|Ahead of print publication
Preoperative neutrophil-to-lymphocyte ratio as a predictive factor for survival in nonmetastatic colorectal cancer
Kaptan Gülben1, Uğur Berberoğlu1, Bahadır Öndeş2, Osman Uyar3, Onur Can Güler1, Sevim Turanlı1
1 Department of General Surgery, University of Health Sciences, Ankara Oncology Training and Research Hospital, Ankara, Turkey
2 Department of General Surgery, Erciş State Hospital, Van, Turkey
3 Department of Gastroenterological Surgery, Türkiye Yüksek İhtisas Teaching and Research Hospital, Ankara, Turkey
Kardelen Mah. 2040. Sok., 2B/27, 06370, Yenimahalle, Ankara
Source of Support: None, Conflict of Interest: None
Background: The pretreatment ratio of neutrophils to lymphocytes (NLR) has been suggested as an indicator of poor outcome in various cancers. This study aimed to determine whether the preoperative NLR may be a predictor of survival in patients who underwent curative resection for colorectal cancer (CRC).
Materials and Methods: The records of 219 CRC patients underwent curative resection between 2008 and 2014 were retrospectively evaluated. NLR was calculated by preoperative complete blood counts. The effects of age, gender, anatomic location, histologic grade, lymphovascular invasion, pathological T, pathological N, and tumor-node-metastasis stages and NLR on disease-free survival (DFS) and overall survival (OS) were analyzed using univariate and multivariate analyses. The optimal cutoff value for NLR was determined using receiver operating characteristic curve analysis.
Results: The best cutoff value of NLR was 2.8. Multivariate analysis showed that NLR was not a predictor of DFS. However, NLR was found as an independent prognostic factor for OS (Hazard ratio, 5.4; 95% confidence interval, 2.3–12.5; P = 0.0001).
Conclusion: A preoperative NLR of more than 2.8 might be an independent predictor for OS in patients with CRC. This simple and routinely available laboratory parameter may be used as a useful marker for identifying patients with a worse prognosis.
Keywords: Colorectal cancer, inflammation, neutrophil/lymphocyte ratio, prognosis, survival
|How to cite this URL:|
Gülben K, Berberoğlu U, Öndeş B, Uyar O, Güler OC, Turanlı S. Preoperative neutrophil-to-lymphocyte ratio as a predictive factor for survival in nonmetastatic colorectal cancer. J Can Res Ther [Epub ahead of print] [cited 2020 Mar 29]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=264699
| > Introduction|| |
There is a close relationship between the development of myriad malignancies, including colorectal cancer (CRC) and inflammation. A lot of cancers result from the sites of chronic irritation, infection, and inflammation. It is being understood better that the tumor microenvironment, which is mostly regulated by inflammatory cells, is a necessary component in the neoplastic process, promoting proliferation, migration, and survival. Therefore, numerous studies have investigated the role of inflammation in carcinogenesis in the recent years.,,
Lymphopenia usually refers the impaired cell-mediated immunity while neutrophilia is associated with response to systemic inflammation. For this reason, the ratio of neutrophils to lymphocytes (NLR) has been proposed not only as a marker of inflammation but also as an indicator of prognosis for some different malignancies.,
In the published reports, several inflammation-based scores including the modified Glasgow prognostic score, NLR, platelet-to-lymphocyte ratio, prognostic index, and prognostic nutritional index have all been compared regarding their prognostic value in CRC.,, Of these, NLR has gained more popularity in the recent studies because it is an inexpensive, noninvasive, and routinely available blood test. However, there are some limitations of the existing studies including the use of heterogeneous patient groups containing those undergoing emergency surgery, incomplete resection, or palliative resection and those receiving preoperative chemotherapy and/or radiotherapy. The aim of this study was to evaluate the prognostic value of NLR on disease-free survival (DFS) and overall survival (OS) in patients undergoing curative surgery for CRC who did not receive preoperative chemotherapy or radiotherapy and define an appropriate NLR that identifies differences in DFS and OS.
| > Materials and Methods|| |
We examined the records of 281 patients with CRC who underwent resection between January 2008 and April 2014 at a tertiary cancer center. The study was approved by the Institutional Review Board. Emergency cases due to tumor obstruction, palliative resections, patients with recurrent or metastatic disease, patients who had received neoadjuvant chemotherapy and/or radiotherapy, patients with additional malignancy, adenomatous polyposis coli, or inflammatory bowel disease, and patients who were with infection, hematologic disorder, or immunosuppression before surgery were excluded from the study. A total of 62 patients who met these criteria were excluded from the study, and the records of the remaining 219 CRC patients who underwent resection for curative intent were included in our retrospective analysis.
Patients' data including age, gender, tumor location, grade, lymphovascular invasion, pathological T (pT), pathological N (pN), and tumor-node-metastasis (TNM) stages, and NLR were recorded to analyze whether there was any correlation with DFS and OS. NLR was calculated by dividing the neutrophil by the lymphocyte count determined from the complete blood count routinely taken within 1 week before the surgery. Tumor staging for all the patients was performed according to the 7th edition of the American Joint Committee on Cancer TNM staging system.
Patients with lymph node involvement received adjuvant 5-fluorouracil-based chemotherapy, and those who had poor prognostic indicators such as perineural invasion, vascular invasion, and preoperative high levels of carcinoembryonic antigen were given chemotherapy regardless of their nodal status.
The primary endpoint of the study was OS. OS time was measured from the date of surgery to the date of death due to any cause. The secondary endpoint was DFS, which was estimated from the date of surgery to all types of the first event as locoregional or distant metastasis. The patients were followed up every 3–4 months for the first 2 years after resection, every 6 months for the 3–5 years, and yearly thereafter until death.
Statistical tests were carried out using the SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA). DFS and OS were calculated using the Kaplan–Meier method, and differences in observed survival distribution among patient subgroups were tested with two-sided log-rank test. Univariate and multivariate analyses were performed using the Cox proportional-hazards regression model. A receiver operating characteristic (ROC) analysis was used to determine the optimum cutoff value of the NLR, which predicts long-term DFS and OS. All statistical tests of significance were two sided, and P < 0.05 was considered to be statistically significant.
| > Results|| |
Clinicopathologic characteristics of 219 CRC patients who underwent curative resection are summarized in [Table 1]. The median age was 62 years (range, 23–86), and the median follow-up time was 40 months (range, 10–96). The median number of lymph nodes removed was 13 (range, 3–53), and the median number of positive lymph nodes was 2 (range, 1–18).
The distribution of neutrophils ranged from 1.9 to 12.5 with a mean of 4.9 (standard deviation [SD] – 2.1) and a median of 4.5. The distribution of lymphocytes ranged from 0.3 to 5.2 with a mean of 1.8 (SD 0.7) and a median of 1.7. The NLR ranged from 0.6 to 19.5 with a mean of 3.1 (SD 2.6) and a median of 2.3. When an ROC analysis was performed in relation to the DFS and OS, a cutoff value of 2.8 for NLR was the best to discriminate between both outcomes in the whole group. A total of 151 patients (69%) of 219 had a low NLR (≤2.8), and 68 patients (31%) had a high NLR (>2.8).
The estimated 5-year DFS and OS rates were 63% and 73%, respectively. During the follow-up period, 16 patients (7.3%) developed local recurrence and 42 patients (19%) developed distant metastasis. Twenty-seven patients died on the last date of follow-up. In the univariate analysis, pT, pN, TNM stage, and NLR were significant risk factors for DFS [Table 2]. However, only pN was significantly associated with DFS in the multivariate analysis (hazard ratio [HR], 7.4; 95% confidence interval [CI], 3.3–15.5; P = 0.0001). NLR was not found as an independent prognostic factor for DFS (HR, 1.4; 95% CI, 1.04–4.2; P = 0.925). When all parameters were assessed for OS, pT, pN, TNM stage, and NLR were predictive factors in the univariate analysis [Table 3]. On the other hand, pN and NLR were identified as independent predictors for OS in the multivariate test. NLR >2.8 was associated with a poorer OS (HR, 5.4; 95% CI, 2.3–12.5; P = 0.0001).
|Table 2: Univariate and multivariate analyses of factors affecting disease-free survival|
Click here to view
|Table 3: Univariate and multivariate analyses of factors affecting overall survival|
Click here to view
The Kaplan–Meier survival estimation revealed significant difference regarding 5-year OS among the patients with ≤2.8 NLR compared with >2.8 NLR [P = 0.0001; [Figure 1]. The 5-year OS rate in patients with ≤2.8 NLR and >2.8 NLR was 84% (median 63 months) and 65% (median 51 months), respectively.
|Figure 1: The Kaplan–Meier curves for overall survival of the patients with colorectal cancer based on the high and low neutrophils to lymphocytes|
Click here to view
| > Discussion|| |
CRC is still one of the most commonly diagnosed malignancies worldwide and has a major role in death from cancer. The long-term outcomes of CRC may be different even in patients with the same stage of disease. Some patients who have similar stages suffer from locoregional recurrence and distant metastasis even after surgical curative resections and adjuvant chemotherapy. Therefore, recent studies are conducted to examine the other predictive factors including NLR, which may influence the survival of patients with CRC. Contemporary knowledge in the field of inflammatory response, which generated by the tumor cells, has guided to the definition of some alterations in the prognosis of patients with CRC.
NLR, which is calculated by dividing absolute neutrophil count to absolute lymphocyte count, has been suggested as an easily accessible prognostic index of systemic inflammatory response in different cancers, including CRC.,,, The first report regarding the prognostic effect of pretreatment high NLR on survival in CRC patients was reported by Walsh et al. Then, a number of studies were published on this topic; however, there is a heterogeneity regarding the patient population, methodology, and study design in some of these studies.,,, Our study population consists of relatively a more homogeneous group when considering the patient selection and management. Excluding patients who received preoperative chemotherapy or radiotherapy from this study precludes the effect of a potential confounder factor on survival.
The role of neutrophils and lymphocytes in cancer-related inflammatory response is different. Halazun et al. suggested two potential mechanisms concerning a high NLR which may be a prognostic indicator for survival: first, the patients with a high NLR have a relatively low lymphocyte count, leading to an inadequate lymphocyte-mediated immune response to cancer and therefore a higher risk for disease recurrence and second, a relatively elevated neutrophil count may contribute to the formation and progression of a neoplastic process through the release of angiogenic and growth factors., An elevated NLR resulting from a high circulating neutrophil count may therefore endorse metastatic colorectal tumor cells to survive, thereby clarifying a worse DFS and OS. Finally, the advancement of a malignant process is dependent on a complex interaction between the tumor, its microenvironment, and the host immune system.
Previous studies reported different results when considering the significance of NLR on DFS and OS. Some of them found a significant correlation between NLR and OS while others showed that NLR was associated with DFS only.,, Furthermore, a number of studies proposed different threshold values of NLR, which have chosen 3, 4, or 5 according to their methods, for its prognostic importance on survival., In this study, the cutoff value of NLR as a prognostic factor in CRC patients who were treated with curative surgery was 2.8. Thirty-one percent of 219 patients had a value of NLR above 2.8.
Malietzis et al. found a preoperative NLR of more than 3 as an independent prognostic factor for DFS but not OS after curative elective CRC surgery. On the other hand, Jankova et al. reported in their study that NLR predicts OS but does not predict recurrence or cancer-specific survival after curative resection of node-positive CRC. In this study, although a high NLR was a significant risk factor for DFS in the univariate analysis, it could not reach a statistically significant value in the multivariable model. Twenty-three percent of 151 patients with a low NLR developed recurrence while recurrence rate of 68 patients with a high NLR was 34%. This difference between recurrence rates of patients with low and high NLR was not statistically significant. On the other hand, longer follow-up may reveal the differences in DFS between low- and high-NLR groups.
The results of the present study found that the NLR was an independent predictor of OS. The patients with >2.8 NLR had a significantly shorter 5-year OS with a median of 51 months than the patients with ≤2.8 NLR with a median of 63 months. It was determined that 6% of 151 patients with a low NLR died at the end of the follow-up whereas the rate of death on the last follow-up in 68 patients with a high NLR was 26%. This difference between the OS of two groups was statistically significant. This result may be a justification for following up more closely of the nonmetastatic CRC patients with preoperative high NLR who treated with curative resection. In addition, a high NLR might submit a support in clinical decision-making in patients with poorer prognosis.
This study has some limitations including relatively small sample size, short median follow-up time, and retrospective study. Nevertheless, we believe that the result is interesting and can be attractive to plan other future investigations.
| > Conclusion|| |
The findings of this study showed that an elevated preoperative NLR was independently associated with a shorter OS in patients with CRC. Preoperative NLR is an inexpensive, simple, and easily accessible laboratory test for patients with poorer prognosis who are treated with curative resection and adjuvant therapy. To contribute the clinical use of preoperative NLR, further researches with large scale should be designed.
Financial support and sponsorship
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.
Ozdemir Y, Akin ML, Sucullu I, Balta AZ, Yucel E. Pretreatment neutrophil/lymphocyte ratio as a prognostic aid in colorectal cancer. Asian Pac J Cancer Prev 2014;15:2647-50.
Waldner M, Schimanski CC, Neurath MF. Colon cancer and the immune system: The role of tumor invading T cells. World J Gastroenterol 2006;12:7233-8.
Roxburgh CS, McMillan DC. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol 2010;6:149-63.
Unal D, Eroglu C, Kurtul N, Oguz A, Tasdemir A. Are neutrophil/lymphocyte and platelet/lymphocyte rates in patients with non-small cell lung cancer associated with treatment response and prognosis? Asian Pac J Cancer Prev 2013;14:5237-42.
Cho H, Hur HW, Kim SW, Kim SH, Kim JH, Kim YT, et al.
Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol Immunother 2009;58:15-23.
Cedrés S, Torrejon D, Martínez A, Martinez P, Navarro A, Zamora E, et al.
Neutrophil to lymphocyte ratio (NLR) as an indicator of poor prognosis in stage IV non-small cell lung cancer. Clin Transl Oncol 2012;14:864-9.
Malietzis G, Giacometti M, Askari A, Nachiappan S, Kennedy RH, Faiz OD, et al.
A preoperative neutrophil to lymphocyte ratio of 3 predicts disease-free survival after curative elective colorectal cancer surgery. Ann Surg 2014;260:287-92.
Proctor MJ, Morrison DS, Talwar D, Balmer SM, Fletcher CD, O'Reilly DS, et al.
A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow inflammation outcome study. Eur J Cancer 2011;47:2633-41.
Kwon HC, Kim SH, Oh SY, Lee S, Lee JH, Choi HJ, et al.
Clinical significance of preoperative neutrophil-lymphocyte versus platelet-lymphocyte ratio in patients with operable colorectal cancer. Biomarkers 2012;17:216-22.
Absenger G, Szkandera J, Stotz M, Postlmayr U, Pichler M, Ress AL, et al.
Preoperative neutrophil-to-lymphocyte ratio predicts clinical outcome in patients with stage II and III colon cancer. Anticancer Res 2013;33:4591-4.
Bolocan A, Ion D, Ciocan DN, Paduraru DN. Prognostic and predictive factors in colorectal cancer. Chirurgia (Bucur) 2012;107:555-63.
Aliustaoglu M, Bilici A, Seker M, Dane F, Gocun M, Konya V, et al.
The association of pre-treatment peripheral blood markers with survival in patients with pancreatic cancer. Hepatogastroenterology 2010;57:640-5.
Azab B, Bhatt VR, Phookan J, Murukutla S, Kohn N, Terjanian T, et al.
Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann Surg Oncol 2012;19:217-24.
Zhang X, Zhang W, Feng LJ. Prognostic significance of neutrophil lymphocyte ratio in patients with gastric cancer: A meta-analysis. PLoS One 2014;9:e111906.
Leitch EF, Chakrabarti M, Crozier JE, McKee RF, Anderson JH, Horgan PG, et al.
Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer. Br J Cancer 2007;97:1266-70.
Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005;91:181-4.
He WZ, Jiang C, Yin CX, Guo GF, Rong RM, Qiu HJ, et al.
Prognostic model built on blood-based biomarkers in patients with metastatic colorectal cancer. Asian Pac J Cancer Prev 2014;15:7327-31.
Ikeguchi M, Urushibara S, Shimoda R, Yamamoto M, Maeta Y, Ashida K, et al.
Inflammation-based prognostic scores and nutritional prognostic index in patients with locally-advanced unresectable colorectal cancer. World J Surg Oncol 2014;12:210.
Jankova L, Dent OF, Chan C, Chapuis P, Clarke SJ. Preoperative neutrophil/lymphocyte ratio predicts overall survival but does not predict recurrence or cancer-specific survival after curative resection of node-positive colorectal cancer. BMC Cancer 2013;13:442.
Borazan E, Balık AA, Bozdağ Z, Arık MK, Aytekin A, Yılmaz L, et al.
Assessment of the relationship between neutrophil lymphocyte ratio and prognostic factors in non-metastatic colorectal cancer. Turk J Surg 2017;33:185-9.
Halazun KJ, Aldoori A, Malik HZ, Al-Mukhtar A, Prasad KR, Toogood GJ, et al.
Elevated preoperative neutrophil to lymphocyte ratio predicts survival following hepatic resection for colorectal liver metastases. Eur J Surg Oncol 2008;34:55-60.
Proctor MJ, McMillan DC, Morrison DS, Fletcher CD, Horgan PG, Clarke SJ, et al.
A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer. Br J Cancer 2012;107:695-9.
Kishi Y, Kopetz S, Chun YS, Palavecino M, Abdalla EK, Vauthey JN, et al.
Blood neutrophil-to-lymphocyte ratio predicts survival in patients with colorectal liver metastases treated with systemic chemotherapy. Ann Surg Oncol 2009;16:614-22.
[Table 1], [Table 2], [Table 3]