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Outcomes of salvage liver transplant for recurrent hepatocellular carcinoma: A comparison with primary liver transplant

Backgrounds/Aims Salvage liver transplantation (SLT) is a therapeutic strategy for recurrent hepatocellular carcinoma (HCC). However, it remains controversial with compromised survival outcomes and increased perioperative morbidity compared to primary liver transplant (PLT). In the present work, we describe our institution's experience on SLT by comparing outcomes of SLT to PLT for HCCs. Methods Retrospective analysis was conducted for 49 transplant patients from 2006–2017. A comparative analysis was carried out between 14 SLT patients and 35 PLT patients. Results SLT patients demonstrated significantly shorter time to recurrence than PLT patients (median=5.5 versus 23 months, p<0.001) with a trend towards increased perioperative major morbidity (42.9% versus 37%, p=0.711), inferior 5-year overall survival (61% versus 75%, p=0.345) and inferior 5-year recurrence-free survival (57% versus 72%, p=0.263). However, overall survival from the point of primary resection over a 10-year period showed no statistical difference between the 2 groups (SLT=60% versus PLT=61%, p=0.685). Conclusions SLT is a viable treatment strategy for HCCs. However, it exhibited poorer short-term perioperative and oncologic outcomes than PLT. SLT requires better patient selection with liver donor grafts for optimization of resource allocation in this era of organ shortage. Considering the worldwide shortages in liver grafts, it is hypothesized that optimization of a salvage transplant strategy may improve resource allocation and reap optimal patient outcomes.


INTRODUCTION
Hepatocellular carcinoma (HCC) remains a leading cause of death from cancer worldwide. 1 While hepatic resection and liver transplantation are curative options, the most optimal treatment modality remains debatable. Liver resection is hampered by high recurrence rates of up to 76%. 2,3 Though primary liver transplantation (PLT) for small resectable HCCs shows favourable survival and disease-free outcomes, its utility is restricted by the limited availability of liver grafts. 4,5 In view of worldwide organ shortage, a salvage liver transplant (SLT) strategy was proposed earlier. For an SLT, hepatic resection is performed as a first-line treatment for HCC and liver transplantation is reserved in the event of tumour recurrence or deterioration in liver function. 2,5 However, several concerns were raised regarding a salvage strategy. Firstly, SLT may be associated with higher perioperative morbidity and mortality due to the technical complexities as a result of dense adhesions and portal hypertension in patients. [6][7][8][9] Secondly, long-term oncological outcomes of SLT for recurrent HCC may be poorer compared to PLT, which potentially leads to organ wastage. 9 Finally, potential SLT and PLT patients run the risk of disease progression beyond criteria while waiting for an available organ. 3,5 Hence, due to limited graft availability, repeat liver resection (RLR) has been widely adopted as a viable alternative to SLT for recurrent HCC. 10,11 However, the feasibility of RLR for recurrent HCC is limited by the adequacy of future liver remnant and liver function. RLR is also associated with a high risk of cancer recurrence. [12][13][14][15] Several studies compared SLT as an integrated strategy to PLT with varying conclusions. Some of the studies associated SLT with poor survival outcomes and greater morbidity 6,16,17 while others supported SLT as a safe and feasible option enabling an effective resource allocation. 17,18 Considering the controversies surrounding SLT, we initiated the present study to evaluate our institution's experience with patients undergoing SLT and to compare their outcomes with patients undergoing PLT for HCC.

RESULTS
Comparison between the two groups demonstrated no significant difference in patient characteristics including age, gender, underlying aetiology and Child-Pugh status.
Moreover, there was no significant difference in baseline tumour characteristics such as frequency of tumours within Milan criteria, tumour size, AFP and previous locoregional treatment including radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and Yttrium-90 (Y-90) radioembolization between the groups ( Table 1).
The two groups were similar in the pathological features of the explanted liver with regards to frequency of cirrhosis, largest tumour size, number of nodules, tumour differentiation, microvascular invasion and satellite nodules.  Fig. 1A) and RFS (PLT=72%    Fig. 1C).

DISCUSSION
In this study, we investigated the viability of SLT as a treatment strategy for recurrent HCC based on the comparison of survival outcomes and perioperative morbidity with that of PLT. Liver transplant is perceived to be the superior treatment modality for HCCs with regards to its improved overall survival and significantly lower cancer recurrence rate. [21][22][23] However, the implementation and success are dependent on the availability of specialised transplant expertise and availability of liver grafts.
In the field of transplantation, comparisons between PLT and SLT frequently surfaces with PLT emerging as superior in prolonging life expectancy than SLT with lower perioperative morbidity. 6,9 SLT was reported to be more technically challenging than PLT, as previous hep- As demonstrated in Table 2, 42.9% of our SLT patients required reoperation compared to 20% of the PLT group, for which, bleeding was the predominant reason for a repeat operation. The reoperation figures, though statistically insignificant, were in general, higher than those reported in the literature (PLT=3-13% and SLT=0-39%). 6,17 We postulate that the relatively high reoperation rates a potential gain in survival and cost-effectiveness. 26 In the absence of a suitable liver graft, however, RLR is a potentially safe and viable option as it offers a bridge to eventual SLT. 27 Though secondary to transplant in terms of disease-free survival benefit, its outcomes may be better Although the data from the present retrospective study is largely congruent to previous papers, it is limited due to a small sample size that prevents the study from being adequately powered in detecting true statistical significance.
Selection bias may be inherent in the matching process as part of a non-randomized retrospective study and incorporating patients beyond the Milan criteria together with the simultaneous application of multiple treatment modalities (i.e., locoregional treatment) may confound overall analysis. Nevertheless, these results may be useful in guiding clinicians and patients for or against SLT.
Patients should be advised about the risks and benefits of each therapeutic strategy in making an informed decision with respect to the availability of liver grafts. Even as transplant shows benefit in RFS and should be offered as a first-line treatment for a selective group of patients, we are limited by scarce liver grafts which emphasises the need for risk stratification and resource allocation so that their utility reaps the most benefit.
In conclusion, SLT is a viable treatment option for the management of HCCs. However, it exhibited poorer shortterm perioperative and long-term oncologic outcomes compared to PLT. Better patient selection is needed for SLT especially with regards to deceased donor grafts in order to optimize resource allocation in this era of organ shortage.