Introduction
The prevalence of cancer is increasing globally, and
lung cancer is the most commonly diagnosed type of cancer,
constituting 11.6% of the total number of cancer cases. Lung cancer
is the primary cause of global cancer-related mortality,
constituting 18.4% of all cancer-related deaths, imposing notable
societal and economic burdens (1).
Therapeutic modalities for lung cancer encompass surgery, radiation
therapy and chemotherapy; nevertheless, medical management is
frequently associated with the emergence of treatment resistance,
resulting in relapse (2).
Consequently, an enhanced comprehension of lung cancer biology has
resulted in the advancement of immunotherapy (3).
Immunotherapies, notably characterized by the use of
immune checkpoint inhibitors (ICIs), enable T-cells to eliminate
cancer cells by obstructing programmed cell death protein 1
(PD-1)/programmed death-ligand 1 (PD-L1) signaling. This markedly
transforms the treatment and outlook of patients with lung cancer
who lack targetable genetic changes (4). The anti-PD-1 antibody, pembrolizumab,
and the anti-PD-L1 antibody, atezolizumab, have demonstrated
notable clinical efficacy in a number of solid tumors, leading to
its US Food and Drug Administration (FDA) approval for patients
with non-small cell lung cancer (NSCLC) (5,6). As
cancer rates increase, immunotherapy has become an increasingly
prevalent treatment option as a monotherapy or adjuvant therapy to
chemotherapy (7).
The equilibrium of the immune system is regulated by
cytokines; these are soluble proteins facilitating cell-to-cell
communications (8). Cytokines are
generated by innate and adaptive immune cells in reaction to tumor
antigens and pathogens. Each cytokine exerts a distinct effect on
the immune system, contingent upon several factors, including local
cytokine concentrations, cytokine receptor expression profiles, and
the interplay of diverse pathways within the immune response
(9). Cytokines can either
stimulate tumor growth (oncogenic cytokines) or prevent it
(antitumor cytokines) by altering variables associated with growth,
proliferation, metastasis and apoptosis (10).
Interleukin (IL)-18 is an immunostimulatory cytokine
that is part of the IL-1 family. It can modulate both innate and
adaptive immune responses by influencing natural killer (NK) cells,
monocytes, dendritic cells, T-cells and B-cells. It can also
function synergistically with other pro-inflammatory cytokines to
enhance interferon (IFN)-γ production by NK cells, T-cells and
potentially, other cell types. IFN-γ is the only identified member
of the type II IFN family, discovered ~60 years ago, and the
paradoxical pathological and biological effects of IFN-γ continue
to be a focal point of research literature (11). According to the current
understanding, host-derived IFN-γ can exert both anti-tumorigenic
and pro-tumorigenic effects due to its complex role in
immunoediting (12). To diminish
lung cancer mortality, the optimal approach is to enhance cancer
preventive efficacy and use screening technologies for risk
evaluation and early-stage diagnosis in lung cancer treatment
(10).
The side-effects of cancer treatments can be
evaluated through the assessment of alterations in the levels of
biochemical parameters. Chemotherapy serves as a systemic
intervention that inhibits the proliferation of cancer cells, which
grow and divide abnormally and rapidly. However, it is unable to
selectively differentiate between healthy and cancerous cells.
Therefore, chemotherapy-induced adverse effects arise from damage
to healthy cells (13). Moreover,
as immunotherapy becomes increasingly prevalent in cancer
treatment, it is crucial to recognize the potential rare, yet
notable immune-related adverse effects associated with these
medicines (14).
The present study aimed to assess the serum levels
of several proinflammatory cytokines and biochemical parameters
prior to and during immunotherapy or chemotherapy, to compare the
impact of these treatments on these markers in patients with
advanced NSCLC. The present study underscores the pivotal
significance of cytokine and biomarker levels in assessing and
enhancing lung cancer therapies, providing essential insight that
may facilitate the development of more effective and specific
treatment strategies.
Patients and methods
Patient selection
The present study prospectively enrolled a total of
120 patients diagnosed with stage IV NSCLC between January, 2024
and February, 2025 at the Oncology Teaching Hospital (Medical City
Center, Baghdad, Iraq). The patients were divided into three groups
based on the type of treatment they received and the level of
PD-L1, as follows: i) Immunotherapy group (PD-L1 score, ≥50%); ii)
chemotherapy group (PD-L1 score, 0%); and iii) combination therapy
group (PD-L1 score, 1-49%). All treatments were administered as
first line treatments. In the immunotherapy group, the patients
were intravenously administered 1,200 mg atezolizumab or 200 mg
pembrolizumab. In the chemotherapy group, the patients were
administered 175 mg/m2 paclitaxel with carboplatin or 60
mg/m2 vinorelbine or carboplatin with 500
mg/m2 pemetrexed. In the combination therapy group,
patients received a combination of both immunotherapy and
chemotherapy. These patients received treatment every 3 weeks until
disease progression or unacceptable toxicities. Relevant clinical
information and blood samples were collected before and after 6
cycles (equivalent to 4.2 months) of treatment. No delays were
noted in the administration of treatment due to toxicity or other
reasons. The Research Ethics Committee of Mustansiriyah University
(Baghdad, Iraq) reviewed and approved the study (approval no.
BCSMU/1024/0050Z). All patients who participated in this study
provided written informed consent for the publication of their
data. The consent form emphasized that participation was entirely
voluntary, and the participants could withdraw at any time without
facing any repercussions. Anonymity and confidentiality were
safeguarded by assigning coded identifiers rather than names or
medical record numbers.
Blood samples
venous blood was collected from 120 patients with
stage IV lung cancer both at pre- and post-treatment to assess
certain immunological and biochemical markers. Blood was collected
in a gel tube and allowed to clot at room temperature for 30 min,
after which the sera were separated by centrifugation for 10 min at
136,955 x g at 4˚C and divided into small, equal portions in
Eppendorf tubes and preserved in a deep freeze at -20˚C until use.
Each sample was designated by a serial number and the name of the
patient. A total of 2 ml serum was used for the analysis of IL-18
and IFN-γ using ELISA kits for humans, according to the
manufacturer's instructions for IL-18 (cat. no. RE1123H from Reed
Biotech Ltd.) and IFN-γ (cat. no. RE1059H from Reed Biotech Ltd.).
Moreover, 3 ml residual serum was used to analyze alanine
aminotransferase (ALT), aspartate aminotransferase (AST), total
serum bilirubin (TSB), creatinine, urea and random blood sugar
(RBS) levels using Cobas® (Roche Diagnostics).
Statistical analysis
Statistical analysis was performed using GraphPad
Prism version 9.2 (IBM Corp.). Quantitative parametric data were
subjected to the Shapiro-Wilk test to confirm the normal
distribution and are expressed as mean ± standard deviation.
One-way analysis of variance and the Student's t-test were used to
determine the significance of group variance. Tukey's post hoc test
was performed to adjust for multiple comparisons. Fisher's exact
test was employed to test count variances. A value of P<0.05 was
considered to indicate a statistically significant difference.
Results
Α total of 120 patients with advanced-stage NSCLC
were enrolled in the present study. These patients were divided
into three groups based on the type of treatment received:
Immunotherapy, chemotherapy and a combination of both. The
demographic and clinical characteristics of the patients were
analyzed, including age, sex, NSCLC subtype, body mass index (BMI),
family history and smoking status (Table I).
 | Table ICharacteristics of the patients in
the present study. |
Table I
Characteristics of the patients in
the present study.
| | Group | |
|---|
| Characteristic | Immunotherapy | Chemotherapy | Combination | P-value |
|---|
| Sex, n (%) | | | | |
|
Male | 39 (97.5%) | 38 (95%) | 37 (92.5%) | 0.4716 |
|
Female | 1 (2.5%) | 2 (5%) | 3 (7.5%) | |
|
Total | 40 (100%) | 40 (100%) | 40 (100%) | |
| Subtype, n (%) | | | | |
|
Adenocarcinoma | 31 (77.5%) | 20 (50%) | 26 (65%) | 0.0251 |
|
Squamous
cell carcinoma | 9 (22.5%) | 20 (50%) | 14 (25%) | |
|
Total | 40 (100%) | 40 (100%) | 40 (100%) | |
| Smoking status, n
(%) | | | | |
|
Never | 7 (17.5%) | 5 (12.5%) | 6 (15%) | 0.8331 |
|
Current | 17 (42.5%) | 15 (37.5%) | 16 (40%) | |
|
Former | 16 (40%) | 20 (50%) | 18 (45%) | |
|
Total | 40 (100%) | 40 (100%) | 40 (100%) | |
| Family history of
any cancer type, n (%) | | | | |
|
Yes | 1 (2.5%) | 4 (10%) | 1 (2.5%) | 0.2043 |
|
No | 39 (97.5%) | 36 (90%) | 39 (97.5%) | |
|
Total | 40 (100%) | 40 (100%) | 40 (100%) | |
| PMH, n (%) | | | | |
|
Yes | 7 (17.5%) | 4 (10%) | 5 (12.5%) | 0.5014 |
|
No | 33 (82.5%) | 36 (90%) | 35 (87.5%) | |
|
Total | 40 (100%) | 40 (100%) | 40 (100%) | |
| Treatment, n
(%) | | | | |
|
Pembrolizumab | 20 (50%) | | 20 (50%) | >0.9999 |
|
Atezolizumab | 20 (50%) | | 20 (50%) | |
|
Total | 40 (100%) | | 40 (100%) | |
| BMI, mean ± SD | 24.2±3.14 | 22.62±3.1 | 23.02±3.14 | 0.3282a |
| Age in years, mean
± SD | 65.41±4.2 | 63.54±9.2 | 61.33±11.24 | 0.6572a |
The patients in the immunotherapy group (n=40) had a
mean age of 65.41 years, with 39 (97.5%) male and 1 (2.5%) female
patients. In total, 77.5% of patients were diagnosed with
adenocarcinoma and 22.5% with squamous cell carcinoma. Furthermore,
17.5% of the patients never smoked, 42.5% were current smokers and
40% were former smokers. The mean BMI of the patients was 24.2
kg/m2. Patients received anti-PD-1/PD-L1 treatments.
Atezolizumab was administered to 20/40 (50%) patients, and
pembrolizumab was administered to the remaining 20/40 (50%)
patients, as a first-line treatment. All the patients in the
immunotherapy group were positive for PD-L1 expression, with a
tumor proportion score ≥50%.
In the chemotherapy group (n=40), the mean BMI was
22.62 kg/m2 and the mean age was 63.54 years, with 38
(95%) male and 2 (5%) female patients. In total, 37.5% of the
patients were current smokers. In the combined therapy group
(n=40), the mean age of the patients was 61.33 years, with 37
(92.5%) male and 3 (7.5%) female patients. A total of 40% were
current smokers. The mean BMI was 23.02 kg/m2. In this
group, 20/40 (50%) patients received chemotherapy in combination
with atezolizumab and 20/40 (50%) received chemotherapy in
combination with pembrolizumab, as a first-line treatment. Patients
were monitored both prior to initiating treatment and six cycles
post-treatment (4.2 months) to assess changes in the levels of
proinflammatory cytokines and biochemical parameters.
The IL-18 and IFN-γ levels were measured both before
and after treatment for each therapeutic group. In the
immunotherapy group, there was a significant elevation in the level
of IL-18 (P=0.0090) and IFN-γ (P<0.0001), with parallel
increases observed in the combination group for IL-18 (P=0.0251)
and IFN-γ (P=0.0012) (Table
II).
| Table IIComparison of IL-18 and IFN-γ levels
before and after treatment across three different therapeutic
groups. |
Table II
Comparison of IL-18 and IFN-γ levels
before and after treatment across three different therapeutic
groups.
| A, Immunotherapy
group |
|---|
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
|---|
| IL-18 (pg/ml) | 42.37±14.2 | 58.61±16.3 | 0.0090 |
| IFN-γ (pg/ml) | 81.32±25.4 | 140.6±44.72 | <0.0001 |
| B, Chemotherapy
group |
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
| IL-18 (pg/ml) | 54.49±21.25 | 43.17±13.6 | 0.1597 |
| IFN-γ (pg/ml) | 119.2±49.3 | 131.4±30.3 | 0.1873 |
| C, Combination
therapy group |
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
| IL-18 (pg/ml) | 45.87±17.2 | 67.56±18.12 | 0.0251 |
| IFN-γ (pg/ml) | 94.78±58.4 | 170.8±62.24 | 0.0012 |
Liver function test levels (ALT, AST and TSB) were
assessed before and after treatment for each therapeutic group. In
the immunotherapy group, there were no significant differences
between pre- and post-treatment levels. However, a significant
difference in ALT levels was found in the chemotherapy group
(P=0.133). Furthermore, in the combination therapy group, there was
a significant difference in TSB levels between pre- and
post-treatment (P=0.0035) (Table
III).
| Table IIIComparison of ALT, AST, TSB levels
before and after treatment across three different therapeutic
groups. |
Table III
Comparison of ALT, AST, TSB levels
before and after treatment across three different therapeutic
groups.
| A, Immunotherapy
group |
|---|
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
|---|
| ALT (U/l) | 24.13±10.9 | 21.14±6.7 | 0.4319 |
| AST (U/l) | 24.04±7.6 | 20.76±2.43 | 0.2215 |
| TSB (mg/dl) | 0.3746±0.2 | 0.4672±0.46 | 0.5789 |
| B, Chemotherapy
group |
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
| ALT (U/l) | 33.41±19.4 | 17.30±14.2 | 0.0133 |
| AST (U/l) | 36.00±19.4 | 27.81±18.4 | 0.4335 |
| TSB (mg/dl) | 0.7972±0.2 | 0.8895±0.3 | 0.2723 |
| C, Combination
therapy group |
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
| ALT (U/l) | 23.42±4.81 | 25.71±2.3 | 0.3891 |
| AST (U/l) | 26.47±2.5 | 20.37±3.4 | 0.0957 |
| TSB (mg/dl) | 0.4298±0.3 | 0.7891±0.13 | 0.0035 |
Renal function tests (creatinine and urea) were
performed both before and after treatment for each therapeutic
group. In the immunotherapy group, there were significant
differences between pre- and post-treatment levels for both
creatinine and urea (P=0.0019 and 0.0115, respectively). However,
in the chemotherapy and combination therapy groups there were no
significant differences in these parameters (Table IV).
| Table IVComparison of creatinine and urea
levels before and after treatment across three different
therapeutic groups. |
Table IV
Comparison of creatinine and urea
levels before and after treatment across three different
therapeutic groups.
| A, Immunotherapy
group |
|---|
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
|---|
| Urea (mg/dl) | 39.18±3.19 | 49.65±12.9 | 0.0115 |
| Creatinine
(mg/dl) | 0.9092±0.2 | 1.162±0.1 | 0.0019 |
| B, Chemotherapy
group |
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
| Urea (mg/dl) | 39.21±5.4 | 46.11±15.3 | 0.1254 |
| Creatinine
(mg/dl) | 0.9945±0.23 | 1.031±0.4 | 0.6545 |
| C, Combination
therapy group |
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
| Urea (mg/dl) | 41.64±11.9 | 46.73±20.8 | 0.2793 |
| Creatinine
(mg/dl) | 0.9821±0.2 | 1.272±0.6 | 0.2186 |
RBS levels were measured both before and after
treatment for each therapeutic group. In the immunotherapy group,
there was a significant difference between pre- and post-treatment
levels (P=0.0088). However, no significant differences were found
in both the chemotherapy and combination therapy groups (Table V).
| Table VComparison of random blood sugar
levels before and after treatment across three different
therapeutic groups. |
Table V
Comparison of random blood sugar
levels before and after treatment across three different
therapeutic groups.
| A, Immunotherapy
group |
|---|
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
|---|
| RBS (mg/dl) | 127.9±15.56 | 159.3±60.51 | 0.0088 |
| B, Chemotherapy
group |
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
| RBS (mg/dl) | 147.5±32.01 | 158.7±52.7 | 0.5363 |
| C, Combination
therapy group |
| Parameter | Pre-treatment (mean
± SD) | Post-treatment
(mean ± SD) | P-value |
| RBS (mg/dl) | 116.4±16.35 | 110.7±23.2 | 0.7816 |
Discussion
Generally, scientific studies tend to assess a
solitary immune system parameter within a single treatment group,
predominantly focusing on immunotherapy as a monotherapy, which may
inadequately reflect the immunological signature associated with
the emergence of a suitable antitumor response. Moreover, they are
unable to compare this response across other treatment groups
(15-17).
The present study followed-up patients with a confirmed diagnosis
of advanced-stage NSCLC that received immunotherapy, chemotherapy
or combination therapy, to evaluate the changes in the levels of
certain proinflammatory cytokines and biochemical parameters before
and after treatment.
The results of the present study demonstrated that
serum IL-18 levels were significantly increased in the
immunotherapy and combination therapy groups following treatment
compared with prior to treatment (P=0.0090 and P=0.0251,
respectively). However, in the chemotherapy group, this increase
was not significant (P=0.1597) (Table
II). A previous study reported that during the first cycle of
anti-PD-L1 immunotherapy, the IL-18 levels increased in the serum
of patients with NSCLC, which was associated with the reactivation
and cytotoxicity of antitumor effector cells, specifically the
production of IFN-γ (18).
Preclinical research has indicated that IL-18 is essential for the
suppression of tumor development (19). An independent investigation
emphasized the potential of IL-18 as a viable biomarker for
response to anti-PD-1 treatment in lung cancer (20). Similar findings have been reported
in pancreatic, metastatic and non-metastatic melanoma mouse models,
wherein the in vivo administration of IL-18 was shown to
inhibit tumor proliferation by enhancing the activation and
cytotoxicity of CD4+ and CD8+ T-cells, as
well as NK cells (21), along with
their interaction with tumor cells and the vigorous production of
memory T-cells (8,22). Furthermore, in a previous study,
elevated levels of IL-18 were detected in the plasma and tissue of
patients with NSCLC treated with immunotherapy, and were associated
with an anticancer immune gene profile (23), and a reduced tumor burden (18,20).
Upon recognition of pathogenic stressors by innate immune cells,
inflammasomes are assembled, leading to the activation of
caspase-1, which converts pro-IL-18 into mature IL-18. Due to the
expression of IL-18 receptors on NK cells, IL-18 may contribute to
the immunological functions of these cells (24). Notably, studies using preclinical
animal models of lung malignancies have reported that IL-18
enhances the sensitivity of lung tumors to anti-PD-1 immunotherapy
(21,25). Moreover, in patients with NSCLC
receiving atezolizumab, IL-18 has been shown to exhibit a
dose-exposure association that is associated with tumor size
(18). Subsequently, IL-18 is a
crucial element in initiating cellular immunity, thereby promoting
an efficient antitumor immune response (25).
Chemotherapy is one of the most effective available
therapies for malignant tumors; however, it is protracted and
non-specific, killing tumor cells whilst injuring normal tissues to
varied degrees, in which the most notable is the phased loss of
lymphocytes, inhibiting normal immune function (26). In the present study, the levels of
IL-18 in the chemotherapy group were not altered when compared with
the other groups, and the increased level was very slight
(P=0.1597). This is consistent with the findings of previous
studies which reported that a non-significant increase in the
levels of IL-18 in the chemotherapy group (27,28).
These findings correspond with previous findings that report that
elevated IL-18 levels in the serum and tissue of patients with
ovarian cancer are inactive due to the absence of IFN-γ production
(29).
Currently, chemotherapy is the primary treatment for
advanced-stage NSCLC; however, the total survival duration for
patients averages ~10 months, with a 2-year survival rate of ~10%
(1). This may be associated with
the deleterious side-effects induced by chemotherapy (30). The factors contributing to the
unfavorable prognosis of patients encompass tumor invasion and the
immunosuppressive effects of chemotherapy (31). Specifically, diminished levels of
IL-18 are associated with metastasis and unfavorable outcomes
(32,33). Consequently, elucidating the impact
of chemotherapy on the organism and providing effective therapies
are essential for enhancing patient prognosis (31). The immunosuppressive effects of
chemotherapy may be associated with this event; however, limited
information has been documented at this time, to the best our
knowledge. Consequently, the combination of chemotherapy and
immunotherapy may amplify the antitumor effect; however, the
precise mechanism underlying this effect remains ambiguous.
Nevertheless, the present study used several chemotherapy regimens
(such as paclitaxel/carboplatin and carboplatin/pemetrexed), which
matches real-world NSCLC treatment patterns where combination
treatments are customized to individual patients. Notably, all
analyses were stratified by treatment method and the consistent
pattern of biomarker alterations across these groups indicated that
the key conclusions were robust despite the variability of
chemotherapy. However, future research utilizing standardized
chemotherapy regimens is necessary to remove potential
regimen-specific confounders and further confirm the findings of
the present study.
Furthermore, in the present study, it was
demonstrated that the level of IFN-γ was significantly increased in
the immunotherapy and combination groups following treatment
(P<0.0001 and 0.0012, respectively), whilst in the chemotherapy
group, this increase was minimal and non-significant (P=0.1873)
(Table II). A previous study
reported that the increased production of IFN-γ was observed with
high doses of IL-18(34). This is
consistent with the results of the present study, reflecting its
reliability. The paradoxical biological and pathological effects of
IFN-γ continue to be a focal point of research in the literature
(11). According to current
knowledge, host-derived IFN-γ can exert both anti-tumorigenic and
pro-tumorigenic effects due to its complex role in immunoediting
(12). The anti-tumoral effects of
IFN-γ include the reduction of growth in several tumor cell lines.
This is achieved by direct antitumor mechanisms and the enhancement
of immune cell-mediated cytotoxicity, alongside the modulation of
PD-L1 expression (35), or by
blocking angiogenesis in neoplastic tissue, inducing regulatory
T-cell death, and/or stimulating the activity of M1 proinflammatory
macrophages to counteract tumor growth (8). Furthermore, another study reported
that tumor cells can evade immune system regulation in the initial
phases of tumor growth, either due to the reduced expression of
IFN-γ or through modifications of its receptors (30). Moreover, IFN-γ may diminish immune
responses by intensifying the activation of specific
immunosuppressive pathways that facilitate cancer progression and
metastasis (36). The study by
Jorgovanovic et al (11)
reported that the concentration of IFN-γ in the tumor
microenvironment was associated with its function. Moreover, it was
revealed that tumors treated with low-dose IFN-γ developed
metastatic characteristics, whereas those administered high doses
resulted in tumor regression (11). Deficiencies in the IFN signaling
pathway are a primary route of resistance to immune checkpoint
inhibition (37,38). Additionally, previous research
reported that high doses of IFN-γ could trigger apoptosis in NSCLC
cell-lines by activating JAK-STAT1-caspase signaling, which
subsequently launched apoptotic processes in cancer cells (39). Moreover, some other research has
examined baseline plasma cytokines, including IFN-γ, in individuals
with advanced-stage NSCLC (40,41).
In response to immunotherapy, IFN-γ levels increased in sera of
patients with lung cancer (40).
These results indicate that serum cytokine level analysis, which is
non-invasive, cost-effective and reproducible, may serve a notable
role in future integrated prediction models. However, future
large-scale research requires tumor cytokine analysis.
Consequently, the findings of the present study may help to
establish a basis for forthcoming extensive validation studies
assessing temporal variations in serum cytokine levels and
exploring their associations with tumor responses to cancer
therapies.
As regards chemical biomarkers, previous studies
have reported that immunomodulating agents targeting cytotoxic
T-lymphocyte-associated protein 4, PD-1 or PD-L1 are associated
with several immune-related adverse effects, including autoimmune
pneumonitis, colitis, hepatitis, nephritis and several
endocrinopathies (42-44).
As immunotherapy becomes increasingly prevalent in cancer
treatment, it is crucial to recognize the potential rare, yet
severe immune-related adverse effects associated with these
treatments (14). This novel
oncological treatment has been reported to be a more effective and
robust alternative to conventional chemotherapy, leading to
extended remission durations and less side effects. However, as ICI
enhances the immune system, subsequent autoimmune diseases may
arise (7).
The incidence of hepatotoxicity in patients with
lung cancer vary by cohort. Liver function tests serve as the
principal baseline indicator of hepatic function and health in
patients undergoing anticancer treatment, with elevations in liver
function tests signifying a predominant portion of therapy-related
hepatotoxicity (45,46). In the present study, ALT, AST and
TSB levels demonstrated non-significant differences in the
immunotherapy group; however, in the chemotherapy group, ALT levels
exhibited a significant difference between pre- and post-treatment
levels (P 0.0133). Moreover, in the combination group, there was a
significant difference in TSB levels (Table III).
The fluctuation of ALT and AST levels due to
chemotherapy has been commonly reported in previous clinical
studies (47-49),
which is in agreement with the results of the present study.
Hepatic dysfunction under chemotherapy mainly consists of abnormal
liver tests indicating changes in the levels of bilirubin and
alkaline phosphatase, with or without abnormal levels of AST and/or
ALT. The mechanism of liver injury following chemotherapy remains
incompletely understood; however, enzymes involved in folate
metabolism may be critical components. These enzymes are present in
both hepatic and neoplastic cells, hence chemotherapy may affect
hepatic cells (50,51). Chemotherapy-induced hepatotoxicity
can generally be effectively controlled through careful monitoring
for elevated liver function tests indicative of liver damage, dose
adjustments and the cessation of the causative agent if liver
function tests do not normalize despite dose reduction (45,52).
Furthermore, previous research has reported that, in
comparison with chemotherapy alone, PD-1/PD-L1 inhibitors, whether
administered with or without chemotherapy, increase the incidence
of both all-grade and high-grade hepatitis; however, they do not
elevate the risk of increased blood markers indicative of
hepatotoxicity (53). This aligns
with the results of the present study, in which the findings in the
combination therapy group demonstrated that there was no elevation
in ALT or AST levels, with a significant difference in TSB levels
only. Moreover, previous research on breast cancer has reported
that combination chemotherapy elevates liver toxicity (54). The incidence of hepatotoxicity
associated with individual anticancer agents differs in clinical
trials; nevertheless, the advent of combination chemotherapy
complicates the current situation and necessitates further
analysis.
The adverse impacts of certain ICIs on hepatic
function remain contentious. Hepatotoxicity subsequent to ICI
treatment is rare, although clinically significant (55). The majority of associated
toxicities are immune-related side-effects, occurring in ≤5% of
patients (56). Hepatocellular or
mixed hepatitis with immunological characteristics typically
manifests within 2-12 weeks following the commencement of ICI
therapy; however, it can arise at any point during treatment,
including ≤1 year post-initial dosage (57). In the immunotherapy group in the
present study, there were no significant differences in the liver
function parameters. This may be attributed to the short follow-up
period, which is a limitation of the present study. However, the
finding is consistent with the findings of previous studies
(58,59), including the study by Guo et
al (53), which reported a
minimal or no difference in the risk of elevated blood indicators
of hepatotoxicity for patients who received PD-1/PD-L1 inhibitor
monotherapy, a PD-1/PD-L1 inhibitor plus chemotherapy, and
chemotherapy alone. Future studies with large sample sizes and
prolonged follow-up are essential to confirm the findings of the
present study and assess long-term toxicity.
Moreover, as regards renal adverse events in the
present study, the levels of creatinine and urea were significantly
elevated in immunotherapy group (P=0.0019 and P=0.0115,
respectively), whilst in the chemotherapy and combination therapy
groups, the differences were not significant (Table IV). These results are agreement
with the findings of previous studies (60,61),
which reported a marked association between immunotherapy and
increased creatinine levels, potentially resulting in renal
toxicity that may be risky if not managed. Generally, the
inhibition of immunological checkpoints augments the ability of the
immune cells of the body to identify foreign cells, which
concurrently increases the likelihood of misidentifying its own
cells as foreign. This underlies the adverse effects that may arise
during therapy with ICIs, potentially affecting almost every system
of the human body (62). Renal
toxicity with ICIs is considered an uncommon consequence; however
it may be underreported (63,64).
In a previous study by Xipell et al (61), following the administration of ICIs
to patients, blood test results indicated an increase in the serum
creatinine level to 5.6 mg/dl, compared with a previous level of
~1.2 mg/dl. Furthermore, Izzedine et al (60), defined a series of renal adverse
events by high creatinine levels in patients treated with
pembrolizumab. These results are in agreement with the findings of
the present study. The precise mechanism causing systemic or organ
damage during or following therapy with ICIs remains ambiguous and
requires additional research (65). However, one suggested mechanism
suggests that the kidneys have immunological checkpoint molecules,
such as PD-L1, which may shield healthy tissue from T-cell
cytotoxicity and invasion. Consequently, tissue damage may arise
from PD-L1 inhibition (66,67).
Another mechanism involves activated T-cells, which can enter
tumors or normal tissue and use T-cell receptors (TCRs) to identify
antigens. A TCR attaches itself to antigens that are expressed on
healthy cells and whose sequences are sufficiently similar to those
of neoantigens in the first instance (66). Additionally, ICIs can reactivate
drug-specific T-cells that have been primed by nephritogenic
medications. As a result, memory T cells are activated against the
drug due to a lack of tolerance (60). Finally, a large number of
pro-inflammatory cytokines are produced following renal damage.
Another mechanistic theory suggests that ICIs may be involved in
the production of certain autoantibodies that harm healthy organs
(66). Finally, a large number of
pro-inflammatory cytokines are produced following renal damage
(68); however, it remains unknown
whether elevated serum levels of cytokines induce or are result of
tissue damage. This finding necessitates more thorough research.
Both the European Society for Medical Oncology and American Society
of Clinical Oncology incorporate suggestions on managing renal
toxicities in the guidelines regarding immunotherapy due to the
increasing usage of ICIs in the treatment of cancer and the growing
understanding of the potential renal side effects of the therapy
(69,70). The noted elevation in creatinine
(P-value 0.0019) and urea (P-value 0.0115) in the present study may
indicate modified renal function during immunotherapy. While these
alterations were often insufficient to warrant the cessation of
treatment in the majority of cases, they highlight the critical
need of regular renal monitoring to identify early indicators of
nephrotoxicity. According to the ASCO/ESMO guidelines, the accurate
monitoring of hepatic and renal functions (including ALT, AST, TSB,
urea and creatinine) should be performed at baseline and every 3-4
weeks during the treatment of patients with lung cancer undergoing
immunotherapy or on combination therapies (69,70).
In the present study, the RBS level was
significantly increased in the immunotherapy group following
treatment (P<0.0088) (Table V).
This result is in agreement with the findings of previous research,
which reported that type 1 diabetes mellitus (T1DM) developed in
conjunction with ICI therapies (71,72).
The FDA has issued a warning that pembrolizumab may induce
immune-mediated endocrinopathies (56).
However, the mechanism linking immunotherapy and the
endocrine system is inadequately understood. It is hypothesized
that the PD-1 receptors on T-cells facilitate the binding and
activation of PD-L1. The interaction between PD-1 and PD-L1
generates an inhibitory signal that modulates activated and
autoreactive T-cells, hence suppressing the immune system.
Consequently, PD-1 inhibitors result in an active immune system
characterized by elevated quantities of functional T-cells.
Moreover, β-cells in the pancreas express PD-1, and the elevation
of T-cells due to PD-1 inhibitors suggests that β-cells may respond
maladaptively to increased autoreactive T-cells, ultimately leading
to their inability to produce insulin and resulting in diabetes
(73).
Furthermore, in the present study, the elevation in
RBS levels within the chemotherapy and combination therapy groups
were non-significant (P=0.5363 and P=0.7816, respectively). This
finding is in agreement with the findings of previous studies
(74,75). The results of the study by Nagy
et al (7) demonstrate that
checkpoint inhibitors are the most frequently associated with
new-onset diabetes compared with conventional chemotherapy.
Moreover, Chae et al (14)
reported that the platinum and taxane types of chemotherapy were
not associated with the onset of T1DM. With the increasing
incidence of immunotherapy-induced diabetes, the ASCO has developed
clinical recommendations for the management of endocrine problems
resulting from ICIs (76). The
guidelines advise that fasting or random blood glucose and HbA1c
tests should be conducted prior to and following the administration
of ICIs (77). According to the
results of the present study, careful glucose monitoring and rapid
dietary or pharmacological therapies are recommended to avoid the
onset of diabetes. However, further research is waranted to
elucidate the underlying process, particularly with checkpoint
inhibitors, which constitute the primary class associated with
autoimmune diabetes. Until the pathogenic process is thoroughly
understood, healthcare personnel must endeavor to avert the
emergence of life-threatening endocrinopathies (7).
Finally, the present study performed a power
analysis test which confirmed that the sample size (n=40/group)
provided adequate statistical power (99.9%) to detect clinically
meaningful effects for the primary endpoints, based on an effect
size of 0.5 and α=0.05. Whilst this sample size was sufficient for
the main outcomes, larger cohort studies are required to confirm
whether the identified changes in immunological and biochemical
variables can function as predictive indicators, and to reduce
immune-related adverse events whilst maintaining treatment
efficacy.
In conclusion, in the complex field of several
therapies designed to eliminate cancer and alleviate its
consequences in patients with lung cancer, there is a critical
necessity for predictive markers to differentiate the varying
implications of these treatments on immunological profiles and
biochemical parameter levels. The present study assessed several
proinflammatory cytokine and biochemical levels in patients with
NSCLC before and after treatments to identify differences among
several treatment groups, and the results highlight the need of
evaluating these parameter levels due to their vital involvement in
anti-tumoral effects and potential side-effects.
Acknowledgements
The authors would like to thank Dr Hiba Q. Mahmoud
at the College of Science, Mustansiriyah University (Baghdad,
Iraq), Dr Hussein I. Hayal at Al-Kindy College of Medicine, Baghdad
University (Baghdad, Iraq), and Dr Ali Z. Al-Saffar at the College
of Biotechnology, Al-Nahrain University (Baghdad, Iraq), for
providing academic assistance and guidance.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be
requested from the corresponding author.
Authors' contributions
TJT contributed to the conception and design of the
study, and wrote and edited the manuscript. SMJ collected and
analyzed data. FAAS reviewed and edited the manuscript, and was
also involved in data curation, and supervised the study. All
authors have read and approved the final manuscript. TJT and SMJ
confirm the authenticity of all the raw data.
Ethics approval and consent to
participate
The present study was reviewed and approved by the
Research Ethics Committee of Mustansiriyah University, Baghdad,
Iraq (approval No. 1024/0050Z) and subsequently authorized by THE
Oncology Teaching Hospital/Medical City administration per standard
institutional collaboration procedures. All patients who
participated in the study provided written informed consent for the
publication of their data. The consent form emphasized that
participation was entirely voluntary, and the participants could
withdraw at any time without facing any repercussions. Anonymity
and confidentiality were safeguarded by assigning coded identifiers
rather than names or medical record numbers. In adherence to
international ethical guidelines, including the Declaration of
Helsinki, the study maintained strict ethical standards. A
statement of consent for publication was obtained from the patient
according to the principles of the Declaration of Helsinki.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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