Liver Dose Research Articles

An image-based notion for therapeuticplanar organ activity dosimetry in a developing country: Masterdose software.

Planar dosimetry is often performed in developing countries due to its simplicity during basic quantitative dosimetry. The geometric mean method is often used during planar dosimetry and imaging counts can be corrected for background, attenuation and scatter. The aim of our study was to develop computerized software called Masterdose that may be used for therapeutic isotope planar organ personalized dosimetry. Masterdose software uses various methods to correct for background, scatter and attenuation.We also introduced a method to convert imaging counts to activity on the software,which is Java based and runs on Windows, Linux and Macintosh platforms. Three user interfaces named image processing, quantification and dosimetry were developed for the software. Masterdose could quantify kidney and liver doses of lutetium-177-DOTA-0-Tyr3-octreotate (177Lu-DOTATATE) patients. The software was validated throughcalculation of the kidney and liver doses of ten neuroendocrine tumour patients (NET) treated with 177Lu-DOTATATE. Masterdose presents an option for planar quantification that can be used as a quality control tool to verify imaging counts and perform dosimetry in particular organs.

A Pilot Study of Hepatic Irradiation with Yttrium-90 Microspheres Followed by Immunotherapy with Ipilimumab and Nivolumab for Metastatic Uveal Melanoma

Background: Liver metastases from uveal melanoma carry a very poor prognosis. Hepatic artery infusions with Yttrium-90 (90Y) resin microspheres have some activity in this disease, and radiation and immunotherapy may be synergistic. The primary objective of this study was to determine the safety and tolerability of sequential 90Y resin microspheres and immunotherapy with ipilimumab and nivolumab in metastatic uveal melanoma.Materials and Methods: Twenty-six patients with uveal melanoma with hepatic metastases were entered into a pilot study. Treatment consisted of two infusions of 90Y resin microspheres, one to each lobe of the liver, followed in 2–4 weeks by immunotherapy with ipilimumab and nivolumab every 3 weeks for four doses, then maintenance immunotherapy with nivolumab alone.Results: Initial dosing of both 90Y and immunotherapy resulted in excessive toxicity. With decreasing the dosage of 90Y to limit the normal liver dose to 35Gy and lowering the ipilimumab dose to 1 mg/kg, the toxicity was tolerable, with no apparent change in efficacy. There was one complete and four confirmed partial responses, for an objective response rate of 20% and a disease control rate of 68%. The median progression-free survival was 5.5 months (95% confidence interval [CI]: 1.3–9.7 months), with a median overall survival of 15 months (95% CI: 9.7–20.1 months).Conclusions: With dose reductions, sequential therapy with 90Y and immunotherapy with ipilimumab and nivolumab is safe and tolerable, and has activity in metastatic uveal melanoma. These results justify a controlled trial to demonstrate whether 90Y resin microspheres add to the utility of combination immunotherapy in this disease.Clinical Trial Registration number: NCT02913417.

Analysis of the amplitude changes and baseline shifts of respiratory motion using intra-fractional CBCT in liver stereotactic body radiation therapy.

Using intra-fractional cone-beam CT (CBCT) to evaluate the amplitude changes and baseline shifts of respiratory motion in liver stereotactic body radiation therapy (SBRT). The amplitude changes and baseline shifts of respiratory motion for 24 liver patients were evaluated by the four-dimensional (4D) CT, inter- and intra-fractional CBCT. The difference of the average liver position errors among all treatment fractions and the 4D CT representthe baseline shifts. According to the baseline shifts, the ITV to PTV margin was recalculated and the plan was re-designed to compare the dosimetric variation. The systematic and random errors of the baseline shifts for intra-fractional CBCT in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) directions were 0.99/1.60mm, 2.03/2.46mm, and 1.02/2.07mm, respectively. The new ITV to PTV margins should be 4.0mm, 7.0mm, and 4.0mm, respectively. The amplitude change of motion between the 4D CT and the intra-fractional CBCT was 1.03±4.35mm, with 31% of fractions exceeding 5mm. To achieve the same dose coverage of the new PTV, the Dmean, V50, V40, V30, V25 of normal liver and maximum dose of the duodenum were significantly different. Significant amplitude changes and baseline shifts of motion occurred during dose delivery compared with those in 4D CT. Using the ITV to PTV margin of 4.0mm (LR), 7.0mm (SI), and 4.0mm (AP) can ensure the target dose coverage and keep the dose constrain of normal tissues at an acceptable level.

Degree of reduction in normal liver complication probability from free-breathing to breath-hold liver SBRT: a dose-escalation strategy using radiation dose-volume effect

Introduction. This study aimed to analyze the degree of reduction in normal liver complication probability (NTCP) from free-breathing (FB) to breath-hold (BH) liver SBRT. The effect of the radiation dose-volume on the mean liver dose (MLD) was also analyzed due to dose prescription, normal liver volume (NLV), and PTV. Materials and Methods. Thirty-three stereotactic body radiation therapy (SBRT) cases of hepatocellular carcinoma were selected, retrospectively. For FB, the treatments were planned on average intensity projection scan (CTavg), and patient-specific internal target volume (ITV) margins were applied. To simulate the BH treatment, computed tomography (CT) scan correspond to the 40%—50% of the respiratory cycle (CT40%-50%) was chosen, and an appropriate intrafraction margin of 2 mm, 1.5 mm, and 1.5 mm were given in craniocaudal (CC), superior-inferior (SI), and lateral direction to generate the final iGTV. As per RTOG 1112, all organs at risk (OAR’s) were considered during the optimization of treatment plans. NTCP was calculated using LKB fractionated model. Multivariate regression analysis was performed to see the effect of EQD2Gy, NLV, and PTV on MLD2Gy. Results. A significant dosimetric difference was observed in the normal liver (liver-ITV/iGTV). A reduction of 1.7% in NTCP was observed from FB to BH technique. The leverage of dose escalation is more in BH because MLD2Gy corresponds to 5%, 10%, 20%, and 50% NTCP was 0.099 Gy, 0.41 Gy, 1.21 Gy, and 3.432 Gy more in BH as compared to FB technique. In MVRA, the major factor which was attributed to a change in MLD2Gy is EQD2Gy. Conclusion. From FB to BH technique, a significant reduction in NTCP was observed. The dose prescription is a major factor attributed to the change in MLD2Gy. Advances in knowledge: If feasible, prefer BH treatment either for tumor dose escalation or for the reduction in NTCP.

Tumour-to-normal tissue (T/N) dosimetry ratios role in assessment of 90Y selective internal radiation therapy (SIRT).

The purpose of our work is to assess the role of tumour-to-normal tissue (T/N) dosimetry ratios for predicting response in patients undergoing locoregional therapy to the liver with 90Y microspheres. A total of 39 patients (7 female:32 male, mean age 68.3 ± 7.6 years), underwent positron emission tomography (PET)/CT imaging after treatment with 90Y microspheres. For attenuation correction and localization of the 90Y microspheres, the low-dose, non-diagnostic CT images from PET/CT were used. The acquisition took 15 min and the reconstruction matrix size was 200 × 200 × 75 mm and voxel size of 4.07 × 4.07 × 3.00 mm. For dosimetry calculations, the local deposition method with known activity of 90Y was used. For each patient, regions of interest for tumour(s) and whole liver were manually created; the normal tissue region of interest was created automatically. mRECIST criteria on MRI done at 1 month post-treatment and subsequently every 3 months after 90Y treatment, were used to assess response. For 39 patients, the mean liver, tumour and normal tissue doses (mean ± SD) were, 55.17 ± 26.04 Gy, 911.87 ± 866.54 Gy and 47.79 ± 20.47 Gy, respectively. Among these patients, 31 (79%) showed complete response (CR) and 8 (21%) showed progression of disease (PD). For patients with CR, the mean T/N dose ratio obtained was 24.91 (range 3.09-80.12) and for patients with PD, the mean T/N dose ratio was significantly lower, at 6.69 (range 0.36-14.75). Our data show that patients with CR have a statistically higher T/N dose ratio than those with PD. Because, the number of PD cases was limited and partial volume effect was not considered, further investigation is warranted. T/N dosimetry ratios can be used for assessing response in patients undergoing locoregional therapy to the liver with 90Y microspheres.

ITV-Negation and Dose Fall-Off Features Result in OAR Dosimetric Superiority Favoring MR-Guided Radiotherapy (MRgRT), and Intensity Modulated Proton Therapy (IMPT) Over Volumetric Modulated Arc Therapy (VMAT) for Treatment of Distal Esophageal Cancer

Purpose/Objective(s)Radiation therapy (RT) for distal esophageal cancer (EC) may deliver significant unintended dose to organs at risk (OARs). Advanced RT modalities and motion management strategies could substantially reduce OAR dose, potentially resulting in clinically meaningful impact on clinical outcomes. The aim of this study is to investigate dosimetric plan quality of intensity modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT), both in free breathing (FB), compared to real-time monitoring breath hold (BH) MR-guided radiotherapy (MRgRT) for distal EC.Materials/MethodsNine EC patients originally treated in mid-inspiration BH on a 0.35T MR-guided LINAC using step-and-shoot IMRT were retrospectively planned in FB using IMPT and VMAT. FB-IMPT and FB-VMAT plans incorporated an internal target volume (ITV) whereas BH-MRgRT plans did not. The prescribed dose was standardized at 50.4 Gy in 28 fractions for all 3 techniques. Both MRgRT and VMAT plans used planning target volumes (PTV) margins for optimization employing Monte Carlo and Acuros dose algorithms, respectively. All IMPT plans used single field optimization (SFO) technique and Monte Carlo dose algorithm (Robust optimization - 5% range and 5mm setup uncertainties) to ITVs. A comparison of plan quality was performed using RTOG-defined metrics for target coverage (TC), high dose conformity (PITV), homogeneity index (HI), and dose fall-off metrics: R50% and D2cm. Additionally, dose metrics to the OARs, (lungs, heart and liver) were evaluated.ResultsThe conformity, target coverage and homogeneity indices among FB-IMPT, BH-MRgRT and FB-VMAT plans were similar; FB-IMPT plans generally had superior dose fall-off (Table 1, top). Achieved lung, liver and heart doses are displayed in Table 1 (bottom).ConclusionBoth FB-IMPT and BH-MRgRT achieved a roughly 2-fold or greater reduction in nearly all assessed heart, lung, and liver dose metrics compared to FB-VMAT. Reducing, or ideally eliminating, respiratory motion should be strongly considered for distal EC management regardless of radiation modality or technique. Radiation therapy (RT) for distal esophageal cancer (EC) may deliver significant unintended dose to organs at risk (OARs). Advanced RT modalities and motion management strategies could substantially reduce OAR dose, potentially resulting in clinically meaningful impact on clinical outcomes. The aim of this study is to investigate dosimetric plan quality of intensity modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT), both in free breathing (FB), compared to real-time monitoring breath hold (BH) MR-guided radiotherapy (MRgRT) for distal EC. Nine EC patients originally treated in mid-inspiration BH on a 0.35T MR-guided LINAC using step-and-shoot IMRT were retrospectively planned in FB using IMPT and VMAT. FB-IMPT and FB-VMAT plans incorporated an internal target volume (ITV) whereas BH-MRgRT plans did not. The prescribed dose was standardized at 50.4 Gy in 28 fractions for all 3 techniques. Both MRgRT and VMAT plans used planning target volumes (PTV) margins for optimization employing Monte Carlo and Acuros dose algorithms, respectively. All IMPT plans used single field optimization (SFO) technique and Monte Carlo dose algorithm (Robust optimization - 5% range and 5mm setup uncertainties) to ITVs. A comparison of plan quality was performed using RTOG-defined metrics for target coverage (TC), high dose conformity (PITV), homogeneity index (HI), and dose fall-off metrics: R50% and D2cm. Additionally, dose metrics to the OARs, (lungs, heart and liver) were evaluated. The conformity, target coverage and homogeneity indices among FB-IMPT, BH-MRgRT and FB-VMAT plans were similar; FB-IMPT plans generally had superior dose fall-off (Table 1, top). Achieved lung, liver and heart doses are displayed in Table 1 (bottom). Both FB-IMPT and BH-MRgRT achieved a roughly 2-fold or greater reduction in nearly all assessed heart, lung, and liver dose metrics compared to FB-VMAT. Reducing, or ideally eliminating, respiratory motion should be strongly considered for distal EC management regardless of radiation modality or technique.

Comparison of NTCP Models Using Liver Function Obtained From Different Contrast Agent-Based DCE-MRI after SBRT in Hepatocellular Carcinoma

<h3>Purpose/Objective(s)</h3> To develop improved NTCP models of liver function using pre-/during-treatment DCE-MRI for adaptation of radiation therapy (RT) in hepatocellular cancer (HCC) patients who receive SBRT. The liver function map based on Gadoxetate uptake rate (k1) is compared to portal venous perfusion for HCC NTCP models. <h3>Materials/Methods</h3> 194 HCC patients who received SBRT were evaluated. Subcohorts of patients (n = 23, each) with either portal venous perfusion or Gadoxetate uptake rate k1 liver function maps calculated from DCE MRI using respective Gd-DTPA or Gadoxetic-Acid were analyzed. In addition, patients with pre-RT Child-Pugh (C-P) score > 8 for the Gadoxetate map subgroup were excluded and the remaining patients (n = 18) analyzed to explore the effect of pre-RT liver condition to the models. Median prescription doses of 50 Gy were delivered in 3 fractions or 5 fractions (split course with a 1-month break). Physical doses were converted into EQD2 for analysis. A logistic dose-response model was used to estimate the fraction of liver functional loss (change of k1 between pre-/during-RT) as a function of subregional liver dose. NTCP was estimated using the cumulative functional reserve model for change in C-P scores (2-point change in the score). Model parameters were calculated using maximum-likelihood estimations. The logistic local dose-response model coupled with the cumulative functional reserve NTCP model were compared between k1 and perfusion portal venous liver function maps. <h3>Results</h3> In the logistic model, dose that causes 50% reduction of function is much lower for k1 map, D50 of 10.2 Gy (all C-P) /14.8 Gy (pre-RT C-P < = 8) compared to 23.5Gy for perfusion. This may be due to the difference in image biomarkers or the population heterogeneity. As noted, excluding the high pre-RT CP patients, the D50 increases from 10.2 Gy to 14.8 Gy, which may indicate that worse pre-RT liver condition patients will tend to lose more liver function at lower dose. k1 map results showed a steeper response curve for C-P change compared to perfusion results using the NTCP Functional reserve model, with of 2.09/1.52 for k1 and 1.08 for perfusion. The position corresponding to 50% complication probability rate (f₅₀) are similar for both. <h3>Conclusion</h3> Functional maps showed steeper and lower dose for 50% complication compared with previous perfusion results. Considering its superiority to perfusion maps in representing liver "function", this may indicate a lower limit for normal liver dose or better dose distribution to preserve more liver function. The preliminary findings will be validated in a larger and independent cohort.

A Dosimetric Comparison of IMRT and 3D-CRT Using Deep Inspiratory Breath Hold (DIBH) and Free-Breathing (FB) Techniques in Gastric Mucosa Lymphoid Tissue Lymphoma (MALT)

Definitive radiation therapy (RT) is a curative treatment modality for gastric MALT. Reducing radiation dose to organs at risk (OAR) is imperative for patients with curative disease and excellent long-term prognosis. Advanced RT planning with DIBH and/or IMRT is available to improve the therapeutic ratio of RT by minimizing dose to normal tissues while maintaining adequate target coverage. We aimed to compare dosimetric parameters when using different radiation planning and delivery techniques in patients with gastric MALT.After institutional review board approval, we identified adult patients (age ≥ 18 years) with biopsy-proven gastric MALT who were treated at our institution from 2010 to 2020. Each patient underwent two simulation CT scans: free breathing (FB) and DIBH. Four plans were generated for each patient including DIBH-IMRT, DIBH-3DCRT, FB-IMRT, and FB-3DCRT with a prescribed dose of 30 Gy in 20 fractions. The CTV was defined as the entire stomach including the gastroesophageal junction to the pylorus. The PTV included a 1 to 1.5 cm expansion from the CTV. Paired t-tests were used to compare mean calculated dose values for each OAR based on treatment technique.Our cohort consisted of 8 patients (6 male, 2 female) with a median age 62.5 years (39 to 83 years). Compared to 3D-CRT, IMRT was associated with significantly decreased heart dose for both DIBH (Dmean 354.7 vs 440.5 cGY, P = 0.029) and FB (Dmean 521.2 vs 699.6 cGY, P = 0.006). IMRT was also associated with decreased dose to the left ventricle (LV), left anterior descending artery (LAD), liver, and lungs compared to 3D in both FB and DIBH. For IMRT plans, DIBH was associated with significantly lower heart V30 and V20 and a trend towards significance for lower heart Dmean (354.7 vs 521.2 cGY, P = 0.059) in comparison to FB. For 3D plans, DIBH was associated with a lower heart V30 and V20, and a higher lung V20, V10, and V5 in comparison to FB.Both IMRT and DIBH represent modalities for reducing heart dose in gastric MALT patients receiving definitive RT. IMRT also reduces LV, LAD, liver and lung dose regardless of technique used to account for respiratory motion whereas DIBH was not associated with reduced doses to the LAD, kidney, or liver.

Toxicity and Dosimetric Parameters of Ablative Radiation Therapy in the Management of Patients with Child-Pugh B/C Liver Function and Unresectable Hepatocellular Carcinoma (HCC)

To date there is no clear standard non-surgical therapeutic option for HCC patients. Ablative radiation therapy (SBRT/HIGRT) is an emerging non-invasive treatment for patients with HCC. However, there is concern about the risk for radiation-induced liver toxicity following radiation in patients with decompensated liver function (Child-Pugh B/C).We retrospectively identified all patients with unresectable, non-metastatic HCC treated with SBRT/HIGRT and underlying Child-Pugh B or C liver function prior to radiation therapy at our University and Veterans Affairs (VA) radiation oncology departments from 2014 to 2019. Primary endpoints included treatment-related toxicity, as well as, evaluation of dosimetric parameters for OAR.38 patients (39 treatment courses) were included. Most patients (97%) had Child-Pugh B7-B9 (62% CP B7, 21% CP B8, 15% CP B9) or ALBI grade 2-3 (69% ALBI grade 2, 31% ALBI grade 3) liver disease prior to radiation therapy. A single patient had Child-Pugh C10 liver function. The most commonly utilized regimens include 50 Gy in either 5 or 10 fractions. The median delivered dose was 50 Gy (range 30-50) in an average of 7.5 fractions (range 5-10). Most patients had a single lesion (63%) with a median lesion size of 3.2 cm (range 1.10-7.40 cm). The mean liver dose was 9.40 Gy (range 3.38-23.94) with a liver D800cc of 4.14 Gy (range 0.35-17.31). All patients completed their intended treatment course with a median follow up of 43 months. Four (10.3%) treatment courses resulted in non-classical radiation-induced liver disease (RILD) (defined as an increase of 2 or more points in Child-Pugh score), compared to 8.3% for patients with Child-Pugh A liver function treated during a similar time period. Otherwise, one patient (2.6%) experienced acute grade 3+ (non-RILD) hepatobiliary toxicity (transient transaminitis). Two-year freedom from local progression was 73% (95% CI 37-90%), median overall survival 12 months (95% CI 5-25 months), and median progression free-survival was not reached.Ablative radiation therapy as definitive management for patients with unresectable, non-metastatic HCC appears to be reasonably well tolerated in patients with decompensated liver function at baseline (Child-Pugh B7-B9), with low rates of RILD and encouraging local control. With careful selection, these patients appear to be reasonable candidates for consideration of SBRT/HIGRT. Our analysis did not include enough patients with Child-Pugh C10+ disease to draw meaningful conclusions.

Dynamic Hepatic Blood Flow Model Shows Greater Impact of Total Treatment Time Than Integral Dose for Assessing Dose to Circulating Lymphocytes

<h3>Purpose/Objective(s)</h3> Radiation-induced lymphocyte depletion has been reported to correlate with survival rate in post-radiotherapy patients with hepatocellular carcinoma. This study aims to assess the impact of integral dose and treatment time on the dose to circulating lymphocytes (CL) with active scanning and passive scattering proton beam therapy (PBS, SOBP), intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT). <h3>Materials/Methods</h3> Four plans based on VMAT, IMRT, PBS and SOBP were created for the same hepatocellular carcinoma patient delivering 52.5 Gy in 15 fractions. Six fields, 1 arc, and 2 fields were used for IMRT, VMAT and proton plans, respectively. The dose to CLs after one RT fraction was computed with a novel 4D dynamic blood flow liver model using realistic treatment times (Table 1), which takes into account hepatic vasculature (arterial, portal venous and hepatic venous trees), blood recirculation and time structure of dose delivery. We varied the delivery speed for each modality to achieve total treatment times in the range of 50-250s. The impact of integral dose and treatment time on dose to CLs across different modalities was quantified by the mean dose to CL, the % CL receiving non-zero dose (V_0Gy), the % CL receiving > 0.5 Gy dose (V_0Gy) and the dose received by highest 2% of CLs (D_2%). <h3>Results</h3> Mean liver dose ranges from 19.4 - 22.2 Gy and treatment time from 60 - 3255s depending on the modality. The PBS and SOBP treatments yield 15% and 10% lower mean dose to CLs compare to VMAT, respectively (Table 1). However, the fraction of lymphocytes receiving any dose varies widely from 37.0% for VMAT to 80.8% for PBS, uncorrelated to integral dose. The fraction of lymphocytes receiving a significant dose (V0.5%) also varies considerably with the highest fraction in VMAT (14.6%) and the lowest for PBS (0.6%). Further analysis indicates that V_0Gy depends on both the mean dose and the total treatment time, which explains the large variations observed among various modalities. Every 10s increase in treatment time leads to approximately 3% increase in V_0Gy. The opposite trend was found for V_0.5Gy and D_2%, both decreasing with increasing treatment time. V_0.5Gy and D_2% decrease approximately 0.6% and 0.01Gy for every 10s increase in treatment time, respectively. <h3>Conclusion</h3> We studied dose to CLs across 4 different treatment modalities and found that to minimize the fraction of CL irradiated, it might be more important to shorten the delivery time than to reduce the dose bath. Further investigation is required to find the dose levels most correlated to lymphocyte depletion to optimize delivery time and to design immune-sparing RT regimen.

Uniform versus non-uniform dose prescription for proton stereotactic body radiotherapy of liver tumors investigated by extensive motion-including treatment simulations

Compared to x-ray-based stereotactic body radiotherapy (SBRT) of liver cancer, proton SBRT may reduce the normal liver tissue dose. For an optimal trade-off between target and liver dose, a non-uniform dose prescription is often applied in x-ray SBRT, but lacks investigation for proton SBRT. Also, proton SBRT is prone to breathing-induced motion-uncertainties causing target mishit or dose alterations by interplay with the proton delivery. This study investigated non-uniform and uniform dose prescription in proton-based liver SBRT, including effects of rigid target motion observed during planning-4DCT and treatment. The study was based on 42 x-ray SBRT fractions delivered to 14 patients under electromagnetic motion-monitoring. For each patient, a non-uniform and uniform proton plan were made. The uniform plan was renormalized to be iso-toxic with the non-uniform plan using a NTCP model for radiation-induced liver disease. The motion data were used in treatment simulations to estimate the delivered target dose with rigid motion. Treatment simulations were performed with and without a repainting scheme designed to mitigate interplay effects. Including rigid motion, the achieved CTV mean dose after three fractions delivered without repainting was on average (±SD) 24.8 ± 8.4% higher and the D98% was 16.2 ± 11.3% higher for non-uniform plans than for uniform plans. The interplay-induced increase in D2% relative to the static plans was reduced from 3.2 ± 4.1% without repainting to −0.5 ± 1.7% with repainting for non-uniform plans and from 1.5 ± 2.0% to 0.1 ± 1.3% for uniform plans. Considerable differences were observed between estimated CTV doses based on 4DCT motion and intra-treatment motion. In conclusion, non-uniform dose prescription in proton SBRT may provide considerably higher tumor doses than uniform prescription for the same complication risk. Due to motion variability, target doses estimated from 4DCT motion may not accurately reflect the delivered dose. Future studies including modelling of deformations and associated range uncertainties are warranted to confirm the findings.

Role of Resin Microsphere Y90 Dosimetry in Predicting Objective Tumor Response, Survival and Treatment Related Toxicity in Surgically Unresectable Colorectal Liver Metastasis: A Retrospective Single Institution Study.

Simple SummaryColorectal liver metastases are difficult to treat, with only a minority of patients eligible for surgical resection. Yttrium-90 selective internal radiation therapy is an alternative treatment currently used for patients who have progressed on chemotherapy. A technique called dosimetry allows clinicians to analyze how much radiation was delivered to target lesions post-treatment. The aim of this study is to evaluate the relationship of various dosimetric parameters with objective tumor response, overall survival, and treatment related toxicity with the potential goal of optimizing Yttrium-90 treatment in this patient population. Additionally, other potential predictors of survival outcomes, including clinical and demographic factors, were also evaluated. We found that delivering a mean tumor dose ≥100 Gy when using resin microspheres was significantly associated with objective tumor response and prolonged overall survival. In this study, no mean non-tumoral liver dose threshold was found to predict treatment related toxicity.Purpose: To Evaluate the correlation between tumor dosimetric parameters with objective tumor response (OR) and overall survival (OS) in patients with surgically unresectable colorectal liver metastasis (CRLM) undergoing resin-based Ytrrium-90 selective internal radiation therapy (Y90 SIRT). Materials and Methods: 45 consecutive patients with CRLM underwent resin-based Y90 SIRT in one or both hepatic lobes (66 treated lobes total). Dose volume histograms were created with MIM Sureplan® v.6.9 using post-treatment SPECT/CT. Dosimetry analyses were based on the cumulative volume of the five largest tumors in each treatment session and non-tumoral liver (NTL) dose. Receiver operating characteristic (ROC) curve was used to evaluate tumor dosimetric factors in predicting OR by Response Evaluation Criteria for Solid Tumors at 3 months post-Y90. Additionally, ROC curve was used to evaluate non-tumoral liver dose as a predictor of grade ≥ 3 liver toxicity and radioembolization induced liver disease (REILD) 3 months post Y90. To minimize for potential confounding demographic and clinical factors, univariate and multivariate analysis of survival with mean tumor dose as one of the factors were also performed. Kaplan-Meier estimation was used for OS analysis from initial Y90 SIRT. Results: 26 out of 45 patients had OR with a median OS of 17.2 months versus 6.8 months for patients without OR (p < 0.001). Mean tumor dose (TD) of the five largest tumors was the strongest predictor of OR with an area under the curve of 0.73 (p < 0.001). Minimum TD, and TD to 30%, 50%, and 70% of tumor volume also predicted OR (p’s < 0.05). Mean TD ≥ 100 Gy predicted a significantly prolonged median OS of 19 vs. 11 months for those receiving TD < 100 Gy (p = 0.016). On univariate analysis, mean TD < 100 Gy, presence of any genomic mutation, presence of MAPK pathway mutation, bilobar hepatic metastases and diffuse metastatic disease (>10 lesions per liver lobe) were found to be predictors of shorter median OS. On multivariate analysis, mean TD < 100 Gy, presence of any genomic mutation, and diffuse hepatic metastatic disease were found to be independent predictors of shorter OS. Overall, six (13.3%) patients developed grade ≥ 3 liver toxicity post Y90 of whom two (4.4%) patients developed REILD. No dose threshold predicting grade ≥ 3 liver toxicity or REILD was identified. Conclusions: Mean TD ≥ 100 Gy in patients with unresectable CRLM undergoing resin-based Y90 SIRT predicts OR and prolonged OS.

Individualised dosimetry and safety of SIRT for intrahepatic cholangiocarcinoma

BackgroundThe aim of this study was to investigate the safety and efficacy of selective internal radiation therapy (SIRT) with 90Y resin microspheres for the treatment of Intrahepatic Cholangiocarcinoma (ICC). A total of 23 SIRT procedures from 18 ICC subjects were analysed to determine a lesion-based dose/response relationship with absorbed dose measures from 90Y PET and metabolic response as measured on [18F]FDG PET. Average absorbed dose (Davg), minimum dose to 70% of the volume (D70), volume receiving at least 50 Gy (V50), biological effective dose (BED) and equivalent uniform dose (EUD), were compared to changes in metabolic volume, maximum standardised uptake value (SUVmax) and total lesion glycolysis (TLG). Dose to normal liver was assessed with changes in liver uptake rate as measured with [99mTc]mebrofenin scintigraphy for a cohort of 20 subjects with primary liver malignancy (12 ICC, 8 hepatocellular carcinoma (HCC)).ResultsThirty-four lesions were included in the analysis. A relationship was found between metabolic response and both Davg and EUD similar to that seen previously in metastatic colorectal cancer (mCRC), albeit trending towards a lower response plateau. Both dose and SUV coefficient of variation within the lesion (CoVdose and CoVSUV), baseline TLG and EUD were found to be mildly significant predictors of response. No strong correlation was seen between normal liver dose and change in [99mTc]mebrofenin liver uptake rate; low baseline uptake rate was not indicative of declining function following SIRT, and no subjects dropped into the ‘poor liver function’ category.ConclusionsICC lesions follow a similar dose–response trend as mCRC, however, despite high lesion doses a full metabolic response was rarely seen. The CoV of lesion dose may have a significant bearing on response, and EUD correlated more tightly with metabolic response compared to Davg. SIRT in primary liver malignancy appears safe in terms of not inducing a clinically significant decline in liver function, and poor baseline uptake rate is not predictive of a reduction in function post SIRT.

Evaluation of Pretreatment Magnetic Resonance Elastography for the Prediction of Radiation-Induced Liver Disease

PurposeMagnetic resonance (MR) elastography (E) is a noninvasive technique for quantifying liver stiffness (LS) for fibrosis. This study evaluates whether LS is associated with risk of developing radiation-induced liver disease (RILD) in patients receiving liver-directed radiation therapy (RT). Methods and MaterialsBased on prior studies, LS ≤3 kPa was considered normal and LS >3.0 kPa as representing fibrosis. RILD was defined as an increase in Child-Pugh (CP) score of ≥2 from baseline within 1 year of RT. Univariate and multivariate Cox models were used to assess correlation. ResultsOne hundred two patients, 51 with primary liver tumors and 51 with liver metastases, were identified with sufficient follow-up. In univariate models, pre-RT LS >3.0 kPa (hazard ratio [HR] 4.9; 95% confidence interval [CI], 1.6-14; P = .004), body mass index (BMI), clinical cirrhosis, CP score, albumin-bilirubin (ALBI) grade 2, primary liver tumor, and mean liver dose were significantly associated with risk of post-RT RILD. In a multivariate analysis, LS >3.0 and mean liver dose both were significantly associated with RILD risk. ConclusionsElevated pre-RT LS is associated with an increased risk of RILD in patients receiving liver-directed RT.

Accurate non-tumoral 99mTc-MAA absorbed dose prediction to plan optimized activities in liver radioembolization using resin microspheres.

The manufacturers' recommended methods to calculate delivered activities in liver radioembolization are simplistic and only slightly personalized. Activity planning could also be based on a 99mTc-macroaggregated albumin SPECT/CT (MAA) using the partition model but its accuracy is controversial. This study evaluates the dose parameters in the normal liver and in the tumor compartments using MAA SPECT/CT (pre-therapeutic imaging) and 90Y TOF-PET/CT (post-therapy imaging). Finally, we propose a prescription of the activity as a function of the normal liver MAA distribution. 66 procedures of RE (with resin microspheres) corresponding to 171 lesions were analyzed. Tumor to normal targeted liver uptake (T/NTL), tumor absorbed dose (TD) and whole normal liver absorbed (WNLD) were assessed with MAA and 90Y imaging. Secondly, activities were recalculated using the MAA distribution in the normal liver compartment to reach the maximal tolerable liver dose. These Activities were compared to activities defined with the BSA method. Compared to 90Y imaging, our study demonstrated an accurate estimation of the WNLD using MAA imaging (Pearson's R=0.97, p<0.001). On the contrary, significant variations were found for TD (R=0.65, p<0.001). The MAA T/NTL ratio has a 85% positive predictive value in identifying patients who will get a 90Y T/NTL ratio above 1.5. Moreover, activities calculated using the MAA distribution in the normal liver compartment were significantly higher to activities defined with the BSA method. Whole normal liver absorbed doses are accurately predicted with MAA imaging and could be used to optimize the activity planning.

Evaluating Size‐Specific Dose Estimate (SSDE) as an estimate of organ doses from routine CT exams derived from Monte Carlo simulations

Size-specific dose estimate (SSDE) is a metric that adjusts CTDIvol to account for patient size. While not intended to be an estimate of organ dose, AAPM Report 204 notes the difference between the patient organ dose and SSDE is expected to be 10-20%. The purpose of this work was therefore to evaluate SSDE against estimates of organ dose obtained using Monte Carlo (MC) simulation techniques applied to routine exams across a wide range of patient sizes. Size-specific dose estimate was evaluated with respect to organ dose based on three routine protocols taken from Siemens scanners: (a) brain parenchyma dose in routine head exams, (b) lung and breast dose in routine chest exams, and (c) liver, kidney, and spleen dose in routine abdomen/pelvis exams. For each exam, voxelized phantom models were created from existing models or derived from clinical patient scans. For routine head exams, 15 patient models were used which consisted of 10 GSF/ICRP voxelized phantom models and five pediatric voxelized patient models created from CT image data. For all exams, the size metric used was water equivalent diameter (Dw ). For the routine chest exams, data from 161 patients were collected with a Dw range of ~16-44cm. For the routine abdomen/pelvis exams, data from 107 patients were collected with a range of Dw from ~16 to 44cm. Image data from these patients were segmented to generate voxelized patient models. For routine head exams, fixed tube current (FTC) was used while tube current modulation (TCM) data for body exams were extracted from raw projection data. The voxelized patient models and tube current information were used in detailed MC simulations for organ dose estimation. Organ doses from MC simulation were normalized by CTDIvol and parameterized as a function of Dw . For each patient scan, the SSDE was obtained using Dw and CTDIvol values of each scan, according to AAPM Report 220 for body scans and Report 293 for head scans. For each protocol and each patient, normalized organ doses were compared with SSDE. A one-sided tolerance limit covering 95% (P=0.95) of the population with 95% confidence (α=0.05) was used to assess the upper tolerance limit (TU ) between SSDE and normalized organ dose. For head exams, the TU between SSDE and brain parenchyma dose was observed to be 12.5%. For routine chest exams, the TU between SSDE and lung and breast dose was observed to be 35.6% and 68.3%, respectively. For routine abdomen/pelvis exams, the TU between SSDE and liver, spleen, and kidney dose was observed to be 30.7%, 33.2%, and 33.0%, respectively. The TU of 20% between SSDE and organ dose was found to be insufficient to cover 95% of the sampled population with 95% confidence for all of the organs and protocols investigated, except for brain parenchyma dose. For the routine body exams, excluding the breasts, a wider threshold difference of ~30-36% would be needed. These results are, however, specific to Siemens scanners.

PD-0878 Reduction of post-operative toxicity in esophageal cancer patients after model based proton therapy

Purpose or Objective During the COVID-19 pandemic, health insurance providers permitted to treat esophageal cancer (EC) patients with proton therapy (PT) when treated in the neo-adjuvant setting. This decision was based on the results of the MD Anderson randomized study showing significantly lower rates of the Total Toxicity Burden (TTB), especially of postoperative toxicity and consequently decreased hospital and intensive care unit (ICU) stay. The TTB combines a large range of toxicities with different incidence rates and severities into a single sum score. For patient selection, we used a model-based approach (MBA) using a model for TTB (>60). The aim of this study was to investigate if the post-operative TTB decreased with PT. Materials and Methods In accordance with the MBA, a plan comparison (photon vs proton radiotherapy (RT)) was performed in all EC patients that were to be treated with neo-adjuvant chemoradiotherapy (nCRT) according to the CROSS regimen. For patient selection, we developed a normal tissue complication probability (NTCP)-model for a TTB > 60, which corresponds to at least one grade > III or 2 grade > II complications. Patients, who were eligible for PT in terms of target motion ( 5%, were selected and treated with PT. Postoperative TTB and hospital and ICU stay were compared with a prospective dataset of patients that were treated with photon RT between 2014 and 2018 (n=224). Results Since March 2020, 26 out of 32 patients were selected for PT. The average reduction in mean lung dose was 5.2 Gy with PT compared to VMAT, with a corresponding average NTCP-reduction for TTB of 9.7%. Mean heart, spleen and liver dose were reduced by 7.9, 7.4 and 7.1 Gy, respectively. At the time of analyses, 14 out of 19 patients underwent esophagectomy. Three patients developed intercurrent metastases, in one a wait and see policy was applied and one switched to definitive CRT. In the resected PT patients, the expected proportion of patients with a TTB>60 was 29.7% for photon and 20.8% for proton RT. After resection, only one out of 14 patients (7.1%) had an TTB>60 ((p=0.051), compared to the expected proportion based on the photon plans). On average, the observed post-operative TTB was 15 (SEM: 6) after PT, compared to the historical photon cohort in which the observed post-operative TTB was 45 (SEM: 5). Hospital and ICU stay were also reduced by PT compared to the photon cohort;12.7 (SEM 1.4) vs. 20.0 (SEM 1.2) and 1.9 days (SEM 0.4) vs. 4.9 (SEM 0.6), resulting in an average cost reduction of about 10,000 euro per patient. Follow up will continuously be updated in our dynamic database. Conclusion In the neo-adjuvant setting, the first results indicate that proton-based nCRT reduces the post-operative TTB compared to historic photon-based nCRT. Moreover, there seems to be a trend towards reduced hospital and ICU stay.

A retrospective comparison of organ dose and effective dose in percutaneous vertebroplasty performed under CT guidance or using a fixed C-arm with a flat-panel detector.

To compare the organ-dose and effective-dose (E) delivered to the patient during percutaneous vertebroplasty (PVP) of one thoracic or lumbar vertebra performed under CT guidance or using a fixed C-arm. Consecutive adult patients undergoing PVP of one vertebra under CT-guidance, with optimized protocol and training of physicians, or using a fixed C-arm were retrospectively included from January 2016 to June 2017. Organ-doses were computed on 16 organs using CT Expo 2.4 software for the CT procedures and PCXMC 2.0 for the fixed C-arm procedures. E was also computed with both software. Dosimetric values per anatomic locations for all procedures were compared using the paired Mann-Whitney-Wilcoxon test. In total, 73 patients were analysed (27 men and 46 women, mean age 78±10years) among whom 35 (48%) underwent PVP under CT guidance and 38 (52%) PVP using a fixed C-arm. The median E was 11.31 [6.54; 15.82] mSv for all PVPs performed under CT guidance and 5.58 [3.33; 8.71] mSv for fixed C-arm and the differences was significant (p<0.001). For lumbar PVP, the organ doses of stomach, liver and colon were significantly higher with CT-scan than with the fixed C-arm: 97% (p=0.02); 21% (p=0.099) and 375% (p=0.002), respectively. For thoracic PVP, the lung organ dose was significantly higher with CT-scan than with the fixed C-arm (127%; p<0.001) and the oesophagus organ doses were not significantly different (p = 0.626). This study showed that the E and the organ dose on directly exposed organs were both higher for PVP performed under CT-guidance than with the fixed C-arm.

Hepatocellular carcinoma patients with portal vein thrombosis treated with robotic radiosurgery: Interim results of a prospective study.

This is a prospective study evaluating the role of stereotactic body radiotherapy (SBRT) with CyberKnife (CK) in Indian patients suffering from hepatocellular carcinoma with portal vein thrombosis (HCC-PVT). Patients with inoperable HCC-PVT, good performance score (PS), and liver function are accrued for treatment on CK (version M6) and planned with Multiplan (iDMS V2.0). Triple-phase contrast computed tomography (CT) scan was done for contouring, and the gross tumor volume (GTV) included contrast-enhancing mass within main portal vein and adjacent parenchymal disease. Dose prescription was as per-risk stratification protocol (22-50 Gy in 5 fractions) while achieving the constraints of mean liver dose <15 Gy, 800 cc liver <8 Gy, and the duodenum max of ≤24 Gy). Seventy-two HCC-PVT accrued till date (mean age 63 years [38-76 years], 96% male; Child-Pugh [CP] A 84%, B 9%; Barcelona-Clinic Liver Cancer [BCLC] C 96%; PS0-1: 80%, Karnofsky performance score [KPS]>70: 88%; co-morbidities 42%; infective 12%, alcohol intake 31%, adjuvant sorafenib 39%). CP scores 5, 6, 7, and 8 were in 35%, 32%, 8%, and 18%, respectively. Focal disease with portal vein thrombus (PVT) in 21%, liver involvement >50% and <50% in 46% and 32%. Liver cancer study group of Japan staging-based portal vein invasion VP2, VP3, and VP4 in 22%, 29%, and 40%. Cancer of the Liver Italian Programm (CLIP) scores 1, 2, 3, 4, and 5 were in 8%, 26%, 31%, 26%, and 7%, respectively. Mean follow-up was 7.3 months (median 6 months, standard deviation [SD] 6; range 3-30 months). Mean actuarial overall survival (OS) was 11.4 months (SE 1.587; 95% CI: 8-14.2 months). Six months and 12 months actuarial OS 55% and 38%, respectively. At last follow-up, 25/69 (36%) were alive and 44/69 (64%) were dead. Among 54 patients evaluated for response assessment, 23 (30%) had radiological confirmed PVT response, 1 (3%) had response of IVC thrombus, and 30 (42%) had no or minimal response to SBRT. Actuarial OS in responders and non-responders were 14.4 months (95% CI 9.4-19.2) and 7.4 months (95% CI 4.9-9.7), p-value: 0.022. Six and 12 months survival in responders and non-responders were 65.7% and 37% and 49% and 24.6%, respectively. Post-SBRT, 4 (12%) patients underwent transarterial chemoembolization (TACE) 3 patients (8%) and 1 patient (4%) transarterial radioembolization (TARE). Post-CK, (<4 weeks) 2 patients (4%) had decompensation. PVT response or recanalization after SBRT is a statistically significant prognostic factor for survival function in HCC-PVT.

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.