Obstet Gynecol Sci.  2019 Jan;62(1):35-45. 10.5468/ogs.2019.62.1.35.

Prognostic significance of pretreatment lymphocyte percentage and age at diagnosis in patients with locally advanced cervical cancer treated with definite radiotherapy

• Jeong MH
• Kim H
• Kim TH
• Kim MH
• Kim BJ
• Ryu SY

• KMID: 2430928
• DOI: http://doi.org/10.5468/ogs.2019.62.1.35

Abstract

OBJECTIVE
This study aimed to evaluate the prognostic impact of age at diagnosis, and pretreatment hematologic markers, including lymphocyte percentage and the neutrophil-to-lymphocyte ratio (NLR), in patients with locally advanced cervical cancer (LACC) treated with definitive radiotherapy (RT).
METHODS
A total of 392 patients with LACC (stage IIb to IVa) treated with cisplatin-based concurrent chemoradiotherapy or RT alone between 2001 and 2012 were retrospectively enrolled. Clinical data and pretreatment complete blood counts were extracted from electronic medical records of the patients, and analyzed. Treatment outcomes, progression-free survival (PFS), and overall survival (OS) were evaluated.
RESULTS
Low lymphocyte percentage and a high NLR were associated with younger age, advanced stage, larger tumor size, lymph nodes metastasis, and treatment failure. The cut-off value for lymphocyte percentage and NLR was determined using a receiver operating characteristic curve. In univariate analysis, low lymphocyte percentage (≤24%) was associated with poor PFS and OS, while high NLR ( > 2.8) was significantly associated only with PFS. In multivariate analysis, both lymphocyte percentage (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.40-0.85; P=0.005) and NLR (HR, 1.55; 95% CI, 1.07-2.25; P=0.022) had independent prognostic value for PFS. Compared to younger patients (age ≤50 years), older patients (age > 60 years) had a lower risk of death.
CONCLUSION
Although the lymphocyte percentage did not remain significant in multivariate analysis for OS, it was predictive of PFS and OS. Thus, lymphocyte percentage is a simple hematologic parameter with a significant prognostic value in patients with LACC treated with definitive RT.

Keyword

Hematologic test; Lymphocytes; Cervical cancer; Radiotherapy; Aging; Prognosis

MeSH Terms

Aging
Blood Cell Count
Chemoradiotherapy
Diagnosis*
Disease-Free Survival
Electronic Health Records
Hematologic Tests
Humans
Lymph Nodes
Lymphocytes*
Multivariate Analysis
Neoplasm Metastasis
Prognosis
Radiotherapy*
Retrospective Studies
ROC Curve
Treatment Failure
Uterine Cervical Neoplasms*

Figure

• 

  Fig. 1 Patient cohort description. FIGO, International Federation of Gynecology and Obstetrics; RT, radiotherapy; CCRT, concurrent chemoradiotherapy.

• 

  Fig. 2 Kaplan-Meier curve of progression-free survival stratified by lymphocyte percentage (A) and neutrophil-to-lymphocyte ratio level (B), overall survival stratified by lymphocyte percentage (C) and neutrophil-to-lymphocyte ratio level (D). NLR, neutrophil-to-lymphocyte ratio.

Reference

1. Jung KW, Won YJ, Oh CM, Kong HJ, Lee DH, Lee KH, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2014. Cancer Res Treat. 2017; 49:292–305.

2. Shim SH, Kim H, Sohn IS, Hwang HS, Kwon HS, Lee SJ, et al. Nationwide cervical cancer screening in Korea: data from the National Health Insurance Service Cancer Screening Program and National Cancer Screening Program, 2009–2014. J Gynecol Oncol. 2017; 28:e63.

3. Wiebe E, Denny L, Thomas G. Cancer of the cervix uteri. Int J Gynaecol Obstet. 2012; 119:Suppl 2. S100–S109.

4. 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; 88:218–230.

5. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011; 480:480–489.

6. Kietlińska Z. T and B lymphocyte counts and blast transformation in patients with Stage I cervical cancer. Gynecol Oncol. 1984; 18:247–256.

7. Shazly SA, Murad MH, Dowdy SC, Gostout BS, Famuyide AO. Robotic radical hysterectomy in early stage cervical cancer: a systematic review and meta-analysis. Gynecol Oncol. 2015; 138:457–471.

8. Choi CH, Kang H, Kim WY, Kim TJ, Lee JW, Huh SJ, et al. Prognostic value of baseline lymphocyte count in cervical carcinoma treated with concurrent chemoradiation. Int J Radiat Oncol Biol Phys. 2008; 71:199–204.

9. 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. Gynecol Oncol. 2016; 140:76–82.

10. Haraga J, Nakamura K, Omichi C, Nishida T, Haruma T, Kusumoto T, et al. Pretreatment prognostic nutritional index is a significant predictor of prognosis in patients with cervical cancer treated with concurrent chemoradiotherapy. Mol Clin Oncol. 2016; 5:567–574.

11. Chen L, Zhang F, Sheng XG, Zhang SQ, Chen YT, Liu BW. Peripheral platelet/lymphocyte ratio predicts lymph node metastasis and acts as a superior prognostic factor for cervical cancer when combined with neutrophil: lymphocyte. Medicine (Baltimore). 2016; 95:e4381.

12. Onal C, Guler OC, Yildirim BA. Prognostic use of pretreatment hematologic parameters in patients receiving definitive chemoradiotherapy for cervical cancer. Int J Gynecol Cancer. 2016; 26:1169–1175.

13. Nakamura K, Nishida T, Haruma T, Haraga J, Omichi C, Ogawa C, et al. Pretreatment platelet-lymphocyte ratio is an independent predictor of cervical cancer recurrence following concurrent chemoradiation therapy. Mol Clin Oncol. 2015; 3:1001–1006.

14. 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; 27:2067–2074.

15. Wang YY, Bai ZL, He JL, Yang Y, Zhao R, Hai P, et al. Prognostic value of neutrophil-related factors in locally advanced cervical squamous cell carcinoma patients treated with cisplatin-based concurrent chemoradiotherapy. Dis Markers. 2016; 2016:3740794.

16. 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; 20:989–996.

17. 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; 32:1555–1561.

18. Zhang Y, Wang L, Liu Y, Wang S, Shang P, Gao Y, et al. Preoperative neutrophil-lymphocyte ratio before platelet-lymphocyte ratio predicts clinical outcome in patients with cervical cancer treated with initial radical surgery. Int J Gynecol Cancer. 2014; 24:1319–1325.

19. Li C, Wen TF, Yan LN, Li B, Yang JY, Xu MQ, et al. Scoring selection criteria including total tumour volume and pretransplant percentage of lymphocytes to predict recurrence of hepatocellular carcinoma after liver transplantation. PLoS One. 2013; 8:e72235.

20. He JR, Shen GP, Ren ZF, Qin H, Cui C, Zhang Y, et al. Pretreatment levels of peripheral neutrophils and lymphocytes as independent prognostic factors in patients with nasopharyngeal carcinoma. Head Neck. 2012; 34:1769–1776.

21. Yoneyama Y, Ito M, Sugitou M, Kobayashi A, Nishizawa Y, Saito N. Postoperative lymphocyte percentage influences the long-term disease-free survival following a resection for colorectal carcinoma. Jpn J Clin Oncol. 2011; 41:343–347.

22. Lee WM, Park SI, Kim BJ, Kim MH, Choi SC, Lee ED, et al. Clinicopathologic factors for central recurrence in patients with locally advanced bulky cervical cancer. Eur J Obstet Gynecol Reprod Biol. 2012; 161:219–223.

23. Lin Y, Kim J, Metter EJ, Nguyen H, Truong T, Lustig A, et al. Changes in blood lymphocyte numbers with age in vivo and their association with the levels of cytokines/cytokine receptors. Immun Ageing. 2016; 13:24.

24. Sansoni P, Cossarizza A, Brianti V, Fagnoni F, Snelli G, Monti D, et al. Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood. 1993; 82:2767–2773.

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

26. Mendivil AA, Rettenmaier MA, Abaid LN, Brown JV 3rd, Micha JP, Lopez KL, et al. Survival rate comparisons amongst cervical cancer patients treated with an open, robotic-assisted or laparoscopic radical hysterectomy: a five year experience. Surg Oncol. 2016; 25:66–71.

27. Conesa-Zamora P. Immune responses against virus and tumor in cervical carcinogenesis: treatment strategies for avoiding the HPV-induced immune escape. Gynecol Oncol. 2013; 131:480–488.

28. 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; 105:427–433.

29. 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; 107:220–223.

30. Mabuchi S, Matsumoto Y, Isohashi F, Yoshioka Y, Ohashi H, Morii E, et al. Pretreatment leukocytosis is an indicator of poor prognosis in patients with cervical cancer. Gynecol Oncol. 2011; 122:25–32.

31. 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 Inst. 2014; 106:dju147.

32. Carus A, Ladekarl M, Hager H, Nedergaard BS, Donskov F. Tumour-associated CD66b+ neutrophil count is an independent prognostic factor for recurrence in localised cervical cancer. Br J Cancer. 2013; 108:2116–2122.

33. 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; 145:584–594.

34. 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; 67:354–361.

35. Kim TH, Kim MH, Kim BJ, Park SI, Ryu SY, Cho CK. Prognostic importance of the site of recurrence in patients with metastatic recurrent cervical cancer. Int J Radiat Oncol Biol Phys. 2017; 98:1124–1131.

36. Nugent EK, Case AS, Hoff JT, Zighelboim I, DeWitt LL, Trinkhaus K, et al. Chemoradiation in locally advanced cervical carcinoma: an analysis of cisplatin dosing and other clinical prognostic factors. Gynecol Oncol. 2010; 116:438–441.

37. Minion LE, Tewari KS. Cervical cancer - state of the science: from angiogenesis blockade to checkpoint inhibition. Gynecol Oncol. 2018; 148:609–621.