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.