Discussion
At present, there are numerous treatment modalities for colorectal
cancer. Firstly, new form of chemotherapeutic drugs, the most
representative of which is irinotecan hydrochloride liposome injection,
PEPCOL21 and other relevant clinical research trials
reveal that the traditional chemotherapeutic drug irinotecan, carried in
liposomes, can play its efficient anti-tumor role while bringing fewer
side effects to the patients22. Secondly, the newly
discovered targeted treatment, KRAS target has been difficult to become
a drug in the past. In recent years, through continuous scientific
research and clinical medicine, it has been found that its corresponding
targeted drugs combined with chemotherapy and immunotherapy can bring
more benefits to colorectal cancer patients23,24.
Moreover, even for antibody-drug conjugates(ADC), claudin 18.2, as a
newly discovered site, has been highly expressed in gastric cancer as
well as colorectal cancer, and the results of existing multi-center
medical institution studies have shown that the relevant targeting drugs
are highly expressed in gastric cancer as well as colorectal
cancer25, and existing multicentre medical institution
studies have shown that related ADC are also effective in anti-tumor
effects26. However, immune checkpoint inhibitors still
has its important position, whether it is chemotherapy combined with
immunotherapy, targeted therapy combined with immunotherapy, or even
chemotherapy, targeted combined immunotherapy, are very common and
efficient anti-tumor integrated treatment in the clinic. From another
point of view, the treatment of immune checkpoint inhibitors throughout
the long cycle of regular treatment of patients with advanced stage as
well as maintenance and consolidation therapy after stabilization of
disease. Immunotherapy, on the one hand, figuratively speaking,
mobilizes the body’s own immune system and organs to attack tumor cells
and thus play an anti-tumor role; on the other hand, it can regulate the
tumor microenvironment, and has a regulatory effect on lymphocytes,
monocytes, and related inflammatory cytokines, which affect the tumor
microenvironment.
In our study, we found that for patients with treated advanced
colorectal cancer who had already received oxaliplatin and irinotecan as
their main chemotherapy treatment, and then changed their treatment
after reviewing imaging tests, such as computed tomography of the
abdomen and pelvic as well as tumor markers, to clarify that the
efficacy of the previous treatment was assessed to be progressive. There
was no statistically significant difference in patient outcomes between
treatment with and without the selection of immune checkpoint
inhibitors. It is well known that there is currently no uniform
guideline or expert consensus on immunotherapy for patients with
advanced colorectal cancer, except for patients with dMMR for whom an
indication for treatment with immune checkpoint
inhibitors27. Especially for patients on back-line
therapy, combined with the patient’s history of previous treatment,
perhaps the guidelines do not specify one or several optimal treatment
modalities, or even participation in a clinical trial as the best
option. So in this case, when the patient’s physical status scores are
good and they are able to tolerate the adverse effects caused by
antineoplastic therapy, the choice of treatment may be varied and even
chaotic. Targeted therapy, ADC, and immune checkpoint inhibitors may all
be effective treatments for prolonging patient’s overall survival or
progression free survival, however there is no doubt that the choice of
immunotherapy will continue to be important, because of maintenance and
consolidation therapy after disease stabilization28.
This study also found no significant difference in the therapeutic
effect of colorectal cancer patients in terms of the choice of domestic
or imported immune checkpoint inhibitors. Pembrolizumab injection is a
PD-1 pathway inhibitor developed by Merck Sharp & Dohme, and is the
immune checkpoint inhibitor with the widest range of indications,
including adenocarcinoma of the lung, squamous carcinoma of the lung,
esophageal carcinoma, gastric carcinoma, squamous cell carcinoma of the
head and neck, triple-negative breast cancer, and hepatocellular
carcinoma. However, due to export and tariff reasons, its price is
relatively high in China, where the proportion of rural patients
suffering from malignant tumors is more than half, which means that the
majority of patients are unable to afford an imported immune checkpoint
inhibitor like pembrolizumab injection due to financial reasons. In this
study, of the 65 patients receiving back-line treatment with immune
checkpoint inhibitors, only 13 patients were treated with imported
immune checkpoint inhibitors, specifically pembrolizumab injection. The
other 52 patients were treated with domestic immune checkpoint
inhibitors, including sintilimab and tislelizumab. The prices of these
domestic immune checkpoint inhibitors are relatively low, and some of
them are also included in the reimbursement scope of China’s national
health insurance, which means that the final price may be one-tenth of
that of the imported immune checkpoint inhibitors, which is the current
status quo in the treatment of malignant tumors. Secondly, putting aside
the economic factor, whether domestic or imported immune checkpoint
inhibitors, their research, development and production processes are
under appropriate national supervision, so the drugs themselves are
absolutely qualified. In terms of the mechanism, all of them inhibit
tumor immune escape and the related changes in the tumor
microenvironment by blocking the PD-1 pathway, thus playing an
anti-tumor therapeutic role. Therefore, fundamentally, the therapeutic
effects of both domestic and imported immune checkpoint inhibitors on
malignant tumors are the same, which was also confirmed in this study
from the perspective of retrospective case analysis.
In addition, the most important point is that in this study, PFS
survival curves were plotted by the Kaplan-Meier survival analysis
method for different factor groups, including gender, MMR, tumor site,
KRAS status, type of immune checkpoint inhibitor, whether or not combine
with targeted therapy, whether or not with liver metastases, whether or
not with lymph nodes metastases, and the level of NLR. These graphs
demonstrate that gender, tumor site, KRAS status, type of immune
checkpoint inhibitor, whether or not combination targeted therapy,
whether or not with liver metastases, and whether or not with lymph
nodes metastases were not statistically different for PFS in patients
with treated advanced colorectal cancer, P >0.05.
However, in the factor of MMR, it can be clearly noticed from the graphs
that there is a clear separation of the PFS survival curves of the dMMR
and pMMR groups and that the PFS of the dMMR group is better than that
of the pMMR, P =0.029, which indicates a statistical difference.
This result is also consistent with KEYNOTE17729,
which concluded that colorectal cancer patients with dMMR who treated
with immune checkpoint inhibitors were able to demonstrate better
efficacy. KEYNOTE177 also demonstrated that immune checkpoint inhibitors
resulted in a more sustained anti-tumor effect and fewer
treatment-related adverse events than chemotherapy, but did not provide
a clear enhancement in overall survival. Therefore, for colorectal
cancer patients, MMR is an important factor in the selection of
immunotherapy. In addition, there was also a statistical difference in
PFS between the high NLR and low NLR groups for patients with treated
advanced colorectal cancer, with P =0.007, suggesting that
patients in the low NLR group undergoing immunotherapy can lead to
longer PFS compared to the high NLR group. Neutrophil infiltration in
the tumor microenvironment is a complex biological process involving
multiple functions and states30. Recent studies have
revealed that neutrophils play an important role in tumor development
and therapy31,32. In cancer, neutrophil infiltration
exhibits a high degree of heterogeneity and can be classified into
different subpopulations based on their specific status in the tumor
microenvironment. For example,
HLA-DR+CD74+ neutrophils were
associated with better patient prognosis, suggesting that such
neutrophils may have stronger anti-tumor activity33.
Neutrophils can be stimulated into either type N1 or N2 depending on
their stimulation and signal transduction in the tumor microenvironment.
Type N1 neutrophils have an anti-tumor effect, releasing reactive oxygen
species and reactive nitrogen species to directly kill tumor cells and
promote T-cell activation. In contrast, type N2 neutrophils have a tumor
growth-promoting effect, promoting tumor angiogenesis by releasing
factors such as MMP934. Therefore, low NLR indicates
that the degree of infiltration of inflammatory-related factors in the
tumor microenvironment of this patient is well expressed, which is
particularly important in terms of more lymphocytes and fewer
neutrophils.
In Cox univariate analysis, it found that among several factors such as
gender, MMR, tumor site, KRAS status, type of immune checkpoint
inhibitor, whether or not combine with targeted therapy, whether or not
with liver metastases, whether or not with lymph nodes metastases, and
the level of NLR, the two factors of MMR and the level of NLR were
correlated with the PFS of patients with advanced colorectal cancer who
had been treated, P <0.05. After Cox multivariate survival
analysis, patients’ NLR level was found to be an important predictor of
PFS, with the low NLR group having a longer PFS than the high NLR group.
Studies have shown that lymphocyte counts and neutrophil counts reflect
the state of systemic inflammation, and that inflammation has a
tumor-promoting effect, which contributes to tumor cell proliferation
and survival as well as promotes angiogenesis and
metastasis35. However, it should be noted that NLR is
only an auxiliary indicator, and its interpretation and application
should be combined with patient’s specific situation and tumor type.
Of course, there are certain shortcomings in this study. Firstly, the
small number in terms of sample size may lead to statistical bias in the
final conclusion. Secondly, as this study only compared the efficacy of
immunotherapy on patients with advanced colorectal cancer, but not the
adverse effects of the treatment, the results may be relatively
one-sided. However, the innovative idea of this study still has some
research value, and more studies will be conducted to confirm this
conclusion.