Abstract
Background/Aim: Patients who are frail with advanced gastric cancer often have a limited tolerance to standard daily chemotherapy, resulting in restricted treatment options. Although alternate-day administration of S-1 has been reported as a low-burden strategy, to the best of our knowledge, the feasibility of alternate-day capecitabine administration has not been evaluated clinically. This study assessed the feasibility and tolerability of alternate-day capecitabine administration in patients with advanced gastric cancer who were frail or pre-frail.
Patients and Methods: Six patients who were frail or pre-frail with histologically confirmed advanced gastric cancer were retrospectively analyzed. Frailty was assessed using the Vulnerable Elders Survey-13 (VES-13), with scores of 2 and ≥3 defined as pre-frail and frail, respectively. Capecitabine was administered at a standard daily dose of 2,000 mg/m2 on alternate days during days 1-14 of a 21-day cycle, with regimen components (oxaliplatin and/or trastuzumab) selected according to the clinical condition and human epidermal growth factor receptor 2 (HER2) status.
Results: The median age was 77 years, and the VES-13 scores ranged from 2 to 7. The overall response rate was 33%, and the disease control rate was 83%. The median overall survival was 11 months, with two patients surviving for over 24 months. The cumulative dose of capecitabine delivered was approximately 57% of that obtained with standard daily administration. Hematologic toxicities included one case each of grade 3 febrile neutropenia and grade 4 anemia, whereas nonhematologic toxicities were mostly grades 1-2. No treatment-related deaths occurred.
Conclusion: Alternate-day capecitabine without a reduction in the daily dose is a feasible treatment modification option, including in combination with trastuzumab, for managing patients with HER2-positive gastric cancer who are frail or pre-frail.
Introduction
Gastric cancer is one of the most common malignancies worldwide, and systemic chemotherapy plays a central role in the management of advanced disease (1). However, patients who are frail often do not tolerate a standard dosing regimen because of their advanced age, multiple comorbidities, and diminished physiological reserves (2). Consequently, treatment options for this population are frequently limited, and strategies that balance clinical benefits with tolerability are urgently needed.
Alternate-day administration of S-1 has been explored as a low-burden chemotherapeutic option for patients with gastrointestinal malignancies who are frail (3). By maintaining the daily dose while reducing cumulative exposure, this approach may preserve clinical activity while minimizing toxicity. However, despite the widespread use of capecitabine as an oral fluoropyrimidine for gastric cancer, to the best of our knowledge, the feasibility of alternate-day administration of capecitabine has not yet been evaluated clinically.
Based on our previous clinical experience with alternate-day S-1 administration in patients with gastrointestinal cancer who are frail (4), we hypothesized that a similar dosing strategy may be applicable for capecitabine. Extending this concept to another oral fluoropyrimidine could provide an additional therapeutic option for patients who cannot tolerate standard daily regimens.
Therefore, we conducted a retrospective analysis of a clinical case series to assess the feasibility and tolerability of alternate-day capecitabine administration in patients with advanced gastric cancer who are frail or pre-frail. In this regimen, the standard daily dose was maintained, whereas the cumulative dose was reduced by administering the drug on alternate days. Herein, we report our clinical experience with this approach, with particular emphasis on the balance between antitumor activity and treatment tolerability in this challenging patient population.
Patients and Methods
Patient selection. Six patients with histologically confirmed advanced gastric cancer who were frail or pre-frail and were hospitalized at Niitsu Medical Center Hospital were retrospectively enrolled. Frailty was assessed using the Vulnerable Elders Survey-13 (VES-13) (5) together with a clinical evaluation of performance status, comorbidities, and overall functional reserve. Patients considered unsuitable for standard daily chemotherapy due to frailty were eligible for alternate-day capecitabine administration. Human epidermal growth factor receptor 2 (HER2) status was determined using immunohistochemistry and/or fluorescence in situ hybridization, and trastuzumab was administered to patients with HER2-positive tumors.
Regimen and treatment algorithm. Capecitabine was administered orally at a standard daily dose of 2,000 mg/m2 (divided into two doses) on alternate days during days 1-14 of each 21-day cycle, followed by a 7-day rest period. Oxaliplatin was administered intravenously at 130 mg/m2 on day 1 of each cycle. In some patients, cisplatin was combined with capecitabine, with or without trastuzumab, depending on the patient’s clinical condition and HER2 status. In patients with HER2-positive disease, trastuzumab was administered intravenously at a loading dose of 8 mg/kg on day 1 of cycle 1, followed by a maintenance dose of 6 mg/kg every three weeks from cycle 2 onward. CAPOX denotes capecitabine plus oxaliplatin (6).
Dose modification. Dose modifications were predefined and implemented according to the clinical conditions and treatment-related toxicities of each patient at the discretion of the treating physicians. In patients with a VES-13 score ≥3 (frail) or 2 (pre-frail) who were considered unfit for standard daily chemotherapy, capecitabine was administered at the standard daily dose of 2,000 mg/m2 (divided into two doses) on alternate days during days 1-14 of each treatment cycle. This schedule reduced the cumulative dose of capecitabine by approximately 50% without reducing the daily dose. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal occurred. Additional dose modifications or temporary interruptions were considered in response to adverse events and managed in accordance with the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
Evaluation of efficacy and safety. Tumor response was assessed by the treating physicians every 6-8 weeks using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (7). The overall response rate (ORR) was defined as the proportion of patients achieving complete or partial response, whereas the disease control rate (DCR) included complete response, partial response, and stable disease lasting for ≥8 weeks. Adverse events were graded according to version 5.0 of the CTCAE.
Statistical analysis. Given the small sample size, all data were analyzed using descriptive statistics. Continuous variables are presented as medians (ranges), and categorical variables are presented as numbers and percentages.
Results
Patient characteristics. Six patients with histologically confirmed HER2-positive advanced gastric cancer who were frail or pre-frail were included in this study (Table I). The median age was 77 years (range=64-82 years), and four patients (67%) were female. The VES-13 scores ranged from 2 to 7. The prognosis after disease progression was poor due to frailty.
Patient characteristics.
Treatment delivery. All patients were managed with capecitabine on an alternate-day schedule while maintaining the standard daily dose of 2,000 mg/m2. The median treatment duration was six months (range=3-36 months). Temporary treatment interruptions occurred in all patients (range=1-4 times) primarily because of treatment-related toxicities (Table II). A mean capecitabine relative dose intensity (RDI) of 57% was calculated based on the entire treatment period, including the initial standard daily dosing phase (100%) and the subsequent alternate-day dosing phase (50%). This value reflects the entire treatment period, encompassing the initial standard daily dosing phase (100% RDI) and the subsequent alternate-day dosing phase (50% RDI) after dose modification.
Treatment delivery and efficacy.
Efficacy. The ORR was 33%, with two patients achieving a partial response. Stable disease was observed in three patients (50%), resulting in a DCR of 83%. The median overall survival was 11 months, with two patients surviving for over 24 months.
Safety. The regimen was generally well tolerated. Hematologic adverse events included one case each of grade 3 febrile neutropenia and grade 4 anemia. Nonhematologic adverse events, including hand-foot syndrome, diarrhea, and fatigue, were mostly grades 1-2 and were managed with supportive care and temporary treatment interruptions when necessary. No treatment-related deaths were observed (Table II).
Representative cases. Case 6 showed a marked reduction in para-aortic and left supraclavicular lymph node metastases (neutrophil-to-lymphocyte ratio (NLR), 3.4; VES-13, 2). At cycle 17, grade 2 peripheral neuropathy developed, leading to the discontinuation of oxaliplatin (NLR, 2.5; VES-13, 4). From cycle 17 onward, treatment was continued with capecitabine plus trastuzumab. The lymph node metastases continued to shrink after 24 cycles. After 32 cycles, brain metastasis developed and the patient was treated with radiotherapy. The patient had no neurological deficits and resumed alternate-day capecitabine plus trastuzumab treatment after a one-cycle interruption (NLR, 3.83; VES-13, 4). During cycle 48, mild cerebral infarction was identified without motor impairment, and treatment was continued with the addition of aspirin (NLR, 2.5; VES-13, 5). Hand-foot syndrome was not observed during treatment. The partial response of the lymph node metastases was maintained throughout the treatment course (Table III).
Clinical course of case 6.
Case 5 had unresectable gastric cancer with P3 peritoneal dissemination (NLR, 2.8; VES-13, 2). Computed tomography revealed a reduction in peritoneal lesions following treatment with capecitabine, oxaliplatin, and trastuzumab. Fourteen months after treatment initiation, oxaliplatin was discontinued because of suspected anaphylaxis, and treatment was continued with alternate-day capecitabine plus trastuzumab (NLR, 5.8; VES-13, 3). Partial response was maintained at 17 months.
Discussion
To the best of our knowledge, this study is the first clinical case series to evaluate alternate-day administration of capecitabine in vulnerable patients with advanced gastric cancer. In this study, a VES-13 score of ≥3 and 2 was defined as frail and pre-frail, respectively; in both groups, alternate-day administration appeared to be an effective treatment adjustment. These results suggest that maintaining the standard daily dose of capecitabine while reducing the cumulative dose through alternate-day administration represents a feasible approach for treatment modification in this vulnerable patient population. In patients who are frail, often older, and have reduced functional reserves, standard daily chemotherapy regimens frequently result in severe toxicity and poor tolerability, thereby limiting the available treatment options. Moreover, these patients are commonly underrepresented in clinical trials, resulting in limited evidence to guide the selection of chemotherapy tailored to their clinical needs; however, recent clinical trials have begun to explore treatment strategies specifically designed for vulnerable older patients with gastric cancer (8).
This study builds directly on our previous report on alternate-day S-1 therapy in patients with gastrointestinal cancer who are frail and extends the same treatment concept to capecitabine in the setting of advanced gastric cancer (4). Alternate-day administration of oral fluoropyrimidines is intended to reduce cumulative drug exposure and associated toxicity, while maintaining per-dose pharmacological activity. Previous studies have demonstrated the feasibility of alternate-day S-1 administration as a less toxic approach in patients with gastrointestinal cancers, including colorectal and pancreatic cancers, who are frail (3). However, despite the widespread global use of capecitabine, to our knowledge, its administration in an alternate-day schedule has not been previously reported. In the present case series, disease control was observed in most patients, and the response outcomes were broadly consistent with those reported for standard daily dosing regimens in comparable patient populations (9). Treatment-related toxicities were generally manageable, and most nonhematologic adverse events, such as hand-foot syndrome and gastrointestinal symptoms, were mild to moderate in severity.
A key characteristic of the present approach is that the treatment intensity was adjusted without reducing the daily dose of capecitabine but rather by decreasing the cumulative dose through modification of the administration schedule. In case 6, after switching to alternate-day administration from cycle 17 (corresponding to administration on alternate days at 50% of the standard daily dose), the NLR did not show a marked increase, and a partial response was maintained, indicating that schedule modification may enable treatment continuation while mitigating toxicity-related discontinuation. This strategy differs from conventional dose-reduction approaches, which often require lowering the per-dose intensity and may limit the available treatment options. Importantly, alternate-day capecitabine administration expands the range of treatment intensity adjustments that can be considered for frail patients. Based on these considerations, we propose a practical treatment algorithm incorporating frailty assessment using VES-13 scores to support clinical decision-making regarding dose modification and regimen selection (Figure 1). Previously, treatment decisions in patients who are frail were frequently limited to a binary choice between the continuation or discontinuation of chemotherapy (10). In contrast, this algorithm provides intermediate options, including continuation with alternate-day capecitabine plus trastuzumab or continuation with alternate-day capecitabine plus oxaliplatin and trastuzumab, thereby enabling adaptation to the heterogeneity of host conditions. This flexibility may help maintain treatment continuity while avoiding unnecessary treatment interruptions.
Proposed treatment algorithm incorporating frailty assessment for patients with advanced gastric cancer. Treatment decisions were guided by the Vulnerable Elders Survey-13 (VES-13) score and treatment-related toxicity. Patients initiated treatment with CAPOX plus trastuzumab (VES-13 ≥2). In cases of treatment-related toxicity and/or worsening frailty (VES-13 ≥3), treatment intensity was modified by administering capecitabine on an alternate-day schedule while maintaining the standard daily dose, with continuation of trastuzumab, with or without oxaliplatin. Subsequent treatment options, including paclitaxel plus ramucirumab, trastuzumab deruxtecan, or best supportive care, were selected according to disease progression, toxicity, and changes in frailty status. CAPOX: Capecitabine plus oxaliplatin; PD: progressive disease.
The clinical algorithm incorporating VES-13, a validated frailty assessment tool (5), may support treatment modifications in patients with advanced gastric cancer who are frail. Serial monitoring of VES-13 scores together with NLR may help predict treatment intolerance and inform timely adjustments to chemotherapy regimens (11, 12). In the present case series, patients with changes in VES-13 scores and NLR were closely monitored and the treatment was modified accordingly. Notably, in case 6, the NLR decreased from 3.4 to 1.69 and remained stable throughout the long-term alternate-day administration. This suggests that the modified schedule not only maintained anti-tumor efficacy but also potentially stabilized the systemic inflammatory status, which is often associated with frailty progression (Table III). These observations indicate that integrating frailty assessment into routine clinical practice may be useful for individualized treatment management of patients who are frail, although further validation is required.
Study limitations. The sample size was small, and the study was retrospective and conducted at a single institution, which may limit the generalizability of the results. In addition, the absence of a control group that received standard daily dosing precluded a direct comparative evaluation. Therefore, further prospective multicenter studies with larger cohorts are warranted to confirm the feasibility and clinical applicability of alternate-day capecitabine administration in patients with advanced gastric cancer who are frail. Moreover, although VES-13 and NLR are useful for monitoring frailty and treatment tolerance, a comprehensive geriatric assessment (13), including cognitive and psychosocial domains, may provide a more holistic evaluation. Finally, multidisciplinary approaches could further support treatment decision-making and patient-centered care in this population (14, 15).
The primary contribution of this study is not the demonstration of antitumor efficacy but rather an illustration of a practical treatment-modification strategy for patients who are frail and often excluded from clinical trials. Alternate-day capecitabine administration may allow the adjustment of treatment intensity without reducing the per-day dose, providing an intermediate option between standard dosing and treatment discontinuation. This approach may be particularly relevant during maintenance therapy, in which treatment continuity and quality of life are major clinical considerations.
Conclusion
To the best of our knowledge, this is the first clinical report of alternate-day capecitabine administration in patients with advanced gastric cancer who are frail or pre-frail. Rather than focusing on a single therapeutic regimen, this dosing approach highlights a treatment-modification strategy that preserves the standard daily dose while reducing cumulative exposure through schedule adjustment. By expanding the range of treatment intensity options available for vulnerable patients, alternate-day capecitabine administration may support individualized clinical decision-making and help maintain treatment continuity in patients who are often considered unsuitable for standard daily chemotherapy.
Acknowledgements
The Authors would like to thank Editage (www.editage.jp) for English language editing.
Footnotes
Authors’ Contributions
K.M. conceived and designed the study. N.O., J.K., and M.S. performed the experiments and wrote the manuscript. K.M. revised the manuscript. All the Authors approved the final version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received January 27, 2026.
- Revision received February 18, 2026.
- Accepted February 19, 2026.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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