Case Report
Extensive Necrotizing Fasciitis Associated With Sunitinib Therapy Jolanta Piszczek,1,2 Bruce Dalton,3 Tess Peters,4 Dean Ruether,5 Stefan Urbanski6 Clinical Practice Points Tyrosine kinase inhibitors (TKIs) inhibit vascular endo-
thelial growth factors (VEGFs), which leads to decreased angiogenesis and impaired tumor blood flow. TKIs such as sunitinib have been implicated in a wide variety of cutaneous adverse effects in clinical trials, but rare and serious events remain uncaptured. Sunitinib-associated necrotizing fasciitis has been acknowledged by the manufacturer in postmarketing surveillance, leading to a recent United States Food and Drug Administration (FDA) black-box warning, but this complication has not previously been reported in medical literature. We report a case of sunitinib-related necrotizing fasciitis. Based on the clinical findings, the timing of
symptom onset with respect to sunitinib therapy, and the Naranjo Adverse Drug Reactions Probability Scale score, sunitinib was deemed the probable cause of the necrotizing fasciitis. We postulate that inhibition of VEGFs in the skin leads to decreased repair of the cutaneous capillaries and subsequent activation of the coagulation cascade, leading to vessel breakdown, thrombosis, and increased susceptibility to bacterial invasion. Given the life-threatening nature of the infection and the necessity for urgent intervention, clinicians should be aware of this possible adverse effect of sunitinib and other TKIs.
Clinical Genitourinary Cancer, Vol. 12, No. 2, e47-9 ª 2014 Elsevier Inc. All rights reserved. Keywords: Adverse drug reaction, Fournier’s gangrene, Renal cell carcinoma, Tyrosine kinase inhibitors, Vascular endothelial growth factors
Background Sunitinib is a tyrosine kinase inhibitor (TKI) that prevents the cellular signal transduction of platelet-derived growth factors and vascular endothelial growth factors (VEGFs), which leads to decreased tumor angiogenesis and inhibition of tumor growth.1 Sunitinib is approved by the United States Food and Drug Administration (FDA) for the treatment of metastatic renal cell carcinoma, unresectable pancreatic endocrine tumors, and gastrointestinal stromal tumors.2 Although necrotizing fasciitis was not observed in clinical trials, skin-related toxicity was frequently noted. In a pooled analysis of published literature, sunitinib-induced 1
University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, Canada Vancouver Island Health Authority, Victoria, Canada Pharmacy Services, Alberta Health Services, Foothills Medical Centre, Calgary, Canada 4 Department of Dermatology, University of Calgary, Calgary, Canada 5 Department of Oncology, University of Calgary, Calgary, Canada 6 Department of Pathology, University of Calgary, Calgary, Canada 2 3
Submitted: Oct 1, 2013; Revised: Oct 20, 2013; Accepted: Nov 8, 2013; Epub: Dec 1, 2013 Address for correspondence: Jolanta Piszczek, PharmD, Royal Jubilee Hospital, 1952 Bay Street, Victoria, BC, V8R 1J8, Canada E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.11.017
dermatologic reactions included handefoot syndrome (650 of 3489 patients), skin rash (406 of 3045), xerosis (61 of 388), and dermatitis (5 of 63).3 To our knowledge, this is the first case report published of sunitinib-associated necrotizing fasciitis.
Case Report Our patient was a 66-year-old man with stage IV renal cell carcinoma with bone metastases. He underwent cytoreductive resection of the primary tumor and palliative radiation to the spine, and he began subsequent treatment with sunitinib. His other medications included zoledronic acid, methylphenidate, bisoprolol, warfarin, and pantoprazole. He completed 4 28-day cycles of sunitinib, which he tolerated relatively well, with the exception of developing severe fatigue and macrocytic anemia. He denied any dermatological adverse effect throughout his therapy. On the last day of his final cycle of sunitinib, the patient developed a wound on his left buttock that progressed to full-thickness necrosis over several days. The patient subsequently developed nausea, vomiting, chills, and fatigue and presented to the emergency department. On examination, he had a blood pressure of 80/40 mm Hg, a pulse of 110 beats per minute, and a respiratory rate of 32, and he was afebrile. A complete blood count revealed a hemoglobin level
Clinical Genitourinary Cancer April 2014
- e47
Sunitinib and Necrotizing Fasciitis of 130 g/L and a white blood cell count of 4.7 109 cells/L, both of which dropped, to 78 g/L and 1.9 109 cells/L, respectively, 6 hours later. A comprehensive metabolic panel was indicative of hypocalcemia (1.57 mmol/L), hypermagnesemia (1.95 mmol/L), urea of 22.9 mmol/L, and serum creatinine of 151 mmol/L. Initial venous blood gas measures were consistent with hypoxemic respiratory failure, and the lactate level was elevated at 11.6 mmol/L. A physical examination of the perineal area revealed a 4-cm black fluctuant wound of the left buttock with purulent drainage and circumferential extension along the rectal wall. The tissue surrounding the wound as well as the scrotum was red, edematous, and tender, sparing only the anus. Preliminary Gram staining of the wound showed heavy mixed Gram-positive and Gram-negative organisms and scant neutrophils. Cultures subsequently grew enterococcus and moderate amounts of Gram-negative enteric bacilli. The patient was started on empiric antibiotic therapy with piperacillin-tazobactam, clindamycin, and vancomycin and was admitted to the intensive care unit with a diagnosis of type 1 necrotizing fasciitis, renal failure, and septic shock. He was intubated and then taken to the operating room for immediate tissue debridement involving the left buttock, perineum, and scrotum amounting to approximately 5% of his total body surface area. A histopathologic examination of tissue specimens revealed inflammation with prominent fat necrosis consistent with necrotizing fasciitis (Fig. 1). A tissue culture was positive for Escherichia coli and mixed enteric flora, including anaerobes. Blood cultures grew Gram-negative bacilli that were later speciated as Campylobacter ureolyticus and a Fusobacterium species, non-necrophorum. The patient underwent 4 other surgeries for creation of a colostomy, further debridement, reconstruction with a left gluteus maximus myocutaneous V-to-Y advancement flap, and skin grafting to the perineal area. The patient was extubated 7 days post admission and discharged on day 49.
Discussion Necrotizing fasciitis is a severe, rapidly progressive, soft tissue infection of bacterial origin.4 It may begin from a minor skin defect, making diagnosis difficult, and progress to extensive necrosis and
Figure 1 Numerous Gram-Positive Bacterial Colonies Within Necrotic Subcutaneous Fat Gram, 3200
life-threatening sepsis.5 The infected area initially presents as exquisitely tender, but anesthesia may develop secondary to vessel thrombosis and damage to superficial nerves.6 Systemic symptoms of hypotension, tachycardia, and hypoxia may be present at later stages as sepsis ensues, as it did with the patient presented.6 Predisposing factors include diabetes, peripheral-vascular disease, recent surgery, alcohol abuse, and chronic liver and kidney diseases,7,8 as well as ingestion of immune-modulating agents. Necrotizing fasciitis is usually classified into 2 categories: type 1, which is polymicrobial, and type 2, which is usually caused by group A Streptococcus. Besides antibiotics, urgent and aggressive surgical intervention, often comprising multiple debridement procedures before eventual definitive reconstruction, is required. Despite these treatments, mortality and morbidity remain high, and immediate intervention is crucial in improving survival.5,8 The mechanism of sunitinib-related skin reactions and tissue infections is likely related to thrombosis of the small subcutaneous vessels leading to tissue hypoxia, necrosis, and increased susceptibility to invasion by pathogenic and opportunistic bacteria. It has been postulated that VEGF is implicated in a paracrine feedback loop between keratinocytes and endothelial cells and is directly involved in the formation and repair of spiral capillaries in the skin.9 The blockade of the VEGF receptor through sunitinib might override the physiological restoration of these capillaries and trigger changes in skin cell proliferation and focal adhesion, which determines the rate of skin cell migration.10 In addition to its correlation with skin-related toxicity, sunitinib has been found to increase the risk of arterial thrombosis.11 The mechanism for increased thromboembolic events has been hypothesized to be similar to that of skin-related toxicity: A perturbation of vascular endothelial cells by the TKIs modulates the activation of systemic coagulation and inflammation necessary for repair.12 Similarly, necrotizing fasciitis has been previously reported in patients treated with bevacizumab, a monoclonal antibody that also targets VGEF and inhibits angiogenesis.13 To date, cases of necrotizing fasciitis in patients treated with have been uncovered through postmarketing surveillance reported to Pfizer, the drug’s manufacturer, although none has been published in the medical literature. Although various sites have been implicated, the product monograph warns specifically about necrotizing fasciitis involving the perineum, the most commonly affected area.2 As some of these reactions were fatal, the FDA published a safety warning regarding sunitinib-related necrotizing fasciitis in November 2012.14
Conclusion
e48
-
According to the Naranjo Adverse Drug Reaction Probability Scale, sunitinib was determined to be the probable cause of the necrotizing fasciitis. This was based on the timing of the reaction after sunitinib was taken, lack of alternative causes, reaction improvement with medication discontinuation, and other objective evidence.15 The presentation of this case is consistent with that of the previous cases reported to the manufacturer, as well as with that of reported cases involving other drugs that affect VEGF. Given the high mortality and morbidity of necrotizing fasciitis, further surveillance and investigation of this phenomenon, as well as other skin and thromboembolic adverse events of sunitinib treatment,
Clinical Genitourinary Cancer April 2014
Jolanta Piszczek et al are warranted. Clinicians should be aware of the possible role of sunitinib in the development of necrotizing fasciitis, a rare but potentially fatal complication of therapy.
Acknowledgments The authors acknowledge the assistance of Duncan Nickerson, MD, FRCSC, FACS, in reviewing the manuscript.
Consent Patient consent for publication of this case report was obtained in accordance to policies of Alberta Health Services.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Carrato Mena A, Grande Pulido E, Guillén-Ponce C. Understanding the molecular-based mechanism of action of the tyrosine kinase inhibitor: sunitinib. Anticancer Drugs 2010; 21(suppl 1):S3-11. 2. Sutent (sunitinib malate) [drug monograph]. Kirkland, Canada: Pfizer Canada; 2013, Available at: http://www.pfizer.ca/en/our_products/products/monograph/ 147. Accessed: May 1, 2013. 3. Rosenbaum SE, Wu S, Newman MA, West DP, Kuzel T, Lacouture ME. Dermatological reactions to the multitargeted tyrosine kinase inhibitor sunitinib. Support Care Cancer 2008; 16:557-66.
4. Anaya D, Dellinger E. Necrotizing soft-tissue infection: diagnosis and management. Clin Infect Dis 2007; 44:705-11. 5. Wong C, Chang H, Pasupathy S, Khin T, Tan J, Low C. Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality. J Bone Joint Surg Am 2003; 85:1454-60. 6. Schwartz MN, Pasternack MS. Cellulitis and subcutaneous tissue infections. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Churchill Livingstone 2005; 1172. 7. McHenry CR, Piotrowski JJ, Petrinic D, Malangoni MA. Determinants of mortality in necrotizing soft tissue infections. Ann Surg 1995; 221:558-63. 8. Yilmazlar T, Ozturk E, Alsoy A, Ozguc H. Necrotizing soft tissue infections: APACHE II score, dissemination, and survival. World J Surg 2007; 31:1858-62. 9. Aparicio-Gallego G, Blanco M, Figueroa A, et al. New insights into molecular mechanisms of sunitinib-associated side effects. Mol Cancer Ther 2011; 10: 2215-23. 10. deBouard S, Herlin P, Christensen JG, et al. Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma. Neuro Oncol 2007; 9: 412-23. 11. Choueiri TK, Schutz F, Je Y, Rosenberg JE, Bellmun J. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and metaanalysis of clinical trials. J Clin Oncol 2010; 28:2280-5. 12. Kuenen BC. Analysis of prothrombotic mechanisms and endothelial perturbation during treatment with angiogenesis inhibitors. Pathophysiol Haemost Thromb 2003; 33(suppl 1):13-4. 13. Gamboa EO, Rehmus EH, Haller N. Fournier’s gangrene as a possible side effect of bevacizumab therapy for resected colorectal cancer. Clin Colorectal Cancer 2010; 9:55-8. 14. Food and Drug Administration. MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Sutent (sunitinib malate) Capsules: November 2012. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/ ucm224050.htm. Accessed: May 1, 2013. 15. Naranjo CA, Busto M, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30:239-45.
Clinical Genitourinary Cancer April 2014
- e49
Extensive Necrotizing Fasciitis Associated With Sunitinib Therapy Jolanta Piszczek,1,2 Bruce Dalton,3 Tess Peters,4 Dean Ruether,5 Stefan Urbanski6 Clinical Practice Points Tyrosine kinase inhibitors (TKIs) inhibit vascular endo-
thelial growth factors (VEGFs), which leads to decreased angiogenesis and impaired tumor blood flow. TKIs such as sunitinib have been implicated in a wide variety of cutaneous adverse effects in clinical trials, but rare and serious events remain uncaptured. Sunitinib-associated necrotizing fasciitis has been acknowledged by the manufacturer in postmarketing surveillance, leading to a recent United States Food and Drug Administration (FDA) black-box warning, but this complication has not previously been reported in medical literature. We report a case of sunitinib-related necrotizing fasciitis. Based on the clinical findings, the timing of
symptom onset with respect to sunitinib therapy, and the Naranjo Adverse Drug Reactions Probability Scale score, sunitinib was deemed the probable cause of the necrotizing fasciitis. We postulate that inhibition of VEGFs in the skin leads to decreased repair of the cutaneous capillaries and subsequent activation of the coagulation cascade, leading to vessel breakdown, thrombosis, and increased susceptibility to bacterial invasion. Given the life-threatening nature of the infection and the necessity for urgent intervention, clinicians should be aware of this possible adverse effect of sunitinib and other TKIs.
Clinical Genitourinary Cancer, Vol. 12, No. 2, e47-9 ª 2014 Elsevier Inc. All rights reserved. Keywords: Adverse drug reaction, Fournier’s gangrene, Renal cell carcinoma, Tyrosine kinase inhibitors, Vascular endothelial growth factors
Background Sunitinib is a tyrosine kinase inhibitor (TKI) that prevents the cellular signal transduction of platelet-derived growth factors and vascular endothelial growth factors (VEGFs), which leads to decreased tumor angiogenesis and inhibition of tumor growth.1 Sunitinib is approved by the United States Food and Drug Administration (FDA) for the treatment of metastatic renal cell carcinoma, unresectable pancreatic endocrine tumors, and gastrointestinal stromal tumors.2 Although necrotizing fasciitis was not observed in clinical trials, skin-related toxicity was frequently noted. In a pooled analysis of published literature, sunitinib-induced 1
University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, Canada Vancouver Island Health Authority, Victoria, Canada Pharmacy Services, Alberta Health Services, Foothills Medical Centre, Calgary, Canada 4 Department of Dermatology, University of Calgary, Calgary, Canada 5 Department of Oncology, University of Calgary, Calgary, Canada 6 Department of Pathology, University of Calgary, Calgary, Canada 2 3
Submitted: Oct 1, 2013; Revised: Oct 20, 2013; Accepted: Nov 8, 2013; Epub: Dec 1, 2013 Address for correspondence: Jolanta Piszczek, PharmD, Royal Jubilee Hospital, 1952 Bay Street, Victoria, BC, V8R 1J8, Canada E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.11.017
dermatologic reactions included handefoot syndrome (650 of 3489 patients), skin rash (406 of 3045), xerosis (61 of 388), and dermatitis (5 of 63).3 To our knowledge, this is the first case report published of sunitinib-associated necrotizing fasciitis.
Case Report Our patient was a 66-year-old man with stage IV renal cell carcinoma with bone metastases. He underwent cytoreductive resection of the primary tumor and palliative radiation to the spine, and he began subsequent treatment with sunitinib. His other medications included zoledronic acid, methylphenidate, bisoprolol, warfarin, and pantoprazole. He completed 4 28-day cycles of sunitinib, which he tolerated relatively well, with the exception of developing severe fatigue and macrocytic anemia. He denied any dermatological adverse effect throughout his therapy. On the last day of his final cycle of sunitinib, the patient developed a wound on his left buttock that progressed to full-thickness necrosis over several days. The patient subsequently developed nausea, vomiting, chills, and fatigue and presented to the emergency department. On examination, he had a blood pressure of 80/40 mm Hg, a pulse of 110 beats per minute, and a respiratory rate of 32, and he was afebrile. A complete blood count revealed a hemoglobin level
Clinical Genitourinary Cancer April 2014
- e47
Sunitinib and Necrotizing Fasciitis of 130 g/L and a white blood cell count of 4.7 109 cells/L, both of which dropped, to 78 g/L and 1.9 109 cells/L, respectively, 6 hours later. A comprehensive metabolic panel was indicative of hypocalcemia (1.57 mmol/L), hypermagnesemia (1.95 mmol/L), urea of 22.9 mmol/L, and serum creatinine of 151 mmol/L. Initial venous blood gas measures were consistent with hypoxemic respiratory failure, and the lactate level was elevated at 11.6 mmol/L. A physical examination of the perineal area revealed a 4-cm black fluctuant wound of the left buttock with purulent drainage and circumferential extension along the rectal wall. The tissue surrounding the wound as well as the scrotum was red, edematous, and tender, sparing only the anus. Preliminary Gram staining of the wound showed heavy mixed Gram-positive and Gram-negative organisms and scant neutrophils. Cultures subsequently grew enterococcus and moderate amounts of Gram-negative enteric bacilli. The patient was started on empiric antibiotic therapy with piperacillin-tazobactam, clindamycin, and vancomycin and was admitted to the intensive care unit with a diagnosis of type 1 necrotizing fasciitis, renal failure, and septic shock. He was intubated and then taken to the operating room for immediate tissue debridement involving the left buttock, perineum, and scrotum amounting to approximately 5% of his total body surface area. A histopathologic examination of tissue specimens revealed inflammation with prominent fat necrosis consistent with necrotizing fasciitis (Fig. 1). A tissue culture was positive for Escherichia coli and mixed enteric flora, including anaerobes. Blood cultures grew Gram-negative bacilli that were later speciated as Campylobacter ureolyticus and a Fusobacterium species, non-necrophorum. The patient underwent 4 other surgeries for creation of a colostomy, further debridement, reconstruction with a left gluteus maximus myocutaneous V-to-Y advancement flap, and skin grafting to the perineal area. The patient was extubated 7 days post admission and discharged on day 49.
Discussion Necrotizing fasciitis is a severe, rapidly progressive, soft tissue infection of bacterial origin.4 It may begin from a minor skin defect, making diagnosis difficult, and progress to extensive necrosis and
Figure 1 Numerous Gram-Positive Bacterial Colonies Within Necrotic Subcutaneous Fat Gram, 3200
life-threatening sepsis.5 The infected area initially presents as exquisitely tender, but anesthesia may develop secondary to vessel thrombosis and damage to superficial nerves.6 Systemic symptoms of hypotension, tachycardia, and hypoxia may be present at later stages as sepsis ensues, as it did with the patient presented.6 Predisposing factors include diabetes, peripheral-vascular disease, recent surgery, alcohol abuse, and chronic liver and kidney diseases,7,8 as well as ingestion of immune-modulating agents. Necrotizing fasciitis is usually classified into 2 categories: type 1, which is polymicrobial, and type 2, which is usually caused by group A Streptococcus. Besides antibiotics, urgent and aggressive surgical intervention, often comprising multiple debridement procedures before eventual definitive reconstruction, is required. Despite these treatments, mortality and morbidity remain high, and immediate intervention is crucial in improving survival.5,8 The mechanism of sunitinib-related skin reactions and tissue infections is likely related to thrombosis of the small subcutaneous vessels leading to tissue hypoxia, necrosis, and increased susceptibility to invasion by pathogenic and opportunistic bacteria. It has been postulated that VEGF is implicated in a paracrine feedback loop between keratinocytes and endothelial cells and is directly involved in the formation and repair of spiral capillaries in the skin.9 The blockade of the VEGF receptor through sunitinib might override the physiological restoration of these capillaries and trigger changes in skin cell proliferation and focal adhesion, which determines the rate of skin cell migration.10 In addition to its correlation with skin-related toxicity, sunitinib has been found to increase the risk of arterial thrombosis.11 The mechanism for increased thromboembolic events has been hypothesized to be similar to that of skin-related toxicity: A perturbation of vascular endothelial cells by the TKIs modulates the activation of systemic coagulation and inflammation necessary for repair.12 Similarly, necrotizing fasciitis has been previously reported in patients treated with bevacizumab, a monoclonal antibody that also targets VGEF and inhibits angiogenesis.13 To date, cases of necrotizing fasciitis in patients treated with have been uncovered through postmarketing surveillance reported to Pfizer, the drug’s manufacturer, although none has been published in the medical literature. Although various sites have been implicated, the product monograph warns specifically about necrotizing fasciitis involving the perineum, the most commonly affected area.2 As some of these reactions were fatal, the FDA published a safety warning regarding sunitinib-related necrotizing fasciitis in November 2012.14
Conclusion
e48
-
According to the Naranjo Adverse Drug Reaction Probability Scale, sunitinib was determined to be the probable cause of the necrotizing fasciitis. This was based on the timing of the reaction after sunitinib was taken, lack of alternative causes, reaction improvement with medication discontinuation, and other objective evidence.15 The presentation of this case is consistent with that of the previous cases reported to the manufacturer, as well as with that of reported cases involving other drugs that affect VEGF. Given the high mortality and morbidity of necrotizing fasciitis, further surveillance and investigation of this phenomenon, as well as other skin and thromboembolic adverse events of sunitinib treatment,
Clinical Genitourinary Cancer April 2014
Jolanta Piszczek et al are warranted. Clinicians should be aware of the possible role of sunitinib in the development of necrotizing fasciitis, a rare but potentially fatal complication of therapy.
Acknowledgments The authors acknowledge the assistance of Duncan Nickerson, MD, FRCSC, FACS, in reviewing the manuscript.
Consent Patient consent for publication of this case report was obtained in accordance to policies of Alberta Health Services.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Carrato Mena A, Grande Pulido E, Guillén-Ponce C. Understanding the molecular-based mechanism of action of the tyrosine kinase inhibitor: sunitinib. Anticancer Drugs 2010; 21(suppl 1):S3-11. 2. Sutent (sunitinib malate) [drug monograph]. Kirkland, Canada: Pfizer Canada; 2013, Available at: http://www.pfizer.ca/en/our_products/products/monograph/ 147. Accessed: May 1, 2013. 3. Rosenbaum SE, Wu S, Newman MA, West DP, Kuzel T, Lacouture ME. Dermatological reactions to the multitargeted tyrosine kinase inhibitor sunitinib. Support Care Cancer 2008; 16:557-66.
4. Anaya D, Dellinger E. Necrotizing soft-tissue infection: diagnosis and management. Clin Infect Dis 2007; 44:705-11. 5. Wong C, Chang H, Pasupathy S, Khin T, Tan J, Low C. Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality. J Bone Joint Surg Am 2003; 85:1454-60. 6. Schwartz MN, Pasternack MS. Cellulitis and subcutaneous tissue infections. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Churchill Livingstone 2005; 1172. 7. McHenry CR, Piotrowski JJ, Petrinic D, Malangoni MA. Determinants of mortality in necrotizing soft tissue infections. Ann Surg 1995; 221:558-63. 8. Yilmazlar T, Ozturk E, Alsoy A, Ozguc H. Necrotizing soft tissue infections: APACHE II score, dissemination, and survival. World J Surg 2007; 31:1858-62. 9. Aparicio-Gallego G, Blanco M, Figueroa A, et al. New insights into molecular mechanisms of sunitinib-associated side effects. Mol Cancer Ther 2011; 10: 2215-23. 10. deBouard S, Herlin P, Christensen JG, et al. Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma. Neuro Oncol 2007; 9: 412-23. 11. Choueiri TK, Schutz F, Je Y, Rosenberg JE, Bellmun J. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and metaanalysis of clinical trials. J Clin Oncol 2010; 28:2280-5. 12. Kuenen BC. Analysis of prothrombotic mechanisms and endothelial perturbation during treatment with angiogenesis inhibitors. Pathophysiol Haemost Thromb 2003; 33(suppl 1):13-4. 13. Gamboa EO, Rehmus EH, Haller N. Fournier’s gangrene as a possible side effect of bevacizumab therapy for resected colorectal cancer. Clin Colorectal Cancer 2010; 9:55-8. 14. Food and Drug Administration. MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Sutent (sunitinib malate) Capsules: November 2012. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/ ucm224050.htm. Accessed: May 1, 2013. 15. Naranjo CA, Busto M, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30:239-45.
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