XELOX linked to better adjusted survival after gastric cancer surgery

A retrospective study of 277 patients with stage I–III gastric adenocarcinoma who received postoperative treatment after surgery found that capecitabine plus oxaliplatin, or XELOX, was associated with lower hazards of recurrence and death than fluorouracil plus folinic acid in its primary adjusted models. The association was not consistent across every analysis: when treatment period was added to the models, the overall-survival association remained statistically significant, but the disease-free-survival association did not. Unadjusted comparisons found no significant difference between XELOX and FUFA, either in the full cohort or in an exploratory analysis of patients with lymph node-positive disease.

Because treatment choice was closely tied to the year of surgery, the investigators said the results are hypothesis-generating and cannot establish that XELOX caused the observed survival differences. The cohort comprised patients treated at the Department of Medical Oncology at Eskisehir Osmangazi University in Türkiye between January 2006 and December 2022. Patients were identified consecutively from institutional records, and their tumors were staged under the eighth edition of the American Joint Committee on Cancer TNM system.

Eligible patients had undergone subtotal or total gastrectomy followed by adjuvant chemotherapy, with or without concurrent chemoradiotherapy. Excluded were patients who had not received curative surgery, received neoadjuvant treatment, had non-adenocarcinoma histology or metastatic disease at diagnosis. Preoperative clinical T and N categories could not be assessed reliably because staging information was not consistently available in the retrospective records.

Three principal treatment approaches were defined by the systemic chemotherapy regimen: FUFA, XELOX and cisplatin-based chemotherapy. The FUFA group contained 156 patients, the XELOX group 58 and the cisplatin-based group 28; the remaining 35 patients received other regimens and were not included in the principal three-way survival comparisons. Concurrent chemoradiotherapy was administered to 98.7% of the FUFA group, 81.0% of the XELOX group and 92.9% of the cisplatin-based group.

FUFA consisted of fluorouracil and folinic acid before, during and after radiotherapy, reflecting an earlier postoperative chemoradiotherapy strategy. XELOX comprised oxaliplatin and twice-daily capecitabine in three-week cycles, with three to eight cycles delivered. The cisplatin-based group received either cisplatin with infusional fluorouracil or cisplatin with capecitabine for three to six cycles.

Across the full cohort, median follow-up was 33.1 months, median disease-free survival was 24.9 months and median overall survival was 39.0 months. Unadjusted survival distributions differed among the three principal treatment groups, with the cisplatin-based group having the shortest median disease-free and overall survival. However, pairwise Kaplan–Meier comparisons did not detect a significant difference between FUFA and XELOX for disease-free survival, with a p value of 0.592, or overall survival, with a p value of 0.734.

The treatment groups were not otherwise directly comparable: 57 of the 58 XELOX recipients were treated during 2017–2022, whereas all 28 cisplatin recipients were treated during 2006–2016. Patients receiving cisplatin-based treatment also had more R1 resections, more extracapsular involvement and more advanced nodal disease than those in the XELOX group. The main multivariable analysis included 177 patients with complete data for the candidate covariates.

After backward stepwise selection, pathological stage, perineural invasion and adjuvant treatment approach remained associated with outcomes, while several other clinical variables were removed from the final models. Relative to FUFA, XELOX was associated with a lower hazard of recurrence, with a hazard ratio of 0.48 and 95% confidence interval of 0.29–0.80, and a lower hazard of death, with a hazard ratio of 0.48 and 95% confidence interval of 0.28–0.82. The cisplatin-based approach did not differ significantly from FUFA in either model.

These adjusted estimates represent associations after accounting for the measured variables in the models, not proof that the regimen itself produced better outcomes. Compared with stage I disease, stage IIIC gastric cancer was associated with substantially higher hazards of recurrence and death in the multivariable models, producing hazard ratios of 8.26 and 7.44, respectively. Perineural invasion was associated with a 1.93-fold higher hazard of recurrence and a 2.03-fold higher hazard of mortality.

In univariable analyses, other adverse features also accompanied shorter survival, including an Eastern Cooperative Oncology Group performance status of 2 or higher, R1 resection, extracapsular extension, high tumor grade, lymphatic and vascular invasion, tumor nodules and treatment discontinuation. Treatment completion itself was not entered into the multivariable models because it was measured after treatment began and could reflect progression or death that prevented completion. The investigators then forced treatment period, divided into 2006–2016 and 2017–2022, into the final models as a sensitivity analysis.

The XELOX point estimates remained below one: the disease-free-survival hazard ratio was 0.40, with a 95% confidence interval of 0.15–1.04 and p value of 0.060, while the overall-survival hazard ratio was 0.32, with a 95% confidence interval of 0.12–0.87 and p value of 0.026. Thus, the adjusted disease-free-survival association lost statistical significance after accounting for period, whereas the overall-survival association did not. Treatment period itself was not significantly associated with either outcome in these models.

The authors emphasized, however, that near-complete separation between XELOX use and the later treatment era prevented the models from reliably distinguishing regimen effects from changes in surgical practice, staging, supportive care or follow-up. An exploratory comparison restricted to 2017–2022 produced essentially identical unadjusted estimates for XELOX and FUFA: the hazard ratio was 0.97 for disease-free survival and 1.01 for overall survival, with wide confidence intervals and p values of 0.947 and 0.985. That period included 57 XELOX recipients but only 11 FUFA recipients, limiting precision.

In the separate exploratory subgroup of 233 patients with lymph node-positive disease, XELOX and FUFA again did not differ significantly in disease-free or overall survival, with p values of 0.088 and 0.132. The full comparison of three treatments in that subgroup favored XELOX over the cisplatin-based approach for both outcomes, but the unequal treatment eras and baseline imbalances mean that this observation cannot be interpreted as a direct regimen comparison. Toxicity records also differed by regimen, although incomplete documentation meant that evaluable denominators varied from 12 to 107 depending on the adverse event and group.

All-grade neutropenia occurred in 24 of 107 evaluable FUFA patients, 14 of 45 XELOX patients and 9 of 17 cisplatin-treated patients, a statistically significant difference across groups. Diarrhea was reported in 3 of 83, 2 of 39 and 3 of 14 patients, respectively, while neuropathy occurred in 2 of 90 FUFA patients, 8 of 41 XELOX patients and 1 of 15 cisplatin recipients. Rates of grade 3–4 events did not differ significantly among the groups, and no treatment-related deaths were recorded.

Retrospective toxicity assessment, including possible underreporting, further limits how confidently these patterns can be compared. The findings offer a detailed picture of the difficulty of evaluating postoperative gastric cancer treatment in routine practice. The apparent advantage of XELOX in the primary adjusted models contrasts with the absence of a significant difference in unadjusted comparisons, the loss of statistical significance for disease-free survival after adjustment for treatment era, and the neutral estimate within the later period.

The single-center retrospective design, small cisplatin group, baseline imbalances, incomplete comorbidity and lymphadenectomy data, differing follow-up durations, and frequent use of chemoradiotherapy further restrict causal interpretation. The investigators therefore did not present the results as evidence that any approach was superior or inferior, and called for validation in prospective multicenter studies with more consistent staging, surgical, treatment and toxicity documentation.

Subject of Research: Comparative postoperative chemotherapy outcomes in resected stage I–III gastric adenocarcinoma

Article Title: Comparative outcomes of adjuvant treatment approaches in resected stage I-III gastric cancer

Article References: Yildiz, B., Karateke, Y. S., Garbioglu, D. B., & Demir, M. (2026). Comparative outcomes of adjuvant treatment approaches in resected stage I-III gastric cancer. Frontiers in Oncology, 16, Article 1933478. https://doi.org/10.3389/fonc.2026.1933478

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1933478

Keywords: gastric cancer, adjuvant chemotherapy, XELOX, FUFA, chemoradiotherapy, disease-free survival, overall survival, retrospective cohort, treatment toxicity, perineural invasion, Comparative, outcomes