Deformable vector fields warping for modelling of irregular breathing.

Purpose 4D computed tomography (4DCT) is the clinical standard to image organ motion in radiotherapy, although it is limited in imaging breathing variability. We propose a method to transfer breathing motion across longitudinal imaging datasets to include intra-patient variability and verify its performance in lung cancer patients. Methods Five repeated control 4DCTs for 6 non-small cell lung cancer patients were combined into multi-breath datasets (m4DCT) by merging stages of deformable image registration to isolate respiratory motion. The displacement of the centre of mass of the primary tumour and its volume changes were evaluated to quantify intra-patient differences. Internal target volumes defined on the m4DCT were compared with those conventionally drawn on the 4DCT. Results Motion analysis suggests no discontinuity at the junction between successive breaths, confirming the method's ability to merge repeated imaging into a continuum. Motion (variability) is primarily in superior-inferior direction and goes from 14.4 mm (8.7 mm) down to 0.1 mm (0.6 mm), respectively for tumours located in the lower lobes or most apical ones. On average, up to 65% and 74% of the tumour volume was subject to expansion or contraction in the inhalation and exhalation phases. These variations lead to an enlargement of the ITV up to 8% of its volume in our dataset. Conclusion 4DCT can be extended to model variable breathing motion by adding synthetic phases from multiple time-resolved images. The inclusion of this improved knowledge of patients' breathing allows better definition of treatment volumes and their margins for radiation therapy. .

Exploring beamline momentum acceptance for tracking respiratory variability in lung cancer proton therapy: a simulation study.

Objective. Investigating the aspects of proton beam delivery to track organ motion with pencil beam scanning therapy. Considering current systems as a reference, specify requirements for next-generation units aiming at real-time image-guided treatments.Approach. Proton treatments for six non-small cell lung cancer (NSCLC) patients were simulated using repeated 4DCTs to model respiratory motion variability. Energy corrections required for this treatment site were evaluated for different approaches to tumour tracking, focusing on the potential for energy adjustment within beamline momentum acceptance (dp/p). A respiration-synchronised tracking, taking into account realistic machine delivery limits, was compared to ideal tracking scenarios, in which unconstrained energy corrections are possible. Rescanning and the use of multiple fields to mitigate residual interplay effects and dose degradation have also been investigated.Main results. Energy correction requirements increased with motion amplitudes, for all patients and tracking scenarios. Higher dose degradation was found for larger motion amplitudes, rescanning has beneficial effects and helped to improve dosimetry metrics for the investigated limited dp/pof 1.2% (realistic) and 2.4%. The median differences between ideal and respiratory-synchronised tracking show minimal discrepancies, 1% and 5% respectively for dose coverage (CTV V95) and homogeneity (D5-D95). Multiple-field planning improves D5-D95 up to 50% in the most extreme cases while it does not show a significant effect on V95.Significance. This work shows the potential of implementing tumour tracking in current proton therapy units and outlines design requirements for future developments. Energy regulation within momentum acceptance was investigated to tracking tumour motion with respiratory-synchronisation, achieving results in line with the performance of ideal tracking scenarios. ±5% Δp/p would allow to compensate for all range offsets in our NSCLC patient cohort, including breathing variability. However, the realistic momentum of 1.2% dp/prepresentative of existing medical units limitations, has been shown to preserve plan quality.

NTCP Modeling for High-Grade Temporal Radionecroses in a Large Cohort of Patients Receiving Pencil Beam Scanning Proton Therapy for Skull Base and Head and Neck Tumors.

PURPOSE: To develop a normal tissue complication probability model including clinical and dosimetric parameters for high-grade temporal lobe radionecroses (TRN) after pencil beam scanning proton therapy. METHODS AND MATERIALS: We included data on 299 patients with skull base and head and neck tumors treated with pencil-beam scan proton therapy, with a total dose of ≥60 GyRBE (relative biological effectiveness) from May 2004 to November 2018. We considered 9 clinical and 27 dosimetric parameters for the structure-wise modeling of high-grade (grade ≥2) TRN. After eliminating strongly cross-correlated variables, we generated logistic regression models using least absolute shrinkage and selection operator regression. We performed bootstrapping to assess parameter selection robustness and evaluated model performance via cross-correlation by assessing the area under the curve of receiver operating characteristic curves and calibration with a Hosmer-Lemeshow test statistic. RESULTS: After a median radiologic follow-up of 51.5 months (range, 4-190), 27 patients (9%) developed grade ≥2 TRN. Eleven patients had bitemporal necrosis, resulting in 38 events in 598 temporal lobes for structure-wise analysis. During our bootstrapping analysis, we found that the highest selection frequency was for prescription dose, followed by age, V40Gy (%), hypertension, and dose to at least 1 cc (D1cc) (Gy) in the temporal lobe. During our cross-validation, we found that age*prescription-dose*D1cc (Gy)*hypertension was superior in all described test statistics. We built full cohort structure-wise and patient-wise models with maximum area under the curve of receiver operating characteristic curves of 0.79 (structure-wise) and 0.76 (patient-wise). CONCLUSIONS: While developing a logistic regression normal tissue complication probability model to predict grade ≥2 TRN, the best fit was found for the model containing age, prescription dose, D1cc (Gy), and hypertensive blood pressure as risk factors. External validation will be the next step to improve generalizability and potential introduction into clinical routine.

The impact of organ motion and the appliance of mitigation strategies on the effectiveness of hypoxia-guided proton therapy for non-small cell lung cancer.

BACKGROUND AND PURPOSE: To investigate the impact of organ motion on hypoxia-guided proton therapy treatments for non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Hypoxia PET and 4D imaging data of six NSCLC patients were used to simulate hypoxia-guided proton therapy with different motion mitigation strategies including rescanning, breath-hold, respiratory gating and tumour tracking. Motion-induced dose degradation was estimated for treatment plans with dose painting of hypoxic tumour sub-volumes at escalated dose levels. Tumour control probability (TCP) and dosimetry indices were assessed to weigh the clinical benefit of dose escalation and motion mitigation. In addition, the difference in normal tissue complication probability (NTCP) between escalated proton and photon VMAT treatments has been assessed. RESULTS: Motion-induced dose degradation was found for target coverage (CTV V95% up to -4%) and quality of the dose-escalation-by-contour (QRMS up to 6%) as a function of motion amplitude and amount of dose escalation. The TCP benefit coming from dose escalation (+4-13%) outweighs the motion-induced losses (<2%). Significant average NTCP reductions of dose-escalated proton plans were found for lungs (-14%), oesophagus (-10%) and heart (-16%) compared to conventional VMAT plans. The best plan dosimetry was obtained with breath hold and respiratory gating with rescanning. CONCLUSION: NSCLC affected by hypoxia appears to be a prime target for proton therapy which, by dose-escalation, allows to mitigate hypoxia-induced radio-resistance despite the sensitivity to organ motion. Furthermore, substantial reduction in normal tissue toxicity can be expected compared to conventional VMAT. Accessibility and standardization of hypoxia imaging and clinical trials are necessary to confirm these findings in a clinical setting.

Investigating the potential of proton therapy for hypoxia-targeted dose escalation in non-small cell lung cancer.

BACKGROUND: Hypoxia is known to be prevalent in solid tumors such as non-small cell lung cancer (NSCLC) and reportedly correlates with poor prognostic clinical outcome. PET imaging can provide in-vivo hypoxia measurements to support targeted radiotherapy treatment planning. We explore the potential of proton therapy in performing patient-specific dose escalation and compare it with photon volumetric modulated arc therapy (VMAT). METHODS: Dose escalation has been calibrated to the patient specific tumor response of ten stage IIb-IIIb NSCLC patients by combining HX4-PET imaging and radiobiological modelling of oxygen enhancement ratio (OER) to target variable tumor hypoxia. In a dose-escalation-by-contour approach, escalated dose levels were simulated to the most hypoxic region of the primary target and its effectiveness in improving loco-regional tumor control was assessed. Furthermore, the impact on normal tissue of proton treatments including dose escalation was evaluated in comparison to the normal tissue complication probability (NTCP) of conventional VMAT plans. RESULTS: Ignoring regions of tumor hypoxia can cause overestimation of TCP values by up to 10%, which can effectively be recovered on average to within 0.9% of the nominal TCP, using patient-specific dose escalations of up to 22% of the prescribed dose to PET defined hypoxic regions. Despite such dose escalations, the use of protons could also simultaneously reduce mean doses to the heart (- 14.3 GyRBE), lung (- 8.3 GyRBE), esophagus (- 6.9 GyRBE) and spinal cord (- 3.8 Gy) compared to non-escalated VMAT plans. These reductions are predicted to lead to clinically relevant decreases in NTCP for radiation-induced pneumonitis (- 11.3%), high grade heart toxicity (- 7.4%) and esophagitis (- 7.5%). CONCLUSIONS: This study suggests that the administration of proton therapy for dose escalation to patient specific regions of tumor hypoxia in the treatment of NSCLC can mitigate TCP reduction due to hypoxia-induced radio resistance, while simultaneously reducing NTCP levels even when compared to non-escalated treatments delivered with state-of-the-art photon techniques.

Assessment of Radiation-Induced Optic Neuropathy in a Multi-Institutional Cohort of Chordoma and Chondrosarcoma Patients Treated with Proton Therapy.

Radiation-induced optic neuropathy (RION) is a rare side effect following radiation therapy involving the optic structures whose onset is, due to the low amount of available data, challenging to predict. We have analyzed a multi-institutional cohort including 289 skull-base cancer patients treated with proton therapy who all received >45 GyRBE to the optic apparatus. An overall incidence rate of 4.2% (12) was observed, with chordoma patients being at higher risk (5.8%) than chondrosarcoma patients (3.2%). Older age and arterial hypertension, tumor involvement, and repeated surgeries (>3) were found to be associated with RION. Based on bootstrapping and cross-validation, a NTCP model based on age and hypertension was determined to be the most robust, showing good classification ability (AUC-ROC 0.77) and calibration on our dataset. We suggest the application of this model with a threshold of 6% to segment patients into low and high-risk groups before treatment planning. However, further data and external validation are warranted before clinical application.

Combining Clinical and Dosimetric Features in a PBS Proton Therapy Cohort to Develop a NTCP Model for Radiation-Induced Optic Neuropathy.

PURPOSE: Radiation-induced optic neuropathy (RION) is a rare, yet severe complication following radiation therapy for brain, head and neck, or skull-base tumors. Although several risk factors, such as age, metabolic syndrome, and delivered dose, have been identified, we aimed at expanding the understanding of the mechanisms of interplay regarding dosimetry and patient variables leading to the onset of RION with a focus on proton therapy. METHODS AND MATERIALS: In this retrospective study, we have investigated proton-specific risk factors by comparing common phenomenological normal tissue complication probability models with a multivariate analysis that includes clinical features on a cohort of patients with skull-base and head and neck cancer treated with pencil beam scanning. RESULTS: Although predictive power of the Lyman-Kutcher-Burman and Poisson models was limited for this data set, the addition of clinical variables such as age, tumor involvement, hypertension, or sex remarkably increased model performance. CONCLUSIONS: Based on our assessment, the maximum dose in the optical apparatus is confirmed the most intuitive risk factor. However, above a certain dose threshold, clinical patient characteristics are the deciding factors for the onset of RION. We observed a tendency toward a volume effect that, if confirmed, would imply a benefit for high precision radiation therapy techniques such as proton therapy for the treatment of patients with high clinical risk for RION.

Differential transcriptome response to proton versus X-ray radiation reveals novel candidate targets for combinatorial PT therapy in lymphoma.

BACKGROUND AND PURPOSE: Knowledge of biological responses to proton therapy (PT) in comparison to X-ray remains in its infancy. Identification of PT specific molecular signals is an important opportunity for the discovery of biomarkers and synergistic drugs to advance clinical application. Since PT is used for the treatment of lymphoma, we report here transcriptomic responses of lymphoma cell lines to PT vs X-ray and identify potential therapeutic targets. MATERIALS AND METHODS: Two lymphoma cell lines of human (BL41) and murine (J3D) origin were irradiated by X-ray and PT. Differential transcriptome regulation was quantified by RNA sequencing for each radiation type at 12 hours post irradiation. Gene-set enrichment analysis revealed deregulated molecular pathways and putative targets for lymphoma cell sensitization to PT. RESULTS: Transcriptomic gene set enrichment analyses uncovered pathways that contribute to the unfolded protein response (UPR) and mitochondrial transport. Functional validation at multiple time points demonstrated increased UPR activation and decreased protein translation, perhaps due to increased oxidative stress and oxidative protein damage after PT. PPARgamma was identified as a potential regulator of the PT transcriptomic response. Inhibition of PPARgamma by two compounds, T0070907 and SR2595, sensitized lymphoma cells to PT. CONCLUSIONS: Proton vs X-ray radiation leads to the transcriptional regulation of a specific subset of genes in line with diminished protein translation and UPR activation that may be due to oxidative stress. This study demonstrates that different radiation qualities trigger distinct cellular responses in lymphoma cells, and identifies PPARgamma inhibition as a potential strategy for the sensitization of lymphoma to PT.