YTTRIUM-90 MICROSPHERES FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA: A REVIEW

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1 doi: /j.ijrobp Int. J. Radiation Oncology Biol. Phys., Vol. 66, No. 2, Supplement, pp. S83 S88, 2006 Copyright 2006 Elsevier Inc. Printed in the USA. All rights reserved /06/$ see front matter STaRT SYMPOSIUM YTTRIUM-90 MICROSPHERES FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA: A REVIEW RIAD SALEM, M.D., M.B.A.,* AND RUSSELL D. HUNTER, B.SC. *Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Chicago, IL; MDS Pharma Services, Global Clinical Development, King of Prussia, PA To present a critical review of yttrium-90 (TheraSphere) for the treatment of hepatocellular carcinoma (HCC). Medical literature databases (Medline, Cochrane Library, and CANCERLIT) were searched for available literature concerning the treatment of HCC with TheraSphere. These publications were reviewed for scientific and clinical validity. Studies pertaining to the use of yttrium-90 for HCC date back to the 1960s. The results from the early animal safety studies established a radiation exposure range of Gy to be used in human studies. Phase I dose escalation studies followed, which were instrumental in delineating radiation dosimetry and safety parameters in humans. These early studies emphasized the importance of differential arteriolar density between hypervascular HCC and surrounding liver parenchyma. Current trends in research have focused on advancing techniques to safely implement this technology as an alternative to traditional methods of treating unresectable HCC, such as external beam radiotherapy, conformal beam radiotherapy, ethanol ablation, trans-arterial chemoembolization, and radiofrequency ablation. Yttrium-90 (TheraSphere) is an outpatient treatment option for HCC. Current and future research should focus on implementing multicenter phase II and III trials comparing TheraSphere with other therapies for HCC Elsevier Inc. Brachytherapy, Hepatocellular carcinoma, Yttrium-90, Microspheres, Radioembolization. INTRODUCTION Hepatocellular carcinoma (HCC) represents one of the most common forms of cancer with more than 1 million new cases estimated annually worldwide. In the United States, the incidence of HCC has steadily increased over the past two decades, with an estimated 18,900 new cases having occurred in 2004 (1). Concurrently, HCC-related mortality has increased with more than 14,000 deaths estimated in the year More concerning is the predicted increase in the incidence of HCC over the next 2 decades because of the growing number of patients with hepatitis C induced cirrhosis (2). The incidence is likely to peak in the next two decades, then decline because of vaccination programs for hepatitis B and reduction in transmission of hepatitis C (3). Traditionally, patients with HCC had limited treatment options because of the locally advanced and multifocal nature of the disease. Most patients with HCC are not surgical candidates, with only 15 25% suitable for resection. Likewise, many patients with HCC do not qualify for liver transplantation because of their advanced stage of cancer at the time of diagnosis. Several radiotherapeutic options are available for patients with unresectable disease. Reprint requests to: Riad Salem, M.D., M.B.A., Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, 676 North St. Claire, Suite 800, Chicago, IL Tel: (312) ; Fax: (312) ; r-salem@northwestern.edu The use of external beam radiotherapy to treat primary hepatoma has limited applicability because of the risk of radiation-induced liver disease (RILD), a clinical syndrome of anicteric hepatomegaly, ascites, and increased liver enzymes occurring weeks to months after therapy. Improved results have been reported with conformal beam radiotherapy, which employs a three-dimensional approach rather than broad axial plane techniques. This permits higher levels of radiation to target regions within the liver, while limiting whole organ exposure (4). However, the total dose that is administered to the liver parenchyma adjacent to the cancer presents a limitation to the use of conformal beam techniques. This restricts the maximum dose that can be safely provided without causing RILD. TheraSphere is selectively administered for HCC by percutaneous access to the hepatic artery. Lobar, segmental, and subsegmental treatment can be performed. This internal radiotherapy for HCC is based on the observation that primary hepatoma is a hypervascular tumor with a differential arteriolar density of the tumor relative to adjacent noncancerous tissue. For example, arterial perfusion to HCC is approximately three times that of surrounding hepatic tissue (5). This perfusion differential improves patient Supported in part by MDS Nordion. R.S. is a consultant; R.D.H. is an employee of MDS Pharma Services, a contract research organization and subsidiary of MDS Inc. Received March 21, 2005, and in revised form Feb 26, Accepted for publication Feb 27, S83

2 S84 I. J. Radiation Oncology Biology Physics Volume 66, Number 2, Supplement, 2006 safety by limiting the radiation dose to surrounding liver parenchyma, and optimizes efficacy by focusing the majority of radiation to tumor containing tissue, resulting in maximal tumoricidal effect. The purpose of this review is to present the available peer-reviewed literature regarding the use of TheraSphere for the treatment of HCC. Historical perspective The use of yttrium-90 to treat HCC dates back to the 1960s when Nolan and Grady described the use of yttrium-90 oxide (Y ) to treat histologically proven cancer in humans (6). These authors presented data regarding 76 patients harboring incurable cancer that were injected intraarterially with particles of Y The radioisotope was contained within a metallic particle, which measured microns in diameter. Although the treatment was limited to 2 patients with HCC, both had favorable objective tumor responses measured by reduction in size of palpable liver masses. These findings represent one of the first reports in which injection of radioactive particles selectively into the vascular system of humans with HCC resulted in a temporary internal radiation field. The next report of radioembolization with Y-90 microspheres for HCC did not appear until 1982, when Mantravadi et al. conducted a study on 15 patients with primary and metastatic liver cancer who were treated with hepatic arterial injection of Y-90 microspheres (7). Whole-organ delivery was performed and bremsstrahlung scans were used to assess the localization and distribution of the isotope within the liver. Among the patients who died or had progression of disease with follow-up, the majority harbored relatively avascular metastatic tumors originating from the lung. Survivors had primary and metastatic tumors that were hypervascular. This study helped clarify criteria for selection (hypervascularity) of patients who might benefit from intra-arterial Y-90 based microspheres. Two animal safety studies were published in 1987 and Wollner et al. (8) used a 22- m glass microsphere in which yttrium-89 was incorporated into a stable glass matrix, which prevented the isotope from leaching from the spheres, eliminating the myelosuppression seen in early forms of Y-90 based therapy. The Y-89 was activated to Y-90 by neutron bombardment before use. The pilot study, published in 1987 employed both hot (radioactive) and cold (nonradioactive) microspheres and the preliminary findings demonstrated that both hot and cold microspheres caused vascular changes in the hepatic central veins and swelling and disorganization of hepatocytes. However, portal fibrosis was only seen after injection of radioactive microspheres. These authors theorized that radiation was the etiology for fibrosis. The next animal study using a dog model (9) employed a dose-escalation design with injections of up to 12 times (on a liver weight basis) the anticipated human dose. These results yielded a proposed human radiation exposure range of Gy. Furthermore, radiation exposure in this animal model in excess of 300 Gy did not cause total hepatic necrosis and was compatible with survival. These two studies formed the safety basis for phase I dose-escalation evaluations in humans. In 1992, Shepherd, et al. conducted a phase I doseescalation study using yttrium-90 microspheres in 10 patients with primary HCC (10). The inclusion criteria included cytologically or histologically confirmed HCC and measurable hepatic lesions, a Karnofsky performance status of 60% or greater, normal bone marrow function, and adequate pulmonary status. Exclusionary criteria included compromised liver function, a history of significant peripheral vascular disease, previous thromboembolism, a bleeding diathesis, or allergy to contrast agents. Treatment was administered in a nuclear medicine laboratory through a previously placed hepatic artery catheter. Bremsstrahlung scans were obtained after dosing to assess distribution. Just before injection of yttrium-90, the presence of extrahepatic shunting was assessed using technetium-99m labeled macroaggregated albumin ( 99m Tc-MAA) microspheres. Scintigraphy was then performed and Y-90 was not administered if there was significant shunting to the lungs, stomach, or bowel. Four patients were treated with 50 Gy, 2 patients received a 75-Gy dose, and 3 patients received a 100-Gy dose. Survival was not an endpoint but was reported in this series, ranging from 16 to 1050 days (median survival, 126 days). The longest survivor had the greatest tumor to liver perfusion ratio and therefore the greatest estimated dose delivered to the tumor. None of the patients experienced myelosuppression. One patient experienced a duodenal ulcer 2 weeks from treatment, which ultimately required surgery. This seminal study provided the initial safety data to enable outcome studies with Y-90 in HCC and provided critical patient selection and technique refinement. For example, the study-defined areas for excluding patients at risk for extrahepatic shunting and suggested the importance of assessing peritumoral hepatic vasculature. The series of reports that followed helped elucidate dosimetry, radioassays, and further experimental models for safety and toxicity (11 15). A 1994 phase I dose-escalation study (16) clarified the importance of optimal microsphere delivery by careful assessment of peritumoral blood flow using angiography. Andrews et al. embolized aberrant hepatic arteries, thereby blocking extrahepatic circulation, and considered the importance of differential arteriolar density. Twenty-four patients with primary and metastatic hepatic cancer were treated with yttrium-90 with doses ranging between 50 Gy and 150 Gy (whole-liver nominal absorbed dose). They reported no myelosuppression and no hepatic or pulmonary complications. Four patients experienced reversible gastritis/duodenitis. The response rates based on computed tomography (CT) scans 4 months from treatment demonstrated progression in 8 patients (33%), stable disease in 7 patients (30%), minor response in 4 (16%), and partial response in 5 patients (21%). There were 3 patients with survival greater than 4 years. In 1993, Yan et al. published similar encouraging data reporting a 50% reduction in tumor mass in 13 of 18 patients (72%) as well as a significant decrease in post-

3 TheraSphere treatment for hepatocellular carcinoma R. SALEM AND R. D. HUNTER S85 treatment -fetoprotein (AFP) (12). Lau et al. (17) reported results of a phase I/II study of 18 patients in which tumor regression was proportional to dose delivered, with improved survival primarily in patients receiving 120 Gy. Technique and clinical considerations The technique for administration of yttrium-90 (TheraSphere) stems from lessons learned in the early clinical studies. The process starts with careful patient selection. Patients with HCC may have undergone one or several rounds of systemic chemotherapy, surgical resection, or radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). The surgical history should be reviewed, paying particular attention to any history of surgically placed intrahepatic chemotherapy pump or any previous surgical resection or external radiation therapy. Hepatocellular carcinoma has a typical appearance with CT, magnetic resonance imaging (MRI), or ultrasound. If a mass is identified in the background of cirrhosis, histology may be required. If ultrasound was the initial diagnostic modality, additional cross-sectional imaging should be obtained. Triple-phase CT is highly sensitive in detecting hepatic malignancies, and because the majority of liver tumors are hypervascular, scanning in the early phases results in the maximum likelihood of detection. Late-phase imaging is also necessary to detect other less vascular lesions, the degree of multifocality, and to identify portal vein patency. MRI with specific attention given to diffusion-weighted imaging sequences is a sensitive modality in the identification and characterization of HCC. Important factors in determining eligibility for TheraSphere radioembolization include Eastern Cooperative Oncology Group performance status, liver function tests, and absence of significant lung shunting or collateral flow to the gastrointestinal tract. Patients presenting with compromised functional status with Eastern Cooperative Oncology Group scores of 2 4 are at high risk for rapid onset of liver failure and associated morbidity with treatment. Notwithstanding this precaution, each patient deserves individual consideration given the favorable toxicity profile of radioembolization; some patients with poor Eastern Cooperative Oncology Group performance may still benefit from therapy. Dosimetry for TheraSphere As described in the product insert (18) and in a 2002 report (19), TheraSphere (MDS Nordion, Ottawa, Ontario, Canada) consists of insoluble glass microspheres in which yttrium-90 is an integral constituent of the glass. The mean sphere diameter ranges from 20 to 30 m. Yttrium-90 is a pure beta emitter with a 64.1-h physical half-life. Each milligram contains between 22,000 and 73,000 microspheres. TheraSphere is supplied in 0.05 ml of sterile, pyrogen-free water contained in a 0.3 ml, veebottom vial secured within a 12-mm clear acrylic vial shield. TheraSphere is available in six activity sizes: 3 GBq (81 mci), 5 GBq (135 mci), 7 GBq (189 mci), 10 GBq (270 mci), 15 GBq (405 mci), and 20 GBq (540 mci). The corresponding number of microspheres per vial is 1.2, 2, 2.8, 4, 6, and 8 million, respectively. The radiation activity per microsphere is approximately 2500 Bq. Assuming TheraSphere microspheres distribute in a uniform manner throughout the liver and Y-90 undergoes complete decay in situ, the radioactivity required to deliver the desired dose to the liver can be calculated using the following formula: TheraSphere Activity (GBq) [D (Gy) M (kg)] 50 When lung shunt fraction (LSF) is taken into account, the actual dose delivered to the target mass becomes: D (Gy) [A (GBq) 50 (1 LSF)] M (kg) Where A is net activity delivered to the liver, D is the absorbed delivered dose to the target liver mass, and M is target liver mass. Liver mass (kg) is estimated by obtaining three-dimensional volumes (ml) of the target lobe with CT, then converted to mass using a conversion factor of 1.03 g/ml (19). Lung dose calculation Radiation pneumonitis is a concern with hepatic-directed radiation treatment. Previous preclinical and clinical studies with Y-90 microspheres demonstrated that up to 30 Gy to the lungs could be tolerated with a single injection, and up to 50 Gy for multiple injections (20). For this reason, patients with 99m Tc-MAA evidence of potential pulmonary shunting resulting in lung doses greater than 30 Gy should not be treated. The absorbed lung radiation dose is the total cumulative dose of all treatments as demonstrated in the following integration. Cumulative absorbed lung radiation dose 50 lung mass i 1 A i LSF i Where A i activity infused, LSF i lung shunt fraction during infusion, n number of infusions, and approximate vascular lung mass (for both lungs, including blood) 1kg (21, 22). This dose should not exceed the limit of 30 Gy per single infusion and 50 Gy cumulatively. For patients who require more than one treatment per target lobe to achieve tumor coverage, or for patients being retreated in the same target volume after progression, repeat 99m Tc-MAA LSF calculations should be performed before each treatment to exclude hyperaugmentation of lung shunting. After treatment with Y-90, it is possible that lung shunt fraction is augmented compared with the previous treatments and hence cumulative lung dose may be underestimated. In cases in which several treatments are administered, the lung dose is the cumulative absorbed lung radiation dose from all treatments. n

4 S86 I. J. Radiation Oncology Biology Physics Volume 66, Number 2, Supplement, 2006 Recent clinical experience with HCC In 2000, Dancey et al. (23) reported results of 22 patients to determine response parameters, survival and toxicity after intraarterial injection of yttrium-90 microspheres. Of the patients who met entry criteria, 20 were evaluated for efficacy, including 9 patients who were Okuda Stage I and II and 11 patients who were Okuda Stage III. The median dose delivered was 104 Gy (range, Gy). There were 31 serious adverse events; the most common were liver enzyme elevation and gastrointestinal ulceration. Treatment efficacy was measured by tumor response, duration of response, time to progression, and overall survival. One complete tumor response and three partial responses were reported. The median time to progression was 44 weeks (95% confidence limit), and the median survival was 54 weeks (range, weeks). Multivariate analysis suggested that a total dose 104 Gy, Okuda Stage I, and tumor to liver uptake ratio 2 were the three factors associated with prolonged survival. Lau et al. in 2001 (24) reported results from data during a treatment period between 1992 and 1996 in which 82 patients with unresectable HCC were treated with yttrium- 90. Analyses of outcomes were used to classify patients as short survivors (died within 1 year; 51 patients, 62%), or long survivors (lived for 1 year or longer from treatment; 31 patients, 34%). Comparisons between groups suggested low pretreatment -fetoprotein (AFP) levels and high tumor to liver uptake ratios favored longer survival. Salem et al. (19) reported on the status of yttrium-90 microsphere therapy in 2002 and described a treatment protocol outlining radiation dosimetry, and technical principles to avoid gastrointestinal complications by selective embolization before therapy. This discussion focused on appropriate patient selection and proposed that the procedure could be safely performed on an outpatient basis. Several recent studies have reported safety data including a 2004 report by Goin et al. who compared chemoembolization (TACE) (29 patients) and TheraSphere (34 patients) for incidence of postembolization syndrome (PES) manifested by posttreatment abdominal pain, nausea, vomiting, and fever in the absence of infection (25). Pain was scored by Southwest Oncology Group criteria. Median survival was similar for each group; however, the incidence of PES was nearly 4 times higher in the TACE group (p 0.003; 95% CI, ), suggesting a favorable toxicity profile for radioembolization in this tumor type. Carr et al. (26) performed a critical study in 2004 supporting the safety and efficacy of TheraSphere for inoperable HCC. Sixty-five patients with biopsy-proven HCC received a median radiation dose of 134 Gy. Toxicities included 9 episodes of abdominal pain (which did not fit criteria for PES), 2 episodes of cholecystitis, and transient elevations in liver functions in 25 patients. A finding previously unreported was lymphopenia in 75% of patients none associated with adverse clinical events or opportunistic infections. Median survival was 649 and 302 days for Okuda I (65%) and Okuda II patients (35%), respectively, compared with 244 and 64 days, respectively, for historical controls. In 2004, Liu et al. presented a retrospective review of 14 patients treated for unresectable HCC (27). Tumor response by CT/MRI and AFP was followed posttreatment. One patient had complete response by CT; however, this patient received TACE before TheraSphere. Eight patients had a partial response and 2 patients had tumor progression. AFPproducing HCC was seen in 8 of the 11 patients treated. Five patients had decreased AFP after treatment. None of the patients treated experienced any serious adverse events, including liver toxicity. The use of TheraSphere for patients with portal vein thrombosis was reported in 2004 (28). A series of 15 patients with unresectable HCC and portal vein thrombosis of 1 or both first order and related segmental portal venous branches received TheraSphere. Two patients developed bilirubin toxicity (Grades 1 and 2) and 1 of these patients developed an increment in toxicity grade from 1 to 3 after treatment. Both of these patients had CT evidence of disease progression on follow-up. In this series, there were no procedure-related complications. Eight patients continued to demonstrate stable (n 7) or improved (n 1) liver function after a second treatment cycle. This clinical experience showed that in a select group of patients with compromised portal venous flow, TheraSphere treatment is technically feasible and relatively safe, although additional research is needed to confirm these findings in a larger patient population. Geschwind et al. in 2004 reported on 80 patients from a relatively large database of 121 patients who were treated with yttrium-90 microspheres using segmental, regional, and whole-liver approach (29). Before therapy, patients were staged using the Child-Pugh, Okuda, or Cancer of the Liver Italian Program scoring systems. The pretreatment Cancer of the Liver Italian Program scores were found to be the best means of stratifying risk. Survival was found to be 628 and 324 days for Okuda I (68%) and II (32%) patients, respectively. These data were instrumental in delineating the essential components to conduct a large randomized control trial comparing TheraSphere with a standard TACE regimen using potential endpoints of survival, tumor response, AFP reduction, and quality of life estimates. Goin et al. (30) reported toxicity and mortality rates for 121 patients (118 with HCC) between 1986 and The majority of patients had advanced disease, all were contraindicated for resection or transplant, and several had limited hepatic reserve. The Okuda stage distribution included: Stage I (57%), Stage II (39%), and Stage III (4%). The corresponding Cancer of the Liver Italian Program scores were 0 (24%), 1 2 (52%), and 2 or more (23%). Specific treatment-related toxicity included 14 patients with liver toxicity and 2 patients with radiation pneumonitis and gastrointestinal bleeding. These reported serious adverse events are higher than those in other series; however, patients with poor hepatic reserve and poor functional status were included in the treatment groups. Prognostic variables associated with lower survival were identified.

5 TheraSphere treatment for hepatocellular carcinoma R. SALEM AND R. D. HUNTER S87 An additional study by Goin et al. (31) detailed the biochemistry of the 88 patients with liver toxicity. Multifocal cancer was present in 45% of these patients, 16% of patients had advance anatomic stage with 50% of liver replaced with tumor and 17% of patients had either portal vein thrombosis or portal vein compromise. The most frequent liver abnormalities included ascites, elevated bilirubin, and increased aminotransferase levels. The majority (78%) of liver toxicity resolved. These data confirmed that treatment-related liver toxicities increase with increasing pretreatment total bilirubin levels. Furthermore, in this patient population, RILD was not seen and other forms of liver dysfunction were only transient. Kennedy et al. (32) analyzed four explanted livers previously treated with yttrium-90 based therapy as a procedural bridge to transplant. Two patients underwent orthotopic liver transplantation, and 2 patients died from advanced metastatic colon cancer. A complete pathology evaluation was performed including gross observations and assessment of the microsphere distribution. Histopathology from the tumor liver parenchyma interface was sectioned for threedimensional radiation dosimetry analysis. Notable findings included a heterogeneous deposition of microspheres at the rim of the tumors compared with the central zones. No RILD was seen. This zone of concentrated microspheres appears to correlate with a zone of fibrosis, which can be demonstrated by MRI scanning. A summary report with regard to the rationale for the use of radiation therapy for HCC in general, and more specifically the advantages of selective administration of yttrium- 90, was recently prepared by Dawson (33). An important point included within this summary is the need for an objective classification system to accurately define low-risk patients from high-risk patients. This would provide more accurate outcome measurements than what exist. There is a trend toward technologies for liver-directed therapy for patients with inoperable HCC. These include ethanol ablation, bland embolization, TACE, RFA, and radioembolization. All of these modalities require a detailed knowledge of the anatomy of the hepatic arterial bed. Appropriately, a comprehensive review of this topic has been performed (34). This thorough review emphasized that approximately 60% of the population have a classic hepatic perfusion pattern. The reasons for these anatomic variations are multifactorial, but stem primarily from variable embryogenesis involving the migration of the early intestinal diverticulum toward the developing hepatobiliary system. These authors describe in detail the wide array of anatomic variants with an extensive anatomically based angiographic presentation of this important topic. Advances in the standard technique of administering TheraSphere have also recently been emphasized. Rhee et al. (35) tested an alternate procedure in 14 patients which employed catheter-directed CT angiography. This technique appears to help delineate the arterial supply to HCC, which in turn allows for superselective administration of Y-90 to segments/lobes of liver containing HCC. This allows for significantly greater radiation doses (range, Gy) to small portions of liver parenchyma eradicating all viable neoplastic and nonneoplastic tissue, a concept referred to as radiation segmentectomy. This approach will require follow-up on a large patient population to determine if there is a statistically significant increase in treatment effectiveness while limiting liver toxicities. Tumor response, safety, and survival were recently reported for 43 consecutive patients with HCC treated with TheraSphere over a 4-year period (36). Based on percent reduction in tumor size, 47% had an objective tumor response. When necrosis was used as a composite measure of response, 34 patients (79%) had an objective tumor response. The median survival reported in this study was 20.8 months for a low-risk group, whereas high-risk patients with diffuse disease faired worse with a median survival from the first treatment of 11.1 months. There were no life-threatening adverse events related to the treatment. CONCLUSIONS There is a significant body of evidence, which documents the safety and efficacy of yttrium-90 (TheraSphere) for the treatment of unresectable HCC. It can be safely performed on an outpatient basis, with a very low incidence of PES. Lobar, segmental, and subsegmental techniques have been developed (35) that optimize the delivery of a maximum radiation dose directed at tumors, with minimal exposure to adjacent hepatic tissue. TheraSphere may be safely performed for patients who would otherwise have no treatment options, such as portal vein thrombosis and in select patients with poor hepatic reserve (28). It may also have the potential for downstaging patients who would otherwise be contraindicated for hepatic transplantation (32). To date, more than 1000 patients have been treated with TheraSphere and the current focus on research is the implementation of multicenter phase II and III trials comparing TheraSphere with a standardized TACE protocol for unresectable HCC and metastatic disease to the liver. 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