Organ preservation in esophageal cancer treatment, is it time now?

Abstract

As esophageal cancer (EC) is a prevalent malignancy of the digestive tract, with esophageal squamous cell carcinoma being its predominant pathological subtype, accounting for nearly 90% of all cases. Current treatment modalities for EC include surgery, chemotherapy, and radiotherapy; however, single-modality therapies are associated with inherent limitations. Advances in endoscopic techniques and the integration of immunotherapy have enhanced the feasibility and safety of organ-preserving strategies for EC. These approaches enable patients to achieve prolonged survival and an improved quality of life. Nevertheless, the criteria for selecting patients suitable for organ preservation require further refinement through active surveillance. The optimal timing for surgical intervention in patients with tumor progression or metastasis remains controversial; however, the "watch and wait" strategy may represent a viable option for selected individuals.

Key Words: Esophageal carcinoma; Neoadjuvant chemoradiotherapy; Immunotherapy; Organ preservation; Randomized clinical trial; Clinical complete response; Active surveillance

Core Tip: Esophageal cancer (EC) ranks among the most prevalent malignant tumors worldwide. Organ preservation (OP) therapy aims to optimize patient quality of life without compromising survival outcomes. Recent advances in endoscopic techniques and immunotherapy have significantly improved the safety and feasibility of OP strategies for EC. However, the widespread implementation of OP remains limited by several challenges. These include discrepancies between clinical complete response and pathological complete response assessments, uncertainties regarding long-term safety, and the absence of standardized patient selection criteria. Future efforts should focus on enhancing the predictive accuracy of treatment response, optimizing active surveillance protocols, strategically integrating immunotherapy into neoadjuvant frameworks, and validating these approaches through rigorously designed, sufficiently powered, multicenter randomized controlled trials.

INTRODUCTION

Esophageal cancer (EC) is a malignancy of global significance, ranking 11^th in incidence and 7^th in mortality worldwide. The highest disease burden is observed in East Asia, where incidence rates are double the global average[1]. In China, EC is predominantly diagnosed at an advanced stage[2], with esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) representing the principal histological subtypes.

Historically, no standardized management strategy has existed for EC. Multidisciplinary approaches involving surgery, radiotherapy, and chemotherapy continue to serve as the cornerstone of treatment[3]. However, the high frequency of advanced-stage diagnosis is directly associated with compromised therapeutic efficacy and poor prognosis[4].

Multi-omics analyses have classified ESCC into four molecular subtypes[5]: Cell cycle activation (CCA), NRF2 activation, immune suppression (IS), and immune modulation (IM). The CCA subtype may benefit from CDK4/6 inhibitors, whereas the IS and IM subtypes, characterized by immune cell infiltration, represent potential candidates for immunotherapy.

Over recent decades, the management of EC has evolved substantially. Contemporary strategies emphasize multimodal approaches that integrate surgery, radiotherapy, chemotherapy, immunotherapy, and targeted therapy. For locally advanced disease in particular, neoadjuvant therapies, including chemotherapy, chemoradiotherapy (CRT), and combinations of chemo-immunotherapy, have demonstrated significant clinical benefits compared to surgery alone. These advancements have progressively contributed to improved patient outcomes and survival[6].

According to multiple clinical guidelines, surgery remains the primary therapeutic option for resectable EC[7,8]. Since its successful introduction in the 1930s, esophagectomy has fundamentally improved the natural course of the disease, offering a curative opportunity for numerous patients[9]. However, the deep anatomical location of the esophagus makes the procedure technically demanding. As a result, the World Health Organization classifies esophagectomy as a high-risk operation, a categorization that has prompted continued investigation into organ-preserving strategies for suitable patients[10].

Organ preservation (OP) therapy seeks to optimize quality of life (QOL) without compromising survival outcomes. This concept has been successfully applied across several oncology fields, including esophageal[11,12], rectal[13], lung[14], and laryngeal cancers[15,16]. In the management of EC, OP denotes strategies that maintain the structural and functional integrity of the esophagus while achieving local tumor control. This approach aims to reduce the impact of surgery on QOL while maintaining effective oncological results. Recent progress in endoscopic techniques and immunotherapy has considerably improved the safety and feasibility of such strategies. It is important to emphasize that preservation protocols should be tailored to the tumor stage in cases of resectable EC.

OP IN EARLY-STAGE EC

Chemotherapy for early-stage EC

The initial approach to esophageal preservation primarily involved CRT. The JCOG9708 trial, a phase II single-arm study, enrolled 72 patients with ESCC classified as AJCC 8^th edition stage I (T1N0M0). The primary treatment consisted of synchronous radiotherapy combined with 5-fluorouracil and cisplatin. Salvage surgery was reserved for patients with residual tumors or local recurrence. In the entire cohort, 63 patients (87.5%; 95%CI: 77.6-94.1) achieved a clinical complete response (cCR), while 6 patients underwent surgical resection due to residual disease. The 4-year overall survival (OS) was 80.5% (95%CI: 71.3-89.7), and the disease-free survival (DFS) was 68.0% (95%CI: 57.3-78.8)[17]. The subsequent JCOG0502 trial[18] compared concurrent CRT with surgery, using the JCOG9708 cohort as the surgical control, in 368 patients with stage I (T1N0M0) ESCC. The CRT and surgery groups demonstrated comparable 5-year OS rates [85.5% vs 86.5%; hazard ratio (HR) = 1.05; 95%CI: 0.67-1.64]. The 5-year progression-free survival (PFS) rates were 71.6% in the CRT group vs 81.7% in the surgery group, with a cCR rate of 87.3% achieved in the CRT arm. These findings suggest that definitive CRT provides long-term survival outcomes similar to those of surgery for early-stage EC, while simultaneously enabling OP in appropriately selected patients.

Endoscopic submucosal dissection for early-stage EC

The National Comprehensive Cancer Network guidelines endorse endoscopic submucosal dissection (ESD) for the treatment of early-stage EC, including pTis, pT1a, and selected superficial pT1b lesions[19]. In contrast, Japanese guidelines recommend endoscopic resection (ER) specifically for mucosal cancers (T1a ESCC), assigning this recommendation an evidence level of IIA[20,21].

Within the TNM staging system for EC, the T1 category is defined by the depth of tumor invasion. pT1a lesions are confined to the mucosal layer and are subclassified as pT1a-EP (M1, indicating intraepithelial carcinoma), pT1a-LPM (M2, representing invasion into the lamina propria mucosae), and pT1a-MM (M3, denoting invasion into the muscularis mucosae). Lesions that penetrate beyond the muscularis mucosae into the submucosa are classified as pT1b. These are further subdivided into pT1b-SM1 (invasion of the superficial third), pT1b-SM2 (middle third), and pT1b-SM3 (deep third) of the submucosal layer.

The risk of lymph node metastasis (LNM) serves as the primary oncologic criterion for treatment selection. This risk is negligible, effectively 0%, for tumors confined to the M1 or M2 Layers. However, the probability of LNM increases significantly upon invasion of the muscularis mucosae (M3). Reported LNM rates range from 8% to 18% for M3 and SM1 Lesions and rise to 25%-50% for deeper submucosal invasion (SM2/SM3)[22-24].

Based on this risk stratification, the Japanese Esophageal Society guidelines consistently recommend ER as a curative treatment exclusively for T1a cancers. The 2017 guidelines specified its use for lesions confined to the epithelium or lamina propria mucosae, classified as M1/M2. Although the 2022 guidelines updated technical recommendations, the fundamental principle remains unchanged[25]: ER is indicated for T1a lesions without lymphovascular invasion, as the risk of LNM beyond this depth precludes endoscopic therapy alone from being considered oncologically curative.

For treatment planning in stage 0-I EC, clinical staging should be established using gastrointestinal endoscopy, cervical-thoracic-abdominal computed tomography (CT), and additional diagnostic investigations as necessary. Precise evaluation of tumor invasion depth is essential to guide optimal treatment selection among endoscopic therapy, surgery, and CRT. ESD for early-stage EC is associated with several clinically significant complications[26]. Common adverse events include peri- or post-procedural bleeding, which is typically managed with endoscopic coagulation or clipping. Although less frequent, perforation represents a serious complication that can often be managed endoscopically, although surgical intervention may be required in selected cases. A major long-term concern is stricture formation, particularly following resections involving more than three-fourths of the esophageal circumference or long segments. Such cases often necessitate prophylactic strategies and may require repeated dilatation or steroid therapy. Post-procedural pain and mediastinal emphysema are generally self-limiting. Proficiency in preventing, recognizing, and managing these complications is essential for achieving optimal oncological and functional outcomes.

In Japan, T1b tumors are generally considered unsuitable for endoscopic treatment as a standalone modality. For patients with stage I (T1b) disease, the decision between surgery and CRT should be guided by an assessment of surgical candidacy. T1b EC is defined by tumor invasion limited to the submucosal layer without involvement of the muscularis propria. The optimal treatment approach, endoscopic therapy vs surgery, for this stage continues to be debated. Endoscopic therapies are minimally invasive but do not provide lymph node clearance, whereas esophagectomy allows for complete lesion removal while being associated with higher risks of complications.

Pathological evaluation after ER is critical for determining whether additional curative treatment is required. Patients with pT1a-EP or pT1a-LPM lesions without lymphovascular invasion may proceed to surveillance after endoscopic procedures. Those with pT1a-MM lesions require comprehensive evaluation to assess the need for adjuvant therapy. Furthermore, evidence indicates that patients with confirmed lymphovascular invasion in pT1a-MM lesions or any pT1b-SM lesion following endoscopic treatment should receive complementary therapy, such as esophagectomy or definitive CRT. However, current evidence remains insufficient to definitively recommend one modality over the other. The JCOG0508 study[27] suggested that endoscopic therapy may be appropriate for cT1bN0 EC with limited invasion depth. In this trial, patients who achieved pathologically complete resection (pT1a) but had lymphovascular invasion or pT1b disease received supplemental CRT. This strategy resulted in a 3-year survival rate of 90.7% (95%CI: 86.2-94.1), demonstrating non-inferior efficacy compared to surgery.

A retrospective analysis of 108 patients who underwent non-curative ER, defined by positive vertical margins, lymphovascular invasion, or submucosal or deeper infiltration, compared outcomes between salvage esophagectomy and CRT[28]. Although OS and disease-specific survival (DSS) did not differ significantly between the two groups, no recurrences were observed in the esophagectomy cohort during follow-up, whereas two recurrence-related deaths occurred in the CRT group. These findings are consistent with the report by Koterazawa et al[29], which indicated superior disease control with esophagectomy compared to CRT following non-curative resection in cases with SM2 invasion depth or lymphovascular invasion. Similarly, Tanaka et al[30] observed disease recurrence only among patients treated with CRT. In contrast, a Chinese study utilizing the Surveillance, Epidemiology, and End Results (SEER) database reported comparable cancer-specific survival (CSS) and OS outcomes. The 5-year CSS rates overlapped between the endoscopic therapy group [69.5% (95%CI: 61.5-77.5)] and the esophagectomy group [75.0% (95%CI: 71.5-78.5)], while the CRT group showed significantly lower survival [42.4% (95%CI: 31.0-53.8)][31]. These results support the potential equivalence of endoscopic therapy to esophagectomy in selected cases of T1b EC.

A meta-analysis further suggests that esophagectomy improves OS in T1b EC, which may be attributed to comprehensive lesion clearance and lymph node assessment[32]. Notably, although endoscopic cohorts demonstrated higher rates of positive margins, this finding did not correlate with increased recurrence, possibly indicating the presence of undetected occult nodal metastases. Subgroup analysis suggests that SM1 infiltration may be suitable for endoscopic management, although further evidence is required to confirm this. The discrepancies observed among the studies mentioned above may be related to differences in the histological composition of their respective cohorts. The study population analyzed by Tanaka et al[30] consisted predominantly (> 95%) of ESCC cases. In contrast, the cohort in the SEER data analysis by Fan et al[31] was composed of 55.79% EAC and 44.21% ESCC. Similarly, the meta-analysis by Zheng et al[32] included a nearly equal distribution of studies focusing on ESCC (6 articles) and EAC (5 articles).

Although prospective comparisons of adjuvant treatment modalities are currently lacking, retrospective series report similar OS outcomes for pT1a-MM or pT1b disease treated with either CRT or surgery. However, CRT is associated with poorer oncologic outcomes in high-risk pathological profiles, including pT1b-SM2-3, pT1a-MM, or lymphovascular invasion (LVI)-positive pT1b-SM1 Lesions. This pattern suggests that surgical intervention may represent the preferred adjuvant approach for patients with these adverse pathological features[33].

OP IN LOCALLY ADVANCED EC

Neoadjuvant therapy, primarily administered as preoperative chemotherapy, aims to reduce tumor burden prior to definitive surgery. This approach improves resectability and R0 resection rates while minimizing the risk of intraoperative tumor dissemination, thereby reducing the likelihood of postoperative recurrence and metastasis. Neoadjuvant CRT further enhances local control and survival outcomes in locally advanced EC. Selected patients achieve a cCR[34], which is objectively defined as the absence of detectable tumor on esophagography and no evidence of malignancy on CT, endoscopy, or positron emission tomography (PET)[35,36]. Accurate assessment of cCR may justify the adoption of OP strategies; however, the risk of false-negative assessments due to undetected residual disease remains a significant concern.

Pathological complete response (pCR), defined as the absence of residual viable tumor in both primary lesions and regional lymph nodes upon surgical pathological examination, represents the gold standard for evaluating neoadjuvant treatment efficacy. In the NEOCRTEC5010 trial cohort, achievement of pCR was associated with significant survival benefits: Median OS was extended by 23.4 months (92.6 months vs 69.2 months; HR = 2.70; 95%CI: 1.48-4.92), and 5-year survival rates were substantially higher (OS: +24.5%; DFS: +25.8%) compared to non-pCR patients (P < 0.001)[37]. Major pathological response (MPR) and pCR commonly serve as primary endpoints in most neoadjuvant clinical trials. The validation of pCR provides critical evidence to support OP strategies following neoadjuvant therapy. Therefore, the successful implementation of esophageal preservation strategies depends on accurate clinical assessment of treatment response and subsequent validation through pCR rates across different neoadjuvant regimens[38].

Neoadjuvant chemotherapy and CRT for EC

Neoadjuvant therapy plays a crucial role in OP strategies for EC. Multiple clinical trials (summarized in Table 1) have demonstrated that patients receiving neoadjuvant therapy show significant improvements in treatment outcomes.

Table 1 Comparison of major clinical trials in esophageal cancer.

Ref.	Study	Sample size	Histology composition	Neoadjuvant therapy	pCR rate	Key findings
Allum et al[40], 2009	OEO2	802	72% ESCC, 28% EAC	2 cycles (cisplatin + 5-FU)	NR	Improved OS (HR = 0.82) with chemo vs surgery alone
van Hagen et al[41], 2012	CROSS	368	75% ESCC, 25% EAC	5 cycles (carboplatin + paclitaxel) + RT (41.4 Gy)	23% (EAC); 49% (ESCC)	CRT improved OS (HR = 0.657) vs surgery
Yang et al[42], 2018	NEOCRTEC5010	451	100% ESCC	2 cycles (vinorelbine/cisplatin) + RT (40 Gy)	43.2%	nCRT significantly improved pCR
Bedenne et al[43], 2007	FFCD9102	259	88.8% ESCC, 11.2% EAC	2 cycles (cisplatin/5-FU) + CRT (46 Gy)	NR	CRT alone (non-surgical) had similar OS as CRT vs surgery
Qian et al[47], 2022		256	100% ESCC	4 cycles (docetaxel + cisplatin) + RT (40 Gy)	48.1%	dCRT vs nCRT → surgery for cCR patients; similar OS, supporting organ preservation in responders
van der Wilk et al[48], 2025	SANO	309	22.7% ESCC, 74.8% EAC	5 cycles (carboplatin + paclitaxel) + RT (41.4 Gy)	NR	Active surveillance feasible for cCR patients with low relapse risk
Yang et al[50], 2025	preSINO	309	100% ESCC	5 cycles (carboplatin + paclitaxel) + RT (41.4 Gy)	NR	Combining EUS-FNA and ctDNA improved residual disease detection sensitivity

NR: Not reported; pCR: Pathological complete response; ESCC: Esophageal squamous cell carcinoma; EAC: Esophageal adenocarcinoma; OS: Overall survival; HR: Hazard ratio; CRT: Chemotherapy, chemoradiotherapy; cCR: Clinical complete response; EUS-FNA: Endoscopic ultrasound-guided fine-needle aspiration; dCRT: Definitive chemoradiotherapy; nCRT: Neoadjuvant chemoradiotherapy; RT: Radiotherapy.

The OEO2 trial[39,40] reported superior 5-year OS with neoadjuvant chemotherapy compared to surgery alone (23% vs 17%). Similarly, the CROSS trial[41] showed a significantly prolonged median OS with nCRT (48.6 months vs 24.0 months), while the NEOCRTEC5010 trial[42] confirmed both increased pCR rates and extended survival in patients with ESCC.

The FFCD 9102 trial[43] found no survival benefit from surgery compared to continued CRT in ESCC patients who responded to initial therapy. The FFCD 9901 trial further indicated no additional benefit from surgery in patients who achieved a cCR[44]. The JCOG9907 trial demonstrated better OS with preoperative chemotherapy compared to postoperative chemotherapy, although the study design limited chemotherapy administration in postoperative patients with pN0 disease[45]. Recent preliminary results from the Japanese CROC trial, which analyzed 90 patients, indicated a 3-year OS rate of 92% following induction docetaxel, platinum, and fluorouracil (DCF) chemotherapy and dCRT[46]. A remarkable response to three courses of DCF therapy was observed in 58.4% of patients. Among these responders, 89.8% achieved a complete response after dCRT. According to a cohort study by Qian et al[47], equivalent OS was observed between consolidative surgery following nCRT and curative-intent CRT in locally advanced ESCC patients who achieved cCR (P = 0.34). These findings support response-driven de-escalation strategies that are contingent upon rigorous restaging protocols[47].

The landmark SANO trial, by van der Wilk et al[48], provides the most recent high-level evidence regarding OP strategies for EC patients. This phase 3 randomized controlled trial compared active surveillance (AS) vs esophagectomy in patients who achieved a cCR after nCRT. The primary endpoint was to determine whether the 2-year OS rate with AS was non-inferior to surgery, defined as not more than 15% lower than the expected survival rate with surgical intervention. The SANO trial successfully met its primary endpoint, building upon the preSANO response assessment framework. At median follow-up durations of 34 months (interquartile range 30-40) for the AS group and 50 months (interquartile range 40-60) for the surgery group, the 2-year OS rates were 74% and 71%, respectively (absolute difference +3%; 95%CI: -7% to +13%). Notably, patients in the surveillance group demonstrated significantly better global health-related QOL at 6 months and 9 months after intervention (P < 0.01). It is important to note that this trial included patients with both EAC and ESCC, with EAC patients constituting the majority.

The preSINO trial enrolled 309 patients with locally advanced ESCC from three Chinese centers, all of whom received nCRT according to the CROSS regimen[49]. Clinical response evaluation (CRE) was performed at 4-6 weeks (CRE-1) and 10-12 weeks (CRE-2) after completion of therapy using bite-on-bite biopsy, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), and PET-CT based on preSANO criteria. Concurrently, ctDNA-based minimal residual disease (MRD) analysis was conducted in a sub-cohort. The combined biopsy and EUS-FNA approach demonstrated a 13.5% missed detection rate for major local residual disease (defined as Trg3-4 or Trg1-2/ypN+), meeting the primary endpoint and validating the system's predictive accuracy for local tumor regression. These findings support the utility of this approach in identifying cCR and facilitate future investigations into surgery deferral or omission in Asian ESCC populations. Furthermore, ctDNA showed promise as a biomarker for detecting systemic residual disease and assessing recurrence risk[50,51].

Two ongoing clinical trials are currently evaluating OP strategies for EC. The German ESORES trial[52] is a multicenter, randomized controlled, parallel-group, non-inferiority study. It randomizes patients to one of two arms: CRE followed by surgery as needed (Arm A), or mandatory surgery with subsequent follow-up (Arm B). The CRE protocol requires three diagnostic modalities: Esophagogastroscopy with deep biopsies (EGD), EUS-FNA of suspicious lymph nodes, and PET-CT imaging. Patients with residual tumor (non-complete response) are directed to immediate surgical resection, while those achieving a cCR enter a structured AS program. This AS protocol involves serial evaluations at 3, 6, 9, 12, 18, and 24 months, followed by annual assessments using EGD, EUS-FNA, and thoraco-abdominal CT. Surgical intervention is reserved exclusively for cases with confirmed local regrowth. The hierarchically tested primary endpoints include the 3-year OS rate and the global QOL subscale of the EORTC QLQ-C30 questionnaire. In parallel, the French ESOSTRATE-PRODIGE 32 trial[53] has been activated. This trial employs a design similar to the SANO trial but utilizes a distinct randomization methodology. It exclusively enrolls patients with EAC, while excluding those with ESCC. The CRE in this trial is scheduled 5-6 weeks after the completion of CRT.

A meta-analysis by van der Wilk et al[54] pooled individual patient data from seven trials, encompassing 788 patients who achieved a cCR following nCRT. After random or propensity score matching, 453 patients were included in the analysis: 196 were assigned to AS and 257 were allocated to immediate surgery. Survival analysis demonstrated a comparable risk of all-cause mortality between the AS and surgery groups (HR = 1.08; 95%CI: 0.62-1.87; P = 0.75). Consistent with this finding, subgroup analyses of patients with ESCC showed overlapping OS curves for AS and surgical strategies. Another meta-analysis by Sun et al[55], which evaluated conservative management vs esophagectomy in cCR patients, included eight retrospective cohort studies and one randomized controlled trial (total n = 749; 333 in the nCRT-only group, 416 in the nCRT plus surgery group). Comparable survival outcomes were observed between the nCRT-only and nCRT plus surgery groups, with no significant differences in 2-year OS [odds ratio (OR) = 1.239; 95%CI: 0.891-1.723] or 5-year OS (OR = 1.369; 95%CI: 0.963-1.947). However, the nCRT plus surgery group demonstrated significantly longer DFS at both 2-year (OR = 0.303) and 5-year (OR = 0.357) timepoints, along with reduced local recurrence rates (OR = 0.179; 95%CI: 0.104-0.291). The rates of distant metastasis were similar between the two groups. The authors concluded that the addition of esophagectomy after nCRT in cCR patients improves DFS and reduces local recurrence compared to conservative management, although this does not translate into a corresponding OS benefit. Salvage surgery remains a feasible option for cases of resectable local recurrence following initial cCR.

Therefore, the adoption of AS with selective OP represents a clinically viable strategy for patients who achieve a cCR following nCRT. Meta-analyses indicate that while the combination of nCRT with surgery delays local recurrence, this approach demonstrates no statistically significant OS advantage compared to nCRT alone. Furthermore, it is associated with increased treatment-related mortality in the surgical cohorts[56]. Reflecting emerging evidence, the Chinese Society of Clinical Oncology Esophageal Cancer Guidelines (2023 edition) have incorporated OP strategies as a Category III recommendation for ESCC. Nevertheless, significant controversy persists regarding this approach, with substantial opposition noted among surgical experts[57].

Neoadjuvant chemo-immunotherapy for EC

Immunotherapy has significantly improved outcomes in the neoadjuvant treatment of EC. In the CheckMate-577 phase III trial[58], adjuvant nivolumab doubled the median PFS compared to placebo (22.4 months vs 11.0 months; HR = 0.69; P < 0.001) among patients who had previously undergone nCRT and surgery.

The phase II PALACE-1 study reported a pCR rate of 55.6% with neoadjuvant pembrolizumab combined with CRT[59]. The KEYNOTE-590 trial[60] established the superiority of first-line pembrolizumab plus chemotherapy over chemotherapy alone in advanced EC, demonstrating improved OS and PFS (median OS 12.4 months vs 9.8 months; HR = 0.73; P < 0.0001). Additional trials, including KEYNOTE-028[61], CheckMate-649[62], and PERFECT[63], further support the survival benefit of immune checkpoint inhibitors (ICIs) across various stages of EC.

Multiple phase I to III prospective single-arm studies[64-74] have consistently reported pCR rates ranging from 20% to 50% with neoadjuvant chemoimmunotherapy, confirming promising pathological responses and an acceptable safety profile. Key results from recent trials are summarized in Table 2.

Table 2 Neoadjuvant immunotherapy trials in esophageal squamous cell carcinoma.

Ref.	Study name/NCT No.	Type of EC	Sample size	Immunotherapy regimen	pCR rate	Other key findings
Zhang et al[64], 2021	ESONICT-1, ChiCTR2100045659	ESCC	30	2 cycles (sintilimab + nab-paclitaxel + cisplatin)	21.7%	MPR: 52.2%
Yang et al[66], 2022	NICE, ChiCTR2000028900	ESCC	23	2 cycles (camrelizumab + nab-paclitaxel + carboplatin)	25.0%	MPR: 50.0%
Liu et al[67], 2022	ChiCTR1900026240	Locally advanced resectable ESCC	60	2 cycles (camrelizumab + nab-paclitaxel + carboplatin)	39.2%	R0 resection: 98%
Yin et al[72], 2023	NATION-1907, NCT04215471	T2-4aN0-2M0 resectable ESCC	30	2 cycles, adebrelimab (1200 mg IV q3w)	8%	MPR: 24%
Zhang et al[65], 2023	ChiCTR1900027160	ESCC	60	2 cycles (toripalimab + nab-paclitaxel + oral S-1)	29.1%	MPR: 49%
Yan et al[68], 2022	TD-NICE, ChiCTR2000037488	ESCC	45	3 cycles (tislelizumab + nab-paclitaxel + carboplatin)	50.0%	MPR: 72%
Liu et al[69], 2022	NIC-ESCC2019, NCT04225364	ESCC	56	2 cycles (camrelizumab + nab-paclitaxel + cisplatin)	35.3%	ORR: 66.7%
Chen et al[70], 2023	KEEP-G 03, NCT03946969	RSCC	30	2 cycles [sintilimab + triplet chemotherapy (liposomal paclitaxel, cisplatin, and S-1)]	20.0%	MPR: 50.0%
Zhang et al[71], 2024	ChiCTR2200056728	Border-line resectable ESCC	32	2-4 cycles (camrelizumab + nab-paclitaxel + cisplatin)	40.9%	MPR: 63.6%
Yang et al[73], 2024	NICE Study, ChiCTR1900026240	Stage N2-3 ESCC	60	2 cycles (camrelizumab + nab-paclitaxel + carboplatin)	39.2%	MPR: 68.6%; RFS: 67.9%; OS: 78.1%
Qin et al[74], 2024	ESCORT-NEO/NCCES01, ChiCTR2000040034	Resectable ESCC (II-IVA)	432	2 cycles (camrelizumab + nab-paclitaxel/paclitaxel + cisplatin)	28.0% vs 15.4%	MPR: 59.1% vs 36.2%; 18-month PFS 69.1% vs 54.7%

EC: Esophageal cancer; pCR: Pathological complete response; ESCC: Esophageal squamous cell carcinoma; PFS: Progression-free survival; OS: Overall survival; ORR: Objective response rate; MPR: Major pathological response.

Beyond pCR, the NICE study with 24-month follow-up demonstrated higher recurrence-free survival (RFS) and OS in surgically resected N2-N3 EC patients treated with neoadjuvant chemoimmunotherapy. Furthermore, MPR was predictive of lower recurrence rates and superior survival outcomes[73,75].

DISCUSSION

OP strategies, particularly the "watch and wait" (W&W) approach, have emerged as promising alternatives to conventional esophagectomy in the management of EC. In clinical practice, two distinct W&W scenarios are commonly observed: The occasional or reactive strategy applied to patients who achieve a cCR after neoadjuvant therapy, where tumor control remains the primary objective; and the proactive strategy implemented specifically with OP as the intended goal in cCR patients.

The SANO trial provided compelling evidence that AS is non-inferior to standard surgery in terms of 2-year OS and DFS) for patients who achieve cCR after nCRT[48]. This finding supports the feasibility of delaying or omitting surgery in selected patients, thereby reducing immediate surgical morbidity and preserving QOL. However, the long-term outcomes of AS remain uncertain and require further investigation.

One of the primary challenges in implementing OP strategies is the accurate assessment of cCR. Current imaging modalities, including CT, PET-CT[76], and magnetic resonance imaging (MRI)[77], exhibit limitations in detecting MRD, which is critical for determining patient eligibility for AS. Advanced techniques such as PET-MRI, dynamic contrast-enhanced MRI[77], and liquid biopsy-based assays are under investigation to improve diagnostic accuracy. The combined diagnostic approach evaluated in the preSINO trial, incorporating bite-on-bite biopsy, EUS-FNA, and ctDNA analysis, demonstrated a 13.5% missed detection rate for major local residual disease (defined as Trg3-4 or Trg1-2/ypN+), meeting the primary endpoint and validating the system's predictive accuracy for local tumor regression[49]. Additionally, the integration of artificial intelligence (AI) in medical image analysis holds potential for refining the detection of subtle tumor regression patterns, thereby enhancing the reliability of cCR assessment. The development of robust predictive biomarkers represents a critical unmet need to better identify patients suitable for AS. Although biomarkers such as PD-L1 expression, tumor mutational burden, and microsatellite instability-high status demonstrate predictive potential for immunotherapy response, their applicability in AS decision-making remains unvalidated[78]. Large-scale, multicenter trials are imperative to confirm the clinical utility and predictive accuracy of these biomarkers.

The SANO trial also underscored the importance of patient-centered decision-making. Although over 90% of patients in the AS group completed the surveillance period, the potential psychological burden and logistical challenges associated with regular follow-up visits, as well as the uncertainty regarding tumor progression, warrant careful consideration. Patients may experience anxiety and face increased healthcare costs, which must be balanced against the potential benefits of AS. Therefore, shared decision-making between clinicians and patients is essential to ensure that the selected treatment aligns with individual values and preferences.

The long-term efficacy of AS represents another area requiring further investigation. Although the SANO trial reported 2-year outcomes, extended follow-up is necessary to evaluate long-term survival and recurrence rates. The observed 35% local recurrence rate in the AS cohort necessitates salvage surgery in eligible patients. As therapeutic paradigms evolve, the safety and efficacy profiles of such interventions within modern immunotherapy contexts require rigorous evaluation.

A critical consideration in the discussion of OP strategies for EC is the potential misinterpretation of the SANO trial results as equating AS with surgery[79]. While the study demonstrated non-inferior 2-year OS rates between AS and standard surgery (74% vs 71%; HR = 1.14; 95%CI: 0.74-1.78), it is essential to clarify that AS does not equate to surgery. In practice, salvage surgery was ultimately required in approximately 50% of the AS cohort due to local recurrence, although postoperative complication profiles were comparable to those in the immediate surgery group. This observation highlights the distinction between AS and complete exemption from surgery, AS represents a delayed, rather than omitted, surgical approach. Consequently, AS should not be regarded as a universal replacement for surgery, but rather as a strategically timed intervention that permits tumor regression assessment and minimizes unnecessary surgical burden in patients who maintain a cCR.

This nuanced perspective is supported by experiences across other oncology domains: AS functions as a viable, low-risk management option in prostate[80] and thyroid malignancies[81], with the inherent understanding that a subset of patients will eventually require intervention. For example, in prostate cancer, approximately 25% to 50% of patients on AS eventually undergo treatment, often due to disease progression or patient preference. Similarly, in thyroid cancer, 5% to 12% of patients under AS for papillary thyroid microcarcinoma proceed to surgery, typically following tumor progression or a patient-driven decision. These patterns underscore the importance of distinguishing AS from complete surgical exemption, as the former constitutes a proactive, time-sensitive strategy rather than a passive approach. However, AS in EC warrants greater caution than in these other malignancies due to its potential for rapid progression and the technical complexity of salvage surgeries.

Although the SANO trial provides compelling evidence supporting the feasibility of AS in selected patients who achieve a cCR, it is essential to avoid oversimplifying its implications. The 50% rate of salvage surgery in the AS group reinforces that AS should be regarded as a flexible and adaptive strategy, one that requires continuous evaluation and readiness for surgical intervention. This distinction is crucial for both clinicians and patients to appropriately contextualize AS within the broader spectrum of cancer management, thereby balancing the benefits of delayed surgery against the risks of disease progression.

Another critical consideration is the distinct pathological distribution of EC between Eastern and Western populations. The SANO trial primarily enrolled patients with EAC, whereas ESCC, the most prevalent histological subtype globally, predominates in East Asia. Further clinical investigations are necessary to determine whether the findings of the SANO trial can be generalized to ESCC and whether a W&W strategy is appropriate for this subtype.

To support personalized clinical decision-making, a more detailed discussion on patient selection for the W&W strategy is warranted. This should emphasize differential applicability and risks across patient subgroups: Frail older adults or individuals with significant comorbidities may be better suited for W&W due to elevated risks associated with salvage surgery, provided they can adhere to a rigorous AS protocol. In contrast, younger, fit patients with high-risk tumor biology require careful counseling, considering their longer life expectancy and cumulative risk of recurrence. The formal integration of factors such as age, performance status, comorbidity indices (e.g., Charlson Comorbidity Index), and patient preferences is essential for nuanced patient selection.

Furthermore, explicit follow-up protocols during the W&W period should be clearly defined. A standardized schedule is recommended, for instance, endoscopic reassessment with bite-on-bite biopsies and EUS-FNA every 3 months during the first year, supplemented by PET-CT and serial ctDNA monitoring at 6 and 12 months. Each evaluation should employ consistent clinical, endoscopic, histologic, and radiographic criteria to confirm an ongoing complete response or to detect early recurrence. Clearly defined triggers for intervention, such as histologic evidence of residual disease or new FDG avidity, are critical to ensure timely transition to salvage therapy.

During the W&W period, patients remain at risk for local tumor regrowth and distant metastasis. Some individuals may also experience long-term adverse effects from prior neoadjuvant therapy. Furthermore, the AS inherent to the W&W approach can impose significant psychological and financial burdens on patients and their families.

It must be emphasized that current cCR criteria imperfectly predict pCR. Clinicians should maintain vigilance regarding the potential for local disease progression, the increased technical complexity of salvage procedures, and the associated medico-legal risks if the W&W strategy is applied without appropriate patient selection.

Therefore, centers considering the implementation of a W&W strategy should fulfill the following prerequisites: (1) Maintain a specialized multidisciplinary team (MDT) that includes experts in surgery, medical oncology, radiation oncology, radiology, endoscopy, and pathology; (2) Ensure structured and rigorous follow-up conducted by experienced clinicians; and (3) Engage in thorough shared decision-making with patients, obtaining fully informed consent. The W&W strategy may be considered for selected patients with locally advanced EC who achieve cCR following neoadjuvant therapy. In cases of near-complete response without definitive evidence of residual disease, W&W may be cautiously offered, with close monitoring and explicit agreement from the patient and family, particularly when patients express a strong preference for OP or face a high risk of significant functional impairment from surgery.

CONCLUSION

OP strategies for EC seek to balance oncological efficacy with QOL preservation. However, their implementation faces significant challenges, including suboptimal concordance between cCR and pCR assessments, the need for long-term safety outcomes validated by prospective studies, and imprecise patient selection criteria. Future progress depends on enhancing diagnostic accuracy, refining AS protocols, and integrating validated immunotherapeutic approaches within neoadjuvant frameworks. Given the predominance of EAC in Western studies (e.g., the SANO trial) compared to the high prevalence of ESCC in East Asia, future validation of the W&W strategy in ESCC populations is necessary, particularly when combined with dynamic monitoring technologies such as ctDNA analysis. For patients with EC who desire OP, the MDT approach will remain essential.