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E-JCRT CORRESPONDENCE
Year : 2015  |  Volume : 11  |  Issue : 4  |  Page : 1029

Spontaneous deep venous thrombosis: An unrecognized entity with sorafenib


1 Department of Medical and Pediatric Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
2 Department of Radiotherapy and Clinical Oncology, Swami Rama Cancer Hospital and Research, Institute, Haldwani, Uttarakhand, India

Date of Web Publication15-Feb-2016

Correspondence Address:
Irappa Madabhavi
Department of Medical and Pediatric Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat - 380 016
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.154025

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 > Abstract 


Hepatocellular carcinoma is the most common, malignant tumor of liver. Most cases of hepatocellular carcinoma are associated with either viral hepatitis or cirrhosis. But major risk factor for hepatocellular carcinoma in developing countries is mainly chronic hepatitis B. Sorafenib is one of the first-line drug which has been extensively used in metastatic and inoperable hepatocellular carcinoma. We report a rare case of spontaneous deep venous thrombosis of bilateral lower limbs as an important unrecognized side effect of sorafenib.

Keywords: Hepatocellular carcinoma, hypercoagulable state, inhibitor, multikinase thrombosis, sorafenib


How to cite this article:
Madabhavi I, Patel A, Anand A, Choudhary M, Revannasiddaiah S. Spontaneous deep venous thrombosis: An unrecognized entity with sorafenib. J Can Res Ther 2015;11:1029

How to cite this URL:
Madabhavi I, Patel A, Anand A, Choudhary M, Revannasiddaiah S. Spontaneous deep venous thrombosis: An unrecognized entity with sorafenib. J Can Res Ther [serial online] 2015 [cited 2019 Nov 22];11:1029. Available from: http://www.cancerjournal.net/text.asp?2015/11/4/1029/154025




 > Introduction Top


Hepatocellular carcinoma happens to be the commonest primary malignancy of the liver. Though amenable to cure if detected in resectable stages, most patients in India present in the advanced stages when the only form of treatment amenable is palliation. Recently, the availablity of sorafenib, an oral tyrosine kinase inhibitor has made possible the provision of effective and convinient (orally administered) mode of palliation. Though sorafenib is not capable of providing cure, it is effective in providing varying time-spans of effective palliation in forms of freedom from progression and progression free survival. In this report, we describe the case of a patient with hepatocellular carinoma who while on treatment with sorafenib developed bilateral deep vein thrombosis. This is a very rare event, and has only been reported once in the published literature before.


 > Case Report Top


A 45-year-old male presented with 1-month history of weight loss, pain abdomen, distension of abdomen, and yellowish discoloration of eyes and urine. On examination; patient was conscious; cooperative; and oriented to time, place, and person. Vitals were within normal limits and icteric tinge was noted in bilateral sclera. Mild hepatomegaly with nodular and irregular surface was present and rest of the systemic examination was within normal limit.

On investigating; patient's total bilirubin was 5.8 mg/dl and transaminase levels and rest of the liver function tests were within normal limits. Serum alpha-fetoprotein (AFP) level was 166,419 ng/ml and patient was seropositive for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) levels were within normal limit. Computed tomography (CT) abdomen showing large hypodense lesion in segment V and VI of right lobe of liver and another hypodense lesion is noted in segment VIII. Ultrasound-guided biopsy suggestive of well-differentiated hepatocellular carcinoma.

Patient was started on sorafenib 400 mg twice a day. After 15 days of starting the sorafenib, patient was symptomatically better and performance status was improving and AFP level was significantly decreased and imaging studies were suggestive of decrease in the size of mass.

But after 5 weeks of sorafenib, patient presented with pain and swelling of bilateral lower limbs. On clinical examination, Homans and Moses' sign were positive. Bilateral lower limb venous Doppler showed thrombosis of right and left common femoral vein thrombosis [Figure 1] and [Figure 2].
Figure 1: Venous doppler showing thrombosis of right common femoral vein thrombosis

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Figure 2: Venous doppler showing thrombosis of left common femoral vein thrombosis

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There was no history suggestive of trauma, bed rest, or any surgical intervention. Coagulation profile was within normal limits. Protein C, protein S, antithrombin III, factor V Leiden mutation, homocysteine levels, and antinuclear antibody (ANA) levels were within normal limits. Patient was put on injectable anticoagulants for 5 days with overlap of oral anticoagulants. After 7 days, patient was symptomatically better and there was decrease in girth of the limbs. Patient was discharged on oral anticoagulant and sorafenib.


 > Discussion Top


Hepatocellular carcinoma is the most common malignant tumor of liver. Most cases of hepatocellular carcinoma are associated with either viral hepatitis or cirrhosis. But major risk factor for hepatocellular carcinoma in developing countries is mainly chronic hepatitis B. Sorafenib is one of the first-line drug which has been extensively used in metastatic and inoperable hepatocellular carcinoma.[1]

Sorafenib is an orally available multikinase inhibitor that inhibits cell surface tyrosine kinase receptors like VEGFR-2/3, PDGFR-Beta, B-raf, C-raf, FLT-3, and RET.[2] Sorafenib inhibits cell growth in a dose- and time-dependent manner by altering the expression of genes involved in angiogenesis, apoptosis, and transcription alregulation. Sorafenib has shown an antitumor activity in hepatocellular carcinoma, renal cell carcinoma, metastatic thyroid cancer, breast, colon, and pancreas.

Toxicity profile of sorafenib is mainly skin rash, liver toxicity, fatigue, and vascular toxicity. Till now in the English literature, deep venous thrombosis has been noted only in one study in patients with advanced biliary carcinoma on sorafenib.[3],[4],[5] This is the first case report as deep venous thrombosis of bilateral lower limbs as an unrecognized side effect of sorafenib.

In underdeveloped countries like southeast Asian region, patients of hepatocellular carcinoma usually presents in late and inoperable stage of the disease. Sorafenib is one of the first-line drug which is being used frequently in metastatic and inoperable cases of hepatocellular carcinoma. Eventhough hepatocellular carcinoma itself can cause deep vein thrombosisby causing inferior vena caval thrombosis, but there was no evidence of inferior venacaval thrombosis in our patient. Sorafenib may cause deep venous thrombosis by inhibiting cell surface tyrosine kinase receptors like VEGFR-2/3, PDGFR-Beta, B-raf, C-raf, FLT-3, and RET.[2],[6]

Learning points

Sorafenib is one of the most commonly used drug in inoperable and metastatic hepatocellular carcinoma, we have to be extra cautious while using this drug in hepatocellular carcinoma patients with deep venous thrombosis.

 
 > References Top

1.
Ibrahim N, Yu Y, Walsh WR, Yang JL. Molecular targeted therapies for cancer: Sorafenib monotherapy and its combination with other therapies (Review). Oncol Rep 2012;1303-11.  Back to cited text no. 1
    
2.
Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099-109.  Back to cited text no. 2
    
3.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. TARGET Study Group Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125-34.  Back to cited text no. 3
    
4.
Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. SHARP Investigators Study Group Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90.  Back to cited text no. 4
    
5.
Bengala C, Bertolini F, Malavasi N, Boni C, Aitini E, Dealis C, et al. Sorafenib in patients with advanced biliary tract carcinoma; A phase II trial. Br J Cancer 2010;102:68-72.  Back to cited text no. 5
    
6.
Cervello M, Bachvarov D, Lampiasi N, Cusimano A, Azzolina A, McCubrey JA, et al. Molecular mechanisms of sorafenib action in liver cancer cells. Cell Cycle 2012;11:2843-55.  Back to cited text no. 6
    


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  [Figure 1], [Figure 2]



 

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