Different prognostic effects of nadirs of neutrophils and lymphocytes during radical (chemo)radiotherapy for cervical cancer

Objective: To study prognostic effects of nadirs of neutrophils and lymphocytes during radical (chemo)radiotherapy for cervical cancer. Methods: Patients with International Federation of Gynecology and Obstetrics (FIGO) IB1-IVA cervical cancer from January 2015 through December 2019 were retrospectively analyzed. All patients were treated with radical (chemo)radiotherapy and had available baseline and weekly complete blood counts with differentials before and during treatment. Results: A total of 107 patients were eligible. Receiver operating characteristic (ROC) curve determined the cutoff values predicting overall survival (OS) of nadirs of absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) during treatment were 2.62 × 109${}^9$/L and 0.2 × 109${}^9$/L, respectively. Compared with ANC nadir ≤2.62 × 109${}^9$/L (N = 94), patients with ANC nadir >2.62 × 109${}^9$/L (N = 13) had lower 2-year OS rate (51.9% vs 88.7%, p = 0.01) and lower 2-year progression-free survival (PFS) rate (52.7% vs 80.8%, p = 0.003); compared with ALC nadir >0.2 × 109${}^9$/L (N = 65), patients with ALC nadir ≤0.2 × 109${}^9$/L (N = 42) had lower 2-year OS rate (74.7% vs 90.0%, p = 0.004) and lower 2-year PFS rate (67.8% vs 83.3%, p = 0.038). Multivariate COX analysis showed that ANC nadir ($>$2.62 vs $\le$2.62 $\times$ 109${}^9$/L) (hazard ratio (HR) 4.729, 95% confidence interval (CI) 1.355–16.505, p = 0.015), ALC nadir ($\le$0.2 vs $>$0.2 $\times$ 109${}^9$/L) (HR 4.463, 95% CI 1.616–12.321, p = 0.004) were associated with OS. Conclusions: Peripheral ANC nadir and ALC nadir during radical (chemo)radiotherapy have different prognostic effects in predicting treatment outcome. ANC and ALC nadir during radical (chemo)radiotherapy may serve as a guide to treatment of cervical cancer.

Absolute lymphocyte count nadir; Absolute neutrophil count nadir; Cervical cancer; Prognosis; Radiotherapy

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2019; 68: 394–424.

[2] National Comprehensive Cancer Network®. NCCN Clinical Prac- tice Guidelines in Oncology (NCCN Guidelines®) Cervical Cancer Version 1.2020 [EB/OL]. 2020. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf (Accessed: 14 January 2020).

[3] Kostova P, Zlatkov V, Danon S. Five-year overall survival and prognostic factors in patients with cervical cancer in Bulgaria. Journal of the Balkan Union of Oncology. 2008; 13: 363–368.

[4] Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011; 331: 1565–1570.

[5] Melis MHM, Simpson KL, Dovedi SJ, Welman A, MacFarlane M, Dive C, et al. Sustained tumour eradication after induced caspase-3 activation and synchronous tumour apoptosis requires an intact host immune response. Cell Death and Differentiation. 2013; 20: 765–773.

[6] 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– 13412.

[7] Palaia I, Tomao F, Di Pinto A, Pernazza A, Santangelo G, D’Alessandris N, et al. Response to Neoadjuvant Chemotherapy in Locally Advanced Cervical Cancer: the Role of Immune-related Factors. In Vivo. 2021; 35: 1277–1283.

[8] Yang L, Xu ZY, Chang AT, Wang Q, Chen X, Shen L, et al. A Potential Survival Impact of Blood Immune Cells in Patients with Cervical Carcinoma Treated with Concurrent Chemoradio- therapy. International Journal of Radiation Oncology, Biology, Physics. 2019; 105: E343.

[9] Yildirim BA, Guler OC, Kose F, Onal C. The prognostic value of haematologic parameter changes during treatment in cervical cancer patients treated with definitive chemoradiotherapy. Journal of Obstetrics and Gynaecology. 2019; 39: 695–701.

[10] Wisdom AJ, Hong CS, Lin AJ, Xiang Y, Cooper DE, Zhang J, et al. Neutrophils promote tumor resistance to radiation therapy. Proceedings of the National Academy of Sciences. 2019; 116: 18584–18589.

[11] Wu ES, Oduyebo T, Cobb LP, Cholakian D, Kong X, Fader AN, et al. Lymphopenia and its association with survival in patients with locally advanced cervical cancer. Gynecologic Oncology. 2016; 140: 76–82.

[12] Cho O, Chun M, Chang S, Oh Y, Noh OK. Prognostic Value of Severe Lymphopenia during Pelvic Concurrent Chemoradiotherapy in Cervical Cancer. Anticancer Research. 2016; 36: 3541–3547.

[13] Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013; 39: 1–10.

[14] Wu L, Saxena S, Singh RK. Neutrophils in the Tumor Microenvironment. Advances in Experimental Medicine and Biology. 2020; 16: 1–20.

[15] Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nature Medicine. 2015; 21: 938–945.

[16] Schernberg A, Blanchard P, Chargari C, Deutsch E. Neutrophils, a candidate biomarker and target for radiation therapy? Acta Oncologica. 2017; 56: 1522–1530.

[17] Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, et al. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). The Lancet. Oncology. 2012; 13: 671– 678.

[18] Staar S, Rudat V, Stuetzer H, Dietz A, Volling P, Schroeder M, et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy–results of a multicentric randomized German trial in advanced head-and- neck cancer. International Journal of Radiation Oncology, Biol- ogy, Physics. 2001; 50: 1161–1171.

[19] 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. Journal of the National Cancer Institute. 2014; 106: dju147.

[20] Kawano M, Mabuchi S, Matsumoto Y, Sasano T, Takahashi R, Kuroda H, et al. The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uter- ine cervical cancer. Scientific Reports. 2015; 5: 18217.

[21] Venkatesulu BP, Mallick S, Lin SH, Krishnan S. A systematic review of the influence of radiation-induced lymphopenia on survival outcomes in solid tumors. Critical Reviews in Oncology/Hematology. 2018; 123: 42–51.

[22] Ray-Coquard I, Cropet C, Van Glabbeke M, Sebban C, Le Cesne A, Judson I, et al. Lymphopenia as a Prognostic Factor for Overall Survival in Advanced Carcinomas, Sarcomas, and Lymphomas. Cancer Research. 2009; 69: 5383–5391.

[23] Nakamura N, Kusunoki Y, Akiyama M. Radiosensitivity of CD4 or CD8 positive human T-lymphocytes by an in vitro colony formation assay. Radiation Research. 1990; 123: 224–227.

[24] Santin AD, Hermonat PL, Ravaggi A, Bellone S, Roman J, Pecorelli S, et al. Effects of concurrent cisplatinum administration during radiotherapy vs. radiotherapy alone on the immune function of patients with cancer of the uterine cervix. International Journal of Radiation Oncology, Biology, Physics. 2000; 48: 997– 1006.

[25] Campian JL, Ye X, Brock M, Grossman SA. Treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. Cancer Investigation. 2013; 31: 183–188.

[26] Di Gioacchino M, Di Giampaolo L, Verna N, Reale M, Di Sciascio MB, Volpe AR, et al. In vitro effects of platinum compounds on lymphocyte proliferation and cytokine release. Annals of Clinical and Laboratory Science. 2004; 34: 195–202.

[27] Ellsworth SG. Field size effects on the risk and severity of treatment-induced lymphopenia in patients undergoing radiation therapy for solid tumors. Advances in Radiation Oncology. 2018; 3: 512–519.