Purpose: Currently, clinical decisions regarding thermoradiotherapy treatments are based on clinical experience. Quantification of the radiosensitising effect of hyperthermia allows comparison of different treatment strategies, and can support clinical decision-making regarding the optimal treatment. The software presented here enables biological evaluation of thermoradiotherapy plans through calculation of equivalent 3D dose distributions.Methods: Our in-house developed software (X-Term) uses an extended version of the linear-quadratic model to calculate equivalent radiation dose, i.e. the radiation dose yielding the same effect as the thermoradiotherapy treatment. Separate sets of model parameters can be assigned to each delineated structure, allowing tissue specific modelling of hyperthermic radiosensitisation. After calculation, the equivalent radiation dose can be evaluated according to conventional radiotherapy planning criteria. The procedure is illustrated using two realistic examples. Fir...

https://tandfonline.com/doi/pdf/10.1080/02656736.2016.1241431

3D radiobiological evaluation of combined radiotherapy and hyperthermia treatments

Purpose: to predict the occurrence of late subcutaneous radiation induced fibrosis (RIF) after partial breast irradiation (PBI) for breast carcinoma by using machine learning (ML) models and radiomic features from 3D Biologically Effective Dose (3D-BED) and Relative Electron Density (3D-RED). Methods: 165 patients underwent external PBI following a hypo-fractionation protocol consisting of 40 Gy/10 fractions, 35 Gy/7 fractions, and 28 Gy/4 fractions, for 73, 60, and 32 patients, respectively. Physicians evaluated toxicity at regular intervals by the Common Terminology Adverse Events (CTAE) version 4.0. RIF was assessed every 3 months after the completion of radiation course and scored prospectively. RIF was experienced by 41 (24.8%) patients after average 5 years of follow up. The Hounsfield Units (HU) of the CT-images were converted into relative electron density (3D-RED) and Dose maps into Biologically Effective Dose (3D-BED), respectively. Shape, first-order and textural features of 3D-RED and 3D-BED were calculated in the planning target volume (PTV) and breast. Clinical and demographic variables were also considered (954 features in total). Imbalance of the dataset was addressed by data augmentation using ADASYN technique. A subset of non-redundant features that best predict the data was identified by sequential feature selection. Support Vector Machines (SVM), ensemble machine learning (EML) using various aggregation algorithms and Naive Bayes (NB) classifiers were trained on patient dataset to predict RIF occurrence. Models were assessed using sensitivity and specificity of the ML classifiers and the area under the receiver operator characteristic curve (AUC) of the score functions in repeated 5-fold cross validation on the augmented dataset. Results: The SVM model with seven features was preferred for RIF prediction and scored sensitivity 0.83 (95% CI 0.80-0.86), specificity 0.75 (95% CI 0.71-0.77) and AUC of the score function 0.86 (0.85-0.88) on cross-validation. The selected features included cluster shade and Run Length Non-uniformity of breast 3D-BED, kurtosis and cluster shade from PTV 3D-RED, and 10th percentile of PTV 3D-BED. Conclusion: Textures extracted from 3D-BED and 3D-RED in the breast and PTV can predict late RIF and may help better select patient candidates to exclusive PBI.

/pdf/electron-density-and-biologically-effective-dose-bed-2spt8poh0v.pdf

Electron Density and Biologically Effective Dose (BED) Radiomics-Based Machine Learning Models to Predict Late Radiation-Induced Subcutaneous Fibrosis

Adverse drug reactions (ADRs) account for a large proportion of hospitalizations among adults, and are more common in multimorbid patients, worsening clinical outcomes and burdening healthcare resources. Over the past decade, pharmacogenomics has been developed as a practical tool for optimizing treatment outcomes by mitigating the risk of ADRs. Some single-gene reactive tests are already used in clinical practice, including the DPYD test for fluoropyrimidines, which demonstrates how integrating pharmacogenomic data into routine care can improve patient safety in a cost-effective manner. The evolution from reactive single-gene testing to comprehensive preemptive genotyping panels holds great potential for refining drug prescribing practices. Several implementation projects have been conducted to test the feasibility of applying different genetic panels in clinical practice. Recently, the results of a large prospective randomized trial in Europe (Ubiquitous Pharmacogenomics-PREPARE study) have provided the first evidence that prospective application of a preemptive pharmacogenomic test panel in clinical practice, in seven European healthcare systems, is feasible and yielded a 30% reduction in the risk of developing clinically relevant toxicities. Nevertheless, some important questions remain unanswered, and will hopefully be addressed by future dedicated studies. These issues include the cost-effectiveness of applying a preemptive genotyping panel, the role of multiple co-medications, the transferability of currently tested pharmacogenetic guidelines among patients of non-European origin, and the impact of rare pharmacogenetic variants that are not detected by currently used genotyping approaches.

Implementation of preemptive testing of a pharmacogenomic panel in clinical practice: Where do we stand?

Partial breast irradiation (PBI) is an effective adjuvant treatment after breast conservative surgery for selected early-stage breast cancer patients. However, the best fractionation scheme is not well defined. Hereby, we report the 5-year clinical outcome and toxicity of a phase II prospective study of a novel regimen to deliver PBI, which consists in 40 Gy delivered in 10 daily fractions. Patients with early-stage (pT1-pT2, pN0-pN1a, M0) invasive breast cancer were enrolled after conservative surgery. The minimum age at diagnosis was 60 years old. PBI was delivered with 3D-conformal radiotherapy technique with a total dose of 40 Gy, fractionated in 10 daily fractions (4 Gy/fraction). Eighty patients were enrolled. The median follow-up was 67 months. Five-year local control (LC), disease-free survival (DFS), and overall survival (OS) were 95%, 91%, and 96%, respectively. Grade I and II subcutaneous fibrosis were documented in 23% and 5% of cases. No grade III late toxicity was observed. PBI delivered in 40 Gy in 10 daily fractions provided good clinical results and was a valid radiotherapy option for early-stage breast cancer patients.

Ten daily fractions for partial breast irradiation. Long-term results of a prospective phase II trial.

The field of pharmacogenetics (PGx) holds great promise in advancing personalized medicine by adapting treatments based on individual genetic profiles. Despite its benefits, there are still economic, ethical and institutional barriers that hinder its implementation in our healthcare environment. A retrospective analysis approach of anonymized data sourced from electronic health records was performed, encompassing a diverse patient population and evaluating key parameters such as prescribing patterns and test results, to assess the impact of pharmacogenetic testing. A head-to-head comparison with previously published activity results within the same pharmacogenetic laboratory was also conducted to contrast the progress made after 10 years. The analysis revealed significant utilization of pharmacogenetic testing in daily clinical practice, with 1,145 pharmacogenetic tests performed over a 1-year period and showing a 35% growth rate increase over time. Of the 17 different medical departments that sought PGx tests, the Oncology department accounted for the highest number, representing 58.47% of all genotyped patients. A total of 1,000 PGx tests were requested for individuals susceptible to receive a dose modification based on genotype, and 76 individuals received a genotype-guided dose adjustment. This study presents a comprehensive descriptive analysis of real-world data obtained from a public tertiary hospital laboratory specialized in pharmacogenetic testing, and presents data that strongly endorse the integration of pharmacogenetic testing into everyday clinical practice.

Advancing pharmacogenetic testing in a tertiary hospital: a retrospective analysis after 10 years of activity

Background: Awareness about the importance of implementing DPYD pharmacogenetics in clinical practice to prevent severe side effects related to the use of fluoropyrimidines has been raised over the years. Since 2012 at the National Cancer Institute, CRO-Aviano (Italy), a diagnostic DPYD genotyping service was set up. Purpose: This study aims to describe the evolution of DPYD diagnostic activity at our center over the last 10 years as a case example of a successful introduction of pharmacogenetic testing in clinical practice. Methods: Data related to the diagnostic activity of in–and out-patients referred to our service between January 2012 and December 2022 were retrieved from the hospital database. Results: DPYD diagnostic activity at our center has greatly evolved over the years, shifting gradually from a post-toxicity to a pre-treatment approach. Development of pharmacogenetic guidelines by national and international consortia, genotyping, and IT technology evolution have impacted DPYD testing uptake in the clinics. Our participation in a large prospective implementation study (Ubiquitous Pharmacogenomics) increased health practitioners’ and patients’ awareness of pharmacogenetic matters and provided additional standardized infrastructures for genotyping and reporting. Nationwide test reimbursement together with recommendations by regulatory agencies in Europe and Italy in 2020 definitely changed the clinical practice guidelines of fluoropyrimidines prescription. A dramatic increase in the number of pre-treatment DPYD genotyping and in the coverage of new fluoropyrimidine prescriptions was noticed by the last year of observation (2022). Conclusion: The long path to a successful DPYD testing implementation in the clinical practice of a National Cancer Center in Italy demonstrated that the development of pharmacogenetic guidelines and genotyping infrastructure standardization as well as capillary training and education activity for all the potential stakeholders are fundamental. However, only national health politics of test reimbursement and clear recommendations by drug regulatory agencies will definitely move the field forward.

/pdf/ten-year-experience-with-pharmacogenetic-testing-for-dpyd-in-1j7lu1sb.pdf

Ten-year experience with pharmacogenetic testing for DPYD in a national cancer center in Italy: Lessons learned on the path to implementation

Hypofractionation of partial breast irradiation using radiobiological models

P198 Applying TDM and PGx in mRCC patients treated with Sunitinib to customize drug dosing

95P Implementation of TDM and PGx in mRCC patients treated with sunitinib to personalize drug dosing

78P The integration of TDM and PGx in patients with mRCC receiving sunitinib treatment

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