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Abstract

Gastric cancer (GC) is the fifth most common malignancy and a leading cause of cancer mortality globally, with particularly high rates in East Asia. The median age at diagnosis is approximately 68 years, and over half of the cases occur in patients aged >65 years. As the life expectancy increases, the proportion of elderly patients with GC increasing, and this population presents unique treatment challenges. Conventional chemotherapy regimens were developed primarily for younger populations and may not be optimal for older adults due to age-related declines in organ function, comorbidities, and differing treatment preferences. The present review discusses the epidemiologic treatment trends among elderly GC patients, the limitations of defining “elderly” solely by chronological age, and the importance of comprehensive geriatric assessments, including the G8 screening tool, for guiding therapy. Evidence indicates that doublet chemotherapy combinations—such as S-1 plus oxaliplatin or capecitabine plus oxaliplatin—benefit fit elderly patients, whereas frailer individuals may be better suited for monotherapy (e.g., S-1 or capecitabine alone) or de-intensified regimens. Although immune checkpoint inhibitors and targeted agents, such as zolbetuximab, are now used in clinical practice, evidence from clinical trials specific to elderly patients remains severely limited. In addition, microsatellite instability-high tumors, more common in older patients, show exceptional responses to immune checkpoint inhibitors, suggesting a potential for chemotherapy-free regimens. This review highlights the importance of personalized, geriatric-guided treatment strategies and discusses pivotal clinical trials involving elderly GC patients. Future research should focus on optimizing regimens and integrating targeted therapies to improve outcomes while minimizing toxicity in this growing population. This review focuses primarily on treatment strategies for elderly patients with advanced or metastatic GC, where systemic therapy decisions must balance efficacy with age-related vulnerabilities.

Keywords

chemotherapy elderly patient gastric cancer MSI-H treatment strategies

Introduction

Gastric cancer (GC) is the fifth most common type of cancer worldwide and the fifth leading cause of cancer-related death.¹ Its incidence and mortality rates are notably high in East Asia. GC primarily affects older adults, with the median age at diagnosis being approximately 68 years, and more than half of the cases occurring in individuals aged ⩾65 years in East Asia.^2,3 Although systemic chemotherapy with several cytotoxic and molecular-targeted agents or immune checkpoint inhibitors has prolonged the survival of patients with advanced GC (AGC), the median overall survival (OS) remains suboptimal.^4–9

As life expectancies have increased worldwide, the number of elderly patients with GC is increasing, and these patients pose unique management challenges.^10,11 However, many standard therapies were assessed in trials that involved mostly younger patients; thus, the optimal treatment of the growing elderly GC population remains unclear. This present review discusses epidemiologic trends, explores the definition of “elderly” in an oncologic rather than merely a chronological context, reviews evidence on chemotherapy efficacy and toxicity in older patients with GC, and explores potential barriers to optimal care. We also highlight the findings from clinical trials that give special consideration to elderly patients. Therefore, this review concentrates on elderly patients with unresectable or metastatic GC, as this population faces the greatest complexity in systemic treatment decisions. While early-stage and potentially curable cases are important, they involve different therapeutic paradigms—such as surgery or endoscopic intervention—and fall outside the primary scope of this article.

Global aging trends and increasing GC incidence among the elderly

The global population is aging at an unprecedented rate, especially in Asia.^1,12 Correspondingly, the incidence of GC among the elderly is increasing. In Japan, the number of GC cases and deaths in patients aged ⩾70 years surpassed that of younger patients as far back as the 1990s (Figure 1), and 85% of new GC cases now occur in patients aged ⩾65 years.^13–15 Similar trends are seen internationally; in the United States, approximately 60% of GC cases occur in those aged ⩾65 years.¹⁶ In addition to biological factors such as organ function and comorbidities, age-related issues—such as decreased physical resilience, limited social support, and psychological readiness for treatment—also play a crucial role in clinical decision-making for older adults. Furthermore, disparities in access to care between older and younger patients deserve careful consideration.¹⁷ Physical limitations, distance from specialized cancer centers, socioeconomic status, and the availability of caregivers may all disproportionately hinder elderly patients from receiving optimal treatment. These barriers are often compounded by perceptions and attitudes—not only among patients themselves but also among healthcare providers. Elderly patients with GC often present with AGC and have distinct clinical needs.

Figure 1.

Annual trends (a) in the incidence and (b) mortality of stomach cancer by age group in Japan (<70 vs ⩾70 years old).

Challenges in defining “elderly” in oncology

In contemporary oncology, defining “elderly” is no longer a matter of setting a chronological age threshold. Instead, the concept is evolving within the broader framework of personalized oncology, which emphasizes tailoring treatment to individual patient characteristics. This shift reflects a growing recognition that functional status, biological age, and psychosocial factors often have greater clinical relevance than chronological age alone. Accordingly, there is a paradigm shift underway—from age-based to function-based treatment models—that better align with the heterogeneity of the older adult population. Identifying which patients comprise the elderly cohort is challenging.^18,19 Historically, the age of ⩾65 years has been used to define the elderly population,^20–22 but no cutoff age is universally accepted in the field of oncology. Instead, geriatric oncologists advocate assessing each patient’s biological and functional ages along with factors such as comorbidities, organ function, cognitive status, and social support.¹¹ For example, the Japanese Clinical Oncology Group Geriatric Study Committee suggests the classification of patients as elderly based on the biological and physiological changes and social issues associated with aging, rather than on a numerical age.²³ In addition to the JCGA guidelines, several international guidelines emphasize function-based treatment approaches for elderly cancer patients. The American Society of Clinical Oncology and National Comprehensive Cancer Network (NCCN) guidelines recommend incorporating geriatric assessments (GAs) to inform treatment decisions beyond chronological age.^24,25 The European Society for Medical Oncology guidelines also emphasize the integration of GA into treatment planning for elderly patients with gastrointestinal cancers, supporting individualized care based on fitness rather than chronological age.²⁶ These guidelines collectively support a shift toward personalized oncology in the aging population.

Screening tests, such as the G8 screening tool, can help to identify older adults who might benefit from further investigation with the comprehensive geriatric assessment (CGA) before management decisions are made. For instance, a robust 75-year-old individual with few comorbidities might be treated similarly to a 60-year-old person, whereas a frail 70-year-old patient might need a modified approach.^27–30

Overview of guidelines

The guidelines in multiple regions acknowledge the need to individualize therapy in elderly patients. The NCCN guidelines for GC emphasize that treatment decisions should be based on the performance status and comorbidity rather than on age alone.³¹ Fit older patients (good organ function and Eastern Cooperative Oncology Group score of 0–1) can generally be offered standard therapies, whereas those who are frail or with significant comorbidities may require modified treatment approaches or best supportive care. Similarly, the Japanese Gastric Cancer Association (JGCA) guidelines explicitly address chemotherapy for elderly patients with GC.³² For fit elderly patients, the JGCA strongly recommends chemotherapy following a comprehensive assessment, citing moderate evidence and unanimous expert consensus. However, owing to few trial data being available for frail elderly and those with impaired organ function or comorbidities, no clear recommendation for chemotherapy could be made. The guidelines acknowledge that, in such cases, the situation varies widely; therefore, treatment decisions should be individualized. Potential approaches may range from dose-reduced chemotherapy to the provision of supportive care.

Both the NCCN and JGCA guidelines stress that chronological age alone is not a contraindication to therapy. They encourage GA-driven decisions. In practice, this often means attempting active treatment in older patients who are predicted to tolerate it, while avoiding harm in those who cannot. In early-stage GC, guidelines, such as JGCA, also note that less-invasive treatments (e.g., endoscopic resection) can be considered for some elderly patients who might not be able to tolerate surgery.³³ Importantly, the alignment of recommendations across both Western (NCCN) and Asian (JGCA) guidelines reflects a growing global consensus on the shift from age-based to fitness-based treatment models. This convergence reinforces the broader paradigm of personalized oncology in the management of elderly patients with GC. However, certain limitations remain. Most guidelines provide insufficient detail for managing truly frail or vulnerable patients, and there is considerable variability in how GAs are operationalized and integrated into clinical decision-making. In addition, standardized treatment pathways tailored specifically for elderly GC patients are still lacking. Real-world implementation of these nuanced guidelines also poses practical challenges. CGA is time-intensive and not uniformly applied in busy clinical settings. Moreover, in the absence of clearly defined tools or protocols, physicians may either under-treat due to caution or over-treat due to uncertainty. Addressing these gaps will be essential for translating guideline recommendations into effective everyday practice.

Chemotherapy toxicity and tolerability

Patient attitudes and psychosocial factors

Older patients are often less willing or motivated than younger individuals to undergo aggressive chemotherapy, due not only to concerns about physical tolerance but also to psychosocial factors. In a survey of colorectal cancer patients, those aged ⩾70 years were significantly less inclined to undergo adjuvant chemotherapy compared to younger cohorts, with patients <50 being the most accepting of treatment.¹⁷ This discrepancy reflects a more cautious risk–benefit evaluation among older adults. Fear of side effects, misconceptions about chemotherapy, reliance on caregivers, and cultural expectations around aging and autonomy often shape treatment preferences. These considerations can influence both initial acceptance and continued adherence to chemotherapy regimens. In addition, a recent European survey reported that older age was frequently cited by physicians as a reason to delay the initiation of systemic treatment in patients with cancer.³⁴ While this may reflect concerns about tolerability or patient readiness, it also raises important questions about potential age-related undertreatment and the need for objective tools to guide timing decisions.

Physiological changes, comorbidities, and toxicity

Elderly patients face an increased risk of chemotherapy-related toxicity due to age-associated physiological decline and a high burden of comorbidities, such as cardiovascular disease, diabetes, and renal insufficiency.^35–37 These conditions complicate drug metabolism and excretion—particularly through reduced renal and hepatic function—which may lead to elevated systemic drug levels and heightened toxicity.^38–41 In addition, polypharmacy is common in this population, raising the potential for harmful drug–drug interactions. Functional impairments such as frailty, malnutrition, and falls are also prevalent and can exacerbate toxicity risk. In clinical practice, dose reductions, prophylactic supportive care, and vigilant monitoring are often necessary to mitigate these risks.⁴² S-1 requires dose adjustment in patients with impaired renal function (e.g., CCr < 50–60 mL/min), as gimeracil accumulation increases systemic 5-FU exposure. Cisplatin, being renally excreted and nephrotoxic, often necessitates dose reduction or substitution with carboplatin when CCr declines below 60 mL/min.⁴³ For trifluridine/tipiracil (TAS-102), impaired renal clearance of tipiracil leads to increased exposure, and reduced starting doses are considered when CCr < 50 mL/min.⁴⁴

Clinical outcomes: Efficacy and real-world experience

Despite concerns about tolerability, numerous studies support the efficacy of chemotherapy in older adults when appropriately selected. A pooled analysis of 8 clinical trials involving 367 patients with metastatic GC or gastroesophageal cancer found that while patients aged ⩾65 experienced higher rates of grade ⩾3 adverse events—especially fatigue (15% vs 5%), infections (9% vs 4%), and stomatitis (6% vs 1%)—the OS and progression-free survival (PFS) outcomes were comparable to those of younger patients.⁴⁵ Treatment completion rates were also similar, suggesting that well-selected elderly patients can derive meaningful benefit from standard therapies. These findings reinforce the importance of stratifying patients by physiological rather than chronological age. In multivariate analysis, age of ⩾70 years was not an independent negative prognostic factor for survival. Real-world Japanese data mirror these findings. In Makiyama et al.⁴⁶’s retrospective analysis (n = 218 patients ⩾70), S-1 + cisplatin yielded mOS of 17.1 versus 13.9 months with S-1 alone (p = 0.63), despite higher grade ⩾3 AEs in the combination arm (49.5% vs 27.5%). Tsushima et al.⁴⁷ stratified 153 GC patients by age (<65, 66–75, and ⩾75), reporting mOS of 16.9, 17.1, and 7.7 months, respectively, and G3 fatigue rates rising from 5% (<65) to 20% (⩾75).⁴⁷ These data underscore the need to bridge the gap between clinical trial populations and real-life elderly patients by applying GA tools and promoting equitable access to care.

Risk stratification and treatment continuation

CGA tools have been prospectively validated to stratify older patients by vulnerability rather than age.^48,49 For example, the Cancer and Aging Research Group (CARG) Toxicity Risk Score—incorporating factors like impaired renal function, hearing loss, falls, and hemoglobin level—categorizes patients into low-, intermediate-, and high-risk groups, with observed grade ⩾3 toxicity rates of approximately 30%, 52%, and 71%, respectively.³⁷ Similarly, the G8 screening tool (score 0–17) identifies vulnerable individuals (G8 ⩽14) with 87% sensitivity and 68% specificity for predicting severe chemotherapy toxicity in a multicenter cohort of older cancer patients.²⁷ In practice, patients in the low-risk or “fit” categories may be offered standard combination regimens, whereas those flagged as high risk or “vulnerable” are often guided toward reduced-intensity therapy or monotherapy, thereby minimizing harm without sacrificing efficacy. Nevertheless, registry data show elderly GC patients are 22% less likely to receive second-line therapy (odds ratio (OR), 0.78; 95% confidence interval (CI), 0.71–0.85).⁵⁰ This gap reflects not only biological frailty but also clinician caution and logistical barriers (limited access to geriatric oncology services). Implementing planned reassessment points—for example, at cycle 3—to downgrade toxicity and re-evaluate fitness can help preserve second-line options.

In summary, elderly GC patients face higher toxicity risk but can safely complete and benefit from chemotherapy when carefully selected and supported. Key strategies include proactive dose modifications, growth-factor prophylaxis, nutritional interventions, and routine GA to guide intensity. These measures allow clinicians to strike an optimal balance between efficacy and safety, ensuring age alone does not preclude life-prolonging therapy.

Pivotal clinical trials for elderly patients (first-line platinum doublets)

Historically, older patients with GC have been under-represented in clinical trials. Nevertheless, several key studies have specifically evaluated chemotherapy regimens in the elderly, particularly the role of combination (platinum doublet) therapy in comparison to monotherapy. Collectively, these trials have helped to shape the first-line treatment strategies for elderly patients with metastatic GC (Table 1).^{46,47,51–53}

Table 1.

Pivotal clinical trials involving elderly patients with metastatic gastric cancer receiving fluoropyrimidine-based chemotherapy as first-line therapy.

Study	Region	Age (years)	Design	N	Control	Experimental	PE	Results
Hwang et al.⁵⁴	South Korea	⩾70	PIII	50	Capecitabine	Capecitabine + oxaliplatin	OS	mOS: 11.1 vs 6.3 mo. HR 0.58 (p = 0.108)
WJOG8315G⁵⁵	Japan	⩾70	PIII	160	S-1	S-1 + oxaliplatin	OS	mOS: 16.2 vs 13.0 mo. HR 0.73 p = 0.0535: Significant, 1-sided p < 0.20
GO2⁵⁶	UK	–^a	PIII	514	CapeOX (100%)	Capecitabine + oxaliplatin at 80% or 60% of the full dose	PFS	mOS: 7.5 vs 6.7 vs 7.6 mo. HR 1.09 (80% vs 100%) HR 1.10 (60% vs 100%)
KCSG ST13-10⁵⁷	South Korea	⩾70	PIII	111	Monotherapy	Platinum doublet	OS	mOS: 11.5 vs 7.5 mo. HR 0.86 (p = 0.231)
Lee et al.⁵²	South Korea	⩾65	rPII	89	Capecitabine	S-1	ORR	ORR: 26.1% vs 28.9% mTTP: 4.7 vs 4.2 mo. mOS: 9.5 vs 8.2 mo. ⩾G3 HFS: 6.8% vs 0%
Kim et al.⁵³	South Korea	⩾70	PII^b	107	S-1	Capecitabine	ORR	ORR: 26.4% vs 24.1% mTTP: 3.2 vs 3.4 mo. (p = 0.813) mOS: 8.5 vs 10.3 mo. (p = 0.691)
Tsushima et al.⁴⁷	Japan	<65 66–75 ⩾75	Retro	153	S-1	S-1 S-1	NA	mPFS: 7.8 vs 5.6 vs 3.9 mo. mOS: 16.9 vs 17.1 vs 7.7 mo. ⩾G3 fatigue: 5% vs 11% vs 20% (p = 0.004)
Makiyama et al.⁴⁶	Japan	⩾70	Retro	218	S-1	S-1 + cisplatin	NA	mPFS: 6.3 vs 7.9 mo. (p = 0.61) mOS: 13.9 vs 17.1 mo. (p = 0.63) ⩾G3 any AEs: 27.5% vs 49.5% (p < 0.001)
Lee et al.⁵¹	South Korea	>70	Retro	273	Monotherapy	Combination therapy	NA	mOS: 5.3 vs 7.1 mo. (p = 0.065)

No chronological age limits provided.

Two simultaneous single-arm phase II.

AE, adverse event; G3, grade 3; HFS, hand–foot syndrome; HR, hazard ratio; mo, months, mOS, median overall survival; mPFS, median progression-free survival; mTTP, median time to treatment progression; NA, not assessed; ORR, objective response rate; OS, overall survival; PE, primary endpoint; PFS, progression-free survival; Retro, retrospective; rPII, randomized phase II.

Hwang et al.’s⁵⁴ multicenter phase III trial conducted in South Korea involved patients with metastatic GC aged ⩾70 years. Patients were randomized to the capecitabine alone or the capecitabine plus oxaliplatin group. The trial only enrolled 50 patients before stopping early, which limited its statistical power. The results showed a trend toward better survival with the platinum doublet, with the median OS being 11.1 months in comparison to 6.3 months with capecitabine alone. This corresponded to a 42% relative risk reduction for mortality, but it did not reach significance given the small sample size. Notably, the toxicity was higher with combination therapy, but still manageable for most.

The WJOG 8315G trial in Japan focused on patients aged ⩾70 years, comparing S-1 alone to S-1 plus oxaliplatin as first-line therapy.⁵⁵ The OS was assessed in 160 patients with AGC. A borderline improvement in OS was seen with combination chemotherapy. The median OS was 16.2 months with S-1 plus oxaliplatin and 13.0 months with S-1 alone, with a hazard ratio (HR) of 0.73 (p = 0.0535). A planned subgroup analysis using the G8 screening tool revealed that even patients classified as frail (G8 score <11) appeared to derive OS benefits from S-1 plus oxaliplatin, comparable with those seen in their fitter counterparts. Overall, WJOG 8315G supports the use of a modified oxaliplatin doublet in well-selected older patients and highlights the importance of geriatric screening.

The KCSG ST13-10 trial aimed to definitively answer whether doublet chemotherapy is superior to monotherapy in the elderly.⁵⁷ Patients aged ⩾70 years with metastatic or recurrent GC were randomized to either the combination therapy (various platinum plus fluoropyrimidine doublets with a 20% reduction in dose to start) or monotherapy (fluoropyrimidine alone) group. Owing to the slow accrual, the trial was terminated early after enrolling only 111 of the planned 238 patients. In the full analysis, the median OS was 11.5 and 7.5 months in the combination and monotherapy arms, respectively. Notably, the PFS improved significantly with combination chemotherapy (5.6 vs 3.7 months, p = 0.005). Toxicity was higher with the combination treatment, but no unexpected safety concerns emerged. The early study closure limits firm conclusions, but the findings suggest a potential OS benefit with doublet combinations.

The GO2 trial in the UK enrolled over 500 older and/or frail patients with advanced gastroesophageal cancer (median age of 77 years).⁵⁶ All patients received an oxaliplatin–capecitabine doublet, but they were randomized to three groups receiving different drug dose levels (full dose, 80% dose, or 60% dose). PFS did not significantly differ among the three dose tiers, and the PFS of the group with the lowest dose was not inferior to that of the group with the full dose (HR, 1.10, 95% CI, 0.90–1.33). Patients on the lowest dose had significantly fewer toxic effects, fewer dose reductions, and a higher therapy completion rate without delays. In addition, the patients’ quality of life was better at lower doses.

Another focus is on refining chemotherapy dosing and combinations for older patients. Although the UK GO2 trial provided some insights into dose optimization, several questions remain. Contrary to standard practice, future trials should explore whether lower starting doses followed by dose escalation could enhance tolerability and outcomes. Some studies have also assessed whether the addition of docetaxel provides any benefit to elderly patients with ACG,^58,59 although the FLOT65+ trial^58,59 has indicated that triplet chemotherapy had no advantage over doublet combinations in patients aged >70 years and had much higher toxicity. Thus, most studies are deescalating rather than escalating therapy for older adults.

In summary, platinum–fluoropyrimidine doublets remain an important option for elderly patients who are fit enough, and such combination chemotherapeutic approaches can improve disease control and possibly patient survival, as compared to monotherapy. However, the benefit may be modest and must be weighed against toxicity and patients’ preferences. The data also suggest that tailored approaches with doublet combinations might be useful to explore for vulnerable and frail patients. Given that the median age of patients in these trials was approximately 70 years, the results are applicable to younger-old and older-old patients, although evidence in the oldest old (>80 years) remains sparse.

Subgroup analyses for OS based on age

Subgroup analyses from large phase III trials offer valuable insights into the treatment effects in older adults with GC, even though the studies were not specifically designed for this population (Figure 2). These analyses typically compare the outcomes, specifically in terms of benefits from treatment, among age-defined cohorts. Reassuringly, most trials show that older patients achieve proportional benefits from therapy similar to those seen in younger patients. In other words, age subgroups generally do not exhibit significant interaction effects for OS.

Figure 2.

Subgroup analyses for overall survival by age-based hazard ratios.

The ToGA trial investigated adding trastuzumab to chemotherapy to treat HER2-positive AGC in 584 patients.⁵ The median OS improved from 11.1 to 13.8 months with trastuzumab (HR, 0.74; 95% CI, 0.60–0.91; p = 0.0046). When assessed by age, the OS benefit persisted among patients aged ⩾60 years and the severe toxicity rate was similar between the older and younger subsets. Recent trials on PD-1 inhibitors (e.g., nivolumab and pembrolizumab) in combination with chemotherapy have transformed the first-line treatment for AGC.^7,8,60 In the CheckMate-649 and KEYNOTE-859 studies, older patients experienced survival benefits from immunotherapy that were comparable to those seen in younger cohorts. For instance, in CheckMate-649, the HR for OS among patients who received nivolumab plus chemotherapy was similar to that in patients aged ⩾65 years and younger patients (HR, 0.82 vs 0.75).⁷ In the KEYNOTE-859 study, the OS benefit of pembrolizumab plus chemotherapy was consistent across age subgroups. Among patients aged ⩾65 years, the HR for OS was 0.77 (95% CI, 0.64–0.92), comparable to that in younger patients, indicating that advanced age did not compromise the efficacy of immune checkpoint blockade.⁵⁴

Novel targeted therapies, such as zolbetuximab (anti-Claudin 18.2), have been tested in AGC.^9,61 The phase III SPOTLIGHT trial, in which zolbetuximab plus FOLFOX was used in patients with claudin-18.2-positive GC, showed improved overall PFS and OS and did not flag any significant loss of benefit in older patients (HR, 0.77 vs 0.71 in ⩽65 vs >65 years); the detailed age subgroup results are pending publication. In addition, recent studies on zolbetuximab have raised concerns regarding gastrointestinal toxicities—particularly nausea and vomiting—during initial administration.⁶² These toxicities may limit feasibility in very elderly patients (e.g., ⩾80 years). Therefore, in clinical practice, for HER2-negative but CLDN18.2-positive elderly patients, immune checkpoint inhibitor-based regimens could be favored due to their comparatively favorable toxicity profiles.

Ramucirumab, an antibody to VEGFR-2, has demonstrated OS improvement in patients with AGC when used as monotherapy and in combination with paclitaxel in a pooled subgroup analyses of REGARD and RAINBOW, respectively, involving patients aged <65 and ⩾65 years, respectively.⁶³ In REGARD, ramucirumab’s OS benefit was virtually identical in the older and younger subgroups (patients aged ⩾65 years: HR, 0.72; 95% CI, 0.48–1.08; patients aged <65 years, 0.80; 95% CI, 0.59–1.10). In RAINBOW, the combination of ramucirumab and paclitaxel improved the OS in both age groups, although the HR was slightly less pronounced in the ⩾65-year-old cohort (HR, 0.88) than in the <65-year-old cohort (HR, 0.78). Moreover, the efficacy in terms of PFS with combined therapy was similarly maintained across the different age groups (e.g., in RAINBOW, HR 0.67 (⩾65-year-old group) vs 0.57 (<65-year-old group)). The toxicity profiles were generally similar in the two age groups, except for the higher rate of baseline neutropenia with chemotherapy observed in the older group. These findings led investigators to conclude that ramucirumab confers meaningful benefits as compared with placebo across age groups.

In aggregate, biologic therapies (targeted drugs, immunotherapy) retain their efficacy in older patients. The forest plots of HRs for OS by age in numerous trials (HER2+, PD-L1+, anti-VEGF, and so on) show overlapping CIs for older and younger subgroups, indicating no significant interaction. Therefore, advanced age alone should not prevent the use of these medical advances, although careful monitoring is needed. A key limitation of these subgroup analyses is that there was a very low number of patients aged >75 years, which restricts the generalizability of our study findings to the oldest-old population. Nonetheless, as discussed earlier in this paper, chronological age alone might not be sufficient as a deciding factor for withholding treatment.

Microsatellite instability-high GC in the elderly

The microsatellite instability-high (MSI-H) molecular subtype is seen in 5%–10% of GCs and have distinct clinical implications that are particularly relevant to older patients. MSI-H tumors are characterized by deficient DNA mismatch repair that leads to a high mutational burden. In the WJOG 13320 trial, MSI-H GC was associated with older age, female sex, distal tumor location, absence of liver metastasis, and HER2 negativity.⁶⁴ The MSI-H status is an important biomarker for predicting the response to immunotherapy. The remarkable efficacy of PD-1 inhibitors in MSI-H cancers, first shown in colorectal cancer, extends to GC as well. This is supported by two key clinical trials (i.e., KEYNOTE-062 and CheckMate-649).

In the KEYNOTE-062 trial (a first-line treatment trial for AGC), a subset analysis examined MSI-H patients. Pembrolizumab monotherapy had dramatically better outcomes than chemotherapy in MSI-H tumors, leading to a 71% reduction in the risk of death as compared to chemotherapy alone (HR, 0.29; 95% CI, 0.11–0.81).⁶ Likewise, a substantial reduction was seen with pembrolizumab plus chemotherapy, as compared with chemotherapy alone (HR, 0.37, 95% CI, 0.14–0.97). Similarly, in the CheckMate-649 trial, nivolumab plus chemotherapy produced an OS HR of 0.38 (95% CI, 0.17–0.84) versus chemotherapy alone in the MSI-H subgroup.⁸ In fact, the median OS for MSI-H patients receiving nivolumab plus chemotherapy was not even reached in one analysis, far exceeding the typical outcomes. Neither study was elderly specific but the findings underscore that MSI-H tumors are highly immunogenic and responsive to the PD-1 blockade. As they most frequently occur in older patients with GC, immunotherapy might be an important option for those patients with this biomarker.

For patients with metastatic MSI-H GC, frontline immunotherapy—either as monotherapy or combined with minimal chemotherapy—should be a primary consideration. The high efficacy of single-agent immunotherapy in MSI-H GC can spare an elderly patient from experiencing the toxicity of cytotoxics.^65–67 This strategy can lead to exceptional outcomes, as evidenced by both clinical trial data and real-world cases of nonagenarians achieving complete responses on immunotherapy. This exemplifies how precision oncology can transform the treatment for older patients by aligning the molecular profiles with highly effective, lower-toxicity therapies. A proposed treatment algorithm reflecting these stratification principles is shown in Figure 3.

Figure 3.

Treatment algorithm for elderly GC patients based on fitness or G8 score.

Ongoing clinical trials and future directions

Several ongoing and recently completed trials are aiming to refine the efficacy and safety of treatment strategies for older adults with GC. The key areas of investigation include treatment customization based on fitness, incorporation of GA, and evaluation of novel agents.

One recognized need is better decision tools for tailoring therapy in older patients. The trials, such as J-SUPPORT 2101 in Japan, are studying treatment modifications guided by GA tools.⁶⁸ In an interim report, providing oncologists with GA results and recommendations improved communication and helped align treatment decisions with patient fitness and preferences. Although the GA tools are still being tested, it is hoped that they will reduce the cases of overtreatment and undertreatment. The GERICO group in France and others have performed similar trials where a geriatrician’s input or GA-driven algorithm is applied to treatment planning for GI cancers.⁶⁹ These studies will inform the systematic use of tools, such as the G8 screening score or CGA, to guide the intensity of chemotherapy regimens.

The WJOG 8315G trial is one of the trials that utilized GA scores, such as the G8, to guide treatment intensity—specifically to determine whether to administer monotherapy or combination chemotherapy.⁵⁵ In a preplanned subgroup analysis, the G8 was used to predict the treatment outcomes with the addition of oxaliplatin in elderly patients (age ⩾70 years) with AGC. Patients were stratified by their G8 score (median value = 11). The superiority of the S-1 plus oxaliplatin regimen in OS over S-1 alone was not demonstrated in patients with G8 scores of ⩽11 (HR, 1.06; 95% CI, 0.64–1.74), suggesting no survival benefit in more vulnerable patients. This finding indicates that the G8 score may help predict which elderly patients are less likely to benefit from a combination regimen, thereby aiding in the personalization of treatment strategies to optimize efficacy while minimizing toxicity.

Currently, immune checkpoint inhibitors and molecular targeted agents, such as zolbetuximab, have been introduced into clinical practice for AGC.^8,9,60,61 However, robust results from clinical trials using these novel agents in the elderly population have yet to be obtained. Given that vulnerable elderly patients often have limited tolerance for conventional chemotherapy, evaluating how best to incorporate biologics, such as checkpoint inhibitors or zolbetuximab, into their treatment is a critical next step. Moving forward, integrating GA into clinical trials and expanding elderly-specific evidence for novel agents will be essential to improving both outcomes and quality of life in this growing patient population.

In addition, the EN-COURAGE study, an ongoing investigator-initiated clinical trial evaluating trastuzumab deruxtecan in HER2-positive GC (UMIN ID: 000052522). This trial incorporates the G8 screening tool to assess patient vulnerability and guide treatment decisions. We believe this represents an important example of how targeted agents can be prospectively studied in elderly patients using GA tools.

Conclusion

The management of GC in elderly patients demands a shift from chronological-age guidance toward a personalized, function-based approach. Epidemiologic data confirm that over half of the GC cases now occur in individuals aged ⩾65, yet pivotal clinical trials have historically under-represented this group. CGA tools—such as the G8 screening scale and CARG Toxicity Score—have demonstrated strong predictive value for chemotherapy tolerance, enabling clinicians to stratify patients into “fit” versus “vulnerable” categories and tailor regimens accordingly. Fit elderly patients derive survival benefits from platinum–fluoropyrimidine doublets and modern targeted or immunotherapeutic agents comparable to younger cohorts, while frailer individuals may benefit more from dose-reduced or single-agent strategies.

Immediate practice recommendations:

Integrate GA at the point of care: Implement brief screening (e.g., G8) in all patients ⩾65 to identify those needing full CGA.

Optimize dosing proactively: Begin renally excreted drugs at 60%–80% of standard doses in those with borderline organ function, with scheduled dose-escalation or de-escalation checkpoints.

Leverage immunotherapy in MSI-H tumors: For elderly patients with MSI-H GC, prioritize PD-1 blockade to maximize efficacy while minimizing cytotoxic exposure.

Research priorities:

Elderly-specific trial design: Mandate inclusion of patients ⩾75–80 years and frail subgroups in prospective studies of novel agents.

Digital frailty assessment: Validate machine-2. learning and wearable-based tools to refine biological-age estimation and treatment selection.

Geriatric co-management models: Evaluate multidisciplinary care pathways that integrate oncologists and geriatricians to reduce overtreatment and under-treatment.

Quality of life endpoints: Incorporate patient-reported outcomes and functional-independence measures into trial protocols to balance efficacy with tolerability.

By embracing these personalized, geriatric-guided strategies and generating robust, age-inclusive evidence, the oncology community can improve both survival and quality of life for the rapidly growing elderly GC population.

Footnotes

Acknowledgements

The authors thank Enago () for English language editing.

Declarations

ORCID iD

Yukiya Narita

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Systemic therapy strategies for elderly patients with gastric cancer

Abstract

Keywords

Introduction

Global aging trends and increasing GC incidence among the elderly

Challenges in defining “elderly” in oncology

Overview of guidelines

Chemotherapy toxicity and tolerability

Patient attitudes and psychosocial factors

Physiological changes, comorbidities, and toxicity

Clinical outcomes: Efficacy and real-world experience

Risk stratification and treatment continuation

Pivotal clinical trials for elderly patients (first-line platinum doublets)

Subgroup analyses for OS based on age

Microsatellite instability-high GC in the elderly

Ongoing clinical trials and future directions

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References