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

Table 1. Main ongoing phase III studies with immune checkpoint inhibitors in the adjuvant setting
Local Expected
Trial Drug Control n Primary end-point
treatment termination
CHECKMATE Nivolumab Placebo 530 Surgery/ablation 2025 Recurrence-free survival
9DX
(NCT03383458)
KEYNOTE 937 Pembrolizumab Placebo 950 Surgery/ablation 2025 Recurrence-free survival and
(NCT03867084) overall survival
IMBRAVE 050 Atezolizumab + Active 662 Surgery/ablation 2027 Recurrence-free survival
(NCT04102098) bevacizumab surveillance
EMERALD-2 Durvalumab + Durvalumab + 888 Surgery/ablation 2024 Recurrence-free survival
(NCT03847428) bevacizumab placebo
Placebo + placebo

NEOADJUVANT TREATMENT
Rationale for neoadjuvant treatment
Hepatocellular carcinoma is an aggressive disease mostly diagnosed in advanced stages and only 15%-20%
of tumors are deemed resectable upfront. Although negative margins are often observed at the time of
resection, most patients present with tumor recurrence. It is hypothesized that recurrence is a result of
persistent micrometastatic disease post-surgical resection. Neoadjuvant therapy could potentially improve
outcomes for patients with HCC.

For the majority of solid tumors, neoadjuvant treatment strategies are tailored to tumor downstaging,
elimination of micrometastatic disease, access tumor response in vivo, and provide conversion from
unresectable to resectable tumor. Regarding HCC, a successful neoadjuvant treatment could enable
parenchymal sparing liver resections, conserving liver function and improving outcomes.

TACE
TACE exerts its activity through the combination of arterial embolization and arterial chemotherapy
infusion. In the case of HCC, this modality has a clear rationale, once the blood supply derives from the
hepatic artery system .
[34]

Most studies regarding neoadjuvant TACE published to date have conflicting results regarding outcomes
such as overall survival, recurrence, and disease-free survival [35-37] . However, studies show that TACE-
induced tumor necrosis might have a relevant impact on patient outcome. Results from a meta-analysis of
32 randomized and nonrandomized studies comparing preoperative TACE to resection show that
preoperative TACE did not improve disease-free survival or overall survival. In this analysis, it was shown
that complete response following TACE was associated with superior survival compared to resection alone.
On the other hand, incomplete or no tumor necrosis did not impact positively in outcomes .
[38]

Some patients may present with liver-only disease, but beyond criteria for resection. In these cases,
neoadjuvant TACE can be an encouraging conversion strategy. In a cohort with 831 patients treated with
TACE over a 10-year period, 82 patients were successfully downstaged and 43 underwent salvage surgery.
Surgical resection provided longer median survival when compared to those who refused a salvage resection
(49 months vs. 31 months, P = 0.027). Among patients who had a complete response, no difference in
survival was demonstrated (50 months vs. 54 months, P = 0.699), but a difference was observed in the
subgroup that had a partial response (49 months vs. 24 months, P < 0.001). Such findings suggest a critical
role for resection following downstaging with TACE in patients with a partial response .
[39]