Conventional Radiotherapy Research Articles

Oxygen Consumption In Vivo by Ultra-High Dose Rate Electron Irradiation Depends Upon Baseline Tissue Oxygenation

Purpose: This study aimed to assess the impact of tissue oxygen levels on transient oxygen consumption induced by ultra-high dose rate (UHDR) electron radiation in murine flank and to examine the effect of dose rate variations on this relationship. Methods: Real-time oximetry using the phosphorescence quenching method and Oxyphor PdG4 molecular probe was employed. Continuous measurements were taken during radiation delivery on a UHDR-capable Mobetron linear accelerator (linac). Oxyphor PdG4 was administered into the subcutaneous tissue of the flank skin one hour before irradiation. Skin oxygen tension (pO2) was manipulated by adjusting oxygen content in the inhaled gas mixture and/or by vasculature compression. A skin surface radiation dose of 19.8±0.3Gy was verified using a calibrated semiconductor diode dosimeter. Dose rate was varied across the UHDR range by changing linac cone length and pulse repetition frequency (PRF). Results: The decrease in pO2 per unit dose during radiation delivery, termed oxygen consumption g-value (gO2, mmHg/Gy), was significantly influenced by tissue oxygen levels in the range 0-65mmHg under UHDR conditions. Within the 0-20mmHg range, gO2 exhibited a sharp increase with rising baseline pO2, plateauing at 0.26mmHg/Gy. Dose rate variations (mean values 25-1170Gy/s, per-pulse doses of 2.5-9.8Gy) were explored by varying both cone length and PRF (10-120Hz) with no significant changes in gO2. Conventional dose rate irradiation resulted in no discernible changes in pO2. Conclusions: The results show significant differences in the radiation-chemical effects of UHDR radiation between hypoxic and well-oxygenated tissues. Similar trends between earlier published in vitro and in vivo experiments presented herein suggest the chemical mechanisms driving the dependencies of gO2 on pO2 are similar, potentially underpinning the FLASH effect. Importantly, significant variations in baseline pO2 were observed in animals kept under identical conditions, underscoring the necessity to control and monitor tissue oxygen levels for preclinical investigations and future clinical applications of FLASH-RT.

Concurrent Chemoradiotherapy versus Radiotherapy Alone in the Treatment of Stage II and T3N0M0 Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis

AimsThe efficacy of concurrent chemoradiotherapy (CCRT) for Stage II and T3N0 nasopharyngeal carcinoma (NPC), particularly during the shift from two-dimensional conventional radiotherapy (2DCRT) to intensity-modulated radiotherapy (IMRT) is debated.Therefore this study aims to systematically evaluate and meta-analyze survival benefits of CCRT versus radiotherapy alone for Stage II and T3N0 NPC, stratified by radiotherapy techniques. Materials and methodsAs of April 1, 2024, we conducted an exhaustive literature search across databases such as PubMed, Embase, Cochrane Library, and Web of Science, with the aim of identifying and screening studies that compare the efficacy of CCRT versus radiotherapy alone in the treatment of Stage II and T3N0 NPC. ResultsA total of 10 studies encompassing 5015 patients were included in this comprehensive analysis. The findings indicate that, apart from progression-free survival (PFS), CCRT did not improve survival outcomes, including overall survival (OS), distant metastasis-free survival (DMFS), local recurrence-free survival (LRRFS), and failure-free survival (FFS), with all P values exceeding 0.05. Concurrently, the incidence of grade ≥3 adverse events associated with CCRT was significantly elevated (odds ratio [OR] = 3.77, 95% confidence interval [CI] = 2.75–5.15, P < 0.0001). Subgroup analysis revealed that, compared with RT, the combination of 2DCRT with concurrent chemotherapy significantly improved OS (hazard ratio [HR] = 0.57, 95% CI = 0.46–0.71, P < 0.00001), PFS (HR = 0.65, 95% CI=0.53–0.78, P < 0.00001), DMFS (HR = 0.54, 95% CI = 0.37–0.79, P = 0.002), and LRRFS (HR = 0.63, 95% CI = 0.49–0.82, P = 0.0005). In contrast, the combination of IMRT with concurrent chemotherapy failed to demonstrate improvements in OS, PFS, DMFS, or LRRFS, with all P values exceeding 0.05. ConclusionIn contrast with RT, CCRT did not enhance survival in stage II and T3N0 NPC patients, yet caused more adverse reactions. 2DCRT combined with concurrent chemotherapy significantly improved OS, PFS, DMFS, and LRRFS, while IMRT with concurrent chemotherapy showed no clinical benefits.

The Role of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma Patients: A Literature Review

Background: Globally, hepatocellular carcinoma (HCC) is the most prevalent kind of primary liver cancer. Treatment options for HCC include radiotherapy, immunotherapy, surgery, targeted therapy, transarterial chemoembolization, and hepatic arterial infusion chemotherapy. Limited efficacy was observed since 70-80% of cases are diagnosed late and unresectable. Growing evidence reported that SBRT is a viable option for locoregional treatments like radiofrequency ablation (RFA) or transarterial chemoembolization (TACE) for patients who did not respond to those treatments. Methods: A thorough search of electronic databases including PubMed, Cochrane Library, and Embase was conducted for studies on Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma published in English over the past 10 years. The review process followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to ensure a systematic approach. Inclusion criteria encompassed studies focusing on SBRT use in HCC treatment, with extracted data synthesized to provide a comprehensive overview of current evidence. Any discrepancies during the review were resolved through consultation with a third reviewer when necessary. Results: In comparison to conventional radiation therapy, Stereotactic Body Radiation Therapy (SBRT) offers precise administration of the high dose of radiotherapy, given in fewer fractions, and may be used in conjunction with other therapy modalities. Global guidelines, including in Indonesia, have proposed the implementation of SBRT. Local control was reportedly achieved in around 90–95% of HCC patients. Multimodal therapies, combined with TACE, showed superior results regarding the local control and overall survival. SBRT may eventually become the definitive treatment for early-stage HCC patients and has a critical role as a transitional therapy for patients awaiting liver transplantation. Improved outcomes and quality of life were also observed in patients with portal vein thrombosis (PVT) and extrahepatic metastases who underwent SBRT. Conclusions: SBRT results in promising local control, raises overall survival, and improves the quality of life in HCC patients with various stages.

A Comprehensive Review of Diffusing Alpha-Emitters Radiation Therapy (DaRT): From Dosimetry to Its Biological Effectiveness

Diffusing alpha-emitters radiation therapy (DaRT) represents a groundbreaking development in cancer therapy, offering a solution to the limitations of conventional radiation therapy. By deploying &lt;sup&gt;224&lt;/sup&gt;Ra embedded seeds, DaRT achieves targeted delivery of high-dose alpha particles directly to tumor sites, showing considerable efficacy in tumor control and minimal damage to adjacent healthy tissues. This comprehensive review analyzes the published literature regarding mechanisms, seed production, dose calculation, measurement, and biological experiments related to DaRT. It includes in-depth discussions on mathematical models, Monte Carlo simulations for dose distribution, real-time &lt;i&gt;in vivo&lt;/i&gt; dosimetry developments, and biological experiments both in vitro and &lt;i&gt;in vivo&lt;/i&gt;. Clinical trial outcomes are also examined to evaluate the therapy’s effectiveness in various cancer types. DaRT utilizes &lt;sup&gt;224&lt;/sup&gt;Ra-labeled seeds, using the decay chain of &lt;sup&gt;224&lt;/sup&gt;Ra to deliver alpha particles effectively within a tumor. Several asymptotic diffusion-leakage models were developed to calculate the alpha dose distribution of DaRT. &lt;i&gt;In vivo&lt;/i&gt; dosimetry techniques have been developed for real-time monitoring. Biological experiments demonstrated the cytotoxic effects of DaRT across various cancer cells, with varying radiosensitivity. Additionally, the enhanced effects of combined therapy with chemotherapy and immunotherapy were suggested by many &lt;i&gt;in vivo&lt;/i&gt; studies. Clinical trials have shown high complete response rate in squamous cell carcinoma, with minimal side effects, suggesting DaRT’s feasibility and safety. DaRT emerges as a highly localized cancer treatment method with minimal side effects compared to traditional radiation therapy. It directly ablates tumors and potentially enhances immune responses, indicating a significant advance in cancer therapy. Future research and ongoing clinical trials will further elucidate its efficacy across different cancer types and in combination with other treatments.

HYBRID PLANNING A SIMPLE TECHNIQUE FOR CRANIOSPINAL IRRADIATION (CSI)

Purpose: A simple planning technique for craniospinal irradiation using Eclipse treatment planning system. Material and methods: In RT treatment planning, base plan optimization feature is used in sequential RT planning by anticipating the dose delivered to organ at risk (OAR) &amp; planning target volume (PTV) in the base plan. In hybrid planning technique, the whole PTV is divided into two parts, Brain PTV &amp; Spine PTV. Spine PTV is overlapped minimum 2-3 cm over the Brain PTV at their junction while creating structures for RT planning. Brain PTV is planned with conventional RT technique &amp; the Spine PTV planned with rapid arc technique (VMAT). In the plan optimization process of spine PTV, first base plan is selected then the optimization parameter is set accordingly as per total prescribed dose of 36 Gy for both the PTVs. The base plan is the dose calculated plan which is incorporated in the rapid arc plan optimization hence the pre-existed doses of Brain PTV &amp; OAR help to understand the plannerfor achieving desired planning objectives during Spine PTV, RT plan optimization. Finally for the dose calculation of Spine PTV RT plan, planner has to copy fields of Brain PTV &amp; paste it in Spine PTV plan and need to calculate dose for these copied fields. The final plan contains a dose calculated of Brain PTV fields and Spine PTV fields termed as hybrid plan. Result: Reduction in the total number of monitor units is observed for the hybrid plan compared to single VMAT plan, which is statistically significant (p&lt;0.05). Conclusion: Present study introduced the hybrid planning technique which can exploit benefits of conventional and modern techniques.

Dosimetric calibration of anatomy-specific ultra-high dose rate electron irradiation platform for preclinical FLASH radiobiology experiments.

FLASH radiation therapy (RT) offers a promising avenue for the broadening of the therapeutic index. However, to leverage the full potential of FLASH in the clinical setting, an improved understanding of the biological principles involved is critical. This requires the availability of specialized equipment optimized for the delivery of conventional (CONV) and ultra-high dose rate (UHDR) irradiation for preclinical studies. One method to conduct such preclinical radiobiological research involves adapting a clinical linear accelerator configured to deliver both CONV and UHDR irradiation. We characterized the dosimetric properties of a clinical linear accelerator configured to deliver ultra-high dose rate irradiation to two anatomic sites in mice and for cell-culture FLASH radiobiology experiments. Delivered doses of UHDR electron beams were controlled by a microcontroller and relay interfaced with the respiratory gating system. We also produced beam collimators with indexed stereotactic mouse positioning devices to provide anatomically specific preclinical treatments. Treatment delivery was monitored directly with an ionization chamber, and charge measurements were correlated with radiochromic film measurements at the entry surface of the mice. The setup for conventional dose rate irradiation utilized the same collimation system but at increased source-to-surface distance. Monte Carlo simulations and film dosimetry were used to characterize beam properties and dose distributions. The mean electron beam energies before the flattening filter were 18.8 MeV (UHDR) and 17.7 MeV (CONV), with corresponding values at the mouse surface of 17.2 and 16.2 MeV. The charges measured with an external ion chamber were linearly correlated with the mouse entrance dose. The use of relay gating for pulse control initially led to a delivery failure rate of 20% (±1 pulse); adjustments to account for the linac latency improved this rate to<1/20. Beam field sizes for two anatomically specific mouse collimators (4 × 4 cm2 for whole-abdomen and 1.5 × 1.5 cm2 for unilateral lung irradiation) were accurate within<5% and had low radiation leakage (<4%). Normalizing the dose at the center of the mouse (∼0.75cm depth) produced UHDR and CONV doses to the irradiated volumes with>95% agreement. We successfully configured a clinical linear accelerator for increased output and developed a robust preclinical platform for anatomically specific irradiation, with highly accurate and precise temporal and spatial dose delivery, for both CONV and UHDR irradiation applications.

Online adaptive radiotherapy in stereotactic body radiotherapy for pancreatic cancer patients.

Stereotactic radiation therapy (SBRT) has emerged as a promising treatment modality for locally advanced pancreatic cancer. The aim of this study is to assess the dosimetric efficacy of online adaptive radiotherapy (ART) in comparison to image-guided radiation therapy (IGRT) for pancreatic cancer. We conducted a retrospective analysis involving 8 patients diagnosed with locally advanced pancreatic cancer. The gross tumor volume (GTV) delineates the visible extent of the tumor on imaging, while the planning tumor volume (PTV) was generated by expanding 5mm from the GTV and ensuring a 3mm distance from the small intestine, duodenum, and stomach simultaneously. Treatment planning was executed using the United Imaging Healthcare Treatment Planning System workstation. The control group underwent evaluation based on daily validated fan-beam CT (FBCT) scans, assessing both the dose delivered to actual organs at risk (OARs) and the target volume. Radiotherapy plans were developed utilizing simulation CT, and conventional radiotherapy with daily image-guided radiation therapy (IGRT) was administered using FBCT-Linac. Conversely, patients in the study group received daily validated FBCT-guided adaptive radiotherapy plans, with a focus on mean dose assessment of both the target volume and OARs. Subsequently, we compared the average outcomes of each treatment fraction between IGRT and online adaptive radiotherapy (ART). Comparison between ART and IGRT treatment plans revealed significant differences in various dosimetric parameters: For PTV: V98%: ART (96.28%) vs IGRT (89.73%), p = 0.000, V95%: ART (96.28%) vs IGRT (89.73%), p = 0.031, V90%: ART (98.58%) vs IGRT (93.65%), p = 0.000, Dmean: ART (4912.91) vs IGRT (4804.11), p = 0.000. For GTV: V100%: ART (97.96%) vs IGRT (94.85%), p = 0.314, V98%: ART (100.00%) vs IGRT (96.83%), p = 0.000, V90%: ART (100.00%) vs IGRT (97.75%), p = 0.000, Dmean: ART (4972.17) vs IGRT (4907.23), p = 0.000. For the duodenum: D0.5cc: ART (2883.92) vs IGRT (3359.35), p = 0.000, D1cc: ART (2726.32) vs IGRT (3128.66), p = 0.001, D5cc: ART (2051.96) vs IGRT (2273.93), p = 0.015, D10cc: ART (1650.73) vs IGRT (1731.74), p = 0.211. For the small bowel: D0.5cc: ART (3022.3) vs IGRT (3142.64), p = 0.037. D5cc: ART (2151.09) vs IGRT (2389.15), p = 0.043, D10cc: ART (1775.20) vs IGRT (1942.00), p = 0.079. For the stomach: D0.5cc: ART (3353.92) vs IGRT (4117.85), p = 0.000, D5cc: ART (2860.20) vs IGRT (3235.41), p = 0.000, D10cc: ART (2553.72) vs IGRT (2836.73), p = 0.000. For the Dmean of the left kidney and right kidney: Left kidney: ART (248.28) vs IGRT (239.65), p = 0.100. Right kidney: ART (314.55) vs IGRT (307.17), p = 0.345. These results suggest significant improvements in PTV coverage and sparing of OARs with ART compared to IGRT, indicating the potential of ART in optimizing treatment outcomes for pancreatic cancer patients.Compared to conventional IGRT-guided SBRT programs, ART-based SBRT for pancreatic cancer not only enhances the dose distribution to the target volume but also mitigates the radiation exposure to critical organs-at-risk (OARs) such as the duodenum, small intestine, and stomach. This approach may offer a more favorable safety profile while concurrently enhancing treatment efficacy.

On the significance of the different geometrical and dosimetric parameters in microbeam and minibeam radiation therapy a retrospective evaluation.

Spatially Fractionated Radiation Therapy (SFRT) is an unconventional therapeutic approach with the potential to disrupt the classical paradigms of conventional radiation therapy. The high spatial dose modulation in SFRT is believed to activate distinct radiobiological mechanisms which lead to remarkable increases in normal tissue tolerance. To make optimal use of SFRT and its benefits, a deeper understanding of the biological response and its relationship with the complex dosimetric and geometric components of SFRT is essential. A retrospective evaluation of preclinical studies was conducted to gain insight into the dosimetric and geometric parameters that are most correlated with normal tissue response. Current literature evaluates the response of tissue to MBRT and MRT according to various end points, e.g. the level of desquamation, degree of necrosis, or the amount of malcalcification. A set of metrics was developed to allow a quantitative comparison of these results. The strongest correlations were observed with the doses in both the peaks and valleys as well as the ratio of the area covered by the peak over the total area. This emphasises the geometry of the beam. MBRT challenged previous uniform dose-distribution paradigms by highlighting the critical role of Peak Dose alongside Valley Dose in tissue sparing whereas MRT underscores the significant influence of geometric beam parameters on tissue preservation. The data exhibits variability in the results obtained using different animal models and endpoints and additional research is warranted to explore the trends observed in this study under controlled conditions.

Comprehensive analysis of multiple regulated cell death risk signatures in lung adenocarcinoma

BackgroundRegulated cell death (RCD) has considerable impact on tumor progress and sensitivity of treatment. Lung adenocarcinoma (LUAD) show a high resistance for conventional radiotherapies and chemotherapies. Currently, regulation of cancer cell death has been emerging as a new promising therapeutic avenue for LUAD patients. However, the crosstalk in each pattern RCD is unclear. MethodsWe integrated collected the hub-genes of 12 RCD subroutines and compressively analyzed these hub-genes synergistic effect in LUAD. The characters of RCD genes expression and prognosis were developed in The Cancer Genome Atlas (TCGA)-LUAD data. We developed and validated an RCD risk model based on TCGA and GSE70294 data set, respectively. Functional annotation and tumor immunotherapy based on the risk model were also investigated. Results28 RCD-related genes and two LUAD molecular cluster were identified. Survival analysis revealed that the prognosis in high-risk group was worser than those in low-risk group. Functional enrichment analysis indicated that the RCD risk model correlated with immune responses. Further analysis indicated that the high-risk group in RCD risk model exhibited an immunosuppressive microenvironment and a lowly immunotherapy responder ratio. ConclusionsWe present an RCD risk model which have a promising ability in predicting LUAD prognosis and immunotherapy response.

Prediction of new-onset atrial fibrillation in patients with non-small cell lung cancer treated with curative-intent conventional radiotherapy

BackgroundAtrial fibrillation (AF) is an important side effect of thoracic Radiotherapy (RT), which may impair quality of life and survival. This study aimed to develop a prediction model for new-onset AF in patients with Non-Small Cell Lung Cancer (NSCLC) receiving RT alone or as a part of their multi-modal treatment. Patients and MethodsPatients with stage I-IV NSCLC treated with curative-intent conventional photon RT were included. The baseline electrocardiogram (ECG) was compared with follow-up ECGs to identify the occurrence of new-onset AF. A wide range of potential clinical predictors and dose-volume measures on the whole heart and six automatically contoured cardiac substructures, including chambers and conduction nodes, were considered for statistical modeling. Internal validation with optimism-correction was performed. A nomogram was made. Results374 patients (mean age 69 ± 10 years, 57 % male) were included. At baseline, 9.1 % of patients had AF, and 42 (11.2 %) patients developed new-onset AF. The following parameters were predictive: older age (OR=1.04, 95 % CI: 1.013–1.068), being overweight or obese (OR=1.791, 95 % CI: 1.139–2.816), alcohol use (OR=4.052, 95 % CI: 2.445–6.715), history of cardiac procedures (OR=2.329, 95 % CI: 1.287–4.215), tumor located in the upper lobe (OR=2.571, 95 % CI: 1.518–4.355), higher forced expiratory volume in 1 s (OR=0.989, 95 % CI: 0.979–0.999), higher creatinine (OR=1.008, 95 % CI: 1.002–1.014), concurrent chemotherapy (OR=3.266, 95 % CI: 1.757 to 6.07) and left atrium Dmax (OR=1.022, 95 % CI: 1.012–1.032). The model showed good discrimination (area under the curve = 0.80, 95 % CI: 0.76–0.84), calibration and positive net benefits. ConclusionThis prediction model employs readily available predictors to identify patients at high risk of new-onset AF who could potentially benefit from active screening and timely management of post-RT AF.

Feasibility, Safety, and Factors Predicting Completion of CROSS Protocol–Based Neoadjuvant Chemoradiotherapy for Esophageal Squamous Carcinoma: Experience from an Indian Tertiary Care Cancer Center

Background Neoadjuvant chemoradiotherapy (NACRT) using the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) protocol has improved esophageal cancer outcomes. This study reports the real-world experience of the CROSS regimen for esophageal squamous cell carcinoma (ESCC) regarding its feasibility, safety, and predictors of treatment completion from an Indian tertiary center. Methodology A retrospective review was conducted for patients with ESCC receiving CROSS (radiation dose: 41.4 Gy) or a modified CROSS (mCROSS; radiation dose: 45 Gy) protocol NACRT between 2015 and 2022. We studied the treatment tolerability, factors predicting NACRT completion, and the effect of completion of its chemotherapy component on the pathological outcomes. Results Of the109 patients (68.8% males; mean age, 56 ± 9 years; Charlson's comorbidity index [CCI] &gt;2, 19.3%; stage III–IVA, 58%; mean tumor length, 5.5 ± 2.1cm; CROSS, 70.6%; mCROSS, 29.4%), all except 4 completed radiotherapy but only 58 (53.2%) patients completed ≥4 cycles of chemotherapy. Forty-nine patients belonged to the “extended” CROSS trial inclusion criteria. Among the 60 patients who fulfilled the CROSS inclusion criteria, only 51.7% were able to complete ≥4 chemotherapy cycles. The commonest reason for noncompletion of chemotherapy was the occurrence of neutropenia (60.8%). Pretreatment hemoglobin (≥12 vs. &lt;12 g%; odds ratio [OR]: 2.76; 95% confidence interval [CI]: 1.10–6.96; p = 0.031), a low CCI (≤2 vs. &gt;2; OR: 2.98; 95% CI: 1.02–8.73; p = 0.047), and radiation therapy techniques (conformal vs. conventional; OR: 3.29; 95% CI: 1.14–9.50; p = 0.028) were associated with completion of chemotherapy (≥4 cycles). Although there was a trend toward improved R0 resection (95.7 vs. 91.4%), reduced node positivity (17.0 vs. 31.4%), and a high pCR (57.4 vs. 48.6%) in patients completing chemotherapy (≥4 cycles) compared with those not completing chemotherapy (&lt;4 cycles), these differences were statistically nonsignificant. Conclusion In this study, ESCC patients receiving the CROSS protocol NACRT could complete their radiotherapy component, but a significant proportion exhibited poor chemotherapy tolerance. Neutropenia was a major factor limiting chemotherapy delivery, but anemia, high CCI, and conventional radiation techniques were also associated with noncompletion of chemotherapy. The omission of a few chemotherapy cycles had no significant effect on the pathological response; however, its impact on cancer survival requires further evaluation.

Novel immunotherapeutic approaches in gastric cancer.

Gastric cancer is a malignant tumor that ranks third in cancer-related deaths worldwide. Early-stage gastric cancer can often be effectively managed through surgical resection. However, the majority of cases are diagnosed in advanced stages, where outcomes with conventional radiotherapy and chemotherapy remain unsatisfactory. Immunotherapy offers a novel approach to treating molecularly heterogeneous gastric cancer by modifying the immunosuppressive tumor microenvironment. Immune checkpoint inhibitors and adoptive cell therapy are regarded as promising modalities in cancer immunotherapy. Food and Drug Administration-approved programmed death-receptor inhibitors, such as pembrolizumab, in combination with chemotherapy, have significantly extended overall survival in gastric cancer patients and is recommended as a first-line treatment. Despite challenges in solid tumor applications, adoptive cell therapy has demonstrated efficacy against various targets in gastric cancer treatment. Among these approaches, chimeric antigen receptor-T cell therapy research is the most widely explored and chimeric antigen receptor-T cell therapy targeting claudin18.2 has shown acceptable safety and robust anti-tumor capabilities. However, these advancements primarily remain in preclinical stages and further investigation should be made to promote their clinical application. This review summarizes the latest research on immune checkpoint inhibitors and adoptive cell therapy and their limitations, as well as the role of nanoparticles in enhancing immunotherapy.

Identifying dose constraints for the parotid ducts to minimize patient-reported xerostomia: Is conventional mean dose sparing of the parotid glands sufficient?

The aim of this study was to identify dose constraints for the parotid ducts that limit patient-reported xerostomia and estimate whether these constraints are achieved during conventional parotid gland sparing radiation therapy (PGS-RT). Thirty-eight oropharyngeal squamous cell carcinoma patients were treated prospectively on trial with MRI sialography-guided parotid duct sparing radiation therapy (PDS-RT). PDS-RT explicitly minimizes dose to the parotid ducts in addition to PGS-RT. Parotid duct dose constraints were identified that distinguished patients reporting high and low rates of xerostomia. Atlas-based parotid duct contours were generated on a retrospective cohort of similar patients where the parotid ducts were not contoured nor explicitly spared to estimate the dose received by the parotid ducts during PGS-RT. Patients whose intraglandular parotid ducts or total parotid ducts were planned for a mean dose<14Gy and<12Gy, respectively, reported significantly (p<0.01) lower rates of xerostomia at 6 and 12 months post-RT. Patients receiving PDS-RT had average total and intraglandular duct doses of 11.6 and 13.6Gy, respectively, compared to an estimated 23.8 and 22.1Gy, for those receiving PGS-RT (p<0.01). Only 6% (6/108) and 20% (22/108) of patients receiving PGS-RT were estimated to meet the dose constraints for the total ducts and intraglandular ducts, respectively. Parotid duct dose thresholds exist that appear to distinguish patients with and without xerostomia. The identified dose thresholds are frequently not met in PGS-RT plans. In addition to reducing the dose to the parotid gland(s), parotid duct sparing may also further reduce xerostomia.

A microscopic oxygen transport model for ultra-high dose rate radiotherapy in vivo: The impact of physiological conditions on FLASH effect.

Ultra-high dose rate irradiation (≥40Gy/s, FLASH) has been shown to reduce normal tissue toxicity, while maintaining tumor control compared to conventional dose-rate radiotherapy. The radiolytic oxygen (O2) depletion (ROD) resulting from FLASH has been proposed to explain the normal tissue protection effect; however, in vivo experiments have not confirmed that FLASH induced global tissue hypoxia. Nonetheless, the experiments reported are based on volume-averaged measurement, which have inherent limitations in detecting microscopic phenomena, including the potential preservation of stem cells niches due to local FLASH-induced O2 depletion. Computational modeling offers a complementary approach to understand the ROD caused by FLASH at the microscopic level. We developed a comprehensive model to describe the spatial and temporal dynamics of O2 consumption and transport in response to irradiation in vivo. The change of oxygen enhancement ratio (OER) was used to quantify and investigate the FLASH effect as a function of physiological and radiation parameters at microscopic scale. We considered time-dependent O2 supply and consumption in a 3D cylindrical geometry, incorporating blood flow linking the O2 concentration ([O2]) in the capillary to that within the tissue through the Hill equation, radial and axial diffusion of O2, metabolic and zero-order radiolytic O2 consumption, and a pulsed radiation structure. Time-evolved distributions of [O2] were obtained by numerically solving perfusion-diffusion equations. The model enables the computation of dynamic O2 distribution and the relative change of OER (δROD) under various physiological and radiation conditions in vivo. Initial [O2] level and the subsequent changes during irradiation determined δROD distribution, which strongly depends on physiological parameters, i.e., intercapillary spacing, ultimately determining the tissue area with enhanced radioresistance. We observed that the δROD/FLASH effect is affected by and sensitive to the interplay effect among physiological and radiation parameters. It renders that the FLASH effect can be tissue environment dependent. The saturation of FLASH normal tissue protection upon dose and dose rate was shown. Beyond ∼60Gy/s, no significant decrease in radiosensitivity within tissue region was observed. In turn, for a given dose rate, the change of radiosensitivity became saturated after a certain dose level. Pulse structures with the same dose and instantaneous dose rate but with different delivery times were shown to have distinguishable δROD thus tissue sparing, suggesting the average dose rate could be a metric assessing the FLASH effect and demonstrating the capability of our model to support experimental findings. On a macroscopic scale, the modeling results align with the experimental findings in terms of dose and dose rate thresholds, and it also indicates that pulse structure can vary the FLASH effect. At the microscopic level, this model enables us to examine the spatially resolved FLASH effect based on physiological and irradiation parameters. Our model thus provides a complementary approach to experimental methods for understanding the underlying mechanism of FLASH radiotherapy. Our results show that physiological conditions can potentially determine the FLASH efficacy in tissue protection. The FLASH effect may be observed under optimal combination of physiological parameters, not limited to radiation conditions alone.

Synergistic effect of Gemcitabin-loaded metal organic frameworks nanoparticles with particle therapy

Combination of nanoagents with radiations has opened up new perspectives in cancer treatment, improving both tumor diagnosis and therapeutic index. This work presents the first investigation of an innovative strategy that combines porous metal–organic frameworks (nanoMOFs) loaded with the anti-cancer drug Gemcitabine monophosphate (GemMP) and particle therapy-a globally emerging technique that offers more precise radiation targeting and enhanced biological efficacy compared to conventional radiotherapy. This radiochemotherapy has been confronted with two major obstacles limiting the efficacy of therapeutics when tested in vivo: (i) the presence of hypoxia, one of the most important causes for radiotherapy failure and (ii) the presence of a microenvironment, main biological barrier to the direct penetration of nanoparticles into cancer cells.On the one hand, this study explore the effects of hypoxia on drug delivery systems in combination with radiation, demonstrating that GemMP-loaded nanoMOFs significantly enhance the anticancer efficacy of particle therapy under both normoxic (pO2 = 20 %) and hypoxic (pO2 = 0.5 %) conditions. Notably, the presence of GemMP-loaded nanoMOFs allows the irradiation dose to be reduced by 1.4-fold in normoxia and at least 1.6-fold in hypoxia, achieving the same cytotoxic effect (SF=10 %) as carbon or helium ions alone. Synergistic effects between GemMP-loaded nanoMOFs and radiations have been observed and quantified. On the other hand, we also highlighted the ability of the nanoMOFs to diffuse through an extracellular matrix and accumulate in cells. An higher effect of the encapsulated GemMP than the free drug was observed, confirming the key role of the nanoMOFs in transporting the active substance to the cancer cells as a Trojan horse. This paves the way to the design of “all-in-one” nanodrugs where each component plays a role in the optimization of cancer therapy to maximize cytotoxic effects on hypoxic tumor cells while minimizing toxicity on healthy tissue.

Cost-effectiveness of proton beam therapy vs. conventional radiotherapy for patients with brain tumors in Sweden: results from a non-randomized prospective multicenter study

BackgroundThis study assessed the cost-effectiveness of proton beam therapy (PBT) compared to conventional radiotherapy (CRT) for treating patients with brain tumors in Sweden.MethodsData from a longitudinal non-randomized study performed between 2015 and 2020 was used, and included adult patients with brain tumors, followed during treatment and through a one-year follow-up. Clinical and demographic data were sourced from the longitudinal study and linked to Swedish national registers to get information on healthcare resource use. A cost-utility framework was used to evaluate the cost-effectiveness of PBT vs. CRT. Patients in PBT group (n = 310) were matched with patients in CRT group (n = 40) on relevant observables using propensity score matching with replacement. Costs were estimated from a healthcare perspective and included costs related to inpatient and specialized outpatient care, and prescribed medications. The health outcome was quality-adjusted life-years (QALYs), derived from the EORTC-QLQ-C30. Generalized linear models (GLM) and two-part models were used to estimate differences in costs and QALYs.ResultsPBT yielded higher total costs, 14,639 US$, than CRT, 13,308 US$, with a difference of 1,372 US$ (95% CI, -4,914–7,659) over a 58 weeks’ time horizon. Further, PBT resulted in non-significantly lower QALYs, 0.746 compared to CRT, 0.774, with a difference of -0.049 (95% CI, -0.195–0.097). The probability of PBT being cost-effective was < 30% at any willingness to pay.ConclusionsThese results suggest that PBT cannot be considered a cost-effective treatment for brain tumours, compared to CRT.Trial registrationNot applicable.

A multifunctional targeted nano-delivery system with radiosensitization and immune activation in glioblastoma

Glioblastoma (GBM), the most common primary brain malignancy in adults, is notoriously difficult to treat due to several factors: tendency to be radiation resistant, the presence of the blood brain barrier (BBB) which limits drug delivery and immune-privileged status which hampers effective immune responses. Traditionally, high-dose irradiation (8 Gy) is known to effectively enhance anti-tumor immune responses, but its application is limited by the risk of severe brain damage. Currently, conventional dose segmentation (2 Gy) is the standard radiotherapy method, which does not fully exploit the potential of high-dose irradiation for immune activation. The hypothesis of our study posits that instead of directly applying high doses of radiation, which is risky, a strategy could be developed to harness the immune-stimulating benefits of high-dose irradiation indirectly. This involves using nanoparticles to enhance antigen presentation and immune responses in a safer manner. Angiopep-2 (A2) was proved a satisfactory BBB and brain targeting and Dbait is a small molecule that hijack DNA double strand break damage (DSB) repair proteins to make cancer cells more sensitive to radiation. In view of that, the following two nanoparticles were designed to combine immunity of GBM, radiation resistance and BBB innovatively. One is cationic liposome nanoparticle interacting with Dbait (A2-CL/Dbait NPs) for radiosensitization effect; the other is PLGA-PEG-Mal nanoparticle conjugated with OX40 antibody (A2-PLGA-PEG-Mal/anti-OX40 NPs) for tumor-derived protein antigens capture and optimistic immunoregulatory effect of anti-OX40 (which is known to enhance the activation and proliferation T cells). Both types of nanoparticles showed favorable targeting and low toxicity in experimental models. Specifically, the combination of A2-CL/Dbait NPs and A2-PLGA-PEG-Mal/anti-OX40 NPs led to a significant extension in the survival time and a significant tumor shrinkage of mice with GBM. The study demonstrates that combining these innovative nanoparticles with conventional radiotherapy can effectively address key challenges in GBM treatment. It represents a significant step toward more effective and safer therapeutic options for GBM patients.

Efficacy and safety of MR-guided adaptive simultaneous integrated boost radiotherapy to primary lesions and positive lymph nodes in the neoadjuvant treatment of locally advanced rectal cancer: a randomized controlled phase III trial

BackgroundIn locally advanced rectal cancer (LARC), optimizing neoadjuvant strategies, including the addition of concurrent chemotherapy and dose escalation of radiotherapy, is essential to improve tumor regression and subsequent implementation of anal preservation strategies. Currently, dose escalation studies in rectal cancer have focused on the primary lesions. However, a common source of recurrence in LARC is the metastasis of cancer cells to the proximal lymph nodes. In our trial, we implement simultaneous integrated boost (SIB) to both primary lesions and positive lymph nodes in the experimental group based on magnetic resonance-guided adaptive radiotherapy (MRgART), which allows for more precise (and consequently intense) targeting while sparing neighboring healthy tissue. The objective of this study is to evaluate the efficacy and safety of MRgART dose escalation to both primary lesions and positive lymph nodes, in comparison with the conventional radiotherapy of long-course concurrent chemoradiotherapy (LCCRT) group, in the neoadjuvant treatment of LARC.MethodsThis is a multi-center, randomized, controlled phase III trial (NCT06246344). 128 patients with LARC (cT3-4/N+) will be enrolled. During LCCRT, patients will be randomized to receive either MRgART with SIB (60–65 Gy in 25–28 fractions to primary lesions and positive lymph nodes; 50–50.4 Gy in 25–28 fractions to the pelvis) or intensity-modulated radiotherapy (50–50.4 Gy in 25–28 fractions). Both groups will receive concurrent chemotherapy with capecitabine and consolidation chemotherapy of either two cycles of CAPEOX or three cycles of FOLFOX between radiotherapy and surgery. The primary endpoints are pathological complete response (pCR) rate and surgical difficulty, while the secondary endpoints are clinical complete response (cCR) rate, 3-year and 5-year disease-free survival (DFS) and overall survival (OS) rates, acute and late toxicity and quality of life.DiscussionSince dose escalation of both primary lesions and positive nodes in LARC is rare, we propose conducting a phase III trial to evaluate the efficacy and safety of SIB for both primary lesions and positive nodes in LARC based on MRgART.Trial registrationThe study was registered at ClinicalTrials.gov with the Identifier: NCT06246344 (Registered 7th Feb 2024).

Synthesis pathways of (HfZrTiCe/La/Y)O2-x nanoparticles via benzyl alcohol route at critical temperature

The controllable synthesis of high-entropy fluorite oxide (HEO) having large ionic radius mismatch remains a challenging due to poor understanding on nucleation. The (HfZrTiLn)-5HEO nanoparticles with 15 % ionic radius mismatch were synthesized via benzyl alcohol route at 220 °C-5 min in presence of PtCl4 and Fe(acac)3, exhibiting novel optical, electrical and magnetic properties. Nucleation pathways of the 5HEO at the critical temperature were elucidated by using a comparison study of conventional heating and microwave irradiation heating. Consistency of XRD patterns and STEM-EDX observation indicate that the resultant Hf-OBn monomers acted as the nucleation center of the 5HEO, determined by diffusion kinetics. The nucleation rate depended on the metal monomers assembly and esterification reaction, which was accelerated by water vapor pressure produced in-situ by 0.5×10−4mol/l PtCl4 catalyst. The Fe-metal organic cages derived from 1.5×10−4mol/l Fe(acac)3 additive served as the structure stabilizer of Zr/Ti monomers, and prevented early hydrothermal reaction route.

Correction of osteopetrosis in the neonate oc/oc murine model after lentiviral vector gene therapy and non-genotoxic conditioning.

Autosomal recessive osteopetrosis (ARO) is a rare genetic disease, characterized by increased bone density due to defective osteoclast function. Most of the cases are due to TCIRG1 gene mutation, leading to severe bone phenotype and death in the first years of life. The standard therapy is the hematopoietic stem cell transplantation (HSCT), but its success is limited by several constraints. Conversely, gene therapy (GT) could minimize the immune-mediated complications of allogeneic HSCT and offer a prompt treatment to these patients. The Tcirg1-defective oc/oc mouse model displays a short lifespan and high bone density, closely mirroring the human condition. In this work, we exploited the oc/oc neonate mice to optimize the critical steps for a successful therapy. First, we showed that lentiviral vector GT can revert the osteopetrotic bone phenotype, allowing long-term survival and reducing extramedullary haematopoiesis. Then, we demonstrated that plerixafor-induced mobilization can further increase the high number of HSPCs circulating in peripheral blood, facilitating the collection of adequate numbers of cells for therapeutic purposes. Finally, pre-transplant non-genotoxic conditioning allowed the stable engraftment of HSPCs, albeit at lower level than conventional total body irradiation, and led to long-term survival and correction of bone phenotype, in the absence of acute toxicity. These results will pave the way to the implementation of an effective GT protocol, reducing the transplant-related complication risks in the very young and severely affected ARO patients.