Kidney Dose Research Articles

Model-Informed Radiopharmaceutical Therapy Optimization: A Study on the Impact of PBPK Model Parameters on Physical, Biological, and Statistical Measures in 177Lu-PSMA Therapy.

Purpose: To investigate the impact of physiologically based pharmacokinetic (PBPK) parameters on physical, biological, and statistical measures in lutetium-177-labeled radiopharmaceutical therapies (RPTs) targeting the prostate-specific membrane antigen (PSMA). Methods: Using a clinically validated PBPK model, realistic time-activity curves (TACs) for tumors, salivary glands, and kidneys were generated based on various model parameters. These TACs were used to calculate the area-under-the-TAC (AUC), dose, biologically effective dose (BED), and figure-of-merit BED (fBED). The effects of these parameters on radiobiological, pharmacokinetic, time, and statistical features were assessed. Results: Manipulating PBPK parameters significantly influenced AUC, dose, BED, and fBED outcomes across four different BED models. Higher association rates increased AUC, dose, and BED values for tumors, with minimal impact on non-target organs. Increased internalization rates reduced AUC and dose for tumors and kidneys. Higher serum protein-binding rates decreased AUC and dose for all tissues. Elevated tumor receptor density and ligand amounts enhanced uptake and effectiveness in tumors. Larger tumor volumes required dosimetry adjustments to maintain efficacy. Setting the tumor release rate to zero intensified the impact of association and internalization rates, enhancing tumor targeting while minimizing the effects on salivary glands and kidneys. Conclusions: Optimizing PBPK parameters can enhance the efficacy of lutetium-177-labeled RPTs targeting PSMA, providing insights for personalized and effective treatment regimens to minimize toxicity and improve therapeutic outcomes.

Treatment Time and Dosimetric Advantage in Cone Beam Computed Tomography-Guided Online Adaptive Radiation Therapy Considering Interfractional and Intrafractional Changes in Patients With Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Radiation therapy is the standard treatment for localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The ETHOS system (Varian Medical System) has enabled us to perform cone beam computed tomography (CBCT)-guided online adaptive radiation therapy (oART). This study presents a retrospective dosimetric analysis for interfractional and intrafractional change and treatment time in oART for gastric MALT lymphoma. We included 3 male patients with gastric MALT lymphoma who underwent exhalation breath-hold fasting oART using the SpiroDynr'X system. Treatment details and plans (3 reference [REF] plans, 51 scheduled [SCH] plans, and adapted [ADP] plans) were retrospectively analyzed. Doses to the clinical target volume in planning CT (CTV_REF), CTV1, and CTV2 (representing the stomach in planning and preirradiation CBCT, respectively) and planning target volume (PTV) in the planning CBCT were estimated. D2%, D98%, D50%, and Dmean for these volumes, along with organ-at-risk doses, were examined across the 3 plans. The PTV dose coverage of CTV2 on preirradiation CBCT was calculated. CBCT-guided oART was completed within the scheduled period, using the ADP plans instead of the SCH plans on each treatment day in all cases. The average treatment time was approximately 45 minutes. CTV1 and CTV2 exhibited intrafractional and interfractional variations, fluctuating above and below CTV_REF. Some ADP plans resulted in incomplete PTV coverage of CTV2, but the unincluded volume was <1% of CTV2. D50%, D98%, and Dmean of CTV1, CTV2, and PTV were significantly improved in the ADP plans than in the SCH plans. Moreover, the Dmean to the liver and kidneys was reduced in the ADP plans. CBCT-guided oART in patients with gastric MALT lymphoma demonstrated that ADP plans improved CTV1, CTV2, and PTV doses and reduced the mean bilateral kidney and liver doses, suggesting that it may offer enhanced treatment precision for gastric MALT lymphoma.

A Multicentric study on a dosimetric comparison of extended SSD technique, VMAT-Based and helical tomotherapy (HT) for total body irradiation (TBI)

PurposeIn study, it was aimed to evaluate the dose volume histograms (DVH) of extended SSD technique, VMAT-based, and helical tomotherapy plans dosimetrically in a multi-institutional context to achieve higher plan quality and to harmonize total body irradiation plans. MethodsFour different clinical centers participated in the study. The CT images of ten patients were used in this study. During the first phase, ten patients enrolled for TBI were planned by multiple centers according to a common protocol. During the second phase, all centers shared their plans’ DVHs. Treatment plans were evaluated according to the critical organ dose limits. Statistical analysis was performed in the SPSS (version 22.0) program (p < 0.05). ResultsIn study, the results indicated that there was a statistically significant and considerable difference in the dose coverage of PTV, beam delivery time and MU, lens doses, and kidney doses between the four techniques (p < 0.001). The mean lung doses of the four centers were below 10 Gy. No significant difference in maximum liver doses between plans was obtained. ConclusionIn conclusion, although four treatment techniques were suitable for TBI treatment, more homogeneous dose distribution, and lower critical organ doses were obtained with the tomotherapy technique. However, treatment time, MU, and dose rate for lung were disadvantages of the tomotherapy technique. When it comes to deciding on the TBI treatment method, it need to be reviewed some important points. It is needed to sufficient data on long-term results to be able to standardize TBI techniques between centers.

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.

Results from a phase I study of 4-l-[131I]iodo-phenylalanine ([131I]IPA) with external radiation therapy in patients with recurrent glioblastoma (IPAX-1).

Glioblastoma (GBM), the most common malignant brain tumor, is associated with devastating outcomes. IPAX-1 was a multicenter, open-label, single-arm phase I study to evaluate carrier-added 4-L-[131I]iodo-phenylalanine ([131I]IPA) plus external radiation therapy (XRT) in recurrent GBM. A total of 10 adults with recurrent GBM who had received first-line debulking surgery plus radio-chemotherapy, were randomized to a single-dose regimen (1f; 131I-IPA 2 GBq before XRT); a fractionated parallel dose regimen (3f-p; 3 131I-IPA 670 MBq fractions, in parallel with second-line XRT), or a fractionated sequential dose regimen (3f-s; 3 131I-IPA 670 MBq fractions before and after XRT). Metabolic tumor responses were determined using O-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography, while single-photon emission computed tomography was used to guide [131I]IPA tumor dosimetry. All dose regimens were well tolerated. Organ-absorbed radiation doses in red marrow (0.38 Gy) and kidney (1.28 Gy) confirmed no radiation-based toxicity. Stable disease was observed in 4 of the 9 patients at 3 months post-treatment (3-month follow-up [FU], 1 patient did not reach protocol-mandated end of study), yielding a response rate of 44.4%. At the 3-month FU, 6 patients demonstrated metabolic stable disease. Median progression-free survival was 4.3 months (95% confidence interval [CI]: 3.3-4.5), while median overall survival was 13 months (95% CI: 7.1-27). Single or fractionated doses of [131I]IPA plus XRT were associated with acceptable tolerability and specific tumor targeting in patients with recurrent GBM, warranting further investigation.

Estimation of kidney doses from [177Lu]Lu-DOTA-TATE PRRT using single time point post-treatment SPECT/CT

BackgroundDosimetry after [177Lu]Lu-DOTA-TATE therapy can be demanding for both patients and the clinical service due to the need for imaging at several time points. In this work we compare three methods of single time point (STP) kidney dosimetry after [177Lu]Lu-DOTA-TATE therapy with a multiple time point (MTP) dosimetry method.MethodMethod 1 (MTP): Kidney doses were calculated from 31 patients including 107 therapy cycles. Post-therapy SPECT images were acquired on day 0, 4 and 7 along with a CT scan on day 4. A mono-exponential fit was used to calculate kidney doses using cycle specific data. Method 2 (Consistent effective half-life): The effective half-life \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\left({\ ext{T}}_{\ ext{e}\ ext{f}\ ext{f}}\\right)$$\\end{document} calculated in cycle 1 was assumed consistent for subsequent cycles of therapy and the activity scaled using a single day 3–5 SPECT/CT. Methods 3 and 4 (Hänscheid and Madsen approximations): The Hänscheid approximation and Madsen approximation were both evaluated using a single SPECT/CT acquired on day 0, 4 and 7. All STP methods were compared to the MTP method for accuracy.ResultsUsing the MTP method, mean right and left kidney doses were calculated to be 2.9 ± 1.1 Gy and 2.8 ± 0.9 Gy respectively and the population \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{T}}_{\ ext{e}\ ext{f}\ ext{f}}$$\\end{document} was 56 ± 13 h. For the consistent \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{T}}_{\ ext{e}\ ext{f}\ ext{f}}$$\\end{document}, Hänscheid and Madsen methods, the percentage of results within ± 20% of MTP method were 96% (n = 70), 95% (n = 80) and 94% (n = 80) respectively.ConclusionAll three single time point methods had > 94% of results within ± 20% of the MTP method, however the consistent \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{T}}_{\ ext{e}\ ext{f}\ ext{f}}$$\\end{document} method resulted in the highest alignment with the MTP method and is the only method which allows for calculation of the patient-specific \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{T}}_{\ ext{e}\ ext{f}\ ext{f}}$$\\end{document}. If only a single scan can be performed, day 4 is optimal for kidney dosimetry where the Hänscheid or Madsen approximation can be implemented with good accuracy.

Dosimetry of [177Lu]Lu-PSMA-Targeted Radiopharmaceutical Therapies in Patients with Prostate Cancer: A Comparative Systematic Review and Metaanalysis.

Novel theranostic approaches using radiopharmaceuticals targeting prostate-specific membrane antigen (PSMA) have emerged for treating metastatic castration-resistant prostate cancer. The physical properties and commercial availability of 177Lu make it one of the most used radionuclides for radiopharmaceutical therapy (RPT). In this literature review, we aimed at comparing the dosimetry of the most used [177Lu]Lu-PSMA RPT compounds. Methods: This was a systematic review and metaanalysis of [177Lu]Lu-PSMA RPT (617, I&T, and J591) dosimetry in patients with prostate cancer. Absorbed doses in Gy/GBq for each organ at risk (kidney, parotid and submandibular glands, bone marrow, liver, and lacrimal glands) and for tumor lesions (bone and nonbone lesions) were extracted from included articles. These were used to estimate the pooled average absorbed dose of each agent in Gy/GBq and in Gy/cycle, normalized to the injected activity (per cycle) used in the VISION (7.4 GBq), SPLASH (6.8 GBq), and PROSTACT trials (5.8 GBq). Results: Twenty-nine published articles comprising 535 patients were included in the metaanalysis. The pooled doses (weighted average across studies) of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T were 4.04 Gy/GBq (17 studies, 297 patients) and 4.70 Gy/GBq (10 studies, 153 patients) for the kidney (P = 0.10), 5.85 Gy/GBq (14 studies, 216 patients) and 2.62 Gy/GBq (5 studies, 86 patients) for the parotids (P < 0.01), 5.15 Gy/GBq (5 studies, 81 patients) and 4.35 Gy/GBq (1 study, 18 patients) for the submandibular glands (P = 0.56), 11.03 Gy/GBq (6 studies, 121 patients) and 19.23 Gy/GBq (3 studies, 53 patients) for the lacrimal glands (P = 0.20), 0.24 Gy/GBq (12 studies, 183 patients) and 0.19 Gy/GBq (4 studies, 68 patients) for the bone marrow (P = 0.31), and 1.11 Gy/GBq (9 studies, 154 patients) and 0.56 Gy/GBq (4 studies, 56 patients) for the liver (P = 0.05), respectively. Average tumor doses tended to be higher for [177Lu]Lu-PSMA-617 than for [177Lu]Lu-PSMA-I&T in soft tissue tumor lesions (4.19 vs. 2.94 Gy/GBq; P = 0.26). Dosimetry data of [177Lu]Lu-J591 were limited to one published study of 35 patients with reported absorbed doses of 1.41, 0.32, and 2.10 Gy/GBq to the kidney, bone marrow, and liver, respectively. Conclusion: In this metaanalysis, there was no significant difference in absorbed dose between [177Lu]Lu-PSMA-I&T and [177Lu]Lu-PSMA-617. There was a possible trend toward a higher kidney dose with [177Lu]Lu-PSMA-I&T and a higher tumor lesion dose with [177Lu]Lu-PSMA-617. It remains unknown whether this finding has any clinical impact. The dosimetry methodologies were strikingly heterogeneous among studies, emphasizing the need for standardization.

Impact of the Reference Multiple-Time-Point Dosimetry Protocol on the Validity of Single-Time-Point Dosimetry for [177Lu]Lu-PSMA-I&T Therapy.

Internal dosimetry supports safe and effective patient management during radionuclide therapy. Yet, it is associated with high clinical workload, costs, and patient burden, as patient scans at multiple time points (MTPs) must be acquired. Dosimetry based on imaging at a single time point (STP) has continuously gained popularity. However, MTP protocols, used as a reference to judge the validity of STP dosimetry, differ depending on local requirements and deviate from the unknown patient-specific ground truth pharmacokinetics. The aim of this study was to compare the error and optimum time point for different STP approaches using different reference MTP protocols. Methods: Whole-body SPECT/CT scans of 7 patients (7.4-8.9 GBq of [177Lu]Lu-PSMA-I&T) were scheduled at 24, 48, 72, and 168 h after injection. Sixty lesions, 14 kidneys, and 10 submandibular glands were delineated in the SPECT/CT data. Two curve models, that is, a mono- and a biexponential model, were fitted to the MTP data, in accordance with goodness-of-fit analysis (coefficients of variation, sum of squared errors). Three population-based STP approaches were compared: one method published by Hänscheid etal., one by Jackson etal., and one using population-based effective half-lives in the mono- or biexponential curve models. Percentage differences between STP and MTP dosimetry were evaluated. Results: Goodness-of-fit parameters show that a monoexponential function and a biexponential function with shared population-based parameters and physical tail are reasonable reference models. When comparing both reference models, we observed maximum differences of -44%, -19%, and -28% in the estimated absorbed doses for lesions, kidneys, and salivary glands, respectively. STP dosimetry with an average deviation of less than 10% from MTP dosimetry may be feasible; however, this deviation and the optimum imaging time point showed a dependence on the chosen reference protocol. Conclusion: STP dosimetry for [177Lu]Lu-PSMA therapy is promising to boost the integration of dosimetry into clinical routine. According to our patient cohort, 48 h after injection may be regarded as a compromise for STP dosimetry for lesions and at-risk organs. The results from this analysis show that a common gold standard for dosimetry is desirable to allow for reliable and comparable STP dosimetry.

Efficient bone marrow irradiation and low uptake by non-haematological organs with an yttrium-90-anti-CD66 antibody prior to haematopoietic stem cell transplantation

We report the results of a Phase I radiation dose escalation study using an yttrium-90 (90Y) labelled anti-CD66 monoclonal antibody given with standard conditioning regimen for patients receiving haematopoietic stem cell transplants for myeloid leukaemia or myeloma. The 90Y-labelled anti-CD66 was infused prior to standard conditioning. In total, 30 patients entered the trial and 29 received 90Y-labelled mAb, at infused radiation activity levels of 5, 10, 25, or 37.5 megaBequerel (MBq)/kg lean body weight. A prerequisite for receiving the 90Y-labelled mAb was favourable dosimetry determined by single-photon emission computerised tomography (SPECT) dosimetry following administration of indium-111 (111In) anti-CD66. Estimated absorbed radiation doses delivered to the red marrow demonstrated a linear relationship with the infused activity of 90Y-labelled mAb. At the highest activity level of 37.5 MBq/kg, mean estimated radiation doses for red marrow, liver, spleen, kidneys and lungs were 24.6 ± 5.6 Gy, 5.8 ± 2.7 Gy, 19.1 ± 8.0 Gy, 2.1 ± 1.1 and 2.2 ± 0.9, respectively. All patients engrafted, treatment-related mortality 1-year post-transplant was zero. Toxicities were no greater than those anticipated for similar conditioning regimens without targeted radiation. The ability to substantially intensify conditioning prior to haematopoietic stem cell transplantation without increasing toxicity warrants further testing to determine efficacy. clinicaltrials.gov identifier: NCT01521611.

Dosimetry of lutetium-177 PSMA-targeted radiopharmaceutical therapies for prostate cancer patients: A comparative systematic review and meta-analysis.

e17033 Background: Novel theranostic approaches using radiopharmaceuticals targeting PSMA have emerged for treating metastatic castrate resistant prostate cancer (mCRPC). The physical properties and commercial availability of Lutetium-177 (Lu177) makes it one of the most used radionuclides for radiopharmaceutical therapy (RPT). In this review we aimed at comparing the dosimetry of the most used Lu177-PSMA RPT compounds. Methods: This is a systematic review and meta-analysis of Lu177-PSMA RPT (617, I&amp;T, and J591) dosimetry for prostate cancer. Absorbed doses in Gy/GBq for each organ (kidney, parotid and submandibular glands, bone marrow, liver, lacrimal glands) and for tumor lesions (bone and non- bone lesions) were extracted. These were used to estimate the pooled average absorbed dose of each RPT, and normalize each to the respective injected activity (Gy/cycle) as determined by the dose per cycles used in VISION (7.4 GBq), SPLASH (6.8 GBq), and PROSTACT Trials (5.8 GBq). Results: 29 published manuscripts comprising 535 patients were included in the meta-analysis. The pooled dose was calculated for kidney based on (28 studies, 485 patients), parotid (20, 309), submandibular (7, 100) and lacrimal glands (9, 174), bone marrow (18, 293), and liver (14, 245) were 4.04 and 4.70, 5.85 and 2.62, 5.15 and 4.35, 11.03 and 19.23, 0.24 and 0.19 and 1.11 and 0.56 Gy respectively for Lu177-PSMA-617 and Lu177-PSMA-I&amp;T. Lu177-PSMA-J591 reported absorbed doses to the kidney, bone marrow and liver were 3.95, 0.90, and 5.88 Gy respectively. There was no significant difference between Lu177-PSMA-I&amp;T and Lu177-PSMA-617 for the dose to kidneys (p=0.10), submandibular glands (p=0.56), bone marrow (p=0.31), lacrimal glands (p=0.20), or tumors (p=0.16). However, parotid dose from Lu177-PSMA-617 was higher than that of Lu177-PSMA-I&amp;T (p=&lt;0.01). Average tumor doses tended to be higher for Lu177-PSMA-617 than for Lu177-PSMA-I&amp;T, (27.94 vs. 21.31 Gy); p=0.16. Lu177-PSMA-J591 exposed the bone marrow and liver, to a significantly higher dose while resulting in a lower dose to the kidney than either of the two small molecule compounds. Absorbed doses to the salivary glands, lacrimal glands, and tumors after the treatment with Lu177-PSMA-J591 have not been published yet. Conclusions: The clinical impact of higher tumor to kidney dose ratio for Lu177-PSMA-617 than Lu177-PSMA-I&amp;T has yet to be determined. Data for Lu177-PSMA-J591 are thus far too limited to draw firm conclusions.

Comparison of novel PSMA-targeting [177Lu]Lu-P17-087 with its albumin binding derivative [177Lu]Lu-P17-088 in metastatic castration-resistant prostate cancer patients: a first-in-human study.

Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and radioligand therapy (RLT) of prostate cancer. Two novel PSMA-targeting radionuclide therapy agents, [177Lu]Lu-P17-087, and its albumin binder modified derivative, [177Lu]Lu-P17-088, were evaluated in metastatic castration-resistant prostate cancer (mCRPC) patients. The primary endpoint was dosimetry evaluation, the second endpoint was radiation toxicity assessment (CTCAE 5.0) and PSA response (PCWG3). Patients with PSMA-positive tumors were enrolled after [68Ga]Ga-PSMA-11 PET/CT scan. Five mCRPC patients received [177Lu]Lu-P17-087 and four other patients received [177Lu]Lu-P17-088 (1.2 GBq/patient). Multiple whole body planar scintigraphy was performed at 1.5, 4, 24, 48, 72, 120 and 168h after injection and one SPECT/CT imaging was performed at 24h post-injection for each patient. Dosimetry evaluation was compared in both patient groups. Patients showed no major clinical side-effects under this low dose treatment. As expected [177Lu]Lu-P17-088 with longer blood circulation (due to its albumin binding) exhibited higher effective doses than [177Lu]Lu-P17-087 (0.151 ± 0.036 vs. 0.056 ± 0.019 mGy/MBq, P = 0.001). Similarly, red marrow received 0.119 ± 0.068 and 0.048 ± 0.020 mGy/MBq, while kidney doses were 0.119 ± 0.068 and 0.046 ± 0.022 mGy/MBq, respectively. [177Lu]Lu-P17-087 demonstrated excellent tumor uptake and faster kinetics; while [177Lu]Lu-P17-088 displayed a slower washout and higher average dose (7.75 ± 4.18 vs. 4.72 ± 2.29 mGy/MBq, P = 0.018). After administration of [177Lu]Lu-P17-087 and [177Lu]Lu-P17-088, 3/5 and 3/4 patients showed reducing PSA values, respectively. [177Lu]Lu-P17-088 and [177Lu]Lu-P17-087 displayed different pharmacokinetics but excellent PSMA-targeting dose delivery in mCRPC patients. These two agents are promising RLT agents for personalized treatment of mCRPC. Further studies with increased dose and frequency of RLT are warranted to evaluate the potential therapeutic efficacy. 177Lu-P17-087/177Lu-P17-088 in Patients with Metastatic Castration-resistant Prostate Cancer (NCT05603559, Registered at 25 October, 2022). URL OF REGISTRY: https://classic. gov/ct2/show/NCT05603559 .

Current practices of craniospinal irradiation techniques in Turkey: a comprehensive dosimetric analysis

ObjectiveThis study evaluates various craniospinal irradiation (CSI) techniques used in Turkish centers to understand their advantages, disadvantages and overall effectiveness, with a focus on enhancing dose distribution.MethodsAnonymized CT scans of adult and pediatric patients, alongside target volumes and organ-at-risk (OAR) structures, were shared with 25 local radiotherapy centers. They were tasked to develop optimal treatment plans delivering 36 Gy in 20 fractions with 95% PTV coverage, while minimizing OAR exposure. The same CT data was sent to a US proton therapy center for comparison. Various planning systems and treatment techniques (3D conformal RT, IMRT, VMAT, tomotherapy) were utilized. Elekta Proknow software was used to analyze parameters, assess dose distributions, mean doses, conformity index (CI), and homogeneity index (HI) for both target volumes and OARs. Comparisons were made against proton therapy.ResultsAll techniques consistently achieved excellent PTV coverage (V95 > 98%) for both adult and pediatric patients. Tomotherapy closely approached ideal Dmean doses for all PTVs, while 3D-CRT had higher Dmean for PTV_brain. Tomotherapy excelled in CI and HI for PTVs. IMRT resulted in lower pediatric heart, kidney, parotid, and eye doses, while 3D-CRT achieved the lowest adult lung doses. Tomotherapy approached proton therapy doses for adult kidneys and thyroid, while IMRT excelled for adult heart, kidney, parotid, esophagus, and eyes.ConclusionModern radiotherapy techniques offer improved target coverage and OAR protection. However, 3D techniques are continued to be used for CSI. Notably, proton therapy stands out as the most efficient approach, closely followed by Tomotherapy in terms of achieving superior target coverage and OAR protection.

Linear Boltzmann equation solver for voxel-level dosimetry in radiopharmaceutical therapy: Comparison with Monte Carlo and kernel convolution.

With recent interest in patient-specific dosimetry for radiopharmaceutical therapy (RPT) and selective internal radiation therapy (SIRT), an increasing number of voxel-based algorithms are being evaluated. Monte Carlo (MC) radiation transport, generally considered to be the most accurate among different methods for voxel-level absorbed dose estimation, can be computationally inefficient for routine clinical use. This work demonstrates a recently implemented grid-based linear Boltzmann transport equation (LBTE) solver for fast and accurate voxel-based dosimetry in RPT and SIRT and benchmarks it against MC. A deterministic LBTE solver (Acuros MRT) was implemented within a commercial RPT dosimetry package (Velocity 4.1). The LBTE is directly discretized using an adaptive mesh refined grid and then the coupled photon-electron radiation transport is iteratively solved inside specified volumes to estimate radiation doses from both photons and charged particles in heterogeneous media. To evaluate the performance of the LBTE solver for RPT and SIRT applications, 177Lu SPECT/CT, 90Y PET/CT, and 131I SPECT/CT images of phantoms and patients were used. Multiple lesions (2-1052mL) and normal organs were delineated for each study. Voxel dosimetry was performed with the LBTE solver, dose voxel kernel (DVK) convolution with density correction, and a validated in-house MC code using the same time-integrated activity and density maps as input to the different dose engines. The resulting dose maps, difference maps, and dose-volume-histogram (DVH) metrics were compared, to assess the voxel-level agreement. Evaluation of mean absorbed dose included comparison with structure-level estimates from OLINDA. In the phantom inserts/compartments, the LBTE solver versus MC and DVK convolution demonstrated good agreement with mean absorbed dose and DVH metrics agreeing to within 5% except for the D90 and D70 metrics of a very low activity concentration insert of 90Y where the agreement was within 15%. In the patient studies (five patients imaged after 177Lu DOTATATE RPT, five after 90Y SIRT, and two after 131I radioimmunotherapy), in general, there was better agreement between the LBTE solver and MC than between LBTE solver and DVK convolution for mean absorbed dose and voxel-level evaluations. Across all patients for all three radionuclides, for soft tissue structures (kidney, liver, lesions), the mean absorbed dose estimates from the LBTE solver were in good agreement with those from MC (median difference<1%, maximum 9%) and those from DVK (median difference<5%, maximum 9%). The LBTE and OLINDA estimates for mean absorbed dose in kidneys and liver agreed to within 10%, but differences for lesions were larger with a maximum 14% for 177Lu, 23% for 90Y, and 26% for 131I. For bone regions, the agreement in mean absorbed doses between LBTE and both MC and DVK were similar (median<11%, max 11%) while for lung the agreement between LBTE and MC (median<1%, max 8%) was substantially better than between LBTE and DVK (median<16%, max 33%). Voxel level estimates for soft tissue structures also showed good agreement between the LBTE solver and both MC and DVK with a median difference<5% (maximum<13%) for the DVH metrics with all three radionuclides. The largest difference in DVH metrics was for the D90 and D70 metric in lung and bone where the uptake was low. Here, the difference between LBTE and MC had a median value<14% (maximum 23%) for bone and<4% (maximum 37%) for lung, while the corresponding differences between LBTE and DVK were<23% (maximum 31%) and<67% (maximum 313%), respectively. For a typical patient with a matrix size of 166×166×129 (voxel size 3×3×3 mm3), voxel dosimetry using the LBTE solver was as fast as ∼2 min on a desktop computer. Having established good agreement between the LBTE solver and MC for RPT and SIRT applications, the LBTE solver is a viable option for voxel dosimetry that can be faster than MC. Further analysis is being performed to encompass the broad range of radionuclides and conditions encountered clinically.

Modeling the effect of daughter migration on dosimetry estimates for unlabeled actinium-225.

Actinium-225 (225Ac) is an alpha emitting radionuclide which has demonstrated promising results in Targeted Alpha Therapy (TAT). A concern with 225Ac is that the decay energy can break the bond to the targeting vehicle, resulting in the release of free alpha-emitting daughter radionuclides in the body. The aim of this work is to develop a compartment model to describe the movement of unlabeled 225Ac in a human where the daughter isotopes of 225Ac have unique biokinetics. The ICRP Occupational Intake of Radionuclides reports were used to construct a compartment model for the 225Ac decay chain where the daughter isotopes of 225Ac are assigned their own unique transfer coefficients (TCs) between compartments. Computer simulations were performed for unlabeled 225Ac uniformly placed in the plasma and only the dose from alpha particles was considered. Absorbed doses to normal organs were determined for the liver, kidneys, bone, soft tissue, active marrow, and blood. Simulations were performed for the case when: (1) the daughters have unique biokinetics and (2) the daughters decay at the site of 225Ac. When the daughters have unique biokinetics, the organs that receive the highest absorbed dose are the liver (male: 1466.6 mGy/MBq, female: 1885.7 mGy/MBq), bone (male: 293.6 mGy/MBq, female: 403.6 mGy/MBq) and kidneys (male: 260.8 mGy/MBq, female: 294.0 mGy/MBq). These doses were compared to the case when the daughters of 225Ac decay at the site of 225Ac. There was a 13.5% increase in kidney dose, a 0.8% decrease in liver dose, and <0.1% decrease in bone dose calculations when the daughters have unique biokinetics compared to assuming the daughters decay at the site of 225Ac. The kidneys received a large dose estimate (260-295 mGy/MBq) as well as a considerable change in dose of +13.5% when the daughters have unique biokinetics compared to assuming the daughters decay at the site of 225Ac. Therefore, to accurately determine the kidney dose from unlabeled 225Ac in a human, the biokinetics of the daughter isotopes should be considered.

Comparative dosimetric study of spot-scanning proton therapy versus volumetric-modulated radiation therapy for extrahepatic bile duct cancer

This study aimed to compare the dose distributions and clarify the dosimetric characteristics of spot-scanning proton therapy (SSPT) and photon volumetric modulated arc therapy (VMAT) for extrahepatic bile duct cancer (EBDC). This retrospective study included 10 patients with EBDC treated with real-time image-gated SSPT. Using the simultaneous integrated boost technique, the 2 prescription dose levels for planning target volumes were 72.6 and 44 Gy, delivered in 22 fractions. Plan quality comparisons were conducted by analyzing various parameters, including homogeneity, conformity, dose to organs at risk, and normal tissue complication probability (NTCP) for radiation-induced liver damage (RILD). The target dose distributions using SSPT were almost equivalent to those achieved using photon VMAT. There was a significant reduction in all liver dose parameters, the NTCP value for RILD, and kidney dose (mean, V12 Gy, and V18 Gy) in SSPT than in photon VMAT. No significant differences were observed in the intestinal doses in the high-dose area. Thus, compared with photon VMAT, SSPT for EBDC significantly reduced radiation doses to the liver and kidneys and has shown potential clinical benefits of reduced radiation-induced toxicity.

Outcomes of Proton Therapy for Patients with Infradiaphragmatic Lymphoma.

While the role of proton radiation (PT) in treating supradiaphragmatic targets in lymphoma patients is becoming increasingly well-established, outcomes of PT for infradiaphragmatic locations have not been reported. We report on the radiation planning details, doses achieved to key organs at risk (OARs), and clinical outcomes for a cohort of lymphoma patients treated with PT to infradiaphragmatic locations. This is a single institution retrospective study of patients with biopsy-proven lymphoma who received PT to an infradiaphragmatic target between 2011-2022. Patient, disease, and radiation details were collected. Comparison photon plans were generated for a subset of patients. Toxicity was reported using CTCAE version 5.0. Dosimetric and clinical factors associated with toxicity and oncologic outcomes were assessed via linear regression, Wilcoxon rank sum test, Fisher's exact test, and/or independent t-test while the paired t-test or Wilcoxon signed rank test was used for dosimetric analyses. 38 patients comprising 40 PT courses were included. Median age was 63 years and median follow-up was 48 months. The most common diagnoses were DLBCL (58%) and Hodgkin lymphoma (18%). 28% of PT courses had direct overlap with a prior radiation field and 20% were palliative. Median dose was 30.6 GyE over 17 fractions to the retroperitoneum (30%), spine/paraspinal region (30%), pelvis (18%), inguinals (8%), spleen (3%), or other (8%). Top G1 toxicities were fatigue (65%), dermatitis (28%), and nausea (23%). 10% of PT courses led to a G2 toxicity and there were no G3+ toxicities. Higher number of fractions was associated with increased incidence of dermatitis (mean 16 vs. 19, p = 0.008), but no OAR parameters were associated with CTCAE toxicities. Among patients treated with curative intent, 44% experienced progression of disease (PD) at a median time of 3 months after PT; of these progressions, 60% were distant only, 20% were marginal only, 10% was marginal and distant, and 10% was in-field and distant. Higher number of systemic therapy lines received prior to PT was associated with increased likelihood of PD (mean 1.4 vs. 4.1, p = 0.01), and PD increased the risk of death (OR 15.3, 95% CI 2.5-95.2). 5/39 patients were diagnosed with a second malignancy after PT, two of which were hematologic. Among the 10 patients with photon comparison plans, PT provided a significant decrease in kidney doses (mean and V5), small bowel V5 Gy, large bowel V5 Gy, bowel bag V15 Gy, and mean liver (all p = 0.045 or less). However, average spinal cord/cauda Dmax was slightly higher with PT (24 vs. 25 Gy, p = 0.0156). PT is a well-tolerated treatment for infradiaphragmatic lymphoma that leads to excellent outcomes with minimal high-grade toxicities. Compared to photon therapy, PT can significantly reduce doses to key abdominopelvic OARs.

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 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.

Dose comparison of robustly optimized intensity modulated proton therapy (IMPT) vs IMRT and VMAT photon plans for testicular seminoma

Background Patients with stage II seminoma have traditionally been treated with photons to the retroperitoneal and iliac space, which leads to a substantial dose bath to abdominal and pelvic organs at risk (OAR). As these patients are young and with excellent prognosis, reducing dose to OAR and thereby the risk of secondary cancer is of utmost importance. We compared IMPT to opposing IMRT fields and VMAT, assessing dose to OAR and both overall and organ-specific secondary cancer risk. Material and methods A comparative treatment planning study was conducted on planning CT-scans from ten patients with stage II seminoma, treated with photons to a ‘dog-leg’ field with doses ranging from 20 to 25 Gy and a 10 Gy sequential boost to the metastatic lymph node(s). Photon plans were either 3–4 field IMRT (Eclipse) or 1–2 arc VMAT (Pinnacle). Proton plans used robust (5 mm; 3.5%) IMPT (Eclipse), multi field optimization with 3 posterior fields supplemented by 2 anterior fields at the level of the iliac vessels. Thirty plans were generated. Mean doses to OARs were compared for IMRT vs IMPT and VMAT vs IMPT. The risk of secondary cancer was calculated according to the model described by Schneider, using excess absolute risk (EAR, per 10,000 persons per year) for body outline, stomach, duodenum, pancreas, bowel, bladder and spinal cord. Results Mean doses to all OARs were significantly lower with IMPT except similar kidney (IMRT) and spinal cord (VMAT) doses. The relative EAR for body outline was 0.59 for IMPT/IMRT (p < .05) and 0.33 for IMPT/VMAT (p < .05). Organ specific secondary cancer risk was also lower for IMPT except for pancreas and duodenum. Conclusion Proton therapy reduced radiation dose to OAR compared to both IMRT and VMAT plans, and potentially reduce the risk of secondary cancer both overall and for most OAR.

149 Accumulated Kidney Dose in Renal Stereotactic Body Radiotherapy: Analysis from a Prospective Phase II Trial

149 Accumulated Kidney Dose in Renal Stereotactic Body Radiotherapy: Analysis from a Prospective Phase II Trial