|Year : 2020 | Volume
| Issue : 5 | Page : 1134-1139
Hemoglobin, albumin, lymphocyte, and platelet score and neutrophil-to-lymphocyte ratio are novel significant prognostic factors for patients with small-cell lung cancer undergoing chemotherapy
Ning Yang1, Xiao Han2, Jinyu Yu3, Weibin Shu1, Feng Qiu4, Junqing Han1
1 Tumor Research and Therapy Center, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China
2 Department of Experiment, Tumor Hospital Affiliated to Guangxi Medical University, Nanning, China
3 Department of Renal Cancer and Melanoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
4 Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
|Date of Submission||01-Dec-2019|
|Date of Decision||16-Apr-2020|
|Date of Acceptance||03-Jun-2020|
|Date of Web Publication||29-Sep-2020|
Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021
Tumor Research and Therapy Center, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021
Source of Support: None, Conflict of Interest: None
Objective: The hemoglobin, albumin, lymphocyte, and platelet (HALP) score, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are the important prognostic markers in some tumor types. This study aimed to evaluate the prognostic impact of pretreatment using HALP, NLR, and PLR for patients with small-cell lung cancer (SCLC), who were undergoing chemotherapy.
Materials and Methods: In this retrospective study, 335 patients with SCLC were included between 2016 and 2018. The cutoff values for HALP, NLR, and PLR were defined using X-tile software. Survival was analyzed by the Kaplan–Meier method, with differences analyzed through the log-rank test. The multivariate Cox proportional hazard model was used to evaluate the prognostic significance of HALP, NLR, and PLR for SCLC.
Results: The median follow-up period was 27.1 months (range: 0.5–46.2 months). Based on the Kaplan–Meier curve analysis, it was noticed that the low pretreatment HALP (≤18.6), high pretreatment NLR (>2.4), and high PLR (>191.6) were significantly associated with worse overall survival (OS) (P = 0.009, 0.001, and 0.033, respectively). Cox multivariate analysis demonstrated that low pretreatment HALP and high pretreatment NLR were the independent prognostic factors for worse OS (hazard ratio [HR] = 1.468, 95% confidence interval [CI]: 1.004–2.146, P = 0.047; HR = 0.722, 95% CI: 0.542–0.960, P = 0.025, respectively).
Conclusion: HALP and NLR were the independent prognostic factors of OS for SCLC patients undergoing chemotherapy.
Keywords: Hemoglobin, albumin, lymphocyte, and platelet, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, prognosis, small-cell lung cancer
|How to cite this article:|
Yang N, Han X, Yu J, Shu W, Qiu F, Han J. Hemoglobin, albumin, lymphocyte, and platelet score and neutrophil-to-lymphocyte ratio are novel significant prognostic factors for patients with small-cell lung cancer undergoing chemotherapy. J Can Res Ther 2020;16:1134-9
|How to cite this URL:|
Yang N, Han X, Yu J, Shu W, Qiu F, Han J. Hemoglobin, albumin, lymphocyte, and platelet score and neutrophil-to-lymphocyte ratio are novel significant prognostic factors for patients with small-cell lung cancer undergoing chemotherapy. J Can Res Ther [serial online] 2020 [cited 2020 Oct 26];16:1134-9. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/1134/296423
| > Introduction|| |
Lung cancer is one of the leading causes of cancer deaths worldwide. Small-cell lung cancer (SCLC) accounts for 15%–17% of all lung cancers. There are two main stages of SCLC: limited-stage (SCLC; Stages I, II, and III) and extensive-stage (SCLC; Stage IV). Platinum-based chemotherapy is the standard of therapy, and the addition of thoracic radiation therapy improves both local control and overall survival (OS). Studies have demonstrated that consolidative thoracic radiation therapy (up to definitive doses) is well tolerated. It also results in fewer symptomatic chest recurrences and improves long-term survival in some patients., Most patients have metastatic disease at the time of diagnosis, with a 5-year survival rate of only 2%–8%.
The type of tumor cell and tumor stage play a vital role in prognosis. In addition, nutrition and immunity are associated with influencing cancer prognosis. Inflammatory cells and immune responses have consistently been recognized as the important factors in the prognosis of cancer., The peripheral blood cells, neutrophils, lymphocytes, platelets, and monocytes, can aggravate the proliferation, invasion, and metastasis of cancer., Many combinations of inflammatory indices, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and hemoglobin, albumin, lymphocyte, and platelet (HALP) score, have been used to predict the prognosis of many kinds of cancers.,,,,,, Here, we evaluated the prognostic value of HALP, NLR, and PLR for patients with SCLC.
| > Materials and Methods|| |
All newly diagnosed SCLC patients were retrospectively reviewed between January 1, 2016, and August 7, 2018, in Shandong Provincial Hospital Affiliated to Shandong University, Shandong Province, China. Patient characteristics are listed in [Table 1]; they include age, gender, smoking history, alcohol-drinking history, body mass index (BMI), tumor stage, radiotherapy, HALP, NLR, and PLR. Hematologic parameters were collected in the week preceding the first chemotherapy session. All patients received first-line treatment with etoposide-based chemotherapy. The HALP score was calculated according to the following formula: hemoglobin (g/L) × albumin (g/L) × lymphocytes (/L)/platelets (/L). The NLR score was calculated as neutrophils (/L) divided by the lymphocytes (/L). The PLR score was calculated by the platelets (/L) divided by the lymphocytes (/L).
|Table 1: Clinicopathological characteristics for 335 small-cell lung cancer patients|
Click here to view
Data analysis was performed using SPSS version 24.0 software (IBM Corporation, Armonk, NY, USA). The optimal cutoff values of the HALP, NLR, and PLR scores were computed using the X-tile software version 3.6.1 (Yale University, NEW Haven CT, USA). The Chi-squared test was used to compare rates. Distributions of OS times were estimated using the Kaplan–Meier method. The OS was compared between different groups using the log-rank test. Important clinicopathological variables, as well as the variables determined to be significant according to the univariate analyses, were included in the multivariate analyses. The median period of follow-up and its interquartile range was calculated for the entire study cohort following the reverse Kaplan–Meier method. For all analyses, P < 0.05 was considered statistically significant.
| > Results|| |
A total of 335 patients were enrolled in this study (75.8% males; median age 61 years) [Table 1]. Two hundred and forty-eight patients (74.0%) had received radical or palliative radiotherapy. The median period of follow-up was 27.1 months (range: 0.5–46.2 months). At the end of follow-up, 208 patients (62.1%) had died. The 1- and 2-year estimated OS was 72.9% and 38.9%. Other clinicopathological characteristics are listed in [Table 1].
The median values of HALP, NLR, and PLR were 36.9 (range: 4.9–169.7), 2.57 (range: 1.0–15.8), and 150.5 (range: 35.4–777.1), respectively. The optimal values of HALP, NLR, and PLR for OS were computed to be 18.6, 2.4, and 191.6, respectively, using the X-tile software version 3.6.1 [Figure 1]. Patients were divided into low and high HALP, NLR, and PLR groups. Then, their clinicopathological characteristics were compared between the low and high groups. The results showed that the differences in all these features between low and high HALP groups were not statistically significant, except the BMI (P = 0.001) and performance status (PS) scores (P < 0.001), respectively. In low and high NLR groups, gender, BMI score, and radiotherapy were statistically significant (P = 0.001, 0.024, and 0.046, respectively). Moreover, in low and high PLR groups, gender, smoking history, alcohol-drinking history, BMI score, and PS score were also statistically significant (P = 0.004, 0.014, 0.031, 0.001, and 0.006, respectively) [Table 2].
|Figure 1: Cutoff values for HALP (a and d); NLR (b and e); and PLR (c and f), as determined by Xtile software|
Click here to view
|Table 2: Association of baseline clinicopathological characteristics and hemoglobin, albumin, lymphocyte, and platelet, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio|
Click here to view
The univariate analysis highlighted that low HALP, high NLR, high PLR, male, smoking, extensive disease (ED), and no radiotherapy were all associated with worse survival rates [Figure 2]. Eleven variables, including age, gender, smoking history, alcohol-drinking history, BMI, stage, radiotherapy, PS, HALP, NLR, and PLR, were included in the multivariate analysis. Independent factors that were associated with worse OS rates were low HALP (hazards ratio [HR] = 1.468, 95% confidence interval [CI]: 1.004–2.146, P = 0.047); high NLR (HR = 0.722, 95% CI: 0.542–0.960, P = 0.025); ED stage (HR = 1.790, 95% CI: 1.361–2.356, P < 0.001); and no radiotherapy (HR = 1.915, 95% CI: 1.417–2.288, P < 0.001) [Table 3].
|Figure 2: Kaplan–Meier curves for overall survival in patients with small cell lung cancer according to HALP (a), NLR (b), PLR (c), gender (d), smoking (e), stage (f), and radiotherapy (g)|
Click here to view
|Table 3: Univariate and multivariate analyses of prognostic factors for overall survival|
Click here to view
| > Discussion|| |
It is widely accepted that an inflammatory response and an overall nutritional status correlate with the survival rates for cancer patients., The presence of a tumor is detrimental due to its chronic resource-consumptive nature, and hemoglobin levels have also been reported to be significantly related to the survival and progression of tumors. Serum albumin is an indicator of nutritional status; many studies have reported that serum albumin levels were significantly correlated with the survival of cancer., Lymphocytes, which can release some cytokines, such as interferon-γ and tumor necrosis factor-alpha (TNF-α), can inhibit tumor growth and improve the prognosis for cancer patients. Some studies indicated that, through mediation by TNF-α, platelets inhibited tumor necrosis. From these findings, it is observed that hemoglobin, albumin, and lymphocytes may be risk factors, where if levels are good, can highlight a good prognosis. However, high platelets may be harmful.
The present study aimed to identify the value of pretreatment HALP, NLR, and PLR in predicting OS in SCLC. It was found that low pretreatment HALP (≤18.6) and high pretreatment NLR (>2.4) scores implied worse OS outcomes in SCLC through multivariate analysis (P = 0.047 and 0.025, respectively). Although not statistically significant in multivariate analysis, the findings presented here suggest that a high pretreatment PLR (>191.6) score implies worse OS outcomes through univariate analysis.
Shen et al. reported that high HALP was an independent predictor of improved outcomes, associated with increased progression-free survival (PFS) in SCLC patients ≥65 years. Guo et al. reported that a low HALP score was an independent prognostic factor for poor OS outcomes for prostate-specific antigen-PFS in patients with metastatic prostate cancer and oligometastatic prostate cancer. Peng et al. reported that HALP might be an excellent prognostic index for OS for patients with bladder cancer after radical cystectomy, and low HALP predicted a decreased OS rate. Jiang et al. reported that low HALP correlated with an increased risk of death and cancer-related death in locally advanced colorectal cancer. To the author's knowledge, this is the first study to show the importance of pretreatment HALP for predicting survival in patients with SCLC. The results here show that low HALP correlated poor outcome is consistent with the literature. Although more studies are needed, it can be postulated that pretreatment HALP may be useful for predicting outcomes in SCLC.
Many studies inferred that a higher NLR score implies a worse outcome. These implications of PLR are not consistent in SCLC. Three studies investigated pretreatment NLR and PLR in patients with SCLC, and both studies found that pretreatment NLR, but not PLR, was an independent predictor of prognosis.,, Our findings show that pretreatment NLR, but not PLR, was a suitable outcome predictor in patients with SCLC, which is consistent with those of previous studies. Several studies have reported controversial results regarding the prognostic values of high NLR and PLR in terms of patient survival., The different cutoff values may have contributed to this debate.
We acknowledge that there were some limitations in our study: first, the retrospective nature of the work has inherent limitations; second, this was a single-center study and could not avoid the bias of population choice; and third, studies on HALP and NLR are rare, and there is no consensus on a cutoff value.
| > Conclusion|| |
The data suggest that pretreatment HALP and NLR were independent prognostic factors of SCLC patients undergoing chemotherapy. Pretreatment HALP and NLR can be used as a new and convenient method to predict the survival rates of SCLC patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Zimmerman S, Das A, Wang S, Julian R, Gandhi L, Wolf J. 2017-2018 scientific advances in thoracic oncology: Small cell lung cancer. J Thorac Oncol 2019;14:768-83.
Jeremic B, Shibamoto Y, Nikolic N, Milicic B, Milisavljevic S, Dagovic A, et al
. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: A randomized study. J Clin Oncol 1999;17:2092-9.
Yee D, Butts C, Reiman A, Joy A, Smylie M, Fenton D, et al
. Clinical trial of post-chemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234-8.
McMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care 2009;12:223-6.
Bindea G, Mlecnik B, Fridman WH, Pagès F, Galon J. Natural immunity to cancer in humans. Curr Opin Immunol 2010;22:215-22.
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-44.
Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860-7.
Coffelt SB, de Visser KE. Cancer: Inflammation lights the way to metastasis. Nature 2014;507:48-9.
Fan L, Wang R, Chi C, Cai W, Zhang Y, Qian H, et al
. Systemic immune-inflammation index predicts the combined clinical outcome after sequential therapy with abiraterone and docetaxel for metastatic castration-resistant prostate cancer patients. Prostate 2018;78:250-6.
Guo Y, Shi D, Zhang J, Mao S, Wang L, Zhang W, et al
. The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is a novel significant prognostic factor for patients with metastatic prostate cancer undergoing cytoreductive radical prostatectomy. J Cancer 2019;10:81-91.
Peng D, Zhang CJ, Gong YQ, Hao H, Guan B, Li XS, et al
. Prognostic significance of HALP (hemoglobin, albumin, lymphocyte and platelet) in patients with bladder cancer after radical cystectomy. Sci Rep 2018;8:794.
Jiang H, Li H, Li A, Tang E, Xu D, Chen Y, et al
. Preoperative combined hemoglobin, albumin, lymphocyte and platelet levels predict survival in patients with locally advanced colorectal cancer. Oncotarget 2016;7:72076-83.
Nomelini RS, Carrijo Chiovato AF, Abdulmassih FB, da Silva RC, Tavares-Murta BM, Murta EF. Neutrophil-to-lymphocyte ratio and platelet count as prognostic factors in ovarian malignancies. J Cancer Res Ther 2019;15:1226-30.
Wang X, Han H, Duan Q, Khan U, Hu Y, Yao X. Changes of serum albumin level and systemic inflammatory response in inoperable non-small cell lung cancer patients after chemotherapy. J Cancer Res Ther 2014;10:1019-23.
Tan W, Sun W, Li X, Zhao L, Wang C, Zang A, et al
. Preablation neutrophil-to-lymphocyte ratio as an independent prognostic factor in locally advanced hepatocellular carcinoma patients following radiofrequency ablation. J Cancer Res Ther 2018;14:84-9.
Camp RL, Dolled-Filhart M, Rimm DL. X-tile: A new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 2004;10:7252-9.
Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, Courneya KS, Schwartz AL, et al
. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin 2012;62:243-74.
Belcher DA, Ju JA, Baek JH, Yalamanoglu A, Buehler PW, Gilkes DM, et al
. The quaternary state of polymerized human hemoglobin regulates oxygenation of breast cancer solid tumors: A theoretical and experimental study. PLoS One 2018;13:e0191275.
Liu X, Meng QH, Ye Y, Hildebrandt MA, Gu J, Wu X. Prognostic significance of pretreatment serum levels of albumin, LDH and total bilirubin in patients with non-metastatic breast cancer. Carcinogenesis 2015;36:243-8.
Ayhan A, Günakan E, Alyazıcı İ, Haberal N, Altundaǧ Ö, Dursun P. The preoperative albumin level is an independent prognostic factor for optimally debulked epithelial ovarian cancer. Arch Gynecol Obstet 2017;296:989-95.
Jurasz P, Alonso-Escolano D, Radomski MW. Platelet-cancer interactions: Mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br J Pharmacol 2004;143:819-26.
Shen XB, Zhang YX, Wang W, Pan YY. The hemoglobin, albumin, lymphocyte, and platelet (HALP) Score in patients with small cell lung cancer before first-line treatment with etoposide and progression-free survival. Med Sci Monit 2019;25:5630-9.
Deng M, Ma X, Liang X, Zhu C, Wang M. Are pretreatment neutrophil-lymphocyte ratio and platelet-lymphocyte ratio useful in predicting the outcomes of patients with small-cell lung cancer? Oncotarget 2017;8:37200-7.
Kang MH, Go SI, Song HN, Lee A, Kim SH, Kang JH, et al
. The prognostic impact of the neutrophil-to-lymphocyte ratio in patients with small-cell lung cancer. Br J Cancer 2014;111:452-60.
Shao N, Cai Q. High pretreatment neutrophil-lymphocyte ratio predicts recurrence and poor prognosis for combined small cell lung cancer. Clin Transl Oncol 2015;17:772-8.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]