Hanan Amro

131I-Tositumomab Radioimmunotherapy: Initial Tumor Dose–Response Results Using 3-Dimensional Dosimetry Including Radiobiologic Modeling

For optimal treatment planning in radionuclide therapy, robust tumor dose–response correlations must be established. Here, fully 3-dimensional (3D) dosimetry was performed coupling SPECT/CT at multiple time points with Monte Carlo–based voxel-by-voxel dosimetry to examine such correlations. Methods: Twenty patients undergoing 131I-tositumomab for the treatment of refractory B-cell lymphoma volunteered for the study. Sixty tumors were imaged. Activity quantification and dosimetry were performed using previously developed 3D algorithms for SPECT reconstruction and absorbed dose estimation. Tumors were outlined on CT at multiple time points to obtain absorbed dose distributions in the presence of tumor deformation and regression. Equivalent uniform dose (EUD) was calculated to assess the biologic effects of the nonuniform absorbed dose, including the cold antibody effect. Response for correlation analysis was determined on the basis of the percentage reduction in the product of the largest perpendicular tumor diameters on CT at 2 mo. Overall response classification (as complete response, partial response, stable disease, or progressive disease) used for prediction analysis was based on criteria that included findings on PET. Results: Of the evaluated tumor-absorbed dose summary measures (mean absorbed dose, EUD, and other measures from dose-volume histogram analysis), a statistically significant correlation with response was seen only with EUD (r = 0.36 and P = 0.006 at the individual tumor level; r = 0.46 and P = 0.048 at the patient level). The median value of mean absorbed dose for stable disease, partial response, and complete response patients was 196, 346, and 342 cGy, respectively, whereas the median value of EUD for each of these categories was 170, 363, and 406 cGy, respectively. At a threshold of 200 cGy, both mean absorbed dose and EUD had a positive predictive value for responders (partial response + complete response) of 0.875 (14/16) and a negative predictive value of 1.0 (3/3). Conclusion: Improved dose–response correlations were demonstrated when EUD incorporating the cold antibody effect was used instead of the conventionally used mean tumor-absorbed dose. This work demonstrates the importance of 3D calculation and radiobiologic modeling when estimating absorbed dose for correlation with outcome.

Methodology to Incorporate Biologically Effective Dose and Equivalent Uniform Dose in Patient-Specific 3-Dimensional Dosimetry for Non-Hodgkin Lymphoma Patients Targeted with 131I-Tositumomab Therapy

A 3-dimensional (3D) imaging–based patient-specific dosimetry methodology incorporating antitumor biologic effects using biologically effective dose (BED) and equivalent uniform dose (EUD) was developed in this study. The methodology was applied to the dosimetry analysis of 6 non-Hodgkin lymphoma patients with a total of 10 tumors. Methods: Six registered SPECT/CT scans were obtained for each patient treated with 131I-labeled antibody. Three scans were obtained after tracer administration and 3 after therapy administration. The SPECT/CT scans were used to generate 3D images of cumulated activity. The cumulated activity images and corresponding CT scans were used as input to Monte Carlo dose-rate calculations. The dose-rate distributions were integrated over time to obtain 3D absorbed dose distributions. The time-dependent 3D cumulative dose distributions were used to generate 3D BED distributions. Techniques to incorporate the effect of unlabeled antibody (cold protein) in the BED analysis were explored. Finally, BED distributions were used to estimate an EUD for each tumor volume. Model parameters were determined from optimal fits to tumor regression data. The efficiency of dose delivery to tumors—the ratio of EUD to cumulative dose—was extracted for each tumor and correlated with patient response parameters. Results: The model developed in this study was validated for dosimetry of non-Hodgkin lymphoma patients treated with 131I-labeled antibody. Correlations between therapy efficiency generated from the model and tumor response were observed using averaged model parameters. Model parameter determination favored a threshold for the cold effect and typical magnitude for tumor radiosensitivity parameters. Conclusion: The inclusion of radiobiologic effects in the dosimetry modeling of internal emitter therapy provides a powerful platform to investigate correlations of patient outcome with planned therapy.

The Dosimetric Impact of Prostate Rotations During Electromagnetically Guided External-Beam Radiation Therapy

PURPOSEnTo study the impact of daily rotations and translations of the prostate on dosimetric coverage during radiation therapy (RT).nnnMETHODS AND MATERIALSnReal-time tracking data for 26 patients were obtained during RT. Intensity modulated radiation therapy plans meeting RTOG 0126 dosimetric criteria were created with 0-, 2-, 3-, and 5-mm planning target volume (PTV) margins. Daily translations and rotations were used to reconstruct prostate delivered dose from the planned dose. D95 and V79 were computed from the delivered dose to evaluate target coverage and the adequacy of PTV margins. Prostate equivalent rotation is a new metric introduced in this study to quantify prostate rotations by accounting for prostate shape and length of rotational lever arm.nnnRESULTSnLarge variations in prostate delivered dose were seen among patients. Adequate target coverage was met in 39%, 65%, and 84% of the patients for plans with 2-, 3-, and 5-mm PTV margins, respectively. Although no correlations between prostate delivered dose and daily rotations were seen, the data showed a clear correlation with prostate equivalent rotation.nnnCONCLUSIONSnProstate rotations during RT could cause significant underdosing even if daily translations were managed. These rotations should be managed with rotational tolerances based on prostate equivalent rotations.

Bio-effect model applied to 131I radioimmunotherapy of refractory non-Hodgkin's lymphoma.

PurposeImproved data collection methods have improved absorbed dose estimation by tracking activity distributions and tumor extent at multiple time points, allowing individualized absorbed dose estimation. Treatment with tositumomab and 131I-tositumomab anti-CD20 radioimmunotherapy (BEXXAR) yields a cold antibody antitumor response (cold protein effect) and a radiation response. Biologically effective contributions, including the cold protein effect, are included in an equivalent biological effect model that was fit to patient data.MethodsFifty-seven tumors in 19 patients were followed using 6 single proton emission computed tomography (SPECT)/CT studies, 3 each post tracer (5xa0mCi) and therapy (∼100xa0mCi) injections with tositumomab and 131I-tositumomab. Both injections used identical antibody mass, a flood dose of 450xa0mg plus 35xa0mg of 131I tagged antibody. The SPECT/CT data were used to calculate absorbed dose rate distributions and tumor and whole-body time-activity curves, yielding a space-time dependent absorbed dose rate description for each tumor. Tumor volume outlines on CT were used to derive the time dependence of tumor size for tracer and therapy time points. A combination of an equivalent biological effect model and an inactivated cell clearance model was used to fit absorbed dose sensitivity and cold effect sensitivity parameters to tumor shrinkage data, from which equivalent therapy values were calculated.ResultsPatient responses were categorized into three groups: standard radiation sensitivity with no cold effect (7 patients), standard radiation sensitivity with cold effect (11 patients), and high radiation sensitivity with cold effect (1 patient).ConclusionFit parameters can be used to categorize patient response, implying a potential predictive capability.

TU‐G‐BRC‐04: The Dosimetric Impact of Prostate Rotations during Electromagnetically Guided External Beam Radiation Therapy

Purpose: To measure the dose decrement to the prostate caused by daily prostate motion and to correlate target coverage with prostate rotations to establish individualized rotational tolerances and PTV margins. Methods: Real—time tracking data for 26 patients were obtained during RT and used to calculate “uf00faverage” prostate rotations and translations. For each patient, IMRTtreatment plans meeting RTOG0126 dosimetric criteria were created with 0, 2, 3, and 5 mm PTV margins. Daily translations and rotations were used to calculate prostate delivered (dynamic) dose from the planned (static) dose.Dose volume histograms, D95, and V79 are computed from the dynamic dose to evaluate the coverage and the adequacy of PTV margins under measured target motion. The intra‐fractional effective rotations of the prostate (rotations weighted by rotation lever arm and prostate geometrical shape) were obtained for each patient. Results: Large variations in dosimetric coverage were seen among patients. Adequate coverage to target was met in 39%, 65%, and 84% of the patients for plans with 2, 3, and 5 mm PTV margins, respectively. This dosimetric coverage could not be correlated with measured rotations for any of the PTV margins. Prostate shape and the length of rotation lever‐arm were parameterized and used to obtain effective rotations from the measured rotations. Clear correlations were seen between effective rotations and the prostate delivered dose. Conclusions: Prostate rotations, if left unmanaged, could cause significant underdosing to the target even if daily translational tolerances applied and a 5 mm PTV margin is used. Unlike translations, effective management of prostate rotations requires individualized rotational tolerances due to variations in prostate shape and rotation lever‐arm length among patients. Consequently, individualized rotational tolerances enable PTV margins to be individualized.

SU‐GG‐T‐28: Patient‐Specific Rotational Tolerances and Margins Based on Prostate Shape

Purpose: To determine the impact of prostate shape and daily intra‐fraction translations and rotations on CTV coverage for PTV margins of 2, 3 and 5 mm. Materials/Methods: Twenty‐six patients with adenocarcinoma of the prostate were treated using the Calypso System on an IRB approved protocol. IMRT treatment plans meeting RTOG0126 dosimetric criteria (Dmin=79.2 Gy to 100% of CTV) were created with 2, 3, and 5 mm CTV‐to‐PTV expansions, where the CTV was the contoured prostate gland on the planning CT. Daily average translations and rotations were determined from daily real‐time electromagnetic tracking data. These rotations and translations were then applied to the planned dose distribution to obtain the daily and accumulated dose to structures for all fractions of each patient with 2, 3 and 5 mm PTV expansions. Dose volume histograms (DVHs) are computed on the planned and accumulated dose distributions to evaluate the PTV margin under real target motion. D95 and V79 were used to assess the CTV coverage of the accumulated dose distributions for each PTV margin. A parameter combining prostate average rotation and prostate elongation was deduced from patient data to assess the impact of non‐spherical geometry on target coverage. Results: When daily translations and rotations are included, V7995% was only achieved in 41%, 69% and 81% of cases with 2,3, and 5 mm margins, respectively. A strong correlation was found between elongated CTVs with large rotations, about the left‐right axis, and poor coverage. Conclusions: Rotations can cause large underdosing of the CTV depending on how elongated the prostate is along the sagittal axis. A patient‐specific geometrical parameter could be extracted from the 3D prostate structure and used to determine a PTV margin for adequate coverage within an allowed angular deviation limit. This work supported by supported by NIH R21 CA110485‐02

Dosimetric impact of density variations in Solid Water 457 water-equivalent slabs

The purpose of this study was to determine the dosimetric impact of density variations observed in water‐equivalent solid slabs. Measurements were performed using two 30u2009cm×30u2009cm water‐equivalent slabs, one being 4 cm think and the other 5 cm thick. The location and extent of density variations were determined by computed tomography (CT) scans. Additional imaging measurements were made with an amorphous silicon megavoltage portal imaging device and an ultrasound unit. Dosimetric measurements were conducted with a 2D ion chamber array, and a scanned diode in water. Additional measurements and calculations were made of small rectilinear void inhomogeneities formed with water‐equivalent slabs, using a 2D ion chamber array and the convolution superposition algorithm. Two general types of density variation features were observed on CT images: 1) regions of many centimeters across, but typically only a few millimeters thick, with electron densities a few percent lower than the bulk material, and 2) cylindrical regions roughly 0.2 cm in diameter and up to 20 cm long with electron densities up to 5% lower than the surrounding material. The density variations were not visible on kilovoltage, megavoltage or ultrasound images. The dosimetric impact of the density variations were not detectable to within 0.1% using the 2D ion chamber array or the scanning photon diode at distances 0.4 cm to 2 cm beyond the features. High‐resolution dosimetric calculations using the convolution–superposition algorithm with density corrections enabled on CT‐based datasets showed no discernable dosimetric impact. Calculations and measurements on simulated voids place the upper limit on possible dosimetric variations from observed density variations at much less than 0.6%. CT imaging of water‐equivalent slabs may reveal density variations which are otherwise unobserved with kV, MV, or ultrasound imaging. No dosimetric impact from these features was measureable with an ion chamber array or scanned photon diode. Consequently, they were determined to be acceptable for all clinical use. PACS numbers: 87.55.km, 87.55.Qr

SU‐FF‐T‐455: Methodology to Incorporate the BED and EUD in Patient‐Specific 3‐Dimensional Dosimetry for Non‐Hodgkin's Lymphoma Patients Targeted with 131I Tositumomab Therapy

Purpose: The efficacy of targeted radionuclide therapy depends on the uniformity of radionuclide distribution within the target volume as well as on the radiosensitivity of the tissue. The inclusion of dose non uniformity and biologic effects in the dosimetry of radionuclide may help in correlating dose with patient outcome. Our goal is to develop a methodology incorporating the biologic equivalent dose (BED) and the equivalent uniform dose (EUD) formalism for radionuclide dosimetry.Materials and Methods: A 3D imaging‐based patient‐specific dosimetry methodology was applied to six non‐Hodgkins lymphoma (NHL) patients treated with I‐131 labeled tositumomab for model evaluation purposes. Six registered SPECT/CT scans were obtained for each patient and used to generate 3D dose rate distributions using a Monte Carlo code. The dose rate distributions were integrated over time to obtain 3D time‐dependent absorbed dose distributions using fitted activity curves. Radial deformation model was used to account for tumor regression during therapy relative to initial volume. 3D time‐dependent biological equivalent dose (BED) distributions were calculated and used to estimate a single equivalent uniform dose (EUD) for each tumor volume. Results: The methodology developed in this work allows for the adjustment of model parameters such as radiosensitivity, proliferation, unlabeled protein effect, and clearance time based on patient data. Model outputs are being validated against tumor regression. The EUD values for the tumors included in this study show a reduction between 11% −23% in the efficiency of dose delivery and appear to correlate with tumor regression better than total tumordose.Conclusions: The methodology developed in this work allows for the inclusion of various effects that influence the effectiveness of targeted radionuclide therapy of NHL. Model parameters could be adjusted to aid in improving predictions of patient outcome.

SU‐GG‐T‐253: Interface Dosimetry in Heterogeneous Water Phantom Using EBT Film

Purpose:Interfacedosimetry measurements in heterogeneous phantoms are subject to additional uncertainties when using solid materials due to the presence of air gaps between the materials and the detector. The use of solid materials also limits the location of dosimeters. In this study, we investigate performing interfacedosimetry using EBT film in a liquid water phantom with lung‐equivalent media inside the phantom. Method and Materials: A 6 MV 10×10 cm2 static field was measured at 90 cm SSD with an ionization chamber and EBT film placed in water. Then, interface measurements were made using EBT film or an ion chamber for a 6 MV beam of a 3×3 cm2 static field at 95 cm SSD. The heterogenous phantom consisted of a 4×4×10 cm3lung equivalent material suspended 5 cm below the water surface in 40×40×40 cm3water phantom. The phantom was CT scanned and the images were used for dose calculations. EBT film was placed perpendicular to the central axis at multiple depths and in a parallel orientation at central axis and at ±1 cm off axis. The film extended from the water surface to 12.5 cm depth. Data were averaged over multiple measurements. Film data were compared to Monte Carlo simulations and convolution/superposition calculations. Results: EBT film data obtained in both orientations in water agree, to within 2%, with ion chamber data. In the heterogeneous water phantom, a 3% agreement with Monte Carlo simulations is achieved. Large deviations with convolution and superposition calculations was observed. Conclusion: EBT film is a reliable dosimeter in water with and without the presence of heterogeneity when the film is irradiated parallel or perpendicular to central axis. The film can be used in a variety of phantoms to obtain more reliable measurements for commissioning of sophisticated dose calculations algorithms.

SU‐GG‐T‐409: Equivalent Uniform Dose Calculation for I‐131 Tositumomab Therapy Including the Cold Protein Effect

Purpose: Individualized treatment planning may benefit from equivalent uniform dose (EUD) techniques to help correlate ‘dose’ with objective patient outcome such as time to recurrence or response rate. Our objective is to illustrate methods used to perform EUD calculations, specifically to incorporate the cold protein effect for non‐Hodgkins lymphoma (NHL) patients treated with I‐131 tositumomab. Method and Materials: Data from NHL patients treated with I‐131 tositumomab were imaged multiple times for tracer and therapy studies using a SPECT/CT system. Dose rate calculations were performed by Monte Carlo technique for each image set. A 3D time dependent dose rate description was developed using measured uptake curves for the whole body and tumor volume(s). Tumor subunits were connected between time points using center‐of‐mass alignment and radial deformation. The EUD = −1/α [ ln (〈 S 〉 min )] , where 〈S〉min is the minimum average relative cell survival. S = exp {−α BED } , where the biological equivalent dose BED ( v,t ) = D ( v,t ) +λ t /α * t +λ p /α * P ( v,t ) for each subvolume; D is the dose; and the λt and λp represent the effects of proliferation and cold protein (P). Results: Parameter fits were performed to match changes in tumor size. The tracer study was used to set λp based on patient‐specific tumor response. The λt parameter was set by typical time to progression‐free recurrence rates. The linear‐quadratic parameters were set consistent with hypersensitivity at low dose rates (α=0.7 Gy−1). EUD was calculated contrasting patients for which there was no cold protein effect with substantial cold protein effect. A common parameter set was used to fit the data, only varying by the cold effect parameter. Conclusion: The cold protein effect can be substantial and is being included in the EUD calculation to help correlate delivered dose with patient outcome. Research Support: NIH 2R01 EB001994.