Esophageal cancer (EC) is one of the life-threatening diseases worldwide, which ranks the 10th and sixth, respectively, in terms of incidence and mortality (1, 2). More than 50% of EC occurs in China, which ranks the sixth and fourth, respectively, in morbidity and mortality (3). There are two main pathological types of ECs, and more than 90% of them in China are esophageal squamous cell carcinoma (ESCC) (3). Patients with ESCC are often diagnosed at locally advanced stages at the time of presentation. Although the therapeutic methods for ESCC have been improved in recent years, the treatment effect is still unsatisfactory (4). Therefore, there is a need to explore more and more reliable indicators with pretreatment variables to predict prognosis before treatment.

For those patients with locally advanced ESCC, the NCCN guidelines recommend neoadjuvant chemoradiotherapy (nCRT) as the golden standard treatment in recent years (5). Due to the differences of races and pathological types between the West and the East, neoadjuvant chemotherapy (nCT) is usually recommended in China and Japan (6). However, the treatment effect and prognosis of neoadjuvant therapy for patients with ESCC are still unsatisfactory. Recently, immunotherapy has become one of the important regimens and has achieved several remarkable results in patients with advanced EC (7, 8). Compared with chemotherapy, immunotherapy has achieved a better long-term survival based on the ATTRACTION-3 and KEYNOTE-181 studies. According to the CheckMate 577 study, moreover, adjuvant nivolumab is also recommended after nCRT in patients with EC (9). Following these encouraging results in advanced EC, several clinical studies were also conducted, and the results revealed that neoadjuvant immunochemotherapy (nICT) followed by surgery is safe and feasible (10–13).

Recently, more and more researchers focus on the relations between the immune-nutritional status and cancer (14). The controlling nutritional status (CONUT), as an immune-nutritional index deriving from peripheral blood variables of albumin (ALB), lymphocyte (LYM), and total cholesterol (TC), has been reported to be related to prognosis in various cancers, including ESCC (15–17). Moreover, pretreatment CONUT was also widely used as a prognostic index in other digestive tract cancers, such as gastric cancer (GC) and colorectal cancer (CRC) (18–20). These results clearly demonstrated that a poor prognosis in various cancers was related to a high CONUT. Moreover, a recent study analyzed the prognostic value of CONUT in advanced EC patients who were treated with immunotherapy (21). The results revealed that a high CONUT score was associated with a significantly worse prognosis in advanced EC. In addition, it has also been shown that CONUT correlates with neoadjuvant response to treatment in several cancers, such as GC and EC (22, 23).

To date, most published studies focus on the efficacy and safety of nICT in local advanced ESCC. No studies on cancer recurrence in ESCC after nICT have been reported. Moreover, prior to nICT treatment, there are no reliable and affordable indexes to predict recurrence in ESCC. Therefore, we herein aimed to verify the recurrence pattern after nICT and explore the predictive value of CONUT in predicting DFS in ESCC with nICT.

In the current study, we initially explored the role of pretreatment CONUT on recurrence prediction in ESCC with nICT. The results revealed that the CONUT score may be used as a predictor for DFS and OS. In addition, a nomogram was also developed to predict recurrence after nICT. To our knowledge, this is the first report that focused on the role of CONUT score in predicting recurrence after nICT in ESCC. Moreover, we initially proposed a predictive model to predict recurrence after nICT for ESCC. The results of our study will have an important significance to local advanced ESCC patients who were treated with nICT.

In recent years, immunotherapy has become the focus of cancer treatment. Recent studies revealed that immunotherapy significantly improved the prognosis in several randomized phase III studies and was approved for first-line treatment for advanced ESCC (7, 8). As an exploratory attempt, nICT has already been investigated for ESCC in several studies. The results as well as our previously published study indicated that a high R0 resection and pCR rate were found in patients with ESCC receiving nICT (10–13). However, most previously published studies focused on the efficiency and safety of nICT. There are no studies regarding recurrence after nICT in patients with ESCC so far. Therefore, it is important to understand the real treatment effect of nICT in patients with ESCC.

As a useful index for immune-nutritional status, recent studies revealed that CONUT score was an effective predictive and prognostic indicator in various cancers (15–17). Since 2016, a few studies on the CONUT score in patients with EC have been reported (16, 23, 31–33). A study including 352 ESCC patients with surgery reported that patients with moderate or severe CONUT score were at a high risk of postoperative complications (31). Another study revealed that patients with moderate or severe CONUT score were related to poor prognosis in 373 ESCC patients with radical resection (16). Compared with other indicators, several studies have also shown the superiority of the CONUT score in predicting the prognosis in ESCC patients undergoing surgery (32, 33). In addition, some studies have evaluated the treatment response of pretreatment CONUT for neoadjuvant therapy in GC and EC patients (22, 23). Recently, a meta-analysis with 952 patients including five studies verified the significant associations between the CONUT and prognosis (34). However, no relevant research has yet been reported regarding the predictive value of the CONUT for response to nICT in ESCC.

A recent study analyzed the prognostic value of CONUT in advanced EC patients who were treated with immunotherapy (21). The results revealed that a high CONUT score was associated with a significantly worse prognosis. Similar results were also found in our study for patients with local advanced ESCC in nICT. Based on these results, the significance of CONUT score as a prognostic index is clearer. The results will bring an important assessment of recurrence pattern before nICT and help clinicians provide a more personalized approach to adjuvant therapy in ESCC after nICT. We believe that patients with high CONUT in ESCC should be regarded with caution. Adjuvant therapy may be required for those with high CONUT.

There are several potential mechanisms that could explain the relationship between CONUT and cancer prognosis. It is well known that CONUT comes from three hematological variables, representing caloric consumption, protein reservation, and impaired immune defense, respectively. LYM, as a determinant of immunity, can inhibit the proliferation, migration, and invasion of cancer cells by initiating a cytotoxic immune response (35, 36). Lymphocytopenia causes an insufficient host immune response, resulting in a poor prognosis in cancers (37). ALB is used as a nutritional score to reflect the nutritional status. It has been reported that the mechanism of hypoproteinemia leading to poor prognosis may be through the release of a variety of inflammatory cytokines, such as IL-6 and TNF-α (38). TC, as a vital component of the cell membrane, participates in various biological signaling pathways. The main effect of hypocholesterolemia on the ability of transmembrane signaling may be due to the increased uptake of TC by tumor cells (39). Thus, combined with these three components, CONUT may provide a better balance of immunological and nutritional status.

Some limitations should be recognized. Firstly, this was a single-center study with retrospective characteristics. Secondly, the CONUT score, as a hematological index, may be affected by various other conditions. Thirdly, although internal validation was verified, there was a lack of an external validation cohort to validate the nomogram. Fourthly, the follow-up time for this study was too short. Therefore, some bias may exist in the prognostic factors. Fifthly, there is no special stratified analysis in the current study due to the short follow-up time. Finally, the basic biological mechanisms with regard to CONUT have not been thoroughly elucidated. However, it is believed that, with more and more studies regarding nICT in ESCC, the CONUT will be better elucidated.

These real-world data revealed that patients with a low score might have a better response and a lower recurrence. As a useful index for immune-nutritional status, the pretreatment CONUT score might be a reliable predictor in ESCC with nICT. The simple and easily obtained feature of the CONUT improves its application in daily clinical work.

The original contributions presented in the study are included in the article/ Supplementary Materials . Further inquiries can be directed to the corresponding authors.

This study was performed in accordance with the Helsinki Declaration. This study was reviewed and approved by the ethics committee of Zhejiang Cancer Hospital (IRB-2020-320). The patients/participants provided their written informed consent to participate in this study.

JF, QC, and XC conceived and designed the study. JF and LW collected the clinical baseline characteristics and drafted the manuscript. LW and XY carried out the follow-up. JF, LW, and XY performed the data analyses. QC and XC helped to draft the manuscript. All authors contributed to the article and approved the submitted version.

This study was supported by Zhejiang TCM Science and Technology Project (2020ZB036, 2021ZB034, and 2022ZB051).

The authors thank all the patients and their families who participated in this study.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.