Esophageal cancer (EC) is the seventh most prevalent malignant neoplasm worldwide and is the sixth leading cause of cancer-related mortality (1). A significant proportion of patients with esophageal squamous cell carcinoma (ESCC) are initially diagnosed at a locally advanced stage. To improve prognosis, the standard treatment approach for these patients entails the administration of neoadjuvant therapy followed by surgical intervention.

Extensive clinical evidence supported the recommendation of neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) as standard treatments for locally advanced esophageal squamous cell carcinoma (LA-ESCC) patients (2, 3). With recent advancements in immunotherapy, its potential as a therapeutic strategy for LA-ESCC has garnered significant attention. The safety profile of neoadjuvant chemoimmunotherapy(nICT) is supported by evidence from multiple clinical trials (4–6), which demonstrate no significant increase in postoperative complications, such as anastomotic leakage. Furthermore, its efficacy is reinforced by elevated rates of major pathological response (MPR) and pathological complete response (pCR), both of which are critical indicators of improved treatment outcomes. In 2012, the U.S. Food and Drug Administration (FDA) recognized pCR as a surrogate endpoint for survival in studies of neoadjuvant therapy, based on the premise that pCR may serve as a predictor of clinical benefit (7). However, apart from pCR, MPR can also serve as an indicator of the sensitivity and efficacy of treatment modalities. Our prior study has demonstrated that MPR can function as a survival surrogate, providing a clinical reference and an evidence-based foundation for decision-making in ESCC patients undergoing nCT/nICT (8).

Previous research has demonstrated that EC patients treated with nCRT who exhibited microscopic residual disease faced an elevated risk of recurrence, however their overall survival paralleled that of patients achieving a pCR (9). Nevertheless, different treatment modalities have been observed to exhibit differing short-term efficacy and long-term prognoses in LA-ESCC patients (10, 11). To the best of our knowledge, there is a paucity of studies directly comparing the prognostic difference of MPR with pCR in ESCC patients undergoing nICT, underscoring the necessity for further research in this area. Therefore, this study aims to examine the prognostic value and clinical significance of MPR in ESCC patients undergoing nICT.

pCR and MPR are utilized as the principal endpoints in assessing the short-term efficacy of neoadjuvant trials. Previous researches showed that nICT could lead to higher rates of MPR and pCR compared to nCT alone (18, 19). Furthermore, in comparison to achieving a pCR, attaining a MPR is more readily achievable in ESCC patients undergoing neoadjuvant therapy (20). However, the question of whether ESCC patients achieving MPR have prognostic outcomes equivalent to those attaining pCR remains unclear. Our study found that patients who achieved MPR following nICT exhibited a more favorable prognosis compared to those who did not achieve MPR. Furthermore, their prognostic outcomes were comparable to those of patients who attained pCR.

This study demonstrated that patients exhibiting a MPR in the nICT group had a significantly improved prognosis compared to those without MPR, both prior to and following propensity score matching. The Cox regression analysis also identified MPR as an independent risk factor. From the perspective of tumor load, the status of MPR indicated that neoadjuvant therapy was particularly effective in reducing preoperative tumor burden and substantially decreasing the risk of tumor recurrence through the more efficient eradication of micro-metastases (21, 22). Furthermore, a distinctive characteristic of immunotherapy is its “tail effect” (23, 24). The tail effect is characterized by the sustained maintenance of therapeutic effects following treatment discontinuation, thereby providing long-term immune responses and better survival benefits for patients with advanced tumors. The development of the tail effect is linked to the “memory function” of immune cells, notably T cells. While, this effect requires a strong interaction between the patient’s immune system and the immunotherapeutic agent. Patients who achieve a MPR are more likely to exhibit an enhanced tail effect in the immune system during neoadjuvant therapy, which sustains anti-tumor activity postoperatively and results in improved clinical outcomes.

In our study, it was observed that the RFS of patients achieving a MPR was comparable to that of patients exhibiting a pCR. Sensitivity analysis indicated that, within the MPR cohort, the RFS of patients attaining pCR did not significantly differ from those who did not, corroborating previous findings (25). These findings implied that nICT may have yielded equivalent therapeutic outcomes to MPR patients and pCR patients. This observation also suggested that the MPR may serve as a surrogate endpoint for pCR in assessing the efficacy of nICT. Given the comparable RFS in MPR and pCR patients, MPR has the potential to merge as a more accessible and cost-effective prognostic indicator in clinical practice. The CROSS study demonstrated that nCRT significantly improves overall survival in EC patients compared to surgery alone; however, it does not confer enhanced survival benefits with respect to distant metastasis (26). Compared to nCRT, nICT offers a systemic therapeutic approach with a distinct advantage in the management of distant metastases, particularly in the control of microscopic metastasis (27).The integration of nICT and surgical intervention constitutes a comprehensive treatment modality that effectively manages locoregional recurrence and distant metastasis of tumors: nICT significantly reduces the quantity of tumor cells within the primary tumor and lymph nodes, especially in patients exhibiting drug sensitivity. During subsequent radical esophagectomy, the residual tumor cells can be effectively excised. The primary aims of neoadjuvant therapy are twofold: first, to achieve tumor downstaging, thereby enhancing the feasibility of curative surgical procedures (28); and second, to mitigate distant metastasis and micrometastasis of tumor cells through systemic drug administration, particularly when the tumor burden is substantial and the likelihood of metastasis is elevated. Numerous studies have documented that patients undergoing neoadjuvant therapy demonstrate superior recurrence-free survival rates in comparison to those receiving adjuvant therapy post-surgery, which implied that chemotherapy or immunotherapy might be more efficacious in managing distant metastasis when the tumor burden is elevated, as is the case prior to surgical intervention (29, 30). Both MPR and pCR reflect a significant sensitivity to the treatment protocol, showing the effective eradication of a considerable proportion of cancer cells. As a result, the prognosis for patients with MPR is notably enhanced due to the effective local tumor control attained through following standardized esophagectomy. This improvement may account for the similar RFS observed between ESCC patients with MPR and those with pCR following surgery.

In our study, pCR was found to be a prognostic factor but not an independent predictor of survival outcome, consistent with findings reported in other studies (31–33). This indicated that pCR can be a useful short-term indicator for evaluating treatment efficacy, but it may not be a reliable surrogate for long-term outcomes, especially in ESCC patients after nICT. The CheckMate 577 trial has shown that adjuvant immunotherapy can enhance survival outcomes for EC patients who have residual tumor cells after nCRT (34). Nonetheless, there are currently no established guidelines delineating the indications for adjuvant therapy in patients undergoing nICT. In our prior investigations, we found that the prognosis for ESCC patients who attained a pCR following nICT was unaffected by adjuvant therapy (35). In this study, it was observed that adjuvant therapy did not provide additional advantages in terms of disease-free survival for patients achieving a MPR, aligning with the outcomes observed in patients with pCR. Prior study has indicated that compared to those who did not undergo AT, the receipt of AT showed shorter disease-free survival following neoadjuvant chemoradiotherapy and surgery (36). Similarly, Yan’s study showed that adjuvant therapy failed to improve survival outcomes in patients receiving neoadjuvant chemotherapy and instead indicated a trend toward worse prognosis (37). It is well recognized that AT does not benefit all ESCC patients. There are three possible reasons for negative impact of AT. Firstly, postoperative impairments such as reduced food intake and swallowing difficulties and postoperative complications can significantly weaken the immune system of ESCC patients (38–40). In such circumstances, adjuvant therapy may further weaken the immune system’s ability to target cancer cells, potentially leading to disease recurrence (41, 42). Secondly, damage to the integrity of Lymph node, particularly as a result of systematic lymphadenectomy, may impair the activation of anti-tumor T cells, consequently diminishing the effectiveness of subsequent immunotherapeutic interventions (43, 44). Thirdly, the reduction of tumor burden after surgery may weaken the efficacy of adjuvant therapy. These findings suggested that clinicians might consider implementing a surveillance approach for patients achieving MPR after surgery, akin to the strategy employed for those with pCR. Besides, clinicians should take both MPR and pCR into account when assessing the prognosis of LA-ESCC patients, as this may facilitate the development of more tailored treatment strategies. However, we still believe this finding still requires further validation from through prospective, nationwide, multi-center clinical trials.

In the nICT cohort of patients with ESCC, the recurrence patterns observed in patients achieving MPR were analogous to those in patients achieving pCR, encompassing both distant metastasis and locoregional recurrence. Furthermore, in instances of distant metastasis, the predominant sites for both MPR and pCR patients were the brain, lungs, and liver. The analogous recurrence patterns and distribution of metastasis sites indicated the necessity for equal consideration to two patients group during follow-up. The recurrence pattern similarities between MPR and pCR patients also implied that these groups could be perceived as having comparable risk levels when devising follow-up strategies. Nonetheless, it is imperative to acknowledge that despite attaining MPR or pCR, patients remain at risk for recurrence. Ongoing surveillance is still essential to enhance prognostic outcomes.

This study has several limitations. First, despite being a multi-center study and employing rigorous selection criteria to mitigate selection bias, its retrospective design introduces inherent limitations. Secondly, this study was limited to patients with esophageal squamous cell carcinoma, and the extent to which our findings can be generalized to patients with adenocarcinoma remains uncertain. In future studies, we plan to conduct a separate analysis of esophageal adenocarcinoma. This approach will be pursued in subsequent research, although it will require additional time to collaborate with more centers due to the relatively low incidence of esophageal adenocarcinoma in China. The visual abstract of this study is shown in Figure 6 .

In conclusion, MPR emerges as a significant prognostic factor in ESCC patients undergoing nICT, with outcomes similar to those achieving pCR. These findings warrant consideration of MPR as a potential surrogate endpoint for pCR and highlight the need to refine treatment strategies based on pathological responses. Further studies are necessary to confirm these results and to explore the integration of MPR into clinical practice, potentially leading to more personalized and effective treatment approaches for ESCC patients.