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Page 10 of 15 Bhangui et al. Hepatoma Res 2020;6:71 I http://dx.doi.org/10.20517/2394-5079.2020.67

and should be performed using modalities that are highly sensitive and specific (whole body FDG-18 PET
scan with triphasic CT angiography abdomen, or contrast computed tomography abdomen and chest with
bone scan). In our study, we found that 68% of recurrences occurred within two years following LT, which
is in accordance with other studies (median time of recurrence 7-36 months) [23-27] .

Sorafenib is known to confer some survival benefit in patients with disseminated recurrence (median
survival of 12 months) [28-33] , but is also associated with some drug limiting side effects. Combined
with mTOR inhibitors, the synergistic effect shows a trend towards better tumour response. High
dose CNI exposure has been shown to be a risk factor for HCC recurrence. Hence, an mTORi based
immunosuppression strategy with reduced CNI has been proposed in HCC patients post LT to reduce
[35]
[34]
recurrence and improve survival benefit as demonstrated in a meta analysis . Sirolimus is generally
well tolerated. Recently, studies using everolimus in both the deceased donor and living donor LT scenario
[36]
have shown a tendency towards lower recurrence . A recent meta analysis comparing everolimus and
sirolimus showed lower recurrence rates in patients on everolimus compared to those on sirolimus or
[37]
calcineurin inhibitors. However, everolimus-treated recipients had a shorter follow-up time and fewer
advanced tumours in the above study. Though data on mTOR inhibitor therapy for established recurrence
after liver transplantation remain scarce, a combination of either sirolimus or everolimus with reduced-
dose tacrolimus may prove beneficial in addition to sorafenib [36,38,39] . Our study showed that recurrence
at multiple sites was a poor prognostic factor for survival post recurrence. In patients with recurrence at
multiple sites where no form of directed therapy is possible, combining TKI’s with mTORi’s, with initial
reduction in CNI dose and then stopping it, may prolong survival. In patients with recurrence who are
not already on mTORi’s, therapy is initiated (initially at a dose of 0.75 mg BD Everolimus or 1 mg OD of
Sirolimus) and maintained with trough levels of 3-5 ng/mL. CNI’s doses are gradually reduced and then
omitted. If required, the patient is additionally maintained on mycophenolate mofetil in a low dose and
titrated based on liver function.

We tried to analyze the change in AFP levels (response to treatment) in our cohort of patients. We looked
at the initial AFP (pre-LDLT) level, AFP at recurrence, and evolution with treatment. AFP was high (> 50 ng/mL
in 57 patients, > 100 ng/mL in 47 patients) in only 50-60% of patients at the time of LDLT (AFP secretors)
itself. Of the 48 patients with AFP > 100 ng/mL at the time of LDLT, only 20 patients presented with high
AFP levels at the time of recurrence, and only 12 patients had AFP levels that were similar to or higher
than those pre LDLT. This could probably be due to early detection of recurrences using a stringent follow
up protocol. Due to this low number of patients with high AFP levels at the time of recurrence, we could
not draw any definite conclusions with respect to change in AFP levels post treatment. Patients who had
high AFP levels were those who had recurrence at multiple sites. Patients whose AFP levels responded
(decreased) to treatment had a longer survival, and most had been treated with a combination of Sorafenib
and Sirolimus.

[40]
In patients who progress on sorafenib, regorafenib may be used as a second-line agent . The utility of
checkpoint inhibitors as immunotherapy in transplant recipients may appear promising, but also poses
[41]
challenges due to the potentially increased risk of allograft rejection and graft loss .

Surgical resection or ablation of HCC recurrence (as opposed to systemic or palliative therapy alone)
has been shown to be an independent predictor of long-term survival if recurrence is isolated to a single
organ, whether it is in the liver or an extrahepatic site [14,22-24,42-44] . Post-LT HCC recurrences develop in
non-cirrhotic livers without portal hypertension, thus qualifying most patients for surgery. Most studies
have shown that resection is safe and significantly prolongs survival after HCC recurrence as compared to
palliative treatment. In a recent study, Fernandez-Sevilla et al. reported a median survival of 35 months
[22]
(vs. 15 months) in patients with resection (vs. non resection) of intra- and extrahepatic recurrences. Actual