Gustave Roussy Immune Score as a prognostic marker in patients with esophageal cancer after neoadjuvant chemoradiotherapy: a retrospective study

Introduction

Esophageal cancer (EC) ranks among the leading malignant neoplasms worldwide, with an annual global burden of 604,100 newly diagnosed incident cases and 544,100 EC-related mortalities reported to date (1). Despite the continuous advancement of diverse therapeutic modalities for EC in clinical practice, the overall clinical prognosis of affected patients remains persistently poor (2-4). Currently, both neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant chemotherapy (NCT) have been established as effective treatment strategies for resectable locally advanced EC (5). These multimodal approaches significantly improve the R0 resection rate and long-term survival compared with surgery alone. In China and some Western countries, nCRT followed by surgery is widely applied as a standard approach (6,7), whereas in Japan and several Asian regions, NCT has been recognized as an alternative standard (8). While nCRT has been demonstrated to enhance survival outcomes in EC patients, with an approximate 15–20% rise in 5-year overall survival (OS) rates, recurrence events still take place in a high proportion of cases, which ultimately culminates in poor survival outcomes. It is thus imperative to identify more clinically valuable and effective preoperative prognostic variables for EC patients who have received nCRT.

Nutritional status and inflammation exert a pivotal role in the prognostic evaluation of malignant tumors (9). Some clinical studies have demonstrated that the neutrophil-lymphocyte ratio (NLR) correlates with prognostic outcomes in multiple malignancies, with EC being one of them (10-12). Furthermore, albumin (ALB)—a core nutritional biomarker—can reflect the nutritional status of patients afflicted with various types of cancer. However, some studies published in recent years have indicated that ALB remains a contentious prognostic factor for patients diagnosed with EC (13,14). Additionally, lactate dehydrogenase (LDH) has been documented to potentially indicate the degree of tumor burden and malignant aggressiveness in cancer patients (15). Elevated serum LDH levels have been associated with unfavorable prognosis in EC; however, their prognostic significance remains a matter of debate (16,17). Remarkably, the Gustave Roussy Immune Score (GRIm-Score) was initially established to facilitate optimal patient stratification and selection within immunotherapy-focused clinical trials (18). Findings from corresponding investigations have validated that the GRIm-Score, which is constructed on the foundation of NLR, LDH, and ALB, functions as a more robust prognostic indicator for individuals recruited into exploratory clinical trials. In recent years, the prognostic performance of the GRIm-Score has been further corroborated in the context of non-small cell lung cancer (19,20). And this index also has predictive value for EC after surgery alone. However, to the best of our knowledge, there are no studies regarding the prognostic value of GRIm-Score in patients with EC especially after nCRT so far, which is the mainstay of treatment for advanced EC and could have influenced preoperative nutritional and inflammatory stage. The primary objective of the present investigation was to assess the prognostic significance of the GRIm-Score among individuals diagnosed with EC who received nCRT. Cox proportional hazard regression analysis and propensity scoring methods were adopted to attenuate the potential influence exerted by confounding variables. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2095/rc).

Methods

Patients

We retrospectively analyzed the clinical characteristics of 432 patients with EC who were undergoing curative esophagectomy after nCRT between March 2018 and August 2021 in West China Hospital, Sichuan University. The inclusion criteria were as follows: (I) locally advanced EC was confirmed by histopathology; (II) R0 resection was performed following nCRT; and (III) clinical characteristics and preoperative laboratory results can be obtained. Patients were excluded on the basis of the following criteria: (I) those who were lost to follow-up assessment or presented with incomplete comprehensive clinical records; (II) individuals in whom M1-stage disease was pathologically confirmed in the course of surgery; (III) subjects diagnosed with neoplasms of the cardia-gastroesophageal junction, a tumor subtype that is uniformly categorized as gastric carcinoma generally. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional ethics board of West China Hospital, Sichuan University [No. 2019(632)] and informed consent was taken from all the patients. The last follow-up time was February 2024.

Data collection

The principal clinical characteristics destined for analytic processing were gathered from our medical records. Quantitative concentrations of neutrophils, lymphocytes, ALB and LDH were derived from laboratory assays performed within the 7-day window prior to surgical treatment. The 8th American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) Tumor, Node, Metastasis (TNM) staging system and tumor regression grade (TRG) based on the Becker system were used in the current study. The GRIm-Score was derived from three distinct biomarkers with predefined scoring criteria, as detailed below: LDH [within normal range: 0 vs. > upper limit of normal (ULN) of each center, 240 U/L in West China Hospital, Sichuan University: +1], ALB (≥40 g/L: 0 vs. <40 g/L: +1), and NLR (≤3.5: 0 vs. >3.5: +1). Based on the aggregate GRIm-Score, all enrolled subjects were stratified into two subgroups: a high-score group (score 2 or 3) and a low-score group (score 0 or 1).

Treatment protocols

All enrolled patients received neoadjuvant treatment consistent with established national clinical guidelines. All participants underwent a standardized radiation scheme consisting of a total dose ranging from 40 to 50.4 Gy, which was separated into 23 to 28 fractions (1.8–2.0 Gy/fraction), and two cycles of concurrent chemotherapy were administered concomitantly. The chemotherapeutic agents included paclitaxel (175 mg/m² body surface area, D1, q3w) and cisplatin (75 mg/m² body surface area, D1, q3w). Intensity-modulated radiotherapy was employed for radiation delivery in all study subjects.

Surgical resection was performed via the standard minimally invasive three-incision McKeown technique 6 to 8 weeks after the completion of nCRT. Routine two-field lymphadenectomy covering the abdominal and thoracic compartments was conducted in all patients. Three-field lymph node dissection was not commonly adopted in this study, and cervical lymphadenectomy was selectively performed for patients with suspected metastatic cervical lymph nodes, as detected by preoperative computed tomography (CT) and ultrasound.

Follow-up

Postoperative surveillance for all study participants was scheduled at 3-month intervals throughout the first year, at 6-month intervals across the second and third postoperative years, and on an annual basis in all subsequent years. Clinical history collection, physical assessment, contrast esophagography, as well as chest/abdominal CT scans were implemented systematically in accordance with the predefined follow-up algorithm. In cases where recurrent disease was clinically suspected, patients received further chest and abdominal evaluations via CT or positron emission tomography (PET)-CT, digestive tract endoscopy to verify locoregional relapse, and cranial CT combined with bone scintigraphy to identify distant metastatic lesions. The diagnosis of recurrent malignancy was confirmed either through cytological or pathological examination, or by unequivocal abnormalities detected on radiological imaging.

Propensity score matching (PSM)

PSM analysis stands as a superior and more refined statistical technique for accounting for preexisting baseline confounding variables. With the goal of mitigating intergroup bias driven by confounding variables, PSM was implemented employing a caliper width of 0.05. Matching covariates consisted of gender, age, tobacco consumption, hypertension, chronic obstructive pulmonary disease (COPD), histopathologic type and grade, tumor site, pathological T and N stage, tumor length, and TRG.

Statistical analyses

The Chi-squared test or fisher was performed to compare the clinical characteristics grouped by GRIm-Score. The Kaplan-Meier method was used to compare the OS and disease-free survival (DFS) by using the log-rank test. Multivariate analyses with Cox regression analyses were used to evaluate the independent prognostic factors. All statistical analyses were performed with SPSS 23.0 (SPSS Inc., Chicago, IL, USA).

Results

Patient characteristics

The clinical characteristics regarding GRIm-Score are shown in Table 1. Of the 432 patients with EC who received nCRT, 58 (13.4%) had a high GRIm-Score calculated by preoperative laboratory results. There were 359 (83.1%) men and 73 (16.9%) women with a mean age of 62.1±7.7 years. According to clinical criteria, all the patients received preoperative nCRT. High GRIm-Score was significantly associated with high N stage (P=0.03), tumor diameter >3 cm (P<0.001), high ALB level (P<0.001) and high NLR (P<0.001). Specifically, high GRIm-Score was more common in patients with N positive (48.3% vs. 33.4%), tumors length >3 cm (55.2% vs. 29.4%), ALB ≤40 g/L (98.3% vs. 17.9%), and NLR >3.5 (86.2% vs. 26.7%).

Survival analyses

Survival was significantly shorter in patients with high GRIm-Score than in those with low GRIm-Score (OS 70.9% vs. 88.0% at 1-year, 51.3% vs. 69.8% at 3-year, P=0.001; DFS 65.7% vs. 81.1% at 1-year, 45.4% vs. 61.7% at 3-year, P=0.001) (Figure 1).

Figure 1 OS and DFS in GRIm-Score-high and -low EC patients after neoadjuvant chemoradiotherapy before propensity score matching. (A) OS and (B) DFS of all study patients (n=432). The OS and DFS rates of patients with high GRIm-Score were significantly poorer than those of patients with low GRIm-Score (P=0.001 and P=0.001, respectively). DFS, disease-free survival; EC, esophageal cancer; GRIm-Score, Gustave Roussy Immune Score; OS, overall survival.

In the univariable analyses of OS, sex [hazard ratio (HR): 2.229, 95% confidence interval (CI): 1.075–4.620], tumor length (HR: 2.395, 95% CI: 1.553–3.692), pT stage (HR: 1.481, 95% CI: 1.241–1.767), pN stage (HR: 2.269, 95% CI: 1.817–2.834), differentiation grade (HR: 1.630, 95% CI: 1.266–2.100), TRG (HR: 1.485, 95% CI: 1.209–1.824), ALB (HR: 1.793, 95% CI: 1.160–2.772), NLR (HR: 1.976, 95% CI: 1.288–3.031), and GRIm-Score (HR: 2.275, 95% CI: 1.376–3.760) were significant predictors of OS (Table 2). Multivariate analyses demonstrated that GRIm-Score (HR: 2.305, 95% CI: 1.146–4.635, P=0.02), instead of NLR, LDH, or ALB, was an independent prognostic factor (Table 2). Furthermore, pN stage (HR: 2.034, 95% CI: 1.570–2.636, P<0.001) was another significant prognostic factors (Table 2).

Likewise, in the univariate analyses of DFS, univariate analyses indicated that several clinical indexes, such as smoking (HR: 1.553, 95% CI: 1.058–2.278), tumor length (HR: 2.123, 95% CI: 1.465–3.078), pT stage (HR: 1.405, 95% CI: 1.210–1.633), pN stage (HR: 2.088, 95% CI: 1.712–2.548), differentiation grade (HR: 1.595, 95% CI: 1.282–1.986), TRG (HR: 1.393, 95% CI: 1.167–1.664), ALB (HR: 1.848, 95% CI: 1.267–2.697), NLR (HR: 1.688, 95% CI: 1.163–2.451), and GRIm-Score (HR: 1.719, 95% CI: 1.344–2.198) were significant predictors of DFS (Table 3). However, the backward conditional Cox regression multivariable analysis showed that the pT stage (HR: 1.344, 95% CI: 1.017–1.776, P=0.04) and pN stage (HR: 1.936, 95% CI: 1.542–2.431, P<0.001) was the only two significant prognostic factor (Table 3).

Propensity matched analysis

After PSM, 55 patients were included in the high GRIm-Score group, and 55 were included in the low GRIm-Score group. Preexisting differences between groups were well balanced, as shown in Table 1.

After balancing differences between groups by PSM, patients with a high GRIm-Score had poor survival (OS 69.5% vs. 92.7% at 1-year, 49.2% vs. 64.3% at 3-year, P=0.007; DFS 85.5% vs. 66.8% at 1-year, 43.1% vs. 58.1% at 3-year, P=0.008) (Figure 2). Univariate analyses indicated that several clinical indexes, such as pT stage (HR: 1.494, 95% CI: 1.136–1.967), pN stage (HR: 2.026, 95% CI: 1.354–3.031), differentiation grade (HR: 1.602, 95% CI: 1.073–2.393), TRG (HR: 1.637, 95% CI: 1.168–2.294), and GRIm-Score (HR: 2.436, 95% CI: 1.251–4.742) were significant predictors of OS (Table 2). The backward conditional Cox regression multivariable analysis showed that GRIm-Score (HR: 2.176, 95% CI: 1.086–4.361, P=0.03), instead of NLR, LDH, or ALB, was an independent prognostic factor (Table 2).

Figure 2 OS and DFS in GRIm-Score-high and -low EC patients following neoadjuvant chemoradiotherapy after propensity score matching. (A) OS and (B) DFS of patients after propensity score matching (n=110). The OS and DFS rates of patients with high GRIm-Score were significantly poorer than those of patients with low GRIm-Score (P=0.007 and P=0.008, respectively). DFS, disease-free survival; EC, esophageal cancer; GRIm-Score, Gustave Roussy Immune Score; OS, overall survival.

Similarly, in the univariate analyses of DFS, tumor length (HR 2.227, 95% CI: 1.164–4.261), pT stage (HR: 1.432, 95% CI: 1.121–1.829), pN stage (HR: 2.147, 95% CI: 1.474–3.126), differentiation grade (HR: 1.543, 95% CI: 1.068–2.228), TRG (HR: 1.672, 95% CI: 1.217–2.298), and GRIm-Score (HR: 2.236, 95% CI: 1.214–4.116) were significant predictors of DFS (Table 3). Multivariate analyses demonstrated that GRIm-Score (HR: 1.935, 95% CI: 1.035–3.615, P=0.04), instead of NLR, LDH, or ALB, was an independent prognostic factor (Table 3). Furthermore, tumor length (HR: 2.099, 95% CI: 1.055–4.178, P=0.04) and pN stage (HR: 1.826, 95% CI: 1.172–2.846, P=0.008) were the other significant prognostic factors (Table 3).

GRIm-Score is a better prognostic indicator for pT3–4 EC than pT0–2 EC

To evaluate the effect of GRIm-Score on pT stage status, all patients were classified into either the pT0–2 group (cohort: n=283; PSM: n=66) or the pT3–4 group (cohort: n=149; PSM: n=44), and the relationship between OS or DFS survival and GRIm-Score was analyzed for each category.

In the pT3–4 subgroup, patients with low GRIm-Score had a better OS than patients with high GRIm-Score (80.0% vs. 45.1% at 1 year, 60.1% vs. 20.0% at 3 years; P<0.001). Similarly, after PSM low GRIm-Score patients had a better OS than high GRIm-Score patients (85.0% vs. 58.2% at 1 year, 60.0% vs. 18.8% at 3 years; P=0.005; Figure 3). However, patients with low or high GRIm-Score had no statistical difference in OS when the pT stage was 0–2 (cohort: P=0.63, PSM: P=0.56; Figure 3).

Figure 3 OS in GRIm-Score-high and -low EC patients after neoadjuvant chemoradiotherapy before and after propensity score matching according to pT. OS of (A) pT0–2 patients (n=283) and (B) pT3–4 patients (n=149) before propensity score matching; OS of (C) pT0–2 patients (n=66) and (D) pT3–4 patients (n=44) after propensity score matching. The OS rate of pT3–4 patients with high GRIm-Score was significantly poorer than that of patients with low GRIm-Score before (P<0.001) and after propensity score matching (P=0.005). EC, esophageal cancer; GRIm-Score, Gustave Roussy Immune Score; OS, overall survival.

With regard to DFS, patients with low GRIm-Score still had a better DFS than patients with high GRIm-Score when the pT stage was 3–4 (70.7% vs. 53.7% at 1 year, 50.4% vs. 25.1% at 3 years; P=0.051). However, after PSM, low GRIm-Score was associated with improved DFS (70.0% vs. 51.6% at 1 year, 50.0% vs. 24.1% at 3 years; P=0.051), although these results were not statistically significant. Similarly, in the pT0–2 subgroup, patients with low or high GRIm-Score had no statistical difference in DFS (cohort: P=0.17, PSM: P=0.13; Figure 4).

Figure 4 DFS in GRIm-Score-high and -low EC patients following neoadjuvant chemoradiotherapy before and after propensity score matching according to pT. DFS of (A) pT0–2 patients (n=283) and (B) pT3–4 patients (n=149) before propensity score matching; DFS of (C) pT0–2 patients (n=66) and (D) pT3–4 patients (n=44) after propensity score matching. The DFS rate of pT3–4 patients with high GRIm-Score was significantly poorer than that of patients with low GRIm-Score before (P=0.005) and after propensity score matching (P=0.051). DFS, disease-free survival; EC, esophageal cancer; GRIm-Score, Gustave Roussy Immune Score.

Discussion

NCT and nCRT have both been validated as effective strategies to improve surgical resectability and long-term survival in patients with locally advanced EC. The JCOG1109 trial demonstrated that neoadjuvant triplet chemotherapy followed by esophagectomy conferred a significant OS advantage compared with conventional doublet chemotherapy in the Japanese population (8). Similarly, the ESOPEC trial reported that perioperative fluorouracil (FU)/leucovorin/oxaliplatin/docetaxel (FLOT) significantly improved OS in patients with esophageal adenocarcinoma (EAC) (7). Collectively, these findings underscore the critical role of neoadjuvant therapy in facilitating EC downstaging and enhancing the probability of achieving curative resection. Past research reports that among EC patients after surgery alone, high GRIm-Score was more common in EC patients with tumor length >3 cm and advanced tumor stage. However, the pathological characteristics of GRIm-Score in patients with EC after nCRT, which might have influenced the results of laboratory indicators, have not been well studied. In this study, high GRIm-Scores were more common in EC patients with tumor lengths greater than three and a high pN stage, which is similar to EC of surgery alone (20).

Similarly, past reports on EC have only described the prognostic value of GRIm-Score in patients undergoing surgery alone, without further investigating their prognostic value after nCRT (21). Therefore, we conducted this study to explore the relationship between GRIm-Score and the prognosis of EC patients after nCRT, which is the main treatment for locally advanced EC. In this study, we observed a significantly shorter OS (51.3% vs. 69.8%, P=0.001) and DFS (45.4% vs. 61.7%, P=0.001) among patients with high GRIm-Score after nCRT compared with those with low GRIm-Score, which was consistent before and after PSM; although GRIm-Score, instead of NLR, ALB or LDH, was a useful independent prognostic factor of OS (HR: 2.305, 95% CI: 1.146–4.635, P=0.02) in the whole cohort, it served as a helpful independent prognostic factor of both OS (HR: 2.176, 95% CI: 1.086–4.361, P=0.03) and DFS (HR: 1.935, 95% CI: 1.035–3.615, P=0.04) after PSM.

Moreover, we also stratified patients by T stage, one of the strongest prognostic factors in patients with EC, to investigate its potential clinical significance. We found that GRIm-Score was associated with decreased OS and DFS in pT3–4 patients, not pT0–2. These results demonstrated that GRIm-Score is a better prognostic indicator for pT3–4 EC, a circumstance that it is difficult to decide the dosage and cycles of adjuvant therapy, than pT0–2 EC. A detrimental impact on the host immune response has been proposed as a plausible mechanism linking poor nutritional and inflammatory status to adverse oncological outcomes. Malnutrition and systemic inflammation can suppress cellular and humoral immunity, reduce the activity of cytotoxic T lymphocytes and natural killer cells, and promote a tumor-permissive microenvironment (22,23). Previous studies have shown that indices reflecting systemic inflammation, such as elevated NLR or C-reactive protein-based scores, are associated with impaired anti-tumor immunity and worse prognosis in EC (24,25). These findings support the hypothesis that high GRIm-Score levels, reflecting both systemic inflammation and nutritional compromise, may contribute to cancer recurrence and mortality by undermining the host’s immune surveillance (26). The high GRIm-Score level was revealed to be an independent poor prognostic factor in this trial, particularly for patients with pT3–4, but not for those with pT0–2. These findings clearly indicated that individuals with local advanced EC were more likely to be influenced by a poor nutritional and inflammatory status on cancer progression than those with early-stage tumors.

In addition to the GRIm-Score, several other nutritional and inflammation-based markers have been proposed as prognostic indicators in EC. Previous studies have shown that body weight, body mass index (BMI), modified Glasgow prognostic score (mGPS), prognostic nutritional index (PNI), platelet-to-lymphocyte ratio (PLR), and the C-reactive protein-to-albumin ratio (CAR) are significantly associated with survival outcomes across various malignancies, including EC. These parameters not only reflect the systemic nutritional and immune-inflammatory status of patients but also provide valuable information regarding their tolerance to multimodality therapy, postoperative recovery, and long-term survival. Given the high prevalence of malnutrition and systemic inflammation in EC, the assessment of these indices in clinical practice can aid in risk stratification, guide perioperative nutritional or immunological interventions, and ultimately contribute to individualized treatment strategies. In the field of neoadjuvant therapy of EC, as far as we know, this study is the first study in patients with EC after nCRT to indicate the prognostic value of GRIm-Score. In addition, this is a retrospective study assessing the ability of GRIm-Score to predict prognosis in a comparatively abundant group of EC after nCRT in a single, high-volume institute. Nonetheless, the present investigation employed a retrospective design, which is inherently accompanied by the innate constraints characteristic of this category. In addition, the survival outcomes derived from this work were restricted by the relatively brief follow-up interval and the coverage of the included dataset [2018–2021]. Nevertheless, a statistically significant impairment of survival was detected in patients with elevated GRIm-Score values even within this truncated follow-up window, which highlights the potent prognostic predictive performance of the GRIm-Score for individuals with EC following nCRT. Collectively, the GRIm-Score constitutes an innovative prognostic index integrated with nutritional and inflammatory profiles, and is correlated with an elevated risk of tumor recurrence. This scoring system may therefore be implemented as a routine surveillance indicator for EC patients who receive surgical intervention after nCRT.

Conclusions

In this study, we found that patients with a high GRIm-Score had a significantly shorter OS and DFS after nCRT than those with a low GRIm-Score, and this was consistent before and after PSM. Moreover, GRIm-Score after nCRT is a better prognostic indicator for pT3–4 EC patients. Therefore, GRIm-Score should be performed as part of a routine reference index, which could aid in predicting the prognosis of EC patients after nCRT, especially for locally advanced patients.

Acknowledgments

This study was submitted as a poster abstract for ISDE 2024, in accordance with the conference’s requirement for unpublished work.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2095/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2095/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2095/prf

Funding: This work was supported by the National Nature Science Foundation of China (Nos. 81970481 and 82000514), Sichuan Science and Technology Program (Nos. 2022YFS0048 and 2021YFS0222), 1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (Nos. 2020HXFH047, ZYJC18010, 20HXJS005, and 2018HXFH020), and China Postdoctoral Science Foundation (No. 2020M673241).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2095/coif). All authors report that this work was supported by the National Nature Science Foundation of China (Nos. 81970481 and 82000514), Sichuan Science and Technology Program (Nos. 2022YFS0048 and 2021YFS0222), 1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (Nos. 2020HXFH047, ZYJC18010, 20HXJS005, and 2018HXFH020), and China Postdoctoral Science Foundation (No. 2020M673241). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional ethics board of West China Hospital, Sichuan University [No. 2019(632)] and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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