Year in Review: Top Papers in Interventional Oncology

SUMMARY

This is a prospective, single-arm, international, multicenter trial evaluating the safety and efficacy of portal and hepatic vein embolization (PVE/HVE) in patients with unresectable colorectal liver metastases (CRLM) and small future liver remnant (FLR). Outcomes evaluated included 90-day mortality, PVE/HVE technical details, FLR volume changes, complications, and resection rates. Overall, 102 patients were enrolled from 43 centers, and 96 of the 102 patients enrolled underwent PVE/HVE. Eighty-nine (93%) patients underwent PVE and HVE in the same session. The most frequently used embolization material for PVE was N-butyl cyanoacrylate/Lipiodol (Guerbet LLC) (66% of PVE cases). For HVE, hepatic veins were occluded by placing at least one vascular plug per hepatic branch (50% oversized); use of glue in the hepatic veins/collaterals was not allowed to prevent nontarget embolization. There was no postembolization mortality, although major complications were reported in two patients—one patient with migration of a vascular plug to the pulmonary vasculature and another with esophageal variceal bleeding. Resection was completed in 86 (90%) of 96 patients, and seven (8%) of these patients died within 90 days. The median baseline FLR was 23.5%, which increased to a median FLR of 34.1% at 3 weeks.

WHY THIS ARTICLE IS IMPORTANT

Patients with insufficient FLR volume/function are at high risk for posthepatectomy liver failure and require FLR hypertrophy–inducing procedures to enable safe resection. Combined PVE/HVE, a variant of liver venous deprivation, is performed by percutaneously occluding one or two ipsilateral hepatic veins simultaneously with PVE and has been shown to accelerate FLR hypertrophy and improve the degree of hypertrophy. Recent data suggest that it may also raise resection rates and survival compared to PVE alone.¹ However, published series on PVE/HVE have predominantly been retrospective and emphasize efficacy over safety. Moreover, there is added cost and time by adding HVE to PVE to increase FLR, so strong data are required to shift practice patterns. This study demonstrates that PVE/HVE is safe, with no embolization-related mortality, low morbidity, and high resection rates in upfront unresectable CRLM (90%). PVE/HVE was shown to lead to a high degree of FLR hypertrophy with a rapid kinetic growth rate, especially in the first week post-PVE/HVE. Moreover, this study is a precursor to a planned multicenter randomized trial, which will investigate the efficacy of PVE/HVE in CRLM patients versus PVE alone.

1. Korenblik R, Heil J, Smits J, et al. Liver regeneration after portal and hepatic vein embolization improves overall survival compared with portal vein embolization alone: mid-term survival analysis of the multicentre DRAGON 0 cohort. Br J Surg. 2024;111: znae087. doi: 10.1093/bjs/znae087

SUMMARY

This study aimed to evaluate the addition of lenvatinib and pembrolizumab to transarterial chemoembolization (TACE) versus dual placebo plus TACE in patients with unresectable, nonmetastatic hepatocellular carcinoma (HCC) (liver-only disease without portal vein invasion). This multicenter, randomized, double-blind, phase 3 study enrolled patients with Child-Pugh class A liver disease and HCC amenable to TACE. Eligible participants were randomly assigned (1:1), stratified by study site, alpha-fetoprotein level, ECOG (Eastern Cooperative Oncology Group) 0 performance status, albumin-bilirubin grade, and tumor burden. Patients received TACE and either oral lenvatinib (8-12 mg once daily) plus intravenous (IV) pembrolizumab (400 mg once every 6 weeks for up to 2 years) or matched dual placebo (oral and IV). Outcomes evaluated included safety, progression-free survival (PFS), and overall survival (OS). Of 480 patients enrolled, 237 were randomly assigned to receive TACE (conventional TACE or TACE with drug-eluting beads) plus lenvatinib plus pembrolizumab, and 243 were assigned to receive TACE plus dual placebo. Median follow-up was 25.6 months, median PFS was 14.6 months with lenvatinib plus pembrolizumab and 10 months with placebo (hazard ratio, 0.66; 95% CI, 0.51-0.84; P = .0002). The 24-month OS rate was 75% in the lenvatinib plus pembrolizumab group and 69% in the placebo group. Grade 3 or worse treatment-related adverse events occurred in 169 (71%) of 237 participants in the lenvatinib plus pembrolizumab group and in 76 (32%) of 241 in the placebo group, the most common of which were hypertension and decreased platelet count. The addition of lenvatinib plus pembrolizumab to TACE resulted in significant, clinically meaningful improvement in PFS in patients with unresectable, nonmetastatic HCC when compared to TACE plus placebo.

WHY THIS ARTICLE IS IMPORTANT

Combination and synergy between liver-directed and systemic therapies to treat unresectable liver tumors is garnering much interest, and what therapies and how to combine them will be informed by ongoing studies such as this one. In the current study, systemic therapy was initiated 2 to 4 weeks before the first TACE procedure and continued after TACE. This is the first randomized, double-blind, placebo-controlled, phase 3 trial to compare the combination of locoregional therapy (TACE) and immune-based systemic therapies (lenvatinib plus pembrolizumab) in patients with unresectable, nonmetastatic HCC and show both superiority in PFS and a trend of clinical benefit in OS. There was significant improvement in PFS for participants who received TACE with lenvatinib plus pembrolizumab compared with placebo, with early separation at the first 9-week imaging that continued beyond 30 months. Previous studies have not consistently shown a survival benefit when other systemic therapies were added to treatment with TACE. Based on these data, lenvatinib plus pembrolizumab plus TACE could be a new option for patients with unresectable, nonmetastatic HCC.

SUMMARY

This article reports a 1-year update on clinical outcomes of patients enrolled in the #HOPE4LIVER study evaluating histotripsy for primary and metastatic tumors of the liver. A total of 47 patients were enrolled at 14 sites, comprising 19 patients with HCC and 28 with metastatic disease—representing 52 tumors that underwent treatment.

Tumor control was evaluated via a core laboratory that performed both a primary assessment at each imaging time point (< 36 hours, 30 days, 6 months, 12 months) and post hoc imaging assessment. Core imaging lab analysis included “involution,” defined as the decrease of treatment zone volume over time, as well as assessment of nodular or mass-like enhancement within or along the margin of the treatment volume. Number of evaluable tumors decreased over time (51 immediate, 47 at 30 days, 35 at 6 months, and 23 at 12 months) and appears to have differed between the primary and post hoc analysis. Additionally, OS and freedom from local tumor progression were evaluated.

Forty-nine device-related adverse events were reported, the most common being procedural pain (24.5%), abdominal pain (22.4%), and pyrexia (12.2%). Six device-related adverse events were classified as serious adverse events, including hepatic failure, portal vein thrombosis, postoperative thrombosis, procedural pain, sepsis, and pleuritic pain.

Primary core lab imaging analysis observed treatment zone involution in 91.3%, 79.4%, and 81.8% of the targeted tumors at the 30-day, 6-month, and 1-year time points, respectively, and primary assessment of nodular or mass-like area of enhancement was absent in 79.2%, 80%, and 91.7% of the tumors at the same time points. Post hoc analysis identified no evidence of residual targeted tumor or progression of tumor in 89.6%, 91.7%, and 96% of the tumors at the same time points. Additionally, primary analysis identified freedom from progression in 86.7%, 81.5%, and 63.4% at the same time points, whereas post hoc analysis identified freedom from progression in 95.6%, 92.9%, and 90% at the same time points. The number of evaluable patients decreased over the time frame, from 39 at 30 days, 28 at 6 months, and 11 at 1 year in the primary assessment, and increased in the post hoc analysis to 43, 34, and 18, respectively.

WHY THIS ARTICLE IS IMPORTANT

Histotripsy has recently been approved as a new nonthermal tumor ablation modality. However, clinical data on the safety and efficacy of histotripsy remain limited. Thus, it is helpful to have an update on clinical outcomes from patients enrolled in the #HOPE4LIVER study, including additional response data on some of the enrolled patients. Importantly, it appears that almost no additional device-related adverse events developed after 30 days, and there were no additional serious adverse events.

Interpreting disease control is challenging due to meaningful discrepancies between the primary and post hoc analyses, which may be attributed to a clinical learning curve in image analysis. In addition, interpreting tumor control is made challenging by how few of the enrolled patients are included in the 6-month and 1-year analyses. The discrepancy between primary and post hoc analyses suggests that postprocedure image analysis may be difficult for institutions adopting histotripsy. Histotripsy will hopefully be successful particularly at addressing anatomically challenging tumors, but more clinical data are still welcome.

SUMMARY

This study reports on a prospective randomized trial of patients with uveal melanoma metastatic to the liver who received either treatment with percutaneous hepatic perfusion (PHP) with melphalan or best alternative care (BAC), which included TACE, pembrolizumab, ipilimumab, or dacarbazine. Due to difficulty with enrollment, the study design was revised to a single-arm study with all participants receiving PHP only. PHP was performed every 6 to 8 weeks, with patients receiving 3 mg/kg ideal body weight of melphalan for a maximum of 6 cycles. Patients then received granulocyte-macrophage colony-stimulating factor within 72 hours of the PHP procedure. The primary endpoint was OS with secondary efficacy endpoints of PFS and objective response rate (ORR). The original planned enrollment was 240 patients, but given the change in study structure, all efficacy analyses of the randomized study (n = 72) were treated as exploratory.

Forty patients received PHP, and 32 received BAC. Median OS was 18.5 months in the PHP group as compared with 14.5 months for the BAC group, although this was not statistically significant because the study was underpowered. Median PFS was 9.1 months in the PHP arm versus 3.3 months in the BAC arm (P = .015). For the PHP and BAC groups, the ORR was 27.5% versus 9.4% (P = .074), respectively, and the hepatic ORR was 35.0% versus 9.4%, respectively. The disease control rate was 80% for PHP as compared with 46.9% for BAC (P = .006). Median hepatic PFS was 11.4 versus 3.3 months for the PHP and BAC groups, respectively (P = .0008).

In the PHP group, 14.6% of patients experienced treatment-emergent adverse events leading to study treatment discontinuation, and an additional 7.3% experienced events leading to dose reduction. All PHP patients and 93.8% of BAC patients experienced at least one treatment-emergent adverse event, with 85.4% of PHP patients and 34.4% of BAC patients experiencing at least one grade 3/4 treatment-emergent adverse event. The most common adverse events were hematologic, with 56.1% of patients experiencing severe thrombocytopenia, 36.6% experiencing severe neutropenia, and 34.1% of patients experiencing severe anemia.

WHY THIS ARTICLE IS IMPORTANT

The results of this study led to the FDA approval of PHP with melphalan (Hepzato Kit, Delcath Systems, Inc.) for the treatment of uveal melanoma metastatic to the liver, currently the only FDA-approved liver-directed therapy for these patients. It is only the second approved therapy for metastatic uveal melanoma—the other is tebentafusp, which is a bispecific T-cell engager approved for a subset of patients who are HLA-A*02:01 positive.

This therapy represents an important new therapeutic option for these patients whose treatment options have been historically limited. Although PHP also has a high adverse event rate, these primarily hematologic sequelae are reversible, and the rate of hepatic adverse events appears low. As a primary goal of liver-directed therapy in the setting of metastatic disease is the preservation of hepatic function, it is helpful to have a liver-directed option that does not appear to damage the liver and can be used sequentially with other commonly used liver-directed therapies such as yttrium-90 radioembolization.

As the authors of the article allude to in their discussion, there are also intriguing synergies between PHP and systemic checkpoint inhibitors that are under clinical investigation. The results of a small phase 1b trial combining PHP and nivolumab/ipilimumab showed a 100% disease control rate and 86% overall response rate. The mechanism by which PHP appears to synergize with checkpoint inhibition is unknown, but if these results are born out in ongoing larger studies, PHP may find a role in the treatment of other primary or metastatic hepatic malignancies to reinvigorate the antitumoral immune response.