|Year : 2012 | Volume
| Issue : 2 | Page : 303-305
Severe perirenal hematoma in a patient with a single kidney treated with sunitinib for metastatic pancreatic neuroendocrine tumor
Jon Zugazagoitia1, Javier Sastre2, Jerónimo Barrera1, Beatriz García1, Eduardo Díaz-Rubio1
1 Department of Medical Oncology, Hospital Clinico San Carlos, Centeraffíliated to the Red Temática de Investigación Cooperativa (RD06/0020/0021). Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid, Spain
2 Department of Radiology, Hospital Clinico San Carlos, Centeraffíliated to the Red Temática de Investigación Cooperativa (RD06/0020/0021). Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid, Spain
|Date of Web Publication||26-Jul-2012|
Department of Medical Oncology, Hospital Clínico San Carlos, Profesor Martín Lagos, s/n 28040 - Madrid
Source of Support: None, Conflict of Interest: None
A better understanding of the angiogenic process has markedly expanded the use of antiangiogenic therapy in many solid tumors. It is known that there is a close relationship between cancer disease, vascular homeostasis, angiogenesis and coagulation cascade. In this setting, antiangiogenic therapy could interfere and potentially increase the risk of bleeding or thromboembolic events. Sunitinib is an orally available smallmolecule multikinase inhibitor recently approved for the treatment of unresectable or metastatic, well-differenciated pancreatic neuroendocrine tumors with disease progression in adults. Here we present the first case of a severe perirenal hematoma in a patient treated with sunitinib for metastatic pancreatic neuroendocrine tumor.
Keywords: Angiogenesis, pancreatic neuroendocrine tumor, perirenal hematoma, sunitinib, vascular homeostasis
|How to cite this article:|
Zugazagoitia J, Sastre J, Barrera J, García B, Díaz-Rubio E. Severe perirenal hematoma in a patient with a single kidney treated with sunitinib for metastatic pancreatic neuroendocrine tumor. J Can Res Ther 2012;8:303-5
|How to cite this URL:|
Zugazagoitia J, Sastre J, Barrera J, García B, Díaz-Rubio E. Severe perirenal hematoma in a patient with a single kidney treated with sunitinib for metastatic pancreatic neuroendocrine tumor. J Can Res Ther [serial online] 2012 [cited 2019 Dec 6];8:303-5. Available from: http://www.cancerjournal.net/text.asp?2012/8/2/303/98997
| > Introduction|| |
Since 1971, when Professor Folkman first formulated the hypothesis that tumor growth depends closely on the neoangiogenic process,  many studies have been carried out to understand the role of different angiogenic factors, their receptors and molecular pathways in the pathogenesis and the development of cancer. The vascular endothelial growth factor (VEGF) family members and their receptors are the key regulators of these processes. 
Sunitinib (Sutent® , Pfizer Ltd.) is an orally available molecule that inhibits multiple tyrosine kinase receptors including VEGFR 1, 2 and 3.
Currently, sunitinib is approved by the European Medicines Agency (EMA) for the treatment of advanced/metastatic renal cell carcinoma (MRCC),  the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumor (GIST) after failure of imatinib mesilate treatment due to resistance or intolerance,  and recently for the treatment of unresectable or metastatic, well-differenciated pancreatic neuroendocrine tumors (pNETs) with disease progression in adults. 
| > Case Report|| |
A 48-year-old woman with a history of controlled hypertension and with multiple endocrine neoplasia (MEN) type I syndrome, was diagnosed in 2007 with a well-differenciated neuroendocrine pancreatic carcinoma (Ki67: 12%) after a surgical approach of a mass including pancreatic tail and left kidney.
In August 2009, the CT scan revealed new multiple liver metastasis, retroperitoneal lymph nodes and soft tissue invasion. She was referred to our Medical Oncology Department for anticancer medical treatment. Octreoscan showed negative somatostatin analog receptor expression, and interferonalpha therapy (5 × 10 6 IU, subcutaneous, 3 times per week) was initiated and maintained until February 2010 when liver and lymph node progression was observed.
At that time, sunitinib treatment was started at 50 mg per day for 4 -weeks in every 6 weeks on a compassionate-use program. After two weeks of treatment, the patient developed pain in the abdominal right upper quadrant and flank accompanied by loss of function for flexion and external rotation of the right hip. The abdomen was painful to deep palpation in the right lower quadrant and right flank with positive rebound tenderness. Laboratory tests showed hemoglobin of 9.7 g/dl with normal platelets and clotting times. An abdominal CT scan showed a large right perirenal hematoma of 6.6 × 2.7 × 9.0 cm in size, which displaced the kidney ahead and caudally to the psoas across the right iliac fosse, with no evidence of active bleeding. Furthermore, three images of renal parenchyma disruption were seen which could be related with small lacerations [Figure 1].
|Figure 1: CT scan showing a large right perirenal hematoma without active bleeding|
Click here to view
The patient was admitted to hospital with a diagnosis of spontaneous perirenal hematoma without active bleeding. Urological assessment was requested, and a conservative approach was adopted. A week after admission, she began to have fever spikes of up to 38.5°. A superinfection of retroperitoneal hematoma was confirmed after the completion of a new abdominal CTscan. Urological reassessment recommended conservative treatment, given the high risk of surgical intervention. She was treated with carbapenems and subsequently linezolid with favorable evolution. Subsequent radiological control showed a progressive resolution of the retroperitoneal hematoma [Figure 2], and so the patient was discharged for outpatient followup. Sunitinib was stopped at admission and was not reintroduced.
|Figure 2: CT scan performed 5 weeks later showing a progressive resolution of the retroperitoneal hematoma|
Click here to view
| > Discussion|| |
Recent studies have established a close genetic and molecular relationship between oncogenesis and hemostasis, showing that genetic mechanisms involved in angiogenesis, tumor growth and metastasis also modulate the expression of genes responsible for coagulation, which may ultimately explain the hypercoagulability in cancer.  On the other hand, it has been shown that many of the coagulation factors promote angiogenesis by coagulation independent mechanisms, mainly through the protease activated receptors (PAR). Moreover, preclinical studies show that VEGF signaling plays an important role in maintaining endothelial
integrity.  In this setting, inhibition of VEGF, its receptors and their interactions with other molecular pathways could eventually lead to an imbalance among pro and antithrombotic factors causing endothelial damage and thus favoring the occurrence of thrombotic events and bleeding. How these events occur and why thrombotic or bleeding events are more prevalent at any time depends on multiple factors, including histology and tumor stage, type of antiangiogenic agents and their possible combination with standard chemotherapy. 
A recent meta-analysis studied the incidence and risk of bleeding events with sunitinib and sorafenib.  A total of 23 phase II and phase III trials of both drugs in different types of solid tumors were included. The overall incidence for any degree of bleeding was 16.7%, while the incidence for major bleeding events (grade 3 or higher) was only 2.4%. Separately, 19.3% of patients treated with sunitinib developed hemorrhagic events of any grade, while the incidence of major events was 3.0%. Moreover, global analysis of studies with controls showed a relative risk [RR] of 2.0 (95% confidence interval [CI]: 1.13.5, P=0.015) for bleeding events of any grade. There was no statistical difference for major events RR: 1.2 (CI 95% 0.701.92 P=0.55). Stratifying groups according to the tyrosine kinase inhibitor used, the RR of developing a hemorrhagic event of any grade with sunitinib was 2.1 (95% CI: 0.67.5, P=0.244), while for serious adverse events was 1.7 (CI 95%: 0.310.0, P=0.543).
In a phase II trial, 107 patients with neuroendocrine tumors (carcinoid, n=41; pNET, n=66) were treated with sunitinib. The most common grade 4 vascular adverse events reported are gastrointestinal bleeding (1.9%), pulmonary embolism (0.9%) and stroke (0.9%). A single case of toxic death secondary to gastrointestinal bleeding has been reported.  In a recent phase III trial, one grade 3-4 bleeding event (epistaxis) was observed in 83 patients with pNETs treated with sunitinib. 
To our knowledge, only one case of perirenal hematoma in a patient receiving the antiangiogenic therapy bevacizumab for metastatic rectal carcinoma has been published.  In our case, other causes of spontaneous nontraumatic perirenal hematoma were ruled out. Furthermore, the temporal relationship with the initiation of the antiangiogenic therapy suggests that this complication may be closely associated with sunitinib.
| > Conclusions|| |
Patients under antiangiogenic therapy should be closely monitored for hemorrhagic events, and medication should be interrupted in case of a serious bleeding episode. In the future, more preclinical and clinical studies are crucial to better understanding of the mechanisms of homeostasis and vascular integrity in order to prevent these potentially lifethreatening complications.
| > References|| |
|1.||Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971;285:1182-6. |
|2.||Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23:1011-27. |
|3.||Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib vs interferon alfa in metastatic renalcell carcinoma. N Engl J Med 2007;356:115-24. |
|4.||Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumor after failure of imatinib: A randomized controlled trial. Lancet 2006;368:1329-38. |
|5.||Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501-13. |
|6.||Boccaccio C, Comoglio PM. Genetic link between cancer and thrombosis. J Clin Oncol 2009;27:4827-33. |
|7.||Elice F, Jacoub J, Rickles FR, Falanga A, Rodeghiero F. Hemostatic complications of angiogenesis inhibitors in cancer patients. Am J Hematol 2008;83:862-70. |
|8.||Je Y, Schutz FA, Choueiri TK. Risk of bleeding with vascular endothelial growth factor receptor tyrosinekinase inhibitors sunitinib and sorafenib: A systematic review and metaanalysis of clinical trials. Lancet Oncol 2009;10:967-74. |
|9.||Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26:3403-10. |
|10.||Hayashi H, Okamoto I, Nakagawa K. Perirenal hematoma associated with bevacizumab treatment. Invest New Drugs 2012;30:808-9. |
[Figure 1], [Figure 2]