Per-fraction planning to enhance optimization degrees of freedom compared to the conventional single-plan approach

Objective. In conventional radiotherapy, a single treatment plan is generated pre-treatment, and delivered in daily fractions. In this study, we propose to generate different treatment plans for all fractions (‘Per-fraction’ planning) to reduce cumulative organs at risk (OAR) doses. Per-fraction planning was compared to the ‘Conventional’ single-plan approach for non-coplanar 4 × 9.5 Gy prostate stereotactic body radiation therapy (SBRT). Approach. An in-house application for fully automated, non-coplanar multi-criterial treatment planning with integrated beam angle and fluence optimization was used for plan generations. For the Conventional approach, a single 12-beam non-coplanar IMRT plan with individualized beam angles was generated for each of the 20 included patients. In Per-fraction planning, four fraction plans were generated for each patient. For each fraction, a different set of patient-specific 12-beam configurations could be automatically selected. Per-fraction plans were sequentially generated by adding dose to already generated fraction plan(s). For each fraction, the cumulative- and fraction dose were simultaneously optimized, allowing some minor constraint violations in fraction doses, but not in cumulative. Main results. In the Per-fraction approach, on average 32.9 ± 3.1 [29;39] unique beams per patient were used. PTV doses in the separate Per-fraction plans were acceptable and highly similar to those in Conventional plans, while also fulfilling all OAR hard constraints. When comparing total cumulative doses, Per-fraction planning showed improved bladder sparing for all patients with reductions in Dmean of 22.6% (p = 0.0001) and in D1cc of 2.0% (p = 0.0001), reductions in patient volumes receiving 30% and 50% of the prescribed dose of 54.7% and 6.3%, respectively, and a 3.1% lower rectum Dmean (p = 0.007). Rectum D1cc was 4.1% higher (p = 0.0001) and Urethra dose was similar. Significance. In this proof-of-concept paper, Per-fraction planning resulted in several dose improvements in healthy tissues compared to the Conventional single-plan approach, for similar PTV dose. By keeping the number of beams per fraction the same as in Conventional planning, reported dosimetric improvements could be obtained without increase in fraction durations. Further research is needed to explore the full potential of the Per-fraction planning approach.</p

Complementing Prostate SBRT VMAT With a Two-Beam Non-Coplanar IMRT Class Solution to Enhance Rectum and Bladder Sparing With Minimum Increase in Treatment Time

Purpose Enhance rectum and bladder sparing in prostate SBRT with minimum increase in treatment time by complementing dual-arc coplanar VMAT with a two-beam non-coplanar IMRT class solution (CS). Methods For twenty patients, an optimizer for automated multi-criterial planning with integrated beam angle optimization (BAO) was used to generate dual-arc VMAT plans, supplemented with five non-coplanar IMRT beams with individually optimized orientations (VMAT+5). In all plan generations, reduction of high rectum dose had the highest priority after obtaining adequate PTV coverage. A CS with two most preferred directions in VMAT+5 and largest rectum dose reductions compared to dual-arc VMAT was then selected to define VMAT+CS. VMAT+CS was compared with automatically generated i) dual-arc coplanar VMAT plans (VMAT), ii) VMAT+5 plans, and iii) IMRT plans with 30 patient-specific non-coplanar beam orientations (30-NCP). Plans were generated for a 4 x 9.5 Gy fractionation scheme. Differences in PTV doses, healthy tissue sparing, and computation and treatment delivery times were quantified. Results For equal PTV coverage, VMAT+CS, consisting of dual-arc VMAT supplemented with two fixed, non-coplanar IMRT beams with fixed Gantry/Couch angles of 65 degrees/30 degrees and 295 degrees/-30 degrees, significantly reduced OAR doses and the dose bath, compared to dual-arc VMAT. Mean relative differences in rectum D-mean, D-1cc, V-40GyEq and V-60GyEq were 19.4 +/- 10.6%, 4.2 +/- 2.7%, 34.9 +/- 20.3%, and 39.7 +/- 23.2%, respectively (all p Conclusions The proposed two-beam non-coplanar class solution to complement coplanar dual-arc VMAT resulted in substantial plan quality improvements for OARs (especially rectum) and reduced irradiated patient volumes with minor increases in treatment delivery times

Automated Radiotherapy Planning for Patient-Specific Exploration of the Trade-Off Between Tumor Dose Coverage and Predicted Radiation-Induced Toxicity-A Proof of Principle Study for Prostate Cancer

Background: Currently, radiation-oncologists generally evaluate a single treatment plan for each patient that is possibly adapted by the planner prior to final app

MR-Linac Radiotherapy - The Beam Angle Selection Problem

BACKGROUND: With the large-scale introduction of volumetric modulated arc therapy (VMAT), selection of optimal beam angles for coplanar static-beam IMRT has increasingly become obsolete. Due to unavailability of VMAT in current MR-linacs, the problem has re-gained importance. An application for automated IMRT treatment planning with integrated, patient-specific computer-optimization of beam angles (BAO) was used to systematically investigate computer-aided generation of beam angle class solutions (CS) for replacement of computationally expensive patient-specific BAO. Rectal cancer was used as a model case. MATERIALS AND METHODS: 23 patients treated at a Unity MR-linac were included. BAO(x) plans (x=7-12 beams) were generated for all patients. Analyses of BAO(12) plans resulted in CS(x) class solutions. BAO(x) plans, CS(x) plans, and plans with equi-angular setups (EQUI(x), x=9-56) were mutually compared. RESULTS: For x>7, plan quality for CS(x) and BAO(x) was highly similar, while both were superior to EQUI(x). E.g. with CS(9), bowel/bladder D(mean) reduced by 22% [11%, 38%] compared to EQUI(9) (p<0.001). For equal plan quality, the number of EQUI beams had to be doubled compared to BAO and CS. CONCLUSIONS: Computer-generated beam angle CS could replace individualized BAO without loss in plan quality, while reducing planning complexity and calculation times, and resulting in a simpler clinical workflow. CS and BAO largely outperformed equi-angular treatment. With the developed CS, time consuming beam angle re-optimization in daily adaptive MR-linac treatment could be avoided. Further systematic research on computerized development of beam angle class solutions for MR-linac treatment planning is warranted

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

First fully automated planning solution for robotic radiosurgery - comparison with automatically planned volumetric arc therapy for prostate cancer

Background: For conventional radiotherapy treatment units, automated planning can significantly improve plan quality. For robotic radiosurgery, systems for automatic generation of clinically deliverable plans do not yet exist. For prostate stereotactic body radiation therapy (SBRT), few studies have systematically compared VMAT with robotic treatment. Material and methods: The multi-criteria autoplanning optimizer, developed at our institute, was coupled to the commercial treatment planning system of our robotic treatment unit, for fully automated generation of clinically deliverable plans (autoROBOT). The system was then validated by comparing autoROBOT plans with manually generated plans. Next, the autoROBOT system was used for systematic comparisons between autoROBOT plans and VMAT plans, that were also automatically generated (autoVMAT). CTV-PTV margins of 3 mm were used for autoROBOT (clinical routine) and autoVMAT plan generation. For autoVMAT, an extra plan was generated with 5 mm margin (often applied for VMAT). Plans were generated for a 4 x 9.5 Gy fractionation scheme. Results: Compared to manual planning, autoROBOT improved rectum D (16%), V (75%) and D (41%), and bladder D (37%) (all p .002), with equal PTV coverage. In the autoROBOT and autoVMAT comparison, both with 3 mm margin, rectum doses were lower for autoROBOT by 5% for rectum D (p=.002), 33% for V (p=.001) and 4% for D (p=.05), with comparable PTV coverage and other OAR sparing. With 5 mm margin for VMAT, 18/20 plans had a PTV coverage lower than requested

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

Individualized automated planning for dose bath reduction in robotic radiosurgery for benign tumors

Object To explore the use of automated planning in robotic radiosurgery of benign vestibular schwannoma (VS) tumors for dose reduction outside the planning target volume (PTV) to potentially reduce risk of secondary tumor induction. Methods A system for automated planning (AUTOplans) for VS patients was set up. The goal of AUTO- planning was to reduce the dose bath, including the occurrence of high dose spikes leaking from the PTV into normal tissues, without worsening PTV coverage, OAR doses, or treatment time. For 20 VS patients treated with 1x12 Gy, the AUTOplan was compared with the plan generated with conventional, manual trial-and-error planning (MANplan). Results With equal PTV coverage, AUTOplans showed clinically negligible differences with MANplans in OAR sparing (largest mean difference for all OARs: ΔD2% = 0.2 Gy). AUTOplan dose distributions were more compact: mean/maximum reductions of 23.6/53.8% and 9.6/ 28.5% in patient volumes receiving more than 1 or 6 Gy, respectively (p<0.001). AUTOplans also showed smaller dose spikes with mean/maximum reductions of 22.8/37.2% and 14.2/ 40.4% in D2% for shells at 1 and 7 cm distance from the PTV, respectively (p<0.001). Conclusion Automated planning for benign VS tumors highly outperformed manual planning with respect to the dose bath outside the PTV, without deteriorating PTV coverage or OAR sparing, or significantly increasing treatment time

Multibody dynamic modeling of the behavior of flexible instruments used in cervical cancer brachytherapy

Background: The steep radiation dose gradients in cervical cancer brachytherapy (BT) necessitate a thorough understanding of the behavior of afterloader source cables or needles in the curved channels of (patient-tailored) applicators. Purpose: The purpose of this study is to develop and validate computer models to simulate: (1) BT source positions, and (2) insertion forces of needles in curved applicator channels. The methodology presented can be used to improve the knowledge of instrument behavior in current applicators and aid the development of novel (3D-printed) BT applicators. Methods: For the computer models, BT instruments were discretized in finite elements. Simulations were performed in SPACAR by formulating nodal contact force and motion input models and specifying the instruments’ kinematic and dynamic properties. To evaluate the source cable model, simulated source paths in ring applicators were compared with manufacturer-measured source paths. The impact of discrepancies on the dosimetry was estimated for standard plans. To validate needle models, simulated needle insertion forces in curved channels with varying curvature, torsion, and clearance, were compared with force measurements in dedicated 3D-printed templates. Results: Comparison of simulated with manufacturer-measured source positions showed 0.5–1.2 mm median and &lt;2.0 mm maximum differences, in all but one applicator geometry. The resulting maximum relative dose differences at the lateral surface and at 5 mm depth were 5.5% and 4.7%, respectively. Simulated insertion forces for BT needles in curved channels accurately resembled the forces experimentally obtained by including experimental uncertainties in the simulation. Conclusion: The models developed can accurately predict source positions and insertion forces in BT applicators. Insights from these models can aid novel applicator design with improved motion and force transmission of BT instruments, and contribute to the estimation of overall treatment precision. The methodology presented can be extended to study other applicator geometries, flexible instruments, and afterloading systems.</p

Response Monitoring with [18F]FLT PET and Diffusion-Weighted MRI After Cytotoxic 5-FU Treatment in an Experimental Rat Model for Colorectal Liver Metastases.

PURPOSE: The aim of the study was to investigate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) and 3'-dexoy-3'-[(¹⁸)F]fluorothymidine ([(¹⁸)F]FLT) positron emission tomography (PET) as early biomarkers of treatment response of 5-fluorouracil (5-FU) in a syngeneic rat model of colorectal cancer liver metastases. PROCEDURES: Wag/Rij rats with intrahepatic syngeneic CC531 tumors were treated with 5-FU (15, 30, or 60 mg/kg in weekly intervals). Before treatment and at days 1, 3, 7, and 14 after treatment rats underwent DW-MRI and [(¹⁸)F]FLT PET. Tumors were analyzed immunohistochemically for Ki67, TK1, and ENT1 expression. RESULTS: 5-FU inhibited the growth of CC531 tumors in a dose-dependent manner. Immunohistochemical analysis did not show significant changes in Ki67, TK1, and ENT1 expression. However, [(¹⁸)F]FLT SUV_mean and SUV_max were significantly increased at days 4 and 7 after treatment with 5-FU (60 mg/kg) and returned to baseline at day 14 (SUV_max at days -1, 4, 7, and 14 was 1.1 ± 0.1, 2.3 ± 0.5, 2.3 ± 0.6, and 1.5 ± 0.4, respectively). No changes in [(¹⁸)F]FLT uptake were observed in the nontreated animals. Furthermore, the apparent diffusion coefficient (ADCmean) did not change in 5-FU-treated rats compared to untreated rats. CONCLUSION: This study suggests that 5-FU treatment induces a flare in [(¹⁸)F]FLT uptake of responsive CC531 tumors in the liver, while the ADC_mean did not change significantly. Future studies in larger groups are warranted to further investigate whether [(¹⁸)F]FLT PET can discriminate between disease progression and treatment response.The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement number 115151, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution