• recurrence rates of HCC after liver transplant are disappointing, (though improvement in outcomes are seen with better case selection) approx 5-year survival rates of 60-80% and recurrence free survival rates of 60-65% when selection criteria are strictly followed.

• recurrence rates of HCC after liver transplant are disappointing (though improvement in outcomes are seen with better case selection).• accepted selection criteria include the Milan criteria and the UCSF criteria.• many patients do not meet the selection criteria.

• recurrence rates of HCC after liver transplant are disappointing (though improvement in outcomes are seen with better case selection).• accepted selection criteria include the Milan criteria and the UCSF criteria.• many patients do not meet the selection criteria.• with LDLT, the demand for liver transplantation for HCC is probably increased, and there has been an attempt to extend selection criteria beyond existing ones.

• recurrence rates of HCC after liver transplant are disappointing (though improvement in outcomes are seen with better case selection).• accepted selection criteria include the Milan criteria and the UCSF criteria.• many patients do not meet the selection criteria.• with LDLT, the demand for liver transplantation for HCC is probably increased, and many times selection criteria have been extended. • Hepatic and/or extra-hepatic recurrence of the HCC obviously reduces the effectiveness of the treatment option, and also is not acceptable in terms of cost effectiveness.

Pre-transplant adjuvant therapy in the form of TACE (trans arterial chemo-embolization, or RFA (radio- frequency ablation) or PEI (per-cutaneous ethanol injection). Intra-operative adjuvant therapy, viz intra-operative chemotherapy.Post transplant adjuvant systemic chemotherapy.

Is transplantation truly superior to resection for HCC in cirrhotics?Ann Surg. 2007 January; 245(1): 51–58.Poon and others; (HK). ….. Diff in Tumor Invasiveness in Cirrhotic Patients With HCC Fulfilling the Milan Criteria Treated by Resectn and Tx. (n=240)

Tumors in the transplanted group were associated with lower incidence of high-grade tumors, microscopic venous invasion, and microsatellite nodules. The overall 5-year survival was better in the transplantation group than the resection group (81% vs. 68%, P = 0.017). However, there were no significant differences in survival between the two groups when stratified according to presence or absence of venous invasion.

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.

Biological basis for the use of adjuvant chemotherapy in the setting of Liver tx for HCC:

Cancer cells may be found in the blood of the right atrium, portal vein and peripheral circulation during hepatectomy.

(this has also been reported to occur during standard liver resection/ recipient hepatectomy for liver tumours)

Micro-metastatic disease may already exist preoperatively or disseminate iatro-genically during OLT.

HCC is moderately chemo-sensitive, and adjuvant chemotherapy may be used without significant adverse effects on the outcome.

Wong IH, Lau WY, Leung T, Yeo W, Johnson PJ.Hematogenous dissemination of hepatocytes and tumor cells after surgical resection of hepatocellular carcinoma: a quantitative analysis.Clin Cancer Res. 1999 Dec;5(12):4021-7.

showed significantly raised afp mRNA levels in postoperative peripheral blood from 9 of 13 HCC patients (70%), among which P3 and P4 showed the clearance of afp mRNA afterward. As a result, seven patients were identified to be at high risk for recurrence or metastasis. Indeed, five of these seven patients (72%) who showed persistently elevated afp mRNA levels died from lung metastasis, liver recurrence, or persistent HCC with intrahepatic metastasis within 1 year after surgery.

80% (four of five) of relapse took place in the liver, a particularly fertile ground for HCC cells to proliferate. In accordance with Paget’s "seed and soil" hypothesis, the disseminating capacity of tumor cells rather than the local outgrowth is controlled by the "soil" characteristic.

S. Marubashi, , K. Dono, Y. Sugita,and others.. (Japan, Osaka Univ.). Transplantation Proceedings Volume 38, Issue 10, December 2006, Pages 3640-3642(n=25 patients who underwent LDLT for HCC with underlying cirrhosis.)

In the patients with HCC exceeding Milan criteria (n = 15), the presence of AFP mRNA-positive cells in the peripheral blood correlated significantly with HCC recurrence (P = .033). We concluded that the presence of AFP mRNA-expressing cells could be a useful predictor of HCC recurrence in liver transplant patients.

Univariate analyses of the risk factors for HCC recurrence using the log-rank test showed that the presence of AFP mRNA-positive cells in the peripheral blood correlated with HCC recurrence both at the peri-operative and pre-operative periods (P = .037 and .007, respectively). Microscopic vascular invasion was also associated with HCC recurrence (P = .005).

Stone MJ, Klintmalm GB, Polter D, Husberg BS, Mennel RG, Ramsay MA, Flemens ER, Goldstein RM.Neoadjuvant chemotherapy and liver transplantation for hepatocellular carcinoma: a pilot study in 20 patients.Gastroenterology. 1993 Jan;104(1):196-202.

N=20, 17 pateients had tumor more than 5cm. Doxorubicin was administered preoperatively,

intraoperatively, and postoperatively at a dose of 10 mg/m2 weekly, totaling 200 mg/m2.

Eight patients died, five of recurrent tumor and three of hepatitis B. Three others remain alive 8-22 months after tumor recurrence. One patient had initial tumor recurrence in the allograft. Actuarial survival is 59% and tumor-free survival is 54% at 3 years. For the 17 patients with tumors > 5 cm, overall survival is 63% and tumor-free survival is 49% at 3 years.

ZHOU Jian, TANG Zhao-you, and others...Liver transplantation for patients with hepatocellular carcinoma at the Liver Cancer Institute of Fudan University, China.Chinese Medical Journal, 2005, Vol. 118 No. 8 : 654-659

65 patients accepted 1-6 cycles (mean: 3.1 cycles) of systemic chemotherapy when the results of liver, kidney, blood routine tests (21-58 days after transplantation, mean 28 days) were within normal limits and their general conditions were good.

A 3-day chemotherapeutic regimen was prescribed with intravenous fluorodeoxyuridine (FuDR) 300 mg/m2 qd for 3 days, cisplatin 20 mg/m2 qd for 2 days, and doxorubicin 20 mg/m2 on the first and the third day. ChemoRx repeated at an interval of 1 month.

Postoperative chemo-therapy, early cessation of prednisolone and reduction of long-term immunosuppressive drugs may reduce the risk of tumor recurrence in patients with HCC after OLT.

1- and 2- year cumulative survival rates were 90.0% and 65.6%, and their disease-free survival (DFS) rates 77.5% and 62.5%, respectively.

N J De La Revilla, et al.Transplantation Proceedings ; Usefulness of chemotherapy as prophylaxis of tumor recurrence after liver transplantation in advanced hepatocellular carcinomas.Volume 35, Issue 5, August 2003, Pages 1830-1831

N=10 patients with aggressive HCC, exceeding the Milan criteria.

The chemotherapy regimen used adriamycin (20 mg/m2 weekly for 20 weeks). Six patients were stage IVA and four stage III.

Disease-free survival rates were 83% in patients with well-differentiated hepatocellular carcinoma at 3 yr and 25% in those with moderately differentiated hepatocellular carcinoma. Tolerance of chemotherapy was good.

The use of adriamycin in patients undergoing liver transplant due to advanced hepatocellular carcinoma may be useful to prevent tumor recurrence; it is well tolerated. The presence of vascular tumor invasion and a lower grade of histologic differentiation were associated with a poor prognosis.

Pre transplant adjuvant therapy:-

AIM OF NEO-ADJUVANT THERAPY:

1.Downstage the tumour?2.Waiting for a cadaveric transplant….3.Extension of criteria used to allocate livers…..?4.Truly adjuvant…. i.e. therapeutic to improve

outcomes of Liver transplantation.

U. Cillo, A. Vitale, and others (2007) Intention-to-Treat Analysis of Liver Transplantation in Selected, Aggressively Treated HCC Patients Exceeding the Milan Criteria. American Journal of Transplantation 7 (4), 972–981.

Aggressive pre-op adjuvant therapy was given, as a bridge to liver transplantation. All tumours were biopsied, and tumours with poor differentiation were excluded from the list.

N=100.Neo-adjuvant treatments used: 1. RFA.2. PEI (used for smaller lesions, and also lesions close to

vascular structures.3. TACE (multi-focal tumours, without vascular anomalies,

and moderately well preserved liver function).4. n=100, of which 40 patients exceeded Milan criteria; of

which 68 underwent liver transplants. The remaining were either excluded, or developed progression of disease, or had no biopsy, or are still awaiting transplant.

The Milan criteria did not prove to be a significant predictor of dropout probability or survival rates using Cox's analysis. Cumulative dropout probability at 6 and 12 months was 0% and 4% for MILAN OUT, and 6% and 11% for MILAN IN. The intention-to-treat survival rates at 1 and 3 years were 95% and 85% in MILAN OUT, and 84% and 69% in MILAN IN. None of the 68 transplanted patients had recurrent HCC after a median 16-month follow-up (0–69 months). In conclusion, LT may be effective for selected, aggressively-treated HCC patients exceeding the Milan criteria.

Role of pre-transplant TACE : survival advantage? -Bridge to transplant?

In conclusion, TACE followed by OLT is associated with an excellent outcome in selected patients. Furthermore, TACE is highly efficacious in preventing tumor progression while waiting for OLT. Although TACE reduced tumor preoperatively, it failed to show a Although TACE reduced tumor preoperatively, it failed to show a beneficial effect on patient survival in advanced-stage HCCs. beneficial effect on patient survival in advanced-stage HCCs. (n=48) Liver Transplantation 2003; Volume 9, Issue 6 , Pages 557 – 563. IW Graziadei et al, Innsbruck.

In conclusion, successful tumor downstaging can be achieved in the majority of carefully selected patients, but longer follow-up is needed to further access the risk of HCC recurrence after OLT. (n=16) A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Yao et al; Liver Transpl. 2005 Dec;11(12):1505-14.

TACE: therapy of the HCC before liver transplantation—experiences. Rofo. 2005 May;177(5):681-90. (German) Herber et al... The sequential TACE is an effective method for the therapy of the HCC before LTx in selected patients. A relevant downsizing could be achieved by TACE in patients with advanced HCC. Patients with larger tumors showed a significantly stronger size reduction after TACE. The recurrence The recurrence rate and the survival rate for patients with advanced or small rate and the survival rate for patients with advanced or small tumors do not differ.tumors do not differ.

..

Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis. Majno PE et al.; Ann Surg. 1997 Dec;226(6):688-701. Downstaging or total necrosis of the tumor with TACE occurred in 62% of the cases and was associated with improved disease-free survival both after liver resection and transplantation. In liver resection, TACE was also useful to improve the resectability of primarily unresectable tumors. In liver transplantation, downstaging in patients with tumors >3 cm was associated with survival similar to that in patients with less extensive disease. (n=49/76 for resection and 54/111 for transp.)

Efficacy of RFA :- In conclusion, percutaneous RFA is an effective bridge to OLT for

patients with compensated liver function and safely accessible tumors. Tumor-related dropout rate and post-OLT outcome compared favorably with published controls of patients with early-stage disease. This can be attributed to the efficacy of RFA in producing local cure or curbing tumor progression during the waiting period. [Hepatology. 2005 May;41(5):1130-7, Lu DS et al..]

RFA is a safe and effective treatment of small HCC in cirrhotics awaiting OLT, although tumor size (>3 cm) and time from treatment (>1 year) predict a high risk of tumor persistence in the targeted nodule. [Ann Surg. 2004 Nov;240(5):900-9, Mazzaferro and others..]

In summary, our data show that RFA is a safe and effective treatment modality for patients with advanced cirrhosis and nonresectable HCC. The ability of RFA to prevent or delay tumor progression needs analysis, its favorable safety profile and promising efficacy make it an attractive treatment option for transplant candidates with unresectable HCC. [Liver Transpl. 2002 Dec;8(12):1165-74, Fontana et al]

Percutaneous ethanol injection:-

Often used for liver tumours <3cm or =3cm …Most often used when the liver condition itself precludes

resection.Of late has been used with RFA and TACE with probably

superior results. Combination treatments are used when the lesion is not

completely accessible or tumour size is larger.PEI seems to be safer when the lesions are situated close to

large vascular structures/ important structures.Attractive option to reduce the size of the tumour when

waiting for Liver Tx.

Efficacy of pre transplant ablative therapy in inducing tumour necrosis…

Efficacy of hepatocellular carcinoma locoregional therapies on patients waiting for liver transplantation. Moreno and others.; (Spain) Transplant Proc. 2005 Apr;37(3):1484-5. (n=13)

Most patients with solitary nodules <4 cm who received PEI had 90% to 100% tumor necrosis. Larger tumors had 25% to 30% necrosis. TACE was employed in six patients with large and/or multiple tumors, obtaining 20% to 50% tumor necrosis. RFA was employed in one case obtaining 85% necrosis (tumor of 4 cm). No serious complications occurred with any technique. According to our experience, PEI and RFA are effective locoregional therapies to treat hepatocellular carcinomas of <4 cm in patients on the waiting list. For larger tumors, their association with other techniques, such as TACE, seems adequate.

However :…….. (Retro-spective case control study, n=100 in each group.)

Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma. Liver Transpl. 2005; 11(7):767-75. Decaens T et al. (France). In the TACE group, 30 patients had tumor necrosis > or =80% on the liver explant with a 5-year survival rate of 63.2%, compared with 54.2% among their matched controls (P = 0.9). In conclusion, with a mean waiting period of 4.2 months and 1 TACE procedure, pre-LT TACE does not influence post-LT overall survival and disease-free survival.

(n=21 in each group, retro spective case control) Arterial chemoembolization before liver transplantation in patients with hepatocellular carcinoma: marked tumor necrosis, but no survival benefit? Oldhafer KJ et al.. J Hepatol. 1998 Dec;29(6):953-9.

Although preoperative chemoembolization or chemotherapy induced marked tumor necrosis, these patients showed no benefit in survival compared to historical controls.

Multi-modality adjuvant therapy for HCC with Liver Transplantation:………Ann Surg. 2002 April; 235(4): 533–539. Long-Term Results With

Multimodal Adjuvant Therapy and Liver Transplantation for the Treatment of Hepatocellular Carcinomas Larger Than 5 Centimeters. Sasan Roayaie et al. (NY.) n=43. HCC > 5 cm were selected.

Pre-operatively sub-selective TACE given with mitomycin C, doxorubicin and cis-platin.

Single intra-operative dose of doxorubicin (10 mg/sq.m at the time of re-vascularisation of the graft.

systemic doxorubicin (50 mg/m2) every 3 weeks as tolerated, for a total of six cycles, beginning on the sixth postoperative week.A significant proportion of patients with HCC measuring 5 cm or larger can achieve long-term survival after liver transplantation

in the context of multimodal adjuvant therapy. Patients with tumors measuring 5 to 7 cm have significantly longer

recurrence-free survival compared with those with larger tumors. RFS at 5 years 55% v/s 34% in those with larger

tumours.

Cherqui D, Piedbois P, et al. Multimodal adjuvant treatment and liver transplantation for advanced hepatocellular carcinoma. A pilot study. Cancer. 1994 Jun 1;73(11):2721-6.

(n=9, pros. study, 3yr actuarial survival 64%. All exceeded UCSF criteria)

Conclusions:- These results show that an aggressive adjuvant therapy can be used in association with liver transplantation in the treatment of advanced hepatocellular carcinoma without increased mortality and suggest that such a protocol could be effective in preventing tumor recurrence.

The treatment consisted of preoperative hepatic arterial chemo-embolization (iodized oil, doxorubicin, and gelatin sponge) and radiotherapy (5 Gy in one fraction immediately before surgery), and postoperative systemic chemotherapy with mitoxantrone.

What agents for chemotherapy……?Doxorubicin (Adriamycin)Cis-platin/ carbo-platin.Capecitabine, gemcitabine, and 5-FU. Interferon/ bevacizumab.Mitoxanrone. Sorafenib.

A combination of drugs is often used… a platin with doxorubicin is the most favoured combination. Recently a combination of Gemcitabine and Oxaliplatin (GEMOX) with Bevacizumab has been quite promosing with 48% progression free survival at 6 mths.

However, no survival advantage has yet been demonstrated with ChemoTh for recurrent disease.

Hence ……the need for adjuvant therapy …....

However, caution is warranted……..

Is there really a benefit? 1. At this stage numbers are probably too small. 2. Impact on viral hepatitis recurrence? 3. Effect on cost-effectiveness….?

Post-OLT adjuvant chemotherapy does not avoid tumor recurrence and its fatal consequences but may contribute to prolonged tumor-free survival among a significant proportion of patients with high-risk HCC. However, the uncertain implications on viral recurrence and the lack of control groups do not allow post-OLT chemotherapy to be recommended outside controlled clinical trials, which are clearly warranted. (n=46) (Transplantation Proceedings: E. Bernal & others; Volume 38, Issue 8, October 2006, Pages 2495-2498).

M Basanello and others., Adjuvant chemotherapy for transplanted hepatocellular carcinoma patients: impact on survival or HCV recurrence timing.Volume 35, Issue 8, Pages 2991-2994 (December 2003).N=48 pts underwent LTx, with HCC, among which 15 pts had

HCC detected only after explant histology.

One-, 3-, and 5-year overall survival rates were 100%, 85%, 79% (CT group), and 89%, 71%, 71% (no CT group), respectively. The HCV recurrence-free survival at 3, 6, and 12 months was 29%, 14%, 0% for the CT group, versus 76%, 38%, 25% for the no CT group (P =.005).

Conclusions:- Discontinuation of chemoRx in HCV-HCC patients after transplantation appears rational due to the early hepatitis C recurrence confirmed in our series. Moreover, few studies have demonstrated that CT prolongs survival of HCC transplanted patients. New pharmacological approaches are necessary to solve these questions.

To Conclude……..To Conclude……..Adjuvant therapy may be useful, but when to use and what to

use…. remains a point of contention.The optimal adjuvant therapy, or the combination of

treatments, and the sequence in which to use, remain ill-defined.

Pre-transplant TACE/ RFA is useful to prevent progression of disease, but does not confer a survival advantage.

Peri-operative chemotherapy and adjuvant chemotherapy may be useful to prevent recurrent HCC, but effect on viral (HBV & HCV) relapse rates might prove detrimental.

Rapid withdrawal of steroids is probably useful in lowering recurrence.

Case selection is probably the most important parameter, with poorly differentiated tumors and tumors with microscopic and macroscopic vascular invasion having high recurrence. Circulating peri-operative AFP-mRNA levels might be able to predict high risk subjects.