Development of coronary artery stenosis in a patient with metastatic renal cell carcinoma treated with sorafenib
© Haltas et al.; licensee BioMed Central Ltd. 2012
Received: 11 January 2012
Accepted: 11 June 2012
Published: 11 June 2012
Tyrosine kinase inhibitors (TKIs) are currently approved for the treatment of metastatic renal cell carcinoma (mRCC). The cardiotoxic effects of sorafenib and sunitinib may cause hypertension, left ventricular ejection fraction (LVEF) dysfunction and/or congestive heart failure (CHF), and arterial thrombo-embolic events (ATE). Only three cases of coronary artery disease related to sorafenib therapy have been described in the literature, and all were due to arterial vasospasm without evidence of coronary artery stenosis on angiography. Cardiotoxicity is commonly associated with the presence of cardiovascular risk factors, such as a history of hypertension or coronary artery disease.
We describe a patient who experienced an unusual cardiac event after 2 years of sorafenib treatment. A 58-year-old man with mRCC developed acute coronary syndrome (ischemia/infarction) associated with critical sub-occlusion of the common trunk of the left coronary artery and some of its branches, which was documented on coronary angiography. The patient underwent triple coronary artery bypass surgery, and sorafenib treatment was discontinued. He did not have any cardiovascular risk factors, and his cardiac function and morphology were normal prior to sorafenib treatment.
Further investigation of a larger patient population is needed to better understand cardiac damage due to TKI treatment. Understanding the usefulness of careful cardiovascular monitoring might be important for the prevention of fatal cardiovascular events, and to avoid discontinuation of therapy for the underlying cancer.
KeywordsSorafenib renal cell carcinoma coronary syndrome cardiotoxicity cardiac ischemia/infarction
Tyrosine kinase inhibitors (TKIs) are currently approved for the treatment of metastatic renal cell carcinoma (mRCC) [1, 2]. Common toxicities due to sorafenib and sunitinib treatment include reversible skin rashes, hand-foot skin reaction, diarrhea, hypertension, hemorrhage, and laboratory findings such as leucopenia, hypophosphatemia, elevated pancreatic enzymes levels, and proteinuria [3, 4]. Other clinical events related to cardiotoxicity include left ventricular ejection fraction (LVEF) dysfunction and/or congestive heart failure (CHF) and arterial thrombo-embolic events (ATE) [3–8]. Several authors have concluded that LVEF dysfunction and/or CHF is more frequent in patients with a history of hypertension or coronary artery disease. Only three cases of coronary artery disease related to sorafenib treatment have been described in the literature. All three cases were associated with the presence of cardiovascular risk factors and were due to arterial vasospasm without evidence of coronary artery stenosis on angiography [9–11].
In 2007, a 58-year-old white male with no history of tobacco use, hypertension, diabetes, or hypercholesterolemia, and no family history of coronary artery disease, was found to have a large solid right renal mass and associated tumor thrombus of the inferior vena cava and right atrium. He underwent right radical nephrectomy and tumor thrombectomy performed under extracorporeal circulation. Cardiac function was investigated, including coronary angiography and transthoracic and transesophageal echocardiography. These studies documented normal cardiac function and normal morphology of the coronary arteries. Pathological examination of the surgical specimens demonstrated pT3cN0Mx conventional (clear cell) renal carcinoma, Fuhrman Grade 3 with negative surgical margins. A regular follow-up program was started. A few months later, hepatic and contralateral renal metastases were detected. The patient started treatment with the tyrosine kinase inhibitor (TKI) sorafenib on a dose-escalation protocol. Treatment led to an initial partial response followed by stable disease for 6 months. During December 2008, in a setting of stable disease, he underwent hepatic resection and enucleation of the left renal mass. The hepatic and renal masses were confirmed to be metastases. Early radiological assessment after surgery showed no residual hepatic or renal disease, but possible involvement of the mesenteric lymph nodes. Sorafenib treatment was therefore restarted at a standard dose of 800 mg/day. Treatment led to complete disease response within a few months, and was very well tolerated by the patient, who did not experience any of the typical adverse effects of the drug.
TKIs are currently approved for the treatment of mRCC [1, 2]. Sorafenib is a multikinase inhibitor, with activity against transmembrane KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-B receptors, and intracellular CRAF and BRAF receptors. These kinases are involved in several angiogenesis systems and intracellular signaling pathways, and their disruption is aimed at inhibiting tumor growth . The clinical efficacy of Sorafenib in the treatment of mRCC was demonstrated in a randomized, double-blind, placebo-controlled, phase III trial (TARGET) involving 903 patients who were resistant to previous therapy. An interim planned analysis of progression-free survival (PFS) showed a statistically significant benefit of sorafenib treatment over placebo (5.5 vs 2.8 months, p < 0.001). Consequently, a crossover was permitted from placebo to sorafenib. The difference in overall survival time was not statistically significant (19.3 vs 15.9 months), which can be explained by an important crossover effect. There was, however, a 28% reduction in the risk of death in patients receiving sorafenib [5, 13]. Sorafenib may also be a suitable alternative treatment for selected naïve patients with clear cell mRCC . A recent multicenter retrospective analysis of sequential treatment with sorafenib and sunitinib showed that initial treatment with either agent was associated with similar PFS times during first-line treatment (median PFS 8.4 months with sorafenib vs 7.8 months with sunitinib; p = 0.758). However, patients treated with sorafenib and then sunitinib appeared to have a slightly longer PFS times during second-line treatment than those treated with sunitinib and then sorafenib (median PFS with second TKI: 7.9 months vs 4.2 months; p < 0.001) .
Data describing the main cardiotoxic events reported in clinical trials of tumor angiogenesis inhibitors
N of pts
Types of events
Ranpura V et al. [] Meta-analysis of 20 RCTs
Bevacizumab in pts with a variety of advanced solid tumors
61 (3.3 %)
111 (2.0 %)
34 (1.5 %)
Richards CJ et al. []
186 (4.1 %)
Congestive heart failure
Choueiri TK et al. [] Meta-analysis of 10 studies
Sunitinb and Sorafenib in pts with advanced cancer
122 (1.4 %) 1.3 % for Sunitinib; 1.7 % for Sorafenib (NS)
Chu TF et al. []
Sunitinib in pts affected by GIST
75 36 75
8 (11 %) 6 (8 %) 10 (28 %) 7 (19 %) 35 (47 %)
Cardiovascular events Congestive heart failure LVEF reduction (at least 10 %) LVEF reduction (15 % or more) Hypertension
Telli ML et al. []
Sunitinib in pts affected by mRCC and GIST
7 (15 %)
Di Lorenzo G et al. []
Sunitinib in pts affected by mRCC
66 (37.7 %) 17 (9.7 %) 12 (6.9 %) 33 (18.9 %) of which 12 (6.9 %)
Hypertension G1-2 Hypertension G3 LVEF dysfunction Cardiac abnormalities LVEF G3 and/or Congestive heart failure
Schmidinger M et al. []
Sunitinib (Su) and Sorafenib (So) in pts with mRCC
25 [11 in Su; 14 in So] (33.8 %) of which: 12 (16.2 %) 13 (17.6 %) of which 7 (9.4 %)
Cardiac event Biochemical signs and ECG changes only Clinical symptoms (angina, dyspnea, dizziness) Life-threatening clinical symptoms
The molecular mechanisms of TKI cardiotoxicity have not been extensively investigated, but seem to be related to the inhibition of kinases that have a crucial role in normal cardiovascular development . The role of BRAF in the heart is not well understood. RAF1 seems to inhibit two pro-apoptotic kinases with ERK-independent effects: apoptosis signal-regulating kinase 1 (ASK1) and mammalian sterile 20 kinase 2 (MST2), which are both involved in oxidant stress-induced injury. If sorafenib disrupts the RAF1–ASK1 and/or RAF1–MST2 interactions, cardiotoxicity might be an even greater concern than if only the ERK cascade is inhibited . To examine the in vivo role of Raf-1 in the heart, Yamaguchy et al. generated cardiac muscle–specific Raf-1–knockout (Raf CKO) mice with Cre-loxP–mediated recombination . The mice demonstrated left ventricular systolic dysfunction and heart dilatation, related to a significant increase in the number of apoptotic cardiomyocytes and fibrosis. The molecular mechanism of ATE has not been well investigated, but it seems to depend on multiple actions of VEGF on vascular walls, and maybe also on components of the coagulation cascade. VEGF stimulates endothelial cell proliferation and promotes endothelial cell survival, thereby helping to maintain vascular integrity. VEGF-signaling inhibition leads to a decrease in the regenerative capacity of endothelial cells, and causes cell wall defects that expose pro-coagulant phospholipids on the luminal plasma membrane or uncover the matrix, favoring thrombosis. VEGF-inhibitors may also inhibit nitric oxide and prostacyclin, increase endothelial cell apoptosis, and promote pro-coagulant changes and proliferation of vascular smooth muscle cells. Finally, VEGF-inhibitors may increase the risk of ATE by increasing the hematocrit and blood viscosity via overproduction of erythropoietin [3, 22].
Descriptions of the three reported cases which developed coronary artery disease during sorafenib treatment
Types of events
Cardiovascolar risck factors
Naib T et al. 
57 years-old patient
multiple coronary vasospasm
history of diabetes, hyperlipidemia, former tobacco use
Arima Y et al. 
65 years-old patient
coronary artery spasm
Porto I et al. 
63 years-old patient
variant angina for spontaneous coronary spasm
history of diabetes and arterial hypertension,
The case presented here indicates that attention should be paid to the potential occurrence of occlusive coronary artery disease during treatment with TKIs, and that patients should be carefully monitored for the development of symptoms of coronary ischemia/infarction. Even though cardiotoxicity is widely reported and recognized as an important though not frequent toxic effect of treatment with sunitinib and other tumor angiogenesis inhibitors, there is currently no consensus regarding the prevention and management of these side effects.
In conclusion, we have presented a brief overview of the available data on cardiovascular events in patients treated with TKIs, and of the potential for the development of occlusive coronary artery disease. Understanding the usefulness of careful cardiovascular monitoring might be important to prevent fatal cardiovascular events and avoid discontinuation of treatment for the underlying cancer.
The patient has given consent for the publication of this report.
- National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology, Kidney Cancer, http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. V. 2.2010
- Molina AM, Motzer RJ: Clinical practice guidelines for the treatment of metastatic renal cell carcinoma: today and tomorrow. Oncologist. 2011, 16 (2): 45-50. 10.1634/theoncologist.2011-S2-45.View ArticlePubMedPubMed CentralGoogle Scholar
- Hudes GR, Carducci MA, Choueiri TK, Esper P, Jonasch E, Kumar R, Margolin KA, Michaelson MD, Motzer RJ, Pili R, Roethke S, Srinivas S: NCCN Task Force report: optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy. J Natl Compr Canc Netw. 2011, 9 (1): 1-29.Google Scholar
- Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH: Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators: Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010, 116 (5): 1272-1280. 10.1002/cncr.24864.View ArticlePubMedGoogle Scholar
- Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R: Bukowski RM; TARGET Study Group: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007, 356 (2): 125-134. 10.1056/NEJMoa060655.View ArticlePubMedGoogle Scholar
- Ranpura V, Hapani S, Chuang J, Wu S: Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol. 2010, 49 (3): 287-297. 10.3109/02841860903524396.View ArticlePubMedGoogle Scholar
- Richards CJ, Je Y, Schutz FAB, Heng DY, Dallabrida SM, Moslehi JJ, Choueiri TK: Incidence and Risk of Congestive Heart Failure in Patients With Renal and Nonrenal Cell Carcinoma Treated With Sunitinib. J Clin Oncol. 2011, 29: 3450-3456. 10.1200/JCO.2010.34.4309.View ArticlePubMedGoogle Scholar
- Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J: Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol. 2010, 28 (13): 2280-2285. 10.1200/JCO.2009.27.2757.View ArticlePubMedGoogle Scholar
- Naib T, Steingart RM, Chen CL: Sorafenib-associated multivessel coronary artery vasospasm. Herz. 2011, 36 (4): 348-351. 10.1007/s00059-011-3444-5.View ArticlePubMedGoogle Scholar
- Arima Y, Oshima S, Noda K, Fukushima H, Taniguchi I, Nakamura S, Shono M, Ogawa H: Sorafenib-induced acute myocardial infarction due to coronary artery spasm. J Cardiol. 2009, 54 (3): 512-515. 10.1016/j.jjcc.2009.03.009.View ArticlePubMedGoogle Scholar
- Porto I, Leo A, Miele L, Pompili M, Landolfi R, Crea F: A case of variant angina in a patient under chronic treatment with sorafenib. Nat Rev Clin Oncol. 2010, 7 (8): 476-480. 10.1038/nrclinonc.2010.67.View ArticlePubMedGoogle Scholar
- Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004, 64 (19): 7099-7109. 10.1158/0008-5472.CAN-04-1443.View ArticlePubMedGoogle Scholar
- Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM: Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009, 27 (20): 3312-3318. 10.1200/JCO.2008.19.5511.View ArticlePubMedGoogle Scholar
- Porta C, Procopio G, Cartenì G, Sabbatini R, Bearz A, Chiappino I, Ruggeri EM, Re GL, Ricotta R, Zustovich F, Landi L, Calcagno A, Imarisio I, Verzoni E, Rizzo M, Paglino C, Guadalupi V, Bajetta E: Sequential use of sorafenib and sunitinib in advanced renal-cell carcinoma (RCC): an Italian multicentre retrospective analysis of 189 patient cases. BJU Int. 2011, 23: 23-Google Scholar
- Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, Woulfe K, Pravda E, Cassiola F, Desai J, George S, Morgan JA, Harris DM, Ismail NS, Chen JH, Schoen FJ, Van den Abbeele AD, Demetri GD, Force T, Chen MH: Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007, 370: 2011-2019. 10.1016/S0140-6736(07)61865-0.View ArticlePubMedPubMed CentralGoogle Scholar
- Telli ML, Witteles RM, Fisher GA, Srinivas S: Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol. 2008, 19 (9): 1613-1618. 10.1093/annonc/mdn168.View ArticlePubMedGoogle Scholar
- Di Lorenzo G, Autorino R, Bruni G, Cartenì G, Ricevuto E, Tudini M, Ficorella C, Romano C, Aieta M, Giordano A, Giuliano M, Gonnella A, De Nunzio C, Rizzo M, Montesarchio V, Ewer M, De Placido S: Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis. Ann Oncol. 2009, 20 (9): 1535-1542. 10.1093/annonc/mdp025.View ArticlePubMedGoogle Scholar
- Schmidinger M, Zielinski CC, Vogl UM, Bojic A, Bojic M, Schukro C, Ruhsam M, Hejna M, Schmidinger H: Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2008, 26 (32): 5204-5212. 10.1200/JCO.2007.15.6331.View ArticlePubMedGoogle Scholar
- Force T, Kolaja KL: Cardiotoxicity of kinase inhibitors: the prediction and traslantion of preclinical models to clinical outcomes. Nat Rev Cancer. 2011, 10: 111-126. 10.1038/nrd3252.Google Scholar
- Force T, Krause DS, Van Etten RA: Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007, 7 (5): 332-344. 10.1038/nrc2106.View ArticlePubMedGoogle Scholar
- Yamaguchi O, Watanabe T, Nishida K, Kashiwase K, Higuchi Y, Takeda T, Hikoso S, Hirotani S, Asahi M, Taniike M, Nakai A, Tsujimoto I, Matsumura Y, Miyazaki J, Chien KR, Matsuzawa A, Sadamitsu C, Ichijo H, Baccarini M, Hori M, Otsu K: Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J Clin Invest. 2004, 114 (7): 937-943.View ArticlePubMedPubMed CentralGoogle Scholar
- Kamba T, McDonald DM: Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007, 96 (12): 1788-1795. 10.1038/sj.bjc.6603813.View ArticlePubMedPubMed CentralGoogle Scholar
- Lim TJ, Lee JH, Chang SG, Lee CH, Min GE, Yoo KH, Jeon SH: Life-threatening complications associated with the tyrosine kinase inhibitor sunitinib malate. Urol Int. 2010, 85 (4): 475-478. 10.1159/000321175.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/12/231/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.