Introduction

Endoscopic full-thickness resection (eFTR) is increasingly used as minimally invasive diagnostic and potential therapeutic treatment option for smaller sized (≤2cm) T1 colorectal cancer (T1CRC). By enabling transmural resection, eFTR has shown to provide: 1) optimal histological risk assessment 2) complete (R0) resection, even in deep-submucosal invasive cancer (D-SMIC). However, longer-term oncological outcomes after eFTR for T1CRC have not been described.

Aims & Methods

All consecutive first-line eFTR procedures for suspect T1CRC with adenocarcinoma at histopathology registered in the Dutch prospective eFTR registry involving 19 centres between November 2015 and January 2023 were analysed. Superficial submucosal invasive cancer (S-SMIC) was defined as Kikuchi level 1 (sm1), D-SMIC as sm2-3. T1CRC was considered high-risk if one of the following was present: lymphovascular invasion, budding grade 2-3, poorly differentiation or tumour positive resection margins (<0.1mm). Deep submucosal invasion was not considered an independent high-risk factor according to Dutch guideline. Oncologic surveillance for pT1 was based on endoscopy and/or cross-sectional imaging as per guideline/local protocol, depending on histology. Outcomes included R0 resection rate, cancer recurrence, 3-year disease-free survival (DFS) and 3-year overall survival (OS).

Results

A total of 320 patients with histologic diagnosis of adenocarcinoma after eFTR were included (median age 70 years, 62% male, median lesion and specimen size 14.7mm and 27.0mm). Histology showed pT1 in 241 patients (75.3%), pT2 in 53 (16.6%), pT3 in 11 (3.4%), inconclusive in 15 (4.7%). Of the 241 pT1, 60/241 (24.9%) were S-SMIC, 171/241 (71.0%) were D-SMIC, inconclusive in 9 (3.7%). R0 resection for pT1 was 87.9%; 92.9% for S-SMIC and 87.0% for D-SMIC. R0 resection for pT1 lesions sized ≤15mm and 16-20mm was similar (89.3% vs 86.7%; p=0.820). No significant difference in R0 resection for colon vs rectum was found (89.5% vs 81.0%; p=0.126). High-risk features were present in 23/60 (38.3%) S-SMIC and 109/171 (63.7%) D-SMIC. Of these, 51/136 (40.4%) underwent completion surgery (CS), with nodal metastasis in 6/51 (11.8%), all had ≥2 risk factors. In the low-risk D-SMIC group, 60/65 (92.3%) did not undergo CS.
Follow-up was available for 174/241 (72.1%) pT1 patients with a median follow-up of 39.5 months (IQR 27.3). During follow-up, a median of 2 endoscopies (0-6) and 1 cross-sectional imaging procedure (0-6) were performed. The follow-up cohort was divided into a high-risk pT1 surveillance group (n=66), a low-risk pT1 surveillance group (n=72) and a pT1 CS group (n=36). In the high-risk pT1 surveillance group, cancer recurred in 4/66 (6.1%); 2 locoregional recurrences (1 endoluminal after R1 resection, 1 positive lymph node), both underwent salvage surgery, and 2 distant metastases. In the low-risk pT1 surveillance group, 2/72 (2.8%) had recurrence; 1/30 (3.3%) S-SMIC with distant metastases and 1/42 (2.4%) D-SMIC with a positive local lymph node treated with salvage surgery. In the pT1 CS group, distant metastases occurred in 2/36 (5.6%) with no curative options. 3-year DFS and 3-year OS were 95.6% and 83.4% for the high-risk pT1 surveillance group, 97.2% and 92.6% for the low-risk pT1 surveillance group, 98.2% and 100% for the pT1 CS group.

Conclusion

EFTR is an effective first-line treatment strategy for T1CRC ≤2cm, demonstrating high R0 resection rates for both S-SMIC and D-SMIC. Furthermore, eFTR allows organ-preserving treatment in a large proportion of patients, with low cancer recurrence over a median follow-up of 39.5 months.

Disclosure

Prof. dr. Fockens reports personal fees from Cook and Olympus
Prof. dr. Dekker has endoscopic equipment on loan of FujiFilm, received a research grant from FujiFilm, received a honorarium for consultancy from FujiFilm, Olympus, Tillots, GI Supply and CPP-FAP and a speakers' fee from Olympus, Roche and GI Supply.
Prof. dr. Weusten received research support from Pentax Medical Inc and Aqua Medical, outside the submitted work.
Dr. Bastiaansen received a speakers’ fee from Olympus, Tillotts Pharma AG and Ovesco Endoscopy AG.
All other authors have nothing to disclose.

Introduction

Watch and wait (WW) and Local Excision (LE) are rectal sparing approaches proposed to rectal cancer patients who achieved a complete (cCR) or major (mCR) response following neoadjuvant therapy, even if no prospective study reported long-term outcomes of both approaches. The aim of this study was to investigate the long-term outcomes of patients treated with both rectal-sparing approaches.

Aims & Methods

This is a long-term analysis of a prospective, multicenter, observational study that investigated the outcomes of patients with clinical stage II-III mid-low rectal adenocarcinoma treated with any neoadjuvant therapy, and either transanal LE and WW based on tumor response (cCR or mCR). The primary endpoints of this analysis are 5-year TME-, overall (OS), disease- (DFS), local (LRFS) and distant recurrence-free survival (DRFS).

Results

Out of 253 patients enrolled in 16 centers, 149 (58.9%) were managed with LE and 104 (41.1%) with WW. Most of the patients underwent long-course chemoradiotherapy (n=212, 83.6%), and 160 (63.2%) patients experienced a cCR, whereas 93 (36.8%) a mCR. Following LE, 40(15.8%) patients had high-risk features at histopathological analysis, and 19 underwent completion TME. At a median (IQR) follow-up of 43.0 (33.0-60.0) months, TME was performed in 47 (18.6%) patients, and the rectum was preserved in 206 (81.4%) patients. The estimated 5-year TME-, OS, DFS, LRFS, and DRFS was 80.7% (95%CI 77.2-86.3), 79.6% (95%CI 79.8-88.5), 92.0%(95%CI 91.7-97.0), 93.0%(95%CI 90.9-96.1), 92.5% (95%CI 91.0-96.3), respectively. In the WW group, 29(11.5%) had a tumor local regrowth, and the 5-year regrowth-free survival was 70.6% (95%CI 62.7-80.2).

Conclusion

Patients with a cCR and mCR enrolled in a rectal sparing approach protocol showed excellent oncological outcomes.

Introduction

There has been an ongoing debate over the appropriate timing of direct endoscopic necrosectomy (DEN) following the initial endoscopic ultrasound (EUS)-guided transmural drainage of walled-off necrosis (WON). We aimed to examine the superiority of immediate DEN over the drainage-oriented step-up approach in terms of the time to WON resolution.

Aims & Methods

This multicentre, open-label, superiority, randomised trial (WONDER-01) was implemented including patients who were scheduled to receive EUS-guided treatment of WON at 23 centres in Japan (1). Eligible patients were randomly assigned at a 1:1 ratio to receive either immediate DEN or the step-up approach. In both arms, a lumen-apposing metal stent was used as the first-choice stent for EUS-guided drainage. In the immediate DEN arm, DEN was initiated during (or within 72 hours of) the initial EUS-guided drainage session. In the step-up approach group, drainage-based step-up treatment with on-demand DEN was considered after clinical observation for 72-96 hours. The primary endpoint was time from the randomization to clinical success, which was defined as a decrease in a WON size to ≤ 3 cm and an improvement of inflammatory markers (i.e., body temperature, white blood cell count, and C-reactive protein). The secondary endpoints included technical success, procedure-related adverse events, and mortality. All efficacy and safety endpoints were analysed on an intention-to-treat basis. This study was registered with ClinicalTrials.gov (registration number, NCT05451901), and the recruitment and follow-up for the primary endpoint have been completed.

Results

Between July 2022 and December 2023, a total of 70 patients were enrolled (33 and 37 patients in the immediate DEN and step-up arms, respectively) with baseline characteristics being well-balanced between the arms. In an analysis of the primary endpoint, the immediate DEN was associated with a shorter time to clinical success compared to the step-up approach (P < 0.001) with median times of 31 days (95% confidence interval, 19-34 days) and 44 days (95% confidence interval, 38-52 days), respectively. As per the protocol, all patients in the immediate DEN arm received DEN compared to 46% in the step-up approach arm (P < 0.001), but the rates of procedure-related adverse events were compatible between the arms (24% vs. 22%, respectively; P = 0.79). No differences were noted between the immediate DEN and step-up approach arms in terms of the rates of technical success (100% vs. 98%, respectively; P = 0.26) and mortality (12% vs. 5.4%, respectively; P = 0.31).

Conclusion

In patients with symptomatic WON, immediate DEN following EUS-guided transmural drainage shortened the time to clinical success compared to the drainage-oriented step-up approach without increase in adverse outcomes. Immediate DEN can be a first-line treatment option for this patient population.

References

(1) Sato T, Saito T, Takenaka M, Iwashita T, Shiomi H, Fujisawa T, et al. WONDER-01: immediate necrosectomy vs. drainage-oriented step-up approach after endoscopic ultrasound-guided drainage of walled-off necrosis-study protocol for a multicentre randomised controlled trial. Trials. 2023;24(1):352.

Disclosure

H.I. declares research funding from Boston Scientific Japan, Fujifilm, and Piolax Medical Devices; honoraria from Boston Scientific Japan, Century Medical, Create Medic, Fujifilm, Gadelius Medical, Hitachi Medical, Japan Lifeline, Kaneka, Kawasumi Laboratories, Olympus Medical, Piolax Medical Devices, Sumitomo Bakelite, UMIDAS, and Zeon Medical; and contributions from Boston Scientific Japan, Gadelius Medical, Japan Lifeline, and Zeon Medical. Y.N. declares research funding from Boston Scientific Japan, Century Medical, Fujifilm, Gadelius Medical, HOYA Pentax Medical, Hitachi Medical, Kaneka, and Medico’s Hirata; and honoraria from Boston Scientific Japan, Fujifilm, Gadelius Medical, Hitachi Medical, J-MIT, Medico’s Hirata, and Olympus Medical. This work was not supported by any of those companies. The other authors declare no conflicts of interest related to this article.

Introduction

Biological treatment in inflammatory bowel disease (IBD) patients is currently hampered by high non-response rates. To enhance personalized medicine and predict response to biological therapeutics such as vedolizumab, the working mechanism should be elucidated. We aimed to visualize macroscopic and microscopic vedolizumab distribution, assess target saturation and detect drug target cells during quantitative fluorescence molecular endoscopy (qFME) to improve understanding of the mechanism of action.

Aims & Methods

Vedolizumab-800CW was developed in-house and GMP produced. Forty-three qFME procedures were performed in thirty-seven IBD patients. Dose escalation was performed using 0.0mg, 4.5mg and 15mg. Subsequently, two patient cohorts were added that received 75mg or 300mg unlabelled vedolizumab prior to vedolizumab-800CW to assess target saturation. Extensive ex vivo analyses were performed to correlate in vivo findings to immune status, fluorescence, microscopic distribution and potential target cells.

Results

Macroscopically and microscopically a significant difference between inflamed and non-inflamed tissue was visualized and quantified (0.0227 and 0.0470 mm^-1, p<0.0001) for the 15 mg cohort. In addition, ex vivo analyses showed a clear dose-dependent increase (p<0.0001) of the fluorescent drug signal, whereas a decrease could be established after adding an unlabelled dose (p<0.0001). Fluorescence microscopy revealed clear membrane binding of vedolizumab-800CW to inflammatory cells and migration into the inflamed mucosa. Various immune cell types were abundantly present in areas with high vedolizumab signal compared to areas with low signal, whereas this was most prominent for plasma cells.

Conclusion

QFME using vedolizumab-800CW enabled visualization and quantification of macroscopic and microscopic vedolizumab distribution in the inflamed target organ. In addition, it showed the potential of qFME to improve understanding in of local drug distribution, target cell identification and target engagement, which could improve understanding of targeted drugs.