B Hrycushko

A technique for pediatric total skin electron irradiation

BackgroundTotal skin electron irradiation (TSEI) is a special radiotherapy technique which has generally been used for treating adult patients with mycosis fungoides. Recently, two infants presented with leukemia cutis isolated to the skin requiring TSEI. This work discusses the commissioning and quality assurance (QA) methods for implementing a modified Stanford technique using a rotating harness system to position sedated pediatric patients treated with electrons to the total skin.Methods and ResultsCommissioning of pediatric TSEI consisted of absolute calibration, measurement of dosimetric parameters, and subsequent verification in a pediatric patient sized cylindrical phantom using radiographic film and optically stimulated luminance (OSL) dosimeters. The depth of dose penetration under TSEI treatment condition was evaluated using radiographic film sandwiched in the phantom and demonstrated a 2 cm penetration depth with the maximum dose located at the phantom surface. Dosimetry measurements on the cylindrical phantom and in-vivo measurements from the patients suggested that, the factor relating the skin and calibration point doses (i.e., the B-factor) was larger for the pediatric TSEI treatments as compared to adult TSEI treatments. Custom made equipment, including a rotating plate and harness, was fabricated and added to a standard total body irradiation stand and tested to facilitate patient setup under sedated condition. A pediatric TSEI QA program, consisting of daily output, energy, flatness, and symmetry measurements as well as in-vivo dosimetry verification for the first cycle was developed. With a long interval between pediatric TSEI cases, absolute dosimetry was also repeated as part of the QA program. In-vivo dosimetry for the first two infants showed that a dose of ± 10% of the prescription dose can be achieved over the entire patient body.ConclusionThough pediatric leukemia cutis and the subsequent need for TSEI are rare, the ability to commission the technique on a modified TBI stand is appealing for clinical implementation and has been successfully used for the treatment of two pediatric patients at our institution.

Optimization of normalized prescription isodose selection for stereotactic body radiation therapy: Conventional vs robotic linac

PURPOSE Although modern technology has allowed for target dose escalation by minimizing normal tissue dose, the dose delivered to a tumor and surrounding tissues still depends largely on the inherent characteristics of the radiation delivery platform. This work aims to determine the optimal prescription isodose line that minimizes normal tissue irradiation for stereotactic body radiation therapy (SBRT) for a conventional linear accelerator and a robotic delivery platform. METHODS Spherical targets with diameters of 10, 20, and 30 mm were constructed in the lungs and liver of a computer based digital torso phantom which simulates respiratory and cardiac motion. Normal tissue contours included normal lung, normal liver, and a concentric 10 mm shell of normal tissue extending from the spherical target surface. For linac planning, noncoplanar, nonopposing three dimensional (3D) conformal beams were designed, and variable prescription isodose lines were achieved by varying the MLC block margin. For CyberKnife planning, variable prescription isodose lines were achieved by inverse planning. True 4D dose calculations were used for the moving target and surrounding tissue based on each of ten phases of a 4D CT dataset. Doses of 60 Gy in three fractions were prescribed to cover 95% of the target tumor. Commonly used conformality, dosimetric, and radiobiological indices for lung and liver SBRT were used to compare different plans and determine the optimally prescribed isodose line for each treatment platform. RESULTS For linac plans, the average optimal prescription isodose line based on all indices evaluated occurred between 59% and 69% for lung tumors and between 67% and 77% for liver tumors depending on the tumor size. CyberKnife plans had average optimal prescription isodose lines occurring between 40% and 48% for lung tumors and between 41% and 42% depending on the tumor size. However, prescription isodose lines under 50% are not advised to prevent large heterogeneous dose distributions within the target. CONCLUSIONS The choice of prescription isodose line was shown to have a significant impact on parameters commonly used as constraints for lung and liver SBRT treatment planning for both linac-based and CyberKnife delivery platforms. By methodically choosing the prescription isodose line, normal tissue toxicities from SBRT may be reduced.

Feasibility of eradication of breast cancer cells remaining in postlumpectomy cavity and draining lymph nodes following intracavitary injection of radioactive immunoliposomes

Most diagnosed early stage breast cancer cases are treated by lumpectomy and adjuvant radiation therapy, which significantly decreases the locoregional recurrence but causes inevitable toxicity to normal tissue. By using a technique of preparing liposomes carrying technetium-99m ((99m)Tc), rhenium-186 ((186)Re), or rhenium-188 ((188)Re) radionuclides, as well as chemotherapeutic agents, or their combination, for cancer therapy with real time image-monitoring of pharmacokinetics and prediction of therapy effect, this study investigated the potential of a novel targeted focal radiotherapy with low systemic toxicity using radioactive immunoliposomes to treat both the surgical cavity and draining lymph nodes in a rat breast cancer xenograft positive surgical margin model. Immunoliposomes modified with either panitumumab (anti-EGFR) or bevacizumab (anti-VEGF) were remote loaded with (99m)Tc diagnostic radionuclide, and injected into the surgical cavity of female nude rats with positive margins postlumpectomy. Locoregional retention and systemic distribution of (99m)Tc-immunoliposomes were investigated by nuclear imaging, stereofluorescent microscopic imaging, and gamma counting. Histopathological examination of excised draining lymph nodes was performed. The locoregional retention of (99m)Tc-immunoliposomes in each animal was influenced by the physiological characteristics of the surgical site of individual animals. Panitumumab- and bevacizumab-liposome groups had higher intracavitary retention compared with the control liposome groups. Draining lymph node uptake was influenced by both the intracavitary radioactivity retention level and metastasis status. The panitumumab-liposome group had higher accumulation on the residual tumor surface and in the metastatic lymph nodes. Radioactive liposomes that were cleared from the cavity were metabolized quickly and accumulated at low levels in vital organs. Therapeutic radionuclide-carrying specifically targeted panitumumab- and bevacizumab-liposomes have increased potential compared to non-antibody targeted liposomes for postlumpectomy focal therapy to eradicate remaining breast cancer cells inside the cavity and draining lymph nodes with low systemic toxicity.

Multi-staged robotic stereotactic radiosurgery for large cerebral arteriovenous malformations

PURPOSE To investigate a multi-staged robotic stereotactic radiosurgery (SRS) delivery technique for the treatment of large cerebral arteriovenous malformations (AVMs). The treatment planning process and strategies to optimize both individual and composite dosimetry are discussed. METHODS Eleven patients with large (30.7 ± 19.2 cm(3)) AVMs were selected for this study. A fiducial system was designed for fusion of targets between planar angiograms and simulation CT scans. AVMs were contoured based on single contrast CT, MRI and orthogonal angiogram images. AVMs were divided into 3-8 sub-target volumes (3-7 cm(3)) for sequential treatment at 1-4 week intervals to a prescription dose of 16-20 Gy. Forward and inversely developed treatment plans were optimized for 95% coverage of the total AVM volume by dose summation from each sub-volume, while minimizing dose to surrounding tissues. Dose-volume analysis was used to evaluate the PTV coverage, dose conformality (CI), and R50 and V12 Gy parameters. RESULTS The treatment workflow was commissioned and able to localize within 1mm. Inverse optimization outperformed forward planning for most patients for each index considered. Dose conformality was shown comparable to staged Gamma Knife treatments. CONCLUSION The CyberKnife system is shown to be a practical delivery platform for multi-staged treatments of large AVMs using forward or inverse planning techniques.

Deep convolutional neural network with transfer learning for rectum toxicity prediction in cervical cancer radiotherapy: a feasibility study

Better understanding of the dose-toxicity relationship is critical for safe dose escalation to improve local control in late-stage cervical cancer radiotherapy. In this study, we introduced a convolutional neural network (CNN) model to analyze rectum dose distribution and predict rectum toxicity. Forty-two cervical cancer patients treated with combined external beam radiotherapy (EBRT) and brachytherapy (BT) were retrospectively collected, including twelve toxicity patients and thirty non-toxicity patients. We adopted a transfer learning strategy to overcome the limited patient data issue. A 16-layers CNN developed by the visual geometry group (VGG-16) of the University of Oxford was pre-trained on a large-scale natural image database, ImageNet, and fine-tuned with patient rectum surface dose maps (RSDMs), which were accumulated EBRT  +  BT doses on the unfolded rectum surface. We used the adaptive synthetic sampling approach and the data augmentation method to address the two challenges, data imbalance and data scarcity. The gradient-weighted class activation maps (Grad-CAM) were also generated to highlight the discriminative regions on the RSDM along with the prediction model. We compare different CNN coefficients fine-tuning strategies, and compare the predictive performance using the traditional dose volume parameters, e.g. D 0.1/1/2cc, and the texture features extracted from the RSDM. Satisfactory prediction performance was achieved with the proposed scheme, and we found that the mean Grad-CAM over the toxicity patient group has geometric consistence of distribution with the statistical analysis result, which indicates possible rectum toxicity location. The evaluation results have demonstrated the feasibility of building a CNN-based rectum dose-toxicity prediction model with transfer learning for cervical cancer radiotherapy.

Direct intratumoral infusion of liposome encapsulated rhenium radionuclides for cancer therapy: Effects of nonuniform intratumoral dose distribution

PURPOSE Focused radiation therapy by direct intratumoral infusion of lipid nanoparticle (liposome)-carried beta-emitting radionuclides has shown promising results in animal model studies; however, little is known about the impact the intratumoral liposomal radionuclide distribution may have on tumor control. The primary objective of this work was to investigate the effects the intratumoral absorbed dose distributions from this cancer therapy modality have on tumor control and treatment planning by combining dosimetric and radiobiological modeling with in vivo imaging data. METHODS 99mTc-encapsulated liposomes were intratumorally infused with a single injection location to human head and neck squamous cell carcinoma xenografts in nude rats. High resolution in vivo planar imaging was performed at various time points for quantifying intratumoral retention following infusion. The intratumoral liposomal radioactivity distribution was obtained from 1 mm resolution pinhole collimator SPECT imaging coregistered with CT imaging of excised tumors at 20 h postinfusion. Coregistered images were used for intratumoral dosimetric and radiobiological modeling at a voxel level following extrapolation to the therapeutic analogs, 186Re/ 18Re liposomes. Effective uniform dose (EUD) and tumor control probability (TCP) were used to assess therapy effectiveness and possible methods of improving upon tumor control with this radiation therapy modality. RESULTS Dosimetric analysis showed that average tumor absorbed doses of 8.6 Gy/MBq (318.2 Gy/mCi) and 5.7 Gy/MBq (209.1 Gy/mCi) could be delivered with this protocol of radiation delivery for 186Re/188Re liposomes, respectively, and 37-92 MBq (1-2.5 mCi)/g tumor administered activity; however, large intratumoral absorbed dose heterogeneity, as seen in dose-volume histograms, resulted in insignificant values of EUD and TCP for achieving tumor control. It is indicated that the use of liposomes encapsulating radionuclides with higher energy beta emissions, dose escalation through increased specific activity, and increasing the number of direct tumor infusion sites improve tumor control. For larger tumors, the use of multiple infusion locations was modeled to be much more efficient, in terms of activity usage, at improving EUD and TCP to achieve a tumoricidal effect. CONCLUSIONS Direct intratumoral infusion of beta-emitting radionuclide encapsulated liposomes shows promise for cancer therapy by achieving large focally delivered tumor doses. However, the results of this work also indicate that average tumor dose may underestimate tumoricidal effect due to substantial heterogeneity in intratumoral liposomal radionuclide distributions. The resulting intratumoral distribution of liposomes following infusion should be taken into account in treatment planning and evaluation in a clinical setting for an optimal cancer therapy.

Postlumpectomy focal brachytherapy for simultaneous treatment of surgical cavity and draining lymph nodes

PURPOSE The primary objective was to investigate a novel focal brachytherapy technique using lipid nanoparticle (liposome)-carried β-emitting radionuclides (rhenium-186 [(186)Re]/rhenium-188 [(188)Re]) to simultaneously treat the postlumpectomy surgical cavity and draining lymph nodes. METHODS AND MATERIALS Cumulative activity distributions in the lumpectomy cavity and lymph nodes were extrapolated from small animal imaging and human lymphoscintigraphy data. Absorbed dose calculations were performed for lumpectomy cavities with spherical and ellipsoidal shapes and lymph nodes within human subjects by use of the dose point kernel convolution method. RESULTS Dose calculations showed that therapeutic dose levels within the lumpectomy cavity wall can cover 2- and 5-mm depths for (186)Re and (188)Re liposomes, respectively. The absorbed doses at 1 cm sharply decreased to only 1.3% to 3.7% of the doses at 2 mm for (186)Re liposomes and 5 mm for (188)Re liposomes. Concurrently, the draining sentinel lymph nodes would receive a high focal therapeutic absorbed dose, whereas the average dose to 1 cm of surrounding tissue received less than 1% of that within the nodes. CONCLUSIONS Focal brachytherapy by use of (186)Re/(188)Re liposomes was theoretically shown to be capable of simultaneously treating the lumpectomy cavity wall and draining sentinel lymph nodes with high absorbed doses while significantly lowering dose to surrounding healthy tissue. In turn, this allows for dose escalation to regions of higher probability of containing residual tumor cells after lumpectomy while reducing normal tissue complications.

Radiobiological characterization of post-lumpectomy focal brachytherapy with lipid nanoparticle-carried radionuclides

Post-operative radiotherapy has commonly been used for early stage breast cancer to treat residual disease. The primary objective of this work was to characterize, through dosimetric and radiobiological modeling, a novel focal brachytherapy technique which uses direct intracavitary infusion of β-emitting radionuclides (186Re/188Re) carried by lipid nanoparticles (liposomes). Absorbed dose calculations were performed for a spherical lumpectomy cavity with a uniformly injected activity distribution using a dose point kernel convolution technique. Radiobiological indices were used to relate predicted therapy outcome and normal tissue complication of this technique with equivalent external beam radiotherapy treatment regimens. Modeled stromal damage was used as a measure of the inhibition of the stimulatory effect on tumor growth driven by the wound healing response. A sample treatment plan delivering 50 Gy at a therapeutic range of 2.0 mm for 186Re-liposomes and 5.0 mm for 188Re-liposomes takes advantage of the dose delivery characteristics of the β-emissions, providing significant EUD (58.2 Gy and 72.5 Gy for 186Re and 188Re, respectively) with a minimal NTCP (0.046%) of the healthy ipsilateral breast. Modeling of kidney BED and ipsilateral breast NTCP showed that large injected activity concentrations of both radionuclides could be safely administered without significant complications.

Dosimetric comparison of Acuros XB with collapsed cone convolution/superposition and anisotropic analytic algorithm for stereotactic ablative radiotherapy of thoracic spinal metastases

The aim of this study is to compare the recent Eclipse Acuros XB (AXB) dose calculation engine with the Pinnacle collapsed cone convolution/superposition (CCC) dose calculation algorithm and the Eclipse anisotropic analytic algorithm (AAA) for stereotactic ablative radiotherapy (SAbR) treatment planning of thoracic spinal (T-spine) metastases using IMRT and VMAT delivery techniques. The three commissioned dose engines (CCC, AAA, and AXB) were validated with ion chamber and EBT2 film measurements utilizing a heterogeneous slab-geometry water phantom and an anthropomorphic phantom. Step-and-shoot IMRT and VMAT treatment plans were developed and optimized for eight patients in Pinnacle, following our institutional SAbR protocol for spinal metastases. The CCC algorithm, with heterogeneity corrections, was used for dose calculations. These plans were then exported to Eclipse and recalculated using the AAA and AXB dose calculation algorithms. Various dosimetric parameters calculated with CCC and AAA were compared to that of the AXB calculations. In regions receiving above 50% of prescription dose, the calculated CCC mean dose is 3.1%-4.1% higher than that of AXB calculations for IMRT plans and 2.8%-3.5% higher for VMAT plans, while the calculated AAA mean dose is 1.5%-2.4% lower for IMRT and 1.2%-1.6% lower for VMAT. Statistically significant differences (p<0.05) were observed for most GTV and PTV indices between the CCC and AXB calculations for IMRT and VMAT, while differences between the AAA and AXB calculations were not statistically significant. For T-spine SAbR treatment planning, the CCC calculations give a statistically significant overestimation of target dose compared to AXB. AAA underestimates target dose with no statistical significance compared to AXB. Further study is needed to determine the clinical impact of these findings. PACS number: 87.55.D-, 87.53.Ly.The aim of this study is to compare the recent Eclipse Acuros XB (AXB) dose calculation engine with the Pinnacle collapsed cone convolution/superposition (CCC) dose calculation algorithm and the Eclipse anisotropic analytic algorithm (AAA) for stereotactic ablative radiotherapy (SAbR) treatment planning of thoracic spinal (T‐spine) metastases using IMRT and VMAT delivery techniques. The three commissioned dose engines (CCC, AAA, and AXB) were validated with ion chamber and EBT2 film measurements utilizing a heterogeneous slab‐geometry water phantom and an anthropomorphic phantom. Step‐and‐shoot IMRT and VMAT treatment plans were developed and optimized for eight patients in Pinnacle, following our institutional SAbR protocol for spinal metastases. The CCC algorithm, with heterogeneity corrections, was used for dose calculations. These plans were then exported to Eclipse and recalculated using the AAA and AXB dose calculation algorithms. Various dosimetric parameters calculated with CCC and AAA were compared to that of the AXB calculations. In regions receiving above 50% of prescription dose, the calculated CCC mean dose is 3.1%–4.1% higher than that of AXB calculations for IMRT plans and 2.8%–3.5% higher for VMAT plans, while the calculated AAA mean dose is 1.5%–2.4% lower for IMRT and 1.2%–1.6% lower for VMAT. Statistically significant differences (p<0.05) were observed for most GTV and PTV indices between the CCC and AXB calculations for IMRT and VMAT, while differences between the AAA and AXB calculations were not statistically significant. For T‐spine SAbR treatment planning, the CCC calculations give a statistically significant overestimation of target dose compared to AXB. AAA underestimates target dose with no statistical significance compared to AXB. Further study is needed to determine the clinical impact of these findings. PACS number: 87.55.D‐, 87.53.Ly

Improved tumour response prediction with equivalent uniform dose in pre-clinical study using direct intratumoural infusion of liposome-encapsulated 186Re radionuclides

Crucial to all cancer therapy modalities is a strong correlation between treatment and effect. Predictability of therapy success/failure allows for the optimization of treatment protocol and aids in the decision of whether additional treatment is necessary to prevent tumour progression. This work evaluated the relationship between cancer treatment and effect for intratumoural infusions of liposome-encapsulated ¹⁸⁶Re to head and neck squamous cell carcinoma xenografts of nude rats. Absorbed dose calculations using a dose-point kernel convolution technique showed significant intratumoural dose heterogeneity due to the short range of the beta-particle emissions. The use of three separate tumour infusion locations improved dose homogeneity compared to a single infusion location as a result of a more uniform radioactivity distribution. An improved dose-response correlation was obtained when using effective uniform dose (EUD) calculations based on a generic set of radiobiological parameters (R² = 0.84) than when using average tumour absorbed dose (R² = 0.22). Varying radiobiological parameter values over ranges commonly used for all types of tumours showed little effect on EUD calculations, which suggests that individualized parameter use is of little significance as long as the intratumoural dose heterogeneity is taken into consideration in the dose-response relationship. The improved predictability achieved when using EUD calculations for this cancer therapy modality may be useful for treatment planning and evaluation.