--Harshal Rajekar

….Why?We do see many a patient with recurrent hepato-

cellular cancer after liver resection.Especially in the setting of a chronic Liver disease….

Hep B, Hep C, ETOH liver disease……etc.Quite a few patients are unable to undergo L Tx due

to extensive disease, and probably the chances of recurrence after LTx would be increased in the event of aggressive HCC.

Often the extent of liver cirrhosis is not apparent on clinical grounds alone. Having had a look at the liver at surgery, and of course, the microscopic assessment of the activity of the liver disease, affords a better judgement.

……Liver Transplant for HCC?Liver transplantation is accepted as the

treatment of choice for HCC in cirrhotics.Defined criteria for transplantation in HCC,

- Milan criteria. - UCSF criteria.Attempt to extend criteria beyond the existing

ones has met with reasonable success.Provides the best chance of long term cure,

with treatment of the primary liver problem.

What is the optimal treatment for Hepatocellular Cancer in patients with Liver disease?

Evidence in literature that Liver transplantation resection have similar 5-year survival after treatment for HCC. (in Child’s A patients)

However, 5-yr recurrence free survival is dismal after resection, as compared to liver transplantation.

But patients assigned to the waiting list for transplantation for HCC stand the risk of drop-out or disease progression while waiting.

Poon RT, Fan ST, Lo CM, Liu CL, Wong J.Difference in tumor invasiveness in cirrhotic patients with hepatocellular carcinoma fulfilling the Milan criteria treated by resection and transplantation: impact on long-term survival.Ann Surg. 2007 Jan;245(1):51-8.

Multivariate analysis showed that hepatitis C virus serology, tumor size, tumor number, and microscopic venous invasion, but not resection or transplantation, were of prognostic significance.

There were significant differences in tumor invasiveness in HCC treated by transplantation and resection as a result of selection bias, even in patients with the tumors fulfilling the Milan criteria.

When the different tumor invasiveness was taken into account, there was no significant difference in the long-term survival after resection or transplantation.

Resection v/s primary liver transplantation…..RESECTION OF HCC:Patients assigned to liver transplant waiting lists run

the risk of not receiving a donor liver, in which case their survival is predicted to be poor.

Survival after resection in a group of patients with advanced tumors is worse than that after transplantation.

Recurrent HCC occurs in 50% to 80% of patients at 5 years after resection, with the majority occurring within 2 years.

LIVER TRANSPLANT:Transplantation seems to be superior because it

treats the underlying liver disease and the HCC.

Drawbacks of Liver transplantation for HCC……?progression of disease/ drop-out while on waiting list.Shortage of donor organs.Risk to living donor in case of LDLT.Cost of transplant surgery.Long term immuno-suppression.

And, the same factors responsible for high And, the same factors responsible for high recurrence rates after surgical resection of recurrence rates after surgical resection of hepato-cellular- cancer; are implicated for high hepato-cellular- cancer; are implicated for high recurrence rates after liver transplant. ….. Viz, recurrence rates after liver transplant. ….. Viz, vascular invasion, large tumour size, poorly vascular invasion, large tumour size, poorly differentiated tumors and serosal involvement differentiated tumors and serosal involvement at the time of surgery.at the time of surgery.

Possible predictors of recurrence of HCC after resection on the background of pre-existing Liver disease…..Various indices have been described to predict the

risk of recurrence/ prognosis of HCC after resection……

1.CLIP (Cancer of the Liver Italian Program).2.BCLC (Barcelona Clinic Liver Cancer) staging.3.Okuda classification.4.TNM , the AJCC staging system.5.CUPI (Chinese Univ. Prognostic Index).6.JIS (Japanese Integrated Score) system.7.S Li De score (stage, liver damage and des-gamma-

prothrombin level).8.?MELD score.

TW Chen, et al (Taiwan)European Journal of Surgical Oncology ;Volume 33, Issue 4, May 2007, Pages 480-487.In our patient cohort, the CLIP and JIS systems gave better

results than did the other staging systems. The discriminatory ability of the CLIP and JIS staging for death, evaluated by ROC curve areas, was also better. In the subgroups of major hepatectomy patients with a non-cirrhotic liver or minor hepatectomy patients with a cirrhotic liver, the CLIP and JIS systems showed similar better performances in these three tests. The discriminatory ability of the CLIP system was the best in major hepatectomy patients with a non-cirrhotic liver while JIS score discriminated best in minor hepatectomy patients with a cirrhotic liver.

Thus, scoring systems which consider tumour factors, Thus, scoring systems which consider tumour factors, in addition to severity of the background liver disease in addition to severity of the background liver disease

are better able to predict the prognosis after are better able to predict the prognosis after resectionresection..

Shirabe K, and others; (Japan)Clinicopathological risk factors linked to recurrence pattern after curative hepatic resection for hepatocellular carcinoma--results of 152 resected cases. Hepatogastroenterology 2007 Oct-Nov; 54(79):2084-7.The risk factors for patients with >4nodules were high levels

of ALT, low Albumin, high values in the ICG retention test at fifteen minutes, hepatitis C antibody positivity. low platelet counts, and high histological hepatitis activity. The risk factors for patients with <4 nodules were large tumor size, histological presence of vascular invasion by cancer cells, intrahepatic metastasis, and poor differentiation.

CONCLUSIONS: The risk factors linked to recurrence with no more than three HCC nodules recurrence were related to host-related factors such as hepatic function, and hepatitis activity, but not tumor related. The risk factors linked to multiple recurrence were tumor related. The analysis of recurrence patterns revealed that completely different mechanisms exist in the patients with recurrence involving no more than four nodules, which may be related to multicentric occurrence, and patients with multiple recurrence, which may be related to the metastasis of cancer cells.

Risk Factors for Different Patterns Risk Factors for Different Patterns of Recurrence after Resection of of Recurrence after Resection of Hepatocellular Carcinoma:Hepatocellular Carcinoma:Kaibori, et al; Kansai Med Univ.; Japan described in

Anticancer Res. 2007 Jul-Aug;27(4C):2809-16.higher levels of protein induced by

absence/antagonism of vitamin K-II, larger tumors, more poorly differentiated tumors, intravascular invasion,Younger patients,Activity of liver disease ……..

All these co-related with prognosis, and All these co-related with prognosis, and recurrence with aggressive disease.recurrence with aggressive disease.

Salvage transplantation

Secondary transplantation.

Both terms have been used interchangeably causing some confusion in drawing up conclusions………

Sala M, Fuster J, et al; Barcelona Clinic Liver Cancer (BCLC) Group.High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation.Liver Transpl. 2004 Oct;10(10):1294-300.

1. 2 major pathways leading to recurrence: tumor dissemination prior to operation and de novo tumor development in an oncogenic cirrhotic liver.

2. With recurrence, less than 20% of the patients are candidates for salvage L Tx.

3. The risk of recurrence can be accurately predicted by pathologic examination of the resected tissue. Micro-vascular invasion and presence of satellite nodules are thought to be related to unrecognized tumor spread prior to resection, and interestingly, those transplanted patients in whom pathology examination depicts these pathologic high risk parameters do not present a prohibitive rate of disease recurrence during follow-up.

…the findings…..:-During the period of the investigation, we operated on 77

patients and 17 of them qualified as candidates both for resection and LT. According to our treatment strategy, they were offered resection as primary treatment, and based on the pathologic findings, 8 patients were classified at high risk and 9 at low risk. All but 1 of those at high risk showed recurrence either prior to LT (n = 2) or in the explanted liver in the absence of disease on imaging techniques (n = 3). 2 patients did not accept to be enlisted who developed multi-focal recurrence.

In addition, we have also evidenced that this policy offers an adequate long-term outcome. Only 1 patient developed massive or extensive tumor dissemination after LT and died 4 months after the operation. The other 4 patients have been followed for a median of 45 months and show no tumor recurrence, there being only 1 death at 84 mths due to recurrent HCV cirrhosis.

On the other hand, the outcome of patients classified as low risk has also been encouraging. Only 2 out of the 9 patients in this group have recurrence.

Probable advantages of this approach……:-1. Could serve as a bridge to liver transplant for those

candidates who are deemed suitable.2. The initial resection of the tumour gives an accurate histo-

pathological analysis of the tumour, and the underlying cirrhosis… i.e. grade of tumour, differentiation, micro- and macro-vascular invasion, lymphatic invasion, mitotic activity, satellite nodules, margins of resection and also the activity of background liver disease (inflammation/ viral hepatitis).

3. Most patients with chronic viral hepatitis in Childs A status, the severity of the background liver disease is not clinically apparent.

4. Patients are divided into low-risk and high risk for recurrence groups. Those in the low risk (not offered L Tx) can be offered a transplant if and when recurrent disease is found.

Disadvantages of transplantation after resection of HCC….:-Surgery technically more difficult.Increased peri-operative blood transfusion

requirement.Increased operative time, and cost.Increased time needed in ICU.Increased peri-operative morbidity and mortality .

Recurrence rates are probably higher once natural selection bias has been ruled out…. And depend on tumour charachteristics.