Radiobiological Evaluation of Combined Gamma Knife Radiosurgery and Hyperthermia for Pediatric Neuro-Oncology

Combining radiotherapy (RT) with hyperthermia (HT) has been proven effective in the treatment of a wide range of tumours, but the combination of externally delivered, focused heat and stereotactic radiosurgery has never been investigated. We explore the potential of such treatment enhancement via radiobiological modelling, specifically via the linear-quadratic (LQ) model adapted to thermoradiotherapy through modulating the radiosensitivity of temperature-dependent parameters. We extend this well-established model by incorporating oxygenation effects. To illustrate the methodology, we present a clinically relevant application in pediatric oncology, which is novel in two ways. First, it deals with medulloblastoma, the most common malignant brain tumour in children, a type of brain tumour not previously reported in the literature of thermoradiotherapy studies. Second, it makes use of the Gamma Knife for the radiotherapy part, thereby being the first of its kind in this context. Quantitative metrics like the biologically effective dose (BED) and the tumour control probability (TCP) are used to assess the efficacy of the combined plan.

Influence of Urethra Sparing on Tumor Control Probability and Normal Tissue Complication Probability in Focal Dose Escalated Hypofractionated Radiotherapy: A Planning Study Based on Histopathology Reference

PurposeMultiparametric magnetic resonance tomography (mpMRI) and prostate specific membrane antigen positron emission tomography (PSMA-PET/CT) are used to guide focal radiotherapy (RT) dose escalation concepts. Besides improvements of treatment effectiveness, maintenance of a good quality of life is essential. Therefore, this planning study investigates whether urethral sparing in moderately hypofractionated RT with focal RT dose escalation influences tumour control probability (TCP) and normal tissue complication probability (NTCP).Patients and Methods10 patients with primary prostate cancer (PCa), who underwent 68Ga PSMA-PET/CT and mpMRI followed by radical prostatectomy were enrolled. Intraprostatic tumour volumes (gross tumor volume, GTV) based on both imaging techniques (GTV-MRI and -PET) were contoured manually using validated contouring techniques and GTV-Union was created by summing both. For each patient three IMRT plans were generated with 60 Gy to the whole prostate and a simultaneous integrated boost up to 70 Gy to GTV-Union in 20 fractions by (Plan 1) not respecting and (Plan 2) respecting dose constraints for urethra as well as (Plan 3) respecting dose constraints for planning organ at risk volume for urethra (PRV = urethra + 2mm expansion). NTCP for urethra was calculated applying a Lyman-Kutcher-Burman model. TCP-Histo was calculated based on PCa distribution in co-registered histology (GTV-Histo). Complication free tumour control probability (P+) was calculated. Furthermore, the intrafractional movement was considered.ResultsMedian overlap of GTV-Union and PRV-Urethra was 1.6% (IQR 0-7%). Median minimum distance of GTV-Histo to urethra was 3.6 mm (IQR 2 – 7 mm) and of GTV-Union to urethra was 1.8 mm (IQR 0.0 – 5.0 mm). The respective prescription doses and dose constraints were reached in all plans. Urethra-sparing in Plans 2 and 3 reached significantly lower NTCP-Urethra (p = 0.002) without significantly affecting TCP-GTV-Histo (p = p > 0.28), NTCP-Bladder (p > 0.85) or NTCP-Rectum (p = 0.85), resulting in better P+ (p = 0.006). Simulation of intrafractional movement yielded even higher P+ values for Plans 2 and 3 compared to Plan 1.ConclusionUrethral sparing may increase the therapeutic ratio and should be implemented in focal RT dose escalation concepts.

Analysis of Hepatocellular Carcinoma Stereotactic Body Radiation Therapy Dose Prescription Method Using Uncomplicated Tumour Control Probability Model

Background: This work was to establish an uncomplicated tumour control probability (UTCP) model using Hepatocellular Carcinoma Stereotactic Body Radiation Therapy (HCC SBRT) clinical data in our institution. The model was then used to analyze the treatment outcome of the current dose prescription method and to seek the opportunity for improvement.Methods: A tumour control probability (TCP) model was generated based on local clinical data using the maximum likelihood method. A UTCP model was then formed by combining the established TCP model with the normal tissue complication probability (NTCP) model based on the study by Dawson et al. The authors investigated the dependence of maximum achievable UTCP on tumor mean biological effective dose (BED) at various ratio between tumour mean biological effective dose (BED) and normal liver mean BED (T/N BED ratios). A new term uncomplicated tumour control efficiency (UTCE) was also introduced to analyze the outcome. A UTCE value of 1 implied that the theoretical maximum UTCP for the corresponding T/N BED ratio was achieved.Results: The UTCE of the HCC SBRT patients based on the current dose prescription method was found to be 0.90±0.08. It was found that the UTCE could be increased to 0.99±0.03 by using a new dose prescription scheme, for which the UTCP could be maximized while keeping the NTCP value smaller than 5 %. Conclusion: The treatment outcome of the current HCC SBRT in our institution was analyzed using a UTCP model established based on local clinical data. It was shown that there could be a potential to increase the prescription dose of HCC SBRT. A new dose prescription scheme was proposed to achieve better treatment outcome.

The effect on tumour control probability of using AXB algorithm in replacement of AAA for SBRT of hepatocellular carcinoma located at lung–liver boundary region

Objective: To retrospectively analyze the clinical impact on stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) located at lung–liver boundary due to the use of Acuros XB algorithm (AXB) in replacement of anisotropic analytical algorithm (AAA). Methods: 23 SBRT volumetric modulated arc therapy (VMAT) plans for HCC located at lung–liver boundary were calculated using AAA and AXB respectively with the same treatment parameters. The dose–volume data of the planned target volumes (PTVs) were compared. A published tumour control probability (TCP) model was used to calculate the effect of dosimetric difference between AAA and AXB on tumour control probability. Results: For dose calculated by AXB (Dose to medium), the D95% and D98% of the PTV were on average 2.4 and 3.1% less than that calculated by AAA. For dose calculated by AXB (dose to water), the D95% and D98% of the PTV were on average 1.8%, and 2.7% less than that calculated by AAA. Up to 5% difference in D95% and 8% difference in D98% were observed in the worst cases. The significant decrease in D95% calculated by AXB compared to AAA could result in a % decrease in 2 year TCP up to 8% in the worst case (from 46.8 to 42.9%). Conclusion: The difference in dose calculated by AAA and AXB could lead to significant difference in TCP for HCC SBRT located at lung–liver boundary region. Advances in knowledge: The difference in calculated dose and tumour control probability for HCC SBRT between AAA and AXB algorithm at lung–liver boundary region was compared.

Theoretical derivation and clinical dose-response quantification of a unified multi-activation (UMA) model of cell survival from a logistic equation

Objective: To theoretically derive a unified multiactivation (UMA) model of cell survival after ionising radiation that can accurately assess doses and responses in radiotherapy and X-ray imaging. Methods: A unified formula with only two parameters in fitting of a cell survival curve (CSC) is first derived from an assumption that radiation-activated cell death pathways compose the first- and second-order reaction kinetics. A logit linear regression of CSC data is used for precise determination of the two model parameters. Intrinsic radiosensitivity, biologically effective dose (BED), equivalent dose to the traditional 2 Gy fractions (EQD2), tumour control probability, normal-tissue complication probability, BED50 and steepness (Γ50) at 50% of tumour control probability (or normal-tissue complication probability) are analytical functions of the model and treatment (or imaging) parameters. Results: The UMA model has almost perfectly fit typical CSCs over the entire dose range with R2≥0.99. Estimated quantities for stereotactic body radiotherapy of early stage lung cancer and the skin reactions from X-ray imaging agree with clinical results. Conclusion: The proposed UMA model has theoretically resolved the catastrophes of the zero slope at zero dose for multiple target model and the bending curve at high dose for the linear quadratic model. More importantly, it analytically predicts dose–responses to various dose–fraction schemes in radiotherapy and to low dose X-ray imaging based on these preclinical CSCs. Advances in knowledge: The discovery of a unified formula of CSC over the entire dose range may reveal a common mechanism of the first- and second-order reaction kinetics among multiple CD pathways activated by ionising radiation at various dose levels.