Abstract
Background
In Japan, nivolumab administration is the standard treatment for patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) who are refractory or intolerant to fluoropyrimidines and platinum-based chemotherapy. We determined if inflammatory prognostic factors are useful in patients with ESCC treated with nivolumab monotherapy.
Methods
The clinical data of patients with ESCC treated with nivolumab monotherapy as the second- or later-line treatment were retrospectively analyzed. Neutrophil/lymphocyte, platelet/lymphocyte, and C-reactive protein/albumin ratios (CAR); prognostic index; and prognostic nutritional index were investigated. Cut-off values for each factor were determined according to overall survival using time-dependent receiver operating characteristic curves.
Results
During January 2017–June 2021, 93 consecutive patients with ESCC were enrolled from five institutions (median age, 70 years; male, 77%). With a median follow-up period of 9.1 (range, 1.0–34.7) months, the median overall and progression-free survival were 12.8 (95% confidence interval [CI], 9.0–16.6) and 4.0 (95% CI, 2.6–5.4) months, respectively. Of five inflammatory prognostic factors, the cut-off value for CAR was 0.62; prognosis was significantly longer in those with CAR < 0.62 (hazard ratio, 0.39; 95% CI, 0.22–0.67; p = 0.001).
Conclusions
Inflammatory prognostic factors were useful in predicting prognosis for ESCC patients pretreated with nivolumab, especially for those with CAR < 0.62, suggesting that CAR adequately reflects prognosis.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00262-022-03265-7.
Keywords: Inflammatory prognostic factors, Advanced esophageal cancer, Nivolumab, Chemotherapy, Prognosis, C-reactive protein/albumin ratio
Introduction
Esophageal cancer (EC) is the eighth most common cancer in the world. In 2005, more than 400,000 people died from EC [1]. The histological types of EC are divided into two main categories: squamous cell carcinoma (SCC) and adenocarcinoma [1]. In Western countries, adenocarcinoma accounts for majority of cases, whereas SCC is more common in Asia, including Japan [2]. EC is a relatively infrequent cancer, but it is one of the most life-threatening cancers. EC detected in the locally advanced stage is treated with surgery or radical chemoradiotherapy, whereas unresectable locally advanced, recurrent, or metastatic EC is treated with palliative systemic chemotherapy.
The National Comprehensive Cancer Network guidelines version 2.2021 recommend that patients with unresectable locally advanced, recurrent, or metastatic EC be treated with a combination of fluoropyrimidines and platinum-based chemotherapy, with or without a programmed cell death protein 1 (PD-1) inhibitor as first-line treatment [3]. However, in Japan, immune checkpoint inhibitors (ICIs) are still unapproved as initial therapy for patients with EC; hence, patients are treated with fluoropyrimidines and platinum-based chemotherapy as first-line treatment[3–5]. Based on the results of the ATTRACTION-3 trial and KEYNOTE-181, PD-1 inhibitors, nivolumab and pembrolizumab, are regarded as the standard treatment for patients with EC who are refractory or intolerant to fluoropyrimidines and platinum-based chemotherapy [6, 7]. ICIs, such as nivolumab, show remarkable and durable responses in some cases, whereas patients treated with ICIs occasionally experience immune-related adverse events, including fatal toxicities. Therefore, there is an urgent need to predict its efficacy before the initiation of treatment.
Inflammatory prognostic factors, such as the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), C-reactive protein (CRP)/albumin (Alb) ratio (CAR), prognostic index (PI), and prognostic nutritional index (PNI), are associated with the effects of anticancer drugs, including nivolumab, and prognosis in various cancers [8–13]. CAR has been reported as a prognostic factor for ICIs in non-small cell lung carcinoma plus head and neck squamous cell carcinoma [14, 15]. Other inflammatory factors, such as NLR, have also been reported [16–21]. However, data on ICIs, including nivolumab in esophageal squamous cell carcinoma (ESCC), are limited, and reports on these inflammatory factors are lacking [22].
These inflammatory prognostic factors, which can easily be calculated from serological data, can have wide applications because of their simplicity. Therefore, this study aimed to analyze the relationship between inflammatory prognostic factors and prognosis in patients treated with nivolumab. Moreover, a baseline value for each factor was proposed to show relevance.
Materials and methods
Patients and characteristics
The clinical data of consecutive patients with ESCC treated with nivolumab as the second- or later-line treatment were retrospectively collected from three participating institutions. The eligible patients were aged 20 years or older, had advanced, recurrent, or metastatic ESCC, and received at least one cycle of nivolumab between January 2017 and June 2021. The patients’ data from the date of registration until February 2022 were evaluated. The enrolled patients were administered nivolumab 240 mg every two weeks or 480 mg every four weeks until tumor progression or the development of intolerance. This study was conducted in accordance with the Helsinki Declaration of 1964 and later versions, and with the Ethical Guidelines for Clinical Studies. This study was approved by the institutional review boards of all five participating institutions: Kobe City Medical Center General Hospital (approval no. zn210501), Kansai Medical University Hospital, Kochi Medical School, Himeji Red Cross Hospital, and Osaka Red Cross hospital.
Definition of the inflammatory prognostic factors
Five factors were investigated; these included NLR, PLR, CAR, PI, and PNI. These factors were measured according to the blood test results on the date nivolumab treatment was first initiated. The NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count; the PLR was defined as the absolute platelet count divided by the absolute lymphocyte count; CAR was measured by dividing the serum CRP value by the serum Alb value; and the PI was measured using the CRP value and white blood cell (WBC) count. A CRP value > 1 mg/dL was given a score of 1, whereas a CRP value ≤ 1 was defined as a score of 0. A WBC count > 11,000/mm3 was defined as 1, whereas a WBC count ≤ 11,000/mm3 was defined as 0. The PI is the sum of the two scores. The PNI was measured using the following formula: PNI = 10 × Alb value (g/dL) + 0.05 × absolute total lymphocyte count (/mm3).
Statistical analysis
The overall survival (OS) was defined as the time from the date of the first nivolumab treatment to the date of death, of any reason. Living patients were censored at the last follow-up visit. Progression-free survival (PFS) was defined as the time from the date of the first nivolumab treatment to initial disease progression or death, whichever occurred first. A disease assessment was usually performed every eight weeks using computed tomography (CT). Response was evaluated using CT images based on Response Evaluation Criteria in Solid Tumors version 1.1. Disease control was defined as having a best disease assessment of a stable disease or better during nivolumab treatment, and objective response was defined as having a best disease assessment of a partial response or better during nivolumab treatment. Statistical analyses were performed using SPSS statistics version 27.0 (IBM Corp., Armonk, NY, USA) and R version 4.1.0 (The R Project, Vienna, Austria), and a p value < 0.05 was considered to be a statistically significant difference. Fisher’s exact test was used to compare patient characteristics. OS and PFS were estimated using the Kaplan–Meier method. The log-rank test was used to compare between groups, whereas Cox regression models were used to calculate the hazard ratio (HR) and 95% confidence interval (95% CI). Inflammatory prognostic factors were analyzed using Cox regression models. A time-dependent receiver operating characteristic (ROC) curve was used to determine the cut-off values for each factor according to OS. The predictive performance was evaluated using Harrell’s concordance index.
Results
Patient characteristics
Between January 2017 and June 2021, 93 consecutive patients with ESCC were treated with nivolumab as a second- or later-line treatment. The patient characteristics are summarized in Table 1. With a median observation period of 9.1 (range, 1.0–34.7) months for censored cases, the median OS and PFS were 12.8 (95% CI, 9.0–16.6) and 4.0 (95% CI, 2.6–5.4) months, respectively (Fig. 1). There were 38 patients with Performance Status (PS) 0–1 and 55 patients with PS 2–3, and the median BMI was 18.8 (range, 13.1–49.7) kg/m2. The median number of previous regimens was one (range, 1–4), and 47 patients (51%) had a prior history of taxane administration. The best effects of nivolumab were complete response in 4 cases (4.3%), partial response in 14 (15.1%), stable disease in 13 (14.0%), and progressive disease in 61 (64.9%). Regarding immune-related adverse events, there were five serious adverse events of grade ≥ 3 comprising four cases of interstitial pneumonia and one case of toxic epidermal necrolysis. The regimens implemented after nivolumab failure were taxanes (n = 36), fluoropyrimidines and platinum combination (n = 6), fluoropyrimidine monotherapy (n = 2), and pembrolizumab (n = 2).
Table 1.
Patient characteristics
| Characteristic | n = 93 | (%) |
|---|---|---|
| Age | ||
| Median [range] | 70 [38–85] | |
| Sex | ||
| Male/Female | 72/21 | (77/23) |
| Primary | ||
| Cervical/Thoracic/EGJ | 6/86/1 | (6/93/1) |
| No. of metastatic sites | ||
| 0–1/2/3 | 38/39/16 | (41/42/17) |
| Lung metastasis | ||
| No/Yes | 58/35 | (62/38) |
| Liver metastasis | ||
| No/Yes | 66/27 | (71/29) |
| Peritoneal metastasis | ||
| No/Yes | 89/4 | (96/4) |
| Previous Surgery | ||
| No/Yes | 56/37 | (60/40) |
| Previous Radiotherapy | ||
| No/Yes | 51/42 | (55/45) |
| No. of previous regimens | ||
| 1/ ≥ 2 | 34/59 | (37/63) |
| Received treatment after nivolumab | ||
| No/Yes | 47/46 | (51/49) |
| BMI | ||
| < 18.5/ ≥ 18.5 | 45/48 | (48/52) |
| ECOG PS | ||
| 0/ ≥ 1 | 42/51 | (45/55) |
| NLR | ||
| < 3.18/ ≥ 3.18 | 50/43 | (54/46) |
| PLR | ||
| < 277/ ≥ 277 | 68/25 | (73/27) |
| CAR | ||
| < 0.62/ ≥ 0.62 | 68/25 | (73/27) |
| PI | ||
| < 1/ ≥ 1 | 50/43 | (54/46) |
| PNI | ||
| ≥ 48.4/ < 48.4 | 29/64 | (31/69) |
| Disease control | ||
| No/Yes | 62/31 | (67/33) |
| Objective response | ||
| No/Yes | 75/18 | (81/19) |
| irAE | ||
| No/Yes | 62/31 | (67/33) |
NLR, neutrophil/lymphocyte ratio; CAR, C-reactive protein/albumin ratio; PI, prognostic index; EGJ, esophagogastric junction; SCC, squamous cell carcinoma; No., number; BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group Performance Status; PLR, platelet/lymphocyte ratio; PNI, prognostic nutritional index; irAE, immune-related adverse events
Fig. 1.
Kaplan–Meier curves of A OS and B PFS OS, overall survival; PFS, progression-free survival
Time-dependent ROC curve results for each inflammatory prognostic factor and patient characteristics for each factor
The time-dependent ROC curves were investigated and the cut-off values of the inflammatory prognostic factors were measured using the method described above. Based on the results, the cut-off values for NLR, PLR, CAR, PI, and PNI were set as 3.18, 277, 0.62, 1, and 48.4, respectively (Harrell’s concordance indices: 0.657, 0.610, 0.674, 0.625, and 0.622, respectively). Based on these values, the study focused on the factor CAR, considering that this factor might be associated with prognosis. The 93 patients were divided into two groups based on each cut-off value, according to the ROC curve: CAR < 0.62 group (n = 68) and CAR ≥ 0.62 group (n = 25) (Table 2). There were no statistically significant differences in all background factors between the two groups.
Table 2.
Patient characteristics in the CAR group
| Characteristic | CAR | ||
|---|---|---|---|
| < 0.62 | ≥ 0.62 | ||
| n = 68 | n = 25 | p Value | |
| (%) | (%) | ||
| Age (years) | 69.0 [38–83] | 70 [42–85] | 0.57 |
| Median [range] | |||
| Sex | 53/15 | 19/6 | 1.00 |
| Male/Female | (78/22) | (76/24) | |
| Primary | 5/62/1 | 1/24/0 | 0.69 |
| Cervical/Thoracic/EGJ | (7/91/2) | (4/96/0) | |
| No. of metastatic sites | 51/17 | 16/9 | 0.31 |
| 1/ ≥ 2 | (75/25) | (64/36) | |
| Lung metastasis | 43/25 | 15/10 | 0.81 |
| No/Yes | (63/37) | (60/40) | |
| Liver metastasis | 48/20 | 18/7 | 1.00 |
| No/Yes | (70/30) | (72/28) | |
| Peritoneal metastasis | 66/2 | 23/2 | 0.29 |
| No/Yes | (97/3) | (92/8) | |
| Previous Surgery | 39/29 | 17/8 | 0.47 |
| No/Yes | (57/43) | (68/32) | |
| Previous Radiotherapy | 40/28 | 11/14 | 0.24 |
| No/Yes | (59/41) | (44/56) | |
| No. of previous regimens | 42/26 | 17/8 | 0.64 |
| 1/ ≥ 2 | (62/38) | (68/32) | |
| Received treatment after nivolumab | 31/37 | 16/9 | 0.16 |
| No/Yes | (46/54) | (64/36) | |
| BMI | 29/39 | 16/9 | 0.10 |
| < 18.5/ ≥ 18.5 | (43/57) | (64/36) | |
| ECOG PS | 34/34 | 8/17 | 0.16 |
| 0/ ≥ 1 | (50/50) | (32/68) | |
| Disease control | 44/24 | 18/7 | 0.62 |
| No/Yes | (65/35) | (72/28) | |
| Objective response | 55/13 | 20/5 | 1.00 |
| No/Yes | (80/20) | (80/20) | |
| irAE | 44/24 | 18/7 | 0.62 |
| No/Yes | (65/35) | (72/28) | |
p Value: Fisher’s exact test and the value of the comparison between the CAR group and the other groups. CAR, C-reactive protein/albumin ratio
Correlation of OS with CAR and the other inflammatory prognostic factors
The OS in CAR and other inflammatory prognostic factors were analyzed (Fig. 2 and Supplementary Fig. 1). The prognosis was significantly prolonged in the CAR < 0.62 group (median OS, 14.6 months; HR, 0.39; 95% CI, 0.22–0.67; p = 0.001). As shown in Supplementary Fig. 1, the prognosis was significantly better in all factors, except in the PNI (HR, 0.71; 95% CI, 0.39–1.31; p = 0.277).
Fig. 2.
Kaplan–Meier curves of OS in the CAR group CAR, C-reactive protein/albumin ratio
Patients in the CAR < 0.62 group had a significantly better prognosis than those in the CAR ≥ 0.62 group. Analysis of the HR of OS was done using Cox regression analysis (n = 93). p Value: log-rank analysis.
Univariate and multivariate analyses of OS with various prognostic factors
Table 3 shows the univariate and multivariate analyses of the prognostic factors, and a CAR < 0.62 might be a better prognostic factor (HR, 0.42; 95% CI, 0.24–0.75; p = 0.003). Although various inflammatory factors were also analyzed for their relationship with prognosis for patients with ESCC, only NLR < 3.18 was shown to be a possible prognostic factor (HR, 0.38; 95% CI, 0.22–0.67; p < 0.001). In terms of patient characteristics, patients with PS 0 (HR, 0.41; 95% CI, 0.23–0.75; p = 0.004) showed a favorable trend toward prognosis. Furthermore, when restricted to patients with PS 0, patients in the CAR < 0.62 group had a significantly better prognosis than those in the CAR ≥ 0.62 group (median OS, 17.0 vs. 14.1 months; HR, 0.33; 95% CI, 0.10–1.05; p = 0.047). Also, when restricted to patients with PS 1–3, patients in the CAR < 0.62 group had a significantly better prognosis than those in the CAR ≥ 0.62 group (median OS, 10.4 vs. 3.8 months; HR, 0.33; 95% CI, 0.20–0.77; p = 0.005). Even when limited to patients who received nivolumab as second-line therapy, patients in the CAR < 0.62 group had a significantly better prognosis than those in the CAR ≥ 0.62 group (median OS, 14.6 vs. 6.7 months; HR, 0.44; 95% CI, 0.22–0.90; p = 0.021).
Table 3.
Univariate and multivariate analyses of OS: relationship between the characteristics and prognostic factors, including inflammatory factors and OS
| Variable | Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|---|
| HR | 95% CI | p Value | HR | 95% CI | p Value | ||
| Age, 65 ≥ | (Ref. 65 <) | 0.99 | 0.51–1.93 | 0.971 | |||
| Sex, Female | (Ref. Male) | 0.78 | 0.36–1.70 | 0.535 | |||
| PS, 0 | (Ref. 0 <) | 041 | 0.21–0.78 | 0.007 | 0.41 | 0.23–0.75 | 0.004 |
| No. of metastatic organs, 1 ≤ | (Ref. 1 >) | 1.13 | 0.57–2.25 | 0.736 | |||
| Previous Surgery, Yes | (Ref. No) | 0.61 | 0.31–1.19 | 0.148 | |||
| Previous Radiotherapy, Yes | (Ref. No) | 1.67 | 0.82–3.39 | 0.156 | |||
| NLR, < 3.18 | (Ref. ≥ 3.18) | 0.29 | 0.13–0.64 | 0.002 | 0.38 | 0.22–0.67 | < .001 |
| PLR, < 277 | (Ref. ≥ 277) | 1.15 | 0.53–2.51 | 0.728 | |||
| CAR, < 0.62 | (Ref. ≥ 0.62) | 0.38 | 0.17–0.83 | 0.015 | 0.42 | 0.24–0.75 | 0.003 |
| PI, < 1 | (Ref. ≥ 1) | 0.62 | 0.27–1.39 | 0.242 | |||
| PNI, ≥ 48.4 | (Ref. < 48.4) | 2.65 | 1.11–6.35 | 0.029 | |||
OS, overall survival
Discussion
In the present study, a retrospective analysis of 93 consecutive patients with ESCC treated with nivolumab was performed in order to investigate the correlation between inflammatory factors and prognosis. Of the five inflammatory factors that were investigated, CAR was focused based on the results of the Harrell’s concordance index (0.674), and finally, a cut-off value of 0.62 was determined. The analysis showed that the OS of the CAR < 0.62 group was significantly longer than that of the CAR ≥ 0.62 group, regardless of the patient background, such as PS. It was believed that CAR has an outstanding use in predicting prognosis, as the multivariate analysis showed its validity when compared with other prognostic factors. This is the first report to show the prognostic value of nivolumab in patients with ESCC, especially CAR.
The concept of CAR was established by Fairclough et al., who showed its usefulness as a prognostic indicator in patients with acute disease [23]. CAR has been reported to be useful as a prognostic factor in various cancers, and to be more strongly linked to prognosis than the other factors; there have been some reports on the efficacy of CAR in ICIs [14, 15, 24–27]. Interleukin-6 (IL-6) produces CRP [1] and affects cancer cell proliferation, invasion and metastasis, angiogenesis, and resistance to treatment through the JAK/STAT3 pathway [28–31]. A study reported that CRP and IL-6 elevation had a negative effect on the response to chemoradiotherapy and survival in patients with ESCC [32]. In addition, Alb is not only a nutritional indicator but also an indicator of inflammatory findings; a previous report showed that the presence of inflammatory cytokines, such as IL-8, reduced the production of Alb from hepatocytes [33]. Compared with other cancers, EC causes more cases of difficulty in oral intake due to the obstruction of the food passage, leading to nutritional disorders and cachexia. CAR is more effective in investigating both nutrition and inflammation; therefore, it might be significantly associated with the prognosis of patients with EC compared to other inflammatory factors [34]. Moreover, CAR was reported to be a better prognosticator for ICIs than NLR because CAR reflects IL-6 and nutrition better; albeit, the report was focused on head and neck squamous cell carcinoma [14]. In this study, the relationship between the prognosis of patients with ESCC treated with nivolumab and various inflammatory factors was analyzed. The results showed that the prognostic factor CAR adequately reflected the prognosis.
In the univariate and multivariate analyses, the CAR < 0.62 group, those with PS 0 and NLR < 3.18 had a better prognosis. Meanwhile, the subgroup analysis of the ATTRACTION-3 trial showed that those treated with nivolumab tended to survive longer with a PS of 1 than PS 0 and without prior surgery than with surgery, when compared with the control arm [6, 35]. This study, which evaluated various prognostic factors in patients with ESCC treated with nivolumab, found that certain groups of patients did not respond well to nivolumab. In other words, nivolumab should be avoided in this population. For patients with ESCC who have poor prognosis at the start of ICIs using CAR as an index, it is important to perform CT at an appropriate time and consider switching to the next treatment, which includes taxanes.
The number of patients with PS ≥ 1 and metastasis to two or more organs was higher in this study than in ATTRACTION-3, but the objective response rate and disease control rate were equivalent to those in ATTRACTION-3, confirming the efficacy of nivolumab monotherapy. Although the follow-up period was relatively short, this real-world evidence suggested that the results of nivolumab monotherapy for patients with ESCC are relatively good, with a median PFS of 4.0 months and median OS of 12.8 months. Based on the evaluation of factors related to the prognosis of nivolumab administration in patients with ESCC, it is desirable to administer nivolumab to more appropriate patients with ESCC.
Several limitations to this study should be mentioned. First, this was a retrospective study with a relatively small sample size; therefore, the data should be re-examined with validation data. Second, approximately 60% of the patients were followed-up in the event of death; therefore, follow-up data might be immature; hence, the possibility exists that the cut-off value and multivariate analysis may be inaccurate. Finally, the tumor microenvironment, such as PD-1 ligand expression, presence of tumor-infiltrating lymphocytes, microsatellite status, and tumor mutational burden could not be investigated [7]. In addition, basic data proving CAR as a meaningful prognostic factor are expected.
Conclusions
In conclusion, this multicenter study showed the potential use of inflammatory prognostic factors in advanced or recurrent ESCC treated with nivolumab in Japan. In the present study, a CAR < 0.62 suggested a better prognosis, and it is hoped that this factor will be reviewed in a large number of cases in order to validate this finding.
Data statement
The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
I am deeply grateful to Prof. Satake and the other co-authors for their guidance. We also thank Editage, which was responsible for English editing.
Author contributions
Tatsuki Ikoma, Hironaga Satake, Mototsugu Shimokawa, Shogen Boku and other authors were involved in investigation, data curation, writing—review & editing and visualization. Tatsuki Ikoma, Hironaga Satake and Shogen Boku were involved in writing—original draft. Tatsuki Ikoma and Hironaga Satake performed conceptualization and methodology. Hironaga Satake was involved in supervision and project administration. Tatsuki Ikoma, Hironaga Satake and Mototsugu Shimokawa were involved in formal analysis.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declarations
Conflict of interest
Hironaga Satake received research funding from Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd., and honoraria from Bayer, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eli Lilly Japan, Merck Bio Pharma, MSD, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical Co., Ltd., Takeda, and Yakult Honsha. However, those funding sources had no involvement with our study. The rest of the authors do not have any conflict of interest.
Ethics approval
This study was conducted in accordance with the Helsinki Declaration of 1964 and later versions, and with the Ethical Guidelines for Clinical Studies. This study was approved by the institutional review boards of all three participating institutions: Kobe City Medical Center General Hospital (approval no. zn210501), Kansai Medical University Hospital, Kochi Medical School, Himeji Red Cross Hospital, and Osaka Red Cross hospital.
Consent to participate
The requirement for informed consent was waived owing to the retrospective nature of the study.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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