Regorafenib is an oral multi-kinase inhibitor that is used in the therapy of refractory metastatic colorectal cancer, hepatocellular carcinoma and gastrointestinal stromal tumor. Regorafenib has been associated with frequent serum aminotransferase elevations during therapy and with rare, but sometimes severe and even fatal instances of clinically apparent liver injury.
Regorafenib (re goe raf’ e nib) is an orally available, small molecule, multi-specific kinase inhibitor with activity against vascular endothelial growth factors (VEGF) receptors -1, -2 and -3, as well as against the receptor for platelet derived growth factor (PDGF) and several RAF kinases, c-Kit and TIE2. Inhibition of these kinases decreases angiogenesis, which plays an important role in the growth and spread of several forms of solid tumors. Regorafenib received approval for use in the United States in 2012 for therapy of metastatic colorectal cancer and advanced, unresectable gastrointestinal stromal tumors after failure of other antineoplastic agents. Indications were extended in 2017 to include refractory hepatocellular carcinoma. Regorafenib is available in tablets of 40 mg under the brand name Stivarga. The typical dose is 160 mg once daily for 21 days in 28 day cycles continued until there is tumor progression or unacceptable toxicity. Side effects are common and can include fatigue, diarrhea, anorexia, weight loss, nausea, abdominal pain, hand-foot syndrome, hypertension, mucositis, dysphonia, infections, rash and fever. Uncommon, but potentially severe side effects include bleeding, poor wound healing, gastrointestinal perforation and fistula, hypertension, severe skin toxicities, cardiac ischemia and reversible posterior leukoencephalopathy syndrome.
In large clinical trials of regorafenib, elevations in serum aminotransferase levels were common, occurring in 39% to 45% of patients, and were greater than 5 times the upper limit of normal (ULN) in 3% to 6%. In addition, there have been several reports of clinically apparent liver injury arising during regorafenib therapy which was often severe and occasionally fatal, estimated to occur in 0.3% of treated subjects. For these reasons, routine monitoring of liver enzymes is recommended. Regorafenib induced liver injury can present in several different patterns or phenotypes. Some patients present within a few days of starting regorafenib with acute hepatic necrosis, high levels of serum aminotransferase and lactic dehydrogenase with mild jaundice, but prolongation of INR and signs of hepatic failure. The injury can be severe but is generally self-limited and recovery is rapid and complete. Other patients present with an acute viral hepatitis like pattern, hepatocelllar (or mixed) serum enzyme elevations and jaundice that can be prolonged and has been fatal in several instances. Autoimmune and immunoallergic features are uncommon. In addition, rare instances of regorafenib associated liver injury have presented with a sinusoidal obstruction-like syndrome or pseudocirrhosis, with marked hepatic nodularity and ascites that eventually improves or resolves. Finally, regorafenib, like other multi-kinase inhibitors [sunitinib, imatinib, sorafenib], has also been associated with episodes of hyperammonemic coma generally arising within a few days or weeks of starting and with rapid reversal upon stopping treatment.
Likelihood score: B (highly likely cause of clinically apparent liver injury).
Mechanism of Injury
The cause of serum enzyme elevations and liver injury during regorafenib therapy is not known. Regorafenib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic intermediate. Because regorafenib inhibits multiple kinases, it may interfere with normal hepatocyte pathways involved in cell metabolism, injury and repair making the cell injury multifactorial. In addition, because regorafenib is metabolized by CYP 3A4, it is susceptible to drug-drug interactions with agents that inhibit or induce this hepatic microsomal enzyme.
Outcome and Management
Routine monitoring of liver tests before and every two weeks during the first 2 months of treatment as well as regularly thereafter is recommended for patients receiving regorafenib. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to at least temporary cessation, and elevations accompanied by jaundice or symptoms to permanent discontinuation. It is not clear whether such monitoring is effective in preventing regorafenib liver injury, but early discontinuation is likely to be helpful in limiting the severity and consequences of the injury. Regorafenib has been implicated in cases of acute liver failure, but not in instances of chronic hepatitis or vanishing bile duct syndrome. There does not appear to be cross reactivity in risk for hepatic injury between regorafenib and other multi-kinase inhibitors such axitinib, sorafenib and sunitinib, but caution and careful monitoring should be used in regarding a kinase inhibitor after clinically apparent liver injury from regorafenib.
Case 1. Pseudocirrhosis due to regorafenib.
[Modified from a case in the database of the Drug-Induced Liver Injury Network]
A 58 year old man with advanced and refractory leiomyosarcoma with metastases to the liver, lungs and bones was placed on an experimental protocol with regorafenib. Within a week of starting the multikinase inhibitor he developed fatigue, nausea, abdominal pain, dark urine and jaundice. Serum enzyme levels were elevated before starting treatment and had increased minimally but bilirubin rose precipitously from 0.6 to 5.3 mg/dL. He had no previous history of liver disease, alcohol abuse or risk factors for viral hepatitis. His other medical conditions included anxiety, insomnia, hypothyroidism and essential hypertension. Regorafenib was stopped and he was followed as an outpatient but admitted one week later when bilirubin had risen to 9.3 mg/dL, prothrombin time increased to 1.3 and peripheral enema, anasarca and ascites developed. He had a prolonged hospital stay with diuretic therapy, paracentesis for ascites, opiates for pain and further investigations that identified brain metastases. Tests for hepatitis A, B, C and E were negative as were autoantibodies. Imaging of the liver showed the previously noted liver metastases but no evidence of biliary obstruction. After several months, jaundice and ascites began to improve. He was discharged to hospice care and died approximately 5 months after onset of jaundice.
||Regorafenib 160 mg daily for 7 days
||4+ (jaundice, coagulopathy, ascites)
||Partial recovery 3 months
||amlodipine, lisinopril, hydrochlorothiazide, labetalol, levothyroxine, alprazolam, diazepam, ondansetron, oxycodone,
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Ultrasound, INR 1.3
||Ascites, albumin 2.8
||INR 1.7, albumin 2.3
A dramatic onset of jaundice within a week of starting regorafenib for metastatic leiomyosarcoma that was rapidly followed by ascites and anasarca. This rapid presentation of what seems to be decompensated cirrhosis is typical of "pseudocirrhosis" complicating high potent targeted anticancer therapy in patients with hepatic metastases. Most evidence suggests that the syndrome is due to rapid shrinkage of tumor resulting in a nodular, somewhat atrophic liver with hepatic synthetic failure and portal hypertension. The majority of patients improve or appear to recover completely, although progress of the metastatic liver disease frequently results in mortality soon after the onset of liver disease. Other interpretations of this course of injury are progression of the metastatic disease and possibly another form of superimposed drug induced liver injury (from labetolol for instance). Neither of these possibilities appear likely. The lack of evidence of biliary obstruction and the eventual resolution of the jaundice and ascites are not well explained by these other possibilities.
REPRESENTATIVE TRADE NAMES
Regorafenib – Stivarga®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO.
References updated: 06 June 2018
Abbreviations: GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma.
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