Rectal Normal Tissue Complication Probability Research Articles

A Novel Framework for Thermoradiotherapy Treatment Planning

Thermoradiotherapy combines radiation therapy with hyperthermia to increase therapeutic effectiveness. Currently, both modalities are optimized separately and in state-of-the-art research the enhanced therapeutic effect is evaluated using equivalent radiation dose in 2-Gy fractions (EQD2). This study proposes a novel thermoradiotherapy treatment planning framework with voxelwise EQD2 radiation therapy optimizing including thermal radiosensitization and direct thermal cytotoxicity. To demonstrate proof-of-concept of the planning framework, 3 strategies consisting of 20 radiation therapy fractions were planned for 4 prostate cancer cases with substantially different temperature distributions: (1) Conventional radiation therapy plan of 60 Gy combined with 4 hyperthermia sessions (RT60 + HT), (2) standalone uniform dose escalation to 68 Gy without hyperthermia (RT68), and (3) uniform target EQD2 that maximizes the tumor control probability (TCP) accounting for voxelwise thermal effects of 4 hyperthermia sessions without increasing normal tissue doses (RTHT + HT). Assessment included dose, EQD2, TCP, and rectal normal tissue complication probability (NTCP), alongside robustness analyses for TCP and NTCP against parameter uncertainties. The estimated TCP of around 76% for RT60 without hyperthermia was increased to an average of 85.9% (range, 81.3%-90.5%) for RT60 + HT, 92.5% (92.4%-92.5%) for RT68, and 94.4% (91.7%-96.6%) for RTHT + HT. The corresponding averaged rectal NTCPs were 8.7% (7.9%-10.0%), 14.9% (13.8%-17.1%), and 8.4% (7.5%-9.7%), respectively. RT68 and RTHT + HT exhibited slightly enhanced TCP robustness against parameter uncertainties compared with RT60 + HT, and RT68 presented higher and less robust rectal NTCP values compared with the other planning strategies. This study introduces an innovative thermoradiotherapy planning approach, integrating thermal effects into EQD2-based radiation therapy optimization. Results demonstrate an ability to achieve enhanced and uniform target EQD2 and TCP across various temperature distributions without elevating normal tissue EQD2 or NTCP compared with conventional methods. Although promising for improving clinical outcomes, realizable enhancements depend on accurate tumor- and tissue-specific data and precise quantification of hyperthermic effects, which are seamlessly integrable in the planning framework as they emerge.

Evaluation of the clinical impact of the differences between planned and delivered dose in prostate cancer radiotherapy based on CT-on-rails IGRT and patient-reported outcome scores.

To estimate the clinical impact of differences between delivered and planned dose using dose metrics and normal tissue complication probability (NTCP) modeling. Forty-six consecutive patients with prostate adenocarcinoma between 2010 and 2015 treated with intensity-modulated radiation therapy (IMRT) and who had undergone computed tomography on rails imaging were included. Delivered doses to bladder and rectum were estimated using a contour-based deformable image registration method. The bladder and rectum NTCP were calculated using dose-response parameters applied to planned and delivered dose distributions. Seven urinary and gastrointestinal symptoms were prospectively collected using the validated prostate cancer symptom indices patient reported outcome (PRO) at pre-treatment, weekly treatment, and post-treatment follow-up visits. Correlations between planned and delivered doses against PRO were evaluated in this study. Planned mean doses to bladder and rectum were 44.9 ± 13.6 Gy and 42.8 ± 7.3 Gy, while delivered doses were 46.1 ± 13.4 Gy and 41.3 ± 8.7 Gy, respectively. D10cc for rectum was 64.1 ± 7.6 Gy for planned and 60.1 ± 9.3 Gy for delivered doses. NTCP values of treatment plan were 22.3% ± 8.4% and 12.6% ± 5.9%, while those for delivered doses were 23.2% ± 8.4% and 9.9% ± 8.3% for bladder and rectum, respectively. Seven of 25 patients with follow-up data showed urinary complications (28%) and three had rectal complications (12%). Correlations of NTCP values of planned and delivered doses with PRO follow-up data were random for bladder and moderate for rectum (0.68 and 0.67, respectively). Sensitivity of bladder to clinical variations of dose accumulation indicates that an automated solution based on a DIR that considers inter-fractional organ deformation could recommend intervention. This is intended to achieve additional rectum sparing in cases that indicate higher than expected dose accumulation early during patient treatment in order to prevent acute severity of bowel symptoms.

Dosimetric feasibility of moderately hypofractionated/dose escalated radiation therapy for localised prostate cancer with intensity-modulated proton beam therapy using simultaneous integrated boost (SIB-IMPT) and impact of hydrogel prostate-rectum spacer

PurposeTo examine the dosimetric feasibility of hypofractionated/dose escalated radiation therapy in patients with localized prostate carcinoma using simultaneous integrated boost intensity-modulated proton beam therapy (SIB-IMPT) in absence or presence of prostate-rectum spacer.MethodsIMPT technique was implemented in 23 patients with intermediate- and high-risk prostate cancer treated at West German Proton Therapy Centre from March 2016 till June 2018, using SIB technique prescribing 60 GyRBE and 72 GyRBE in 30 fractions to PTV1 (prostate and seminal vesicle) and PTV2 boost (prostate and proximal seminal vesicle), respectively. In 15 patients, a transperineal injection of hydrogel was applied prior to radiotherapy to increase the distance between prostate and rectum. Planning and all treatments were performed with a 120 ml fluid-filled endorectal balloon customised daily for each patient. For each patient, 2 lateral IMPT beams were implemented taking a field-specific range uncertainty (RU) into account. Dose volume histograms (DVH) were analyzed for PTV2, PTV2 with range uncertainty margin (PTV2RU), rectum, bladder, right/left femoral heads, and penile bulb. For late rectal toxicities, the normal tissue complication probabilities (NTCP) were calculated using different biological models. A DVH- and NTCP-based dosimetric comparison was carried out between non-spacer and spacer groups.ResultsFor the 23 patients, high-quality plans could be achieved for target volume and for other organs at risk (OARs). For PTV2, the V107% was 0% and the Dmax did not exceed 106.2% of the prescribed dose. The volume PTV2RU covered by 95% of the dose ranged from 96.16 to 99.95%. The conformality index for PTV2RU was 1.12 ± 0.057 and the homogeneity index (HI) was 1.04 ± 0.014. Rectum Dmax and rectal volume receiving 73–50 Gy could be further reduced for the spacer-group. Significant reductions in mean and median rectal NTCPs (stenosis/necrosis, late rectal bleeding ≥ 2, and late rectal toxicities ≥ 3) were predicted for the spacer group in comparison to the non-spacer group.ConclusionHypofractionated/dose escalated radiotherapy with SIB-IMPT is dosimetrically feasible. Further reduction of the rectal volumes receiving high and medium dose levels (73–50 Gy) and rectal NTCP could be achieved through injection of spacers between rectum and prostate.

Photon beam energy dependent single-arc volumetric modulated arc optimization.

The purpose of this work was to present a new single-arc mixed photon (6&18MV) VMAT (SAMP) optimization framework that concurrently optimizes for two photon energies with corresponding partial arc lengths. Owing to simultaneous optimization of energy dependent intensity maps and corresponding arc locations, the proposed model poses nonlinearity. Unique relaxation constraints based on McCormick approximations were introduced for linearization. Energy dependent intensity maps were then decomposed to generate apertures. Feasibility of the proposed framework was tested on a sample of ten prostate cancer cases with lateral separation ranging from 34 cm (case no.1) to 52cm (case no.6). The SAMP plans were compared against single energy (6MV) VMAT (SE) plans through dose volume histograms (DVHs) and radiobiological parameters including normal tissue complication probability (NTCP) and equivalent uniform dose (EUD). The contribution of higher energy photon beam optimized by the algorithm demonstrated an increase for cases with a lateral separation >40cm. SAMP-VMAT notably improved bladder and rectum sparing in large size cases. Compared to single energy, SAMP-VMAT plans reduced bladder and rectum NTCP in cases with large lateral separation. With the exception of one case, SAMP-VMAT either improved or maintained femoral heads compared to SE-VMAT. SAMP-VMAT reduced the nontarget tissue integral dose in all ten cases. A single-arc VMAT optimization framework comprising mixed photon energy partial arcs was presented. Overall results underline the feasibility and potential of the proposed approach for improving OAR sparing in large size patients without compromising the target homogeneity and coverage.

Evaluation of Dose Distribution and Normal Tissue Complication Probability of a Combined Dose of Cone-Beam Computed Tomography Imaging with Treatment in Prostate Intensity-Modulated Radiation Therapy.

Purpose:The purpose of this study is to evaluate the effects of cone-beam computed tomography (CBCT) on dose distribution and normal tissue complication probability (NTCP) by constructing a comprehensive dose evaluation system for prostate intensity-modulated radiation therapy (IMRT).Methods:A system that could combine CBCT and treatment doses with MATLAB was constructed. Twenty patients treated with prostate IMRT were studied. A mean dose of 78 Gy was prescribed to the prostate region, excluding the rectal volume from the target volume, with margins of 4 mm to the dorsal side of the prostate and 7 mm to the entire circumference. CBCT and treatment doses were combined, and the dose distribution and the NTCP of the rectum and bladder were evaluated.Results:The radiation dose delivered to 2% and 98% of the target volume increased by 0.90 and 0.74 Gy on average, respectively, in the half-fan mode and on average 0.76 and 0.72 Gy, respectively, in the full-fan mode. The homogeneity index remained constant. The percent volume of the rectum and bladder irradiated at each dose increased slightly, with a maximum increase of <1%. The rectal NTCP increased by approximately 0.07% from 0.46% to 0.53% with the addition of a CBCT dose, while the maximum NTCP in the bladder was approximately 0.02%.Conclusions:This study demonstrated a method to evaluate a combined dose of CBCT and a treatment dose using the constructed system. The combined dose distribution revealed increases of <1% volume in the rectal and bladder doses and approximately 0.07% in the rectal NTCP.

Cross-modality applicability of rectal normal tissue complication probability models from photon- to proton-based radiotherapy

Background and purposeProton therapy (PT) is currently being studied to improve normal tissue (NT) sparing beyond what can be achieved with conventional photon-based therapy. Compared to photons, PT dose distributions have a reduced NT low-to-intermediate ‘dose bath’ and a different biological effectiveness, questioning the applicability of photon-based NT complication probability (NTCP) models to PT. The aim of this study was to assess the applicability of photon-based NTCP models to rectum morbidity outcomes following PT. Materials and methodsTreatment planning and morbidity data from 1151 prostate cancer patients treated with passive scattering PT and from 159 patients treated with conventional 3D conformal four-field photon therapy were analysed. Prospectively scored gastrointestinal morbidities (grade >=2) were analysed, with a total of 184 events (protons; medical and procedural) and 12 events (photons; procedural only), respectively. Rectal dose volume histograms were extracted for all patients in both cohorts and used as input to two different NTCP models, with up to six different published photon-based parameter sets. ResultsPhoton-based rectal NTCP models either over- or underestimated the clinically observed gastrointestinal morbidity when used on the proton cohort, depending on the choice of endpoint (p < 0.05 for all parameter sets, for both morbidity classifications). Four of the six photon-based NTCP models showed a good fit to the photon outcome data (p > 0.05). ConclusionThere were large differences in morbidity predictions between cohorts and modalities, indicating that the validity of NTCP models and parameters across institutions and treatment modalities should be carefully investigated prior to clinical application.

Dosimetric Evaluation of PSMA PET-Delineated Dominant Intraprostatic Lesion Simultaneous Infield Boosts

PurposeProstate cancer is multifocal. However, there often exists a single dominant focus in the gland responsible for driving the biology of the disease. Dose escalation to the dominant lesion is a proposed strategy to increase tumor control. We applied radiobiological modeling to evaluate the dosimetric feasibility and benefit of dominant intraprostatic lesion simultaneous in-field boosts (DIL-SIB) to the gross tumor volume (GTV), defined using a novel molecular positron emission tomography (PET) probe (18F-DCFPyL) directed against prostate specific membrane antigen (PSMA). Methods and MaterialsPatients with clinically localized, biopsy-proven prostate cancer underwent preoperative [18F]-DCFPyL PET/computed tomography (CT). DIL-SIB plans were generated by importing the PET/CT into the RayStation treatment planning system. GTV-PET for the DIL-SIB was defined by the highest %SUVmax (percentage of maximum standardized uptake value) that generated a biologically plausible volume. Volumetric arc–based plans incorporating prostate plus DIL-SIB treatment were generated. Tumor control probability (TCP) and normal tissue complication probability (NTCP) with fractionation schemes and boost doses specified in the FLAME (Investigate the Benefit of a Focal Lesion Ablative Microboost in Prostate Cancer; NCT01168479), PROFIT (Prostate Fractionated Irradiation Trial; NCT00304759), PACE (Prostate Advances in Comparative Evidence; NCT01584258), and hypoFLAME (Hypofractionated Focal Lesion Ablative Microboost in prostatE Cancer 2.0; NCT02853110) protocols were compared. ResultsComparative DIL-SIB plans for 6 men were generated from preoperative [18F]-DCFPyL PET/CT. Median boost GTV volume was 1.015 cm3 (0.42-1.83 cm3). Median minimum (D99%) DIL-SIB dose for F35BS, F20BS, F5BS, and F5BSH were 97.3 Gy, 80.8 Gy, 46.5 Gy, and 51.5Gy. TCP within the GTV ranged from 84% to 88% for the standard plan and 95% to 96% for the DIL-SIB plans. Within the rest of the prostate, TCP ranged from 89% to 91% for the standard plans and 90% to 92% for the DIL-SIB plans. NTCP for the rectum NTCP was similar for the DIL-SIB plans (0.3%-2.7%) compared with standard plans (0.7%-2.6%). Overall, DIL-SIB plans yielded higher uncomplicated TCP (NTCP, 90%-94%) versus standard plans (NTCP, 83%-85%). ConclusionsPSMA PET provides a novel approach to define GTV for SIB-DIL dose escalation. Work is ongoing to validate PSMA PET-delineated GTV through correlation to coregistered postprostatectomy digitized histopathology.

Applying a variable relative biological effectiveness (RBE) might affect the analysis of clinical trials comparing photon and proton therapy for prostate cancer

The purpose of this study was the evaluation of the impact of a variable relative biological effectiveness (RBE) compared to a constant RBE value of 1.1 in proton therapy prostate trials due to uncertainties in α/β ratio.Twenty patients receiving passive scattered proton therapy (PSPT) and fifteen patients receiving intensity modulated proton therapy (IMPT) were compared to twenty patients treated with 7-field intensity modulated photon therapy (IMRT). For proton beam therapy (PBT), the RBE was estimated using two different RBE models. Tumor control probabilities (TCP) and normal tissue complication probabilities (NTCP) were assessed.For one of the RBE models, dosimetric indices assuming a low α/β were ~10%–11% larger compared to using a fixed RBE. A different model resulted in 1%–3% lower values independent of α/β. Comparing PBT with IMRT revealed a negligible difference in TCP for a fixed RBE. Applying a variable RBE revealed an increase in TCP by 6% for PBT compared to IMRT for one model but a decrease of 2% for the other. Variable RBE values in PSPT resulted in an increase in NTCP for rectum from 7% to 11% for a fixed RBE with one model but a decrease to 6% for another. For IMPT, NTCP increased from 5% to 9% for a fixed RBE for one model but decreased to 3% using the other. The NTCP for bladder increased for PSPT for both models, from 11% to 19% and 14%, respectively. For IMPT, the NTCP increased from 12% to 17% using one model but decreased to 11% with the other.In radiation therapy for prostate cancer, disregarding variable RBE may lead to either underestimation or overestimation of the expected TCP and NTCP, depending on the RBE model and α/β. This should be considered when estimating uncertainties when comparing PBT and IMRT outcomes in clinical trials.

Complementary Relation Between the Improvement of Dose Delivery Technique and PTV Margin Reduction in Dose-Escalated Radiation Therapy for Prostate Cancer

PurposeThe purpose of this study is to demonstrate quantitatively the complementary relationship between the introduction of intensity modulated radiation therapy (IMRT) and planning target volume (PTV) margin reduction with an image guided technique in reducing the risk of rectal toxicity in dose-escalating prostate radiation therapy. Methods and MaterialsThree-dimensional conformal radiation therapy (CRT) and IMRT plans were generated for 10 patients with prostate cancer based on 2 PTV margin protocols (10/8 mm and 6/5 mm) and 2 dose prescriptions (70 Gy and 78 Gy). The normal tissue complication probability (NTCP) for each of the 8 scenarios was calculated using the Lyman-Kutcher-Burman model to estimate the risk of rectal and bladder late toxicity. The conformity and homogeneity indices of PTVs were calculated for each plan. ResultsThe IMRT plans showed superiority in conformity and inferiority in homogeneity over 3-dimensional CRT plans. The rectal NTCPs were increased 3.5 to 4.1 times when the prescribed total dose was changed from 70 Gy to 78 Gy and the dose delivery and the image guided radiation therapy techniques remained unchanged. PTV margin reduction was shown to reduce the value of rectal NTCP significantly. Overall, implementing the IMRT technique alone could reduce the NTCP values only by 2.1% to 7.3% from those of 3-dimensional CRT. The introduction of both IMRT and PTV margin reduction was found to be necessary for rectal NTCP to remain <5% in the dose escalation from 70 to 78 Gy. ConclusionsThe complementary relationship between the introduction of IMRT and PTV margin reduction was proven. We found that both approaches need to be implemented to safely deliver a curative dose in dose-escalating prostate radiation therapy.

A quantitative assessment of the consequences of allowing dose heterogeneity in prostate radiation therapy planning.

Target dose uniformity has been historically an aim of volumetric modulated arc therapy (VMAT) planning. However, for some sites, this may not be strictly necessary and removing this constraint could theoretically improve organ‐at‐risk (OAR) sparing and tumor control probability (TCP). This study systematically investigates the consequences of PTV dose uniformity that results from the application or removal of an upper dose constraint (UDC) in the inverse planning process for prostate VMAT treatments. OAR sparing, target coverage, hotspots, and plan complexity were compared between prostate VMAT plans with and without the PTV UDC optimized using the progressive resolution optimizer (PRO, Varian Medical Systems, Palo Alto, CA). Removing the PTV UDC, the median D1cc reached 144.6% for the CTV and the PTV, and an average increase of 3.2% TCP was demonstrated, while CTV and PTV coverage evaluated by D99% was decreased by less than 0.6% with statistical significance. Moreover, systematic improvement in the rectum dose volume histograms was shown (a 5–10% decrease in the volume receiving 50% to 75% prescribed dose), resulting in an average decrease of 1.3% (P < 0.01) in the rectum normal tissue complication probability. Additional consequences included potentially increased dose to the urethra as evaluated by PTV D0.035cc (median: 153.4%), delivering 283 extra monitor units (MUs), and slightly higher degrees of modulation. In general, the results were consistent when a different optimizer (Photon Optimizer, Varian Medical Systems) was used. In conclusion, removing the PTV UDC is acceptable for localized prostate cases given the systematic improvement of rectal dose and TCP. It can be particularly useful for cases that do not meet the rectum dose constraints with the PTV UDC on. This comes with the foreseeable consequences of increased dose heterogeneity in the PTV and an increase in MUs and plan complexity. It also has a higher requirement for reproducing the position and size of the target and OARs during treatment. Finally, with the PTV UDC completely removed, in some cases the maximum doses within the PTV did approach levels that may be of concern for urethral toxicity and therefore in clinical implementation it may still be necessary to include a PTV UDC, but one based on limiting toxicity rather than enforcing dose homogeneity.

Late toxicity in the randomized multicenter HYPRO trial for prostate cancer analyzed with automated treatment planning

Purpose/objectiveAssess to what extent the use of automated treatment planning would have reduced organ-at-risk dose delivery observed in the randomized HYPRO trial for prostate cancer, and estimate related toxicity reductions. Investigate to what extent improved plan quality for hypofractionation scheme as achieved with automated planning can potentially reduce observed enhanced toxicity for the investigated hypofractionation scheme to levels observed for conventional fractionation scheme. Material/methodsFor 725 trial patients, VMAT plans were generated with an algorithm for automated multi-criterial plan generation (autoVMAT). All clinically delivered plans (CLINICAL), generated with commonly applied interactive trial-and-error planning were also available for the investigations. Analyses were based on dose-volume histograms (DVH) and predicted normal tissue complication probabilities (NTCP) for late gastrointestinal (GI) toxicity. ResultsCompared to CLINICAL, autoVMAT plans had similar or higher PTV coverage, while large and statistically significant OAR sparing was achieved. Mean doses in the rectum, anus and bladder were reduced by 7.8 ± 4.7 Gy, 7.9 ± 6.0 Gy and 4.2 ± 2.9 Gy, respectively (p < 0.001). NTCPs for late grade ≥2 GI toxicity, rectal bleeding and stool incontinence were reduced from 23.3 ± 9.1% to 19.7 ± 8.9%, from 9.7 ± 2.8% to 8.2 ± 2.8%, and from 16.8 ± 8.5% to 13.1 ± 7.2%, respectively (p < 0.001). Reductions in rectal bleeding NTCP were observed for all published Equivalent Uniform Dose volume parameters, n. AutoVMAT allowed hypofractionation with predicted toxicity similar to conventional fractionation with CLINICAL plans. ConclusionCompared to CLINICAL, autoVMAT had superior plan quality, with meaningful NTCP reductions for both conventional fractionation and hypofractionation schemes. AutoVMAT plans might reduce toxicity for hypofractionation to levels that were clinically observed (and accepted) for conventional fractionation. This may be relevant when considering clinical use of the investigated hypofractionation schedule with relatively high fraction dose (3.4 Gy).

A biological modelling based comparison of radiotherapy plan robustness using photons vs protons for focal prostate boosting.

Background and purposeFocal tumour boosting is currently explored in radiotherapy of prostate cancer to increase tumour control. In this study we applied dose response models for both tumour control and normal tissue complications to explore the benefit of proton therapy (PT) combined with focal tumour boosting, also when accounting for inter-fractional motion.Materials and methodsCT scans of seven patients fused with MRI-based index volumes were used. Two volumetric modulated arc therapy (VMAT) plans were created for each patient; one with conventional dose (77 Gy) to the entire prostate, and one with an additional integrated boost (total dose of 95 Gy) to the index lesion. Two corresponding intensity modulated PT (IMPT) plans were created using two lateral opposing spot scanning beams. All plans were evaluated using an MRI-based tumour control probability (TCP) model and normal tissue complication probability (NTCP) models for the rectum and bladder. Plan robustness was evaluated using dose re-calculations on repeat cone-beam CTs.ResultsAcross all plans, median TCP increased from 86% (range: 59–98%) without boost to 97% (range: 96–99%) with boost. IMPT plans had lower rectum NTCPs (e.g. 3% vs. 4% for boost plans) but higher bladder NTCPs (20% vs. 18% for boost plans), yet only the bladder NTCPs remained different in the cone beam CT-based re-calculations.ConclusionsFocal tumour boosting can be delivered with either VMAT or protons, and increases the predicted TCP. The small benefit of IMPT when assessing the planned dose distributions was lost when accounting for inter-fractional motion.

Correlations between contouring similarity metrics and simulated treatment outcome for prostate radiotherapy

Many similarity metrics exist for inter-observer contouring variation studies, however no correlation between metric choice and prostate cancer radiotherapy dosimetry has been explored. These correlations were investigated in this study. Two separate trials were undertaken, the first a thirty-five patient cohort with three observers, the second a five patient dataset with ten observers. Clinical and planning target volumes (CTV and PTV), rectum, and bladder were independently contoured by all observers in each trial. Structures were contoured on T2-weighted MRI and transferred onto CT following rigid registration for treatment planning in the first trial. Structures were contoured directly on CT in the second trial. STAPLE and majority voting volumes were generated as reference gold standard volumes for each structure for the two trials respectively. VMAT treatment plans (78 Gy to PTV) were simulated for observer and gold standard volumes, and dosimetry assessed using multiple radiobiological metrics. Correlations between contouring similarity metrics and dosimetry were calculated using Spearman’s rank correlation coefficient.No correlations were observed between contouring similarity metrics and dosimetry for CTV within either trial. Volume similarity correlated most strongly with radiobiological metrics for PTV in both trials, including TCPPoisson (ρ = 0.57, 0.65), TCPLogit (ρ = 0.39, 0.62), and EUD (ρ = 0.43, 0.61) for each respective trial. Rectum and bladder metric correlations displayed no consistency for the two trials. PTV volume similarity was found to significantly correlate with rectum normal tissue complication probability (ρ = 0.33, 0.48). Minimal to no correlations with dosimetry were observed for overlap or boundary contouring metrics. Future inter-observer contouring variation studies for prostate cancer should incorporate volume similarity to provide additional insights into dosimetry during analysis.

45. Salvage re-irradiation for local failure of prostate cancer after curative radiotherapy: Dosimetric and radiobiological modelling of rectal toxicity

Introduction To assess the impact of radiation dose and clinical parameters on rectal toxicity following salvage external beam radiation therapy (EBRT) with or without a brachytherapy (BT) boost for exclusive local failure after primary-EBRT for prostate cancer. Methods Fourteen patients with no residual toxicity after primary EBRT ( ± BT) were re-irradiated after a median time interval of 6.1 years (4.7–10.2). The median NTD2Gy was 74 Gy (66–98.4) at primary-RT and 85.1 Gy (70–93.4) at re-irradiation. Rectal dose volume histograms of both treatments (converted to NTD2Gy) and the corresponding normal-tissue-complication-probability (NTCP) values for gastro-intestinal (GI) toxicity were calculated. Results The 5-year Grade ⩾3 GI toxicity-free survival rate was 57.1 ± 13.1%. Five patients developed Grade 4 GI toxicity. Rectal V70Gy and the maximum dose to 1 cc of rectum at primary EBRT were both predictive for Grade ⩾3 GI toxicity; 12.2% vs. 3.8%, p = .042 and 72.2 Gy vs. 66.8 Gy, p = .0027, respectively. When adding primary-RT and re-irradiation plans, the median maximum dose to 1 cc of rectum was 139.8 Gy (126.7–147.8) vs. 125.9 Gy (99.1–133.1) (p = .0063) for Grade ⩾3 and Grade ⩽2 GI toxicity groups. Higher NTCP values at primary-RT were predictive for Grade ⩾3 toxicity (p Conclusions A higher rectal NTCP value, even in the absence of high-grade late-toxicity after primary-RT, is correlated with an increased risk of severe rectal side-effects after salvage re-irradiation. Rectum doses greater than 70 Gy at primary-RT, and NTCP values of more than 10%, might predict for grade ⩾3 rectal toxicity at re-irradiation, with a possible threshold for total rectum dose of around 130 Gy.

Evaluation of intensity modulated radiation therapy dose painting for localized prostate cancer using 68Ga-HBED-CC PSMA-PET/CT: A planning study based on histopathology reference

PurposeTo demonstrate the feasibility and to evaluate the tumour control probability (TCP) and normal tissue complication probability (NTCP) of IMRT dose painting using 68Ga-HBED-CC PSMA PET/CT for target delineation in prostate cancer (PCa). Methods and materials10 patients had PSMA PET/CT scans prior to prostatectomy. GTV-PET was generated on the basis of an intraprostatic SUVmax of 30%. Two IMRT plans were generated for each patient: Plan77 which consisted of whole-prostate IMRT to 77Gy, and Plan95 which consisted of whole-prostate IMRT to 77Gy and a simultaneous integrated boost to the GTV-PET up to 95Gy (35 fractions). The feasibility of these plans was judged by their ability to adhere to the FLAME trial protocol. TCP-histo/-PET were calculated on co-registered histology (GTV-histo) and GTV-PET, respectively. NTCPs for rectum and bladder were calculated. ResultsAll plans reached prescription doses whilst adhering to dose constraints. In Plan77 and Plan95 mean doses in GTV-histo were 75.8±0.3Gy and 96.9±1Gy, respectively. Average TCP-histo values for Plan77 and Plan95 were 70% (range: 15–97%), and 96% (range: 78–100%, p<0.0001). Average TCP-PET values for Plan77 and Plan95 were 55% (range: 27–82%), and 100% (range: 99–100%, p<0.0001). There was no significant difference between TCP-PET and TCP-histo in Plan95 (p=0.25). There were no significant differences in rectal (p=0.563) and bladder (p=0.3) NTCPs. ConclusionsIMRT dose painting using PSMA PET/CT was technically feasible and resulted in significantly higher TCPs without higher NTCPs.

Uncomplicated and Cancer-Free Control Probability (UCFCP): A new integral approach to treatment plan optimization in photon radiation therapy

PurposeBiological treatment plan evaluation does not currently consider second cancer induction from peripheral doses associated to photon radiotherapy. The aim is to propose a methodology to characterize the therapeutic window by means of an integral radiobiological approach, which considers not only Tumour Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) but also Secondary Cancer Probability (SCP). MethodsUncomplicated and Cancer-Free Control Probability (UCFCP) function has been proposed assuming a statistically uncorrelated response for tumour and normal tissues. The Poisson’s and Lyman’s models were chosen for TCP and NTCP calculations, respectively. SCP was modelled as the summation of risks associated to photon and neutron irradiation of radiosensitive organs. For the medium (>4Gy) and low dose regions, mechanistic and linear secondary cancer risks models were used, respectively. Two conformal and intensity-modulated prostate plans at 15MV (same prescription dose) were selected to illustrate the UCFCP features. ResultsUCFCP exhibits a bell-shaped behaviour with its maximum inside the therapeutic window. SCP values were not different for the plans analysed (∼2.4%) and agreed with published epidemiological results. Therefore, main differences in UCFCP came from differences in rectal NTCP (18% vs 9% for 3D-CRT and IMRT, respectively). According to UCFCP values, the evaluated IMRT plan ranked first. ConclusionsThe level of SCP was found to be similar to that of NTCP complications which reinforces the importance of considering second cancer risks as part of the possible late sequelae due to treatment. Previous concerns about the effect of peripheral radiation, especially neutrons, in the induction of secondary cancers can be evaluated by quantifying the UCFCP.

A modeling study of functional magnetic resonance imaging to individualize target definition of seminal vesicles for external beam radiotherapy

Background: Pre-treatment magnetic resonance imaging (MRI) can give patient-specific evaluation of suspected pathologically involved volumes in the seminal vesicles (SV) in prostate cancer patients. By targeting this suspicious volume we hypothesize that radiotherapy is more efficient without introducing more toxicity. In this study we evaluate the concept of using MRI-defined target volumes in terms of tumor control probability (TCP) and rectal normal tissue complication probability (NTCP).Material and methods: Twenty-one high-risk prostate cancer patients were included. Pre-treatment CT images, T2 weighted (T2w) MRI and two multi-parametric MRI were acquired. Overlap between a suspicious volume in the SV observed on T2w images and a suspicious volume observed on either multi-parametric MRI was assumed to reflect a true malignant region (named ‘MRI positive’). In addition the entire SV on the CT-scan was delineated. Three treatment plans of 2 Gy ×39 fractions were generated per patient: one covering the MRI positive volume in SV and prostate with margin of 11 mm to the MRI positive in the SV and two plans covering prostate and SV using 11 and 7 mm SV margin, respectively. All plans were prescribed the same PTV mean dose. Rectal NTCP grade ≥2 was evaluated with the Lyman–Kutcher–Burman model and TCP was estimated by a logistic model using the combined MRI positive volume in SV and prostate as region-of-interest.Results: Fourteen of twenty-one patients were classified as MRI positive, six of which had suspicious volumes in all three MRI modalities. On average TCP for the plan covering prostate and the MRI positive volume was 3% higher (up to 11%) than the two other plans which was statistically significant. The increased TCP was obtained without increasing rectal NTCP grade ≥2.Conclusions: Using functional MRI for individualized target delineation in the SV may improve the treatment outcome in radiotherapy of prostate cancer without increasing the rectal toxicity.

Inclusion of a variable RBE into proton and photon plan comparison for various fractionation schedules in prostate radiation therapy.

A constant relative biological effectiveness (RBE) of 1.1 is currently used in proton radiation therapy to account for the increased biological effectiveness compared to photon therapy. However, there is increasing evidence that proton RBE vary with the linear energy transfer (LET), the dose per fraction, and the type of the tissue. Therefore, this study aims to evaluate the impact of disregarding variations in RBE when comparing proton and photon dose plans for prostate treatments for various fractionation schedules using published RBE models and several α/β assumptions. Photon and proton dose plans were created for three generic prostate cancer cases. Three BED3Gy equivalent schedules were studied, 78, 57.2, and 42.8Gy in 39, 15, and 7 fractions, respectively. The proton plans were optimized assuming a constant RBE of 1.1. By using the Monte Carlo calculated dose-averaged LET (LETd ) distribution and assuming α/β values on voxel level, three variable RBE models were applied to the proton dose plans. The impact of the variable RBE was studied in the plan comparison, which was based on the dose distribution, DVHs, and normal tissue complication probabilities (NTCP) for the rectum. Subsequently, the physical proton dose was reoptimized for each proton plan based on the LETd distribution, to achieve a homogeneous RBE-weighted target dose when applying a specific RBE model and still fulfill the clinical goals for the rectum and bladder. All the photon and proton plans assuming RBE=1.1 met the clinical goals with similar target coverage. The proton plans fulfilled the robustness criteria in terms of range and setup uncertainty. Applying the variable RBE models generally resulted in higher target doses and rectum NTCP compared to the photon plans. The increase was most pronounced for the fractionation dose of 2Gy(RBE), whereas it was of less magnitude and more dependent on model and α/β assumption for the hypofractionated schedules. The reoptimized proton plans proved to be robust and showed similar target coverage and doses to the organs at risk as the proton plans optimized with a constant RBE. Model predicted RBE values may differ substantially from 1.1. This is most pronounced for fractionation doses of around 2Gy(RBE) with higher doses to the target and the OARs, whereas the effect seems to be of less importance for the hypofractionated schedules. This could result in misleading conclusions when comparing proton plans to photon plans. By accounting for a variable RBE in the optimization process, robust and clinically acceptable dose plans, with the potential of lowering rectal NTCP, may be generated by reoptimizing the physical dose. However, the direction and magnitude of the changes in the physical proton dose to the prostate are dependent on RBE model and α/β assumptions and should therefore be used conservatively.

Dose-volume consistency and radiobiological characterization between prostate IMRT and VMAT plans

Purpose: Dose-volume consistency of the planning target volume (PTV) and rectum for the prostate intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans were evaluated and compared. Dependences of radiobiological parameters of the prostate and rectum on the PTV and rectal volume were also investigated. Methods: From 40 prostate IMRT and 50 VMAT patients treated with the same prescription (78 Gy per 39 fractions) and dose-volume criteria in the inverse planning, the prostate tumour control probability (TCP), rectal equivalent uniform dose (EUD) and rectal normal tissue complication probability (NTCP) were calculated. The dose-volume consistency of the PTV and rectum, demonstrating the variability of dose-volume histogram (DVH) among patients, was defined and calculated as per the deviation between the corresponding and mean DVH. Results: For the IMRT plans, the prostate TCP was found increasing with the PTV with a rate equal to 1.05 × 10 -3 % cm -3 , which was lower than 1.11 × 10 -3 % cm -3 for the VMAT plans. Both the rectal EUD and rectal NTCP were found decreasing with the rectal volume. The decrease rates for the IMRT plans (EUD = 0.47 × 10 -3 Gy cm -3 and NTCP = 3.94 × 10 -2 % cm -3 ) were higher than those for the VMAT (EUD = 0.28 × 10 -3 Gy cm -3 and NTCP = 2.61 × 10 -2 % cm -3 ). Conclusion: For the dose-volume consistency, small prostate TCP variation could be achieved by decreasing the dose-volume variability among the IMRT and VMAT plans. However, dependences of the rectal EUD and rectal NTCP on the dose-volume variability were not significant. It is concluded that maintaining a good dose-volume consistency in prostate plans can decrease the prostate TCP variation among the IMRT and VMAT patients. However, dose-volume variability is not affected by variations of the rectal EUD and rectal NTCP.

The benefit of using bladder sub-volume equivalent uniform dose constraints in prostate intensity-modulated radiotherapy planning.

BackgroundTo assess the benefits of bladder wall sub-volume equivalent uniform dose (EUD) constraints in prostate cancer intensity-modulated radiotherapy (IMRT) planning.MethodsTwo IMRT plans, with and without EUD constraints on the bladder wall, were generated using beams that deliver 80 Gy to the prostate and 46 Gy to the seminal vesicles and were compared in 53 prostate cancer patients. The bladder wall was defined as the volume between the external manually delineated wall and a contraction of 7 mm apart from it. The bladder wall was then separated into two parts: the internal-bladder wall (bla-in) represented by the portion of the bladder wall that intersected with the planning target volume (PTV) plus 5 mm extension; the external-bladder wall (bla-ex) represented by the remaining part of the bladder wall. In the IMRT plan with EUD constraints, the values of “a” parameter for the EUD models were 10.0 for bla-in and 2.3 for bla-ex. The plans with and without EUD constraints were compared in terms of dose–volume histograms, 5-year bladder and rectum normal tissue complication probability values, as well as tumor control probability (TCP) values.ResultsThe use of bladder sub-volume EUD constraints decreased both the doses to the bladder wall (V70: 22.76% vs 19.65%, Dmean: 39.82 Gy vs 35.45 Gy) and the 5-year bladder complication probabilities (≥LENT/SOMA Grade 2: 20.35% vs 17.96%; bladder bleeding: 10.63% vs 8.64%). The doses to the rectum wall and the rectum complication probabilities were also slightly decreased by the EUD constraints compared to physical constraints only. The minimal dose and the V76Gy of PTVprostate were, however, slightly decreased by EUD optimization, nevertheless without significant difference in TCP values between the two plans, and the PTV parameters finally respected the Groupe d’Etude des Tumeurs Uro-Génitales recommendations.ConclusionSeparating the bladder wall into two parts with appropriate EUD optimization may reduce bladder toxicity in prostate IMRT. Combining biological constraints with physical constraints in the organs at risk at the inverse planning step of IMRT may improve the dose distribution.