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Fractionated radiotherapy was established in the 1920s based upon two principles: (1) delivering daily treatments of equal quantity, unless the clinical situation requires adjustment, and (2) defining a specific treatment period to deliver a total dosage. Modern fractionated radiotherapy continues to adhere to these century-old principles, despite significant advancements in our understanding of radiobiology. At UT Southwestern, we are exploring a novel treatment approach called PULSAR (Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy). This method involves administering tumoricidal doses in a pulse mode with extended intervals, typically spanning weeks or even a month. Extended intervals permit substantial recovery of normal tissues and afford the tumor and tumor microenvironment ample time to undergo significant changes, enabling more meaningful adaptation in response to the evolving characteristics of the tumor. The notion of dose painting in the realm of radiation therapy has long been a subject of contention. The debate primarily revolves around its clinical effectiveness and optimal methods of implementation. In this perspective, we discuss two facets concerning the potential integration of dose painting with PULSAR, along with several practical considerations. If successful, the combination of the two may not only provide another level of personal adaptation ("adaptive dose painting"), but also contribute to the establishment of a timely feedback loop throughout the treatment process. To substantiate our perspective, we conducted a fundamental modeling study focusing on PET-guided dose painting, incorporating tumor heterogeneity and tumor control probability (TCP). [ABSTRACT FROM AUTHOR]

BackgroundGlioblastoma (GBM) is the most aggressive type of brain cancer, with a 5-year survival rate of ~5% and most tumours recurring locally within months of first-line treatment. Hypoxia is associated with worse clinical outcomes in GBM, as it leads to localized resistance to radiotherapy and subsequent tumour recurrence. Current standard of care treatment does not account for tumour hypoxia, due to the challenges of mapping tumour hypoxia in routine clinical practice. In this clinical study, we aim to investigate the role of oxygen enhanced (OE) and blood-oxygen level dependent (BOLD) MRI as non-invasive imaging biomarkers of hypoxia in GBM, and to evaluate their potential role in dose-painting radiotherapy planning and treatment response assessment.MethodsThe primary endpoint is to evaluate the quantitative and spatial correlation between OE and BOLD MRI measurements and [18F]MISO values of uptake in the tumour. The secondary endpoints are to evaluate the repeatability of MRI biomarkers of hypoxia in a test-retest study, to estimate the potential clinical benefits of using MRI biomarkers of hypoxia to guide dose-painting radiotherapy, and to evaluate the ability of MRI biomarkers of hypoxia to assess treatment response. Twenty newly diagnosed GBM patients will be enrolled in this study. Patients will undergo standard of care treatment while receiving additional OE/BOLD MRI and [18F]MISO PET scans at several timepoints during treatment. The ability of OE/BOLD MRI to map hypoxic tumour regions will be evaluated by assessing spatial and quantitative correlations with areas of hypoxic tumour identified via [18F]MISO PET imaging.DiscussionMANGO (Magnetic resonance imaging of hypoxia for radiation treatment guidance in glioblastoma multiforme) is a diagnostic/prognostic study investigating the role of imaging biomarkers of hypoxia in GBM management. The study will generate a large amount of longitudinal multimodal MRI and PET imaging data that could be used to unveil dynamic changes in tumour physiology that currently limit treatment efficacy, thereby providing a means to develop more effective and personalised treatments.

Purpose: To investigate the feasibility and dosimetric index features of dose painting guided by perfusion heterogeneity for brain metastasis (BMs) patients. Methods: A total of 50 patients with single BMs were selected for this study. CT and MR simulation images were obtained, including contrast-enhanced T1-weighted images (T1WI+C) and cerebral blood flow (CBF) maps from 3Darterial spin labeling (ASL). The gross tumor volume (GTV) was determined by fusion of CT and T1WI+C images. Hypoperfused subvolumes (GTVH) with less than 25% of the maximum CBF value were defined as the dose escalation region. The planning target volume (PTV) and PTVH were calculated from GTV and GTVH respectively. The PTVN was obtained by subtracting PTVH from PTV, and conventional dose was given. Three kinds of radiotherapy plans were designed based on the CBF values. Plan 1 was defined as the conventional plan with an arbitrary prescription dose of 60 Gy for PTV. For dose painting, Plan 2 and Plan 3 escalated the prescription dose for PTVH to 72 Gy based on Plan 1, but Plan 3 removed the maximum dose constraint. Dosimetric indices were compared among the three plans. Results: The mean GTV volume was 34.5 (8.4-118.0) cm³, and mean GTVH volume was 17.0 (4.5-58.3) cm³, accounting for 49.3% of GTV. Both conventional plan and dose painting plans achieved 98% target coverage. The conformity index of PTVH were 0.44 (Plan1), 0.64 and 0.72 (Plan 2 and Plan 3, P<0.05). Compared to Plan 1, the D2%, D98% and Dmean values of the PTVH escalated by 20.50%, 19.32%, and 19.60% in Plan 2 and by 24.88%, 17.22% and 19.22% in Plan 3 respectively (P<0.05). In the three plans, the index of achievement value for PTVH was between 1.01 and 1.03 (P<0.05). The dose increment rates of Plan 2 and Plan 3 for each organs at risk (OARs) was controlled at 2.19% - 5.61% compared with Plan 1. The doses received by OARs did not significantly differ among the three plans (P >0.05). Conclusions: BMs are associated with significant heterogeneity, and effective escalation of the dose delivered to target subvolumes can be achieved with dose painting guided by 3D-ASL without extra doses to OARs. [ABSTRACT FROM AUTHOR]

Purpose: Dose painting (DP) is a radiation therapy (RT) strategy for patients with heterogeneous tumors delivering higher dose to radiation resistant regions and less to sensitive ones, thus aiming to maximize tumor control with limited side effects. The success of DP treatments is influenced by the spatial accuracy in dose delivery. Adaptive RT (ART) workflows can reduce the overall geometric dose delivery uncertainty. The purpose of this study is to dosimetrically compare ART and non-adaptive conventional RT workflows for delivery of DP prescriptions in the treatment of prostate cancer (PCa). Materials and methods: We performed a planning and treatment simulation study of four study arms. Adaptive and conventional workflows were tested in combination with DP and Homogeneous dose. We used image data from 5 PCa patients that had been treated on the Elekta Unity MR linac; the patients had been imaged in treatment position before each treatment fraction (7 in total). The local radiation sensitivity from apparent diffusion coefficient maps of 15 high-risk PCa patients was modelled in a previous study. these maps were used as input for optimization of DP plans aiming for maximization of tumor control probability (TCP) under rectum dose constraints. A range of prostate doses were planned for the homogeneous arms. Adaptive plans were replanned based on the anatomy-of-the-day, whereas conventional plans were planned using a pre-treatment image and subsequently recalculated on the anatomy-of-the-day. The dose from 7 fractions was accumulated using dose mapping. The endpoints studied were the TCP and dose-volume histogram metrics for organs at risk. Results: Accumulated DP doses (adaptive and conventional) resulted in high TCP, between 96-99%. The largest difference between adaptive and conventional DP was 2.6 percentage points (in favor of adaptive DP). An analysis of the dose per fraction revealed substantial target misses for one patient in the conventional workflow that—if systematic—could jeopardize the TCP. Compared to homogeneous prescriptions with equal mean prostate dose, DP resulted in slightly higher TCP. Conclusion: Compared to homogeneous dose, DP maintains or marginally increases the TCP. Adaptive DP workflows could avoid target misses compared to conventional workflows. [ABSTRACT FROM AUTHOR]

PurposeDose painting (DP) is a radiation therapy (RT) strategy for patients with heterogeneous tumors delivering higher dose to radiation resistant regions and less to sensitive ones, thus aiming to maximize tumor control with limited side effects. The success of DP treatments is influenced by the spatial accuracy in dose delivery. Adaptive RT (ART) workflows can reduce the overall geometric dose delivery uncertainty. The purpose of this study is to dosimetrically compare ART and non-adaptive conventional RT workflows for delivery of DP prescriptions in the treatment of prostate cancer (PCa).Materials and methodsWe performed a planning and treatment simulation study of four study arms. Adaptive and conventional workflows were tested in combination with DP and Homogeneous dose. We used image data from 5 PCa patients that had been treated on the Elekta Unity MR linac; the patients had been imaged in treatment position before each treatment fraction (7 in total). The local radiation sensitivity from apparent diffusion coefficient maps of 15 high-risk PCa patients was modelled in a previous study. these maps were used as input for optimization of DP plans aiming for maximization of tumor control probability (TCP) under rectum dose constraints. A range of prostate doses were planned for the homogeneous arms. Adaptive plans were replanned based on the anatomy-of-the-day, whereas conventional plans were planned using a pre-treatment image and subsequently recalculated on the anatomy-of-the-day. The dose from 7 fractions was accumulated using dose mapping. The endpoints studied were the TCP and dose-volume histogram metrics for organs at risk.ResultsAccumulated DP doses (adaptive and conventional) resulted in high TCP, between 96-99%. The largest difference between adaptive and conventional DP was 2.6 percentage points (in favor of adaptive DP). An analysis of the dose per fraction revealed substantial target misses for one patient in the conventional workflow that—if systematic—could jeopardize the TCP. Compared to homogeneous prescriptions with equal mean prostate dose, DP resulted in slightly higher TCP.ConclusionCompared to homogeneous dose, DP maintains or marginally increases the TCP. Adaptive DP workflows could avoid target misses compared to conventional workflows.

Fractionated radiotherapy was established in the 1920s based upon two principles: (1) delivering daily treatments of equal quantity, unless the clinical situation requires adjustment, and (2) defining a specific treatment period to deliver a total dosage. Modern fractionated radiotherapy continues to adhere to these century-old principles, despite significant advancements in our understanding of radiobiology. At UT Southwestern, we are exploring a novel treatment approach called PULSAR (Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy). This method involves administering tumoricidal doses in a pulse mode with extended intervals, typically spanning weeks or even a month. Extended intervals permit substantial recovery of normal tissues and afford the tumor and tumor microenvironment ample time to undergo significant changes, enabling more meaningful adaptation in response to the evolving characteristics of the tumor. The notion of dose painting in the realm of radiation therapy has long been a subject of contention. The debate primarily revolves around its clinical effectiveness and optimal methods of implementation. In this perspective, we discuss two facets concerning the potential integration of dose painting with PULSAR, along with several practical considerations. If successful, the combination of the two may not only provide another level of personal adaptation ("adaptive dose painting"), but also contribute to the establishment of a timely feedback loop throughout the treatment process. To substantiate our perspective, we conducted a fundamental modeling study focusing on PET-guided dose painting, incorporating tumor heterogeneity and tumor control probability (TCP)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Peng, Deng, Jiang and Timmerman.)

Background: Glioblastoma (GBM) is the most aggressive type of brain cancer, with a 5-year survival rate of ~5% and most tumours recurring locally within months of first-line treatment. Hypoxia is associated with worse clinical outcomes in GBM, as it leads to localized resistance to radiotherapy and subsequent tumour recurrence. Current standard of care treatment does not account for tumour hypoxia, due to the challenges of mapping tumour hypoxia in routine clinical practice. In this clinical study, we aim to investigate the role of oxygen enhanced (OE) and blood-oxygen level dependent (BOLD) MRI as non-invasive imaging biomarkers of hypoxia in GBM, and to evaluate their potential role in dose-painting radiotherapy planning and treatment response assessment., Methods: The primary endpoint is to evaluate the quantitative and spatial correlation between OE and BOLD MRI measurements and [ 18 F]MISO values of uptake in the tumour. The secondary endpoints are to evaluate the repeatability of MRI biomarkers of hypoxia in a test-retest study, to estimate the potential clinical benefits of using MRI biomarkers of hypoxia to guide dose-painting radiotherapy, and to evaluate the ability of MRI biomarkers of hypoxia to assess treatment response. Twenty newly diagnosed GBM patients will be enrolled in this study. Patients will undergo standard of care treatment while receiving additional OE/BOLD MRI and [ 18 F]MISO PET scans at several timepoints during treatment. The ability of OE/BOLD MRI to map hypoxic tumour regions will be evaluated by assessing spatial and quantitative correlations with areas of hypoxic tumour identified via [ 18 F]MISO PET imaging., Discussion: MANGO (Magnetic resonance imaging of hypoxia for radiation treatment guidance in glioblastoma multiforme) is a diagnostic/prognostic study investigating the role of imaging biomarkers of hypoxia in GBM management. The study will generate a large amount of longitudinal multimodal MRI and PET imaging data that could be used to unveil dynamic changes in tumour physiology that currently limit treatment efficacy, thereby providing a means to develop more effective and personalised treatments., Competing Interests: Authors KO’B and MM was employed by the company Siemens Healthcare Pty Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Brighi, Waddington, Keall, Booth, O’Brien, Silvester, Parkinson, Mueller, Yim, Bailey, Back and Drummond.)

Purpose: To investigate the feasibility and dosimetric index features of dose painting guided by perfusion heterogeneity for brain metastasis (BMs) patients., Methods: A total of 50 patients with single BMs were selected for this study. CT and MR simulation images were obtained, including contrast-enhanced T1-weighted images (T1WI+C) and cerebral blood flow (CBF) maps from 3D-arterial spin labeling (ASL). The gross tumor volume (GTV) was determined by fusion of CT and T1WI+C images. Hypoperfused subvolumes (GTV H ) with less than 25% of the maximum CBF value were defined as the dose escalation region. The planning target volume (PTV) and PTV H were calculated from GTV and GTV H respectively. The PTV N was obtained by subtracting PTV H from PTV, and conventional dose was given. Three kinds of radiotherapy plans were designed based on the CBF values. Plan 1 was defined as the conventional plan with an arbitrary prescription dose of 60 Gy for PTV. For dose painting, Plan 2 and Plan 3 escalated the prescription dose for PTV H to 72 Gy based on Plan 1, but Plan 3 removed the maximum dose constraint. Dosimetric indices were compared among the three plans., Results: The mean GTV volume was 34.5 (8.4-118.0) cm 3 , and mean GTV H volume was 17.0 (4.5-58.3) cm 3 , accounting for 49.3% of GTV. Both conventional plan and dose painting plans achieved 98% target coverage. The conformity index of PTV H were 0.44 (Plan1), 0.64 and 0.72 (Plan 2 and Plan 3, P< 0.05). Compared to Plan 1, the D 2% , D 98% and D mean values of the PTV H escalated by 20.50%, 19.32%, and 19.60% in Plan 2 and by 24.88%, 17.22% and 19.22% in Plan 3 respectively ( P< 0.05). In the three plans, the index of achievement value for PTV H was between 1.01 and 1.03 ( P< 0.05). The dose increment rates of Plan 2 and Plan 3 for each organs at risk (OARs) was controlled at 2.19% - 5.61% compared with Plan 1. The doses received by OARs did not significantly differ among the three plans ( P > 0.05)., Conclusions: BMs are associated with significant heterogeneity, and effective escalation of the dose delivered to target subvolumes can be achieved with dose painting guided by 3D-ASL without extra doses to OARs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hou, Yin, Gong, Wang, Su, Lu and Yin.)