P Mavroidis

Cardiac toxicity after radiotherapy for stage III non-small-cell lung cancer: Pooled analysis of dose-escalation trials delivering 70 to 90 Gy

Purpose The significance of radiotherapy (RT) -associated cardiac injury for stage III non-small-cell lung cancer (NSCLC) is unclear, but higher heart doses were associated with worse overall survival in the Radiation Therapy Oncology Group (RTOG) 0617 study. We assessed the impact of heart dose in patients treated at our institution on several prospective dose-escalation trials. Patients and Methods From 1996 to 2009, 127 patients with stage III NSCLC (Eastern Cooperative Oncology Group performance status, 0 to 1) received dose-escalated RT to 70 to 90 Gy (median, 74 Gy) in six trials. RT plans and cardiac doses were reviewed. Records were reviewed for the primary end point: symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure). Cardiac risk was assessed by noting baseline coronary artery disease and calculating the WHO/International Society of Hypertension score. Competing risks analysis was used. Results In all, 112 patients were analyzed. Median follow-up for surviving patients was 8.8 years. Twenty-six patients (23%) had one or more events at a median of 26 months to first event (effusion [n = 7], myocardial infarction [n = 5], unstable angina [n = 3], pericarditis [n = 2], arrhythmia [n = 12], and heart failure [n = 1]). Heart doses (eg, heart mean dose; hazard ratio, 1.03/Gy; P = .002,), coronary artery disease ( P < .001), and WHO/International Society of Hypertension score ( P = .04) were associated with events on univariable analysis. Heart doses remained significant on multivariable analysis that accounted for baseline risk. Two-year competing risk-adjusted event rates for patients with heart mean dose < 10 Gy, 10 to 20 Gy, or ≥ 20 Gy were 4%, 7%, and 21%, respectively. Heart doses were not associated with overall survival. Conclusion Cardiac events were relatively common after high-dose thoracic RT and were independently associated with both heart dose and baseline cardiac risk. RT-associated cardiac toxicity after treatment of stage III NSCLC may occur earlier than historically understood, and heart doses should be minimized.

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

PURPOSE To 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 MATERIALS 10 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. RESULTS All 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. CONCLUSIONS IMRT dose painting using PSMA PET/CT was technically feasible and resulted in significantly higher TCPs without higher NTCPs.

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.

PURPOSE 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. METHODS AND MATERIALS 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. RESULTS 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%. CONCLUSIONS 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%.

Heart dosimetric analysis of three types of cardiac toxicity in patients treated on dose-escalation trials for Stage III non-small-cell lung cancer

BACKGROUND AND PURPOSE To assess associations between radiation dose/volume parameters for cardiac subvolumes and different types of cardiac events in patients treated on radiation dose-escalation trials. MATERIAL AND METHODS Patients with Stage III non-small-cell lung cancer received dose-escalated radiation (median 74 Gy) using 3D-conformal radiotherapy on six prospective trials from 1996 to 2009. Volumes analyzed included whole heart, left ventricle (LV), right atrium (RA), and left atrium (LA). Cardiac events were divided into three categories: pericardial (symptomatic effusion and pericarditis), ischemia (myocardial infarction and unstable angina), and arrhythmia. Univariable competing risks analysis was used. RESULTS 112 patients were analyzed, with median follow-up 8.8 years for surviving patients. Nine patients had pericardial, seven patients had ischemic, and 12 patients had arrhythmic events. Pericardial events were correlated with whole heart, RA, and LA dose (eg, heart-V30 [p=0.024], RA-V30 [p=0.013], and LA-V30 [p=0.001]), but not LV dose. Ischemic events were correlated with LV and whole heart dose (eg, LV-V30 [p=0.012], heart-V30 [p=0.048]). Arrhythmic events showed borderline significant associations with RA, LA, and whole heart dose (eg, RA-V30 [p=0.082], LA-V30 [p=0.076], heart-V30 [p=0.051]). Cardiac events were associated with decreased survival on univariable analysis (p=0.008, HR 2.09), but only disease progression predicted for decreased survival on multivariable analysis. CONCLUSIONS Cardiac events were heterogeneous and associated with distinct heart subvolume doses. These data support the hypothesis of distinct etiologies for different types of radiation-associated cardiotoxicity.

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.

Brain imaging: Comparison of T1W FLAIR BLADE with conventional T1W SE

INTRODUCTION Although T1 weighted spin echo (T1W SE) images are widely used to study anatomical details and pathologic abnormalities of the brain, its role in delineation of lesions and reduction of artifacts has not been thoroughly investigated. BLADE is a fairly new technique that has been reported to reduce motion artifacts and improve image quality. OBJECTIVE The primary objective of this study is to compare the quality of T1-weighted fluid attenuated inversion recovery (FLAIR) images with BLADE technique (T1W FLAIR BLADE) and the quality of T1W SE images in the MR imaging of the brain. The goal is to highlight the advantages of the two sequences as well as which one can better reduce flow and motion artifacts so that the imaging of the lesions will not be impaired. MATERIALS AND METHODS Brain examinations with T1W FLAIR BLADE and T1W SE sequences were performed on 48 patients using a 1.5T scanner. These techniques were evaluated by two radiologists based on: a) a qualitative analysis i.e. overall image quality, presence of artifacts, CSF nulling; and b) a quantitative analysis of signal-to-noise ratios (SNR), contrast-to-noise ratios (CNR) and Relative Contrast. The statistical analysis was performed using the Kruskal-Wallis non-parametric system. RESULTS In the qualitative analysis, BLADE sequences had a higher scoring than the conventional sequences in all the cases. The overall image quality was better on T1W FLAIR BLADE. Motion and flow-related artifacts were lower in T1W FLAIR BLADE. Regarding the SNR measurements, T1W SE appeared to have higher values in the majority of cases, whilst T1W-FLAIR BLADE had higher values in the CNR and Relative Contrast measurements. CONCLUSION T1W FLAIR BLADE sequence appears to be superior to T1W SE in overall image quality and reduction of motion and flow-pulsation artifacts as well as in nulling CSF and has been preferred by the clinicians. T1W FLAIR BLADE may be an alternative approach in brain MRI imaging.

Investigation of error detection capabilities of phantom, EPID and MLC log file based IMRT QA methods

Abstract A patient specific quality assurance (QA) should detect errors that originate anywhere in the treatment planning process. However, the increasing complexity of treatment plans has increased the need for improvements in the accuracy of the patient specific pretreatment verification process. This has led to the utilization of higher resolution QA methods such as the electronic portal imaging device (EPID) as well as MLC log files and it is important to know the types of errors that can be detected with these methods. In this study, we will compare the ability of three QA methods (Delta4®, MU‐EPID, Dynalog QA) to detect specific errors. Multileaf collimator (MLC) errors, gantry angle, and dose errors were introduced into five volumetric modulated arc therapy (VMAT) plans for a total of 30 plans containing errors. The original plans (without errors) were measured five times with each method to set a threshold for detectability using two standard deviations from the mean and receiver operating characteristic (ROC) derived limits. Gamma passing percentages as well as percentage error of planning target volume (PTV) were used for passing determination. When applying the standard 95% pass rate at 3%/3 mm gamma analysis errors were detected at a rate of 47, 70, and 27% for the Delta4, MU‐EPID and Dynalog QA respectively. When using thresholds set at 2 standard deviations from our base line measurements errors were detected at a rate of 60, 30, and 47% for the Delta4, MU‐EPID and Dynalog QA respectively. When using ROC derived thresholds errors were detected at a rate of 60, 27, and 47% for the Delta4, MU‐EPID and Dynalog QA respectively. When using dose to the PTV and the Dynalog method 11 of the 15 small MLC errors were detected while none were caught using gamma analysis. A combination of the EPID and Dynalog QA methods (scaling Dynalog doses using EPID images) matches the detection capabilities of the Delta4 by adding additional comparison metrics. These additional metrics are vital in relating the QA measurement to the dose received by the patient which is ultimately what is being confirmed.

SU-F-T-546: A Radiobiological Comparative Study of Robotic and LINAC-Based Lung SBRT

PURPOSE To expand the dosimetric comparison of CyberKnife and Elekta Versa HD regarding their capability to perform SBRT in lung cases by including radiobiological measures, which can estimate the clinical impact of the observed differences. METHODS This study analyzes treatment data of 10 patients, who were treated with SBRT on Elekta Versa HD and replanned using CyberKnife. The original structure sets from the RayStation treatment plans were transferred to MultiPlan and were used for planning, with the exception of the PTV. Special attention was given to the following structures during optimization in MultiPlan: PTV (expanded off GTV instead of ITV), ipsilateral and contralateral lungs, and chest wall. For each patient, the same dosimetric constraints were applied to both plans. The dose volume histograms (DVH) of the targets and organs at risk (OAR) were computed and used to compare the dosimetric differences between the two modalities. Additionally, the tumor control probability (TCP), normal tissue complication probability (NTCP) and complication-free tumor control probability (P+) radiobiological indices were calculated and compared. RESULTS The dosimetric indices show a negligible differences (Versa - CK) for the PTV (mean dose difference of 1.7 Gy and average minimum dose difference of -0.3 Gy). For the OARs, the average differences in mean and maximum doses, which varied between 0.4 to 1.7 Gy and 1.1 to 4.7Gy, respectively. The average differences in the radiobiological indices were also similar TCP = 0.3±0.6%, Composite NTCP = 2.4±2.9%, and P+ = -.1±3.3%, respectively. CONCLUSION Both modalities managed to meet the same dosimetric goals equally well. The similarities between the dosimetric and radiobiological indices indicate that the two treatment modalities are comparable. A larger patient cohort involving patients of different complexities would give a better insight for this comparison.

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.

Radiobiological evaluation of intensity modulated radiation therapy treatments of patients with head and neck cancer: A dual-institutional study.

In clinical practice, evaluation of clinical efficacy of treatment planning stems from the radiation oncologists experience in accurately targeting tumors, while keeping minimal toxicity to various organs at risk (OAR) involved. A more objective, quantitative method may be raised by using radiobiological models. The purpose of this work is to evaluate the potential correlation of OAR-related toxicities to its radiobiologically estimated parameters in simultaneously integrated boost (SIB) intensity modulated radiation therapy (IMRT) plans of patients with head and neck tumors at two institutions. Lyman model for normal tissue complication probability (NTCP) and the Poisson model for tumor control probability (TCP) models were used in the Histogram Analysis in Radiation Therapy (HART) analysis. In this study, 33 patients with oropharyngeal primaries in the head and neck region were used to establish the correlation between NTCP values of (a) bilateral parotids with clinically observed rates of xerostomia, (b) esophagus with dysphagia, and (c) larynx with dysphagia. The results of the study indicated a strong correlation between the severity of xerostomia and dysphagia with Lyman NTCP of bilateral parotids and esophagus, respectively, but not with the larynx. In patients without complications, NTCP values of these organs were negligible. Using appropriate radiobiological models, the presence of a moderate to strong correlation between the severities of complications with NTCP of selected OARs suggested that the clinical outcome could be estimated prior to treatment.