INTRODUCTION
The second most common cancer in the world according to GLOBOCAN is lung cancer (11.4%), followed by breast cancer (11.7%). It has the first rank among cancers that cause death in the world (18%)1. In metastatic (Stage 4) lung cancer patients, the rate for 5-year survival is less than five percent2. In a meta-analysis, the frequency of major depression was found to be 15% in cancer patients, while anxiety rate was found to be 10%3. Although the frequency varies with the type of cancer, the highest rates of anxiety and depression are seen in lung cancer. Because metastatic patients have a poor prognosis, from the time of diagnosis, these patients tend to have anxiety and depression4. Diagnosis of cancer and initiation of treatment disrupt the physical, emotional, social and economic balances of the individual and family, prevent them from getting satisfaction from life and reduce their quality of life. Since the presence of depression predicts worse survival in patients with metastasis, unmanaged psychosocial difficulties may have important implications for cancer treatment4-6.
It is known that cancer and inflammation are related to each other and the cellular immune system plays a significant role in inflammation7. In literature, the studies have also underlined that inflammation response may alter neurotransmission and neuroendocrine pathways that play a role in depression. In addition, recent studies have revealed that rheumatological diseases and increase in proinflammatory markers are related to a higher risk of depression8,9.
Neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), C-reactive protein to lymphocyte ratio (CRP/L), neutrophil to lymphocyte, platelet ratio (NLPR), and systemic inflammation response index (SII) are biomarkers that can be obtained from the complete blood count test. As depression is a psychiatric disorder related to inflammation, the relationship between inflammation markers such as NLR, PLR and depression has also been explored by numerous studies, but the results showing the relationship between depression and NLR and PLR are controversial10,11. Studies have shown that depression is associated with inflammation in patients with cancer and other chronic medical diseases12,13. The importance of identification of depression in lung cancer patients may be essential to improve disease outcome. In spite of all efforts to screen for depression, depression is still inadequately treated14.
The meanings that patients attribute to cancer and the way they perceive the disease affect the response to cancer, impair treatment adherence, increase the length of hospital stay and treatment costs, and may adversely affect the course of the disease. We aimed to investigate the relationship between inflammatory markers and depression in patients with de novo diagnosed metastatic lung cancer, which causes one of the highest rates of depression among all cancer types (16-29%)4,15,16.
MATERIALS AND METHODS
Study Population and Sample
Sixty-six patients newly diagnosed with metastatic (Stage 4) lung cancer were included in our study (Figure 1). Cancer patients were recruited from the Medical Oncology Clinic of University Hospital between January and December 2021. Inclusion criteria included age of 18≥ years, willingness and ability to provide written informed consent. Patients with a history of psychiatric disorder prior to their cancer diagnosis, with a history of dementia or any other organic neurological disorders, with Eastern Cooperative Oncology Group >2 were excluded. Baseline characteristics, clinical and laboratory findings, and the Beck Depression Inventory (BDI) of patients with newly diagnosed de novo metastatic lung cancer were evaluated at the pre-chemotherapy visit.
The Ethics Committee of the Bezmialem Vakıf University approved this cross-sectional study with reference number 16/330 on date 22.09.2020. It was performed in accordance with the Declaration of Helsinki. All patients provided written informed consent for attendance.
The Beck Depression Inventory
It consists of 21 questions and a scoring system between 0 and 3. The severity of depression experienced by individuals is determined by the high scores obtained from the scale. Each question is scored in the range of 0-3 points and results ranging from 0 to 63 are obtained17. Validity and reliability studies of BDI for adaptation to the Turkish language have been conducted18. In the Turkish reliability and validity study, the cut-off point was 17. It was determined that scores of 17 and above on the scale might require treatment. It has been stated that it can distinguish over 90% of depressive disorders19. In our study, the cut-off point was 17 based on Hisli’s18 recommended cut-off scores.
Laboratory Findings and Inflammation Markers
The results of blood tests, which were routinely requested from cancer patients for treatment evaluation, were obtained from the laboratory findings. Blood tests before the chemotherapy were examined.
They were calculated as follows: NLR=Neutrophil/lymphocyte count, PLR=Platelet/lymphocyte count, NLPR=Neutrophil/(lymphocyte × platelet count), CRP/L=C-reactive protein levels/lymphocyte count, SII=Platelet × neutrophil/lymphocyte count.
Statistical Analysis
Statistical Package for Social Sciences (SPSS) 22 software (SPSS, IBM Inc. IL, USA) was used to analyze the study. The normal distribution was evaluated with the Kolmogorov-Smirnov test and Skewness-Kurtosis values. Normally distributed data are presented with mean and standard deviations in analytical evaluation; Non-normally distributed data are presented with median and minimum-maximum values. The Mann-Whitney U test was used for the comparison of the independent groups without normal distribution. The Student’s t-test was employed to compare two independent groups with normal distribution. The chi-square tests were employed to compare categorical data. The Spearman correlation test was performed for correlation analysis of non-normally distributed data. Moreover, the univariate logistic regression analysis was used to determine factors predicting depression in lung cancer patients. With receiver operating characteristic (ROC) analysis, cut off values for NLR, PLR, NLPR, CRP/L and SII for depressive symptoms in cancer patients were investigated. A p value <0.05 was considered statistically significant.
RESULTS
Our study group consisted of 66 de novo metastatic lung cancer patients (mean age 61.97±10.74 years). Male/female (M/F) ratio was 55/11. When the education levels of the individuals were examined, it was determined that 61 (92.4%) were primary, secondary or high school graduates and 5 (7.6%) were university graduates or had PhD. Furthermore, it was determined that 8 (12.1%) patients lived in the countryside, whereas 58 (87.9%) patients lived in the city center. Forty-three of the patients (65.2%) had a previously known chronic disease, and there were 13 (19.7%) patients with polypharmacy. Clinically significant depression was endorsed by 45.5% (BDI ≥17) with a mean BDI score of 17.14±9.52. Regarding the histological type, 20 (30.3%) patients had small-cell lung carcinoma and 46 (69.7%) patients had non-small cell lung cancer. 60 (90.9%) patients were smokers, whereas 23 (34.8%) patients had a history of alcohol consumption. Descriptive characteristics of the study population are presented in Table 1.
Sixty-six patients were divided into two subgroups with the scores of BDI <17 and ≥17 as patients with depression. Patients with depression had significantly higher NLR [2.88 (1.13-14.12) vs. 4.37 (1.29-23.51), p=0.006], PLR [0.15 (0.06-0.71) vs. 0.21 (0.07-1.12), p=0.007] and SII [962 (205-3650) vs. 1510 (344-6173), p=0.002] levels compared to patients without depression (Table 1).
Spearman correlation analysis revealed that there was a significant positive relationship between BDI scores and NLR (r=0.298, p=0.015), PLR (r=0.308, p=0.012), CRP/L (r=0.254, p=0.039) and SII (r=0.353, p=0.004) (Table 2).
Since there is no shared and approved NLR cut-off value for depression in cancer patients in the literature, we consider the value of 3.5 close to the median NLR considering our study data. The univariate analysis results revealed that a statistically significant relationship was found between depression and various risk factors, such as NLR >3.5 [odds ratio (OR): 3.06, 95% confidence interval: 1.12-8.37, p=0.030] and higher SII values (OR: 1.001, 95% confidence interval: 1.00-1.01, p=0.014) (Table 3).
In the ROC curve analysis performed in metastatic lung cancer patients, inflammation markers such as NLR, PLR, and SII were statistically significantly associated with depression (Figure 2). The cut-off, sensitivity, specificity and AUC values are shown in Table 4. SII had the highest AUC value for detecting depression (AUC=0.725, cut-off >1208.8, p=0.002, sensitivity 63.3%, specificity 63.9%).
DISCUSSION
NLR, PLR and SII values were statistically significantly higher in the group with depression. NLR, PLR, CRP/L and SII values showed a positive correlation with BDI scores indicating depression. Considering the NLR value, it was determined that an NLR value above 3.5 was predictive of depression, and an increase in the SII value also predicted the presence of depression. Therefore, it has been determined that the values of 3.63 for NLR, 173 for PLR and 1208 for SII can be used as cut-off values to detect depression in patients with de novo metastatic lung cancer.
Our results showed no significant difference in neutrophil count between patients with and without depression, whereas the depressive patient group had significantly lower lymphocyte levels. In a study that emphasized the importance of NLR, similar to our results, lymphocyte count was significantly lower in patients with depression. On the other hand, neutrophil count was higher, controversial to our study20. Evaluating inflammation in relation to neutrophil or lymphocyte separately can be challenging, supporting the need to evaluate NLR, PLR, CRP/L or SII in inflammation.
Our results showed that higher depression scores were associated with increased inflammation, that can be detected by increased NLR, PLR, CRP/L and SII levels. Recently, there are some studies investigating the relationship between NLR and depression in cancer patients or other populations, which is an interesting area for clinicians nowadays. McFarland stated that there was a significant correlation between NLR and depression21. Besides, it has been shown that NLR and PLR levels were significantly higher in patients with major depressive disorders compared to the healthy individuals22,23. The PLR of patients with severe depression was found to be higher than that of patients with other types of depression (without psychotic features etc.), but there was no significant difference in NLRs among different types of depression24. Demir et al.20 showed that NLR tended to be higher in patients with depression, and so they stated the fact that higher NLR values supported the approach that inflammation played critical role in the etiology of depression. A study found that after adjustment for values of hemoglobin, RDW and NLR, RDW and NLR were associated with depression independently of hemoglobin25.
The NLR is calculated by two types of cell counts mediating two different immune pathways. Having a phagocytic and apoptotic function neutrophil plays role at the first line of immunity26. As specific inflammation mediators, lymphocytes play an important role in host defense mechanisms with regulatory or protective effects. Since NLR covers both immune responses, it is expected to be more predictive and valuable than neutrophil and lymphocyte counts alone24. Increased neutrophil levels and decreased lymphocyte levels by production of pro-inflammatory cytokines cause elevated NLR values in different kinds of inflammatory processes. PLR is another potential and easy to measure parameter27. In the first-line immune response, the platelets regulate permeability of endothelium, migration of neutrophils, macrophages and other mediators. Glutamate and serotonin pathways and other proinflammatory molecules have originated from the activated thrombocytes and so, the function of thrombocytes is modulated, resulting in alterations in pathophysiology ending up with mood disorders28,29. A meta-analysis mentioned above has also demonstrated that NLR and PLR levels are significantly higher in major depression and patients with mood disorders than in healthy individuals26. In another study it has been revealed that high NLR levels are found to be independently related to depressive symptoms in female group, but not in males30.
The potential usage of the newly discovered CRP/L ratio as a biomarker has attracted our attention31. So, as an important study presenting real-life data, we examined the relationship between CRP/L ratio and depression, we found a positive correlation between CRP/L levels and the severity of depression in our study. However, according to univariate analysis results, CRP/L was not found to be a risk factor for depression, or a cut-off value that would shed light on the presence of depression risk could not be reached according to the ROC analysis results. Comprehensive studies are needed to clarify the relationship.
In our study, high SII values were found to be a risk factor for depression, consistent with the recent studies. Wang et al.32 stated that after adjusting for socio-demographic and clinical features, high SII levels were found to be a risk factor for depression in patients with diabetes.
Clinical Implications
NLR, PLR, CRP/L and SII can be calculated easily and cheaply via routinely used laboratory findings. Although the biopsychosocial approach is important in terms of disease prognosis during oncological evaluation, the fact that cancer remains the main life-threatening disease makes it difficult for clinicians to screen for depression unless the patient has an additional request. Predicting the possible risk of depression via routine laboratory values measured at the time of diagnosis will greatly contribute to the treatment process of the patients. Since the diagnosis and treatment process and quality of life of patients are negatively affected by depression levels, it is important to determine the need for support in the early period to be able to screen individuals under cancer treatment for depression and to intervene in the psychosocial problems of patients at risk.
Study Limitations
This study was an important research presenting real-life data, investigating the relationship among NLR, PLR, NLPR, CRP/L and SII and depression in metastatic lung cancer patients. However, we had some limitations in our study. Patients admitted to a single center were included. This study had a small sample size. While providing valuable information for this area, reaching more patients could help us draw precise conclusions. Finally, the study’s cross-sectional design could not explain causal relations well. Patients’ socio-demographic, clinical characteristics, and cancer status can affect depression and inflammation processes in patients with de novo metastatic lung cancer; therefore, we believe these factors may not be considered independently. Longitudinal studies with larger clinical samples could provide more comprehensive findings.
CONCLUSION
Our study revealed that a high NLR, PLR, CRP/L and SII might be a predictive factor for higher depression levels in patients with metastatic cancer. Our results may underline the importance of an altered inflammation process in set of causes of depression. The current study was an important study with real-life data that evaluated the diagnostic power of inflammatory markers such as NLR, PLR, CRP/L and SII for indicating depression in cancer patients. As the management of cancer patients should also focus on providing patients with psychological support regarding its improving effect on treatment response, detecting the presence of depression or identifying patients at high risk of depression is of great importance, promisingly done easily by clinicians via inflammatory markers screening.
Acknowledgments
The authors sincerely thank Dr. Ayşe İrem YASİN and Dr. Zehra SUCUOĞLU İŞLEYEN for their help during the study period.
Ethics
Ethics Committee Approval: The Ethics Committee of the Bezmialem Vakıf University approved this cross-sectional study with reference number 16/330 on date 22.09.2020.
Informed Consent: All patients provided written informed consent for attendance.
Peer-review: Externally peer-reviewed.
Authorship Contributions
Surgical and Medical Practices - Concept - Design - Data Collection or Processing - Analysis or Interpretation - Literature Search - Writing: İ.Ö.Ü., A.T.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.