Machine learning identifies multi-parametric functional PET/MR imaging cluster to predict radiation resistance in preclinical head and neck cancer models.

PURPOSE: Tumor hypoxia and other microenvironmental factors are key determinants of treatment resistance. Hypoxia positron emission tomography (PET) and functional magnetic resonance imaging (MRI) are established prognostic imaging modalities to identify radiation resistance in head-and-neck cancer (HNC). The aim of this preclinical study was to develop a multi-parametric imaging parameter specifically for focal radiotherapy (RT) dose escalation using HNC xenografts of different radiation sensitivities. METHODS: A total of eight human HNC xenograft models were implanted into 68 immunodeficient mice. Combined PET/MRI using dynamic [18F]-fluoromisonidazole (FMISO) hypoxia PET, diffusion-weighted (DW), and dynamic contrast-enhanced MRI was carried out before and after fractionated RT (10 × 2 Gy). Imaging data were analyzed on voxel-basis using principal component (PC) analysis for dynamic data and apparent diffusion coefficients (ADCs) for DW-MRI. A data- and hypothesis-driven machine learning model was trained to identify clusters of high-risk subvolumes (HRSs) from multi-dimensional (1-5D) pre-clinical imaging data before and after RT. The stratification potential of each 1D to 5D model with respect to radiation sensitivity was evaluated using Cohen's d-score and compared to classical features such as mean/peak/maximum standardized uptake values (SUVmean/peak/max) and tumor-to-muscle-ratios (TMRpeak/max) as well as minimum/valley/maximum/mean ADC. RESULTS: Complete 5D imaging data were available for 42 animals. The final preclinical model for HRS identification at baseline yielding the highest stratification potential was defined in 3D imaging space based on ADC and two FMISO PCs ([Formula: see text]). In 1D imaging space, only clusters of ADC revealed significant stratification potential ([Formula: see text]). Among all classical features, only ADCvalley showed significant correlation to radiation resistance ([Formula: see text]). After 2 weeks of RT, FMISO_c1 showed significant correlation to radiation resistance ([Formula: see text]). CONCLUSION: A quantitative imaging metric was described in a preclinical study indicating that radiation-resistant subvolumes in HNC may be detected by clusters of ADC and FMISO using combined PET/MRI which are potential targets for future functional image-guided RT dose-painting approaches and require clinical validation.

Hypoxia dose painting in SBRT - the virtual clinical trial approach.

BACKGROUND: Treating hypoxic tumours remains a challenge in radiotherapy as hypoxia leads to enhanced tumour aggressiveness and resistance to radiation. As escalating the doses is rarely feasible within the healthy tissue constraints, dose-painting strategies have been explored. Consensus about the best of care for hypoxic tumours has however not been reached because, among other reasons, the limits of current functional in-vivo imaging systems in resolving the details and dynamics of oxygen transport in tissue. Computational modelling of the tumour microenvironment enables the design and conduction of virtual clinical trials by providing relationships between biological features and treatment outcomes. This study presents a framework for assessing the therapeutic influence of the individual characteristics of the vasculature and the resulting oxygenation of hypoxic tumours in a virtual clinical trial on dose painting in stereotactic body radiotherapy (SBRT) circumventing the limitations of the imaging systems. MATERIAL AND METHODS: The homogeneous doses required to overcome hypoxia in simulated SBRT treatments of 1, 3 or 5 fractions were calculated for tumours with heterogeneous oxygenation derived from virtual vascular networks. The tumour control probability (TCP) was calculated for different scenarios for oxygenation dynamics resulting on cellular reoxygenation. RESULTS: A three-fractions SBRT treatment delivering 41.9 Gy (SD 2.8) and 26.5 Gy (SD 0.1) achieved only 21% (SD 12) and 48% (SD 17) control in the hypoxic and normoxic subvolumes, respectively whereas fast reoxygenation improved the control by 30% to 50%. TCP values for the individual tumours with similar characteristics, however, might differ substantially, highlighting the crucial role of the magnitude and time evolution of hypoxia at the microscale. CONCLUSION: The results show that local microvascular heterogeneities may affect the predicted outcome in the hypoxic core despite escalated doses, emphasizing the role of theoretical modelling in understanding of and accounting for the dominant factors of the tumour microenvironment.

Photon and Proton Dose Painting Based on Oxygen Distribution - Feasibility Study and Tumour Control Probability Assessment.

Solid tumours may present hypoxic sub-regions of increased radioresistance. Hypoxia quantification requires of clinically implementable, non-invasive and reproducible techniques as positron emission tomography (PET). PET-based dose painting strategies aiming at targeting those sub-regions may be limited by the resolution gap between the PET imaging resolution and the smaller scale at which hypoxia occurs. The ultimate benefit of the usage of dose painting may be reached if the planned dose distribution can be performed and delivered consistently. This study aimed at assessing the feasibility of two PET-based dose painting strategies using two beam qualities (photon or proton beams) in terms of tumour control probability (TCP), accounting for underlying oxygen distribution at sub-millimetre scale.A tumour oxygenation model at submillimetre scale was created consisting of three regions with different oxygen partial pressure distributions, being hypoxia decreasing from core to periphery. A published relationship between uptake and oxygen partial pressure was used and a PET image of the tumour was simulated. The fundamental effects that limit the PET camera resolution were considered by processing the uptake distribution with a Gaussian 3D filter and re-binning to a PET image voxel size of 2 mm. Prescription doses to overcome tumour hypoxia were calculated based on the processed images, and planned using robust optimisation.Normal tissue complication probabilities and TCPs after the delivery of the planned doses were calculated for the nominal plan and the lowest bounds of the dose volume histograms resulting from the robust scenarios planned, taking into account the underlying oxygenation at submillimetre scale. Results were presented for the two beam qualities and the two dose painting strategies: by contours (DPBC) and by using a voxel grouping-based approach (DPBOX).In the studied case, DPBOX outperforms DPBC with respect to TCP regardless the beam quality, although both dose painting strategy plans demonstrated robust target coverage.

Robust treatment planning of dose painting for prostate cancer based on ADC-to-Gleason score mappings - what is the potential to increase the tumor control probability?

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the potential to increase the tumor control probability (TCP) with 'dose painting by numbers' (DPBN) plans optimized in a treatment planning system (TPS) compared to uniform dose plans. The DPBN optimization was based on our earlier published formalism for prostate cancer that is driven by dose-responses of Gleason scores mapped from apparent diffusion coefficients (ADC). MATERIAL AND METHODS: For 17 included patients, a set of DPBN plans were optimized in a TPS by maximizing the TCP for an equal average dose to the prostate volume (CTVT) as for a conventional uniform dose treatment. For the plan optimizations we applied different photon energies, different precisions for the ADC-to-Gleason mappings, and different CTVT positioning uncertainties. The TCP increasing potential was evaluated by the DPBN efficiency, defined as the ratio of TCP increases for DPBN plans by TCP increases for ideal DPBN prescriptions (optimized without considering radiation transport phenomena, uncertainties of the CTVT positioning, and uncertainties of the ADC-to-Gleason mapping). RESULTS: The median DPBN efficiency for the most conservative planning scenario optimized with a low precision ADC-to-Gleason mapping, and a positioning uncertainty of 0.6 cm was 10%, meaning that more than half of the patients had a TCP gain of at least 10% of the TCP for an ideal DPBN prescription. By increasing the precision of the ADC-to-Gleason mapping, and decreasing the positioning uncertainty the median DPBN efficiency increased by up to 40%. CONCLUSIONS: TCP increases with DPBN plans optimized in a TPS were found more likely with a high precision mapping of image data into dose-responses and a high certainty of the tumor positioning. These findings motivate further development to ensure precise mappings of image data into dose-responses and to ensure a high spatial certainty of the tumor positioning when implementing DPBN clinically.

Repeatability of hypoxia dose painting by numbers based on EF5-PET in head and neck cancer.

BACKGROUND: Hypoxia dose painting is a radiotherapy technique to increase the dose to hypoxic regions of the tumour. Still, the clinical effect relies on the reproducibility of the hypoxic region shown in the medical image. 18F-EF5 is a hypoxia tracer for positron emission tomography (PET), and this study investigated the repeatability of 18F-EF5-based dose painting by numbers (DPBN) in head and neck cancer (HNC). MATERIALS AND METHODS: Eight HNC patients undergoing two 18F-EF5-PET/CT sessions (A and B) before radiotherapy were included. A linear conversion of PET signal intensity to radiotherapy dose prescription was employed and DPBN treatment plans were created using the image basis acquired at each PET/CT session. Also, plan A was recalculated on the image basis for session B. Voxel-by-voxel Pearson's correlation and quality factor were calculated to assess the DPBN plan quality and repeatability. RESULTS: The mean (SD) correlation coefficient between DPBN prescription and plan was 0.92 (0.02) and 0.93 (0.02) for sessions A and B, respectively, with corresponding quality factors of 0.02 (0.002) and 0.02 (0.003), respectively. The mean correlation between dose prescriptions at day A and B was 0.72 (0.13), and 0.77 (0.12) for the corresponding plans. A mean correlation of 0.80 (0.08) was found between plan A, recalculated on image basis B, and plan B. CONCLUSION: Hypoxia DPBN planning based on 18F-EF5-PET/CT showed high repeatability. This illustrates that 18F-EF5-PET provides a robust target for dose painting.

Assessment of the Probability of Tumour Control for Prescribed Doses Based on Imaging of Oxygen Partial Pressure.

In radiotherapy, hypoxia is a known negative factor, occurring especially in solid malignant tumours. Nitroimidazole-based positron emission tomography (PET) tracers, due to their selective binding to hypoxic cells, could be used as surrogates to image and quantify the underlying oxygen distributions in tissues. The spatial resolution of a clinical PET image, however, is much larger than the cellular spatial scale where hypoxia occurs. A question therefore arises regarding the possibility of quantifying different hypoxia levels based on PET images, and the aim of the present study is the prescription of corresponding therapeutic doses and its exploration.A tumour oxygenation model was created consisting of two concentric spheres with different oxygen partial pressure (pO2) distributions. In order to mimic a PET image of the simulated tumour, given the relation between uptake and pO2, fundamental effects that limit spatial resolution in a PET imaging system were considered: the uptake distribution was processed with a Gaussian 3D filter, and a re-binning to reach a typical PET image voxel size was performed. Prescription doses to overcome tumour hypoxia and predicted tumour control probability (TCP) were calculated based on the processed images for several fractionation schemes. Knowing the underlying oxygenation at microscopic scale, the actual TCP expected after the delivery of the calculated prescription doses was evaluated. Results are presented for three different dose painting strategies: by numbers, by contours and by using a voxel grouping-based approach.The differences between predicted TCP and evaluated TCP indicate that careful consideration must be taken on the dose prescription strategy and the selection of the number of fractions, depending on the severity of hypoxia.

Dose-painting multicenter phase III trial in newly diagnosed glioblastoma: the SPECTRO-GLIO trial comparing arm A standard radiochemotherapy to arm B radiochemotherapy with simultaneous integrated boost guided by MR spectroscopic imaging.

BACKGROUND: Glioblastoma, a high-grade glial infiltrating tumor, is the most frequent malignant brain tumor in adults and carries a dismal prognosis. External beam radiotherapy (EBRT) increases overall survival but this is still low due to local relapses, mostly occurring in the irradiation field. As the ratio of spectra of choline/N acetyl aspartate> 2 (CNR2) on MR spectroscopic imaging has been described as predictive for the site of local relapse, we hypothesized that dose escalation on these regions would increase local control and hence global survival. METHODS/DESIGN: In this multicenter prospective phase III trial for newly diagnosed glioblastoma, 220 patients having undergone biopsy or surgery are planned for randomization to two arms. Arm A is the Stupp protocol (EBRT 60 Gy on contrast enhancement + 2 cm margin with concomitant temozolomide (TMZ) and 6 months of TMZ maintenance); Arm B is the same treatment with an additional simultaneous integrated boost of intensity-modulated radiotherapy (IMRT) of 72Gy/2.4Gy delivered on the MR spectroscopic imaging metabolic volumes of CHO/NAA > 2 and contrast-enhancing lesions or resection cavity. Stratification is performed on surgical and MGMT status. DISCUSSION: This is a dose-painting trial, i.e. delivery of heterogeneous dose guided by metabolic imaging. The principal endpoint is overall survival. An online prospective quality control of volumes and dose is performed in the experimental arm. The study will yield a large amount of longitudinal multimodal MR imaging data including planning CT, radiotherapy dosimetry, MR spectroscopic, diffusion and perfusion imaging. TRIAL REGISTRATION: NCT01507506 , registration date December 20, 2011.

A feasibility study on adaptive 18F-FDG-PET-guided radiotherapy for recurrent and second primary head and neck cancer in the previously irradiated territory.

PURPOSE: To evaluate feasibility, disease control, survival, and toxicity after adaptive 18F-fluorodeoxyglucose (FDG) positron emisson tomography (PET) guided radiotherapy in patients with recurrent and second primary head and neck squamous cell carcinoma. METHODS: A prospective trial investigated the feasibility of adaptive intensity modulated radiotherapy (IMRT) ± concomitant cetuximab in 10 patients. The primary endpoint was achieving a 2-year survival free of grade >3 toxicity in ≥30% of patients. Three treatment plans based on 3 PET/CT scans were consecutively delivered in 6 weeks. The range of dose painting was 66.0-85.0 Gy in the dose-painted tumoral volumes in 30 fractions. RESULTS: Two-year locoregional and distant control rates were 38 and 76%, respectively. Overall and disease-free survival at 2 years was 20%. No grade 4 or 5 acute toxicity was observed in any of the patients, except for arterial mucosal hemorrhage in 1 patient. Three months after radiotherapy, grade 4 dysphagia and mucosal wound healing problems were observed in 1/7 and 1/6 of patients, respectively. Grade 5 toxicity (fatal bleeding) was seen in 2 patients, at 3.8 and 4.1 months of follow-up. Data on 2­year toxicity could only be assessed in 1 of the 2 surviving patients, in whom grade 4 mucosal wound healing problems were observed; no other grade >3 toxicity was observed. In this respect, a 30% 2­year survival free of grade >3 toxicity will not be achieved. CONCLUSIONS: Adaptive PET-guided reirradiation is feasible. However, due to slow accrual and treatment results that seemed inconsistent with achieving the primary endpoint, the trial was stopped early.

Personalized radiotherapy treatment planning based on functional imaging.

In recent years, a huge progress in the field of radiotherapy could be observed. From treating patients with kilo-voltage X-rays units to cutting edge technology that can deliver a certain dose with an extreme precision. Modern radiotherapy is characterized, among others, by an individualized approach to the patient. This can be provided by functional imaging which is another step toward a better tumor control. In this paper, we discuss the potential application of functional imaging modalities in personalized radiotherapy planning with emphasis on dose painting. Some limitations of this approach will also be evaluated.

[Treatment planning with functional MRI]. / Strahlentherapieplanung mit der funktionellen MRT.

CLINICAL/METHODICAL ISSUE: The aim of magnetic resonance imaging (MRI) guided radiotherapy is high precision in treatment delivery. With new developments it is possible to focus the high dose irradiation on the tumor while sparing the surrounding tissue. The achievements in precision of the treatment planning and delivery warrant equally precise tumor definition. STANDARD RADIOLOGICAL METHODS: In conventional radiation therapy it is necessary to carry out a planning computed tomography (CT). For many tumors there is also need for an additional morphological MRI because of more accurate tumor definition. In standard radiotherapy the tumor volume is irradiated with a homogeneous dose. METHODICAL INNOVATIONS: The aim of functional multiparametric MRI is to visualize and quantify biological, physiological and pathological processes at the cellular and molecular levels. Based on this information it is possible to elucidate tumor biology and identify subvolumes of more aggressive behavior. They are often radiotherapy-resistant, leading to tumor recurrence thus requiring further dose escalation. The concept of inhomogeneous tumor irradiation according to its biological behavior is called dose painting. PERFORMANCE: Dose painting is technically feasible. The expected clinical benefit is motivated by selective treatment adaptations based on biological tumor characteristics. Tumors show variable response to therapy underlining the need for individual treatment plans. This approach may lead not only to higher local control but also to better sparing of normal surrounding tissue. ACHIEVEMENTS: With the clinical implementation of dose painting, improvements in the therapeutic outcome can be expected. PRACTICAL RECOMMENDATIONS: Due to the existing technical challenges, extensive collaboration between radiation oncologists, radiologists, medical physicists and radiation biologists is needed.

Long-term Results of Hypofractionated Radiotherapy With Intra-prostatic Boosts in Men With Intermediate- and High-risk Prostate Cancer: A Phase II Trial.

AIMS: In the conventionally fractionated phase III FLAME prostate trial, focal boosts improved local control and biochemical disease-free survival (bDFS). We explored the toxicity and effectiveness of a moderately hypofractionated schedule with focal boosts. MATERIAL AND METHODS: BIOPROP20 is a phase II single-arm non-randomised trial for intermediate- to very high-risk localised prostate cancer patients with bulky tumour volumes. Multi-parametric magnetic resonance imaging (MRI) and 18F-choline positron emission tomography-computed tomography (PET-CT) scans were used for staging and boost volume definition. Patients were treated with 60Gy in 20 fractions with a boost dose up to 68Gy. Five patients with positive lymph nodes on the PET-CT scan received radiotherapy to pelvic lymph nodes (45Gy to elective nodes, boosted up to 50Gy to involved nodes). Primary outcomes were acute (≤18 weeks) and late urinary and gastrointestinal toxicity, prospectively recorded up to 5 years with Common Terminology Criteria for Adverse Events v4 (CTCAE). Secondary outcomes were biochemical or clinical progression, metastasis-free survival (MFS), and overall survival (OS). RESULTS: 61 patients completed radiotherapy with hormone therapy (range: 6-36 months). Cumulative acute and late gastrointestinal toxicity was low at 6.6% and 5.0%, respectively. Cumulative acute and late urinary toxicity was 49.2% and 30.1%, respectively; the prevalence reduced to 5.9% at 5 years. At 5 years: 6 patients had biochemical progression (bDFS: 88.5%; 95% CI: 80.2-97.6%), the MFS was 82.4% (95% CI: 73.0-92.9%), 5 patients died (OS: 91.2%; 95% CI: 84.1-98.9%), one with prostate cancer. The prostate, boost, nodal planning volumes, and the organs at risk (rectum, bowel, urethra, and bladder) met the optimal protocol dose constraints. There was a trend to increased urinary toxicity with increasing urethral (RR: 1.95, 95% CI: 0.73-5.22, p = 0.18), but not bladder dose. CONCLUSION: Focal boosts with a 20 fraction hypofractionated prostate radiotherapy schedule are associated with an acceptable risk of gastrointestinal and urinary toxicity and achieve good cancer control. GOV IDENTIFIER: NCT02125175.

Evaluating the impact of a rigid and a deformable registration method of pre-treatment images for hypoxia-based dose painting.

PURPOSE: To assess the impact of rigid and deformable image registration methods (RIR, DIR) on the outcome of a hypoxia-based dose painting strategy. MATERIALS AND METHODS: Thirty head and neck cancer patients were imaged with [18F]FMISO-PET/CT before radiotherapy. [18F]FMISO-PET/CT images were registered to the planning-CT by RIR or DIR. The [18F]FMISO uptake was converted into oxygen partial pressure (pO2) maps. Hypoxic Target Volumes were contoured on pO2 maps for the deformed (HTVdef) and non-deformed (HTV) cases. A dose escalation strategy by contours, aiming at 95 % tumour control probability (TCP), was applied. HTVs were characterised based on geometry-related metrics, the underlying pO2 distribution, and the dose boost level. A dosimetric and radiobiological evaluation of selected treatment plans made considering RIR and DIR was performed. Moreover, the TCP of the RIR dose distribution was evaluated when considering the deformed [18F]FMISO-PET image as an indicator of the actual target radiosensitivity to determine the potential impact of an unalignment. RESULTS: Statistically significant differences were found between HTV and HTVdef for volume-based metrics and underlying pO2 distribution. Eight out of nine treatment plans for HTV and HTVdef showed differences on the level 10 %/3 mm on a gamma analysis. The TCP difference, however, between RIR and the case when the RIR dose distribution was used with the deformed radiosensitivity map was below 2 pp. CONCLUSIONS: Although the choice of the CTplan-to-PET registration method pre-treatment impacts the HTV localisation and morphology and the corresponding dose distribution, it negligibly affects the TCP in the proposed dose escalation strategy by contours.

Rethinking the potential role of dose painting in personalized ultra-fractionated stereotactic adaptive radiotherapy.

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).

From protons to Picasso: recreating famous paintings using proton beams as a "Paintbrush".

In pencil-beam-scanning proton therapy, the dose is painted spot-by-spot, layer-by-layer, allowing for significantly more control compared to conventional radiation. This work intends to showcase the impressive ability of intensity-modulated proton therapy (IMPT) to shape complex dose distributions by recreating some of history's most renowned artworks as treatment plans. Five (5) well-recognized paintings were recreated in our clinical treatment planning system using a water phantom as a "canvas" and radiation dose as "paint." For each "painting," colors were assigned to various isodose levels, and the treatment plans were inversely optimized to achieve the desired tones. Using the above methods, we were able to recreate The Starry Night by Vincent Van Gogh, Girl with a Pearl Earring by Johannes Vermeer, and The Scream by Edvard Munch, among others. The results of this work have potential applications in patient education, medical education, and medical physics education by providing a unique and interesting platform for learning.

Prediction of radiologic outcome-optimized dose plans and post-treatment magnetic resonance images: A proof-of-concept study in breast cancer brain metastases treated with stereotactic radiosurgery.

Background and purpose: Information in multiparametric Magnetic Resonance (mpMR) images is relatable to voxel-level tumor response to Radiation Treatment (RT). We have investigated a deep learning framework to predict (i) post-treatment mpMR images from pre-treatment mpMR images and the dose map ("forward models"), and, (ii) the RT dose map that will produce prescribed changes within the Gross Tumor Volume (GTV) on post-treatment mpMR images ("inverse model"), in Breast Cancer Metastases to the Brain (BCMB) treated with Stereotactic Radiosurgery (SRS). Materials and methods: Local outcomes, planning computed tomography (CT) images, dose maps, and pre-treatment and post-treatment Apparent Diffusion Coefficient of water (ADC) maps, T1-weighted unenhanced (T1w) and contrast-enhanced (T1wCE), T2-weighted (T2w) and Fluid-Attenuated Inversion Recovery (FLAIR) mpMR images were curated from 39 BCMB patients. mpMR images were co-registered to the planning CT and intensity-calibrated. A 2D pix2pix architecture was used to train 5 forward models (ADC, T2w, FLAIR, T1w, T1wCE) and 1 inverse model on 1940 slices from 18 BCMB patients, and tested on 437 slices from another 9 BCMB patients. Results: Root Mean Square Percent Error (RMSPE) within the GTV between predicted and ground-truth post-RT images for the 5 forward models, in 136 test slices containing GTV, were (mean ± SD) 0.12 ± 0.044 (ADC), 0.14 ± 0.066 (T2w), 0.08 ± 0.038 (T1w), 0.13 ± 0.058 (T1wCE), and 0.09 ± 0.056 (FLAIR). RMSPE within the GTV on the same 136 test slices, between the predicted and ground-truth dose maps, was 0.37 ± 0.20 for the inverse model. Conclusions: A deep learning-based approach for radiologic outcome-optimized dose planning in SRS of BCMB has been demonstrated.

Dose-Painting Proton Radiotherapy Guided by Functional MRI in Non-enhancing High-Grade Gliomas.

AIMS: This study aimed to demonstrate the feasibility and evaluate the dosimetric effect and clinical impact of dose-painting proton radiotherapy (PRT) guided by functional MRI in non-enhancing high-grade gliomas (NE-HGGs). MATERIALS AND METHODS: The 3D-ASL and T2 FLAIR MR images of ten patients with NE-HGGs before radiotherapy were studied retrospectively. The hyperintensity on T2 FLAIR was used to generate the planning target volume (PTV), and the high-perfusion volume on 3D-ASL (PTV-ASL) was used to generate the simultaneous integrated boost (SIB) volume. Each patient received pencil beam scanning PRT and photon intensity-modulated radiotherapy (IMRT). There were five plans in each modality: (1) Uniform plans (IMRT60 vs. PRT60): 60Gy in 30 fractions to the PTV. (2)-(5) SIB plans (IMRT72, 84, 96, 108 vs. PRT72, 84, 96, 108): Uniform plan plus additional dose boost to PTV-ASL in 30 fractions to 72, 84, 96, 108 Gy. The dosimetric differences between various plans were compared. The clinical effects of target volume and organs at risk (OARs) were assessed using biological models for both tumor control probability (TCP) and normal tissue complication probability (NTCP). RESULTS: Compared with the IMRT plan, the D2 and D50 of the PRT plans with the same prescription dose increased by 1.27-4.12% and 0.64-2.01%, respectively; the R30 decreased by > 32%; the dose of brainstem and chiasma decreased by > 27% and >32%; and the dose of normal brain tissue (Br-PTV), optic nerves, eyeballs, lens, cochlea, spinal cord, and hippocampus decreased by > 50% (P < 0.05). The maximum necessary dose was 96GyE to achieve >98% TCP for PRT, and it was 84Gy to achieve >91% TCP for IMRT. The average NTCP of Br-PTV was 1.30% and 1.90% for PRT and IMRT at the maximum dose escalation, respectively. The NTCP values of the remaining OARs approached zero in all PRT plans. CONCLUSION: The functional MRI-guided dose escalation using PRT is feasible while sparing the OARs constraints and demonstrates a potential clinical benefit by improving TCP with no or minimal increase in NCTP for tissues outside the PTV. This retrospective study suggested that the use of PRT-based SIB guided by functional MRI may represent a strategy to provide benefits for patients with NE-HGGs.

Advancements and future directions in positron emission tomography-guided radiotherapy: a narrative review.

BACKGROUND AND OBJECTIVE: Positron emission tomography (PET) imaging has been useful in delineating tumor volumes and allowing for improved radiation treatment. The field of PET-guided radiotherapy is rapidly growing and will have significant impact on radiotherapy delivery in the future. This narrative review provides an overview of the current state of PET-guided radiotherapy as well as the future directions of the field. METHODS: For this narrative review, PubMed was searched for articles from 2010-2023. A total of 18 keywords or phrases were searched to provide an overview of PET-guided radiotherapy, radiotracers, the role of PET-guided radiotherapy in oligometastatic disease, and biology-guided radiotherapy (BgRT). The first 300 results for each keyword were searched and relevant articles were extracted. The references of these articles were also reviewed for relevant articles. KEY CONTENT AND FINDINGS: In radiotherapy, 18F-2-fluoro-2-deoxy-D-glucose (F-FDG or FDG) is the major radiotracer for PET and when combined with computed tomography (CT) scan allows for anatomic visualization of metabolically active malignancy. Novel radiotracers are being explored to delineate certain cell types and numerous tumor metrics including metabolism, hypoxia, vascularity, and cellular proliferation. This molecular and functional imaging will provide improved tumor characterization. Through these radiotracers, radiation plans can employ dose painting by creating different dose levels based upon specific risk factors of the target volume. Additionally, biologic imaging during radiotherapy can allow for adaptation of the radiation plan based on response to treatment. Dose painting and adaptive radiotherapy should improve the therapeutic ratio through more selective dose delivery. The novel PET-linear accelerator hopes to combine these techniques and more by using radiotracers to deliver BgRT. The areas of radiotracer uptake will serve as fiducials to guide radiotherapy to themselves. This technique may prove promising in the growing area of oligometastatic radiation treatment. CONCLUSIONS: Significant challenges exist for the future of PET-guided radiotherapy. However, with the advancements being made, PET imaging is set to change the delivery of radiotherapy.

A multicentric randomized controlled phase III trial of adaptive and 18F-FDG-PET-guided dose-redistribution in locally advanced head and neck squamous cell carcinoma (ARTFORCE).

BACKGROUND AND PURPOSE: This multicenter randomized phase III trial evaluated whether locoregional control of patients with LAHNSCC could be improved by fluorodeoxyglucose-positron emission tomography (FDG-PET)-guided dose-escalation while minimizing the risk of increasing toxicity using a dose-redistribution and scheduled adaptation strategy. MATERIALS AND METHODS: Patients with T3-4-N0-3-M0 LAHNSCC were randomly assigned (1:1) to either receive a dose distribution ranging from 64-84 Gy/35 fractions with adaptation at the 10thfraction (rRT) or conventional 70 Gy/35 fractions (cRT). Both arms received concurrent three-cycle 100 mg/m2cisplatin. Primary endpoints were 2-year locoregional control (LRC) and toxicity. Primary analysis was based on the intention-to-treat principle. RESULTS: Due to slow accrual, the study was prematurely closed (at 84 %) after randomizing 221 eligible patients between 2012 and 2019 to receive rRT (N = 109) or cRT (N = 112). The 2-year LRC estimate difference of 81 % (95 %CI 74-89 %) vs. 74 % (66-83 %) in the rRT and cRT arm, respectively, was not found statistically significant (HR 0.75, 95 %CI 0.43-1.31,P=.31). Toxicity prevalence and incidence rates were similar between trial arms, with exception for a significant increased grade ≥ 3 pharyngolaryngeal stenoses incidence rate in the rRT arm (0 versus 4 %,P=.05). In post-hoc subgroup analyses, rRT improved LRC for patients with N0-1 disease (HR 0.21, 95 %CI 0.05-0.93) and oropharyngeal cancer (0.31, 0.10-0.95), regardless of HPV. CONCLUSION: Adaptive and dose redistributed radiotherapy enabled dose-escalation with similar toxicity rates compared to conventional radiotherapy. While FDG-PET-guided dose-escalation did overall not lead to significant tumor control or survival improvements, post-hoc results showed improved locoregional control for patients with N0-1 disease or oropharyngeal cancer treated with rRT.

Intensity-modulated radiotherapy (IMRT) in pediatric low-grade glioma.

BACKGROUND: The objective of this study was to evaluate local control and patterns of failure in pediatric patients with low-grade glioma (LGG) who received treatment with intensity-modulated radiation therapy (IMRT). METHODS: In total, 39 children received IMRT after incomplete resection or disease progression. Three methods of target delineation were used. The first was to delineate the gross tumor volume (GTV) and add a 1-cm margin to create the clinical target volume (CTV) (Method 1; n = 19). The second was to add a 0.5-cm margin around the GTV to create the CTV (Method 2; n = 6). The prescribed dose to the GTV was the same as dose to the CTV for both Methods 1 and 2 (median, 50.4 grays [Gy]). The final method was dose painting, in which a GTV was delineated with a second target volume (2TV) created by adding 1 cm to the GTV (Method 3; n = 14). Different doses were prescribed to the GTV (median, 50.4 Gy) and the 2TV (median, 41.4 Gy). RESULTS: The 8-year progression-free and overall survival rates were 78.2% and 93.7%, respectively. Seven failures occurred, all of which were local in the high-dose (≥95%) region of the IMRT field. On multivariate analysis, age ≤5 years at time of IMRT had a detrimental impact on progression-free survival. CONCLUSIONS: IMRT provided local control rates comparable to those provided by 2-dimensional and 3-dimensional radiotherapy. Margins ≥1 cm added to the GTV may not be necessary, because excellent local control was achieved by adding a 0.5-cm margin (Method 2) and by dose painting (Method 3).

Intensity-modulated radiation therapy with dose-painting for pediatric sarcomas with pulmonary metastases.

BACKGROUND: We examined patterns of failure in pediatric patients with thoracic sarcoma and pulmonary metastases treated with intensity-modulated radiation therapy with dose-painting (DP-IMRT). PROCEDURE: Eleven pediatric patients, five with Ewing sarcoma family tumors (ESFT) and six with rhabdomyosarcoma (RMS), with primary thoracic tumors and pulmonary metastases underwent DP-IMRT with chemotherapy for definitive treatment. Eight patients also underwent surgery. Median time to RT was 21 (15-31) weeks. Nine patients received 45-50.4-Gy in 1.8 Gy fractions to the primary tumor (n = 3) or post-operative tumor bed (n = 6). Two patients ≤4 years received 12 Gy intraoperative radiation therapy and 30.6-36 Gy IMRT postoperatively to the tumor bed. All patients received 14-16.8 Gy in 0.54-0.88 Gy fractions to the whole lungs (n = 6) or hemithorax (n = 5) using dose-painting technique. A representative case was re-planned with IMRT plus standard AP/PA whole lung irradiation (WLI) for dosimetric comparison. RESULTS: With 27-month median follow-up, 3-year pulmonary relapse-free survival in all patients was 61%: 80% for RMS and 40% for ESFT. Five patients (4 ESFT and 1 RMS) experienced pulmonary relapse at median 16 (9-41) months. There were no local failures. Our representative case demonstrated more homogeneous target volume coverage of the whole lungs and decreased mean dose to esophagus (15%), heart (31%), spinal cord (15%), and liver (19%) with DP-IMRT. CONCLUSIONS: The treatment of children with a primary thoracic tumor and pulmonary metastases poses a significant challenge. DP-IMRT is one solution to this technical problem. Initial data from this small series suggest DP-IMRT is feasible and produces superior sparing of critical normal tissues.