| Device Problem
Adverse Event Without Identified Device or Use Problem (2993)
|
| Patient Problems
Abdominal Pain (1685); Fatigue (1849); Discomfort (2330); Toxicity (2333)
|
|
Event Type
Injury
|
|
Event Description
|
|
Hepatic cirrhosis [hepatic cirrhosis]; large biloma [biloma]; mildly active steatohepatitis [steatohepatitis]; progressive disease [disease progression]; damage to the biliary tree with elevated liver enzymes [biliary tract disorder]; postembolization liver edema [localised oedema]; abdominal pain [abdominal pain]; nausea [nausea]; therasphere use for metastatic pancreatic neuroendocrine tumors [off label use].Case description: initial information received on 11-may-2017: this literature report was received from a literature article by loree j.M., hiruki t., kennecke h.F entitled "case report of cirrhosis following yttrium-90 radioembolization for pancreatic neuroendocrine liver metastases" published in case reports in oncology journal concerning (b)(6) year-old female patient.The patient's medical history included metastatic pnet to the liver known since an unknown date.The patient did not drink alcohol excessively, performed no high-risk activities for viral hepatitis, and had no family history of liver disease.Serology was non reactive for hbsag, hbcab, and hepatitis c virus, and the patient had immunity to hepatitis b virus.Her antinuclear antibody was equivocal, and her anti-smooth muscle antibody and antimitochondrial antibody were negative.On an unknown date, the patient presented with abdominal discomfort and decreased appetite.Ultrasonography and computed tomography (ct) of the abdomen revealed a 9.5 x 8.6 x 10.5 cm, heterogeneous, hypervascular mass adjacent to the spleen and abutting the stomach wall and tail of the pancreas.Fine-needle aspiration guided by endoscopic ultrasound revealed cytologic evidence of a neuroendocrine tumor.The patient proceeded to a distal pancreatectomy, splenectomy, wedge resection of the stomach, and partial resection of the left adrenal gland.Pathology demonstrated a 13-cm, well-differentiated neuroendocrine tumor of the pancreas with perineural invasion, but no vascular invasion and negative margins.It was found to be adherent to both the spleen and the stomach, but did not invade either.Two lymph nodes were removed, and both were negative for metastases.It had a mitotic rate of 2 mitoses/high-power field and a ki-67 index of <2%.There were no signs of metastatic disease on staging.Two months postoperatively, the patient was found to have 4 subcentimeter hypervascular lesions in the liver which were 111in octreotide scan negative.Over the following 9 months, the patient developed 8 new lesions, while the original lesions increased to a maximum size of 1.2 cm.Therapy with octreotide lar 20 mg intramuscularly once monthly was initiated but discontinued after 9 months due to progressive hepatic disease.The patient subsequently underwent a bland embolization of the right hepatic artery.A ct scan of the liver performed 3 months after embolization demonstrated a mixed tumor response with the overall impression of progressive disease and development of new liver metastasis.The patient's concomitant medications were unknown.On an unknown date, prior to 90y therasphere treatment, there was no radiologic evidence of cirrhosis and the liver enzymes were within normal ranges (ast 24 u/l [normal range (n) 10-38 u/l], alt 36 u/l [n <50 u/l], alkaline phosphatase 156 u/l [n 50-200 u/l], total bilirubin 5 micromol/l [n 0-18 micromol/l]).She had a technetium-99 macroaggregate albumin planning spect ct demonstrating multiple focal regions of increased activity in the left and right lobes of the liver which corresponded to the patient's known metastases.On an unknown date, the patient received radioembolization with 90y therasphere (lot number and expiration date were unknown), liver-directed therapy for metastatic pnets without extrahepatic metastasis, 3.5 gbq to the right hepatic artery, delivering a total dose of 140 gy to the right lobe of the liver, and 1.8 gbq through the left hepatic artery with a dosing of 140 gy to the left lobe of the liver on the same day.Over the following 3 months, the patient developed abdominal pain [abdominal pain] and nausea [nausea] and was found to have elevated liver enzymes, in a pattern suggesting damage to the biliary tree (ast 52 u/l, alt 86 u/l, alkaline phosphatase 405 u/l, ggt 604 u/l, total bilirubin 5 micromol/l) [biliary tract disorder].Ct scanning of the abdomen demonstrated generalized mottling of the liver, compatible with postembolization edema [localised oedema] with a substantial decrease in tumor burden and 2 significant lesions remaining.A repeat 90y therasphere radioembolization focused on the residual lesions was not technically feasible.The patient's liver enzymes remained elevated over the following 6 months until she developed significant right upper quadrant pain.Nine (9) months after 90y therasphere treatment, a ct revealed a very inhomogeneous liver texture and a large biloma traversing segments 5 and 8 of the liver [biloma], measuring 8.5 x 6.5 x 5.5 cm.A radiographic impression of liver surface nodularity was noted.This was initially noted 10 months after 90y treatment and was slightly progressive on the 14-month scan.Imaging also demonstrated multiple subcentimeter right hepatic lesions raising concern for metastatic disease, some of which had not previously been seen.On an unknown date, due to radiographic evidence of progressive disease, the co-suspect drug everolimus 10 mg once daily was initiated, and the patient continued on this for 36 months with stabilization of the disease.Her liver enzymes remained unchanged over this time, with elevated hepatobiliary enzymes and borderline-elevated hepatocellular enzymes.At 25 months after initiation of everolimus therapy, progressive disease was noted in 2 solitary hepatic lesions and was treated with radiofrequency ablation.Due to disease control in the remainder of the hepatic parenchyma, everolimus was resumed after radiofrequency ablation.Thirty-five (35) months after initiation of everolimus therapy, radiographic note was made of the advanced cirrhotic appearance of the liver and the increase in size of a left hepatic lesion.There was no evidence of portal hypertension.Due to the radiographic evidence of progressive disease and the cirrhotic appearance of the liver, everolimus therapy was interrupted and a liver biopsy to further characterize the nature of the parenchymal disease was performed.A single 18-gauge core was obtained from the left lobe of the liver in order to avoid the biloma involving the right lobe.Non-tumor-containing tissue was biopsied.The biopsy demonstrated large fibrotic bands in keeping with cirrhosis with mildly active steatohepatitis (approx.10% macrovesicular steatosis)[steatohepatitis].The patient had not been started on any other new medications.Given the chronologic association of 90y therasphere administration with liver enzyme elevation, with the exclusion of other causes of cirrhosis, the diagnosis of 90y-induced cirrhosis [hepatic cirrhosis] was made.She has not suffered any cirrhosis-associated complications and is currently child-turcotte-pugh class a.The outcome of the events was unknown.The authors assessed the event hepatic cirrhosis as clinically relevant as it may influence therapy sequencing and did not provide any seriousness assessment of the other events.Given the timeline of patient's various treatments and the lack of any other identifiable etiology for cirrhosis, the authors believe this to be a potential long-term complication of y90 therasphere therapy.Imaging was reported as being consistent with prior radioembolization, with a progressive worsening noted over time.While differentiating this from cirrhosis is very difficult, the differential for these radiographic changes needs to include cirrhosis.The only other agent that could be chronologically associated with cirrhosis in this patient was everolimus; however, this was started after radiographic changes had already been seen in the liver.In addition, early preclinical work suggests that inhibition of the mtor pathway with mtor inhibitors may be antifibrotic.While the patient did not have steatosis severe enough to be considered solely responsible for the observed cirrhosis, it is possible that she suffered an initial insult from 90y therasphere administration and had impaired hepatic regeneration subsequently due to everolimus-induced steatosis, thus causing accelerated progression to cirrhosis.The company assessed the events hepatic cirrhosis, biloma, disease progression and steatohepatitis to be serious and the events biliary tract disorder, localised oedema, abdominal pain, nausea and off label use (therasphere use for metastatic pancreatic neuroendocrine tumors) to be non-serious.Follow-up information has been requested.Case comment: hepatic cirrhosis, biloma, steatohepatitis, disease progression and off label use were considered unanticipated according to therasphere current reference safety information whereas biliary tract disorder, abdominal pain, localised oedema and nausea were considered anticipated.The company considered that hepatic cirrhosis and biloma were possibly related to the administration of therasphere.Cirrhosis could be also due to disease progression therefore may be confounded and bilomas are very rarely reported.The company considered that biliary tract disorder, abdominal pain, nausea and localised oedema were related to the administration of therasphere whereas steatohepatitis was not related to the administration of therasphere and rather related to everolimus treatment.The company considered disease progression not related to the use of therasphere and rather related to underlying disease.Off label use is not an adverse event per se but special scenarios and therefore not assessable.There is no report of device failure 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.
|
| |
|
Event Description
|
|
Hepatic cirrhosis [hepatic cirrhosis].Large biloma [biloma].Mildly active (b)(6)].Progressive disease [disease progression].Damage to the biliary tree with elevated liver enzymes [biliary tract disorder].Postembolization liver edema [localised oedema].Abdominal pain [abdominal pain.] nausea [nausea.] therasphere use for metastatic pancreatic neuroendocrine tumors [off label use].Case description: initial information received on 11-may-2017: this literature report was received from a literature article by loree j.M., hiruki t., kennecke h.F entitled "case report of cirrhosis following yttrium-90 radioembolization for pancreatic neuroendocrine liver metastases" published in case reports in oncology journal concerning (b)(6) female patient.The patient's medical history included metastatic pnet to the liver known since an unknown date.The patient did not drink alcohol excessively, performed no high-risk activities for (b)(6), and had no family history of liver disease.Serology was (b)(6), and the patient had immunity to (b)(6).Her antinuclear antibody was equivocal, and her anti-smooth muscle antibody and antimitochondrial antibody were negative.On an unknown date, the patient presented with abdominal discomfort and decreased appetite.Ultrasonography and computed tomography (ct) of the abdomen revealed a 9.5 x 8.6 x 10.5 cm, heterogeneous, hypervascular mass adjacent to the spleen and abutting the stomach wall and tail of the pancreas.Fine-needle aspiration guided by endoscopic ultrasound revealed cytologic evidence of a neuroendocrine tumor.The patient proceeded to a distal pancreatectomy, splenectomy, wedge resection of the stomach, and partial resection of the left adrenal gland.Pathology demonstrated a 13-cm, well-differentiated neuroendocrine tumor of the pancreas with perineural invasion, but no vascular invasion and negative margins.It was found to be adherent to both the spleen and the stomach, but did not invade either.Two lymph nodes were removed, and both were negative for metastases.It had a mitotic rate of 2 mitoses/high-power field and a ki-67 index of <2%.There were no signs of metastatic disease on staging.Two months postoperatively, the patient was found to have 4 sub centimeter hypervascular lesions in the liver which were 111in octreotide scan negative.Over the following 9 months, the patient developed 8 new lesions, while the original lesions increased to a maximum size of 1.2 cm.Therapy with octreotide lar 20 mg intramuscularly once monthly was initiated but discontinued after 9 months due to progressive hepatic disease.The patient subsequently underwent a bland embolization of the right hepatic artery.A ct scan of the liver performed 3 months after embolization demonstrated a mixed tumor response with the overall impression of progressive disease and development of new liver metastasis.The patient's concomitant medications were unknown.On an unknown date, prior to 90y therasphere treatment, there was no radiologic evidence of cirrhosis and the liver enzymes were within normal ranges (ast 24 u/l [normal range (n) 10-38 u/l], alt 36 u/l [n <50 u/l], alkaline phosphatase 156 u/l [n 50-200 u/l], total bilirubin 5 micromol/l [n 0-18 micromol/l]).She had a technetium-99 macroaggregate albumin planning spect ct demonstrating multiple focal regions of increased activity in the left and right lobes of the liver which corresponded to the patient's known metastases.On an unknown date, the patient received radioembolization with 90y therasphere (lot number and expiration date were unknown), liver-directed therapy for metastatic pnets without extrahepatic metastasis, 3.5 gbq to the right hepatic artery, delivering a total dose of 140 gy to the right lobe of the liver, and 1.8 gbq through the left hepatic artery with a dosing of 140 gy to the left lobe of the liver on the same day.Over the following 3 months, the patient developed abdominal pain [abdominal pain] and nausea [nausea] and was found to have elevated liver enzymes, in a pattern suggesting damage to the biliary tree (ast 52 u/l, alt 86 u/l, alkaline phosphatase 405 u/l, ggt 604 u/l, total bilirubin 5 micromol/l) [biliary tract disorder].Ct scanning of the abdomen demonstrated generalized mottling of the liver, compatible with postembolization edema [localised oedema] with a substantial decrease in tumor burden and 2 significant lesions remaining.A repeat 90y therasphere radioembolization focused on the residual lesions was not technically feasible.The patient's liver enzymes remained elevated over the following 6 months until she developed significant right upper quadrant pain.Nine (9) months after 90y therasphere treatment, a ct revealed a very inhomogeneous liver texture and a large biloma traversing segments 5 and 8 of the liver [biloma], measuring 8.5 x 6.5 x 5.5 cm.A radiographic impression of liver surface nodularity was noted.This was initially noted 10 months after 90y treatment and was slightly progressive on the 14-month scan.Imaging also demonstrated multiple sub centimeter right hepatic lesions raising concern for metastatic disease, some of which had not previously been seen.On an unknown date, due to radiographic evidence of progressive disease, the co-suspect drug everolimus 10 mg once daily was initiated, and the patient continued on this for 36 months with stabilization of the disease.Her liver enzymes remained unchanged over this time, with elevated hepatobiliary enzymes and borderline-elevated hepatocellular enzymes.At 25 months after initiation of everolimus therapy, progressive disease was noted in 2 solitary hepatic lesions and was treated with radiofrequency ablation.Due to disease control in the remainder of the hepatic parenchyma, everolimus was resumed after radiofrequency ablation.Thirty-five (35) months after initiation of everolimus therapy, radiographic note was made of the advanced cirrhotic appearance of the liver and the increase in size of a left hepatic lesion.There was no evidence of portal hypertension.Due to the radiographic evidence of progressive disease and the cirrhotic appearance of the liver, everolimus therapy was interrupted and a liver biopsy to further characterize the nature of the parenchymal disease was performed.A single 18-gauge core was obtained from the left lobe of the liver in order to avoid the biloma involving the right lobe.Non-tumor-containing tissue was biopsied.The biopsy demonstrated large fibrotic bands in keeping with cirrhosis with mildly active (b)(6) (approx.10% macrovesicular steatosis)[(b)(6)].The patient had not been started on any other new medications.Given the chronologic association of 90y therasphere administration with liver enzyme elevation, with the exclusion of other causes of cirrhosis, the diagnosis of 90y-induced cirrhosis [hepatic cirrhosis] was made.She has not suffered any cirrhosis-associated complications and is currently child-turcotte-pugh class a.The outcome of the events was unknown.The authors assessed the event hepatic cirrhosis as clinically relevant as it may influence therapy sequencing and did not provide any seriousness assessment of the other events.Given the timeline of patient's various treatments and the lack of any other identifiable etiology for cirrhosis, the authors believe this to be a potential long-term complication of y90 therasphere therapy.Imaging was reported as being consistent with prior radioembolization, with a progressive worsening noted over time.While differentiating this from cirrhosis is very difficult, the differential for these radiographic changes needs to include cirrhosis.The only other agent that could be chronologically associated with cirrhosis in this patient was everolimus; however, this was started after radiographic changes had already been seen in the liver.In addition, early preclinical work suggests that inhibition of the mtor pathway with mtor inhibitors may be antifibrotic.While the patient did not have steatosis severe enough to be considered solely responsible for the observed cirrhosis, it is possible that she suffered an initial insult from 90y therasphere administration and had impaired hepatic regeneration subsequently due to everolimus-induced steatosis, thus causing accelerated progression to cirrhosis.The company assessed the events hepatic cirrhosis, biloma, disease progression and (b)(6) to be serious and the events biliary tract disorder, localised oedema, abdominal pain, nausea and off label use (therasphere use for metastatic pancreatic neuroendocrine tumors) to be non-serious.Follow-up information has been requested.Final assessment on 12-jun-2017: it should be noted the use of therasphere for treatment of pancreatic neuroendocrine liver metastases is considered off label/abnormal use.Follow up information has been sought to further investigate the events but no new information has been received.The physician has declined to provide any additional information, the case is considered lost to follow up.No device failure has been identified as a result of these adverse events.It has been assessed that no corrective action is necessary at this time and the report is considered final.Case comment: hepatic cirrhosis, biloma, (b)(6), disease progression and off label use were considered unanticipated according to therasphere current reference safety information whereas biliary tract disorder, abdominal pain, localised oedema and nausea were considered anticipated.The company considered that hepatic cirrhosis and biloma were possibly related to the administration of therasphere.Cirrhosis could be also due to disease progression therefore may be confounded and bilomas are very rarely reported.The company considered that biliary tract disorder, abdominal pain, nausea and localised oedema were related to the administration of therasphere whereas (b)(6) was not related to the administration of therasphere and rather related to everolimus treatment.The company considered disease progression not related to the use of therasphere and rather related to underlying disease.Off label use is not an adverse event per se but special scenarios and therefore not assessable.There is no report of device failure 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.
|
| |
|
Search Alerts/Recalls
|
|
