Uncertainty-aware MR-based CT synthesis for robust proton therapy planning of brain tumour.

BACKGROUND AND PURPOSE: Deep learning techniques excel in MR-based CT synthesis, but missing uncertainty prediction limits its clinical use in proton therapy. We developed an uncertainty-aware framework and evaluated its efficiency in robust proton planning. MATERIALS AND METHODS: A conditional generative-adversarial network was trained on 64 brain tumour patients with paired MR-CT images to generate synthetic CTs (sCT) from combined T1-T2 MRs of three orthogonal planes. A Bayesian neural network predicts Laplacian distributions for all voxels with parameters (µ, b). A robust proton plan was optimized using three sCTs of µ and µ±b. The dosimetric differences between the plan from sCT (sPlan) and the recalculated plan (rPlan) on planning CT (pCT) were quantified for each patient. The uncertainty-aware robust plan was compared to conventional robust (global ± 3 %) and non-robust plans. RESULTS: In 8-fold cross-validation, sCT-pCT image differences (Mean-Absolute-Error) were 80.84 ± 9.84HU (body), 35.78 ± 6.07HU (soft tissues) and 221.88 ± 31.69HU (bones), with Dice scores of 90.33 ± 2.43 %, 95.13 ± 0.80 %, and 85.53 ± 4.16 %, respectively. The uncertainty distribution positively correlated with absolute prediction error (Correlation Coefficient: 0.62 ± 0.01). The uncertainty-conditioned robust optimisation improved the rPlan-sPlan agreement, e.g., D95 absolute difference (CTV) was 1.10 ± 1.24 % compared to conventional (1.64 ± 2.71 %) and non-robust (2.08 ± 2.96 %) optimisation. This trend was consistent across all target and organs-at-risk indexes. CONCLUSION: The enhanced framework incorporates 3D uncertainty prediction and generates high-quality sCTs from MR images. The framework also facilitates conditioned robust optimisation, bolstering proton plan robustness against network prediction errors. The innovative feature of uncertainty visualisation and robust analyses contribute to evaluating sCT clinical utility for individual patients.

Evaluation of robustness of optimization methods in breast intensity-modulated radiation therapy using TomoTherapy.

Intensity-modulated radiation therapy (IMRT) has become a popular choice for breast cancer treatment. We aimed to evaluate and compare the robustness of each optimization method used for breast IMRT using TomoTherapy. A retrospective analysis was performed on 10 patients with left breast cancer. For each optimization method (clipping, virtual bolus, and skin flash), a corresponding 50 Gy/25 fr plan was created in the helical and direct TomoTherapy modes. The dose-volume histogram parameters were compared after shifting the patients anteriorly and posteriorly. In the helical mode, when the patient was not shifted, the median D1cc (minimum dose delivered to 1 cc of the organ volume) of the breast skin for the clipping and virtual bolus plans was 52.2 (interquartile range: 51.9-52.6) and 50.4 (50.1-50.8) Gy, respectively. After an anterior shift, D1cc of the breast skin for the clipping and virtual bolus plans was 56.0 (55.6-56.8) and 50.9 (50.5-51.3) Gy, respectively. When the direct mode was used without shifting the patient, D1cc of the breast skin for the clipping, virtual bolus, and skin flash plans was 52.6 (51.9-53.1), 53.4 (52.6-53.9), and 52.3 (51.7-53.0) Gy, respectively. After shifting anteriorly, D1cc of the breast skin for the clipping, virtual bolus, and skin flash plans was 55.6 (54.1-56.4), 52.4 (52.0-53.0), and 53.6 (52.6-54.6) Gy, respectively. The clipping method is not sufficient for breast IMRT. The virtual bolus and skin flash methods were more robust optimization methods according to our analyses.

Robustness evaluation of pencil beam scanning proton therapy treatment planning: A systematic review.

Compared to conventional radiotherapy using X-rays, proton therapy, in principle, allows better conformity of the dose distribution to target volumes, at the cost of greater sensitivity to physical, anatomical, and positioning uncertainties. Robust planning, both in terms of plan optimization and evaluation, has gained high visibility in publications on the subject and is part of clinical practice in many centers. However, there is currently no consensus on the methods and parameters to be used for robust optimization or robustness evaluation. We propose to overcome this deficiency by following the modified Delphi consensus method. This method first requires a systematic review of the literature. We performed this review using the PubMed and Web Of Science databases, via two different experts. Potential conflicts were resolved by a third expert. We then explored the different methods before focusing on clinical studies that evaluate robustness on a significant number of patients. Many robustness assessment methods are proposed in the literature. Some are more successful than others and their implementation varies between centers. Moreover, they are not all statistically or mathematically equivalent. The most sophisticated and rigorous methods have seen more limited application due to the difficulty of their implementation and their lack of widespread availability.

A probabilistic evaluation of the Dutch robustness and model-based selection protocols for Head-and-Neck IMPT: A multi-institutional study.

BACKGROUND AND PURPOSE: In the Netherlands, 2 protocols have been standardized for PT among the 3 proton centers: a robustness evaluation (RE) to ensure adequate CTV dose and a model-based selection (MBS) approach for IMPT patient-selection. This multi-institutional study investigates (i) inter-patient and inter-center variation of target dose from the RE protocol and (ii) the robustness of the MBS protocol against treatment errors for a cohort of head-and-neck cancer (HNC) patients treated in the 3 Dutch proton centers. MATERIALS AND METHODS: Clinical treatment plans of 100 HNC patients were evaluated. Polynomial Chaos Expansion (PCE) was used to perform a comprehensive robustness evaluation per plan, enabling the probabilistic evaluation of 100,000 complete fractionated treatments. PCE allowed to derive scenario distributions of clinically relevant dosimetric parameters to assess CTV dose (D99.8%/D0.2%, based on a prior photon plan calibration) and tumour control probabilities (TCP) as well as the evaluation of the dose to OARs and normal tissue complication probabilities (NTCP) per center. RESULTS: For the CTV70.00, doses from the RE protocol were consistent with the clinical plan evaluation metrics used in the 3 centers. For the CTV54.25, D99.8% were consistent with the clinical plan evaluation metrics at center 1 and 2 while, for center 3, a reduction of 1 GyRBE was found on average. This difference did not impact modelled TCP at center 3. Differences between expected and nominal NTCP were below 0.3 percentage point for most patients. CONCLUSION: The standardization of the RE and MBS protocol lead to comparable results in terms of TCP and the NTCPs. Still, significant inter-patient and inter-center variation in dosimetric parameters remained due to clinical practice differences at each institution. The MBS approach is a robust protocol to qualify patients for PT.

Dosimetric impact of systematic spot position errors in spot scanning proton therapy of head and neck tumor.

Purpose: The spot position is an important beam parameter in the quality assurance of scanning proton therapy. In this study, we investigated dosimetric impact of systematic 15 spot position errors (SSPE) in spot scanning proton therapy using three types of optimization methods of head and neck tumor. Materials and Methods: The planning simulation was performed with ± 2 mm model SSPE in the X and Y directions. Treatment plans were created using intensity-modulated proton therapy (IMPT) and single-field uniform dose (SFUD). IMPT plans were created by two optimization methods: with worst-case optimization (WCO-IMPT) and without (IMPT). For clinical target volume (CTV), D95%, D50%, and D2cc were used for analysis. For organs at risk (OAR), Dmean was used to analyze the brain, cochlea, and parotid, and Dmax was used to analyze brainsetem, chiasm, optic nerve, and cord. Results: For CTV, the variation (1 standard deviation) of D95% was ± 0.88%, 0.97% and 0.97% to WCO-IMPT, IMPT, and SFUD plan. The variation of D50% and D2cc of CTV showed <0.5% variation in all plans. The dose variation due to SSPE was larger in OAR, and worst-case optimization reduced the dose variation, especially in Dmax. The analysis results showed that SSPE has little impact on SFUD. Conclusions: We clarified the impact of SSPE on dose distribution for three optimization methods. SFUD was shown to be a robust treatment plan for OARs, and the WCO can be used to increase robustness to SSPE in IMPT.

Planning strategies for robust carbon-ion scanning radiotherapy for stage I esophageal cancer: a retrospective study.

This study aimed to establish a treatment planning strategy with carbon-ion scanning radiotherapy (CIRTs) for stage I esophageal cancer. The clinical data of seven patients treated with CIRTs were used. The setup error and interfractional and intrafractional motion error were analyzed using in-room computed tomography (CT) images for each treatment day. Finally, the planning target volume (PTV) margin was identified according to the accuracy of the treatment system. To ensure robustness against the positional displacements of the target and organs at risk (OAR), the replacement areas were placed as a contour adjacent to the tumor or OAR on the CT-image. The CT values of these areas were replaced by those of the target or OAR. Further, the dose distributions were optimized. Moreover, the variations in the target coverage from the initial plan for each treatment day (ΔV95%) were evaluated. By contrast, the risk of OAR was not evaluated in this study. The setup error was within 1.0 mm. The interfractional and intrafractional target motion errors were 2.8 and 5.0 mm, respectively. The PTV margins were 6.5 and 6.8 mm in the axial and depth directions, respectively. The robustness to target and OAR displacement was evaluated. The results showed that the target coverage with replacement could suppress decreased target coverage more than that without replacement. The PTV determination and replacement methods used in this study improved the target coverage in CIRTs for stage I esophageal cancer. Despite the need for a clinical follow-up, this method may help to improve clinical outcomes.

Single-institution clinical experience using robust intensity modulated proton therapy in chordoma and chondrosarcoma of the mobile spine and sacrum: Feasibility and need for plan adaptation.

BACKGROUND: Due to its specific physical characteristics, proton irradiation is especially suited for irradiation of chordomas and chondrosarcoma in the axial skeleton. Robust plan optimization renders the proton beam therapy more predictable upon individual setup errors. Reported experience with the planning and delivery of robustly optimized plans in chordoma and chondrosarcoma of the mobile spine and sacrum, is limited. In this study, we report on the clinical use of robustly optimized, intensity modulated proton beam therapy in these patients. METHODS: We retrospectively reviewed patient, treatment and acute toxicity data of all patients with chordoma and chondrosarcoma of the mobile spine and sacrum, treated between 1 April 2019 and 1 April 2020 at our institute. Anatomy changes during treatment were evaluated by weekly cone-beam CTs (CBCT), supplemented by scheduled control-CTs or ad-hoc control-CTs. Acute toxicity was scored weekly during treatment and at 3 months after therapy according to CTCAE 4.0. RESULTS: 17 chordoma and 3 chondrosarcoma patients were included. Coverage of the high dose clinical target volume was 99.8% (range 56.1-100%) in the nominal and 80.9% (range 14.3-99.6%) in the voxel-wise minimum dose distribution. Treatment plan adaptation was needed in 5 out of 22 (22.7%) plans. Reasons for plan adaptation were either reduced tumor coverage or increased dose to the OAR. CONCLUSIONS: Robustly optimized intensity modulated proton beam therapy for chordoma and chondrosarcoma of the mobile spine is feasible. Plan adaptations due to anatomical changes were required in approximately 23 percent of treatment courses.

Automated robust SBPT planning using EUD-based prediction of SBRT plan for patients with lung cancer.

PURPOSE: To evaluate the quality of robust stereotactic body proton therapy (RSBPT) plans generated by one-clicking scripting method for patients with lung cancer. MATERIALS AND METHODS: Retrospective analysis was performed on fifty lung cancer patients whose plan with robustly stereotactic body radiation therapy (SBRT). Thirty out of fifty patients were used for training to build a regression model, based on robust SBRT reference doses, to predict EUD values of ROIs for robust SBPT planning. Thereafter, robust SBPT plans with both automated EUD-Based mimicking (Automated Robust Proton ARP) and manual (Manual Robust Proton MRP) methods were evaluated in the remaining 20 patients. Plans were compared in terms of dosimetric parameters and planning time. RESULTS: A statistically significantly improvement in target dose fall off was observed for ARP plans compare to MRP plans (Dose fall off: 135 for MRP and 88 for ARP, p < 0.01), while no differences in target coverage and conformity. A statistically significantly reduce in normal lung tissue were observed for ARP plans compare to MRP plans (Lung [Dmean cGy (RBE)]: MRP: 478 vs. ARP: 351, p < 0.01; Lung [V5Gy (RBE) (%)]: MRP: 16.1 vs. ARP: 12.1, p < 0.01; Lung [V20Gy (RBE) (%)]: MRP: 8.5 vs. ARP: 6.8, p < 0.01). Planning time was reduced for ARP plans compare to MRP plans (optimization time: 12 min for MRP vs. 8 min for ARP; total plan time: 23 min for MRP vs. 18 min for ARP). CONCLUSION: The automated robust SBPT plans using EUD-Based mimicking of SBRT reference dose improve target dose fall off, reduced the radiation doses to the lungs, reduce planning time, which might be beneficial for patient with lung cancer in clinical.

Robust Angle Selection in Particle Therapy.

The popularity of particle radiotherapy has grown exponentially over recent years owing to the marked advantage of the depth-dose curve and its unique biological property. However, particle therapy is sensitive to changes in anatomical structure, and the dose distribution may deteriorate. In particle therapy, robust beam angle selection plays a crucial role in mitigating inter- and intrafractional variation, including daily patient setup uncertainties and tumor motion. With the development of a rotating gantry, angle optimization has gained increasing attention. Currently, several studies use the variation in the water equivalent thickness to quantify anatomical changes during treatment. This method seems helpful in determining better beam angles and improving the robustness of planning. Therefore, this review will discuss and summarize the robust beam angles at different tumor sites in particle radiotherapy.

Use of uniform shots for robust planning of mask-based treatment in Gamma Knife Icon.

PURPOSE: To verify whether Icon automatic correction is robust in preserving plan quality. MATERIALS/METHODS: An end-to-end phantom was used to verify Icon's correction accuracy qualitatively. For quantitative assessment, two plans, a composite- and a uniform-shot-only, were created for an elliptical- (E) and a sausage-shaped (S) lesion inside a PseudoPatient head phantom with a film insert. The phantom was irradiated in the planned and three other positions under each plan: 14° pitch (B); 14° rotation + 8° pitch (C); 95° rotation + 4-cm shift (D). RESULTS: Icon accurately corrects the locations of the shots. For the uniform-shot plans: all gamma index passing rates were >97%, and the differences between the planned and the delivery doses (minimum, maximum, and mean) were all ≤0.1 Gy. For the composite-shot plans, however, the dose differences increased as the phantom was shifted through positions B-D, with a gamma index passing rate of 61% for lesion-E in position D, and 92%, 79%, and 45% for lesion-S in positions B, C, and D, respectively. CONCLUSIONS: Plans using only uniform shots are more robust to deviations in treatment position. The tolerance for such deviations may be lower for plans using composite shots.

Robust path planning for flexible needle insertion using Markov decision processes.

PURPOSE: Flexible needle has the potential to accurately navigate to a treatment region in the least invasive manner. We propose a new planning method using Markov decision processes (MDPs) for flexible needle navigation that can perform robust path planning and steering under the circumstance of complex tissue-needle interactions. METHODS: This method enhances the robustness of flexible needle steering from three different perspectives. First, the method considers the problem caused by soft tissue deformation. The method then resolves the common needle penetration failure caused by patterns of targets, while the last solution addresses the uncertainty issues in flexible needle motion due to complex and unpredictable tissue-needle interaction. RESULTS: Computer simulation and phantom experimental results show that the proposed method can perform robust planning and generate a secure control policy for flexible needle steering. Compared with a traditional method using MDPs, the proposed method achieves higher accuracy and probability of success in avoiding obstacles under complicated and uncertain tissue-needle interactions. Future work will involve experiment with biological tissue in vivo. CONCLUSION: The proposed robust path planning method can securely steer flexible needle within soft phantom tissues and achieve high adaptability in computer simulation.

Robust Planning for a Patient Treated in Decubitus Position with Proton Pencil Beam Scanning Radiotherapy.

A challenging case was reported for a patient treated in decubitus position with proton pencil beam scanning. A regular robust plan with the consideration of the uncertainties of translational alignment and range accuracy cannot ensure the target coverage as revealed in two verification computed tomography (CT) scans during the first week of the treatment. The irreproducibility of daily alignment and anatomical variations in such a position is mainly due to patient's roll. To mitigate the interfractional effect on the target coverage, a novel robust optimization against the patient's angular setup uncertainties was implemented to improve the plan quality by introducing two artificial CT image sets by rolling the planning CT three degrees in both clockwise and counter-clockwise directions and adding them into robust optimization scenarios, which was shown to be an effective and simple way to mitigate target dose degradation with respect to interfractional variations. This method can be easily generalized and applied to other situations where angular variations in patient's setup can introduce large dosimetric effects. It is recommended that angularly robust optimization method should be integrated into the treatment planning system as an option particularly for patient's treatment subject to large angular variations, such as the one in the decubitus position reported here.

Postoperative Intensity-Modulated Proton Therapy for Head and Neck Adenoid Cystic Carcinoma.

PURPOSE: Postoperative radiation therapy can improve control for adenoid cystic carcinoma (ACC) of the head and neck; however, delivering adequate dose to the tumor bed must be balanced with limiting dose to nearby critical organs. Intensity-modulated proton therapy (IMPT) may help improve the therapeutic ratio, though concerns exist regarding tissue heterogeneity and other sources of uncertainty in several head and neck subsites. We report control and toxicity outcomes for patients with ACC of the head and neck treated at a single institution with postoperative IMPT and robust planning and analysis. PATIENTS AND METHODS: Sixteen patients with head and neck ACC treated with postoperative IMPT were identified. Intensity-modulated proton therapy was delivered by using multifield optimization. Robust planning and analysis were performed. The median dose was 60 (range, 60 to 70) Gy (RBE) (Gy [relative biological effectiveness]). Adjuvant IMPT was given with (N = 12) or without (N = 4) platinum-based chemotherapy. Tumor control outcomes were recorded from the medical record, and acute and chronic toxicities were graded weekly during treatment and upon follow-up per Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4). RESULTS: Median follow-up is 24.9 (range, 9.2 to 40.2) months. One patient developed local and distant recurrence and subsequently died. The remaining 15 patients are alive without evidence of disease. Four patients experienced acute grade 3 toxicities: dermatitis (N = 3) and oral mucositis (N = 1). One patient developed a chronic grade 4 optic nerve disorder. There were no grade 5 toxicities. CONCLUSIONS: Intensity-modulated proton therapy is a feasible option for patients with ACC of the head and neck in the postoperative setting. Robust treatment planning and plan analysis can be performed such that uncertainties and tissue heterogeneities do not appear to limit safe and effective IMPT delivery. Safety and efficacy appear comparable to those of other types of radiation therapy, but further follow-up of clinical outcomes is needed.