Purpose. To evaluate the safety and efficacy of yttrium-90 (⁹⁰Y) radioembolization with extended-shelf-life glass microspheres. We postulated that this approach, for the same planned tissue dose of 120 Gy, would increase the embolic load, improve distribution, and result in enhanced tumor response without causing additional adverse events.
Materials and Methods. Between June 2007 and September 2008, 50 patients with extensive tumor burden and/or markedly hypervascular tumors (13 hepatocellular carcinomas, and 37 liver metastases) underwent radioembolization with extended-shelf-life microspheres at a planned dose of 120 Gy. Baseline and follow-up imaging and laboratory data were obtained. Response in the target lesion was assessed with cross-sectional imaging by using World Health Organization (WHO) and European Association for the Study of the Liver (EASL) guidelines.
Results. The mean delivered radiation dose was 126 Gy. The mean increase in embolic load with this approach was 111%, corresponding to an increase from 3.6 to 7.3 million microspheres. Clinical toxicities included fatigue (28 patients, 56%), abdominal pain (19 patients, 38%), and nausea/vomiting (six patients, 12%). Grade 3-4 bilirubin toxicity was seen in one patient. Two gastroduodenal ulcers were observed. With cross-sectional imaging, response rates according to WHO and EASL guidelines were 51% and 69%, respectively.
Conclusions. The results demonstrate the safety and efficacy of extended-shelf-life ⁹⁰Y glass microspheres. The increased embolic load and lowered activity per microsphere theoretically resulted in better tumor coverage and, hence, improved response rates. This standardizable treatment paradigm provides a minimally embolic therapy for liver tumors.

Purpose. To describe volumetric changes of ‘‘radiation lobectomy,’’ a manifestation of hepatic parenchymal response to lobar 90Y microsphere radioembolization.
Methods. Twenty patients exhibiting this phenomenon were identified. Pre- and post treatment absolute right and left hepatic lobar volume (HLV), relative HLV (rHLV = HLV/total liver volume), and degree of lobar atrophy (DA) or hypertrophy (DH) (DA or DH = |post-treatment rHLV – pretreatment rHLV|) were determined. Laboratory toxicities, tumor response, and patient survival were also assessed.
Results. Twenty patients with primary (HCC, n = 17; peripheral cholangiocarcinoma, n = 3) liver malignancies demonstrated findings of radiation lobectomy. Initial absolute right and left HLV was 955 cm³ (range 644–1,842 cm³, rHLV = 57%) and 719 cm³ (range 328–1,387 cm³, rHLV = 43%), respectively. Following ⁹⁰Y, absolute right HLV decreased to 460 cm³ (range 185–948 cm³, 52% reduction, rHLV = 31%, DA = 26%, P<0.0001), while absolute left HLV increased to 1,004 cm³ (range 560–1,558 cm³, 40% increase, rHLV = 69%, DH = 26%, P<0.0001). No grade 3 or 4 bilirubin toxicities were encountered. Tumor response ranged from 55% to 70% by size criteria. Forty-six percent 5-year survival was achieved in HCC patients.
Conclusions. Radiation lobectomy following 90Y radioembolization of right lobe tumors manifests extensive contralateral lobar hypertrophy, high response rates, and prolonged survival. This phenomenon was noted in 6.4% (20/315) of the entire cohort and 19.8% (20/101) of patients with unilobar right lobe tumors. Further investigation is necessary to determine contributing factors that may predict this effect.

BACKGROUND: The objective of the current study was to determine the safety and efficacy of Yttrium-90 (Y90) microsphere treatment in patients with liver-dominant colorectal metastases.  METHODS: Seventy-two patients with unresectable hepatic colorectal metastases were treated at a targeted absorbed dose of 120 Gray (Gy). Safety and toxicity were assessed using version 3 of the National Cancer Institute Common Terminology Criteria.  Response was assessed by anatomic imaging and positron emission tomography (PET).  Survival from the diagnosis of hepatic metastases and first treatment were estimated using the Kaplan-Meier method. Substratification analyses were performed. RESULTS:  The median dose delivered was 118 Gy. Treatment-related toxicities included fatigue (61%), nausea (21%), and abdominal pain (25%).  Grade 3 and 4 bilirubin toxicities were observed in 9 of 72 patients (12.6%).  The tumor response rate was 40.3%. The median time to hepatic progression was 15.4 months, and the median response duration was 15 months. The PET response rate was 77%. Overall survival from the first Y90 treatment was 14.5 months. Tumor replacement (≤25% vs >25%) was associated with significantly greater median survival (18.7 months vs 5.2 months).  The presence of extrahepatic disease was associated negatively with overall survival (7.9 months vs 21 months). Overall survival from the date of initial hepatic metastases was 34.6 months.  A subset analysis of patients who had an Eastern Cooperative Oncology Group performance status of 0 demonstrated a median survival of 42.8 months and 23.5 months from the time of hepatic metastases and Y90 treatment, respectively.  CONCLUSIONS: Y90 liver therapy appears to provide sustained disease stabilization with acceptable toxicity. Asymptomatic patients with preserved liver function at the time of Y90 appeared to benefit most from treatment.

Key Words: ¹⁸[F]fluorodeoxyglucose-positron emission tomography, hepatic arterial infusion chemotherapy, radiofrequency ablation, systemic agents, time to hepatic progression, transarterial chemoembolization, yttrium-90, TheraSphere, radioembolization, internal radiation

This retrospective study was undertaken to obtain information regarding the survival and toxicities after Yttrium-90 microspheres treatment in patients with primary liver malignancies.  Baseline, treatment, and follow-up data were collected and analyzed for 21 patients treated with Yttrium-90 microspheres.  Survival analysis was then performed.  The results of this study showed that median survival for all the patients was 120 days.  Twenty of 21 patients were categorized as high-risk with a median survival of 114 days.  It was also found that one high-risk patient has survived 858 days with no recurrence of disease.  Acute grade 3-5 toxicities were recorded for nine patients and consisted of elevations in AST and bilirubin, thrombocytopenia, abdominal pain, ascites, nausea, fatigue, and death.  This study concluded that Yttrium-90 is a low-toxicity, outpatient alternative for individuals with liver cancer and without many options.  The maximal value, however, may lie in the treatment of low-risk patients.

Key Words:  Hepatocellular carcinoma; Yttrium-90; Microspheres; TheraSphere; SIR-Spheres; Liver cancer.

The purpose of our study was to determine if preferential radiographic tumor response occurs in tumors located in posterior versus anterior liver segments following radioembolization with yttrium-90 glass microspheres.  One hundred thirty-seven patients with chemorefractory liver metastases of various primaries were treated with yttrium-90 glass microspheres. Of these, a subset analysis was performed on 89 patients who underwent 101 whole-right-lobe infusions to liver segments V, VI, VII, and VIII.  Pre- and post-treatment imaging included either triphasic contrast material-enhanced CT or gadolinium-enhanced MRI. Responses to treatment were compared in anterior versus posterior right lobe lesions using both RECIST and WHO criteria. Statistical comparative studies were conducted in 42 patients with both anterior and posterior segment lesions using the paired-sample t-test.  Pearson correlation was used to determine the relationship between pretreatment tumor size and post-treatment tumor response.  Median administered activity, delivered radiation dose, and treatment volume were 2.3 GBq, 118.2 Gy, and 1,072 cm3, respectively.  Differences between the pretreatment tumor size of anterior and posterior liver segments were not statistically significant (p = 0.7981).  Differences in tumor response between anterior and posterior liver segments were not statistically significant using WHO criteria (p = 0.8557).  A statistically significant correlation did not exist between pretreatment tumor size and post-treatment tumor response (r = 0.0554, p = 0.4434).  On imaging follow-up using WHO criteria, for anterior and posterior regions of the liver, (1) response rates were 50% (PR = 50%) and 45% (CR = 9%, PR = 36%), and (2) mean changes in tumor size were -41% and -40%.  In conclusion, this study did not find evidence of preferential radiographic tumor response in posterior versus anterior liver segments treated with yttrium-90 glass microspheres.

Key Words: Liver metastases - Tumor response - Radioembolization - Yttrium-90 - TheraSphere - SIR-spheres

PURPOSE: To identify changes in hepatic parenchymal volume, fibrosis, and induction of portal hypertension following radioembolization with glass microspheres for patients with metastatic disease to the liver. RESULTS: In our series of sequential bilobar (n=17) treatments, a mean decrease in liver volume of 11.8% was noted. In this group, a mean splenic volume increase of 27.9% and portal vein diameter increase of 4.8% were noted. For patients receiving unilobar treatments (n = 15), mean ipsilateral lobar volume decrease of 8.9%, contralateral lobar hypertrophy of 21.2%, and a 5.4% increase in portal vein diameter were also noted. These findings were not associated with clinical toxicities. CONCLUSION: ⁽⁹⁰⁾Yttrium radioembolization utilizing glass microspheres in patients with liver metastases results in changes of hepatic parenchymal volume and also induced findings suggestive of fibrosis and portal hypertension. Further studies assessing the long-term effects are warranted.

PURPOSE: Minimally invasive therapies such as transarterial chemoembolization and radiofrequency ablation are used for hepatic metastatic neuroendocrine tumor (NET) therapy. Results from another minimally invasive therapy, radioembolization, remain unknown. The purpose of this multicenter open label phase II study was to assess the efficacy and safety of yttrium-90 (Y) radioembolization for treating hepatic metastatic NET using a primary outcome of tumor response and secondary outcomes of serologic toxicities and survival.
MATERIAL/METHODS: In this multicenter study, all patients underwent lobar radioembolization using glass or resin Y radioembolic agents. Patients were assessed serologically and radiographically at 2 to 4 weeks and then at 1 to 3 month intervals after treatment. We 1) compared liver volumes, radiation doses, and serologic liver function tests (unpaired t test, P = 0.05) and 2) assessed tumor response, serologic toxicity, and median survival from first Y therapy. The clinicaltrials.gov identifier was NCT00532740.
RESULTS: Forty-two patients underwent radioembolization using glass (mean age 58 +/- 12 years) or resin (mean age 61 +/- 11 years) microspheres. A statistically significant greater median radiation dose was delivered to each lobe using glass (right lobe 117 Gy; left lobe 108 Gy) than using resin (right 50.8 Gy; left 44.5 Gy) (P < 0.01). Using Response Criteria in Solid Tumors, 92% of glass and 94% of resin patients were classified as partial response or stable disease at 6 months after treatment. Six patients experienced grade 3/4 toxicities during the follow-up period. Median survival was 22 months (glass) and 28 months (resin) (P = 0.82).
CONCLUSION: Y radioembolization of metastatic NET is a viable therapy with acceptable toxicity. Further investigation is warranted.

PURPOSE: To prospectively evaluate the safety, efficacy, and survival of patients with chemorefractory liver metastases who have been treated with yttrium 90 (90Y) glass microspheres.
MATERIALS AND METHODS: Institutional review boards from two institutions approved the HIPAA-compliant study; all patients provided informed consent. One hundred thirty-seven patients underwent 225 administrations of 90Y microspheres by using intraarterial infusion. Primary sites (origins) included colon, breast, neuroendocrine, pancreas, lung, cholangiocarcinoma, melanoma, renal, esophageal, ovary, adenocarcinoma of unknown primary, lymphoma, gastric, duodenal, bladder, angiosarcoma, squamous cell carcinoma, thyroid, adrenal, and parotid. Patients underwent evaluation of baseline and follow-up liver function and tumor markers and computed tomographic or magnetic resonance imaging. Patients were observed for survival from first treatment. Median survival (in days) and corresponding 95% confidence intervals were computed by using the Kaplan- Meier method. The log-rank statistic was used for statistical significance testing of survival distributions between various subgroups of patients.
RESULTS: There were 66 men and 71 women. All patients were treated on an outpatient basis. Median age was 61 years. The mean number of treatments was 1.6. The median activity and dose infused were 1.83 GBq and 112.8 Gy, respectively. Clinical toxicities included fatigue (56%), vague abdominal pain (26%), and nausea (23%). At follow-up imaging, according to World Health Organization criteria, there was a 42.8% response rate (2.1% complete response, 40.7% partial response). There was a biologic tumor response (any decrease in tumor size) of 87%. Overall median survival was 300 days. One-year survival was 47.8%, and 2-year survival was 30.9%. Median survival was 457 days for patients with colorectal tumors, 776 days for those with neuroendocrine tumors, and 207 days for those with noncolorectal, nonneuroendocrine tumors.
CONCLUSION: 90Y hepatic treatments are well tolerated with acceptable toxicities; tumor response and median survival are promising.

PURPOSE : Yttrium-90 (90Y) radioembolization has emerged as a promising and safe therapeutic modality for patients with hepatocellular carcinoma (HCC) or metastatic liver cancer. The present report describes biliary sequelae following intraarterial 90Y therapy in patients with HCC or liver metastases.
MATERIALS AND METHODS: All patients were treated with 90Y therapy according to standard lobar treatment protocol. Pre- and posttreatment imaging, liver function tests, and serum total bilirubin measurements were performed. Three to 6 months after treatment, biliary sequelae were evaluated with computed tomography and magnetic resonance imaging, and any liver-related laboratory adverse events were noted.
RESULTS: A total of 327 patients (HCC, n _ 190; liver metastases, n _ 137) received 569 infusions of 90Y. At follow-up imaging, 33 patients (10.1%; liver metastases, n _ 26; HCC, n _ 7) had 40 imaging findings related to the biliary tree, including biliary necrosis (n _ 17), biloma (n _ 3), cholecystitis (n _ 2), gallbladder wall enhancement (n _ 6), gallbladder wall rent (n _ 3), abscess (n _ 1), and stricture (n _ 8). A total of 31 patients exhibited grade 3/4 bilirubin toxicities (13 [6.8%] with HCC, 18 [13.1%] with liver metastases). Unplanned interventions prompted by biliary sequelae were necessary in six of 327 patients (1.8%).
CONCLUSIONS : 90Y therapy in patients with HCC or metastatic disease to the liver is associated with an acceptable rate of biliary toxicities. Further studies assessing long-term biliary sequelae are warranted.

Radioembolization with yttrium 90 (90Y) microspheres represents an emerging transarterial therapy for the treatment of liver malignancies that continues to generate interest in the medical community. The classic indication of treatment response is a reduction in tumor size; however, parenchymal changes (eg, necrosis, lack of enhancement, specific findings at positron emission tomography and functional magnetic resonance imaging) and other benign findings (pleural effusions, perivascular edema, contralateral hypertrophy, ring enhancement, perihepatic fluid, fibrosis) may occur following treatment, requiring proper image interpretation. With classic imaging findings and surrogates (time to progression, duration of response, disease-free interval), response rates range from 20% to 80% in patients treated for hepatocellular carcinoma or metastatic disease to the liver. Complications of 90Y radioembolization include cholecystitis, abscess, and bilomas and should be recognized early in the imaging follow-up of these patients. Radiologists who are involved in the posttreatment assessment of patients undergoing 90Y radioembolization should be familiar with the imaging findings and potential imaging pitfalls associated with this therapy.

BACKGROUND. The objective of this report was to present data from an open-label cohort study in which patients with intrahepatic cholangiocarcinoma (ICC) underwent radioembolization with yttrium-90 (90Y) microspheres.
METHODS. Twenty-four patients with histologically proven ICC were treated. The planned target dose was 120 Gray. Patients were stratified according to Eastern Cooperation Oncology Group (ECOG) performance status, tumor morphology (infiltrative vs peripheral), tumor distribution (solitary vs multifocal), and the presence or absence of portal vein thrombosis (PVT). Before and after the procedure, the following variables were assessed: 1) biochemical and clinical toxicity, 2) imaging (computed tomography/magnetic resonance imaging) response according to World Health Organization and European Association for the Study of Liver Disease (EASL) criteria, and 3) median survival after the first treatment using Kaplan-Meier methodology.
RESULTS. In total, 48 ⁹⁰Y treatments were administered to hepatic segments or lobes. Fatigue and transient abdominal pain were reported in 18 patients (75%) and 10 patients (42%), respectively. One patient (4%) developed grade 3 bilirubin toxicity. One patient (4%) developed a treatment-related gastroduodenal ulcer. On imaging follow-up of 22 patients, tumors demonstrated a partial response in 6 patients (27%), stable disease in 15 patients (68%), and progressive disease in 1 patient (5%). By using EASL guidelines, 17 patients (77%) showed >50% tumor necrosis on imaging follow-up. Two patients (9%) demonstrated 100% tumor necrosis. The median overall survival for the entire cohort (n = 24) was 14.9 months. The median survival for patients with an ECOG performance status of 0, 1, and 2 was 31.8 months, 6.1 months, and 1 month, respectively (P <.0001); the median survival for patients without and with PVT was 31.8 months and 5.7 months, respectively (P = .0003); and the median survival for patients with peripheral versus periductal-infiltrative tumors was 31.8 months and 5.7 months, respectively (P =.0005).
CONCLUSIONS. Radioembolization with ⁹⁰Y may be a therapeutic option for the treatment of unresectable ICC.

Key Words: radioembolization, yttrium-90 microspheres, TheraSphere, SIRSpheres,
brachytherapy, selective internal radiation.

MATERIALS AND METHODS. We reviewed the imaging studies of 42 patients with unresectable liver metastases treated with lobar radioembolization with 90Y. CT response was determined using traditional size criteria (World Health Organization [WHO] and Response Evaluation Criteria in Solid Tumors [RECIST]), necrosis criteria, and combined criteria (RECIST and necrosis). We compared the response on CT with the response on PET. Complications of treatment were assessed.
RESULTS. The response rate was 19% (8/42) by WHO criteria, 24% (10/42) by RECIST, 45% (19/42) by necrosis criteria, and 50% (21/42) by combined criteria. Stabilization of lesion size occurred in 50% of patients. Necrosis and combined criteria identified responders earlier than RECIST and WHO criteria. Seven responders by combined criteria had an increase in lesion size on initial follow-up and would have been considered nonresponders. PET scans were obtained in 23 patients (33 treated lobes). PET detected significantly more responses to treatment (21/33, 63%) than CT using RECIST (2/33, 6%) or combined criteria (8/33, 24%) (p < 0.05, McNemar test). Complications of treatment included radiation cholecystitis (10 patients, 23%) and liver edema (18 patients, 42%).
CONCLUSION. The use of necrosis and size criteria on CT and correlation with PET may improve the accuracy of assessment of response to 90Y treatment in patients with liver metastases and detect response earlier than standard size criteria.

PURPOSE: To standardize the indications, techniques, multimodality treatment approaches, and dosimetry to be used for yttrium-90 (Y90) microsphere hepatic brachytherapy. Methods and Materials: Members of the Radioembolization Brachytherapy Oncology Consortium met as an independent group of experts in interventional radiology, radiation oncology, nuclear medicine, medical oncology, and surgical oncology to identify areas of consensus and controversy and to issue clinical guidelines for Y90 microsphere brachytherapy.
RESULTS: A total of 14 recommendations are made with category 2A consensus. Key findings include the following. Sufficient evidence exists to support the safety and effectiveness of Y90 microsphere therapy. A meticulous angiographic technique is required to prevent complications. Resin microsphere prescribed activity is best estimated by the body surface area method. By virtue of their training, certification, and contribution to Y90 microsphere treatment programs, the disciplines of radiation oncology, nuclear medicine, and interventional radiology are all qualified to use Y90 microspheres. The panel strongly advocates the creation of a treatment registry with uniform reporting criteria. Initiation of clinical trials is essential to further define the safety and role of Y90 microspheres in the context of currently available therapies.
CONCLUSIONS: Yttrium-90 microsphere therapy is a complex procedure that requires multidisciplinary management for safety and success. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies.

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Treatment options for primary and secondary liver tumors that cannot be resected or ablated are based on transarterial techniques. Although the majority of these are based on bland and chemoembolization techniques, yttrium-90 microspheres represent an alternate transarterial option. Although the amount of literature on 90Y does not rival that of bland or chemoembolization, there nevertheless are ample data that support its use for primary and metastatic liver tumors. A comprehensive review of the entire available literature dating from the early 1960s is presented, as is a discussion of the possibilities for future research with use of radioembolization as a platform.

Yttrium-90 microspheres are increasingly being used as a treatment modality for primary and secondary liver tumors. As these therapies continue to be accepted, it is natural that their application in more complex clinical scenarios will become more common. This article is meant to introduce these controversies and to generate interest and dialogue by the interventional oncology community. This discussion is based on more than 900 90Y radioembolization procedures performed over a 5-year period.

Microsphere and particle technology represent the next-generation agents that have formed the basis of interventional oncology, an evolving subspecialty of interventional radiology. One of these platforms, yttrium-90 microspheres, is rapidly being adopted in the medical community as an adjunctive therapeutic tool in the management of primary and secondary liver malignancies. Given the complexity of the treatment algorithm of patients who may be candidates for this therapy and the need for clinical guidance, a comprehensive review of the methodologic and technical considerations was undertaken. This experience is based on more than 900 90Y infusions performed over a 5-year period.

PURPOSE: The purpose of this phase II study was to determine the safety and efficacy of TheraSphere treatment (90Y microspheres) in patients with liver-dominant colorectal metastases in whom standard therapies had failed or were judged to be inappropriate.
MATERIALS AND METHODS: Twenty-seven patients with unresectable hepatic colorectal metastases were treated at a targeted absorbed dose of 135–150 Gy. Safety and toxicity were assessed according to the National Cancer Institute's Common Toxicity Criteria, version 3.0. Response was assessed with use of computed tomography (CT) and was correlated with response on [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Survival from first treatment was estimated with use of the Kaplan-Meier method.
RESULTS: Tumor response measured by FDG PET imaging exceeded that measured by CT imaging for the first (88% vs 35%) and second (73% vs 36%) treated lobes. Tumor replacement of 25% or less (vs >25%) was associated with a statistically significant increase in median survival (339 days vs 162 days; P = .002). Treatment-related toxicities included mild fatigue (n = 13; 48%), nausea (n = 4; 15%), and vague abdominal pain (n = 5; 19%). There was one case of radiation-induced gastritis from inadvertent deposition of microspheres to the gastrointestinal tract (n = 1; 4%). Three patients (11%) experienced ascites/pleural effusion after treatment with TheraSphere as a consequence of liver failure in advanced-stage metastatic disease. With the exception of these three patients whose sequelae were not considered to be related to treatment, all observed toxicities were transient and resolved without medical intervention.
CONCLUSION: TheraSphere administration appears to provide stabilization of liver disease with minimal toxicity in patients in whom standard systemic chemotherapy regimens have failed.

Our aim was to assess the feasibility of using PET for quantifying metabolic response after intraarterial 90Y-glass microspheres for metastatic colorectal cancer to the liver by comparing visual estimates with hepatic standardized uptake values (SUVs).
Methods: Twenty-seven patients (15 men, 12 women; age, 68 ± 12 y [±SD]) with metastatic colorectal cancer to the liver, and tumor progression despite polychemotherapy, were included. All patients had baseline CT or MRI, 18F-FDG PET, hepatic angiography, and intraarterial 99mTc-labeled macroaggregated albumin scanning. Patients were treated with 90Y-glass microspheres and were monitored for 3 mo using PET and serum carcinoembryonic antigen. The average absorbed dose was 139 ± 22 Gy. All treatments were performed on a lobar basis. For each case analyzed, regions of interest were drawn along the liver edge to measure SUVs on maximum-intensity-projection (MIP) and resliced axial images. Concomitantly, the visual estimate was graded as +1, 0, –1, –2, or –3 for progression, no change, and mild, moderate, and dramatic improvement at posttreatment PET.
Results: Visual estimates placed 20 patients in the response category (–3 to –1) and 7 patients in the nonresponse category (0 to +1). There was a significant drop in the median SUV on the resliced axial images from 10,455 at baseline to 9,075 after treatment (P = 0.011) for the entire group. The percentage of metabolic response was significantly greater in the response group compared with that of the nonresponse group (–26% ± 25% vs. +6% ± 15%, P = 0.004). This correlated significantly with the respective visual estimates (r = 0.75, P < 0.0001). Furthermore, the direction of change agreed in 85% of patients using both methods. There was no significant correlation when the SUV from the simplified MIP images were used in the coronal or sagittal manner.
Conclusion: It is feasible to quantify reduction of hepatic tumor metabolism objectively after 90Y treatment for unresectable metastatic disease to the liver. SUVs of the entire axial slices of liver agree well with subjective visual evaluations. Quantitative PET is a useful technique in the treatment response evaluation of patients after 90Y-glass microspheres.

The purpose of this prospective study was to evaluate yttrium-90 glass microsphere treatment of unresectable liver metastases by fluorine-18 fluorodeoxyglucose positron emission tomography ([18F]FDG PET), and to compare the effectiveness of [18F]FDG PET for this purpose with that of computed tomography (CT) or magnetic resonance imaging (MRI) and determination of the serum carcinoembryonic antigen (CEA) level. Thirteen hepatic lobes from eight consecutive patients with colorectal cancer referred for 90Y-glass microsphere treatment of unresectable liver metastases who underwent both baseline (pretreatment) and 3-month posttreatment PET were studied. All patients also had correlative pre- and posttreatment CT or MRI for evaluation of the anatomic response and serum CEA determination for assessment of the total tumor load, as well as pretreatment hepatic intra-arterial technetium-99m macroaggregated albumin scan for lung shunting evaluation and hepatic arteriography for assessment of vascular anatomy and treatment. 90Y-glass microspheres were infused via an intra-arterial catheter under low pressure. Dedicated whole-body PET scans were analyzed visually and compared by lesion and by lobe with CT or MRI. A metabolic response after 90Y treatment to single or both hepatic lobes, assessed by PET, was present in a significantly higher proportion of the lobes than was an anatomic response, evaluated by CT or MRI (12 vs 2 lobes respectively, P<0.0002). Posttreatment PET showed no, stable, progressive, and new extrahepatic metastases in two, three, one, and two patients respectively. Following treatment, serum CEA decreased significantly, correlating with PET but not with CT or MRI. Thus, the study demonstrated a significant difference between the metabolic and the anatomic response after 90Y-glass microsphere treatment for unresectable liver metastases in colorectal cancer. PET appears to be an accurate indicator of treatment response.

BACKGROUND: Radioembolization has been demonstrated to allow locoregional therapy of patients with hepatocellular carcinoma not eligible for transarterial chemoembolization or other local therapies. The aim of this study was to validate evidence of the safety and efficacy of this treatment in a European sample of patients with advanced hepatocellular carcinoma (HCC). Therefore, 108 consecutive patients with advanced HCC and liver cirrhosis were included. Yttrium-90 (Y-90) microspheres were administered in a lobar fashion over the right or left branch of the hepatic artery. The response to treatment was evaluated by computed tomography (CT) imaging applying Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria with recent European Association for the Study of the Liver / National Cancer Institute (EASL/NCI) amendments. Time to progression (TTP) and overall survival were estimated by the Kaplan-Meier method. In all, 159 treatment sessions were performed ranging between one to three treatments per patient. The mean radiation dose per treatment was 120 (618) Gy. According to EASL criteria, complete responses were determined in 3% of patients, partial responses in 37%, stable disease 53%, and primary progression in 6% of patients. TTP was 10.0 months, whereas the median overall survival was 16.4 months. No lung or visceral toxicity was observed. The most frequently observed adverse event was a transient fatigue-syndrome. CONCLUSIONS: Radioembolization with Y-90 glass microspheres for patients with advanced HCC is a safe and effective treatment which can be utilized even in patients with compromised liver function. Because TTP and survival appear to be comparable to systemic therapy in selected patients with advanced HCC, randomized controlled trials in combination with systemic therapy are warranted.

BACKGROUND: Intrahepatic arterial yttrium 90 (⁹⁰Y) microspheres have been proposed as a less toxic, less invasive therapeutic option to transhepatic arterial chemoembolization (TACE) for patients with surgically unresectable hepatocellular carcinoma (HCC). TACE has demonstrated the ability to prolong survival. However, long-term survival remains uncertain. METHODS: In a 2-cohort experience in the treatment of North American patients who had advanced, unresectable, biopsy-proven HCC, 691 patients received repetitive, cisplatin-based chemoembolization; and a separate cohort of 99 patients who had similar treatment criteria received a planned, single dose of ⁹⁰Y. Over the study period, an additional 142 patients were followed without treatment (total, 932 patients). RESULTS: Overall survival was slightly better in the ⁹⁰Y group compared with the TACE group (median survival, 11.5 months vs 8.5 months). However, the selection criteria indicated a small but significant bias toward milder disease in the ⁹⁰Y group.  By using stratification into a 3-tier model with patients dichotomized according to bilirubin levels <1.5 mg/dL, the absence of portal vein thrombosis (PVT), and low a-fetoprotein plasma levels (<25 U/dL), an analysis of survival in clinical subgroups indicated that the 2 treatments resulted in similar survival. In addition, patients who had PVT or high afetoprotein levels also had similar survival in both treatment groups. CONCLUSIONS: Given the current evidence of therapeutic equivalence in survival, ⁹⁰Y and TACE appeared to be equivalent regional therapies for patients with unresectable, nonmetastatic HCC.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has limited treatment options; long-term outcomes following intra-arterial radiation are unknown. We assessed clinical outcomes of patients treated with intra-arterial yttrium-90 microspheres (Y90). METHODS: Patients with HCC (n = 291) were treated with Y90 as part of a single-center, prospective, longitudinal cohort study. Toxicities were recorded using the Common Terminology Criteria version 3.0. Response rate and time to progression (TTP) were determined using World Health Organization (WHO) and European Association for the Study of the Liver (EASL) guidelines. Survival by stage was assessed. Univariate/multivariate analyses were performed. RESULTS: A total of 526 treatments were administered (mean, 1.8; range, 1-5). Toxicities included fatigue (57%), pain (23%), and nausea/vomiting (20%); 19% exhibited grade 3/4 bilirubin toxicity. The 30-day mortality rate was 3%. Response rates were 42% and 57% based on WHO and EASL criteria, respectively. The overall TTP was 7.9 months (95% confidence interval, 6-10.3). Survival times differed between patients with Child-Pugh A and B disease (A, 17.2 months; B, 7.7 months; P = .002). Patients with Child-Pugh B disease who had portal vein thrombosis (PVT) survived 5.6 months (95% confidence interval, 4.5-6.7). Baseline age; sex; performance status; presence of portal hypertension; tumor distribution; levels of bilirubin, albumin, and alpha-fetoprotein; and WHO/EASL response rate predicted survival. CONCLUSIONS: Patients with Child-Pugh A disease, with or without PVT, benefited most from treatment. Patients with Child-Pugh B disease who had PVT had poor outcomes. TTP and overall survival varied by patient stage at baseline. These data can be used to design future Y90 trials and to describe Y90 as a potential treatment option for patients with HCC.

The past decade has seen significant advancement in the locoregional management of liver tumors; novel and promising therapies such as transarterial chemoembolization, radioembolization, and radiofrequency ablation are now available. The development of new techniques and devices has led to the improved safety and efficacy profiles of external-beam radiation. Radioembolization with yttrium-90 (⁹⁰Y) microspheres has emerged as a safe and efficacious treatment modality for liver malignancies. The purpose of this article is to present a comprehensive evidence-based review of the complications and adverse events that may be associated with radioembolization with ⁹⁰Y microspheres. Strategies to mitigate these adverse events are also discussed.

Radioembolization with ⁹⁰Y microspheres is a novel treatment for hepatic tumors. Generally, hepatic arteriography and ⁹⁹mTc-macroaggregated albumin (MAA) scanning are performed before selective internal radiation therapy to detect extrahepatic shunting to the lung or the gastrointestinal tract.  Whereas previous studies have used only planar or SPECT scans, the present study used ⁹⁹mTc-MAA SPECT/CT scintigraphy (SPECT with integrated low-dose CT) to evaluate whether SPECT/CT and additional diagnostic contrast-enhanced CT before  radioembolization with ⁹⁰Y microspheres are superior to SPECT or planar imaging alone for detection of gastrointestinal shunting. Methods: In a prospective study, we enrolled 58 patients
(mean age, 66 y; SD, 12 y; 10 women and 48 men) with hepatocellular carcinoma who underwent hepatic arteriography and scintigraphy with ⁹⁹mTc-MAA using planar imaging, SPECT, and SPECT with integrated low-dose CT of the upper abdomen (acquired with a hybrid SPECT/CT camera). The ability of the different imaging modalities to detect extrahepatic MAA shunting was compared. Patient follow-up of a mean of 180 d served as the standard of reference. Results: Gastrointestinal shunting was revealed by planar imaging in 4, by SPECT in 9, and by SPECT/CT in 16 of the 68 examinations. For planar imaging, the sensitivity for detection of gastrointestinal shunting was 25%, the specificity 87%, and the accuracy 72%. For SPECT without CT, the sensitivity was 56%, the specificity 87%, and the accuracy 79%. SPECT with CT fusion had a sensitivity of 100%, a specificity of 94%, and an accuracy of 96%. In 3 patients, MAA deposits in the portal vein could accurately be attributed to tumor thrombus only with additional information from contrast-enhanced CT. The follow-up did not show any gastrointestinal complications. Conclusion: SPECT with integrated low-dose CT using ⁹⁹mTc-MAA is beneficial in radioembolization with ⁹⁰Y microspheres because it increases the sensitivity and specificity of ⁹⁹mTc-MAA SPECT when detecting extrahepatic arterial shunting. The overall low risk of gastrointestinal complications in radioembolization may therefore be further reduced by SPECT/CT.

Key Words: hepatocellular carcinoma; SPECT/CT; radioembolization; ⁹⁰Y; microspheres

Chemoembolization and other ablative therapies are routinely utilized in downstaging from United Network for Organ Sharing (UNOS) T3 to T2, thus potentially making patients transplant candidates under the UNOS model for end-stage liver disease (MELD) upgrade for hepatocellular carcinoma (HCC). This study was undertaken to compare the downstaging efficacy of transarterial chemoembolization (TACE) versus transarterial radioembolization. Eighty-six patients were treated with either TACE (n = 43) or transarterial radioembolization with Yttrium-90 microspheres (TARE-Y90; n = 43). Median tumor size was similar (TACE: 5.7 cm, TARE-Y90: 5.6 cm). Partial response rates favored TARE-Y90 versus TACE (61% vs. 37%).  Downstaging to UNOS T2 was achieved in 31% of TACE and 58% of TARE-Y90 patients. Time to progression according to UNOS criteria was similar for both groups (18.2 months for TACE vs. 33.3 months for TARE-Y90, p = 0.098). Event-free survival was significantly greater
for TARE-Y90 than TACE (17.7 vs. 7.1 months, p = 0.0017). Overall survival favored TARE-Y90 compared to TACE (censored 35.7/18.7 months; p = 0.18; uncensored 41.6/19.2 months; p = 0.008). In conclusion, TARE-Y90 appears to outperform TACE for downstaging HCC from UNOS T3 to T2.

Key Words: Chemoembolization, downstaging, hepatocellular carcinoma, radioembolization, Yttrium-90 microspheres

We present the correlation between radiologic and pathologic findings in HCC patients who underwent radioembolization with yttrium-90 (⁹⁰Y) microspheres prior to resection or transplantation.  Thirty-five patients with a total of 38 lesions who underwent liver explantation after ⁹⁰Y radioembolization were studied. Imaging surrogates following treatment were evaluated; the explants were examined for assessment of necrosis by pathology.  The correlation between radiologic and histologic findings of the treated lesions was analyzed.  Twenty-three of 38 (61%) target lesions showed complete pathologic necrosis. All target lesions demonstrated some degree of histologic necrosis at explant.  Complete histologic necrosis was seen in 89% of lesions with pretreatment size <3 cm.  Complete pathologic necrosis was seen in 100%, 78%, and 93% of the lesions that were shown to have complete response by European Association for the Study of the Liver (EASL) necrosis criteria, partial response by World Health Organization (WHO) criteria, or thin rim enhancement on post-treatment imaging, respectively.  In contrast, complete pathologic necrosis was seen in only 52% and 38% of the lesions that showed partial response by EASL criteria and peripheral nodular enhancement, respectively.  Conclusion: Post-radioembolization imaging findings of response by EASL and WHO criteria are predictive of the degree of pathologic necrosis.  Rim enhancement was an imaging characteristic that correlated well with histologic necrosis.

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third most common cause of death from cancer worldwide.¹  The incidence of HCC in the US is increasing because of the rise in the prevalence of hepatitis C virus infection.^2,3 HCC-related mortality is high because most cases are diagnosed at an advanced stage, when potentially curative therapies such as liver transplantation, surgical resection, and local ablation are not feasible.^4–7 The majority of patients are therefore candidates for palliative therapies only.⁸ Due to the capacity of liver cells to detoxify and excrete drugs, HCCs are relatively resistant to chemotherapy; in addition, the splenomegaly and cytopenias associated with cirrhosis with portal hypertension render patients prone to systemic chemotherapy-related toxicity.⁹ Transarterial  chemoembolization (TACE) is a loco-regional therapy that delivers high doses of chemotherapy to HCCs through the hepatic artery, with limited systemic effect. TACE has been proven to improve survival of patients with unresectable HCC without portal vein thrombosis (PVT).^10–12  Recently, a number of devices for transarterial radioembolization (TARE) have been tested for treatment of HCC in early-phase studies. This article will summarize the results thus far, with an emphasis on yttrium-90 (⁹⁰Y) radioactive glass microspheres, which are the only modality currently approved for use in the US.

A therapy gaining rapid clinical adoption involves radioembolization with the use of Yttrium-90 (90Y) microspheres.  The 20–60 µm-sized microspheres are injected trans-arterially and flow to hepatic tumors given their preferential blood supply from the hepatic artery.  Once they lodge in the arterioles, they impart a very intense local radiotherapeutic effect.  Given the combined radiation and embolic effect, the imaging findings imparted by this mode of action differ significantly from other treatments.  This work represents a comprehensive review of the imaging findings following radioembolization in patients with primary liver tumors.  The report discusses imaging response, benign secondary effects, and complications.  This should help educate the radiologist on imaging findings that should be expected following radioembolization and therefore aid in the proper image interpretation.

Key Words: Radioembolization—Yttrium 90—TheraSphere—SIR-Spheres—Selective—Internal radiation.

This study was undertaken to present data from a phase 2 study in which patients with unresectable hepatocellular carcinoma (HCC) with and without portal vein thrombosis underwent radioembolization with Yttrium ((90)Y) microspheres. Patients treated were stratified by Okuda, Child-Pugh, baseline bilirubin, tumor burden, Eastern Cooperative Oncology Group (ECOG), presence of cirrhosis and portal vein thrombosis (PVT) (none, branch, and main). Clinical and biochemical data were obtained at baseline and at 4-week intervals following treatment for up to 6 months. Tumor response was obtained using computed tomography (CT). Patients were followed for survival. One hundred eight patients were treated during the study period. Thirty-seven (34%) patients had PVT, 12 (32%) of which involved the main PV. The cumulative dose for those with and without PVT was 139.7 Gy and 131.9 Gy, respectively. The partial response rate using world Health Organization (WHO) criteria was 42.2%. Using European Association for the Study of the Liver (EASL), the response rate was 70%. Kaplan-Meier survival varied depending on location of PVT and presence of cirrhosis. The adverse event (AE) rates were highest in patients with main PVT and cirrhosis. There were no cases of radiation pneumonitis. Conclusion: The use of minimally embolic (90)Y glass microspheres to treat patients with HCC complicated by branch/lobar PVT may be clinically indicated and appears to have a favorable toxicity profile. Further investigation is warranted in patients with main PVT.
Plus Editorial:
Forner A., and Bruix J. (2008)
Locoregional treatment for hepatocellular carcinoma: From clinical exploration to robust clinical data, changing standards of care
Hepatology; 47(1):5-7.

OBJECTIVE. Yttrium-90 radioembolization is an emerging therapy for unresectable hepatocellular carcinoma (HCC). Although therapeutic response based on size has been evaluated in numerous studies, necrosis has been used as a criterion of response in only a few studies. The purpose of our study was to describe the imaging features of HCC after 90Y treatment and to compare size criteria (World Health Organization [WHO] and Response Evaluation Criteria in Solid Tumors [RECIST]) with necrosis criteria and combined criteria (RECIST and necrosis) for assessment of response.
MATERIALS AND METHODS. CT images of 42 patients with 76 90Y-treated HCC lesions were analyzed. We used four response criteria: WHO size, RECIST size, necrosis, and combined criteria (RECIST and necrosis). Imaging features of treated lesions included both nodular and peripheral rim enhancement. Survival was assessed with the Kaplan-Meier method.
RESULTS. The response rate was 23% according to RECIST criteria, 26% according to WHO criteria, 57% according to necrosis criteria, and 59% according to combined criteria. Response according to necrosis and combined criteria was detected earlier than response according to size criteria alone. Ten responding lesions initially increased in size. After therapy, enhancing peripheral nodules increased in size in 10 lesions, decreased in size in two lesions, and disappeared in two lesions. Twenty-one of 25 lesions with thin rim enhancement after 90Y administration responded to treatment. The median survival times were 660 and 236 days for Okuda stage I and Okuda stage II disease, respectively.
CONCLUSION. Use of combined size and necrosis criteria may lead to more accurate assessment of response to 90Y therapy than use of size criteria alone. Imaging features after 90Y treatment, including size, necrosis, peripheral enhancing nodules, and thin rim enhancement, are described.

The anatomy of the mesenteric system and the hepatic arterial bed has been demonstrated to have a high degree of variation. This is important when considering pre-surgical planning, catheterization, and trans-arterial hepatic therapies. Although anatomical variants have been well described, the characterization and understanding of regional hepatic perfusion in the context of radioembolization have not been studied with great depth. The purpose of this review is to provide a thorough discussion and detailed presentation of the angiographic and technical aspects of radioembolization. Normal vascular anatomy, commonly encountered variants, and factors involved in changes to regional perfusion in the presence of liver tumors are discussed. Furthermore, the principles described here apply to all liver-directed transarterial therapies.

Purpose To present the clinical data of 35 patients with T3 unresectable hepatocellular carcinoma (HCC) that were treated with 90Y with the specific intent of downstaging to resection, radiofrequency ablation (RFA) candidate, United Network for Organ Sharing (UNOS) stage T2 or liver transplantation.
Materials and Methods
One hundred fifty patients with unresectable HCC were treated with 90Y microspheres. Of these, 35 patients were UNOS stage T3 at the time of treatment. Patients were followed for clinical toxicities, alterations in model for end-stage-liver disease (MELD) score, tumor response, downstaging to RFA, resection, transplantation, and survival.
Results Nineteen of 34 patients (56%) were successfully downstaged from T3 to T2 following treatment. 11 of 34 (32%) patients treated were downstaged to target lesions measuring 3.0 cm or less. Twenty-three of 35 (66%) were downstaged to either T2 status, lesion < 3.0 cm (RFA candidate), or resection. Seventeen of 34 (50%) had an objective tumor response by WHO criteria. Eight patients (23%) were successfully downstaged and underwent OLT following treatment. 1, 2, and 3-year survival was 84%, 54%, and 27%, respectively. Median survival by Kaplan-Meier analysis for the entire cohort was 800 days.
Conclusion These data suggest that intra-arterial 90Y microspheres can be used as a bridge to transplantation, surgical resection, or RFA. J. Surg. Oncol. 2006;94:572-586. © 2006 Wiley-Liss, Inc.

We report a case of a patient with end-stage liver disease secondary to hepatitis C, complicated by a large hepatocellular carcinoma. Because of the size of the tumor exceeded the Milan criteria, he was not a candidate for liver transplantation. However, after two treatments with yttrium-90 glass microsphere infusions, the tumor became smaller and the patient’s a-fetoprotein level dropped to normal range. He was listed for transplantation and subsequently received a deceased donor liver transplant. Two years after his transplantation, he remains tumor free and has normal a-fetoprotein levels. This is the first reported case in the literature of using yttrium-90 microspheres as a bridge to liver transplantation in a patient with a large hepatocellular carcinoma. This therapy should be considered in patients with cirrhosis and large hepatocellular carcinomas exceeding current size criterion, who would otherwise be good candidates for transplantation.

Microsphere and particle technology represent the next-generation agents that have formed the basis of interventional oncology, an evolving subspecialty of interventional radiology. One of these platforms, yttrium-90 microspheres, is rapidly being adopted in the medical community as an adjunctive therapeutic tool in the management of primary and secondary liver malignancies. Given the complexity of the treatment algorithm of patients who may be candidates for this therapy and the need for clinical guidance, a comprehensive review of the methodologic and technical considerations was undertaken. This experience is based on more than 900 90Y infusions performed over a 5-year period.

Laura Dawson, Radiation Oncologist, provides review of radiation therapy treatment options for unresectable HCC. Editorial includes review of external beam and conformal beam radiation, proton therapy, interstitial brachytherapy and yttrium-90 microspheres.

PURPOSE: To present the findings of a risk-stratification survival analysis, using data collected on a heterogeneous group of hepatocellular carcinoma (HCC) patients treated with TheraSphere^®.
PATIENTS AND METHODS: Clinical and dosing data were collected and analyzed from 121 TheraSphere^®-treated patients. Survival analyses were performed, combining clinical judgment and statistical analyses, to identify those variables most closely associated with 3-month mortality. The presence of any of these variables resulted in the assignment of a patient to the high-risk category.
RESULTS: Five liver reserve and two non-liver reserve variables were used to stratify patients into the low or high-risk group. Sixteen (49%) of the 33 patients assigned to the high-risk group did not survive the first three months after treatment, compared to 6 (7%) of the 88 patients assigned to the low risk group (Fishers’ exact; P<.0001). Median survival for the low and high risk groups were 466 days and 108 days, respectively (hazard ratio=6.0; P<.0001). Eleven of twelve patients experiencing a treatment-related serious adverse event ending in death originated from the high-risk group. The developed risk-stratification criteria resulted in low and high-risk group assignments associated with Child-Pugh liver function staging, and the Okuda and CLIP HCC survival prognosis staging systems.
CONCLUSION: HCC patients being considered for treatment with TheraSphere^® should be evaluated for the presence of the risk variables described here. The absence of these variables is predictive of improved survival (median of 466 days) compared to high-risk patients (median of 108 days).

Intraarterial injection of 90Y-microspheres is used in the treatment of hepatocellular carcinoma (HCC). This report presents an analysis of the incidence of treatment-emergent liver toxicities (events), and factors influencing those toxicities, following 90Y-microspheres treatment.
METHODS: Eighty-eight patients were treated, with liver toxicities coded using standard oncology criteria. Descriptive and inferential statistical methods were applied, to estimate incidence of liver toxicities, and to evaluate the influence of liver dose and various pre-treatment factors on the risk of their occurrence.
RESULTS: Sixty-eight liver toxicities occurred in 37 (42%) of the 88 treated patients. Thirty-two (36%) patients experienced 50 liver toxicities after the first treatment and 9 (39%) of 23 patients receiving a second treatment experienced 18 liver toxicities. Pre-treatment total bilirubin and liver dose was found to be associated with the risk of at least one liver toxicity, and the time to first occurrence after first treatment. Pre-treatment total bilirubin was associated with toxicities for the second treatment. Most of the toxicities resolved, or were associated with tumor progression or advancing cirrhosis.
CONCLUSION: The risk of liver toxicities in patients with unresectable HCC treated with 90Y-microspheres, increases with increasing pre-treatment total bilirubin and liver dose up to 150 Gy for a single administration. The toxicities attributed to treatment resolve over time, and no patient studied had confirmed radiation induced liver disease. Consequently, a dose up to 150 Gy on a single administration, and up to 268 Gy on repeated administration, was well tolerated.

Prior to therapy, model for end stage liver disease (MELD) scoring, diagnostic imaging and tumor staging were performed in a patient with T3 HCC. The patient received an orthotopic liver transplant (OLT) 42 days after treatment. The explant specimen showed complete necrosis of the target tumor. Follow-up of this patient has demonstrated no evidence of recurrence. There was no life threatening or fatal adverse experiences related to treatment. This case report documents the natural course, history and outcome of a patient treated with yttrium-90 for unresectable HCC. The patient was downstaged from T3 to T2 and was subsequently transplanted.

The rapid evolution and increasing complexity of liver-directed therapies has forced the medical community to further advance its understanding of hepatic arterial anatomy. The anatomy of the mesenteric system, and particularly the hepatic arterial bed, has been demonstrated to have a high degree of variation. This is important when considering presurgical planning, catheterization, and transarterial hepatic therapies. Although anatomic variants have been well described, the characterization and understanding of regional hepatic perfusion is also required to optimize endovascular therapy and intervention. Although this is true for patients undergoing bland embolization or chemoembolization, drug delivery, and hepatic infusional pump therapy, it is particularly true for intraarterial brachytherapy. The purpose of this review is to provide historical perspective in angiographic aspects of liver-directed therapy, as well as a discussion of normal vascular anatomy, commonly encountered variants, and factors involved in changes to regional perfusion in the presence of liver tumors. Methods of optimizing the safety and efficacy of liver-directed therapies with use of percutaneous techniques will be discussed. This review is based on the experience gained in treating more than 500 patients with transarterial liver-directed therapies. Although the principles described in this article apply to all liver-directed therapies such as chemoembolization and administration of drug-coated microspheres, they apply particularly to intraarterial brachytherapy.

PURPOSE: Yttrium 90 radioembolization is a transcatheter therapy for unresectable hepatocellular carcinoma (HCC) that delivers internal radiation to tumors. In contrast to the usual method of lobar regional delivery, catheter-directed computed tomographic (CT) angiography was investigated as a potentially useful technique to evaluate the administration of segmental90Y tumor radiation doses superselectively without significantly altering liver function or Child-Pugh classification.
MATERIALS AND METHODS: Fourteen patients underwent 90Y therapy for unresectable HCC. After standard angiographic placement of a 3-F microcatheter in a segmental hepatic artery supplying the tumor, each patient underwent CT angiography with use of segmental hepatic artery injection of iodinated contrast agent to confirm segmental perfusion and delineate segmental liver volume. 90Y was later injected into the same segmental artery. Target dose was calculated according to infused 90Y activity and targeted hepatic volume with standard lobar volume (before CT angiography) versus segmental liver volume (after CT angiography). The Wilcoxon signed-rank test (α0.05) was used to compare the estimated 90Y dose before CT angiography with the actual 90Y dose after CT angiography, as well as changes in serum bilirubin level and Child-Pugh classification as a result of treatment.
RESULTS: The mean estimated tumor dose before CT angiography (SD) was 100 Gy±43 (range, 35–169 Gy). The mean actual tumor dose after CT angiography was 348 Gy±204 (range, 105–857 Gy), which was significantly greater (P < .001). The mean bilirubin level before treatment was 1.0 mg/dL ±0.97 (range, 0.2–4.0 mg/dL), whereas the mean bilirubin level after treatment was 1.3 mg/dL ±0.85 (range, 0.5–3.8 mg/dL). This difference, although statistically significant (P=.03), was not clinically important. Thirteen of 14 patients had no change in Child-Pugh class.
CONCLUSION: CT angiography can be used to delineate the blood supply and volume to a targeted hepatic segment, allowing superselective90Y radioembolization. This approach significantly increases effective 90Y tumor radiation dose without clinically altering liver function or Child-Pugh class

PURPOSE: To present safety and efficacy results obtained in treatment of a cohort of patients with unresectable hepatocellular carcinoma (HCC) with use of 90Y microspheres (TheraSphere).
PATIENTS AND METHODS: Forty-three consecutive patients with HCC were treated with 90Y microspheres over a 4-year period. Patients were treated by liver segment or lobe on one or more occasions based on tumor distribution, liver function, and vascular flow dynamics. Patients were followed for adverse events, objective tumor response, and survival. Patients were stratified into three risk groups according to method of treatment and risk stratification (group 0, segmental; group 1, lobar low-risk; group 2, lobar high-risk) and Okuda and Child-Pugh scoring systems.
RESULTS: Based on follow-up data from 43 treated patients, 20 patients (47%) had an objective tumor response based on percent reduction in tumor size and 34 patients (79%) had a tumor response when percent reduction and/or tumor necrosis were used as a composite measure of tumor response. There was no statistical difference among the three risk groups with respect to tumor response. Survival times from date of diagnosis were different among the risk groups (P < .0001). Median survival times were 46.5 months, 16.9 months, and 11.1 months for groups 0, 1, and 2, respectively. Median survival times of 24.4 months and 12.5 months by Okuda scores of I and II, respectively, were achieved (mean, 25.8 months vs 13.1). Patients had median survival times of 20.5 months and 13.8 months according to Child class A and class B/C disease, respectively (mean, 22.7 months vs 13.6 months). Patients classified as having diffuse disease exhibited decreased survival and reduced tumor response. There were no life-threatening adverse events related to treatment.
CONCLUSIONS: Use of 90Y microspheres (TheraSpheres) provides a safe and effective method of treatment for a broad spectrum of patients presenting with unresectable HCC. Further investigation is warranted.

Hepatocellular carcinoma (HCC) generally arises in a cirrhotic liver and, in most cases, is multifocal and bilobar. Although trans-hepatic artery chemoembolization (TACE) can be highly affective in shrinking tumors, it is limited by virtue of the damage that it can cause to the liver that is already damaged by chronic disease. A high priority in HCC research, after primary prevention and early detection, is to find new treatment modalities that are both effective and non-toxic to the underlying cirrhotic liver. A cohort of 65 patients with biopsy-proven unresectable HCC have been treated with hepatic arterial 90Yttrium microspheres (Therasphere), and the interim results are reported here. Only 1 cycle of Therasphere treatment ever was performed on 46 patients, 17 patients had 2 cycles, and 2 patients had 3 cycles of therapy. The median dose delivered was 134 Gy, typically as either 5 or 10 GBq (2-4 million microspheres). Clinical toxicities include 9 episodes of abdominal pain and 2 episodes of acute cholecystitis, requiring cholecystectomy. A main lab toxicity was elevated bilirubin which increased by more than 200% in 25 patients (30.5%) during 6 months of therapy, although 18 of these patients had only transient elevation. A prominent finding was prolonged and profound (>70%) lymphopenia in more than 75% of the patients, but without clinical significance. Forty-two patients (64.6%) had a substantial decrease in tumor vascularity in response to therapy, and 25 patients (38.4%) had a partial response, by computed tomography scan. Median survival for Okuda stage I patients (n=42) was 649 days (historical comparison 244) and for Okuda stage II patients (n=23) was 302 days (historical comparison 64 days). All patients were followed after therapy for a minimum of 6 months. There were 42 deaths, 21 due to liver failure, 6 from HCC progression, and 3 from metastases. Therasphere appears to be a relatively safe and effective therapy for advanced-stage unresectable HCC.

INTRODUCTION: Unresectable hepatocellular carcinoma (HCC) is extremely difficult to treat. TheraSphere^® consists of yttrium-90 microspheres, a pure beta emitter, which are injected into the hepatic arteries. This article reports on the safety and survival experience of patients with HCC, who were treated with TheraSphere^®.
METHODS: Eighty patients were selected from a database containing data on 121 TheraSphere^® treated patients, and staged using Child-Pugh, Okuda and CLIP scoring systems. Patients were treated using local, regional and whole liver treatment approaches. Survival from first treatment was analyzed using Kaplan-Meier and Cox regression methods. Adverse events and complications of treatment were uniformly coded using the Southwest Oncology Group (SWOG) scoring system.
RESULTS: Patients received liver doses of 47 Gy to 270 Gy, by either regional or whole liver treatment. Thirty-two (40%) patients received more than one treatment. CLIP scores were associated with survival prognosis (P=0.002), with Child-Pugh, AFP and tumor replacement percent contributing quantitatively, with hazard ratios of 4.3, 2.3 and 2.0, respectively. Okuda stage I (N=54) and II (N=26) classified patients had median and one-year survivals of 628 days and 63%, and 384 days and 51%, respectively (P=0.09). One patient died of liver failure judged as possibly related to treatment.
CONCLUSIONS: In selected patients, TheraSphere^® treatment is safe and well tolerated. The CLIP scoring system provides prognostic stratification for TheraSphere^® -treated patients. Based on the results of this investigation, an RCT comparing TheraSphere^® with TACE is justified and should be undertaken, using CLIP for prospective stratified-randomization.

INTRODUCTION: Radioactive microsphere (90)Y therapy is increasingly used for primary and metastatic solid tumors in the liver. We present an analysis of 4 explanted livers previously treated with (90)Y microsphere agents (glass or resin). One tumor nodule was analyzed with submillimeter three-dimensional microdosimetry.
METHODS AND MATERIALS: Four patients received hepatic artery delivery of (90)Y microspheres for unresectable hepatocellular and colon cancers. Whole livers were explanted as part of lifesaving cadaveric transplant in 2 patients with hepatoma. These patients had received glass microspheres as a procedural bridge to transplant. Autopsy was performed on 2 patients with colon cancer who died of progressive metastatic disease and who had been treated with resin microspheres. Complete pathologic review was performed on each whole liver, including estimation of the response of the tumor to therapy, distribution of microspheres in the tumor and normal liver tissues, and normal-tissue radiation response. A biopsy taken from the edge of a tumor nodule was sectioned serially for three-dimensional radiation dosimetry analyses. Three-dimensional microsphere coordinates within the biopsy specimen were used to calculate dosage using a three-dimensional dose kernel. Isodose coverage of tumor and normal liver areas and total dose delivered were determined.
RESULTS: Preferential and heterogeneous deposition of microspheres was noted at the edge of tumor nodules compared with the center portion of the tumor or normal liver parenchyma. Both glass and resin microspheres delivered high cumulative doses to the tumor, which varied from 100 Gy to more than 3000 Gy. No veno-occlusive disease or widespread radiation hepatitis was seen.
CONCLUSION: Microsphere ((90)Y) therapy delivers high numbers of spheres with resulting high total doses of radiation, preferentially in the periphery of tumors. Normal liver parenchyma showed little radiation effect away from the tumors. Heterogeneous high-dose regions in the tumor were produced by both glass and resin microspheres.

This is a retrospective analysis of a new treatment modality, intra-arterial administration of Yttrium-90 TheraSphere, for unresectable hepatocellular carcinoma (HCC). Patients with HCC not amenable to surgical treatment who had satisfactory physiological function without comorbid disease or significant pulmonary shunting were eligible for treatment. Patients were categorized into complete, partial, or no response based on serum alpha-fetoprotein (AFP) levels and CT or MRI imaging. Fourteen patients were considered candidates for treatment. Three patients were excluded due to significant hepatopulmonary shunting. Eleven patients were treated with TheraSphere. One patient (9%) had a complete response, eight patients (78%) had a partial response, and two patients (18%) showed no response. Partial and complete responders with AFP-associated HCC demonstrated a median decrease in AFP levels of 79 per cent at 73 days. No patients developed liver toxicity nor died due to treatment. Five patients (45%) died of progressive disease at a median of 7 months post-treatment. Six patients (54%) were alive at a median of 11 months (range, 9 to 20 months). Okuda stage 2 and 3 patients showed a median survival of 11 months and 7 months, respectively. Yttrium-90 TheraSphere treatment for unresectable hepatocellular carcinoma is well tolerated and appears to extend survival.

We have implemented a three-dimensional dose calculation technique accounting for dose inhomogeneity within the liver and tumor of a patient treated with 90Y microspheres. Single-photon emission computed tomography (SPECT) images were used to derive the activity distribution within liver. A Monte Carlo calculation was performed to create a voxel dose kernel for the 90Y source. The activity distribution was convolved with the voxel dose kernel to obtain the three-dimensional (3D) radiation absorbed dose distribution. An automated technique was developed to accurately register the computed tomography (CT) and SPECT scans in order to display the 3D dose distribution on the CT scans. In addition, dose-volume histograms were generated to fully analyze the tumor and liver doses. The calculated dose-volume histogram indicated that although the patient was treated to the nominal whole liver dose of 110 Gy, only 16% of the liver and 83% of the tumor received a dose higher than 110 Gy. The mean tumor and liver doses were 163 and 58 Gy, respectively.

PURPOSE: Intra-arterial injection of Yttrium-90 glass microspheres ((90)Y- microS; TheraSphere, MDS Nordion, Ottawa, Canada) is indicated for treatment of unresectable hepatocellular carcinoma (HCC) in the presence of acceptable liver function. This study presents hepatic toxicity results after unilobar and bilobar intra-arterial administration of (90)Y- microS in patients with unresectable HCC who had known portal vein thrombosis (PVT) without evidence of cavernous transformation.
MATERIALS AND METHODS: Fifteen patients with unresectable HCC and PVT of one or both first order and related segmental portal venous branches received a total of 29 infusions of (90)Y- microS for treatment of HCC. All patients had pretreatment evaluation including: computed tomography (CT) imaging, alpha-fetoprotein (AFP) levels, liver function tests, technetium-99m macroaggregated albumin ((99)Tc-MAA) scan for evaluation of lung and visceral shunting, and angiography with visualization into the portal venous phase. (90)Y- micro S dose was based on lobar hepatic volume with adjustment for lung shunt activity. Liver toxicity was assessed by serum total bilirubin graded for severity according to the NIH NCI Clinical Toxicity Criteria (CTC version 2.0). Other adverse events were reported according to the standards established by the Society of Interventional Radiology.
RESULTS: There were no procedural complications with delivery of (90)Y- microS, and treatment was well tolerated by all patients. Increased post-treatment bilirubin levels were observed across all treatments in five patients, four of whom had CT or AFP evidence of intrahepatic disease progression. After initial treatment, two patients developed bilirubin toxicity (grades 1 and 2); one patient demonstrated an increment in bilirubin toxicity grade (grade 1 to grade 3) and one patient had an improvement in grade after initial treatment. There were no new treatment-related toxicities in nine patients after a second treatment.
CONCLUSIONS: (90)Y- microS treatment was well tolerated and appears to be safe to use in patients with compromised portal venous flow in one or both first order and related segmental portal venous branches and no evidence of cavernous transformation. In patients who did not exhibit disease progression, there appeared to be no clinically significant change in bilirubin.

BACKGROUND: The aims of the study were to test the difference in health-related quality (HRQL) of life and survival in patients diagnosed with primary hepatocellular carcionma (HCC) and treated with either hepatic arterial infusion (HAI) of Cisplatin or 90-Yttrium microspheres (Therasphere).
METHOD: The design of the study was a non-randomized parallel cohort study. Twenty-eight patients participated in the present study. HRQL was assessed by administration of the Functional Assessment of Cancer Therapy-Hepatobiliary. Survival was measured using Kaplan Meier methods.
RESULTS: The results of present study suggest treatment with Therasphere) had an advantage in regard to HRQL and survival when compared to Cisplatin. At 3-month follow-up, patients who were treated with Therasphere had a higher level of functional well-being as well as overall quality of life when compared to patients treated with Cisplatin. At 6-month follow-up patients (treated with Therasphere) continued to have better functional well-being when compared to patients being treated with HAI of Cisplatin. At 6-month follow-up, survival was found to be similar for patients treated with Therasphere when compared to patients being treated with Cisplatin.
CONCLUSIONS: Preliminary data suggest that treatment with Therasphere has a modest advantage in regard to HRQL when compared patients treated with HAI of Cisplatin. Future research with Therasphere, that includes a larger sample size and longer follow-up, is necessary to make definitive conclusions regarding the efficacy and effect on HRQL. Copyright 2003 John Wiley & Sons, Ltd.

Hepatocellular carcinoma (HCC) constitutes a difficult health challenge because of its poor prognosis and limited treatment options. Most available therapies are used only for palliation. The use of yttrium-90 microspheres is a new intraarterial therapy consisting of beta-irradiating microspheres measuring 20-30 micro m in diameter that can be delivered directly to the tumors. (90)Y microspheres, which carry the radiation, are selectively taken up by the tumors, thus preserving normal liver. In several studies to date, (90)Y microspheres have proved to have a low toxicity profile and have generally been well tolerated by patients. Other than transient elevation in liver enzyme levels and mild fatigue and fever, no substantial treatment-related toxicities have been observed. Gastrointestinal toxicities occur in a limited number of cases and are preventable with proper knowledge of visceral arterial anatomy. The effect on survival is also promising, with median survival rates of 23 months (95% confidence interval = 14, 44) and 11 months (95% confidence interval = 6, 26) for patients with Okuda stage I and stage II disease, respectively. On the basis of these data, intraarterial delivery of (90)Y microspheres offers a new alternative in the treatment of unresectable HCC.

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Treatment for nonresectable hepatocellular carcinoma (HCC) is palliative. The relatively greater arteriolar density of hepatic tumors compared with normal liver suggests that intrahepatic arterial administration of 90Y-microspheres can be selectively deposited in tumor nodules and results in significantly greater radiation exposure to the tumor than external irradiation. The purpose of this study was to determine the proportion (frequency) and duration of response, survival, and toxicity after intrahepatic arterial injection of 90Y-microspheres in patients with HCC.
METHODS: Patients with documented HCC, Eastern Cooperative Oncology Group performance status 0-3, adequate bone marrow, and hepatic and pulmonary function were eligible for study. Patients who had significant shunting of blood to the lungs or gastrointestinal (GI) tract or who could not undergo cannulation of the hepatic artery were excluded. Patients received a planned dose of 100 Gy through a catheter placed into the hepatic artery.
RESULTS: Twenty-two patients were treated with 90Y-microspheres; 20 of the treated patients (median age, 62.5 y) were evaluated for treatment efficacy. Nine patients were Okuda stage I, and 11 were Okuda stage II. The median dose delivered was 104 Gy (range, 46-145 Gy). All 22 treated patients experienced at least 1 adverse event. Of the 31 (15%) serious adverse events, the most common were elevations in liver enzymes and bilirubin and upper GI ulceration. The response rate was 20%. The median duration of response was 127 wk; the median survival was 54 wk. Multivariable analysis suggested that a dose >104 Gy (P = 0.06), tumor-to-liver activity uptake ratio >2 (P = 0.06), and Okuda stage I (P = 0.07) were associated with longer survival.
CONCLUSION: Significantly higher doses of radiation can be delivered to a HCC tumor by intrahepatic arterial administration of 90Y-microspheres than by external beam radiation. This treatment appears to be beneficial in nonresectable HCC with acceptable toxicity.

METHODS. Ten patients with primary hepatocellular carcinoma were treated with intraarterial instillation of yttrium-90 (Y-90) microspheres, including eight men and two women (median age, 52 years; range, 29-69 years). Four patients were treated at a targeted hepatic dose of 50 Gy, two at 75 Gy, and four at 100 Gy.
RESULTS. In 8 of the 10 patients, there was a significant concentration of Y-90 in localized tumor masses with tumor-to-liver perfusion ratios from 1.0:1-10.0:1. No patient had a complete or partial response, but 10 patients had stable disease (median duration, 10 weeks; range, 5-64 weeks). The median survival was 18 weeks (range, 2-150 weeks), and three patients lived longer than 1 year. Significant bone marrow or hepatic toxicity was not seen. One patient had a radiation-induced duodenal ulcer that required surgical management.
CONCLUSIONS. Intraarterial instillation of Y-90 microspheres appears to be safe and deserves additional evaluation to determine whether there is meaningful activity in patients with primary hepatocellular carcinoma.

The potential use of yttrium-90 glass microspheres in the treatment of hepatocellular carcinoma was assessed in a pilot study of seven patients. The Y-90 microspheres were injected via a hepatic artery catheter. In this group of patients, no toxicity was observed for absorbed doses of between 5,000 and 10,000 cGy to the liver and up to 32,000 cGy to the tumor itself. Tumor response was seen only at the higher absorbed doses. The new Y-90 glass microspheres can safely deliver large doses of internal radiation to hepatic tumors as long as extrahepatic shunting can be excluded. Extrahepatic shunting will be the main limitation to this form of radiation therapy.