The incidence of CRC ranks third among all malignant tumours, and it is the fourth most deadly cancer worldwide . The incidence and mortality of CRC in Asia have shown upward trends . The early diagnosis rate of CRC in mainland China is low, and the disease is often in the late stage when diagnosed. At that point, the opportunity for surgical resection has been lost, the survival rate is low, and the mortality rate is high. Targeted therapy combined with chemotherapy has significantly improved the survival of patients with advanced CRC . The targeted drugs for CRC that have been approved in China are bevacizumab and cetuximab. Cetuximab is mainly used for KRAS, NRAS, and BRAF wild-type CRC. Bevacizumab has obvious adverse reactions when applied to patients with bleeding, obstruction, and perforation tendencies, so many factors should be considered in the clinic when deciding which targeted drugs should be used. FOLFOX and FOLFIRI are commonly used options for metastatic CRC, and the two are used equivalently in first-line treatment. The two chemotherapy regimens have their own adverse reaction spectrum and are applied to different groups of people. Targeted drugs combined with chemotherapy regimens are currently the main means for treating advanced CRC. The selection of suitable targeted drugs and chemotherapy regimens is the main factor affecting the survival of advanced CRC patients. There are still many patients in the clinic who cannot be treated with the above two targeted drugs due to various factors, so more treatment methods need to be explored.
Apatinib is a small molecule inhibitor that specifically binds to vascular endothelial growth factor receptor 2 (VEGFR-2). Blocking VEGFR-2 can inhibit the migration and proliferation of vascular endothelial cells and reduce the microvessel density of tumours, thereby inhibiting tumour angiogenesis and exerting antitumour effects [12,13]. Apatinib can enhance endoplasmic reticulum autophagy by enhancing the stress of oestrogen receptors to promote proteasome degradation, thereby inducing the apoptosis of CRC cells . At the same time, apatinib inhibits the AKT-mTOR signalling pathway and increases the expression of Lc3-II to induce autophagy. In the process of autophagy, the UIK1 autophagy complex can be positively regulated by inhibiting mTORC1, thereby promoting autophagy and apoptosis . Studies have shown that apatinib increases the ubiquitination of β-catenin and reduces the phosphorylation of Ser-9 in GSK3β, thereby reducing the nuclear localization of β-catenin and inhibiting the VEGFR2-β-catenin pathway to exert an antitumour effect . Studies have shown that apatinib monotherapy for the late-line treatment of patients with advanced metastatic CRC who have failed chemotherapy has shown a good clinical effect compared with the control. The median PFS was 2 months, and the OS was 5 months longer than that of the control observation group. It is believed that apatinib has a certain clinical effect on the improvement of OS . Therefore, we designed the regimen of apatinib combined with FOLFIRI to explore the efficacy and safety of this regimen as first-line therapy for advanced metastatic CRC.
In our study, the median OS of apatinib combined with FOLFIRI in the treatment of advanced unresectable CRC was 16.135 months (95% CI: 9.211–22.929), and the median PFS was 6 months (95% CI: 5.475–6.525). The ORR was 35%, and the DCR was 80%. The common adverse events were hypertension (90%), vomiting (90%), fatigue (65%), hand-foot syndrome (65%), white blood cell reduction (80%), neutropenia (45%), and hyperbilirubinemia (45%). Serious adverse events (grade >3) were hypertension (11.1%), diarrhoea (5%), increased ALP (5%), leukopenia (5%), and neutropenia (5%). This study shows that the combination of apatinib and FOLFIRI as a first-line treatment for advanced unresectable metastatic CRC has good efficacy and tolerable adverse reactions. Compared with the previous treatment data of regorafenib, the first-line application of an apatinib combination regimen can give patients a better benefit. In the global CORRECT  study, regorafenib was used as a third-line targeted drug to treat advanced metastatic CRC in subjects who were frail or unsuitable for treatment. The median PFS was 1.9 months, and the OS was 6.4 months, which were improved compared to those of previous placebo treatment and best supportive treatment. In the CONCUR study, the median PFS and OS of Asians using regorafenib were 3.2 months and 8.8 months, respectively . In clinical studies of regorafenib as a first-line application, the median PFS was 5.6 months, and the median OS was 16 months . Our results are better than the first-line treatment data of single-agent regorafenib. The subjects we enrolled had the following characteristics: all subjects were stage IV patients at the time of enrolment, 14 (70%) subjects had more than two metastatic sites, and of 15 (75%) subjects with simultaneous liver metastases, 11 (55%) subjects had lung metastasis, and 6 (30%) subjects had an ECOG performance status score of 2 points. The liver is the most common site of metastasis in patients with advanced CRC. Approximately half of CRC patients will develop liver metastasis because most of the mesentery drains into the hepatic portal vein system , and liver invasion and metastasis can lead to poor prognosis [twenty-two]. The lobe of the lung is the second most common metastatic site of CRC after the liver , and lung metastasis develops more slowly than liver metastasis. This study included many patients with multisite metastases. At the time of enrolment, the subjects had a poor physical condition and poor tolerance, so the prognosis was poor. However, after the administration of apatinib combined with the FOLFIRI regimen, a certain curative effect was achieved, and there were tolerable adverse reactions.
In our study, the subjects’ OS varied in length, with the longest being 26.7 months and the shortest being 4.47 months. For this reason, an effective predictive marker must be identified. There has been much research evidence that the NLR is significantly related to the prognosis of CRC. The NLR is a potential prognostic and predictive factor for a variety of tumours, including CRC . In the tumour microenvironment, genes encoding tumour-related macrophage activities, such as the LYZ (lysozyme), TYMP (thymidine phosphorylase), and CD68 (pan-macrophage) genes, may affect the NLR. TYMP promotes angiogenesis, escapes apoptosis, and stimulates tumour growth , and the accumulation of high levels of macrophages is positively correlated with high NLR levels. Neutrophils secrete a variety of proinflammatory, angiogenic and immunomodulatory factors, which have paracrine effects on tumour cell biology . Lymphocytes induce cytotoxic cell death and produce cytokines that inhibit the proliferation and metastasis of cancer cells, thereby playing an important role in tumour suppression . Neutrophils can inhibit the cytolytic activity of lymphocytes to tumour cells. In CRC, an increase in the NLR value has an adverse effect on the survival rate of patients with CRC. However, this molecular mechanism is still complex and uncertain . High NLR is associated with a highly aggressive tumour phenotype, and the degree of systemic inflammation is related to the subject's own physical state, which may weaken the subject's own tolerance and compliance, leading to reduced survival rates . Our results show that the prognosis of subjects with NLR <3.855 is better than that of subjects with NLR ≥3.855. Therefore, the NLR at baseline is an independent predictor of the OS of subjects treated with apatinib.
This study is a rigorously executed prospective study with strict ethical review. However, because one-third of the subjects in our clinical study had a baseline ECOG performance status score of 2 with simultaneous multisite metastases, the physical status of patients was relatively poor. Thus, the factors related to the poor prognosis of the subjects and biased enrolment led to unsatisfactory endpoints of OS and PFS in the study. In particular, the mismatch repair protein, RAS, RAF, and HER2 statuses were not standardized during enrolment. Accurate diagnosis has certain limitations. Our study is a single-arm design, and the small sample size affects the objectivity of our data. In the future, we will continue to carry out prospective randomized controlled clinical studies to include more subjects in strict accordance with the inclusion criteria, verify the efficacy and safety of apatinib combined with the FOLFIRI regimen, and further explore the relationship between the NLR and the curative effect of this treatment regimen.