Abstract
Objective: To evaluate and compare the efficacy of oxaliplatin-based and irinotecan-based chemotherapy regimens, both combined with capecitabine and bevacizumab, in patients with colorectal cancer and liver metastases. Methods: A retrospective analysis was conducted on 276 patients from Shanxi Province Cancer Hospital. Patients were divided into two groups (n = 138 each) based on treatment regimens. The control group received irinotecan hydrochloride, capecitabine, and bevacizumab, while the research group received oxaliplatin, capecitabine, and bevacizumab. Outcomes compared included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS), serum vascular endothelial growth factor (VEGF), carbohydrate antigen 19-9 (CA19-9), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP), immunoglobulin levels (IgM, IgG), quality of life (QoL), pain scores (VAS), and adverse reactions. Results: The research group showed significantly higher ORR (21.74%) and DCR (63.77%) than the control group (12.32% and 50.00%, respectively; both P < 0.05). One-year PFS, and OS were all significantly improved in the research group (both P < 0.05). Post-treatment, VEGF, CA19-9, LDH, and ALP levels decreased significantly in both groups, with greater reductions in the research group (all P < 0.05). The research group also reported lower VAS pain scores, better QoL improvements, higher IgM and IgG levels, and a lower incidence of adverse reactions (all P < 0.05). Conclusion: The oxaliplatin-based regimen significantly improves tumor control, biomarker profiles, survival, and patient well-being, with fewer adverse effects, supporting its clinical applicability.
Keywords: Irinotecan, oxaliplatin, capecitabine, bevacizumab, colorectal cancer
Introduction
According to global cancer statistics, the incidence of colorectal cancer (CRC) varies geographically, with higher rates observed in Europe and North America [1]. In recent years, the incidence in China has also been rising, now accounting for approximately 45.9% of newly diagnosed cases worldwide [1].
Data from the Global Burden of Disease indicate that CRC ranks among the top cancers in both incidence and mortality, with its mortality rate being the second highest globally [2]. Liver metastasis has become a leading cause of death in patients with advanced CRC [2]. Approximately 20%-34% of patients present with synchronous liver metastases at diagnosis, and over 50% develop liver metastases during the disease course, posing significant therapeutic challenges [3-5].
While conventional treatments have improved survival to some extent, the prognosis for many patients remains poor due to drug resistance, recurrence, and tumor heterogeneity, which also negatively impact quality of life [6].
Currently, chemotherapy remains the primary treatment for CRC with liver metastases. Irinotecan, a commonly used chemotherapeutic agent, inhibits topoisomerase I activity, thereby blocking DNA replication and suppressing tumor cell proliferation [7]. Oxaliplatin inhibits DNA synthesis and tumor cell growth, and demonstrates synergistic effects when combined with fluoropyrimidines such as capecitabine [8]. Bevacizumab, a targeted anti-angiogenic agent, enhances chemotherapy efficacy by inhibiting vascular endothelial growth factor (VEGF) and reducing tumor neovascularization [9]. However, due to the complexity of advanced CRC, these regimens are still limited by resistance, variable therapeutic responses, and adverse effects. Therefore, new therapeutic strategies are urgently needed.
In recent years, tumor biomarkers have received increasing attention. Lactate dehydrogenase (LDH) and alkaline phosphatase (ALP), as indicators of cellular injury and liver function, have been widely used in tumor monitoring and prognostic assessment [10,11]. Tumor markers such as VEGF and carbohydrate antigen 19-9 (CA19-9) are also regarded as important indicators for evaluating treatment efficacy and prognosis in CRC [12,13].
This study specifically focuses on patients with CRC and liver metastases, comparing two commonly used first-line regimens: oxaliplatin + capecitabine + bevacizumab versus irinotecan + capecitabine + bevacizumab. While prior studies have investigated the efficacy of chemotherapy combinations, few have comprehensively assessed the role of multiple biomarkers and immune indicators. This retrospective analysis aims to compare the clinical efficacy and safety of these two regimens and to evaluate associated changes in LDH, ALP, and other biomarkers, thereby providing reference data for personalized treatment strategies in CRC.
Materials and methods
General information
This was a retrospective study. The sample size was estimated based on the expected difference in objective response rate (ORR) between the two treatment groups. Referring to previous studies, the ORR for the oxaliplatin + capecitabine + bevacizumab regimen was approximately 65%, while for the irinotecan + capecitabine + bevacizumab regimen it was about 45%, with an expected intergroup difference of 20%. Using G*Power 3.1 software (chi-square test module), and setting a two-sided α = 0.05 and a power (1-β) = 0.85, the minimum required sample size was 110 patients per group. Considering a 20% dropout rate, a final sample size of 138 patients per group was determined.
A total of 276 patients with colorectal cancer and liver metastases who received chemotherapy between May 2019 and June 2023 were included from Shanxi Province Cancer Hospital. Patients were divided into a research group (n = 138) and a control group (n = 138). The study was approved by the ethics committees of Shanxi Province Cancer Hospital. The study flowchart is shown in Figure 1.
Figure 1.
Research flowchart.
Inclusion criteria: (1) Diagnosed with colorectal cancer according to the 2020 edition of the Chinese Guidelines for the Diagnosis and Treatment of Colorectal Cancer and confirmed to have liver metastases by magnetic resonance imaging (MRI) (Figure 2) [14]; (2) Expected survival of more than 3 months; (3) Complete medical records and measurable lesions.
Figure 2.
Liver magnetic resonance imaging confirming hepatic metastases in a patient with colorectal cancer.
Exclusion criteria: Patients were excluded if they had: (1) Severe dysfunction of the heart, lungs, kidneys, or other major organs; (2) Other concurrent malignancies; (3) Extrahepatic metastases (e.g., lung metastases); (4) Hypersensitivity or intolerance to study drugs; (5) Acute conditions requiring immediate intervention (e.g., intestinal obstruction, perforation, massive hemorrhage); (6) Consciousness disorders or psychiatric illnesses; or (7) Diseases involving the immune or hematological systems.
Treatment methods
The control group received a combination of irinotecan hydrochloride injection (150 mg/m2, IV infusion on Day 1; Jiangsu Hengrui Pharmaceuticals, H20061276), bevacizumab injection (7.5 mg/m2, IV infusion on Day 1; Jiangsu Hengrui Pharmaceuticals, S20120068), and capecitabine tablets (1000 mg/m2, orally, twice daily, Days 1-14; Qilu Pharmaceutical, H20133361).
The research group received oxaliplatin injection (130 mg/m2, IV infusion on Day 1; Jiangsu Hengrui Pharmaceuticals, H20133247), along with the same bevacizumab injection and capecitabine tablets as the control group. Each treatment cycle lasted 21 days, and both groups received a total of four treatment cycles.
Observation indicators
Primary outcomes
(1) Clinical efficacy was assessed after completion of four chemotherapy cycles based on standardized response criteria [15]. (2) Survival outcomes, including progression-free survival (PFS) and overall survival (OS), were retrospectively analyzed. (3) Serum LDH levels were measured using the enzyme rate method with a Beckman automatic biochemical analyzer (LDH kit: Wuhan Gilead Biotechnology, Cat# E-EL-H1378, Lot# 20200416). (4) Serum ALP levels were measured by enzyme-linked immunosorbent assay (ELISA) (ALP kit: Shenyang Wanlei Biotechnology, Cat# E-EL-H1450, Lot# 20240520). (5) VEGF and CA19-9 levels were assessed before treatment and after four cycles using ELISA. Blood samples (5 mL) were collected from fasting peripheral veins and centrifuged to obtain serum. ELISA kits were purchased from R&D Systems (VEGF: Cat# DVE00, Lot# 20200815; CA19-9: Cat# DCA19-9, Lot# 20190920).
Secondary outcomes
(1) Pain scores were evaluated before and after treatment using the visual analog scale (VAS), where 0 indicates no pain and 10 indicates the worst possible pain [16]. (2) Quality of life was assessed using the Medical Outcomes Study 36-Item Short Form Health Survey (MOS SF-36) scale before and after treatment, with higher scores indicating better quality of life [17]. (3) Inflammatory markers including C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured by ELISA before and after treatment. Kits were sourced from R&D Systems (IL-6: Cat# JL20256, Lot# 20200523; CRP: Cat# DCRP00, Lot# 20210314; TNF-α: Cat# DTA00C, Lot# 20200402). (4) Immunoglobulin levels: Serum levels of immunoglobulin G (IgG) and immunoglobulin M (IgM) were measured using immunoturbidimetry. Kits were provided by Roche (IgG: Cat# IGG0026, Lot# 2211001; IgM: Cat# YM-1214B, Lot# 2112002). (5) Safety evaluation: Adverse reactions such as myelosuppression, rash, fatigue, diarrhea, hepatic dysfunction, nausea and vomiting, thrombocytopenia, anemia, and peripheral neuropathy were monitored and recorded during treatment.
Statistical analysis
All statistical analyses were performed using SPSS version 20.0. Continuous variables were expressed as mean ± standard deviation (x̅ ± sd). Between-group comparisons were conducted using independent sample t-tests, and within-group (pre- and post-treatment) comparisons were analyzed using paired t-tests. Categorical variables were expressed as frequencies and percentages (n, %) and compared using chi-square (χ2) tests. Survival analysis was performed using Kaplan-Meier curves. Logistic regression analysis was used to explore factors influencing treatment efficacy.
Results
Comparison of general data
There were no statistically significant differences between the two groups in terms of age, sex, body mass index, disease duration, primary tumor type, lymph node metastasis, tumor differentiation, or comorbidities (all P > 0.05). See Table 1.
Table 1.
Comparison of general information
| Project | Control group (n = 138) | Research group (n = 138) | χ2 | P |
|---|---|---|---|---|
| Gender | 2.945 | 0.086 | ||
| Male | 75 | 89 | ||
| Female | 63 | 49 | ||
| Age (years) | 61.5±7.8 | 62.2±7.3 | 0.784 | 0.433 |
| BMI (kg.m-2) | 22.1±1.7 | 21.7±1.7 | 1.647 | 0.101 |
| Disease course (years) | 3.7±0.7 | 3.5±0.8 | 1.887 | 0.060 |
| Primary tumor type | 3.354 | 0.187 | ||
| Left colon | 33 | 39 | ||
| Right colon | 39 | 48 | ||
| Rectum | 66 | 51 | ||
| Degree of differentiation | ||||
| Low | 33 | 37 | ||
| Middle | 84 | 70 | ||
| High | 21 | 31 | ||
| Complications | ||||
| Diabetes | 8 | 10 | 0.238 | 0.626 |
| Hypertension | 9 | 7 | 0.265 | 0.606 |
| Heart disease | 10 | 10 | 1.062 | 0.303 |
| Chronic kidney disease | 6 | 4 | 0.415 | 0.519 |
| Heart rate (time·min-1) | 81.2±9.4 | 80.7±8.5 | 0.451 | 0.653 |
| Systolic blood pressure (mmHg) | 125.8±12.8 | 127.5±12.2 | 1.149 | 0.252 |
| Diastolic blood pressure (mmHg) | 81.2±9.1 | 82.2±9.5 | 0.895 | 0.371 |
Comparison of tumor efficacy and survival outcomes
The overall response rate (ORR) and disease control rate (DCR) were 12.32% and 50.00% in the control group, and 21.74% and 63.77% in the research group, respectively. The research group showed significantly better outcomes than the control group (both P < 0.05, Table 2). Representative pre- and post-treatment CT images are shown in Figure 3.
Table 2.
Comparison of tumor efficacy and survival outcomes (n, %)
| Group | Complete remission | Partial remission | Stable disease | Disease progression | Total effective rate | Disease control rate |
|---|---|---|---|---|---|---|
| Control group (n = 138) | 0 | 17 | 52 | 69 | 17 (12.32%) | 69 (50.00%) |
| Research group (n = 138) | 0 | 30 | 58 | 50 | 30 (21.74%) | 88 (63.77%) |
| χ2 | 4.334 | 5.333 | ||||
| P | 0.037 | 0.021 |
Figure 3.
Representative CT images of patients in the research and control groups before and after treatment. A: Research group, before treatment; B: Research group, after treatment; C: Control group, before treatment; D: Control group, after treatment.
A logistic regression analysis was conducted using gender, age, primary tumor type, tumor differentiation, disease duration, systolic and diastolic blood pressure, heart rate, and treatment regimen as independent variables, with treatment response (effective vs. ineffective) as the dependent variable. The analysis showed that the treatment regimen was an independent predictor of therapeutic efficacy. See Table 3.
Table 3.
Analysis of influencing factors of logistic regression on therapeutic effect
| Variable | P | Exp (B) |
|---|---|---|
| Treatment plan | 0.007 | 5.827 (1.605-21.155) |
| Gender | 1.000 | 1.000 (0.900-1.111) |
| Age | 0.063 | 0.920 (0.843-1.004) |
| Primary tumor type | 0.344 | 1.670 (0.577-4.827) |
| Degree of differentiation | 0.994 | / |
| Disease course | 0.541 | 0.780 (0.352-1.730) |
| Systolic blood pressure | 0.081 | 0.953 (0.902-1.006) |
| Diastolic blood pressure | 0.723 | 1.013 (0.942-1.090) |
| Heart rate | 0.989 | 1.001 (0.929-1.077) |
| BMI | 0.339 | 1.200 (0.826-1.745) |
Kaplan-Meier analysis revealed that the median PFS at one year was 7.45 months in the control group and 11.20 months in the research group. The one-year PFS rate was 26.81% (37/138) in the control group and 49.28% (68/138) in the research group (χ2 = 14.772, P < 0.05).
Similarly, the one-year OS rate was 81.88% (113/138) in the research group and 57.97% (80/138) in the control group, also demonstrating a statistically significant difference (χ2 = 18.763, P < 0.05). See Figure 4.
Figure 4.
Comparison of progression-free survival and overall survival rates one year after treatment between the two groups. A: Comparison of progression-free survival; B: Comparison of the overall survival rates. PFS, Progression-free survival.
Comparison of serum tumor-related factors, and enzymatic marker levels
After treatment, VEGF and CA19-9 levels significantly decreased in both groups compared to baseline, with post-treatment levels in the research group significantly lower than those in the control group (both P < 0.001). See Figure 5.
Figure 5.
Comparison of serum tumor-related factor levels between the two groups. A: Comparison of VEGF; B: Comparison of CA199. Note: Compared with the control group, ***P < 0.001; Compared with before treatment in the same group, ###P < 0.001. VEGF, Vascular endothelial growth factor, CA19-9, carbohydrate antigen 19-9.
Serum LDH and ALP levels decreased in both groups after treatment (both P < 0.001). The reductions were more pronounced in the research group, and differences were statistically significant compared to the control group (both P < 0.001). See Figure 6.
Figure 6.
Comparison of enzymatic marker levels between the two groups. A: Comparison of LDH between the two groups of patients; B: Comparison of ALP between the two groups of patients. Note: Compared with the control group, ***P < 0.001; Compared with before treatment, ###P < 0.001. LDH, Lactate dehydrogenase; ALP, alkaline phosphatase.
Comparison of inflammatory factors and immune markers
Post-treatment, serum levels of IL-6, TNF-α, and CRP were significantly reduced in both groups (all P < 0.05), with lower levels observed in the research group compared to the control group (all P < 0.05). See Table 4.
Table 4.
Comparison of serum inflammatory factor levels (x̅±s)
| Group | IL-6 (pg/mL) | TNF-α (pg/mL) | CRP (mg/L) | |||
|---|---|---|---|---|---|---|
|
|
|
|
||||
| Before treatment | After treatment | Before treatment | After treatment | Before treatment | After treatment | |
| Research group (n = 138) | 46.22±8.85 | 30.17±3.08*,# | 20.96±5.22 | 11.60±1.85*,# | 14.02±5.12 | 5.45±2.06*,# |
| Control group (n = 138) | 47.37±7.25 | 35.35±2.13 | 21.23±5.11 | 14.40±1.60 | 14.31±5.04 | 8.76±1.00 |
| t | 1.181 | 16.250 | 0.434 | 13.448 | 0.474 | 16.981 |
| P | 0.239 | < 0.001 | 0.664 | < 0.001 | 0.636 | < 0.001 |
Note: Compared with the control group;
P < 0.017.
Compared with before treatment;
P < 0.05.
IL-6: interleukin-6; TNF-α: tumor necrosis factor-α; CRP: C-reactive protein.
Before treatment, IgM and IgG levels did not differ significantly between the two groups (both P > 0.05). After treatment, the research group showed significantly higher IgM and IgG levels than the control group (both P < 0.001). See Figure 7.
Figure 7.
Comparison of immunoglobulin levels between the two groups. A: Comparison of IgM; B: Comparison of IgG. Note: Compared with the control group, ***P < 0.001; Compared with before treatment, ###P < 0.001. IgG, Immunoglobulin G, IgM, immunoglobulin M.
Comparison of quality of life and pain scores
No significant differences in MOS SF-36 scores were observed between the two groups before treatment (P > 0.05). After treatment, both groups showed improvements in physical functioning, general health, social functioning, and emotional and psychological well-being, with significantly higher post-treatment scores in the study group (P < 0.05). See Table 5.
Table 5.
Comparison of MOS SF-36 (points, x̅±s)
| Group | Physical function | Overall health | Social function | Emotional role | Mental health | |||||
|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|
|
|
||||||
| Before treatment | After treatment | Before treatment | After treatment | Before treatment | After treatment | Before treatment | After treatment | Before treatment | After treatment | |
| Research group (n = 138) | 62.10±8.55 | 78.20±11.16# | 81.20±11.78 | 92.61±7.21# | 60.21±10.22 | 73.83±11.21# | 50.54±8.13 | 64.76±9.64# | 49.42±7.52 | 69.20±10.65# |
| Control group (n = 138) | 62.34±8.06 | 66.23±9.30# | 81.19±9.18 | 86.62±12.10# | 60.86±10.21 | 65.52±10.33# | 50.56±8.16 | 56.42±7.23# | 49.41±7.42 | 56.33±7.65# |
| t | 0.199 | 6.357 | 0.053 | 2.795 | 0.492 | 4.175 | 0.038 | 5.308 | 0.018 | 7.428 |
| P | 0.844 | < 0.001 | 0.962 | 0.003 | 0.624 | < 0.001 | 0.971 | < 0.001 | 0.990 | < 0.001 |
Note: Compared with that before the intervention in the same group;
P < 0.05.
MOS SF-36: Medical Outcomes Study 36-Item Short Form Health Survey.
VAS pain scores decreased significantly in both groups after treatment (P < 0.001). The research group exhibited significantly lower VAS scores than the control group (P < 0.001). See Figure 8.
Figure 8.
Comparison of VAS scores between the two groups. Note: Compared with the control group, ***P < 0.001; Compared with before treatment in the same group, ###P < 0.001. VAS, Visual analog scale.
Comparison of adverse reactions
During treatment, the incidence rates of adverse reactions including bone marrow suppression, rash, fatigue, diarrhea, liver dysfunction, nausea and vomiting, thrombocytopenia, anemia, and peripheral neuropathy were significantly lower in the research group compared to the control group (P < 0.05). See Table 6.
Table 6.
Comparison of the total incidence of adverse reactions
| Group | Bone marrow suppression | Rash | Fatigue | Diarrhea | Liver dysfunction | Nausea and vomiting | Thrombocytopenia | Anemia | Peripheral neuropathy | Total incidence rate [n (%)] |
|---|---|---|---|---|---|---|---|---|---|---|
| Research group (n = 138) | 6 | 0 | 1 | 8 | 1 | 1 | 2 | 0 | 1 | 20 (14.49) |
| Control group (n = 138) | 6 | 1 | 1 | 24 | 0 | 1 | 1 | 1 | 1 | 36 (26.09) |
| χ2 | 5.735 | |||||||||
| P | 0.017 |
Discussion
This retrospective study compared the efficacy and safety of two first-line regimens - oxaliplatin plus capecitabine and bevacizumab versus irinotecan plus capecitabine and bevacizumab - in patients with CRC and liver metastases. The results showed that the ORR and DCR in the oxaliplatin-based regimen group were significantly higher than those in the control group, consistent with findings from Tang et al. and Bond et al. [18,19]. These results suggest that the combination of oxaliplatin, capecitabine, and bevacizumab offers favorable efficacy in treating CRC with liver metastases.
Oxaliplatin, a platinum-based chemotherapeutic agent, inhibits tumor cell DNA synthesis and proliferation, and can induce pyroptosis, thereby activating antitumor immune responses. Yu et al. demonstrated that platinum-induced pyroptosis enhances immune cell-mediated tumor clearance, thereby improving clinical efficacy [20]. When combined with capecitabine, oxaliplatin exhibits a synergistic effect, further enhancing therapeutic outcomes. Bevacizumab, a VEGF-targeted monoclonal antibody, inhibits angiogenesis and also modulates the tumor immune microenvironment by improving dendritic cell function and reducing regulatory T cell infiltration, thereby amplifying the antitumor effects of chemotherapy [21].
Survival analysis showed significantly higher one-year PFS and OS rates in the research group. These findings are consistent with previous studies, such as that by Aranda et al., who found that oxaliplatin combined with bevacizumab significantly improved PFS and OS in patients with advanced CRC [22]. The improved outcomes may be attributed to the ability of the oxaliplatin-capecitabine combination to overcome irinotecan resistance, while bevacizumab prolongs survival by targeting angiogenesis [21].
LDH is a marker of cellular damage and is associated with tumor proliferation and metastasis. A post-treatment decrease in LDH, especially in the research group, likely reflects tumor regression. Oxaliplatin’s ability to inhibit DNA synthesis and promote apoptosis reduces tumor burden, resulting in lower LDH levels. ALP, a liver- and bone-associated enzyme, is often elevated in patients with liver metastases. Its reduction following treatment is typically associated with tumor shrinkage and improved hepatic function. Our findings suggest that the oxaliplatin-capecitabine regimen effectively inhibits tumor growth in the liver and contributes to liver function improvement.
VEGF, a central driver of tumor angiogenesis, promotes cancer cell proliferation and metastasis, making it a key therapeutic target [23]. Bevacizumab reduces angiogenesis and nutrient supply to the tumor, thereby inhibiting tumor growth and dissemination. In this study, post-treatment VEGF levels were significantly lower in the research group, indicating that bevacizumab effectively suppressed tumor vascularization and enhanced chemotherapy efficacy. CA19-9, a biomarker for CRC, reflects tumor burden and prognosis. Its significant post-treatment decrease in the research group suggests reduced tumor load. The combination of bevacizumab likely contributed by limiting vascular supply and tumor spread, leading to further reductions in CA19-9. These findings are consistent with previous reports demonstrating the efficacy of such regimens in reducing tumor burden and suppressing tumor progression [24-26].
Higher IgM and IgG levels observed in the research group indicate improved immune function and recovery of antitumor immunity. Previous studies have shown that oxaliplatin can relieve tumor-induced immunosuppression and promote antitumor immune responses [27]. Quality of life scores - including physical function, general health, and emotional well-being - were significantly better in the research group, suggesting that this regimen not only enhances efficacy but also improves patient well-being. In contrast, irinotecan is frequently associated with more severe side effects and reduced quality of life, while oxaliplatin has a milder toxicity profile, contributing to better health status [28].
Furthermore, the study group experienced lower rates of common adverse reactions such as myelosuppression, fatigue, and diarrhea, which may be related to the tolerability of the oxaliplatin-bevacizumab combination [29]. This supports the conclusion that this regimen offers both enhanced efficacy and improved safety.
However, this study had several limitations. The treatment regimens were not randomized, and potential baseline imbalances may have influenced outcome assessment. Although 276 patients were included, the sample size remains modest and all patients were enrolled from a single center, which may limit the generalizability of the results. Additionally, the follow-up period was limited to one year, restricting evaluation of long-term outcomes. Future studies with larger, multicenter cohorts and extended follow-up are needed to validate these findings.
In conclusion, oxaliplatin combined with capecitabine and bevacizumab significantly improved clinical outcomes in patients with colorectal cancer and liver metastases, prolonging both PFS and OS. The regimen also modulated VEGF and CA19-9 expression and demonstrated a favorable safety profile, supporting its potential as a valuable treatment option in this patient population.
Disclosure of conflict of interest
None.
References
- 1.Zhou J, Zheng R, Zhang S, Zeng H, Wang S, Chen R, Sun K, Li M, Gu J, Zhuang G, Wei W. Colorectal cancer burden and trends: comparison between China and major burden countries in the world. Chin J Cancer Res. 2021;33:1–10. doi: 10.21147/j.issn.1000-9604.2021.01.01. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Ai XN, Zhang Q, Jin CG, Hu H, Zhang WX, Wu ZY, Xiu DR. Relationship between hepatic surgical margins of colorectal cancer liver metastases and prognosis: a review. Medicine (Baltimore) 2024;103:e37038. doi: 10.1097/MD.0000000000037038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Li Y, Liu W, Zhao L, Güngör C, Xu Y, Song X, Wang D, Zhou Z, Zhou Y, Li C, Pei Q, Tan F, Pei H. Nomograms predicting overall survival and cancer-specific survival for synchronous colorectal liver-limited metastasis. J Cancer. 2020;11:6213–6225. doi: 10.7150/jca.46155. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sun L, Li X, Xiao Y, Yu W, Chen X, Wang Z, Xia N, Chen X, Chen M, Zhu H, Li J, Wei J, Han S, Pu L. Mfsd2a suppresses colorectal cancer progression and liver metastasis via the S100A14/STAT3 axis. J Transl Med. 2025;23:59. doi: 10.1186/s12967-024-05994-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kwan J, Pua U. Review of intra-arterial therapies for colorectal cancer liver metastasis. Cancers (Basel) 2021;13:1371. doi: 10.3390/cancers13061371. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Fan H, Wen R, Zhou L, Gao X, Lou Z, Hao L, Meng R, Gong H, Yu G, Zhang W. Clinicopathological features and prognosis of synchronous and metachronous colorectal cancer: a retrospective cohort study. Int J Surg. 2023;109:4073–4090. doi: 10.1097/JS9.0000000000000709. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Marx C, Sonnemann J, Maddocks ODK, Marx-Blümel L, Beyer M, Hoelzer D, Thierbach R, Maletzki C, Linnebacher M, Heinzel T, Krämer OH. Global metabolic alterations in colorectal cancer cells during irinotecan-induced DNA replication stress. Cancer Metab. 2022;10:10. doi: 10.1186/s40170-022-00286-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Chen H, Yang F, Zhao Q, Wang H, Zhu M, Li H, Ge Z, Zhang S, Guo Q, Hui H. GL-V9 synergizes with oxaliplatin of colorectal cancer via Wee1 degradation mediated by HSP90 inhibition. J Pharm Pharmacol. 2024;76:1006–1017. doi: 10.1093/jpp/rgae060. [DOI] [PubMed] [Google Scholar]
- 9.Fang X, Zhong C, Weng S, Hu H, Wang J, Xiao Q, Wang J, Sun L, Xu D, Liao X, Dong C, Zhang S, Li J, Ding K, Yuan Y. Sintilimab plus bevacizumab and CapeOx (BBCAPX) on first-line treatment in patients with RAS mutant, microsatellite stable, metastatic colorectal cancer: study protocol of a randomized, open-label, multicentric study. BMC Cancer. 2023;23:676. doi: 10.1186/s12885-023-11139-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Vlasiou M, Nicolaidou V, Papaneophytou C. Targeting lactate dehydrogenase-B as a strategy to fight cancer: identification of potential inhibitors by in silico analysis and in vitro screening. Pharmaceutics. 2023;15:2411. doi: 10.3390/pharmaceutics15102411. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Su K, Huang W, Li X, Xu K, Gu T, Liu Y, Song J, Qian K, Xu Y, Zeng H, Yang Y, Guo L, Han Y. Evaluation of lactate dehydrogenase and alkaline phosphatase as predictive biomarkers in the prognosis of hepatocellular carcinoma and development of a new nomogram. J Hepatocell Carcinoma. 2023;10:69–79. doi: 10.2147/JHC.S398632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Chen B, Zhou J, Ma Y, Sun Q, Ren J, Wang D. Evaluation of multiple biological indicators for the combined diagnosis of metastases from colorectal cancer-a retrospective study based on 1163 patients. World J Surg Oncol. 2023;21:229. doi: 10.1186/s12957-023-03108-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Wang J, Sun Q, Zhao J, Li Z, Kou D, Qu D. Efficacy of apatinib as third-line treatment of advanced colorectal cancer and prognostic analysis. J BUON. 2021;26:93–100. [PubMed] [Google Scholar]
- 14.National Health Commission of the People’s Republic of China. Diagnosis and Treatment Guidelines for Colorectal Cancer in China (2020 Edition) Chin J Surg. 2020;58:561–585. doi: 10.21147/j.issn.1000-9604.2020.04.01. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026. [DOI] [PubMed] [Google Scholar]
- 16.Maxwell C. Sensitivity and accuracy of the visual analogue scale: a psycho-physical classroom experiment. Br J Clin Pharmacol. 1978;6:15–24. doi: 10.1111/j.1365-2125.1978.tb01676.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Vitorino DF de M, Martins FLM, Souza A de C, Prado GF. Utilizao do SF-36 em ensaios clínicos envolvendo pacientes fibromiálgicos: determinao de critérios mínimos de melhora clínica. Rev Neurociênc. 2019;12:147–151. [Google Scholar]
- 18.Tang W, Ren L, Liu T, Ye Q, Wei Y, He G, Lin Q, Wang X, Wang M, Liang F, Cui Y, Xu J. Bevacizumab plus mFOLFOX6 versus mFOLFOX6 alone as first-line treatment for RAS mutant unresectable colorectal liver-limited metastases: the BECOME randomized controlled trial. J. Clin. Oncol. 2020;38:3175–3184. doi: 10.1200/JCO.20.00174. [DOI] [PubMed] [Google Scholar]
- 19.Bond MJG, Bolhuis K, Loosveld OJL, de Groot JWB, Droogendijk H, Helgason HH, Hendriks MP, Klaase JM, Kazemier G, Liem MSL, Rijken AM, Verhoef C, de Wilt JHW, de Jong KP, Gerhards MF, van Amerongen MJ, Engelbrecht MRW, van Lienden KP, Hermans JJ, Molenaar IQ, Grünhagen DJ, de Valk B, Haberkorn BCM, Kerver ED, Erdkamp F, van Alphen RJ, Mathijssen-van Stein D, Komurcu A, May AM, Swijnenburg RJ, Punt CJA Dutch Colorectal Cancer Group. First-line systemic treatment for initially unresectable colorectal liver metastases: post hoc analysis of the CAIRO5 randomized clinical trial. JAMA Oncol. 2025;11:36–45. doi: 10.1001/jamaoncol.2024.5174. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Yu B, Wang Y, Bing T, Tang Y, Huang J, Xiao H, Liu C, Yu Y. Platinum prodrug nanoparticles with COX-2 inhibition amplify pyroptosis for enhanced chemotherapy and immune activation of pancreatic cancer. Adv Mater. 2024;36:e2310456. doi: 10.1002/adma.202310456. [DOI] [PubMed] [Google Scholar]
- 21.Ribatti D. Immunosuppressive effects of vascular endothelial growth factor. Oncol Lett. 2022;24:369. doi: 10.3892/ol.2022.13489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Aranda E, Viéitez JM, Gómez-España A, Gil Calle S, Salud-Salvia A, Graña B, Garcia-Alfonso P, Rivera F, Quintero-Aldana GA, Reina-Zoilo JJ, González-Flores E, Salgado Fernández M, Guillén-Ponce C, Garcia-Carbonero R, Safont MJ, La Casta Munoa A, García-Paredes B, López López R, Sastre J, Díaz-Rubio E Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥ 3 circulating tumour cells: the randomised phase III VISNÚ-1 trial. ESMO Open. 2020;5:e000944. doi: 10.1136/esmoopen-2020-000944. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Shaw P, Dwivedi SKD, Bhattacharya R, Mukherjee P, Rao G. VEGF signaling: role in angiogenesis and beyond. Biochim Biophys Acta Rev Cancer. 2024;1879:189079. doi: 10.1016/j.bbcan.2024.189079. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Chen Y, Zhu D, Yu Y, Chang W, Ye L, Feng Q, Xu P, Chen M, Ji M, Wei Y, Liu T, Xu J. VIC regimen (vemurafenib/irinotecan/cetuximab) versus bevacizumab plus chemotherapy as first-line treatment for BRAF V600E-mutated unresectable or metastatic colorectal cancer in asian patients: a prospective cohort study. Clin Colorectal Cancer. 2024;23:354–363. e4. doi: 10.1016/j.clcc.2024.05.006. [DOI] [PubMed] [Google Scholar]
- 25.Camacho X, Perroni C, Alfaya L, Cabrera M, Tassano M, García MF, Fernández M, Reyes AL, Paolino A, Savio E, Cerecetto H, Cabral P, Gambini JP. Molecular imaging of melanoma vegf-expressing tumors through [99mTc]Tc-HYNIC-Fab(Bevacizumab) Anticancer Agents Med Chem. 2024;24:1347–1359. doi: 10.2174/0118715206294297240805073550. [DOI] [PubMed] [Google Scholar]
- 26.Jiang YL, Fu XY, Yin ZH. Retrospective efficacy analysis of olaparib combined with bevacizumab in the treatment of advanced colorectal cancer. World J Gastrointest Surg. 2023;15:906–916. doi: 10.4240/wjgs.v15.i5.906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Deng M, Zhao R, Zou H, Guan R, Wang J, Lee C, He B, Zhou J, Li S, Wei W, Cai H, Guo R. Oxaliplatin induces pyroptosis in hepatoma cells and enhances antitumor immunity against hepatocellular carcinoma. Br J Cancer. 2025;132:371–383. doi: 10.1038/s41416-024-02908-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Lopes GS, Tournigand C, Olswold CL, Cohen R, Kempf E, Saltz L, Goldberg RM, Hurwitz H, Fuchs C, de Gramont A, Shi Q. Adverse event load, onset, and maximum grade: a novel method of reporting adverse events in cancer clinical trials. Clin Trials. 2021;18:51–60. doi: 10.1177/1740774520959313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Casak SJ, Donoghue M, Fashoyin-Aje L, Jiang X, Rodriguez L, Shen YL, Xu Y, Jiang X, Liu J, Zhao H, Pierce WF, Mehta S, Goldberg KB, Theoret MR, Kluetz PG, Pazdur RB, Lemery SJ. FDA approval summary: atezolizumab plus bevacizumab for the treatment of patients with advanced unresectable or metastatic hepatocellular carcinoma. Clin Cancer Res. 2021;27:1836–1841. doi: 10.1158/1078-0432.CCR-20-3407. [DOI] [PubMed] [Google Scholar]