Safety of surveillance endoscopy and EUS of the esophagus after neoadjuvant chemoradiotherapy: Results from the (pre)SANO trial

Abstract

Background and study aims

Active surveillance has been proposed for patients with esophageal cancer and a clinical complete response after neoadjuvant chemoradiotherapy (nCRT). This strategy involves repeated esophagogastroduodenoscopy (EGD) with bite-on-bite biopsies and endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) to detect tumor regrowth or residual disease. The aim of this study was to assess safety of endoscopic procedures during active surveillance.

Patients and methods

A prospective multicenter cohort including patients who were treated with nCRT for esophageal cancer and who underwent EGD with bite-on-bite biopsies and/or EUS (with fine-needle aspiration) was retrospectively analyzed. The primary outcome was the difference in number of serious adverse events (SAEs) in endoscopic procedures performed within vs. more than 3 months after nCRT. The secondary outcome was mechanical injury.

Results

In 920 patients, 2291 endoscopic procedures were performed (57% EGD combined with EUS, 39% EGD only and 4% EUS only). Of these procedures, 819 (36%) were performed more than 3 months after nCRT in 186 patients. Two gastrointestinal bleedings were reported during endoscopic procedures performed within 3 months after nCRT. One gastrointestinal bleeding and two infections were reported after 3 months following nCRT. Frequency of SAEs before and after 3 months following completion of nCRT was not significantly different (2 vs. 3, odds ratio 2.7, 95% confidence interval 0.3–32.4, P = 0.36).

Conclusions

EGD with bite-on-bite biopsies and EUS with FNA seem to be safe during an active surveillance strategy in esophageal cancer patients after nCRT.

 

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Keywords

Endoscopy Upper GI Tract - Barrett's and adenocarcinoma - Diagnosis and imaging (inc chromoendoscopy, NBI, iSCAN, FICE, CLE) - Endoscopic ultrasonography - Esophageal cancer

Introduction

Following results of the CROSS study, locoregionally advanced esophageal cancer is treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery [1]. Esophagectomy is a procedure with high morbidity and has persistent major impact on quality of life (QoL) [2] [3]. Moreover, in 29% of patients, no viable tumor cells are found in the resection specimen after esophagectomy and a significant number of patients develops early metastases after esophagectomy [4]. Based on this, it was hypothesized that active surveillance is an alternative treatment option, in which patients undergo surgery only if locoregional regrowth is detected in the absence of distant metastases.

The pre Surgery As Needed for Oesophageal cancer (SANO) trial investigated the efficacy of using a combination of diagnostic tests to accurately identify patients who achieved a clinical complete response (CCR) after nCRT [5]. Recent results from the SANO trial showed noninferior 2-year survival for patients undergoing active surveillance compared with patients undergoing standard surgery [6]. Furthermore, short-term global QoL was better in the active surveillance arm [6]. During active surveillance, repeated diagnostic tests are performed to detect residual malignancy with positron emission tomography-computed tomography (PET-CT), esophagogastroduodenoscopy (EGD) with bite-on-bite biopsies, and endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) in case of suspected lymph nodes. EGD and EUS are generally considered safe procedures, with complication rates less than 2.5% in various studies [7] [8] [9] [10]. Previously, the preSANO and SANO trials showed that these endoscopic procedures can be performed without relevant complications within 3 months after nCRT for identification of patients with a CCR [5] [11]. However, the safety of these procedures more than 3 months after nCRT is largely uncharted territory and the number of endoscopic evaluations in previous publications on this topic was too small to detect possible complications. It could be hypothesized that the preserved esophagus may become increasingly vulnerable to endoscopic procedures over time due to irradiation-induced chronic ulceration or fibrosis of the mucosal wall leading to stenosis, which could increase risk of perforation [12].

Therefore, this study aimed to investigate complications associated with EGD and EUS procedures in patients with esophageal cancer after nCRT and to assess differences in safety of endoscopic surveillance in the first 3 months after nCRT versus those performed thereafter in the context of active surveillance.

 

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Patients and methods

Study design and patients

A prospective multicenter cohort including patients with esophageal or gastroesophageal junction cancer who underwent nCRT according to CROSS in the preSANO and SANO trials with at least one endoscopic response evaluation was retrospectively analyzed [5] [6]. Patients were identified from the trial databases. Endoscopic procedures with regular biopsies were excluded. Because the current study constitutes a substudy of the (pre)SANO trials, which had already received ethical approval from the Medical Ethics Committee of Erasmus MC (MEC-2013–211, MEC-2017–392), no additional ethical approval was necessary.

 

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Procedures

The first clinical response evaluation was conducted according to a standardized protocol at 4 to 6 weeks after nCRT and consisted of an EGD with at least four bite-on-bite biopsies from the primary tumor location [13]. The bite-on-bite technique involves taking a second biopsy at the same site to sample deeper tissue. When no vital tumor cells were identified, patients were scheduled for a second response evaluation. This consisted of an identical EGD and an EUS with FNA of suspected lymph nodes detected during EUS or on PET-CT at 10 to 12 weeks after nCRT. These endoscopic response evaluations were repeated at 6, 9, 12, 16, 20, 24, 30, 36, 48, and 60 months after completion of nCRT in patients with a CCR who underwent active surveillance in the SANO trial. Surgery was planned when residual tumor was histologically proven or highly suspected and response evaluations were no longer necessary [13] [14]. All patients in the preSANO trial and in the surgery arm of the SANO trial were referred for surgery after two response evaluations at 10 to 12 weeks after nCRT.

 

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Outcomes

The primary outcome was difference in number of serious adverse events (SAEs) in endoscopic procedures performed within 3 months after completion of nCRT versus more than 3 months after nCRT. An SAE was defined as an AE (possibly) related to the intervention (i.e., the endoscopic procedure) requiring hospital admission or extending a hospital admission, and/or that was fatal and/or life-threatening to the patient [13]. SAEs were mandatory for the hospitals to report and were reviewed by the SANO study team. AEs from endoscopic procedures were classified according to the AGREE classification system, in which the severity of AEs is graded with increasing clinical impact from Grade 1 to Grade 5 (Supplementary appendix and Supplementary Table 1) [15]. Grade 1 AEs were not mandatory to report. Secondary outcome was mechanical injury to the mucosa, which was reported if regular biopsies were taken afterwards. These injuries did not require medical intervention. Endoscopic reports and follow-up visits were collected and reviewed by data managers and the SANO study team.

 

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Statistical analysis

Frequencies and percentages were used to describe baseline clinical and tumor characteristics, incidence of SAEs, and occurrence of mechanical injury. Baseline characteristics were compared using Student’s t-test for continuous variables and Chi-squared test for categorical variables. Patients who underwent endoscopic response evaluations after 3 months were also assessed within the 3-month period. Consequently, their data were incorporated into the analysis for both time frames. Fisher’s exact test (expected cell frequencies < 5) was used to identify a statistically significant difference in percentage of SAEs that occurred within 3 months after the end of nCRT versus those that occurred thereafter. Data were analyzed using R version 4.2.2 (R: A Language and Environment for Statistical Computing; The R Foundation for Statistical Computing, Vienna, Austria).

 

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Results

A total of 920 patients underwent at least one clinical response evaluation and were included in the study ([Fig. 1]). Of these patients, 186 underwent a clinical response evaluation beyond 3 months. Baseline characteristics are shown in [Table 1]. Between June 2015 and January 2024, 2291 endoscopic procedures were performed in 14 Dutch hospitals, with a mean (SD) of 4.90 (1.28) bite-on-bite biopsies. These were conducted at a median of 3 months (interquartile range [IQR] 1–9) after completion of nCRT. Among them, there were 1302 EGDs (56%) with bite-on-bite biopsies combined with an EUS during a single session, 896 EGDs (39%) with bite-on-bite biopsies only, and 93 EUSs (4%) only. FNA was performed in 377 of 1395 EUSs (27%) and fine-needle biopsy (FNB) during four EUSs (4/1395, 0.3%). A total of 819 (36%) endoscopic procedures was performed more than 3 months after nCRT ([Table 2]).

Fig. 1 Patient flowcharts for inclusion of patients from the preSANO and SANO trial. b-o-b, bite-on-bite; CCR, clinical complete response; CRE, clinical response evaluation; EGD, esophagogastroduodenoscopy; EUS, endoscopic ultrasound; nCRT, neoadjuvant chemoradiotherapy. *36 patients underwent an extra endoscopic procedure; ^6 patients did not undergo the endoscopic procedure at 6 months after nCRT.

Table 1 Baseline characteristics of study population (≤ or > 3 months after nCRT).

	Patients ≤ 3 months N = 920	≤ 3 months and > 3 months n = 186	P value
Percentages may not add up to 100 because of rounding. Characteristics are displayed as number (%), except age (median, IQR). IQR, interquartile range; nCRT, neoadjuvant chemoradiotherapy; WHO, World Health Organization. *80 missing (all preSANO): ≤ 3 months. †150 missing (63 preSANO): ≤ 3 months = 143 vs > 3 months = 7.
Age, years			0.068
Median	68	69
IQR	61–73	63–74
Male sex	760 (83)	146 (79)	0.221
Histology			0.269
Adenocarcinoma	731 (80)	139 (75)
Squamous cell carcinoma	166 (18)	43 (23)
Other	23 (3)	4 (2)
Tumor differentiation grade*			0.530
G1	117 (14)	32 (17)
G2	392 (47)	90 (48)
G3	316 (38)	61 (33)
Could not be determined	15 (2)	3 (2)
Tumor location			0.615
Proximal esophagus	10 (1)	2 (1)
Middle esophagus	91 (10)	23 (12)
Distal esophagus	588 (64)	110 (59)
Esophagogastric junction	231 (25)	51 (27)
Clinical T-category			0.960
T1	4 (0)	1 (1)
T2	178 (19)	35 (19)
T3	660 (72)	137 (74)
T4	21 (2)	3 (2)
Could not be determined	57 (6)	10 (5)
Clinical N-category			0.298
N0	328 (36)	79 (43)
N1	333 (36)	66 (36)
N2	187 (20)	31 (17)
N3	19 (2)	4 (2)
Could not be determined	53 (6)	6 (3)
WHO performance status†			0.519
0	517 (67)	126 (70)
1	245 (32)	50 (28)
2	7 (1)	2 (1)
3	1 (0)	1 (1)

Table 2 Endoscopic procedures per time point.

Time point after nCRT (months)	Total endoscopic procedures	SANO	preSANO
nCRT, neoadjuvant chemoradiotherapy. *72 unique patients were included at the second time point, because regular biopsies were taken at the first time point
1	848*	728	120
3	624	490	134
6	180	180	–
9	122	122	–
12	105	105	–
16	92	92	–
20	76	76	–
24	80	80	–
30	72	72	–
36	64	64	–
48	26	26	–
60	2	2	–

Primary outcome: Serious adverse events

SAEs were reported for five endoscopic procedures (0.22%). Two patients had gastrointestinal bleeding after EGD with bite-on-bite biopsies, one patient had gastrointestinal bleeding of a preexisting non-malignant gastric ulcer, and two patients had an infection secondary to EUS with FNA/FNB ([Table 3]). The rate of ≥ Grade 2 gastrointestinal bleeding after EGD caused by bite-on-bite biopsies was 0.09% (2/2198) and the rate of ≥ Grade 2 infection after EUS with FNA/FNB was 0.53% (2/377). No significant difference was found in the number of SAEs between the procedures conducted within 3 months after nCRT and more than 3 months after nCRT (2 vs. 3, odds ratio 2.70 (95% confidence interval 0.31–32.41; P = 0.36).

Table 3 SAEs per endoscopic procedure type.

Endoscopic procedure	Total	SAE	Total
b-o-b, bite-one-bite; EGD, esophagogastroduodenoscopy; EUS, endoscopic ultrasound; FNA, fine-needle aspiration; SAE, serious adverse event.
EGD with b-o-b biopsies and EUS	2291	Gastrointestinal bleeding due to manipulation	1 (0.04)
EGD with b-o-b biopsies	2198	Gastrointestinal bleeding due to biopsies	2 (0.09)
EUS with FNA	377	Infection due to EUS with FNA/FNB	2 (0.53)

 

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Gastrointestinal bleeding

One patient presented with hematemesis at the Emergency Department (ED) 1 day after EGD with bite-on-bite biopsies at 6 months after nCRT and used apixaban during the EGD. An EGD showed active bleeding at the biopsy site and hemostasis was achieved by use of a endoscopic hemostat. The patient was discharged in good condition after 2 days. The complication was scored as a Grade 3a AE. Another patient used dual antiplatelet therapy (aspirin and ticagrelor) during the EGD and collapsed a few hours after EGD with bite-on-bite biopsies at 1 month after nCRT. The hemoglobin level had dropped from 10 g/dL to 7.1 g/dL, making the patient suspicious for bleeding. The patient was transfused with two units of packed red blood cells (RBCs) and was discharged in good condition after 2 days. The adverse event was defined as a Grade 2. A third patient presented with hematemesis and melena at the emergency department on the day of EGD with bite-on-bite biopsies at 1 month after nCRT. This patient used aspirin during the EGD. An EGD was performed and a bleeding ulcer in the angulus of the stomach (not at the biopsy site) was injected with adrenaline and the vessel was clipped. The patient was transfused with two units of packed RBCs and observed in the Intensive Care Unit for one night. After 4 days, the patient was discharged in good condition. The severity was scored as a Grade 4 AE.

 

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Infection/inflammation

One patient presented with pain in the abdomen, normal vital parameters, and a C-reactive protein (CRP) level of 100 mg/L at 3 days after EUS with FNA, 8 months after nCRT. This patient was diagnosed with mucositis after EUS-FNA and was admitted to the hospital for 1 day (> 24 hours) without medical intervention, scored as a Grade 2 AE. The second patient presented at the ED 5 days after EUS with FNB at 6 months after nCRT with fever, nausea/vomiting, and diarrhea. The CRP level was 251 mg/L. Vital parameters normalized after administration of intravenous (IV) fluids. Blood cultures were positive for Streptococcus anginosus and the patient received IV antibiotics for 5 days. The sepsis was deemed to be related to the EUS with FNB. The patient was discharged in good condition after 4 days and the complication was scored as a Grade 2 AE.

 

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Secondary outcome: mucosal injury

Four severe mucosal injuries (4/2291, 0.17%) were reported, two of which occurred within 3 months after nCRT and two of which occurred more than 3 months after nCRT. One reported laceration was caused by introduction of the EUS endoscope. The other three injuries were caused by the bite-on-bite biopsy procedures.

 

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Discussion

In this study, it was demonstrated that endoscopic SAEs are uncommon in patients with esophageal cancer who undergo active surveillance after nCRT. The complication rate recorded in this study was 0.2% for all 2291 endoscopic procedures. Endoscopy-related SAEs during the early (≤ 3 months) and late period (> 3 months) post chemoradiotherapy were similar in the present study (2 vs. 3, P = 0.36). Therefore, timing of endoscopic procedures did not seem to affect risk of complications. Three patients developed upper gastrointestinal bleeding after EGD with bite-on-bite biopsies and two patients developed an infection related to EUS with FNA/FNB. There was no reported case of perforation or mortality and all affected patients with complications could be discharged without long-term sequelae.

In previous studies, the safety of endoscopic procedures in the irradiated esophagus was studied no longer than 3 months after nCRT [16]. SAEs did not occur in these endoscopic response evaluations, shortly after nCRT, which supports the hypothesis that EGD and EUS are safe after nCRT. However, safety of endoscopic procedures beyond 3 months after nCRT was not yet established. In watch-and-wait regimes for rectal cancer, patients also undergo repeated endoscopies of the irradiated rectum.

Literature does not report complications of endoscopy in the irradiated rectum [17] [18].

Radiotherapy of the esophagus induces radiation esophagitis, which is exacerbated by the addition of chemotherapy. Radiation esophagitis can be classified as acute (≤ 90 days after completion of radiotherapy) and late (> 90). In the acute phase, radiotherapy acts as a pro-inflammatory signal causing mucosal breakdown and release of pro-inflammatory cytokines, which in turn cause fragility of the mucosal wall [19]. In the later phase, radiotherapy may cause chronic ulceration or fibrosis of the mucosal wall leading to stenosis [12].

Two of the three patients with upper gastrointestinal bleeding after EGD developed the bleeding within the first 3 months after nCRT. Although our study was not designed to directly compare complication rates between patients with and without neoadjuvant chemoradiotherapy, it is important to contextualize our findings. The observed bleeding rate is in line with current literature, with reported incidences of less than 0.01% after diagnostic endoscopy with biopsies [20]. In two of the three bleeding patients, bleeding was biopsy-related. Biopsy-related bleeding occurred in patients who were on direct oral anticoagulants (DOACs) or dual antiplatelet therapy. DOACs and dual antiplatelet therapy are known risk factors for gastrointestinal bleeding, which is why they were withheld during EUS with FNA, according to the protocol [21] [22]. EGD with regular biopsies in the standard population is regarded as a low-risk procedure and can be performed without pausing anticoagulants. Results of the present study suggest that bite-on-bite biopsies in an irradiated esophagus can be regarded as low-risk procedures too. In addition, based on the findings that bite-on-bite biopsies are not necessarily deeper than regular biopsies, the remaining risk may be insignificant [11]. However, use of anticoagulants during EGD with bite-on-bite biopsies was not documented.

Literature reports overall complication rates for regular EUS with FNA of 0.98% and an infection rate of less than 0.05% [23]. In the present study, there were two patients (0.52%) with EUS-FNA/FNB-related complications, both of which were infections. Although comparison of these results with literature is hampered by the low incidence of complications and the relatively small sample size of the present study, risk of AEs does not seem to be increased after nCRT.

An important strength of this study is that data collection was prospective and SAEs were systematically recorded and reported. As compared with previous studies, there were considerably more endoscopic procedures after nCRT including many beyond 3 months, allowing for a more comprehensive assessment of safety during long-term surveillance [5] [11]. Furthermore, this was a multicenter study with dedicated endoscopists, simulating real-life practice.

A limitation of the study is that the reporting of (non-serious) AEs was not mandatory. Although all endoscopic reports were reviewed centrally by the SANO study team during follow-up, if an endoscopist did not consider a laceration to be relevant, it might not have been documented. In addition, if SAEs occurred after the procedure and were not noticed by the SANO study team, we primarily had to rely on the hospital to report them. Although it is theoretically possible that some patients were hospitalized for complications at non-affiliated hospitals, this is unlikely to have significantly impacted our data. In the Dutch healthcare system, inter-hospital communication is standard practice, especially for post-procedure complications, making underreporting unlikely. Although these data suggest acceptable complication rates, it is important to realize that safety data on response evaluations beyond 2 years after nCRT remain limited. This might increase with newly implemented active surveillance strategies for esophageal cancer. It can be hypothesized that endoscopic procedures remain safe over a longer term after nCRT in the irradiated esophagus because we do not expect an increase of fibrosis, strictures, or ulceration more than 2 years after nCRT.

 

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Conclusions

In conclusion, EGD with bite-on-bite biopsies and EUS with FNA are safe procedures to perform during active surveillance strategies within the irradiated esophagus with an acceptable SAE rate. There were no differences in SAE rates for procedures performed within 3 months after nCRT compared with more than 3 months after nCRT.

 

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Conflict of Interest

Bianca Mostert has a consultancy role for Lilly, Servier, BMS, Amgen, and AstraZeneca and receives research funding from BMS, Pfizer and Sanofi. Bas P.L. Wijnhoven receives research funding from BMS and has a consultancy role for Medtronic. The remaining authors declare that there is no conflict of interest.

Acknowledgement

We would like to thank the Dutch Cancer Society (KWF) and Netherlands Organization for Health Research and Development (ZonMw) for their financial support of the present study. Furthermore, we would like to thank all patients for participation in our trial. Furthermore, we would like to thank all nurse practitioners from participating centers for their clinical assistance and the data managers for their support in storing our data safely.

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Publication History

Received: 19 February 2025

Accepted after revision: 25 June 2025

Accepted Manuscript online:
30 June 2025

Article published online:
31 July 2025