Mean Kidney Dose Research Articles

A Four-dimensional Computed Tomography Generated Internal Target Volume Approach to Paediatric High Risk Neuroblastoma to Reduce Organ at Risk and Normal Tissue Irradiation

AimsThe magnitude of upper abdominal organ motion in children may be overestimated by current planning target volumes (PTV). A four-dimensional computed tomography (4DCT) – derived internal target volume (ITV) is frequently used in adult radiotherapy to take respiratory-related organ motion into account. In this study, the dosimetric consequences for target coverage and organs at risk from the use of an ITV approach compared to standard PTV margins in children with high-risk neuroblastoma were investigated. Materials and methods14 patients, median age 4.1 years, range 1.5 – 18.9 years, (9 midline targets, 5 lateralised) each had two dual arc volumetric modulated arc therapy (VMAT) plans (14 ×1.5 Gy) generated. One used an ITV-approach; motion information derived from 4DCT (PTV_itv) with a 5mm ITV to PTV expansion, and the other a PTV margin of 10mm from CTV to PTV (PTV_standard). Differences in absolute PTV volume and organ at risk doses are described. ResultsThe ITV approach resulted in a highly significant reduction in PTV size of 38% (p<0.0001). For midline targets, an ITV approach resulted in a small but statistically significant reduction in combined mean kidney dose of 0.8Gy, p 0.01. Mean heart and lung dose were reduced by an average of 1 Gy with an ITV approach. Non-PTV integral dose from 30.4 Gy L to 27.8 Gy L using an ITV approach. ConclusionAn ITV-approach to respiratory related organ motion management in children can significantly reduce absolute PTV volumes, maintain target coverage and reduce dose delivered to normal tissue in proximity to the target. This is an essential step to maximising the benefits of highly conformal radiotherapy techniques including VMAT for this patient group, and in the future with Proton Therapy.

Clinical Outcomes of Image-Guided Volumetric Modulated Arc Therapy for Total Body Irradiation

Volumetric modulated arc therapy (VMAT)-based total body irradiation (TBI) with image guidance is a novel technique that is increasing in implementation. Compared to conventional TBI, VMAT-TBI offers favorable dose homogeneity, better organ-at-risk sparing, and enhanced patient comfort. However, whether these dosimetric advantages translate to improved clinical outcomes that justify the increased planning and delivery burden is not well understood. Only a single study of clinical outcomes of VMAT-TBI exists in the literature. We present the largest study to date of clinical outcomes of VMAT-TBI. In this IRB-approved retrospective single-institution study, all patients treated with VMAT-TBI conditioning for allogeneic stem cell transplant, per the institution's published protocol, were identified. Dosimetric data were abstracted from the radiation oncology treatment planning system. Clinical data were abstracted from the electronic medical record. The primary outcome was six-month overall survival (6M OS) from the last day of TBI by Kaplan-Meier method. Fifty-five patients (47 adult and 8 pediatric) were treated with VMAT-TBI between June 2020 and December 2022. All patients received conditioning chemotherapy with standard-dose TBI of 12 or 13.2 Gy in 8 twice-daily fractions. The PTV coverage (V95%) mean was 95.3% ± 1.2%. Mean lung dose was 9.5 Gy ± 0.6 for adult patients and 8.4 Gy ± 0.9 for pediatric patients. Mean lung dose rate was 18.0 cGy/min ± 4.4. Mean kidney dose was 5.9 Gy ± 0.6. Mean skin dose measured by MOSFET was 12.7 Gy ± 1.2. Median treatment time was 63 minutes (range: 53-104). Median follow-up was 7.7 months. At most recent follow-up, 78% of patients were alive. 6M OS was 82%. Common acute toxicities were fatigue (90.9% of patients, all grade 1-2), diarrhea (70.9%, all grade 1-2), nausea (76.4%, all grade 1-2), mucositis (60% grade 1-2, 12.7% grade 3, 1.8% grade 4, no grade 5), and xerostomia (54.5%, all grade 1). Mean pretreatment FEV1 was 98.3 percent of predicted (%p) ± 11.9%p and mean posttreatment FEV1 was 94.7%p ± 13.8%p. Mean pretreatment GFR was 101.4mL/min/1.73m² ± 17.4, mean 3-month posttreatment GFR was 92.4 ± 20.0, and mean 6-month posttreatment GFR was 97.5 ± 26.48. One patient experienced grade 2 pneumonitis; there were no other cases of pneumonitis. There were no acute grade 3+ toxicities aside from mucositis. Observed late toxicities were cataracts (7.3%, all grades 1-3) and hypothyroidism (12.7%, all grades 1-2). There were no grade 3+ late toxicities. Mild acute graft-versus-host disease (GVHD) was noted in 27.2% of patients and mild chronic GVHD was noted in 14.5% of patients, with no other cases of GVHD. In the largest series to date, VMAT-TBI had excellent oncologic and toxicity outcomes. A randomized trial of VMAT-TBI versus standard TBI is warranted.

Autologous Stem Cell Transplantation with Intensity Modulated Total Body Irradiation Conditioning for Systemic Sclerosis

Based on the seminal SCOT trial, autologous stem cell transplantation (HSCT) using myeloablative total body irradiation (TBI) and anti-thymocyte globulin (ATG) as a conditioning regimen has become a standard treatment option for certain patients with systemic sclerosis (SSc). In patients with SSc, normal organs are more radiosensitive and prone to compromised function, and therefore lungs and kidneys require dose reduction. With traditional techniques, TBI requires heavy and thick physical blocks, which can be cumbersome and have poor reproducibility. We hypothesized that intensity modulated radiation therapy (IMRT) TBI compared to standard anteroposterior (AP)/posteroanterior (PA) TBI would facilitate improvements in dosimetry and reproducibility (due to not requiring physical blocks) without compromising outcomes. Herein, we report a single-institution retrospective analysis of patients with SSc treated with an IMRT TBI. Patients with SSc who underwent HSCT with TBI between 2017 and 2022 were eligible. All patients underwent conditioning with equine ATG, cyclophosphamide 120 mg/kg, and IMRT TBI administered twice-daily to a total dose of 800 cGy in 200 cGy fractions. A minimum of 80% of the PTV was to receive prescription dose. Mean lung and kidney dose were to be less than 200 cGy. Patients were then replanned using an AP/PA technique for dosimetric comparison. The primary endpoint was planning target volume (PTV), lung, and kidney dosimetry. Secondary endpoints included event-free survival (EFS), overall survival (OS), disease-modifying antirheumatic drug-free survival (DMARD-FS), treatment related mortality (TRM), and toxicity. A total of 14 patients were eligible for our analysis. On dosimetric analysis, the mean dose to the PTV was significantly higher on the IMRT compared to the AP/PA plans (809.4 cGy versus 728.5 cGy, p<0.001). The mean dose to the lungs (239.5 cGy versus 443.9 cGy, p<0.001) and kidneys (204.9 cGy versus 281.2 cGy, p<0.001) was significantly lower. Median follow-up was 34.6 months (1.0-51.7 months). There was one case of TRM secondary to respiratory failure. The 24-month OS, EFS, and DMARD-FS estimates were 92.9%, 74.3%, and 70.0%, respectively. Three patients experienced adverse events, which included respiratory failure (n = 1), renal failure (n = 1), and death (n = 1). No patients experienced clinically significant pneumonitis or nephritis that were deemed to be a likely consequence of TBI. Five patients subsequently initiated DMARDs, but three did so due to worsening skin symptoms without other major organ dysfunction. Use of IMRT TBI as part of the conditioning regimen for HSCT for SSc yields improved dosimetry relative to a standard AP/PA technique, with efficacy and toxicity outcomes comparable with published data. This technique should be considered for patients undergoing HSCT for SSc and warrants inclusion in prospective trials for SSc that involve TBI.

Clinical Characterization of a Table Mounted Range Shifter Board for Synchrotron-Based Intensity Modulated Proton Therapy for Pediatric Craniospinal Irradiation.

Purpose: To report our design, manufacturing, commissioning and initial clinical experience with a table-mounted range shifter board (RSB) intended to replace the machine-mounted range shifter (MRS) in a synchrotron-based pencil beam scanning (PBS) system to reduce penumbra and normal tissue dose for image-guided pediatric craniospinal irradiation (CSI). Methods: A custom RSB was designed and manufactured from a 3.5 cm thick slab of polymethyl methacrylate (PMMA) to be placed directly under patients, on top of our existing couch top. The relative linear stopping power (RLSP) of the RSB was measured using a multi-layer ionization chamber, and output constancy was measured using an ion chamber. End-to-end tests were performed using the MRS and RSB approaches using an anthropomorphic phantom and radiochromic film measurements. Cone beam CT (CBCT) and 2D planar kV X-ray image quality were compared with and without the RSB present using image quality phantoms. CSI plans were produced using MRS and RSB approaches for two retrospective pediatric patients, and the resultant normal tissue doses were compared. Results: The RLSP of the RSB was found to be 1.163 and provided computed penumbra of 6.9 mm in the phantom compared to 11.8 mm using the MRS. Phantom measurements using the RSB demonstrated errors in output constancy, range, and penumbra of 0.3%, -0.8%, and 0.6 mm, respectively. The RSB reduced mean kidney and lung dose compared to the MRS by 57.7% and 46.3%, respectively. The RSB decreased mean CBCT image intensities by 86.8 HU but did not significantly impact CBCT or kV spatial resolution providing acceptable image quality for patient setup. Conclusions: A custom RSB for pediatric proton CSI was designed, manufactured, modeled in our TPS, and found to significantly reduce lateral proton beam penumbra compared to a standard MRS while maintaining CBCT and kV image-quality and is in routine use at our center.

Comparison of Craniospinal Irradiation Using Proton Beams According to Irradiation Method and Initial Experience Treating Pediatric Patients

This study compared craniospinal irradiation using proton beam therapy (PBT) according to irradiation method and investigated the initial effects. Twenty-four pediatric patients (1-24 years old) who received proton craniospinal irradiation were examined. Passive scattered PBT (PSPT) and intensity modulated PBT (IMPT) were used in 8 and 16 patients, respectively. The whole vertebral body technique was used for 13 patients <10 years old, and the vertebral body sparing (VBS) technique was used for the remaining 11 patients aged ≥10 years. The follow-up period was 17 to 44 (median, 27) months. Organ-at-risk and planning target volume (PTV) doses and other clinical data were examined. The maximum lens dose using IMPT was lower than that using PSPT (P=.008). The mean thyroid, lung, esophagus, and kidney doses were lower in patients treated using the VBS technique compared with the whole vertebral body technique (all P < .001). The minimum PTV dose of IMPT was higher than that of PSPT (P=.01). The inhomogeneity index of IMPT was lower than that of PSPT (P=.004). IMPT is better than PSPT at reducing the dose to the lens. The VBS technique can decrease the doses to neck-chest-abdomen organs. The PTV coverage of IMPT is superior to that of PSPT.

A Realistic Multiregion Mouse Kidney Dosimetry Model to Support the Preclinical Evaluation of Potential Nephrotoxicity of Radiopharmaceutical Therapy.

Suborgan absorbed dose estimates in mouse kidneys are crucial to support preclinical nephrotoxicity analyses of α- and β-particle-emitting radioligands exhibiting a heterogeneous activity distribution in the kidneys. This is, however, limited by the scarcity of reference dose factors (S values) available in the literature for specific mouse kidney tissues. Methods: A computational multiregion model of a mouse kidney based on high-resolution MRI data from a healthy mouse kidney was developed. The model was used to calculate S values for 5 kidney tissues (cortex, outer and inner stripes of outer medulla, inner medulla, and papilla and pelvis) for a wide range of β- or α-emitting radionuclides (45 in total) of interest for radiopharmaceutical therapy, using Monte Carlo calculations. Additionally, regional S values were applied for a 131I-labeled single-domain antibody fragment with predominant retention in the outer stripe of the renal outer medulla. Results: The heterogeneous activity distribution in kidneys of considered α- and low- to medium-energy β-emitters considerably affected the absorbed dose estimation in specific suborgan regions. The suborgan tissue doses resulting from the nonuniform distribution of the 131I-labeled antibody fragment largely deviated (from -40% to 57%) from the mean kidney dose resulting from an assumed uniform activity distribution throughout the whole kidney. The absorbed dose in the renal outer stripe was about 2.0 times higher than in the cortex and in the inner stripe and about 2.6 times higher than in inner tissues. Conclusion: The use of kidney regional S values allows a more realistic estimation of the absorbed dose in different renal tissues from therapeutic radioligands with a heterogeneous uptake in the kidneys. This constitutes an improvement from the simplistic (less accurate) renal dose estimates assuming a uniform distribution of activity throughout kidney tissues. Such improvement in dosimetry is expected to support preclinical studies essential for a better understanding of nephrotoxicity in humans. The dosimetric database has added value in the development of new molecular vectors for radiopharmaceutical therapy.

A dosimetric comparison of 3D DCAT vs VMAT for palliative and early-stage liver lesions using eclipse TPS.

Volumetric modulated arc therapy (VMAT) and 3D dynamic conformal arc therapy (DCAT) are 2 methods proven useful for the clinical implementation of stereotactic body radiation therapy (SBRT) for lung lesions however, similar comparisons of SBRT liver lesions are lacking. The purpose of this study was to determine if the conformity of dose, irradiated volume, and dose to organs at risk (OAR) are equivalent or improved with the use of DCAT as an alternative treatment method when compared to standard VMAT for SBRT delivery of palliative and early-stage liver lesions. Twenty patients with liver lesions sized 2.0 to 5.0 cm were selected for this study. Plans were created with both DCAT and VMAT techniques for each patient. Metrics evaluated included the mean heart, kidney, large bowel, small bowel, esophagus, and stomach doses, the lung volume receiving 20 Gy (V20), the volume of the normal liver receiving 15 Gy (V15), conformity index (CI), heterogeneity index (HI), and the irradiated volume or volume receiving 25 Gy (V25). The p-values for the mean dose to kidneys, small bowel, esophagus, and the lung V20 were greater than 0.05, and no statistical difference could be determined between DCAT and VMAT. The p-values for the mean heart, large bowel, stomach, and liver V15 were less than 0.05, indicating statistical significance and superiority of VMAT for minimizing dose to these organs, especially V15 of the liver. The DCAT technique produced CI greater than 1.0 for all patients proving superior coverage, while standard VMAT produced significantly improved V25 with p-values less than 0.0001, and consequently higher HI.

Dosimetric Comparison of Volumetric Modulated Arc Therapy with Tomotherapy Based Total Body Irradiation for Patients Undergoing Conditioning Prior to Hematopoietic Stem Cell Transplantation for Acute Lymphocytic Leukemia

Total body irradiation (TBI) as a component of myeloablative condition prior to hematopoietic stem cell transplantation (HSCT) for acute leukemia has been associated with high rates of pulmonary toxicity. The purpose of this study is to compare the dosimetry of volumetric modulated arc radiotherapy (VMAT) with tomotherapy (tomo) for TBI in patients undergoing myeloablative conditioning prior to HSCT for acute lymphocytic leukemia (ALL), and to report acute toxicity associated with these regimens.Sixteen patients with ALL undergoing high dose TBI at our institution were retrospectively identified. Prescription dose was to 13.2 Gy for 15 patients and 12 Gy for one patient, delivered in 8 twice daily fractions, at least 6 hours apart. The planning target volume was defined as the external body contour minus the lung, heart, and kidneys. Six or seven isocenters were utilized with VMAT plans with two arcs delivered at each isocenter. Immobilization was achieved with a vacuum cradle for tomo patients and with a stereotactic body radiotherapy (SBRT) board with rigid thermoplastic immobilization for VMAT patients. Daily cone beam CT was acquired at each isocenter for VMAT patients. Mean dose to organs at risk (OARs) were compared with T-tests. Results are presented with 95% confidence intervals (CI).Sixteen patients with ALL planned for high dose TBI were identified for analysis. Ten patients were planned for VMAT-based TBI while six patients were planned for tomo-based treatment. There was no significant difference between mean heart dose for VMAT plans (5.71 Gy, 95% CI 5.16-6.27) vs tomo plans (6.26 Gy, 95% CI 5.51-7.01), P = 0.18. Mean lung dose was lower for VMAT (7.20 Gy, 95% CI 7.01-7.40) compared to tomo (7.75 Gy, 95% CI 7.24-8.26), P = 0.04. The mean kidney dose was lower for tomo-based plans (5.55 Gy, 95% CI 4.91-6.19) vs VMAT (6.31 Gy, 95% CI 5.87-6.75), P = 0.03. The median follow-up from completion of TBI was 198.5 days and the median time to HSCT after completion of TBI was four days. No acute or late pulmonary toxicity was observed. Seven of the 14 patients (50%, 95% CI 23-77) who completed TBI developed acute grade 3 or grade 4 mucositis, including 2 of the 5 tomo patients (40%, 95% CI 5-85) and 5 of the 9 VMAT patients (56%, 95% CI 21-86). One patient treated with VMAT developed acute grade 3 diarrhea while one patient treated with Tomo experienced acute grade 3 enteritis and dermatitis. One patient treated with tomo developed late grade 2 xerophthalmia, and there were no other late radiotherapy related toxicities observed. Four patients expired during the study follow-up period at a median of 21 days following TBI. One patient had relapsed disease approximately 8 months following completion of TBI.High dose TBI planned with VMAT and delivered with SBRT board and thermoplastic immobilization is feasible and decreases mean lung dose compared to tomotherapy based plans. While mucositis was a common adverse event, no pulmonary toxicity was observed.

Effect of Peptide Dose on Radiation Dosimetry for Peptide Receptor Radionuclide Therapy with 177Lu-DOTATOC: A Pilot Study.

Background:Optimal peptide concentration in treatment with 177Lu-DOTATOC/DOTATATE is a matter of debate. Most of the studies with peptide receptor radionuclide therapy mention peptide dose ranging between 100 and 250 μg. The aim of this is to identify possible differences in radiation-absorbed doses (D/Gy) to tumor and kidney as a function of the peptide mass dose in order to identify the most suitable peptide dose for treatment. The therapeutic index (Dtumor/Dkidneys) was assessed as a key parameter for the treatment response.Materials and Methods:Five patients with metastasized Grade 1 to Grade 2 neuroendocrine tumor were analyzed in this study. Patients (n = 4) received two cycles of treatment with intravenously injected 177Lu-DOTATOC containing peptide mass doses of 200 μg and 90 μg, alternatively; one patient was treated with 90 μg peptide mass in both the therapy cycles. Whole-body (head to mid-thigh) three-dimensional single-photon emission computerized tomography (3D SPECT)/CT images were acquired at 1, 4, 24, 48, and 72 h following the injection of 177Lu-DOTATOC. Attenuation correction for 3D SPECT images was performed using CT data acquired and fused with the SPECT data (SPECT/CT).Results:Overall, 28 target lesions (liver n = 17, lung n = 4, lymph nodes n = 1, and bone n = 2) were analyzed after 1st and 2nd therapy cycles. Tumor normalized absorbed doses varied by a factor of 74 between 0.35 and 26 mGy/MBq. Averaged over all patients, a higher normalized mean tumor dose (10.51 mGy/MBq) was achieved for a peptide dose of 200 μg compared to 90 μg (4.58 mGy/MBq). Kidneys doses varied by a factor of up to 4 between patients (0.25–1.0 mGy/MBq) (independent of dose cycle and peptide dose) and by a factor of up to 2 between dose cycles. The mean kidney dose was 13.7% higher for the 90 μg peptide dose compared to 200 μg. Given the higher tumor dose, the mean therapeutic index of a 200 μg mass dose was considerably higher (16.95), compared to a 90 μg mass dose (9.63). This coincided with the observation, that lesion volume reduction was more pronounced after an initial treatment with a 200 μg mass dose. Biologically effective dose was only 5. 1%–19.3% higher than the absorbed dose for individual dose cycles.Conclusions:Higher peptide dose of 200 μg appears to be more suitable than 90 μg in terms of tumor dose, kidney dose, and therapeutic index for treatment with 177Lu-DOTATOC.

Dosimetry and Acute Toxicity Profile of Patients With Esophageal Cancer Treated With Proton Beam Radiation Therapy: Outcomes From the Proton Collaborative Group REG001-09 Trial

PurposeConcurrent chemoradiation plays an integral role in the treatment of esophageal cancer. Proton beam radiation therapy has the potential to spare adjacent critical organs, improving toxicity profiles and potentially improving clinical outcomes. Methods and MaterialsWe evaluated the REG001-09 registry for patients undergoing proton radiation therapy for esophageal cancer. Demographic, clinicopathologic, toxicity, and dosimetry information were compiled. ResultsWe identified 155 patients treated at 10 institutions between 2010 and 2019. One hundred twenty (77%) had adenocarcinoma and 34 (22%) had squamous cell carcinoma. One hundred thirty-seven (88%) received concurrent chemotherapy. The median delivered dose was 50.51 Gy-equivalent (GyE; range, 41.4-70.1). Grade ≥3 toxicities occurred in 22 (14%) of patients and were most commonly dysphagia (6%), esophagitis (4%), anorexia (4%), and nausea (2%). There were no episodes of grade ≥4 lymphopenia and no grade 5 toxicities. The average mean heart, lung, and liver doses and average maximum spinal cord dose were 10.0 GyE, 4.8 GyE, 3.8 GyE, and 34.2 GyE, respectively. For gastroesophageal junction tumors, 8% of patients developed acute grade ≥3 toxicity and the mean heart, liver, right kidney, and left kidney doses were 10.5 GyE, 3.9 GyE, 0.4 GyE, and 4.9 GyE, respectively. Gastroesophageal junction location was protective against development of grade ≥3 toxicity on univariate (P = .0009) and multivariate (P = .004) analysis. ConclusionsProton beam radiation therapy affords excellent dosimetric parameters and low toxicity in patients with esophageal cancer treated with curative intent. Prospective trials are underway investigating the comparative benefit of proton-based therapy.

Kidney Doses in 177Lu-Based Radioligand Therapy in Prostate Cancer: Is Dose Estimation Based on Reduced Dosimetry Measurements Feasible?

The radiation dose to the kidneys should be monitored in prostate cancer patients treated with radioligand therapy (RLT) targeting the prostate-specific membrane antigen (PSMA). We analyzed whether pretherapeutic kidney function is predictive of subsequent kidney dose and to what extent the cumulative kidney dose at the end of multiple therapy cycles can be predicted from a dosimetry based on the first cycle. Methods: Data of 59 patients treated with at least 2 cycles of 177Lu-PSMA-617 (PSMA RLT) were analyzed. Treatment (median, 6 GBq/cycle) was performed at 6- to 8-wk intervals, accompanied by voxel-based 3-dimensional dosimetry (measured kidney dose) with SPECT/CT on each of days 0-3 and once during days 6-9. Pretherapeutic kidney function (estimated glomerular filtration rate, mercaptoacetyltriglycine clearance) was correlated to the kidney doses. Cumulative kidney doses at the end of treatment were compared with a dose estimated from the population-based mean kidney dose, individual first-cycle kidney dose, and mean kidney doses of cycles 1, 3, and 5 per administered activity. Results: In total, 176 PSMA RLT cycles were performed, with a median of 3 cycles per patient. The average kidney dose per administered activity of all 176 cycles was 0.67 ± 0.24 Gy/GBq (range, 0.21-1.60 Gy/GBq). Mercaptoacetyltriglycine clearance and estimated glomerular filtration rate were no reliable predictors of subsequent absorbed kidney dose and showed only small effect sizes (R 2 = 0.080 and 0.014 [P = 0.039 and 0.375], respectively). All simplified estimations of cumulative kidney dose correlated significantly (P < 0.001) with measured kidney doses: estimations based on the individual first-cycle dose were more accurate than the use of the population-based average kidney dose (R 2 = 0.853 vs. 0.560). Dose estimation was best when the doses of cycles 3 and 5 were included as well (R 2 = 0.960). Conclusion: Pretherapeutic renal function was not predictive of subsequent kidney dose during therapy. Extrapolation of individual data from dosimetry of the first cycle was highly predictive of the cumulative kidney dose at the end of treatment. This prediction was further improved by the integration of dose information from every other cycle. In any case, because of a high interindividual variance, an individual dosimetry is advisable.

Evaluation of volumetric modulated arc therapy (VMAT) - based total body irradiation (TBI) in pediatric patients.

The dosimetric characterization of volumetric modulated arc therapy (VMAT)-based total-body irradiation (TBI) in pediatric patients is evaluated. Twenty-two patients between the ages of 2 and 12 years were enrolled for VMAT-based TBI from 2018 to 2020. Three isocenters were irradiated over three overlapping arcs. While prescribing 90% of the TBI dose to the planning treatment volume (PTV), two fractions (2 Gy each) were delivered each day; hence 12 Gy was delivered in six fractions. During treatment optimization, the mean lung and kidney doses were set not to exceed 7 Gy and 7.5 Gy, respectively. The maximum lens dose was also set to less than 4 Gy. Patient quality assurance was carried out by comparing treatment planning system doses to the 3-dimensional measured doses by the ArcCHECK® detector. The electronic portal imaging device (EPID) gamma indices were also obtained. The average mean lung dose was 7.75 ± 0.18 Gy, mean kidney dose 7.63 ± 0.26 Gy, maximum lens dose 4.41 ± 0.39 Gy, and the mean PTV dose 12.69 ± 0.16 Gy. The average PTV heterogeneity index was 1.15 ± 0.03. Average differences in mean kidney dose, mean lung dose, and mean target dose were 2.79% ± 0.88, 0.84% ± 0.45 and 0.93% ± 0.47, respectively; when comparing planned and ArcCHECK® measured doses. Only grade 1-2 radiation toxicities were recorded, based on CTCAE v5.0 scoring criteria. VMAT-TBI was characterized with good PTV coverage, homogeneous dose distribution, planned and measured dose agreement, and low toxicity.

Total Body Irradiation Among Recipients of Tcrαβ /CD19- Depleted Grafts in a Cohort of Children with Hematologic Malignances: Single Center Experience

Purpose: to analyze the radiation-induced organ-specific toxicity and survival outcomes in pediatric patients after hematopoietic stem cell transplantation (HSCT) with TCRαβ /CD19- depletion and myeloablative total body irradiation (TBI)-based conditioning regimen. Methods and Materials: We analyzed retrospectively a cohort of 197 patients (pts) with different hematological malignances. ALL - 150 pts: 1st CR - 40 pts; 2nd CR - 77; advanced - 33 pts; AML - 24 pts: active disease - 20 pts, 1st CR - 1 pt; 2nd CR - 3 pts; others (JMML, NHL etc.) - 23 pts. All the patients received allo-HSCT with TCRαβ /CD19- Depletion at Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology between 07/2014 and 04/2020. TBI (1200 cGy given twice daily in 6 fractions or once daily given in 4 fractions) was used as a part of HSCT conditioning regimens. The TBI technique included the irradiation of whole body using IMRT (TomoTherapy Helical System and IMRT Vmat on Elekta Linac) with following organ sparing: lungs, kidneys, lenses. The lung dose was prescribed as V8&amp;lt;40% (i.e the volume of each lung receiving 8 Gy, not to exceed 40%). The mean kidney dose was prescribed at &amp;lt; 8Gy. Forty-four patients received additional simultaneous integrated boost (SIB) up to 15 Gy or consecutive boost up to 18 Gy to different sites (bone marrow, etc.). Age of patients was from 3 to 21 y.o. (median - 10 y.o.). 26 pts were treated under anesthesia. Haploidentical HSCT was performed in 172 pts, allo-HSCT from matched unrelated donor was performed in 14 pts, from matched related donor - in 12 pts. We register acute toxicity (nausea/vomit/diarrhea, headache, veno-occlusive disease (VOD)) - during radiation therapy and 30 days after SCT, subacute toxicity - up to 100th day after SCT and late toxicity - at least 100 days after SCT according RTOG scale. Results: Follow-up period was from 0,3 to 7,2 years (median follow up period - 2 years). OS for all the patients was 66,7%±3,8%; EFS was 63,0%±3,6%; the transplant-related mortality rate was 8,9±2,1%. OS in patients with acute leukemia was 69,9±4,2% in ALL-group and 44,8±11,0% in AML-group (p=0,015). Mean survival time for patients with ALL was 4,3 years. EFS for pts with ALL was 66,7±4,1%; TRM = 8,4±2,3%. EFS for pts with AML was 43,1±10,3%; TRM = 16,3±7,5%. TRM in patients with 1st and 2nd CR was 5,5%±2,9%. TBI-related toxicity not significantly contribute to TRM, as most cases were infection-related. Acute toxicity during radiation therapy was registered among 100% of pts, in 97% of pts acute toxicity didn't exceed grade 1-2 according to RTOG scale. Among 3% of pts - grade 3 acute toxicity (nausea/vomiting/headache/diarrhea) was observed. We also registered VOD in 3 pts (all of them received SIB to bone marrow). Subacute toxicity was registered in 0.5% of patients (n=1) (interstitial pneumonia 3-4 stage according RTOG). Radiation-induced kidney toxicity was not registered. Conclusion: The developed TBI method included in conditioning regimen before allogenic SCT with TCRαβ /CD19-depletion in pediatric pts has tolerable organ-specific toxicity and predictable results of survival outcomes. Disclosures No relevant conflicts of interest to declare.

Cone Beam CT-Based Daily Adaptive Planning or Defined-Filling Protocol for Neoadjuvant Gastric Cancer Radiation Therapy: A Comparison

PurposeThis study aimed to investigate, in the setting of neoadjuvant gastric irradiation with integrated boost, whether cone beam computed tomography (CBCT)-based adaptive radiation therapy compared with a defined-filling protocol would be beneficial in terms of feasibility and achieving daily reproducible dose volume indexes of the planning target volume (PTV) and organs at risk (OARs) and workflow. Methods and materialsPlanning computed tomography (PCT) and 25 CBCT scans of a previously treated patient were used, and neoadjuvant therapy of gastric carcinoma was simulated offline. PTVs and OARs were defined per the TOPGEAR protocol (PTV: 45 Gy/1.8 Gy), and an integrated boost (gross tumor volume [GTV]: 50.4 Gy/2.016 Gy) was added. The patient followed a filling regimen consisting of 12-hour fasting followed by 200 mL of water intake (2 glasses of water) immediately before irradiation. OARs and PTVs were newly contoured on each CBCT. Nonrigid registration of PCT and CBCT scans was performed. Nonadapted plans were recalculated on each CBCT (R-CBCT). Furthermore, an adapted plan was created for the new anatomy (A-CBCT). Dose parameters and comparison of R-CBCT and A-CBCT for the kidneys, liver, and heart were analyzed using a paired t test. ResultsA total of 200 plans for R-CBCT and A-CBCT were obtained. Mean gastric volumes were 277.32 cm3 (±54.40 cm3) in CBCT scans and 519.2 cm3 in PCT. Mean doses to the PTV did not differ meaningfully within the CBCT scans, with an average of 1.54%. The D95 improved in GTV coverage by 5.26% compared with the R-CBCT plan. Mean heart, liver, and right kidney doses were reduced with the A-CBCT plan by 35.74%, 10.71% and 29.47%, respectively. The R- and A-CBCT comparison for GTV and OARs was significantly different in all cases (P < .0001). ConclusionsAdaptive radiation therapy through deformable registration represents an important tool in neoadjuvant gastric irradiation, encompassing daily variability and organ motion, compared with the defined-filling protocol while improving OAR sparing.

RESIST-PC phase 2 trial: 177Lu-PSMA-617 radionuclide therapy for metastatic castrate-resistant prostate cancer.

5028 Background: This is an investigator-initiated open-label prospective bi-centric single-arm phase 2 clinical trial (NCT03042312) of 177Lu-PSMA-617 radionuclide therapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC). Methods: Patients with progressive mCRPC (biochemical, radiographic or clinical) after ≥1 novel androgen axis drug (NAAD), either chemotherapy (CTX) naïve or post-CTX, with sufficient bone marrow reserve and normal kidney function were eligible. All patients underwent a screening PSMA PET/CT to confirm target expression. Patients received up to 4 cycles of 177Lu-PSMA-617 every 8±1 weeks and were randomized into 2 treatment activities groups (6.0 or 7.4 GBq). Kidney dosimetry was performed for the first cycle. Efficacy was defined as serum PSA decline of ≥50% from baseline at 12 weeks and served as primary endpoint. Results: 64 patients (median PSA 75 ng/ml; range 0.5-2425) were included in the study. 20% were CTX naïve while 80% were post-CTX (1.9 CTX regimens on average, range 1-4). 45% completed 4 cycles of 177Lu-PSMA-617. Androgen deprivation therapy was given concomitantly in 83%, NAAD in 23% and immunotherapy in 6%. PSA decline of ≥50% was observed in 23% of patients at 12 weeks and in 38% of patients at any time (best PSA response). The median time to best PSA response was 22 weeks (range 6-49 weeks). 16% had a PSA decline of ≥90% and 59% had any PSA decline ( &gt; 0%). Mild and transient (CTCAE grade 1-2) side effects included xerostomia (72%), nausea/vomiting (69%) and bowel movement disorders (45%). CTCAE grade 3 toxicity included nausea/vomiting (6%), anemia (8%), leukopenia (5%), kidney failure (3%), thrombocytopenia (3%), and neutropenia (3%). The mean kidney dose was 2.7 Gy for the first cycle (range 0.9-5.9) i.e. 0.4 Gy/GBq (range 0.15-0.9). There was no difference between the efficacy and toxicity for the 6.0 GBq (n = 23) and 7.4 GBq (n = 41) treatment arms. Conclusions: 177Lu-PSMA-617 radionuclide therapy is well tolerated in patients with progressive mCRPC. PSA declined by ≥50% in 38% of patients. The best PSA response rate occurred after 3 cycles. Updated data will be provided at the time of the conference. Clinical trial information: NCT03042312.

Dosimetry Estimate and Initial Clinical Experience with 90Y-PSMA-617.

Because of different physical properties, the β-emitters 177Lu and 90Y offer specific radiologic-biologic advantages in dedicated clinical situations. Our objective was to introduce 90Y-labeled prostate-specific membrane antigen (PSMA)-617 to clinical application, providing additional avenues for personalized medicine. Here, we present our dosimetry estimate for 90Y-PSMA-617, report first clinical experiences, and discuss the advantages and drawbacks of varying the β-emitter in PSMA-targeting radioligand therapy. Methods: To approximate radiation dosimetry, 4 patients with metastatic castration-resistant prostate cancer underwent serially performed imaging up to 1 wk after 177Lu-PSMA-617 therapy. Time-activity curves were extrapolated to the half-life of 90Y, and OLINDA was used to calculate the dosimetry estimate. In clinical practice, 11 patients with PSMA-positive lymph-nodal bulk disease were stratified to receive 90Y-PSMA-617 radioligand therapy (mean, 3.2 GBq; range, 2.8-3.7 GBq); afterward, safety lab tests, prostate-specific antigen (PSA) response, and clinical findings were thoroughly followed. Results: The projected dosimetry for 90Y-PSMA-617 estimated a mean kidney dose of 3.47 ± 1.40 Gy/GBq, red marrow dose of 0.11 ± 0.04 Gy/GBq, and salivary gland dose of 5.57 ± 1.34 Gy/GBq; randomly chosen metastases were approximated with 22.8 ± 16.10 Gy/GBq. The observed acute hematologic toxicity (5 cases of leukopenia and 2 of thrombocytopenia, all grade 1 or 2) and clinical side effects (2 cases of transient xerostomia and 1 of nausea, all grade 1 or 2), as well as PSA response (any PSA response, 7/11 patients; >50% PSA decline, 5/11 patients), were comparable to 177Lu-PSMA-617 literature data. Conclusion: A factor 3-4 lower treatment activity for 90Y-PSMA-617 translates into a comparable dosimetry estimate and clinical findings similar to those of 177Lu-PSMA-617. However, safety was demonstrated only for patients with oligometastatic disease. Further studies are needed to evaluate its potential in patients with more disseminated bone involvement or visceral metastasis.

Monte-Carlo Based Total-Body Irradiation Using Linac-Based Volumetric Modulated Arc Therapy

To assess the accuracy, feasibility, and reliability of a total-body irradiation (TBI) technique with linac-based volumetric modulated arc therapy (VMAT) in patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). From 2015-2017, 26 patients (15 men, 11 women) with AML or ALL underwent allogenic stem-cell transplantation following TBI with linac-based VMAT technique, which consisted of three isocenters and three overlapping arcs for head first CT sets. We added one or two more overlapping arcs, depending on the height of the patient for feet first CT sets. Patient age ranged from 6-63 years with a mean and median age of 20.5 and 17.5 years, respectively. TBI dose was prescribed to 90% of the clinical target volume receiving 12 Gy in six fractions, at two fractions per day. Mean lung and kidney doses were restricted less than 10 Gy, and maximum lens dose less than 6 Gy. Dose rate was variable, and mean dose rate was 250 MU/min. Calculation parameters were grid spacing 0.4 cm, minimum segment width 0.5 cm, maximum 180 control points per arc, fluence-smoothing medium, statistical uncertainty 1.0% per calculation, gantry increment of 30°, and calculate dose deposition to medium. Patients were immobilized in supine position using customized thermoplastic masks for head support and a vacuum cushion for body support on an adjustable combined immobilization board. Laser-based optical surface-guided devices were used for patient positioning and intra-fraction motion detection. Quality assurance (QA) comprised the verification of the radiation plans via dose-volume histograms (DVH) based 3D patient QA system. Average mean lung dose was 9.7 ± 0.2 Gy, mean kidney dose 9.6 ± 0.2 Gy, maximum lens dose 4.5 ± 0.4 Gy, mean planning treatment volume (PTV) dose 12.7 ± 0.1 Gy, and heterogenity index of PTV was 1.16 ± 0.02 in all patients. Overall acute toxicity was low with only grade 1 and 2 morbidity: patchy mucositis in 16 (62%), nausea not requiring antiemetics in 12 (46%), headache in 11 (42%), fatigue in 9 (35%), neck pain in 8 (31%), xerostomia in 7 (27%), loss of appetite in 6 (23%), and faint or dull erythema in 4 (15%) patients. Grade 3 and more acute radiation toxicity was not observed. All patients are stil alive. When comparing plan and DVH-based 3D patient QA results, average differences of 3.4% ± 1.3 in mean kidney doses, 1.0% ± 0.7 in mean lung doses, and 0.9% ± 0.4 in mean target doses were observed. Linac-based VMAT simplifies the process of TBI, and is accurate, feasible, and reliable. Partial cone-beam CT and optical surface-guided system assure patient positioning. Moreover, up to 6-mm longitudinal misalignment does not cause an average more than 3.5% mean lung dose enhancement. DVH-based 3D patient dose verification QA was possible with linac-based VMAT showing small differences between planned and delivered doses.

Assessment of Online Adaptive MR-Guided SBRT of Liver Cancers

Online Adaptive Radiotherapy (ART) with daily MR imaging has the potential to improve target coverage by taking into account for anatomical changes during radiotherapy. The purpose of this study is to provide an assessment of potential benefits of online adaptive MRI-Guided Stereotactic Body Radiotherapy (SBRT) for treatment of liver cancer. Five patients with liver cancer who were treated with MR-Guided SBRT were included. Prescription doses ranged between 27-50 Gy in 3-5fx, with the 90%-95% of the PTV covered by 100% of the prescription dose. All patients underwent a planning MRI and setup MRIs prior to each fraction, all acquisitions utilized breath-hold conditions. All SBRT fractions were delivered under MR guidance with cine-MR gating of the gross tumor volume (GTV) based on a modified breath-hold technique. Patients received visual feedback throughout treatment delivery. The planning target volume (PTV) was created by expanding the GTV by 3mm uniform margin. The initial treatment plan was generated using step-and-shoot IMRT and utilized 9-12 beam groups, each beam group consisted of 3 equally spaced Co-60 beams. The electron density (ED) map and contours from planning MR were propagated to daily setup MRI using deformable image registration and were reviewed/edited by the physician. Each adapted plan was obtained by re-optimizing based on the contours on daily setup MRI using the same beam parameters and optimization objectives from the initial MR plan. Non-adaptive plans for each patient were created by recalculating the dose from the initial plan on the daily setup MRI, daily ED map and edited contours. The non-adaptive and adaptive plans were compared using PTV coverage and dose-volume constraints for OARs: duodenum, bowel, stomach, kidneys, and spinal cord. Daily plan adaptation provided increased PTV coverage for 11 of 23 fractions. While 7 fractions required adaptations due to violation of maximum dose constraint for duodenum and 3 fractions required adaptation due to violation of V30Gy <5cc constraint for bowel. Up to 27% decrease in mean dose to liver-GTV was achieved when using daily adaption even though this constraint was satisfied for all fractions. Similarly, up to 28% reduction in maximum cord dose and up to 18% reduction in mean kidney dose was achieved with daily adaptation. Online ART MR-Guided SBRT of liver cancer using daily re-optimization resulted in better target conformity and OAR sparing compared with non-adaptive SBRT. In our experience, adaptation provides the largest benefit when two or more OARs are proximal to the target additionally the larger the intra-fractional motion of the target and OARs the greater the benefit. Significant OAR sparing was still achieved for fractions that did not exceed OAR tolerances. Daily adaptation may allow for PTV dose escalation without compromising OAR sparing as compared to non-adaptive treatments. Further studies are needed to determine the limits to any dose escalation strategy.

Total-body irradiation using linac-based volumetric modulated arc therapy: Its clinical accuracy, feasibility and reliability

PurposeTo report the feasibility, accuracy, and reliability of volumetric modulated arc therapy (VMAT)-based total-body irradiation (TBI) treatment in patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). Materials and methodsFrom 2015 to 2018, 30 patients with AML or ALL were planned and treated with VMAT-based TBI, which consisted of three isocenters and three overlapping arcs. TBI dose was prescribed to 90% of the planning treatment volume (PTV) receiving 12 Gy in six fractions, at two fractions per day. Mean lung and kidney doses were restricted less than 10 Gy, and maximum lens dose less than 6 Gy. Quality assurance (QA) comprised the verification of the irradiation plans via dose–volume histogram (DVH) based 3D patient QA system. ResultsAverage mean lung dose was 9.7 ± 0.2 Gy, mean kidney dose 9.6 ± 0.2 Gy, maximum lens dose 4.5 ± 0.4 Gy, mean PTV dose 12.7 ± 0.1 Gy, and heterogeneity index of PTV was 1.16 ± 0.02 in all patients. Grade 3 or more acute radiation toxicity was not observed. When comparing plan and DVH-based 3D patient QA results, average differences of 3.3% ± 1.3 in mean kidney doses, 1.1% ± 0.7 in mean lung doses, and 0.9% ± 0.4 in mean target doses were observed. ConclusionLinac-based VMAT increased the dose homogeneity of TBI treatment more than extended SSD techniques. Partial cone-beam CT and optical surface-guided system assure patient positioning. DVH-based 3D patient dose verification QA was possible with linac-based VMAT showing small differences between planned and delivered doses. It is feasible, accurate, and reliable.

Kinetics and dosimetric predictors of acute radiation-induced lymphopenia in pancreatic cancer.

300 Background: Radiation (RT) induced lymphopenia (RIL) is an adverse prognostic factor in pancreatic cancer (PC) and is likely due to the irradiation of lymphocytes in the RT field. The goal of this study was to identify dosimetric predictors for high rates of absolute lymphocyte count (ALC) loss during RT for PC. Methods: This was a retrospective study of 34 PC patients in an institutional database who had received concurrent 5-FU or gemcitabine-based chemoradiation (50-54 Gy) and had ≥ 3 ALCs measured during RT. Baseline ALC was normal (&gt;1000 cells/uL) in 28/34 (82%) and grade 3-4 RIL occurred in 24/34 (71%). ALC was plotted against fraction # and a best-fit line for each patient was created to determine per-fraction loss in ALC (PFLAC). Linear regression was used to correlate PFLAC with dosimetric parameters including mean dose to gut, liver, kidney, spleen, and cisterna chyli, as well as estimated dose to immune cells (EDIC), which calculates dose to immune cells according to the % of body lymphocytes contained in each organ. Results: All patients exhibited exponential loss in ALC during RT. Mean PFLAC was 6.8% (range 1.7-13.4); fraction # was strongly correlated with ALC (mean R2 = 0.89). Patients with &gt;/= grade 3 lymphopenia had a significantly higher PFLAC than those with grade 0 - 2 lymphopenia (mean daily loss 7.8% in Gr 3-4 vs. 4.8% in Gr 0-2, p = 0.001; independent sample T test). Field size was not correlated with PFLAC for high (&gt; 1 Gy) or low (&lt; 0.5 Gy) isodose volumes. Mean whole body (r = 0.59, p &lt; 0.001), bowel (r = 0.39, p = 0.012), liver (r = 0.42, p = 0.007), and cisterna chyli (r = 0.583, p = 0.004) doses were moderately correlated with PFLAC; mean kidney (r = 0.22, p = 0.11) and spleen (r = 0.26, p = 0.06) doses were weakly correlated with PFLAC. EDIC was more strongly correlated with PFLAC than any individual organ mean dose (r = 0.69, p &lt; 0.001). Conclusions: Patients undergoing RT for PC experience a predictable RIL characterized by an exponential loss of lymphocytes per day. PFLAC is a useful method of characterizing RIL and facilitates evaluation of dosimetric predictors of RIL. We identified dose to cisterna chyli as a significant contributor to RIL in PC; however, EDIC has a stronger correlation with RIL severity than any single organ dose.