Introduction

Underwater endoscopic mucosal resection (UEMR) is an alternative to conventional EMR (CEMR) offering consistent negative horizontal margins. However, UEMR does not involve submucosal injection; thus, its ability to achieve a sufficient resection depth comparable to that of CEMR remains uncertain. This randomized controlled trial (RCT) aimed to compare UEMR and CEMR in terms of resection depth.

Aims & Methods

This multicenter, parallel two-arm, open-label, noninferiority RCT was conducted across four Japanese institutions enrolling patients with colorectal tumors measuring 10–20 mm. Participants were randomly assigned in a 1:1 ratio to either to UEMR or CEMR group, using a computerized random-number generator. The primary outcome was the resection depth, which is the distance from the lower edge of the muscularis mucosa to the deep margin of the resected specimen, analyzed based on per-protocol (PP) principles (noninferiority margin of 400 µm).

Results

This study screened 217 patients from September 21, 2022, to December 2, 2024, and randomly assigned them to the UEMR (n =109) or CEMR (n =108) group. The PP analysis revealed that the mean resection depths of the UEMR and CEMR groups were 1688.9 ± 1510.0 µm and 1432.3 ± 1294.2 µm, respectively (mean difference: 256.6 µm, 95% confidence interval: -119.9 µm to 633.1 µm; P = 0.18), indicating the noninferiority of UEMR compared with CEMR in terms of resection depth. Subgroup analyses revealed that the resection depth of lesions by UEMR, especially at the cecum/ascending colon (1822.4 ± 1469.7 µm vs. 1096.5 ± 1007.6 µm; P = 0.01), and those with superficial morphology (1238.7 ± 862.2 µm vs. 731.6 ± 376.1 µm; P < 0.01), was significantly deeper than that achieved by CEMR. Moreover, even for nonexperts, UEMR tended to provide adequate resection depth compared with CEMR, approaching the proficiency level exhibited by experts (1786.6 ± 1471.6 µm vs. 1192.4 ± 1074.7 µm; P = 0.07). There were no significant differences in adverse events between the two groups, including one case of intraoperative perforation (0.9%) in the CEMR group and one case of delayed bleeding (0.9%) in the UEMR group. No EMR-related deaths were reported.

Conclusion

UEMR maintains the equivalent resection depth as CEMR and could become the gold standard endoscopic resection technique for intermediate-size colorectal tumors. UEMR is strongly recommended, especially for lesions at the cecum, ascending colon, and superficial lesions, because it could resect significantly deeper than CEMR. Furthermore, UEMR is recommended for nonexperts as a resection method that provides sufficient resection depth (Clinical trial registration number: UMIN000047432).

Introduction

An important issue for unresectable advanced stage hepatocellular carcinoma (uHCC) patients with Child-Pugh class B liver cirrhosis (CP-B), is lack of safe treatment options that show therapeutic efficacy, thus it is considered to be an unmet need. Atezolizumab plus bevacizumab (At/Bv) and durvalumab plus tremelimumab (Dur/Tre) have each been used as first-line systemic immunotherapy for uHCC.

Aims & Methods

The present study aimed to elucidate clinical outcomes of uHCC patients with CP-B treated with those combination treatments. The records of 169 uHCC patients with CP-B in Japan, treated with At/Bv or Dur/Tre as first-line systemic therapy from 2020 to 2024 at participating institutions were examined (median age: 73 years, males: 143, Child-Pugh score 7:8:9 = 121:43:5, BCLC stage B:C = 65:104, At/Bv:Dur/Tre = 131:38). Each regimen was analyzed for therapeutic efficacy and safety, and the results compared, in a retrospective manner.

Results

Using RECIST, ver. 1.1, the objective response rate (ORR) was shown to be 25.9% in the At/Bv group, and 18.4% in the Dur/Tre group (p=0.08). Disease control rate (DCR) was significantly higher in the At/Bv group (64.9% vs. 39.5%, p=0.01). There were no significant differences between the groups for progression-free survival (PFS) [At/Bv vs. Dur/Tre=5.3 vs. 3.5 months (95% CI: 3.9–6.5 and 2.3–7.2, respectively), p=0.90], overall survival (OS) [10.5 vs. 12.5 months (95% CI: 9.1–13.3 and 7.9–NA, respectively), p=0.58], or post-progression survival (PPS) [4.9 vs. 7.5 months (95% CI: 3.7–7.5 and 2.2–NA, respectively), p=0.60]. The rate of incidence of immune-related adverse events (irAEs) of any grade was 11.5% in the At/Bv group and 23.7% in the Dur/Tre group (p=0.07), while irAEs of grade 3 or higher were noted in 3.1% and 15.8%, respectively (p=0.02) significantly greater in the Dur/Tre group).

Conclusion

The incidence rate of irAEs in each group was similar to that observed in clinical trials previously performed for these regimens. uHCC patients with CP-B, who received Dur/Tre had a greater rate of incidence of high-grade irAEs, while the At/Bv group had a better DCR, though there were no significant differences for PFS, OS, or PPS between the groups. Neither treatment was found to sufficiently improve the prognosis of uHCC patients with CP-B. Development of safe and effective treatment options for patients affected by uHCC, that can be administered even to those with CP-B remains necessary.

Disclosure

Atsushi Hiraoka: lecture fee Chugai, AstraZeneca, and Lilly.