Abstract
Purpose
The neutrophil/lymphocyte ratio (NLR) is a novel prognostic marker in several malignancies, whereas its function in patients with early-stage extranodal NK-T-cell lymphoma (ENKTL) hasn’t been explored. Therefore, we expolored the predictive value of NLR for early-stage ENKTL in this study.
Methods
We evaluated the prognostic value of NLR in 132 patients with early-stage ENKTL based on L-asparaginase-containing regimens. Their characteristics, treatment responses, survival outcomes, prognostic factors, and the prognostic value of NLR were analyzed.
Results
All patients were followed up for median 54 months. The optimal NLR cutoff value was 3.77 by receiver operating curve(ROC). For all patients, the complete response (CR) and the overall response rate (ORR) were 74.2% and 85.6%. Patients with NLR < 3.77 had higher CR and ORR than patients with NLR ≥ 3.77(CR, 81% vs. 53.1%; ORR, 90% vs. 71.9%). For all patients, the 3-year overall survival (OS) and progression-free survival (PFS) based on L-asparaginase-containing chemotherapy were 80.4% and 76%. Patients with NLR < 3.77 had better survival outcomes than patients with NLR ≥ 3.77(3-year OS, 86.9% vs. 60.3%, p = 0.002; 3-year PFS, 81.8% vs. 54.5%, p = 0.001). By univariate and multivariate analyses, NLR ≥ 3.77 was an independent poor prognostic factor for both OS and PFS. Additionally, NLR ≥ 3.77 was associated with poor survival outcomes in patients with low-risk International Prognostic Index (IPI) and Prognostic Index of Natural Killer lymphoma with Epstein-Barr virus (PINK-E).
Conclusion
A high NLR is a poor prognostic marker of survival in patients with early-stage ENKTL, and could be applied to risk-stratify for low-risk patients.
Keywords: extranodal NK-T-cell lymphoma, neutrophil-to-lymphocyte ratio, prognoses, survival
Introduction
Extranodal NK-T-cell lymphoma (ENKTL) is uncommon and highly aggressive non-Hodgkin lymphoma[1]. It is associated with Epstein-Barr virus infection (EBV) and has a higher rate of incidence in East Asia and Latin America[2–4]. Up to 80% of ENKTL patients are early-stage (I/II) based on the Ann Arbor staging system[3, 5]. Survival outcomes of ENKTL patients have been markedly improved by using L-asparaginase-based regimens and the development of radiotherapy technology; indeed, early-stage patients exhibit promising 5 years progression-free survival (PFS) rate of 55.9–85.7% and 5 years overall survival (OS) rate of 78.6–89.0%[5]. Nevertheless, a large proportion of patients inevitably relapse and become refractory, and prognosis is deemed unsatisfactory[6–8].
Previous prognostic models for ENKTL, such as the Korean Prognostic Index (KPI) and the International Prognostic Index (IPI), were developed on the basis of patients who were anthracycline-based chemotherapy regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens. However, these models couldn’t accurately stratify the survival of patients with ENKTL in the non-anthracycline chemotherapy era[9, 10]. Therefore, a new prognostic model has been proposed: the Prognostic Index for Natural Killer lymphoma with Epstein-Barr virus (PINK-E), which uses five clinical risk parameters (age older than 60 years, advanced disease, distant lymph node involvement, non-nasal type, and EBV data) for risk stratification[11]. Based on the PINK-E model, most early-stage patients are low-risk, but a significant difference is not found in OS and PFS among the low-risk and the intermediate-risk group (p = 0.068 and p = 0.079, respectively)[11]. In addition, considering that the establishment of these prognostic models was according to patients with all stages of ENKTL, the real prognostic value for patients with early-stage ENKTL needs to be further validated. Therefore, a new prognostic index based on non-anthracycline chemotherapy is necessary to early-stage ENKTL.
Most recently, it has been suggested that the efficacy of anticancer therapies and corresponding prognoses is strongly related to the host’s systemic inflammatory response, which is reflected by the ratio of neutrophil-to-lymphocyte (NLR)[12–15]. A body of evidence has shown that the pre-treatment NLR has an important prognostic value in different types of solid malignancies and lymphomas, such as lung cancer, gastrointestinal cancer, breast cancer and diffuse large B-cell lymphoma[15–20]. Previous studies have uniformly found that a high NLR of pre-treatment is related to poor survival outcomes[14]. Therefore, in this study, we conducted a retrospective study to assess the prognostic value of the NLR in patients with early-stage ENKTL based on L-asparaginase-containing chemotherapy.
Patients and Methods
Patients
Patients with newly diagnosed early-stage ENKTL from September 2010 to September 2019 were registered. The inclusion criteria were: (a) diagnosed ENKTL by the immunohistochemistry that included CD20, CD3, CD5, CD56, cytotoxic granules(TIA-1/GrB), and EBV-encoded small RNAs(EBER) in situ hybridization, based on the 2008 World Health Organization (WHO) classification of lymphomas[21]; (b) disease staged IE or IIE by Ann Arbor staging system[22]; (c) chemotherapy regimens including L-asparaginase or pegaspargase; (d) absence of infection or other malignancies; and (e) availability of complete clinical data.
Clinical and laboratory data before treatment were collected for analysis and included the following: age, sex, Eastern Cooperative Oncology Group performance status (ECOG) score, presence of B symptoms, complete blood cell count (CBC), lactate dehydrogenase (LDH), peripheral plasma EBV-DNA, and bone marrow examination including biopsies. Computed tomography (CT) of head, neck, the chest, abdomen, and pelvis; and positron emission tomography/computed tomography (PET/CT) scans were used for staging. PET/CT was also applied for efficacy assessment. IPI and PINK-E score were calculated in this study.
Treatment
Due to a lack of consensus, treatment methods varied and depended largely on physician choice. Excluding 11 patients who received only radiotherapy, all patients received combined chemoradiotherapy, and of this group, 83.5% (n = 101/121) received the applied ‘sandwich’ protocol (inductive chemotherapy-radiotherapy-consolidation chemotherapy). Chemotherapy treatments were based on L-asparaginase or pegaspargase and were mainly comprised of the following regimens: L-asparaginase, cisplatin, etoposide, and dexamethasone (LVDP); L-asparaginase, vincristine, and prednisone (LVP); dexamethasone, cisplatin, gemcitabline, and pegaspargase (DDGP); or pegaspargase, gemcitabine, and oxaliplatin (P-GEMOX). The aforementioned chemotherapy regimens were administrated based on prevous studies[23–26]. Patients’ median chemotherapy cycle was 4 (range, 2 to 8 cycles), and all patients were treated with a median radiotherapy dose of 50 Gy at the involved field with each fraction of 1.8 to 2.0 Gy, totaling 5 fractions per week.
Efficacy Evaluation
All patients underwent interim and post-therapy efficacy evaluation. The treatment effect was assessed based on the response criteria of malignant lymphoma and included complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD)[27]. The overall response rate (ORR) had the proportion of patients having CR or PR. OS was calculated from the date of diagnosis to any-cause death. PFS referred to as the time from the date of diagnosis to the date of disease recurrence, progression, or any-cause death.
Statistical Analysis
Statistical analyses were done by SPSS version 22.0 (SPSS Inc, Chicago, IL). The Shapiro-Wilk test was used to classify continuous variables into normal and non-normal distribution. Variables with normal distribution were shown with mean ± SD. Variables with non-normal distribution were presented with median (interquartile range), and the nonparametric test was used for comparisons between the two groups. All categorical variables were presented through frequency with percentage, and the Pearson’s chi-squared test or Fisher’s exact test was used for comparisons between the two groups. NLR was described as the absolute neutrophil count (ANC) divided by the absolute lymphocyte count (ALC). Receiver operating curve (ROC) analysis via the method of DeLong et al.was used to calculate optimal cutoff value for NLR as a variable of OS[28]. The correlations between NLR and the treatment response were examined via Chi-square test or Fisher’s exact test. Survival results were performed via the Kaplan-Meier method and the log-rank test was used to compare the survival curves. The Cox proportional hazards regression model was used for univariate and multivariate analyses. If the two-sided p-value was lower than 0.05, it was considered as statistically significant.
Results
Patient Characteristics
In total, this study included 132 patients, and EBER was positive for all patients. The baseline characteristics were listed in Table 1. The median age was 47 years (range, 16–78 years), and 22 (16.7%) patients were older than 60. Male patients accounted for 77 (58.3%), and the male-to-female ratio was 1.4:1. About 69 (52.3%) patients had B symptoms. Patients with stage IE and IIE disease numbered 92 (69.7%) and 40 (30.3%), respectively. One-hundred and twenty five (94.7%) patients had ECOG scores of 0 or 1 and 45 (34.1%) patients with elevated LDH levels. One-hundred and seventeen patients had plasma EBV-DNA tests and 84 (71.7%) patients had positive results, which was defined as any detectable EBV-DNA. Based on IPI scoring, most patients (90.9%) were low-risk. Based on PINK-E scoring, 118 (89.4%) patients were low-risk (0 or 1), and only 14 (10.6%) patients were high-intermediate risk (≥ 2). The median ANC was 3.5 × 109 L−1, the median ALC was 1.4 × 109 L−1, and the median NLR was 2.49.
Table 1.
The correlation between NLR and pre-treatment characteristics in patients with early-stage ENKTL
| All patients (n = 132) |
low-NLR (< 3.77) group (n = 100) | high-NLR (≥ 3.77) group (n = 32) | p-value | |
|---|---|---|---|---|
| Age (year) | ||||
| Mean ± SD | 45.6 ± 13.6 | 45.4 ± 14 | 46.3 ± 12.5 | 0.907 |
| < 60 | 110 (83.3) | 84 (84) | 26 (81.3) | 0.716 |
| ≥ 60 | 22 (16.7) | 16 (16) | 6 (18.8) | |
| Sex | ||||
| Female | 55 (41.7) | 44 (44) | 11 (34.4) | 0.336 |
| Male | 77 (58.3) | 56 (56) | 21 (65.6) | |
| ECOG score | ||||
| 0 or 1 | 125 (94.7) | 94 (94) | 31 (96.9) | 0.858 |
| ≥ 2 | 7 (5.3) | 6 (6) | 1 (3.1) | |
| B symptoms | ||||
| Absence | 63 (47.7) | 47 (47) | 22 (68.8) | 0.032 |
| Presence | 69 (52.3) | 53 (53) | 10 (31.3) | |
| Stage | ||||
| IE | 92 (69.7) | 70 (70) | 22 (68.8) | 0.893 |
| IIE | 40 (30.3) | 30 (30) | 10 (31.3) | |
| IPI score | ||||
| 0 or 1 | 120 (90.9) | 91 (91) | 29 (90.6) | 1 |
| ≥ 2 | 12 (9.1) | 9 (9) | 3 (9.4) | |
| PINK-E score | ||||
| 0 or 1 | 118 (89.4) | 90 (90) | 28 (87.5) | 0.689 |
| ≥ 2 | 14 (10.6) | 10 (10) | 4 (12.5) | |
| Serum LDH | ||||
| <ULN | 87 (65.9) | 71 (71) | 16 (50) | 0.029 |
| ≥ULN | 45 (34.1) | 29 (29) | 16 (50) | |
| Plasma EBV DNA | ||||
| Positive | 84 (71.8) | 59 (67.8) | 25 (83.3) | 0.103 |
| Negative | 33 (28.2) | 28 (32.2) | 5 (16.7) | |
| ANC(×109 L−1), median(IQR) | 3.5(2.7–4.5) | 3.27(2.56–4.03) | 5.08(3.86–7.08) | < 0.01 |
| ALC(×109 L−1), median(IQR) | 1.4(1.1–1.77) | 1.55(1.24–1.83) | 0.95(0.56–1.3) | < 0.01 |
| NLR, median(IQR) | 2.49(1.75–3.76) | 2.09(1.62–2.83) | 5.39(4.6–6.71) | < 0.01 |
Abbreviations: ALC, absolute lymphocyte count; ANC, absolute neutrophil count ;EBV, Epstein–Barr virus; ECOG score, Eastern Cooperative Oncology Group performance status; IPI, international prognostic index; LDH, lactate dehydrogenase; NLR, neutrophil-to-lymphocyte ratio; PINK-E, prognostic index of natural killer lymphoma with Epstein-Barr virus
Relationships between NLR and clinical variables
The absolute neutrophil and lymphocyte counts were derived from the pre-treatment CBC. The specificity and sensitivity of the NLR were calculated by ROC analysis, and 3.77 was the most optimal cutoff value of a NLR (AUC = 0.637, 95% confidence interval [CI], 0.516–0.757, p = 0.029, sensitivity = 0.812, specificity = 0.444) (Fig. 1). From our cohort, 100 (75.8%) patients had an NLR<3.77, while 32 (24.2%) patients had an NLR ≥ 3.77. Relationships between NLR and clinical variables were listed in Table 1. There were important associations between LDH levels (p = 0.029), B symptom (p = 0.032) and NLR. However, NLR wasn’t associated with age, sex, ECOG, EBV-DNA, the Ann Arbor stage, the IPI, or the PINK-E.
Fig. 1.
The ROC curve for NLR before treatment
Short-term efficacy
The short-term efficacy of 132 patients were assessed. L-asparaginase-based chemotherapy regimens achieved promising treatment responses, including 98 (74.2%) CRs, 15 (11.4%) PRs, 3 (2.3%) SDs, and 16 (12.1%) PDs, with an ORR of 85.6%. Among the low NLR group, there were 81 (81%) CRs, 9 (9%) PRs, one case (1%) SD, and 9 (9%) PDs. There were 17 (53.1%) CRs, 6 (18.8%) PRs, 2 cases (6.3%) SD, and 7 (21.9%) PDs in the high NLR group. The CR and ORR of the low NLR group were clearly higher than the high NLR group (CR, 81% vs. 53.1%, p = 0.002; ORR, 90% vs. 71.9%, p = 0.024)(Table 2).
Table 2.
Treatment outcomes among the low-NLR group and the high-NLR group
| Treatment outcomes | N (%) | Low-NLR (< 3.77) group n (%) | High-NLR (≥ 3.77) group n (%) | χ2 | P-value |
|---|---|---|---|---|---|
| CR | 98 (74.2) | 81 (81) | 17 (53.1) | 9.85 | 0.002 |
| PR | 15 (11.4) | 9 (9) | 6 (18.8) | 1.422 | 0.233 |
| SD | 3 (2.3) | 1 (1) | 2 (6.3) | 3.008 | 0.083 |
| PD | 16 (12.1) | 9 (9) | 7 (21.9) | 3.773 | 0.065 |
| ORR | 113 (85.6) | 90 (90) | 23 (71.9) | 5.076 | 0.024 |
Abbreviations: CR, complete remission; ORR, overall response rate; PD, progressive disease; PR, partial remission; SD, stable disease
Long-term efficacy
The median follow-up time for patients was 54 months (range, 2 to 117). Among the 132 patients, 27 died. Of these, 25 patients died of PD, and the other two patients died of myocardial infarction and unknown causes. For all patients, the 3- and 5- year OS was 80.4% and 75.4% (Fig. 2a). Patients with low NLR had a better 3-year OS (86.9% vs. 60.3%) and 5-year OS (81.4% vs. 56.1%) than those with high NLR. The difference of OS between the two groups was remarkably significant (χ2 = 9.337, p = 0.002)(Fig. 2b). For all patients, the 3- and 5-year PFS were 76% and 72.9%, respectively (Fig. 3a). Patients with low NLR had better 3-year PFS (81.8% vs. 54.5%) and 5-year PFS (79.4% vs. 52.7%) than those with high NLR. There was a statistical difference of PFS between the two groups (χ2 = 10.61, p = 0.001) (Fig. 3b).
Fig. 2.
OS in patients with early-stage ENKTL estimated using the NLR before treatment a: OS in all patients; b: OS in the low-NLR and the high-NLR groups
Fig. 3.
PFS in patients with early-stage ENKTL a: PFS of all patients; b: PFS in the low-NLR and the high-NLR groups
Prognostic factor
To explore the correlations between clinical variables and survival outcomes of early-stage ENKTL patients, we applied univariate and multivariate Cox regression analyses for all patients. In univariate Cox regression analyses, we found that the PFS was significantly associated with stage IIE (HR, 2.507; 95% CI, 1.252–5.02; p = 0.009), and the NLR ≥ 3.77 (HR, 3.073; 95% CI, 1.436–6.574; p = 0.002). Similarly, the OS was significantly associated with stage IIE (HR, 2.747; 95% CI, 1.288–5.858; p = 0.009), the NLR ≥ 3.77 (HR, 3.073; 95% CI, 1.436–6.574; p = 0.004), and ECOG score ≥ 2 (HR, 3.719; 95% CI, 1.28-10.803; p = 0.016)(Table 3). These three clinical variables were included in multivariate Cox regression analyses(Table 4). We found that the NLR ≥ 3.77 (HR, 2.875; 95% CI, 1.426–5.794; p = 0.003) and stage IIE (HR, 2.389; 95% CI, 1.192–4.789; p = 0.014) were independent prognostic factors for PFS, and the NLR ≥ 3.77 (HR, 3.073; 95% CI, 1.439–6.678; p = 0.004) was an independent prognostic factor for OS.
Table 3.
Univariate analysis of progression-free survival and overall survival in early-stage ENKTL
| Progression-free survival | Overall survival | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | ||||
| Age ≥ 60 | 1.541 | (0.540–4.395) | 0.419 | 1.624 | (0.487–5.415) | 0.43 | |||
| Sex male | 1.472 | (0.709–3.053) | 0.299 | 1.17 | (0.537–2.549) | 0.692 | |||
| ECOG score ≥ 2 | 2.049 | (1.280-10.803) | 0.237 | 3.719 | (1.28-10.803) | 0.016 | |||
| B symptom | 1.676 | (0.807–3.478) | 0.166 | 1.237 | (0.573–2.669) | 0.588 | |||
| Stage IIE | 2.507 | (1.252–5.02) | 0.009 | 2.747 | (1.288–5.858) | 0.009 | |||
| IPI score ≥ 2 | 1.475 | (0.517–4.206) | 0.468 | 2.001 | (0.689–5.812) | 0.202 | |||
| PINK-E score ≥ 2 | 0.253 | (0.034–1.853) | 0.176 | 0.346 | (0.047–2.56) | 0.299 | |||
| LDH > normal | 1.362 | (0.672–2.759) | 0.391 | 1.592 | (0.745–3.404) | 0.23 | |||
| EBV DNA | 1.669 | (0.935–2.98) | 0.083 | 1.696 | (0.912–3.152) | 0.095 | |||
| NLR ≥ 3.77 | 3.004 | (1.492–6.05) | 0.002 | 3.073 | (1.436–6.574) | 0.004 | |||
Abbreviations: CI, confidence interval; EBV, Epstein–Barr virus; ECOG, Eastern Cooperative Oncology Group performance status; HR, hazard rate; IPI, international prognostic index; LDH, lactate dehydrogenase; NLR, neutrophil-to-lymphocyte ratio; PINK-E, prognostic index of natural killer lymphoma with Epstein-Barr virus
Table 4.
Multivariable analysis of progression-free survival and overall survival in early-stage ENKTL
| Progression-free survival | Overall survival | |||||||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | |||
| ECOG score ≥ 2 | n.d. | n.d. | n.d. | 2.489 | (0.772–8.018) | 0.127 | ||
| Stage IIE | 2.389 | (1.192–4.789) | 0.014 | 2.182 | (0.951–5.007) | 0.066 | ||
| NLR ≥ 3.77 | 2.875 | (1.426–5.794) | 0.003 | 3.099 | (1.439–6.678) | 0.004 | ||
Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group performance status; HR, hazard rate; n.d., not done in multivariate analysis; NLR, neutrophil-to-lymphocyte ratio
Further stratification by the NLR in low-risk patients
In patients with early-stage ENKTL, we found that the NLR ≥ 3.77 was considered as a poor factor for PFS and OS; thus, we tried to further stratify low-risk patients(IPI score 0 or 1, and PINK-E score 0 or 1 ) by NLR. Based on IPI prognostic model, 120 patients were low-risk. Of them, 91 patients had low NLR, and the OS of them was greater than 29 patients with high NLR, and there was a statistical difference among two groups (χ2 = 10.921, p = 0.001) (Fig. 4a). Likewise, for PFS, a statistical difference was observed between the low NLR and the high NLR group (χ2 = 11.866, p = 0.001, Fig. 4b). According to the PINK-E scoring, 118 patients were low-risk. Of them, 90 patients had low NLR ,and the OS and PFS of them were significantly better than patients with high NLR(OS, χ2 = 10.588, p = 0.001; PFS, χ2 = 12.530, p = 0.002) (Fig. 5a-b).
Fig. 4.
OS and PFS in patients with low-risk IPI a: OS in the low-NLR and the high-NLR groups; b: PFS in the low-NLR and the high-NLR groups
Fig. 5.
OS and PFS in patients with low-risk PINK-E a: OS in the low-NLR and the high-NLR groups; b: PFS in the low-NLR and the high-NLR groups
Discussion
Inflammation is considered to be a major factor in cancer development, as it promotes disease progression and affects treatment response[12, 13, 29]. Neutrophils, an inflammatory cell, are the major type of peripheral blood leukocytes in human adults, and play a critical role in regulating tumor cell proliferation, angiogenesis, and metastasis by releasing cytokines and chemokines[30, 31]. In addition, lymphocytes are an important part of patient’s immune system, and can inhibit tumor cell proliferation and metastasis, induce apoptosis, and also play a key role in immune surveillance[32]. The NLR, as an inflammation marker of peripheral blood, has proved to have value as a prognostic factor in predicting treatment efficacy and survival in different cancers, including solid tumors and lymphomas[16, 20]. The prognostic value of NLR in ENKTL patients prior to treatment has been discussed in previous studies[8, 33]. However, based on the L-asparaginase-based chemotherapy, the prognostic value of the NLR in early-stage ENKTL has not been studied.
First, we found that treatment of L-asparaginase-based regimens for patients with early-stage ENKTL achieved promising results in both short-term and long-term efficacy. The ORR was 85.6% and 74.2% of patients had CR. The 3-year OS and PFS were 80.4% and 76%, and the 5-year OS and PFS were 75.4% and 72.9%, respectively. These results were comparable with previous studies. Hu et al. reported a L-asparaginase, vincristine and dexamethasone regimen with sequential radiotherapy for 94 early-stage ENKTL[34]. In their study, the ORR was 86.2% and the 3-year PFS and OS were 73.5% and 74.2%, respectively. Kim et al. conducted a phase II trial of the L-asparaginase-containing chemotherapy regimen for 30 early-stage ENKTL patients, and they reported that the 5-year PFS and OS rates were 73% and 60%, respectively[35]. Additionally, in a large-scale, multicenter study, Qi reported the survival outcomes of 1351 ENKTL patients based on non-anthracycline chemotherapy and reported a 5-year OS rate and PFS rate of 68.9% and 59.5%, respectively[36]. Therefore, the efficacy of L-asparaginase-based regimens supports this treatment for patients with early-stage ENKTL.
Second, we found that NLR was associated with several clinical parameters in our study, including B symptoms and elevated LDH. This result was similar to previous studies. A study including 33 newly diagnosed patients of ENKTL presented strong evidence that a high NLR correlated with worse clinical parameters in patients, including advanced disease stage, B symptoms, and ECOG score (≥ 2), elevated serum LDH levels, and IPI score [33]. Moreover, a recent retrospective study of 213 adult peripheral T cell lymphoma (PTCL) cases found that high NLR was associated with ECOG score and IPI score, elevated C-reactive protein and abnormal LDH levels, and B symptoms[37]. However, another study reported the opposite result, finding no statistical correlation between age, sex, serum LDH levels, B symptoms, and high or low NLR group[38]. The reasons for the relationship between NLR and the basic variables of ENKTL remain speculative, and larger population studies are necessary to further elucidate the nature of the relationship.
Third, we found that early-stage ENKTL patients with low NLR (< 3.77) presented higher CR (81% vs. 53.1%, p = 0.002), and higher ORR (90% vs. 71.9%, p = 0.024). Our data suggested that the NLR was related to treatment response. This result was similar to prior studies. In a previous study, 213 patients with PTCL were included. Of them, 112 presented with NLR < 3.7, while the remaining 101 presented with NLR ≥ 3.7. Within the NLR < 3.7 group, 68 patients(60.7%) achieved CR, while only 32 (31.7%) in the NLR ≥ 3.7 group achieved CR. There was a significant difference between two groups(p < 0.01)[37]. In another study, fourty-eight patients with PTCL, those with NLR < 4 had a better CR rate than those within the NLR ≥ 4 group (74% vs. 29%, p = 0.01)[38]. The prognostic value of NLR may be attributed to a correlation between peripheral blood neutrophils and tumor microenvironment neutrophils[39]. In the tumor microenvironment, tumor cell or tumor-related macrophages release chemokines CXCL-5/6/8, and recruit neutrophils in peripheral blood to achieve the tumor. Once neutrophils are recruited into tumor microenvironment, they release reactive oxygen species (ROS), VEGF, and arginase 1 (Arg-1), which, in turn, facilitate tumor growth, angiogenesis, and immunosuppression[40]; these three factors may reduce the likelihood of response to therapy.
Furthermore, we found that a high NLR was a poor independent predictor for both OS and PFS. This result was compatible with previous reports. For instance, in a study which stipulated a higher cut-off value at NLR ≥ 5 in analyzing patients with NSCLC, a high NLR was independently associated with worse OS when compared to patients in the NLR < 5 group(median, 5.1 months vs. not reached; HR 3.3, 95% CI, 1.3–8.5, p = 0.013)[16]. Moreover, Tan et al. reported that high NLR was an independent prognostic marker for survival outcomes of ENKTL patients[8]. In their study, 113 patients with early-stage ENKTL were included, and 11.2% of patients received anthracycline-based chemotherapy. The 5-year OS was 53% in patients with low NLR compared to 25% in those with high NLR. Compare to their study, our study included 132 patients with early-stage ENKTL and all patients received L-asparaginase-based regimens. Among 132 patients with early-stage ENKTL, the low NLR group exhibited a better 5-year OS rate (81.4% vs. 56.1%) than the high NLR group.
According to the IPI and PINK-E prognostic systems, most patients with early-stage disease are low-risk[9, 11]. In our study, we showed that approximately 90% of patients were low-risk. Through stratified analysis, it was found that high NLR was an adverse prognostic factor of PFS and OS in low-risk patients. In a respective analysis of PTCL patients, it was observed that NLR ≥ 4 was a worse prognostic factor in patients with low/low-intermediate IPI; however, no further study or analysis was performed for the low IPI group in this study[38].To our knowledge, this study reported the prognostic value of NLR in the largest cases of low-risk early-stage ENKTL. The value of NLR in predicting PFS and OS in patients with low IPI/PINK-E may be attributed to tumor pathogenesis. Cancer is thought to be a type of chronic inflammation, and NLR is regarded as a marker of systemic inflammation[41]. Neutrophils and lymphocytes play a crucial role in the tumor microenvironment, and neutrophils can release various cytokines, including ROS, Arg-1, and tumor necrosis factor α (TNF α), which are known promotors of tumorigenesis[40]. Based on the aforementioned factors, NLR could be deemed a better predictor of prognosis of early-stage ENKTL than IPI and PINK-E, which are established prognostic models based on clinical symptoms.
Although this is the first study on early-stage ENKTL patients, certain limitations should be thought pertaining to our study. First, this was a single center retrospective study with no verification group. Second, the number of cases collected in this study was quite small. Third,. treatment methods varied, and may have an impact on this result. Therefore, a multicenter and wider retrospective study should be designed to evaluate the role of NLR among patients with early-stage ENKTL.
Conclusion
In summary, we found that high NLR was correlated with inferior survival and worse therapeutic response in early-stage ENKTL, and it could further starify the PFS and OS in low-risk patients. Inspired by the results of our study, the NLR could potentially be applicable as a prognostic predictor for early-stage ENKTL patients.
Author Contributions
All authors contributed to the study conception and design. Data collection and analysis were performed by Wanchun Wu and Xi Chen. The first draft of the manuscript was written by Wanchun Wu and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by Sichuan science and technology department for key research and development projects(2019YFS0027).
Statements and Declarations
Competing Interests
The authors have no relevant financial or non-financial interests to disclose.
Ethics approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of West China Hospital, Sichuan University (ID.20201039).
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Wanchun Wu, Email: wwchospital@163.com.
Xi Chen, Email: chenxisnile@163.com.
Na Li, Email: 281422934@qq.com.
Qian Luo, Email: luoqian@stu.scu.edu.cn.
Liqun Zou, Email: zouliqun1971@wchscu.cn.
References
- 1.Kwong YL. Natural killer-cell malignancies: diagnosis and treatment. Leukemia. 2005;19(12):2186–2194. doi: 10.1038/sj.leu.2403955. [DOI] [PubMed] [Google Scholar]
- 2.Haverkos BM, Pan Z, Gru AA, et al. Extranodal NK/T Cell Lymphoma, Nasal Type (ENKTL-NT): An Update on Epidemiology, Clinical Presentation, and Natural History in North American and European Cases. Curr Hematol Malig Rep. 2016;11(6):514–527. doi: 10.1007/s11899-016-0355-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Fox CP, Civallero M, Ko YH, et al. Survival outcomes of patients with extranodal natural-killer T-cell lymphoma: a prospective cohort study from the international T-cell Project. Lancet Haematol. 2020;7(4):e284–e294. doi: 10.1016/S2352-3026(19)30283-2. [DOI] [PubMed] [Google Scholar]
- 4.Yang QP, Zhang WY, Yu JB, et al. Subtype distribution of lymphomas in Southwest China: analysis of 6,382 cases using WHO classification in a single institution. Diagn Pathol. 2011;6:77. doi: 10.1186/1746-1596-6-77. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Bi XW, Xia Y, Zhang WW, et al. Radiotherapy and PGEMOX/GELOX regimen improved prognosis in elderly patients with early-stage extranodal NK/T-cell lymphoma. Ann Hematol. 2015;94(9):1525–1533. doi: 10.1007/s00277-015-2395-y. [DOI] [PubMed] [Google Scholar]
- 6.Cheung MM, Chan JK, Lau WH, Ngan RK, Foo WW. Early stage nasal NK/T-cell lymphoma: clinical outcome, prognostic factors, and the effect of treatment modality. Int J Radiat Oncol Biol Phys. 2002;54(1):182–190. doi: 10.1016/s0360-3016(02)02916-4. [DOI] [PubMed] [Google Scholar]
- 7.Hong H, Li Y, Lim ST, et al. A proposal for a new staging system for extranodal natural killer T-cell lymphoma: a multicenter study from China and Asia Lymphoma Study Group. Leukemia. 2020;34(8):2243–2248. doi: 10.1038/s41375-020-0740-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Tan KM, Chia B, Lim JQ et al (2019) A clinicohaematological prognostic model for nasal-type natural killer/T-cell lymphoma: A multicenter study. Sci Rep. ;9(1):14961. Published 2019 Oct 18. doi:10.1038/s41598-019-51522-0 [DOI] [PMC free article] [PubMed]
- 9.International Non-Hodgkin’s Lymphoma Prognostic Factors Project A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1993;329(14):987–994. doi: 10.1056/NEJM199309303291402. [DOI] [PubMed] [Google Scholar]
- 10.Lee J, Suh C, Park YH, et al. Extranodal natural killer T-cell lymphoma, nasal-type: a prognostic model from a retrospective multicenter study. J Clin Oncol. 2006;24(4):612–618. doi: 10.1200/JCO.2005.04.1384. [DOI] [PubMed] [Google Scholar]
- 11.Kim SJ, Yoon DH, Jaccard A, et al. A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis. Lancet Oncol. 2016;17(3):389–400. doi: 10.1016/S1470-2045(15)00533-1. [DOI] [PubMed] [Google Scholar]
- 12.Greten FR, Grivennikov SI. Inflammation and Cancer: Triggers, Mechanisms, and Consequences. Immunity. 2019;51(1):27–41. doi: 10.1016/j.immuni.2019.06.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13(11):759–771. doi: 10.1038/nrc3611. [DOI] [PubMed] [Google Scholar]
- 14.Guthrie GJ, Charles KA, Roxburgh CS, Horgan PG, McMillan DC, Clarke SJ. The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol. 2013;88(1):218–230. doi: 10.1016/j.critrevonc.2013.03.010. [DOI] [PubMed] [Google Scholar]
- 15.Templeton AJ, McNamara MG, Šeruga B et al (2014) Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. ;106(6):dju124. Published 2014 May 29. doi:10.1093/jnci/dju124 [DOI] [PubMed]
- 16.Diem S, Schmid S, Krapf M, et al. Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer. 2017;111:176–181. doi: 10.1016/j.lungcan.2017.07.024. [DOI] [PubMed] [Google Scholar]
- 17.Chen MF, Chen PT, Kuan FC, Chen WC. The Predictive Value of Pretreatment Neutrophil-To-Lymphocyte Ratio in Esophageal Squamous Cell Carcinoma. Ann Surg Oncol. 2019;26(1):190–199. doi: 10.1245/s10434-018-6944-1. [DOI] [PubMed] [Google Scholar]
- 18.Zheng L, Zou K, Yang C, Chen F, Guo T, Xiong B. Inflammation-based indexes and clinicopathologic features are strong predictive values of preoperative circulating tumor cell detection in gastric cancer patients. Clin Transl Oncol. 2017;19(9):1125–1132. doi: 10.1007/s12094-017-1649-7. [DOI] [PubMed] [Google Scholar]
- 19.Sherry AD, von Eyben R, Newman NB, et al. Systemic Inflammation After Radiation Predicts Locoregional Recurrence, Progression, and Mortality in Stage II-III Triple-Negative Breast Cancer. Int J Radiat Oncol Biol Phys. 2020;108(1):268–276. doi: 10.1016/j.ijrobp.2019.11.398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Wang S, Ma Y, Sun L et al Prognostic Significance of Pretreatment Neutrophil/Lymphocyte Ratio and Platelet/Lymphocyte Ratio in Patients with Diffuse Large B-Cell Lymphoma.Biomed Res Int. 2018;2018:9651254. Published 2018 Dec 12. doi: 10.1155/2018/9651254 [DOI] [PMC free article] [PubMed]
- 21.Sabattini E, Bacci F, Sagramoso C, Pileri SA. WHO classification of tumours of haematopoietic and lymphoid tissues in 2008: an overview. Pathologica. 2010;102(3):83–87. [PubMed] [Google Scholar]
- 22.Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res. 1971;31(11):1860–1861. [PubMed] [Google Scholar]
- 23.Jiang M, Zhang L, Xie L, et al. A phase II prospective study of the “Sandwich” protocol, L-asparaginase, cisplatin, dexamethasone and etoposide chemotherapy combined with concurrent radiation and cisplatin, in newly diagnosed, I/II stage, nasal type, extranodal natural killer/T-cell lymphoma. Oncotarget. 2017;8(30):50155–50163. doi: 10.18632/oncotarget.16334. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Jiang M, Zhang H, Jiang Y, et al. Phase 2 trial of “sandwich” L-asparaginase, vincristine, and prednisone chemotherapy with radiotherapy in newly diagnosed, stage IE to IIE, nasal type, extranodal natural killer/T-cell lymphoma. Cancer. 2012;118(13):3294–3301. doi: 10.1002/cncr.26629. [DOI] [PubMed] [Google Scholar]
- 25.Zhang L, Li S, Jia S, et al. The DDGP (cisplatin, dexamethasone, gemcitabine, and pegaspargase) regimen for treatment of extranodal natural killer (NK)/T-cell lymphoma, nasal type. Oncotarget. 2016;7(36):58396–58404. doi: 10.18632/oncotarget.11135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Wei W, Wu P, Li L, Zhang ZH. Effectiveness of pegaspargase, gemcitabine, and oxaliplatin (P-GEMOX) chemotherapy combined with radiotherapy in newly diagnosed, stage IE to IIE, nasal-type, extranodal natural killer/T-cell lymphoma. Hematology. 2017;22(6):320–329. doi: 10.1080/10245332.2016.1264163. [DOI] [PubMed] [Google Scholar]
- 27.Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–3068. doi: 10.1200/JCO.2013.54.8800. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44(3):837–845. doi: 10.2307/2531595. [DOI] [PubMed] [Google Scholar]
- 29.Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013. [DOI] [PubMed] [Google Scholar]
- 30.Mollinedo F. Neutrophil Degranulation, Plasticity, and Cancer Metastasis. Trends Immunol. 2019;40(3):228–242. doi: 10.1016/j.it.2019.01.006. [DOI] [PubMed] [Google Scholar]
- 31.Shaul ME, Fridlender ZG. Tumour-associated neutrophils in patients with cancer. Nat Rev Clin Oncol. 2019;16(10):601–620. doi: 10.1038/s41571-019-0222-4. [DOI] [PubMed] [Google Scholar]
- 32.Farkas T, Müller J, Erdelyi DJ, Csoka M, Kovacs GT. Absolute Lymphocyte Count (ALC) after Induction Treatment Predicts Survival of Pediatric Patients with Acute Lymphoblastic Leukemia. Pathol Oncol Res. 2017;23(4):889–897. doi: 10.1007/s12253-017-0192-8. [DOI] [PubMed] [Google Scholar]
- 33.Zhou X, Sun X, Zhao W, Fang X, Wang X. Prognostic significance of peripheral blood absolute lymphocyte count and derived neutrophil to lymphocyte ratio in patients with newly diagnosed extranodal natural killer/T-cell lymphoma. Cancer Manag Res. 2019;11:4243–4254. doi: 10.2147/CMAR.S193397. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Hu Y, Chen M, Song Y, et al. Study of L-Asparaginase, Vincristine, and Dexamethasone Combined With Intensity-modulated Radiation Therapy in Early-Stage Nasal NK/T-Cell Lymphoma. Am J Clin Oncol. 2020;43(4):257–262. doi: 10.1097/COC.0000000000000647. [DOI] [PubMed] [Google Scholar]
- 35.Kim SJ, Yang DH, Kim JS, et al. Concurrent chemoradiotherapy followed by L-asparaginase-containing chemotherapy, VIDL, for localized nasal extranodal NK/T cell lymphoma: CISL08-01 phase II study. Ann Hematol. 2014;93(11):1895–1901. doi: 10.1007/s00277-014-2137-6. [DOI] [PubMed] [Google Scholar]
- 36.Qi SN, Yang Y, Song YQ et al (2020) First-line non-anthracycline-based chemotherapy for extranodal nasal-type NK/T-cell lymphoma: a retrospective analysis from the CLCG [published correction appears in Blood Adv. 2021 Jun 17;5(12):2576]. Blood Adv. ;4(13):3141–3153. doi:10.1182/bloodadvances.2020001852 [DOI] [PMC free article] [PubMed]
- 37.Zhao Y, Shi Y, Shen H, et al. The prognostic value of platelet-lymphocyte ratio and neutrophil-lymphocyte ratio in the treatment response and survival of patients with peripheral T-cell lymphoma. Leuk Lymphoma. 2020;61(3):623–630. doi: 10.1080/10428194.2019.1700244. [DOI] [PubMed] [Google Scholar]
- 38.Beltran BE, Castro D, De La Cruz-Vargas JA, Cotrina E, Gallo A, Sotomayor EM, Castillo JJ. The neutrophil-lymphocyte ratio is prognostic in patients with early stage aggressive peripheral T cell lymphoma. Br J Haematol. 2019;184:650–653. doi: 10.1111/bjh.15141. [DOI] [PubMed] [Google Scholar]
- 39.Moses K, Brandau S. Human neutrophils: Their role in cancer and relation to myeloid-derived suppressor cells. Semin Immunol. 2016;28(2):187–196. doi: 10.1016/j.smim.2016.03.018. [DOI] [PubMed] [Google Scholar]
- 40.Long W, Chen J, Gao C, Lin Z, Xie X, Dai H. Brief review on the roles of neutrophils in cancer development. J Leukoc Biol. 2021;109(2):407–413. doi: 10.1002/JLB.4MR0820-011R. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Stefaniuk P, Szymczyk A, Podhorecka M. The Neutrophil to Lymphocyte and Lymphocyte to Monocyte Ratios as New Prognostic Factors in Hematological Malignancies - A Narrative Review. Cancer Manag Res. 2020;12:2961–2977. doi: 10.2147/CMAR.S245928. [DOI] [PMC free article] [PubMed] [Google Scholar]