Research ArticleClinical Studies
Open Access

Neutrophil-to-Lymphocyte Ratio to Predict the Efficacy of Immune Checkpoint Inhibitor in Upper Gastrointestinal Cancer

EISUKE BOOKA, HIROTOSHI KIKUCHI, RYOMA HANEDA, WATARU SONEDA, SANSHIRO KAWATA, TOMOHIRO MURAKAMI, TOMOHIRO MATSUMOTO, YOSHIHIRO HIRAMATSU and HIROYA TAKEUCHI
Anticancer Research June 2022, 42 (6) 2977-2987; DOI: https://doi.org/10.21873/anticanres.15781

Abstract

Background/Aim: Although the effectiveness of immune checkpoint inhibitors (ICIs) in upper gastrointestinal (UGI) cancer including esophageal squamous cell carcinoma (ESCC) and gastric/gastroesophageal adenocarcinoma (GEA) has been proven, prediction of their efficacy remains unknown. This study aimed to develop optimal serum nutritional indicators or a combination of blood cell components to predict the efficacy of ICI before beginning UGI cancer treatment. Patients and Methods: We retrospectively reviewed the data of 61 UGI cancers (31 ESCC and 30 GEA) patients treated with nivolumab or pembrolizumab. We investigated the impact of serum albumin level, total lymphocyte count (TLC), prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) on the efficacy of ICIs and long-term survival. The median cutoff value was adopted separately in ESCC and GEA. Results: NLR-Low was significantly correlated with better overall survival (p=0.014), and PLR-Low was significantly correlated with improved disease control rate and better progression-free survival in UGI cancer patients. Both results indicate that a better prognosis is correlated to a greater number of lymphocytes. Multivariate analysis revealed that NLR-High [hazard ratio (HR)=2.865; 95% confidence interval (CI)=1.030-7.937; p=0.044] was the only independent poor prognostic factor. Conclusion: NLR-Low has the potential to predict the good efficacy of ICIs and survival outcomes in patients with UGI cancer. NLR could be useful in determining the optimal treatment strategies for these patients.

Key Words:

Upper gastrointestinal (UGI) cancer, including esophageal squamous cell carcinoma (ESCC) and gastric/gastroesophageal adenocarcinoma (GEA), is associated with high malignant potential and poor prognosis, causing ESCC and GEA to be the sixth and third leading cause of cancer-related mortality worldwide with more than 1.2 million deaths in 2020 (1). Chemotherapy is the standard treatment method for unresectable advanced or recurrent UGI cancer; however, the available anticancer drugs are limited. For many years, cisplatin and 5-fluorouracil (5-FU) have been the mainstays of therapy for ESCC (2), whereas doublet platinum with the addition of trastuzumab has been the primary treatment for human epidermal growth factor receptor 2-positive GEA (3). The recent development of immunotherapy has improved treatment outcomes in various types of cancer including UGI cancer. Nivolumab and pembrolizumab, monoclonal antibodies that target programmed cell death protein 1 (PD-1), have been approved for the treatment of advanced or recurrent unresectable ESCC on the basis of recent clinical trials demonstrating that these agents could prolong survival compared with cytotoxic chemotherapy (4, 5). More recently, pembrolizumab plus cisplatin and 5-FU have been approved as the first-line treatment for ESCC (6), and the use such immune checkpoint inhibitors (ICIs) for the treatment of ESCC and GEA is increasing (7).

Combined positive score (CPS) and tumor proportion score (TPS) have been reported as efficacy predictors of ICI; nevertheless, it is both difficult and time consuming to measure CPS and TPS (5, 6). Therefore, a simpler effect predictor should be developed. Serum nutritional indicators, such as the prognostic nutritional index (PNI), and the combination of blood cell components, such as neutrophil-to-lymphocyte ratio (NLR), have been reported to be effective prognostic markers of patients with various types of cancer, including UGI cancer, but also predictors of chemotherapy efficacy (8-10). However, the relationship between these markers and the therapeutic effect of ICIs on UGI cancer is currently unknown. We hypothesized that the serum nutritional indicators or the combination of blood cell components could predict the efficacy of ICIs on UGI cancer. In this study, we investigated the relationship between serum albumin levels and PNI as serum nutritional indicators or NLR, platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) as the combination of blood cell components, and the efficacy of ICIs on UGI cancer.

Patients and Methods

Patients. We retrospectively collected data from the electronic medical records of all patients with unresectable locally advanced, metastatic, or recurrent UGI cancer who were treated with nivolumab or pembrolizumab at the Department of Surgery, Hamamatsu University School of Medicine between November 2017 and December 2021. The end of the follow-up period was February 28, 2022. All procedures were conducted according to the institutional and national standards on human experimentation and with the Declaration of Helsinki of 1964 and its later versions. The ethics committee of Hamamatsu University School of Medicine approved this study (IRB No. 17-165). The board waived the requirement for written patient consent for the use of clinicopathological data, and all patients agreed to participate through an opt-out approach.

Procedure. Nivolumab was administered intravenously for over 30 min at a dose of 240 mg every 2 weeks until disease progression was assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, or unacceptable toxicity (11). Similarly, Pembrolizumab was targeted for ESCC with a CPS of 10 or higher and was administered intravenously for over 30 min at a dose of 200 mg every 3 weeks until disease progression or unacceptable toxicity.

Tumors were assessed using computed tomography per RECIST version 1.1 at baseline and every 2 months from the start of cycle 1 or at the time when the symptoms began to develop. Accordingly, tumor response was classified into four groups as follows: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Adverse events were assessed throughout the treatment period and for 28 days after the end of treatment according to the National Cancer Institute Common Terminology Criteria for Adverse Event, version 5.0 (12).

Blood assessment for albumin, total lymphocyte count, PNI, NLR, PLR, and LMR and determination of the cutoff values. Blood samples were obtained on the day of ICI administration or the day before. PNI was calculated as 10× serum albumin (g/dl) + 0.005× total lymphocyte counts (TLCs) (per mm3) (13). NLR, PLR, and LMR were indicated as the total neutrophil counts (per mm3) divided by the lymphocyte count (per mm3), platelet counts (per mm3) divided by the TLCs (per mm3), and the TLCs divided by the total monocyte counts (per mm3), respectively. The median cutoff value was adopted separately in ESCC and GEA, and was 3.8 g/dl and 3.3 g/dl for albumin, 869/μl and 1,211/μl for TLC, 42.8 and 37.2 for PNI, 6.0 and 2.5 for NLR, 185 and 77 for PLR, and 1.8 and 2.6 for LMR. The group larger than the median was defined as the high group, and the group smaller than the median was defined as the low group.

Statistical analysis. Statistical analyses were performed using SPSS version 27.0 software (IBM Corp., Armonk, NY, USA). Categorical data were analyzed using Fisher’s exact test or the chi-squared test as appropriate. Quantitative data were analyzed using the unpaired Student’s t-test. Overall survival (OS) was calculated from the day of ICI administration to the day of death. Progression-free survival (PFS) was calculated from the day of ICI administration to the day of progression of esophageal cancer. Patients were followed up until death or until the end of the study (February 28, 2022). Patients who interrupted or underwent follow-up assessment were recognized as censored during the follow-up period, and OS and PFS were calculated based on the days until censoring. Survival was analyzed using the Kaplan–Meier method and log-rank test. Multivariate comparisons of survival time were performed using Cox regression analysis. A value of p<0.05 was considered statistically significant.

Results

Patient characteristics and best overall response in patients treated with ICIs. Table I shows the characteristics of all study participants. There were 31 ESCC and 30 GEA patients whose ages ranged from 46 to 86 years (median 71), most of whom were male (80.3%) and had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or less at the administration of ICIs (80.3%). Postoperative recurrences were observed in 42 cases (68.9%). Lymph node metastasis was high in ESCC and peritoneal dissemination was high in GEA. Nivolumab was administered to all patients with GEA, and ESCC patients with CPS of 10 or higher received pembrolizumab, following its approval. Therefore, six patients received pembrolizumab, and two of six patients received pembrolizumab followed by nivolumab. Second-line treatment was predominant for ESCC and third-line treatment was predominant for GEA. Of all participants, 16 patients (26.2%) suffered from immune-related adverse events (irAE). Regarding the best overall response, CR was not observed, PR was found in two cases (3.3%), SD was found in 12 cases (19.7%), PD was found in 47 cases (77.7%), and the disease control rate (CR+SD+PR) was observed in 23.0% of cases. There was no significant difference in the efficacies between ESCC and GEA.

View this table:
Table I.

Clinicopathological characteristics.

Impact of albumin, TLC, PNI, NLR, PLR, and LMR levels on the efficacy of ICIs. Table II shows the relationships between serum albumin, TLC, PNI, NLR, PLR, and LMR levels and the efficacy of ICIs. PLR-Low was significantly correlated with a better disease control rate (36.7%) compared with PLR-High (9.7%). Moreover, PNI-High (32.3%) and NLR-Low (33.3%) tended to have better efficacy of ICIs compared with PNI-Low (13.3%) and NLR-High (12.9%) in disease control rate. However, albumin, TLC, or LMR level did not impact the efficacy of ICIs.

View this table:
Table II.

Relationships between albumin, total lymphocyte count (TLC), prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) levels and the efficacy of immune checkpoint inhibitors (ICIs).

Impact of albumin, TLC, PNI, NLR, PLR, and LMR levels on the OS and PFS. Figure 1 shows the Kaplan–Meier curves for OS according to the serum albumin, TLC, PNI, NLR, PLR, and LMR levels. The NLR-Low group had significantly better OS than the NLR-High group (p=0.014) (Figure 1D). Similarly, the PNI-High group and the PLR-Low group tended to have better OS than the PNI-Low group and the PLR-High group (p=0.111 and p=0.067, respectively) (Figure 1C and E). By contrast, albumin, TLC, PNI, and LMR levels were not found to have any significant impact on OS (Figure 1A, B, and F).

Figure 1.
Figure 1.

Kaplan–Meier overall survival curves divided by median albumin level (A), total lymphocyte count (TLC) (B), prognostic nutritional index (PNI) (C), neutrophil-to-lymphocyte ratio (NLR) (D), platelet-to-lymphocyte ratio (PLR) (E), and lymphocyte-to-monocyte ratio LMR (F) for patients with upper gastrointestinal cancer treated with immune checkpoint inhibitors (ICI).

Figure 2 shows the Kaplan–Meier curves for PFS according to the serum albumin, TLC, PNI, NLR, PLR, and LMR levels. The PLR-Low group had significantly better PFS than the PLR-High group (p=0.042) (Figure 2E). Furthermore, the PNI-High group and the NLR-Low group tended to have better PFS than the PNI-Low group and the NLR-High group (p=0.381 and p=0.286, respectively) (Figure 2C and D). However, albumin, TLC, and LMR levels did not impact PFS significantly (Figure 2A, B, and F).

Figure 2.
Figure 2.

Kaplan–Meier survival curves of progression-free survival divided by median albumin level (A), total lymphocyte count (TLC) (B), prognostic nutritional index (PNI) (C), neutrophil-to-lymphocyte ratio (NLR) (D), platelet-to-lymphocyte ratio (PLR) (E), and lymphocyte-to-monocyte ratio (LMR) (F) for patients with upper gastrointestinal cancer treated with immune checkpoint inhibitors (ICI).

Subgroup analyses for OS in ESCC are shown in Figure 3. Patients with albumin ≥3.8 g/dl, PNI≥42.8, and NLR<6.0 had significantly better OS than patients with albumin <3.8 g/dl, PNI<42.8, and NLR≥6.0 (p=0.035, 0.004, 0.019, respectively) (Figure 3A, B, and C). Subgroup analyses for OS in GEA are also shown in Figure 4. Our findings demonstrate that there were no significant differences between the higher and lower groups in GEA.

Figure 3.
Figure 3.

Kaplan–Meier overall survival curves divided by the median albumin level (A), total lymphocyte count (TLC) (B), prognostic nutritional index (PNI) (C), neutrophil-to-lymphocyte ratio (NLR) (D), platelet-to-lymphocyte ratio (PLR) (E), and lymphocyte-to-monocyte ratio (LMR) (F) for patients with esophageal squamous cell carcinoma treated with immune checkpoint inhibitors (ICIs).

Figure 4.
Figure 4.

Kaplan–Meier overall survival curves divided by the median albumin level (A), total lymphocyte count (TLC) (B), prognostic nutritional index (PNI) (C), neutrophil-to-lymphocyte ratio (NLR) (D), platelet-to-lymphocyte ratio (PLR) (E), and lymphocyte-to-monocyte ratio (LMR) (F) for patients with gastric/gastroesophageal adenocarcinoma treated with immune checkpoint inhibitors (ICIs).

Prognostic factors predicting poor survival in patients treated with ICIs. Multivariate analysis was performed using NLR and PLR, which had a significant difference in OS and PFS, respectively, and TLC. Our analysis revealed that the NLR-High group [HR=2.865; 95%CI=1.030–7.937; p=0.044] was the only independent poor prognostic factor (Table III).

View this table:
Table III.

Results of multivariate analyses showing the factors that affect overall survival.

Discussion

In this study, serum albumin and PNI were used as nutritional indicators, whereas NLR, PLR, and LMR were used as systemic inflammatory response (SIR) indicators, all of which have been reported to be associated with the prognosis of UGI cancer (9, 10, 14-18). Nevertheless, the best indicators for predicting prognosis vary depending on the report. Reportedly SIRs, such as NLR, are associated with the effects of ICI in other types of cancer such as lung cancer (19). Recently, high NLR was reported to be associated with inferior survival in advanced ESCC patients receiving ICIs (20). To the best of our knowledge, this is the first study reporting on the relationship between various indicators and ICI efficacy in UGI cancer.

At the beginning of the treatment, serum albumin tended to be associated with OS, but not with PFS and ICI efficacy. Since good nutrition improves the prognosis of UGI cancer regardless of ICI efficacy, it is important to maintain good nutrition when treating UGI cancer at all times. Lower NLR showed significantly better OS, and higher PNI and lower PLR tended to have better OS. These findings suggest that more TLC induces better OS. However, TLC alone was not associated with prognosis, suggesting that NLR and PLR are important prognostic indicators.

Circulating neutrophils contribute to tumor progression and invasiveness by secreting cytokines, vascular endothelial growth factors, and chemokines (18). Lymphocytes are components of the immune system that play a crucial role in antitumor immunity because they can inhibit the proliferation and metastasis of tumors (21). The NLR represents the balance between inflammatory and immune responses in peripheral blood. Previous studies have shown that a high pretreatment NLR is associated with a poor outcome in many solid tumors (22-24), whereas a low posttreatment NLR can indicate a favorable prognosis (25).

The reasons explaining why low lymphocyte counts are associated with poor prognosis could be described as follows. In cancer patients, low lymphocyte counts may result in an inadequate immune response to cancer cells (26). It has been reported that a decrease in the number of lymphocytes in peripheral blood also reduces the number of tumor-infiltrating lymphocytes (TIL), which are known to have an antitumor effect. Also, reportedly, an increase in TIL is associated with an improved prognosis in cancer patients (27). Monocytes in the blood enter the tissue and have the capacity to differentiate into macrophages as they mature, and macrophages that invade the stroma of the cancer tissue are called tumor-related macrophages (TAM). TAM-released chemokines are called Th2 cells that suppress tumor immunity by acting on regulatory T cells and promote cancer cell proliferation by releasing growth factors and cytokines involved in angiogenesis (28). Additionally, lymphocytes express immune responses in the tumor microenvironment, and they may be an indicator of an individual’s immunity. Thus, it is hypothesized that the efficacy of ICIs in our study might have been increased as a result of the high lymphocyte ratio.

Joseph et al. reported that lymphocytopenia was an independent poor prognostic factor in 131 patients with advanced bladder cancer who received systemic chemotherapy (29). Moreover, the absolute number of lymphocytes was significant as a continuous variable. Nonetheless, the number of neutrophils was not found to be an independent poor prognosis factor; hence, the increase or decrease in NLR could be regulated by the number of lymphocytes (29). In our study, all factors associated with a good prognosis had an increased number of lymphocytes, a finding that supports this hypothesis. Also, reportedly, higher CPS is associated with ICI efficacy (4-6). However, CPS is evaluated by a past specimen with a time difference or a biopsy sample in which intratumoral heterogeneity becomes a problem. By contrast, NLR, which is very useful as a predictor of ICI efficacy in clinical practice, can be easily measured by blood sampling in real time.

Regarding OS, NLR-Low had a significantly better prognosis compared to NLR-High (p=0.014) and PLR-Low tended to have a better prognosis compared to PLR-High (p=0.067). When it comes to PFS, PLR-Low had a significantly better prognosis compared to PLR-High (p=0.042) and NLR-Low tended to have a better prognosis compared to NLR-High (p=0.286). These seem to be the statistical limits due to the small number of cases included in this study, and it seems that both NLR-Low and PLR-Low would be significantly related to both better OS and PFS with the accumulation of more cases. Multivariate analysis showed that the NLR-High was the only independent poor prognosis factor, and NLR is considered to be a promising indicator.

In this study, ICI has been used after the second-line treatment of patients with advanced UGI cancer. Nevertheless, in recent years, the effectiveness of ICI as a first-line treatment for patients with advanced UGI cancer, and also as an adjuvant therapy after esophagectomy, has been reported and approved for insurance coverage (6, 7, 30). Subgroup analysis showed that NLR-Low was significantly correlated with better OS in ESCC but not in GEA. Since ICI is used significantly in GEA compared with ESCC, it is considered that the effect of ICI itself is attenuated and the impact of NLR is reduced. We previously reported that the development of irAEs has the potential to predict survival outcomes in patients with UGI cancer treated with nivolumab (31). In the subgroup analysis, patients with irAE had significantly better OS compared with patients without irAE in GEA but not in ESCC. We also reported that ESCC and GEA were genetically different (32), and the impact of irAE or NLR may differ between ESCC and GEA. In the future, the role of ICI in the treatment of UGI cancer is expected to increase. NLR is considered to play a key role in treatment choices in various situations. In this study, the median values of 6.0 and 2.5 were used as the NLR cutoff values in ESCC and GEA, respectively. Cutoff values vary by reports (8, 9, 14). In the future, it will be necessary to determine the optimal cutoff value from a large number of cases.

This study has several limitations. Most importantly, it was a retrospective single-center investigation with a small number of patients. Second, the follow-up time was not adequately long to allow us to fully address the long-term survival outcome. Further studies with larger cohorts will be needed to confirm the association between the NLR and the efficacy of ICIs.

To conclude, NLR-Low has the potential to predict the good efficacy of ICIs and the survival outcomes in patients with UGI cancer treated with ICIs. NLR could be useful to determine the optimal treatment strategies in patients with UGI cancer.

Acknowledgements

The Authors would like to thank all the patients and medical staff at the institutions who contributed to this study.

Footnotes

  • Authors’ Contributions

    E.B. and H.T. drafted and wrote the manuscript. E.B., H.K., and H.T. were involved in the study design and data interpretation. E.B., R.H., W.S., S.K., T.M., T.M., H.K., and Y.H. were involved in data acquisition. E.B. analyzed the data. All Authors read and approved the manuscript.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest in relation to this study.

  • Received April 6, 2022.
  • Revision received April 21, 2022.
  • Accepted April 26, 2022.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Neutrophil-to-Lymphocyte Ratio to Predict the Efficacy of Immune Checkpoint Inhibitor in Upper Gastrointestinal Cancer
EISUKE BOOKA, HIROTOSHI KIKUCHI, RYOMA HANEDA, WATARU SONEDA, SANSHIRO KAWATA, TOMOHIRO MURAKAMI, TOMOHIRO MATSUMOTO, YOSHIHIRO HIRAMATSU, HIROYA TAKEUCHI
Anticancer Research Jun 2022, 42 (6) 2977-2987; DOI: 10.21873/anticanres.15781
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