|Year : 2022 | Volume
| Issue : 3 | Page : 691-696
Prognostic significance of novel inflammatory markers in extensive-stage small-cell lung cancer
Hatice Yilmaz, Özlem Yersal
Department of Medical Oncology, Adnan Menderes University Faculty of Medicine, Aydin, Turkey
|Date of Submission||27-Oct-2021|
|Date of Acceptance||13-Dec-2021|
|Date of Web Publication||23-Feb-2022|
Department of Medical Oncology, Adnan Menderes University Faculty of Medicine, Aydın 09010
Source of Support: None, Conflict of Interest: None
Objective: Novel hematological inflammation-based parameters, such as neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), lymphocyte-to-C-reactive protein ratio (LCR), systemic inflammatory response index (SIRI), and hemoglobin-to-red cell distribution width ratio (HRR), have been determined to be linked to prognosis of various cancer types, although the predictive impact of these parameters on extensive-stage small-cell lung cancer (SCLC) is not exactly known. In this study, we aimed to demonstrate the prognostic significance of these novel parameters.
Materials and Methods: This retrospective study included 162 patients who were under follow-up with a diagnosis of extensive-stage SCLC. The receiver operating characteristic curve analysis revealed that the optimal cutoff values for NLR, SII, PNI, LCR, SIRI, and HRR were 2.34, 787, 46.13, 0.29, 1.5, and 1.05, respectively. Cox regression analyses were done to determine the predictive impact of these parameters on progression-free survival (PFS) and overall survival (OS).
Results: Patients with higher LCRs and HRRs had longer PFS and OS than patients with lower LCRs and HRRs (P < 0.001, P < 0.001, P < 0.001, P < 0.001, respectively). PFS and OS were significantly shorter in the group with high SIRIs than in the group with low SIRIs (P < 0.001, P < 0.001, respectively). A multivariate analysis identified LCR and SIRI as independent prognosticators for both PFS and OS (P < 0.001, P < 0.001; P = 0.002, P < 0.001, respectively), and HRR as an independent prognostic factor only for OS (P = 0.046).
Conclusion: LCR, SIRI, and HRR are independent prognostic parameters that predict survival times in patients with extensive-stage SCLC.
Keywords: C-reactive protein, lymphocyte, red cell distribution width, small-cell lung cancer, systemic inflammatory response index
|How to cite this article:|
Yilmaz H, Yersal &. Prognostic significance of novel inflammatory markers in extensive-stage small-cell lung cancer. J Can Res Ther 2022;18:691-6
| > Introduction|| |
Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers (LC) and is the most aggressive histological type among them. Approximately 60%–70% of patients with SCLC have extensive-stage disease, and the median overall survival (OS) is on average 6–8 months. Various prognostic factors have been investigated to predict prognosis in SCLC; however, there is still no standardized prognostic marker, and so new prognostic markers are needed.
It is known that a close relationship exists between carcinogenesis and systemic inflammation. The pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, and interferon-γ increase during the development of cancer cells, and these increased cytokines mediate the proliferation, invasion, and migration of tumor cells while impairing the immune response of the host. Markers such as the systemic immune-inflammation index (SII), the prognostic nutritional index (PNI), and the neutrophil-to-lymphocyte ratio (NLR) – all of which are systemic immune-inflammatory indicators – have been associated with prognosis in many solid organ malignancies, including esophageal cancer (EC) and LC. A novel marker that has recently been introduced is lymphocyte-to-C-reactive protein ratio (LCR), which has been shown to be a prognostic factor for cancers such as EC.
Furthermore, the systemic inflammation response index (SIRI) – as another inflammatory indicator – has also been identified as a prognostic and predictive factor for several types of cancer, including pancreatic cancer and non-SCLC (NSCLC)., The hemoglobin (Hb)-to-red cell distribution width (RDW) ratio (HRR) is another new prognostic marker, with a low HRR having been shown to be associated with shorter survival in cancer types such as NSCLC. Despite the increasing evidence of the effects of inflammation-based scores on the prognosis of SCLC patients, there is limited knowledge on the prognostic significance of novel parameters. Therefore, in this study, we aimed to reveal the prognostic importance of LCR, SIRI, and HRR in extensive-stage SCLC.
| > Materials and Methods|| |
In this study, a retrospective analysis was made of 220 patients who were under follow-up with a pathologically confirmed histological diagnosis of extensive-stage pure SCLC at the hospital medical oncology clinic between December 2009 and June 2019. The inclusion criteria of this study were as follows: (1) cytologically or histologically diagnosed as SCLC, (2) pathologically or radiologically confirmed extensive-stage SCLC, (3) an age of at least 18 years, and (4) having a pretreatment blood test and sufficient laboratory data. Patients with second primary solid organ malignancy, benign or malignant hematological diseases, acute infectious diseases, and chronic inflammatory or autoimmune diseases, along with those with no signs of metastasis, were excluded from the study. Patients with neuroendocrine carcinomas and mixed-type histologies were also excluded. Consequently, 58 patients were excluded, and 162 patients with extensive-stage SCLC were included in the study. Tumor staging was assessed in accordance with the American Joint Committee on Cancer guidelines, 8th edition.
The authors state that they have been approved by the Ethics Committee of Adnan Menderes University (2021-182) and have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.
Data collection and definitions
Clinical variables such as gender, age, Eastern Cooperative Oncology Group performance status, and tumor characteristics were retrieved from the patient records. Laboratory findings such as neutrophil, lymphocyte, and platelet counts at the time of diagnosis were retrieved from the hospital electronic data system. NLR was calculated by dividing the neutrophil count by the lymphocyte count. SII was determined using the formula: platelet count × neutrophil count/lymphocyte count. PNI values were calculated using the following formula: ([10 × serum albumin (g/L)] + [0.005 × lymphocyte count]). LCR was determined as follows: lymphocyte count (number/L)/C-reactive protein (CRP) (mg/L). SIRI and HRR were calculated using the following formulas: SIRI = monocyte count × neutrophil count/lymphocyte count; HRR = Hb (g/dl)/RDW (%).
Physical examination and evaluation of serum chemistry of the patients were done monthly starting from the diagnosis, and chest-abdominal computed tomography (CT) was assessed when necessary. Bimonthly, quarterly, semi-annually, and annually follow-up periods were used for the 1st year, 2nd–3rd years, 4th–5th years, and after 5th years, respectively. Chest-abdominal CT was assessed at each visit, CT or magnetic resonance imaging for brain was done every 3 months in the 1st year and then every 6 months for 2 years.
Progression-free survival (PFS) was defined as the time interval between treatment initiation and progression and/or death, and OS was defined as the time interval between treatment initiation and last follow-up and/or death.
The best cutoff values for variables were determined by the receiver operating characteristic curve analysis. Shapiro–Wilk test was used for normally distributed variables. The Fisher's exact test or Chi-square test was done to examine the relationship between prognostic groups and clinic-pathological parameters. Kaplan–Meier curves were plotted to analyze the associations between potential prognostic variables and survival outcomes, and the long-rank test was used for comparisons of survival times among prognostic subgroups. The prognostic importance of LCR, SIRI, HRR, and other parameters on survival outcomes was evaluated using univariate and multivariate Cox analyses. Statistical Package for the Social Sciences (version 21 SPSS, Inc., Chicago, IL, USA) was used for all the statistical analyses in the present study, and P < 0.05 was considered for statistical significance.
| > Results|| |
Determination of optimal cutoff values for lymphocyte-to-C-reactive protein ratio, systemic inflammatory response index, hemoglobin-to-red cell distribution width ratio, and other parameters
The optimal cutoff values for NLR, SII, PNI, LCR, and HRR were 2.34, 787, 46.13, 0.29, and 1.05, respectively. In addition, the best cutoff point for SIRI was 1.5 with 80% sensitivity and 70% specificity. Among the prognostic factors, SIRI had the highest area under the curve (AUC) (0.72). The AUC value was 0.68, 0.61, 0.67, 0.55, and 0.55 for NLR, SII, PNI, LCR, and HRR, respectively.
Association of lymphocyte-to-C-reactive protein ratio, systemic inflammatory response index, and hemoglobin-to-red cell distribution width ratio with clinicopathological variables
The median age of the 162 study patients was 62 (36–80) years, among which 88 (54%) were over 60 years of age, and 74 (45%) were aged 60 years and below. Of the patients, 23 (14%) were female and 139 (85%) were male. The clinicodemographic characteristics of our cohort are presented in [Table 1].
Association of lymphocyte-to-C-reactive protein ratio, systemic inflammatory response index, and hemoglobin-to-red cell distribution width ratio with survival
After a median follow-up of 17 (1–65) months, the disease of 151 (93.2%) patients had progressed, while 142 (87.7%) patients had died. The median PFS and median OS of the patients were 6 months and 9 months, respectively. According to a Kaplan–Meier analysis, both PFS (P < 0.001) and OS (P < 0.001) were also significantly longer in the patient group with high LCR than in the low LCR group. PFS (P < 0.001) and OS (P < 0.001) were significantly shorter in the high SIRI group than in the low SIRI group. Both PFS (P < 0.001) and OS (P < 0.001) were longer in the patient group with high HRR than in the low HRR group, and the difference was significant. PFS (7.9 vs. 9.3 months, P = 0.412) and OS (11.0 vs. 14.8 months, P = 0.025) were shorter in the group with NLR ≥ 2.34 than in the low NLR group, and the difference was significant only for OS.
As seen in [Table 2], the univariate Cox regression analysis identified PNI (heart rate [HR]: 0.593, P = 0.003), LCR (HR: 0.308, P < 0.001), SIRI (HR: 1.970, P = 0.001), and HRR (HR: 0.442, P < 0.001) as significant parameters for PFS. The univariate analysis showed further that NLR (HR: 1.585, P = 0.035), PNI (HR: 0.638, P = 0.012), LCR (HR: 0.332, P < 0.001), SIRI (HR: 2.546, P < 0.001), and HRR (HR: 0.413, P < 0.001) were significant prognostic parameters for OS [Table 2]. A multivariate analysis identified LCR (HR: 0.335, P < 0.001; HR: 0.386, P < 0.001) and SIRI (HR: 1.979, P = 0.002; HR: 2.965, P < 0.001) as independent prognostic factors for both PFS and OS, while HRR (HR: 0.645, P = 0.046) was an independent prognostic factor only for OS.
|Table 2: Univariate and multivariate Cox regression analyses for factors predicting progression-free survival and overall survival|
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| > Discussion|| |
Known for its aggressive biological behavior, SCLC has a poor prognosis, and despite new treatment modalities, no improved survival time has been achieved. In this study, for the first time, LCR and SIRI were identified as independent prognostic factors for both PFS and OS, while HRR was found to be an independent prognostic factor only for OS. To the best of our knowledge, this study is the first to demonstrate the prognostic significance of LCR, SIRI, and HRR in patients with extensive-stage SCLC.
It is known that NLR – one of the systemic inflammatory indicators – has prognostic significance in several cancers, such as gastric cancer (GC). In a study of extensive-stage SCLC, NLR was found to be higher in patients with skin metastasis than in those without metastasis, and NLR was shown to be a prognostic factor for survival. In another study, no significant relationship was found between NLR and OS in limited-stage SCLC patients who underwent thoracic chemoradiotherapy. In our study, although both PFS and OS were shorter in patients with high NLR, the difference between the groups reached statistical significance only for OS (P = 0.412, P = 0.025).
SII – another systemic inflammatory indicator – was also examined in a meta-analysis that included a number of malignancies such as hepatocellular cancer (HCC) and SCLC, and it was found that patients with higher SII had poorer OS than patients with lower ones. It was reported that a low SII value (<1600) was associated with better treatment response and longer OS in SCLC. In the present study, although PFS and OS were shorter in the high SII (≥787) group, the difference between the groups was insignificant.
In a meta-analysis investigating the clinical significance of PNI, an immune-nutritional indicator, and including several types of cancer such as HCC, GC, and colorectal cancer, a low PNI value was found to be associated with shortened OS and increased postoperative complications. In a study of limited-stage SCLC patients, PFS and OS were found to be statistically significantly longer in patients with a high PNI value (≥53). A study of 97 patients with advanced SCLC established no difference in PFS between the high and low PNI groups (cutoff: 44.3), while PNI was identified as an independent prognostic factor for OS. Our study, similar to other studies, found both PFS and OS to be longer in the group with high PNI (≥46.13), although PNI could not be identified as an independent prognostic factor.
LCR is another inflammatory marker. Lymphocytes are responsible for the host's cellular immune response and inhibit migration and proliferation of tumor cell by stimulating apoptosis with their cytotoxic capacities in the tumor microenvironment. There is a close relationship between pro-inflammatory cytokines, which are elevated in inflammation, and CRP, which is an acute-phase protein synthesized by hepatocytes. Elevated pro-inflammatory cytokines, and IL-6 in particular, are the main regulators of CRP. With the onset of an acute inflammatory reaction CRP level rises. In a study of 607 patients with GC took, in which the cutoff point for LCR was 0.63, and LCR was identified as an independent prognostic factor for OS. In another study, involving a total of 1,005 patients (76 SCLC and 929 NSCLC patients), in which the cutoff point for LCR was determined as 6000, LCR was established as an independent prognosticator for both PFS and OS. In the present study, we found that LCR was an independent prognosticator for both PFS and OS, concurring with the findings of previous studies.
SIRI is another indicator of systemic inflammatory balance. The prognostic significance of SIRI has been demonstrated in various malignancies, such as HCC and GC., Neutrophils increase tumor invasion by stimulating the factors responsible for angiogenesis and tumorigenesis, such as vascular endothelial growth factor (VEGF) and nuclear factor kappa-B (NF-κB). Monocytes, in turn, differentiate into tumor-associated macrophages, and thereby induce the secretion of TNF-α and VEGF, facilitating the proliferation and angiogenesis of tumor cells. Thus, changes in the distribution of these immune-inflammatory cells in peripheral blood contribute to tumor progression. In the study by Kucuk et al., OS was found to be longer in the group with low SIRI (cutoff: 1.93) among limited-stage SCLC patients, and SIRI was identified as an independent prognostic factor for survival. Li et al. established that both OS and DFS were significantly shorter in NSCLC patients with postoperative SIRI >0.99 than in those with SIRI ≤0.99, and SIRI was identified as an independent prognostic factor for both DFS and OS. While a study by Kucuk et al. found a high SIRI to be associated with shorter OS, our study found a high SIRI to be significantly associated with both shorter PFS and shorter OS. Further, in our study, SIRI was found for the first time as an independent prognostic factor for both PFS and OS in extensive-stage SCLC.
Another immune marker is HRR. Although anemia is a commonly detected finding in many solid tumors such as LC, prostate cancer, and in hematological malignancies, it has also been shown to be a poor prognostic factor. As the release of IL-6 and TNF-α in the tumor microenvironment increases, the severity of inflammation increases, anemia deepens, and the resulting hypoxia contributes to tumor progression. RDW, one of the parameters used to determine anemia type, has been shown to be linked to poorer survival outcomes in many malignancies, such as LC, BC. The increased cytokines in tumor-associated inflammations prevent the maturation of erythroid stem cells in the bone marrow, leading to an increased RDW through the increase in circulating immature blood cells. This association between increased RDW and inflammatory cytokines contributes to tumor progression. HRR has been reported as a prognostic factor for NSCLC. Concerning SCLC, there has been only one study to date investigating HRR (cutoff ≥0.985), which included 146 newly diagnosed SCLC patients. The study found both PFS and OS to be longer in the group with higher HRR values and identified HRR as an independent prognostic factor for both. In our study, we found PFS and OS to be significantly longer in those with HRR ≥1.05 and identified HRR as an independent prognostic factor only for OS.
The limiting point of our study is that it was single institution, retrospective, and included a relatively small number of patients. Since the study was conducted in one country and in a single center, it may not fully reflect racial and genetic differences. Being retrospective may be another limitation because objective indicators of inflammation such as high-sensitivity CRP and procalcitonin, which are not checked in routine practice, are not evaluated. In addition, since each of the previous studies determined a cutoff value using different statistical methods, it was not a standard cutoff value and may have led to differences in the evaluation of the results. For these reasons, prospective and multicenter cohort studies involving more variables are needed. Despite its limitations, we believe our study will contribute to the elucidation of SCLC and encourage further research for this type of lung cancer with limited data on prognosis and survival.
| > Conclusion|| |
To our best knowledge, the present study is the first to report LCR and SIRI as independent prognosticators for both PFS and OS in patients with extensive-stage SCLC, and HRR as an independent prognostic factor only for OS. LCR, SIRI, and HRR derived from routine laboratory parameters can facilitate clinician decision-making and treatment management. LCR, SIRI, and HRR are immuno-inflammatory indicators that are inexpensive, reproducible, and reflect the patient's dynamic status.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]