Comparative efficacy of cetuximab combined with FOLFOX or CAPEOX in first-line treatment of RAS/BRAF wild-type metastatic colorectal cancer: a multicenter case-control study

Abstract

FOLFOX combined with cetuximab is a recommended first-line treatment regimen for RAS/BRAF wild-type metastatic colorectal cancer (mCRC). CAPEOX combined with cetuximab differs from the FOLFOX regimen by using oral capecitabine instead of continuous infusion of fluorouracil, offering greater convenience and cost-effectiveness with higher patient acceptance. However, the comparative efficacy of these two regimens remains debatable, necessitating further evidence to explore any differences in their efficacy. This study collected medical records of mCRC patients who were treated with CAPEOX or FOLFOX combined with cetuximab from 1 October 2021 to 16 October 2023 at Harbin Medical University Cancer Hospital and the First Hospital of Shanxi Medical University. Eligible patients were selected based on inclusion criteria and followed up through the hospital’s follow-up system and telephone interviews. Kaplan–Meier survival analysis and Cox proportional hazards regression analysis were used to assess patients’ progression-free survival (PFS) and overall survival (OS). A total of 71 eligible patients were enrolled in this study; 43 patients received CAPEOX combined with cetuximab (Group A, n = 43), and 28 patients received FOLFOX combined with cetuximab (Group B, n = 28). The two groups achieved similar median PFS (mPFS) and median OS (mOS), with mPFS of 18 months and 12 months, respectively (P = 0.23), and mOS of 33 months and 20 months, respectively (P = 0.21), with no statistically significant differences. The results of this study demonstrated that CAPEOX combined with cetuximab is an equally viable option for first-line treatment of RAS/BRAF wild-type mCRC as FOLFOX combined with cetuximab.

Introduction

Colorectal cancer is one of the most common malignant tumors, ranking third in global incidence and second in mortality among all cancer [1]. Approximately 20% of patients with colorectal cancer are diagnosed with synchronous metastasis, and over 50% of patients progress to metastatic disease during the course of the illness [2]. The mutational status of RAS/BRAF genes is closely associated with the biological behavior of metastatic colorectal cancer (mCRC), and the prognosis differs accordingly [3]. Among all mCRC patients, approximately 45–55% are RAS wild-type, while about 90% are BRAF wild type [2,4]. Currently, based on several clinical studies such as the phase III TAILOR and CRYSTAL trials, the first-line treatment strategy for RAS/BRAF wild-type mCRC involves combining FOLFOX or FOLFIRI with the epidermal growth factor receptor (EGFR) antibody cetuximab, which is widely adopted in current clinical practice [5,6].

Capecitabine is a prodrug of 5-fluorouracil and an oral fluoropyrimidine chemotherapy drug. Both drugs exert similar antitumor mechanisms in the human body [7]. In terms of efficacy and safety, several large-scale clinical studies have shown that CAPEOX and FOLFOX regimens exhibit comparable effectiveness as first-line treatments for mCRC [8,9]. Furthermore, some researches suggest that CAPEOX-based chemotherapy leads to fewer adverse effects compared to FOLFOX [10]. There is no significant difference between the two regimens in terms of health-related quality of life [11]. Moreover, capecitabine offers the advantages of easier administration and lower cost compared to 5-fluorouracil [12,13]. These studies indicate that capecitabine can be a viable alternative to fluorouracil in certain situations, providing greater benefits for mCRC patients. However, there is ongoing debate regarding the comparative efficacy of CAPEOX and FOLFOX combined with cetuximab as first-line treatments for RAS/BRAF wild-type mCRC, as many clinical trial results evaluating these two combinations are inconsistent. For example, the large phase III COIN study demonstrated the inferiority of CAPEOX combined with cetuximab compared to FOLFOX combined with cetuximab [14], while the FLEET study showed comparable efficacy between the two regimens [15].

Therefore, this study aims to compare the efficacy of CAPEOX and FOLFOX in combination with cetuximab as first-line treatments for RAS/BRAF wild-type mCRC through a retrospective analysis. By conducting this research, we hope to provide more accurate and individualized therapy recommendations for clinical practice, thereby improving patient survival and quality of life from various aspects.

Materials and Methods

Study design and participants

This retrospective study included mCRC patients who received cetuximab in combination with CAPEOX or FOLFOX regimen at Harbin Medical University Cancer Hospital and the First Hospital of Shanxi Medical University from October 2021 to October 2023. The follow-up period was extended until 4 January 2024. We started with a total of 329 patients who had received cetuximab and thoroughly screened them in accordance with the inclusion and exclusion criteria in order to gather as many medical records as possible that satisfied the inclusion criteria, resulting in a final inclusion of 71 patients (Fig. 1). Patients were divided into two groups based on the different combination treatment regimens they received: cetuximab plus CAPEOX group (Group A, n = 43) and cetuximab plus FOLFOX group (Group B, n = 28). This study was approved by the Ethics Committee of Harbin Medical University Cancer Hospital and the First Hospital of Shanxi Medical University and conducted in accordance with the principles outlined in the Helsinki Declaration. All patient data were kept confidential.

Fig. 1.

Flowchart of the study population.

Inclusion criteria

• (1) Histologically confirmed colorectal cancer by endoscopic biopsy or postoperative pathological diagnosis.

• (2) Advanced, unresectable, or mCRC.

• (3) RAS and BRAF wild-type.

• (4) Cetuximab in combination with CAPEOX or FOLFOX as first-line treatment for advanced disease, with a minimum treatment duration of three cycles.

• (5) Assessable lesions on imaging.

• (6) Eastern Cooperative Oncology Group/Performance Status score of 0–1.

Exclusion criteria

• (1) Cetuximab in combination with chemotherapy regimens other than CAPEOX or FOLFOX.

• (2) Concurrent use of CAPEOX and FOLFOX in the cetuximab combination regimen.

• (3) Complete loss to follow-up for disease progression and death.

• (4) Concurrent other malignancies.

Therapeutic standards

According to the National Comprehensive Cancer Network (NCCN) reference, the dosages and administration of FOLFOX plus cetuximab and CAPEOX plus cetuximab regimens (as there is no specific dosage mentioned in the NCCN guidelines for the combination of CAPEOX plus cetuximab, the following are commonly used in clinical practice) are as follows:

• (1) CAPEOX plus cetuximab: oxaliplatin 85 mg/m², intravenous infusion over 2 h on day 1; capecitabine 1000 mg/m², orally, twice daily from day 1 to day 7, repeated every 2 weeks; cetuximab 500 mg/m², intravenous infusion over more than 2 h on the first day, repeated every 2 weeks.

• (2) FOLFOX plus cetuximab: oxaliplatin 85 mg/m², intravenous infusion over 2 h on day 1; calcium folinate 400 mg/m², intravenous infusion over 2 h on day 1; 5-fluorouracil 400 mg/m², intravenous bolus on day 1, followed by continuous intravenous infusion of 1200 mg/m²/day for 2 days (total dose of 2400 mg/m², infusion for 46–48 h), repeated every 2 weeks; cetuximab 500 mg/m², intravenous infusion over more than 2 h on the first day, repeated every 2 weeks.

Study endpoints

Patient follow-up information was obtained from records in the hospitals’ follow-up center or through telephone interviews with patients and their families. Progression-free survival (PFS) was the primary endpoint of this study, defined as the time from the first standard treatment to disease progression or death from any cause, whichever occurred first. Overall survival (OS), overall response rate (ORR), and disease control rate (DCR) were secondary endpoints. OS was defined as the time from the first standard treatment to death from any cause. For patients with lost follow-up information for PFS or OS, the time from the first application of cetuximab in combination with CAPEOX or FOLFOX regimen to the final follow-up date was recorded as PFS or OS. Every patient had at least one evaluable lesion at baseline, and imaging examinations (including contrast-enhanced computed tomography and superficial lymph node color Doppler ultrasound) were performed every three treatment cycles for evaluation according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) criteria. ORR was defined as the proportion of patients with complete response (CR) and partial response (PR) who achieved tumor volume reduction to a predetermined threshold and maintained it for a minimum duration. DCR was defined as the percentage of patients who achieved CR, PR, or stable disease after treatment among evaluable cases.

Statistical analysis

The clinical characteristics of the enrolled patients were analyzed using Chi-square tests or Fisher’s exact tests. Cox regression analysis with multiple factors was employed to assess the confounding factors influencing PFS and OS. Hazard ratios and 95% confidence intervals (CIs) were estimated using the Cox regression model, and the Wald test was employed for evaluation. Additionally, subgroup analysis was conducted using the Cox proportional hazards regression model to create a forest plot, analyzing the factors influencing the risk of death in patients with advanced colorectal cancer. Univariate analysis was performed using the log-rank test and Kaplan–Meier method, and survival curves for PFS and OS were generated and compared, considering P < 0.05 as statistically significant. SPSS (IBM SPSS Statistics for Windows, version 27.0; IBMCorp., Armonk, New York, USA) and R software (version 4.3.1, New Zealand) were utilized for the statistical analysis.

Results

Patient clinical characteristics

A total of 71 patients with advanced colorectal cancer were included in this study, with 43 in Group A and 28 in Group B. Among them, a higher proportion of patients in Group A and Group B were younger than 65 years old, accounting for 31 cases (72%) and 20 cases (71%), respectively. The proportion of patients aged 65 or older was smaller, accounting for 12 cases (28%) in Group A and 8 cases (29%) in Group B. There was no significant difference in the proportion of male and female patients. In Group A, there were 25 male patients (58%) and 18 female patients (42%), while in Group B, there were 16 male patients (57%) and 12 female patients (43%). The proportion of patients with tumors located in the left colon or rectum was similar. In Group A, 20 patients (47%) had tumors located in the left colon, and 22 patients (51%) had tumors located in the rectum. In Group B, 15 patients (54%) had tumors located in the left colon, and 13 patients (46%) had tumors located in the rectum. The majority of patients had non-special type adenocarcinoma as the pathological type, accounting for 88% and 93% in Group A and Group B, respectively. In terms of histological grade, approximately half of the patients had moderate differentiation, with 51% in Group A and 50% in Group B, while a smaller proportion had poor differentiation, with 21% in Group A and 18% in Group B. Regarding surgical procedures, palliative surgery was the most common in Group A (17 cases, 40%), followed by radical surgery (16 cases, 37%). In Group B, radical surgery was the most common (12 cases, 43%), followed by patients who did not undergo surgery (9 cases, 32%). Both groups had no patients with microsatellite instability-high status, and the majority of patients had microsatellite stable status, accounting for 60% and 75% in Group A and Group B, respectively. The most common treatment after surgery in both Group A and Group B was no adjuvant therapy, accounting for 79% and 75%, respectively. The majority of patients in both Group A and Group B had multiple metastases, accounting for 91% and 89%, respectively. Regarding the location of metastases, liver metastasis alone was present in 37% and 36% of patients in Group A and Group B, respectively, while liver metastasis combined with other sites accounted for 19% and 21%.

There were no statistically significant differences (P > 0.05) between the two groups in terms of age, sex, tumor location, pathological type, histological grade, surgical procedure, MSI status, adjuvant therapy, number of metastatic lesions, and site of metastases (Table 1). In the Cox regression multivariate analysis for OS, special types of adenocarcinoma (including mucinous adenocarcinoma and signet ring cell carcinoma) had statistically significant predictive value for favorable survival prognosis comparing to nonspecific adenocarcinoma (hazard ratio 0.051, 95% CI: 0.003–0.794, P = 0.034). Poorly differentiated histological grade was an indicator of poor prognosis (hazard ratio 8.933, 95% CI: 1.961–40.691, P = 0.005), while other indicators had no statistical significance (Table 2).

Table 1.

Baseline clinical characteristics of patients

Characteristic	Group A (n = 43)	Group B (n = 28)	χ 2	P value
Age
<65 years	31 (72%)	20 (71%)	0.004	0.951
≥65 years	12 (28%)	8 (29%)
Gender
Male	25 (58%)	16 (57%)	0.007	0.934
Female	18 (42%)	12 (43%)
Tumor site
Left half of the colon	20 (47%)	15 (54%)	0.870	0.883
Rectum	22 (51%)	13 (46%)
Missing	1 (2%)	0 (0%)
Pathological classification
Nonspecific adenocarcinoma	38 (88%)	26 (93%)	3.173	0.392
Mucinous adenocarcinoma	3 (7%)	0 (0%)
Signet-ring cell carcinoma	0 (0%)	1 (4%)
Mixed cancer	2 (5%)	1 (4%)
Histological grade
Well differentiated	2 (5%)	0 (0%)	1.557	0.710
Moderately differentiated	22 (51%)	14 (50%)
Poorly differentiated	9 (21%)	5 (18%)
Missing	10 (23%)	9 (32%)
Surgery
Radical resection	16 (37%)	12 (43%)	1.697	0.428
Palliative resection	17 (40%)	7 (25%)
No	10 (23%)	9 (32%)
MSI status
MSS/MSI-L	26 (60%)	21 (75%)	1.601	0.206
MSI-H	0 (0%)	0 (0%)
Missing	17 (40%)	7 (25%)
Postoperative adjuvant therapy
Yes	8 (19%)	7 (25%)	1.021	0.738
No	34 (79%)	21 (75%)
Missing	1 (2%)	0 (0%)
Number of metastatic sites
Single	4 (9%)	3 (11%)	0.000	1.000
Multiple	39 (91%)	25 (89%)
Metastatic sites
Liver only	16 (37%)	10 (36%)	0.086	0.958
Liver plus others	8 (19%)	6 (21%)
Non-liver	19 (44%)	12 (43%)

Group A, CAPEOX + Cetuximab; Group B, FOLFOX + Cetuximab; MSI-L, microsatellite instability-low; MSI-H, microsatellite instability-high; MSS, microsatellite stable.

Table 2.

Multivariate analysis of PFS and OS

Characteristic	PFS			OS
	P value	HR	HR (95% CI)	P value	HR	HR (95% CI)
Age
≥65 years	Ref			Ref
<65 years	0.231	1.765	0.696–4.475	0.077	0.378	0.129–1.111
Gender
Male	Ref			Ref
Female	0.289	1.483	0.716–3.070	0.162	0.488	0.179–1.333
Tumor site	0.878			0.646
Left half of the colon
Rectum	0.610	1.220	0.568–2.617	0.350	1.529	0.628–3.719
Pathological classification	0.204			0.101
Nonspecific adenocarcinoma
Specific adenocarcinoma	0.684	1.727	0.124–24.092	0.034*	0.051	0.003–0.794
Mixed cancer	0.075	5.684	0.840–38.447	0.498	0.470	0.053–4.160
Histological grade	0.610			0.020*
Moderately differentiated
Highly differentiated				0.212	3.517	0.487–25.378
Poorly differentiated	0.185	0.402	0.105–1.545	0.005*	8.933	1.961–40.691
Missing	0.323	0.423	0.077–2.332	0.039*	11.766	1.130–122.495
Surgery	0.290			0.323
No
Radical resection	0.117	0.220	0.033–1.462	0.155	5.847	0.514–66.487
Palliative resection	0.248	0.370	0.068–2.004	0.139	6.347	0.548–73.508
Postoperative adjuvant therapy	0.809			0.796
Yes
No	0.809	0.861	0.256–2.899	0.796	0.846	0.238–3.007
Number of metastatic sites
Single	Ref			Ref
Multiple	0.253	3.370	0.420–27.040	0.879	0.884	0.181–4.326
Metastatic sites	0.411			0.807
Liver only
Liver plus others	0.460	1.450	0.541–3.891	0.513	1.686	0.353–8.058
Non-liver	0.482	0.712	0.276–1.834	0.857	1.109	0.359–3.427

^*P<0.05.

CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; Ref, reference value.

Efficacy analysis

The Kaplan–Meier survival analysis revealed that Group A and Group B achieved similar median PFS (mPFS) and median OS (mOS) The mPFS was 18 months for Group A and 12 months for Group B (P = 0.23), while the mOS was 33 months for Group A and 20 months for Group B (P = 0.21) (Fig. 2a and b). However, these results did not reach statistical significance. The 6-month PFS rates were 74.4% for Group A and 67.5% for Group B, showing a modest improvement of 6.9%. The 1-year PFS rates were 56.8% for Group A and 48.8% for Group B, while the 2-year OS rates were 62.9% for Group A and 48.9% for Group B. These findings suggest that the use of cetuximab in combination with CAPEOX or FOLFOX as first-line treatment for advanced colorectal cancer does not significantly impact the patients’ survival prognosis.

Fig. 2.

Kaplan–Meier analysis for PFS and OS. Kaplan–Meier analysis of (a) PFS and (b) OS in CAPEOX + Cetuximab group and FOLFOX + Cetuximab group. OS, overall survival; PFS, progression-free survival.

According to the RECIST 1.1 criteria for treatment evaluation, among all patients, 12 cases (12/71, 17%) achieved a PR, resulting in an ORR of 17%, and 90% of patients achieved DCR. In Group A, 6 patients (6/43, 14%) achieved PR, and 31 patients (31/43, 72%) achieved stable disease. In Group B, 6 patients (6/28, 21%) achieved PR, and 21 patients (21/28, 75%) achieved stable disease. The ORR was 14% for Group A and 21% for Group B (P = 0.494), indicating a 7% improvement in Group B. The DCR was 86% for Group A and 96% for Group B (P = 0.498), showing a 10% improvement in Group B. However, these differences were not statistically significant (Table 3). These results suggest that Group B, compared to Group A, exhibited a certain degree of improvement in ORR and DCR for patients, but the magnitude of improvement did not reach statistical significance.

Table 3.

Response of patients with measurable disease

	All (n = 71)	Group A (n = 43)	Group B (n = 28)
PR	12 (17%)	6 (14%)	6 (21%)
SD	52 (73%)	31 (72%)	21 (75%)
PD	4 (6%)	3 (7%)	1 (4%)
Unknown	3 (4%)	3 (7%)	0 (0%)
ORR	17%	14%	21%
P value (ORR)	–	0.494
χ 2	–	0.468
DCR	90%	86%	96%
P value (DCR)	–	0.498
χ 2	–	0.459

Group A, CAPEOX + Cetuximab; Group B, FOLFOX + Cetuximab.

DCR, disease control rate; ORR, objective response rate; PD, progression disease; PR, partial response; SD, stable disease.

Subgroup analysis

A forest plot was constructed using the Cox proportional hazards model to perform subgroup analysis on factors that may influence the prognosis of patients with advanced colorectal cancer. In terms of PFS, for patients with colorectal cancer who had undergone curative surgery benefit more from CAPEOX + Cetuximab compared with FOLFOX + Cetuximab, revealing a reduced risk of disease progression as a protective factor (hazard ratio 4.810, 95% CI: 1.021–22.666, P = 0.047). However, other factors such as age, gender, tumor location, histological subtype, and histological grade did not significantly influence the risk of death (Fig. 3).

Fig. 3.

Subgroup analysis of PFS in CAPEOX + Cetuximab group and FOLFOX + Cetuximab group. *P < 0.05. MSI-L, microsatellite instability-low; MSI-H, microsatellite instability-high; MSS, microsatellite stable.

Discussion

In this retrospective study, we analyzed and compared the efficacy of first-line treatment with CAPEOX or FOLFOX in combination with cetuximab in a cohort of 71 RAS/BRAF wild-type mCRC patients. We found no statistically significant difference in PFS (P = 0.23) and OS (P = 0.21) between the CAPEOX plus cetuximab group (n = 43) and the FOLFOX plus cetuximab group (n = 28). These findings indicate that CAPEOX plus cetuximab is equally viable as FOLFOX plus cetuximab in the first-line treatment of RAS/BRAF wild-type mCRC patients.

Previous studies have suggested that left-sided colon cancer, characterized by specific gene expression profiles (such as EGFR amplification and high epiregulin expression) and typical chromosomal instability, is more likely to exhibit a phenotype sensitive to EGFR inhibitors [16–19]. On the other hand, right-sided colon cancer (typically defined as tumors originating from the cecum, appendix, ascending colon, hepatic flexure, or transverse colon) showed inferior OS with the EGFR inhibitor cetuximab compared to the vascular endothelial growth factor antagonist bevacizumab [20]. Therefore, the use of cetuximab is more recommended in the first-line treatment of RAS/BRAF wild-type left-sided colon cancer. In the previous COIN study, CAPEOX plus cetuximab demonstrated inferior efficacy compared to FOLFOX plus cetuximab in RAS/BRAF wild-type mCRC patients. It cannot be ruled out that the unequal distribution of left-sided and right-sided colon cancer patients between the CAPEOX and FOLFOX groups in the COIN study may have been a contributing factor, as the baseline information of patients in the COIN study did not clearly distinguish between left-sided and right-sided colon cancer. However, this is only one of our speculations regarding the difference in efficacy between the two treatment groups in the COIN study. The COIN study also had other issues, such as dose reduction of capecitabine in 73% of patients in the CAPEOX plus cetuximab group due to adverse reactions, which could potentially affect the efficacy of CAPEOX plus cetuximab to some extent [21].In our study, patients with right-sided colon cancer were excluded due to irregular treatment practices. All subjects included in the final data analysis had tumors located in the left colon, including the rectum. This selection was intended to minimize confounding factors. Thus, we believe that, to some extent, it could help eliminate confounding factors. Among the 71 patients included in our study, no adjustments in drug dosage were found according to the historical medical records. We believe that these factors contributed to the different results obtained compared to the COIN study.

In a later phase I/II randomized controlled trial (RCT) study, the FLEET, there was no significant difference in PFS between the CAPEOX plus cetuximab group and the FOLFOX plus cetuximab group (P = 0.99), which is consistent with the results obtained in our retrospective study. In our study, the mPFS for the CAPEOX plus cetuximab group and the FOLFOX plus cetuximab group were 18 months and 12 months, respectively (P = 0.23), and the mOS were 33 months and 20 months, respectively (P = 0.21), which has similar trend toward the FLEET 1/2 study and both differ significantly from the COIN study [15,21,22]. In addition to the previously mentioned dose adjustments in the COIN study, we believe that the improvement in mOS in our data was attributed to a higher proportion of patients undergoing curative or palliative surgery before receiving cetuximab-based combination therapy, resulting in tumor eradication or reduction in tumor burden. Furthermore, a higher proportion of patients received second-line or subsequent treatments.

From the perspective of tumor response, the ORR for the CAPEOX plus cetuximab group and the FOLFOX plus cetuximab group were 14% and 21%, respectively (P = 0.494). The DCR for the two groups was 86% and 96%, respectively (P = 0.498), with no significant differences observed. We found that the DCR in our study was not significantly different from previous studies. However, the ORR reported in previous studies for both CAPEOX and FOLFOX plus cetuximab ranged between 57 and 72%, significantly higher than our study results [5,15,21,23–29]. This suggests that a majority of patients in our study, who achieved disease control, were categorized as stable disease in previous studies. We speculate that this difference may be due to evaluation bias caused by different evaluators in retrospective analysis or a relatively conservative evaluation process. In subgroup analysis, the forest plot revealed that radical surgery reduced the risk of disease progression for patients in the CAPEOX plus cetuximab group compared to the FOLFOX plus cetuximab group. This indicates that after curative surgery if there is a recurrence, the first-line treatment option could consider using CAPEOX plus cetuximab combination therapy. However, further studies with expanded sample sizes or RCTs are still needed to confirm this finding.

The adverse reactions of the two regimens include common gastrointestinal adverse events (such as nausea, vomiting, and diarrhea), hematological toxicity (neutropenia, anemia, and thrombocytopenia), and oxaliplatin-related neurotoxicity [15,21,22]. Some phase III trials have shown that CAPEOX and standard FOLFOX have comparable activity and balanced toxicity [30–33]. It is worth noting that the FOLFOX regimen has a unique intravenous administration method, usually requiring continuous infusion of 5-fluorouracil through a central venous port or a peripherally inserted central catheter to achieve sustained drug delivery. The implantation of infusion devices inevitably increases the risk of infection and thrombosis [34–36]. On the other hand, the CAPEOX group has an increased risk of hand-foot syndrome due to the presence of capecitabine [37–39], and the use of cetuximab significantly increases the incidence of skin toxicity [40–42]. However, studies have shown that capecitabine-induced skin toxicity is associated with treatment efficacy in mCRC patients, and compared to grade 0 toxicity, grades 1–3 skin toxicity attributed to capecitabine significantly correlates with DCR, prolonged PFS, and OS [43,44]. Similar results have been observed with cetuximab [45–47]. Nevertheless, even though mild to moderate skin toxicity is associated with better efficacy, further research on the management of such adverse reactions is necessary as it remains a significant barrier to patient treatment compliance in clinical practice.

In addition, many social factors need to be considered for patients with mCRC. Several studies have shown that the CAPEOX-based regimen significantly reduces the average disease management costs and patient expenses compared to the FOLFOX-based regimen, with fewer and shorter hospitalizations (both daytime and overnight), and significantly reduced loss of work and daily activity time for patients. Overall, the CAPEOX regimen is more convenient and has higher patient satisfaction [48–52]. Furthermore, studies have indicated that although cetuximab provides survival benefits, the cetuximab plus FOLFOX-4 regimen is not cost-effective as a first-line treatment option for RAS wild-type mCRC patients in China [53,54]. This suggests that, based on comparable efficacy, the CAPEOX-based regimen seems to offer greater overall benefits, relieving patients of financial burden and potentially improving treatment compliance and therapeutic outcomes due to its convenience.

A study has demonstrated that the plasma concentrations of capecitabine and its metabolites are not influenced even when coadministered with cetuximab [55]. Furthermore, there is no evidence indicating that the combination administration of oxaliplatin, capecitabine, and cetuximab alters the plasma concentrations of any of these three drugs. Based on our study, we have reason to believe that CAPEOX in combination with cetuximab can be considered an equally viable option as FOLFOX in combination with cetuximab for first-line treatment selection in RAS/BRAF wild-type mCRC patients. Moreover, it may provide a more convenient, cost-effective, and patient-friendly alternative. However, our study has limitations inherent to retrospective research, such as selection bias due to case selection from only two hospitals and recall bias in patient or family member recollection of the endpoint dates during follow-up. Additionally, the sample size of our study was relatively small, which may limit the statistical power of the results.

In future research, conducting RCTs to obtain statistical information on specific tumor changes can provide valuable insight. Combined with subgroup analysis, we can assess the degree of tumor reduction benefit for different populations using the two treatment regimens. This will contribute to providing additional supporting evidence for the selection of treatment strategies in the context of personalized medicine. Additionally, it is important to investigate adverse reactions associated with both treatment regimens and identify populations that may experience fewer toxic side effects with either approach. Therefore, achieving individualized treatment by appropriately selecting treatment strategies based on patients’ baseline conditions remains a critical and ongoing challenge.

Conclusion

The results of this study demonstrated that CAPEOX combined with cetuximab is an equally viable option for first-line treatment of RAS/BRAF wild-type mCRC as FOLFOX combined with cetuximab.

Acknowledgements

The present study was supported by Program for Young Talents of Basic Research in Universities of Heilongjiang Province (grant no. YQJH2024123) (G.W.).

C.X., J.R., and C.L. served as co-first authors and contributed equally to the work. C.X. and J.R. contributed in the data curation, formal analysis, data collection, validation, and writing – original draft. J.R. and C.L. contributed in the data collection. Y.G. and X.C. contributed in the modification of the draft. Y.W. contributed in the conceptualization, supervision, and writing – review and editing. G.W. contributed in the conceptualization, data curation, funding acquisition, methodology, project administration, resources, supervision, and writing – review and editing. All authors read and approved the final manuscript.

This study was reviewed and approved by the Ethics Committee of Harbin Medical University Cancer Hospital and First Hospital of Shanxi Medical University (Ethics No. KY2022-32), and was conducted in accordance with the committee’s charter and the Helsinki Declaration. The patient/participant provided written informed consent to participate in this study.

Informed consent was obtained from all subjects or their legal guardian(s) to use their data for scientific research.

The original contributions presented in the study are included in the article/Supplementary material. Further inquiries can be directed to the corresponding author.

Conflicts of interest

There are no conflicts of interest.