Comparative effectiveness of bevacizumab, cetuximab, and panitumumab for improving outcomes in metastatic colorectal cancer: a propensity overlap weighting analysis

Yi-Chia Su; Chien-Chou Su; Pei-Ting Lee; Chih-Chien Wu

doi:10.3393/ac.2025.00059.0008

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Original Article Metastasis or chemotherapy Comparative effectiveness of bevacizumab, cetuximab, and panitumumab for improving outcomes in metastatic colorectal cancer: a propensity overlap weighting analysis: Yi-Chia Su^1,2,3,*, Chien-Chou Su^4,*, Pei-Ting Lee^1,5, Chih-Chien Wu^6,7; Annals of Coloproctology 2025;41(5):462-472.
DOI: https://doi.org/10.3393/ac.2025.00059.0008
Published online: October 27, 2025

¹Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

²Department of Pharmacy, Kaohsiung Medical University School of Pharmacy, Kaohsiung, Taiwan

³Department of Nursing, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan

⁴Clinical Innovation and Research Center, National Cheng Kung University Hospital, National Cheng Kung University College of Medicine, Tainan, Taiwan

⁵Department of Public Health, National Cheng Kung University College of Medicine, Tainan, Taiwan

⁶Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

⁷Department of Surgery, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan

Correspondence to: Chih-Chien Wu, MD Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, No. 386, Dazhong 1st Rd, Zuoying District, Kaohsiung 813414, Taiwan Email: pauleoswu@vghks.gov.tw

*Yi-Chia Su and Chien-Chou Su contributed equally to this work as co-first authors.

• Received: January 26, 2025 • Revised: April 30, 2025 • Accepted: May 14, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ARTICLE INFORMATION
SUPPLEMENTARY MATERIALS
REFERENCES

Abstract

Purpose
Metastatic colorectal cancer (mCRC) remains a leading cause of cancer-related mortality despite advancements in targeted therapies. Monoclonal antibody medications—namely, bevacizumab, cetuximab, and panitumumab—are widely used in combination with chemotherapy as first-line treatments for unresectable mCRC in patients harboring wild-type KRAS tumors. However, the comparative effectiveness of these treatments in improving survival outcomes has not been clearly evaluated. This study aimed to directly compare the effectiveness of these 3 targeted therapies on survival outcomes in patients with unresectable mCRC.
Methods
In this retrospective cohort study, we utilized Taiwan’s National Health Insurance Database and Taiwan Cancer Registry to identify patients newly diagnosed with mCRC who were treated with at least 6 cycles of bevacizumab, cetuximab, or panitumumab between 2011 and 2021. Propensity score overlap weighting was applied to adjust for baseline differences, and outcomes were evaluated using Cox proportional hazards models. Additionally, subgroup analyses were performed separately for left- and right-sided tumors.
Results
Among 4,849 patients, treatment with cetuximab and panitumumab was associated with improved overall survival compared to bevacizumab, particularly in patients with left-sided tumors (adjusted hazard ratio, 0.77 and 0.75, respectively). Both cetuximab and panitumumab also showed significantly higher rates of conversion surgery, with panitumumab demonstrating the strongest effect. For right-sided tumors, however, the effectiveness of all 3 agents was limited, and no significant differences were observed in overall survival.
Conclusion
Cetuximab and panitumumab were more effective than bevacizumab at improving survival outcomes and facilitating conversion surgery in left-sided mCRC. These findings highlight the importance of tumor laterality and molecular profiling in guiding therapeutic strategies.
Keywords: Colorectal neoplasms; Bevacizumab; Cetuximab; Panitumumab

INTRODUCTION

Colorectal cancer (CRC) is a prevalent malignancy, with an incidence rate of 38.7 per 100,000 people worldwide and 45.6 per 100,000 people in Taiwan. It remains a leading cause of cancer-related mortality [1–3]. At initial diagnosis, approximately 20% to 25% of patients with CRC present with metastatic disease [4]. Over recent decades, mortality rates associated with metastatic CRC (mCRC) have significantly decreased, primarily due to advancements in early detection and the development of comprehensive treatment strategies, particularly the use of combination chemotherapy and targeted monoclonal antibody (mAb) therapies [5].

Combination therapy is the current standard approach for treating CRC. Recent guidelines from the European Society for Medical Oncology (ESMO) and the US National Comprehensive Cancer Network (NCCN) recommend using anti–epidermal growth factor receptor (anti-EGFR) agents in combination with chemotherapy regimens such as FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) or FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) for patients with unresectable left-sided mCRC harboring wild-type KRAS genes.

In Taiwan, the National Health Insurance has reimbursed bevacizumab, cetuximab, and panitumumab for use in combination with chemotherapy as first-line systemic therapies for wild-type KRAS mCRC since June 2011, December 2012, and April 2016, respectively [6]. Bevacizumab is a mAb that targets vascular endothelial growth factor (VEGF), whereas cetuximab and panitumumab target EGFR. All 3 mAbs are approved as first-line treatments for unresectable mCRC. However, the comparative effectiveness of these 3 targeted therapies used as first-line treatments for unresectable mCRC has not yet been directly evaluated. Therefore, this study aimed to directly compare the effects of bevacizumab, cetuximab, and panitumumab combined with chemotherapy on survival outcomes in patients with unresectable mCRC. Additionally, we performed subgroup analyses to identify optimal treatment strategies for patients with varying characteristics.

METHODS

Ethics statement

The study protocol was approved by the Institutional Review Board of Kaohsiung Veterans General Hospital (No. KSVGH22-EM10-01). The requirement for informed consent was waived because a consistent encryption procedure to de-identify the original identification numbers of each patient in the Taiwan's National Health Insurance Research Database (NHIRD) was employed. This study followed the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guidelines. This study adhered to the principles of the Declaration of Helsinki.

Data sources

This study utilized the NHIRD and the Taiwan Cancer Registry, both of which are provided and maintained by the Health and Welfare Data Science Center of the Taiwanese Ministry of Health and Welfare. These databases can be linked to obtain clinical information at an individual level using personal identification numbers [7].

The NHIRD includes a registry of beneficiaries, ambulatory care claims, inpatient claims, and prescription dispensing claims from pharmacies. Each claim contains diagnosis codes according to the International Classification of Diseases, 9th and 10th Revisions, Clinical Modification (ICD‐9‐CM and ICD‐10‐CM). The NHIRD was used to collect complete records of prescriptions for targeted agents (bevacizumab, cetuximab, and panitumumab), surgical status, and surgical procedures. Information extracted from the Taiwan Cancer Registry included the date of diagnosis, tumor grade, morphological type of cancer, tumor size, origin, stage at diagnosis, lymph node status, radiotherapy status, tumor obstruction, and tumor perforation. Death dates were obtained from the cause of death data, with follow-up continued until December 31, 2022. All data were anonymized.

Study population

We conducted a retrospective cohort study using an active comparator and a new-user design. Patients newly diagnosed with mCRC from January 1, 2011, to December 31, 2021, were identified from the Taiwan Cancer Registry using the 3rd edition of International Classification of Diseases for Oncology (ICD-O) codes C180–C189, C199, and C209, and treated with bevacizumab, cetuximab, or panitumumab as first-line targeted therapy. The index date was defined as the date on which a patient received the first cycle of bevacizumab, cetuximab, or panitumumab during the study period. We included patients who received at least 6 cycles of targeted therapy, with intervals between consecutive cycles of less than 60 days. Patients were excluded if they met any of the following criteria: (1) younger than 20 years of age; (2) synchronous left- and right-sided tumors; (3) received targeted therapy within 1 year before the index date; (4) received fewer than 6 cycles of first-line therapy or had less than 3 months of follow-up; (5) intervals between targeted therapy cycles exceeded 60 days; (6) switched targeted therapies; (7) had a KRAS mutation or missing KRAS status; or (8) underwent metastasectomy before the index date. The definitions of therapy lines were as follows: first-line therapy was the initial use of bevacizumab, cetuximab, or panitumumab with or without chemotherapy, while second-line and third-line therapies were defined as subsequent changes to different targeted agents or chemotherapy regimens following failure of prior treatments.

Outcome and covariates

The primary outcome was overall survival (OS), measured from the index date until the end of 2022. The secondary outcome was conversion surgery after the index date, with censoring occurring at death or at the end of 2022, whichever occurred first. Covariates included the year of diagnosis, year of targeted therapy initiation, age, sex, tumor histological grade and type, primary tumor location, tumor stage (IVA, IVB, or IVC), tumor size, lymph node status, radiotherapy, Charlson Comorbidity Index, medications including glycosides, antidyslipidemia agents, β-blockers, calcium channel blockers, diuretic agents, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antidiabetic agents, antihemorrhagic agents, antiarrhythmic agents, antifungal agents, antibacterial agents, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), selective NSAIDs, tumor obstruction, tumor perforation, carcinoembryonic antigen, hospital level, and the multimorbidity frailty index (mFI). The mFI was developed by Wen et al. [8] and Lai et al. [9] and constructed using a cumulative deficit approach with a nonweighted method, and calculated as the number of deficits a patient has (numerator) divided by the total possible deficits (denominator). A higher mFI indicates greater frailty.

Statistical analysis

Descriptive statistics were used to summarize baseline characteristics. Continuous variables were described as means and standard deviations, while categorical variables were described as frequencies and proportions. The Kruskal-Wallis rank sum test was used for continuous variables, and the Pearson chi-square test or the Fisher exact test was used for categorical variables to compare differences in baseline characteristics among patients treated with bevacizumab, cetuximab, or panitumumab. Time to death since initiation of therapy was estimated using Kaplan-Meier survival analysis and compared using the log-rank test.

Inverse probability overlap weighting (IPOW) was used to reduce the effects of confounding factors in multiple treatments [10, 11]. Conventional inverse probability weighting is robust when patient cohorts have similar baseline characteristics without extreme outliers. However, extreme propensity score values can bias conventional inverse probability weighting; IPOW addresses this limitation, reducing both bias and error. The absolute standardized mean difference [12] was employed to compare the differences between the unweighted and overlap-weighted samples. The figure presents the comparison of the 2 groups among the 3 targeted therapies with the largest absolute standardized mean differences.

Subgroup analyses were performed for left- and right-sided tumors to evaluate the comparative effectiveness of bevacizumab, cetuximab, and panitumumab. IPOW was also applied to reduce confounding effects and compare effectiveness among patients with left-sided tumors. For right-sided tumors, due to a small sample size resulting in unsatisfactory IPOW performance, a multivariable Cox proportional hazards model was used to adjust for covariates.

Cox proportional hazard models were utilized to estimate adjusted hazard ratios (aHRs) for OS and incidence of conversion surgery with IPOW. All analyses were performed using SAS ver. 9.4 (SAS Institute Inc) and R ver. 4.2.1 (R Foundation for Statistical Computing). A 2-tailed P-value less than 0.05 was considered statistically significant for all tested hypotheses.

RESULTS

Baseline characteristics

A total of 4,849 patients who received targeted therapy combined with chemotherapy as first-line treatment were enrolled in the study. Among these, 3,025 patients were treated with bevacizumab, 1,448 with cetuximab, and 376 with panitumumab (Fig. 1). The mean patient age ranged from 59 to 60 years across all treatment groups. Most patients were male (approximately 60% in each group). The distribution of patients according to the year of targeted therapy significantly varied across groups (P<0.001), reflecting the changing availability of these treatment regimens in Taiwan. Some variations existed at the hospital level, with medical centers slightly more frequently prescribing bevacizumab (58.4%) compared to cetuximab (60.5%) and panitumumab (53.2%). Most patients presented with stage IVA disease in all treatment groups (bevacizumab group, 46.2%; cetuximab group, 53.1%; panitumumab group, 52.1%). Additionally, most tumors were moderately differentiated. Regarding tumor laterality, left-sided tumors were more prevalent than right-sided tumors in each treatment group (bevacizumab, 71.8% vs. 28.2%; cetuximab, 84.8% vs. 15.2%; panitumumab, 86.2% vs. 13.8%) (Table 1).

Survival outcomes

The absolute standardized mean differences among most baseline characteristics were notably reduced after applying IPOW. After adjustment through IPOW, patients treated with cetuximab and panitumumab showed significantly improved OS compared to those treated with bevacizumab (Table 2). Median OS values are presented in Fig. 2. The aHR for OS comparing cetuximab to bevacizumab was 0.81 (95% confidence interval [CI], 0.73–0.90), and the aHR for panitumumab versus bevacizumab was 0.76 (95% CI, 0.65–0.88; both P<0.001). No significant difference in OS was observed between cetuximab and panitumumab (aHR, 0.93; 95% CI, 0.79–1.10; P=0.395). In the subgroup analysis for patients with left-sided tumors, cetuximab and panitumumab both demonstrated greater survival benefits compared to bevacizumab, with respective aHRs of 0.77 (95% CI, 0.68–0.86) and 0.75 (95% CI, 0.64–0.89; both P<0.001). There was no significant difference in OS between cetuximab and panitumumab for left-sided tumors (aHR, 0.98; 95% CI, 0.83–1.17; P=0.855). For patients with right-sided tumors, no significant differences in OS were found among the 3 treatment groups (Supplementary Table 1, Supplementary Fig. 1).

Conversion surgery

The results of conversion surgery after applying IPOW are presented in Table 3. Both cetuximab (aHR, 1.73; 95% CI, 1.42–2.10) and panitumumab (aHR, 2.22; 95% CI, 1.76–2.81) were associated with significantly higher rates of conversion surgery compared to bevacizumab (P<0.001). This trend remained consistent among patients with left-sided tumors (cetuximab: aHR, 1.77 [95% CI, 1.43–2.19]; panitumumab: aHR, 2.20 [95% CI, 1.71–2.84]; both P<0.001). Significant differences in conversion surgery rates favoring cetuximab and panitumumab compared to bevacizumab were also observed among patients with right-sided tumors (P=0.005 and P=0.016, respectively) (Supplementary Table 2). Overall, panitumumab and cetuximab demonstrated significantly higher conversion rates than bevacizumab.

DISCUSSION

In this study, we compared the effects of 3 targeted therapies (bevacizumab, cetuximab, and panitumumab) combined with chemotherapy on survival outcomes in the treatment of unresectable mCRC. Our findings suggest that cetuximab and panitumumab offer superior survival benefits compared with bevacizumab, particularly for patients with left-sided mCRC. The lack of a significant difference in efficacy between cetuximab and panitumumab suggests comparable effectiveness. Cetuximab and panitumumab significantly increased the likelihood of achieving resectable disease and conversion surgery, especially for left-sided tumors. Panitumumab demonstrated the strongest association with conversion therapy, suggesting superior efficacy in converting unresectable tumors into resectable tumors. Conversely, bevacizumab was less frequently associated with conversion surgery, potentially owing to differences in tumor biology or treatment mechanisms. Panitumumab and cetuximab are mAbs that specifically target EGFR. EGFR activation stimulates the RAS/RAF/MEK/ERK signaling pathway, promoting tumor cell proliferation. Panitumumab and cetuximab function by blocking EGFR activation, thereby hindering tumor cell proliferation and differentiation, ultimately slowing tumor growth. Bevacizumab, on the other hand, is a mAb that targets VEGF, inhibiting angiogenesis and consequently reducing blood flow and the supply of nutrients and oxygen to tumors [13]. Patients with left-sided tumors exhibit increased activation of the EGFR pathway, making them more responsive to EGFR inhibitors [14–16]. Approximately 80% of cases in our cohort had left-sided malignancies, which helps explain why panitumumab and cetuximab efficiently blocked EGFR signaling pathways, reducing tumor cell proliferation and enhancing therapeutic outcomes.

The FIRE-3 trial was a randomized, open-label, phase 3 clinical trial evaluating first-line FOLFIRI with cetuximab versus FOLFIRI with bevacizumab in patients with KRAS exon 2 wild-type mCRC. By contrast, our study was a large, nationwide, retrospective cohort analysis based on data from NHIRD and Taiwan Cancer Registry. To reduce the impact of confounding factors and emulate the balance achieved in randomized controlled trials, we applied propensity score overlap weighting. This method created comparable baseline characteristics across the 3 treatment groups, facilitating direct comparison of survival outcomes for first-line chemotherapy combined with bevacizumab, cetuximab, or panitumumab in patients with unresectable, KRAS wild-type mCRC. Our findings demonstrated OS outcomes comparable to those observed in the FIRE-3 trial (our study: HR, 0.81 [95% CI, 0.73–0.90]; FIRE-3: HR, 0.77 [95% CI, 0.62–0.96]) [17]. Consistent results were also observed in subgroup analyses based on tumor sidedness. Patients with left-sided tumors in our study showed better survival outcomes when treated with EGFR inhibitors than those in the FIRE-3 trial (our study: HR, 0.77 [95% CI, 0.68–0.86]; FIRE-3: HR, 0.63 [95% CI, 0.48–0.85]), while no significant difference was noted in patients with right-sided tumors (our study: HR, 1.02 [95% CI, 0.86–1.21]; FIRE-3: HR, 1.31 [95% CI, 0.81–2.11]) [14]. It is notable that, unlike the FIRE-3 trial, which included exclusively metastatic patients, our study cohort also included patients with locally advanced but unresectable tumors. This difference in patient populations may explain the relatively shorter median survival observed in our study (24.9 months in the cetuximab group and 21.2 months in the bevacizumab group) compared to that reported in FIRE-3 (28.7 months and 25.0 months, respectively). In FIRE-3, similar proportions of patients received second-line therapies, with comparable crossover rates to alternative targeted agents (anti-VEGF or anti-EGFR therapy) [18]. However, in our study, most patients received oxaliplatin-based chemotherapy after first-line treatment. Previous studies have indicated that approximately 70% to 80% of patients with mCRC proceed to second-line therapy. Nevertheless, first-line therapy remains the most critical determinant of prognosis, primarily because differences in OS outcomes might reflect biological changes within the tumor occurring during initial therapy [19, 20], often outweighing the impact of later lines of treatment [21–23]. Even in carefully designed clinical trials using intensive second-line regimens, improvements in median OS are generally modest. Thus, selecting an optimal first-line treatment strategy is crucial and substantially influences long-term survival outcomes in patients with mCRC.

In right-sided mCRC, cetuximab and panitumumab showed no significant OS difference compared with bevacizumab, suggesting limited efficacy in these tumors. This observation aligns with previous findings that right-sided mCRC responds differently to targeted therapies than left-sided tumors due to distinct tumor biology. This effect may result from the higher prevalence of adverse biological features in right-sided tumors, including BRAF mutations, KRAS mutations, and mucinous histology [24, 25]. These factors are strongly associated with worse prognosis and higher mortality. BRAF mutations, predominantly observed in right-sided malignancies, are associated with aggressive tumor characteristics and poorer treatment response. Similarly, KRAS mutations, indicative of resistance to anti-EGFR therapies such as cetuximab and panitumumab, are more frequent in right-sided tumors [26]. In KRAS-mutant mCRC, resistance to anti-EGFR agents arises due to constitutive activation of the KRAS protein by mutations, independent of EGFR signaling. This activation perpetually stimulates downstream pathways such as RAS/RAF/MEK/ERK and PI3K/AKT, rendering anti-EGFR agents ineffective at curbing tumor proliferation driven by mutated KRAS [27]. Additionally, mucinous histology, characterized by excessive mucus production within tumors, further exacerbates treatment resistance, leading to poor outcomes [24, 25]. These biological differences collectively explain the limited effectiveness of cetuximab and panitumumab in improving OS in right-sided mCRC, emphasizing the need for individualized treatments based on tumor sidedness and molecular characteristics.

Based on the findings in Table 3, both panitumumab and cetuximab demonstrated significantly better outcomes regarding conversion surgery compared with bevacizumab in patients with right-sided mCRC. These findings may inform treatment decisions and highlight the efficacy of EGFR inhibitors for right-sided tumors in achieving surgical conversion. In wild-type KRAS/BRAF right-sided cancers, the EGFR signaling pathway remains active, and EGFR inhibitors, such as panitumumab and cetuximab, effectively suppress this pathway. Such suppression curtails tumor growth and promotes tumor reduction, thereby increasing the feasibility of tumor resection. Yoshino et al. [28] reported that in patients with RAS wild-type mCRC, anti-EGFR agents significantly enhanced early tumor shrinkage compared with bevacizumab, irrespective of tumor location (OR, 1.72; 95% CI, 1.36–2.17). Furthermore, subgroup analyses involving right-sided tumors indicated a trend toward improved early tumor shrinkage with anti-EGFR agents compared to bevacizumab. Thus, a key advantage of anti-EGFR agents is their capability to rapidly induce early tumor shrinkage. For patients with borderline resectable tumors, early tumor shrinkage provides an opportunity for surgical teams to evaluate and plan potential conversion surgery. Additionally, although right-sided tumors are typically associated with unfavorable prognostic features such as KRAS mutations, carefully selected patients with RAS wild-type tumors may achieve higher early tumor shrinkage rates with anti-EGFR therapy compared to bevacizumab. In our study, the patient cohort predominantly consisted of KRAS wild-type mCRC patients, aligning closely with findings from these previous studies. Furthermore, angiogenic patterns and the tumor microenvironment in right-sided tumors may exhibit decreased sensitivity to bevacizumab, thereby limiting the effectiveness of anti-VEGF therapy in facilitating tumor reduction [29]. Numerous studies have indicated that in patients with wild-type RAS/BRAF right-sided mCRC, treatment with EGFR inhibitors can significantly improve the objective response rate and tumor reduction rate, both crucial for surgical conversion [14, 30, 31].

This study possesses numerous strengths, including its reflection of real-world clinical practice and the use of IPOW to assess OS outcomes with panitumumab, cetuximab, and bevacizumab in patients with wild-type KRAS and unresectable mCRC. A robust patient cohort was assembled using a national claims database that provided precise information on comorbidities, treatment regimens, and tumor characteristics through the Taiwan’s National Health Insurance system. Diagnoses were validated by linkage with the Taiwan Cancer Registry, ensuring data accuracy. Moreover, the sample size in this study exceeds those of previous investigations, thereby increasing statistical power and precision. These methodological strengths facilitated a comprehensive evaluation of the comparative efficacy of the 3 targeted therapies.

However, our study has several limitations. First, the databases lacked information on performance status, nutritional condition, life expectancy, and hematologic, hepatic, and renal functions. We addressed surrogate differences between targeted therapy cohorts by balancing factors such as age, comorbidities, and tumor characteristics. Second, detailed data on disease severity, the number of metastatic organs, and the extent of metastatic disease were not available. To mitigate confounding effects, we employed tumor staging (IVA and IVB, where stage IVA was defined as metastasis confined to a single organ and stage IVB indicated multiple organ involvement) as a proxy measure. Additionally, the databases did not provide information on surgical quality. Instead, we balanced differences between groups by incorporating variables including age, tumor characteristics, comorbidities, and comedications to substantially reduce confounding effects. Third, residual confounding cannot be entirely excluded; however, we included multiple potential measured and unmeasured covariates and employed propensity score overlap weighting to minimize confounding to the greatest possible extent. Future prospective studies incorporating more detailed clinical data are required to validate and strengthen our findings further.

In conclusion, direct comparisons among these 3 targeted therapies demonstrated that panitumumab and cetuximab are more effective than bevacizumab in facilitating conversion surgery and confer greater survival advantages in left-sided mCRC. These findings underscore the necessity of stratifying patients according to tumor sidedness when applying current treatment guidelines and designing future clinical trials.

ARTICLE INFORMATION

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Funding

This study was funded by Kaohsiung Veterans General Hospital (No. KSVGH113-083).

Acknowledgments

The authors thank the Health Data Science Center, National Cheng Kung University Hospital for providing administrative and technical support and Ms. Hsiao-Ling Chiu of the Cancer Center, Kaohsiung Veterans General Hospital for her advisory comments on interpreting the results.

Author contributions

Conceptualization: YCS, CCS, CCW; Data curation: all authors; Formal analysis: all authors; Funding acquisition: YCS; Investigation: all authors; Methodology: all authors; Project administration: PTL; Visualization: CCW; Writing–original draft: YCS, CCS, CCW; Writing–review & editing: all authors. All authors read and approved the final manuscript.

SUPPLEMENTARY MATERIALS

Supplementary Fig. 1.

Standardized mean differences in patients with left-sided tumors before and after propensity score overlap weighting.

ac-2025-00059-0008-Supplementary-Fig-1.pdf

Supplementary Table 1.

The aHRs of overall survival for bevacizumab, cetuximab, and panitumumab in patients with right-sided metastatic colorectal cancer

ac-2025-00059-0008-Supplementary-Table-1.pdf

Supplementary Table 2.

The aHRs of conversion surgery for bevacizumab, cetuximab, and panitumumab in patients with right-sided metastatic colorectal cancer

ac-2025-00059-0008-Supplementary-Table-2.pdf

Supplementary materials are available from https://doi.org/10.3393/ac.2025.00059.0008.

Fig. 1.

Flowchart of cohort selection. mCRC, metastatic colorectal cancer.

Fig. 2.

Unadjusted Kaplan-Meier survival curves for bevacizumab, cetuximab, and panitumumab. CI, confidence interval; HR, hazard ratio.

Table 1.

Baseline characteristics of the study population before propensity score overlap weighting

Characteristic	Bevacizumab (n=3,025)	Cetuximab (n=1,448)	Panitumumab (n=376)	P-value^a
Sex				0.042
Female	1,254 (41.5)	544 (37.6)	147 (39.1)
Male	1,771 (58.5)	904 (62.4)	229 (60.9)
Age (yr)	59±12	60±13	59±12	0.130
Age group (yr)				0.150
<50	671 (22.2)	310 (21.4)	79 (21.0)
50–59	851 (28.1)	372 (25.7)	111 (29.5)
60–69	902 (29.8)	436 (30.1)	120 (31.9)
≥70	601 (19.9)	330 (22.8)	66 (17.6)
Year of targeted therapy				<0.001
2011	177 (5.9)	0 (0)	0 (0)
2012	297 (9.8)	5 (0.3)	0 (0)
2013	308 (10.2)	134 (9.3)	0 (0)
2014	266 (8.8)	175 (12.1)	0 (0)
2015	265 (8.8)	160 (11.0)	0 (0)
2016	309 (10.2)	171 (11.8)	7 (1.9)
2017	315 (10.4)	189 (13.1)	34 (9.0)
2018	361 (11.9)	195 (13.5)	65 (17.3)
2019	323 (10.7)	212 (14.6)	125 (33.2)
2020	330 (10.9)	173 (11.9)	120 (31.9)
2021	74 (2.4)	34 (2.3)	25 (6.6)
Hospital level				0.034
Not medical center	1,259 (41.6)	572 (39.5)	176 (46.8)
Medical center	1,766 (58.4)	876 (60.5)	200 (53.2)
Charlson Comorbidity Index	9±2	9±2	9±2	0.200
Modified frailty index	0.08±0.06	0.08±0.06	0.08±0.06	0.051
Tumor stage				<0.001
IVA	1,398 (46.2)	769 (53.1)	196 (52.1)
IVB	1,295 (42.8)	531 (36.7)	93 (24.7)
IVC	332 (11.0)	148 (10.2)	87 (23.1)
Tumor size (cm)				0.300
<4	814 (26.9)	371 (25.6)	87 (23.1)
4–5	641 (21.2)	292 (20.2)	75 (19.9)
>5	1,570 (51.9)	785 (54.2)	214 (56.9)
Tumor differentiation grade				0.002
Well differentiated	94 (3.1)	49 (3.4)	17 (4.5)
Moderately differentiated	2,287 (75.6)	1,156 (79.8)	304 (80.9)
Poorly differentiated and undifferentiated or anaplastic	644 (21.3)	243 (16.8)	55 (14.6)
No. of positive lymph nodes	7±8	6±8	6±7	<0.001
Histologic type				<0.001
Adenocarcinoma	2,796 (92.4)	1,382 (95.4)	364 (96.8)
Signet ring	58 (1.9)	21 (1.5)	3 (0.8)
Mucinous	171 (5.7)	45 (3.1)	9 (2.4)
Tumor sidedness				<0.001
Right	853 (28.2)	220 (15.2)	52 (13.8)
Left	2,172 (71.8)	1,228 (84.8)	324 (86.2)
Obstruction^b				0.075
No	1,471 (48.6)	672 (46.4)	162 (43.1)
Yes	1,554 (51.4)	776 (53.6)	214 (56.9)
Perforation				0.500
No	2,869 (94.8)	1,361 (94.0)	357 (94.9)
Yes	156 (5.2)	87 (6.0)	19 (5.1)
Carcinoembryonic antigen				0.031
Negative	661 (21.9)	269 (18.6)	72 (19.1)
Positive	2,364 (78.1)	1,179 (81.4)	304 (80.9)
Radiotherapy				0.057
No	2,627 (86.8)	1,222 (84.4)	317 (84.3)
Yes	398 (13.2)	226 (15.6)	59 (15.7)
Conversion surgery				<0.001
No	2,571 (85.0)	1,064 (73.5)	258 (68.6)
Yes	454 (15.0)	384 (26.5)	118 (31.4)

Values are presented as number (%) or mean±standard deviation. Percentages may not total 100 due to rounding.

^aPearson chi-square test, Kruskal-Wallis rank sum test, or Fisher exact test. ^bDefined as bowel obstruction identified on any imaging study or confirmed intraoperatively, according to the Taiwan Cancer Registry definition.

Table 2.

The aHRs of overall survival for bevacizumab, cetuximab, and panitumumab after propensity score overlap weighting in patients with metastatic colorectal cancer

Overall survival	No. of deaths	Mortality rate (per 100 person-years)	aHR (95% CI)	P-value
Overall
Bevacizumab (reference)	2,627	39.55	1.00 (Reference)	-
Cetuximab	1,164	33.94	0.81 (0.73–0.90)	<0.001
Panitumumab	242	29.20	0.76 (0.65–0.88)	<0.001
Cetuximab (reference)	1,164	33.94	1.00 (Reference)	-
Bevacizumab	2,627	39.55	1.23 (1.11–1.37)	<0.001
Panitumumab	242	29.20	0.93 (0.79–1.10)	0.395
Left-sided tumor
Bevacizumab (reference)	1,873	37.30	1.00 (Reference)	-
Cetuximab	964	32.42	0.77 (0.68–0.86)	<0.001
Panitumumab	207	28.76	0.75 (0.64–0.89)	<0.001
Cetuximab (reference)	964	32.42	1.00 (Reference)	-
Bevacizumab	1,873	37.30	1.31 (1.16–1.47)	<0.001
Panitumumab	207	28.76	0.98 (0.83–1.17)	0.855

aHR, adjusted hazard ratio; CI, confidence interval.

Table 3.

The aHRs of conversion surgery for bevacizumab, cetuximab, and panitumumab after propensity score overlap weighting in patients with metastatic colorectal cancer

Conversion surgery	No. of events	Incidence rate (per 100 person-years)	aHR (95% CI)	P-value
Overall
Bevacizumab (reference)	454	8.27	1.00 (Reference)	-
Cetuximab	384	16.15	1.73 (1.42–2.10)	<0.001
Panitumumab	118	21.15	2.22 (1.76–2.81)	<0.001
Cetuximab (reference)	384	16.15	1.00 (Reference)	-
Bevacizumab	454	8.27	0.58 (0.48–0.70)	<0.001
Panitumumab	118	21.15	1.29 (1.02–1.62)	0.034
Left-sided tumor
Bevacizumab (reference)	355	8.74	1.00 (Reference)	-
Cetuximab	346	17.07	1.77 (1.43–2.19)	<0.001
Panitumumab	103	21.26	2.20 (1.71–2.84)	<0.001
Cetuximab (reference)	346	17.07	1.00 (Reference)	-
Bevacizumab	355	8.74	0.56 (0.46–0.70)	<0.001
Panitumumab	103	21.26	1.24 (0.97–1.59)	0.086

aHR, adjusted hazard ratio; CI, confidence interval.

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Comparative effectiveness of bevacizumab, cetuximab, and panitumumab for improving outcomes in metastatic colorectal cancer: a propensity overlap weighting analysis

Ann Coloproctol. 2025;41(5):462-472. Published online October 27, 2025

DOI: https://doi.org/10.3393/ac.2025.00059.0008

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Comparative effectiveness of bevacizumab, cetuximab, and panitumumab for improving outcomes in metastatic colorectal cancer: a propensity overlap weighting analysis

Fig. 1. Flowchart of cohort selection. mCRC, metastatic colorectal cancer.

Fig. 2. Unadjusted Kaplan-Meier survival curves for bevacizumab, cetuximab, and panitumumab. CI, confidence interval; HR, hazard ratio.

Fig. 1.

Fig. 2.

Comparative effectiveness of bevacizumab, cetuximab, and panitumumab for improving outcomes in metastatic colorectal cancer: a propensity overlap weighting analysis

Characteristic	Bevacizumab (n=3,025)	Cetuximab (n=1,448)	Panitumumab (n=376)	P-value^a
Sex				0.042
Female	1,254 (41.5)	544 (37.6)	147 (39.1)
Male	1,771 (58.5)	904 (62.4)	229 (60.9)
Age (yr)	59±12	60±13	59±12	0.130
Age group (yr)				0.150
<50	671 (22.2)	310 (21.4)	79 (21.0)
50–59	851 (28.1)	372 (25.7)	111 (29.5)
60–69	902 (29.8)	436 (30.1)	120 (31.9)
≥70	601 (19.9)	330 (22.8)	66 (17.6)
Year of targeted therapy				<0.001
2011	177 (5.9)	0 (0)	0 (0)
2012	297 (9.8)	5 (0.3)	0 (0)
2013	308 (10.2)	134 (9.3)	0 (0)
2014	266 (8.8)	175 (12.1)	0 (0)
2015	265 (8.8)	160 (11.0)	0 (0)
2016	309 (10.2)	171 (11.8)	7 (1.9)
2017	315 (10.4)	189 (13.1)	34 (9.0)
2018	361 (11.9)	195 (13.5)	65 (17.3)
2019	323 (10.7)	212 (14.6)	125 (33.2)
2020	330 (10.9)	173 (11.9)	120 (31.9)
2021	74 (2.4)	34 (2.3)	25 (6.6)
Hospital level				0.034
Not medical center	1,259 (41.6)	572 (39.5)	176 (46.8)
Medical center	1,766 (58.4)	876 (60.5)	200 (53.2)
Charlson Comorbidity Index	9±2	9±2	9±2	0.200
Modified frailty index	0.08±0.06	0.08±0.06	0.08±0.06	0.051
Tumor stage				<0.001
IVA	1,398 (46.2)	769 (53.1)	196 (52.1)
IVB	1,295 (42.8)	531 (36.7)	93 (24.7)
IVC	332 (11.0)	148 (10.2)	87 (23.1)
Tumor size (cm)				0.300
<4	814 (26.9)	371 (25.6)	87 (23.1)
4–5	641 (21.2)	292 (20.2)	75 (19.9)
>5	1,570 (51.9)	785 (54.2)	214 (56.9)
Tumor differentiation grade				0.002
Well differentiated	94 (3.1)	49 (3.4)	17 (4.5)
Moderately differentiated	2,287 (75.6)	1,156 (79.8)	304 (80.9)
Poorly differentiated and undifferentiated or anaplastic	644 (21.3)	243 (16.8)	55 (14.6)
No. of positive lymph nodes	7±8	6±8	6±7	<0.001
Histologic type				<0.001
Adenocarcinoma	2,796 (92.4)	1,382 (95.4)	364 (96.8)
Signet ring	58 (1.9)	21 (1.5)	3 (0.8)
Mucinous	171 (5.7)	45 (3.1)	9 (2.4)
Tumor sidedness				<0.001
Right	853 (28.2)	220 (15.2)	52 (13.8)
Left	2,172 (71.8)	1,228 (84.8)	324 (86.2)
Obstruction^b				0.075
No	1,471 (48.6)	672 (46.4)	162 (43.1)
Yes	1,554 (51.4)	776 (53.6)	214 (56.9)
Perforation				0.500
No	2,869 (94.8)	1,361 (94.0)	357 (94.9)
Yes	156 (5.2)	87 (6.0)	19 (5.1)
Carcinoembryonic antigen				0.031
Negative	661 (21.9)	269 (18.6)	72 (19.1)
Positive	2,364 (78.1)	1,179 (81.4)	304 (80.9)
Radiotherapy				0.057
No	2,627 (86.8)	1,222 (84.4)	317 (84.3)
Yes	398 (13.2)	226 (15.6)	59 (15.7)
Conversion surgery				<0.001
No	2,571 (85.0)	1,064 (73.5)	258 (68.6)
Yes	454 (15.0)	384 (26.5)	118 (31.4)

Overall survival	No. of deaths	Mortality rate (per 100 person-years)	aHR (95% CI)	P-value
Overall
Bevacizumab (reference)	2,627	39.55	1.00 (Reference)	-
Cetuximab	1,164	33.94	0.81 (0.73–0.90)	<0.001
Panitumumab	242	29.20	0.76 (0.65–0.88)	<0.001
Cetuximab (reference)	1,164	33.94	1.00 (Reference)	-
Bevacizumab	2,627	39.55	1.23 (1.11–1.37)	<0.001
Panitumumab	242	29.20	0.93 (0.79–1.10)	0.395
Left-sided tumor
Bevacizumab (reference)	1,873	37.30	1.00 (Reference)	-
Cetuximab	964	32.42	0.77 (0.68–0.86)	<0.001
Panitumumab	207	28.76	0.75 (0.64–0.89)	<0.001
Cetuximab (reference)	964	32.42	1.00 (Reference)	-
Bevacizumab	1,873	37.30	1.31 (1.16–1.47)	<0.001
Panitumumab	207	28.76	0.98 (0.83–1.17)	0.855

Conversion surgery	No. of events	Incidence rate (per 100 person-years)	aHR (95% CI)	P-value
Overall
Bevacizumab (reference)	454	8.27	1.00 (Reference)	-
Cetuximab	384	16.15	1.73 (1.42–2.10)	<0.001
Panitumumab	118	21.15	2.22 (1.76–2.81)	<0.001
Cetuximab (reference)	384	16.15	1.00 (Reference)	-
Bevacizumab	454	8.27	0.58 (0.48–0.70)	<0.001
Panitumumab	118	21.15	1.29 (1.02–1.62)	0.034
Left-sided tumor
Bevacizumab (reference)	355	8.74	1.00 (Reference)	-
Cetuximab	346	17.07	1.77 (1.43–2.19)	<0.001
Panitumumab	103	21.26	2.20 (1.71–2.84)	<0.001
Cetuximab (reference)	346	17.07	1.00 (Reference)	-
Bevacizumab	355	8.74	0.56 (0.46–0.70)	<0.001
Panitumumab	103	21.26	1.24 (0.97–1.59)	0.086

Table 1. Baseline characteristics of the study population before propensity score overlap weighting

Values are presented as number (%) or mean±standard deviation. Percentages may not total 100 due to rounding.

Table 2. The aHRs of overall survival for bevacizumab, cetuximab, and panitumumab after propensity score overlap weighting in patients with metastatic colorectal cancer

aHR, adjusted hazard ratio; CI, confidence interval.

Table 3. The aHRs of conversion surgery for bevacizumab, cetuximab, and panitumumab after propensity score overlap weighting in patients with metastatic colorectal cancer

aHR, adjusted hazard ratio; CI, confidence interval.