C-reactive Protein to Albumin Ratio as a Prognostic Biomarker in Patients with Esophageal Squamous Cell Carcinoma Receiving Immune Checkpoint Inhibitor- based Therapy

C-reactive Protein to Albumin Ratio as a Prognostic Biomarker in Patients with Esophageal Squamous Cell Carcinoma Receiving Immune Checkpoint Inhibitor- based Therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article C-reactive Protein to Albumin Ratio as a Prognostic Biomarker in Patients with Esophageal Squamous Cell Carcinoma Receiving Immune Checkpoint Inhibitor- based Therapy Koichiro Yoshino, Akihiko Okamura, Suguru Maruyama, Mikako Tamba, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8463955/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 18 You are reading this latest preprint version Abstract Background The C-reactive protein to albumin ratio (CAR) reflects systemic inflammation and nutritional status, but its prognostic value in esophageal squamous cell carcinoma (ESCC) treated with immune checkpoint inhibitor (ICI)-based therapy remains unclear. Methods We retrospectively analyzed 199 patients with unresectable advanced or recurrent ESCC who received ICI-based therapy across three cohorts: second- or later-line nivolumab monotherapy (n = 107), first-line chemotherapy plus ICI (n = 60), and first-line nivolumab plus ipilimumab (n = 32). The CAR cutoff values were determined using time-dependent receiver operating characteristic curve analysis. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and Cox proportional hazards models. Results In the nivolumab monotherapy cohort, patients with a low CAR (< 0.072) had significantly better PFS (median 5.6 vs. 1.9 months; p = 0.001) and OS (median 20.0 vs. 5.5 months; p < 0.01) than those with a high CAR. In the first-line chemotherapy plus ICI cohort, patients with a low CAR (< 0.090) were associated with longer OS (median, 21.2 vs. 8.8 months; P = 0.03). A similar association was observed in the nivolumab plus ipilimumab cohort (median OS, 22.3 vs. 13.1 months; P = 0.003). In multivariable analyses, CAR remained an independent prognostic factor for OS in both the nivolumab monotherapy cohort (hazard ratio (HR) 2.36; 95% confidence interval (CI) 1.35–4.12; p = 0.002) and the first-line cohort (HR 2.38; 95% CI 1.24–4.56; p = 0.009). Patients with a high CAR were more likely to transition directly to best supportive care after discontinuing ICI-based therapy. Conclusions CAR is a simple, reliable, and independent prognostic biomarker in patients with unresectable advanced or recurrent ESCC receiving ICI-based therapy. C-reactive protein to albumin ratio esophageal squamous cell carcinoma immune checkpoint inhibitor nivolumab prognosis biomarker Figures Figure 1 Figure 2 Introduction Esophageal cancer is the seventh most common cancer and sixth leading cause of cancer-related mortality worldwide, with esophageal squamous cell carcinoma (ESCC) being the predominant histological subtype in Asia [ 1 , 2 ]. Despite advances in multimodal treatment strategies, the prognosis of advanced ESCC remains poor, with a five-year survival rate < 20% [ 3 ]. The introduction of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape of advanced ESCC. Nivolumab, an anti-programmed cell death-1 (PD-1) antibody, yielded survival benefits in patients with non-resectable advanced or recurrent ESCC who had progressed after chemotherapy [ 4 ]. Subsequently, the combination of chemotherapy and ICIs has been established as the standard first-line treatment for non-resectable advanced or recurrent ESCC, yielding improved survival outcomes compared with chemotherapy alone [ 5 – 7 ]. Additionally, the combination of nivolumab and ipilimumab has demonstrated promising efficacy as a first-line treatment [ 7 ]. Systemic inflammation and nutritional status play a critical role in cancer progression and treatment outcomes. The host immune response to cancer is influenced by both systemic inflammation and nutritional status, which can affect the efficacy of immunotherapy [ 8 , 9 ]. Several inflammation- and nutrition-related indices have been proposed as prognostic markers in patients with cancer, including the neutrophil-to-lymphocyte ratio (NLR) and Prognostic Nutritional Index (PNI) [ 10 – 12 ]. C-reactive protein (CRP)-to-albumin ratio (CAR) is a simple biomarker that integrates inflammatory and nutritional components. CRP is an acute-phase protein, the levels of which increase during systemic inflammation, whereas albumin levels reflect nutritional status and decrease during states of malnutrition and chronic inflammation [ 13 , 14 ]. Baseline CAR has been reported to be a prognostic indicator in various malignancies, including gastric cancer, colorectal cancer, and hepatocellular carcinoma [ 15 – 17 ]. However, its prognostic utility in patients with esophageal squamous cell carcinoma receiving ICI-based therapy, particularly first-line chemotherapy plus ICI or nivolumab plus ipilimumab, has not yet been fully defined. Furthermore, dynamic changes in inflammatory and nutritional markers during treatment may provide additional prognostic information beyond baseline values. Previous studies have suggested that treatment-induced changes in these biomarkers can reflect treatment response and predict outcomes [ 18 , 19 ]. However, the prognostic significance of dynamic changes in CAR (dCAR) in immunotherapy-treated patients with non-resectable advanced or recurrent ESCC remains unclear. In this study, we aimed to evaluate the prognostic utility of baseline CAR and its dynamic changes (i.e., dCAR) in patients with non-resectable advanced or recurrent ESCC undergoing different ICI-based treatment regimens, including nivolumab monotherapy as second-line or later therapy, first-line chemotherapy plus ICI, and first-line nivolumab plus ipilimumab combination therapy. Methods Patients and study design This retrospective study included patients with non-resectable advanced or recurrent ESCC, who underwent nivolumab monotherapy between April 2019 and April 2023 or first-line ICI-based therapy between January 2022 and July 2024, at the authors’ institution. The study was approved by the Institutional Review Board (IRB number: 2021-GB-095), and the requirement for informed consent was waived due to the retrospective design of the study. Patients were eligible for inclusion if they fulfilled the following criteria: histologically confirmed ESCC; received ≥ 1 cycle(s) of ICI-based therapy for non-resectable advanced or recurrent disease; availability of baseline laboratory data, including CRP and albumin measurements, within 4 weeks before treatment initiation; and adequate follow-up data. The exclusion criteria were as follows: concurrent active infection or inflammatory disease at baseline; missing baseline laboratory data; and other active malignancies. Patients were divided into 3 cohorts according to treatment regimen (Supplementary Figure S1 and S2): nivolumab monotherapy (n = 107 [received nivolumab as a second-line or later therapy]); first-line chemotherapy plus ICI (n = 60 [treated with fluorouracil and cisplatin in combination with ICI]); and first-line nivolumab plus ipilimumab (n = 32). Treatment Patients in the nivolumab monotherapy cohort were administered 240 mg biweekly or 480 mg every 4 weeks. In the nivolumab plus ipilimumab cohort, nivolumab was administered at a dose of 240 mg biweekly or 360 mg every three weeks, along with ipilimumab 1 mg/kg intravenously every 6 weeks. In the chemotherapy plus ICI cohort, patients received pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks, and nivolumab 240 mg biweekly or 480 mg every 4 weeks, in combination with fluorouracil and cisplatin. The chemotherapy regimen consisted of intravenous cisplatin 80 mg/m² every 3–4 weeks and fluorouracil 800 mg/m²/day as a continuous infusion on days 1–5 of each 3–4 week cycle. Treatment protocols were selected by the attending physicians according to established clinical guidelines and administered until disease progression, intolerable toxicity, or patient withdrawal. ICI-based therapy is designated as the first-line treatment for residual or recurrent diseases following chemoradiotherapy. Assessment Baseline clinical and laboratory data, including age, sex, performance status (PS), disease stage, tumor location, treatment history, and laboratory parameters, were collected from medical records. Laboratory data included white blood cell, neutrophil, and lymphocyte counts, and CRP and albumin levels. The CAR was calculated as the ratio of CRP level (mg/dL) to albumin level (g/dL). Dynamic CAR change (i.e., dCAR) was calculated as follows: dCAR = CAR at 4 weeks – baseline CAR. Hematological and non-hematological toxicities during ICI-based therapy were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (i.e., “RECIST”) version 1.1 in patients with ≥ 1 measurable lesion(s). Statistical analysis Progression-free survival (PFS) was defined as the interval from treatment initiation to disease progression or death from any cause. Overall survival (OS) was defined as the interval from treatment initiation to death from any cause. Patients without adverse events were censored at the last follow-up visit. Time-dependent receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off values for CAR in predicting the median OS. The area under the ROC curve (AUC) was calculated to assess discriminative ability. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Hazard ratio (HR) and corresponding 95% confidence interval (CI) were calculated using Cox proportional hazard models. In multivariate analysis, clinically relevant variables were incorporated based on previously published data. Categorical variables were compared using Fisher’s exact test, whereas continuous variables were compared using the Mann–Whitney U test. All statistical analyses were performed using EZR version 1.55 (Saitama Medical Center, Jichi Medical University), based on R and R Commander (R Core Team, R Foundation for Statistical Computing, Vienna, Austria) [ 20 ]. Differences with a two-sided p < 0.05 were considered to be statistically significant. Results Determination of optimal CAR cut-off values Time-dependent ROC curve analysis was performed to determine the optimal cut-off values for CAR in predicting the median OS in each treatment cohort (Supplementary Figure S3 ). In the nivolumab monotherapy cohort, the optimal CAR cut-off value was 0.072 (AUC, 0.72; sensitivity, 59%; specificity, 87%), and was used to define low (< 0.072) and high (≥ 0.072) CAR groups (Supplementary Figure S3 a). To further refine prognostic stratification within the high baseline CAR cohort, changes in dCAR were evaluated after 4 weeks of therapy (i.e., dCAR). A dCAR cut-off of 0.42 (AUC, 0.61; sensitivity, 91%; specificity, 63%) distinguished patients with stable or improving values (dCAR < 0.42) from those with a substantial CAR increase (dCAR ≥ 0.42) (Supplementary Figure S3 b). In the pooled first-line cohort (chemotherapy plus ICI and nivolumab plus ipilimumab cohorts), the optimal CAR cut-off value was 0.090 (AUC, 0.74; sensitivity, 68%; specificity, 79%) (Supplementary Figure S3 c). Patients with a high CAR were further divided according to an optimal dCAR cut-off of -0.20 (AUC, 0.58; sensitivity, 55%; specificity, 63%) (Supplementary Figure S3 d). Nivolumab monotherapy cohort Baseline characteristics according to CAR group are summarized in Table 1a. Patients with a high CAR were more likely to have poor PS (p = 0.001). Other clinical variables, including age, sex, primary tumor location, and previous treatment lines did not differ significantly between the groups. The median PFS was 5.6 months (95% CI 3.8–8.5) in the low CAR group and 1.9 months (95% CI 1.4–2.3) in the high CAR group (Fig. 1 a). The median OS was 20.0 months (95% CI 15.4–4.5) in the low CAR group and 5.5 months (95% CI 3.7–8.2) in the high CAR group (Fig. 1 b). The objective tumor response also differed according to CAR (Supplementary Table S1 a). The disease control rate (DCR) was significantly higher in the low-CAR group than that in the high-CAR group (71% versus [vs.] 38%; p = 0.001), whereas the overall response rate (ORR) was numerically higher, but not significantly different (34% vs. 25%; p = 0.50). Among the 61 patients with high baseline CAR, early changes in CAR provided further prognostic discrimination (Supplementary Fig. S4 ). Patients with dCAR < 0.42 experienced a median PFS of 4.9 months (95% CI 2.1–5.6) compared with 1.3 months (95% CI 0.9–1.6) in those with dCAR ≥ 0.42 (p < 0.001) (Supplementary Figure S4 a). The corresponding median OS was 9.2 months (95% CI 7.3–11.6) and 2.8 months (95% CI 1.9–4.2) months, respectively (p < 0.001) (Supplementary Figure S4 b). Withing the high CAR subgroup, both ORR (40% vs. 5%; p = 0.003) and DCR (58% vs. 14%; p = 0.001) were significantly higher in patients with dCAR < 0.42 than in those with dCAR ≥ 0.42 (Supplementary Table S1 b). First-line chemotherapy plus ICI cohort A similar pattern was observed in baseline characteristics, which was consistent with the trends observed in the nivolumab monotherapy cohort (Table 1b). Compared with low CAR, high CAR was associated with a higher proportion of poor PS (p < 0.001), whereas age, sex, and primary tumor location did not differ significantly. The median PFS was 8.1 months (95% CI 4.2–12.9) in the low CAR group and 4.1 months (95% CI 3.0–7.9) in the high CAR group (p = 0.18) (Fig. 2 a). The median OS was 21.2 months (95% CI 11.7–not reached [NR]) in the low CAR group and 8.8 months (95% CI 6.1–18.5) in the high CAR group (p = 0.03) (Fig. 2 b). The ORR was 56% and 40% in the low-CAR and high-CAR groups, respectively, and the DCR was 84% and 74%, respectively (Supplementary Table S1 c). However, these differences were not statistically significant. Among 33 patients with high baseline CAR, 14 had dCAR < -0.20 and 19 had dCAR ≥ -0.20. Median PFS was 5.4 months (95% CI 2.5–NR) and 4.3 months (95% CI 2.1–8.0), respectively (p = 0.29) (Supplementary Figure S5 a). The median OS was 8.9 months (95% CI 5.1–NR) and 8.8 months (95% CI 4.3–12.8), respectively (p = 0.41) (Supplementary Figure S5 b). ORR and DCR did not differ significantly between patients with dCAR < − 0.20 and those with dCAR ≥ − 0.20 (ORR, 50% vs. 37%; p = 0.50; DCR, 86% vs. 74%; p = 0.67) (Supplementary Table S1 d). First-line nivolumab plus ipilimumab cohort Baseline characteristics are summarized in Table 1b. The high CAR group had significantly more females than the low CAR group (p = 0.04), whereas age, PS, primary tumor location, and previous treatment lines were similar between the groups. The median PFS was 3.5 months (95% CI 2.1–8.5) in the low CAR group and 3.0 months (95% CI 0.9–4.8) in the high CAR group (p = 0.29) (Fig. 2 c). The median OS was 22.3 months (95% CI 22.3–NR) and 13.1 months (95% CI 1.8–NR), respectively (p = 0.003) (Fig. 2 d). ORR and DCR were not significantly different between the 2 groups (ORR, 27% vs. 29%; p = 1.00; DCR, 67% vs. 59%; p = 0.73) (Supplementary Table S1 e). Among 14 patients with high CAR, 7 patients had dCAR < -0.20 and 7 had dCAR ≥ -0.20. Early CAR dynamics are not clearly prognostic. The median PFS was 4.8 months (95% CI 1.3–NR) in patients with dCAR < − 0.20 and 3.0 months (95% CI 0.5 to 4.4) in those with dCAR ≥ − 0.20 (p = 0.17) (Supplementary Figure S5 c). The median OS was 13.1 months (95% CI 6.4–NR) and 16.9 months (95% CI 1.0–NR), respectively (p = 0.94) (Supplementary Figure S5 d). Similarly, the ORR (57% vs. 14%; p = 0.27) and DCR (71% vs. 57%; p = 1.00) did not differ significantly between the dCAR strata within the high-CAR subgroup (Supplementary Table S1 f). Multivariate analysis In the nivolumab monotherapy cohort, CAR ≥ 0.072 was an independent adverse prognostic factor for OS (HR, 2.36; 95% CI 1.35–4.12; p = 0.002), along with a greater number of metastatic organs (HR 1.73; 95% CI 1.03–2.90; p = 0.04) (Table 2a). For PFS, CAR ≥ 0.072 was also independently associated with shorter survival (HR 1.80; 95% CI 1.13–2.84; p = 0.012), as was PS 2–3 (HR 1.92; 95% CI 1.10–3.32; p = 0.021) (Supplementary Table S2 a). In the pooled first-line ICI-based treatment cohort, CAR ≥ 0.090 was independently associated with inferior OS (HR 2.38; 95% CI 1.24–4.56; p = 0.009), together with PS 2–3 (HR 7.11; 95% CI 2.44–20.7; p < 0.001) (Table 2b). For PFS, PS 2–3, but not CAR, was independently associated with worse outcome (HR 5.89; 95% CI 2.25–15.4; p < 0.001) (Supplementary Table S2 b). Safety In the nivolumab monotherapy cohort, overall adverse events (AEs) of any grade occurred in 7 patients (3 with grade ≥ 3) in the low-CAR group and in 11 (2 with grade ≥ 3) in the high-CAR group (p = 0.79) (Supplementary Table S3 a). In the first-line chemotherapy plus ICI cohort, the AE profiles differed between the CAR groups, with the low CAR group experiencing significantly more anorexia (Supplementary Table S3 b). Thirty-four (57%) patients experienced anorexia, with 19 and 15 patients in the low- and high-CAR groups, respectively (p = 0.02). Total immune-related AEs (irAEs) occurred in 16 (27%) patients, with grade ≥ 3 irAEs in 5 (8%) patients. The distribution was 9 patients (2 with grade ≥ 3) in the low-CAR group and 8 (3 with grade ≥ 3) in the high-CAR group (p = 0.38). In the first-line nivolumab plus ipilimumab cohort, the high CAR group experienced a significantly higher overall incidence of AEs (Supplementary Table S3 c). Total AEs occurred in 17 patients (53%), with grade ≥ 3 AEs in 8 (25%) patients. The distribution was 13 patients (5 with grade ≥ 3) in the low-CAR group and 8 (3 with grade ≥ 3) in the high-CAR group (p = 0.03), indicating a significantly higher overall AE rate in the low-CAR group. Subsequent therapies In the nivolumab monotherapy cohort, 102 patients discontinued treatment, with 5 ongoing at the time of analysis. The high CAR group had a significantly higher rate of discontinuation due to PD (94% vs. 80%; p = 0.04) (Supplementary Table S4 a). Conversely, the low CAR group had numerically higher rates of discontinuation owing to irAEs and poor PS, although these differences did not reach statistical significance. Patients with low CAR were significantly more likely to receive subsequent chemotherapy (63% vs. 30%; p = 0.002), whereas those with high CAR more often transitioned directly to the best supportive care (70% vs. 37%; p = 0.002) (Supplementary Table S5 a). In the first-line chemotherapy plus ICI cohort, 49 patients discontinued treatment, with 11 patients ongoing treatment at the time of the analysis. PD was the predominant reason for treatment discontinuation in both groups, accounting for 100% of the discontinuations in the low CAR group and 83% in the high CAR group (p = 0.07) (Supplementary Table S4 b). Patients with a low CAR were significantly less likely to receive the best supportive care only (5% vs. 45%; p = 0.003) and tended to receive subsequent chemotherapy (70% vs. 41%; p = 0.08) (Supplementary Table S5 b). In the first-line nivolumab plus ipilimumab cohort, 25 patients discontinued treatment, with 7 ongoing at the time of analysis. PD was the most common reason for discontinuation in both groups, with similar rates (78% vs. 81%, p = 1.00). The rates of discontinuation owing to irAEs were also comparable between the groups (11% vs. 19%; p = 1.00) (Supplementary Table S4 c). Patients in the low-CAR group had higher rates of subsequent chemotherapy (80% vs. 53%) and lower rates of best supportive care (20% vs. 47%); however, these differences were not statistically significant (Supplementary Table S5 c). Discussion Several studies have reported the prognostic utility of CAR in ESCC across different treatment modalities. An elevated CAR has been associated with poor outcomes in patients undergoing nivolumab monotherapy [ 21 ], consistent with our findings. A high CAR has also been linked to inferior outcomes after chemoradiotherapy [ 22 ] and worse postoperative survival after esophagectomy [ 23 , 24 ]. Several reports have evaluated CAR as a pure prognostic indicator without treatment-specific analyses [ 25 , 26 ]. Our study extends these findings by evaluating CAR across multiple ICI-based regimens, including combination approaches (e.g., chemotherapy plus ICI and nivolumab plus ipilimumab), and by incorporating longitudinal CAR assessment as a novel analytical dimension. Results of this study demonstrate that CAR is a simple, reliable, and independent prognostic biomarker in patients with ESCC undergoing ICI-based therapy. A low baseline CAR identified patients with significantly improved survival and, in the nivolumab monotherapy cohort, both baseline CAR and dCAR provided strong prognostic stratification. In the chemotherapy plus ICI cohort, baseline CAR was significantly associated with OS, but not PFS. Chemotherapy combined with ICI therapy results in complex interactions between direct cytotoxic and immunological mechanisms. While chemotherapy can enhance antitumor immunity through immunogenic cell death, increased neoantigen presentation, and the depletion of immunosuppressive cells [ 27 – 29 ], these immune-enhancing effects occur alongside the immediate direct cytotoxic effects of chemotherapy on tumor cells. In the short term, direct tumor cell killing may affect disease control (i.e., PFS), partially masking the prognostic impact of baseline host factors reflected by the CAR. However, host factors reflected by the CAR become more influential for long-term outcomes (i.e., OS) as these direct effects wane over time. Additionally, the effects of chemotherapy on systemic inflammation [ 9 ], nutritional status [ 30 , 31 ], and immune cell populations [ 32 ], independent of tumor response, may attenuate the prognostic utility of dCAR in this setting. The particularly strong prognostic impact of CAR in the nivolumab monotherapy cohort may reflect the fact that patients had received previous chemotherapy or chemoradiotherapy, which can prime the immune system by increasing tumor immunogenicity [ 27 , 33 ]. In this post-chemotherapy setting, in which tumor antigens are released and the immune landscape is remodeled, the subsequent efficacy of immunotherapy becomes dependent on the host’s immune competence [ 32 , 34 ]. Here, baseline inflammatory and nutritional status, reflected by CAR, may serve as determinants of whether patients can mount effective antitumor immune responses. Patients with a low CAR—indicating lower systemic inflammation and better nutritional status—possess more favorable conditions for effective immune responses to checkpoint blockade. Conversely, patients with high CAR may have immunosuppressive systemic environments that limit immunotherapy efficacy despite previous chemotherapy-induced immunogenic priming [ 35 , 36 ]. This interpretation aligns with observations for other inflammation-based biomarkers such as NLR, which demonstrate stronger prognostic utility in immunotherapy monotherapy than in chemotherapy or concurrent chemoimmunotherapy [ 19 , 36 ]. In the nivolumab plus ipilimumab group, trends in prognostic stratification based on CAR and dCAR were observed; however, the difference was not statistically significant, possibly because of the small sample size. These findings have important clinical implications. First, high CAR was correlated with poor PS, and patients with both PS 2 and high CAR experienced strikingly short survival (median PFS, 0.9 months; median OS, 1.8 months) (Supplementary Fig. S6 A and S6B), suggesting minimal therapeutic benefits for this subgroup. Supportive care may be a more appropriate option than active treatment for such patients. Second, subsequent treatment availability varied according to the baseline CAR. Patients with low CAR were significantly more likely to receive subsequent active treatment after ICI failure (63% vs. 30%; p = 0.002 in nivolumab monotherapy; 70% vs. 41%; p = 0.08 in chemotherapy plus ICI), whereas those with high CAR more often transitioned directly to best supportive care. These differences likely contributed to the observed survival disparities and highlighted the need to address inflammation and nutritional status throughout the disease course. Therefore, early engagement with palliative care should be considered for patients with high CAR—irrespective of PS—to support timely advance care planning and symptom management. Among patients with high CAR, chemotherapy plus an ICI exhibited a numerical trend toward longer PFS than nivolumab plus ipilimumab (4.1 vs. 3.0 months; p = 0.14) (Supplementary Fig. S6 C and S6D), whereas OS was similar (8.8 vs. 13.1 months; p = 0.56). These findings should be interpreted cautiously because of the potential selection bias, and both regimens remain appropriate options depending on patient-specific clinical considerations. Finally, dCAR monitoring demonstrated prognostic utility in nivolumab monotherapy but limited utility in the chemotherapy plus ICI cohort due to the confounding effects of chemotherapy on inflammatory markers. However, dCAR may be valuable in the nivolumab plus ipilimumab cohort, in which the trends suggest prognostic information with larger sample sizes. For patients receiving immunotherapy without chemotherapy, monitoring dCAR may provide early signals of treatment response or failure. This retrospective, single-center study may have had selection bias and, thus, limited generalizability. CAR can be influenced by unmeasured confounders such as subclinical infections or chronic inflammatory conditions. The cut-off value for CAR was determined using time-dependent ROC analysis within the same dataset used for outcome evaluation. Although this approach is acceptable for exploratory biomarker discovery, it introduces the potential risk for overfitting, and the observed differences may, in part, reflect this optimization process. The optimal cut-off values differed between cohorts (0.072 vs. 0.090), requiring external validation. Small sample sizes in subgroup analyses, particularly for dCAR in first-line treatment, had limited statistical power. Comprehensive biomarker data (PD-L1 expression and tumor mutational burden) were not available for comparison. In conclusion, CAR is a simple and widely available prognostic biomarker in patients with non-resectable advanced or recurrent ESCC undergoing ICI-based therapy. Its impact is most pronounced in those undergoing nivolumab monotherapy, with more complex patterns in chemotherapy-containing regimens due to concurrent treatment effects. The baseline CAR can guide treatment decisions, including the identification of patients suitable for supportive care and those requiring early palliative care integration. Dynamic CAR monitoring provides additional information in selected settings. Given its simplicity and accessibility, CAR has significant potential for clinical implementation to improve patient selection and treatment planning for cancer immunotherapy. Declarations Ethics approval and consent to participate This study involved human participants and was approved by the Certified Review Board of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (IRB number: 2021-GB-095). The protocol was described on the hospital website, and subjects were provided the opportunity to opt‐out; therefore, no additional consent was required from patients. Consent to publish the study Consent to publish the study was obtained from all participants. Funding None declared Author Contributions Conception and design: K.Y. and A.O.; acquisition of data: K.Y.; analysis and interpretation of data: K.Y. and A.O.; writing: K.Y. and A.O.; review and/or revision of the manuscript: all authors; administrative, technical, or material support: all authors; and study supervision: A.O. Conflicts of interest The authors declare no conflicts of interest. Acknowledgements We are deeply indebted to the patients who participated in this study and to their families. The authors thank Ms. Yuki Horiike, Ms. Hitomi Hannan, and Ms. Yukie Naito for providing data management. We would like to thank Editage (www.editage.jp) for English language editing. Data Availability The data used in this study, although not available in a public repository, will be made available to other researchers upon reasonable request. References Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. Abnet CC, Arnold M, Wei WQ. Epidemiology of Esophageal Squamous Cell Carcinoma. Gastroenterology. 2018;154(2):360–73. Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med. 2014;371(26):2499–509. Kato K, Cho BC, Takahashi M, et al. 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Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non-Small Cell Lung Cancer. JAMA Oncol. 2018;4(3):351–7. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transpl. 2013;48(3):452–8. Ikoma T, Shimokawa M, Matsumoto T, Boku S, Yasuda T, Shibata N, et al. Inflammatory prognostic factors in advanced or recurrent esophageal squamous cell carcinoma treated with nivolumab. Cancer Immunol Immunother. 2023;72(2):427–35. Sugawara K, Yagi K, Yajima S, Miwa Y, Oya S, Okamoto A, et al. Outcomes of patients with clinical stage IV esophageal squamous cell carcinoma treated initially with definitive chemoradiotherapy: a single-institution observational study and literature review. Surg Today. 2025;55(12):1856–67. Otowa Y, Nakamura T, Yamamoto M, Kanaji S, Matsuda Y, Matsuda T, et al. 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Nat Reviews Clin Oncol. 2020;17(12):725–41. Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, et al. Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity. 2016;44(2):343–54. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8(1):59–73. Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F, et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr. 2017;36(1):11–48. Ryan AM, Power DG, Daly L, Cushen SJ, Ní Bhuachalla Ē, Prado CM. Cancer-associated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later. Proceedings of the Nutrition Society. 2016;75(2):199–211. Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21(1):15–25. Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nat Rev Cancer. 2021;21(6):345–59. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44. Grivennikov SI, Greten FR, Karin M. Immunity, Inflammation, and Cancer. Cell. 2010;140(6):883–99. Diem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, et al. Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer. 2017;111:176–81. Tables Tables 1 to 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table2.xlsx SupplementaryTableS1.xlsx SupplementaryTableS4.xlsx SupplementaryTableS5.xlsx SupplementaryTableS2.xlsx SupplementaryTableS3.xlsx SupplementaryFigureS5.pptx SupplementaryFigureS4.pptx SupplementaryFigureS2.pptx SupplementaryFigureS6.pptx SupplementaryFigureS3.pptx SupplementaryFigureS1.pptx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 15 Feb, 2026 Reviews received at journal 15 Feb, 2026 Reviewers agreed at journal 15 Feb, 2026 Reviewers agreed at journal 14 Feb, 2026 Reviewers agreed at journal 13 Feb, 2026 Reviews received at journal 08 Feb, 2026 Reviews received at journal 25 Jan, 2026 Reviewers agreed at journal 22 Jan, 2026 Reviewers agreed at journal 21 Jan, 2026 Reviewers agreed at journal 21 Jan, 2026 Reviewers agreed at journal 21 Jan, 2026 Reviewers agreed at journal 21 Jan, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviewers invited by journal 20 Jan, 2026 Editor invited by journal 29 Dec, 2025 Editor assigned by journal 28 Dec, 2025 Submission checks completed at journal 28 Dec, 2025 First submitted to journal 27 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8463955","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":578400987,"identity":"8b91b61b-9105-4f6b-8184-9c43a26c6bd6","order_by":0,"name":"Koichiro Yoshino","email":"","orcid":"","institution":"The Cancer Institute Hospital","correspondingAuthor":false,"prefix":"","firstName":"Koichiro","middleName":"","lastName":"Yoshino","suffix":""},{"id":578400991,"identity":"95838f4b-9d08-48eb-821f-89cb107eeefe","order_by":1,"name":"Akihiko Okamura","email":"","orcid":"","institution":"The Cancer Institute 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survival; OS, overall survival; CI, confidence interval.\u003c/p\u003e","description":"","filename":"Figure11.png","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/79a77e1671bcb553d8a76b69.png"},{"id":100950797,"identity":"7451d76b-c55f-49fa-a24a-75dfc3eea581","added_by":"auto","created_at":"2026-01-23 07:09:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":60227,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier estimates of (\u003cstrong\u003eA\u003c/strong\u003e) PFS and (\u003cstrong\u003eB\u003c/strong\u003e) OS in 60 patients with advanced ESCC treated with first-line chemotherapy plus ICI and (\u003cstrong\u003eC\u003c/strong\u003e) PFS (\u003cstrong\u003eD\u003c/strong\u003e) OS in 32 patients treated with nivolumab plus ipilimumab.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations\u003c/strong\u003e: Chemo, chemotherapy; ICI, immune checkpoint inhibitor; CAR, C-reactive protein to albumin ratio; PFS, progression-free survival; OS, overall survival; CI, confidence interval; NR; not reached.\u003c/p\u003e","description":"","filename":"Figure21.png","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/d151af13d5429f5df5f229c3.png"},{"id":101207775,"identity":"93c7b219-9066-413c-8521-68cd0cdd16c9","added_by":"auto","created_at":"2026-01-27 10:07:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":805989,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/d0267d53-7fad-4a38-baaf-15795cf9e7ce.pdf"},{"id":100896743,"identity":"ad3dc115-675f-4ad2-b8e8-f35cac405d20","added_by":"auto","created_at":"2026-01-22 14:17:23","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":16703,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/524bf6c8333c6efa30ce4ea0.xlsx"},{"id":100951029,"identity":"6548c686-8d4f-430c-ba25-e894b5696768","added_by":"auto","created_at":"2026-01-23 07:09:51","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13436,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/d3488534eb87a41d64cb575c.xlsx"},{"id":100896747,"identity":"f8a7c122-e92d-460c-b811-5564e4822513","added_by":"auto","created_at":"2026-01-22 14:17:23","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":12388,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/5c4e25c0e06fd4b9841dafd4.xlsx"},{"id":100896786,"identity":"27ec86ff-9997-4451-8713-47b6b26b14e5","added_by":"auto","created_at":"2026-01-22 14:17:25","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":11409,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/8b38a6c3e41cc1f9b590ea04.xlsx"},{"id":100896751,"identity":"83fb3e58-a93f-432a-9e98-0b36262bfd92","added_by":"auto","created_at":"2026-01-22 14:17:23","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":11254,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS5.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/38d1960041a6ad7f85477d8f.xlsx"},{"id":100896753,"identity":"26d988ef-75fd-40ac-97e8-3ae4e6cebff8","added_by":"auto","created_at":"2026-01-22 14:17:23","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":12375,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/a4055294ec2598b921af5a24.xlsx"},{"id":100896762,"identity":"3902173f-b10d-4f80-931e-185c6b401b36","added_by":"auto","created_at":"2026-01-22 14:17:24","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":12353,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/3ae331647a4451cac7332014.xlsx"},{"id":100896765,"identity":"c78c9a5e-e271-4b83-a7ff-d91c3fecdcbc","added_by":"auto","created_at":"2026-01-22 14:17:24","extension":"pptx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":78349,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS5.pptx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/3922eab5341f2b776019b7ae.pptx"},{"id":100896750,"identity":"5922c92f-d035-4215-8213-b115b5e60f7a","added_by":"auto","created_at":"2026-01-22 14:17:23","extension":"pptx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":64902,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS4.pptx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/581bc5a8611fe4393d3a294b.pptx"},{"id":100949559,"identity":"4c150baf-c6fd-45f5-b823-77cdabd470b2","added_by":"auto","created_at":"2026-01-23 07:04:13","extension":"pptx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":42855,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS2.pptx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/bbbb2afc27d58590d7edbb6d.pptx"},{"id":100950842,"identity":"ebfb8fed-6ebb-4249-872b-543f663bd44d","added_by":"auto","created_at":"2026-01-23 07:09:22","extension":"pptx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":78008,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS6.pptx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/0a052bd324e0bbc3ac2ff990.pptx"},{"id":100896771,"identity":"52bacac9-e96c-451f-a0cb-acafba21dd65","added_by":"auto","created_at":"2026-01-22 14:17:24","extension":"pptx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":185740,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS3.pptx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/1d4d5cedcdb32221d19e7d8f.pptx"},{"id":100951119,"identity":"ae5ca33f-1781-4e8d-8ff8-36f21b8ca4a4","added_by":"auto","created_at":"2026-01-23 07:10:00","extension":"pptx","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":38929,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS1.pptx","url":"https://assets-eu.researchsquare.com/files/rs-8463955/v1/627d055cde2216e548071d40.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"C-reactive Protein to Albumin Ratio as a Prognostic Biomarker in Patients with Esophageal Squamous Cell Carcinoma Receiving Immune Checkpoint Inhibitor- based Therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEsophageal cancer is the seventh most common cancer and sixth leading cause of cancer-related mortality worldwide, with esophageal squamous cell carcinoma (ESCC) being the predominant histological subtype in Asia [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Despite advances in multimodal treatment strategies, the prognosis of advanced ESCC remains poor, with a five-year survival rate\u0026thinsp;\u0026lt;\u0026thinsp;20% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe introduction of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape of advanced ESCC. Nivolumab, an anti-programmed cell death-1 (PD-1) antibody, yielded survival benefits in patients with non-resectable advanced or recurrent ESCC who had progressed after chemotherapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Subsequently, the combination of chemotherapy and ICIs has been established as the standard first-line treatment for non-resectable advanced or recurrent ESCC, yielding improved survival outcomes compared with chemotherapy alone [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Additionally, the combination of nivolumab and ipilimumab has demonstrated promising efficacy as a first-line treatment [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSystemic inflammation and nutritional status play a critical role in cancer progression and treatment outcomes. The host immune response to cancer is influenced by both systemic inflammation and nutritional status, which can affect the efficacy of immunotherapy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Several inflammation- and nutrition-related indices have been proposed as prognostic markers in patients with cancer, including the neutrophil-to-lymphocyte ratio (NLR) and Prognostic Nutritional Index (PNI) [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eC-reactive protein (CRP)-to-albumin ratio (CAR) is a simple biomarker that integrates inflammatory and nutritional components. CRP is an acute-phase protein, the levels of which increase during systemic inflammation, whereas albumin levels reflect nutritional status and decrease during states of malnutrition and chronic inflammation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Baseline CAR has been reported to be a prognostic indicator in various malignancies, including gastric cancer, colorectal cancer, and hepatocellular carcinoma [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, its prognostic utility in patients with esophageal squamous cell carcinoma receiving ICI-based therapy, particularly first-line chemotherapy plus ICI or nivolumab plus ipilimumab, has not yet been fully defined.\u003c/p\u003e \u003cp\u003eFurthermore, dynamic changes in inflammatory and nutritional markers during treatment may provide additional prognostic information beyond baseline values. Previous studies have suggested that treatment-induced changes in these biomarkers can reflect treatment response and predict outcomes [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, the prognostic significance of dynamic changes in CAR (dCAR) in immunotherapy-treated patients with non-resectable advanced or recurrent ESCC remains unclear.\u003c/p\u003e \u003cp\u003eIn this study, we aimed to evaluate the prognostic utility of baseline CAR and its dynamic changes (i.e., dCAR) in patients with non-resectable advanced or recurrent ESCC undergoing different ICI-based treatment regimens, including nivolumab monotherapy as second-line or later therapy, first-line chemotherapy plus ICI, and first-line nivolumab plus ipilimumab combination therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and study design\u003c/h2\u003e \u003cp\u003eThis retrospective study included patients with non-resectable advanced or recurrent ESCC, who underwent nivolumab monotherapy between April 2019 and April 2023 or first-line ICI-based therapy between January 2022 and July 2024, at the authors\u0026rsquo; institution. The study was approved by the Institutional Review Board (IRB number: 2021-GB-095), and the requirement for informed consent was waived due to the retrospective design of the study.\u003c/p\u003e \u003cp\u003ePatients were eligible for inclusion if they fulfilled the following criteria: histologically confirmed ESCC; received\u0026thinsp;\u0026ge;\u0026thinsp;1 cycle(s) of ICI-based therapy for non-resectable advanced or recurrent disease; availability of baseline laboratory data, including CRP and albumin measurements, within 4 weeks before treatment initiation; and adequate follow-up data. The exclusion criteria were as follows: concurrent active infection or inflammatory disease at baseline; missing baseline laboratory data; and other active malignancies.\u003c/p\u003e \u003cp\u003ePatients were divided into 3 cohorts according to treatment regimen (Supplementary Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e and S2): nivolumab monotherapy (n\u0026thinsp;=\u0026thinsp;107 [received nivolumab as a second-line or later therapy]); first-line chemotherapy plus ICI (n\u0026thinsp;=\u0026thinsp;60 [treated with fluorouracil and cisplatin in combination with ICI]); and first-line nivolumab plus ipilimumab (n\u0026thinsp;=\u0026thinsp;32).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003ePatients in the nivolumab monotherapy cohort were administered 240 mg biweekly or 480 mg every 4 weeks. In the nivolumab plus ipilimumab cohort, nivolumab was administered at a dose of 240 mg biweekly or 360 mg every three weeks, along with ipilimumab 1 mg/kg intravenously every 6 weeks. In the chemotherapy plus ICI cohort, patients received pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks, and nivolumab 240 mg biweekly or 480 mg every 4 weeks, in combination with fluorouracil and cisplatin. The chemotherapy regimen consisted of intravenous cisplatin 80 mg/m\u0026sup2; every 3\u0026ndash;4 weeks and fluorouracil 800 mg/m\u0026sup2;/day as a continuous infusion on days 1\u0026ndash;5 of each 3\u0026ndash;4 week cycle.\u003c/p\u003e \u003cp\u003e Treatment protocols were selected by the attending physicians according to established clinical guidelines and administered until disease progression, intolerable toxicity, or patient withdrawal. ICI-based therapy is designated as the first-line treatment for residual or recurrent diseases following chemoradiotherapy.\u003c/p\u003e\n\u003ch3\u003eAssessment\u003c/h3\u003e\n\u003cp\u003eBaseline clinical and laboratory data, including age, sex, performance status (PS), disease stage, tumor location, treatment history, and laboratory parameters, were collected from medical records. Laboratory data included white blood cell, neutrophil, and lymphocyte counts, and CRP and albumin levels. The CAR was calculated as the ratio of CRP level (mg/dL) to albumin level (g/dL). Dynamic CAR change (i.e., dCAR) was calculated as follows: dCAR\u0026thinsp;=\u0026thinsp;CAR at 4 weeks \u0026ndash; baseline CAR. Hematological and non-hematological toxicities during ICI-based therapy were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (i.e., \u0026ldquo;RECIST\u0026rdquo;) version 1.1 in patients with \u0026ge;\u0026thinsp;1 measurable lesion(s).\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eProgression-free survival (PFS) was defined as the interval from treatment initiation to disease progression or death from any cause. Overall survival (OS) was defined as the interval from treatment initiation to death from any cause. Patients without adverse events were censored at the last follow-up visit. Time-dependent receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off values for CAR in predicting the median OS. The area under the ROC curve (AUC) was calculated to assess discriminative ability. Survival curves were estimated using the Kaplan\u0026ndash;Meier method and compared using the log-rank test. Hazard ratio (HR) and corresponding 95% confidence interval (CI) were calculated using Cox proportional hazard models. In multivariate analysis, clinically relevant variables were incorporated based on previously published data. Categorical variables were compared using Fisher\u0026rsquo;s exact test, whereas continuous variables were compared using the Mann\u0026ndash;Whitney U test. All statistical analyses were performed using EZR version 1.55 (Saitama Medical Center, Jichi Medical University), based on R and R Commander (R Core Team, R Foundation for Statistical Computing, Vienna, Austria) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Differences with a two-sided p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered to be statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDetermination of optimal CAR cut-off values\u003c/h2\u003e \u003cp\u003eTime-dependent ROC curve analysis was performed to determine the optimal cut-off values for CAR in predicting the median OS in each treatment cohort (Supplementary Figure \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the nivolumab monotherapy cohort, the optimal CAR cut-off value was 0.072 (AUC, 0.72; sensitivity, 59%; specificity, 87%), and was used to define low (\u0026lt;\u0026thinsp;0.072) and high (\u0026ge;\u0026thinsp;0.072) CAR groups (Supplementary Figure \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003ea). To further refine prognostic stratification within the high baseline CAR cohort, changes in dCAR were evaluated after 4 weeks of therapy (i.e., dCAR). A dCAR cut-off of 0.42 (AUC, 0.61; sensitivity, 91%; specificity, 63%) distinguished patients with stable or improving values (dCAR\u0026thinsp;\u0026lt;\u0026thinsp;0.42) from those with a substantial CAR increase (dCAR\u0026thinsp;\u0026ge;\u0026thinsp;0.42) (Supplementary Figure \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003eIn the pooled first-line cohort (chemotherapy plus ICI and nivolumab plus ipilimumab cohorts), the optimal CAR cut-off value was 0.090 (AUC, 0.74; sensitivity, 68%; specificity, 79%) (Supplementary Figure \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003ec). Patients with a high CAR were further divided according to an optimal dCAR cut-off of -0.20 (AUC, 0.58; sensitivity, 55%; specificity, 63%) (Supplementary Figure \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003ed).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eNivolumab monotherapy cohort\u003c/h3\u003e\n\u003cp\u003eBaseline characteristics according to CAR group are summarized in Table\u0026nbsp;1a. Patients with a high CAR were more likely to have poor PS (p\u0026thinsp;=\u0026thinsp;0.001). Other clinical variables, including age, sex, primary tumor location, and previous treatment lines did not differ significantly between the groups.\u003c/p\u003e \u003cp\u003eThe median PFS was 5.6 months (95% CI 3.8\u0026ndash;8.5) in the low CAR group and 1.9 months (95% CI 1.4\u0026ndash;2.3) in the high CAR group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The median OS was 20.0 months (95% CI 15.4\u0026ndash;4.5) in the low CAR group and 5.5 months (95% CI 3.7\u0026ndash;8.2) in the high CAR group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). The objective tumor response also differed according to CAR (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003ea). The disease control rate (DCR) was significantly higher in the low-CAR group than that in the high-CAR group (71% versus [vs.] 38%; p\u0026thinsp;=\u0026thinsp;0.001), whereas the overall response rate (ORR) was numerically higher, but not significantly different (34% vs. 25%; p\u0026thinsp;=\u0026thinsp;0.50).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong the 61 patients with high baseline CAR, early changes in CAR provided further prognostic discrimination (Supplementary Fig. \u003cspan refid=\"MOESM4\" class=\"InternalRef\"\u003eS4\u003c/span\u003e). Patients with dCAR\u0026thinsp;\u0026lt;\u0026thinsp;0.42 experienced a median PFS of 4.9 months (95% CI 2.1\u0026ndash;5.6) compared with 1.3 months (95% CI 0.9\u0026ndash;1.6) in those with dCAR\u0026thinsp;\u0026ge;\u0026thinsp;0.42 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Supplementary Figure \u003cspan refid=\"MOESM4\" class=\"InternalRef\"\u003eS4\u003c/span\u003ea). The corresponding median OS was 9.2 months (95% CI 7.3\u0026ndash;11.6) and 2.8 months (95% CI 1.9\u0026ndash;4.2) months, respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Supplementary Figure \u003cspan refid=\"MOESM4\" class=\"InternalRef\"\u003eS4\u003c/span\u003eb). Withing the high CAR subgroup, both ORR (40% vs. 5%; p\u0026thinsp;=\u0026thinsp;0.003) and DCR (58% vs. 14%; p\u0026thinsp;=\u0026thinsp;0.001) were significantly higher in patients with dCAR\u0026thinsp;\u0026lt;\u0026thinsp;0.42 than in those with dCAR\u0026thinsp;\u0026ge;\u0026thinsp;0.42 (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eb).\u003c/p\u003e\n\u003ch3\u003eFirst-line chemotherapy plus ICI cohort\u003c/h3\u003e\n\u003cp\u003eA similar pattern was observed in baseline characteristics, which was consistent with the trends observed in the nivolumab monotherapy cohort (Table\u0026nbsp;1b). Compared with low CAR, high CAR was associated with a higher proportion of poor PS (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas age, sex, and primary tumor location did not differ significantly.\u003c/p\u003e \u003cp\u003eThe median PFS was 8.1 months (95% CI 4.2\u0026ndash;12.9) in the low CAR group and 4.1 months (95% CI 3.0\u0026ndash;7.9) in the high CAR group (p\u0026thinsp;=\u0026thinsp;0.18) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The median OS was 21.2 months (95% CI 11.7\u0026ndash;not reached [NR]) in the low CAR group and 8.8 months (95% CI 6.1\u0026ndash;18.5) in the high CAR group (p\u0026thinsp;=\u0026thinsp;0.03) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). The ORR was 56% and 40% in the low-CAR and high-CAR groups, respectively, and the DCR was 84% and 74%, respectively (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003ec). However, these differences were not statistically significant.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong 33 patients with high baseline CAR, 14 had dCAR \u0026lt; -0.20 and 19 had dCAR \u0026ge; -0.20. Median PFS was 5.4 months (95% CI 2.5\u0026ndash;NR) and 4.3 months (95% CI 2.1\u0026ndash;8.0), respectively (p\u0026thinsp;=\u0026thinsp;0.29) (Supplementary Figure \u003cspan refid=\"MOESM5\" class=\"InternalRef\"\u003eS5\u003c/span\u003ea). The median OS was 8.9 months (95% CI 5.1\u0026ndash;NR) and 8.8 months (95% CI 4.3\u0026ndash;12.8), respectively (p\u0026thinsp;=\u0026thinsp;0.41) (Supplementary Figure \u003cspan refid=\"MOESM5\" class=\"InternalRef\"\u003eS5\u003c/span\u003eb). ORR and DCR did not differ significantly between patients with dCAR \u0026lt; \u0026minus;\u0026thinsp;0.20 and those with dCAR \u0026ge; \u0026minus;\u0026thinsp;0.20 (ORR, 50% vs. 37%; p\u0026thinsp;=\u0026thinsp;0.50; DCR, 86% vs. 74%; p\u0026thinsp;=\u0026thinsp;0.67) (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003ed).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eFirst-line nivolumab plus ipilimumab cohort\u003c/h2\u003e \u003cp\u003eBaseline characteristics are summarized in Table\u0026nbsp;1b. The high CAR group had significantly more females than the low CAR group (p\u0026thinsp;=\u0026thinsp;0.04), whereas age, PS, primary tumor location, and previous treatment lines were similar between the groups.\u003c/p\u003e \u003cp\u003eThe median PFS was 3.5 months (95% CI 2.1\u0026ndash;8.5) in the low CAR group and 3.0 months (95% CI 0.9\u0026ndash;4.8) in the high CAR group (p\u0026thinsp;=\u0026thinsp;0.29) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). The median OS was 22.3 months (95% CI 22.3\u0026ndash;NR) and 13.1 months (95% CI 1.8\u0026ndash;NR), respectively (p\u0026thinsp;=\u0026thinsp;0.003) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). ORR and DCR were not significantly different between the 2 groups (ORR, 27% vs. 29%; p\u0026thinsp;=\u0026thinsp;1.00; DCR, 67% vs. 59%; p\u0026thinsp;=\u0026thinsp;0.73) (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003ee).\u003c/p\u003e \u003cp\u003eAmong 14 patients with high CAR, 7 patients had dCAR \u0026lt; -0.20 and 7 had dCAR \u0026ge; -0.20. Early CAR dynamics are not clearly prognostic. The median PFS was 4.8 months (95% CI 1.3\u0026ndash;NR) in patients with dCAR \u0026lt; \u0026minus;\u0026thinsp;0.20 and 3.0 months (95% CI 0.5 to 4.4) in those with dCAR \u0026ge; \u0026minus;\u0026thinsp;0.20 (p\u0026thinsp;=\u0026thinsp;0.17) (Supplementary Figure \u003cspan refid=\"MOESM5\" class=\"InternalRef\"\u003eS5\u003c/span\u003ec). The median OS was 13.1 months (95% CI 6.4\u0026ndash;NR) and 16.9 months (95% CI 1.0\u0026ndash;NR), respectively (p\u0026thinsp;=\u0026thinsp;0.94) (Supplementary Figure \u003cspan refid=\"MOESM5\" class=\"InternalRef\"\u003eS5\u003c/span\u003ed). Similarly, the ORR (57% vs. 14%; p\u0026thinsp;=\u0026thinsp;0.27) and DCR (71% vs. 57%; p\u0026thinsp;=\u0026thinsp;1.00) did not differ significantly between the dCAR strata within the high-CAR subgroup (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003ef).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eMultivariate analysis\u003c/h2\u003e \u003cp\u003eIn the nivolumab monotherapy cohort, CAR\u0026thinsp;\u0026ge;\u0026thinsp;0.072 was an independent adverse prognostic factor for OS (HR, 2.36; 95% CI 1.35\u0026ndash;4.12; p\u0026thinsp;=\u0026thinsp;0.002), along with a greater number of metastatic organs (HR 1.73; 95% CI 1.03\u0026ndash;2.90; p\u0026thinsp;=\u0026thinsp;0.04) (Table\u0026nbsp;2a). For PFS, CAR\u0026thinsp;\u0026ge;\u0026thinsp;0.072 was also independently associated with shorter survival (HR 1.80; 95% CI 1.13\u0026ndash;2.84; p\u0026thinsp;=\u0026thinsp;0.012), as was PS 2\u0026ndash;3 (HR 1.92; 95% CI 1.10\u0026ndash;3.32; p\u0026thinsp;=\u0026thinsp;0.021) (Supplementary Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003eIn the pooled first-line ICI-based treatment cohort, CAR\u0026thinsp;\u0026ge;\u0026thinsp;0.090 was independently associated with inferior OS (HR 2.38; 95% CI 1.24\u0026ndash;4.56; p\u0026thinsp;=\u0026thinsp;0.009), together with PS 2\u0026ndash;3 (HR 7.11; 95% CI 2.44\u0026ndash;20.7; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;2b). For PFS, PS 2\u0026ndash;3, but not CAR, was independently associated with worse outcome (HR 5.89; 95% CI 2.25\u0026ndash;15.4; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Supplementary Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003eb).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eIn the nivolumab monotherapy cohort, overall adverse events (AEs) of any grade occurred in 7 patients (3 with grade\u0026thinsp;\u0026ge;\u0026thinsp;3) in the low-CAR group and in 11 (2 with grade\u0026thinsp;\u0026ge;\u0026thinsp;3) in the high-CAR group (p\u0026thinsp;=\u0026thinsp;0.79) (Supplementary Table \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003eIn the first-line chemotherapy plus ICI cohort, the AE profiles differed between the CAR groups, with the low CAR group experiencing significantly more anorexia (Supplementary Table \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003eb). Thirty-four (57%) patients experienced anorexia, with 19 and 15 patients in the low- and high-CAR groups, respectively (p\u0026thinsp;=\u0026thinsp;0.02). Total immune-related AEs (irAEs) occurred in 16 (27%) patients, with grade\u0026thinsp;\u0026ge;\u0026thinsp;3 irAEs in 5 (8%) patients. The distribution was 9 patients (2 with grade\u0026thinsp;\u0026ge;\u0026thinsp;3) in the low-CAR group and 8 (3 with grade\u0026thinsp;\u0026ge;\u0026thinsp;3) in the high-CAR group (p\u0026thinsp;=\u0026thinsp;0.38).\u003c/p\u003e \u003cp\u003eIn the first-line nivolumab plus ipilimumab cohort, the high CAR group experienced a significantly higher overall incidence of AEs (Supplementary Table \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003ec). Total AEs occurred in 17 patients (53%), with grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs in 8 (25%) patients. The distribution was 13 patients (5 with grade\u0026thinsp;\u0026ge;\u0026thinsp;3) in the low-CAR group and 8 (3 with grade\u0026thinsp;\u0026ge;\u0026thinsp;3) in the high-CAR group (p\u0026thinsp;=\u0026thinsp;0.03), indicating a significantly higher overall AE rate in the low-CAR group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSubsequent therapies\u003c/h2\u003e \u003cp\u003eIn the nivolumab monotherapy cohort, 102 patients discontinued treatment, with 5 ongoing at the time of analysis. The high CAR group had a significantly higher rate of discontinuation due to PD (94% vs. 80%; p\u0026thinsp;=\u0026thinsp;0.04) (Supplementary Table \u003cspan refid=\"MOESM4\" class=\"InternalRef\"\u003eS4\u003c/span\u003ea). Conversely, the low CAR group had numerically higher rates of discontinuation owing to irAEs and poor PS, although these differences did not reach statistical significance. Patients with low CAR were significantly more likely to receive subsequent chemotherapy (63% vs. 30%; p\u0026thinsp;=\u0026thinsp;0.002), whereas those with high CAR more often transitioned directly to the best supportive care (70% vs. 37%; p\u0026thinsp;=\u0026thinsp;0.002) (Supplementary Table \u003cspan refid=\"MOESM5\" class=\"InternalRef\"\u003eS5\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003eIn the first-line chemotherapy plus ICI cohort, 49 patients discontinued treatment, with 11 patients ongoing treatment at the time of the analysis. PD was the predominant reason for treatment discontinuation in both groups, accounting for 100% of the discontinuations in the low CAR group and 83% in the high CAR group (p\u0026thinsp;=\u0026thinsp;0.07) (Supplementary Table \u003cspan refid=\"MOESM4\" class=\"InternalRef\"\u003eS4\u003c/span\u003eb). Patients with a low CAR were significantly less likely to receive the best supportive care only (5% vs. 45%; p\u0026thinsp;=\u0026thinsp;0.003) and tended to receive subsequent chemotherapy (70% vs. 41%; p\u0026thinsp;=\u0026thinsp;0.08) (Supplementary Table \u003cspan refid=\"MOESM5\" class=\"InternalRef\"\u003eS5\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003eIn the first-line nivolumab plus ipilimumab cohort, 25 patients discontinued treatment, with 7 ongoing at the time of analysis. PD was the most common reason for discontinuation in both groups, with similar rates (78% vs. 81%, p\u0026thinsp;=\u0026thinsp;1.00). The rates of discontinuation owing to irAEs were also comparable between the groups (11% vs. 19%; p\u0026thinsp;=\u0026thinsp;1.00) (Supplementary Table \u003cspan refid=\"MOESM4\" class=\"InternalRef\"\u003eS4\u003c/span\u003ec). Patients in the low-CAR group had higher rates of subsequent chemotherapy (80% vs. 53%) and lower rates of best supportive care (20% vs. 47%); however, these differences were not statistically significant (Supplementary Table \u003cspan refid=\"MOESM5\" class=\"InternalRef\"\u003eS5\u003c/span\u003ec).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSeveral studies have reported the prognostic utility of CAR in ESCC across different treatment modalities. An elevated CAR has been associated with poor outcomes in patients undergoing nivolumab monotherapy [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], consistent with our findings. A high CAR has also been linked to inferior outcomes after chemoradiotherapy [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and worse postoperative survival after esophagectomy [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Several reports have evaluated CAR as a pure prognostic indicator without treatment-specific analyses [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Our study extends these findings by evaluating CAR across multiple ICI-based regimens, including combination approaches (e.g., chemotherapy plus ICI and nivolumab plus ipilimumab), and by incorporating longitudinal CAR assessment as a novel analytical dimension. Results of this study demonstrate that CAR is a simple, reliable, and independent prognostic biomarker in patients with ESCC undergoing ICI-based therapy. A low baseline CAR identified patients with significantly improved survival and, in the nivolumab monotherapy cohort, both baseline CAR and dCAR provided strong prognostic stratification.\u003c/p\u003e \u003cp\u003eIn the chemotherapy plus ICI cohort, baseline CAR was significantly associated with OS, but not PFS. Chemotherapy combined with ICI therapy results in complex interactions between direct cytotoxic and immunological mechanisms. While chemotherapy can enhance antitumor immunity through immunogenic cell death, increased neoantigen presentation, and the depletion of immunosuppressive cells [\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], these immune-enhancing effects occur alongside the immediate direct cytotoxic effects of chemotherapy on tumor cells. In the short term, direct tumor cell killing may affect disease control (i.e., PFS), partially masking the prognostic impact of baseline host factors reflected by the CAR. However, host factors reflected by the CAR become more influential for long-term outcomes (i.e., OS) as these direct effects wane over time. Additionally, the effects of chemotherapy on systemic inflammation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], nutritional status [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], and immune cell populations [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], independent of tumor response, may attenuate the prognostic utility of dCAR in this setting.\u003c/p\u003e \u003cp\u003eThe particularly strong prognostic impact of CAR in the nivolumab monotherapy cohort may reflect the fact that patients had received previous chemotherapy or chemoradiotherapy, which can prime the immune system by increasing tumor immunogenicity [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In this post-chemotherapy setting, in which tumor antigens are released and the immune landscape is remodeled, the subsequent efficacy of immunotherapy becomes dependent on the host\u0026rsquo;s immune competence [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Here, baseline inflammatory and nutritional status, reflected by CAR, may serve as determinants of whether patients can mount effective antitumor immune responses. Patients with a low CAR\u0026mdash;indicating lower systemic inflammation and better nutritional status\u0026mdash;possess more favorable conditions for effective immune responses to checkpoint blockade. Conversely, patients with high CAR may have immunosuppressive systemic environments that limit immunotherapy efficacy despite previous chemotherapy-induced immunogenic priming [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. This interpretation aligns with observations for other inflammation-based biomarkers such as NLR, which demonstrate stronger prognostic utility in immunotherapy monotherapy than in chemotherapy or concurrent chemoimmunotherapy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In the nivolumab plus ipilimumab group, trends in prognostic stratification based on CAR and dCAR were observed; however, the difference was not statistically significant, possibly because of the small sample size.\u003c/p\u003e \u003cp\u003eThese findings have important clinical implications. First, high CAR was correlated with poor PS, and patients with both PS 2 and high CAR experienced strikingly short survival (median PFS, 0.9 months; median OS, 1.8 months) (Supplementary Fig. \u003cspan refid=\"MOESM6\" class=\"InternalRef\"\u003eS6\u003c/span\u003eA and S6B), suggesting minimal therapeutic benefits for this subgroup. Supportive care may be a more appropriate option than active treatment for such patients. Second, subsequent treatment availability varied according to the baseline CAR. Patients with low CAR were significantly more likely to receive subsequent active treatment after ICI failure (63% vs. 30%; p\u0026thinsp;=\u0026thinsp;0.002 in nivolumab monotherapy; 70% vs. 41%; p\u0026thinsp;=\u0026thinsp;0.08 in chemotherapy plus ICI), whereas those with high CAR more often transitioned directly to best supportive care. These differences likely contributed to the observed survival disparities and highlighted the need to address inflammation and nutritional status throughout the disease course. Therefore, early engagement with palliative care should be considered for patients with high CAR\u0026mdash;irrespective of PS\u0026mdash;to support timely advance care planning and symptom management. Among patients with high CAR, chemotherapy plus an ICI exhibited a numerical trend toward longer PFS than nivolumab plus ipilimumab (4.1 vs. 3.0 months; p\u0026thinsp;=\u0026thinsp;0.14) (Supplementary Fig. \u003cspan refid=\"MOESM6\" class=\"InternalRef\"\u003eS6\u003c/span\u003eC and S6D), whereas OS was similar (8.8 vs. 13.1 months; p\u0026thinsp;=\u0026thinsp;0.56). These findings should be interpreted cautiously because of the potential selection bias, and both regimens remain appropriate options depending on patient-specific clinical considerations. Finally, dCAR monitoring demonstrated prognostic utility in nivolumab monotherapy but limited utility in the chemotherapy plus ICI cohort due to the confounding effects of chemotherapy on inflammatory markers. However, dCAR may be valuable in the nivolumab plus ipilimumab cohort, in which the trends suggest prognostic information with larger sample sizes. For patients receiving immunotherapy without chemotherapy, monitoring dCAR may provide early signals of treatment response or failure.\u003c/p\u003e \u003cp\u003eThis retrospective, single-center study may have had selection bias and, thus, limited generalizability. CAR can be influenced by unmeasured confounders such as subclinical infections or chronic inflammatory conditions. The cut-off value for CAR was determined using time-dependent ROC analysis within the same dataset used for outcome evaluation. Although this approach is acceptable for exploratory biomarker discovery, it introduces the potential risk for overfitting, and the observed differences may, in part, reflect this optimization process. The optimal cut-off values differed between cohorts (0.072 vs. 0.090), requiring external validation. Small sample sizes in subgroup analyses, particularly for dCAR in first-line treatment, had limited statistical power. Comprehensive biomarker data (PD-L1 expression and tumor mutational burden) were not available for comparison.\u003c/p\u003e \u003cp\u003eIn conclusion, CAR is a simple and widely available prognostic biomarker in patients with non-resectable advanced or recurrent ESCC undergoing ICI-based therapy. Its impact is most pronounced in those undergoing nivolumab monotherapy, with more complex patterns in chemotherapy-containing regimens due to concurrent treatment effects. The baseline CAR can guide treatment decisions, including the identification of patients suitable for supportive care and those requiring early palliative care integration. Dynamic CAR monitoring provides additional information in selected settings. Given its simplicity and accessibility, CAR has significant potential for clinical implementation to improve patient selection and treatment planning for cancer immunotherapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study involved human participants and was approved by the Certified Review Board of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (IRB number: 2021-GB-095). The protocol was described on the hospital website, and subjects were provided the opportunity to opt‐out; therefore, no additional consent was required from patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish the study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent to publish the study was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: K.Y. and A.O.; acquisition of data: K.Y.; analysis and interpretation of data: K.Y. and A.O.; writing: K.Y. and A.O.; review and/or revision of the manuscript: all authors; administrative, technical, or material support: all authors; and study supervision: A.O.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are deeply indebted to the patients who participated in this study and to their families. The authors thank Ms. Yuki Horiike, Ms. Hitomi Hannan, and Ms. Yukie Naito for providing data management. We would like to thank Editage (www.editage.jp) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this study, although not available in a public repository, will be made available to other researchers upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbnet CC, Arnold M, Wei WQ. Epidemiology of Esophageal Squamous Cell Carcinoma. 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Lung Cancer. 2017;111:176\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"C-reactive protein to albumin ratio, esophageal squamous cell carcinoma, immune checkpoint inhibitor, nivolumab, prognosis, biomarker","lastPublishedDoi":"10.21203/rs.3.rs-8463955/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8463955/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe C-reactive protein to albumin ratio (CAR) reflects systemic inflammation and nutritional status, but its prognostic value in esophageal squamous cell carcinoma (ESCC) treated with immune checkpoint inhibitor (ICI)-based therapy remains unclear.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed 199 patients with unresectable advanced or recurrent ESCC who received ICI-based therapy across three cohorts: second- or later-line nivolumab monotherapy (n\u0026thinsp;=\u0026thinsp;107), first-line chemotherapy plus ICI (n\u0026thinsp;=\u0026thinsp;60), and first-line nivolumab plus ipilimumab (n\u0026thinsp;=\u0026thinsp;32). The CAR cutoff values were determined using time-dependent receiver operating characteristic curve analysis. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and Cox proportional hazards models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the nivolumab monotherapy cohort, patients with a low CAR (\u0026lt;\u0026thinsp;0.072) had significantly better PFS (median 5.6 vs. 1.9 months; p\u0026thinsp;=\u0026thinsp;0.001) and OS (median 20.0 vs. 5.5 months; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) than those with a high CAR. In the first-line chemotherapy plus ICI cohort, patients with a low CAR (\u0026lt;\u0026thinsp;0.090) were associated with longer OS (median, 21.2 vs. 8.8 months; P\u0026thinsp;=\u0026thinsp;0.03). A similar association was observed in the nivolumab plus ipilimumab cohort (median OS, 22.3 vs. 13.1 months; P\u0026thinsp;=\u0026thinsp;0.003). In multivariable analyses, CAR remained an independent prognostic factor for OS in both the nivolumab monotherapy cohort (hazard ratio (HR) 2.36; 95% confidence interval (CI) 1.35\u0026ndash;4.12; p\u0026thinsp;=\u0026thinsp;0.002) and the first-line cohort (HR 2.38; 95% CI 1.24\u0026ndash;4.56; p\u0026thinsp;=\u0026thinsp;0.009). Patients with a high CAR were more likely to transition directly to best supportive care after discontinuing ICI-based therapy.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCAR is a simple, reliable, and independent prognostic biomarker in patients with unresectable advanced or recurrent ESCC receiving ICI-based therapy.\u003c/p\u003e","manuscriptTitle":"C-reactive Protein to Albumin Ratio as a Prognostic Biomarker in Patients with Esophageal Squamous Cell Carcinoma Receiving Immune Checkpoint Inhibitor- based Therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-22 14:17:18","doi":"10.21203/rs.3.rs-8463955/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-16T04:17:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-15T19:00:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"331341686228289400953316481107333055490","date":"2026-02-15T13:38:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"135618850723137754588981105837275754238","date":"2026-02-14T14:41:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"260132095678533312264223187925134491232","date":"2026-02-13T18:43:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-08T14:34:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-25T08:27:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"301527202498204111479264472763694759715","date":"2026-01-22T15:04:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"34742279231742877466320728721375793892","date":"2026-01-21T23:24:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"325985941634469425203319537007349948121","date":"2026-01-21T14:19:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"212064481335117847742075759625343696745","date":"2026-01-21T07:29:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"67232607297629779500420445620646937882","date":"2026-01-21T06:41:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"273896288959448545621708328597453567873","date":"2026-01-21T00:05:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-20T14:50:21+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-29T14:33:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-29T04:17:05+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-29T04:16:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-12-28T04:48:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d7f92506-d8fd-405f-9e96-c5a681600e84","owner":[],"postedDate":"January 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T11:08:51+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-22 14:17:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8463955","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8463955","identity":"rs-8463955","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}