Neutrophil-lymphocyte Ratio at the Beginning of Third-line Chemotherapy Seems to be a Useful Predictor for Unresectable Colorectal Cancer


 Aim: This study aimed to evaluate a long-term outcome predictor after second-line chemotherapy for unresectable colorectal cancer.Methods: Between 2013 and 2018, sixteen patients (twelve males, four females) with unresectable colorectal cancer who were administered TAS-102 as third-line chemotherapy in our institution were retrospectively enrolled in this study. The mean age was 65.4 (range: 46-79) years. Patients were administered oxaliplatin with oral S-1 (tegafur, gimeracil, oteracil potassium) (SOX) as first-line chemotherapy followed by irinotecan with oral S-1 (IRIS) as second-line chemotherapy.Results: The median survival time after second-line chemotherapy was 19.2 months. Significant differences in mean age, gender, body mass index, primary site of disease, pathology of primary tumor, depth of primary tumor invasion, serum carcinoembryonic antigen (CEA) level, serum carbohydrate antigen 19-9 (CA19-9) level, and recurrence site of disease were not observed between patients with less than one year of survival versus greater than one year of survival. However, neutrophil-lymphocyte ratio (NLR) at the beginning of third-line chemotherapy was the only factor of the ten evaluated that exhibited a significant difference. Primary tumor site (p=0.015) and NLR at the beginning of third-line chemotherapy (p=0.010) were independent contributing factors to predict survival after second-line chemotherapy based on Cox proportional hazards regression.Conclusion: NLR at the beginning of third-line chemotherapy is a useful predictor for unresectable colorectal cancer after second-line chemotherapy.


Introduction
TAS-102 (Taiho Pharmaceutical Co. Ltd, Tokyo, Japan) is a novel oral antitumor agent recommended as third-or fourth-line chemotherapy for patients with unresectable colorectal cancer by the Japanese Society for Cancer of the Colon and Rectum Guidelines [1]. We have reported the usefulness of TAS-102 as third-line chemotherapy for patient with unresectable colorectal cancer [2]. However, we have noticed highly variable prognoses in patients administered TAS-102 after second-line chemotherapy. This study aimed to evaluate a long-term outcome predictor after second-line chemotherapy for unresectable colorectal cancer.

Methods
The Ethics Committee for Biomedical Research of the Jikei Institutional Review Board approved the protocol [29-041 (8657)], and all patients or their family members provided written informed consent.
Physical examinations, routine blood analyses, and CEA and CA19-9 measurements were performed every month before chemotherapy. Computed tomography (CT) was performed every two months or when a patient's serum CEA value on the treatment day was higher than it was before the initial chemotherapy. The responses of the measurable and accessible disease sites were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) [5].
SOX [6] was employed as the rst-line treatment. Oxaliplatin at 130 mg/m 2 was administered on the rst day followed by 14-day administration and 6-day withdrawal of oral S-1 (Taiho Pharmaceutical, Tokyo, Japan) at 80 mg or 100 mg per day according to the patient's body surface area (BSA). Speci cally, 80 mg/day S-1 was administered to those patients with BSA<1.5 m 2 , and 100 mg/day S-1 was administered to those patients with BSA>1.5 m 2 . S-1 was administered orally twice daily after meals.
Irinotecan with oral S-1 (IRIS) [7] was employed as the second-line treatment. Irinotecan at 120 mg/m 2 was administered on the rst day followed by 14-day administration and 6-day withdrawal of oral S-1 (Taiho Pharmaceutical, Tokyo, Japan) at 80 mg or 100 mg per day according to the patient's BSA.
Speci cally, 80 mg/day S-1 was administered to those patients with BSA<1.5 m 2 , and 100 mg/day S-1 was administered to those patients with BSA>1.5 m 2 . S-1 was administered orally twice daily after meals.
In the third-line treatment, TAS-102 at 35 mg/m 2 was administered twice daily after morning and evening meals 5 days a week for 2 weeks followed by a 14-day rest period, thus completing one treatment cycle. The regimen was repeated every 4 weeks.
Adverse events were classi ed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 [8].

Statistical analysis.
Continuous variables are expressed as the mean and range. The Wilcoxon rank-sum test was used for the comparison of continuous variables, and the chi-square test was used for the comparison of categorical data. Postoperative survival time was examined by the Kaplan-Meier method and log-rank analysis.
Variables affecting postoperative survival were analyzed using the Cox proportional hazards regression. A P-value of less than 0.05 indicated signi cance. All data were analyzed with IBM SPSS Statistics, version 24.0 (IBM Japan, Ltd, Tokyo, Japan).

Results
Comparison between groups with less than versus greater than one year survival after second-line chemotherapy The median survival time after second-line chemotherapy was 19.2 months (Figure 1). In comparison no signi cant differences in mean age, gender, body mass index, primary site of disease, pathology of primary tumor, depth of primary tumor invasion, serum CEA level, CA19-9 level, and recurrence site of disease were not observed between patients with less than one year of survival compared with those with greater than one year survival. However, NLR at the beginning of third-line chemotherapy was the only factor of the ten evaluated factors that exhibited a signi cant difference ( Table 2).

Multivariate analyses for postoperative recurrence
To determine variables affecting survival after second-line chemotherapy, seven variables (age, gender, serum CEA and CA19-9 levels at the beginning of third-line chemotherapy, primary site of disease, depth of primary tumor invasion, and NLR at the beginning of third-line chemotherapy) were analyzed using Cox proportional hazard regression. Only two factors, primary tumor location (p=0.015) and NLR at the beginning of third-line chemotherapy (p=0.010), were identi ed as independent contributing factors to predict survival after second-line chemotherapy. (Table 3).

Adverse effects after second-line chemotherapy using TAS-102
No serious adverse effects greater than grade 2 were noted for chemotherapy regimens using TAS-102. When white blood cell counts were less than 3,000, a 14-day rest period was added to the regular rest period.

Discussion
The infusion of uorouracil and leucovorin combined with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) as well as oral drugs combined with either oxaliplatin (SOX [6], CapeOX [9]) or irinotecan (IRIS [7], XELIRI [10]) have been widely used as rst-line or second-line chemotherapy for unresectable colorectal cancer. However, there are no effective regimens for third-line chemotherapy compared with rst-or second-line chemotherapy. We have reported that the usefulness of TAS-102 as third-line chemotherapy for patient with unresectable colorectal cancer [2]. However, we have noticed highly variable prognoses in patients administered TAS-102 after second-line chemotherapy.
In this study, NLR at the beginning of third-line chemotherapy was identi ed as an independent contributing factor to predict survival after second-line chemotherapy. The NLR, which is de ned by the absolute number of neutrophils divided by the absolute number of lymphocytes, is considered an in ammatory biomarker. Several studies have reported that an elevated NLR is associated with a poor prognosis in patients with various malignant diseases [11][12][13][14][15]. The effectiveness of chemotherapy seems greatly involved in not only chemosensitivity of anticancer drugs but also immunosuppression. The optimal cutoff value was 3.0 based on receiver operating characteristic (ROC) curve analysis [4]. When patients exhibit an NLR greater than 3.0 at the beginning of third-line chemotherapy, we should carefully select an optimal regimen as third-and/or fourth-line chemotherapy.
In conclusion, NLR at the beginning of third-line chemotherapy seems to be a useful predictor for unresectable colorectal cancer after second-line chemotherapy; however, a large-scale prospective study is needed.

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Availability of data and materials
All data generated or analysed during this study are included in this published article.