Acute Liver Failure Due to Regorafenib May Be Caused by Impaired Liver Blood Flow: a Case Report

ANTICANCER RESEARCH 35: 4037-4042 (2015)

Acute Liver Failure Due to Regorafenib May Be Caused by Impaired Liver Blood Flow: A Case Report

TAKAKI AKAMINE, KOJI ANDO, EIJI OKI, HIROSHI SAEKI, YUICHIRO NAKASHIMA, YU IMAMURA, KIPPEI OHGAKI and YOSHIHIKO MAEHARA

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Abstract. Background/Aim: Regorafenib has been approved Regorafenib, an oral inhibitor of several protein kinases for treatment of patients with unresectable or recurrent involved in tumor growth and angiogenesis, was recently gastrointestinal stromal tumors resistant to imatinib or approved to treat patients with unresectable and recurrent sunitinib. However, regorafenib has severe side-effects, GISTs resistant to imatinib or sunitinib. Regorafenib was including acute liver failure. We describe the case of a patient found to significantly enhance progression-free survival with multiple liver metastases of a small intestinal stromal compared to placebo in patients with metastatic GIST after tumor who experienced acute liver failure while being treated progression on imatinib and sunitinib (6). However, the with regorafenib. Case Report: A 50-year-old patient with an incidence of adverse events was high, with side-effects unresectable small intestinal stromal tumor resistant to prior observed in 93% of patients. The most common side-effects treatment with imatinib and sunitinib was started on of regorafenib included hand-foot syndrome (45.0%), regorafenib, but experienced acute liver failure 10 days later. diarrhoea (33.8 %), decreased appetite (30.4%), fatigue Plasma exchange and steroid pulse treatment improved her (29.0%), dysphonia (28.4%), hypertension (27.8%), and rash liver function. During liver failure, abdominal ultrasonography (22.6%). The most severe side-effect was liver failure, with showed to-and-fro flow in the portal vein. Lactate two Japanese patients dying of severe liver failure. Acute dehydrogenase concentration was markedly elevated to 1633 liver failure induced by regorafenib is of hepatocellular type U/l. These findings indicate that liver failure in this patient (6-8), but its precise mechanism is not known. was due to impaired liver blood flow. Conclusion: Regorafenib This report describes a patient with GIST of the small may impair liver blood flow, inducing acute liver failure. intestine who experienced severe liver failure due to regorafenib. Ultrasonography showed to-and-fro flow in the Gastrointestinal stromal tumors (GISTs) are among bloodstream, and blood tests showed elevated lactate mesenchymal tumors that occur in the gastrointestinal tract. dehydrogenase (LDH) concentrations, indicating that GISTs arise from the interstitial cells of Cajal, which are impaired liver blood flow resulted in severe liver failure. To present in the neuroplexus of the digestive tract wall (1, 2). our knowledge, this is the first report to show that liver The treatment- of- choice for primary GIST is surgery, with failure due to regorafenib resulted from impaired liver chemotherapy prescribed for patients with recurrent or blood flow. unresectable GIST. The treatment for unresectable and recurrent GISTs was revolutionized by the introduction of Case Report inhibitors of KIT and platelet-derived growth factor receptor- α (PDGFRA) kinase, such as imatinib (3, 4) and sunitinib A 50-year-old woman with a good performance status was (5). Unfortunately however, most tumors develop resistance admitted to our Department in 2007 with a stomach tumor. to these agents. She was diagnosed with a tumor of the small intestine and underwent partial resection of the intestine. The tumor was pathologically diagnosed as GIST. Two years later, GIST recurrence was found in S6 of the liver, and she underwent Correspondence to: Eiji Oki, MD, Ph.D., Department of Surgery partial resection of the liver. In 2011, many new liver and Science, Graduate School of Medical Sciences, Kyushu metastases were observed. As these tumors were University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 821-8582, unresectable, the patient was treated with imatinib and Japan. Tel: +81 926425466, Fax: +81 926425482, e-mail: [email protected] sunitinib. She achieved a partial response and underwent partial liver resection for these metastases. An examination Key Words: GIST, regorafenib monotherapy, liver failure, case report. in February 2014 showed multiple liver metastases (Figure

0250-7005/2015 $2.00+.40 4037 ANTICANCER RESEARCH 35: 4037-4042 (2015)

Figure 1. Multiple liver metastases before regorafenib treatment. Magnetic resonance imaging shows multiple liver metastases in S2, S4, S7 and S8.

1). As these tumors could not be resected, the patient was markedly elevated, at 1633 U/l (Figure 2). These results started on chemotherapy with regorafenib (160 mg/day). Ten indicated that regorafenib-induced acute liver failure in this days after starting regorafenib, the patient visited our patient was due to impaired liver blood flow. Outpatient Clinic with a high fever of 40˚C and general Her liver function improved three days after plasma fatigue. Blood tests showed elevated hepatic enzymes, exchange (Figure 2). The patient was moved back to the including aspartate aminotransferase (AST) and alanine ward 10 days after emergency treatment, 20 days after aminotransferase (ALT) concentrations of 145 U/l and 103 starting regorafenib. She now attends an Outpatient Clinic U/l, respectively, and a low platelet count of 54000/μl undergoing strict follow-up. (Figure 2). She was immediately hospitalized and started on liver support therapy with ursodeoxycholic acid, while Discussion regorafenib was stopped. However, her liver function seriously worsened four days This report describes a patient with multiple liver metastases after admission, 15 days after starting regorafenib (Figure 2). of a GIST of the small intestine who experienced acute liver She was moved to the Intensive Care Unit, where she was failure due to regorafenib administration. treated with plasma exchange and steroid pulse therapy (1 Regorafenib inhibits several tyrosine kinases, including g/day) for three days. At that time, abdominal VEGFR, TIE2, c-KIT, rearrangement during transfection ultrasonography showed to-and-fro flow in the portal vein (RET), v-raf murine sarcoma viral oncogene homolog B1 (Figure 3), an indicator of impaired hepatic blood flow, and (BRAF), PDGFR and fibroblast growth factor receptor her lactate dehydrogenase (LDH) concentration was (FGFR). VEGFR and TIE2 are associated with

4038 Akamine et al: Regorafenib May Cause Impaired Liver Flow

Figure 2. Effects of treatment on concentrations of the liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-bil) and lactate dehydrogenase (LDH), and on platelet counts. LDH was significantly elevated 16 days after starting regorafenib treatment.

angiogenesis; c-KIT, RET and BRAF with tumor Drug-induced liver failure can be classified into three progression; and PDGFR and FGFR are growth factor groups: hepatocellular, cholestatic, and mixed type. receptors. Regorafenib is used to treat patients with Regorafenib induces hepatocellular-type failure. Findings in recurrent or unresectable colorectal cancer, and GIST. The our patient, including the highly elevated LDH level and to- CORRECT study showed that regorafenib has survival and-fro flow in the portal vein, indicate that regorafenib may benefits in patients with metastatic colorectal cancer whose have impaired liver blood flow, resulting in severe liver disease progressed after all standard therapies (7). In dysfunction. addition, the GRID trial showed that regorafenib can LDH, an enzyme found in almost all tissues in the body, significantly improve progression-free survival compared to plays an important role in cellular respiration. Although LDH placebo in patients with metastatic GIST after progression is abundant in tissue cells, its levels in blood are normally on standard treatments (6). low. However, tissues damaged by injury or disease release Despite its activity in patients with colorectal cancer and LDH into the bloodstream. Conditions that increase LDH in GIST, regorafenib has many side-effects, the most severe the blood include liver disease, heart attack, anaemia, muscle being liver failure. An analysis of Japanese and non-Japanese trauma, bone fractures, cancer, and infections such as sub-populations in the CORRECT study found that meningitis, encephalitis and HIV. The combination of a two- indicators of liver failure, including elevated ALT (and AST) to five-fold elevation in LDH with elevations in enzymes concentrations, were frequently observed in Japanese related to liver function indicates both necrotic and patients (9). Moreover, one Japanese patient experienced obstructive liver disease (10). The to-and-fro flow observed lethal liver dysfunction related to regorafenib. by ultrasonography is indicative of impaired blood flow in

4039 ANTICANCER RESEARCH 35: 4037-4042 (2015)

Figure 3. Ultrasonography of the portal vein, showing the to-and-fro flow pattern indicative of impaired blood flow in the liver.

the liver. Chemotherapy, including treatment with Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, actinomycin, azathioprine, dacarbazine, 6-thioguanine, 6- Corless C, Fletcher CD and Joensuu H: Efficacy and safety of mercaptopurine, and cyclophosphamide has been shown to imatinib mesylate in advanced gastrointestinal stromal tumors. The New England journal of medicine 347(7): 472-480, 2002. impair liver blood flow and induce veno-occlusive disease 4 Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay (11, 12). Our findings suggested that regorafenib may also JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke cause veno-occlusive disease. M, Bertulli R and Judson I: Progression-free survival in In conclusion, we described a patient with GIST of the gastrointestinal stromal tumors with high-dose imatinib: small intestine who experienced acute liver failure after randomised trial. Lancet 364(9440): 1127-1134, 2004. regorafenib treatment. Regorafenib may impair liver blood 5 Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, flow, resulting in severe liver failure. Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM and Casali PG: Efficacy and safety of sunitinib in References patients with advanced gastrointestinal stromal tumor after failure of imatinib: a randomised controlled trial. Lancet 1 Kindblom LG, Remotti HE, Aldenborg F and Meis-Kindblom 368(9544): 1329-1338, 2006. JM: Gastrointestinal pacemaker cell tumor (GIPACT): 6 Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, gastrointestinal stromal tumors show phenotypic characteristics Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu of the interstitial cells of Cajal. The American journal of H, Badalamenti G, Blackstein M, Le Cesne A, Schöffski P, Maki pathology 152(5): 1259-1269, 1998. RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, 2 Robinson TL, Sircar K, Hewlett BR, Chorneyko K, Riddell RH Kuss I, Laurent D, Casali PG and GRID study investigators: and Huizinga JD: Gastrointestinal stromal tumors may originate Efficacy and safety of regorafenib for advanced gastrointestinal from a subset of CD34-positive interstitial cells of Cajal. The stromal tumors after failure of imatinib and sunitinib (GRID): an American journal of pathology 156(4): 1157-1163, 2000. international, multicentre, randomised, placebo-controlled, phase 3 Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, III trial. Lancet 381(9863): 295-302, 2013. Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, 7 Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis

4040 Akamine et al: Regorafenib May Cause Impaired Liver Flow

A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, 11 Czauderna P, Katski K, Kowalczyk J, Kurylak A, Lopatka B, Cihon F, Cupit L, Wagner A, Laurent D and CORRECT Study Skotnicka-Klonowicz G. Sawicz-Birkowska K and Godziński J: Group: Regorafenib monotherapy for previously treated Venoocclusive liver disease (VOD) as a complication of metastatic colorectal cancer (CORRECT): an international, management in the series of consecutive 206 patients. Eur J multicentre, randomised, placebo-controlled, phase III trial. Pediatr Surg 10(5): 300-303, 2000. Lancet 381(9863): 303-12, 2013. 12 Ortega JA, Donaldson SA, Ivy SP, Pappo A and Maurer HM. 8 Mieke De Wit, Christine B. Boers-Doets, Alessandra Saettini, Venoocclusive disease of the liver after chemotherapy with Kristina Vermeersch, Carmen Roncero de Juan, Jan Ouwerkerk, vincristine, actinomycin D, and cyclophosphamide for the See-See Raynard, Ashley Bazin and Chiara Cremolini: treatment of rhabdomyosarcoma. Cancer 79(12): 2435-2439, Prevention and management of adverse events related to 1997. regorafenib. Support Care Cancer 22(3): 837-846, 2014. 9 Yoshino T, Komatsu Y, Yamada Y, Yamazaki K, Tsuji A, Ura T, Grothey A, Van Cutsem E, Wagner A, Cihon F, Hamada Y and Ohtsu A: Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non- Japanese subpopulations. Investigational new drugs Epub in Sep 2014. 10 Henry JB: Clinical Diagnosis and Management by Laboratory Received March 28, 2015 Methods. 20th Edition. Philadelphia, PA: W. B. Saunders Revised April 30, 2015 Company, 2001. Accepted May 4, 2015

4041