Prognostic Effect of the Controlling Nutritional Status Score in Patients With Esophageal Cancer Treated With Immune Checkpoint Inhibitor.

In recent years, a growing number of clinical studies have shown that immune checkpoint inhibitor (ICI) can increase the remission rate and improve the prognosis of patients with esophageal cancer. The Controlling Nutritional Status (CONUT) score is a novel nutritional indicator that can predict the prognosis of certain malignancies. We retrospectively analyzed the clinical data of 69 patients with advanced esophageal cancer treated with ICI and assessed the relationship between clinicopathological factors including CONUT score, systemic immune-inflammatory index (SII), and neutrophil-to-lymphocyte ratio and the prognosis. We found the CONUT score and SII, neutrophil-to-lymphocyte ratio were an independent prognostic factor for overall survival ( P <0.05). Furthermore, among patients treated with ICI, a high CONUT score was associated with a significantly worse progression-free survival (PFS) and overall survival compared with a low CONUT group. In conclusion, the CONUT can be used to predict the efficacy and prognosis of ICI therapy in patients with esophageal cancer. Our studies have shown that the CONUT score can be used as an effective indicator for the prognosis of patients with esophageal cancer receiving ICI.

As one of the most common malignant tumors in the world, esophageal cancer ranks seventh and sixth in terms of morbidity and mortality,1 and the 5-year survival rate is extremely low.2 For patients with early esophageal cancer, timely diagnosis and radical surgery can effectively control the progression of cancer to a certain extent, whereas for patients with advanced esophageal cancer, cytotoxic chemotherapy is the main treatment method. Recently, various molecularly targeted drugs have achieved good results in the treatment of patients with esophageal cancer.3,4 In addition, immunotherapy, including immune checkpoint inhibitor (ICI), has greatly advanced the treatment of esophageal cancer.5–9

The first ICI nivolumab, a programmed cell death-1 (PD-1) inhibitor, to show effectiveness in the treatment of esophageal cancer. The ATTRACTION-1 study, an open-label, multicenter phase II study, administered nivolumab to patients with advanced esophageal cancer who had previously failed or were intolerant of chemotherapy showed a favorable overall response rate and median overall survival (mOS) was significantly improved.5 The results from the ATTRACTION-3 study demonstrated that nivolumab conferred a survival benefit regardless of tumor programmed death ligand-1 (PD-L1) expression.8 The KEYNOTE-028 study showed that pembrolizumab can achieve an overall response rate of 30% in overall patients, with a mOS of 7 months and a median progression-free survival of 1.8 months.10 The KEYNOTE-180 study showed higher OS in PD-L1-positive patients.11

There is increasing evidence that the presence of systemic inflammatory responses and malnutrition is associated with poorer prognosis in various malignancies.12–14 Recently, several inflammation-based markers, such as neutrophil-to-lymphocyte ratio (NLR), SII, Godzilla Prognostic Score, were reported to be prognostic factors for immunotherapy in various malignancies,15–19 including esophageal cancer.20–23 The Controlling Nutritional Status (CONUT), which consists of serum albumin, peripheral lymphocyte count, and serum total cholesterol, was used to assess early nutritional status.24,25 The relationship between the CONUT score and the perioperative surgical risk and postoperative prognosis of malignancies such as gastric, esophageal, pancreatic, liver, cervical, and bladder cancers has been reported.26–31 Studies have shown that the CONUT score is related to the prognosis of cancer patients receiving chemotherapy. However, its effectiveness in patients receiving ICI has not been studied.32–34 The primary objective of this study was to investigate the clinical significance of the CONUT score in patients with esophageal cancer who were treated with ICI.

METHODS

Patients

This retrospective study included data of patients diagnosed with esophageal cancer at the Harbin Medical University Cancer Hospital between January 2017 and October 2020. The inclusion criteria were as follows: (1) patients aged 18–80 years; (2) histologically or cytologically confirmed unresectable locally advanced/recurrent or distant metastatic esophageal cancer; unresectable locally advanced patients who cannot receive curative treatment (including curative chemoradiotherapy or radical radiotherapy, etc.); patients who have progressed or relapsed after neoadjuvant or adjuvant therapy; (3) Eastern Cooperative Oncology Group (ECOG) score 0–2; and (4) patients receiving ICI therapy. The exclusion criteria include (1) history or coexisting with another malignant tumors; (2) patients with acute inflammation, hematological diseases, or autoimmune diseases; and (3) the serum level of cholesterol data not available. Finally, 69 patients were included in this study.

Data Collection

We collected the basic clinical information of these patients, mainly including age, sex, ECOG performance status (PS), smoking history, drinking history, body mass index (BMI), the location of primary tumor, pathologic type, ICI treatments cycle, squamous cell carcinoma antigen (SCC-Ag), and number of prior treatments. In addition, we also evaluate NLR and SII. The time-dependent receiver operating characteristic curves for 1-year OS showed that the optimal cutoff values for NLR and SII were 2.24 and 837.05, respectively (Fig. 1). We collected data including the serum albumin, total cholesterol, and peripheral blood lymphocyte count within 1 month before the first ICI treatment, as the assessment of the CONUT score (Table 1). A study of the cutoff value of CONUT score based on the 1-year OS time-dependent receiver operating characteristic curve showed that the most suitable cutoff value for CONUT score was 1 [area under the curve (AUC): 0.619, 95% confidence interval (CI), 0.477–0.762; sensitivity: 0.565; specificity: 0.696] (Fig. 1). Therefore, we chose the optimal cutoff value of the CONUT score as 1 and divided 69 patients into the low CONUT score group (CONUT≤1) and the high CONUT score group (CONUT>1). NLR was calculated by dividing the neutrophil count by the lymphocyte count. SII was calculated by multiplying the platelet count by the neutrophil count divided by the lymphocyte count. We collected patient follow-up data until December 9, 2021, or the date of death.

FIGURE 1

The time-dependent ROC curve for 1-year overall survival. ROC according to systemic immune-inflammatory index (A). AUC=0.742. ROC according to neutrophil-to-lymphocyte ratio (B). AUC=0.706. ROC according to controlling Nutritional Status (C). AUC=0.619. AUC indicates area under the curve; CONUT, Controlling Nutritional Status; NLR, neutrophil-to-lymphocyte ratio; ROC, receiver operating characteristic; SII, systemic immune-inflammatory index.

TABLE 1

Assessment of the Nutritional Status According to the CONUT Score

Variable	Range	Score
Serum albumin (g/dL)	≥3.50	0
	3.00–3.49	2
	2.50–3.49	4
	<2.50	6
Cholesterol (mg/dL)	≥180	0
	140–179	1
	100–139	2
	<100	3
Cholesterol (mg/dL)	≥1600	0
	1200–1599	1
	800–1199	2
	<800	3

CONUT indicates Controlling Nutritional Status.

Informed consent was waived due to retrospective retrieval of patient data. Ethical approval was obtained before the study began from the Ethics Committee of Harbin Medical University Cancer Hospital.

Tumor Assessment

To assess treatment response, planned computed tomography or magnetic resonance imaging was performed every 3 months according to the RECIST criteria 1.1 or clinical deterioration in patients. To eliminate the influence of immunotherapy pseudoprogression, we selected the response rate (RR) and the disease control rate (DCR) after 12 weeks of treatment. The RR was defined as the ratio of the sum of complete response (CR) plus partial response (PR). The DCR was defined as the ratio of the sum of CR and PR and stable disease. The PFS was defined as the time from the first treatment cycle with ICI agent to radiographically recorded disease progression or death or the last follow-up. The OS was defined as the time from the first treatment with ICI agent to death or was censored at the date of last patient contact.

Statistical Analyses

All of the statistical analyses were performed using SPSS v23.0 (IBM, Armonk, NY) and R software programs. The Fisher exact test was used to compare categorical data. The Kaplan-Meier method was used to estimate survival probabilities, and differences in survival probabilities were analyzed using the Wilcoxon test and the log-rank test. Cox multivariate regression analysis was performed, and hazard ratio (HR) and 95% CIs were calculated. And P-value of <0.05 were considered to indicate statistical significance.

RESULTS

Patients’ Characteristics

The baseline characteristics of the 69 patients are summarized in Table 2. The median age of patients was 60 years (range: 44–78 y), and 67 patients (97.1%) were male. Thirty-seven patients (53.6%) had a history of smoking, and 46 patients (66.7%) had a history of drinking. Twenty-one patients (30.4%) had an ECOG PS of 1. According to the assessment of BMI, 30 patients (43.5%) were divided into low BMI group (BMI: <21.87 kg/m2), and 39 patients (56.5%) were divided into high BMI group (BMI: ≥21.87 kg/m2). The location of the primary tumor in all patients was as follows: cervical esophagus, n=2 (2.9%); upper thoracic, n=11 (15.9%); middle thoracic, n=32 (46.4%); lower thoracic, n=24 (34.8%); esophagogastric junction, n=0 (0%). The pathologic type of all patients (100%) was squamous cell carcinoma. Thirty-one patients (44.9%) received radiotherapy and all patients (100%) received chemotherapy. Camrelizumab was used in 21 patients (30.4%); sintilimab was used in 38 patients (55.1%); and toripalimab was used in 10 patients (14.5%). Nine patients (13.0%) used ICI for more than 6 cycles. ICI was administered to 59 patients (85.5%) for the first treatment; 8 (11.6%) for the second treatment; and 2 (2.9%) for the third and subsequent treatment. According to the assessment of SCC-Ag, 49 patients (71.0%) were classified into the low SCC group (<2.6 μg/L), whereas 20 patients (29.0%) were classified into the high SCC group (≥2.6 μg/L). The mean SII was 637.41 (range: 145.41–3987.28). Forty-five patients (65.2%) were classified as the low SII group (<837.05). The mean NLR was 2.43 (range: 0.77–20.44). Forty-one patients (59.4%) were classified in the high NLR group (≥2.24). The mean CONUT score was 1.62 (range: 0–7), of which 42 (60.9%) were classified as the low CONUT (CONUT ≤1).

TABLE 2

Patient Characteristics Treated With ICI

Variable	Value
Age (years old)
Median (range)	60 (44–78)
<52	9
≥52	60
Sex
Male	67
Female	2
PS
0	48
1	21
Smoking history
Yes	37
No	32
Drinking history
Yes	46
No	23
BMI (kg/m²)
<21.87	30
≥21.87	39
The location of primary tumor
Cervical esophagus	2
Upper thoracic	11
Middle thoracic	32
Lower thoracic	24
Esophagogastric junction	0
Pathologic type
Adenocarcinoma	0
Squamous cell carcinoma	69
Radiotherapy or not
Yes	31
No	38
Types of ICI
Camrelizumab	21
Sintilimab	38
Toripalimab	10
ICI treatments cycle
<6	60
≥6	9
Number of prior treatments
0	59
1	8
≥2	2
Squamous cell carcinoma antigen (μg/L)
<2.6	49
≥2.6	20
SII
Median (range)	637.41 (145.41–3987.28)
<837.05	45
≥837.05	24
NLR
Median (range)	2.43 (0.77–20.44)
<2.24	28
≥2.24	41
CONUT score
Median (range)	1.62 (0–7)
0	18
1	24
2	11
3	7
4	4
5	3
6	0
7	2
8	0
9	0

BMI indicates body mass index; CONUT, Controlling Nutritional Status; ICI, immune checkpoint inhibitors; NLR, neutrophile-to-lymphocyte rate; PS, performance status; SII, systemic immune-inflammation index.

Associations Between CONUT Score and Clinicopathological Parameters in Esophageal Cancer Patients Treated With ICI

We assessed the associations between CONUT score and clinicopathological parameters in esophageal cancer patients treated with ICI (Table 3). There were no significant differences in age, sex, PS, smoking history, drinking history, BMI, the location of primary tumor, radiotherapy history, ICI treatment cycle, number of prior treatments, SCC, and SII between the high and low CONUT groups. In addition, patients with the low NLR in the low CONUT group were significantly higher than those in the high CONUT group [23/42 (54.76%) vs. 5/27 (18.52%), respectively; P=0.003].

TABLE 3

Associations Between CONUT Score and Clinicopathological Parameters in Esophageal Cancer Patients Treated With ICI

Variable	Group	Total	Low CONUT(≤1)	High CONUT(>1)	P *
Age (years old)	<52	9	4	5	0.299
	≥52	60	38	22	—
Sex	Male	67	40	27	0.517
	Female	2	2	0	—
PS	0	48	33	18	0.116
	1	21	9	12	—
Smoking history	Yes	37	24	13	0.621
	No	32	18	14	—
Drinking history	Yes	46	29	17	0.612
	No	23	13	10	—
BMI (kg/m²)	<21.87	30	15	15	0.137
	≥21.87	39	27	12	—
The location of primary tumor	Middle thoracic	32	21	11	0.471
	Non–middle thoracic	37	21	16	—
Radiotherapy or not	Yes	31	16	15	0.216
	No	38	26	12	—
ICI treatments cycle	<6	60	35	25	0.466
	≥6	9	7	2	—
No. prior treatments	0	59	36	23	0.432
	≥1	10	6	4	—
SCC-Ag (μg/L)	<2.6	49	32	17	0.283
	≥2.6	20	10	10	—
SII	<837.05	45	30	15	0.203
	≥837.05	24	12	12	—
NLR	<2.24	28	23	5	0.003
	≥2.24	41	19	22	—

The significance for bold values is the number of patients.

Fisher exact test.

BMI indicates body mass index; CONUT, Controlling Nutritional Status; ICI, immune checkpoint inhibitors; NLR, neutrophile-to-lymphocyte rate; PS, performance status; SCC-Ag, squamous cell carcinoma antigen; SII, systemic immune-inflammation index.

The Response and Survival in Esophageal Cancer Patients Treated With ICI

The clinical responses of the 69 patients were as follows: PR, n=28; CR, n=6; stable disease, n=14; and progress disease, n=21. Therefore, the RR was 49.28% (34/69), and the DCR was 69.57% (48/69). The DCR of the high SII group was significantly lower than that of the low SII group (78.26% vs. 52.17%, P=0.050) (Table 4). The RR of the high NLR group was significantly lower than that of the low NLR group (67.86% and 36.59%, P=0.015). The DCR of the high NLR group was significantly lower than that of the low NLR group (92.86% and 53.66%, P=0.000). The DCR was worse in the high CONUT group than the low CONUT group (80.95% vs. 51.85%, P=0.016). Other factors were not related to RR or DCR.

TABLE 4

Response and Disease Control Rate in Esophageal Cancer Patients Treated With ICI

Variable	RR	DCR
Age (<52 vs. ≥52)	33.33% vs. 51.67%	44.44% vs.73.33%
Sex (male vs. female)	50.75% vs. 0.00%	70.15% vs. 50.00%
PS (0 VS. 1)	45.83% vs. 57.14 %	72.92% vs. 61.90%
Smoking history (yes vs. no)	45.95% vs. 53.13%	67.57% vs. 71.88%
Drinking history (yes vs. no)	54.35% vs. 39.13%	71.74% vs. 65.22%
BMI (<21.87 vs. ≥21.87)	46.67% vs. 51.28%	63.33% vs. 74.36%
The location of primary tumor (M vs. non-M)	43.75% vs. 54.05%	68.75% vs. 70.27%
Pathologic type (SCC vs. Non-SCC)	49.28% vs. 0.00%	69.56% vs. 0.00%
Radiotherapy or not (yes vs. no)	48.39% vs. 50.00%	70.97% vs. 68.42%
Number of ICI treatments (<6 vs. ≥6)	46.67% vs. 66.67%	65.00% vs. 100.00%
Number of prior treatments (0 vs. ≥1)	54.24% vs. 20.00%	76.27% vs. 30.00%
SCC-Ag (<2.6 vs. ≥2.6)	53.06% vs. 40.00%	73.47% vs. 60.00%
SII (<837.05 vs. ≥837.05)	56.52% vs. 34.78%	78.26% vs. 52.17%*
NLR (<2.24 vs. ≥2.24)	67.86% vs. 36.59%**	92.86% vs. 53.66%***
CONUT score (≤1 vs. >1)	57.14% vs. 37.04%	80.95% vs. 51.85%****

P=0.050.

P=0.015.

P=0.000.

P=0.016 (Fisher exact test).

BMI indicates body mass index; CONUT, Controlling Nutritional Status; ICI, immune checkpoint inhibitors; M, middle thoracic; NLR, neutrophile-to-lymphocyte rate; Non-M, Non–middle thoracic; Non-SCC, non-squamous cell carcinoma; PS, performance status; SCC, squamous cell carcinoma; SCC-Ag, squamous cell carcinoma antigen; SII, systemic immune-inflammation index.

The PFS and OS of all esophageal cancer patients treated with ICI are shown in Figure 2. The 1-year PFS rate and median progression-free survival were 49.28% and not reached, respectively. The 1-year OS rate and mOS were 66.67% and 18.3 months, respectively.

FIGURE 2

Survival curves of the esophageal cancer patients treated with ICI. Kaplan-Meier estimates of progression-free survival (A) and overall survival (B). OS indicates overall survival; PFS, progression-free survival.

On the basis of the univariate analysis, we found that the presence of prior therapy and non-midthoracic esophageal cancer were significantly associated with shorter PFS. According to the Kaplan-Meier survival analysis, 1-year PFS rate of patients with middle thoracic esophageal cancer was 62.50%, whereas the 1-year PFS rate of patients with non–middle thoracic esophageal cancer was 37.84% (P=0.043). The 1-year PFS rate was 55.93% in no prior treatment patients, whereas that of the patients with prior treatment was 10.00% (P=0.008). The 1-year PFS rates of the high NLR group and the low NLR group were 34.15% and 71.43%, respectively (P=0.003). The 1-year PFS rates of the low CONUT and high CONUT groups were 60.00% and 29.17%, respectively (P=0.028) (Table 5). The PFS curves in ICI patients according to SII, NLR, and CONUT scores are shown in Figure 3.

TABLE 5

Results of the Univariate Analysis of Factors Predicting the PFS and OS

	PFS		OS
Variable	1-y Survival Rate	P*	1-y Survival Rate	P *
Age (<52 vs. ≥52)	33.33% vs. 50.82%	0.308	33.33% vs. 71.67%	0.024
Sex (male vs. female)	49.25% vs. 50.00%	0.984	67.16% vs. 50.00%	0.614
PS (0 vs. 1)	54.17% vs. 38.10%	0.223	70.83% vs. 57.14%	0.270
Smoking history (yes vs. no)	51.35% vs. 46.88%	0.713	64.86% vs. 68.75%	0.735
Drinking history (yes vs. no)	52.17% vs. 43.48%	0.499	67.39% vs. 65.21%	0.858
BMI(<21.87 vs. ≥21.87)	40.00% vs. 56.41%	0.111	56.67% vs. 74.36%	0.087
The location of primary tumor (M vs. non-M)	62.50% vs. 37.84%	0.043	68.75% vs. 64.86%	0.735
Radiotherapy or not (yes vs. no)	61.29% vs. 39.47%	0.073	67.74% vs. 65.79%	0.865
Number of ICI treatments (<6 vs. ≥6)	48.33% vs. 55.56%	0.688	61.67% vs. 100.0%	0.024
No. prior treatments (0 VS. ≥1)	55.93% vs. 10.00%	0.008	72.88% vs. 30.00%	0.008
SCC-Ag (<2.6 vs. ≥2.6 )	55.10% vs. 35.00%	0.133	73.47% vs. 50.00%	0.063
SII (<837.05 vs. ≥837.05 )	57.14% vs. 37.04%	0.106	82.22% vs. 37.50%	0.001
NLR (<2.24 vs. ≥2.24 )	71.43% vs. 34.15%	0.003	92.86% vs. 48.78%	0.000
CONUT score (≤1 vs. >1 )	60.00% vs. 29.17%	0.028	76.19% vs. 51.85%	0.038

Wilcoxon test.

BMI indicates body mass index; CONUT, Controlling Nutritional Status; ICI, immune checkpoint inhibitors; M, middle thoracic; NLR, neutrophile-to-lymphocyte rate; non-M, non–middle thoracic; OS, overall survival; PFS, progression-free survival; PS, performance status; SCC-Ag, squamous cell carcinoma antigen; SII, systemic immune-inflammation index.

FIGURE 3

Progression-free survival (PFS) curves in esophageal cancer patients treated with ICI. PFS according to the SII (A); PFS according to the NLR (B); and PFS according to the CONUT score (C). CONUT indicates Controlling Nutritional Status; HR, hazard ratio; NLR, neutrophile-to-lymphocyte rate; SII, systemic immune-inflammation index.

On the basis of the univariate analysis of OS-related factors showed that patients with not <6 cycles of immunotherapy and no prior treatment were associated with longer OS. In a Kaplan-Meier survival analysis showed that the 1-year OS rate of esophageal cancer patients with not <6 cycles immunotherapy was 100.00%, whereas the 1-year OS rate of patients with <6 cycles immunotherapy was 61.67% (P=0.024). The 1-year OS rate was 72.88% in patients with no prior treatment compared with 30.00% in patients with prior treatment (P=0.008). The 1-year OS rate of patients in the high SII group was 37.50%, and the 1-year OS rate of the patients in the low SII group was 82.22% (P=0.001). The 1-year OS rates of patients in the low NLR group and the high NLR group were 92.86% and 48.78%, respectively (P=0.000). The 1-year OS rates of patients in the low and high CONUT groups were 76.19% and 51.85%, respectively (P=0.038) (Table 5). The OS curves in ICI patients according to SII, NLR, and CONUT scores are shown in Figure 4. A multivariate analysis revealed that the CONUT score, NLR, and SII were the independent prognostic factors in esophageal cancer patients treated with ICI (HR: 2.056; 95% CI, 1.031–4.098, P=0.041; HR: 2.830; 95% CI, 1.235–6.482, P=0.014; HR: 2.487; 95% CI, 1.245–4.969, P=0.010; respectively) (Table 6).

FIGURE 4

Overall survival (OS) curves in the esophageal cancer patients treated with immune checkpoint inhibitor. OS according to the systemic immune-inflammation index (A); OS according to the neutrophile-to-lymphocyte rate (B); and OS according to the Controlling Nutritional Status score (C). CONUT indicates Controlling Nutritional Status; HR, hazard ratio; NLR, neutrophile-to-lymphocyte rate; SII, systemic immune-inflammation index.

TABLE 6

Results of the Multivariate Cox Regression Analysis of Factors Predicting the PFS and OS

	PFS		OS
Variable	Hazard ratio (95%)	P *	Hazard ratio (95%)	P *
SII (<837.05 vs. ≥837.05)	1.644 (0.590–4.579)	0.341	2.487 (1.245–4.969)	0.010
NLR (<2.24 vs. ≥2.24)	1.098 (0.382–3.157)	0.862	2.830 (1.235–6.482)	0.014
CONUT score (≤1 vs. >1)	1.299 (0.521–3.239)	0.575	2.056 (1.031–4.098)	0.041

A proportional regression hazard model.

CONUT indicates Controlling Nutritional Status; NLR, neutrophile-to-lymphocyte rate; OS, overall survival; PFS, progression-free survival; SII, systemic immune-inflammation index.

DISCUSSION

This is the first study to examine the relationship between ICI therapy and the nutritional status in patients with esophageal cancer. In our study, ICI-treated esophageal cancer patients in the high CONUT group (CONUT > 1) had significantly worse OS and PFS compared with the low CONUT group (CONUT ≤1). We also found that the CONUT score was an independent predictor of ICI treatment effect and OS. We therefore believe that the CONUT score may serve as a potential early predictive marker in esophageal cancer patients who want to benefit from ICI therapy.

The CONUT scores included serum albumin and total cholesterol and total lymphocyte count in peripheral blood. Serum albumin mainly reflects the body’s ability to synthesize protein, serum total cholesterol reflects the body’s ability to metabolize lipids, and the total lymphocyte count in peripheral blood reflects the body’s immune function.35 Subjective Global Assessment and the Full Nutritional Assessment are relatively complex, whereas the CONUT score provides an easier and more objective assessment of a patient’s nutritional status.36 Thus, a higher CONUT scores could reflect not only malnutrition but also systemic inflammation and an impaired immune responses. In addition, the CONUT scores can be retrospectively studied in relation to clinical outcomes. Therefore, we retrospectively investigated the relationship between the CONUT scores and patient outcomes. We found that the proportion of patients with a lower CONUT score in the low NLR group tended to be significantly higher than the proportion of patients with a low CONUT score in the high NLR group (Table 3). One possible explanation is that both the COUNT score and the NLR are related to the total lymphocyte count in peripheral blood.

Previous studies have reported the influence of the CONUT score on preoperative prognosis.27,28 Studies have shown that the CONUT score is an independent prognostic factor for relapse-free survival and OS in patients with resectable thoracic esophageal squamous cell carcinoma (ESCC).35 Recently, it was reported37 that the CONUT score could be used to predict the prognosis of non–small cell lung cancer patients receiving pembrolizumab. In this report, compared with the high CONUT score group (CONUT>2), the low CONUT score group (CONUT≤2) was associated with significantly longer PFS and OS. And they found that the CONUT score were the independent prognostic factors of OS (P<0.05). However, this retrospective study had a small number of patients and may be biased. Currently, there are no relevant reports on the CONUT score in predicting treatment outcome in patients with esophageal cancer treated with ICI. In this study, we show for the first time that patients with esophageal cancer with the high CONUT score treated with ICI had significantly worse OS and PFS compared with patients with the low CONUT score.

ICI is a cancer therapy that targets coinhibitory signaling on the surface of T cells, resulting in long-lasting antitumor responses by disabling the braking mechanism of the immune system.38 Phase II clinical trials ATTRACTION-1 study and KEYNOTE-180 study showed the efficacy and safety of ICI as third-line treatment of advanced esophageal cancer.5,11 In 2019, the phase III KEYNOTE-1817 study showed that among patients with a PD-L1 combined positive score ≥10, the mOS in the pembrolizumab group was 9.3 months compared with 6.7 months in the chemotherapy group, and there was no significant difference in PFS between the 2 groups. Subgroup analysis found that Asian patients benefited more from pembrolizumab treatment. The results of the ATTRACTION-3 study showed that8 regardless of the level of PD-L1 expression in patients, the nivolumab group could improve the OS of patients by 2.5 months and reduce the risk of death by 23%. More and more studies have demonstrated the safety and efficacy of ICI in patients with advanced esophageal cancer. ONO4538 is a phase II clinical study6 to investigate the efficacy of nivolumab in patients with advanced ESCC who are refractory or intolerant to fluoropyrimidine, platinum, and taxane chemotherapy. The results showed an OS of 10.8 months and a PFS of 2.8 months, suggesting that nivolumab may be a potential treatment option for patients with advanced ESCC who are refractory or intolerant. At this stage, we still need to further explore the role and mechanism of ICI in patients with esophageal cancer, so that more advanced esophageal cancer patients can benefit from ICI.

As immunotherapy plays an increasingly important role in cancer treatment, the research on tumor biomarkers related to its therapeutic effect is also continuously applied. Biomarkers currently used to assess whether there is a good response to immunotherapy mainly include PD-L1 expression, tumor mutational burden, and microsatellite instability. The expression of MHC-II molecules,39 CD8 expression in tumor-infiltrating lymphocytes, and lack of DNA mismatch repair system40 have also recently been shown to be biomarkers. Neoantigen41 is another biomarker that has been used to predict the effect of anti-PD-1 therapy in esophageal cancer. However, the correlation between these biomarkers has not yet been investigated, so we plan to study the correlation of various biomarkers in ICI treatment in the future.

This study has certain limitations. First, because this study was a single-institution retrospective study, the number of patients treated with ICI was relatively small. In addition, many patients are lost because serum total cholesterol levels are not considered important in esophageal cancer chemotherapy treatment. Third, the current retrospective study cannot include factors that may influence inflammation and nutritional status. Therefore, we need prospective studies to overcome these problems.

In conclusion, the CONUT score can be used as a biomarker to predict the efficacy and prognosis of esophageal cancer patients receiving ICI therapy and can be used to guide advanced esophageal cancer patients who want to benefit from ICI therapy.