Prognostic and safety analysis of capecitabine monotherapy versus CapeOx (capecitabine plus oxaliplatin) in elderly patients with high-risk stage II and stage III MRD-negative colorectal cancer

Introduction

Background

Colorectal cancer (CRC) is the third most common cancer worldwide and a leading cause of cancer-related mortality (1). For patients with high-risk stage II and stage III CRC, postoperative adjuvant chemotherapy is a critical intervention to reduce recurrence rates and improve survival outcomes. The Chinese Society of Clinical Oncology (CSCO) guidelines recommend 3–6 months of combination chemotherapy (Category I) for high-risk patients, with the CapeOx regimen (capecitabine plus oxaliplatin) being the preferred option (2). However, for elderly patients, who often present with comorbidities and reduced physiological reserve, the toxicity associated with combination chemotherapy can outweigh its benefits, leading to compromised quality of life and treatment discontinuation (3-5).

Rationale and knowledge gap

Minimal residual disease (MRD), as detected by circulating tumor DNA (ctDNA) analysis, has emerged as a promising biomarker for risk stratification in CRC (6-10). MRD negativity indicates the low risk of recurrence, potentially enabling de-escalation of adjuvant therapy (7,11,12). While the CapeOx regimen has demonstrated efficacy in improving survival, its associated toxicities, particularly neurotoxicity and hematological adverse events, are a significant concern in elderly populations (13-18). In contrast, capecitabine monotherapy offers a more favorable safety profile but is often considered less effective in high-risk patients (5). Moreover, the role of MRD status in guiding chemotherapy decisions for elderly patients with high-risk CRC remains underexplored.

Objective

This study aimed to evaluate the efficacy and safety of capecitabine monotherapy versus the CapeOx regimen in elderly patients with high-risk stage II and stage III CRC who were MRD-negative. By comparing disease-free survival (DFS) and adverse event rates between the two regimens, we sought to determine whether MRD negativity could identify a subgroup of patients who could safely forego further intensive combination chemotherapy without compromising survival outcomes. Our study provides valuable insights into personalized treatment strategies for elderly CRC patients, with the potential to optimize therapeutic outcomes while minimizing toxicity. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-504/rc).

Methods

Study design and population

This retrospective study included 117 elderly patients (aged 65–85 years) with high-risk stage II and stage III CRC who underwent curative surgery and tested negative for MRD between January 2018 and December 2022 at the Affiliated Hospital of Guangdong Medical University (Figure 1). Patients were excluded if they had recurrent tumors, familial adenomatous polyposis, or hereditary non-polyposis CRC.

Figure 1 Flow chart of the study. MRD-negative patients with high-risk stage II and stage III CRC were included. CapeOx, capecitabine plus oxaliplatin; CRC, colorectal cancer; MRD, minimal residual disease.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Human Ethics Committee of the Affiliated Hospital of Guangdong Medical University (No. PJKT2024-063). The requirement for patient approval or informed consent was waived by the Affiliated Hospital of Guangdong Medical University, owing to the retrospective nature of the study and the athe use of de-identified data.

MRD assessment

MRD status was determined within 14–21 days postoperatively. A negative MRD result was defined as the absence of the tumor-derived molecular variant in peripheral blood samples. The tumor-derived molecular variant is the total number of driver genes or other class I/II gene variants (i.e., clinically significant or potentially clinically significant gene variants) detected in blood samples. The classification of gene variation is referred to OncoKB, ClinVar, COSMIC and other databases. The MRD assay was performed on blood samples using a next-generation sequencing (NGS) panel on Illumina’s high-throughput sequencing platform, with reference to the Human Genome UCSC hg19 Feb. 2009. Covered genes include ALK, CD274, EGFR, ERBB2(HER2), FGFR1, FGFR2, FGFR3, MET, NTRK1, NTRK2, NTRK3, PDCD1LG2, PDGFRA, RET, ROS1, DDR2, ERBB4, MAP2K1, NOTCH1, PTEN, STK11, SMAD4, TP53, AKT1, APC, BRAF, CTNNB1, ERBB3, FBXW7, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, RNF43, POLE.

Treatment regimens

Patients were divided into two groups based on postoperative chemotherapy: (I) capecitabine monotherapy group: patients received capecitabine 1,250 mg/m² orally twice daily on days 1–14, repeated every 3 weeks for 8 cycles. (II) CapeOx Group: patients received oxaliplatin 130 mg/m² intravenously on day 1 and capecitabine 1,000 mg/m² orally twice daily on days 1–14, repeated every 3 weeks for 4–8 cycles.

Data collection and outcomes

Baseline characteristics, including age, sex, body mass index (BMI), tumor stage, and pathological features, were collected from the hospital database. Hemoglobin, preoperative serum biochemical indicators (albumin, anemia status), and tumor markers (CEA, CA19-9, CA125) were categorized based on hospital laboratory standards. All the blood test results were derived from one week before the operation. Pathological features assessed included histological type, tumor differentiation grade, tumor stage, high-risk factors (T4, vascular invasion, neural invasion, number of lymph nodes examined, preoperative intestinal obstruction), P53 expression, and BRAF-V600E expression. Tumor differentiation was classified as well-differentiated, moderately differentiated, or poorly differentiated. Histological types included classic adenocarcinoma and mucinous adenocarcinoma. Mismatch repair (MMR) protein expression (MLH1, PMS2, MSH2, and MSH6) was detected using immunohistochemistry. Negative expression of one or more MMR proteins was considered mismatch repair deficiency (dMMR), while positive expression of all four proteins was considered mismatch repair proficiency (pMMR). Adverse reactions after chemotherapy, including gastrointestinal toxicity, neurotoxicity, hematological toxicity, and overall systemic conditions, were observed during follow-up. Follow-up data were obtained from the institutional follow-up center. The follow-up protocol primarily comprised tumor marker assays and contrast-enhanced computed tomography (CT) imaging. The primary outcome was DFS, defined as the time from surgery to recurrence or death. Secondary outcomes included 3-year DFS rates and chemotherapy-related adverse events, which were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Statistical analysis

Categorical variables were expressed as frequencies and percentages and compared using the chi-square test or Fisher’s exact test. Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range, IQR) and compared using the t-test or Mann-Whitney U test, as appropriate. Univariate and multivariate Cox regression analyses were used to assess independent risk factors. No attrition adjustment was performed because no patients were lost to long-term follow-up. Survival outcomes were analyzed using the Kaplan-Meier method and compared using the log-rank test. Subgroup analysis was used to evaluate the heterogeneity of the results. Propensity score matching (PSM) was performed to balance baseline differences between the two groups, with a caliper value of 0.1. Standardized mean differences (SMD) were used to evaluate the effect of balance. All statistical analyses were conducted using IBM SPSS Statistics 27.0 (IBM Corp., Armonk, NY, USA) and R 4.4.1 (R Foundation for Statistical Computing, Vienna, Austria), with a two-sided P value <0.05 considered statistically significant.

Results

Baseline characteristics

All datasets were fully documented with no missing records. The study included 117 patients, with 58 in the capecitabine monotherapy group and 59 in the CapeOx group (Figure 1, Table 1). All patients underwent laparoscopic radical resection for CRC and received at least one cycle of chemotherapy. The median age was 69 years (range, 60–85), and the majority of patients were male (58%). The ratio of stage II to III patients was approximately 1:1. Most tumors were moderately differentiated (92%) and pMMR (92%). All patients exhibited postoperative pathological high-risk features, including T4 stage, poor differentiation, vascular invasion, neural invasion, preoperative intestinal obstruction, or fewer than 12 lymph nodes examined. As shown in Table 1, significant differences (all P<0.05) were observed in age, tumor stage, N stage, CA19-9 levels, and hemoglobin (Hb) between the groups. No significant differences (all P>0.05) were found in BMI, sex, T stage, differentiation grade, MMR status, albumin (ALB), or CEA levels. PSM (1:1 nearest-neighbor matching with a caliper of 0.1) was performed using covariates with significant baseline differences (age, tumor stage, N stage, CA19-9, and Hb). After PSM, 29 matched pairs were included in the analysis, with no significant differences in baseline characteristics between the two groups (all P>0.05) (Table 1). Timing of treatment, DFS and overall survival (OS) were illustrated in Figure 2.

Figure 2 Timing of treatment for each patient. Patients are grouped by the pathological stage and ordered by total months of clinical follow up from surgery. CapeOx, capecitabine plus oxaliplatin.

Independent risk factors

The univariate Cox analysis and multivariate Cox analysis were used. As shown in Table 2, stage III [hazard ratio (HR) =3.176, 95% CI: 1.241–8.126, P=0.016] and vascular invasion (HR =3.167, 95% CI: 1.348–7.442, P=0.008) were the independent risk factors among the elderly patients with high-risk stage II and stage III CRC and negative MRD.

Survival outcomes

Patients were followed postoperatively for a median of 35 months (range, 14–81) (Figure 2). The median DFS was 31 months in the capecitabine group and 40 months in the CapeOx group, with no significant difference between the two regimens (P=0.26) (Figure 3). The 3-year DFS rates were comparable (90% vs. 81%, HR 0.565, 95% CI: 0.209–1.528, P=0.26). Subgroup analysis showed no significant heterogeneity in DFS across sex, BMI, or tumor location (all P>0.05) (Table 3). After conducting separate analyses of patients in high-risk stage II and stage III, we found that there was still no significant difference in the 3-year DFS rate between the capecitabine group and the CapeOx group (all P>0.05) (Figure 4). PSM was used to control for confounding factors. As shown in Figure 5, confounding factors such as age, stage III, N stage, CA19-9, and Hb were well balanced (all SMD <0.2). After PSM, the survival outcomes remained similar between the two groups (P=0.73) (Figure 6), with a 3-year DFS rate of 90% in the capecitabine group and 86% in the CapeOx group (HR =0.718, 95% CI: 0.161–3.213, P=0.67).

Figure 3 Prognostic difference in the elderly patients with high-risk stage II and stage III CRC with negative MRD. CapeOx, capecitabine plus oxaliplatin; CRC, colorectal cancer; MRD, minimal residual disease.

Figure 4 Prognostic difference in the elderly patients with negative MRD. (A) Prognostic difference in the elderly patients with high-risk stage II. (B) Prognostic difference in the elderly patients with stage III. CapeOx, capecitabine plus oxaliplatin; MRD, minimal residual disease.

Figure 5 Distribution of concomitant variables. (A) Distributional balance for age. (B) Distributional balance for stage. (C) Distributional balance for N stage. (D) Distributional balance for CA19-9. (E) Distributional balance for Hb. (F) Standardized mean differences of covariate. Hb, hemoglobin.

Figure 6 Prognostic difference in the elderly patients with high-risk stage II and stage III CRC with negative MRD after the propensity match. CapeOx, capecitabine plus oxaliplatin; CRC, colorectal cancer; MRD, minimal residual disease.

Adverse events

As summarized in Table 4, both groups experienced common chemotherapy-related adverse reactions, including appetite loss, nausea/vomiting (54%), leukopenia (36%), thrombocytopenia (28%), and fatigue. However, the CapeOx group exhibited significantly higher rates of neurotoxicity (61% vs. 7%, P<0.001), leukopenia (49% vs. 22%, P=0.002), and thrombocytopenia (44% vs. 10%, P<0.001) compared to the capecitabine group. Moderate-to-severe hematological adverse events were observed exclusively in the CapeOx group, including 6 cases (5%) of moderate leukopenia and 4 cases (6%) of moderate-to-severe thrombocytopenia. In contrast, no moderate or severe hematological adverse events were reported in the capecitabine group.

Discussion

CRC remains a leading cause of cancer-related mortality worldwide (1). Postoperative adjuvant chemotherapy plays a pivotal role in reducing recurrence and improves survival outcomes, particularly in high-risk stage II and stage III patients. However, the optimal chemotherapy regimen for elderly patients, who often present with comorbidities and reduced physiological reserve, remains a subject of debate (16-18). While the MOSAIC trial raised doubts regarding the OS benefit of oxaliplatin in elderly patients (3), the IDEA study proposed a strategy to optimize its use in this population by shortening the treatment duration (19). However, for the elderly patients with MRD-negative status, our findings suggest that completely omitting oxaliplatin may represent a rational and more profound de-escalation strategy compared to merely shortening the course of therapy. Our study provided compelling evidence that capecitabine monotherapy offers comparable DFS to the CapeOx regimen in elderly patients with high-risk stage II and stage III CRC who are MRD-negative, while significantly reducing treatment-related toxicities.

The comparable DFS between capecitabine monotherapy and CapeOx in our study (median DFS: 31 vs. 40 months, P=0.26) aligns with findings from previous studies. For instance, van Erning et al. (20) reported similar survival outcomes between monotherapy and combination chemotherapy in elderly CRC patients, particularly in those with low recurrence risk. Similarly, Okamoto et al. (21) demonstrated that elderly patients with stage III CRC could achieve favorable outcomes with capecitabine monotherapy, especially when stratified based on molecular markers. Our study extends these findings by incorporating MRD status as a stratification factor, suggesting that MRD negativity may identify a subgroup of patients who can safely forego more intensive combination chemotherapy without compromising survival outcomes. This reflects the growing emphasis on precision oncology and the need to balance efficacy with quality of life in the elderly population (22). On the other hand, stage III and vascular invasion were independent risk factors for high-risk stage II and stage III elderly CRC patients with MRD-negative status in our study, suggesting that postoperative treatment plans may still need to be closely combined with pathological features. For patients with stage III CRC, who generally demonstrate a less favorable prognosis, the CSCO guidelines (2) recommend considering combination therapies, including immunotherapy or targeted agents, in addition to adjuvant chemotherapy to further improve clinical outcomes, particularly for those with dMMR/MSI-H or high-risk pathological characteristics.

The superior safety profile of capecitabine monotherapy observed in our study further supports its use in elderly patients. The CapeOx group exhibited significantly higher rates of neurotoxicity (61% vs. 7%, P<0.001), leukopenia (49% vs. 22%, P=0.002), and thrombocytopenia (44% vs. 10%, P<0.001), consistent with prior studies (3,5,23,24) highlighting the toxicity burden of oxaliplatin-based regimens. Notably, moderate-to-severe hematological adverse events were observed in the CapeOx group, underscoring the potential risks of combination chemotherapy in elderly patients. These findings are significantly relevant given the importance of maintaining quality of life in cancer treatment, especially for elderly patients who may prioritize minimizing treatment-related toxicity over marginal survival benefits.

The integration of MRD status into treatment decision-making represents a significant advancement in personalized oncology. MRD, as assessed by ctDNA analysis, provides a dynamic and sensitive measure of residual disease burden, enabling more precise risk stratification than traditional clinicopathological features alone (25-29). Our study adds to the growing body of evidence that MRD negativity may serve as a biomarker for identifying patients who can benefit from de-escalated therapy. This approach not only reduces unnecessary treatment-related toxicity but also optimizes resource utilization in healthcare systems. However, the mechanisms associated with MRD negativity and its relationship with tumor biology remain incompletely understood. Future studies should explore the molecular characteristics of MRD-negative tumors, such as specific gene mutations or immune microenvironment features, to better understand their low recurrence risk and identify potential therapeutic targets.

Despite these promising findings, our study has several limitations that warrant consideration. First, the definition of ‘high-risk’ for stage III patients was based on pathological features typically applied to stage II disease, rather than the conventional anatomical risk stratification (e.g., T4 and/or N2 disease as per the IDEA criteria). This was done to create a homogeneous cohort with both stage II and III patients sharing aggressive tumor biological features. However, we acknowledge that this may not fully capture the distinct risk profile defined by nodal tumor burden in stage III disease. Second, the retrospective design introduces potential biases, particularly in patient selection and treatment allocation. Although PSM was employed to balance baseline characteristics, residual confounding factors may persist. Third, the sample size, which was sufficient for the initial analysis, may limit the generalizability of our findings. Larger, multicenter studies are needed to validate these results. Fourth, the follow-up duration, with a median of 38 months, may be insufficient to capture long-term survival outcomes and late recurrences. Extended follow-up will be necessary to ascertain the durability of the observed survival benefits. Finally, the study population was limited to elderly patients, and the applicability of these findings to younger populations remains uncertain.

Future research is needed to focus on prospective validation of our findings, particularly through randomized controlled trials (RCTs) comparing capecitabine monotherapy with CapeOx in MRD-negative patients. Additionally, the study of Tie et al. (29), exploring the role of dynamic MRD monitoring, such as serial ctDNA testing during and after chemotherapy, is likely to provide further insights into the optimal timing and duration of adjuvant therapy. The integration of molecular profiling, including genomic and immune markers, is expected to enhance our ability to predict which patients are most likely to benefit from de-escalated therapy.

Conclusions

For elderly patients with high-risk stage II and stage III CRC who are MRD-negative, capecitabine monotherapy might provide comparable survival outcomes with CapeOx while offering a superior safety profile. These findings suggest that MRD status might guide the implementation of personalized dose-reduction strategies in this population.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-504/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-504/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-504/prf

Funding: This work was supported by Clinical Research Project of the Affiliated Hospital of Guangdong Medical University (No. LCYJ2023B005) and Guangdong Provincial Medical Science and Technology Research Fund (No. A2024383).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-504/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in compliance with the postulates of Declaration of Helsinki and its subsequent amendments and was approved by the Human Ethics Committee of the Affiliated Hospital of Guangdong Medical University (No. PJKT2024-063). The requirement for patient approval or informed consent was waived by the Affiliated Hospital of Guangdong Medical University, owing to the retrospective nature of the study and the athe use of de-identified data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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