The #HOPE4LIVER Single-Arm Pivotal Trial for Histotripsy of Primary and Metastatic Liver Tumors

Abstract

Background Histotripsy is a nonthermal, nonionizing, noninvasive, focused US technique that relies on cavitation for mechanical tissue breakdown at the focal point. Preclinical data have shown its safety and technical success in the ablation of liver tumors. Purpose To evaluate the safety and technical success of histotripsy in destroying primary or metastatic liver tumors. Materials and Methods The parallel United States and European Union and England #HOPE4LIVER trials were prospective, multicenter, single-arm studies. Eligible patients were recruited at 14 sites in Europe and the United States from January 2021 to July 2022. Up to three tumors smaller than 3 cm in size could be treated. CT or MRI and clinic visits were performed at 1 week or less preprocedure, at index-procedure, 36 hours or less postprocedure, and 30 days postprocedure. There were co-primary end points of technical success of tumor treatment and absence of procedure-related major complications within 30 days, with performance goals of greater than 70% and less than 25%, respectively. A two-sided 95% Wilson score CI was derived for each end point. Results Forty-four participants (21 from the United States, 23 from the European Union or England; 22 female participants, 22 male participants; mean age, 64 years ± 12 [SD]) with 49 tumors were enrolled and treated. Eighteen participants (41%) had hepatocellular carcinoma and 26 (59%) had non-hepatocellular carcinoma liver metastases. The maximum pretreatment tumor diameter was 1.5 cm ± 0.6 and the maximum post-histotripsy treatment zone diameter was 3.6 cm ± 1.4. Technical success was observed in 42 of 44 treated tumors (95%; 95% CI: 84, 100) and procedure-related major complications were reported in three of 44 participants (7%; 95% CI: 2, 18), both meeting the performance goal. Conclusion The #HOPE4LIVER trials met the co-primary end-point performance goals for technical success and the absence of procedure-related major complications, supporting early clinical adoption. Clinical trial registration nos. NCT04572633, NCT04573881 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Nezami and Georgiades in this issue.

Graphical abstract

Figure 1:

Study design flowchart. * = Incomplete due to poor image quality (three tumors in three participants) and lack of contrast (two tumors in one participant). ** = Six lesions (five participants) did not have 30-day imaging and the core laboratory could not assess technique efficacy in two lesions (two participants).

Figure 2:

Images in a participant with a 2.3-cm hepatocellular carcinoma in segment III of the liver. (A) Preprocedure contrast-enhanced MRI scan in the late arterial phase shows hyperenhancing hepatocellular carcinoma (arrow). (B) Intraprocedural US image shows defined treatment volume; the orange circle outlines the hyperechoic targeted tumor and the red circle outlines the planned margin. The treatment effect is visible as an echogenic bubble cloud at the red crosshair, the focal point of the transducer. The robotic arm moves the focal point through the planned treatment volume to create the volumetric treatment. (C) Contrast-enhanced MRI scan obtained less than 36 hours postprocedure in the late arterial phase shows the nonenhancing treatment zone (black arrow). Note patent blood vessels (dashed white arrows). (D) Contrast-enhanced MRI scan obtained 30 days postprocedure in the late arterial phase shows partial involution of the treatment zone (arrow).

Figure 3:

Graphs show primary end points of (A) technical success and (B) safety of procedure-related major complications. * = Estimated by bootstrap sampling with replacement method to account for potential within-subject lesion correlations. Subject was the bootstrap sampling unit, 1 000 000 iterations for bootstrap resampling were performed, and the bootstrap method was the bias-corrected and accelerated method. † = Two-sided 95% Wilson score CI.

Figure 4:

Images show a 1.3-cm metastatic colorectal cancer in segment III of the liver. (A) Preprocedure contrast-enhanced MRI scan shows tumor (arrow). (B) Contrast-enhanced MRI scan obtained fewer than 36 hours postprocedure with treatment zone (solid arrow) encompassing the site of the tumor and a margin. Patent blood vessel (dashed arrow) traverses the treatment zone. (C) Contrast-enhanced MRI scan obtained at 30 days postprocedure shows involution of the treatment zone (solid arrow) with maintained patent vessel (dashed arrow).