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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 4  |  Page : 170-178

Neutrophil lymphocyte ratio is an independent prognosticator in patients with locally advanced head and neck squamous cell carcinoma receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil


1 Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
2 Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
3 Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

Date of Submission19-Feb-2019
Date of Decision21-Apr-2019
Date of Acceptance08-May-2019
Date of Web Publication22-Nov-2019

Correspondence Address:
Dr. Shau-Hsuan Li
Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital, No.123, Dapi Road, Niaosong Dist., Kaohsiung City 833
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCRP.JCRP_12_19

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  Abstract 


Background: The aim of the present study was to evaluate the prognostic value of neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF). Materials and Methods: We performed a single-center retrospective analysis of 126 patients with locally advanced HNSCC treated with TPF as induction chemotherapy at Kaohsiung Chang Gung Memorial Hospital. NLR and PLR were calculated from blood tests before induction chemotherapy and correlated with clinical parameters and treatment outcomes. Results: A NLR ≧3 was significantly associated with advanced clinical American Joint Committee on Cancer (AJCC) 7th stage, higher clinical T classification, oral cavity primary tumor site, and alcohol history. A PLR ≧120 was significantly correlated with advanced clinical AJCC 7th stage and oral cavity primary tumor site. The overall response rates of induction chemotherapy were 70% and 50% (P = 0.022) in patients with a NLR <3 and NLR ≧3 and 78% and 52% (P = 0.008) in patients with a PLR <120 and PLR ≧120, respectively. Univariate analysis showed 5-year progression-free survival (PFS) rates of 58% and 32% (P < 0.001) in the patients with a NLR <3 and NLR ≧3 and 59% and 38% (P = 0.022) in those with a PLR <120 and PLR ≧120, respectively. The 5-year overall survival (OS) rates were 51% and 24% (P < 0.001) in the patients with a NLR <3 and NLR ≧3 and 52% and 31% (P = 0.011) in those with a PLR <120 and PLR ≧120, respectively. In multivariate analysis, NLR ≧3 was significantly independently associated with worse PFS (P = 0.018, odds ratio [OR]: 2.11) and OS (P = 0.026, OR: 1.87). Conclusions: Our findings suggested that an elevated NLR was independently associated with the prognosis of patients with locally advanced HNSCC treated with induction chemotherapy with TPF, and that, it may be helpful in clinical practice.

Keywords: Head and neck cancer, induction chemotherapy, neutrophil lymphocyte ratio, platelet lymphocyte ratio, squamous cell carcinoma


How to cite this article:
Lai HL, Tang Y, Chien CY, Fang FM, Huang TL, Chiu TJ, Li SH. Neutrophil lymphocyte ratio is an independent prognosticator in patients with locally advanced head and neck squamous cell carcinoma receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil. J Cancer Res Pract 2019;6:170-8

How to cite this URL:
Lai HL, Tang Y, Chien CY, Fang FM, Huang TL, Chiu TJ, Li SH. Neutrophil lymphocyte ratio is an independent prognosticator in patients with locally advanced head and neck squamous cell carcinoma receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil. J Cancer Res Pract [serial online] 2019 [cited 2019 Dec 6];6:170-8. Available from: http://www.ejcrp.org/text.asp?2019/6/4/170/271493




  Introduction Top


Head and neck squamous cell carcinoma (HNSCC) remain a significant public health problem, with a reported incidence rate of over 800,000 per year globally in 2015.[1] In Taiwan, HNSCC had a reported incidence rate of over 8000 per year in 2014, accounting for 8.0% of all new cancer diagnoses and 6.3% of all cancer deaths.[2] In general, over half of patients with HNSCC present with locally advanced disease, for which local treatment is challenging due to complex regional anatomy and organ function. To address this issue, personalized multimodal strategies involving chemotherapy, radiotherapy, and surgery have been developed to maximize the therapeutic benefit and minimize treatment-related toxicity and morbidity.

Since 2007, induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (5-FU) (TPF regimen[3],[4],[5],[6]) followed by chemoradiotherapy has become one of the standard treatment modalities for locally advanced HNSCC with better disease control compared to cisplatin and fluorouracil alone. Despite its efficacy, this regimen is associated with a high risk of severe hematological toxicity (e.g., Grade 3 or 4 neutropenia) complicated with increased treatment-related mortality. Caudell et al.[3] reported a 15.3% mortality rate in patients with locally advanced HNSCC receiving the TPF regimen in a population with low socioeconomic status. Better patient selection and dose adjustment is thought to be the key to prevent severe complications in patients receiving induction chemotherapy with TPF.

To date, there are limited data regarding the factors that may predict the prognosis or response to chemotherapy in patients with locally advanced HNSCC receiving induction chemotherapy with TPF. Neutrophilia and leukocytosis have been associated with worse outcomes in many types of cancer, and an increased platelet count may affect the efficacy of cisplatin-based chemotherapy. Among the factors reported, inflammation-based prognostic scores such as neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) have been shown to predict the prognosis in cancer patients receiving surgery or other curative treatments for epithelial cancers including colon cancer,[7],[8] cholangiocarcinoma,[9],[10] and esophageal cancer.[11],[12],[13],[14] However, it is unclear whether NLR and PLR can predict the treatment outcomes of patients with locally advanced HNSCC receiving induction chemotherapy with TPF. The present study aimed to assess the prognostic value of NLR and PLR before TPF induction chemotherapy in patients with locally advanced HNSCC.


  Materials and Methods Top


Patient population

Patients with locally advanced HNSCC who were treated with induction chemotherapy with TPF at Kaohsiung Chang Gung Memorial Hospital between August 2009 and October 2013 were retrospectively reviewed. The current study was approved by the Chang Gung Medical Foundation Institutional Review Board (No. 201900684B0) and written informed consent by patient or family was not necessary judged by the review board. All patients selected for this retrospective study were required to have pretreatment complete blood count and basic biochemistry data. Clinical staging was determined according to the American Joint Committee on Cancer (AJCC) staging system, seventh edition. To be selected for induction chemotherapy with TPF in the present study, patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1, age above 18 years, adequate bone marrow function (absolute neutrophil count ≧1.75 × 109/L, platelet count ≧100 × 109/L), hepatic function (serum total bilirubin ≦1.5 mg/dL and serum levels of aspartate aminotransferase and alanine aminotransferase ≦2.5 × the upper limit of normal), and renal function (serum creatinine ≦1.5 mg/dL). A total of 126 patients were identified.

Treatment and assessment

Since severe hematological toxicity has been reported in Asian patients and those with a low socioeconomic status,[3] a modified TPF regimen was used instead of the standard dose to reduce toxicity and increase tolerability.[4],[15],[16] Docetaxel was administered at a dosage of approximately 60–65 mg/m2 by intravenous infusion for 1.5 h, cisplatin at a dosage of approximately 60–75 mg/m2 by intravenous infusion for 4 h, and 5-fluorouracil at a dosage of approximately 600–750 mg/m2 per 24 h as a 96-h continuous intravenous infusion, which was repeated every 3 weeks per cycle. All patients received 2–3 cycles of induction chemotherapy with the dose-modified TPF regimen. Prophylactic granulocyte colony-stimulating factor and antibiotics were not routinely used. Within 3–6 weeks after the last cycle of induction chemotherapy, radiation was delivered during a 7-week period with the use of conventional fractionation (total dose, 66–70 Gy) and was performed concurrently with chemotherapy of weekly cisplatin at a dosage of 40 mg/m2 by intravenous infusion. Salvage surgery was performed 6–12 weeks after the completion of chemoradiotherapy for the patients who had residual disease after chemoradiotherapy and also for patients with no response to induction chemotherapy with resectable disease. Tumor responses were assessed by clinical evaluation and imaging studies according to the Response Evaluation Criteria in Solid Tumors guidelines version 1.0.

Progression-free survival (PFS) was calculated from the date of the first induction of chemotherapy to the date of progression or death from any cause, whichever occurred first. Overall survival (OS) was calculated from the date of diagnosis until death or last follow-up.

Neutrophil lymphocyte ratio and platelet lymphocyte ratio

NLR was calculated as neutrophil count divided by lymphocyte count when the patients had no clinical signs of sepsis before the first course of TPF. PLR was calculated as platelet count divided by lymphocyte count. A cutoff value of the PLR ≧120 was used to distinguish between a high (PLR ≧120) and low (PLR <120) PLR according to previous studies. A cutoff value of the NLR ≧3.0 was used to distinguish between a high (NLR ≧3.0) and low (NLR <3.0) NLR according to previous studies.[8],[10],[17]

Immunohistochemistry

Immunohistochemistry staining was performed using an immunoperoxidase technique. Staining was performed on slides (4 μm) of formalin-fixed, paraffin-embedded tissue sections with primary antibodies against p16INK4 (BD Biosciences, San Jose, CA, USA). Briefly, after deparaffinization and rehydration, retrieval of the antigen was performed by placing the slides in 10 mmol/L citrate buffer (pH 6.0) in a hot water bath (95°C) for 20 min. Endogenous peroxidase activity was blocked for 15 min in 0.3% hydrogen peroxide. After blocking with 1% goat serum for 1 h at room temperature, the sections were incubated with primary antibodies for at least 18 h at 4°C overnight. Immunodetection was performed using an LSAB2 kit (Dako, Carpinteria, CA) followed by 3-3'-diaminobenzidine for color development and hematoxylin for counterstaining. Incubation without the primary antibody was used as a negative control. Positive p16 expression was defined as nuclear staining in 50% or more of the tumor cells.[18],[19]

Statistical analysis

For patient data, statistical analysis was performed using SPSS version 20 (IBM Corp, NY, USA). The Chi-square test or Fisher's exact test was used to compare data between two groups. For survival analysis, the Kaplan–Meier method was used for univariate analysis, and the difference between survival curves was tested using a log-rank test. All parameters were in principle entered into a Cox regression model to analyze their relative prognostic importance. For all analyses, two-sided tests of significance were used, with P< 0.05 considered to be significant.


  Results Top


Patient characteristics

A total of 126 patients (120 men, 6 women; median age 53 years [range, 29–82 years]) with locally advanced HNSCC receiving induction chemotherapy with TPF were collected in this study [Table 1]. The analyses of T classification revealed T1 in 1 (0.8%) patient, T2 in 19 (15.1%) patients, T3 in 13 (10.3%) patients, T4a in 36 (28.6%) patients, and T4b in 55 (43.7%) patients. Further analyses of nodal status showed N0 in 30 (23.8%) patients, N1 in 14 (11.1%) patients, N2a in 1 (0.8%) patients, N2b in 40 (31.8%) patients, N2c in 31 (24.6%) patients, and N3 in 10 (7.9%) patients. Additional analyses according to the AJCC 7th staging system demonstrated stage II for 4 (3.2%) patients, stage III for 7 (5.6%) patients, stage IVA for 52 (41.3%) patients, and stage IVB for 63 (50%) patients. The primary tumor site was the hypopharynx in 13 (10.3%) patients, larynx in 17 (13.5%) patients, oropharynx in 38 (30.2%) patients, oral cavity in 55 (43.7%) patients, and unknown primary in 3 (2.4%) patients. Furthermore, the p16 expression was negative in 121 (96%) patients and positive in 5 (4%) patients. The overall response rate for the 126 patients was 59.5%. Seven patients (5.4%) achieved a complete response (CR), 68 patients (54.0%) achieved a partial response (PR), 36 patients (28.6%) had stable disease, and 15 patients (11.9%) had progressive disease. After induction chemotherapy and concurrent chemoradiotherapy, 82 patients (65%) received salvage surgery and 44 patients (35%) did not. Human papillomavirus was negative in 121 patients (96.0%) and positive in 5 patients (4.0%).
Table 1: Characteristics of 126 patients with head and neck squamous cell carcinoma receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil

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At the time of the last analysis, the median periods of follow-up were 71 months (range, 5.1–101.5 months) for the 46 survivors and 21 months (range, 2–101.5) for all 126 patients. The median PFS and OS rates were 14.3 and 21.1 months, respectively, and the 5-year PFS and OS rates were 44% and 36.5%, respectively.

Neutrophil lymphocyte ratio and platelet lymphocyte ratio in the patients with locally advanced head and neck squamous cell carcinoma

Among the 126 patients, 66 (52.3%) had a high NLR (NLR ≧3) and 90 (71.4%) had a high PLR (PLR ≧120). A high NLR was associated with more advanced clinical AJCC 7th stage, primary oral cavity tumor, and history of alcohol consumption. A high PLR was associated with more advanced clinical AJCC 7th stage and primary oral cavity tumor [Table 2].
Table 2: Demographic and clinical features of 126 head and neck squamous cell carcinoma patients receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil with different neutrophil lymphocyte ratio and platelet lymphocyte ratio

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The relationships between clinicopathological parameters and the response to induction chemotherapy are summarized in [Table 3]. A high NLR and high PLR were both significantly (P = 0.022 and P = 0.008, respectively) associated with a poor response to induction chemotherapy. The overall response (CR plus PR) rate was 70% in the patients with a low NLR compared to 50% in those with a high NLR. The overall response rate was 77.8% in the patients with a low PLR compared to 52.2% in those with a high PLR. Oral cavity primary tumor site was also significantly (P< 0.001) correlated with a poor response to induction chemotherapy.
Table 3: Associations between the response to induction chemotherapy with docetaxel, cisplatin, and fluorouracil and clinicopathologic parameters in 126 patients with head and neck squamous cell carcinoma receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil

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Survival analyses

The correlations between patient survival and various clinicopathological factors at the univariate level are shown in [Table 4]. High NLR [NLR ≧3, P< 0.001, [Figure 1]a, high PLR [PLR ≧120, P = 0.018, [Figure 1]b, and oral cavity (P = 0.011), hypopharynx or larynx primary tumor site (P = 0.021) were significantly related to worse PFS. In addition, high NLR [NLR ≧3, P< 0.001, [Figure 1]c, high PLR [PLR≧120, P = 0.011, [Figure 1]d, clinical N classification (N2 or 3, P = 0.003), more advanced clinical 7th AJCC stage (P = 0.043), and oral cavity primary tumor site (P = 0.01) were also significantly related to worse OS.
Table 4: Results of univariate log-rank analysis of prognostic factors for progression-free survival and overall survival in 126 patients with head and neck squamous cell carcinoma receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil

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Figure 1: (a) Progression-free survival according to NLR. (b) Progressionfree survival according to PLR. (c) Overall survival according to NLR. (d) Overall survival according to PLR. NLR: Neutrophil lymphocyte ratio, PLR: Platelet lymphocyte ratio

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In multivariate analysis, a high NLR (NLR ≧3, P = 0.018, odds ratio [OR]: 2.11, 95% confidence interval [CI]: 1.13–3.93) was an independent adverse prognosticator for PFS. Moreover, a high NLR (NLR ≧3, P = 0.026, OR: 1.87, 95% CI: 1.07–3.25) and clinical nodal status (N2 or 3, P = 0.007, OR: 2.10, 95% CI: 1.23–3.60) remained independent adverse prognosticators for OS. The 5-year PFS and OS rates were 31.6% and 23.8% in the patients with a high NLR (NLR ≧3) and 58.4% and 50.9% in those with a low NLR (NLR <3), respectively.


  Discussion Top


Signs of inflammation such as tumor fever, leukocytosis, and elevated platelet count in cancer patients have been associated with advanced stage, tumor aggressiveness, drug resistance, and poor prognosis, and the NLR and PLR have also been used to predict the prognosis after definite cancer treatment and to evaluate treatment response.[7],[8],[10],[11],[12],[13],[14],[17],[20],[21],[22],[23],[24],[25],[26],[27],[28] Wood et al.[7] reported that the NLR could be used to predict the benefits from cisplatin in patients with advanced biliary tract cancer, and Yao et al.[29] reported that the NLR was associated with benefits from platinum-based chemotherapy in advanced nonsmall cell lung cancer. In addition, a previous meta-analysis showed that the NLR could be used to predict worse disease-free survival and OS, and that, it could potentially be used to stratify high-risk HNSCC patients who may be candidates for adjuvant therapy.[30] Muhaxheri et al.[31] reported that preoperative NLR could be used to predict the outcomes of HNSCC patients receiving surgery, and both Cho et al. and Baba and Kato[32],[33] reported that an elevated NLR was associated with a worse prognosis in HNSCC patients treated with definitive chemoradiotherapy or radiotherapy. To the best of our knowledge, this is the first study to evaluate the prognostic role of NLR and PLR in patients with locally advanced HNSCC receiving induction chemotherapy with TPF.

An overall tumor response rate of 60%–70% has been reported in patients after TPF induction chemotherapy.[4],[15] However, some patients still do not respond well to TPF induction chemotherapy. In addition, substantial differences in the response to induction chemotherapy and survival between patients with the same clinical stage have been reported. Therefore, it is important to identify patients who are unlikely to respond to induction chemotherapy to spare them from the toxic effects of ineffective chemotherapy and delay other therapeutic options. An easily available marker that can correctly predict the tumor response to induction chemotherapy in patients with locally advanced HNSCC is thus required to identify these patients. In the current study, we found that the response rate was higher in the patients with a low NLR (NLR < 3). After induction chemotherapy with TPF, 42 (70%) of 60 patients with a low NLR (NLR < 3) had a response, while only 33 (48%) of 68 patients with a high NLR (NLR ≧3) had a response. Moreover, the overall response rates of induction chemotherapy were 78% and 51% in the patients with a PLR < 120 and PLR ≧120, respectively. The 5-year PFS rates were 58.4% and 31.6% (P< 0.001) in the patients with a NLR < 3 and NLR ≧3 and 59.1% and 38.3% (P = 0.022) in the patients with a PLR < 120 and PLR ≧120, respectively. The 5-year OS rates were 50.9% and 23.8% (P< 0.001) in the patients with a NLR < 3 and NLR ≧3 and 52.1% and 30.6% in the patients with a PLR <120 and PLR ≧120 (P = 0.011), respectively. Our findings suggest that the NLR and PLR may be useful to predict the response to induction chemotherapy and treatment outcomes in patients with locally advanced HNSCC, and that, they may be helpful when selecting suitable patients for treatment.

In multivariate analysis, OS was correlated to NLR (NLR ≧3, P = 0.026, OR: 1.87, 95% CI: 1.07–3.25). The patients with a higher NLR had a worse prognosis even after receiving induction TPF. Previous studies have reported a positive correlation between the NLR and AJCC stage;[14],[25],[31],[32],[34] however, we found that it was an independent risk factor for death. This may be due to tumor aggressiveness and a lower response rate compared to the low NLR group, which led to worse survival.

Tumor proliferation, invasion, angiogenesis, and metastasis are affected by host inflammation and immune response in the tumor microenvironment.[35] A high NLR and PLR reflect an increase in neutrophil and platelet counts and decrease in lymphocyte count. Previous studies have suggested that tumor-associated neutrophils are involved in protumoral activities and in the inhibition of antitumoral immune surveillance.[36] The majority of circulating vascular endothelial growth factor is contained in neutrophils and platelets, and the level has been shown to be higher in cancer patients compared to healthy volunteers.[37],[38] An elevated platelet count has also been shown to stimulate cell proliferation and thus attenuate the response to cisplatin in nonsmall cell lung cancer.[39] Lymphocytes play a role in cytotoxic cell death and are associated with antitumor activities.[40] Lymphopenia is common in patients with advanced cancer, and it has been associated with a decreased response to checkpoint inhibitors and chemotherapy. In retrospective studies, pretreatment lymphopenia was associated with a worse response and shorter PFS in patients with breast cancer, sarcoma, and lymphoma receiving chemotherapy.[41] These findings suggest that the NLR could be used to evaluate the composite status of protumor inflammation and antitumor immunity. Compared to tumor-infiltrating lymphocytes or other tissue-based scores, which have also been proposed to be predictive of antitumor immunity, blood samples are easier to acquire and can be closely monitored.

There are several limitations to this study. First, this was a retrospective study conducted at a single center, and thus, referral and selection bias were possible. Second, there could have been minor differences in the cycles of induction chemotherapy the patients received and the policy of chemotherapy dose adjustments between physicians.


  Conclusions Top


We found that the NLR was independently associated with the prognosis in patients with locally advanced HNSCC treated with induction chemotherapy with TPF. Further studies of the impact of inflammatory markers are warranted to identify factors that are more predictive of chemotherapy response and prognosis.

Acknowledgements

This work was supported by grants from Chang Gung Memorial Hospital (CMRPG8G0892 and CMRPG8J0401).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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