[186900148]
Mfr report number: 3002124543-2020-00006. (b)(4). Sae: liver abscess (liver abscess) cholecystitis (cholecystitis) this report concerns subject (b)(4), a male subject born in (b)(6), who was enrolled in study (b)(6) entitled "(b)(6) evaluating therasphere? In subjects with metastatic colorectal carcinoma of the liver who has failed first line chemotherapy". The subject was randomized to receive treatment with therasphere? For metastatic colorectal carcinoma and second-line chemotherapy. On (b)(6) 2016, the subject received treatment with total 1 vial of therasphere? In the right hepatic lobe (lot no 1699117, expiry date: 13 may 2016) at a dose of 110 gy. The subject commenced the first cycle of study second line therapy folfox regimen on (b)(6) 2016. The folfox regimen was (oxaliplatin 148. 75 mg iv, folinic acid 700 mg iv, fluorouracil bolus 700 mg iv and fluorouracil 4200 mg iv continuous infusion). On (b)(6) 2016 the subject was also started on avastin (bevacizumab) from the second cycle of study second line therapy with total dose of 325 mg iv. Avastin was not administered from the sixth ((b)(6) 2016) through eighth ((b)(6) 2016) cycle and tenth ((b)(6) 2016) through twelfth cycle ((b)(6) 2016). On (b)(6) 2016, the subject received the most recent cycle (12) of folfox regimen (oxaliplatin 141. 10 mg iv, folinic acid 664 mg iv, fluorouracil bolus 664 mg iv and fluorouracil 3984 mg iv continuous infusion which completed on (b)(6) 2016). Subject medical history included cholecystitis. Concomitant medications included emconcor (bisoprolol), totalip (atorvastatin), asaflow (acetylsalicylic acid) and coruno (molsidomine). On (b)(6) 2016, ct images showed potential metastases. On (b)(6) 2016, pet-ct scan confirmed possibly radiation necrosis. The subject has been complaining of pain in the upper abdomen since (b)(6) 2016. On (b)(6) 2016, computed tomography (ct) showed dilatation of the bile duct in the left lobe. On (b)(6) 2016, ct performed showed intra and extra hepatic biliary engorgement and cholecystitis was suspected. The subject also had persistent high values for ast (aspartate amino transferase) 142 u/l (normal range 19-48 u/l), alt (alanine amino transferase) 165 u/l (normal range 10-40 u/l), alp (alkaline phosphatase) 803 u/l (normal range 40-129 u/l) and total bilirubin 1. 26 mg/dl (normal value 0. 2 - 1. 1 mg/dl mg/dl). On (b)(6) 2016, mri showed a significant stricture of the common bile duct. On (b)(6) 2016, laboratory values showed ast 135 u/l (normal range 15-40 u/l), alt 134 u/l (normal range 10-40 u/l), alp 1039 u/l (normal range 40-129 u/l), ldh (lactate dehydrogenase) 238 u/l (normal range 135-225 u/l), gamma glutamyl transferase 2007 u/l (normal range <60 u/l, c-reactive protein 19 mg/l (normal value <5 mg/l), total bilirubin 1. 54 mg/dl (normal value 0. 2 - 1. 1 mg/dl) and direct bilirubin 1. 39 mg/dl (normal value <0. 30 mg/dl). On the same day, the subject was examined with ultrasound (us) examination for right upper quadrant pain and abnormal blood liver tests. The us showed a globally thickened and irregularly shaped gallbladder wall. There seemed to be sludge and possibly also lithiasis in the lumen. A ductal intraluminal stent did seem to function well, there was no biliary tree dilatation. On (b)(6) 2016, the event was diagnosed as cholecystitis and the subject was treated with diclophenac (diclofenac) 75 mg, tradanol odis (tramadol) 50 mg and zaldiar (acetaminophen). On (b)(6) 2016, the subject was hospitalized for cholecystitis. On (b)(6) 2016, a cholecystectomy was performed. During cholecystectomy the subject seemed to have a necrotic gallbladder wall. Pathologic examination revealed chronic cholecystitis with complete necrosis of the wall. There was no proof of malignancy. On (b)(6) 2016, the subject recovered with sequelae of liver abscess as complication of the event of cholecystitis and was discharged from the hospital on the same day. On (b)(6) 2016, c-reactive protein was 47 mg/dl (normal range: <5) on (b)(6) 2016, an ultrasound echography of the liver revealed a liver abscess. On (b)(6) 2016, laboratory test showed ast 82 u/l, alt 101 u/l, alp 1711 u/l and total bilirubin 0. 97 mg/dl. On (b)(6) 2016, the subject was hospitalized for liver abscess. C-reactive protein was 172 mg/dl (normal range: <5). Antibiotic therapy and anti-fungal treatment were initiated on the same day. The subject was initially treated with levofloxacin and metronidazole. On (b)(6) 2016, c-reactive protein was 122 mg/dl (normal range: <5). On (b)(6) 2016, drainage for liver abscess was introduced. After diagnosis of colonization with c. Albicans, treatment was shifted to iv levofloxacin-clindamycin and fluconazole. This treatment was continued until the day of discharge from the hospital (17 dec 2016), when the subject recovered with sequelae. On (b)(6) 2016, c-reactive protein was 17 mg/dl (normal range: <5). The subject continued participation in the study. Treatment with second line therapy folfox was discontinued in response to the event. The investigator assessed the event of cholecystitis as grade iii (severe), serious due to hospitalization of the subject and other liver abscess caused. The event was assessed as probably related to study device and procedure. The event was also considered as possibly related to the second line chemotherapy (folfox). The investigator assessed the event of liver abscess as grade iv, serious due to hospitalization of the subject. The event was assessed as probably related to study device and study procedure. The event was also considered as possibly related to the second line chemotherapy (folfox). Radio-embolization was done on (b)(6) 2016. 1) three necrotic areas developed shortly after therasphere? Administration (ct images dated (b)(6) 2016). These were firstly considered as potential metastases, but later by pet-ct scan confirmed possibly to correspond to radiation necrosis. ((b)(6) 2016). 2) ct performed on (b)(6) 2016 showed cicatricial deformation of the target lesions (segments 4, 6 and 7). The aforementioned hypo dense lesions ("necrotic areas") seemed to have vanished. 3) the investigator supposed that, in parallel with the radiation treatment with 90-yttrium, radiation damage occurred at the level of the gall bladder. Investigator did not succeed to find glass particles in the resected gallbladder fragments. However, they found a concentration of radiation in segment 4 of the liver at the time of the sirt. The post-sirt-radio-isotope-measurement of bremsstrahlung did show the margin of the radiation field may have crossed the gallbladder wall. 4) also, as seen on mri of (b)(6) 2016: a significant stricture of the common bile duct was seen. Investigator compared the cross-sectional medical imaging with the last pet-scan and have concluded: a) the region of the proximal common bile duct stricture is not contiguous with the region of 90-yttrium irradiation. They hypothesize that the bile duct stricture had been caused by ischemia due to the intra-arterial embolization during the pre-sirt-angio. Investigator mentioned that subject had an aberrant anatomy of some upper abdominal arterial vessels. B) the liver abscess is located on a certain distance from the applied irradiation and from the gall bladder resection region. Abscedation must be consequence of cholangitis due to the common bile duct stricture and may be due to suboptimal gall drainage by the first stent. C) the investigator was not able to discriminate whether the cholecystitis was caused by leakage of therasphere? Device through the arteria cystica or has also been caused by devascularization of the arteria cystic during embolization procedure. D) there is actually -after comparison of all medical imaging- no prove that the abscess has been directly caused by superinfection of a region of radiation necrosis. In the blood cultures strep. Anginosus and clostridium perfringens were found. Later on, c. Albicans was found in the drainage fluid of the collection. The investigator believes that the liver collection, has been consequence of cholangitis. Actually it is not possible to exclude a possible link of the liver collection with events at the time point of the cholecystectomy. E) in any case, it should not be forgotten that this chain of saes did happen in a subject that was already heavily pretreated with chemotherapy, which can induce chronic parenchymal damage. The investigator concluded that etiology of this liver abscess is directly related to cholangitis and probably and indirectly related the yttrium-90-radioembolization. On one end, the bile duct stricture is most probably an ischemic event. On the other hand, the cholecystitis can be related to radiation damage or ischemia. An important precipitating factor for the liver abscess is probably the heavily pretreated liver parenchyma of the liver that may include chronic chemotherapy-induced liver damage. The company agreed with the investigator's assessment. No additional information is expected at this time.
Patient Sequence No: 1, Text Type: D, B5