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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 7  |  Issue : 1  |  Page : 20-25

Blood neutrophil-to-lymphocyte ratio as a predictor of response to chemotherapy in head-and-neck cancers


1 Department of Pathology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Department of Radiotherapy and Oncology, Faculty of Medicine, Haft-e-Tir Hospital, Iran University of Medical Sciences, Tehran, Iran
3 Department of Radiotherapy and Oncology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4 Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Date of Web Publication26-Jul-2019

Correspondence Address:
Kambiz Novin
Department of Radiotherapy and Oncology, Haft-e-Tir Medical and Educational Center, Rajaee Street, Postal Code: 1886718136, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jhnps.jhnps_31_18

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  Abstract 


Background: The aim of this study was to investigate whether pretreatment blood neutrophil-to-lymphocyte ratio (NLR) could serve as a bio-predictor of response to chemotherapy for head-and-neck cancers (HNCs). Materials and Methods: Patients with newly diagnosed epithelial HNC were consecutively enrolled in the study. The pretreatment percent of neutrophils and lymphocytes in the peripheral blood smear slides and NLR for each patient were calculated. For patients that received chemotherapy, response rates and treatment toxicities were analyzed due to pretreatment mean NLR. Results: Of the total 46 included patients, 38 were men and 8 were women, with a mean age of 54 years (27–82 years). The mean NLR of the whole patients was 2.8. The overall response rate (complete response plus partial response) was 86%. The mean NLR was significantly lower in the group with higher response compared to no-response group (2.5 and 5.8, respectively; P= 0.027). The differences were also significant for percent of neutrophil and lymphocyte between these groups. There was no correlation between NLR and treatment toxicities. Conclusions: Our study proposed that pretreatment NLR might predict response to chemotherapy in epithelial HNCs.

Keywords: Chemotherapy, head-and-neck cancer, neutrophil-to-lymphocyte ratio, response rate


How to cite this article:
Hashemi-Bahremani M, Mortazavi N, Novin K, Ameri A, Razzaghi Z. Blood neutrophil-to-lymphocyte ratio as a predictor of response to chemotherapy in head-and-neck cancers. J Head Neck Physicians Surg 2019;7:20-5

How to cite this URL:
Hashemi-Bahremani M, Mortazavi N, Novin K, Ameri A, Razzaghi Z. Blood neutrophil-to-lymphocyte ratio as a predictor of response to chemotherapy in head-and-neck cancers. J Head Neck Physicians Surg [serial online] 2019 [cited 2019 Aug 18];7:20-5. Available from: http://www.jhnps.org/text.asp?2019/7/1/20/263517




  Introduction Top


Head-and-neck cancer (HNC) is the seventh most common malignancy comprising 15% of all cancers in males.[1] It is a major cause of morbidity and is responsible for many deaths worldwide.[2] Squamous cell carcinoma is the most common histologic subtype of HNC that originates from the epithelial membrane of the upper aerodigestive tract.[3] It accounts for 90% of all malignancies in this region, and is significantly more common in men than women.[4] Several prognostic factors have been defined for HNCs that can influence response to therapy and eventual outcome. These factors may be categorized as follows: (a) prognostic factors related to the primary tumor such as tumor, node, and metastasis (TNM) stage, malignancy grading, perineural invasion, and vascular invasion; (b) prognostic factors related to the patient such as age, sex, and general medical condition; and (c) prognostic factors related to the treatment.[5] Recent studies show that host inflammatory response to the tumor and immunology can influence cancer characteristics and play important roles in tumor progression and final outcome.[6] Although not fully understood, it has been proposed that inflammatory response could alter the tumor cells' behavior by inhibition of apoptosis, promotion of angiogenesis, or damage of DNA.[7] It has been also suggested that neutrophils and lymphocytes play these key roles in the tumor inflammation and immunology.[8],[9] Recently, elevated peripheral blood neutrophil-to-lymphocyte ratio (NLR) before starting the treatment has been introduced as an independent prognostic factor associated with poor survival in different types of malignancy, including colon cancer, esophageal cancer, gastric cancer, and breast cancer.[10],[11],[12],[13],[14],[15],[16] There is some evidence that NLR can also be used as a predictive biomarker of outcome in patients treated with systemic therapy for metastatic renal cell carcinoma, pancreatic cancer, ovarian cancer, and gastric cancer.[13],[17],[18],[19] In terms of response to treatment, NLR was also shown to be predictive so that high NLR before either neoadjuvant chemoradiation for rectal cancer or systemic chemotherapy for lung cancer and esophageal cancer was a reliable predictor of poor clinical or pathologic response to treatment.[20],[21],[22] In locally advanced gastric cancer receiving neoadjuvant chemotherapy, high prechemotherapy circulating lymphocyte ratios were positively associated with pathological complete response (CR).[23]

There are also studies that examined the prognostic significance of pretreatment blood inflammatory cells in HNCs. In a cohort of 97 patients, Perisanidis et al. showed that a high pretreatment NLR could be a significant independent predictor of shorter disease-specific survival in patients with locally advanced oral cancer receiving preoperative chemoradiotherapy.[24] In a retrospective analysis of 262 early-stage tongue cancer patients postoperatively, the 5-year overall and disease-specific survival among patients with NLR <2.95 were much higher than that in patients with NLR ≥2.95.[25]

Another study on laryngeal cancer patients after surgery also showed NLR as an independent prognostic factor for overall and progressionfree survival.[26]

Similar results were observed when pretreatment NLR was examined as a predictor of outcome for nasopharyngeal cancer patients.[27],[28] We conducted the present study to investigate whether NLR could serve as a bio-predictor of response to chemotherapy for HNCs.


  Materials and Methods Top


Consecutive newly diagnosed HNC patients admitted between December 2013 and December 2014 at our clinical oncology center (Jorjani Cancer Center, Emam Hossein Hospital, Tehran, Iran) were investigated. The study inclusion criteria were as follows: (a) patients of any age with a biopsy-proven diagnosis of epithelial primary or metastatic HNC; (b) the primary or metastatic disease was measurable by physical examination or imaging studies; (c) the patient had not underwent definitive surgical treatment; (d) the patient had not received oncological treatments such as chemotherapy, radiotherapy, or hormonal therapy during the past year; (e) no history of previous HNC; (f) the patient was not a known case of an inflammatory disease such as inflammatory bowel disease, rheumatic disease, and chronic infection; and (g) the patient had not received systemic corticosteroid nor been diagnosed of an acute infectious disease during the past month. After physical examination and necessary imaging studies to define TNM staging, of all the included patients, two peripheral blood smear (PBS) slides were obtained (by patient's fingertip blood) and after fixation with methanol, the slides were sent to the hospital's laboratory for Wright/Giemsa staining (the patients were asked not to smoke and not to do physical exercise at least 1 day before obtaining PBS; all PBSs were obtained in the morning). Two pathologists separately viewed the stained slides under a light microscope using magnification up to ×1000, and the mean percent of neutrophils and lymphocytes and NLR for each patient were calculated. With a previously prepared fact sheet, the following data for each patient were collected: patient's age, sex, weight and height, date of diagnosis, primary tumor site, histologic grade of primary tumor, TNM stage, and location of metastasis if present. For patients that received cytotoxic therapy, date of chemotherapy cycles, chemotherapy regimen, number of cycles, hematologic indices (white blood cell, hemoglobin, and platelet) and serum creatinine before each chemotherapy cycle, and tumor response to treatment were determined. Response rate determination was based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1 published in January 2009) on imaging studies with four categories of CR, partial response (PR), stable disease (SD), and progressive disease (PD). Hematological and nonhematological toxicity grading was done based on the Common Terminology Criteria for Adverse Events (CTCAE Version 4.02 published in September 2009). This study was approved by the local scientific and ethical committee.

Statistical methods

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS Inc. Chicago, IL, USA) software version 21.0. Statistical analysis for continuous and categorical variables was done with t-test and Chi-square test, respectively. The relationship between NLR and response to chemotherapy was described with Pearson's correlation coefficient. The level of significance was considered 0.05, and power of the study was 90%.


  Results Top


Patient and tumor characteristics

Of the 51 included cases, five patients were excluded; one for undiagnosed acute bacterial infection at the time of first admission and four because they did not come back to the clinic after planned staging workups. Of the 46 remaining patients, 38 were male and 8 were female, with a mean age of 54 years (27–82 years). For 14 patients (30%), the primary tumor site was nasopharyngeal and for 32 nonnasopharyngeal cases, larynx was the most common primary tumor site (39% of all patients). In four patients (7%), distant metastasis was detected at the time of first diagnosis. Most patients (78%) were classified as Stage 3/4 disease. The tumor clinicopathologic characteristics are detailed in [Table 1].
Table 1: The tumor clinicopathologic characteristics

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Treatment efficacy

A total of 39 patients received platinum-based chemotherapy including 18 patients (46%) who received docetaxel plus cisplatin plus 5-fluorouracil (DCF regimen), 16 patients (41%) who received weekly paclitaxel plus carboplatin (wTC regimen), and the remaining 5 patients (13%) who received (CF regimen). After 6 weeks of treatment, the patients took computed tomography scan or magnetic resonance imaging of the metastatic and/or primary tumor site (s), and clinical response was evaluated. Among 35 patients whose response evaluations were available, 8 (23%) patients got CR, 22 (63%) patients had PR, one (3%) patient had SD, and 4 (11%) patients had PD. The overall response rate (CR plus PR) was 29%.

Neutrophil-to-lymphocyte ratio analysis

For the total cohort of patients, the mean pretreatment NLR and the mean neutrophil and lymphocyte percent in PBS were 2.8, 64, and 30, respectively. These items were compared between good response (CR+PR) and poor response (SD+PD) cases. As shown in [Table 2], PBSs derived from patients of good response group tended to have less NLR (2.5) and neutrophil percent (63%) and more lymphocyte percent (32%) than those from the poor response one (5.8, 77%, and 19%, respectively), and these differences were statistically significant. These PBS indices were not significantly different between patient groups according to sex, age, primary tumor site, primary tumor grade, total stage, and chemotherapy regimen. There were trends to higher NLR in higher tumor stage (T-stage) and lymph node stage (N-stage) groups compared to lower one, but these differences again were not significant [Table 2].
Table 2: Comparison of mean neutrophil-to-lymphocyte ratio and neutrophil and lymphocyte percent between different patient-, tumor-, and treatment-related groups

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According to the receiver operating characteristic curve, the best cutoff value of NLR was 2.6. NLR values <2.6 with a sensitivity of 77% and a specificity of 80% could predict good response to treatment [Figure 1].
Figure 1: Receiver operating characteristic cur ve for neutrophil-to-lymphocyte ratio predicting response to chemotherapy

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We analyzed the distribution of some variables other than NLR that probably could interfere with response to treatment. As shown in [Table 3], distributions of these confounding variables in good and poor response groups were not significantly different.
Table 3: Distribution of probable confounding variables in good and poor response groups

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Hematologic toxicity

Of the total 201 chemotherapy cycles administered to the patients, 139 cycles were wTC, 49 were DCF, and 13 were CF regimen. In six patients who experienced Grade 3/4 hematological toxicity, the mean NLR was lower than what was observed in others (2.6 vs. 3), but this difference was not statistically significant (P = 0.535).


  Discussion Top


There are different original studies and meta-analyses also that show the prognostic and predictive role of NLR in solid tumors and also head-and-neck malignancies.[29],[30] In the present study, pretreatment NLR was demonstrated to be associated with response to platinum-based chemotherapy in epithelial HNCs. Patients in poor response group had significantly higher mean NLR compared with good response one. We also revealed that mean pretreatment NLR and neutrophil and lymphocyte percent in PBS of our patient population did not correlate with chemotherapy-induced hematological toxicities. Demographic characteristics such as age and sex in our patients were similar to ones in other studies (both local and in other geographic regions of the world).[1],[2],[3],[31] Nasopharyngeal carcinoma consisted 30% of all primary sites in the resent study. Malignancies of nasopharynx are not eligible for surgery in most situations and are referred for nonsurgical treatments, so that is why nasopharyngeal cancers included considerable percent of our study population. However, larynx and oral cavity were the most common nonnasopharyngeal primary sites, and this is in concordance with most other reports.[1],[2],[3],[31] The mean NLR for total cohort of patients in our study was 2.8 and for nasopharyngeal and nonnasopharyngeal primaries, this value was 3.4 and 2.5, respectively. In a study to evaluate the association between pretreatment NLR and outcome for locally advanced oral cavity cancers, Perisanidis et al. obtained 2.6 for mean NLR of their patients.[24] An et al. in a similar study reported mean NLR value of 3.07 for their total cohort of patients with nasopharyngeal cancer.[27] The overall response rate (CR+PR) to platinum-based chemotherapy in the present study was 86%, which is also in concordance with other studies on HNCs that revealed a range of 70%–97% for response to chemotherapy.[32],[33],[34],[35],[36] In our study, NLR and percent of neutrophil and lymphocyte were the only variables associated with response to chemotherapy. Other variables such as sex, age, stage of disease, primary tumor site, and chemotherapy regimen were not significantly different between poor and good responders [Table 2] and [Table 3]. Several previous studies reported the association between NLR and clinical response to therapy in different types of cancers. These studies all revealed that elevated pretreatment NLR was a predictor of worse therapy response.[20],[21],[22] In one of the few published studies that evaluated this association in HNC, Jin et al. compared outcome and response to platinum-based chemotherapy in metastatic nasopharyngeal carcinoma. They determined a 3.6 cutoff for NLR based on the median of the values and showed that the response (CR + PR) rate was not significantly different between patients with a baseline NLR ≤3.6 and those with NLR >3.6.[37] The discordance between their results and those observed in our study can be explained by (1) they studied only patients with metastatic nasopharyngeal cancer with possible different natural history from our most nonmetastatic and nonnasopharyngeal cases and (2) may be, if they compared mean NLR values between poor and good response groups like we did in our study, they would get similar results. Karpathiou et al. in a retrospective study analyzed the clinical and histologic predictive factors of response to induction chemotherapy in 81 HNC patients. The patients were divided into good (62%) and poor (38%) responder groups. They selected a cutoff of 7 for NLR, and no significant difference for response rate between the two groups of low and high NLR was detected although the survival was significantly different.[38] The most common primary sites in their study were hypopharynx and oropharynx (totally 86%). The discrepancy between their results and what reached in our study may be explained with the different primary sites and also the unusual NLR cutoff selected by them.

To date, there is much evidence that shows the prognostic and predictive roles of the host inflammatory response and specifically pretreatment NLR in different types of cancers. The exact mechanisms by which the immune system can do these roles still must be determined.


  Conclusions Top


Our study proposed that pretreatment NLR might predict response to chemotherapy in epithelial HNCs. For patients with locoregionally advanced disease, NLR may also be a useful indicator for selection of induction chemotherapy strategy.

Acknowledgment

The authors thank the Clinical Research Development Unit, Emam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Disclosure

This material has never been published and is not currently under evaluation in any other peer reviewed publication.

Ethical approval

The permission was taken from Institutional Ethics Committee prior to starting the project. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.



 
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