William A. Dezarn

Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: Early results in 148 patients

Purpose:The use of 90Y-microspheres to treat unresectable liver metastases originating from a variety of neuroendocrine tumors was reviewed. Materials and Methods:This is a retrospective review from 10 institutions of patients given 90Y-microsphere therapy for neuroendocrine hepatic metastases. Physical, radiographic, biochemical, and clinical factors associated with treatment and response were examined. All patients were followed with laboratory and imaging studies at regular intervals until death, or censured whether other therapy was given after brachytherapy. Toxicities (acute and late) were recorded, and survival of the group determined. Results:A total of 148 patients were treated with 185 separate procedures. The median age was 58 years (26–95 years) at treatment with median performance status of Eastern Cooperative Oncology Group (0). The median activity delivered was 1.14 GBq (0.33–3.30 GBq) with a median of 99% of the planned activity able to be given (38.1%–147.4%). There were no acute or delayed toxicity of Common Terminology Criteria for Adverse Events v3.0 grade 3 in 67% of patients, with fatigue (6.5%) the most common side effect. Imaging response was stable in 22.7%, partial response in 60.5%, complete in 2.7% and progressive disease in 4.9%. No radiation liver failure occurred. The median survival is 70 months. Conclusion:Radioembolization with 90Y-microspheres to the whole liver, or lobe with single or multiple fractions are safe and produce high response rates, even with extensive tumor replacement of normal liver and/or heavy pretreatment. The acute and delayed toxicity was very low without a treatment related grade 4 acute event or radiation induced liver disease in this modest-sized cohort. The significant objective response suggests that further investigation of this approach is warranted.

Treatment Parameters and Outcome in 680 Treatments of Internal Radiation With Resin 90Y-Microspheres for Unresectable Hepatic Tumors

PURPOSE Radioembolization (RE) using (90)Y-microspheres is an effective and safe treatment for patients with unresectable liver malignancies. Radiation-induced liver disease (RILD) is rare after RE; however, greater understanding of radiation-related factors leading to serious liver toxicity is needed. METHODS AND MATERIALS Retrospective review of radiation parameters was performed. All data pertaining to demographics, tumor, radiation, and outcomes were analyzed for significance and dependencies to develop a predictive model for RILD. Toxicity was scored using the National Cancer Institute Common Toxicity Criteria Adverse Events Version 3.0 scale. RESULTS A total of 515 patients (287 men; 228 women) from 14 US and 2 EU centers underwent 680 separate RE treatments with resin (90)Y-microspheres in 2003-2006. Multifactorial analyses identified factors related to toxicity, including activity (GBq) Selective Internal Radiation Therapy delivered (p < 0.0001), prescribed (GBq) activity (p < 0.0001), percentage of empiric activity (GBq) delivered (p < 0.0001), number of prior liver treatments (p < 0.0008), and medical center (p < 0.0001). The RILD was diagnosed in 28 of 680 treatments (4%), with 21 of 28 cases (75%) from one center, which used the empiric method. CONCLUSIONS There was an association between the empiric method, percentage of calculated activity delivered to the patient, and the most severe toxicity, RILD. A predictive model for RILD is not yet possible given the large variance in these data.

Recommendations of the American Association of Physicists in Medicine on dosimetry, imaging, and quality assurance procedures for 90Y microsphere brachytherapy in the treatment of hepatic malignancies.

Yttrium-90 microsphere brachytherapy of the liver exploits the distinctive features of the liver anatomy to treat liver malignancies with beta radiation and is gaining more wide spread clinical use. This report provides a general overview of microsphere liver brachytherapy and assists the treatment team in creating local treatment practices to provide safe and efficient patient treatment. Suggestions for future improvements are incorporated with the basic rationale for the therapy and currently used procedures. Imaging modalities utilized and their respective quality assurance are discussed. General as well as vendor specific delivery procedures are reviewed. The current dosimetry models are reviewed and suggestions for dosimetry advancement are made. Beta activity standards are reviewed and vendor implementation strategies are discussed. Radioactive material licensing and radiation safety are discussed given the unique requirements of microsphere brachytherapy. A general, team-based quality assurance program is reviewed to provide guidance for the creation of the local procedures. Finally, recommendations are given on how to deliver the current state of the art treatments and directions for future improvements in the therapy.

Safety and efficacy of Y-90 microsphere treatment in patients with primary and metastatic liver cancer: The tumor selectivity of the treatment as a function of tumor to liver flow ratio

BackgroundTreatment records and follow-up data on 40 patients with primary and metastatic liver malignancies who underwent a single whole-liver treatment with Y-90 resin microspheres (SIR-Spheres® Sirtex Medical, Lake Forest, IL) were retrospectively reviewed. The objective of the study was to evaluate the anatomic and physiologic determinants of radiation dose distribution, and the dose response of tumor and liver toxicity in patients with liver malignancies who underwent hepatic arterial Y-90 resin microsphere treatment.MethodsLiver and tumor volume calculations were performed on pre-treatment CT scans. Fractional tumor and liver flow characteristics and lung shunt fractions were determined using hepatic arterial Tc-99m MAA imaging. Absorbed dose calculations were performed using the MIRD equations. Liver toxicity was assessed clinically and by liver function tests. Tumor response to therapy was assessed by CT and/or tumor markers.ResultsOf the 40 patients, 5 had hepatocellular cancer (HCC), and 35 had metastatic liver tumors (15 colorectal cancer, 10 neuroendocrine tumors, 4 breast cancer, 2 lung cancer, 1 ovarian cancer, 1 endometrial cancer, and 2 unknown primary adenocarcinoma). All patients were treated in a salvage setting with a 3 to 80 week follow-up (mean: 19 weeks). Tumor volumes ranged from 15.0 to 984.2 cc (mean: 294.9 cc) and tumor to normal liver uptake ratios ranged from 2.8 to 15.4 (mean: 5.4). Average administered activity was 1.2 GBq (0.4 to 2.4 GBq). Liver absorbed doses ranged from 0.7 to 99.5 Gy (mean: 17.2 Gy). Tumor absorbed doses ranged from 40.1 to 494.8 Gy (mean: 121.5 Gy). None of the patients had clinical venoocclusive disease or therapy-induced liver failure. Seven patients (17.5 %) had transient and 7 patients (17.5 %) had persistent LFT abnormalities. There were 27 (67.5%) responders (complete response, partial response, and stable disease). Tumor response correlated with higher tumor flow ratio as measured by Tc-99m MAA imaging.ConclusionDoses up to 99.5 Gy to uninvolved liver are tolerated with no clinical venoocclusive disease or liver failure. The lowest tumor dose producing a detectable response is 40.1 Gy. The utilization of MAA-based imaging techniques to determine tumor and liver blood flow for clinical treatment planning and the calculation of administered activity may improve clinical outcomes.

COMPUTER MODELING OF YTTRIUM-90-MICROSPHERE TRANSPORT IN THE HEPATIC ARTERIAL TREE TO IMPROVE CLINICAL OUTCOMES

PURPOSE Radioembolization (RE) via yttrium-90 ((90)Y) microspheres is an effective and safe treatment for unresectable liver malignancies. However, no data are available regarding the impact of local blood flow dynamics on (90)Y-microsphere transport and distribution in the human hepatic arterial system. METHODS AND MATERIALS A three-dimensional (3-D) computer model was developed to analyze and simulate blood-microsphere flow dynamics in the hepatic arterial system with tumor. Supplemental geometric and flow data sets from patients undergoing RE were also available to validate the accuracy of the computer simulation model. Specifically, vessel diameters, curvatures, and branching patterns, as well as blood flow velocities/pressures and microsphere characteristics (i.e., diameter and specific gravity), were measured. Three-dimensional computer-aided design software was used to create the vessel geometries. Initial trials, with 10,000 noninteracting microspheres released into the hepatic artery, used resin spheres 32-microm in diameter with a density twice that of blood. RESULTS Simulations of blood flow subject to different branch-outlet pressures as well as blood-microsphere transport were successfully carried out, allowing testing of two types of microsphere release distributions in the inlet plane of the main hepatic artery. If the inlet distribution of microspheres was uniform (evenly spaced particles), a greater percentage would exit into the vessel branch feeding the tumor. Conversely, a parabolic inlet distribution of microspheres (more particles around the vessel center) showed a high percentage of microspheres exiting the branch vessel leading to the normal liver. CONCLUSIONS Computer simulations of both blood flow patterns and microsphere dynamics have the potential to provide valuable insight on how to optimize (90)Y-microsphere implantation into hepatic tumors while sparing normal tissue.

A First Report of Radioembolization for Hepatic Metastases From Ocular Melanoma

Background: Ocular melanoma (OM) metastasizes to the liver and is rapidly fatal despite aggressive therapy. Yttrium-90 microspheres (radioembolization) delivered via the hepatic artery is an established and effective approach for primary and metastatic hepatic tumors, although 90Y use in OM has not been reported previously. Methods: A retrospective review was performed for all patients with OM who received radioembolization at 5 centers. Results: 11 patients received 12 treatments with a median activity of 1.55 GBq delivered per treatment. Toxicity was minimal, with PET/CT at 3 months posttreatment showing a response in all patients; 1 patient had a complete response. Conclusions: Radioembolization can control hepatic metastases of OM with very few side effects.

Guidelines by the AAPM and GEC-ESTRO on the use of innovative brachytherapy devices and applications: Report of Task Group 167

Although a multicenter, Phase III, prospective, randomized trial is the gold standard for evidence-based medicine, it is rarely used in the evaluation of innovative devices because of many practical and ethical reasons. It is usually sufficient to compare the dose distributions and dose rates for determining the equivalence of the innovative treatment modality to an existing one. Thus, quantitative evaluation of the dosimetric characteristics of innovative radiotherapy devices or applications is a critical part in which physicists should be actively involved. The physicists role, along with physician colleagues, in this process is highlighted for innovative brachytherapy devices and applications and includes evaluation of (1) dosimetric considerations for clinical implementation (including calibrations, dose calculations, and radiobiological aspects) to comply with existing societal dosimetric prerequisites for sources in routine clinical use, (2) risks and benefits from a regulatory and safety perspective, and (3) resource assessment and preparedness. Further, it is suggested that any developed calibration methods be traceable to a primary standards dosimetry laboratory (PSDL) such as the National Institute of Standards and Technology in the U.S. or to other PSDLs located elsewhere such as in Europe. Clinical users should follow standards as approved by their countrys regulatory agencies that approved such a brachytherapy device. Integration of this system into the medical source calibration infrastructure of secondary standard dosimetry laboratories such as the Accredited Dosimetry Calibration Laboratories in the U.S. is encouraged before a source is introduced into widespread routine clinical use. The American Association of Physicists in Medicine and the Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology (GEC-ESTRO) have developed guidelines for the safe and consistent application of brachytherapy using innovative devices and applications. The current report covers regulatory approvals, calibration, dose calculations, radiobiological issues, and overall safety concerns that should be addressed during the commissioning stage preceding clinical use. These guidelines are based on review of requirements of the U.S. Nuclear Regulatory Commission, U.S. Department of Transportation, International Electrotechnical Commission Medical Electrical Equipment Standard 60601, U.S. Food and Drug Administration, European Commission for CE Marking (Conformité Européenne), and institutional review boards and radiation safety committees.

Patient Specific 3D Image-Based Radiation Dose Estimates for 90Y Microsphere Hepatic Radioembolization in Metastatic Tumors

Introduction: Hepatic brachytherapy using either resin or glass 90Y microspheres is an established therapy for unresectable primary and metastatic tumors. Unlike conventional brachytherapy, microsphere brachytherapy has no software currently available for pretreatment evaluation and radiation planning. A non-MIRD radiation dose calculation approach is desired to accurately utilize spatial relationships in the liver and tumor distribution. Materials and methods: A newly developed software tool employing the technetium-99m macro aggregated albumin (99mTc-MAA) SPECT 3-D dataset and CT scan was used to estimate the likely absorbed dose in normal liver and tumor tissue from 90Y microsphere brachytherapy (radioembolization). Monte Carlo algorithms were utilized to maximize true 3D dose estimates for each patients unique liver and tumor geometry. Clinical correlation was completed regarding toxicity, imaging response, and complications as an independent measure of the softwares usefulness in predicting radiation effects. Comparisons were made to MIRD, Body Surface Area method, and physician prescription for 90Y activity. Results: The software performed accurately in estimating absorbed dose in phantom testing. Patient data from 50 consecutive patients with metastatic tumors (26 colon, 24 neuroendocrine) to the liver receiving 59 radioembolization treatments were studied. The software estimate of median normal liver and tumor absorbed doses were 27.6 Gy and 41.2 Gy, respectively. Conclusions: The use of pretreatment 99mTc-MAA SPECT co-registered to a CT scan provides useful and unique data for a newly developed non-MIRD, Monte Carlo-based radiation dosimetry software program in 90Y microsphere brachytherapy. Software estimates of radiation dose preserving critical spatial information in the liver and tumors appeared reasonable based on clinical outcomes. Further testing and refinement of the software interface is ongoing with plans to distribute it to research organizations.

90 Y Microspheres: Concepts and Principles

Why use radiation in the liver at all since it is known to be much more sensitive to radiation damage than the tumors growing in it? This is an excellent and oft-stated question by many in oncology. With the development of internal brachytherapy, the delivery of tumoricidal doses of radiation to tumors of all origins and in all segments of the liver became a reality. Recent advances in medical oncology (anti-angiogenic agents, new systemic chemotherapy agents) have produced encouraging response rates and increased median survivals for many solid tumors. However, despite clearance of disease elsewhere in the body, the liver is usually the site of tumor resistance and ultimately the patient’s death. Moreover, with increased skill and more sophisticated and specialized catheters, today’s interventional radiologists are able to help oncology patients more than ever before. Precise access to the particular artery feeding a chemoinsensitive or unresectable tumor is now a widely available service in most medical centers that treat cancer patients.

Resin 90Y microsphere activity measurements for liver brachytherapy.

The measurement of the radioactivity administered to the patient is one of the major components of 90Y microsphere liver brachytherapy. The activity of 90Y microspheres in a glass delivery vial was measured in a dose calibrator. The calibration value to use for 90Y in the dose calibrator was verified using an activity calibration standard provided by the microsphere manufacturer. This method allowed for the determination of a consistent, reproducible local activity standard. Additional measurements were made to determine some of the factors that could affect activity measurement. The axial response of the dose calibrator was determined by the ratio of activity measurements at the bottom and center of the dose calibrator. The axial response was 0.964 for a glass shipping vial, 1.001 for a glass V-vial, and 0.988 for a polycarbonate V-vial. Comparisons between activity measurements in the dose calibrator and those using a radiation survey meter were found to agree within 10%. It was determined that the dose calibrator method was superior to the survey meter method because the former allowed better defined measurement geometry and traceability of the activity standard back to the manufacturer. Part of the preparation of resin 9()Y microspheres for patient delivery is to draw out a predetermined activity from a shipping vial and place it into a V-vial for delivery to the patient. If the drawn activity was placed in a glass V-vial, the activity measured in the dose calibrator with a glass V-vial was 4% higher than the drawn activity from the shipping vial standard. If the drawn activity was placed in a polycarbonate V-vial, the activity measured in the dose calibrator with a polycarbonate V-vial activity was 20% higher than the drawn activity from the shipping vial standard. Careful characterization of the local activity measurement standard is recommended instead of simply accepting the calibration value of the dose calibrator manufacturer.