Introduction
Lung cancer (LC) is the leading cause of cancer death
worldwide, with non-small-cell LC (NSCLC) and smallcell LC (SCLC) accounting for approximately 85% of all
malign lung tumors.[,] Although rapid advances have
been achieved in LC detection and treatment, 5-year survival
rates are still inconclusive.[] Multiple studies have shown tumor progression and prognosis to be associated
with immune status and nutritional condition.[-]
Nearly, a quarter of all NSCLC patients are diagnosed
at a locally advanced stage (stage III) and have
a poor prognosis.[] There are two treatment choices
available for this condition: Induction chemotherapy
followed by surgery, or concurrent chemoradiation
therapy.[,] Even with advanced surgical techniques
and post-operative consolidation chemotherapies, local
recurrence rates are 20-40%.[] Most of the remaining
patients are diagnosed in the metastatic stage, resulting
in palliative chemotherapy or radiation therapy.[]
The previous studies have described inflammationinduced
cancer progression leading to cancer cell proliferation
and angiogenesis.[] Accordingly, multiple
blood inflammation markers are evaluated in different
cancer types and stages that include neutrophils, lymphocytes,
thrombocytes, and lipid and protein profiles,
although the utility of these parameters is controversial.
[-] Changing blood lipid levels have been identified
as a risk factor for LC, and patients with LC tend to
have low levels of low-density lipoprotein (LDL), HDL,
and total cholesterol, while high triglyceride levels have
been observed in blood samples.[,] Changes in
blood lipid levels during therapy are considered to be
an indicator of prognosis.[,]
The systemic inflammatory response in many solid
tumors plays an essential role in development and progression.[] A number of approaches to the measurement
of systemic inflammation have been established,
such as platelet-to-lymphocyte ratio (PLR), prognostic
nutritional index (PNI), and neutrophil-to-lymphocyte
ratio (NLR), and these parameters have been shown to
be correlated with a poor prognosis in a variety of cancers,
including NSCLC.[-]
Several hypotheses have been put forward to explain
the relationship between prognosis and lymphocyte
count. Lymphocytes are essential components of
the immune system, being both controllers and effectors
in response to tumor progression.[] Low lymphocyte
counts have been linked to decreased survival
in cancer patients.[-] The systemic inflammatory
response seen in many solid tumors plays an essential
role in development and progression.[] Several
approaches to the measurement of systemic inflammation
have been established, such as PLR, PNI, and
NLR, and these parameters have been reported to be
correlated with poor prognosis in a variety of cancers,
including NSCLC.[-]
In the present study, we evaluate the effect of blood
parameters on brain metastasis in LC.
Methods
Study Participants
In this retrospective cohort study, the archival records
of patients diagnosed with LC in the Eskişehir City
Hospital Oncology Department were analyzed retrospectively
between 2018 and 2020. Patients identified
with brain metastases during diagnosis or therapy and
who underwent radiation therapy were included in the
study. Patient characteristics, lymphocyte-neutrophil
count, hemoglobin, albumin, C-reactive protein (CRP)
levels, lipid parameters, pathologic subtype, disease
stage, treatment modality, and treatment outcomes
were recorded, as well as the patients" calculated PFS
and OS. The exclusion criteria were lack of adequate
cancer diagnosis and follow-up.
Ethics
Approval for the study was granted by the Eskişehir
Osmangazi University Faculty of Medicine Institutional
Board (March 02, 2021, dated and 06 numbered),
and the study was carried out in accordance with the
principles set out in the Declaration of Helsinki and all
applicable regulations.
Statistical Analysis
IBM SPSS Statistics (Version 22.0. Armonk, NY: IBM
Corp.) was used for the statistical analysis in the study. A
Kolmogorov?Smirnov test was used to determine whether
the data conformed to a normal distribution. Descriptive
data were presented as either mean or median for
continuous variables, while frequencies and percentages
were reported for categorical variables. A Pearson X2 test
was used to assess the associations between categorical
variables; OS and PFS curves were estimated using the
Kaplan-Meier product-limit method; and a ROC analysis
was performed to determine the optimal value.
Results
A total of 200 patients were enrolled in the study with
a mean age of 65.6 years, of which 180 were male and
20 were female. The most common diagnoses were squamous
cell carcinomas, adenocarcinomas, and undifferentiated
lung carcinomas. The characteristics of the study
population are summarized in Table 1. In a univariate
analysis, neutrophil, LDL, NLR, and CRP levels were
significantly different between groups splitted by brain
metastases (Table 2). In a subgroup analysis of the different
cancer subtypes, LDL and lymphocyte levels differed
significantly in squamous cell cancer, while LDL was different in the undifferentiated subtype. No significant
differences were noted in the other histologic subtypes.
Table 1: The characteristics of the study population
Table 2: The comparison of the patient characteristics
according to brain metastases
There was no optimal cutoff due to ROC analyses
among groups. Median values were determined as cutoff,
and groups were splitted due to these terms. The OS differed between the NLR low and high groups, favoring the
NLR low group (p=0.015; OS: 12 vs. 9 months) (Fig. 1),
while the monocyte/lymphocyte ratio was significant in
terms of OS favoring the low group with a cutoff value of
0.56. (p=0.002; OS: 13 vs. 9 months) (Fig. 2). NLR has still
had the prognostic effect in patients stratified according
to brain metastases (p=004). The stage and performance
status differed in terms of OS (p<0.001, p<0.001). In a
multivariate analysis, no prognostic factor for OS was determined
aside from performance status (p<0.001).
Fig. 1: Kaplan-Meier curves of patients according to
neutrophil-to-lymphocyte ratio groups in general
population.
NLR: Neutrophil-to-lymphocyte ratio.
Fig. 2: Kaplan-Meier curves of patients according to
monocyte/lymphocyte ratio group in general
population.
Lipid parameters were tested for correlation with
inflammatory markers, revealing a significant inverse
correlation between HDL and CRP (p<0.001,
r: -0.28). A significant difference was noted in lymphocyte
levels in the patients who had an initial brain
metastasis at the time of diagnosis and late developers
(p=0.02), and OS was also different for this group favoring
late developers (p<0.001).
Discussion
In the present study, a difference was identified in the
inflammatory markers of the brain metastatic and nonmetastatic
patients, and LDL, neutrophil, NLR, and
CRP levels differed between the groups. Furthermore, the monocyte?lymphocyte ratio and NLR were found to
be prognostic indicators of OS in the study population.
The SCLC metastasis site was found to influence
mortality, and liver, bone, and brain metastasis decreased
the duration of survival in this group.[] In
addition, high NLR values were reported to be related
to early recurrences and reduced survival.[] NLR
values higher than 2.5 were found to be associated with
decreased PFS in cancer patients.[] A large-scale
study determined a link between NLR>5 and poor
prognosis in SCLC patients.[] In another study, NLR
was found significantly higher in the metastatic group.
[] In our research, NLR played a role in predicting
brain metastasis and survival, concurring with the previous
studies in the literature.
In patients with NSCLC, brain metastasis is associated
with a decreased quality of life and survival. Multiple
factors facilitate brain metastasis, one such factor
being local and systemic immunosuppression.[] The
alterations in PD-1 expression lymphocytes have been
shown to be a factor in the development of brain metastasis.[] In another study, immune cells were found
to be correlated with PS, decreased brain, and distant
metastasis in EGFR mutant NSCLC.[] The mechanisms
of anti-cancer response with lymphocytes and
the re-modeling effect of monocytes facilitate cancer
proliferation and invasion, as demonstrated in the previous studies.[,] Although our study showed no
difference in the effect of the monocyte?lymphocyte
ratio on brain metastasis, a prognostic effect of monocyte-
lymphocyte ratio OS was identified.
A previous study reported that Vitamin E levels alter
the lipid profiles of cancer patients and increase oxidative
stress, leading to cancer growth,[] and other experimental
studies support this suggestion. Alfa-tocopherol
has been shown to play a therapeutic role under such circumstances.[,] Hyperlipidemia has been shown to
be an adverse prognostic factor in stomach and prostate
cancers, while studies of LC in this regard are limited.
[,,,] Although all cholesterol types are reported
to be lower in LC patients than in healthy controls, only
HDL has been shown to have a prognostic effect. Low
HDL levels are thought to be related to increased inflammatory
cytokines such as CRP,[] and this is supported
by the present study. In contrast to other literature, however,
our study revealed a significant between-group difference
in LDL in brain metastasis.
Limitations
The retrospective nature of this study decreased the
data quality. Furthermore, some of the patients had
brain metastases at the time of diagnosis, which was
confusing for the mechanisms behind the metastatic
process. Although most of the patients were treated for
brain metastasis, five patients did not undergo RT.
Conclusion
Our study identified a difference in the inflammatory
and lipid profiles of LC patients in terms of brain
metastases and survival. Other than the literature, LDL
levels were different among groups and may be a subject
of interest for future studies. Additional studies
are needed to identify the parameters affecting brain
metastases.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved
by the Eskişehir Osmangazi University Non-Interventional
Clinical Research Ethics Committee (no: 06, date:
02/03/2021).
Financial Support: None declared.
Authorship contributions: Concept - F.T., İ.B., A.U.; Design
- A.U.; Supervision - F.T., İ.B.; Funding - F.T., İ.B.;
Materials - İ.B.; Data collection and/or processing - F.T.,
İ.B., A.U.; Data analysis and/or interpretation - F.T., İ.B.;
Literature search - F.T.; Writing - F.T., İ.B.; Critical review
- F.T., İ.B., A.U.
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