Effectiveness of oxaliplatin-based second-line therapy following cetuximab+FOLFIRI or bevacizumab+FOLFIRI in KRAS wild-type metastatic colorectal cancer without primary tumor resection

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

doi:10.3393/ac.2025.00087.0012

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Original Article Metastasis or chemotherapy Effectiveness of oxaliplatin-based second-line therapy following cetuximab+FOLFIRI or bevacizumab+FOLFIRI in KRAS wild-type metastatic colorectal cancer without primary tumor resection: Yi-Chia Su^1,2,3, Chien-Chou Su⁴, Pei-Ting Lee^1,5, Chih-Chien Wu^6,7; Annals of Coloproctology 2025;41(4):319-329.
DOI: https://doi.org/10.3393/ac.2025.00087.0012
Published online: August 21, 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

• Received: January 28, 2025 • Revised: April 5, 2025 • Accepted: April 9, 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
REFERENCES

Abstract

Purpose
Wild-type unresectable metastatic colorectal cancer (mCRC) poses challenges for treatment optimization. Effective first-line targeted therapies are crucial for improving outcomes, particularly when combined with second-line oxaliplatin-based chemotherapies. This study examined the effects of first-line cetuximab+FOLFIRI versus bevacizumab+FOLFIRI, followed by second-line oxaliplatin-based chemotherapy, on survival among patients with KRAS wild-type mCRC without primary tumor resection (PTR).
Methods
A retrospective analysis of Taiwanese data (2013–2019) included patients with KRAS wild-type unresectable mCRC who received first-line cetuximab+FOLFIRI or bevacizumab+FOLFIRI, followed by second-line oxaliplatin-based chemotherapy. Survival outcomes—overall survival (OS) and time to treatment discontinuation (TTD)—were compared between these regimens using stabilized inverse probability of treatment weighting to adjust for potential confounders, followed by multivariate Cox proportional hazards regression analysis to account for clinical and biological variables.
Results
In patients without PTR, first-line cetuximab+FOLFIRI with second-line oxaliplatin-based chemotherapy significantly improved OS from the start dates of first- and second-line treatment compared to first-line bevacizumab+FOLFIRI with second-line oxaliplatin-based therapy, yielding adjusted hazard ratios (HRs) of 0.60 (95% confidence interval [CI], 0.46–0.78) and 0.56 (95% CI, 0.42–0.73), respectively. No significant difference in TTD was observed (HR, 0.82; 95% CI, 0.65–1.04).
Conclusion
First-line cetuximab+FOLFIRI followed by second-line oxaliplatin-based chemotherapy offers superior OS compared to bevacizumab+FOLFIRI followed by second-line oxaliplatin‑based chemotherapy in KRAS wild-type mCRC without PTR. These findings underscore the importance of personalized treatment sequencing, highlighting the need for further research to optimize mCRC management.
Keywords: Colorectal neoplasms; KRAS gene; Cetuximab; Bevacizumab; Oxaliplatin

INTRODUCTION

Colorectal cancer (CRC) is a common malignancy worldwide and a leading cause of cancer-related mortality [1]. Approximately 20% to 25% of patients with CRC present with metastasis at diagnosis, with the liver and lungs being the most common sites of distant spread [2]. Among patients, about 80% to 90% are not candidates for surgical resection of distant metastatic sites or primary colorectal tumors [3, 4]. Therefore, the selection of effective drug therapies is crucial for patients with unresectable metastatic CRC (mCRC).

For patients initially diagnosed with unresectable mCRC, the first step is to administer targeted therapy combined with chemotherapy. Current targeted therapies, including cetuximab and bevacizumab, are approved as first-line treatments. Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor, whereas cetuximab targets the epidermal growth factor receptor (EGFR). Chemotherapy with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) combined with targeted monoclonal antibodies is the most frequently administered first-line therapeutic regimen for patients with mCRC [5, 6].

In a network meta-analysis of 15 clinical trials involving 5,337 patients with mCRC, first-line cetuximab plus chemotherapy demonstrated efficacy comparable to that of bevacizumab plus chemotherapy [6]. The analysis included 2 head-to-head clinical trials, CALGB 80405 and FIRE-3, comparing these treatment options. In the CALGB 80405 trial, no significant difference in overall survival (OS) was observed between the cetuximab and bevacizumab treatment groups [7]; however, the FIRE-3 trial results indicated that the cetuximab group achieved significantly superior OS [8]. In the FIRE-3 and CALGB 80405 studies, 80% of patients underwent primary tumor resection (PTR) before targeted therapy, meaning that 20% did not undergo surgical resection. Imbalance and diversity in later-line therapies were critical factors impacting OS.

PTR can alleviate tumor-related symptoms, such as bowel obstruction or bleeding [9], and may increase treatment efficacy by reducing tumor burden and improving the tumor microenvironment (TME) [10, 11]. However, the differential effects of PTR on the efficacy of cetuximab- and bevacizumab-based chemotherapy remain unclear.

Since 2011 and 2012, in Taiwan, patients with wild-type KRAS mCRC have been eligible for reimbursement through Taiwan's National Health Insurance for first-line treatment with bevacizumab or cetuximab, respectively, combined with FOLFIRI [12]. Second-line treatment strategies typically involve switching to oxaliplatin-based chemotherapy. However, the optimal strategy for selecting first-line targeted therapies to optimize second-line oxaliplatin management in patients with PTR and non-PTR KRAS wild-type mCRC remains unclear. This study aimed to investigate the impact of PTR on survival outcomes, including OS and time to treatment discontinuation (TTD), in patients with KRAS wild-type mCRC treated with first-line cetuximab+FOLFIRI or bevacizumab+FOLFIRI, followed by second-line oxaliplatin-based chemotherapy. Evaluating the differential effects of PTR on these therapeutic approaches may provide insights to inform clinical decision-making and optimize treatment sequencing in this patient population.

METHODS

Ethics statement

The study protocol was reviewed and 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 was used to de-identify the original identification numbers of patients in Taiwan's National Health Insurance Research Database (NHIRD). All data were anonymized, and the study adhered to the principles of the Declaration of Helsinki. This study followed the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guidelines.

Data source

The NHIRD is derived from Taiwan's National Health Insurance, a single-payer insurance program that covers over 99.99% of the Taiwanese population. Complete records of prescriptions for bevacizumab, cetuximab, fluorouracil, irinotecan, and oxaliplatin—as well as associated surgical statuses—were extracted. Mortality data, including causes of death, were traced up to December 31, 2020. The Taiwan Cancer Registry (TCR) database, managed by Taiwan Ministry of Health and Welfare, has a high coverage rate at 97%. The registry ensures data quality through a self-check procedure that employs standardized logic algorithms at the TCR central office to identify and correct potential errors before data submission. Both databases are maintained by the Health and Welfare Data Science Center, under Taiwan Ministry of Health and Welfare.

Study population and therapies

In this study, the diagnosis of mCRC was based on the International Classification of Diseases (ICD) for Oncology, 3rd Edition, using codes C180–C189, C199, and C209. Patients were eligible for this study if they were diagnosed between January 1, 2013, and December 31, 2019; were registered in the TCR database; and had undergone first-line therapy with bevacizumab+FOLFIRI or cetuximab+FOLFIRI. The index date for first-line therapy was defined as the date when the patient received the first cycle of bevacizumab or cetuximab+FOLFIRI during the study period, while that for second-line therapy was defined as the date when the patient received the first cycle of oxaliplatin-based treatment.

Patients were enrolled if they completed at least 6 cycles of bevacizumab+FOLFIRI or cetuximab+FOLFIRI, maintained intervals of less than 60 days between consecutive cycles, and received only up to second-line therapy. Patients were excluded if they met any of the following criteria: (1) were younger than 20 years; (2) had synchronous left- and right-sided tumors; (3) received targeted therapy within 1 year before the date of diagnosis; (4) underwent metastasectomy before the index date; (5) had a KRAS gene mutation or missing data; (6) received fewer than 6 consistent cycles of first-line targeted therapy+FOLFIRI; (7) had a follow-up duration of less than 3 months; (8) received targeted therapy with intervals greater than 60 days between cycles; or (9) received treatment beyond second-line therapy (Fig. 1). First-line therapy was defined as the administration of the initial cycle of bevacizumab+FOLFIRI or cetuximab+FOLFIRI during the study period. Second-line therapy was defined as any targeted therapy or chemotherapy different from the first-line regimen. According to national reimbursement policies, first-line chemotherapy for mCRC is limited to FOLFIRI-based regimens combined with targeted agents (cetuximab or bevacizumab). Therefore, the study’s first-line regimen consisted of a targeted agent plus FOLFIRI, while second-line therapy was defined as a switch to a chemotherapy regimen different from FOLFIRI, which in most cases was an oxaliplatin-based regimen.

Study variables and outcomes

The demographic variables examined included the year of targeted therapy, age, sex, histological grade and type (mucinous, signet ring cell, or adenocarcinoma), primary tumor location, stage (IVA, IVB, or IVC), tumor size, carcinoembryonic antigen (CEA) status, bowel obstruction, bowel perforation, radiotherapy, metastasectomy type, surgical status prior to the index date, and Charlson Comorbidity Index score (using corresponding ICD 9th and 10th Revision data) [13, 14] recorded 1 year before the index date. Other variables included hospital level (medical center or regional hospital), time of metastasectomy, total duration of second-line oxaliplatin therapy, total number of second-line oxaliplatin cycles, and whether second-line oxaliplatin was combined with targeted therapy. Patients with KRAS wild-type mCRC were divided into 2 groups: those who underwent PTR and those who did not. The primary outcome was OS, specifically referred to as OS1 and OS2, which were measured from the initiation of first- and second-line therapies, respectively, to the end of 2020, death, or censoring. The secondary outcome was TTD, measured from the initiation of first-line therapy to the administration of second-line chemotherapy or death.

Statistical analysis

Descriptive statistics were calculated for demographic and tumor characteristics. A standardized mean difference greater than 0.2 was employed to assess differences in baseline covariates between cetuximab+FOLFIRI and bevacizumab+FOLFIRI in patients with KRAS wild-type unresectable mCRC. Additionally, OS and TTD were calculated and compared using the Kaplan-Meier method and the log-rank test to assess unadjusted survival differences between the 2 treatment groups. Adjusted survival comparisons between cetuximab+FOLFIRI and bevacizumab+FOLFIRI were estimated using multivariate analysis with a Cox proportional hazards model, and the results were expressed as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). Covariates were included in a logistic regression model to generate a propensity score (PS) for patients receiving treatment, and a Cox proportional hazards model adjusted for PS and baseline characteristics was then generated to compare the survival HRs between the groups. The inverse probability of receiving cetuximab+FOLFIRI therapy was calculated for weighting purposes. OS and TTD were estimated after applying stabilized inverse probability of treatment weights (SIPTW) to control for confounding factors and ensure comparability between groups. Potential confounders and covariates related to outcomes, such as comorbidities and tumor patterns, were included in the PS model, and SIPTW was used to minimize sample loss when estimating the average treatment effect. Robustness was assessed by fitting competing risk models, including the cause-specific hazard model and the Fine-Gray subdistribution hazard model, with non-CRC death considered a competing risk for CRC death. All analyses were performed using SAS ver. 9.4 (SAS Institute Inc) and RStudio ver. 2024.09.1+341 (Posit PBC). For all tested hypotheses, a 2-tailed P-value of less than 0.05 was considered to indicate statistical significance. Missing values were imputed using multivariate imputation by chained equations based on a fully conditional specification, in which each incomplete variable was imputed using a Bayesian model [15]. The imputed variables included histological grade, tumor size, tumor sidedness, CEA status, hospital level, bowel obstruction, and bowel perforation.

RESULTS

Cohort characteristics

We identified 13,473 patients with mCRC during the study period (Fig. 1). A total of 664 patients who received targeted therapy combined with chemotherapy as the first-line regimen and oxaliplatin-based chemotherapy as the second-line regimen were included. Among the 367 patients who did not undergo PTR before the index date of first-line therapy, 202 received first-line bevacizumab+FOLFIRI followed by second-line oxaliplatin-based bevacizumab, while 165 received first-line cetuximab+FOLFIRI followed by second-line oxaliplatin-based cetuximab. Among the 297 patients who underwent PTR before the index date of first-line therapy, 157 received first‐line bevacizumab+FOLFIRI followed by a second‐line oxaliplatin-based regimen with or without bevacizumab, and 140 received first‐line cetuximab+FOLFIRI followed by a second-line oxaliplatin-based regimen with or without cetuximab (Table 1).

OS and TTD

Among patients who did not undergo PTR, 275 of 367 (74.9%) died during follow-up: 155 of 202 (76.7%) in the first‐line bevacizumab+FOLFIRI group with subsequent second-line oxaliplatin-based therapy with or without bevacizumab, and 120 of 165 (72.7%) in the first‐line cetuximab+FOLFIRI group with subsequent second-line oxaliplatin-based therapy with or without cetuximab. The median OS1 was significantly longer in the first‐line cetuximab+FOLFIRI group followed by second‐line oxaliplatin-based therapy with or without cetuximab (22.2 months; 95% CI, 18.4–24.4 months) compared to the first‐line bevacizumab+FOLFIRI group followed by second-line oxaliplatin-based therapy with or without bevacizumab (15.2 months; 95% CI, 13.5–17.0 months; crude HR, 0.61 [95% CI, 0.48–0.78]; adjusted HR, 0.60 [95% CI, 0.46–0.78]). Similarly, the median OS2 for non-PTR patients receiving second-line oxaliplatin-based therapy was significantly better in the first-line cetuximab+FOLFIRI group (9.6 months; 95% CI, 8.7–11.8 months) than in the first-line bevacizumab+FOLFIRI group (5.2 months; 95% CI, 4.5–6.1 months; crude HR, 0.58 [95% CI, 0.46–0.74]; adjusted HR, 0.56 [95% CI, 0.42–0.73]). The median TTD was significantly longer in the first‐line cetuximab+FOLFIRI group followed by second-line oxaliplatin-based therapy with or without cetuximab (10.4 months; 95% CI, 9.4–12.1 months) compared to the first‐line bevacizumab+FOLFIRI group followed by second-line oxaliplatin-based therapy with or without bevacizumab (9.2 months; 95% CI, 8.5–9.9 months; crude HR, 0.75 [95% CI, 0.61–0.92]), although the adjusted HR of 0.82 (95% CI, 0.65–1.04) lacked statistical significance. Among the patients who underwent PTR, the median OS1, OS2, and TTD did not differ significantly between treatment groups (Figs. 2, 3).

The results of the subgroup analysis by tumor sidedness are presented in Fig. 3. The findings from the competing risk models were consistent with those of the Cox proportional hazards models (Fig. 4).

DISCUSSION

Among the non-PTR group, TTD analysis indicated that the duration of therapy failure was significantly shorter in the bevacizumab+FOLFIRI cohort than in the cetuximab+FOLFIRI cohort, suggesting that bevacizumab+FOLFIRI may be less effective in managing tumor progression and may prompt an earlier initiation of second line therapy. The first-line cetuximab+FOLFIRI cohort exhibited a significant survival benefit over the bevacizumab+FOLFIRI cohort among patients who did not undergo PTR. An OS analysis using the initiation of second-line oxaliplatin-based cetuximab treatment as the index date confirmed this trend, demonstrating that the cetuximab+FOLFIRI cohort maintained an early survival advantage throughout the second-line treatment phase. Among patients who underwent PTR, OS and TTD analyses indicated that the survival differences between the 2 groups were less pronounced than those observed in the non-PTR subset. This suggests that PTR may partially mitigate the impact of first-line treatment on OS. In patients who do not receive PTR, early-stage tumor progression control may rely more heavily on pharmaceutical therapies, with cetuximab potentially providing a greater benefit in delaying disease progression. Our findings also suggest that in patients without PTR, when first-line treatment involves targeted therapy+FOLFIRI and subsequent treatment is limited to second-line oxaliplatin-based chemotherapy, the subgroup receiving second-line treatment may have tumors with comparatively rapid progression, as reflected in a median OS of 5.2 to 9.6 months. Consequently, the choice of first line therapy is critically important for this patient group.

Among patients treated with bevacizumab+FOLFIRI, the median OS1 durations for those without PTR and with PTR were 15 and 19 months, respectively. In contrast, for cetuximab+FOLFIRI, the median OS1 values were 22 months and 21 months for patients without and with PTR, respectively. This suggests that the median OS1 for cetuximab+FOLFIRI was similar regardless of PTR status, whereas PTR had a greater impact on the median OS1 for bevacizumab+FOLFIRI. The primary reason for this difference lies in the distinct mechanisms of action of these therapies. Cetuximab exerts its antitumor effects by inhibiting the intracellular signaling pathway of tumor cells (EGFR-RAS-RAF-MEK-ERK), suppressing tumor cell proliferation, and promoting apoptosis rather than relying on alterations in tumor angiogenesis or the surrounding microenvironment [16, 17]. Therefore, PTR status has a relatively minor impact on efficacy. The direct action of cetuximab on tumor cells may remain effective even without PTR, allowing patients to achieve survival outcomes comparable to those who undergo resection. In contrast, the antitumor effects of bevacizumab depend on modifying the TME, particularly by inhibiting tumor angiogenesis [11, 18]. In patients without PTR, the higher tumor vasculature burden may reduce the therapeutic efficacy of bevacizumab, whereas after PTR, the reduction in tumor vasculature may increase its efficacy and yield significantly prolonged survival [18, 19].

In left-sided unresectable KRAS wild-type mCRC, OS1 and OS2 were significantly longer in patients treated with first-line cetuximab+FOLFIRI followed by second-line oxaliplatin-based chemotherapy than in those treated with first-line bevacizumab+FOLFIRI followed by second-line oxaliplatin-based chemotherapy. However, these groups exhibited no significant difference in TTD. In right-sided unresectable KRAS wild-type mCRC, no significant difference in efficacy was noted between the treatment regimens. Left-sided mCRC typically exhibits higher EGFR expression, making anti-EGFR therapies such as cetuximab more effective in these patients [17, 20]. In contrast, right-sided tumors express lower levels of EGFR, resulting in a weaker response to cetuximab [11]. After first-line treatment with cetuximab, tumor progression slows; thus, when patients transition to second-line therapy, the tumor’s biological behavior is typically more indolent, prolonging survival. In contrast, bevacizumab primarily targets the TME; accordingly, more rapid tumor progression may occur, potentially reducing the effectiveness of second line treatments [21]. TTD, which reflects the duration of treatment until disease progression or discontinuation due to poor tolerance, is influenced by factors including tumor biology, treatment tolerance, and clinical decision making. Although cetuximab demonstrates superior OS compared to bevacizumab, its effect on TTD may be limited by these factors, potentially explaining the lack of a significant difference in TTD between the treatments [21].

The major strengths of this study are as follows. First, the use of real world data from comprehensive databases encompassing a large and diverse patient population enhances the generalizability and external validity of the findings. Second, the large sample size increases statistical power and promotes the reliability of comparisons between different treatment regimens. Third, the study compares the efficacy of first line cetuximab+FOLFIRI and bevacizumab+FOLFIRI in patients with KRAS wild type unresectable mCRC, as well as the impact of second line oxaliplatin based therapies, providing a complete analysis of treatment sequencing. Fourth, by accounting for both clinical factors and biological markers, such as KRAS status, the study offers a better understanding of factors influencing treatment outcomes. Fifth, focusing on the differing responses of left and right sided mCRC provides valuable insights into how tumor location influences treatment efficacy. Sixth, this study included extensive follow-up and evaluation of long-term outcomes such as OS and TTD, offering key data on the sustainability of treatment effects. Finally, advanced statistical methods—including multivariate adjustments and PS matching—were employed to control for confounding factors and ensure robust, accurate results. Overall, the findings provide actionable insights to guide clinical decision making and optimize treatment strategies and sequencing for patients with KRAS wild type mCRC.

Our study has certain limitations. First, while the use of real world data provides valuable insights, it also introduces potential biases, such as incomplete data (e.g., regarding disease severity, the number of metastatic organs, the extent of metastatic disease, microsatellite instability, and the statuses of NRAS and BRAF, which were unavailable for analysis). We employed stage covariates (IVA, IVB, and IVC) to adjust for these confounding effects. Second, the retrospective study design is subject to selection bias, as treatment regimens were not randomly assigned and patient characteristics may have influenced treatment decisions. PS adjustment models, such as SIPTW, were used to produce comparable baseline characteristics among patients receiving different targeted therapies. Third, the study focused on Taiwanese patients. Thus, although this provided a well-defined cohort, the findings may not be directly applicable to populations in countries with different healthcare systems, treatment protocols, or genetic backgrounds. However, our results align with those from other countries comparing first-line cetuximab+FOLFIRI with bevacizumab+FOLFIRI, suggesting that our findings may be extrapolated beyond the population studied. Fourth, although long term outcomes such as OS and TTD were assessed, other relevant endpoints—such as quality of life and progression free survival—were not included, limiting the overall scope of the findings. Despite these limitations, this study provides valuable clinical insights and highlights areas for future research.

This study underscores the importance of selecting optimal first line targeted therapies to improve second line oxaliplatin management in patients with wild type KRAS unresectable mCRC. Our findings indicate that first line cetuximab+FOLFIRI followed by second line oxaliplatin based therapy enhances OS compared to bevacizumab+FOLFIRI followed by second line oxaliplatin in mCRC without PTR. These results suggest that personalized treatment sequencing can maximize survival benefits, highlighting the need for further research to refine mCRC treatment strategies.

ARTICLE INFORMATION

Conflict of interest

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

Funding

This research was funded by Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (No. KSVGH-113-129).

Acknowledgments

The authors are grateful to the Health Data Science Center, National Cheng Kung University Hospital (Tainan, Taiwan), for providing administrative and technical support.

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.

Fig. 1.

Flowchart of cohort selection. mCRC, metastatic colorectal cancer; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; PTR, primary tumor resection.

Fig. 2.

Kaplan-Meier survival curve estimates of patients (A–C) without and (D–F) with primary tumor resection. (A, D) Overall survival (OS) from the index date (OS1). (B, E) OS from the start of second-line treatment (OS2). (C, F) Time to treatment discontinuation (TTD) from the first index date. FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; CI, confidence interval; HR, hazard ratio.

Fig. 3.

Hazard ratios (HRs) of overall survival (OS) from the index date (OS1), OS from the start of second-line treatment (OS2), and time to treatment discontinuation (TTD) from the first index date among patients who did not undergo primary tumor resection (PTR), including the subgroup of patients with left-sided tumors, and those who underwent PTR. CI, confidence interval; SIPTW, stabilized inverse probability of treatment weights.

Fig. 4.

Results of competing risk analyses for overall survival (OS) from the index date (OS1) and OS from the start of second-line treatment (OS2), among patients who did not undergo primary tumor resection (PTR), including the subgroup of patients with left-sided tumors, and those who underwent PTR. HR, hazard ratio; CI, confidence interval; CSH, cause-specific hazard function; SDH, subdistribution hazard function.

Table 1.

Baseline characteristics of the cohort

Characteristic	Without PTR		SMD	With PTR		SMD
Characteristic	Bevacizumab (n=202)	Cetuximab (n=165)	SMD	Bevacizumab (n=157)	Cetuximab (n=140)	SMD
Death	155 (76.7)	120 (72.7)	0.09	110 (70.1)	105 (75.0)	0.11
Male sex	120 (59.4)	105 (63.6)	0.09	83 (52.9)	85 (60.7)	0.16
Age (yr)	58±12	58±13	0.01	59±12	61±12	0.21
Age group (yr)			0.30			0.24
<50	44 (21.8)	42 (25.5)		38 (24.2)	22 (15.7)
50–59	69 (34.2)	35 (21.2)		39 (24.8)	31 (22.1)
60–69	54 (26.7)	57 (34.5)		51 (32.5)	53 (37.9)
≥70	35 (17.3)	31 (18.8)		29 (18.5)	34 (24.3)
Year of targeted therapy			0.32			0.32
2013	14 (6.9)	16 (9.7)		23 (14.6)	15 (10.7)
2014	30 (14.9)	27 (16.4)		23 (14.6)	29 (20.7)
2015	21 (10.4)	15 (9.1)		17 (10.8)	17 (12.1)
2016	25 (12.4)	24 (14.5)		18 (11.5)	23 (16.4)
2017	23 (11.4)	28 (17.0)		25 (15.9)	17 (12.1)
2018	37 (18.3)	27 (16.4)		22 (14.0)	16 (11.4)
≥2019	52 (25.7)	28 (17.0)		29 (18.5)	23 (16.4)
Radiotherapy	24 (11.9)	40 (24.2)	0.33	11 (7.0)	12 (8.6)	0.06
Charlson Comorbidity Index	9±2	9±2	0	8±2	9±2	0.28
Stage			0.40			0.24
IVA	65 (32.2)	81 (49.1)		64 (40.8)	72 (51.4)
IVB	109 (54.0)	74 (44.8)		70 (44.6)	58 (41.4)
IVC	28 (13.9)	10 (6.1)		23 (14.6)	10 (7.1)
Histological type			0.28			0.06
Adenocarcinoma	187 (92.6)	161 (97.6)		138 (87.9)	121 (86.4)
Signet ring cell carcinoma or mucinous	15 (7.4)	4 (2.4)		19 (12.1)	19 (13.6)
Tumor differentiation grade			0.20			0.38
Well differentiated	7 (3.5)	8 (4.8)		107 (68.2)^a	100 (71.4)^a
Moderately differentiated	147 (72.8)	129 (78.2)		-	-
Poorly differentiated	39 (19.3)	23 (13.9)		50 (31.8)	40 (28.6)
Undifferentiated (anaplastic)	9 (4.5)	5 (3.0)		50 (31.8)	40 (28.6)
Tumor size (cm)			0.10			0.15
<4	49 (24.3)	35 (21.2)		49 (31.2)	35 (25.0)
4–5	47 (23.3)	35 (21.2)		30 (19.1)	32 (22.9)
>5	106 (52.5)	95 (57.6)		78 (49.7)	73 (52.1)
Tumor sidedness			0.42			0.33
Right	55 (27.2)	18 (10.9)		54 (34.4)	28 (20)
Left	147 (72.8)	147 (89.1)		103 (65.6)	112 (80)
Obstruction	101 (50.0)	82 (49.7)	0.01	92 (58.6)	85 (60.7)	0.04
Perforation	7 (3.5)	4 (2.4)	0.06	8 (5.1)	18 (12.9)	0.27
CEA positive	126 (62.4)	146 (88.5)	0.18	112 (71.3)	109 (77.9)	0.15
Hospital level (medical center)	101 (50)	113 (68.5)	0.13	93 (59.2)	87 (62.1)	0.06
Type of metastasectomy			0.46			0.11
Liver resection	23 (11.4)	44 (26.7)		29 (18.5)	32 (22.9)
Lung resection	0 (0)	7 (4.2)		10 (6.4)	8 (5.7)
Time of metastasectomy (between first- and second-line therapy)	17 (8.4)	39 (23.6)	0.45	30 (19.1)	32 (22.9)	0.11
Total second-line oxaliplatin duration (mo)	1.85 (0.60–3.70)	3.83 (1.88–6.02)	0.69	2.31 (0.60–3.93)	3.29 (1.17–5.74)	0.35
Total no. of second-line oxaliplatin cycles	4 (2–6)	7 (4–11)	0.71	4 (2–6)	6 (3–10)	0.41
Second-line oxaliplatin+targeted therapy	64 (31.7)	48 (29.1)	0.06	37 (23.6)	37 (26.4)	0.07

Values are presented as number (%), mean±standard deviation, or median (interquartile range). Percentages may not total 100 due to rounding. The rates of missing values for the population without PTR were as follows: tumor differentiation grade, 40.1%; tumor differentiation grade, 40.1%; tumor size, 21.3%; tumor sidedness, 1.1%; bowel obstruction, 0.3%; bowel perforation, 0.3%; CEA status, 4.9%; and hospital level, 19.1%. For the population with PTR, the rates of missing values were: tumor differentiation grade, 1.7%; tumor size, 1.0%; tumor sidedness, 0%; bowel obstruction, 0%; bowel perforation, 0%; CEA status, 8.4%; and hospital level, 16.2%. Missing data were imputed according to multivariate imputation using chained equations.

PTR, primary tumor resection; SMD, standardized mean difference; CEA, carcinoembryonic antigen.

^aModerately differentiated cases were combined with well-differentiated cases, as case numbers fewer than 3 (but not 0) must be combined with a similar category to allow data release under Taiwan’s National Health Insurance Research Database policy.

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Effectiveness of oxaliplatin-based second-line therapy following cetuximab+FOLFIRI or bevacizumab+FOLFIRI in KRAS wild-type metastatic colorectal cancer without primary tumor resection

Ann Coloproctol. 2025;41(4):319-329. Published online August 21, 2025

DOI: https://doi.org/10.3393/ac.2025.00087.0012

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Figure

Effectiveness of oxaliplatin-based second-line therapy following cetuximab+FOLFIRI or bevacizumab+FOLFIRI in KRAS wild-type metastatic colorectal cancer without primary tumor resection

Fig. 1. Flowchart of cohort selection. mCRC, metastatic colorectal cancer; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; PTR, primary tumor resection.

Fig. 2. Kaplan-Meier survival curve estimates of patients (A–C) without and (D–F) with primary tumor resection. (A, D) Overall survival (OS) from the index date (OS1). (B, E) OS from the start of second-line treatment (OS2). (C, F) Time to treatment discontinuation (TTD) from the first index date. FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; CI, confidence interval; HR, hazard ratio.

Fig. 3. Hazard ratios (HRs) of overall survival (OS) from the index date (OS1), OS from the start of second-line treatment (OS2), and time to treatment discontinuation (TTD) from the first index date among patients who did not undergo primary tumor resection (PTR), including the subgroup of patients with left-sided tumors, and those who underwent PTR. CI, confidence interval; SIPTW, stabilized inverse probability of treatment weights.

Fig. 4. Results of competing risk analyses for overall survival (OS) from the index date (OS1) and OS from the start of second-line treatment (OS2), among patients who did not undergo primary tumor resection (PTR), including the subgroup of patients with left-sided tumors, and those who underwent PTR. HR, hazard ratio; CI, confidence interval; CSH, cause-specific hazard function; SDH, subdistribution hazard function.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Effectiveness of oxaliplatin-based second-line therapy following cetuximab+FOLFIRI or bevacizumab+FOLFIRI in KRAS wild-type metastatic colorectal cancer without primary tumor resection

Characteristic	Without PTR		SMD	With PTR		SMD
Characteristic	Bevacizumab (n=202)	Cetuximab (n=165)	SMD	Bevacizumab (n=157)	Cetuximab (n=140)	SMD
Death	155 (76.7)	120 (72.7)	0.09	110 (70.1)	105 (75.0)	0.11
Male sex	120 (59.4)	105 (63.6)	0.09	83 (52.9)	85 (60.7)	0.16
Age (yr)	58±12	58±13	0.01	59±12	61±12	0.21
Age group (yr)			0.30			0.24
<50	44 (21.8)	42 (25.5)		38 (24.2)	22 (15.7)
50–59	69 (34.2)	35 (21.2)		39 (24.8)	31 (22.1)
60–69	54 (26.7)	57 (34.5)		51 (32.5)	53 (37.9)
≥70	35 (17.3)	31 (18.8)		29 (18.5)	34 (24.3)
Year of targeted therapy			0.32			0.32
2013	14 (6.9)	16 (9.7)		23 (14.6)	15 (10.7)
2014	30 (14.9)	27 (16.4)		23 (14.6)	29 (20.7)
2015	21 (10.4)	15 (9.1)		17 (10.8)	17 (12.1)
2016	25 (12.4)	24 (14.5)		18 (11.5)	23 (16.4)
2017	23 (11.4)	28 (17.0)		25 (15.9)	17 (12.1)
2018	37 (18.3)	27 (16.4)		22 (14.0)	16 (11.4)
≥2019	52 (25.7)	28 (17.0)		29 (18.5)	23 (16.4)
Radiotherapy	24 (11.9)	40 (24.2)	0.33	11 (7.0)	12 (8.6)	0.06
Charlson Comorbidity Index	9±2	9±2	0	8±2	9±2	0.28
Stage			0.40			0.24
IVA	65 (32.2)	81 (49.1)		64 (40.8)	72 (51.4)
IVB	109 (54.0)	74 (44.8)		70 (44.6)	58 (41.4)
IVC	28 (13.9)	10 (6.1)		23 (14.6)	10 (7.1)
Histological type			0.28			0.06
Adenocarcinoma	187 (92.6)	161 (97.6)		138 (87.9)	121 (86.4)
Signet ring cell carcinoma or mucinous	15 (7.4)	4 (2.4)		19 (12.1)	19 (13.6)
Tumor differentiation grade			0.20			0.38
Well differentiated	7 (3.5)	8 (4.8)		107 (68.2)^a	100 (71.4)^a
Moderately differentiated	147 (72.8)	129 (78.2)		-	-
Poorly differentiated	39 (19.3)	23 (13.9)		50 (31.8)	40 (28.6)
Undifferentiated (anaplastic)	9 (4.5)	5 (3.0)		50 (31.8)	40 (28.6)
Tumor size (cm)			0.10			0.15
<4	49 (24.3)	35 (21.2)		49 (31.2)	35 (25.0)
4–5	47 (23.3)	35 (21.2)		30 (19.1)	32 (22.9)
>5	106 (52.5)	95 (57.6)		78 (49.7)	73 (52.1)
Tumor sidedness			0.42			0.33
Right	55 (27.2)	18 (10.9)		54 (34.4)	28 (20)
Left	147 (72.8)	147 (89.1)		103 (65.6)	112 (80)
Obstruction	101 (50.0)	82 (49.7)	0.01	92 (58.6)	85 (60.7)	0.04
Perforation	7 (3.5)	4 (2.4)	0.06	8 (5.1)	18 (12.9)	0.27
CEA positive	126 (62.4)	146 (88.5)	0.18	112 (71.3)	109 (77.9)	0.15
Hospital level (medical center)	101 (50)	113 (68.5)	0.13	93 (59.2)	87 (62.1)	0.06
Type of metastasectomy			0.46			0.11
Liver resection	23 (11.4)	44 (26.7)		29 (18.5)	32 (22.9)
Lung resection	0 (0)	7 (4.2)		10 (6.4)	8 (5.7)
Time of metastasectomy (between first- and second-line therapy)	17 (8.4)	39 (23.6)	0.45	30 (19.1)	32 (22.9)	0.11
Total second-line oxaliplatin duration (mo)	1.85 (0.60–3.70)	3.83 (1.88–6.02)	0.69	2.31 (0.60–3.93)	3.29 (1.17–5.74)	0.35
Total no. of second-line oxaliplatin cycles	4 (2–6)	7 (4–11)	0.71	4 (2–6)	6 (3–10)	0.41
Second-line oxaliplatin+targeted therapy	64 (31.7)	48 (29.1)	0.06	37 (23.6)	37 (26.4)	0.07

Table 1. Baseline characteristics of the cohort

PTR, primary tumor resection; SMD, standardized mean difference; CEA, carcinoembryonic antigen.