A.L. Hoffmann

Mixed integer programming improves comprehensibility and plan quality in inverse optimization of prostate HDR brachytherapy

Current inverse treatment planning methods that optimize both catheter positions and dwell times in prostate HDR brachytherapy use surrogate linear or quadratic objective functions that have no direct interpretation in terms of dose-volume histogram (DVH) criteria, do not result in an optimum or have long solution times. We decrease the solution time of the existing linear and quadratic dose-based programming models (LP and QP, respectively) to allow optimizing over potential catheter positions using mixed integer programming. An additional average speed-up of 75% can be obtained by stopping the solver at an early stage, without deterioration of the plan quality. For a fixed catheter configuration, the dwell time optimization model LP solves to optimality in less than 15xa0s, which confirms earlier results. We propose an iterative procedure for QP that allows us to prescribe the target dose as an interval, while retaining independence between the solution time and the number of dose calculation points. This iterative procedure is comparable in speed to the LP model and produces better plans than the non-iterative QP. We formulate a new dose-volume-based model that maximizes V(100%) while satisfying pre-set DVH criteria. This model optimizes both catheter positions and dwell times within a few minutes depending on prostate volume and number of catheters, optimizes dwell times within 35xa0s and gives better DVH statistics than dose-based models. The solutions suggest that the correlation between the objective value and the clinical plan quality is weak in the existing dose-based models.

The contribution from transit dose for Ir-192 HDR brachytherapy treatments

Brachytherapy treatment planning systems that use model-based dose calculation algorithms employ a more accurate approach that replaces the TG43-U1 water dose formalism and adopt the TG-186 recommendations regarding composition and geometry of patients and other relevant effects. However, no recommendations were provided on the transit dose due to the source traveling inside the patient. This study describes a methodology to calculate the transit dose using information from the treatment planning system (TPS) and considering the sources instantaneous and average speed for two prostate and two gynecological cases. The trajectory of the (192)Ir HDR source was defined by importing applicator contour points and dwell positions from the TPS. The transit dose distribution was calculated using the maximum speed, the average speed and uniform accelerations obtained from the literature to obtain an approximate continuous source distribution simulated with a Monte Carlo code. The transit component can be negligible or significant depending on the speed profile adopted, which is not clearly reported in the literature. The significance of the transit dose can also be due to the treatment modality; in our study interstitial treatments exhibited the largest effects. Considering the worst case scenario the transit dose can reach 3% of the prescribed dose in a gynecological case with four catheters and up to 11.1% when comparing the average prostate dose for a case with 16 catheters. The transit dose component increases by increasing the number of catheters used for HDR brachytherapy, reducing the total dwell time per catheter or increasing the number of dwell positions with low dwell times. This contribution may become significant (>5%) if it is not corrected appropriately. The transit dose cannot be completely compensated using simple dwell time corrections since it may have a non-uniform distribution. An accurate measurement of the source acceleration and maximum speed should be incorporated in clinical practice or provided by the manufacturer to determine the transit dose component with high accuracy.

A framework for inverse planning of beam-on times for 3D small animal radiotherapy using interactive multi-objective optimisation.

Advances in precision small animal radiotherapy hardware enable the delivery of increasingly complicated dose distributions on the millimeter scale. Manual creation and evaluation of treatment plans becomes difficult or even infeasible with an increasing number of degrees of freedom for dose delivery and available image data. The goal of this work is to develop an optimisation model that determines beam-on times for a given beam configuration, and to assess the feasibility and benefits of an automated treatment planning system for small animal radiotherapy. The developed model determines a Pareto optimal solution using operator-defined weights for a multiple-objective treatment planning problem. An interactive approach allows the planner to navigate towards, and to select the Pareto optimal treatment plan that yields the most preferred trade-off of the conflicting objectives. This model was evaluated using four small animal cases based on cone-beam computed tomography images. Resulting treatment plan quality was compared to the quality of manually optimised treatment plans using dose-volume histograms and metrics. Results show that the developed framework is well capable of optimising beam-on times for 3D dose distributions and offers several advantages over manual treatment plan optimisation. For all cases but the simple flank tumour case, a similar amount of time was needed for manual and automated beam-on time optimisation. In this time frame, manual optimisation generates a single treatment plan, while the inverse planning system yields a set of Pareto optimal solutions which provides quantitative insight on the sensitivity of conflicting objectives. Treatment planning automation decreases the dependence on operator experience and allows for the use of class solutions for similar treatment scenarios. This can shorten the time required for treatment planning and therefore increase animal throughput. In addition, this can improve treatment standardisation and comparability of research data within studies and among different institutes.

Dwell time modulation restrictions do not necessarily improve treatment plan quality for prostate HDR brachytherapy

Inverse planning algorithms for dwell time optimisation in interstitial high-dose-rate (HDR) brachytherapy may produce solutions with large dwell time variations within catheters, which may result in undesirable selective high-dose subvolumes. Extending the dwell time optimisation model with a dwell time modulation restriction (DTMR) that limits dwell time differences between neighboring dwell positions has been suggested to eliminate this problem. DTMRs may additionally reduce the sensitivity for uncertainties in dwell positions that inevitably result from catheter reconstruction errors and afterloader source positioning inaccuracies. This study quantifies the reduction of high-dose subvolumes and the robustness against these uncertainties by applying a DTMR to template-based prostate HDR brachytherapy implants. Three different DTMRs were consecutively applied to a linear dose-based penalty model (LD) and a dose-volume based model (LDV), both obtained from literature. The models were solved with DTMR levels ranging from no restriction to uniform dwell times within catheters in discrete steps. Uncertainties were simulated on clinical cases using in-house developed software, and dose-volume metrics were calculated in each simulation. For the assessment of high-dose subvolumes, the dose homogeneity index (DHI) and the contiguous dose volume histogram were analysed. Robustness was measured by the improvement of the lowest D90% of the planning target volume (PTV) observed in the simulations. For (LD), a DTMR yields an increase in DHI of approximately 30% and reduces the size of the largest high-dose volume by 2-5 cc. However, this comes at a cost of a reduction in D90% of the PTV of 10%, which often implies that it drops below the desired minimum of 100%. For (LDV), none of the DTMRs were able to improve high-dose volume measures. DTMRs were not capable of improving robustness of PTV D90% against uncertainty in dwell positions for both models.Comparison of optimization algorithms for inverse treatment planning requires objective function value evaluation.

Fractionation in normal tissues: the (α/β)eff concept can account for dose heterogeneity and volume effects.

The simple Linear-Quadratic (LQ)-based Withers iso-effect formula (WIF) is widely used in external-beam radiotherapy to derive a new tumour dose prescription such that there is normal-tissue (NT) iso-effect when changing the fraction size and/or number. However, as conventionally applied, the WIF is invalid unless the normal-tissue response is solely determined by the tumour dose. We propose a generalized WIF (gWIF) which retains the tumour prescription dose, but replaces the intrinsic fractionation sensitivity measure (α/β) by a new concept, the normal-tissue effective fractionation sensitivity, [Formula: see text], which takes into account both the dose heterogeneity in, and the volume effect of, the late-responding normal-tissue in question. Closed-form analytical expressions for [Formula: see text] ensuring exact normal-tissue iso-effect are derived for: (i) uniform dose, and (ii) arbitrary dose distributions with volume-effect parameter n = 1 from the normal-tissue dose-volume histogram. For arbitrary dose distributions and arbitrary n, a numerical solution for [Formula: see text] exhibits a weak dependence on the number of fractions. As n is increased, [Formula: see text] increases from its intrinsic value at n = 0 (100% serial normal-tissue) to values close to or even exceeding the tumour (α/β) at n = 1 (100% parallel normal-tissue), with the highest values of [Formula: see text] corresponding to the most conformal dose distributions. Applications of this new concept to inverse planning and to highly conformal modalities are discussed, as is the effect of possible deviations from LQ behaviour at large fraction sizes.

Dynamics of rectal balloon implant shrinkage in prostate VMAT

PurposeTo assess the effect of axa0shrinking rectal balloon implant (RBI) on the anorectal dose and complication risk during the course of moderately hypofractionated prostate radiotherapy.MethodsIn 15xa0patients with localized prostate cancer, an RBI was implanted. Axa0weekly kilovolt cone-beam computed tomography (CBCT) scan was acquired to measure the dynamics of RBI volume and prostate–rectum separation. The absolute anorectal volume encompassed by the 2u2009Gy equieffective 75u2009Gy isodose (V75Gy) was recalculated as well as the mean anorectal dose. The increase in estimated risk of grade 2–3xa0late rectal bleeding (LRB) between the start and end of treatment was predicted using nomograms. The observed acute and late toxicities were evaluated.ResultsAxa0significant shrinkage of RBI volumes was observed, with an average volume of 70.4% of baseline at the end of the treatment. Although the prostate–rectum separation significantly decreased over time, it remained at least 1u2009cm. No significant increase in V75Gy of the anorectum was observed, except in one patient whose RBI had completely deflated in the third week of treatment. No correlation between mean anorectal dose and balloon deflation was found. The increase in predicted LRB risk was not significant, except in the one patient whose RBI completely deflated. The observed toxicities confirmed these findings.ConclusionsDespite significant decrease in RBI volume the high-dose rectal volume and the predicted LRB risk were unaffected due to axa0persistent spacing between the prostate and the anterior rectal wall.ZusammenfassungZielsetzungBeurteilung der Wirkung eines schrumpfenden rektalen Ballonimplantats (RBI) auf die anorektale Dosis und das Komplikationsrisiko im Verlauf einer mäßig hypofraktionierten Strahlentherapie der Prostata.MethodenEin RBI wurde 15xa0Patienten mit lokal begrenztem Prostatakarzinom implantiert. Zur Messung der Dynamik des RBI-Volumens und der Prostata-Rektum-Trennung wurde eine wöchentliche Kilovolt-Cone-beam-Computertomographie (CBCT) aufgenommen. Das absolute anorektale Volumen, das von der 2u2009Gy äquieffektiven 75-Gy-Isodose (V75Gy) umfasst wurde, wurde ebenso berechnet wie die mittlere anorektale Dosis. Die Zunahme des geschätzten Risikos für späte rektale Blutungen (LRB) vom Gradxa02–3 zwischen Beginn und Ende der Behandlung wurde mit Nomogrammen vorhergesagt. Die beobachteten akuten und späten Toxizitäten wurden ausgewertet.ErgebnisseEs wurde eine signifikante Schrumpfung der RBI-Volumina beobachtet, mit einem durchschnittlichen Volumen am Ende der Behandlung von 70,4u2009% des Baseline-Volumens. Obwohl die Prostata-Rektum-Trennung im Verlauf der Therapie deutlich abnahm, betrug diese durchgehend mindestens 1u2009cm. Es wurde kein signifikanter V75Gy-Anstieg des Anorektums beobachtet, außer bei einem Patienten, dessen RBI in der dritten Behandlungswoche vollständig entleert war. Zwischen der mittleren anorektalen Dosis und der Ballonvolumenabnahme wurde keine Korrelation festgestellt. Die Zunahme des LRB-Risikos war nicht signifikant, außer bei dem Patienten mit vollständig entleertem RBI. Die beobachteten Toxizitäten bestätigten diese Befunde.SchlussfolgerungTrotz signifikanter Abnahme des RBI-Volumens waren das Hochdosis-Rektumvolumen und das vorhergesagte LRB-Risiko aufgrund eines anhaltenden Abstands zwischen der Prostata und der anterioren Rektumwand davon nicht nachteilig betroffen.

Improved effectiveness of stereotactic radiosurgery in large brain metastases by individualized isotoxic dose prescription: an in silico study

IntroductionIn large brain metastases (BM) with axa0diameter of more than 2u202fcm there is an increased risk of radionecrosis (RN) with standard stereotactic radiosurgery (SRS) dose prescription, while the normal tissue constraint is exceeded. The tumor control probability (TCP) with axa0single dose of 15u202fGy is only 42%. This in silico study tests the hypothesis that isotoxic dose prescription (IDP) can increase the therapeutic ratio (TCP/Risk of RN) of SRS in large BM.Materials and methodsA treatment-planning study with 8xa0perfectly spherical and 46xa0clinically realistic gross tumor volumes (GTV) was conducted. The effects of GTV size (0.5–4u202fcm diameter), set-up margins (0, 1, and 2u202fmm), and beam arrangements (coplanar vs non-coplanar) on the predicted TCP using IDP were assessed. For single-, three-, and five-fraction IDP dose–volume constraints of V12Gyu202f=u200910u202fcm3, V19.2u202fGyu202f=u200910u202fcm3, and axa0V20Gyu202f=u200920u202fcm3, respectively, were used to maintain axa0low risk of radionecrosis.ResultsIn BM of 4u202fcm in diameter, the maximum achievable single-fraction IDP dose was 14u202fGy compared to 15u202fGy for standard SRS dose prescription, with respective TCPs of 32 and 42%. Fractionated SRS with IDP was needed to improve the TCP. For three- and five-fraction IDP, axa0maximum predicted TCP of 55 and 68% was achieved respectively (non-coplanar beams and axa01u202fmm GTV-PTV margin).ConclusionsUsing three-fraction or five-fraction IDP the predicted TCP can be increased safely to 55 and 68%, respectively, in large BM with axa0diameter of 4u202fcm with axa0low risk of RN. Using IDP, the therapeutic ratio of SRS in large BM can be increased compared to current SRS dose prescription.ZusammenfassungEinleitungBei einer Standarddosisverschreibung für eine stereotaktische Radiochirurgie (SRS) von großen Hirnmetastasen (BM) mit einem Durchmesser von ≥2u202fcm ist das Risiko für eine Strahlennekrose (RN) erhöht, da die Toleranzdosis des Hirngewebes überschritten wird. Die Tumorkontrollwahrscheinlichkeit (TCP) ist bei 15u202fGy lediglich 42u202f%. Diese In-silico-Studie testet die Hypothese, dass eine isotoxische Dosisverschreibung (IDP) das Potenzial hat, das therapeutische Fenster (TCP/RN-Risiko) von SRS bei großen BM zu vergrößern.Material und MethodenEine Planungsstudie mit 8xa0perfekt sphärischen und 46xa0klinisch realistischen Tumorvolumen (GTV) wurde durchgeführt. Die Effekte der GTV-Größe (Durchmesser 0,5–4,0u202fcm), des Set-up-Saums (0, 1, 2u202fmm) und der Strahlanordnung (koplanar vs. nichtkoplanar) auf die erwartete TCP bei Anwendung der IDP wurden untersucht. Für IDP in 1, 3 oder 5xa0Fraktionen wurden die entsprechenden Dosis-Volumen-Einschränkungen V12Gyu202f=u200910u202fcm3, V19,2u202fGyu202f=u200910u202fcm3 und V20Gyu202f=u200920u202fcm3 verwendet, um das RN-Risiko gering zu halten.ErgebnisseFür BM mit einem Durchmesser von 4u202fcm war die maximal erreichbare IDP-Dosis in einer Bestrahlung 14u202fGy im Vergleich zu 15u202fGy bei der Standarddosisverschreibung, mit entsprechender TCP von 32u202f% bzw. 42u202f%. Fraktionierte SRS mit IDP war notwendig, um die TCP zu erhöhen. Für IDP in 3 und 5xa0Fraktionen wurde eine maximal vorhergesagte TCP von 55 und 68u202f% erreicht (nichtkoplanare Strahlenbündel und GTV-PTV-Saum von 1u202fmm).SchlussfolgerungMit einer IDP in 3 oder 5xa0Fraktionen kann die vorhergesagte TCP bei BM mit einem Durchmesser von 4u202fcm jeweils auf 55 bzw. 68u202f% erhöht werden, mit gleichzeitig geringem Risiko auf RN. Mit IDP kann das therapeutische Fenster einer SRS großer BM im Vergleich zur Standarddosisverschreibung erhöht werden.

Employing the therapeutic operating characteristic (TOC) graph for individualised dose prescription

BackgroundIn current practice, patients scheduled for radiotherapy are treated according to ‘rigid’ protocols with predefined dose prescriptions that do not consider risk-taking preferences of individuals. The therapeutic operating characteristic (TOC) graph is applied as a decision-aid to assess the trade-off between treatment benefit and morbidity to facilitate dose prescription customisation.MethodsHistorical dose-response data from prostate cancer patient cohorts treated with 3D-conformal radiotherapy is used to construct TOC graphs. Next, intensity-modulated (IMRT) plans are generated by optimisation based on dosimetric criteria and dose-response relationships. TOC graphs are constructed for dose-scaling of the optimised IMRT plan and individualised dose prescription. The area under the TOC curve (AUC) is estimated to measure the therapeutic power of these plans.ResultsOn a continuous scale, the TOC graph directly visualises treatment benefit and morbidity risk of physicians’ or patients’ choices for dose (de-)escalation. The trade-off between these probabilities facilitates the selection of an individualised dose prescription. TOC graphs show broader therapeutic window and higher AUCs with increasing target dose heterogeneity.ConclusionsThe TOC graph gives patients and physicians access to a decision-aid and read-out of the trade-off between treatment benefit and morbidity risks for individualised dose prescription customisation over a continuous range of dose levels.

EP-1233: Model-based prediction of rectal toxicity reduction in prostate cancer IMRT with hydrogel rectum spacer

Purpose/Objective: This study aimed to investigate the impact of increasing radiation delivery time on the outcome of hypofractionated radiation therapy for prostate cancer. Intrafraction repair is seldom discussed in relation to external beam radiation therapy as most fractional doses are delivered in the course of a few minutes and the beam-on time is not very much different from the time to deliver all individual fields. Advanced techniques aimed at delivering high fractional dose, employing multiple fields, scanning the target volume or requiring multiple imaging sessions may however take considerably longer, increasing the importance of intrafraction repair. Materials and Methods: Mono-exponential and bi-exponential repair models have been used in prostate patients to study the loss of biologically effective dose for several clinicallyrelevant irradiation times between 5 and 60 minutes. These were then converted into loss of biochemical control at 5 years using clinically-relevant dose response curves derived from 10688 prostate patients treated with conventional fractionation. The theoretical predictions were subsequently compared with clinical results from 14 newly reported studies totalling 4363 patients undergoing conventionallyfractionated and hypofractionated prostate radiotherapy. Results: For low-risk patients the equivalent doses delivered were quite high and consequently the reported results were very good and in agreement with theoretical predictions. For intermediateand high-risk patients however, the results from hypofractionated schedules delivered with timeconsuming techniques appear to be compatible with predictions accounting for intrafraction repair taking place during longer irradiations, while results from moderately hypofractionated or conventionally-fractionated schedules are in agreement with short irradiation times. Treatment sessions lasting more than about 20 minutes could lead to significant loss of biochemical control even when relatively slow repair is relevant for prostate tumours. Large effect losses could therefore be expected from extremely hypofractionated schedules with long irradiation sessions as might be the case of scanned beams and/or with multiple intrafraction imaging sessions to check the positioning of the patient. The loss of effect might also be reflected into an apparent reduced sensitivity to fractionation for the tumours. Conclusions: Intrafraction repair plays an important role for prostate radiation therapy and may lead to loss of biological effect in the case of extremely hypofractionated techniques requiring increased irradiation times Neglecting intrafraction could also interfere with the derivation of the fractionation sensitivity for prostate tumours.

PO-0785 : Inverse planning of beam-on times for precision image-guided 3D small animal radiotherapy treatments

PO-0785 Inverse planning of beam-on times for precision imageguided 3D small animal radiotherapy treatments M. Balvert, S.J. Van Hoof, P.V. Granton, D. Trani, D. Den Hertog, A.L. Hoffmann, F. Verhaegen Center for Economic Research (CentER) Tilburg University, Econometric and Operations Research, Tilburg, The Netherlands Maastricht Radiation Oncology (MAASTRO Clinic), Physics Research, Maastricht, The Netherlands Purpose/Objective: Advances in small animal radiotherapy enable the delivery of increasingly complex heterogeneous dose distributions on the millimeter scale, but methods to plan complicated small animal treatments remain in their infancy. A pre-clinical irradiation plan is usually created based on cone beam CT data with the animal in treatment position under anesthesia. Combined with demands on throughput, fast and easy treatment planning methods and algorithms are required. The purpose of this study is to develop an optimization model that determines beam-on times for a given beam configuration, and to assess the benefits of automated treatment planning for small animal radiotherapy. Materials and Methods: The applied model determines a Pareto-optimal solution based on user-provided weights for objectives. An interactive approach allows the user to select the plan that yields the most preferred trade-offs. Two cases based on cone beam CT data of a rat were used, and manual and model-based optimization results were compared using dose-volume metrics. The kidneys, spine and gastrointestinal tract (GI) were delineated as organs at risk (OARs) and a fictitious planning target volume (PTV) was created around the spine. In case 1, the left kidney was targeted as PTV with four 10x10 mm beams and for case 2, twelve 8x10 mm beams were used to target the PTV around the spine. A PTV dose of 8 Gy was prescribed, with a mean dose between 8 and 10 Gy as constraint. Differences between prescribed and planned PTV dose, as well as OAR doses were included in penalty objectives. The model was integrated in a research version of Monte Carlo based small animal treatment planning system SmART-Plan (v2.0 Precision X-ray). Results: Results show that manual and automated treatment planning yields plans of similar quality as shown in the figure and table. A similar amount of time was needed for manual and model-based optimization. In this period, manual optimization generates a single plan, while a set of Paretooptimal plans is created with automated optimization, allowing for a more substantiated choice on trade-offs. Automated optimization often uses fewer beams than manual optimized plans, therewith lowering treatment delivery time. Additional benefits of automated planning include a decreased dependence on the planning skills of the user (often absent in pre-clinical research), and the potential to improve treatment standardization among institutions. For more complex irradiations, manual planning becomes infeasible, making automation a necessity.