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Bhangui et al. Hepatoma Res 2020;6:71 I http://dx.doi.org/10.20517/2394-5079.2020.67 Page 11 of 15

benefit following surgery in patients with HCC recurrence post LT could of course be challenged, as only
some patients with a limited disease burden may be amenable to resection.

Lung is the most common site of recurrence, probably owing to proximity to the liver at the time of
[45]
hepatectomy, and the lymphatic drainage . In our study, we also observed that lungs were the most
frequent site of HCC recurrence. Resection of pulmonary metastases is often not attempted owing to their
multiplicity, frequent multiorgan involvement, and unclear impact on survival. However, some centers have
reported good outcomes of pulmonary metastases resection (PMR) in patients treated by liver resection
or ablative procedures for the liver recurrence [24,46,47] . In a large series of pulmonary metastatectomy cases
[48]
post LT, Hwang et al. showed that those patients who were selected for surgery based on the feasibility
of complete resection and sufficient pulmonary function after surgery, the 5-year survival rate was
[45]
significantly better. A large Italian multicenter study found that pulmonary metastatectomy with a low
complication rate was feasible in patients who were judged operable when they developed pulmonary
metastasis as the first metastasis after LT for HCC. One year, 3-yr, and 5-yr cumulative overall survival rates
of 100%, 66%, and 43%, respectively, were reported in this study, with a median OS of 51 months. They
selected patients with lung only metastasis, and a good liver function for surgery. Repeat metastatectomy
for recurrence after the first surgery has also been proposed [49-53] . In the 5 patients who underwent VATS
resection of pulmonary metastases in our series, the median survival post recurrence was 18 months (range
10-52 months). When pulmonary metastatectomy is precluded by inadequate lung function, SBRT is
considered an alternative .
[54]
Ablative therapy in the form of RFA or MWA , TACE , and TARE using Yttrium-90 microspheres (Y-90)
[56]
[55]
[57]
for unresectable intrahepatic HCC recurrence , have also occasionally shown good results. A retrospective
cohort study compared results in 15 patients who were treated with surgery vs. 11 who underwent RFA
[58]
for intrahepatic recurrence . A similar 3-year (51% vs. 51%, P = 0.88) and 5-year (35% vs. 28%, P = 0.88)
overall survival was reported in the two groups. Zhou et al. prospectively compared TACE vs. systemic
[59]
therapy in patients with unresectable intrahepatic recurrence. Survival benefits were achieved in the TACE
arm (P = 0.013), indicating that regional control could have contributed to the improvement in overall
survival.

Ablative treatment modalities are usually safe and well tolerated, and may be repeated multiple times or
combined in a multimodality approach. Some also propose that early intrahepatic HCC recurrences may
be better “tested” by a locoregional treatment, prior to performing a resection, provided no further disease
[60]
appears in the mean time .

Use of non-invasive radiotherapy such as SBRT is also effective for local control of pulmonary and
skeletal oligo-recurrences. Similarly, focused ablation of intrahepatic HCC recurrence spares the adjacent
normal liver parenchyma. A higher dose of radiation is delivered while the risk of collateral damage
[61]
is minimized . An abbreviated duration of treatment with SBRT (usually completed in 1-5 fractions)
compared to the 10-20 days for conventional radiotherapy (during which systemic therapy is usually
deferred) is an added advantage. It is now also established in pre-clinical models that stereotactic radiation
may up regulate antitumour immunity [62-64] .

Results of our analysis also emphasized the utility of multimodality treatment. including systemic therapy
combined with surgery/ablation/radiotherapy. In 32 patients undergoing resection or ablative treatment
in addition to systemic therapy, the post recurrence survival was superior to systemic therapy alone. This
is in line with the limited studies that have been published on this topic [65-67] . It is however also true that
resection or ablation is not possible in all patients with recurrence, especially in those with recurrence
at multiple sites or multiple nodules at the time of recurrence. One may argue that due to this reason,