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Page 8 of 12 Mathias-Machado et al. Hepatoma Res 2021;7:67 https://dx.doi.org/10.20517/2394-5079.2021.84

TACE can implicate in severe post-embolization syndrome and severe inflammation leading to adhesions.
Therefore, current evidence is insufficient to determine which patients will develop a satisfactory response
and, thus, would be an adequate candidate for such therapeutic approach.

Transarterial radioembolization
Transarterial radioembolization (TARE) is an intraarterial modality that uses microspheres loaded with
[40]
radioactive isotopes, such as Ytrium-90 . TARE is associated with a lower risk of post-embolization
syndrome compared to TACE. Besides, TARE can induce hypertrophy of the contralateral future liver
[41]
remnant, being an important tool in potentially resectable disease .

Interesting results were reported from the LEGACY study, a multicenter, single-arm, retrospective study
that included patients with solitary HCC ≤ 8 cm. Among the 162 patients included, TARE served as
neoadjuvant therapy for transplantation or resection in 21.0% (34 of 162) and 6.8% (11 of 162) of patients,
respectively, and as primary treatment for all others. Three-year overall survival was 92.8% for those
[42]
neoadjuvant patients with resected or transplanted liver .
Although most guidelines do not recommend TARE for downstaging, an expert consensus group suggested
that TARE can be a potential bridging/downstaging therapy . Therefore, while further research is
[43]
warranted, including prospective clinical trials, neoadjuvant TARE with Y-90 may be appropriate for
patients with advanced HCC who require downstaging for resection.

Chemotherapy
Direct delivery of chemotherapy into hepatic arteries can maximize chemotherapy delivery to liver tumors
and minimize systemic toxic effects due to first-pass liver metabolism. A randomized controlled phase III
trial randomly assigned patients with resectable BCLC stage A/B HCC beyond Milan criteria before
hepatectomy to receive either neoadjuvant transarterial infusion chemotherapy (TAI) with FOLFOX or
operation directly without any neoadjuvant treatment. The one-, two-, and three-year survival rates for TAI
group were 92.9%, 78.6%, and 63.5%, respectively, and they were 79.5%, 62.0%, and 46.3% for the group that
underwent direct surgical resection, respectively. In addition, the 6-, 12-, and 18-month PFS rates for TAI
group were 77.6%, 50.4%, and 47.4%, respectively, and they were 52.7%, 42.8%, and 34.8% for patients who
did not receive neoadjuvant treatment, respectively. The overall survival and recurrence-free survival were
[44]
significantly better in the neoadjuvant treatment group (P = 0.016 and 0.017, respectively) .

Ongoing trials
A phase IIa open label study presented the results of neoadjuvant cemiplimab, an anti-PD-L1
(NCT03916627). In this study, significant tumor necrosis, defined as greater than 70% necrosis of the
resected tumor, was reported in 4 of 20 patients following treatment with neoadjuvant cemiplimab, meeting
the primary end point of the study. Additionally, 15% of patients (n = 3/20) achieved complete tumor
necrosis of 100%, while 35% of patients (n = 7/20) had tumor necrosis of at least 50% .
[45]
More recently, the preliminary results of a two-part, multicenter, phase Ib study (NCT03682276) designed
to assess safety and bioactivity of nivolumab plus ipilimumab combination prior to liver resection in early-
stage HCC were reported. Of the seven patients enrolled, ORR in efficacy-evaluable patients (n = 5) was
20%, including one partial response and four disease stabilizations. Pathological responses were observed in
three out of five pathologically evaluable patients (60%) . Other ongoing studies involving neoadjuvant
[46]
treatment approaches to HCC treatment are reported in Table 2.