Research ArticleClinical Studies

The Pre-treatment Lymphocyte-to-Monocyte Ratio Predicts Efficacy in Metastatic Colorectal Cancer Treated With TAS-102 and Bevacizumab

HIDEKAZU KURAMOCHI, TAKESHI YAMADA, YOICHIRO YOSHIDA, AKIHISA MATSUDA, HIROHIKO KAMIYAMA, CHIHIRO KOSUGI, KEIICHIRO ISHIBASHI, ATSUKO FUKAZAWA, KEISUKE IHARA, HIROMICHI SONODA, KAZUHIKO YOSHIMATSU, HIROSHI YOSHIDA, SUGURU HASEGAWA, KAZUHIRO SAKAMOTO, HIDEYUKI ISHIDA, KEIJI KODA and On behalf of the TAS CC3 Study Group
Anticancer Research June 2021, 41 (6) 3131-3137; DOI: https://doi.org/10.21873/anticanres.15098

Abstract

Background/Aim: Our multicenter phase II TAS-CC3 study demonstrated favorable median progression-free survival (PFS) and overall survival (OS) of 32 metastatic colorectal cancer (mCRC) patients treated with TAS-102 + bevacizumab as 3rd-line treatment. Patients and Methods: We investigated the predictive and prognostic values of pre-treatment blood inflammation-based scores, including the neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR) and lymphocyte-to-monocyte ratio (LMR) on disease-control (DC), PFS and OS by a post-hoc analysis. Results: Receiver operating characteristic curve analyses of the 3 inflammation-based scores versus DC showed the best predictive performance for LMR, followed by NLR and PLR. The high-LMR group had a significantly higher DC rate than the low group (87.5 vs. 43.8%). The high-LMR group showed significantly longer survival than the low group (4.9 vs. 2.3 m for median PFS) (21.0 vs. 6.1 m for median OS). Conclusion: The pre-treatment LMR is a valid predictive and prognostic biomarker for mCRC patients undergoing TAS-102 and bevacizumab treatment.

Key Words:

TAS-102 is an oral anticancer agent comprising trifluridine (FTD) and tipiracil hydrochloride (1). For patients with metastatic colorectal cancer (mCRC), significantly better progression-free survival (PFS) and overall survival (OS) were shown in those treated with TAS-102 than in those treated with placebo in the global phase III RECOURSE trial (2). Additionally, the combination therapy of TAS-102 and bevacizumab was reported to show favorable PFS in the phase II C-TASK FORCE trial (3). We also previously reported that our single-arm multicenter phase II trial (TAS-CC03 study) using the combination of TAS-102 and bevacizumab showed comparable favorable PFS (4.5 months) and OS (9.3 months) as 3rd-line treatment for patients with mCRC (4). Several previous single-arm phase II studies, including our study, supported the benefit of adding bevacizumab to TAS-102 (3-6). Additionally, a recent randomized phase II trial demonstrated that the combination of TAS-102 and bevacizumab significantly improved PFS compared with TAS-102 alone in mCRC patients (7). Although a large phase III study has not been performed yet, the combination therapy of TAS102 and bevacizumab is a new salvage chemotherapy option for mCRC. Thus, practical predictors for the efficacy and prognostic markers are warranted.

Inflammation-based indicators, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), C-reactive protein (CRP), and modified Glasgow prognostic score (mGPS), have been widely used as prognostic factors for the oncologic outcomes of cancer treatment. We previously reported the relationship between NLR and survival after TAS-102 treatment (8). In this study, we investigated the association of these inflammation-based indicators with the efficacy of TAS-102 and bevacizumab treatment using the data of patients registered in the TAS-CC3 study to determine whether these indicators predicted the treatment efficacy and prognosis of the patients.

Patients and Methods

Study design and patient population. We performed a post hoc analysis of a prospective investigator-initiated, open-label, single-arm, multicentered phase II study (TAS-CC3) in Japan comprising 32 mCRC patients treated with the combination of TAS102 and bevacizumab as 3rd-line therapy. Patients who were administered first- and second-line chemotherapy and whose tumors were diagnosed as progressive disease were treated with TAS-102 (orally administered at a dose of 35 mg/m2 twice daily on days 1-5 and 8-12 of every 28-day cycle) plus bevacizumab (5.0 mg/kg by intravenous infusion on days 1 and 15). Tumor response was evaluated by one investigator using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in patients with measurable disease at baseline. Adverse events were assessed using the Common Terminology Criteria for Adverse Events ver. 4.0 (CTCAE ver. 4.0). Clinical evaluations and computed tomography (CT) scans were performed 8 (±2) weeks after starting chemotherapy and then every 8 (±2) weeks until progression. This study was conducted in accordance with the Declaration of Helsinki and was registered at the University Hospital Medical Information Network as UMIN#000022438.

The white blood cell, neutrophil, lymphocyte, monocyte, and platelet counts were routinely measured at a central laboratory, and the pre-treatment NLR, PLR, and LMR were calculated for each patient. These parameters were divided into two groups (high and low) using as cut-offs the median values.

Statistical analysis. The primary endpoint of TAS-CC3 study was PFS. Secondary endpoints were the time to treatment failure (TTF), response rate, and OS. The median PFS and OS were calculated using the Kaplan–Meier method. Differences in survival between the two patient groups were evaluated using the log-rank test. Spearman’s correlation analysis was conducted to examine the correlation between LMR and PFS, OS. Receiver operating characteristic (ROC) curve analysis was conducted to determine the predictive performance of the three inflammation-based scores in tumor response. Continuous variables were expressed as medians and ranges. Variables in univariate analysis for which p<0.1 were entered into multivariate Cox proportional hazard models. p-Values less than 0.05 were considered significant. All the statistical analyses were performed using R, version 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Summary of the TAS CC03 study. Thirty-two patients (median age: 67 years, range=45-78 years) were enrolled in the TAS-CC03 study from June 2016 to August 2017. All the patients were treated with 3rd-line chemotherapy and had a history of receiving bevacizumab in previous lines. The characteristics of patients are shown in Table I. The median number of treatment cycles was four. A partial response was observed in 2 patients, and the disease control (DC) rate was 65.6%. The median PFS was 4.5 months [95% confidence interval (CI)=1.8-7.1], and the median OS was 9.2 months (95%CI=5.5-12.8) as previously reported (4). The pre-treatment median values of NLR, LMR, and PLR were 2.67, 3.18, and 135.2, respectively.

View this table:
Table I.

Characteristics of the included patients.

ROC curve analysis. In this post hoc analysis, ROC curve analyses of the three pre-treatment inflammation-based scores, NLR, PLR, and LMR, versus DC according to the RECIST criteria showed a best predictive performance in LMR, followed by NLR and PLR (AUC: 0.88, 0.85, and 0.68, respectively) (Figure 1).

Figure 1.
Figure 1.

Receiver operating characteristic curve analysis of inflammation-based indicators in disease control. Lymphocyte-to-monocyte ratio (LMR) showed the best predictive performance, followed by neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) [Area under the curve (AUC): 0.88, 0.85, and 0.68, respectively].

LMR, tumor response and adverse events. Table II shows the efficacy and safety profiles according to LMR. The high-LMR group had a significantly higher DC rate than the low group (87.5 vs. 43.8%). Two patients with partial responses were in the high-LMR group. No significant association was observed between LMR and adverse events (≥grade 3).

View this table:
Table II.

Efficacy and safety according to LMR.

LMR and survival. The LMR values were significantly correlated with PFS and OS (PFS: r=0.56, p<0.001, OS: r=0.62, p<0.001; Figure 2A and B). The high-LMR group showed significantly longer survival than the low group in both PFS (median: 4.9 vs. 2.3 m; Figure 3A) and OS (median: 21.0 vs. 6.1 m; Figure 3B).

Figure 2.
Figure 2.

Correlation between lymphocyte-to-monocyte ratio (LMR) and survival. LMR was significantly correlated with progression-free survival (PFS) (p<0.001) (A) and overall survival (OS) (p<0.001) (B).

Figure 3.
Figure 3.

Kaplan–Meier curves of progression-free survival (PFS) and overall survival (OS) according to lymphocyte-to-monocyte ratio (LMR). The high-LMR group showed significantly longer survival than the low group in both PFS (median: 4.9 vs. 2.3 m) (Figure 3A) and OS (median: 21.0 vs. 6.1 m) (Figure 3B).

Cox proportional hazards model. Exploratory analyses were performed to identify potential predictive factors for PFS and OS (Table III). In this univariate analysis, both LMR and NLR were significantly associated with PFS (LMR: p=0.011; NLR: p<0.001) and OS (LMR: p<0.001; NLR: p<0.001). PLR was significantly associated with PFS (p<0.011) but not with OS (p=0.097). In multivariate analysis (Table IV), LMR remained significantly correlated with OS (95%CI=0.26-0.79; p=0.005).

View this table:
Table III.

PFS and OS according to prognostic factors.

View this table:
Table IV.

Multivariate analysis.

Discussion

In this study, LMR was the most informative marker for predicting treatment efficacy and prognosis in patients treated with TAS-102 + bevacizumab. NLR also showed a relatively good association with the tumor response, while PLR did not show a good association with OS. In multivariate analysis, only LMR, but not NLR, remained significantly correlated with OS.

NLR, LMR, and PLR are inflammatory-based markers that have been reported to be associated with patients’ prognosis in various cancers. Neutrophils are the predominant leukocyte subset in human peripheral blood, with a well-established role in the first line of defense against microbial pathogens (9). Neutrophils produce serum vascular endothelial growth factor (VEGF) and various matrix proteases. This tumor-promoting microenvironment facilitates tumor invasion and metastasis (10). Thus, neutrophils are associated with cancer-related inflammation and a worse prognosis. Lymphocytes play a primary role in antitumor immunology, prohibiting tumor progression and metastasis (11). The infiltration of CD4+ T cells activates CD8+ T cells, which induce cancer cell apoptosis and exhibit cytotoxic activity toward cancer cells (12, 13). Lymphocyte depletion attenuates tumor-specific immunity, including reducing the number of tumor-infiltrating lymphocytes (14, 15). Lower pre-treatment peripheral lymphocyte counts are associated with a poor prognosis in CRC (16). Monocytes, particularly those differentiated into tumor-associated macrophages (TAMs), are involved in tumorigenesis (17). TAMs sustain tumor growth by producing growth factors (e.g., EGF, VEGF, and bFGF), promote the remodeling of the extracellular matrix by releasing proteases (e.g., cathepsins, MMP-2, and MMP-9) and soluble mediators (e.g., TGF-beta and LL37), favorable angiogenesis and lymphangiogenesis by releasing MMP-9 or other soluble factors (e.g., VEGFs, PDGF, thymidine phosphorylase, and CXCL8) and suppress the anti-tumoral immune response by releasing soluble mediators, such as IL-10, IDO and TGF-beta, as well as through a cell–cell contact mechanism (9). In CRC patients, the peripheral monocyte count was associated with a poor outcome (18, 19).

Although NLR is a well-reported index for predicting the prognosis of cancer patients, many previous studies reported the usefulness of LMR as a prognostic marker in several cancer types, such as gastric cancer (20), esophageal squamous cell cancer (21), Hodgkin’s lymphoma (22), pancreatic cancer (17), and gastrointestinal stromal tumors (23). Regarding CRC, the usefulness of LMR was also reported in both curatively resected CRC patients (24-26) and mCRC patients (27, 28). Stotz et al. reported that the elevated preoperative LMR was significantly associated with increased time to recurrence and overall survival in stage III CRC patients (25). Chan et al. reported that elevated LMR was associated with better OS in retrospectively collected data from 1,623 CRC patients with curative resection (26). Shibutani et al. demonstrated that low pre-treatment LMR was associated with a significantly worse overall survival in mCRC patients receiving palliative chemotherapy (27). Several CRC-related meta-analyses also showed consistent results (29-32).

Although the association of NLR and efficacy of chemotherapy was also demonstrated in this study, the association of NLR with OS was weaker than that of LMR. Only 3rd-line mCRC patients were included in this study, therefore, the pre-treatment blood data were affected by previous chemotherapy. Shibutani et al. determined the pre-treatment and post-treatment absolute neutrophil/lymphocyte/monocyte counts in 104 patients with unresectable mCRC who had undergone palliative chemotherapy (27). According to these data, the neutrophil counts were highly decreased and the monocyte counts were slightly elevated, however, the lymphocyte counts were not strongly affected after chemotherapy. Thus, in this late-line setting, NLR was affected by previous chemotherapy and was decreased, inaccurately indicating a better prognosis. Although LMR was elevated, the difference in the monocyte counts pre- and post-chemotherapy was smaller than the change in the neutrophil count. Therefore, NLR in this late-line setting cannot predict a precise prognosis, likely because of the influence of previous chemotherapy.

There are some limitations in this study. First, the number of included patients was relatively small. Second, the median values of each marker were used as cut-off values to divide the high and low groups, while the appropriate cut-off value to show the best segregation was not determined. Third, we did not specify 4th-line chemotherapy; thus, we cannot discount the possibility that OS was influenced by the type of 4th-line chemotherapy.

In conclusion, our study indicated that pre-treatment LMR is a valid predictive and prognostic biomarker for mCRC patients treated with TAS-102 and bevacizumab and may be clinically useful for selecting responder patients.

Acknowledgements

The Authors thank all the patients and co-workers for their participation and cooperation in the TAS-CC3 study. The Authors also thank Nicole Okoh, PhD, from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.

Footnotes

  • Authors’ Contributions

    HK participated in the clinical trial and drafted the manuscript. TY designed this clinical trial and helped editing the manuscript. AM performed the statistical analysis. YY, HiK, CK, KI, AF, KI, HS, KY, HY, SH, KS, HI, and KK participated in this clinical trial. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    H.Kuramochi received scholarship donation from Chugai pharmaceuticals, Ltd. and Taiho Pharmaceutical Co, Ltd. H.Ishida received research funding from Chugai pharmaceuticals, Ltd. and Taiho Pharmaceutical Co, Ltd.

  • Funding

    All the treatments in this study were covered by national health insurance. There are no competing interests between pharmaceutical companies and the investigators regarding this study that require disclosure.

  • Trial Registration Information

    Registry name: TAS-102 and Bevacizumab as third-line chemotherapy for colorectal cancer. Phase 2 trial (TAS-CC3 study). Trial ID: UMIN000022438. URL: https://upload.umin.ac.jp/cgi-open-in/ctr/ctr_view.cgi?recptno=R000025861

  • Received April 8, 2021.
  • Revision received April 20, 2021.
  • Accepted April 21, 2021.

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The Pre-treatment Lymphocyte-to-Monocyte Ratio Predicts Efficacy in Metastatic Colorectal Cancer Treated With TAS-102 and Bevacizumab
HIDEKAZU KURAMOCHI, TAKESHI YAMADA, YOICHIRO YOSHIDA, AKIHISA MATSUDA, HIROHIKO KAMIYAMA, CHIHIRO KOSUGI, KEIICHIRO ISHIBASHI, ATSUKO FUKAZAWA, KEISUKE IHARA, HIROMICHI SONODA, KAZUHIKO YOSHIMATSU, HIROSHI YOSHIDA, SUGURU HASEGAWA, KAZUHIRO SAKAMOTO, HIDEYUKI ISHIDA, KEIJI KODA, On behalf of the TAS CC3 Study Group
Anticancer Research Jun 2021, 41 (6) 3131-3137; DOI: 10.21873/anticanres.15098
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