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Progressive hepatic decompensation/dysfunction [hepatic failure] cirrhosis-like morphology [liver disorder] intrahepatic biliary ductal dilatation [biliary dilatation] varices [varices oesophageal] ascites [ascites] significant increase in spleen volume [splenomegaly] more severe hyperbilirubinemia (>1 mg/dl) compared with baseline [hyperbilirubinaemia] significant serum platelet count reduction (from 255x10^9/l to 201x10^9/l; p<.023) [platelet count decreased] significant decrease in serum albumin level (from 3.4 g/dl to 2.9 g/dl; p<.0002) [blood albumin decreased] significant increase in aspartate aminotransferase level (from 27 u/l to 53 u/l; p<.0014) [aspartate amino transferase increased] significant increase in alkaline phosphatase level (from 110 u/l to 359 u/l; p<.00001) [blood alkaline phosphatase increased] tumour progression [neoplasm progression] off label use in patients with mnet to the liver [off label use of device] case description: initial information received on 25-jul-2017: this serious literature medical device report was received from a literature article by su yk.Et al.Entitled "long-term hepatotoxicity of yttrium-90 radioembolization as treatment of metastatic neuroendocrine tumor to the liver" concerning multiple patients (mean age 58 years (range, 27-85 y), 52% of the cohort was female).The patients' medical history included liver-dominant metastatic neuroendocrine tumors (mnet).The patients' concomitant medication was not provided.On unspecified dates, between 2003 and 2014, 154 patients received yttrium-90 (90y) radioembolization (therasphere) for liver-dominant metastatic neuroendocrine tumors [off label use of device].Mean radiation dose for each lobar treatment session was 114 gy (range, 11-340 gy).Two experienced interventional radiologists performed all radioembolization procedures.All patients underwent lobar treatments, and the mean radiation dose to each hepatic lobe was calculated.Fifty-four of the 154 patients had > 2-year imaging and clinical follow-up from the date of first radioembolization and were stratified into 2 groups: unilobar 90y treatment (n = 15) and sequential lobar (ie, whole-liver) 90y treatment (n = 39).Patients who underwent unilobar treatment did not undergo treatment to the contralateral lobe during the follow-up period.Patients with initial unilobar disease who subsequently showed disease progression that required contralateral lobar treatment were grouped in the whole-liver radioembolization group.Repeat treatments were allowed.The primary sites of mnets were the stomach in 2% (1 of 54), the colon in 2% (1 of 54), the small bowel in 35% (19 of 54), the pancreas in 35% (19 of 54), the lung in 11% (6 of 54), and an unknown primary lesion in 15% (8 of 54).Patients were seen in follow-up (at medical oncology and/or interventional radiology clinic) approximately 4 weeks, 3 months, and 6 months after radioembolization.After this, patients maintained a minimum of 6-month interval follow-up.All patients underwent imaging, laboratory, and clinical follow-up 2 years after the first radioembolization.Patients were followed until death by using the social security death index or via direct family confirmation regarding the date of death or last known follow-up clinic visit.Images were studied for development of a nodular cirrhosis-like morphology and/or signs of portal hypertension (ascites graded as trace, small, moderate, or large by the interpreting diagnostic radiologist; varices; and splenomegaly defined as > 12 cm in length).The distinction was made between the classical "cirrhotic" appearance as a result of infection (hepatitis b or c) or alcohol and the "cirrhosis-like" morphology caused by the postulated long-term radiation-induced liver injury from 90y.This concept of "pseudocirrhosis" has been previously described in the literature to differentiate the underlying cause of liver morphology that describes drug-induced hepatotoxicity, resulting in a nodular shrunken liver pattern in patients with metastatic breast cancer.Further analyses were performed by stratifying patients based on cirrhosis-like morphology and clinical symptoms of hepatic dysfunction into the following 3 groups: patients without cirrhosis-like morphology, patients with cirrhosis-like morphology without clinical implications, and patients with cirrhosis-like morphology with clinical implications.The mean radiation dose to each hepatic lobe was included in this analysis.Liver and spleen volumetric calculations were performed at baseline and at the most recent imaging follow-up.The hepatic hilum (main biliary ducts and vessels, eg, portal vein, hepatic artery), gallbladder, and inferior vena cava were excluded from the volumetric measurement.Of the patients with new cirrhosis-like liver morphology after 90y radioembolization, those with progressive clinical signs of liver decompensation from their most recent clinical visits were identified.Clinical symptoms of progressive hepatic decompensation were defined as worsening hepatic encephalopathy, jaundice, upper gastrointestinal bleeding, ascites, anasarca, or lower-extremity edema.Relevant but nonspecific symptoms such as anorexia, weight loss weakness, and fatigue were not included.On unknown dates, cirrhosis-like morphology developed in 22 of 39 patients (56.4%) [liver disorder] who underwent whole-liver 90y radioembolization, ascites developed in 16 of 39 (41.0%; n = 6 large, n = 4 moderate, n = 5 small, and n = 1 trace) [ascites], and varices developed in six of 39 (15.4%) [varices oesophageal].Compared with baseline, tumor progression had developed at the most recent follow-up in 18 patients (46.2%) [neoplasm progression] treated with whole-liver 90y radioembolization: 94.4% (17 of 18) had > 50% liver involvement, 66.7% (12 of 18) had > 75% liver involvement, including 2 patients with tumor invading the inferior vena cava and 1 patient with tumor invading the extrahepatic bile ducts, and the remaining 5.6% (1 of 18) had 25%-50% liver involvement.Nine of 39 patients (23.1%) showed new findings of intrahepatic biliary ductal dilation [biliary dilatation].5 developed in the setting of tumor progression compressing bile ducts, 2 were transient and remote from treatment, 1 patient had extraanatomic liver surgery that resulted in biliary injury, and 1 was remote from the 90y treatment site.There was no statistically significant change in whole liver volume for patients undergoing whole-liver (p =.433) or unilobar (p =.213) radioembolization.There was a significant increase in spleen volume (whole-liver, 64.7%, 335 cm3 vs 223 cm3, p =.0009; unilobar, 21.9%, 275 cm^3 vs 224 cm^3, p =.0464) [splenomegaly].For whole-liver 90y radioembolization treated patients there was a significant serum platelet count reduction (from 255 x 10^9/l to 201 x 10^9/l; p =.023) [platelet count decreased], decrease in serum albumin level (from 3.4 g/dl to 2.9 g/dl; p =.0002) [blood albumin decreased], increase in aspartate aminotransferase level (from 27 u/l to 53 u/l; p =.0014) [aspartate aminotransferase increased], and increase in alkaline phosphatase level (from 110 u/l to 359 u/l; p <.00001) [blood alkaline phosphatase increased].There were no statistically significant abnormalities in laboratory values for patients treated with unilobar 90y radioembolization.At the most recent follow-up, 14 of 54 total patients had more severe hyperbilirubinemia (> 1 mg/dl) compared with baseline [hyperbilirubinaemia].Of these 14 patients, 21.4% (n = 3) had developed biliary obstruction, 57.1% (n = 8) were exposed to systemic therapies, and 78.6% (n = 11) had tumor progression.Eight of 22 patients treated with whole-liver 90y radioembolization (20.5%) with new cirrhosis-like morphology on recent follow-up imaging exhibited worsening clinical symptoms of progressive hepatic decompensation [hepatic failure].Six of 8 patients (75%) with clinical progression correlating with imaging and laboratory findings of liver decompensation showed the development of hepatic tumor progression; all had > 50% tumor progression, and 4 had > 75% liver involvement.These 6 patients were subsequently exposed to hepatotoxic systemic therapies.Only 2 patients (5.1%) treated with whole-liver 90y radioembolization exhibited clinical progression of hepatic decompensation without another potential confounding cause.One patient died at 4.7 years, and the other at 3.8 years, after first 90y treatment.Four patients treated with unilobar 90y radioembolization had exhibited cirrhosis-like liver morphology on recent imaging, one of whom (25%) had clinical symptoms of hepatic decompensation.This patient had severe disease progression (> 90% liver involvement) with tumor invasion of the ivc.Only 2 patients in the present study exhibited clinical signs of hepatic dysfunction without other potential confounding factors.Both patients received whole-liver radioembolization, and both died of progressive hepatic dysfunction despite transjugular intrahepatic portosystemic shunt creation.The outcome of all other events was unknown.The reporter did not provide an assessment of the seriousness of the event intrahepatic biliary ductal dilation and assessed it as not related to the administration of therasphere.The reporter assessed the event progressive hepatic decompensation/dysfunction as serious (fatal) and related to the administration of therasphere.For all other events the reporter did not provide an assessment of the seriousness or causality to the therasphere.(clinically significant hepatotoxicity was solely attributed to 90y only when patients showed imaging and laboratory findings of portal hypertension with associated clinical symptoms of hepatic decompensation in the absence of other potentially confounding hepatic insults (disease progression and/or exposure to hepatotoxic drugs).The company assessed the events hepatic failure, liver disorder, varices oesophageal, biliary dilatation and ascites as serious, and the events splenomegaly, hyperbilirubinaemia, platelet count decreased, blood albumin decreased, aspartate aminotransferase increased, blood alkaline phosphatase increased, neoplasm progression and off label use of device as non-serious.Follow-up information will be requested.Company comment: hepatic failure, ascites, hyperbilirubinaemia, platelet count decreased, blood albumin decreased, aspartate aminotransferase increased, blood alkaline phosphatase increased were considered anticipated according to therasphere current reference safety information, whereas liver disorder, biliary dilatation, splenomegaly, varices oesophageal, and neoplasm progression were considered unanticipated.In the absence of an assessment made by the reporting author, the company considered the events liver disorder, ascites, splenomegaly, hyperbilirubinaemia, platelet count decreased, blood albumin decreased, aspartate aminotransferase increased and blood alkaline phosphatase increased related to the administration of therasphere.In the absence of an assessment made by the reporting author, the company considered the events neoplasm progression, splenomegaly and varices oesophageal not related to the administration of therasphere, but rather related to the underlying disease.In agreement with the assessment made by the reporter, the company considered the event hepatic failure related to the administration of therasphere.In agreement with the assessment made by the reporter, the company considered the event biliary dilatation not related to the administration of therasphere.The company considered off label use not an adverse event per se but a special scenario and therefore not assessable.There was no report of device deficiency or malfunction.This single case report does not modify the risk benefit balance of therasphere.The company is continuously monitoring all respective reports received and, based on cumulative experience, will re-evaluate the available evidence on an ongoing basis.
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