Selective Internal Radiation Therapy with SIR-Spheres in Patients with Nonresectable Liver Tumors

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1 CANCER BIOTHERAPY & RADIOPHARMACEUTICALS Volume 20, Number 2, 2005 Mary Ann Liebert, Inc. Selective Internal Radiation Therapy with SIR-Spheres in Patients with Nonresectable Liver Tumors Gabriele Pöpperl, 1 Thomas Helmberger, 2 Wolfgang Münzing, 1 Rupert Schmid, 1 Tobias Franz Jacobs, 2 and Klaus Tatsch 1 1 Department of Nuclear Medicine, Klinikum Großhadern, University of Munich, Munich, Germany 2 Department of Radiology, Klinikum Großhadern, University of Munich, Munich, Germany Downloaded by from online.liebertpub.com at 01/18/18. For personal use only. ABSTRACT Aim: Transarterial embolization of branches of the hepatic artery with biocompatible 90 Y-labeled microspheres (SIR-Spheres ) is a local treatment modality for patients with liver tumors, which, most recently, has become available in Europe. The aim of this study was to evaluate the feasibility and efficacy of this selective internal radiation therapy (SIRT). Methods: Twenty-three patients with nonresectable hepatic metastases or hepatocellular carcinoma nonresponding to polychemotherapy and/or other local treatment were treated with SIRT. SIR-Spheres (mean activity, 2270 MBq) were administered by gentle intra-arterial infusion in the hepatic artery. A follow-up was documented by fluorodeoxyglucose positron emission tomography (FDG-PET), course of tumor markers, and computed tomography (CT). Results: Common minor side-effects were abdominal pain, nausea, and fever. Mild pancreatitis and peptic ulceration were observed once each. Currently, all patients are still alive, with survival times ranging from 11 to 518 days from SIRT up to the present. Three-month follow-up investigations are available in 13 of 23 patients, which, so far, are showing a marked decrease of FDG uptake, a drop of tumor markers, and unchanged or slightly decreasing lesion size (CT) in 10 of 13 patients. Two patients showed stable findings, while another patient showed progressive disease. Long-term follow-up investigations are available in 2 of 23 patients, showing hepatic and extrahepatic progression 6 and 9 months after SIRT. Conclusions: Our initial experience confirms that SIRT is a promising local therapeutic approach in patients with nonresectable liver tumors which is feasible and has an acceptable toxicity profile. Prospective data on comparing this treatment alone or in combination with other modalities are needed to answer whether longterm survival in this unfavorable stage of disease can be markedly improved. Key words: selective internal radiation therapy (SIRT), [ 90 Y]microspheres, nonresectable liver tumors INTRODUCTION Address reprint requests to: Gabriele Pöpperl; Department of Nuclear Medicine, Klinikum Großhadern, University of Munich; Marchioninistraße 15, 81377, Munich, Germany; Tel.: 49/89/ ; Fax: 49/89/ Gabriele.Poepperl@med.uni-muenchen.de Hepatic metastases, especially of colorectal and breast cancer and hepatocellular carcinoma (HCC), are among the most common cancer manifestations worldwide. For many patients with those liver tumors, liver failure is the primary cause of death. 1 Surgical resection is considered to be the only curative treatment for HCC or metastases confined to the liver. 1 However, only a small number of patients are candidates for this type of treatment. For the majority of those patients, hepatic resection is not a therapeutic option owing to the size, number, or location of the lesions. Therefore, a number of palliative local treatment modalities, including cryotherapy and 200

2 radiofrequency or laser ablation, have gained importance in recent years. These methods, however, are only applicable to patients with a limited number of small lesions. Unfortunately, at the time of recognition, most patients already have extended liver disease. Selective internal radiation therapy (SIRT) with embolization of branches of the hepatic artery with biocompatible resin-based 90 Y-labeled microspheres (SIR-Spheres, SIRTeX Medical; North Ryde, New South Wales, Australia) is another therapeutic approach for patients with extended liver disease, 2 6 which, most recently, has become available in Europe. Compared to external radiation therapy, which has little impact on the management of this type of patient owing to a high risk of radiation hepatitis, SIRT achieves high radiation doses within the tumor lesions at lower doses to normal liver parenchyma. This somewhat selective tumor uptake is obtained by the delivery of microspheres directly into the hepatic artery, which represents, almost exclusively, the arterial supply to liver tumors, compared to the predominantly portal supply to a normal liver. 7,8 This study summarizes our first experience with SIRT in evaluating its feasibility and efficacy in patients with advanced hepatic metastases and HCC. Our further aim is to direct attention to this new treatment modality in Europe and to encourage its further investigation. MATERIALS AND METHODS Patients Twenty-three patients (10 females and 13 males, with a mean age of 56 9 years; range: years) with extensive liver metastases (n 21) or HCC (n 2) who were not suitable for resection and were no longer responding to polychemotherapy and/or other local forms of treatment, such as radiofrequency or chemoablation, were included in this pilot study. Primary tumors in patients with liver metastases consisted of colorectal cancer (n 12), breast cancer (n 4), pancreatic cancer (n 2), thymic carcinoma (n 1), choroidal melanoma (n 1), and neuroendocrine tumor (n 1). Prior to SIRT, all patients had undergone systemic chemotherapy; 6 of 23 patients, in addition, had local chemoembolization or radiofrequency ablation of singular lesions, and 3 of 23 patients previously had partial liver resection. The main inclusion criteria were a Karnofsky performance score 70, adequate liver function with a total bilirubin 2.0 mg/dl, and no evidence of tumor invasion into the portal vein, the hepatic artery, hepatic vein, or inferior vena cava. Exclusion criteria were previous external radiation therapy to the liver, malignant ascites or clinical liver failure, markedly abnormal liver function tests (total bilirubin 2.0 mg/dl), aberrant blood circulation owing to anatomic variations resulting in backflow to the stomach, pancreas, or bowel, major extrahepatic manifestations, liver or lung shunting 20%, and treatment with capecitabine within the previous 2 months or planned treatment at any time following SIRT. Patients had to comprehend and sign an informed consent agreement. Sixteen of 23 patients showed no extrahepatic manifestations in whole-body FDG-PET and thoracic or abdominal CT scanning before SIRT. Seven of 23 patients presented with major liver disease and only minor extrahepatic manifestations (3 abdominal lymph node involvement, 1 pleural infiltration, 2 pulmonary metastases, 3 bone metastases, and 1 local recurrence of colorectal cancer). SIRT Assessment of liver/lung shunting Prior to SIRT, arteriovenous liver or lung shunting was scintigraphically assessed after an intraarterial administration of 99m Tc-labeled macroaggregated albumin (MAA; Amersham Health AG, Wådenswil, Switzerland) during a diagnostic hepatic angiography. After a gentle administration of approximately 80 MBq [ 99m Tc]MAA, which has an average particle size similar to that of [ 90 Y]microspheres, a static ventral and dorsal scan was obtained. Using the geometric mean of both images, the percentage of lung shunting was determined from the total counts within regions of interest (ROIs) over both lobes of the lung and the liver. For this purpose, delineation of the lung was done by the help of a 57 Co flood phantom (Fig. 1). For shunt volumes exceeding 10%, dose reduction is necessary because of a higher risk of radiation pneumonitis (10% 15% shunt volume: calculated dose minus 20%; 15% 20% shunt volume: calculated dose minus 40%). A shunt greater than 20% was determined as exclusion criteria. Administered activity The administered activity of SIR-Spheres was adapted to the estimated tumor load of the liver 201

3 Figure 1. Ventral and dorsal [ 99m Tc]MAA scans for determination of the liver/lung shunt (here 4%); lung borders can be better delineated by the help of a 57 Co flood phantom (lower row). based on the following empiric calculation: 25% liver replacement: 2000 MBq; 25% 50% liver replacement: 2500 MBq; 50% liver replacement: 3000 MBq. According to the hepatic tumor load, which was assessed on the baseline CT prior to therapy, the determined dose was 2000 MBq for 5 of 23 patients and 2500 MBq for 18 of 23 patients. Effectively administered activity in some cases, however, was somewhat lower (mean activity: 2270 MBq, ranging from 1250 MBq to 2500 MBq), as in 7 of 23 patients administration of SIR-Spheres had to be stopped before the determined activity was completely given. The reason for the stoppage was a marked decrease of peripheral perfusion in control angiograms during therapy, indicating an increased risk of extrahepatic back-flow of microspheres if therapy would have been continued. Treatment Diagnostic and therapeutic hepatic angiographic procedures were only performed by well-trained, interventional radiologists from the department of radiology at the University of Munich, Munich, Germany. To avoid extrahepatic deposition of SIR-Spheres in the duodenum, stomach, or pancreas, the gastroduodenal artery and, optionally, the right gastric artery or pancreaticoduodenal branches were coiled before treatment. SIRT was performed with 90 Y-labeled SIR- Spheres (particle size, m) through a percutaneous transfemoral hepatic artery catheter. Microspheres were administered by gentle pulsatile intra-arterial infusion in the right and left hepatic artery separately and under low pressure to strictly avoid back-flow. For application, a specific device provided by the manufacturer was used. During SIRT, repeatedly hepatic angiograms were obtained to follow the decrease in peripheral perfusion induced by the embolization. Figure 2 shows representative angiograms of 2 patients before and after SIRT clearly showing the rarefaction of peripheral vessels. Approximately 1 hour and 24 hours after SIRT, post-therapeutic scintigrams were performed to document the distribution of 202

4 Figure 2. Hepatic angiograms of 2 patients of (A) a multifocal HCC and (B) liver metastases of pancreatic cancer before and immediately after SIRT showing marked rarefaction of peripheral vessels after SIRT resulting from successful embolization by the administration of SIR-Spheres. HCC, hepatocellular carcinoma; SIRT, selective internal radiation therapy. SIR-Spheres. Routinely given concomitant medication consisted of analgetics, antiemetics, steroids, drugs for gastric protection, and antibiotics for the prevention of superinfection. Furthermore, sufficient hydration and light diet during and after SIRT had to be maintained. 203

5 Follow-up Follow-up was documented by FDG-PET, CT, and course of tumor markers, such as CEA, CA 19-9, CA 15-3, and special markers for neuroendocrine tumors (Cyfra 21-1, ProGRP, NSE) in 3- month intervals after SIRT. FDG-PET investigations and contrast-enhanced (portal venous phase), multislice CT examinations were performed either on a combined scanner (Gemini, Philips Medical Systems, Cleveland, OH) or on 2 separate devices (PET: ECAT EXACT HR, Siemens Medical Systems, Knoxville, TN: Sensation 4 or 16 multislice scanners, Siemens), according to the routinely used protocols. RESULTS Baseline Results At baseline, all patients with liver metastases showed high FDG uptake, whereas the patients with HCC presented only with slightly increased FDG accumulation, compared to the normal liver parenchyma. Pretherapeutic [ 99m Tc]MAA scans revealed a mean liver-lung shunt of % (range: 2% 8%). Therefore, because none of the patients presented with shunt volumes greater than 10%, in no case was reduction of the empirically calculated activity necessary. Side-Effects No deaths or life-threatening morbidity resulted from the angiographic and therapeutic procedure. During and immediately after SIR- Spheres administration, acute abdominal pain was observed in 20 of 23 patients. Pain intensity was rated as mild in 11 of 20 patients, moderate in 3 of 20 patients, and intense in 6 of 20 patients. Nausea was seen in 5 of 23 patients. Both pain and nausea could be adequately treated with analgetic and antiemetic medication. Following SIRT, transient elevation of C- reactive protein was evident in all patients (range, mg/dl) and pancreatic enzymes transiently increased in 5 of 23 patients 1 of them developed mild pancreatitis showing moderate edema of the pancreatic head on magnetic resonance imaging (MRI) 3 days after treatment. Transient low-grade fever was seen in 8 of 23 patients. Overall, SIRT was well tolerated, and no serious in-hospital morbidity occurred. One patient suffered from gastric ulceration 2 months after SIRT, and another patient developed acute myelotic leucemia (AML), which, however, was most reasonably caused by several previous cycles of haematotoxic polychemotherapy. Response All patients are still alive, with survival times ranging from 11 to 518 days from the date of treatment up to the present. Currently, 3-month follow-up investigations with FDG-PET are already available in 13 of 23 treated patients, showing in 10 of 13 patients markedly decreasing FDG uptake of liver metastases (n 9) or HCC (n 1), reaching even normal hepatic FDG uptake in 3 of 10 patients (Fig. 3A). In parallel, tumor markers also decreased in all those 10 patients, reaching even normal levels approximately 3 months after SIRT in 5 of 10 patients. In contrast, CT showed only a slight decrease or stable findings of hepatic tumor load. FDG-PET revealed extrahepatic progression in 7 of those 10 patients who showed a beneficial therapeutic effect in the liver. In 4 of those 7 patients, minor extrahepatic disease was already known from the baseline examinations, and in 3 of 7 patients, extrahepatic manifestation was newly diagnosed in the 3-month follow-up. Patients presenting with solitary, but extended, liver metastasis before treatment (n 2) showed only minor or no response on FDG uptake during the follow-up (Fig. 3B). In 1 patient, carcinoembryonic antigen (CEA) levels concordantly further increased after treatment, while in the other patient, tumor markers remained negative before and after treatment. Only in 1 of 13 patients did FDG-PET reveal a progression of liver metastases, as well as a newly diagnosed inguinal lymph node involvement 3 months after SIRT. Table 1 summarizes FDG-PET results and tumor-marker levels before and 3 months after SIRT of the first 13 patients. Follow-up investigations beyond the 3-month period after SIRT (up to 9 and 14 months) are available in 2 of 23 patients, showing a progression of hepatic and extrahepatic manifestations in both of these patients approximately 6 and 9 months after SIRT. In 9 of 23 patients, the follow-up so far is too short; therefore, the respective investigations were not yet performed. One of 23 patients was lost for the follow-up. 204

6 Figure 3. MIP images of representative FDG-PET scans of patients with colorectal cancer before and 3 months after SIRT showing (A) markedly decreasing FDG uptake, indicating good response to therapy and (B) almost no change of FDG uptake within a centrally located hugh liver metastasis, indicating no response. SIRT, selective internal radiation therapy; MIP, maximum intensity projection. DISCUSSION Systemic treatment of nonresectable HCC and liver metastases is palliative and often has no significant impact on overall survival. Because clinical observations suggest that especially liver metastases progress more quickly than those at most other sites and, therefore, will determine the prognosis, there is increasing interest in aggressive local treatment forms. In recent years, many locoregional ablative techniques, such as cryotherapy and radiofrequency or laser ablation, have been evaluated and have shown to be helpful in selected patients. However, in many cases, liver tumors are too extended for any of these techniques. SIRT is a potential alternative therapeutic option for such patients. SIR-Spheres are resin-based microspheres with a lower specific gravity compared to glass microspheres, which are used by some other groups. 9,10 Therefore, resin-based microspheres probably possess better distribution characteristics when injected into the hepatic artery and, thus, may be safer and more effective. Initial clinical studies with SIR-Spheres done in Australia have shown that treatment of liver metastases from primary colorectal cancer results in a high rate of tumor regression. 6 A recently published clinical trial on SIRT in combination with hepatic artery chemotherapy (HAC) demonstrated that SIRT more than doubled the response rate and the time-to-disease progression of HAC alone. 3 Other groups from New Zealand and Hong Kong confirmed these encouraging results 4,5 and extended the use of SIR-Spheres to the therapy of primary hepatocellular carcinoma Another more recent randomized phase II trial also conducted by the Australian group demonstrated that an additive single administration of SIR-Spheres to a regimen of systemic fluorouracil-leucovorin chemotherapy significantly increased the treatment related response, the time to progression, and the survival of patients. 2 Recently, SIRTeX Medical has obtained regulatory approval for marketing SIR-Spheres also in the European Union (CE Mark) and, therefore, this technique has become available in Europe as well. Because experience in Europe with SIRT is still limited, we report in this paper on the first 23 patients treated in our hospital. Our prelimi- 205

7 Table 1. Response to SIRT Therapy According to FDG-PET Results and Course of Tumor Markers Prae SIRT 3 months post-sirt Primary tumor PET TU marker PET TU marker Further follow-up CRC Multiple liver metastases CEA: 8.3 Regression liver CEA: 1.0 Hepatic/extrahepatic n.e.m. CA 19-9: 59.1 n.e.m. CA 19-9: 16.3 progression (9 months after SIRT) CRC Hugh liver metastasis CEA: 472 No change of liver metastasis CEA: 894 not done yet small local recurrence extrahepatic progression CRC Multiple liver metastases CEA: 438 Regression liver (no FDG uptake) CEA: 39.0 not done yet bone metastasis (Os ilium) CA 19-9: 992 progression bone/lung (new) CA 19-9: 97.9 CRC Hugh liver metastasis CEA: 1.1 No change of liver metastasis CEA: 1.2 not done yet n.e.m. n.e.m. CRC Multiple liver metastases CEA: 20.8 Regression liver (no FDG uptake) CEA: 2.7 not done yet n.e.m. n.e.m. CRC Multiple liver metastases CEA: 28.2 Partial regression liver CEA: 61.8 not done yet pulmonary/peritoneal metastases massive extrahepatic progression CRC Multiple liver metastases CEA: 74.8 Progression liver CEA: 58.5 not done yet n.e.m. progression inguinal LN (new) breast Multiple liver metastases CEA: 26.7 Regression liver CEA: 1.9. Hepatic/extrahepatic small abdnominal LN CA 15-3: 55.9 extrahepatic progression CA 15-3: 24.6 progression (6 months after SIRT) breast Multiple liver metastases CEA: 2.0 Regression liver not done not done yet n.e.m. CA 15-3: 94.2 progressive lung/peritoneal LN (new) breast Multiple liver metastases CEA: 9.7 not done CEA 6.7 not done yet hilar LN/bone metastases CA 15-3: 36.3 CA 15-3: 36.6 breast Multiple liver metastases CEA: 3.9 Regression liver CEA 2.3 not done yet n.e.m. CA 15-3: 88.2 progressive pleural metastasis (new) CA 15-3: 71.7 Neuroendocrine Multiple liver metastases Cyfra 21-1 S: 4.7 Regression liver Cyfra 21-1 S: 2.7 not done yet TU n.e.m. ProGRP S: 61.2 progression para-aortal LN (new) ProGRP S: 16.2 NSE S: 159 NSE S: 10.1 pancreas Multiple liver metastases CA 19-9: 1665 Regression liver (no FDG uptake) CA 19-9: 42.0 not done yet n.e.m. n.e.m. HCC Multilocular liver lesions AFP S: 2053 Partial regression liver AFP S: 1466 not done yet n.e.m. n.e.m. TU markers (normal values): CEA ( 3); CA 15-3 ( 28); CA 19-9 ( 37); Cyfra 21-1 S ( 3.3); ProGRP S ( 38); NSE S ( 16.3); AFP S ( 15). CRC, colorectal cancer; n.e.m., no extrahepatic manifestations; SIRT, selective internal radiation therapy; PET, positron emission tomography; TU, tumor uptake; HCC, hepatocellular carcinoma; CEA, carcinoembryonic antigen.

8 nary experience with SIRT confirms that the intra-arterial application of [ 90 Y]microspheres is a feasible treatment for patients suffering from nonresectable liver tumors which no longer responded to chemotherapy. By superselective catheterization of the main branches of the hepatic artery, very high radiation doses can be achieved within the tumors, whereas the normal liver parenchyma remains largely spared. Because by this procedure the gastroduodenal artery, the right gastric artery, and pancreaticoduodenal branches are bypassed, radiation-induced severe toxicity to other organs could be avoided in most cases. Only 1 patient experienced gastric ulceration approximately 2 months after treatment, most reasonably caused by a slight back-flow of microspheres at the end of the therapeutic procedure, which was suggested by a faint gastric uptake seen in the post-therapeutic scan. So far, neither the dose to the tumor required for complete remission nor the maximum tolerance of normal liver parenchyma for SIR-Spheres therapy are exactly known from the literature. Intraoperatively determined radiation doses to the liver and tumor using a beta probe and liquid scintillation counting of multiple liver biopsies 13 ranged between 18 and 77 Gy to normal liver parenchyma and 26 to 409 Gy to the tumor. Radiation doses could also be estimated by a partition model. Assuming that relative distribution of [ 99m Tc]MAA is similar to that of [ 90 Y]microspheres, tumor and nontumor doses could be estimated using the percentage of lung shunting and tumor-to-nontumor ratio determined from the pretherapeutic [ 99m Tc]MAA scan. Using this partition model, radiation doses for hepatic tumors and normal liver parenchyma were estimated by Ho et al., 14,15 showing that doses to the lung greater than 30 Gy from a single treatment and greater than 50 Gy from repeated treatments resulted in an increased risk of radiation pneumonitis. Tumor doses ranged from 83 to 748 Gy (median, 225 Gy), showing better response rates in patients who received doses above 225 Gy. The tolerance limit of the normal human liver for SIRT proposed by Fox et al. was 80 Gy. 16 No dosimetric estimations have been performed for our patient group yet. However, taking into account that the delivered activities were similar to these given by Ho et al., 14 the tumor doses achieved in our patients should be in a similar and, herewith, also tumoricidal range ( 120 Gy). Assessment of tumor response to treatment can generally be based on different parameters, such as course of tumor markers, as well as metabolic or morphologic changes. The marked decrease in FDG uptake, as well as the immediate drop of tumor markers post-treatment, in most patients indicate a positive therapeutic effect of SIRT and are not commonly observed after other palliative treatment modalities, such as systemic chemotherapy. The response rate based on changes in tumor volume according to the CT scans, however, was much lower than that based on changes in FDG uptake and tumor-marker levels. Because FDG-PET has been shown to be more accurate than CT in detecting liver metastases and Wong et al. 17 demonstrated a significant difference between the metabolic response and the morphological response assessed by CT following 90 Y microsphere treatment, PET may be a more sensitive and accurate indicator of treatment response. In our patients, the early response assessed by FDG-PET and the tumor-marker levels, so far, is encouraging. In the long-term followup, which is, so far, limited to 2 patients, extrahepatic progression, as well as regrowth of hepatic disease, occurred. Based on these data, it can only be speculated whether SIRT might have protracted progression and prolonged survival time. There is evidence from the literature, 3 however, that SIRT might be less appropriate as a stand-alone modality but should rather be considered in conjunction with modern systemic chemotherapy to avoid extrahepatic progression and/or other local treatment modalities to prolong the local effects of SIRT. CONCLUSIONS Our initial experience with the intra-arterial administration of [ 90 Y]microspheres show that SIRT is a promising local therapeutic approach for patients with nonresectable liver tumors. This type of therapy is feasible and has an acceptable toxicity profile. The response rates assessed by FDG-PET and tumor-marker levels in our patient group were sufficiently high to support a more widespread use of SIR-Spheres in Europe and to further evaluate the potential of SIRT systematically in prospective multicenter studies. This may answer the question of whether long-term survival in this unfavorable stage of disease can be improved by SIRT alone or, what seems to be more appropriate, in combination with other systemic and/or local treatment modalities. Patient 207

9 selection, however, has to be done very carefully, as a subgroup of patients with hugh metastases or pre-existing extrahepatic manifestations seem to benefit less of this therapeutic modality. Moreover, administration of microspheres has to be done by trained staff only to avoid severe sideeffects such as, for example, radiation pneumonitis, radiation hepatitis, gastric ulceration, or gastrointestinal bleeding. REFERENCES 1. Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 1985; 56: Van Hazel G, Blackwell A, Anderson J, et al. Randomized phase 2 trial of SIR-Spheres(R) plus fluorouracil/leucovorin chemotherapy versus fluorouracil/ leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol 2004;88: Gray B, Van Hazel G, Hope M, et al. Randomized trial of SIR-Spheres plus chemotherapy versus chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol 2001;12: Stubbs RS, Cannan RJ, Mitchell AW. Selective internal radiation therapy (SIRT) with 90 Yttrium microspheres for extensive colorectal liver metastases. Hepatogastroenterology 2001;48: Stubbs RS, Cannan RJ, Mitchell AW. Selective internal radiation therapy with 90 yttrium microspheres for extensive colorectal liver metastases. J Gastrointest Surg 2001;5: Gray BN, Burton MA, Kelleher DK, et al. Selective internal radiation (SIR) therapy for treatment of liver metastases: Measurement of response rate. J Surg Oncol 1989;42: Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol 1954;30: Sigurdson ER, Ridge JA, Kemeny N, et al. Tumor and liver drug uptake following hepatic artery and portal vein infusion. J Clin Oncol 1987;5: Carr BI. Hepatic arterial 90 Yttrium glass microspheres (Therasphere) for unresectable hepatocellular carcinoma: Interim safety and survival data on 65 patients. Liver Transpl 2004;10:S Yan ZP, Lin G, Zhao HY, et al. An experimental study and clinical pilot trials on yttrium-90 glass microspheres through the hepatic artery for treatment of primary liver cancer. Cancer 1993;72: Lau WY, Ho S, Leung TW, et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intra-arterial infusion of 90 yttrium microspheres. Int J Radiat Oncol Biol Phys 1998;40: Lau WY, Ho S, Leung WT, et al. What determines survival duration in hepatocellular carcinoma treated with intra-arterial Yttrium-90 microspheres? Hepatogastroenterology 2001;48: Lau WY, Leung WT, Ho S, et al. Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: A phase I and II study. Br J Cancer 1994;70: Ho S, Lau WY, Leung TW, et al. Clinical evaluation of the partition model for estimating radiation doses from yttrium-90 microspheres in the treatment of hepatic cancer. Eur J Nucl Med 1997;24: Ho S, Lau WY, Leung TW, et al. Partition model for estimating radiation doses from yttrium-90 microspheres in treating hepatic tumours. Eur J Nucl Med 1996;23: Fox RA, Klemp PF, Egan G, et al. Dose distribution following selective internal radiation therapy. Int J Radiat Oncol Biol Phys 1991;21: Wong CY, Salem R, Raman S, et al. Evaluating 90 Y- glass microsphere treatment response of unresectable colorectal liver metastases by [ 18 F]FDG PET: A comparison with CT or MRI. Eur J Nucl Med Mol Imaging 2002;29: