Efficacy and Toxicity Related to Treatment of Hepatocellular Carcinoma with ⁹⁰Y-SIR Spheres: Radiobiologic Considerations

Abstract

Radioactive 90 Y-selective internal radiation (SIR) sphere therapy is increasingly used for the treatment of nonresectable hepatocellular carcinoma (HCC). However, the maximum delivered dose is limited by severe injury to the nontarget tissue, including liver parenchyma. Our study aimed to implement radiobiologic models for both tumor control probability (TCP) and normaltissue complication probability (NTCP) to describe more effectively local response and the liver toxicity rate, respectively. Methods: Patients with documented HCC, adequate bone marrow parameters, and regular hepatic and pulmonary function were eligible for the study. Patients who had pulmonary shunt greater than 20% of 99m Tc-labeled macroaggregated albumin or any uncorrectable delivery to the gastrointestinal tract, reverse blood flow out of the liver, or complete portal vein thrombosis were excluded. Patients received a planned activity of the 90 Y-SIR spheres, determined using the empiric body surface area method. The dose distribution was determined using posttreatment (3-dimensional) activity distribution and Monte Carlo dose voxel kernel calculations, and the mean doses to healthy liver and tumor were calculated for each patient. Response was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) and recommendations of the European Association for the Study of the Liver (EASL). Criteria were used to assess possible liver toxicities. The parameters of TCP and NTCP models were established by direct maximization of the likelihood. Results: Seventy-three patients were treated. With an average dose of 110 Gy to the tumor, complete or partial response was observed in 74% and 55% of patients according to the EASL guideline and RECIST, respectively, and the predicted TCPs were 73% and 55%, respectively. With a median liver dose of 36 Gy (range, 6-78 Gy), the $grade 2 (G2), $grade 3 (G3), and $grade 4 (G4) liver toxicities were observed in 32% (23/73), 21% (15/73), and 11% (8/73) of patients, respectively. The parameters describing the $G2 liver toxicity data using the NTCP model were a tolerance dose of the whole organ leading to a 50% complication probability of 52 Gy (95% confidence interval, 44-61 Gy) and a slope of NTCP versus dose of 0.28 (95% confidence interval, 0.18-0.60), assuming n 5 1. Conclusion: The radiobiologic approach, based on patient-specific dosimetry, could improve the 90 Y-microsphere therapeutic approach of HCC, maintaining an acceptable liver toxicity.

A review of 3D image-based dosimetry, technical considerations and emerging perspectives in 90Y microsphere therapy

“…Their results provide reasoning to the D NL threshold noted in other clinical studies of 70 Gy using GMS [44] and approximately 40-50 Gy using RMS [13,45]. It should be noted that although no toxicity was noted with absorbed doses of up to 100 Gy [46], the manufacturer of RMS recommends a D NL of 80 Gy, and a recent summary suggests a preferable D NL of 50 Gy [29].…”

“…Gy [13]. They also observed (and predicted) toxicity of 34%, and calculated a BED50 of 93 Gy, close to the values of 72 Gy derived from EBRT [116].…”

“…A recent review by the EANM Dosimetry Committee identified 48 papers (out of 79 surveyed) employing the use of radionuclide dosimetry showing a strong correlation between absorbed dose and the tumour response & toxicity over a wide range of radionuclide treatments (including 90 Y-RE) [9], and many works have noted the lack of randomized trials comparing dosimetry-based radionuclide therapy to fixed dosing, or dosing per kg body weight [10,11]. For routine use, there is a requirement of standardized procedures for absorbed dose calculations [12] and improved reliability of radiobiological models used to convert dosimetric data to biologic endpoints [13]. 90 Y-RE treatment planning should be based on a priori knowledge to predict the total absorbed tumour/normal liver doses (hereon denoted D T and D NL respectively) and intended responses before or during the therapeutic intervention, as is common in brachytherapy or external beam radiotherapy (EBRT).…”

Biologically effective dose in fractionated molecular radiotherapy—application to treatment of neuroblastoma with131I-mIBG

“…Currently in molecular radiotherapy (MRT), there is an increasing interest in exposure parameters based on radiobiological models, which are believed to have the potential to better predict the effect of the treatment than absorbed dose alone (Barone et al 2005;Dewaraja et al, 2010;Strigari et al, 2010;Strigari et al, 2011;Strigari et al, 2014). The most commonly used quantity is the biologically effective dose (BED), a radiobiological concept which was first introduced with a different name by Barendsen (1982) and was later renamed BED by Fowler (1989).…”

General Theory of Predictive Dosimetry for Yttrium-90 Radioembolization to Sites Other Than the Liver: Reply

“…A possible methodology to overcome these limitations is a dose volume histogram (DVH) based evaluation of the dose distribution for the clinical target volume and organs at risk. This approach is well known from other radiation-based ablative therapies, such as CT-guided brachytherapy [11][12][13] and recently has been demonstrated in radioembolization as well [4,14].…”