MAUDE Adverse Event Report: BIOCOMPATIBLES UK LTD THERASPHERE; YTTRIUM-90 GLASS MICROSPHERES, PRODUCT CODE: NAW, PRODUCT

Model Number UNKNOWN

Device Problem Adverse Event Without Identified Device or Use Problem (2993)

Patient Problems Hyperbilirubinemia (1903); Pneumonia (2011); Ascites (2596)

Event Type  Injury  

Manufacturer Narrative

Company medical assessment comments: this article presents the safety and adverse events associated with the combination of checkpoint inhibitors (nivolumab +/- ipilimumab) immunotherapy and radioembolization for patients with hcc.All patients included in the study received therasphere.This single-center retrospective study.26 consecutive patients (18 males and 8 females;median 66 years of age, range 34-86 years of age) with hcc who received therapy consisting of sirt combined with systemic immune checkpoint inhibitor.Immunotherapy between april 2015 and may 2018.Population: patients were bclc c or bclc b and child pugh score a-b7 and tumor volume representing <50% of the total liver volume, patients were intolerant of or ineligibility for sorafenib.Prior to radioembolization, 11 patients had received other local therapy for hcc, including resection, ablation, trans-arterial chemoembolization, or sbrt.4 patients received sorafenib prior to radioembolization or immunotherapy.5 patients (19%) bclc b received systemic immunotherapy within 90 days after sirt treatments: 44 sirt were performed in 26 patients.9 patients received 1 sirt, 16 patients received 2 sirt, 1 patient received 3 sirt, the median number was 2 (range, 1-3).3 patients received sir-spheres and 23 patients were treated with therasphere lobar administrations were performed in 32 of the procedures (73%)with a median dose of 122 gy (93-145) segmental administrations were performed in 12 of the procedures (27%) with a median dose of 138 gy (117-543 gy).Activity delivered to the treatment site was 1.8 gbq (range, 0.3-5.6 gbq).18 patients received iv nivolumab, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity.8 patients received nivolumab, 3 mg/kg every 2 weeks, plus ipilimumab, 1 mg/kg every 6 weeks.Until disease progression or unacceptable toxicity.11 patients (42%) received immunotherapy prior to the first radioembolization; 15 patients (58%) received immunotherapy within 30 days of first radioembolization; 11 patients (42%) received immunotherapy 30-90 days after the first radioembolization.The median time between the first radioembolization and checkpoint inhibitor immunotherapy was 23.5 days (4.0-44.0) interquartile range [iqr], 44.5 days).Follow up: laboratory values and clinical status were recorded within 1 month before radioembolization.After radioembolization, at 1- and 3-month follow-up intervals.Imaging was performed at 1 and 3 months after radioembolization and were repeated approximately every 3 months.Results: median follow-up time for the patient cohort was 7.8 months (5.6-11.8 months), and all patients completed 30-day clinical follow-up, including laboratory assessments.A 30-day mortality rate after the first radioembolization was 0%, and no grade 3 or 4 hepatobiliary or immunotherapy related toxicities.One patient died approximately 60 days after radioembolization due to sepsis secondary to osteomyelitis, the patient had severe and poorly managed diabetes, and peripheral arterial disease (pad) with severe arterial insufficiency to both lower extremities that existed prior to treatment with therasphere.The osteomyelitis was secondary to his poorly controlled diabetes and pad, which then led to septicaemia.No bone surgery was performed.Grade 3 / 4 aes, occurred 1-3 months post first sirt.1 patient with grade 3 hyperbilirubinemia and grade 3 hypoalbuminemia (partial response and 22 days delay between sirt and io).1 patient developed grade 4 hyperbilirubinemia and grade 3 ascites (stable disease and start io 14 days before sirt).2 patients developed ascites that required paracentesis (stable disease, one started io 22 days before sirt and one 44 days after sirt).All these patients had significant disease progression so the toxicities were felt to be due to disease progression, not the device or procedure.1 patient developed pneumonitis 4 months after radioembolization and 1 month after start io.This patient had lung shunt of (30%) the pneumonitis resolved with steroid therapy.(partial response, started io 78 days after sirt).Providing that side effect of immunotherapy are immune related and are mainly alt/ast/alkaline phosphatase increase, less frequently ascites and elevated bilirubin.The liver side effect seems more device related than io related also for the pneumonitis, the introduction of io was 78 days after sirt (3.5 months) and the event occurred at 4 months, it is therefore unlikely that the event is io related and also patient had a ls of 30%.The reported events are anticipated events associated with sirt and are listed in the ifu/risk management documentation.No batch review was possible for these cases as the information is from literature and batch number information is not available.The devices will not be returned for evaluation.No corrective/preventative action has been identified.Should we receive any information to enable further investigations, a follow-up report will be submitted.At this time this report is considered final.

Event Description

Review of literature article: safety of combined yttrium-90 radioembolization and immune checkpoint inhibitor immunotherapy for hcc author: chenyang zhan, md, phd, david ruohoniemi, ba, krishna p.Shanbhogue, md, jason wei, ba, theodore h.Welling, md, ping gu, md, phd, james s.Park, md, nabil n.Dagher, md, bedros taslakian, md, and ryan m.Hickey, md et al.Purpose: to investigate the safety of yttrium-90 radioembolization in combination with checkpoint inhibitor immunotherapy for the treatment of hepatocellular carcinoma (hcc).Materials and methods: this single-center retrospective study included 26 consecutive patients with hcc who received checkpoint inhibitor immunotherapy within 90 days of radioembolization from april 2015 to may 2018.Patients had preserved liver function (child-pugh scores a-b7) and either advanced hcc due to macrovascular invasion or limited extrahepatic disease (21 patients) or aggressive intermediate stage hcc that resulted in earlier incorporation of systemic immunotherapy (5 patients).Clinical documentation, laboratory results, and imaging results at 1- and 3-month follow-up intervals were reviewed to assess treatment-related adverse events and treatment responses.Radioembolization technique: 23 patients were treated with glass microspheres (therasphere).Dosimetry was determined using the medical internal radiation dose method for the therasphere microspheres.Lung dose was calculated based on the estimated lung shunt fraction.Prescribed activity to the treatment site was reduced as necessary to maintain lung dose of <30 gy per treatment and 50 gy cumulatively.Lobar versus segmental injection of yttrium-90 microspheres was determined based on the ability to provide complete tumor perfusion.For lobar treatment with glass microspheres, an estimated lobar dose of 120 gy was calculated.For segmental injection, radiation segmentectomy dosimetry was not adopted until 2017.Patients with bilobar disease received separate treatments for each lobe approximately 4-6 weeks apart.Lobar administrations were performed in 32 of the procedures (73%)with a median dose of 122 gy (range, 93-145 gy), whereas segmental administrations were performed in 12 of the procedures (27%) with a median dose of 138 gy (range, 117-543 gy).The median activity delivered to the treatment site was 1.8 gbq (range, 0.3-5.6 gbq).Median lung shunt fraction was 5.0% (range, 1.4%-30.0%), and median dose to the lungs per treatment was 4.1 gy (range, 0.4-28.2 gy).Radioembolization procedures were performed by 1 of 6 operators with a median of 6 years of experience performing radioembolization.Immunotherapy: patients received intravenous nivolumab, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity occurred.For dual-agent immunotherapy regimens, patients received nivolumab, 3 mg/kg every 2 weeks, plus ipilimumab, 1 mg/kg every 6 weeks.Events: one patient died approximately 60 days after radioembolization due to sepsis secondary to osteomyelitis and did not complete the 3-month clinical follow-up or any imaging follow-up.Delayed grades 3 / 4 toxicities (1-3 months) occurred in 1 patient with grade 3 hyperbilirubinemia and grade 3 hypoalbuminemia and in a second patient with grade 4 hyperbilirubinemia both in the setting of disease progression.Three patients developed ascites that required paracentesis (the intervals between the first radioembolization and the first paracentesis were 57, 110, and 113 days), 1 of whom was also the patient who had developed grade 4 hyperbilirubinemia.One patient developed pneumonitis 4 months after radioembolization and 1 month after initiation of immunotherapy.This patient had a high lung shunt fraction (30%), and the prescribed activity had been reduced in order to maintain the estimated lung dose <30 gy.The pneumonitis resolved with steroid therapy.Additional information received from author as follows: all patients included in the study received therasphere as indicated in the materials & methods section.The incidences of hyperbilirubinemia and ascites all occurred in the setting of significant disease progression and was consistent with their burden of disease, so the toxicities were felt to be due to disease progression, not the device or procedure.Steroids would be considered medical intervention.It is unknown whether the pneumonitis was due to therasphere or immunotherapy, given that immunotherapy is known to cause pneumonitis as well.The time course would suggest immunotherapy, but there is no way to know for sure.None of the events were felt to be directly attributable to therasphere and therefore not reported.Additional information received from author 04-may-2020: the patient had severe and poorly managed diabetes, and peripheral arterial disease (pad) with severe arterial insufficiency to both lower extremities that existed prior to treatment with therasphere.The osteomyelitis was secondary to his poorly controlled diabetes and pad, which then led to septicaemia.No prior bone surgery.No causal link of osteomyelitis associated with therasphere administration.

• Brand Name: THERASPHERE
• Type of Device: YTTRIUM-90 GLASS MICROSPHERES, PRODUCT CODE: NAW, PRODUCT
• Manufacturer (Section D): BIOCOMPATIBLES UK LTD; chapman house farnham bus park; weydon lane; farnham, GU9 8 QL; UK GU9 8QL
• Manufacturer (Section G): BIOCOMPATIBLES UK; chapman house; weydon lane; farnham, surrey ; UK
• Manufacturer Contact: sandra bausback-aballo ; 300 four falls corporate cntr; 300 conshohocken state road; west conshohocken, pa ; 3311537
• MDR Report Key: 10023505
• MDR Text Key: 200978250
• Report Number: 3002124543-2020-00013
• Device Sequence Number: 1
• Product Code: NAW
• Combination Product (y/n): N
• Reporter Country Code: US
• PMA/PMN Number: H980006
• Number of Events Reported: 1
• Summary Report (Y/N): N
• Report Source: Manufacturer
• Source Type: health professional,literatur
• Reporter Occupation: Other Health Care Professional
• Type of Report: Initial
• Report Date: 04/27/2020

1 Device was Involved in the Event

1 Patient was Involved in the Event

• Date FDA Received: 05/05/2020
• Is this an Adverse Event Report?: Yes
• Is this a Product Problem Report?: No
• Device Operator: Health Professional
• Device Model Number: UNKNOWN
• Device Catalogue Number: N/A
• Device Lot Number: UNKNOWN
• Was Device Available for Evaluation?: No
• Is the Reporter a Health Professional?: Yes
• Date Manufacturer Received: 04/27/2020
• Was Device Evaluated by Manufacturer?: Device Not Returned to Manufacturer
• Is the Device Single Use?: Yes
• Is This a Reprocessed and Reused Single-Use Device?: No
• Type of Device Usage: Initial
• Patient Sequence Number: 1
• Patient Outcome(s): Required Intervention