Adjuvant chemotherapy in elderly colon cancer patients: when less may be more

The benefit of oxaliplatin-based adjuvant chemotherapy is limited among elderly patients with resected stage III or high-risk stage II colon cancer, with no consistent survival advantage over fluoropyrimidine monotherapy and a higher burden of treatment-related toxicity (1). In a retrospective analysis published in the Journal of Gastrointestinal Oncology, Zhai et al. evaluated 117 elderly patients (65–85 years) with clinically high-risk stage II and stage III colon cancer who underwent resection and were minimal residual disease (MRD)-negative postoperatively. Patients were treated with capecitabine plus oxaliplatin (CAPEOX) or capecitabine monotherapy (2). They found no meaningful improvement in survival outcomes with the addition of oxaliplatin, despite higher rates of toxicity. Collectively, these findings suggest that the modest efficacy historically attributed to oxaliplatin rarely translates into meaningful clinical benefit in older adults with negative MRD, while treatment-related morbidity remains substantial, emphasizing the need to examine real-world outcomes in this population.

Observational data from Surveillance, Epidemiology, and End Results (SEER)-Medicare and other retrospective cohorts suggest that adjuvant chemotherapy may confer a survival advantage in older adults with stage III colon cancer (3). These findings, however, may be influenced by selection bias, reflecting the preferential treatment of fitter patients. Because the study by Zhai et al. defined elderly as ≥65 years, slightly younger than the ≥70-year threshold used in many population-based analyses, these cross-study comparisons should be interpreted with this difference in mind. For example, SEER data show that patients aged 70 years or older with stage III disease had a 5-year cancer-specific survival of 61.3% with chemotherapy compared with 50.7% without, corresponding to a 35.8% reduction in cancer-specific mortality. Outside of the United States (US), a German population-based study of patients aged 75 years or older also reported improvements in 5-year overall survival among treated vs. untreated patients (4). In contrast, SEER-Medicare analyses of stage II disease demonstrated minimal to no survival benefit from adjuvant chemotherapy, with no improvement observed across tumor locations and, in some cases, paradoxically lower cancer-specific survival among treated patients (5). While multi-agent chemotherapy has generally been associated with better outcomes than single-agent therapy in stage III disease, evidence specifically supporting the addition of oxaliplatin in patients aged 70 years or older is limited. Notably, subgroup analyses from the MOSAIC trial demonstrated no significant disease-free or overall survival benefit from adding oxaliplatin in patients aged ≥70 years, despite a clear benefit in the overall stage III population (1). Furthermore, observational studies from the US, Germany, and Canada consistently show lower utilization in elderly patients compared with younger cohorts, suggesting that the differences in survival may be driven more by patient fitness and comorbidities than by the effectiveness of the therapy itself (4,6-8).

This interpretation aligns with current National Comprehensive Cancer Network (NCCN) Colon Cancer guidelines, which note that a survival benefit from the addition of oxaliplatin to fluoropyrimidine therapy in patients aged 70 years or older has not been definitively established, and lists capecitabine monotherapy as an acceptable alternative to CAPEOX in elderly patients (9). Several large real-world cohorts support this observation. A Chinese national cohort study of 468 patients aged 70 years or older with stage III or high-risk stage II colon cancer found no statistically significant differences in overall survival, cancer-specific survival, local recurrence-free survival, or distant metastasis-free survival between oxaliplatin-based regimens and capecitabine monotherapy (10). Similarly, a Dutch population-based analysis of 982 elderly patients with stage III colon cancer reported no difference in 5-year recurrence-free survival or overall survival between combination therapy and capecitabine alone (11). In a complementary real-world cohort of patients aged 70 years or older, only 33% of those treated with the oxaliplatin-containing regimen completed all planned cycles, compared with 55% receiving capecitabine monotherapy, and cumulative dosing was lower because of treatment interruptions and dose reductions (12). Severe toxicities were also substantially higher with the multi-agent regimen, with over half of patients experiencing grades III–V events compared to 38% with single-agent chemotherapy.

When examined in randomized trials and pooled analyses, a similar pattern emerges, with oxaliplatin-based therapy conferring at most modest disease-free survival advantages in older adults that are attenuated compared with younger patients and do not consistently translate into meaningful overall survival gains. A pooled analysis of four randomized trials (NSABP C-08, XELOXA, X-ACT, and AVANT) demonstrated a reduced magnitude of benefit from oxaliplatin in patients aged 70 years or older compared with those younger than 70 years (hazard ratio =0.77 vs. 0.68) (13-17). Similarly, a pooled analysis of the MOSAIC, NSABP C-07, and XELOXA trials found that patients aged 70 years or older did not experience a statistically significant improvement in disease-free survival, overall survival, or time to recurrence with the addition of oxaliplatin to fluoropyrimidine therapy (15,18-20) (Table 1). The ACCENT and IDEA pooled analysis of 17,909 patients, including nearly one quarter aged 70 years or older, showed no significant difference in time to recurrence between older and younger patients receiving oxaliplatin-based therapy, while overall survival and disease-free survival were shorter in older patients due largely to competing non-cancer mortality (21-23).

In contrast to the modest and inconsistent efficacy signal, the toxicity burden associated with CAPEOX in elderly patients is substantial and reproducible across real-world datasets. Population-based analyses from the Netherlands Cancer Registry demonstrate that oxaliplatin-containing regimens are associated with markedly higher rates of severe toxicity and lower treatment completion compared with capecitabine monotherapy, with fewer patients able to complete planned therapy and frequent dose interruptions limiting cumulative drug exposure (12). Similar patterns have been observed in large national cohorts from China, where oxaliplatin use was uncommon in patients aged 70 years or older and full-course completion was substantially lower than with capecitabine alone, underscoring the practical challenges of delivering combination therapy in routine practice (10). These findings are further supported by pooled analyses from ACCENT and IDEA, which demonstrate a clear duration-dependent increase in severe neuropathy, diarrhea, and neutropenia with oxaliplatin-based therapy in older adults. Collectively, these data indicate that oxaliplatin-related toxicity in this population is frequent, cumulative, and treatment-limiting, often constraining delivery without conferring proportional survival benefit, a pattern that aligns with current guideline recommendations favoring fluoropyrimidine monotherapy for many elderly patients (21).

Amid limited benefit and increased toxicity of oxaliplatin in older adults, biomarker-driven strategies to identify those who can safely forgo oxaliplatin are critically needed. A key contribution of the study by Zhai et al. is the demonstration that postoperative circulating tumor DNA (ctDNA) negativity provided meaningful reassurance even in clinically high-risk stage II and stage III disease, since MRD-negative elderly patients who received capecitabine alone experienced disease-free survival that was comparable to CAPEOX while also having substantially less toxicity. These observations are consistent with prospective studies showing that postoperative ctDNA negativity identifies patients at much lower risk of recurrence (24-26). However, results from the DYNAMIC-III trial highlight important limitations of relying on MRD status alone when making decisions about treatment intensity (27). Although outcomes were excellent among ctDNA-negative patients assigned to reduced-intensity therapy, the trial did not meet its noninferiority endpoint in the overall population, and the age-stratified forest plot suggested that noninferiority was achieved only for patients younger than 70 years. When these data are considered together, they indicate that while ctDNA negativity is a favorable prognostic marker, its ability to support the omission of oxaliplatin in elderly patients has not been definitively established. MRD-guided de-escalation should therefore be interpreted with caution, and oxaliplatin omission should remain the default approach in older adults until future trials provide more definitive evidence.

The existing literature consistently suggests that the addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy in elderly patients with resected stage III or high-risk stage II colon cancer confers limited incremental benefit while increasing toxicity. In a retrospective analysis published in the Journal of Gastrointestinal Oncology, Zhai et al. demonstrated no meaningful survival advantage of CAPEOX over capecitabine monotherapy in older adults with resected, MRD-negative high-risk stage II or stage III colon cancer, despite higher rates of grades III–V adverse events. These findings are supported by international retrospective studies, pooled analyses of major adjuvant trials, and population-based cohorts. The ongoing ADAGE phase III trial is expected to provide prospective data clarifying whether oxaliplatin offers a clinically meaningful benefit in carefully selected elderly patients (NCT02355379). Until such data are available, capecitabine monotherapy appears to represent the most appropriate adjuvant strategy for the majority of elderly patients, with oxaliplatin reserved for select individuals following individualized risk-benefit assessment.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0175/coif). M.B.S. reports consulting fees (self) from Novartis; consulting fees (inst) from Boehringer Ingelheim; and research support (inst) from Taiho and Eli Lilly. The other author has 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.

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