|Year : 2020 | Volume
| Issue : 3 | Page : 92-97
Prognostic significance of neutrophil lymphocyte ratio in patients of carcinoma cervix treated with radiotherapy
B M. Muhammed Ali Azher, Niketa Thakur, Sonal Patel
Department of Radiation Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
|Date of Submission||27-Apr-2020|
|Date of Decision||09-Jun-2020|
|Date of Acceptance||26-Aug-2020|
|Date of Web Publication||26-Nov-2020|
Department of Radiation Oncology, Gujarat Cancer and Research Institute, New Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat
Source of Support: None, Conflict of Interest: None
Background: The elevated neutrophil-to-lymphocyte ratio (NLR) has been identified as a poor prognostic indicator in various malignancies. The progression of malignancies is manifested as alteration in blood counts which can be used as the prognostic markers. Aim: The aim of the present study is to analyze the effect of pretreatment NLR and other hematological variables on progression-free survival (PFS) and overall survival (OS) among cervical cancers patients. Materials and Methods: The present retrospective study enrolled 303 cervical cancer (Stage IIB–IVA) patients treated by radical radiotherapy from January 2016 to December 2018. The pretreatment values of NLR, absolute neutrophil count, and absolute lymphocyte count (ALC) were recorded for each patient and their associations with the clinicopathologic variables, PFS, and OS were analyzed. Results: The optimal cutoff value of NLR was 3.0. The median follow-up period was 19 months. On univariate analysis, PFS rates during the follow-up period were significantly lower in NLR-high versus NLR-low group (P = 0.042) and in low-ALC versus high-ALC group (P = 0.018). Multivariate Cox-proportional hazards model identified NLR and ALC as the strongest prognostic factors for PFS. On univariate analysis, OS was better for patients with the International Federation of Gynecology and Obstetrics Stage IIB versus III–IVA (P = 0.046) and ALC >2000/c.mm versus ≤2000/c.mm (P = 0.050), respectively. None of the hematological variables remained significant for OS on the multivariate analysis. Conclusion: High-NLR is associated with worse survival outcomes in cervical cancer patients. NLR and ALC are the independent prognostic factors for PFS in cervical cancer patients.
Keywords: Cervical cancer, chemoradiotherapy, neutrophil lymphocyte ratio, prognosis, survival outcomes
|How to cite this article:|
Ali Azher B M, Thakur N, Patel S. Prognostic significance of neutrophil lymphocyte ratio in patients of carcinoma cervix treated with radiotherapy. Oncol J India 2020;4:92-7
|How to cite this URL:|
Ali Azher B M, Thakur N, Patel S. Prognostic significance of neutrophil lymphocyte ratio in patients of carcinoma cervix treated with radiotherapy. Oncol J India [serial online] 2020 [cited 2021 Jan 26];4:92-7. Available from: https://www.ojionline.org/text.asp?2020/4/3/92/301578
| Introduction|| |
Systemic inflammation is one of the important manifestations of malignancy development and progression resulting in neutrophilia, thrombocytosis, and relative lymphocytopenia in the peripheral blood. These changes in peripheral blood have the potential for the use as preoperative prognostic markers.,,,. Preclinical data have shown that immune deregulating effects of neutrophil may potentially contribute to tumor progression in cervical and ovarian cancers.,, There are various hematological parameters of systemic inflammation that have been investigated for prognostic significance.,, The increase neutrophil-to-lymphocyte ratio (NLR) in peripheral blood has been identified as a poor prognostic factor in various cancers. It is a relatively simple and cost-effective alternative for quantifying subclinical inflammation than disease-specific biomarkers that are expensive and require time to obtain results.
Cisplatin-based concurrent chemoradiotherapy (CCRT) followed by brachytherapy is the standard treatment for patients with locally advanced cervical cancer (LACC) and reduces the rates of local, and distant recurrence. However, the recurrence rate is high in patients with large or advanced-stage tumors. Various peripheral blood parameters have been shown to have effect on treatment outcomes. However, a few studies have been reported on the potential role of NLR as a predictive factor. Keeping this in background, we aimed to evaluate the prognostic value of NLR in predicting clinical outcomes in patients treated with RT alone or CCRT.
| Materials and Methods|| |
The present retrospective study enrolled 303 patients diagnosed with cervical cancer staged as International Federation of Gynecology and Obstetrics (FIGO) Stage IIB to IVA and treated at tertiary care institute from January 2016 to December 2018. The study was approved by the Institutional Ethics Committee. The study was carried out to estimate prognostic significance of the pretreatment NLR, absolute neutrophil count (ANC), and absolute lymphocyte count (ALC) on survival outcomes in adult women with cervical cancers in terms of overall survival (OS) and progression free survival (PFS). The patients having recurrent cervical cancer, known hematologic or infectious disease, undergoing radical hysterectomy, and/or absence of complete blood cell count data with differential cell counts within 2 weeks of initiation of RT were excluded from the study.
The demographic characteristics of the patients, including pretreatment haematological parameters were recorded in the structured pro forma. The values of ANC and ALC were obtained from complete blood cell count data. The NLR was calculated by dividing ANC with ALC. The association of clinicopathological variables such as age, FIGO stage, histology, grade of the tumor, and response to therapy with NLR, ALC, and ANC was analyzed.
The pretreatment evaluation such as patient's history, performance status, physical and gynecological examination, complete blood count, blood biochemistry profile, chest radiograph, and contrast-enhanced computed tomography (CECT) scan of the abdomen and pelvis were recorded. Cystoscopy and sigmoidoscopy were performed when required. All the patients were treated with external-beam radiotherapy (EBRT) with or without concurrent chemotherapy followed by brachytherapy under proper dose schedule. EBRT was given up to a dose of 50 Gy in 25 fractions. High dose-rate brachytherapy was given at a dose rate of 7.5 Gy per fraction up to two fractions. Concurrent chemotherapy consisted of weekly intravenous cisplatin administration at a dose of 40 mg/m2 body surface area for 5 cycles. RECIST criteria version 1.1 was used to assess the treatment response in terms of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). After treatment, the patients were followed-up as per the schedule of every 3–4 months for the first 2 years, every 6–12 months for the next 3 years and yearly thereafter. During each follow-up, a complete physical examination, including per vaginal and per rectal examination, was scheduled. CECT scan of the abdomen pelvis was done 3 months after treatment completion. During the routine follow-up, imaging studies including CECT or magnetic resonance imaging of the abdomen and pelvis, and chest X-ray were performed annually. When tumor recurrence was suspected based on the clinical findings or imaging studies, biopsy of that lesion was performed. OS is defined as the period between the date of diagnosis and last documented follow-up. PFS is defined as the time elapsed between treatment initiation and tumor progression or death.
The associations between NLR, ANC, and ALC and the clinicopathologic variables were analyzed using a Chi-square test. OS and PFS were analyzed using the Kaplan–Meier method. The log-rank test was used to study the association of prognostic factors with survival. The univariate and multivariate Cox-proportional hazard models were used to identify the most significant independent prognostic factor for PFS and OS. IBM SPSS version. 25.0. (Armonk, NY: IBM Corp.) was used for the statistical analysis.
| Results|| |
Baseline patient characteristics are highlighted in [Table 1]. The median age of presentation was 50 years within the range of 25–80 years. The majority of cases were of FIGO stage IIIB and squamous cell carcinoma histology. The optimal cutoff value of the NLR was determined to be 3.0 by the receiver-operating characteristic curve. CCRT was administrated in 272 patients (89.8%), whereas 31 patients (10.2%) received only radiotherapy (RT). After completion of primary treatment, 46 patients (15.2%) relapsed.
[Table 2] showed the comparison of baseline characteristics between the two groups NLR-low and NLR-high as categorized according to the NLR cutoff value (3.0). NLR-low (≤3.0) and NLR-high (>3.0) were seen in 146 (42.8%) and 157 (51.2%) cases, respectively. The mean differences between the two groups were found to be significant in ANC (P = 0.000) and ALC (P = 0.003). The difference between the two groups was not significant for the categorical variables such as histological type and grade. However, the difference was significant for stage between the two groups (P = 0.007). The differences in ANC, ALC, and NLR according to clinical characteristics of the patients are mentioned in [Table 2] and [Table 3]. There was a trend for higher ANC (>6500/c.mm) among patients who were younger than 50 years (P = 0.745) and had a more advanced-stage disease (P = 0.072), although not statistically significant. In contrast, low-ALC (≤2000/c.mm) was seen in patients with a more advanced stage disease (P = 0.050). NLR >3.0 was found to be significantly higher in patients with more advanced stage disease (P = 0.007). There was no significant association of histologic grade with ANC, ALC and NLR values. Among the 46 patients who relapsed, 25 patients (54.3%) had a higher NLR cutoff value (P = 0.709). Low-ALC was significantly seen in patients who had relapsed (P = 0.034).
|Table 2: Comparison of the clinicopathological and laboratory parameters between neutrophil-lymphocyte ratio-low and neutrophil-lymphocyte ratio-high groups|
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|Table 3: Comparison of the clinicopathological parameters with absolute lymphocyte count and absolute neutrophil count cutoff values|
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The median follow-up period was 19 months. The PFS rates during the follow-up period were significantly lower in the NLR-high versus NLR-low groups (P <0.05) and in low-ALC versus high-ALC groups (P <0.05) [Figure 1] and [Figure 2]. There was a trend toward high PFS rates in the group with low-ANC (P = 0.222). There was a trend toward high OS rates in the group with low NLR (P = 0.296) [Figure 3], low-ANC (P = 0.665), and high-ALC (P = 0.647) [Figure 4]. We did univariate analysis for various prognostic factors such as age, FIGO stage, NLR, ALC, and ANC. On univariate analysis, the PFS rates during the follow-up were significantly lower in the NLR-high versus NLR-low group (hazard ratio [HR] =3.222; 95% confidence interval [CI] =1.741–3.409; P = 0.042), low-ALC versus high-ALC group (HR = 0.478; 95% CI = 0.259–0.880; P = 0.018), FIGO stage III-IV versus stage II (HR = 2.400; 95% CI = 1.116-5.159; P = 0.025) [Table 4]. Using the multivariate Cox-proportional hazards model, we identified NLR (HR = 3.170; 95% CI = 1.307–4.459, P = 0.049), and ALC (HR = 0.480; 95% CI = 0.235–0.982, P = 0.045), as the independent prognostic factors significant for PFS [Table 4]. On univariate analysis, we found better OS for patients with FIGO Stage II versus stage III and IV (P = 0.046) and ALC >2000/c.mm versus ALC ≤2000/c.mm (P = 0.050), respectively. On multivariate analysis, none of the above hematological variables were found to be statistically significant for OS [Table 5].
|Figure 1: Progression-free survival stratified by neutrophil lymphocyte ratio|
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|Figure 2: Progression-free survival stratified by absolute lymphocyte count|
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|Table 4: Univariate and multivariate survival analysis for progression-free survival|
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|Table 5: Univariate and multivariate survival analysis for overall survival|
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| Discussion|| |
In the present study, we assessed the prognostic value of pretreatment NLR in patients of cervical cancers who underwent RT. We found the association of NLR and various hematologic variables with treatment outcomes and survival.
There is enough evidence that inflammation has a pivotal role in carcinogenesis, development, invasion, and progression.,,,,, Neutrophils have significant potential for providing fertile soil for tumor associated angiogenesis by means of circulating vascular endothelial growth factor (VEGF) and many inflammatory cytokines such as tumor necrosis factor and interleukin 1. The tumor micro environment also has a paramount role in progression of tumor by aggregation of inflammatory cells and vascular permeability. The VEGF in circulation as a result of host tumor interactions increases the vascular permeability which is significantly higher in tumor cells. Conversely, lymphocytes exert a critical role in cancer. VEGF-C appears to play a central role in tumor associated lymphangiogenesis which can be translated into lymphatic metastasis and poor clinical outcomes. Lymphocytes are most radiosensitive cells and lymphocytopenia occurs after radiation, whereas neutrophils are maintained in huge number. RT-induced lymphopenia along with tumor-induced granulocytosis contributes to an increase in NLR which act as an independent prognosticator for OS.
It is well-established that systemic inflammation is a prognostic factor in various cancers including colorectal, anal canal, and other solid tumors. Neutrophils can produce certain chemokines and cytokines which cause the suppression of immune activity of lymphocytes and natural killer cells. A greater inflammation response would be generated by the interaction of cancer cells with neutrophils that lead to proliferation, invasion, and metastasis of cancer cell. NLR is an indicator of systemic inflammation and tumor immune response in the various stages of cancer. High blood NLR is a surrogate of poor survival outcomes for cancer patients, and the mechanism of this is not clearly evident. Some advanced and metastatic tumors portend the role of NLR which can be manipulated to give some therapeutic advances.
We found poor outcomes in patients with high NLR. Elevated NLR trigger circulating concentrations of cytokines and chemokines in systemic inflammatory response. Tumor growth promoting factors such as transforming growth factor-beta can also activate other growth factors to enhance tumor progression, immune suppression, angiogenesis, and peritumoral stroma formation.,,, Moreover, it may promote the increase in the number of neutrophil which in turn can cause a reduction in the number of lymphocytes. Inflammatory cells may infiltrate the extracellular matrix and adjacent normal tissues thereby secrete modulators of immune suppression and tumor progression. Some studies found the association of lymphopenia with cancer-related immunosuppression, which gives a chance to evade immune system and early infiltration by tumors., In our study, we found poor outcomes in young patients, patients with pretreatment neutrophilia, relative lymphocytopenia, high NLR, higher relapse rates, and poor response to RT. These findings match with the findings of previous studies.,,,
There is a robust data suggesting that high NLR has a significant association with tumor burden, advanced clinical stage, and positive lymph node metastasis. The relationship between the pretreatment NLR and clinicopathological features pointed out that high NLR is a surrogate of poor clinical outcome and it can be used as a prognostic tool for clinical judgement. Again, high NLR is closely correlated with more aggressive tumor behavior which in turn contributes to more relapse rates and thus shorter OS and PFS.
There are several inflammatory markers which have shown a prognostic value in cervical cancer. There is a need for high cost and advanced technology in assessing protein biomarkers and gene polymorphism. This creates a problem to use them as routine prognostic predictor in clinical scenario, especially in developing countries. On the other hand, hematological test can be carried out conveniently at a low cost before the treatment of cancer patients, making it an effective, accessible, affordable, and reproducible laboratory parameter to reflect the inflammatory status in the body.
NLR is a well-established host immune parameter in cancer patients. A recent meta-analysis on gynecologic cancers reported that NLR had a strong association with PFS and OS in patients who received definitive RT. In 2016, Cho et al. reported the results of a retrospective study with 2456 patients of LACC who were treated with definitive RT. This study suggested that both leukocytosis (>9000/cmm) and high NLR (>2.5) were the prognostic factors for loco regional failure-free survival and OS. In our study, we found that a more advanced stage, high NLR, low ALC were associated with poor OS and PFS. Among the hematologic variables, NLR and ALC had a prognostic significance for both PFS and OS in the univariate analysis.
The presence of tumor-infiltrating lymphocytes (TIL) have been associated with better outcomes in early-stage cervical cancer patients treated by surgery. However, the evidence on the association between TIL and response to RT in patients of LACC is lacking, probably because of insufficient tissue available for evaluating TIL in most cases. Since lymphocyte percentage reflects leukocytosis more directly than NLR does, it can be used as a hematologic parameter reflecting host immune status relating to RT response. Lymphocyte percentage, along with NLR, is an easy and cost-effective index to determine the prognosis of patients who have received RT.
The present study has some limitations. At first, patients from a single institution were included and retrospectively designed for which existing bias could not be controlled. Second, tumor tissue samples were not evaluated to know whether NLR was correlated with tumor immune microenvironment, such as TILs. Moreover, pretreatment performance status and detailed data on chemotherapy from the medical record review were not obtained. Therefore, further large-scale prospective studies are necessary to overcome these limitations.
| Conclusion|| |
The increase in pretreatment NLR have been associated with poorer survival outcomes in patients of cervical carcinoma treated with RT. NLR and ALC are the independent prognostic factors for PFS in patients of cervical cancer. Therefore, risk stratification of patients based on the evaluation of NLR or other similar parameters before treatment could help in customizing the treatment. It might help in determining the approach for a more aggressive treatment strategy and exploring the role of targeted agents to counteract high NLR, thus opening a new paradigm for cancer treatment. As our study was retrospectively designed from a single institution, further large-scale prospective clinical trials are needed for customized treatment.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011;144:646-74.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883-99.
McMillan DC. The systemic inflammation-based Glasgow Prognostic Score: A decade of experience in patients with cancer. Cancer Treat Rev 2013;39:534-40.
Gavalas NG, Karadimou A, Dimopoulos MA, Bamias A. Immune response in ovarian cancer: How is the immune system involved in prognosis and therapy: Potential for treatment utilization, Clin Dev Immunol 2010;2010:791603.
Preston CC, Goode EL, Hartmann LC, Kalli KR, Knutson KL. Immunity and immune suppression in human ovarian cancer. Immunotherapy 2011;3:539-56.
Klink M, Jastrzembska K, Nowak M, Bednarska K, Szpakowski M, Szyllo K, et al
. Ovarian cancer cells modulate human blood neutrophils response to activation in vitro
. Scand J Immunol 2008;68:328-36.
Fernandes PC, Garcia CB, Micheli DC, Cunha FQ, Murta EF, Tavares-Murta BM. Circulating neutrophils may play a role in the host response in cervical cancer, Int J Gynecol Cancer 2007;17:1068-74.
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;88:218-30.
Yodying H, Matsuda A, Miyashita M, Matsumoto S, Sakurazawa N, Yamada M, et al
. Prognostic significance of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in oncologic outcomes of esophageal cancer: A systematic review and meta-analysis. Ann Surg Oncol 2016;23:646-54.
Templeton AJ, McNamara MG, Šeruga B, Vera-Badillo FE, Aneja P, Ocaña A, et al
. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: A systematic review and meta-analysis. J Natl Cancer Inst 2014;106:dju124.
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-44.
Mishalian I, Bayuh R, Levy L, Zolotarov L, Michaeli J, Fridlender ZG. Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression. Cancer Immunol Immunother 2013;62:1745-56.
Märkl B, Wieberneit J, Kretsinger H, Mayr P, Anthuber M, Arnholdt HM, et al
. Number of intratumoral T lymphocytes is associated with lymph node size, lymph node harvest, and outcome in node-negative colon cancer. Am J Clin Pathol 2016;145:826-36.
Noble F, Mellows T, McCormick Matthews LH, Bateman AC, Harris S, Underwood TJ, et al
. Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma. Cancer Immunol Immunother 2016;65:651-62.
Kumar R, Geuna E, Michalarea V, Guardascione M, Naumann U, Lorente D, et al
. The neutrophil-lymphocyte ratio and its utilisation for the management of cancer patients in early clinical trials. Br J Cancer 2015;112:1157-65.
Petrie HT, Klassen LW, Kay HD. Inhibition of human cytotoxic T lymphocyte activity in vitro
by autologous peripheral blood granulocytes. J Immunol 1985;134:230-4.
Chow MT, Möller A, Smyth MJ. Inflammation and immune surveillance in cancer. Semin Cancer Biol 2012;22:23-32.
Tsushima H, Kawata S, Tamura S, Ito N, Shirai Y, Kiso S, et al
. High levels of transforming growth factor beta 1 in patients with colorectal cancer: Association with disease progression. Gastroenterology 1996;110:375-82.
Gupta S, Hau AM, Al-Ahmadie HA, Harwalkar J, Shoskes AC, Elson P, et al
. Transforming growth factor-b Is an upstream regulator of mammalian target of rapamycin complex 2–dependent bladder cancer cell migration and invasion. Am J Pathol 2016;186:1351-60.
Elliott RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol 2005;23:2078-93.
Calon A, Tauriello DV, Batlle E. TGF-beta in CAF-mediated tumor growth and metastasis. Semin Cancer Biol 2014;25:15-22.
Nakamura Y, Watanabe R, Katagiri M, Saida Y, Katada N, Watanabe M, et al
. Neutrophil/lymphocyte ratio has a prognostic value for patients with terminal cancer. World J Surg Oncol 2016;14:148.
Cézé N, Thibault G, Goujon G, Viguier J, Watier H, Dorval E, et al
. Pre-treatment lymphopenia as a prognostic biomarker in colorectal cancer patients receiving chemotherapy. Cancer Chemother Pharmacol 2011;68:1305-13.
Cho Y, Kim KH, Yoon HI, Kim GE, Kim YB. Tumor-related leukocytosis is associated with poor radiation response and clinical outcome in uterine cervical cancer patients. Ann Oncol 2016;27:2067-74.
Lee YY, Choi CH, Kim HJ, Kim TJ, Lee JW, Lee JH, et al
. Pretreatment neutrophil: lymphocyte ratio as a prognostic factor in cervical carcinoma. Anticancer Res 2012;32:1555-61.
Monk BJ, Tian C, Rose PG, Lanciano R. Which clinical/pathologic factors matter in the era of chemoradiation as treatment for locally advanced cervical carcinoma? Analysis of two Gynecologic Oncology Group (GOG) trials. Gynecol Oncol 2007;105:427-33.
Lau HY, Juang CM, Chen YJ, Twu NF, Yen MS, Chao KC. Aggressive characteristics of cervical cancer in young women in Taiwan. Int J Gynaecol Obstet 2009;107:220-3.
Ethier JL, Desautels DN, Templeton AJ, Oza A, Amir E, Lheureux S. Is the neutrophil-to-lymphocyte ratio prognostic of survival outcomes in gynecologic cancers? A systematic review and meta-analysis. Gynecol Oncol 2017;145:584-94.
Piersma SJ, Jordanova ES, van Poelgeest MI, Kwappenberg KM, van der Hulst JM, Drijfhout JW, et al
. High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. Cancer Res 2007;67:354-61.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]