new research avenues in cancer stem cell imaging.

Evaluation of the effectiveness of steel for shielding photoneutrons produced in medical linear accelerators: A Monte Carlo particle transport study.

PURPOSE: To confirm the effectiveness of steel as a material for shielding photoneutrons produced in medical linear accelerators and report values for neutron first and second tenth value layer to be used as radiation protection quantities. METHODS: Monte Carlo code Geant4 was used to simulate transport of photoneutrons through primary barriers containing layers of concrete and steel. The photoneutron spectrum generated in high energy modern accelerator head components was simulated and projected to barriers of different thicknesses of steel including a control case of no barrier. To derive the neutron tenth value layer (TVLn), absorbed dose was evaluated at 1 cm depth in a water phantom outside the barrier. The fluence and energy spectrum of neutrons leaking outside the barrier were also calculated. The neutron source model was used to quantitatively assess the neutron shielding for a newly designed bunker. RESULTS: For an 18 MV photon beam produced by a linear accelerator, the first and second TVLn, for steel as a neutron shielding material were determined to be 15.7-16.1 cm and 28.5-32.4 cm, respectively, depending on the vendor. The lateral distribution of neutrons outside steel barriers is investigated. Also, we show the relative efficiency of steel for fast and epithermal neutrons and determine the neutron energy spectrum outside a steel barrier. CONCLUSION: This paper agrees with previous studies for Pu-Be sources, and we would advocate using these values for the purposes of high energy linear accelerator bunker design.

Radiobiological and Treatment-Related Aspects of Spatially Fractionated Radiotherapy.

The continuously evolving field of radiotherapy aims to devise and implement techniques that allow for greater tumour control and better sparing of critical organs. Investigations into the complexity of tumour radiobiology confirmed the high heterogeneity of tumours as being responsible for the often poor treatment outcome. Hypoxic subvolumes, a subpopulation of cancer stem cells, as well as the inherent or acquired radioresistance define tumour aggressiveness and metastatic potential, which remain a therapeutic challenge. Non-conventional irradiation techniques, such as spatially fractionated radiotherapy, have been developed to tackle some of these challenges and to offer a high therapeutic index when treating radioresistant tumours. The goal of this article was to highlight the current knowledge on the molecular and radiobiological mechanisms behind spatially fractionated radiotherapy and to present the up-to-date preclinical and clinical evidence towards the therapeutic potential of this technique involving both photon and proton beams.

Characteristic differences in radiation-induced DNA damage response in human papillomavirus-negative and human papillomavirus-positive head and neck cancers with accumulation of fractional radiation dose.

BACKGROUND: Superior treatment responses by patients with human papillomavirus (HPV) positive head and neck squamous cell carcinoma (HNSCC), compared to patients with HNSCC from other causes, drive biomarker research to optimize treatment. Most HNSCC patients receive radiation therapy delivered as a fractionated course. Changing HPV status in HNSCC from a positive prognostic marker to a predictive one requires biomarkers that capture cellular radiation response to cumulative dose. METHODS: Nuclear enlargement, γH2AX expression and micronuclei count, were studied in six HNSCC cell lines after 4 Gy fractionated X-irradiation. RESULTS: All HNSCC cell lines displayed altered cellular responses, indicating increasing inability to repair radiation damage with subsequent radiation fractions. Increases in nuclear area were significantly greater among HPV positive cell lines (207% and 67% for the HPV positive and HPV negative groups, respectively). CONCLUSIONS: A different character of DNA repair dysfunction in the HPV positive group suggests greater chromosomal translocation with accumulated radiation dose.

Intrinsic Radiosensitivity Is Not the Determining Factor in Treatment Response Differences between HPV Negative and HPV Positive Head and Neck Cancers.

Head and neck squamous cell carcinomas (HNSCC) resulting from human papillomavirus (HPV) are increasing in incidence but demonstrate significantly better treatment response than HNSCC from other causes such as tobacco and alcohol. This study sought to identify differences in HNSCC, intrinsic to HPV status, in their response to radiation dose. Previously unexamined changes in radio-responsiveness following fractionated X-ray irradiation were compared between HPV positive and negative statuses of HNSCC. Six HNSCC cell lines, 3 of each HPV status, were investigated for radiosensitivity by clonogenic assay and modelled by response as a function of dose. Generational cultures of each cell line were developed to follow changes in radiosensitivity after repeated irradiations simulating fractionated radiation therapy. As a group, the HPV positive cell lines were more radiosensitive, but with changes following repeated fractions of dose, and modelling of response as a function of dose, both statuses displayed large radiobiological heterogeneity. These findings challenge current radiobiological assumptions of head and neck cancers as early responding tissue to radiation and may go some way in explaining difficulties reaching consensus in stratification of treatment by HPV status. Consequently, results from this study do not support stratifying radiation therapy by HPV status.

Influence of the human papillomavirus on the radio-responsiveness of cancer stem cells in head and neck cancers.

A growing proportion of head and neck cancers (HNC) result from HPV infection. Between HNC aetiological groups (HPV positive and HPV negative) clinical evidence demonstrates significantly better treatment response among HPV positive cancers. Cancer stem cells (CSCs) are identified in HNC tumour populations as agents of treatment resistance and a target for tumour control. This study examines dynamic responses in populations of a CSC phenotype in HNC cell lines following X-irradiation at therapeutic levels, and comparing between HPV statuses. Variations in CSC density between HPV groups showed no correlation with better clinical outcomes seen in the HPV positive status. CSC populations in HPV positive cell lines ranged from 1.9 to 4.8%, and 2.6 to 9.9% for HPV negative. Following 4 Gy X- irradiation however, HPV negative cell lines demonstrated more frequent and significantly greater escalation in CSC proportions, being 3-fold that of the HPV positive group at 72 hours post irradiation. CSC proportions of tumour populations are not fixed but subject to change in response to radiation at therapeutic dose levels. These findings imply a potential effect of aetiology on radio-responsiveness in CSCs, illustrating that clonogen treatment response may be more informative of therapy outcomes than inherent population density alone.

Design and verification of an external radiobiological beam port on a 16.5 MeV GE PETtrace proton cyclotron.

PURPOSE: Protons and heavy ions are considered to be ideal particles for use in external beam radiotherapy due to the superior properties of the dose distribution. While a photon (x-ray) beam delivers considerable dose to healthy tissues around the tumor, a proton beam that is delivered with sufficient energies has: a low entrance dose (the dose in front of the tumor); a high-dose region within the tumor, known as the Bragg peak; and, no exit dose beyond the tumor. Proton therapy is the next major step in advancing radiotherapy treatment. The purpose of this project was to adapt an existing radioisotope production cyclotron, a General Electric (GE) PETtrace, to enable radiobiological studies using proton beams. During routine use the PETtrace delivers 16.5 MeV protons to target with beam currents in the range of 10-100 µA resulting in dose rates in the order of kGy/s. To achieve the aim of the project the dose rate had to be reduced to the Gy/min range, without attenuating the proton energy below 5 MeV. This paper covers the design, construction and validation of the beam port. METHODS: Monte Carlo simulations were performed, using GEANT4, SRIM and PACE4 to design the beam port and optimize its components. Once the beam port was fabricated, validation experiments were performed using EBT3 and HD-V2 Gafchromic™ films, and a Keithley 6485 picoampere meter. RESULTS AND CONCLUSION: The external beam port was successfully modeled, designed and fabricated. By using a 0.25 mm thick gold foil and a brass pin-hole collimator the beam was spread from a narrow full beam diameter of 10 mm to a wide beam with a 5% flatness area in the center of the beam that had a diameter of ~20 mm. In using this system the dose rate was reduced from kGy/s to ~30 Gy/min.

Diversity of cancer stem cells in head and neck carcinomas: The role of HPV in cancer stem cell heterogeneity, plasticity and treatment response.

Head and neck squamous cell carcinomas (HNSCC) resulting from oncogenic transformations following human papillomavirus (HPV) infection consistently demonstrate better treatment outcomes than HNSCC from other aetiologies. Squamous cell carcinoma of the oropharynx (OPSCC) shows the highest prevalence of HPV involvement at around 70-80%. While strongly prognostic, HPV status alone is not sufficient to predict therapy response or any potential dose de-escalation. Cancer stem cell (CSC) populations within these tumour types represent the most therapy-resistant cells and are the source of recurrence and metastases, setting a benchmark for tumour control. This review examines clinical and preclinical evidence of differences in response to treatment by the HPV statuses of HNSCC and the role played by CSCs in treatment resistance and their repopulation from non-CSCs. Evidence was collated from literature searches of PubMed, Scopus and Ovid for differential treatment response by HPV status and contribution by critical biomarkers including CSC fractions and chemo-radiosensitivity. While HPV and CSC are yet to fulfil promise as biomarkers of treatment response, understanding how HPV positive and negative aetiologies affect CSC response to treatment and tumour plasticity will facilitate their use for greater treatment individualisation.

Imaging of Tumor Characteristics and Molecular Pathways With PET: Developments Over the Last Decade Toward Personalized Cancer Therapy.

PURPOSE: Improvements in personalized therapy are made possible by the advances in molecular biology that led to developments in molecular imaging, allowing highly specific in vivo imaging of biological processes. Positron emission tomography (PET) is the most specific and sensitive imaging technique for in vivo molecular targets and pathways, offering quantification and evaluation of functional properties of the targeted anatomy. MATERIALS AND METHODS: This work is an integrative research review that summarizes and evaluates the accumulated current status of knowledge of recent advances in PET imaging for cancer diagnosis and treatment, concentrating on novel radiotracers and evaluating their advantages and disadvantages in cancer characterization. Medline search was conducted, limited to English publications from 2007 onward. Identified manuscripts were evaluated for most recent developments in PET imaging of cancer hypoxia, angiogenesis, proliferation, and clonogenic cancer stem cells (CSC). RESULTS: There is an expansion observed from purely metabolic-based PET imaging toward antibody-based PET to achieve more information on cancer characteristics to identify hypoxia, proangiogenic factors, CSC, and others. 64Cu-ATSM, for example, can be used both as a hypoxia and a CSC marker. CONCLUSIONS: Progress in the field of functional imaging will possibly lead to more specific tumor targeting and personalized treatment, increasing tumor control and improving quality of life.

Geant4 beam model for boron neutron capture therapy: investigation of neutron dose components.

Boron neutron capture therapy (BNCT) is a biochemically-targeted type of radiotherapy, selectively delivering localized dose to tumour cells diffused in normal tissue, while minimizing normal tissue toxicity. BNCT is based on thermal neutron capture by stable [Formula: see text]B nuclei resulting in emission of short-ranged alpha particles and recoil [Formula: see text]Li nuclei. The purpose of the current work was to develop and validate a Monte Carlo BNCT beam model and to investigate contribution of individual dose components resulting of neutron interactions. A neutron beam model was developed in Geant4 and validated against published data. The neutron beam spectrum, obtained from literature for a cyclotron-produced beam, was irradiated to a water phantom with boron concentrations of 100 µg/g. The calculated percentage depth dose curves (PDDs) in the phantom were compared with published data to validate the beam model in terms of total and boron depth dose deposition. Subsequently, two sensitivity studies were conducted to quantify the impact of: (1) neutron beam spectrum, and (2) various boron concentrations on the boron dose component. Good agreement was achieved between the calculated and measured neutron beam PDDs (within 1%). The resulting boron depth dose deposition was also in agreement with measured data. The sensitivity study of several boron concentrations showed that the calculated boron dose gradually converged beyond 100 µg/g boron concentration. This results suggest that 100µg/g tumour boron concentration may be optimal and above this value limited increase in boron dose is expected for a given neutron flux.

Development of an integrated Monte Carlo model for glioblastoma multiforme treated with boron neutron capture therapy.

Glioblastomas (GBM) are notorious for their high fatality rate. Boron Neutron Capture Therapy (BNCT) being a biochemically targeted type of radiotherapy is a potent modality for GBM. In the current work, a BNCT treatment modelling framework for GBM was developed. Optimal Clinical Target Volume (CTV) margins for GBM-BNCT and the BNCT efficacy have been investigated. The model integrated a cell-based dosimetry model, an in-house-developed epithermal neutron beam model and previously-developed Microscopic Extension Probability (MEP) model. The system was defined as a cubic ICRP-brain phantom divided into 20 µm side voxels. The corresponding 10B concentrations in GBM and normal brain cells were applied. The in-silico model was irradiated with the epithermal neutron beam using 2 and 2.5 cm CTV margins. Results from the cell-based dosimetry and the MEP models were combined to calculate GBM cell survival fractions (SF) post BNCT and compared to x-ray radiotherapy (XRT) SFs. Compared to XRT, the SF within the beam decreased by five orders of magnitudes and the total SF was reduced three times following BNCT. CTV extension by 0.5 cm reduced the SF by additional (53.8 ± 0.3)%. In conclusion, BNCT results in a more efficient cell kill. The extension of the CTV margin, however, may not increase the treatment outcome significantly.

Current challenges in clinical target volume definition: tumour margins and microscopic extensions.

Determination of optimal clinical target volume (CTV) margins around gross tumour volume (GTV) for modern radiotherapy techniques, requiring more precise target definitions, is controversial and complex. Tumour localisation has been greatly improved using molecular imaging integrated with conventional imaging techniques. However, the exact incidence and extent of microscopic disease, to be encompassed by CTV, cannot be visualised by any techniques developed to date and remain uncertain. As a result, the CTV is generally determined by clinicians based on their experience and patients' histopathological data. In this article we review histopathological studies addressing the extent of subclinical disease and its possible correlation with tumour characteristics in various tumour sites. The data have been tabulated to facilitate a comparison between proposed margins by different investigations and with current margins generally accepted for each tumour site. It is concluded that there is a need for further studies to reach a consensus on the optimal CTV pertaining to each tumour site.