Prognostic value of baseline white blood cell count and neutrophil–lymphocyte ratio in carcinoma cervix

Amani Bhogadi; Rohith Singareddy; Harjot Kaur Bajwa; Alluri Krishnam Raju

doi:10.4103/bjoc.bjoc_10_21

ORIGINAL ARTICLES

Year : 2021 | Volume : 1 | Issue : 1 | Page : 8-11

Prognostic value of baseline white blood cell count and neutrophil–lymphocyte ratio in carcinoma cervix

Amani Bhogadi, Rohith Singareddy, Harjot Kaur Bajwa, Alluri Krishnam Raju
Department of Radiation Oncology, Basavatarakam Indo, American Cancer Hospital and Research Institute, Hyderabad, Telangana, India

Date of Submission	05-Aug-2021
Date of Acceptance	27-Nov-2021
Date of Web Publication	06-Jan-2022

Correspondence Address:
Dr. Amani Bhogadi
Department of Radiation Oncology, Basavatarakam Indo American Cancer Hospital and Research Institute, Road number 10, Banjara Hills, Hyderabad 500034, Telangana.
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bjoc.bjoc_10_21

Abstract

Aims: To evaluate the impact of baseline white blood cell (WBC) count and neutrophil–lymphocyte ratio (NLR) in carcinoma cervix patients treated with definitive chemoradiotherapy. Settings and Design: Retrospective cohort study, original research article in Department of Radiation Oncology, Basavatarakam Indo American Cancer hospital. Materials and Methods: Patients of squamous cell carcinoma cervix treated with radical chemoradiotherapy from January 2017 to August 2017 were included in the analysis. All patients had baseline blood counts, local imaging, and metastatic workup at diagnosis. Patients received external beam radiotherapy to a total dose of 50 Gy in 25 fractions along with weekly cisplatin (40 mg/m²) and brachytherapy (21 Gy in 3 fractions). Baseline WBC counts and baseline NLR were correlated with outcomes using chi square test and receiver operating characteristic curves. Statistical analysis used: The patients were divided into two groups based on high-baseline WBC count and normal-baseline WBC count. Baseline WBC counts and baseline NLR were correlated with patterns of recurrence using chi square test. The sensitivity and specificity of prognostic factors for recurrence were computed using ROC curves. Results: The NLR cut-off value of 3.47 had high sensitivity and specificity for predicting recurrence in these patients. Majority of the recurrences in patients having high WBC count and high NLR were distant recurrences. Conclusions: A high-baseline WBC count and high NLR resulted in higher rates of recurrence and inferior survival in carcinoma cervix patients in our study. These biomarkers can be used as predictors of outcomes in carcinoma cervix.

Keywords: Carcinoma cervix, high white blood cells, neutrophil–lymphocyte ratio

How to cite this article:
Bhogadi A, Singareddy R, Bajwa HK, Raju AK. Prognostic value of baseline white blood cell count and neutrophil–lymphocyte ratio in carcinoma cervix. Bengal J Cancer 2021;1:8-11

How to cite this URL:
Bhogadi A, Singareddy R, Bajwa HK, Raju AK. Prognostic value of baseline white blood cell count and neutrophil–lymphocyte ratio in carcinoma cervix. Bengal J Cancer [serial online] 2021 [cited 2023 Mar 25];1:8-11. Available from: http://www.bengaljcancer.org/text.asp?2021/1/1/8/335054

Introduction

Cervical cancer continues to be a major public health problem affecting middle-aged women, particularly in low-middle income countries.^[1] The treatment of advanced carcinoma cervix is radical chemoradiotherapy and brachytherapy.^[2] Over the years, advances in treatment have led to increased survival in patients presenting with advanced stage.^[3] However, certain patients continue to have poorer outcomes despite receiving standard of care. There are various ongoing studies to evaluate biomarkers that predict outcomes in these patients.

An inflammatory microenvironment can promote carcinogenesis and tumor progression in various cancers. Neutrophils and lymphocytes are the principal components of the tumor-related stroma and correlate with local inflammation and immune responses, respectively.^[4],[5] Baseline white blood cell (WBC) count and neutrophil–lymphocyte ratio (NLR) indicate the balance of the inflammatory and immune systems, making it a useful index for predicting prognosis in malignancies. Recent studies have declared the prognostic significance of NLR in patients with carcinoma cervix; however, these studies presented conflicting data due to the variance in study design, sample size, and patient characteristics.^[6],[7],[8]

In India, majority of carcinoma cervix patients present in advanced stage and may have pelvic inflammatory disease complicating treatment. There is no data regarding the relationship between baseline hematological parameters with outcomes in the Indian scenario. We report the prognostic significance of baseline white blood cell (WBC) count and NLR in carcinoma cervix patients treated at a tertiary cancer center in India.

Materials and Methods

We analyzed biopsy-proven patients of squamous cell carcinoma cervix treated at our center from January 2017 till August 2017. An institutional ethics and scientific committee approval was taken for the study. Written informed consent was taken from all patients prior to treatment. All patients had baseline blood counts, local imaging, and metastatic workup at diagnosis. Staging investigations included chest X-ray or chest CT, ultrasound abdomen, and pelvis with or without abdominal/pelvic CT or pelvic MRI. Patients were staged using FIGO 2009 classification. All baseline blood counts were taken within ten days of initiation of treatment.

Treatment details

Patients received radical external beam radiotherapy to the pelvis to a total dose of 50 Gy in 25 fractions along with concurrent weekly Cisplatin (40 mg/m²). This was followed by a HDR brachytherapy for a total dose of 21 Gy in 3 fractions, 7 Gy per fraction, 1 week apart. Cisplatin was withheld if the absolute neutrophil count (ANC) was <1.5×10⁹/L or the platelet count was <100×10⁹/L and reassessed the following week. Adjuvant or neoadjuvant chemotherapy was not used.

Follow up

Patients were assessed every 3 months for the first 2 years following treatment, and every 4–6 months during years 3, 4, and 5. During routine follow-up, gynecological pelvic examinations were performed. Cytology and imaging studies including CT, MRI, or PET-CT were performed only if examination findings were suspicious of recurrence or patient was symptomatic.

Statistical analysis

The patients were divided into two groups based on high-baseline WBC count (more than 12,000 cells/mm³) and normal-baseline WBC count (less than 12,000 cells/mm³). Baseline WBC counts and baseline NLR were correlated with patterns of recurrence using chi square test. The sensitivity and specificity of prognostic factors were computed using ROC curves. Recurrences involving the cervix, vagina, or parametrial tissue were classified as local, whereas LN failures within the radiotherapy field were defined as regional recurrence. Recurrence outside the radiotherapy field was defined as distant metastasis.

Results

A total of 108 patients of carcinoma cervix received treatment during the study period of which 52 belonged to normal-baseline WBC count group (Group 1) and 56 belonged to high -baseline WBC count group (Group 2). The most common stage in both groups was FIGO stage IIIB. The baseline NLR was higher in high-baseline WBC count group as compared to normal-baseline WBC count group. The patient characteristics are listed in [Table 1].

Table 1: Characteristics of carcinoma cervix patients receiving radical chemoradiation

Click here to view

All patients completed treatment with a median overall treatment time of 7 weeks. The median number of chemotherapy cycles in both groups was 4 (range 2–5). At a median follow-up of 32 months (28–36 months), 8 patients were lost to follow-up and 100 patients were available for final analysis. The most common pattern of recurrence was distant metastasis. Distant recurrences were significantly higher in patients with high-baseline WBC count as compared to those with normal-baseline WBC count (P = 0.001). The median disease-free interval was 20 months in Group 1 whereas it was 12 months in Group 2. The patterns of recurrence of carcinoma cervix patients belonging to the two groups are depicted in [Table 2].

Table 2: Patterns of recurrence in carcinoma cervix patients based on baseline WBC count

Click here to view

Based on ROC curve analysis, the NLR cutoff of 3.47 had 62% sensitivity and 69% specificity for predicting recurrence in these patients [Figure 1].

Figure 1: ROC curve for threshold of NLR with respect to recurrence

Click here to view

Discussion

Our patients of carcinoma cervix treated with standard of care (radical chemoradiation) had high rates of recurrence if the baseline WBC counts and baseline NLR was high as compared to those with normal WBC counts at baseline. This was in concordance with data published by Mizunuma M et al.^[5] They concluded that high pretreatment NLR resulted in shorter progression-free and overall survival in carcinoma cervix patients treated with radiation alone or chemoradiation. Thirty-four percent of patients in their study received radiotherapy alone and the arbitrary level of high NLR (more than 2.5) was chosen based on median NLR of the study population.

A meta-analysis by Wu et al.^[9] based on the data from 13 studies with 3729 patients concluded that elevated pretreatment NLR was a poor prognostic marker for patients with cervical cancer because it predicted unfavorable overall survival (HR = 1.375, 95% CI: 1.200–1.576) and progression-free survival (HR = 1.646, 95% CI: 1.313–2.065). Another retrospective analysis of 2456 cervical cancer patients by Cho et al. demonstrated that tumor-related leukocytosis (TRL) was associated with poor radiation response and unfavorable prognosis.^[10] TRL was defined as at least two separate occasions of leukocytosis exceeding 9000/µl without any evidence of infection. Patients with TRL had higher rates of locoregional and distant recurrences compared to those without TRL. The majority of the recurrences were locoregional recurrences in their study. This was contradictory to our study where majority of the recurrences were distant metastasis. The reasons attributing to good local control in our study are delivery of adequate doses of radiation and brachytherapy along with concurrent chemotherapy and maintaining overall treatment time to less than 7 weeks.

Several inflammatory markers, such as CRP and modified Glasgow prognostic score (mGPS) have been reported to show prognostic value in carcinoma cervix.^[11],[12] Their utility in low-middle income countries and high-volume centers is minimal due to high cost and resource limitations. A baseline hematological test is carried out routinely at a low cost before the treatment of cancer patients. This makes it a convenient and reproducible laboratory parameter to reflect the inflammatory status in body.

Our study has the limitations of a small sample size and moderate follow-up of 32 months. Since majority of the recurrences in carcinoma cervix occur within the first two years of treatment, we believe our findings add value to the current evidence. The strengths of our study are uniform standard of care across the entire cohort of patients and inclusion of only squamous histology. To our knowledge, this is the first study from India correlating baseline WBC counts and NLR with patient outcomes in carcinoma cervix. We believe these parameters can serve as effective low-cost biomarkers in conjunction with other factors to predict response in our patients. The high rates of distant metastasis in these patients warrant further studies evaluating the role of adjuvant chemotherapy in improving outcomes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

The authors declare no potential conflict of interest. No funding was obtained to perform the study.

References

1.	Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Glob Health 2020;8:e191-203. Erratum in: Lancet Glob Health2022;10:e41.
2.	Bhatla N, Aoki D, Sharma DN, Sankaranarayanan R . Cancer of the cervix uteri: 2021 update. Int J Gynaecol Obstet 2021;155(Suppl 1):28-44.
3.	Sturdza A, Pötter R, Fokdal LU, Haie-Meder C, Tan LT, Mazeron R, et al. Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in retroembrace, a multicenter cohort study. Radiother Oncol 2016;120:428-33.
4.	Schreiber RD, Old LJ, Smyth MJ Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science 2011;331:1565-70.
5.	Schetter AJ, Heegaard NH, Harris CC Inflammation and cancer: Interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis 2010;31:37-49.
6.	Mabuchi S, Matsumoto Y, Kawano M, Minami K, Seo Y, Sasano T, et al. Uterine cervical cancer displaying tumor-related leukocytosis: A distinct clinical entity with radioresistant feature. J Natl Cancer Inst2014;106:5-10.
7.	Mizunuma M, Yokoyama Y, Futagami M, Aoki M, Takai Y, Mizunuma H The pretreatment neutrophil-to-lymphocyte ratio predicts therapeutic response to radiation therapy and concurrent chemoradiation therapy in uterine cervical cancer. Int J Clin Oncol 2015;20:989-96.
8.	Jonska-Gmyrek J, Gmyrek L, Zolciak-Siwinska A, Kowalska M, Fuksiewicz M, Kotowicz B Pretreatment neutrophil to lymphocyte and platelet to lymphocyte ratios as predictive factors for the survival of cervical adenocarcinoma patients. Cancer Manag Res 2018;10:6029-38.
9.	Wu J, Chen M, Liang C, Su W Prognostic value of the pretreatment neutrophil-to-lymphocyte ratio in cervical cancer: A meta-analysis and systematic review. Oncotarget 2017;8:13400-12.
10.	Cho Y, Kim KH, Yoon HI, Kim GE, Kim YB Tumor-related leucocytosis is associated with poor radiation response and clinical outcome in uterine cervical cancer patients. Ann Oncol 2016;27:2067-74.
11.	Zhi W, Ferris D, Sharma A, Purohit S, Santos C, He M, et al. Twelve serum proteins progressively increase with disease stage in squamous cell cervical cancer patients. Int J Gynecol Cancer 2014;24:1085-92.
12.	Xiao Y, Ren YK, Cheng HJ, Wang L, Luo SX Modified Glasgow prognostic score is an independent prognostic factor in patients with cervical cancer undergoing chemoradiotherapy. Int J Clin Exp Pathol 2015;8:5273-81.