Liver Radiation Dose Research Articles

Phase I trial of single-photon emission computed tomography-guided liver-directed radiotherapy for patients with low functional liver volume.

Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were assessed 6-8 weeks and 6 months after completing radiotherapy. All 12 patients had colorectal liver metastases and received prior hepatotoxic chemotherapy; 8 patients underwent prior liver resection. Median computed tomography anatomical nontumor liver volume was 1584 cc (range = 764-2699 cc). Median SPECT functional liver volume was 1117 cc (range = 570-1928 cc). Median nontarget computed tomography and SPECT liver volumes below the volumetric dose constraint were 997 cc (range = 544-1576 cc) and 684 cc (range = 429-1244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No dose-limiting toxicities were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process, which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. NCT02626312.

Phase 1 Trial of SPECT-Guided Liver-Directed Ablative Radiotherapy for Patients with Low Functional Liver Volume

Traditional liver dose constraints specify that a critical volume of 700 cc of non-tumor liver should be spared from receiving a hepatotoxic dose. We evaluated the safety of liver-directed ablative radiotherapy for patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or liver metastases (LM) with Child-Pugh (CP) A5 liver function at baseline and with low functional liver volume as estimated by Tc-99m sulfur colloid single photon emission computed tomography (SPECT). We hypothesized that functional liver image guidance with SPECT would allow safe delivery of ablative radiotherapy in patients with limited liver volume. A phase 1 trial with a 3+3 design was conducted to evaluate the safety of comprehensive ablative radiotherapy to the liver disease using escalating functional non-target liver radiation dose constraints. Eligibility criteria included (1) a diagnosis of HCC, iCCA, or LM, (2) prior treatment with irinotecan or oxaliplatin chemotherapy or liver resection, and (3) a minimum functional liver volume of 400 cc as estimated by SPECT using a threshold of 40% maximum intensity. Patients with CP >A5 liver function, prior liver-directed radiotherapy, or prior Yttrium-90 therapy were excluded. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. The volumetric dose constraint for functional non-target liver receiving <24 Gy for 15 fractions or <27 Gy for 25 fractions was determined by the dose level of trial enrollment: level 0 was ≥400 cc and level +1 was ≥300 cc. A level -1 was included if needed. We used standard 15 and 25 fraction dose constraints for other organs at risk. The following dose limiting toxicities (DLTs) were assessed within 6-8 weeks of completing radiotherapy: Grade 3 hypoalbuminemia, increase in INR, increase in bilirubin, or ascites, or Grade 4 hepatic failure or any radiation-related toxicity. Twelve patients enrolled between February 2016 and June 2022. The median (range) GTV was 36 (2-651) cc. The median CT anatomical non-tumor liver volume was 1584 (764-2699) cc, and the median SPECT functional liver volume was 1117 (570-1928) cc, with a Pearson correlation coefficient of 0.98 (p<0.001). The median non-target SPECT functional liver volume below the volumetric dose constraint was 684 (429-1244) cc. None of the 3 patients treated in dose level 0, and none of the 9 patients treated in dose level +1 experienced any DLTs. The 1-year in-treatment-field control rate was 55%, and 1-year overall survival was 71%. Ablative radiotherapy can be safely delivered using functional SPECT image guidance, which enables sparing lower volumes of functional liver than traditionally accepted in patients with CP A5 liver function. Further evaluation with a phase 2 study is warranted.

Serum Levels of Hepatocyte Growth Factor and CD40 Ligand Predict Radiation-Induced Liver Injury

BACKGROUND: Declining liver function is a concerning side effect associated with radiation therapy. Biomarkers of liver toxicity would be useful in personalizing therapy. METHODS: As part of two prospective clinical trials examining adaptive radiation therapy, we collected serum samples from patients receiving liver radiation. We performed a screen of 22 cytokines using a multiplex assay then used ELISA to quantify the cytokines of greatest interest. Subjects were split into screening and validation cohorts. Toxicity was defined as an increase in Child-Pugh score of 2 points or greater within 6 months. Logistic regression models were used to estimate the relationship between our toxicity endpoint and serum cytokine concentrations. RESULTS: Our initial screen (46 subjects, 11 events) identified hepatocyte growth factor (HGF), CD40L (CD154), and eotaxin (CCL11) as potentially predictive of toxicity. We then tested these markers in an expanded patient cohort (104 subjects, 18 events) with a batch correction due to varying age of the samples which confirmed that high HGF and low CD40L were associated with a subsequent decline in liver function following radiation therapy. Multivariate analysis factoring in baseline Child-Pugh score and mean liver radiation dose demonstrated that HGF and CD40L were potentially predictive of toxicity (HGF OR 4.3, P = .009; CD40L OR 0.5 P = .06). Additionally, higher than median baseline HGF levels (1.4 ng/ml) were significantly associated with decreased survival following liver radiation (27.1 vs 14.5 months, P = .03). CONCLUSIONS: Our study identifies high HGF and low CD40L as potential markers of liver toxicity following radiation therapy.

In vivo Evaluation of Free and Chelated Accelerator-produced Actinium- 225 - Radiation Dosimetry and Toxicity Results.

The demand for the alpha-emitting radionuclide Actinium-225 (225Ac) for use in radionuclide therapy is growing. Producing 225Ac using high energy linear accelerators, cyclotrons or photoinduction could increase its supply. One potential problem with accelerator produced 225Ac using Thorium-232 targets is the presence in final product of 0.1-0.3% by activity of the long-lived 227Ac impurity at the end of irradiation. It is important to comprehensively evaluate the behavior of accelerator-produced 225Ac in vivo before using it in pre-clinical and clinical applications. Biodistribution of accelerator-produced 225Ac in acetate (free) and DOTA complex forms was performed in male and female CD-1 mice. The biodistribution data was used for radiation dosimetry calculations. The toxicity studies of free 225Ac were conducted in CD-1 mice at 1.036 and 2.035 kBq/g body weight. Blood counts, body weight and post-mortem histology were evaluated. In both genders, there was a pronounced uptake of free 225Ac in the liver when compared to 225Ac-DOTA which resulted in 200 and 50 times higher liver radiation dose for free 225Ac in male and female mice, respectively. 227Ac contribution to radiation dose delivered by 225Ac was calculated to be negligible. Mice given free 225Ac did not lose weight, had only transient effect on their blood counts and showed no histological damage to the liver and bone marrow. Our biodistribution/dosimetry/toxicity study of accelerator-produced 225Ac demonstrated the patterns very similar to 229Th-derived 225Ac. We conclude that accelerator-produced 225Ac is suitable for the developmental work of targeted radionuclide therapy.

Radiotherapy for Hepatocellular Carcinoma With Tumor Vascular Thrombus: Ready for Prime Time?

Radiotherapy for Hepatocellular Carcinoma With Tumor Vascular Thrombus: Ready for Prime Time?

Evaluation of S-values and dose distributions for90Y,131I,166Ho, and188Re in seven lobes of the rat liver

Rats have been widely used in radionuclide therapy research for the treatment of hepatocellular carcinoma (HCC). This has created the need to assess rat liver absorbed radiation dose. In most dose estimation studies, the rat liver is considered as a homogeneous integrated target organ with a tissue composition assumed to be similar to that of human liver tissue. However, the rat liver is composed of several lobes having different anatomical and chemical characteristics. To assess the overall impact on rat liver dose calculation, the authors use a new voxel-based rat model with identified suborgan regions of the liver.The liver in the original cryosectional color images was manually segmented into seven individual lobes and subsequently integrated into a voxel-based computational rat model. Photon and electron particle transport was simulated using the MCNPX Monte Carlo code to calculate absorbed fractions and S-values for (90)Y, (131)I, (166)Ho, and (188)Re for the seven liver lobes. The effect of chemical composition on organ-specific absorbed dose was investigated by changing the chemical composition of the voxel filling liver material. Radionuclide-specific absorbed doses at the voxel level were further assessed for a small spherical hepatic tumor.The self-absorbed dose for different liver lobes varied depending on their respective masses. A maximum difference of 3.5% was observed for the liver self-absorbed fraction between rat and human tissues for photon energies below 100 keV. (166)Ho and (188)Re produce a uniformly distributed high dose in the tumor and relatively low absorbed dose for surrounding tissues.The authors evaluated rat liver radiation doses from various radionuclides used in HCC treatments using a realistic computational rat model. This work contributes to a better understanding of all aspects influencing radiation transport in organ-specific radiation dose evaluation for preclinical therapy studies, from tissue composition to organ morphology and activity distribution.

Quantitative Comparison of Yttrium-90 (90 Y)-Microspheres and Technetium-99m (99m Tc)-Macroaggregated Albumin SPECT Images for Planning 90 Y Therapy of Liver Cancer

Yttrium-90 ((90)Y)-microspheres administered via the hepatic artery has been used for the treatment of unresectable primary or metastatic cancer in the liver. Prior to (90)Y therapy, however, the (90)Y administered activity and the percent shunting to lungs must be determined, most commonly by gamma camera imaging of technetium-99m ((99m)Tc)-macroaggregated albumin (MAA). The purpose of the current study was to identify and evaluate an objective measure of the correlation of (90)Y and MAA activity distributions and thus assess the reliability of MAA imaging for evaluation of (90)Y administered activity and tumor and liver radiation doses. The MAA study consisted of two acquisitions. After administration of 185 MBq of MAA, a partial-body or so-called breakthrough scan was performed in order to determine the percent shunting to lungs. Immediately after a breakthrough scan, a combined single-photon emission computed tomography (SPECT)/transmission computed tomography (CT) scanner was used to image MAA distribution in order to derived the prescribed (90)Y administered activity based on tumor and liver dosimetry. (90)Y SPECT/CT was performed 2-4 weeks later and activities used were in the range of 777-2,442 MBq. In order to compare (90)Y and MAA SPECT images, first the respective CT image sets were registered using a transform based on normalized mutual information. The transform thus derived was used to align the 90Y and MAA SPECT image sets, and the Spearman's (rho) rank correlation as well as image distance (L2-norm) between the registered SPECT images were then calculated. The Spearman's rank correlation values ranged from 0.451 to 0.818 and the L2 distances from 0.626 to 2.889. Based on visual inspection, the registration of the (90)Y and MAA SPECT images appeared reasonably accurate. The regression coefficient (r) between visual scoring and the Spearman's rank correlation was 0.65 and between visual scoring and L2 distance 0.61. The Spearman's rank correlation thus appears to be more reliable than the image distance for assessing the correlation of the (90)Y and MAA images.

Treatment of Unresectable Hepatocellular Carcinoma with Intrahepatic Yttrium 90 Microspheres: Factors Associated with Liver Toxicities

Intraarterial injection of yttrium 90 microspheres (TheraSpheres) is used in the treatment of hepatocellular carcinoma (HCC). This article presents an analysis of the incidence of liver toxicities (liver-related events) and pretreatment factors associated with liver toxicities after TheraSphere treatment. Eighty-eight TheraSphere-treated patients with low 90-day mortality risk were selected for analysis, with liver toxicities coded with use of standard oncology criteria. Descriptive and inferential statistical methods were applied to estimate the incidence of liver toxicities and to evaluate the influence of liver radiation dose and various pretreatment factors on the risk of their occurrence. Sixty-eight liver toxicities occurred in 37 of the 88 patients (42%). Thirty-two patients (36%) experienced 50 liver toxicities after the first treatment and nine of 23 patients (39%) who received a second treatment experienced 18 liver toxicities. Pretreatment total bilirubin and liver radiation dose were found to be associated with the risk of at least one liver toxicity and with the time to first occurrence of a liver toxicity after first treatment. Pretreatment total bilirubin also was associated with liver toxicities after the second treatment. Most of the toxicities resolved; however, those that did not resolve were attributed to tumor progression or advancing cirrhosis. The risk of liver toxicities in patients with unresectable HCC treated with TheraSpheres increases with increasing pretreatment total bilirubin level and liver radiation dose to a maximum of 150 Gy for a single administration. The toxicities attributed to treatment resolved over time, and none of the patients studied had confirmed radiation-induced liver disease. Consequently, doses as high as 150 Gy on a single administration and as high as 268 Gy on repeated administrations were well tolerated.

Relationship between ZCE 025 blood clearance and liver accumulation in patients with colorectal cancer

Clinical interest in radiolabelled monoclonal antibodies (mAbs) derives from their ability to target tissues and deliver radioisotopes thereto. Diagnostic and therapeutic trials suggest that the potential of mAbs would be optimized with better understanding of factors which influence blood clearance. This study sought to advance that understanding. Nine colon cancer patients were injected with 20 mg111In radiolabelled ZCE 025 mAb, then laser-positioned and imaged daily for one week via nuclear medicine views. Laser-positioned CT images were also obtained, enabling image registration. Blood samples were taken at 30, 60, and 90 min and at every imaging time point. Sample activity was plotted to estimate the elimination half-life (t12 β). Liver radiation dose was calculated from the images and evaluated for total organ (mCi-h) and region of interest (μCi-h/g). Laboratory values and patients' physical parameters were also studied to determine their impact on liver uptake and mAb blood clearance. Liver radiation dose, as measured in this study, correlated with terminal half-life of the mAb in blood; patients' liver enzymes and physical parameters did not. Radioactivity in a 48-h or 72-h blood sample correlates with t12 β and liver radiation dose, suggesting that a single 72-h sample can predict both.

Long term liver radiation damage in the rat following internal and external irradiation.

SummaryLiver radiation damage has been assessed and compared in the rat following two different liver irradiation regimes. (i) One group of rats received liver radiation doses ranging from 4,250 rads to 8,500 rads delivered externally in fractionated doses over 11 days by a 240 kV X‐ray machine. Liver damage was assessed by determining serum levels of alanine aminotransferase, aspartate aminotransferase and total haemolytic complement. (ii) A second group of rats received a liver radiation dose of 8,500 rads delivered internally via intravenously injected radioactive colloidal gold–198, and similar serum parameters were studied. Liver histology was also carried out on both groups of rats.Both treatments result in abnormal serum levels of enzymes and complement, and a comparison of results for both irradiation regimes indicates that, while there are slight differences in early response, particularly in serum complement levels, nevertheless similar long term liver damage results.

Clinical applications of the short lived radioisotopes (liver scanning with 113m-In (OH) 3 -colloids).

ABSTRACT 99m Tc and 113m In are much harmless to the patients than the other radioisotopes, such as 198Au, 131I, 203Hg, etc., since their half lives are shorter. So that they can be given in much more doses and used broadly in scanning the brain, lung, liver, spleen, kidney, placenta, bone marrow, cardiac pool, etc. 113m In is produced from 113Sn‐113mIn generator by milking and due to its short half life, the generator can be eluted several times a day, and can be used for a long time, even more than 6 months, because the half life of 113Sn is 118 days long.The simplified preparation of reliable scanning agents is made possible by use of a closed generator system and pre‐sterilized vials containing the appropriate chemicals to make the specific radio‐pharmaceuticals.Liver scanning with 113mIn(OH)3‐colloids was tried on 70 cases, such as hepatitis, cirrhosis, tumors, etc.The liver uptake of injected 113mIn(OH)3‐colloids intravenously was 85% on an average in normal cases, and liver radiation dose from 2mCi 113mIn(OH)3‐colloids was about 0.85 rads.Contamination of 113Sn in 113mIn was identified with hematoxylin method, and it was less than 0.003% in concentration. This amount raises no problem in its practical use.