Plan Selection in Proton Therapy of Locally Advanced Prostate Cancer with Simultaneous Treatment of Multiple Targets

Purpose Intensity modulated proton therapy (IMPT) of locally advanced prostate cancer can spare the bowel considerably compared with modern photon therapy, but simultaneous treatment of the prostate (p), seminal vesicles (sv), and lymph nodes is challenging owing to day-to-day organ motion and range uncertainties. Our purpose was, therefore, to generate a plan library for use in adaptive IMPT to mitigate these uncertainties. Methods and Materials We retrospectively included 27 patients with a series of computed tomography scans throughout their treatment representing day-to-day variation. In 18 of the patients, target motion was analyzed using rigid shifts of prostate gold markers relative to bony anatomy. A plan library with different p and sv planning target volume (p/sv-PTV) positions was defined from the distribution and direction of these shifts. Delivery of IMPT using plan selection from the library was simulated for image guidance on bony anatomy, in the remaining patients and compared with nonadaptive IMPT. Results The plan library consisted of 3 small margin p/sv-PTVs: (1) p/sv-PTV shifted 1.5 systematic error (Σ) of the population mean in the anterior and cranial directions, (2) p/sv-PTV shifted 1.5Σ in the posterior and caudal directions, and (3) p/sv-PTV in the planning position. The conventional p/sv-PTV was also available for backup. Plan selection compared with nonadaptive IMPT resulted in a reduction of the rectum volume receiving 60 Gy relative biological effect (RBE) (V60GyRBE) from on average 12 mL to 9 mL. For the bladder the average V45GyRBE was reduced from 36% to 30%. Large and small bowel doses were also reduced, whereas target coverage was comparable or improved compared with nonadaptive IMPT. Conclusions Plan selection based on a population model of rigid target motion was feasible for all patients. Compared with conventional IMPT, plan selection resulted in significant dosimetric sparing of rectum and bladder without compromising target coverage.publishedVersio

Substantial Sparing of Organs at Risk with Modern Proton Therapy in Lung Cancer, but Altered Breathing Patterns Can Jeopardize Target Coverage

Enhancing treatment of locally advanced non-small cell lung cancer (LA-NSCLC) by using pencil beam scanning proton therapy (PBS-PT) is attractive, but little knowledge exists on the effects of uncertainties occurring between the planning (Plan) and the start of treatment (Start). In this prospective simulation study, we investigated the clinical potential for PBS-PT under the influence of such uncertainties. Imaging with 4DCT at Plan and Start was carried out for 15 patients that received state-of-the-art intensity-modulated radiotherapy (IMRT). Three PBS-PT plans were created per patient: 3D robust single-field uniform dose (SFUD), 3D robust intensity-modulated proton therapy (IMPT), and 4D robust IMPT (4DIMPT). These were exposed to setup and range uncertainties and breathing motion at Plan, and changes in breathing motion and anatomy at Start. Target coverage and dose-volume parameters relevant for toxicity were compared. The organ at risk sparing at Plan was greatest with IMPT, followed by 4DIMPT, SFUD and IMRT, and persisted at Start. All plans met the preset criteria for target robustness at Plan. At Start, three patients had a lack of CTV coverage with PBS-PT. In conclusion, the clinical potential for heart and lung toxicity reduction with PBS-PT was substantial and persistent. Altered breathing patterns between Plan and Start jeopardized target coverage for all PBS-PT techniques.publishedVersio

Influence of organ motion on conformal vs. intensity-modulated pelvic radiotherapy for prostate cancer

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Enhancing Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer Patients with iCE, a Novel System for Automated Multi-Criterial Treatment Planning Including Beam Angle Optimization

In this study, the novel iCE radiotherapy treatment planning system (TPS) for automated multi-criterial planning with integrated beam angle optimization (BAO) was developed, and applied to optimize organ at risk (OAR) sparing and systematically investigate the impact of beam angles on radiotherapy dose in locally advanced non-small cell lung cancer (LA-NSCLC). iCE consists of an in-house, sophisticated multi-criterial optimizer with integrated BAO, coupled to a broadly used commercial TPS. The in-house optimizer performs fluence map optimization to automatically generate an intensity-modulated radiotherapy (IMRT) plan with optimal beam angles for each patient. The obtained angles and dose-volume histograms are then used to automatically generate the final deliverable plan with the commercial TPS. For the majority of 26 LA-NSCLC patients, iCE achieved improved heart and esophagus sparing compared to the manually created clinical plans, with significant reductions in the median heart Dmean (8.1 vs. 9.0 Gy, p = 0.02) and esophagus Dmean (18.5 vs. 20.3 Gy, p = 0.02), and reductions of up to 6.7 Gy and 5.8 Gy for individual patients. iCE was superior to automated planning using manually selected beam angles. Differences in the OAR doses of iCE plans with 6 beams compared to 4 and 8 beams were statistically significant overall, but highly patient-specific. In conclusion, automated planning with integrated BAO can further enhance and individualize radiotherapy for LA-NSCLC.publishedVersio

Improving knowledge-based treatment planning for lung cancer radiotherapy with automatic multi-criteria optimized training plans

Background: Knowledge-based planning (KBP) is a method for automated radiotherapy treatment planning where appropriate optimization objectives for new patients are predicted based on a library of training plans. KBP can save time and improve organ at-risk sparing and inter-patient consistency compared to manual planning, but its performance depends on the quality of the training plans. We used another system for automated planning, which generates multi-criteria optimized (MCO) plans based on a wish list, to create training plans for the KBP model, to allow seamless integration of knowledge from a new system into clinical routine. Model performance was compared for KBP models trained with manually created and automatic MCO treatment plans. Material and Methods: Two RapidPlan models with the same 30 locally advanced non-small cell lung cancer patients included were created, one containing manually created clinical plans (RP_CLIN) and one containing fully automatic multi-criteria optimized plans (RP_MCO). For 15 validation patients, model performance was compared in terms of dose-volume parameters and normal tissue complication probabilities, and an oncologist performed a blind comparison of the clinical (CLIN), RP_CLIN, and RP_MCO plans. Results: The heart and esophagus doses were lower for RP_MCO compared to RP_CLIN, resulting in an average reduction in the risk of 2-year mortality by 0.9 percentage points and the risk of acute esophageal toxicity by 1.6 percentage points with RP_MCO. The oncologist preferred the RP_MCO plan for 8 patients and the CLIN plan for 7 patients, while the RP_CLIN plan was not preferred for any patients. Conclusion: RP_MCO improved OAR sparing compared to RP_CLIN and was selected for implementation in the clinic. Training a KBP model with clinical plans may lead to suboptimal output plans, and making an extra effort to optimize the library plans in the KBP model creation phase can improve the plan quality for many future patients.</p

Mixed Effect Modeling of Dose and Linear Energy Transfer Correlations With Brain Image Changes After Intensity Modulated Proton Therapy for Skull Base Head and Neck Cancer

Purpose Intensity modulated proton therapy (IMPT) could yield high linear energy transfer (LET) in critical structures and increased biological effect. For head and neck cancers at the skull base this could potentially result in radiation-associated brain image change (RAIC). The purpose of the current study was to investigate voxel-wise dose and LET correlations with RAIC after IMPT. Methods and Materials For 15 patients with RAIC after IMPT, contrast enhancement observed on T1-weighted magnetic resonance imaging was contoured and coregistered to the planning computed tomography. Monte Carlo calculated dose and dose-averaged LET (LETd) distributions were extracted at voxel level and associations with RAIC were modelled using uni- and multivariate mixed effect logistic regression. Model performance was evaluated using the area under the receiver operating characteristic curve and precision-recall curve. Results An overall statistically significant RAIC association with dose and LETd was found in both the uni- and multivariate analysis. Patient heterogeneity was considerable, with standard deviation of the random effects of 1.81 (1.30-2.72) for dose and 2.68 (1.93-4.93) for LETd, respectively. Area under the receiver operating characteristic curve was 0.93 and 0.95 for the univariate dose-response model and multivariate model, respectively. Analysis of the LETd effect demonstrated increased risk of RAIC with increasing LETd for the majority of patients. Estimated probability of RAIC with LETd = 1 keV/µm was 4% (95% confidence interval, 0%, 0.44%) and 29% (95% confidence interval, 0.01%, 0.92%) for 60 and 70 Gy, respectively. The TD15 were estimated to be 63.6 and 50.1 Gy with LETd equal to 2 and 5 keV/µm, respectively. Conclusions Our results suggest that the LETd effect could be of clinical significance for some patients; LETd assessment in clinical treatment plans should therefore be taken into consideration.publishedVersio

A hybrid multi-particle approach to range assessment-based treatment verification in particle therapy

Particle therapy (PT) used for cancer treatment can spare healthy tissue and reduce treatment toxicity. However, full exploitation of the dosimetric advantages of PT is not yet possible due to range uncertainties, warranting development of range-monitoring techniques. This study proposes a novel range-monitoring technique introducing the yet unexplored concept of simultaneous detection and imaging of fast neutrons and prompt-gamma rays produced in beam-tissue interactions. A quasimonolithic organic detector array is proposed, and its feasibility for detecting range shifts in the context of proton therapy is explored through Monte Carlo simulations of realistic patient models and detector resolution efects. The results indicate that range shifts of 1 mm can be detected at relatively low proton intensities (22.30(13) × 107 protons/spot) when spatial information obtained through imaging of both particle species are used simultaneously. This study lays the foundation for multiparticle detection and imaging systems in the context of range verifcation in PTpublishedVersio

Reducing systematic errors due to deformation of organs at risk in radiotherapy

Purpose In radiotherapy (RT), the planning CT (pCT) is commonly used to plan the full RT-course. Due to organ deformation and motion, the organ shapes seen at the pCT will not be identical to their shapes during RT. Any difference between the pCT organ shape and the organ's mean shape during RT will cause systematic errors. We propose to use statistical shrinkage estimation to reduce this error using only the pCT and the population mean shape computed from training data. Methods The method was evaluated for the rectum in a cohort of 37 prostate cancer patients that had a pCT and 7–10 treatment CTs with rectum delineations. Deformable registration was performed both within-patient and between patients, resulting in point-to-point correspondence between all rectum shapes, which enabled us to compute a population mean rectum. Shrinkage estimates were found by combining the pCTs linearly with the population mean. The method was trained and evaluated using leave-one-out cross validation. The shrinkage estimates and the patient mean shapes were compared geometrically using the Dice similarity index (DSI), Hausdorff distance (HD), and bidirectional local distance. Clinical dose/volume histograms, equivalent uniform dose (EUD) and minimum dose to the hottest 5% volume (D5%) were compared for the shrinkage estimate and the pCT. Results The method resulted in moderate but statistically significant increase in similarity to the patient mean shape over the pCT. On average, the HD was reduced from 15.6 to 13.4 mm, while the DSI was increased from 0.74 to 0.78. Significant reduction in the bias of volume estimates was found in the DVH-range of 52.5–65 Gy, where the bias was reduced from −1.3 to −0.2 percentage points, but no significant improvement was found in EUD or D5%, Conclusions The results suggest that shrinkage estimation can reduce systematic errors due to organ deformations in RT. The method has potential to increase the accuracy in RT of deformable organs and can improve motion modeling.publishedVersio