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Paper text:
a 54-year - old gentleman with cirrhosis and end - stage liver disease secondary to chronic hepatitis c presented for evaluation for liver transplantation .
the patient was first diagnosed with hepatitis c in 1990 , and subsequently diagnosed with cirrhosis in 1991 by liver biopsy . at that time
he was briefly treated with interferon , but sustained a severe allergic reaction following his fourth dose prompting discontinuation . in february of 2007
a computed tomographic ( ct ) scan was performed which demonstrated a small , irregular - appearing liver consistent with cirrhosis , but no liver masses were appreciated and the portal venous system was patent ( fig . 
level was noted to be elevated at 7,100  ng / ml in september of 2007 .
a ct scan was repeated in october of 2007 and demonstrated thrombus within the left portal vein ( fig . 
magnetic resonance imaging of the liver was performed and demonstrated cirrhosis with left portal vein occlusion .
a heterogeneous nodular mass had replaced the entire left lobe of the liver and the caudate lobe of the liver with evidence of increased enhancement .
there was another heterogeneous lesion with abnormally increased signal intensity in the medial segment of the left lobe measuring 2  cm in diameter .
a metastatic evaluation was negative and a repeat afp level was 24,100  ng / ml . the patient was referred to an outside institution for transplant evaluation , and was deemed unsuitable due to evidence of an infiltrating form of hcc with evidence of portal vein thrombosis . by december of 2007 ,
the patient 's afp level had increased to 194,000  ng / ml . a ct scan at that time demonstrated extensive thrombus within the main portal vein near the bifurcation that extended into the right and left portal veins .
sorafenib was started at a dose of 400  mg twice daily in january of 2008 .
the afp level decreased to 84,800  ng / ml and continued to exhibit a remarkable decline to 7,300  ng / ml by february of 2008 , and 117  ng / ml by march of 2008 .
as the patient developed leukopenia and thrombocytopenia , his sorafenib dose was reduced to 200  mg twice daily . by april of 2008
this was further reduced to 200  mg a day , and ultimately to 200  mg twice weekly , on which he is currently maintained . by may of 2008 ,
his afp level was 3.7  ng / ml , and subsequent testing at monthly intervals have shown a persistently low afp level between 3 and 5  ng / ml ( table  1 ) . 

1ct scan of the abdomen july 2007 demonstrating a cirrhotic liver , and no evidence of portal thrombus ( a ) .
follow - up ct scan of the abdomen performed october 2007 demonstrating thrombus within the left portal vein ( b , arrow)table  1afp levels in a patient with hccsorafenib therapy was initiated in january of 2008 ( red arrow ) resulting in a remarkable decrease in afp levels , which have persisted ct scan of the abdomen july 2007 demonstrating a cirrhotic liver , and no evidence of portal thrombus ( a ) .
follow - up ct scan of the abdomen performed october 2007 demonstrating thrombus within the left portal vein ( b , arrow ) afp levels in a patient with hcc sorafenib therapy was initiated in january of 2008 ( red arrow ) resulting in a remarkable decrease in afp levels , which have persisted the patient was subsequently referred to our institution for consideration for transplantation in march of 2009 . on evaluation he reported mental slowing and difficulty with memory , and
laboratory testing at that time was significant for a platelet count of 57,000 , an international normalized ratio of 1.4 , serum albumin of 3.0 , total bilirubin of 2.1 , ast of 76 , alt of 68 , alkaline phosphatase of 50 , and an afp level of 3.4  ng / ml . his calculated model for end - stage liver disease ( meld ) score was 13 .
the patient underwent exploratory laparoscopy and was found to have a grossly cirrhotic liver with no definitive mass appreciated .
intraoperative laparoscopic ultrasound examination of the liver did visualize an area in segment 4 that consisted of a nest of abnormal blood vessels .
this area was thoroughly biopsied , following which radiofrequency ablation was performed due to concern for malignancy .
notably , all of the liver biopsies demonstrated cirrhosis with focal scar and chronic inflammation , and no evidence of carcinoma .
follow - up imaging in october of 2009 demonstrated a well - defined area of peripheral low density involving the anterior aspect of segment 4 of the liver , which corresponded to the site of prior rfa ablation .
just medial to this ablation site was an area of more ill - defined low density , which was suspicious for residual / recurrent tumor .
a non - occlusive thrombus involving the splenic vein , extending to the portosplenic confluence was noted .
in addition , non - opacification of the left portal vein , with numerous associated collaterals consistent with cavernous transformation , was appreciated .
the main portal vein and right portal vein were patent . as the patient s tumor burden decreased to within the milan criteria , and as he had demonstrated stability at that tumor burden , the patient was subsequently listed for transplantation with meld exception points .
hepatocellular carcinoma ( hcc ) is the third most common cause of cancer mortality worldwide , with a 626,000 new cases reported yearly .
the incidence of hcc remains high in asia and parts of africa , but there is clear evidence of increasing incidence in the usa and europe , likely related , at least in part , to an increasing incidence of hepatitis c infection . although hcc can present in a patient with a noncirrhotic liver , cirrhosis remains the main risk factor that predisposes to the development of hcc .
although surgical resection remains an accepted form of therapy for noncirrhotic patients with hcc , liver transplantation currently remains the optimal treatment for the cirrhotic patient .
early results with liver transplantation were unfavorable , plagued by poor survival rates and a high incidence of post - transplantation recurrence .
defined a subset of patients with unresectable hcc for whom liver transplantation was the appropriate treatment , now referred to as the  milan criteria  .
transplantation within the milan criteria ( single tumor 5  cm in diameter , or two to three tumors 3  cm in diameter ) resulted in overall and recurrence - free survival rates of 85% and 92% , respectively , at 4  years .
liver transplantation for hcc with tumor burden within the milan criteria has gained wide acceptance as a legitimate , and optimal , treatment .
the excellent results obtained subsequently prompted further investigation into whether the milan criteria could be expanded to include patients with a larger hcc tumor burden . in 2001 , yao et al . proposed expansion of the milan criteria for hcc liver transplant candidates .
termed the ucsf criteria , these patients had a single tumor 6.5  cm in diameter , or two or three tumors none exceeding 4.5  cm in diameter and whose sum of tumor diameters did not exceed 8  cm .
patient transplanted within the ucsf criteria demonstrated 1- and 5-year survival rates of 90% and 75% , respectively , results which were equivalent when compared with survival rates of those transplanted within the milan criteria .
the shortage of organs , in conjunction with the risk of hcc progression beyond the milan criteria prompting dropout from the liver transplant waitlist , has fueled investigation into a wide array of locoregional therapies for the management of hcc in candidates awaiting liver transplantation .
these therapies range from surgical resection , cryotherapy , radiofrequency ablation , percutaneous ethanol injection , microwave ablation , interstitial laser coagulation , and transarterial chemoembolization .
locoregional therapy has been proposed as a strategy to not only retard hcc progression and prevent dropout from the transplant waitlist , but also as a means of downstaging patients to within milan criteria , and thus achieve eligibility for transplantation .
in addition , pre - transplant locoregional therapy may serve a role in improving survival following liver transplantation for hcc .
data from the scientific registry of transplant recipients demonstrated improved patient and graft survival rates at 3  years for patients with hcc treated with pre - operative locoregional therapy , when compared to untreated patients ( patient survival , 79% versus 75% , p  =  0.03 ; graft survival , 76% versus 71% , p  =  0.03 ) .
indeed , to achieve complete tumor necrosis may require multiple sessions , or even multiple forms , of locoregional therapy .
therapy not only serves as a bridge for those patients within the milan criteria awaiting transplantation , but also may allow for those patients with tumors beyond the milan criteria to obtain eligibility for transplantation by demonstrating a response to locoregional therapy .
hcc is highly refractory to traditional cytotoxic chemotherapy , with no evidence to date of a survival benefit from its use [ 8 , 9 ] .
the relatively chemo - resistant phenotype has prompted further investigation into the use of novel small molecule drugs for improved clinical efficacy in the treatment of hcc .
recently , the sharp trial , a large randomized phase iii study of patients with biopsy - proven advanced hcc , was completed . in this study , patients were randomized to receive either oral sorafenib or a placebo .
sorafenib ( nexavar , bayer healthcare pharmaceuticals  onyx pharmaceuticals ) , a small molecule multi - kinase inhibitor , acts via inhibition of tumor - cell proliferation and tumor angiogenesis , as well as augmentation of the rate of apoptosis .
the sharp trial was the first randomized systemic therapy trial in patients with advanced hcc which demonstrated an overall , albeit modest , survival benefit .
patients receiving sorafenib , versus the placebo group , demonstrated improvement in both overall survival ( median 10.7  months versus 7.9  months ) as well as time to progression ( median 5.5  months versus 2.8  months ) .
a second phase iii study of sorafenib versus placebo was completed in an asian - pacific population , and also demonstrated significant improvement in overall survival ( median 6.5  months versus 4.2  months ) as well as progression - free survival ( median 2.8  months versus 1.4  months ) in patients treated with sorafenib versus placebo , respectively .
we present a remarkable case of hcc tumor response to adjuvant sorafenib therapy , with effective downstaging to allow for liver transplant listing .
although there has been demonstration of improved survival in patients with unresectable hcc treated with sorafenib , the tumor response rate of patients with hcc treated with sorafenib has remained low ( 2% ) .
however , it remains to be determined whether sorafenib , in conjunction with locoregional therapy , can prove to be either effective in preventing progression beyond the milan criteria or facilitating downstaging to within the milan criteria , in patients with hcc awaiting liver transplantation [ 12 , 13 ] .
hepatocellular carcinoma ( hcc ) remains a common cause of mortality worldwide . 
 liver transplantation has emerged as the optimal treatment for cirrhotic patients with hcc ; however , the shortage of donor organs leaves waitlisted patients at risk for disease progression beyond transplant criteria . 
 prevention of waitlist dropout has fueled investigation into a wide array of locoregional therapies for the management of hcc in candidates awaiting liver transplantation . 
 we present a patient with hcc who underwent treatment with sorafenib , which resulted in a remarkable reduction in tumor burden to allow for liver transplant listing .