Prediction of Tumor Control in 90Y Radioembolization by Logit Models with PET/CT-Based Dose Metrics.

The aim of this work was to develop models for tumor control probability (TCP) in radioembolization with 90Y PET/CT-derived radiobiologic dose metrics. Methods: Patients with primary liver cancer or liver metastases who underwent radioembolization with glass microspheres were imaged with 90Y PET/CT for voxel-level dosimetry to determine lesion absorbed dose (AD) metrics, biological effective dose (BED) metrics, equivalent uniform dose, and equivalent uniform BED for 28 treatments (89 lesions). The lesion dose-shrinkage correlation was assessed on the basis of RECIST and, when available, modified RECIST (mRECIST) at first follow-up. For a subset with mRECIST, logit regression TCP models were fit via maximum likelihood to relate lesion-level binary response to the dose metrics. As an exploratory analysis, the nontumoral liver dose-toxicity relationship was also evaluated. Results: Lesion dose-shrinkage analysis showed that there were no significant differences between model parameters for primary and metastatic subgroups and that correlation coefficients were superior with mRECIST. Therefore, subsequent TCP analysis was performed for the combined group using mRECIST only. The overall lesion-level mRECIST response rate was 57%. The AD and BED metrics yielding 50% TCP were 292 and 441 Gy, respectively. All dose metrics considered for TCP modeling, including mean AD, were significantly associated with the probability of response, with high areas under the curve (0.87-0.90, P < 0.0001) and high sensitivity (>0.75) and specificity (>0.83) calculated using a threshold corresponding to 50% TCP. Because nonuniform AD deposition by microspheres cannot be determined by PET at a microscopic scale, radiosensitivity values extracted here by fitting models to clinical response data were substantially lower than reported for in vitro cell cultures or for external-beam radiotherapy clinical studies. There was no correlation between nontumoral liver AD and toxicity measures. Conclusion: Despite the heterogeneous patient cohort, logistic regression TCP models showed a strong association between various dose metrics and the probability of response. The performance of mean AD was comparable to that of radiobiologic dose metrics that involve more complex calculations. These results demonstrate the importance of considering TCP in treatment planning for radioembolization.

Impact of 90Y PET gradient-based tumor segmentation on voxel-level dosimetry in liver radioembolization.

BACKGROUND: The purpose was to validate 90Y PET gradient-based tumor segmentation in phantoms and to evaluate the impact of the segmentation method on reported tumor absorbed dose (AD) and biological effective dose (BED) in 90Y microsphere radioembolization (RE) patients. A semi-automated gradient-based method was applied to phantoms and patient tumors on the 90Y PET with the initial bounding volume for gradient detection determined from a registered diagnostic CT or MR; this PET-based segmentation (PS) was compared with radiologist-defined morphologic segmentation (MS) on CT or MRI. AD and BED volume histogram metrics (D90, D70, mean) were calculated using both segmentations and concordance/correlations were investigated. Spatial concordance was assessed using Dice similarity coefficient (DSC) and mean distance to agreement (MDA). PS was repeated to assess intra-observer variability. RESULTS: In phantoms, PS demonstrated high accuracy in lesion volumes (within 15%), AD metrics (within 11%), high spatial concordance relative to morphologic segmentation (DSC > 0.86 and MDA < 1.5 mm), and low intra-observer variability (DSC > 0.99, MDA < 0.2 mm, AD/BED metrics within 2%). For patients (58 lesions), spatial concordance between PS and MS was degraded compared to in-phantom (average DSC = 0.54, average MDA = 4.8 mm); the average mean tumor AD was 226 ± 153 and 197 ± 138 Gy, respectively for PS and MS. For patient AD metrics, the best Pearson correlation (r) and concordance correlation coefficient (ccc) between segmentation methods was found for mean AD (r = 0.94, ccc = 0.92), but worsened as the metric approached the minimum dose (for D90, r = 0.77, ccc = 0.69); BED metrics exhibited a similar trend. Patient PS showed low intra-observer variability (average DSC = 0.81, average MDA = 2.2 mm, average AD/BED metrics within 3.0%). CONCLUSIONS: 90Y PET gradient-based segmentation led to accurate/robust results in phantoms, and showed high concordance with MS for reporting mean tumor AD/BED in patients. However, tumor coverage metrics such as D90 exhibited worse concordance between segmentation methods, highlighting the need to standardize segmentation methods when reporting AD/BED metrics from post-therapy 90Y PET. Estimated differences in reported AD/BED metrics due to segmentation method will be useful for interpreting RE dosimetry results in the literature including tumor response data.

Beyond Dose: Using Pretherapy Biomarkers to Improve Dose Prediction of Outcomes for Radioimmunotherapy of Non-Hodgkin Lymphoma.

INTRODUCTION: Non-Hodgkin Lymphoma patients respond differently to therapy according to inherent biological variations. Pretherapy biomarkers may improve dose-response prediction. MATERIALS AND METHODS: Hybrid single-photon emission computed tomography (SPECT)/computed tomography (CT) three-dimensional imaging at multiple time points plus follow-up positron emission tomography (PET)/CT or CT at 2 and 6 months post therapy were used to fit tumor response to combined biological effect and cell clearance models from which three biological effect response parameters (radiosensitivity, cold effect sensitivity, and proliferation potential) were determined per patient. A correlation of biological effect parameters and pretherapy biomarker data (ki67, p53, and phospho-histone H3) allowed a dose-based equivalent biological effect (EBE) to be calculated for each patient. RESULTS: Significant correlations were found between biological effect parameters and pretherapy biomarkers. Optimum correlations were found by splitting the patient data according to p53 status. Response correlation of progression free survival (PFS) and EBE were significantly improved compared with PFS and absorbed dose alone. CONCLUSIONS: It is possible and desirable to use pretherapy biomarkers to enhance the predictive potential of dose calculations for patient-specific treatment planning.

Using a 2D detector array for meaningful and efficient linear accelerator beam property validations.

Following linear accelerator commissioning, the qualified medical physicist is responsible for monitoring the machine's ongoing performance, detecting and investigating any changes in beam properties, and assessing the impact of unscheduled repairs. In support of these responsibilities, the authors developed a method of using a 2D ionization chamber array to efficiently test and validate important linear accelerator photon beam properties. A team of three physicists identified critical properties of the accelerator and developed constancy tests that were sensitive to each of the properties. The result was a 14-field test plan. The test plan includes large and small fields at varying depths, a reduced SSD field at shallow depth for sensitivity to extra focal photon and electron components, and analysis of flatness, symmetry, dose, dose profiles, and dose ratios. Constancy tests were repeated five times over a period of six weeks and used to set upper and lower investigation levels at ± 3 SDs. Deliberate variations in output, penumbra, and energy were tested to determine the suitability of the proposed method. Measurements were also performed on a similar, but distinct, machine to assess test sensitivity. The results demonstrated upper and lower investigation levels significantly smaller than the comparable TG-142 annual recommendations, with the exception of the surrogate used for output calibration, which still fell within the TG-142 monthly recommendation. Subtle changes in output, beam energy, and penumbra were swiftly identified for further investigation. The test set identified the distinct nature of the second accelerator. The beam properties of two photon energies can be validated in approximately 1.5 hrs using this method. The test suite can be used to evaluate the impact of minor repairs, detect changes in machine performance over time, and supplement other machine quality assurance testing.

Tumor-Absorbed Dose Predicts Progression-Free Survival Following (131)I-Tositumomab Radioimmunotherapy.

UNLABELLED: The study aimed at identifying patient-specific dosimetric and nondosimetric factors predicting outcome of non-Hodgkin lymphoma patients after (131)I-tositumomab radioimmunotherapy for potential use in treatment planning. METHODS: Tumor-absorbed dose measures were estimated for 130 tumors in 39 relapsed or refractory non-Hodgkin lymphoma patients by coupling SPECT/CT imaging with the Dose Planning Method (DPM) Monte Carlo code. Equivalent biologic effect was calculated to assess the biologic effects of nonuniform absorbed dose including the effects of the unlabeled antibody. Evaluated nondosimetric covariates included histology, presence of bulky disease, and prior treatment history. Tumor level outcome was based on volume shrinkage assessed on follow-up CT. Patient level outcome measures were overall response (OR), complete response (CR), and progression-free survival (PFS), determined from clinical assessments that included PET/CT. RESULTS: The estimated mean tumor-absorbed dose had a median value of 275 cGy (range, 94-711 cGy). A high correlation was observed between tracer-predicted and therapy-delivered mean tumor-absorbed doses (P < 0.001; r = 0.85). In univariate tumor-level analysis, tumor shrinkage correlated significantly with almost all of the evaluated dosimetric factors, including equivalent biologic effect. Regression analysis showed that OR, CR, and PFS were associated with the dosimetric factors and equivalent biologic effect. Both mean tumor-absorbed dose (P = 0.025) and equivalent biologic effect (P = 0.035) were significant predictors of PFS whereas none of the nondosimetric covariates were found to be statistically significant factors affecting PFS. The most important finding of the study was that in Kaplan-Meier curves stratified by mean dose, longer PFS was observed in patients receiving mean tumor-absorbed doses greater than 200 cGy than in those receiving 200 cGy or less (median PFS, 13.6 vs. 1.9 mo for the 2 dose groups; log-rank P < 0.0001). CONCLUSION: A higher mean tumor-absorbed dose was significantly predictive of improved PFS after (131)I-tositumomab radioimmunotherapy. Hence tumor-absorbed dose, which can be estimated before therapy, can potentially be used to design radioimmunotherapy protocols to improve efficacy.

Biological-effect modeling of radioimmunotherapy for non-hodgkins lymphoma: determination of model parameters.

UNLABELLED: Treatment with Tositumomab and 131I tositumomab anti-CD20 radioimmunotherapy (Bexxar) yields a nonradioactive antibody antitumor response (the so-called cold effect) and a radiation response. Numerical parameter determination by least-squares (LS) fitting was implemented for more accurate parameter estimates in equivalent biological-effect calculations. METHODS: One hundred thirty-two tumors in 37 patients were followed using five or six SPECT/CT studies per patient, three each (typical) post-tracer (0.2 GBq) and post-therapy (∼3 GBq) injections. The SPECT/CT data were used to calculate position- and time-dependent dose rates and antibody concentrations for each tumor. CT-defined tumor volumes were used to track tumor volume changes. Combined biological-effect and cell-clearance models were fit to tumor volume changes. Optimized parameter values determined using LS fitting were compared to previous fitted values that were determined by matching calculated to measured tumor volume changes using visual assessment. Absorbed dose sensitivity (α) and cold-effect sensitivity (λp) parameters were the primary fitted parameters, yielding equivalent biological-effect (E) values. RESULTS: Individual parameter uncertainties were approximately 10% and 30% for α and λp, respectively. LS versus previously fit parameter values were highly correlated, although the averaged α value decreased and the averaged λp value increased for the LS fits compared to the previous fits. Correlation of E with 2-month tumor shrinkage data was similar for the two fitting techniques. The LS fitting yielded improved fit quality and likely improved parameter estimation.

Audit tool for external beam radiation therapy departments.

PURPOSE: Development of a self-contained audit tool for external beam radiation therapy to assess compliance with the major recommendations from professional organizations and generally accepted standards of practice. Intensity modulated radiation therapy, stereotactic body radiation therapy, stereotactic radiosurgery, and volumetric modulated arc therapy were included in this review. METHODS AND MATERIALS: A physics quality working group developed a department vision, distinguished and summarized key references, and condensed important elements of good documentation practices. The results were then compiled in a checklist format and used to perform audits at 3 sites. RESULTS: The final audit tool contains 65 items spanning a wide range of external beam radiation therapy practices. Several of the audit items address issues not commonly identified by other authoritative sources. A total of 48 process improvements were identified at the 3 sites audited. CONCLUSIONS: The enclosed self-inspection list may be useful to a site as an annual review tool, as an aid in preparation for the American College of Radiology-American Society for Therapeutic Radiology and Oncology practice accreditation, or as a catalyst for general quality improvement. Sites can quickly identify opportunities for improvement by concentrating on high importance items and commonly identified areas of noncompliance.

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

PURPOSE: Improved 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 (131)I-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. METHODS: Fifty-seven tumors in 19 patients were followed using 6 single proton emission computed tomography (SPECT)/CT studies, 3 each post tracer (5 mCi) and therapy (∼100 mCi) injections with tositumomab and (131)I-tositumomab. Both injections used identical antibody mass, a flood dose of 450 mg plus 35 mg of (131)I 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. RESULTS: Patient 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). CONCLUSION: Fit parameters can be used to categorize patient response, implying a potential predictive capability.

Analysis of variation in calibration curves for Kodak XV radiographic film using model-based parameters.

Film calibration is time-consuming work when dose accuracy is essential while working in a range of photon scatter environments. This study uses the single-target single-hit model of film response to fit the calibration curves as a function of calibration method, processor condition, field size and depth. Kodak XV film was irradiated perpendicular to the beam axis in a solid water phantom. Standard calibration films (one dose point per film) were irradiated at 90 cm source-to-surface distance (SSD) for various doses (16-128 cGy), depths (0.2, 0.5, 1.5, 5, 10 cm) and field sizes (5 × 5, 10 × 10 and 20 × 20 cm²). The 8-field calibration method (eight dose points per film) was used as a reference for each experiment, taken at 95 cm SSD and 5 cm depth. The delivered doses were measured using an Attix parallel plate chamber for improved accuracy of dose estimation in the buildup region. Three fitting methods with one to three dose points per calibration curve were investigated for the field sizes of 5 × 5, 10 × 10 and 20 × 20 cm². The inter-day variation of model parameters (background, saturation and slope) were 1.8%, 5.7%, and 7.7% (1 σ) using the 8-field method. The saturation parameter ratio of standard to 8-field curves was 1.083 ± 0.005. The slope parameter ratio of standard to 8-field curves ranged from 0.99 to 1.05, depending on field size and depth. The slope parameter ratio decreases with increasing depth below 0.5 cm for the three field sizes. It increases with increasing depths above 0.5 cm. A calibration curve with one to three dose points fitted with the model is possible with 2% accuracy in film dosimetry for various irradiation conditions. The proposed fitting methods may reduce workload while providing energy dependence correction in radiographic film dosimetry. This study is limited to radiographic XV film with a Lumisys scanner.

Dose discrepancies in the buildup region and their impact on dose calculations for IMRT fields.

PURPOSE: Dose accuracy in the buildup region for radiotherapy treatment planning suffers from challenges in both measurement and calculation. This study investigates the dosimetry in the buildup region at normal and oblique incidences for open and IMRT fields and assesses the quality of the treatment planning calculations. METHODS: This study was divided into three parts. First, percent depth doses and profiles (for 5 x 5, 10 x 10, 20 x 20, and 30 x 30 cm2 field sizes at 0 degrees, 45 degrees, and 70 degrees incidences) were measured in the buildup region in Solid Water using an Attix parallel plate chamber and Kodak XV film, respectively. Second, the parameters in the empirical contamination (EC) term of the convolution/ superposition (CVSP) calculation algorithm were fitted based on open field measurements. Finally, seven segmental head-and-neck IMRT fields were measured on a flat phantom geometry and compared to calculations using gamma and dose-gradient compensation (C) indices to evaluate the impact of residual discrepancies and to assess the adequacy of the contamination term for IMRT fields. RESULTS: Local deviations between measurements and calculations for open fields were within 1% and 4% in the buildup region for normal and oblique incidences, respectively. The C index with 5%/1 mm criteria for IMRT fields ranged from 89% to 99% and from 96% to 98% at 2 mm and 10 cm depths, respectively. The quality of agreement in the buildup region for open and IMRT fields is comparable to that in nonbuildup regions. CONCLUSIONS: The added EC term in CVSP was determined to be adequate for both open and IMRT fields. Due to the dependence of calculation accuracy on (1) EC modeling, (2) internal convolution and density grid sizes, (3) implementation details in the algorithm, and (4) the accuracy of measurements used for treatment planning system commissioning, the authors recommend an evaluation of the accuracy of near-surface dose calculations as a part of treatment planning commissioning.

131I-tositumomab radioimmunotherapy: initial tumor dose-response results using 3-dimensional dosimetry including radiobiologic modeling.

UNLABELLED: 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 (131)I-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.

UNLABELLED: 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 (131)I-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 (131)I-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.

Radiographic film dosimetry for IMRT fields in the nearsurface buildup region.

Radiographic film dosimetry provides fast, convenient 2-D dose distributions, but is challenged by the dependence of film response on scatter conditions (i.e., energy dependence). Verification of delivered dose in the surface buildup region is important for intensity modulated radiation therapy (IMRT) when volumes of interest encroach on these regions (e.g., head/neck, breast). The current work demonstrates that film dosimetry can accurately predict the dose in the buildup region for IMRT, since 1) film dosimetry can be performed with sufficient accuracy for small fields and 2) IMRT is delivered by a series of "small" segments (step and shoot IMRT). This work evaluates the accuracy of X-OMAT V (XV) and Extended Dose Range (EDR) film for measurements from 2 mm to 15 mm depths for small fields and clinical IMRT beams. Film measurements have been compared to single point measurements made with a stereotactic diode and parallel plate ionization chamber (P11) and thermoluminescent dosimeters (TLD) at various depths for square (diode, P11) and IMRT (diode, TLD) fields. Film calibration was performed using an 8-field step exposure on a single film at 5 cm depth, which has been corrected to represent either small field or large field depth dependent film calibration techniques. Up to 10% correction for film response variation as a function of depth was required for measurements in the buildup region. A depth-dependent calibration can sufficiently improve the accuracy for IMRT calculation verification (i.e., < or = 5% uncertainty). A small field film calibration technique was most appropriate for IMRT field measurements. Improved buildup region dose measurements for clinical IMRT fields promotes improved dose estimation performance for (inverse) treatment planning and allows more quantitative treatment delivery validation.

Assessment of skin dose for breast chest wall radiotherapy as a function of bolus material.

Skin dose assessment for chest wall radiotherapy is important to ensure sufficient dose to the surface target volume without excessive skin reaction. This study quantified changes to the surface doses as a function of bolus material for conventional and intensity modulated radiation therapy (IMRT) tangential fields. Three types of bolus materials (2 mm solid, 2 mm fine mesh and 3.2 mm large mesh Aquaplast) were compared with Superflab. Surface dose measurements were performed using an Attix parallel plate chamber in a flat solid water phantom at 0 degrees , 45 degrees and 70 degrees incident angles. Over-response correction factors were applied to the Attix chamber results for different incident angles. Surface dose measurements on an anthropomorphic phantom were done using a thermoluminescent dosimeter extrapolation method. Dose characteristics of Superflab and solid Aquaplast were within 2% of solid water material. No significant differences (within 3%) in the surface dose were found between conventional and IMRT tangential techniques. The bolus effect was large for chest wall tangential radiotherapy, with up to an 82% increase using 2 mm fine mesh Aquaplast. The dosimetric effect of different Aquaplast materials has been quantified in this work. These materials can be used to create a custom bolus with potentially better reproducibility of placement.

Accuracy of rapid radiographic film calibration for intensity-modulated radiation therapy verification.

A single calibration film method was evaluated for use with intensity-modulated radiation therapy film quality assurance measurements. The single-film method has the potential advantages of exposure simplicity, less media consumption, and improved processor quality control. Potential disadvantages include cross contamination of film exposure, implementation effort to document delivered dose, and added complication of film response analysis. Film response differences were measured between standard and single-film calibration methods. Additional measurements were performed to help trace causes for the observed discrepancies. Kodak X-OmatV (XV) film was found to have greater response variability than extended dose range (EDR) film. We found it advisable for XV film to relate the film response calibration for the single-film method to a user-defined optimal calibration geometry. Using a single calibration film exposed at the time of experiment, the total uncertainty of film response was estimated to be <2% (1%) for XV (EDR) film at 50 (100) cGy and higher, respectively.

Intraperitoneal radioimmunotherapy with a humanized anti-TAG-72 (CC49) antibody with a deleted CH2 region.

The application of intraperitoneal (i.p.) radioimmunotherapy to treat i.p. tumor loci has been limited by bone marrow toxicity secondary to circulating radiolabeled antibodies. The generation of novel genetically engineered monoclonal antibodies, which can achieve high tumor uptake and rapid blood clearance, should enhance the therapeutic index of i.p. radioimmunotherapy. In this regard, a novel humanized anti-TAG-72 monoclonal antibody with a deleted CH2 region (HuCC49DeltaCH2) has been described, which localized well to subcutaneous xenograft tumors and had a rapid plasma clearance. The aim of this study was to examine the characteristics of this radiolabeled reagent when administered through the i.p. route in mice bearing i.p. tumor (LS174T). The DeltaCH2 molecule and intact humanized CC49 (HuCC49) monoclonal antibody were conjugated to PA-DOTA and radiolabeled with (177)Lu. Both molecules retained high-affinity binding to TAG-72 positive LS174T tumor cells in vitro. The radiolabeled DeltaCH2 molecule had a modest decrease in tumor localization, as compared to the intact molecule when administered i.p. to tumor-bearing mice and a dramatically shorter plasma disappearance T(1/2) at 2.7 hours compared to 61.2 hours for the intact antibody. The radiolabeled DeltaCH2 molecule thus had very high tumor:blood ratios. Using an (131)I-labeled system, the maximum tolerated dose of DeltaCH2 was >3x that of intact HuCC49. Autoradiography of tumors showed low radiation dose rates at tumor centers early (1 and 4 hours), as compared to higher dose rates at tumor periphery but a more uniform distribution by 24 hours. Dose-rate distributions were similar for both reagents. Animals bearing LS174T i.p. tumors were treated with 300 microCi of (177)Lu-labeled DeltaCH2 or intact HuCC49 by i.p. route daily x 3. The (177)Lu-DeltaCH(2) molecule mediated an increase in median survival compared to controls (67.5 +/- 7.5 days versus controls of 32 +/- 3.3) while the same dose of (177)Lu-HuCC49 produced early toxic deaths. These studies suggest that i.p. radioimmunotherapy using radiolabeled HuCC49DeltaCH2 should allow higher radiation doses to be administered with less marrow toxicity and potentially improved efficacy.

Functional anatomy of the prostate: implications for treatment planning.

PURPOSE: To summarize the functional anatomy relevant to prostate cancer treatment planning. METHODS AND MATERIALS: Coronal, axial, and sagittal T2 magnetic resonance imaging (MRI) and MRI angiography were fused by mutual information and registered with computed tomography (CT) scan data sets to improve definition of zonal anatomy of the prostate and critical adjacent structures. RESULTS: The three major prostate zones (inner, outer, and anterior fibromuscular) are visible by T2 MRI imaging. The bladder, bladder neck, and internal (preprostatic) sphincter are a continuous muscular structure and clear definition of the preprostatic sphincter is difficult by MRI. Transition zone hypertrophy may efface the bladder neck and internal sphincter. The external "lower" sphincter is clearly visible by T2 MRI with wide variations in length. The critical erectile structures are the internal pudendal artery (defined by MRI angiogram or T2 MRI), corpus cavernosum, and neurovascular bundle. The neurovascular bundle is visible along the posterior lateral surface of the prostate on CT and MRI, but its terminal branches (cavernosal nerves) are not visible and must be defined by their relationship to the urethra within the genitourinary diaphragm. Visualization of the ejaculatory ducts within the prostate is possible on sagittal MRI. The anatomy of the prostate-rectum interface is clarified by MRI, as is the potentially important distinction of rectal muscle and rectal mucosa. CONCLUSION: Improved understanding of functional anatomy and imaging of the prostate and critical adjacent structures will improve prostate radiation therapy by improvement of dose and toxicity correlation, limitation of dose to critical structures, and potential improvement in post therapy quality of life.

Use and uncertainties of mutual information for computed tomography/ magnetic resonance (CT/MR) registration post permanent implant of the prostate.

Post-implant dosimetric analysis for permanent implant of the prostate benefits from the use of a computed tomography (CT) dataset for optimal identification of the radioactive source (seed) positions and a magnetic resonance (MR) dataset for optimal description of the target and normal tissue volumes. The CT/MR registration process should be fast and sufficiently accurate to yield a reliable dosimetric analysis. Since critical normal tissues typically reside in dose gradient regions, small shifts in the dose distribution could impact the prediction of complication or complication severity. Standard procedures include the use of the seed distribution as fiducial markers (seed match), a time consuming process that relies on the proper identification of signals due to the same seed on both datasets. Mutual information (MI) is more efficient because it uses image data requiring minimal preparation effort. A comparison of MI registration and seed-match registration was performed for twelve patients. MI was applied to a volume limited to the prostate and surrounding structures, excluding most of the pelvic bone structures (margins around the prostate gland were approximately 2 cm right-left, approximately 1 cm anterior-posterior, and approximately 2 cm superior-inferior). Seeds were identified on a 2 mm slice CT dataset using an automatic seed identification procedure on reconstructed three-dimensional data. Seed positions on the 3 mm slice thickness T2 MR data set were identified using a point-and-click method on each image. Seed images were identified on more than one MR slice, and the results used to determine average seed coordinates for MR images and matched seed pairs between CT and MR images. On average, 42% (19%-64%) of the seeds (19-54 seeds) were identified and matched to their CT counterparts. A least-squares method applied to the CT and MR seed coordinates was used to produce the optimum seed-match registration. MI registration and seed match registration angle differences averaged 0.5 degrees, which was not significantly different from zero. Translation differences averaged 0.6 (1.2 standard deviation) mm right-left, -0.5(1.5) mm posterior-anterior, and -1.2(2.0) mm inferior-superior. Registration error estimates were approximately 2 mm for both the MI and seed-match methods. The observed standard deviations in the offset values were consistent with propagation of error. Registration methods as applied here using mutual information and seed matching are consistent, except for a small systematic difference in the inferior-superior axis for a minority of cases (approximately 15%). Cases registered with mutual information and with bony anatomy misregistration of greater than approximately 5 mm should be evaluated for rescan or seed-match registration. The improvement in efficiency of use for the MI registration method is substantial, approximately 30 min compared to several hours using seed match registration.

Vessel-sparing prostate radiotherapy: dose limitation to critical erectile vascular structures (internal pudendal artery and corpus cavernosum) defined by MRI.

PURPOSE: Most evidence suggests that impotence after prostate radiation therapy has a vascular etiology. The corpus cavernosum (CC) and the internal pudendal artery (IPA) are the critical vascular structures related to erectile function. This study suggests that it is feasible to markedly decrease radiation dose to the CC and the IPA and directly determine the impact of dose limitation on potency. METHODS AND MATERIALS: Twenty-five patients (10 external beam, 15 brachytherapy) underwent MRI/CT-based treatment planning for prostate cancer. In addition, 10 patients entered on the vessel-sparing protocol underwent a time-of-flight MRI angiography sequence to define the IPA. The distance from the MRI-defined prostate apex to the penile bulb (PB), CC, and IPA was measured and compared to the distance from the CT-defined apex. Doses (D5 and D50) to the PB, CC, and IPA were determined for an 80 Gy external beam course. In 5 patients, CT plans were generated and compared to MRI-based plans. RESULTS: The combination of coronal, sagittal, and axial MRI data sets allowed superior definition of the prostate apex and its relationship to critical vascular structures. The apex to PB distance averaged 1.45 cm (0.36 standard deviation) with a range of 0.7 cm to 2.1 cm. Peak dose (D5) to the proximal CC in the MRI-planned 80 Gy course was 26 (9) Gy (0.36 of CT-planned dose), and peak dose to the IPA was 39 (13) Gy (0.61 of CT-planned dose). CONCLUSION: The distance between the prostate apex and critical vascular structures is highly variable. Current empiric rules for CT contouring (apex 1.5 cm above PB) overestimate or underestimate the distance between the prostate apex and critical vascular structures. When defined by MRI T2 and MRI angiogram with CT registration, limitation of dose to critical erectile structures is possible, with a more significant gain than has been previously reported using dose limitation by commonly applied intensity modulated radiation therapy studies based on CT imaging. These techniques make "vessel-sparing" prostate radiotherapy feasible.