Hypofractionation Research Articles

Impact of daily plan adaptation on accumulated doses in ultra-hypofractionated magnetic resonance-guided radiation therapy of prostate cancer

Background and purposeUltra-hypofractionated online adaptive magnetic resonance-guided radiotherapy (MRgRT) is promising for prostate cancer. However, the impact of online adaptation on target coverage and organ-at-risk (OAR) sparing at the level of accumulated dose has not yet been reported. Using deformable image registration (DIR)-based accumulation, we compared the delivered adapted dose with the simulated non-adapted dose. Materials and methodsTwenty-three prostate cancer patients treated at two clinics with 0.35 T magnetic resonance-guided linear accelerator (MR-linac) following the same treatment protocol (5×7.5 Gy with urethral sparing and daily adaptation) were included. The fraction MR images were deformably registered to the planning MR image. Both non-adapted and adapted fraction doses were accumulated with the corresponding vector fields. Two DIR approaches were implemented. PTV* (planning target volume minus urethra+2mm) D95%, CTV* (clinical target volume minus urethra) D98%, and OARs (urethra+2mm, bladder, and rectum) D0.2cc, were evaluated. Statistical significance was inferred from a two-tailed Wilcoxon signed-rank test (p < 0.05). ResultsNormalized to the baseline, the accumulated PTV* D95% increased significantly by 2.7 % ([1.5, 4.3]%) through adaptation, and the CTV* D98% by 1.2 % ([0.1, 1.7]%). For the OARs after adaptation, accumulated bladder D0.2cc decreased by 0.4 % ([−1.2, 0.4]%), urethra+2mmD0.2cc by 0.8 % ([−1.6, −0.1]%), while rectum D0.2cc increased by 2.6 % ([1.2, 4.9]%). For all patients, rectum D0.2cc was still below the clinical constraint. Results of both DIR approaches differed on average by less than 0.2 %. ConclusionsOnline adaptation in MRgRT improved target coverage and OARs sparing at the level of accumulated dose.

Use of Radiation Therapy for the Treatment of Breast Cancer in 2019 Versus 2020

PurposeThe COVID-19 pandemic disrupted medical care. Little is known about how radiation therapy (RT) ordering behavior changed during the pandemic. This study examined: 1. whether there was a change in the rate at which orders for lumpectomy were followed by orders for RT, and 2. whether there was a change in the percentage of RT orders that were for hypofractionated (HF) RT, rather than conventionally fractionated (CF) RT. Materials and MethodsPrior authorization order data from 2019 and 2020, pertaining to patients with commercial and Medicare Advantage health plans were reviewed to determine whether patients had an order for RT in the 90 days following lumpectomy, and if it was for CF or HF RT. Univariate analyses were conducted using Chi-square tests, and adjusted analyses were conducted using multivariate logistic regression, controlling for patient age, urbanicity, local median income, region, if the lumpectomy facility was academic, and if the lumpectomy facility was a hospital. ResultsIn 2019, 47.7% (2,200/4,610) of included lumpectomy orders were followed by an RT order within 90 days, in contrast to 45.6% (1,944/4,263) in 2020 (P=0.048). Of the RT orders meeting this study's definition of CF or HF, 75.3% (1,387/1,843) of orders placed in 2019 and 79.0% (1,261/1,597) of orders placed in 2020 were for HF (P=0.011). Adjusted analysis found patients receiving a lumpectomy order in the 1st quarter of 2020 had significantly reduced odds (OR: 0.84; 95% CI: 0.71-0.99) of receiving an order for RT following lumpectomy relative to those with orders placed in the 1st quarter of 2019. Adjusted analysis likewise found significant evidence of increased use of HF RT during the pandemic. ConclusionIn the population examined, physicians were less likely to order RT following lumpectomy in 2020 than in 2019, and if they did, were more likely to order HF RT.

Investigation of Dosage Distributions of Polyvinyl Siloxane Dental Impression Shields for Head and Neck Radiotherapy with Thermoluminances Dosimeters

Objective: This study aimed to assess the effects of denture materials on dose distribution on a head and neck radiotherapy-appropriate model and calculate the thickness of a stent by polyvinyl siloxane dental impression material for shielding scattered radiation from dental restorations.&#x0D; Methods: In the first step of the study, 5mm diameter and 5mm height of cylindrical dental material of titanium, zirconia lithium disilicate were irradiated with 6-Megavoltage photons from a clinical linear accelerator. In the second step, dental materials at the center of polyvinyl siloxane thicknesses of 5, 10, and 20mm were irradiated with 2 Gray and 10 Gray fractional doses. Measurements were made using three thermoluminescent dosimeters positioned laterally. The percentage backscattered dose and percentage dose decrease values were calculated to interpret the results. &#x0D; Results: According to the result, dosages scattered from dental materials increased for samples irradiated with 2Gy; a decreased dose was reported for samples irradiated with a 10Gy. 5mm PVS samples provided higher dose attenuation than others. Regardless of dental material, it is seen that the attenuation intensities calculated from TLD-100 dosimeters ranged from 22.7 to 38,62 for 2Gy, and 10.01 to 38,87 for 10Gy.&#x0D; Conclusion: Dental material alters the scattered radiation. In irradiated head and neck cancer patients, a 5mm thick guard is sufficient to prevent radiation diffused from dental materials in clinical usage.

Monte Carlo investigation of S-values for 111In radionuclide therapy

Novel therapeutic strategy in radionuclide therapy use cell-penetrating monoclonal antibodies to carry Auger-emitting radionuclides into the cells. Estimation of dose in normal and tumor cells are important to investigate the efficacy and toxicity of treatment. Monte Carlo simulation is the most suitable method for estimation of absorbed dose at microscopic level. It is therefore useful to carry out Monte Carlo simulation of Auger emitting radionuclides in order to assess the sensitivity of the results with respect to transport approximations generally used in Monte Carlo codes. There are several Auger emitting radionuclides with potential clinical applications, however, based on their half-life 111In is the most suitable for Auger therapeutic purposes and was considered in the present investigation. Geant4 Monte Carlo simulation was performed and specific absorbed dose fraction (or S-values) for 111In were calculated by using different physics model (Standard, Livermore, Penelope and Geant4-DNA) and compared with Medical Internal Radiation Dosimetry (MIRD) S-values. Source was distributed in the cytoplasm (Cy), surface (Cs) and nucleus (N). Average of relative differences (RD) (%) were calculated for self and cross absorbed dose. RD(%) for self-absorption (NßN) were 4.4, 2.36, 6.21 and 1.1 for Standard, Penelope, Livermore and Geant4-DNA respectively. For cross-absorption these values were higher (e.g. for NßCy 15.4, 18.36, 19.21 and 24.8 for Standard, Penelope, Livermore and Geant4-DNA respectively). Cutoff energy considered for electrons and gamma photons affect the results in dose estimation for Auger electrons in Monte Carlo simulation.

Matrix metal collimators studies for the spatially fractionated radiation therapy

Traditional radiation therapy is hindered by limitations in dose delivery and the risk of over-irradiation, which can harm healthy tissues surrounding tumors. Spatially fractionated and intensity-modulated radiation therapies have emerged as promising techniques to mitigate these issues by reducing damage to healthy tissues. This study explores the potential of enhancing radiation therapy's therapeutic efficacy through spatial fractionation of X-ray beams, a technique that can significantly increase radiation efficiency by reducing the dose load on healthy tissues. This research hypothesizes that microscopic lesions within the paths of micro/mini-beams can be repaired by minimally irradiated cells adjacent to the irradiated tissue slices, based on observations with high-energy (MV) photons. Spatial fractionation is particularly valuable for X-ray and electron radiation therapy, which is more widespread and cost-effective than proton therapy. The study introduces a new type of cost-effective metal matrix collimators designed for beam fractionation. These collimators are constructed using lead plates for thickness variation implementation and employ a 5x5 hole matrix with 1 mm diameter and 3 mm pitch, covering an area of 14x14 mm². To visualize beam distribution, a Timepix detector, capable of providing real-time 2D beam profiles, was employed. Experiments were conducted using a medical LINAC with typical therapeutic energy ranging from 6 to 18 MeV. Results indicate that spatial fractionation can be achieved for X-ray radiation, with a PVDR of approximately 3 for a 3 cm lead collimator. However, issues with hole uniformity and blurring in the peak area prompted a shift to using copper collimators due to their superior manufacturing properties. This study presents a novel matrix collimator design made from various materials for shaping mini beams, aimed at improving the efficiency of spatial dose fractionation for different ionizing radiation types. Geant4 simulations have been instrumental in optimizing collimator features. The findings suggest that high levels of dose fractionization can be achieved for X-rays, electrons, and proton beams. These results warrant further biological studies to evaluate the effects of fractionation on normal and tumoral tissues, supporting the practical implementation of collimation in radiation therapy.

The effect of cardarine on the behavior of rats in a lithium-pylocarpine model of temporal lobe epilepsy

Epilepsy is a serious neuropsychiatric disorder characterized by the occurrence of spontaneous recurrent seizures and linked cognitive, psychoemotional, and social impairments. Objective research showed that up to 30% of epilepsy patients do not respond to current therapeutic interventions, necessitating the development of novel treatment options. In recent years, researchers actively studied the neuroprotective properties of peroxisome proliferator-activated receptor agonists (PPAR α, β/δ, γ). As nuclear transcription factors involved in inflammatory signaling pathways, PPARs play a role in the pathogenesis of neuropsychiatric disorders, such as epilepsy. Various nervous pathology models were used for the investigations. The neuroprotective properties of PPAR γ agonists were reported in epilepsy models, whereas sufficient investigation into PPAR β/δ agonists’ effects is lacking. The aim of this study was to evaluate the effectiveness of the PPAR β/δ receptor agonist cardarine in alleviating behavioral disruptions observed in rats exhibiting temporal lobe epilepsy in response to the lithium-pilocarpine model. The lithium-pilocarpine model is considered one of the most effective experimental models for studying temporal lobe epilepsy in humans. Administration of pilocarpine in animals results in acute seizures, followed by a latent period devoid of seizures. Subsequently, spontaneous recurrent seizures appear, marking the chronic phase of the model. Epilepsy was induced in male Wistar rats that were 7 weeks old, through the administration of pilocarpine, 24 hours after being injected with LiCl (127 mg/kg). The peripheral effects of pilocarpine were negated through the use of methyl bromide-scopolamine (1 mg/kg, administered intraperitoneally 1 hour before pilocarpine). Pilocarpine was administered in fractional doses of 10 mg/kg, every half hour, until the seizures reached at least stage 4 on the Racine scale, with a dose range of 20–40 mg/kg. Following pilocarpine administration, Cardarine was administered intraperitoneally at a dose of 2.5 mg/kg daily for a period of 7 days, with the initial injection taking place 24 hours post-administration. Behavioral tests were conducted during the chronic phase of the model, 2-2.5 months after pilocarpine injection, using several tests, including the Open Field (to measure exploratory behavior, motor activity, and anxiety levels), the Intruder-Resident test (to measure communicative behavior), the Y-maze test (to measure working memory), and the Morris Water Maze (to measure spatial memory in the short and long term). Untreated experimental animals with temporal lobe epilepsy exhibited heightened vertical and horizontal motor activity, increased anxiety in the Open Field test, reduced communicative activity in the Intruder-Resident test, and impaired memory in the Y-maze test and the Morris Water Maze. Cardarine reduced alterations in vertical movement (time of climbing) and anxiety levels (number of grooming behaviors) in the Open Field, hindered short-term memory in the Y-maze, and restrained communicative conduct in the Intruder-Resident test. However, the medication did not impact the rats’ survival rate, body weight changes, overall activity (distance traveled in the Open Field), and damage to learning and long-term memory in the Morris Water Maze. Thus, administration of cardarine partially neutralized behavioral disorders developing in rats in the lithium-pylocarpine model of temporal lobe epilepsy.

Bilateral avascular necrosis of femoral heads after pelvic irradiation: A case report and systematic review

The development of radiation induced changes in bone is related to multiple factors such as total dose, per fraction dose, irradiated volume, bone structure and localization, patient age, and chemo-radiotherapy. It is known that chang-es in bone occur after 30-40 Gy. There are very few publications on this subject in the literature, mostly case reports. Therefore, there is no definite consensus about the pathogenesis, diagnosis, and treatment. In this report, a case of avascular necrosis of bilateral femoral heads after pelvic radiotherapy will be presented and the relevant literature will be reviewed.

Experimental Study on the Combustion of Flexible Polyurethane Foam Under Marine Environment Conditions

ABSTRACTThe common upholstered furniture filler flexible polyurethane foam (FPUF) is a synthetic polymer whose wide range of application environments include not only land but also sea, especially in ship cabins, where FUPF is used extensively to improve the comfort and aesthetics of passenger cabins. In marine air, halogen ions in marine air can act as quenchers of gas-phase radicals, blocking the conversion of CO to CO2 in the combustion of polyurethane foam, which causes different combustion characteristics of FPUF. Therefore, the combustion characteristics of FPUF and the content of asphyxiating gas components in the combustion flue gas were studied by using a conical calorimeter and a steady-state tube furnace (SSTF) to simulate a marine air environment with high salinity and humidity, as well as the fractional effective dose (FED) model to evaluate the flue gas toxicity. The results show that the heat release rate (HRR) curves of FPUF combustion are similar for pilot ignition and non-pilot ignition modes in air with different salinity and humidity, and the ignition time of FPUF will increase about 1% with the salinity of air droplets increase 1% in both non-pilot and pilot ignition modes. The variation of flue gas components from FPUF combustion in air with different salinity and humidity has a similar pattern: the generation of CO and HCN increases with increasing Φ values (the ratio of actual fuel-air ratio to the ratio of stoichiometric fuel-air ratio), while the generation of CO2 and NO decreases with increasing Φ values. When the Φ value is is close to 0.9 or 2.33, the ventilation conditions play a dominant role in the generation of each component in the flue gas. And the air with high salinity and humidity has a greater effect on the generation of each flue gas component when the equivalent ratio Φ is in the range of 0.9 to 1.8. As the salinity in air increases, the threshold for FED to reach danger shifts from Φ = 1.61 to Φ = 1.36. The presence of NaCl in the air with high salinity and humidity increases the generation of asphyxiating gas components in FPUF combustion, the study has practical implications for evacuation, toxicity prediction, and safety evaluation.

Simultaneous Prediction Method for Intestinal Absorption and Metabolism Using the Mini-Ussing Chamber System.

Many evaluation tools for predicting human absorption are well-known for using cultured cell lines such as Caco-2, MDCK, and so on. Since the combinatorial chemistry and high throughput screening system, pharmacological assay, and pharmaceutical profiling assay are mainstays of drug development, PAMPA has been used to evaluate human drug absorption. In addition, cultured cell lines from iPS cells have been attracting attention because they morphologically resemble human intestinal tissues. In this review, we used human intestinal tissues to estimate human intestinal absorption and metabolism. The Ussing chamber uses human intestinal tissues to directly assay a drug candidate's permeability and determine the electrophysiological parameters such as potential differences (PD), short circuit current (Isc), and resistance (R). Thus, it is an attractive tool for elucidating human intestinal permeability and metabolism. We have presented a novel prediction method for intestinal absorption and metabolism by utilizing a mini-Ussing chamber using human intestinal tissues and animal intestinal tissues, based on the transport index (TI). The TI value was calculated by taking the change in drug concentrations on the apical side due to precipitation and the total amounts accumulated in the tissue (Tcorr) and transported to the basal side (Xcorr). The drug absorbability in rank order, as well as the fraction of dose absorbed (Fa) in humans, was predicted, and the intestinal metabolism of dogs and rats was also predicted, although it was not quantitative. However, the metabolites formation index (MFI) values, which are included in the TI values, can predict the evaluation of intestinal metabolism and absorption by using ketoconazole. Therefore, the mini-Ussing chamber, equipped with human and animal intestinal tissues, would be an ultimate method to predict intestinal absorption and metabolism simultaneously.

Comparison of Local Disease Control and Toxicities in Two High Dose Rate Intracavitatory Brachytherapy Dose Fractionation Regimens (7Gy/3# v/s 9Gy/2#) in the Radical Treatment of Carcinoma Cervix: a Prospective Randomized Trial in Sub-Himalayan Region

Comparison of Local Disease Control and Toxicities in Two High Dose Rate Intracavitatory Brachytherapy Dose Fractionation Regimens (7Gy/3# v/s 9Gy/2#) in the Radical Treatment of Carcinoma Cervix: a Prospective Randomized Trial in Sub-Himalayan Region

Effect of different CTV shrinkage and skin flash margins on skin dose for left chest wall IMRT: A dosimetric study

In postmastectomy radiation therapy (PMRT), the adequate skin surface dose remains a problem. In this study, the effect of different CTV shrinkage and Skin flash margins on skin dose was investigated, and the accuracy of skin surface dose calculated by TPS for PMRT using thermoluminescent dosimeters (TLDs) was evaluated. Eighty-eight measurement points were determined on the Alderson Rando phantom. To determine the effects of shrinkage margin on skin dose, separate CTVs were generated for 2 mm, 3 mm and 5 mm shrinkage. The prescribed dose was 50 Gy to CTV with a daily fraction dose of 2 Gy. A total of 12 plans were created using four different skin flash thicknesses for each CTV shrinkage margin. After applying 0 mm, 10 mm, 15 mm and 20 mm skin flash thicknesses for each area of the 7F-IMRT treatment plan, the plans were recalculated, and the SF-0, SF-10, SF-15 and SF-20 plans were created, respectively. The increase in skin flash thickness in IMRT plans resulted in a significant increase in skin dose. There was a significant difference between TPS and TLD doses in all chest wall areas for SF-0, SF-10, and SF-15 (p < 0.05). However, there was no significant difference in all areas of the chest wall for SF-20 (p > 0.05). The shrinkage margin thickness of the CTV was found to be inversely proportional to the skin dose for all treatment plans. In tumors near the surface, bolus or skin flash techniques can get the skin adequately dosed. However, the skin flash technique has shown superiority in the application. In PMRT, it is recommended to keep the shrinkage margin as small as possible and use the skin flash thickness of 20 mm for the skin to receive a sufficient dose.

Survival and Toxicity in Patients With Unresectable or Inoperable Biliary Tract Cancers With Ablative Radiation Therapy Versus Nonablative Chemoradiation

Conventional chemoradiation (CCRT) is inadequately effective for the treatment of unresectable or inoperable biliary tract cancers (UIBC). Ablative radiation therapy (AR), typically defined as a biologically effective dose (BED) ≥80.5 Gy, has shown some promise in terms of local control and survival in these patients. We compare the efficacy and toxicity of AR to non-AR in UIBC patients. Patients with UIBC treated with stereotactic body radiation therapy (SBRT; n = 18) or CCRT (n = 28) between 2006 and 2021 were retrospectively analyzed. The associations of treatment, BED groups, selected characteristics with overall survival (OS), progression-free survival (PFS), and local control were estimated separately using Cox proportional hazards regression. Toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Median dose fractionation was 60 Gy in 5 fractions (median BED, 127 Gy) for SBRT and 50 Gy in 25 fractions (median BED, 64 Gy) for CCRT. The median follow-up of the entire cohort was 11.5 months. The 1-year OS rate was 62% for BED <80.5 versus 66% for BED ≥80.5 (P = .069). The 1-year PFS rate was 24% for BED <80.5 and 29% for BED ≥80.5 (P = .050). The 1-year local control rate was 20% for BED <80.5 and 41% for BED ≥80.5 (P = .097). BED as a continuous variable (P = .013), BED ≥100 Gy (P = .044), and race (white versus nonwhite) (P = .037) were associated with improved overall mortality. BED ≥80.5 Gy (P = .046), smaller tumor size (<5 cm; P = .038) and N0 disease (P <.0001) were associated with improved disease progression rates. Local control was improved in patients with N0 disease compared with N1 disease (P <.0001). Both treatments were well tolerated; there was no difference in acute and late toxicity between AR and non-AR. In this review, there was improved PFS with BED ≥80.5 Gy with a trend toward OS benefit. BED ≥80.5 Gy was achieved mostly through SBRT and was well tolerated. AR could be considered a more effective treatment modality than CCRT in patients with UIBC.

In vivo dose measurements for tangential field-in-field ultra-hypofractionated breast radiotherapy

IntroductionUltra-hypofractionated radiotherapy (UHF-RT) mandates more accuracy in each part of the treatment cycle to maximize cure rates and minimize toxicities. In vivo dosimetry is a direct method for verifying overall treatment accuracy. This study evaluated uncertainties in the delivered dose of Hypofractionated (HF) and UHF Whole Breast Irradiation (WBI) and to analyze the accuracy of the workflow to pave the way for a wide-scale use of UHF-RT. MethodsThirty-three breast cancer cases, including 16 HF-WBI and 17 UHF-WBI were treated with 3D conformal Radiotherapy (3D-CRT), where 79 fields were analyzed for dose verification. The measurement point was set at the beam entrance (1.5 cm depth). The expected dose at Dmax was calculated via TPS. Before in vivo measurements, diode detectors were tested and calibrated. We developed initial validation measurements for UHF-RT on an anthropomorphic breast phantom for the first time. ResultsFor RANDO phantom, the percentage difference between measured and calculated doses showed an average of -0.52 ± 5.4%, in addition to an excellent dose reproducibility within 0.6%. The overall in vivo measurements for studied cases showed that 83.5% of the measured doses were within ±5% and only 1.8% of the measured doses were greater than ±10% of the calculated doses. The percentage accuracy was slightly larger for UHF cohort (84.2%) compared to HF cohort (83.2%). The maximum percentage difference between them was less than 1%. ConclusionBreast in vivo dosimetry is an adequate tool for treatment verification that improves the accuracy of the treatment cycle. UHF-RT may contribute in reducing the long waiting lists, increasing patient convenience, and saving the available resources for breast cancer patients.

Abstract A025: Combination of anti-CTLA4 and radiation induce synergistic tumor control in radiorecurrent prostate cancer

Abstract Background: Advanced prostate cancer (PCa) is a leading cause in cancer death and can elicit significant morbidity and mortality. A common treatment modality for advanced PCa is radiation therapy (RT). Currently, salvage of local disease recurrence after RT is a major clinical problem. Emerging evidence indicates the importance of the immune system in governing RT response. In support of this, immune checkpoint inhibitors (ICIs), which enhance immune activation, have demonstrated clinical therapeutic promise in combination with RT in certain advanced cancers. Irradiation (IR) combined with ICIs may prime the immune system to recognize and target recurrent cancer. Purpose: Investigate the therapeutic efficacy of ICIs in combination with RT for radiorecurrent PCa in a syngeneic pre-clinical model. Methods: TRAMP-C2 cells were treated with 10 Gy of radiation over 5 fractions (similar to clinical hypofractionated (HF) schedule) to generate TRAMP-C2 HF cells. Immune-competent mice were transplanted subcutaneously with TRAMP-C2 HF cells. Once tumors reached palpable size, mice were administered either ICIs (αPDL1 or αCTLA4) alone or in combination with RT. Tumor volume was monitored to determine the treatment effect. Correlative studies on excised tumors and secondary lymphoid organs included flow cytometry and NanoString gene expression panel to evaluate immunological mechanisms that contribute to anti-tumor effects[SL1]. Results: TRAMP-C2 HF cells were validated for radiation resistance and exhibited a more aggressive phenotype (reduction in senescence, increase in clonogenicity) similar to clinically recurrent PCa. Radiation resistance of TRAMP-C2 HF tumors was validated in vivo. Administration of αPDL1 and αCTLA4 as monotherapy or in combination did not achieve significant tumor growth delay compared to control. IR alone produced an observable tumor growth delay compared to ICIs alone. The combination of αPDL1 and IR did not yield additional growth delay compared to IR alone. Strikingly, significant tumor growth delay was seen with the combination of IR and αCTLA4 compared to IR alone, while also resulting in complete cure in a third of the mice. NanoString analysis of lymph nodes from mice treated with αCTLA4 and IR vs. IR alone demonstrated differential expression of genes regulating CD molecules, interleukins, and T-cell functions. Furthermore, enrichment of CD45 and CD8a RNA following αCTLA4 and IR was observed. Validation by flow cytometry is currently ongoing. Conclusion: We generated the first syngeneic radiorecurrent PCa model and demonstrated that combining αCTLA4 and IR results in synergistic tumor response. Combined therapy resulted in augmented immune response, most notably enhancement of CD8 T cell activity. Significance: These findings contribute to our understanding of immunological events associated with RT and ICIs in the context of radiorecurrent PCa and support new avenues for salvage therapy in clinical trials. Citation Format: Hanzhi Wang, Xiaoyong Huang, Stepahnie D White, Linsey Gong, Tera N Petchiny, Hans Chung, Emmanouil Fokas, Robert S Kerbel, Stanley K Liu. Combination of anti-CTLA4 and radiation induce synergistic tumor control in radiorecurrent prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A025.

Estimation of Human Oral Fraction Dose Absorbed of Simvastatin from Various Formulations using in-situ Single Pass Intestinal Perfusion Method

Background: SIM is a poorly water-soluble drug with dissolution-dependent bioavaila-bility. A solid dispersion and self-emulsifying drug delivery system was developed, optimized, and evaluated to improve its bioavailability. The permeability coefficient in rats was determined using the in-situ single-pass intestinal perfusion (SPIP) technique. Further, the permeability coefficient (Peff, humans) was used to calculate the permeability and fraction of SIM bioavailable to humans which have not yet been reported for these formulations. Objective: To estimate and compare various formulations of Simvastatin (SIM) for bioavailable fraction to humans (Fa) as a function of solubility enhancement. Methods: In this study, the preparation and evaluation of SIM formulations i.e., Self-emulsifying drug delivery system (SEDDS) and Solid dispersions (SD) are discussed in brief. An uncomplicat-ed, precise, and accurate HPLC method was validated for simultaneous determination of SIM and phenol red as per ICH guidelines. A comparative in-vitro dissolution test, pharmacokinetic studies, and in-situ SPIP technique in rats were carried out amongst optimized formulations of SIM-SD and SIM-SEDDS, SIM suspension (SIM-SUSP), and SIM marketed preparation (SIM-MP). Results: The HPLC method was successfully validated. In-vitro dissolution test displays that both the SIM formulations i.e., SIM-SEDDS and SIM-SD shows better dissolution rate than SIM-MP and SIM-SUSP. Pharmacokinetic studies revealed that SIM-SEDDS, SIM-SD, and SIM-MP showed significant differences when compared to SIM-SUSP in terms of Cmax, [AUC] 0-∞, at P ≤ 0.05. The comparison of permeability coefficient between SIM SEDDS vs. SIM MP and SIM SEDDS vs. SIM SD were non-significant. In contrast, SIM- SUSP vs. all other formulations were significantly different at P ≤ 0.05 (employing two-way ANOVA followed by post-Bonferroni Test). Fa for SIM SUSP, an optimized formulation of SIM-SEDDS, SIM-MP, and SIM-SD are 0.353, 0.977, 0.975, and 0.987 respectively. It is revealed that SIM-SEDDS and SIM-SD showed enhanced absorption and the results are confirmed by in-vitro data, pharmacokinetic studies, and In-situ SPIP techniques. Conclusion: The permeability prediction method is a rapid and economical method for screening chemical compounds with the least possible utilization of resources. So, its use can be extended in prime and initial screening prototypes for the evaluation of compounds in the early stages of their formulations.

Dosimetric comparison of postoperative interstitial high-dose-rate brachytherapy and modern external beam radiotherapy modalities in tongue and floor of the mouth tumours in terms of doses to critical organs.

The aim of the study was to dosimetrically compare interstitial high-dose-rate (HDR) brachytherapy (BT) and modern external beam radiotherapy modalities, as volumetric modulated arc therapy (VMAT) and stereotactic radiotherapy with Cyberknife (CK) of tumours of the tongue and floor of the mouth in terms of dose to the critical organs. In National Institute of Oncology, Budapest, between March 2013 and August 2022 twenty patients (11 male/9 female) with stage T1-3N0M0 tongue (n = 14) and floor of mouth (n = 6) tumours received postoperative radiotherapy because of close/positive surgical margin and/or lymphovascular and/or perineural invasion. High-dose-rate interstitial brachytherapy applying flexible plastic catheters with a total dose of 15 × 3 Gy was used for treatment. In addition to BT plans VMAT and stereotactic CK plans were also made in all cases, using the same fractionation scheme and dose prescription. As for the organs at risk, the doses to the mandible, the ipsilateral and the contralateral salivary glands were compared. The mean volume of the planning target volume (PTV) was 12.5 cm3, 26.5 cm3 and 17.5 cm3 in BT, VMAT and CK techniques, respectively, due to different safety margin protocols. The dose to the mandible was the most favourable with BT, as for the salivary glands (parotid and submandibular) the CK technique resulted in the lowest dose. The highest dose to the critical organs was observed with the VMAT technique. The mean values of D2cm3 and D0.1cm3 for the critical organs were as follows for BT, VMAT and CK plans: 47.4% and 73.9%, 92.2% and 101.8%, 68.4% and 92.3% for the mandible, 4.8% and 6.7%, 7.3% and 13.8%, 2.3% and 5.1% for the ipsilateral parotid gland, 3.5% and 4.9%, 6.8% and 10.9%, 1.5% and 3.3% for the contralateral parotid gland, 7.3% and 9.4%, 9.0% and 14.3%, 3.6% and 5.6% for the contralateral submandibular gland. The present results confirm that BT, despite being an invasive technique, is dosimetrically clearly beneficial in the treatment of oral cavity tumours and is a modality worth considering when applying radiotherapy, not only as definitive treatment, but also postoperatively. The use of the CK in the head and neck region requires further investigation.

Biologically effective dose (BED) value lower than 120Gy improve outcomes in lung SBRT.

Lung SBRT has a well-defined role in the treatment of patients with early stage non-small cell lung cancer who are not surgical candidates or refuse surgery. Biologically effective dose (BED) of greater than or equal to 100Gy has been recommended. However, optimal fractionationremains unclear. Our objective was analyze patients treated with lung SBRT in our institution and evaluate outcomes according prescribed dose. One hundred nine patients with early non-small cell lung cancer and treated with lung SBRT were retrospectively analyzed. Differences between dose received, local control, and survival were evaluated. For comparison of BEDs, the prescribed dose for SBRT was stratified according to two groups: high (BED > 120Gy) and low (BED < 120Gy). A relationship between mortality and total dose (54.7Gy ± 4.8) was observed. Significantly worse survival was observed for patients with higher total doses (p < 0.003). It was found that patients receiving BED > 120 had increased mortality compared to patients receiving BED < 120 (p = 0.021). It was observed mean dose/fraction 12.6Gy/f was a protective factor and decreased the probability of death. Our data suggest that mean total dose lower 54 and a calculated BED < 120Gy is the optimal. Further prospective data are needed to confirm these results and determine the optimal dose fractionation scheme as a function of tumor size and location of volume.

Dose to Organ at Risk and its Characteristic Variation with the Clinically Used Different Prescription Levels for Early-stage Left-sided Breast Cancer

AimsTo evaluate the organ at risk (OAR) dose and its characteristic variation with different clinically usable prescription doses (RxD) for breast and chest wall radiotherapy in patients with early-stage left-sided breast cancer. Materials and methodsIn total, 145 patients with early-stage breast cancers (T1N0M0-T2N0M0) on the left side were treated with radiotherapy after a modified radical mastectomy or breast conservation surgery, with a mean age of 45.1 ± 21.6 years. The patient received 4050 cGy of field-in-field (three-dimensional conformal radiotherapy) treatment limited to the breast or chest wall, excluding the supraclavicular node, axillary node and internal mammary chain, over 15 fractions. Additional plans of 5000 cGy/25 fractions, 4500 cGy/20 fractions and 2600 cGy/5 fractions were created with no or minor changes to the original plan. Mathematical modelling was used to study the distinctive change in the dose–volume characteristics for various OARs as a function of the RxD. OAR dosages, both absolute and normalised, were expressed in terms of the RxD. The mathematical (functional) relationship between OAR doses and different prescription levels was deduced by the least squares fit method. ResultThe left lung mean dose, V5Gy (%), V10Gy (%) and V20Gy (%) and the heart mean dose, V10Gy (%) and V20Gy (%) were evaluated. The dose–volume parameters showed a parabolic variation (x2) with the RxD. Prescription normalised OAR doses showed a linear relationship with the RxD; relative dose increased with diminishing RxD. Normalised lung and heart mean doses exhibited saturation (linear relationship) with RxD variation. Paired sample t-test results between RxD versus all evaluated parameters were found to be statistically significant (P = 0.004). The Pearson correlation coefficient between different prescription levels for left lung mean dose (range 0.942–1.0), heart mean dose (range 1.0–1.0), left lung V5Gy (%) (range 0.987–1.0), left lung V10Gy (%) (range 0.991–0.999), heart V10Gy (%) (range 0.998–1.0). ConclusionThe functional form of absolute OAR dose–volume parameters versus RxD is parabolic and the RxD normalised OAR dose–volume parameter versus RxD is a straight line with a negative slope as RxD increases. This indicates an increase in the relative OAR dose–volume parameters if the RxD is reduced. This study is the first of its kind to compare the OAR doses as a function of clinically used degenerate prescription levels. These data will help to comprehend the OAR doses while adopting a new dose fractionation regimen and reviewing the radiotherapy treatment plans.

Online Adaptive Magnetic Resonance-guided Radiation Therapy for Gynaecological Cancers: Preliminary Results of Feasibility and Outcome

AimsTo present the preliminary results on the clinical utilisation of an online daily adaptive magnetic resonance-guided radiation therapy (MRgRT) for various gynaecological cancers. Materials and methodsTwelve patients treated between September 2018 and June 2022 were included. Six patients (50%) were treated with pelvic radiation therapy followed by MRgRT boost as brachytherapy boost was ineligible or unavailable, three patients (25%) were treated with pelvic MRgRT followed by high dose rate brachytherapy, two patients (16.7%) were treated with only MRgRT, one patient (8.3%) was treated with linear accelerator-based radiation therapy followed by MRgRT boost for bulky iliac lymph nodes. ResultsThe median age was 56.5 years (range 31–86 years). Eight patients (66.7%) had a complete response, three patients (25%) had a partial response and one patient (8.3%) died due to acute renal failure. The mean follow-up time was 11.2 months (range 3.1–42.6 months). The estimated 1-year overall survival was 88.9%. The median treatment time was 47 days (range 10–87 days). During external beam radiation therapy, 10 (83.3%) patients had concomitant chemoradiotherapy. Pelvic external beam radiation therapy doses for all cohorts were 45–50.4 Gy with a fraction dose of 1.8 Gy. The median magnetic resonance-guided boost dose was 32 Gy (range 20–50 Gy) and fraction doses ranged between 4 and 10 Gy. Three patients were treated with intracavitary high dose rate brachytherapy (26–28 Gy in four to five fractions). None of the patients had grade >3 late genitourinary toxicities. ConclusionMRgRT is reliable and clinically feasible for treating patients with gynaecological cancers alone or in combination with brachytherapy with an acceptable toxicity and outcome. MRgRT boost could be an option when brachytherapy is not available or ineligible.

Dose-dependent effect on skin permeation of polar and non-polar compounds

The study of the relationship between the amount of drug applied to the skin and fraction of drug absorbed can improve our understanding of finite-dose percutaneous absorption in the development of topical products and risk assessment of hazardous chemical exposure. It has been previously shown that an increase in the dose applied to the skin leads to a decrease in the fraction of drug permeated the skin (dose-dependent effect). The objective of this research was to examine the dose-dependent effect using permeants of varying physiochemical properties. The dose-dependent effect was studied using human epidermal membrane under finite dose conditions in Franz diffusion cell with model permeants at doses ranging from 0.1 to 200 μg. The dose-dependent effect was evident with model permeants caffeine, corticosterone, dexamethasone, and estradiol, consistent with the relationship of decreasing fraction of dose permeated the skin at increasing the applied dose. However, no significant dose-dependent effect was observed for the polar model permeants urea, mannitol, tetraethyl ammonium, and ethylene glycol, suggesting different transport mechanisms for these permeants. It was also found that, at relatively high doses, estradiol, dexamethasone, and corticosterone could increase the permeation of polar and lipophilic permeants, which could counter the dose-dependent effect under the conditions studied.