HepatologyVolume 47, Issue 1 p. 71-81 Hepatobiliary MalignanciesFree Access Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis† Laura M. Kulik, Laura M. Kulik Department of Hepatology, Northwestern University, Chicago, ILSearch for more papers by this authorBrian I. Carr, Brian I. Carr Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PASearch for more papers by this authorMary F. Mulcahy, Mary F. Mulcahy Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern Memorial Hospital, Chicago, IL Potential conflict of interest: MFM, AB, RS have received grant support from MDS Nordion. RS is an advisor to MDS Nordion. None of the other authors have disclosed a potential conflict of interest.Search for more papers by this authorRobert J. Lewandowski, Robert J. Lewandowski Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorBassel Atassi, Bassel Atassi Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorRobert K. Ryu, Robert K. Ryu Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorKent T. Sato, Kent T. Sato Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorAl Benson III, Al Benson III Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern Memorial Hospital, Chicago, IL Potential conflict of interest: MFM, AB, RS have received grant support from MDS Nordion. RS is an advisor to MDS Nordion. None of the other authors have disclosed a potential conflict of interest.Search for more papers by this authorAlbert A. Nemcek Jr., Albert A. Nemcek Jr. Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorVanessa L. Gates, Vanessa L. Gates Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorMichael Abecassis, Michael Abecassis Division of Transplant Surgery, Northwestern Memorial Hospital, Chicago, ILSearch for more papers by this authorReed A. Omary, Reed A. Omary Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorRiad Salem, Corresponding Author Riad Salem [email protected] Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern Memorial Hospital, Chicago, IL Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago IL Potential conflict of interest: MFM, AB, RS have received grant support from MDS Nordion. RS is an advisor to MDS Nordion. None of the other authors have disclosed a potential conflict of interest. fax: 312-695-0654Interventional Oncology, Department of Radiology, 676 N. St. Clair, Suite 800, Chicago, IL 60611===Search for more papers by this author Laura M. Kulik, Laura M. Kulik Department of Hepatology, Northwestern University, Chicago, ILSearch for more papers by this authorBrian I. Carr, Brian I. Carr Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PASearch for more papers by this authorMary F. Mulcahy, Mary F. Mulcahy Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern Memorial Hospital, Chicago, IL Potential conflict of interest: MFM, AB, RS have received grant support from MDS Nordion. RS is an advisor to MDS Nordion. None of the other authors have disclosed a potential conflict of interest.Search for more papers by this authorRobert J. Lewandowski, Robert J. Lewandowski Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorBassel Atassi, Bassel Atassi Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorRobert K. Ryu, Robert K. Ryu Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorKent T. Sato, Kent T. Sato Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorAl Benson III, Al Benson III Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern Memorial Hospital, Chicago, IL Potential conflict of interest: MFM, AB, RS have received grant support from MDS Nordion. RS is an advisor to MDS Nordion. None of the other authors have disclosed a potential conflict of interest.Search for more papers by this authorAlbert A. Nemcek Jr., Albert A. Nemcek Jr. Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorVanessa L. Gates, Vanessa L. Gates Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorMichael Abecassis, Michael Abecassis Division of Transplant Surgery, Northwestern Memorial Hospital, Chicago, ILSearch for more papers by this authorReed A. Omary, Reed A. Omary Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago ILSearch for more papers by this authorRiad Salem, Corresponding Author Riad Salem [email protected] Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern Memorial Hospital, Chicago, IL Department of Radiology, Section of Interventional Radiology, Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, Chicago IL Potential conflict of interest: MFM, AB, RS have received grant support from MDS Nordion. RS is an advisor to MDS Nordion. None of the other authors have disclosed a potential conflict of interest. fax: 312-695-0654Interventional Oncology, Department of Radiology, 676 N. St. Clair, Suite 800, Chicago, IL 60611===Search for more papers by this author First published: 26 December 2007 https://doi.org/10.1002/hep.21980Citations: 452 ‡ fax: 312-695-0654 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract 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 (90Y) 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 90Y 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. (HEPATOLOGY 2007.) A substantial proportion of patients develop portal vein thrombosis (PVT) during the natural history of hepatocellular carcinoma (HCC).1 Reports of PVT in orthotopic liver transplantation range from 26.0% to 35.0%.2 The presence of PVT represents a challenging treatment dilemma for these patients. Patients with HCC and PVT generally have a significant degree of underlying hepatic disease and synthetic dysfunction. There is a risk of hepatic decompensation associated with embolic liver-directed intraarterial therapies such as transarterial embolization (TAE) or transarterial chemoembolization (TACE). When hepatic arterial vessel(s) are occluded, the portal venous system compensates to maintain adequate perfusion. If the portal circulation is compromised by thrombosis, direct tumor invasion (portal tumor thrombosis), or compression of the portal system by an extrinsic tumor mass, arterial embolization procedures can increase the risk of liver failure. For these reasons, the presence of portal vein occlusion has been considered by some to be a contraindication to TAE or TACE.3, 4 In fact, studies documenting the survival benefits of TACE have been in selected patients without portal vein thrombosis or vascular invasion.5 Other investigators have found that intraarterial hepatic regional therapies can be safely performed in the presence of partial portal vein occlusion if a modified, low-dose, superselective or segmental technique is used.6, 7 When portal flow is hepatofugal, TAE and TACE remain relatively contraindicated. Given that approximately one third of all patients with unresectable HCC will develop PVT during the natural history of the disease, a large number of patients are left with no effective treatment options. Recently, the investigators of the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial, a large, multicenter, randomized placebo-controlled phase III trial, reported a significant improvement in overall survival in Child A patients with advanced HCC treated with Sorafenib.8 These represent the first positive findings with survival as the endpoint in advanced HCC patients, setting the stage for an established gold standard and potential control arm in this patient cohort. Radioembolization with 90Y (TheraSphere) represents a novel form of liver-directed brachytherapy.9, 10 This device may be indicated as a radiation treatment, or as a neoadjuvant to surgery or transplantation in patients with unresectable HCC. It also may be used for the treatment of unresectable HCC in patients with branch/partial portal vein thrombosis. Clinical experience with this device has shown a low incidence of post embolization syndrome, directly supporting its minimally embolic effect.11, 12 A preliminary safety analysis in 15 patients with unresectable HCC and PVT without cavernous transformation has been reported. 90Y therapy was well tolerated, and in the absence of disease progression, no clinically significant post-treatment bilirubin elevations were noted.13 The current study was undertaken to further assess the safety and clinical benefit of radioembolization in a larger cohort of patients with unresectable HCC complicated by PVT. Abbreviations AE, adverse events; CT, computed tomography; EASL, European Association for the Study of the Liver; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; PVT, portal vein thrombosis; SWOG, South West Oncology Group; TACE, transarterial chemoembolization; TAE, transarterial embolization; WHO, World Health Organization. Patients and Methods Patient Cohort and Follow-Up. This study included 108 patients from 2 centers treated under an open-label Institutional Review Board–approved phase 2 protocol. Patients provided written informed consent before treatment. Inclusion criteria for treatment included (1) HCC by imaging or pathology as outlined by the European Association for the Study of the Liver 2000 consensus document14; (2) nonsurgical candidate; (3) Eastern Cooperative Oncology Group (ECOG) 0 to 2; (4) noncompromised pulmonary function (assessed by history of severe chronic obstructive pulmonary disease, physical examination, and auscultation); (5) able to undergo angiography and selective visceral catheterization; (6) adequate hematology (granulocyte count ≥ 1.5 × 109/L, platelets ≥ 50 × 109/L), renal function (creatinine ≤ 2.0 mg/dL); (7) liver function (bilirubin ≤ 2.0 mg/dL). Exclusion criteria were (1) other planned therapy systemic/locoregional therapy for their cancer; (2) liver failure (bilirubin > 2.0 mg/dL); (3) evidence of any uncorrectable flow to the gastrointestinal tract observed on angiography or technetium-99m macroaggregated albumin scan; (4) greater than 30 Gy (16.5 mCi) estimated to be delivered to the lungs in a single administration or 50 Gy on multiple administrations; and (5) significant extrahepatic disease. Of note, patients were not excluded from therapy on the basis of portal hypertension or hepatofugal flow. Clinical and biochemical data were obtained at baseline and at 4-week intervals following treatment. A 6-month (180 days) follow-up period from treatment was used as the cutoff for the safety and toxicity analysis. This interval was chosen because it represents the most conservative timeline during which acute radiation toxicities possibly related to treatment may occur. Toxicities occurring beyond this time were not considered to be treatment-related. The data from both sites were pooled and summarized for HCC patients with and without PVT (further delineated anatomically by branch or main PVT), and by presence or absence of cirrhosis. Tumor response and overall survival were assessed. Data Collection. Data comprised information on demographics, tumor characteristics, and radiation dosimetry. Baseline tumor and disease presentation were stratified by tumor burden (> or < 50%), aspartate aminotransferase, alanine aminotransferase, total bilirubin (> or ≤ 2 mg/dL), Okuda stage, Child-Pugh, ECOG, the presence of hepatitis B/C, and cirrhosis. Cirrhosis was defined by cirrhotic morphology on imaging [computed tomography (CT)/magnetic resonance imaging] or presence of portal hypertension (hepatofugal flow, gastrointestinal varices, or splenomegaly). Liver function tests were collected at enrollment (approximately 10–14 days before therapy), day of therapy (baseline), and every 30 to 60 days after therapy. The dosing information consisted of the dose received for the first treatment cycle and the total cumulative dose received for all subsequent treatment cycles. Outcome data after treatment included treatment-related adverse events (AEs), liver-related AEs, imaging response, and Kaplan-Meier survival (stratified by presence/absence of cirrhosis). Toxicity, response, and survival analyses were censored at time of last clinic visit or death; data were not imputed for visits after a patient was lost to follow-up. All adverse events were classified and coded for severity using the Southwest Oncology Group (SWOG) toxicity criteria (grading system).15 Any grade 3 or greater adverse events occurring within 180 days following first treatment with TheraSphere was considered to be a possibly related adverse event (AE) and are therefore reported herein without definite attribution to treatment. These toxicities were further stratified by presence/absence of cirrhosis. Tumor Response. Assessment for tumor response was performed at 1 month following initial treatment, and subsequently every 3 months routinely. World Health Organization (WHO) tumor response on imaging was determined for measurable lesions (>1 cm) by using the cross-product of perpendicular diameters. “Complete response” was defined as a change in the sum of the cross-products to zero (in other words, a 100% reduction), “partial response” as a decrease in the sum of cross-products by at least 50%, “stable disease” as a decrease in the sum of cross-products by less than 50% or an increase less than 25%, and “progression” as an increase in the sum of cross-products by at least 25%. The European Association for the Study of Liver Disease (EASL) modification of WHO was also implemented. Tumors exhibiting significant lack of enhancement (>50% necrosis) and reduction in vascularity following treatment were categorized as EASL-responders.14 Dosimetry. TheraSphere (MDS Nordion, Ottawa, Canada) consists of insoluble glass microspheres where 90Y is an integral constituent of the glass.16, 17 The mean sphere diameter ranges from 20 to 30 μm. 90Y is a pure beta emitter with a 64.1-hour physical half-life. Six activity sizes are available: 3 GBq (81 mCi), 5 GBq (135 mCi), 7 GBq (189 mCi), 10 GBq (270 mCi), 15 GBq (405 mCi), and 20 GBq (540 mCi). The corresponding number of microspheres per vial is 1.2, 2, 2.8, 4, 6, and 8 million, respectively. Hence, depending on the vial infused and the time of the week, different levels of radioembolic effects are generated. When treatments are performed later in the week, a greater radioembolic effect is achieved for any given activity infused.18 The radiation activity per microsphere is approximately 2500 Bq at the time of calibration. Assuming 90Y microspheres distribute in a uniform manner throughout the liver, the radioactivity required to deliver the desired dose to the liver can be calculated using the following formula: Activity (GBq) = [D (Gy) × M (kg)]/50 When liver shunt fraction and system residual are taken into account, the actual dose delivered to the target mass becomes: D (Gy) = [A (GBq) * 50 * (1−lung shunt fraction) * (1 − residual)]/M (kg) Where A is actual activity delivered to the target, D is the absorbed delivered dose to the target liver mass, and M is target liver mass. Liver mass (kg) is estimated by obtaining 3-dimensional volumes (cc) of the liver target with CT, then converted to mass using a conversion factor of 1.03 g/cc.17, 18 Radiation-induced gastrointestinal injury (ulceration, cholecystitis) and radiation pneumonitis represent possible toxicities associated with radioembolization. For this reason, all patients underwent 99technetium-labeled microaggregate array (technetium-99m macroaggregated albumin) scanning prior to treatment to assess the degree of gastrointestinal uptake lung shunting. Previous preclinical and clinical studies with 90Y microspheres have demonstrated that up to 30 Gy to the lungs could be tolerated with a single injection, and up to 50 Gy for multiple injections.19 In cases where several treatments are administered, the lung dose is the cumulative absorbed lung radiation dose from all treatments and should not exceed 50 Gy. Results Patient Demographics. There were 37 (34%) patients with PVT and 71 (66%) patients without PVT. The median age of the entire cohort was 69 years (range, 28-92). Most were male (69%) and white (85%), with the remainder comprising African-American (9%), Hispanic (2%), Asian (2%), and other (2%). Age, sex, and ethnic distribution were similar between the 2 treatment centers. Baseline Disease/Tumor Characteristics. Patient baseline characteristics and anatomic location of PVT are presented in Table 1. Liver tumor burden at baseline for the total patient cohort included 90 patients (83%) with less than 50% burden and 18 patients (17%) with greater than 50% burden. A higher proportion of patients with PVT presented with a tumor burden of 50% or greater compared with patients with no PVT (P = 0.0025). A baseline transaminase greater than 5× upper limit of normal was rare (n = 5, 5%). Similarly, baseline serum bilirubin elevation greater than 2 mg/dL was present in 10 patients on the day of therapy (9.3%) (all patients had a bilirubin of ≤2 mg/dL at the time of enrollment). Most patients had good hepatic reserve and performance status as shown by the percentage of patients with Okuda Stage 1 disease (n = 63, 58%) and ECOG Grade ≤ 2 (n = 103, 95%). Causes of liver disease included alcohol, alcohol + hepatitis C virus, hepatitis C virus, hepatitis B virus, cryptogenic cirrhosis, and unknown. Evidence of cirrhosis was present in 82 patients (76%) defined by cirrhotic morphology on imaging or the presence of portal hypertension (hepatofugal flow, gastrointestinal varices or splenomegaly). Limited extrahepatic disease was noted in 13 patients (12%) [(lymph node > 2 cm; n = 5), (small lung nodule, n = 3), (adrenal; n = 1), (solitary bone lesion; n = 4)]. The anatomic location of PVT in the 37 patients was most commonly the right portal vein (n = 21, 57%). Six PVT (16%) occurred at the level of the bifurcation into the right and left main branches (main PVT). In the remaining 10 patients, the location of PVT was distributed amongst the main, left + main, right + main, and right + left + main anatomic segments. The diagnosis of HCC was confirmed by biopsy in 90 cases (83%), 2 coincidental imaging techniques in 13 (12%), and 1 imaging technique with associated elevated alpha fetoprotein in 5 (5%).14 Table 1. Patient Baseline/Tumor Characteristics Characteristic N (%) No PVT PVT Total P Value Number of patients 1 (66) 37 (34) 108 Tumor burden (%) 0.0025 < 50 65 (92) 25 (68) 90 ≥ 50 6 (8) 12 (32) 18 Median (% burden) 21 36 25 Pretreatment bilirubin > 2 mg/dL 0.0298 Yes 3 (4) 7 (19) 10 No 68 (96) 30 (81) 98 OKUDA stage 0.0401 I 46 (65) 17 (46) 63 II 25 (35) 18 (49) 43 III 0 2 (5) 2 ECOG score 0.1858 0 39 (55) 16 (43) 55 1 30 (42) 18 (49) 48 2 2 (3) 3 (8) 5 Portal hypertension 0.0152 Present 32 (45) 26 (70) 58 Absent 39 (55) 11 (30) 50 Etiology 0.0222 Alcohol 10 (14) 13 (35) 23 Alcohol + HCV 17 (24) 3 (8) 20 HCV 16 (23) 3 (8) 19 HBV 4 (6) 5 (14) 9 Cryptogenic cirrhosis 14 (20) 7 (19) 21 Unknown 10 (14) 6 (16) 16 Table 2 lists the baseline characteristics of the patients with cirrhosis (n = 82, 76%) with and without PVT. Most were Okuda stage 1 (n = 47, 57%), Child-Pugh A (n = 54, 66%), and had baseline bilirubin of ≤2 mg/dL (n = 72, 88%) and evidence of portal hypertension (n = 58, 71%). Baseline bilirubin greater than 2 mg/dL and evidence of portal hypertension were significantly higher in those with PVT versus no PVT (P = 0.0324 and 0.0160, respectively). Table 3 lists the baseline characteristics of the patients without cirrhosis (n = 26, 24%) with and without PVT. Most were Okuda stage 1 (n = 16, 62%), and all had a baseline bilirubin of 2 mg/dL or less (n = 26, 100%). Table 2. Patient Baseline/Tumor Characteristics/with Cirrhosis Characteristic N (%) No PVT PVT Total P Value Number of patients 52 (63) 30 (37) 82 Tumor burden (%) <0.001 > 50 50 (96) 20 (67) 70 ≥ 50 2 (4) 10 (33) 12 Median (% burden) 19 31 25 AST/ALT > 5× ULN 0.1364 Yes 1 (2) 3 (10) 4 No 51 (98) 27 (90) 78 Pretreatment bilirubin > 2 mg/dL 0.0324 Yes 3 (6) 7 (23) 10 No 49 (94) 23 (77) 72 OKUDA stage 0.0947 I 33 (63) 14 (47) 47 II 19 (37) 14 (47) 33 III 0 2 (7) 2 Child-Pugh class 0.1591 A 37 (71) 17 (57) 54 B 15 (29) 12 (40) 27 C 0 1 (3) 1 ECOG score 0.1790 0 28 (54) 12 (40) 40 1 23 (44) 16 (53) 39 2 1 (2) 2 (7) 3 PVT location n.e. None 52 (100) - 52 PVT present 30 (100) Right - 17 (57) Left - 2 (7) Main - 3 (10) Right/main - 2 (7) Left/main - 0 Right/left/main - 6 (20) Portal hypertension 0.0160 Present 32 (62) 26 (87) 58 Absent 20 (38) 4 (13) 24 Etiology 0.0146 Alcohol 9 (17) 12 (40) 21 Alcohol + HCV 13 (25) 3 (10) 16 HCV 14 (27) 3 (10) 17 HBV 2 (4) 5 (17) 7 Cryptogenic cirrhosis 14 (27) 7 (23) 21 Abbreviation: n.e., cannot be estimated. Table 3. Patient Baseline/Tumor Characteristics/Without Cirrhosis Characteristic N (%) No PVT PVT Total P Value Number of patients 19 (73) 7 (27) 26 Tumor burden (%) 1.0000 < 50 15 (79) 5 (71) 20 ≥ 50 4 (21) 2 (29) 6 Median (% burden) 25 49 25 AST/ALT > 5× ULN 0.2692 Yes 0 1 (14) 1 No 19 (100) 6 (86) 25 Pretreatment bilirubin > 2 mg/dL n.e. Yes 0 0 0 No 19 (100) 7 (100) 26 OKUDA stage 0.2439 I 13 (68) 3 (43) 16 II 6 (32) 4 (57) 10 III 0 0 0 ECOG score 0.8430 0 11 (58) 4 (57) 15 1 7 (37) 2 (29) 9 2 1 (5) 1 (14) 2 PVT location n.e. None 19 (100) - 19 PVT present 7 (100) Right - 4 (57) Left - 2 (29) Main - 0 Right/main - 0 Left/main - 1 (14) Right/left/main - 0 Portal hypertension n.e. Present 0 0 0 Absent 19 (100) 7 (100) 26 Etiology 0.4128 Alcohol 1 (5) 1 (14) 2 Alcohol + HCV 4 (21) 0 4 HCV 2 (11) 0 2 HBV 2 (11) 0 2 Unknown 10 (53) 6 (86) 16 Abbreviation: n.e., cannot be estimated. Treatment. The summary of dosimetry is presented in Table 4. Seventy-three patients (68%) underwent 1 treatment. Two treatments were administered to 34 patients (31%). Only 1 patient (<1.0%) received 3 treatments. The median first treatment dose was 131.4 Gy. The median first dose administered to the PVT and non-PVT groups were 134.4 and 129.6 Gy, respectively. For the entire cohort, patients with PVT were administered slightly higher cumulative doses (139.7 Gy) than patients without PVT (131.9 Gy). This difference was not statistically different (P = 0.2022). In some cases, the clinician elected to use a lower dose than that specified in the package insert to minimize radiation exposure to normal liver tissue. Because of the hypervascularity of the tumor and resulting uptake of 90Y concentrated in the tumor, a tumoricidal dose was delivered with minimal radiation to normal tissue. Furthermore, in cases of variant anatomy (for exanmple, medial and lateral branches to the left lobe), it is possible that that tumor was perfused by more than 1 vessel. Since the tumor bed was perfused by 2 vessels with independent origins, 2 infusions were required, with selective placement of the catheter in the feeding vessel. Thus, a smaller target area was exposed to radiation, resulting in a dose higher than that specified in the package insert. Table 4. Dosimetry Characteristic No PVT PVT Total P Value Number of Patients 71 (66) 37 (34) 108 Total no. of treatment cycles/patient N (%) 0.0021 1 55 (77) 18 (49) 73 (68) 2 16 (23) 18 (49) 34 (31) 3 0 1 (3) 1 (<1) First treatment dose (Gy) Median (range) 129.6 (31–244) 134.4 (38–192) 131.4 (31–244) 0.4764 Accumulated dose (Gy) Median (range) 131.9 (31–266) 139.7 (48–305) 134.4 (31–305) 0.2022 Table 5 summarizes the doses received by the patients with cirrhosis. There was no significant difference in the accumulated dose received when comparing the PVT and no-PVT patients (P = 0.3191). Table 6 summarizes the dosimetry data in the patients without cirrhosis. Although the no-PVT patients received more treatment cycles (P = 0.0077), the accumulated dose was no different between the groups (P = 0.2035). Table 5. Dosimetry/with Cirrhosis Characteristic No PVT PVT Total P-value Number of patients 52 (63) 30 (37) 82 Total no. of treatment cycles/patient N (%) 0.0296 1 41 (79) 17 (57) 58 (71) 2 11 (21) 12 (40) 23 (28) 3 0 1 (3) 1 (1) First treatment dose (Gy) Median (range) 129.3 (31–177) 131.2 (48–192) 130.4 (31–192) 0.6614 Accumulated dose (Gy) Median (range) 131.7 (31–251) 136.8 (48–305) 132.9 (31–305) 0.3191 Table 6. Dosimetry/Without Cirrhosis Characteristic No PVT PVT Total P Value No. of patients 19 (73) 7 (27) 26 Total # of treatment cycles/patient N (%) 0.0077 1 14 (74) 1 (14) 15 (58) 2 5 (26) 6 (86) 11 (42) 3 0 0 0 First treatment dose (Gy) Median (range) 131.8 (93 – 244) 141.4 (38 – 182) 135.3 (38 – 244) 0.2981 Accumulated dose (Gy) Median (range) 134.8 (109 – 266) 144.8 (86 – 169) 139.6 (86 – 266) 0.2035 Treatment-Related Clinical Adverse Events. Clinical AEs were classified into gastrointestinal, hematologic, pulmonary, renal, and infectious. There was one case each of radiation cholecystitis, spontaneous bacterial peritonitis, pleural effusion, and hepatorenal syndrome. Vague abdominal pain was reported as a treatment-related AE in 10 patients (9%). There were no cases of radiation-induced gastritis or pneumonitis. There were no grade 4 events related to the lungs. One grade
