Impact of Neoadjuvant Immunotherapy on Recurrence-Free Survival in Patients with High-Risk Localized HCC

Abstract

Surgical resection for localized hepatocellular carcinoma (HCC) is typically reserved for a minority of patients with favorable tumor features and anatomy. Neoadjuvant immunotherapy can expand the number of patients who are candidates for surgical resection and potentially reduce the chance for recurrence, but its role in HCC not defined. We retrospectively examined the outcomes of patients who underwent surgical resection for HCC at the Johns Hopkins Hospital and compared the clinical outcomes of patients who received neoadjuvant immunotherapy with those who underwent upfront resection. The clinical cohort included a total of 92 patients, 36 of whom received neoadjuvant immune checkpoint inhibitor (ICI)-based treatment. A majority of patients (61.1%) who received neoadjuvant ICI-based therapy were outside of standard resectability criteria and were more likely to have features known to confer risk of disease recurrence, including α-fetoprotein ≥ 400 ng/mL (P = 0.02), tumor diameter ≥ 5 cm (P = 0.001), portal vein invasion (P < 0.001), and multifocality (P < 0.001). Patients who received neoadjuvant immunotherapy had similar rates of margin-negative resection (P = 0.47) and recurrence-free survival (RFS) as those who underwent upfront surgical resection (median RFS 44.8 months compared with 49.3 months, respectively, log-rank P = 0.66). There was a nonsignificant trend toward superior RFS in the subset of patients with a pathologic response (tumor necrosis ≥ 70%) with neoadjuvant immunotherapy. Neoadjuvant ICI-based therapy may allow high-risk patients, including those who are outside traditional resectability criteria, to achieve comparable clinical outcomes with those who undergo upfront resection.

Significance: Surgical resection for localized HCC is typically only reserved for those with solitary tumors without vascular invasion. In this retrospective analysis, we show that neoadjuvant immunotherapy may allow high-risk patients, including those who are outside of standard resection criteria, to undergo successful margin-negative resection and achieve comparable long-term clinical outcomes compared with upfront resection. These findings highlight need for prospective studies on neoadjuvant immunotherapy in HCC.

Figure 1

A, Kaplan–Meier survival curve RFS of patients with resectable HCC who underwent neoadjuvant ICI therapy and upfront surgery. B, Kaplan–Meier survival curve depicting OS of same cohorts.

Figure 2

Alluvial diagram depicting patterns of recurrence and subsequent line of therapy in patients with recurrence in patients treated with upfront surgery and neoadjuvant ICI. MWA, microwave ablation; TACE, transarterial chemoembolization, RT, radiation therapy.

Figure 3

A, RFS in the neoadjuvant ICI–treated cohort by the presence of major pathologic response at time of surgery, defined as tumor necrosis ≥70%. Three patients who underwent neoadjuvant locoregional procedures following the receipt of ICI were omitted. B, Forest plot depicting HR for RFS following resection in the neoadjuvant ICI–treated cohort. Resectability is as defined by current BCLC staging. Vascular invasion indicates the presence of micro/macrovascular invasion on final pathology. ALBI, albumin–bilirubin; major path response, major pathologic response at the time of surgery, defined as tumor necrosis ≥70%.

Figure 4

Baseline, presurgery, and postsurgery contrast-enhanced CT images of three BCLC C patients (vascular invasion present) treated with neoadjuvant ICI–based therapy with successful R0 resection. Patient A: CT venous phase imaging showing a large left-liver mass measuring 13.1 cm (yellow arrow) with associated occlusion of the left portal vein (not shown) at baseline. Patient B: CT venous phase imaging showing a 5.3-cm mass with necrosis (yellow arrows) and tumor thrombus within the right portal vein (red arrow); additional multifocal disease (not shown) at baseline. Patient C: CT arterial phase imaging showing large infiltrative lesion involving entirety of the left liver at baseline (yellow arrows) and associated left portal vein invasion (not shown), with complete radiographic response to ICI therapy prior to surgery.