Research ArticleClinical Studies

Clinical Significance of Neutrophil-to-Lymphocyte Ratio/Serum Albumin Ratio in Patients With Metastatic Gastric or Gastroesophageal Junction Cancer Administered Trifluridine/Tipiracil

ITARU HASHIMOTO, KAZUKI KANO, SHIZUNE ONUMA, HIDEAKI SUEMATSU, SHINSUKE NAGASAWA, KYOHEI KANEMATSU, KYOKO FURUSAWA, TOMOMI HAMAGUCHI, MAMORU WATANABE, KEI HAYASHI, MITSUHIRO FURUTA, YASUHIRO INOKUCHI, NOZOMU MACHIDA, TORU AOYAMA, TAKANOBU YAMADA, YASUSHI RINO, TAKASHI OGATA and TAKASHI OSHIMA
Anticancer Research April 2023, 43 (4) 1689-1697; DOI: https://doi.org/10.21873/anticanres.16321

Abstract

Background/Aim: Trifluridine/tipiracil (FTD/TPI) is an anticancer-agent that is administered as third-line or later chemotherapy for metastatic gastric/gastroesophageal junction cancer (mGC/GEJC). Although inflammatory and nutritional statuses have attracted attention as prognostic factors for patients with mGC/GEJC in this therapy, their usefulness has not been fully clarified. Thus, this study investigated the clinical significance of prognostic nutritional index (PNI), neutrophil/lymphocyte ratio (NLR), and NLR/serum albumin (Alb) ratio in patients administered FTD/TPI. Patients and Methods: This retrospective study included 64 patients who underwent FTD/TPI treatment for mGC/GEJC at Kanagawa Cancer Center, Kanagawa, Japan, between October 2019 and June 2022. Patients were divided into high and low PNI, NLR, and NLR/Alb groups according to their pretreatment blood data. This study evaluated the associations between the inflammatory and nutritional indexes and survivals. Results: Overall survival (OS) and progression-free survival (PFS) of patients with low PNI were significantly poorer than those with high PNI. However, low PNI was not an independent prognostic factor for OS and PFS. There was no significant association between NLR and OS or PFS. In contrast, the OS of patients with high NLR/Alb was significantly poorer than those with high PNI and low NLR/Alb. Furthermore, multivariate analysis showed that high NLR/Alb was an independent prognostic factor for OS. Conclusion: The NLR/Alb may be a useful prognostic factor in patients with mGC/GEJC being administered FTD/TPI as third-line or later chemotherapy.

Key Words:

Gastric cancer (GC) is the fifth most frequent cause of new cancer cases and the fourth leading cause of cancer-related mortality (1). Even with recent advances in diagnosis, surgery, and chemotherapy, GC treatment outcomes remain insufficient and require improvement (2). Recently, novel systemic chemotherapy regimens for metastatic gastric cancer/gastroesophageal junction cancer (mGC/GEJC) have become available, especially as after third-line treatment, including nivolumab (3), trastuzumab deruxtecan (4), and trifluridine/tipiracil (FTD/TPI) (5).

FTD/TPI is a novel oral cytotoxic chemotherapy that includes the combination of a thymidine-based nucleoside analogue, FTD, and a thymidine phosphorylase inhibitor, TPI. FTD/TPI has a specific mechanism of action in which FTD is incorporated into DNA instead of thymidine, leading to DNA dysfunction (6-8); and TPI inhibits degradation of FTD, thereby improving the bioavailability of TPI (9). In 2018, the results of the TAGS study showed that FTD/TPI therapy was effective in treating patients with heavily treated mGC (5), and became a standard third-line chemotherapy (10). Recently, several subgroup analyses have reported efficacy benefits and tolerability for patients with gastrectomy (11), GEJC (12), and elderly patients (13), though prognostic factors for patients with mGC/GEJC being administered FTD/TPI have not been fully explored.

Inflammation and nutritional status are highly important to evaluate during treatment for mGC/GEJC, as they influence the oncological outcomes (14, 15). Several tools for assessing inflammation and nutrition using peripheral blood have been shown to be useful as prognostic factors in patients with GC/GEJC undergoing surgery and chemotherapy (16-18). Recently, retrospective studies have shown the usefulness of neutrophil to lymphocyte ratio (NLR) (19) and prognostic nutrition index (PNI) (20) as prognostic factors for patients with mGC/EGJC undergoing immune checkpoint inhibitor (ICI) therapy as third-line or later treatment. Moreover, NLR/serum albumin (NLR/Alb), has been reported as a novel combined inflammatory status and nutritional index in several cancers (21, 22). However, the exploration of inflammatory and nutritional prognostic markers, such as PNI, NLR, and NLR/Alb has been inadequate in patients with mGC/EGJC being administered FTD/TPI. Therefore, this study aimed to investigate the usefulness of PNI, NLR, and NLR/Alb as prognostic factors for patients with mGC/EGJC being administered FTD/TPI as third-line or later chemotherapy.

Patients and Methods

Ethical approval. All study protocols were approved by the Ethics Committee of Kanagawa Cancer Center (approval number: 2022epidemiologic study-108) and all procedures were conducted following the Declaration of Helsinki of 1996. Informed consent was obtained from all subjects involved in the study.

Patients. We retrospectively examined patients with mGC/GEJC who were administered FTD/TPI as a third-line or later chemotherapy at Kanagawa Cancer Center. Patients were selected from our clinical database between October 2019 and June 2022. All included patients had 1) histologically proven GC or GEJC (adenocarcinoma), 2) non-resectable and metastatic cancer, 3) an Eastern Cooperative Oncology Group performance status between 0 and 2, and 4) history of FTD/TPI therapy. The exclusion criterion was a history of any other cancers, which had needed to receive other aggressive treatment.

Assessment of treatment response and adverse events after FTD/TPI therapy. Patients with mGC/GEJC received an oral FTD/TPI therapy (35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days) (5) until disease progression, unacceptable adverse event, or patient’s refusal. The treatment response was evaluated by the Response Evaluation Criteria in Solid Tumors version 1.1 (23) using tomography scans. Adverse events (AEs) were evaluated by the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 5.0.

Definition of PNI, NLR, and NLR/Alb. We defined PNI, NLR, and NLR/Alb using blood test data before initiating the first FTD/TPI cycle as follows:

  • PNI=10 * Alb (g/dl) + 0.005 * Lymphocyte (/μl).

  • NLR= Neutrophil (/μl)/lymphocyte (/μl).

  • NLR/Alb=Neutrophil (/μl)/lymphocyte (/μl)/Alb (g/dl).

The patients were divided, according to medians, into high and low groups for PNI (cutoff: 35.0), NLR (cutoff: 2.85), and NLR/Alb (cutoff: 0.83).

Statistical analyses. Categorical variables were compared using the χ2 test or Fisher exact test, as appropriate. Overall survival (OS) and progression-free survival (PFS) rates after initiating FTD/TPI therapy were evaluated using Kaplan–Meier methods and the log-rank test. Variables identified as significant (p<0.05) in univariate analysis were considered candidates for multivariate COX regression analysis, and the results are given as hazard ratios (HRs) with 95% confidence interval (CI). Values of p<0.05 were considered statistically significant. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).

Results

Patients. This investigation enrolled 64 participants. By utilizing median values as the cutoff points for NLR, PNI, and NLR/Alb, the high and low groups had 32 patients, respectively.

OS and PFS rates according to PNI, NLR, and NLR/Alb in patients with mGC/GEJC who were administered FTD/TPI. Regarding PNI, OS and PFS of patients with low PNI were significantly poorer than those with high PNI (p=0.006 and p=0.03, respectively) (Figure 1A and B). As for NLR, there were no significant differences in OS and PFS between patients with high and low NLR (p=0.09 and p=0.39, respectively) (Figure 1A and B). With regard to NLR/Alb, OS of patients with high NLR/Alb was significantly poorer than those with low NLR/Alb (p=0.004) (Figure 1A). However, there was no significant difference in PFS between patients with high and low NLR/Alb (p=0.07) (Figure 1B).

Figure 1.
Figure 1.

Overall survival (OS) and progression-free survival (PFS) according to prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), and NLR/serum albumin (Alb) levels. (A) OS of patients with low PNI was significantly poorer than that of patients with high PNI (p=0.006). There was no significant difference in OS between patients with high and low NLR (p=0.09). OS of patients with high NLR/Alb was significantly poorer than that of those with low NLR/Alb (p=0.004). (B) PFS of patients with low PNI were significantly poorer than that of those with high PNI (p=0.03). There was no significant difference in PFS between patients with high and low NLR (p=0.39), or between patients with high and low NLR/Alb (p=0.07).

Univariate and multivariate analyses of OS and PFS. Univariate and multivariate analyses showed that only the OS of patients with low NLR/Alb levels was an independent predictor of poor survival. Table I shows the results of the univariate and multivariate analyses of OS among patients with mGC/GEJC who underwent FTD/TPI according to NLR/Alb. Peritoneal metastasis (HR=2.51; 95%CI=1.32-4.76; p=0.005) and high NLR/Alb (HR=2.25; 95%CI=1.18-4.29; p=0.01) were independent risk factors for poor OS. Table II and Table III show the result of the univariate and multivariate analyses of OS and PFS among patients with mGC/GEJC who underwent FTD/TPI according to PNI. In the multivariate analyses, low PNI was not an independent risk factor for poor OS or PFS.

View this table:
Table I.

Univariate and multivariate analyses of clinicopathological factors and neutrophil-to-lymphocyte ratio/serum albumin (NLR/Alb) for overall survival.

View this table:
Table II.

Univariate and multivariate analyses of clinicopathological factors and prognostic nutritional index (PNI) for overall survival.

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Table III.

Univariate and multivariate analyses of clinicopathological factors and prognostic nutritional index (PNI) for progression-free survival.

Relationship between NLR/Alb and clinicopathological factors. There were significant relationships between NLR/Alb and ECOG PS (p<0.003), and disease status (p=0.04) (Table IV). There were no significant relationships with other clinicopathological factors.

View this table:
Table IV.

Clinicopathological data comparing high versus low neutrophil-to-lymphocyte ratio/serum albumin (NLR/Alb) groups.

Relationship between NLR/Alb and treatment response to FTD/TPI therapy. The overall response rate (ORR) was 6.2% in the high NLR/Alb group and 18.8% in the low NLR/Alb group, which were superior to the high NLR/Alb group but did not reach a significant difference (Table V). The disease control rates (DCRs) were 28.1% in the high NLR/Alb group and 40.6% in the low NLR/Alb group, which was superior to the high NLR/Alb group but did not reach a significant difference (Table V).

View this table:
Table V.

Association between neutrophil-to-lymphocyte ratio/serum albumin (NLR/Alb) and treatment response.

AEs of FTD/TPI therapy in the high and low NLR/Alb groups. There was no difference in AEs between the high and low NLR/Alb groups (Table VI).

View this table:
Table VI.

Comparison of adverse events between low and high neutrophil-to-lymphocyte ratio/serum albumin (NLR/Alb) groups.

Discussion

Peri-treatment inflammatory and nutritional statuses have been attracting attention as prognostic factors for patients with cancer (24, 25). NLR as an inflammatory status index (17, 26, 27) and PNI as a nutritional status index (20, 28) have been reported to be useful prognostic factors in patients with mGC/GEJC. Additionally, NLR/Alb has been reported to be a novel inflammatory and nutritional index in several cancers (21, 22). However, the inflammatory and nutritional assessment index for patients with mGC/GEJC being administered FTD/TPI therapy as third-line or later chemotherapy has not been adequately evaluated. Hence, we focused on the NLR, PNI, and NLR/Alb, which are indicators of inflammation and nutrition, to investigate their usefulness as a novel prognostic factor for patients with mGC/GEJC being administered FTD/TPI therapy as third-line or later chemotherapy. This study showed that only NLR/Alb was an independent risk factor for poor OS in these patients. Significant differences were observed in ECOG PS and disease status between the high and low groups.

The NLR/Alb was first reported by Zhao et al. (21) to minimize the potential bias related to nutritional and immune statuses among patients with cancer. Their study showed that patients with esophageal squamous cell carcinoma and NLR/Alb >1.0 had significantly worse 5-year cancer specific survival (5Y-CSS) than patients with NLR/Alb ≤0.1 (11.0% vs. 39.1%, p<0.001). On multivariate analysis, the NLR/Alb was an independent poor 5Y-CSS factor (p=0.001). Moreover, a retrospective study in advanced renal cell carcinoma showed that high NLR/Alb had significantly worse PFS and OS than low NLR/Alb. On multivariate analysis in the study, high NLR/Alb was shown to be an independent prognostic factor for OS (p=0.03) (22). The current study showed that patients with mGC/GEJC being administered FTD/TPI had a median OS of 4.2 months, which was similar to the median OS of 4.7 months in the TAGS study (5), a phase III trial of FTD/TPI therapy; and the median OS in patients with low and high NLR/Alb was 6.9 months and 3.8 months, respectively.

The mechanism by which NLR/Alb is useful as a prognostic factor for patients with mGC/EGJC undergoing FTD/TPI therapy has not been elucidated; however, there are potential explanations related to nutrition and inflammatory statuses. Malnutrition affects a significant proportion (48% to 83%) of patients with GC (29-31), and can be caused by decreased dietary intake due to gastrointestinal obstruction, peritoneal dissemination, gastrectomy, or systemic chemotherapy (32). Additionally, it has been noted that malnutrition is closely linked to treatment efficacy and is associated with poorer prognosis, reduced treatment adherence, increased postoperative complications, and more adverse events (14, 33). Furthermore, it was previously reported that cancer-related cachexia was related to adverse events and was useful as a prognostic factor for OS in patients with unresectable GC who received chemotherapy (34, 35). The nutritional immune status of patients with mGC/GEJC is essential to assess as it is likely to deteriorate as their disease progresses. As a composite measure of nutritional immune status, NLR/Alb may be useful because it includes neutrophils (36, 37) and lymphocytes (38, 39), which reflect inflammation and anti-tumor immunity, and Alb, which reflects inflammation and nutritional status (40).

Considering the clinical application of NLR/Alb in mGC/EGJC patients undergoing FTD/TPI, using NLR/Alb as a composite measure of nutrition and inflammation and prognostic predictor for mGC/EGJC patients, more intensive nutritional intervention in patients with high NLR/Alb could improve treatment efficacy and potentially improve prognosis (32). Additionally, it may serve as a factor in the decision to transition to the next line of treatment. A retrospective study showed that high NLR was significantly associated with the deterioration of oral intake during third-line chemotherapy for patients with advanced GC (odds ratio=2.65; 95%CI=1.32-5.31; p=0.006) (41). Hence, patients with high NLR/Alb may have reduced oral intake and NLR/Alb might be useful as an early indicator for choosing an intravenous regimen as the next line of treatment.

There are several limitations to this study. First, because there are relatively few reports on NLR/Alb ratio to date, a clinically relevant cutoff for the NLR/Alb ratio may require further investigation. Second, this was a single cohort study, and the number of cases may have been too small to confirm the robustness of NLR/Alb as a useful prognostic factor. Third, this study did not compare the FTD/TPI group to a placebo group, thus further validation is needed to determine whether NLR/Alb is a true prognostic factor.

In conclusion, the NLR/Alb may be a useful prognostic factor for patients with mGC/GEJC undergoing FTD/TPI as third-line or later chemotherapy.

Acknowledgements

The Authors thank all the patients, their families, and the site staff for their participation in this study. This work was supported by JSPS KAKENHI Grant Number 22H04990.

Footnotes

  • Authors’ Contributions

    IH, KK, and TO contributed to the study concept and design. Data collection and literature search were performed by IH, KK, SO, HS, SN, K. Kanematsu, KF, TH, MW, KH, MF, YI, NM, TA, TY, YR, T. Ogata, and TO. Data analyses were performed by IH, KK, and TO. Data interpretation was performed by all the investigators. The article and figures were drafted by IH, KK, and TO. The article was revised and approved by all the investigators. All the Authors actively participated in this study.

  • Conflicts of Interest

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

  • Received January 16, 2023.
  • Revision received January 28, 2023.
  • Accepted January 30, 2023.

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Clinical Significance of Neutrophil-to-Lymphocyte Ratio/Serum Albumin Ratio in Patients With Metastatic Gastric or Gastroesophageal Junction Cancer Administered Trifluridine/Tipiracil
ITARU HASHIMOTO, KAZUKI KANO, SHIZUNE ONUMA, HIDEAKI SUEMATSU, SHINSUKE NAGASAWA, KYOHEI KANEMATSU, KYOKO FURUSAWA, TOMOMI HAMAGUCHI, MAMORU WATANABE, KEI HAYASHI, MITSUHIRO FURUTA, YASUHIRO INOKUCHI, NOZOMU MACHIDA, TORU AOYAMA, TAKANOBU YAMADA, YASUSHI RINO, TAKASHI OGATA, TAKASHI OSHIMA
Anticancer Research Apr 2023, 43 (4) 1689-1697; DOI: 10.21873/anticanres.16321
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