478 Case report
Axitinib-induced acute pancreatitis: a case report Julien Pe´rona, Safia Khenifera, Vale´rie Potierb, Thierry Vitryc, Florian Pasqueta, Robin Rassata and Michel Pavica Axitinib is an oral second-generation selective inhibitor of vascular endothelial growth factor receptors recently approved for the treatment of advanced renal cell carcinoma. Numerous cases of acute pancreatitis have been reported after treatment with nonselective tyrosine kinase inhibitors such as sorafenib and sunitinib. We present the first report of a patient under axitinib treatment presenting with acute pancreatitis for which no other etiology has been found. The patient was a 29-yearold woman treated for renal cell carcinoma. The patient had no history of chronic illness, gallstone-related disease, or alcohol consumption. She had been previously treated with sunitinib and everolimus. Four months after the onset of axitinib treatment she was hospitalized for acute pancreatitis. Symptoms and blood lipase levels
Introduction Axitinib is an oral second-generation selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. It was approved in 2012 for the treatment of advanced renal cell carcinoma as it has been shown to improve the progression-free survival of patients compared with sorafenib [1,2]. Common adverse events associated with axitinib include diarrhea, hypertension, hand–foot syndrome, decreased appetite, nausea, and fatigue [3]. Numerous cases of acute pancreatitis have been reported after treatment with nonselective tyrosine kinase inhibitors such as sorafenib and sunitinib [4–8]. We present the case of a patient under axitinib treatment presenting with acute pancreatitis for which no other etiology has been found.
Case report A 29-year-old woman was treated for renal cell carcinoma. The patient had no history of chronic illness and was a nonsmoker. Metastatic relapse occurred 2 years following a nephrectomy for locally advanced renal cancer. The patient presented with bone and lung metastases. She was first treated with sunitinib for 8 months. Because of the occurrence of nephrotic syndrome, severe hypothyroidism, and grade 3 fatigue, treatment with sunitinib was discontinued. The best recorded response after initiating treatment with sunitinib was stable disease. The patient was then treated with everolimus, but the disease continued to progress after 3 months of therapy. Axitinib was proposed to the patient as a third line of treatment. At the onset of axitinib treatment, the patient had a good functional status (ECOG score 1) and c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-4973
normalized within a few days after axitinib was withheld. We believe that acute pancreatitis should be recognized as a potential axitinib-related adverse event. Anti-Cancer c 2014 Wolters Kluwer Health | Drugs 25:478–479 Lippincott Williams & Wilkins. Anti-Cancer Drugs 2014, 25:478–479 Keywords: acute pancreatitis, adverse effects, axitinib, renal cell carcinoma Departments of aOncology and Internal Medicine, bDigestive Diseases and cRadiology, Desgenettes Hospital, University of Lyon, Lyon, France Correspondence to Julien Pe´ron, MD, Department of Oncology, Desgenettes Hospital, University of Lyon, 108 Boulevard Pinel, 69003 Lyon, France Tel: + 33 6 16 25 89 91; fax: + 33 4 72 36 25 26; e-mail: [email protected] Received 22 November 2013 Revised form accepted 15 December 2013
recovered from the toxicity of the previous therapies. The dose of axitinib was increased after 14 days from 5 mg twice daily to 7 mg twice daily. The best objective response was stable disease. During the first 4 months of treatment, the patient experienced only mild to moderate adverse events (fatigue grade 2 and mucositis grade 1). Four months after the onset of axitinib therapy, the patient was hospitalized in the Internal Medicine Department for abdominal pain and vomiting. Importantly, her only medication at the time of presentation was L-thyroxine and pantoprazole. The patient was not a consumer of alcohol. The pain began in the epigastric area and moved to the lower right abdomen after 2 days. The patient had no fever and no sign of bowel obstruction. White blood cell count was elevated at 10.3 109/l, hematocrit (43%; reference range: 37–48%) and platelet counts were normal (308 000 mm3; reference range: 150–400 000 mm3). Creatinine was at its baseline level of 96 mmol/dl. Liver function tests were normal. The amount of lipase was elevated at 654 U/l (reference range: 73–393 U/l). Blood glucose level was within the normal range. The level of C-reactive protein was elevated at 398 mg/l. Calcium, triglyceride, and immunoglobulin G4 levels were within normal ranges. An abdominal ultrasound determined that the gallbladder was acalculous and free from sludge. A 48-h delayed computed tomography (CT) scan of the abdomen revealed low-density edema and an enlarged pancreatic head, with an infiltration of surrounding fat and right perinephric fluid collection (Fig. 1). The CT scan revealed no evidence of gallstones, cholecystitis, or choledocholithiasis. DOI: 10.1097/CAD.0000000000000076
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Axitinib-induced acute pancreatitis Pe´ron et al. 479
Fig. 1
∗
The 48-h delayed computed tomography (CT) scan of the abdomen revealed low-density edema and an enlarged head of the pancreas (*), with an infiltration of surrounding fat and right perinephric fluid collection (arrow). The CT scan revealed no evidence of gallstones, cholecystitis, or choledocholithiasis.
As far as we know, this is the first report of axitinibinduced pancreatitis. In the absence of any other recognized etiology, one might deduce that the case of pancreatitis presented here was likely caused by axitinib. The rapid clinical and biological recovery of the patient after axitinib discontinuation was another argument to attribute the pancreatitis to axitinib intake [12]. This adverse event was reported to the pharmacovigilance center and to the vigilance and safety services of the relevant pharmaceutical company. We believe that physicians should anticipate acute pancreatitis when patients present with acute abdominal pain on treatment with axitinib, and, more generally, all tyrosine kinase inhibitors. We also believe that acute pancreatitis should be added to the list of potential axitinib-related adverse events with unknown frequency.
Acknowledgements Dr Julien Pe´ron is the recipient of a grant from the Nuovo-Soldati research foundation.
The abdominal MRI revealed no evidence of cholangitis and no evidence of a pancreatic tumor. The patient was requested to fast, with fluid hydration and administration of electrolytes and pain medication as needed until symptom relief, and axitinib was withheld. Symptoms and blood lipase levels normalized within a few days. After discharge from the hospital, there was no rechallenge with axitinib. Sorafenib was introduced as fourth-line treatment. Pancreatic enzymes have maintained a normal level after 2 months of this treatment.
Discussion Sorafenib and sunitinib are multikinase inhibitors and have been associated with pancreatitis in numerous clinical reports. The mechanism remains unclear but might include pancreatic ischemia as a part of the antiangiogenic effect [9] and a reduction in the protective effect of VEGF and platelet-derived growth factor, which would increase the severity of pancreatitis [10]. It has also been hypothesized that kinase inhibitors may cause gastrointestinal motility abnormalities that, in turn, may result in a reflux of the duodenal contents into the pancreatic duct [11]. Whether acute pancreatitis due to tyrosine kinase inhibitors is associated only with sorafenib and sunitinib or may also be caused by other drugs of the same class remains an open question. It is unclear whether the mechanism is common to all anti-VEGF tyrosine kinase inhibitors. Axitinib is a selective tyrosine kinase inhibitor of VEGF receptors and has been shown to significantly inhibit VEGFmediated endothelial cell proliferation and survival. Axitinib might then induce acute pancreatitis following the same mechanism as sorafenib and sunitinib.
Conflicts of interest
There are no conflicts of interest.
References 1
Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013; 14:552–562. 2 Facchini G, Perri F, Caraglia M, Pisano C, Striano S, Marra L, et al. New treatment approaches in renal cell carcinoma. Anticancer Drugs 2009; 20:893–900. 3 European Medicines Agency. Axitinib – summary of product characteristics. 2013. Available at: http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Product_Information/human/002406/ WC500132188.pdf. [Accessed date 13 October 2013]. 4 European Medicines Agency. Sorafenib – summary of product characteristics. 2013. Available at: http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Product_Information/human/000690/ WC500027704.pdf. [Accessed date 13 October 2013]. 5 European Medicines Agency. Sunitinib – summary of product characteristics. 2013. Available at: http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Product_Information/human/000687/ WC500057737.pdf. [Accessed date 13 October 2013]. 6 Pezzilli R, Corinaldesi R, Morselli-Labate AM. Tyrosine kinase inhibitors and acute pancreatitis. JOP 2010; 11:291–293. 7 Saadati H, Saif MW. Sorafenib-induced acute pancreatitis. JOP 2010; 11:283–284. 8 Sevin A, Chen A, Atkinson B. Tyrosine kinase inhibitor induced pancreatitis. J Oncol Pharm Pract 2013; 19:257–260. 9 Ueda T, Takeyama Y, Yasuda T, Matsumura N, Sawa H, Nakajima T, et al. Vascular endothelial growth factor increases in serum and protects against the organ injuries in severe acute pancreatitis. J Surg Res 2006; 134:223–230. 10 Pierce GF, Mustoe TA, Lingelbach J, Masakowski VR, Griffin GL, Senior RM, et al. Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms. J Cell Biol 1989; 109:429–440. 11 Li M, Srinivas S. Acute pancreatitis associated with sorafenib. South Med J 2007; 100:909–911. 12 Badalov N, Baradarian R, Iswara K, Li J, Steinberg W, Tenner S. Druginduced acute pancreatitis: an evidence-based review. Clin Gastroenterol Hepatol 2007; 5:648–661.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Axitinib-induced acute pancreatitis: a case report Julien Pe´rona, Safia Khenifera, Vale´rie Potierb, Thierry Vitryc, Florian Pasqueta, Robin Rassata and Michel Pavica Axitinib is an oral second-generation selective inhibitor of vascular endothelial growth factor receptors recently approved for the treatment of advanced renal cell carcinoma. Numerous cases of acute pancreatitis have been reported after treatment with nonselective tyrosine kinase inhibitors such as sorafenib and sunitinib. We present the first report of a patient under axitinib treatment presenting with acute pancreatitis for which no other etiology has been found. The patient was a 29-yearold woman treated for renal cell carcinoma. The patient had no history of chronic illness, gallstone-related disease, or alcohol consumption. She had been previously treated with sunitinib and everolimus. Four months after the onset of axitinib treatment she was hospitalized for acute pancreatitis. Symptoms and blood lipase levels
Introduction Axitinib is an oral second-generation selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. It was approved in 2012 for the treatment of advanced renal cell carcinoma as it has been shown to improve the progression-free survival of patients compared with sorafenib [1,2]. Common adverse events associated with axitinib include diarrhea, hypertension, hand–foot syndrome, decreased appetite, nausea, and fatigue [3]. Numerous cases of acute pancreatitis have been reported after treatment with nonselective tyrosine kinase inhibitors such as sorafenib and sunitinib [4–8]. We present the case of a patient under axitinib treatment presenting with acute pancreatitis for which no other etiology has been found.
Case report A 29-year-old woman was treated for renal cell carcinoma. The patient had no history of chronic illness and was a nonsmoker. Metastatic relapse occurred 2 years following a nephrectomy for locally advanced renal cancer. The patient presented with bone and lung metastases. She was first treated with sunitinib for 8 months. Because of the occurrence of nephrotic syndrome, severe hypothyroidism, and grade 3 fatigue, treatment with sunitinib was discontinued. The best recorded response after initiating treatment with sunitinib was stable disease. The patient was then treated with everolimus, but the disease continued to progress after 3 months of therapy. Axitinib was proposed to the patient as a third line of treatment. At the onset of axitinib treatment, the patient had a good functional status (ECOG score 1) and c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-4973
normalized within a few days after axitinib was withheld. We believe that acute pancreatitis should be recognized as a potential axitinib-related adverse event. Anti-Cancer c 2014 Wolters Kluwer Health | Drugs 25:478–479 Lippincott Williams & Wilkins. Anti-Cancer Drugs 2014, 25:478–479 Keywords: acute pancreatitis, adverse effects, axitinib, renal cell carcinoma Departments of aOncology and Internal Medicine, bDigestive Diseases and cRadiology, Desgenettes Hospital, University of Lyon, Lyon, France Correspondence to Julien Pe´ron, MD, Department of Oncology, Desgenettes Hospital, University of Lyon, 108 Boulevard Pinel, 69003 Lyon, France Tel: + 33 6 16 25 89 91; fax: + 33 4 72 36 25 26; e-mail: [email protected] Received 22 November 2013 Revised form accepted 15 December 2013
recovered from the toxicity of the previous therapies. The dose of axitinib was increased after 14 days from 5 mg twice daily to 7 mg twice daily. The best objective response was stable disease. During the first 4 months of treatment, the patient experienced only mild to moderate adverse events (fatigue grade 2 and mucositis grade 1). Four months after the onset of axitinib therapy, the patient was hospitalized in the Internal Medicine Department for abdominal pain and vomiting. Importantly, her only medication at the time of presentation was L-thyroxine and pantoprazole. The patient was not a consumer of alcohol. The pain began in the epigastric area and moved to the lower right abdomen after 2 days. The patient had no fever and no sign of bowel obstruction. White blood cell count was elevated at 10.3 109/l, hematocrit (43%; reference range: 37–48%) and platelet counts were normal (308 000 mm3; reference range: 150–400 000 mm3). Creatinine was at its baseline level of 96 mmol/dl. Liver function tests were normal. The amount of lipase was elevated at 654 U/l (reference range: 73–393 U/l). Blood glucose level was within the normal range. The level of C-reactive protein was elevated at 398 mg/l. Calcium, triglyceride, and immunoglobulin G4 levels were within normal ranges. An abdominal ultrasound determined that the gallbladder was acalculous and free from sludge. A 48-h delayed computed tomography (CT) scan of the abdomen revealed low-density edema and an enlarged pancreatic head, with an infiltration of surrounding fat and right perinephric fluid collection (Fig. 1). The CT scan revealed no evidence of gallstones, cholecystitis, or choledocholithiasis. DOI: 10.1097/CAD.0000000000000076
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Axitinib-induced acute pancreatitis Pe´ron et al. 479
Fig. 1
∗
The 48-h delayed computed tomography (CT) scan of the abdomen revealed low-density edema and an enlarged head of the pancreas (*), with an infiltration of surrounding fat and right perinephric fluid collection (arrow). The CT scan revealed no evidence of gallstones, cholecystitis, or choledocholithiasis.
As far as we know, this is the first report of axitinibinduced pancreatitis. In the absence of any other recognized etiology, one might deduce that the case of pancreatitis presented here was likely caused by axitinib. The rapid clinical and biological recovery of the patient after axitinib discontinuation was another argument to attribute the pancreatitis to axitinib intake [12]. This adverse event was reported to the pharmacovigilance center and to the vigilance and safety services of the relevant pharmaceutical company. We believe that physicians should anticipate acute pancreatitis when patients present with acute abdominal pain on treatment with axitinib, and, more generally, all tyrosine kinase inhibitors. We also believe that acute pancreatitis should be added to the list of potential axitinib-related adverse events with unknown frequency.
Acknowledgements Dr Julien Pe´ron is the recipient of a grant from the Nuovo-Soldati research foundation.
The abdominal MRI revealed no evidence of cholangitis and no evidence of a pancreatic tumor. The patient was requested to fast, with fluid hydration and administration of electrolytes and pain medication as needed until symptom relief, and axitinib was withheld. Symptoms and blood lipase levels normalized within a few days. After discharge from the hospital, there was no rechallenge with axitinib. Sorafenib was introduced as fourth-line treatment. Pancreatic enzymes have maintained a normal level after 2 months of this treatment.
Discussion Sorafenib and sunitinib are multikinase inhibitors and have been associated with pancreatitis in numerous clinical reports. The mechanism remains unclear but might include pancreatic ischemia as a part of the antiangiogenic effect [9] and a reduction in the protective effect of VEGF and platelet-derived growth factor, which would increase the severity of pancreatitis [10]. It has also been hypothesized that kinase inhibitors may cause gastrointestinal motility abnormalities that, in turn, may result in a reflux of the duodenal contents into the pancreatic duct [11]. Whether acute pancreatitis due to tyrosine kinase inhibitors is associated only with sorafenib and sunitinib or may also be caused by other drugs of the same class remains an open question. It is unclear whether the mechanism is common to all anti-VEGF tyrosine kinase inhibitors. Axitinib is a selective tyrosine kinase inhibitor of VEGF receptors and has been shown to significantly inhibit VEGFmediated endothelial cell proliferation and survival. Axitinib might then induce acute pancreatitis following the same mechanism as sorafenib and sunitinib.
Conflicts of interest
There are no conflicts of interest.
References 1
Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013; 14:552–562. 2 Facchini G, Perri F, Caraglia M, Pisano C, Striano S, Marra L, et al. New treatment approaches in renal cell carcinoma. Anticancer Drugs 2009; 20:893–900. 3 European Medicines Agency. Axitinib – summary of product characteristics. 2013. Available at: http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Product_Information/human/002406/ WC500132188.pdf. [Accessed date 13 October 2013]. 4 European Medicines Agency. Sorafenib – summary of product characteristics. 2013. Available at: http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Product_Information/human/000690/ WC500027704.pdf. [Accessed date 13 October 2013]. 5 European Medicines Agency. Sunitinib – summary of product characteristics. 2013. Available at: http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Product_Information/human/000687/ WC500057737.pdf. [Accessed date 13 October 2013]. 6 Pezzilli R, Corinaldesi R, Morselli-Labate AM. Tyrosine kinase inhibitors and acute pancreatitis. JOP 2010; 11:291–293. 7 Saadati H, Saif MW. Sorafenib-induced acute pancreatitis. JOP 2010; 11:283–284. 8 Sevin A, Chen A, Atkinson B. Tyrosine kinase inhibitor induced pancreatitis. J Oncol Pharm Pract 2013; 19:257–260. 9 Ueda T, Takeyama Y, Yasuda T, Matsumura N, Sawa H, Nakajima T, et al. Vascular endothelial growth factor increases in serum and protects against the organ injuries in severe acute pancreatitis. J Surg Res 2006; 134:223–230. 10 Pierce GF, Mustoe TA, Lingelbach J, Masakowski VR, Griffin GL, Senior RM, et al. Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms. J Cell Biol 1989; 109:429–440. 11 Li M, Srinivas S. Acute pancreatitis associated with sorafenib. South Med J 2007; 100:909–911. 12 Badalov N, Baradarian R, Iswara K, Li J, Steinberg W, Tenner S. Druginduced acute pancreatitis: an evidence-based review. Clin Gastroenterol Hepatol 2007; 5:648–661.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
