Complication-free Tumor Control Probability Research Articles

COMPARISON OF COPLANAR AND NON- COPLANARVMAT FOR BRAIN CANCER BY USING THE DOSIMETRICAL AND RADIOBIOLOGICAL INDICES

Background: Recent techniques of radiotherapy such as volumetric modulated arc therapy (VMAT) that delivered in Coplanar technique or non-coplanar technique allows to deliver high doses to the brain tumors, at the same time reducing the risk of normal tissues as compared with intensity modulated radiotherapy (IMRT) and the three-dimensional conformal radiotherapy (3D-CRT). Aim: The aim of the current work is to compare dosimetrical and radiobiological indices of treatment plans for brain tumor using CO-VMAT and NC-VMAT techniques to choose the optimum technique for the treated cases. Patients and methods: Twenty-one cases with brain tumors were performed for the treatment planning study. The cases are planned by using the coplanar and non coplanar VMAT techniques and optimized to evaluate and compare dosimetrical and radiobiological parameters related to PTV dose coverage and sparing of organs at risk. The total dose of CO-VMAT and NC-VMAT plans is 60 Gray in 30 fractions during a single phase with a daily dose of 2 Gray. Results: In dosimetrical calculations, CO-VMAT and NC-VMAT techniques gave similar (homogeneity index HI, modified homogeneity index MHI, conformity index CI and quality factor QF) values for the PTV, while CO-VMAT was the higher in (target coverage index TCI, prescription isodose to target volume ratio PITV and conformity number CN) values and the lower in (gradient index GI, gradient measure GM) values, and NC-VMAT was the lower in Monitor units MUs values. In radiobiological calculations, equivalent uniform dose EUD values, tumor control probability TCP and complication free tumor control probability P+ were large in CO-VMAT and normal tissue complication probability NTCP was less in NC-VMAT. Conclusion: While the previous studies showed that CO-VMAT technique was used when the tumor is far from the organs at risk, the present work found CO-VMAT can be used when the tumor is near to or far from organs at risk (OARs) because it can achieve the target dose coverage and sparing of OARs together. We strongly recommend that NC-VMAT technique should be used when the OARs are located inside the tumor to be able to achieve more sparing of them.

Influence of Urethra Sparing on Tumor Control Probability and Normal Tissue Complication Probability in Focal Dose Escalated Hypofractionated Radiotherapy: A Planning Study Based on Histopathology Reference.

PurposeMultiparametric magnetic resonance tomography (mpMRI) and prostate specific membrane antigen positron emission tomography (PSMA-PET/CT) are used to guide focal radiotherapy (RT) dose escalation concepts. Besides improvements of treatment effectiveness, maintenance of a good quality of life is essential. Therefore, this planning study investigates whether urethral sparing in moderately hypofractionated RT with focal RT dose escalation influences tumour control probability (TCP) and normal tissue complication probability (NTCP).Patients and Methods10 patients with primary prostate cancer (PCa), who underwent 68Ga PSMA-PET/CT and mpMRI followed by radical prostatectomy were enrolled. Intraprostatic tumour volumes (gross tumor volume, GTV) based on both imaging techniques (GTV-MRI and -PET) were contoured manually using validated contouring techniques and GTV-Union was created by summing both. For each patient three IMRT plans were generated with 60 Gy to the whole prostate and a simultaneous integrated boost up to 70 Gy to GTV-Union in 20 fractions by (Plan 1) not respecting and (Plan 2) respecting dose constraints for urethra as well as (Plan 3) respecting dose constraints for planning organ at risk volume for urethra (PRV = urethra + 2mm expansion). NTCP for urethra was calculated applying a Lyman-Kutcher-Burman model. TCP-Histo was calculated based on PCa distribution in co-registered histology (GTV-Histo). Complication free tumour control probability (P+) was calculated. Furthermore, the intrafractional movement was considered.ResultsMedian overlap of GTV-Union and PRV-Urethra was 1.6% (IQR 0-7%). Median minimum distance of GTV-Histo to urethra was 3.6 mm (IQR 2 – 7 mm) and of GTV-Union to urethra was 1.8 mm (IQR 0.0 – 5.0 mm). The respective prescription doses and dose constraints were reached in all plans. Urethra-sparing in Plans 2 and 3 reached significantly lower NTCP-Urethra (p = 0.002) without significantly affecting TCP-GTV-Histo (p = p > 0.28), NTCP-Bladder (p > 0.85) or NTCP-Rectum (p = 0.85), resulting in better P+ (p = 0.006). Simulation of intrafractional movement yielded even higher P+ values for Plans 2 and 3 compared to Plan 1.ConclusionUrethral sparing may increase the therapeutic ratio and should be implemented in focal RT dose escalation concepts.

Radiobiological Evaluation of Dosimetric Plans for Stereotactic Radiotherapy for Prostate Cancer According to Fractionation Regimen

Objective. To determine the most effective irradiation regimen (total dose and dose per fraction) for hypofractionated treatment for prostate carcinomas according the TCP/NTCP radiobiological criteria.Material and methods. Using the tomographic information of five patients with low-risk prostate adenocarcinoma as an example, the authors devised dosimetric radiation therapy plans using the volumetric modulated arc therapy (VMAT) procedure. They considered the range of total doses of 33.5 to 38 Gy administered in 4 and 5 fractions. Based on the equivalent uniform dose concept proposed by A. Niemierko and on the computed differential dose volume histograms, the investigators modeled local tumor control probability (TCP) values, by taking into account the uncertainties of main radiobiological parameters, and estimated normal tissue complication probabilities (NTCP) for the anterior rectal wall as the organ most at risk of irradiation. An effective dosimetric plan was selected according to the UTCP criterion and the probability of complication-free tumor control, i.e. TCP (1 – NTCP).Results. The results of modeling the UTCP criterion show that with a higher total dose, the TCP value increases and so does the NTCP value, therefore the optimal radiation therapy plans are to irradiate with a total dose of 34 Gy over 4 fractions or with a dose of 36–37 Gy over 5 fractions. The difference between the fractionation regimens is that the UTCP value is achieved with a higher TCP value over 4 fractions and with a lower load on the rectal wall over 5 fractions.Conclusion. The choice of a specific fractionation regimen should be determined from the calculated values of differential dose volume histograms for each patient, as well as from radiobiological criteria, such as TCP, NTCP and UTCP.

Investigating the role of constrained CVT and CVT in HIPO inverse planning for HDR brachytherapy of prostate cancer.

The purpose of this study is to investigate the role of the centroidal Voronoi tessellation (CVT) and constrained CVT (CCVT) in inverse planning in combination with the Hybrid Inverse Planning Optimization (HIPO) algorithm in HDR brachytherapy of prostate cancer. HIPO implemented in Oncentra© Prostate treatment planning system, is used for three-dimensional (3D)-ultrasound-based intraoperative treatment planning in high dose rate brachytherapy. HIPO utilizes a hybrid iterative process to determine the most appropriate placement of a given number of catheters to fulfil predefined dose-volume constraints. The main goals of the current investigation were to identify a way of improving the performance of HIPO inverse planning; accelerating the HIPO, and to evaluate the effect of the two CVT-based initialization methods on the dose distribution in the sub-region of prostate that is not accessible by catheters, when trying to avoid perforation of urethra. We implemented the CVT algorithm to generate initial catheter configurations before the initialization of the HIPO algorithm. We introduced the CCVT algorithm to improve the dose distribution to the sub-volume of prostate within the bounding box of the urethra contours including its upper vertical extension (U-P). For the evaluation, we considered a total of 15 3D ultrasound-based HDRBT prostate implants. Execution time and treatment plan quality were evaluated based on the dose-volume histograms of prostate (PTV), its sub-volume U-P, and organs at risk (OARs). Furthermore, the conformity index COIN, the homogeneity index HI and the complication-free tumor control probability (P+ ) were used for our treatment plan comparisons. Finally, the plans with the recommended HIPO execution mode were compared to the clinically used intraoperative pre-plans. The plan quality achieved with CCVT-based HIPO initialization was superior to the default HIPO initialization method. Focusing on the U-P sub-region of the prostate, the CCVT method resulted in a significant improvement of all dosimetric indices compared to the default HIPO, when both were executed in the adaptive mode. For that recommended HIPO execution mode, and for U-P, CCVT demonstrated in general higher dosimetric indices than CVT. Additionally, the execution time of CCVT initialized HIPO was lower compared to both alternative initialization methods. This is also valid for the values of the aggregate objective function with the differences to the default initialization method being highly significant. Paired non-parametric statistical tests (Wilcoxon signed-rank) showed a significant improvement of dose-volume indices, COIN and P+ for the plans generated by the CCVT-based catheter configuration initialization in HIPO compared to the default HIPO initialization process. Furthermore, in ten out of 15 cases, the CCVT-based HIPO plans fulfilled all the clinical dose-volume constraints in a single trial without any need for further catheter position adaption. HIPO with CCVT-based initialization demonstrates better performance regarding the aggregate objective function and convergence when compared to the CVT-based and default catheter configuration initialization methods. This improved performance of HIPO inverse planning is clearly not at the cost of the dosimetric and radiobiologically evaluated plan quality. We recommend the use of the CCVT method for HIPO initialization especially in the adaptive planning mode.

Evaluation of various common prostate IMRT techniques based on estimated tumor control and normal tissue complication probabilities in correlation with patients anatomical parameters derived from the CT scans

Abstract Background: The relationship between the prostate IMRT techniques and patients anatomical parameters has been rarely investigated. Objective: to evaluate various prostate IMRT techniques based on tumor control and normal tissue complication probability (TCP and NTCP) values and also the correlation of such techniques with patients anatomical parameters. Methods: Four IMRT techniques (9, 7 and 5 fields and also automatic) were planned on the CT scans of 63 prostate cancer patients. The sum of distances between the organs at risk (OARs) and target tissue and also their average joint volumes were measured and assumed as anatomical parameters. Selected dosimetric and radiobiological parameters (TCP and NTCP) values were compared among various techniques and the correlation with the above anatomical parameters were assessed using Pearsons’ correlation. Results: High correlations were found between the dosimetric/radiobiological parameters of OARs with the joint volumes and with the distances between the OARs and target tissue in all the techniques. The TCP and complication free tumor control probability (P+) values were decreased with increasing the joint volume and decreasing the distances between the OARs and target tissue (as poly-nominal functions). The NTCP values were increased with increasing the joint volumes and decreasing the distances (3-degree poly-nominal functions). For the low percent joint volumes (<20%) and high distances (>7 cm), The TCP, NTCP and P+ showed no statistical differences between various techniques (P-value>0.07). However, 9 and 7 fields techniques indicated better radiobiological results (P-value<0.05) in almost other ranges (>20% joint volumes and <7 cm distances). Conclusion: Based on our results, it would be possible to compare radiobiological effects of various common IMRT techniques and choose the best one regarding to patients anatomical parameters derived from the CT scans.

Dosimetric and Radiobiological Evaluation of Patient Setup Accuracy in Head-and-neck Radiotherapy Using Daily Computed Tomography-on-rails-based Corrections.

Introduction:This study evaluates treatment plans aiming at determining the expected impact of daily patient setup corrections on the delivered dose distribution and plan parameters in head-and-neck radiotherapy.Materials and Methods:In this study, 10 head-and-neck cancer patients are evaluated. For the evaluation of daily changes of the patient internal anatomy, image-guided radiation therapy based on computed tomography (CT)-on-rails was used. The daily-acquired CT-on-rails images were deformedly registered to the CT scan that was used during treatment planning. Two approaches were used during data analysis (“cascade” and “one-to-all”). The dosimetric and radiobiological differences of the dose distributions with and without patient setup correction were calculated. The evaluation is performed using dose–volume histograms; the biologically effective uniform dose () and the complication-free tumor control probability (P+) were also calculated. The dose–response curves of each target and organ at risk (OAR), as well as the corresponding P+ curves, were calculated.Results:The average difference for the “one-to-all” case is 0.6 ± 1.8 Gy and for the “cascade” case is 0.5 ± 1.8 Gy. The value of P+ was lowest for the cascade case (in 80% of the patients).Discussion:Overall, the lowest PI is observed in the one-to-all cases. Dosimetrically, CT-on-rails data are not worse or better than the planned data.Conclusions:The differences between the evaluated “one-to-all” and “cascade” dose distributions were small. Although the differences of those doses against the “planned” dose distributions were small for the majority of the patients, they were large for given patients at risk and OAR.

Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols

The purpose of this study is to evaluate the clinical efficacy of both step-and-shoot IMRT and 3D-Conformal Radiation Therapy modalities (CRT) in treating prostate cancer using radiobiological measures. Another aim was to estimate the risks for developing secondary malignancies in bladder and rectum due to radiotherapy from the corresponding modalities. The treatment plans of ten prostate cancer patients were developed using IMRT and CRT. For the IMRT plans, two beam energies and two treatment protocols were used (the RTOG 0415 and a most restrictive one proposed by Fox Chase Cancer Center (FCCC)). For the evaluation of these plans, the complication-free tumor control probability, the total probability of injury, the total probability of control/benefit, and the biologically effective uniform dose were employed. Furthermore, based on the dosimetric data of IMRT and CRT, the risk for secondary malignancies was calculated for bladder and rectum. The average risk for secondary malignancy was lower for the bladder (0.37%) compared to the rectum (0.81%) based on all the treatment plans of the ten prostate cancer patients. The highest average risk for secondary malignancy for bladder and rectum was for the CRT-6X modality (0.46% and 1.12%, respectively) and the lowest was for the IMRT RTOG-18X modality (0.33% and 0.56%, respectively). The ≥ Grade 2 LENT/SOMA response probability was lower for the bladder than for the rectum in all the plans. For the bladder the highest average value was for the IMRT RTOG-18X (0.9%) and the lowest was for the CRT-18X modality (0.1%). For the rectum, the highest average value was for the IMRT RTOG-6X (11.9%) and the lowest was for the IMRT FCCC-18X modality (2.2%). By using radiobiological measures it is shown that the IMRT FCCC plans had the lowest risks for normal tissue complications, whereas the IMRT RTOG had the highest. Regarding the risk for secondary malignancies, the CRT plans showed the highest values for both bladder and rectum.

SU‐F‐T‐680: Radiobiological Analysis of the Impact of Daily Patient Deformation and Setup Variations Through the Use of the Cone Beam CT and Deformable Image Registration in Lung Cancer IMRT

Purpose:To estimate the dose distributions delivered to the patient in each treatment fraction using deformable image registration (DIR) and assess the radiobiological impact of the inter‐fraction variations due to patient deformation and setup.Methods:The work is based on the cone beam CT (CBCT) images and treatment plans of two lung cancer patients. Both patients were treated with intensity modulated radiation therapy (IMRT) to 66Gy in 2Gy/fraction. The treatment plans were exported from the treatment planning system (TPS) to the Velocity AI where DIR was performed and the same deformation matrix was used for the deformation of the planned dose distribution and organ contours to each CBCT dataset. A radiobiological analysis was performed based on the radiobiological parameters of the involved organs at risk (OARs) and planning target volume (PTV). Using the complication free tumor control probability (P+) index, differences in P+ were observed between each CBCT as well as between CBCT and planning dose distributions.Results:The optimal CBCT P? values ranged from 91.6 % to 94.8 % for patient #1 and from 88.8 % to 90.6 % for patient #2. At the dose level of the clinical prescription, the CBCT P+ values ranged from 80.3% to 80.7% for patient #1 and from 80.7% to 81.0% for the patient #2. The planning CT P+ values were 81.0% and 80.7% for the two patients, respectively. These differences emphasize the significance of using the radiobiological analysis when assessing changes in the dose distribution due to the tumor motion and lung deformations.Conclusion:Daily setup variations yield to differences in the actual dose delivered versus the planned one. The observed differences were rather small when only looking at the dosimetric comparison of the dose distributions, however the radiobiology analysis was able to detect clinically relevant differences among the studied dose distributions.

Evaluation of the generalized gamma as a tool for treatment planning optimization

Purpose: The aim of that work is to study the theoretical behavior and merits of the Generalized Gamma (generalized dose response gradient) as well as to investigate the usefulness of this concept in practical radiobiological treatment planning. Methods: In this study, the treatment planning system RayStation 1.9 (Raysearch Laboratories AB, Stockholm, Sweden) was used. Furthermore, radiobiological models that provide the tumor control probability (TCP), normal tissue complication probability (NTCP), complication-free tumor control probability ( P + ) and the Generalized Gamma were employed. The Generalized Gammas of TCP and NTCP, respectively were calculated for given heterogeneous dose distributions to different organs in order to verify the TCP and NTCP computations of the treatment planning system. In this process, a treatment plan was created, where the target and the organs at risk were included in the same ROI in order to check the validity of the system regarding the objective function P + and the Generalized Gamma. Subsequently, six additional treatment plans were created with the target organ and the organs at risk placed in the same or different ROIs. In these plans, the mean dose was increased in order to investigate the behavior of dose change on tissue response and on Generalized Gamma before and after the change in dose. By theoretically calculating these quantities, the agreement of different theoretical expressions compared to the values that the treatment planning system provides could be evaluated. Finally, the relative error between the real and approximate response values using the Poisson and the Probit models, for the case of having a target organ consisting of two compartments in a parallel architecture and with the same number of clonogens could be investigated and quantified. Results: The computations of the RayStation regarding the values of the Generalized Gamma and the objective function ( P + ) were verified by using an independent software. Furthermore, it was proved that after a small change in dose, the organ that is being affected most is the organ with the highest Generalized Gamma. Apart from that, the validity of the theoretical expressions that describe the change in response and the associated Generalized Gamma was verified but only for the case of small change in dose. Especially for the case of 50% TCP and NTCP, the theoretical values (Δ P approx. ) and those calculated by the RayStation show close agreement, which proves the high importance of the D 50 parameter in specifying clinical response levels. Finally, the presented findings show that the behavior of Δ P approx. looks sensible because, for both of the models that were used (Poisson and Probit), it significantly approaches the real Δ P around the region of 37% and 50% response. The present study managed to evaluate the mathematical expression of Generalized Gamma for the case of non-uniform dose delivery and the accuracy of the RayStation to calculate its values for different organs. Conclusion: A very important finding of this work is the establishment of the usefulness and clinical relevance of Generalized Gamma. That is because it gives the planner the opportunity to precisely determine which organ will be affected most after a small increase in dose and as a result an optimal treatment plan regarding tumor control and normal tissue complications can be found.

γ+ index: A new evaluation parameter for quantitative quality assurance

PurposeThe accuracy of dose delivery and the evaluation of differences between calculated and delivered dose distributions, has been studied by several groups. The aim of this investigation is to extend the gamma index by including radiobiological information and to propose a new index that we will here forth refer to as the gamma plus (γ+). Furthermore, to validate the robustness of this new index in performing a quality control analysis of an IMRT treatment plan using pure radiobiological measures such as the biologically effective uniform dose (D¯¯) and complication-free tumor control probability (P+). Material and methodsA new quality assurance index, the (γ+), is proposed based on the theoretical concept of gamma index presented by Low et al. (1998). In this study, the dose difference, including the radiobiological dose information (biological effective dose, BED) is used instead of just the physical dose difference when performing the γ+ calculation. An in-house software was developed to compare different dose distributions based on the γ+ concept. A test pattern for a two-dimensional dose comparison was built using the in-house software platform. The γ+ index was tested using planar dose distributions (exported from the treatment planning system) and delivered (film) dose distributions acquired in a solid water phantom using a test pattern and a theoretical clinical case. Furthermore, a lung cancer case for a patient treated with IMRT was also selected for the analysis. The respective planar dose distributions from the treatment plan and the film were compared based on the γ+ index and were evaluated using the radiobiological measures of P+ and D¯¯. ResultsThe results for the test pattern analysis indicate that the γ+ index distributions differ from those of the gamma index since the former considers radiobiological parameters that may affect treatment outcome. For the theoretical clinical case, it is observed that the γ+ index varies for different treatment parameters (e.g. dose per fraction). The dose area histogram (DAH) from the plan and film dose distributions are associated with P+ values of 50.8% and 49.0%, for a D¯¯ to the target of 54.0Gy and 53.3Gy, respectively. ConclusionThe γ+ index shows advantageous properties in the quantitative evaluation of dose delivery and quality control of IMRT treatments because it includes information about the expected responses and radiobiological doses of the individual tissues.

Radiobiologic comparison of helical tomotherapy, intensity modulated radiotherapy, and conformal radiotherapy in treating lung cancer accounting for secondary malignancy risks

The aim of the present study is to examine the importance of using measures to predict the risk of inducing secondary malignancies in association with the clinical effectiveness of treatment plans in terms of tumor control and normal tissue complication probabilities. This is achieved by using radiobiologic parameters and measures, which may provide a closer association between clinical outcome and treatment delivery. Overall, 4 patients having been treated for lung cancer were examined. For each of them, 3 treatment plans were developed based on the helical tomotherapy (HT), multileaf collimator-based intensity modulated radiation therapy (IMRT), and 3-dimensional conformal radiation therapy (CRT) modalities. The different plans were evaluated using the complication-free tumor control probability (p+), the overall probability of injury (pI), the overall probability of control/benefit (pB), and the biologically effective uniform dose (D¯¯). These radiobiologic measures were used to develop dose-response curves (p-D¯¯ diagram), which can help to evaluate different treatment plans when used in conjunction with standard dosimetric criteria. The risks for secondary malignancies in the heart and the contralateral lung were calculated for the 3 radiation modalities based on the corresponding dose-volume histograms (DVHs) of each patient. Regarding the overall evaluation of the different radiation modalities based on the p+ index, the average values of the HT, IMRT, and CRT are 67.3%, 61.2%, and 68.2%, respectively. The corresponding average values of pB are 75.6%, 70.5%, and 71.0%, respectively, whereas the average values of pI are 8.3%, 9.3%, and 2.8%, respectively. Among the organs at risk (OARs), lungs show the highest probabilities for complications, which are 7.1%, 8.0%, and 1.3% for the HT, IMRT, and CRT modalities, respectively. Similarly, the biologically effective prescription doses (DB¯¯) for the HT, IMRT, and CRT modalities are 64.0, 60.9, and 60.8Gy, respectively. Regarding the risk for secondary cancer, for the heart, the lowest average risk is produced by IMRT (0.10%) compared with the HT (0.17%) and CRT (0.12%) modalities, whereas the 3 radiation modalities show almost equivalent results regarding the contralateral lung (0.8% for HT, 0.9% for IMRT, and 0.9% for CRT). The use of radiobiologic parameters in the evaluation of different treatment plans and estimation of their expected clinical outcome is shown to provide very useful clinical information. The radiobiologic analysis of the response probabilities showed that different radiation modalities appear to be more effective in different patient geometries and target sizes and locations. Furthermore, there is not a clear pattern between the plans that appear to be more effective for the treatment and the risk of secondary malignancy. It seems that radiobiologically based treatment planning taking into account the risk of secondary cancer can be established as an effective clinical tool for a more clinically relevant treatment optimization.

Comparison of Different Fractionation Schedules Toward a Single Fraction in High-Dose-Rate Brachytherapy as Monotherapy for Low-Risk Prostate Cancer Using 3-Dimensional Radiobiological Models

The aim of the present study was the investigation of different fractionation schemes to estimate their clinical impact. For this purpose, widely applied radiobiological models and dosimetric measures were used to associate their results with clinical findings. The dose distributions of 12 clinical high-dose-rate brachytherapy implants for prostate were evaluated in relation to different fractionation schemes. The fractionation schemes compared were: (1) 1 fraction of 20 Gy; (2) 2 fractions of 14 Gy; (3) 3 fractions of 11 Gy; and (4) 4 fractions of 9.5 Gy. The clinical effectiveness of the different fractionation schemes was estimated through the complication-free tumor control probability (P+), the biologically effective uniform dose, and the generalized equivalent uniform dose index. For the different fractionation schemes, the tumor control probabilities were 98.5% in 1×20 Gy, 98.6% in 2×14 Gy, 97.5% in 3×11 Gy, and 97.8% in 4×9.5 Gy. The corresponding P+ values were 88.8% in 1×20 Gy, 83.9% in 2×14 Gy, 86.0% in 3×11 Gy, and 82.3% in 4×9.5 Gy. With use of the fractionation scheme 4×9.5 Gy as reference, the isoeffective schemes regarding tumor control for 1, 2, and 3 fractions were 1×19.68 Gy, 2×13.75 Gy, and 3×11.05 Gy. The optimum fractionation schemes for 1, 2, 3, and 4 fractions were 1×19.16 Gy with a P+ of 91.8%, 2×13.2 Gy with a P+ of 89.6%, 3×10.6 Gy with a P+ of 88.4%, and 4×9.02 Gy with a P+ of 86.9%. Among the fractionation schemes 1×20 Gy, 2×14 Gy, 3×11 Gy, and 4×9.5 Gy, the first scheme was more effective in terms of P+. After performance of a radiobiological optimization, it was shown that a single fraction of 19.2 to 19.7 Gy (average 19.5 Gy) should produce at least the same benefit as that given by the 4×9.5 Gy scheme, and it should reduce the expected total complication probability by approximately 40% to 55%.

An assessment of PTV margin based on actual accumulated dose for prostate cancer radiotherapy

The purpose of this work is to present the results of a margin reduction study involving dosimetric and radiobiologic assessment of cumulative dose distributions, computed using an image guided adaptive radiotherapy based framework. Eight prostate cancer patients, treated with 7–9, 6 MV, intensity modulated radiation therapy (IMRT) fields, were included in this study. The workflow consists of cone beam CT (CBCT) based localization, deformable image registration of the CBCT to simulation CT image datasets (SIM-CT), dose reconstruction and dose accumulation on the SIM-CT, and plan evaluation using radiobiological models. For each patient, three IMRT plans were generated with different margins applied to the CTV. The PTV margin for the original plan was 10 mm and 6 mm at the prostate/anterior rectal wall interface (10/6 mm) and was reduced to: (a) 5/3 mm, and (b) 3 mm uniformly. The average percent reductions in predicted tumor control probability (TCP) in the accumulated (actual) plans in comparison to the original plans over eight patients were 0.4%, 0.7% and 11.0% with 10/6 mm, 5/3 mm and 3 mm uniform margin respectively. The mean increase in predicted normal tissue complication probability (NTCP) for grades 2/3 rectal bleeding for the actual plans in comparison to the static plans with margins of 10/6, 5/3 and 3 mm uniformly was 3.5%, 2.8% and 2.4% respectively. For the actual dose distributions, predicted NTCP for late rectal bleeding was reduced by 3.6% on average when the margin was reduced from 10/6 mm to 5/3 mm, and further reduced by 1.0% on average when the margin was reduced to 3 mm. The average reduction in complication free tumor control probability (P+) in the actual plans in comparison to the original plans with margins of 10/6, 5/3 and 3 mm was 3.7%, 2.4% and 13.6% correspondingly. The significant reduction of TCP and P+ in the actual plan with 3 mm margin came from one outlier, where individualizing patient treatment plans through margin adaptation based on biological models, might yield higher quality treatments.

SU-E-T-299: Sensitivity Analysis of the Radiobiological Parameters Used to Examine the Effectiveness of Different Fractionation Schedules in Prostate Cancer HDR Brachytherapy

Purpose: The aim of the present study is to evaluate the robustness of the effectiveness of different fractionation schemes of HDR brachytherapy (to be applied as monotherapy for low-risk prostate cancer) by using radiobiological models and dosimetric measures. Methods: In this study, the treatment plans of 12 patients who had undergone clinical implants for HDR brachytherapy of prostate cancer were evaluated using the response probabilities of the individual organs, the complication-free tumor control probability (P+), the total tumor control probability (PB), the total normal tissue complication probability (PI), the biologically effective uniform dose (BEUD) and the generalized equivalent uniform dose (gEUD) as measures. These indices use the D50, γ, s, α/β and alpha radiobiological parameters together with the corresponding tissue DVH data. The values of those parameters were varied around their reference values in order to examine the impact of their uncertainty on the values of the radiobiological measures in the evaluation of four fractionation schemes. Results: For the four examined fractionation schemes, the tumor control probabilities are 98.5% in 1×20Gy, 98.6% in 2×14Gy, 97.5% in 3×11Gy and 97.8% in 4x9.5Gy. The corresponding total normal tissue complication probabilities are 9.7% in 1×20Gy, 14.6% in 2×14Gy, 11.5% in 3×11Gy and 15.6% in 4×9.5Gy. The complication-free tumor control probabilities are 88.8% in 1x20Gy, 83.9% in 2×14Gy, 86.0% in 3×11Gy and 82.3% in 4×9.5Gy. The sensitivity analysis showed that the values of P+, PB, PI and BEUD varied by 6.1–7.3%, 5.8–9.3%, 5.6–7.2% and 7.6–9.0 Gy, respectively. Conclusion: The present analysis indicates that among the fractionation schemes of 1×20Gy, 2×14Gy, 3×11Gy and 4×9.5Gy the first scheme is more effective. The sensitivity analysis shows that the variation of the radiobiological parameters considerably affects the values of the response indices, especially the α/β parameter.

Analysis of fractionation correction methodologies for multiple phase treatment plans in radiation therapy

Radiation therapy is often delivered by multiple sequential treatment plans. For an accurate radiobiological evaluation of the overall treatment, fractionation corrections to each dose distribution must be applied before summing the three-dimensional dose matrix of each plan since the simpler approach of performing the fractionation correction to the total dose-volume histograms, obtained by the arithmetical sum of the different plans, becomes inaccurate for more heterogeneous dose patterns. In this study, the differences between these two fractionation correction methods, named here as exact (corrected before) and approximate (after summation), respectively, are assessed for different cancer types. Prostate, breast, and head and neck (HN) tumor patients were selected to quantify the differences between two fractionation correction methods (the exact vs the approximate). For each cancer type, two different treatment plans were developed using uniform (CRT) and intensity modulated beams (IMRT), respectively. The responses of the target and normal tissue were calculated using the Poisson linear-quadratic-time model and the relative seriality model, respectively. All treatments were radiobiologically evaluated and compared using the complication-free tumor control probability (P+), the biologically effective uniform dose (D) together with common dosimetric criteria. For the prostate cancer patient, an underestimation of around 14%-15% in P+ was obtained when the fractionation correction was applied after summation compared to the exact approach due to significant biological and dosimetric variations obtained between the two fractionation correction methods in the involved lymph nodes. For the breast cancer patient, an underestimation of around 3%-4% in the maximum dose in the heart was obtained. Despite the dosimetric differences in this organ, no significant variations were obtained in treatment outcome. For the HN tumor patient, an underestimation of about 5% in treatment outcome was obtained for the CRT plan as a result of an underestimation of the planning target volume control probability by about 10%. An underestimation of about 6% in the complication probability of the right parotid was also obtained. For all the other organs at risk, dosimetric differences of up to 4% were obtained but with no significant impact in the expected clinical outcome. However, for the IMRT plan, an overestimation in P+ of 4.3% was obtained mainly due to an underestimation of the complication probability of the left and right parotids (2.9% and 5.8%, respectively). The use of the exact fractionation correction method, which is applying fractionation correction on the separate dose distributions of a multiple phase treatment before their summation was found to have a significant expected clinical impact. For regions of interest that are irradiated with very heterogeneous dose distributions and significantly different doses per fraction in the different treatment phases, the exact fractionation correction method needs to be applied since a significant underestimation of the true patient outcome can be introduced otherwise.

Radiobiological Evaluation of Breast Cancer Radiotherapy Accounting for the Effects of Patient Positioning and Breathing in Dose Delivery. A Meta Analysis

In breast cancer radiotherapy, significant discrepancies in dose delivery can contribute to underdosage of the tumor or overdosage of normal tissue, which is potentially related to a reduction of local tumor control and an increase of side effects. To study the impact of these factors in breast cancer radiotherapy, a meta analysis of the clinical data reported by Mavroidis et al. (2002) in Acta Oncol (41:471-85), showing the patient setup and breathing uncertainties characterizing three different irradiation techniques, were employed. The uncertainties in dose delivery are simulated based on fifteen breast cancer patients (5 mastectomized, 5 resected with negative node involvement (R-) and 5 resected with positive node involvement (R1)), who were treated by three different irradiation techniques, respectively. The positioning and breathing effects were taken into consideration in the determination of the real dose distributions delivered to the CTV and lung in each patient. The combined frequency distributions of the positioning and breathing distributions were obtained by convolution. For each patient the effectiveness of the dose distribution applied is calculated by the Poisson and relative seriality models and a set of parameters that describe the dose-response relations of the target and lung. The three representative radiation techniques are compared based on radiobiological measures by using the complication-free tumor control probability, P(+) and the biologically effective uniform dose, (BEUD)concepts. For the Mastectomy case, the average P(+) values of the planned and delivered dose distributions are 93.8% for a (BEUD)(CTV) of 51.8 Gy and 85.0% for a (BEUD)(CTV) of 50.3 Gy, respectively. The respective total control probabilities, P(B) values are 94.8% and 92.5%, whereas the corresponding total complication probabilities, P(1) values are 0.9% and 7.4%. For the R- case, the average P(+) values are 89.4% for a (BEUD)(CTV) of 48.9 Gy and 88.6% for a (BEUD)(CTV) of 49.2 Gy and 85.5% for a (BEUD)(CTV) of 49.1 Gy, respectively. The respective PB values are 90.2% and 90.1%, whereas the corresponding P(+) values are 4.1% and 4.6%. The combined effects of positioning uncertainties and breathing can introduce a significant deviation between the planned and delivered dose distributions in lung in breast cancer radiotherapy. The positioning and breathing uncertainties do not affect much the dose distribution to the CTV. The simulated delivered dose distributions show larger lung complication probabilities than the treatment plans. This means that in clinical practice the true expected complications are underestimated. Radiation pneumonitis of Grade 1-2 is more frequent and any radiotherapy optimization should use this as a more clinically relevant endpoint.

The radiobiological P+ index for pretreatment plan assessment with emphasis on four‐dimensional radiotherapy modalities

Radiation treatment modalities will continue to emerge that promise better clinical outcomes albeit technologically challenging to implement. An important question facing the radiotherapy community then is the need to justify the added technological effort for the clinical return. Mobile tumor radiotherapy is a typical example, where 4D tumor tracking radiotherapy (4DTRT) has been proposed over the simpler conventional modality for better results. The modality choice per patient can depend on a wide variety of factors. In this work, we studied the complication-free tumor control probability (P(+)) index, which combines the physical complexity of the treatment plan with the radiobiological characteristics of the clinical case at hand and therefore found to be useful in evaluating different treatment techniques and estimating the expected clinical effectiveness of different radiation modalities. 4DCT volumes of 18 previously treated lung cancer patients with tumor motion and size ranging from 2 mm to 15 mm and from 4 cc to 462 cc, respectively, were used. For each patient, 4D treatment plans were generated to extract the 4D dose distributions, which were subsequently used with clinically derived radiobiological parameters to compute the P(+) index per modality. The authors observed, on average, a statistically significant increase in P(+) of 3.4% ± 3.8% (p < 0.003) in favor of 4DTRT. There was high variability among the patients with a <0.5% up to 13.4% improvement in P(+). The observed variability in the improvement of the clinical effectiveness suggests that the relative benefit of tracking should be evaluated on a per patient basis. Most importantly, this variability could be effectively captured in the computed P(+). The index can thus be useful to discriminate and hence point out the need for a complex modality like 4DTRT over another. Besides tumor mobility, a wide range of other factors, e.g., size, location, fractionation, etc., can affect the relative benefits. Application of the P(+) objective is a simple and effective way to combine these factors in the evaluation of a treatment plan.

Automated Volumetric Modulated Arc Therapy Treatment Planning for Stage III Lung Cancer: How Does It Compare With Intensity-Modulated Radio Therapy?

To compare the quality of volumetric modulated arc therapy (VMAT) or intensity-modulated radiation therapy (IMRT) plans generated by an automated inverse planning system with that of dosimetrist-generated IMRT treatment plans for patients with stage III lung cancer. Two groups of 8 patients with stage III lung cancer were randomly selected. For group 1, the dosimetrists spent their best effort in designing IMRT plans to compete with the automated inverse planning system (mdaccAutoPlan); for group 2, the dosimetrists were not in competition and spent their regular effort. Five experienced radiation oncologists independently blind-reviewed and ranked the three plans for each patient: a rank of 1 was the best and 3 was the worst. Dosimetric measures were also performed to quantitatively evaluate the three types of plans. Blind rankings from different oncologists were generally consistent. For group 1, the auto-VMAT, auto-IMRT, and manual IMRT plans received average ranks of 1.6, 2.13, and 2.18, respectively. The auto-VMAT plans in group 1 had 10% higher planning tumor volume (PTV) conformality and 24% lower esophagus V70 (the volume receiving 70 Gy or more) than the manual IMRT plans; they also resulted in more than 20% higher complication-free tumor control probability (P+) than either type of IMRT plans. The auto- and manual IMRT plans in this group yielded generally comparable dosimetric measures. For group 2, the auto-VMAT, auto-IMRT, and manual IMRT plans received average ranks of 1.55, 1.75, and 2.75, respectively. Compared to the manual IMRT plans in this group, the auto-VMAT plans and auto-IMRT plans showed, respectively, 17% and 14% higher PTV dose conformality, 8% and 17% lower mean lung dose, 17% and 26% lower mean heart dose, and 36% and 23% higher P+. mdaccAutoPlan is capable of generating high-quality VMAT and IMRT treatment plans for stage III lung cancer. Manual IMRT plans could achieve quality similar to auto-IMRT plans if best effort was spent.

PO-0782 TARGET DELINEATION IN RECTAL CANCER RADIOTHERAPY: RADIOBIOLOGICAL CONSEQUENCES OF ATLAS IMPLEMENTATION

Purpose/Objective: Target volume delineation variability is a major concern for cooperative groups and multi-center clinical trials. The aim of this study is to ascertain the dosimetric and radiobiologic impact of using a consensus guideline target volume delineation atlas regarding the reduction of inter-observer target delineation variation. Materials and Methods: Using a representative case and target volume delineation instructions and a standardized case derived from a proposed SWOG IMRT rectal cancer clinical trial, gross tumor volume (GTV), and clinical target volumes (CTV) were contoured by 13 physician observers. Observers were then randomly assigned to receipt (atlas) or non-receipt (control) of a cooperative-group supported consensus guideline/atlas for anorectal cancers, then instructed to re-contour the same case. PTV margin expansion and plan optimization were performed using standardized parameters from the study protocol, using sequential dynamic arc IMRT. The calculation of tumor control probability (TCP), normal tissue complication probability (NTCP), complication-free tumor control probability (P+), biologically effective uniform dose and generalized equivalent uniform dose (gEUD) was performed for all the plans. Grouped Atlas/Control TCP values were compared using Wilcoxon rank sum test and Levene’s test of variance equality for the grouped cohort GTV, CTV, and PTV inter-observer TCP grand mean (TCP’; i.e. the mean of all interobserver TCP calculations) Results: Although the variation of P+ among the members of the atlasassisted group (0.8%) was larger than that of the control group (0.5%) initially, in the second delineation the reduction of the deviation was lower for the atlas-assisted group (0.7% against 1.0%). Atlas implementation resulted in mean±SD P+ of 85.7±0.8, 78.1±2.0, and 76.8±1.1 for GTV, CTV, and PTV respectively, while for the control group the equivalent values were 85.1±0.6, 78.1±1.3, 76.4±0.6. Reduction in TCP’ variation between plans was observed with atlas use for CTV and PTV ROIs, with a reduction in TCP’ difference between plans from 13.7% (pre-atlas) to <1% (post atlas) for CTV, and from 32.5% (pre-atlas) to 7.7% (post-atlas) [p<0.01]. For the control cohort, no statistically significant differential in grand mean difference was noted, with TCP’ values for CTV of 10.2 and 6.5%, and PTV of 23.6% and 28.2% on sequential recontouring. A <1% TCP’ difference was observed in TCP for both atlas or control cohorts, suggesting minimal influence of the atlas upon GTV definition. Conclusions: The use of a visual atlas and consensus treatment guidelines in the development of rectal cancer IMRT treatment plans resulted in at least 4-fold reduction in the inter-observer dependent radiobiologic variability in TCP’ for CTV and PTV volumes. The observed differences in tumor control probability for the CTV and PTV due to the use of the atlas are potentially clinically meaningful, and suggest routine atlas implementation is a key component for reducing potential confounders of outcome in conformal radiotherapy trials. PO-0783 CONE BEAM CT BASED MARGIN GENERATION: DO WE REQUIRE DIFFERENT MARGINS FOR SUB-REGIONS OF HEAD AND NECK? A. Budrukkar 1 , R. Krishnatry 1 , K. Rajput 2 , S. Yadadu 2 , B. George 2 , S. Chaudhari 2 , S. Ghosh Laskar 1 , V. Murthy 1 , T. Gupta 1 , J. Agarwal 1

Investigating the Clinical Aspects of Using CT vs. CT-MRI Images during Organ Delineation and Treatment Planning in Prostate Cancer Radiotherapy

In order to apply highly conformal dose distributions, which are characterized by steep dose fall-offs, it is necessary to know the exact target location and extension. This study aims at evaluating the impact of using combined CT-MRI images in organ delineation compared to using CT images alone, on the clinical results. For 10 prostate cancer patients, the respective CT and MRI images at treatment position were acquired. The CTV was delineated using the CT and MRI images, separately, whereas bladder and rectum were delineated using the CT images alone. Based on the CT and MRI images, two CTVs were produced for each patient. The mutual information algorithm was used in the fusion of the two image sets. In this way, the structures drawn on the MRI images were transferred to the CT images in order to produce the treatment plans. For each set of structures of each patient, IMRT and 3D-CRT treatment plans were produced. The individual treatment plans were compared using the biologically effective uniform dose () and the complication-free tumor control probability (P(+)) concepts together with the DVHs of the targets and organs at risk and common dosimetric criteria. For the IMRT treatment, at the optimum dose level of the average CT and CT-MRI delineated CTV dose distributions, the P(+) values are 74.7% in both cases for a of 91.5 Gy and 92.1 Gy, respectively. The respective average total control probabilities, PB are 90.0% and 90.2%, whereas the corresponding average total complication probabilities, P(I) are 15.3% and 15.4%. Similarly, for the 3D-CRT treatment, the average P(+) values are 42.5% and 46.7%, respectively for a of 86.4 Gy and 86.7 Gy, respectively. The respective average P(B) values are 80.0% and 80.6%, whereas the corresponding average P(I) values are 37.4% and 33.8%, respectively. For both radiation modalities, the improvement mainly stems from the better sparing of rectum. According to these results, the expected clinical effectiveness of IMRT can be increased by a maximum ΔP(+) of around 0.9%, whereas of 3D-CRT by about 4.2% when combined CT-MRI delineation is performed instead of using CT images alone. It is apparent that in both IMRT and 3D-CRT radiation modalities, the better knowledge of the CTV extension improved the produced dose distribution. It is shown that the CTV is irradiated more effectively, while the complication probabilities of bladder and rectum, which is the principal organs at risk, are lower in the CT-MRI based treatment plans.