Gastric cancer remains a formidable global health challenge, ranking as the fifth most common cancer and the fifth leading cause of cancer death worldwide. In Japan the burden is especially heavy: tumors of the stomach caused 38,711 deaths in 2023, roughly one in ten of all cancer deaths in the country, and an estimated 80,700 new cases were expected among men in 2025 alongside 37,800 in women. Outcomes for advanced, unresectable or recurrent disease have long been poor, which is why each successive therapeutic advance has been tracked closely by clinicians and guideline committees. Patients whose tumors test negative for the protein HER2, the focus of this study, do not benefit from anti-HER2 targeted drugs, making the evolution of their chemotherapy and immunotherapy options particularly consequential.

The story begins in 2008, when the phase 3 SPIRITS trial showed that the oral fluoropyrimidine S-1 combined with cisplatin, a regimen known as SP, improved overall survival compared with S-1 alone, prompting SP to become the Japanese standard first-line therapy. By 2011, capecitabine plus cisplatin had been added to the guideline repertoire, and in 2015 the phase 3 G-SOX program established S-1 plus oxaliplatin, or SOX, as non-inferior to SP in progression-free survival. Oxaliplatin offered practical advantages: unlike cisplatin it does not require mandatory hydration, an important consideration for older patients or those with compromised cardiac or renal function. Later milestones followed in rapid succession, including ramucirumab as a second-line option in 2015, nivolumab as third-line monotherapy in 2017, trifluridine/tipiracil in 2019, and finally, in November 2021, first-line nivolumab plus a fluoropyrimidine and oxaliplatin doublet, based on the CheckMate 649 and ATTRACTION-4 trials.

To quantify how these approvals translated into routine care, the researchers identified adults aged 20 or older who initiated a guideline-recommended first-line regimen for HER2-negative advanced gastric cancer between January 2012 and December 2023. Because HER2 status itself is not recorded in the claims database, patients were classified as HER2-negative if they had no record of ever receiving trastuzumab or trastuzumab deruxtecan. After exclusions designed to remove perioperative regimens, clinical trial participants, and non-guideline agents, the final cohort comprised 16,573 patients, growing from just 782 in the 2012–2013 era to 4,099 in 2022–2023. The cohort was 72.1 percent male, with a median age of 70 years, and more than 82 percent were treated at designated cancer hospitals.

The first-line findings chart a dramatic generational change. In 2012–2013, a striking 94.0 percent of patients received SP, with capecitabine plus cisplatin accounting for another 3.1 percent. After oxaliplatin regimens entered the guidelines in 2014, SOX use climbed from 22.4 percent in 2014–2015 to a peak of 66.3 percent in 2020–2021, while capecitabine plus oxaliplatin and FOLFOX also gained ground, reaching 6.0 and 10.5 percent respectively by 2020–2021. Meanwhile SP collapsed to just 14.8 percent in that era. The seismic moment came in 2022–2023, when nivolumab-containing combinations became the most common first-line regimens overall: 61.7 percent of all first-line patients received an immunotherapy combination, with nivolumab plus SOX alone used in 48.1 percent of patients, nivolumab plus FOLFOX in 11.0 percent, and nivolumab plus capecitabine plus oxaliplatin in 2.6 percent. Chemotherapy-only SOX fell to 26.2 percent and SP to a residual 2.0 percent.

The downstream lines of treatment shifted in parallel. Paclitaxel monotherapy dominated second-line care in the earliest era, but ramucirumab-containing combinations rapidly became the norm, with paclitaxel plus ramucirumab used in 68.4 percent of second-line patients by 2016–2017 and nab-paclitaxel plus ramucirumab rising to 38.3 percent by 2022–2023. In the third line, irinotecan was the mainstay until 2017, after which nivolumab monotherapy surged to become the dominant choice, peaking at nearly 80 percent of third-line use. Intriguingly, once first-line nivolumab combinations were approved in 2021, third-line nivolumab monotherapy dropped sharply to 31.0 percent in 2022–2023, while trifluridine/tipiracil and irinotecan reclaimed larger shares of that space, a logical reshuffling now that many patients had already been exposed to checkpoint inhibition years earlier.

Treatment duration data provided the clearest signal of cumulative clinical benefit. Median first-line duration of therapy hovered between 4.7 and 5.0 months from 2012 through 2021, then rose to 5.8 months in 2022–2023. Second-line duration crept from roughly 2.6 to 3.5 months, and third-line duration remained essentially flat at 2.3 to 2.6 months throughout. The overall duration across all lines, however, expanded from 8.5 months in the earliest era to 12.5 months in the latest, with the proportion of patients still on treatment at 24 months nearly doubling from 16 percent to 32 percent. Because second- and third-line durations barely moved, the authors attribute much of the earlier gains in overall duration to improved transition rates to later lines, while the era 6 jump reflects longer first-line therapy itself, with about 10 percent of patients still receiving first-line treatment at 24 months.

The head-to-head comparison of immunotherapy and chemotherapy in the final era was particularly striking. Patients who began first-line nivolumab plus chemotherapy in 2022–2023 stayed on first-line treatment for a median of 6.3 months, compared with 5.0 months for chemotherapy alone in the same era and 4.6 months in the prior era. The divergence widened further down the line: median overall duration of therapy reached 15.9 months with nivolumab combinations versus 8.1 months with chemotherapy alone, and the 24-month on-treatment rate was 41 percent versus 18 percent. Multivariate analysis confirmed that first-line nivolumab, first-line oral fluoropyrimidine, and treatment at a designated cancer hospital were each independently associated with significantly longer overall duration of therapy, while edema, peritoneal metastasis or ascites, and renal disease predicted shorter duration. Notably, transition rates to second-line treatment were higher with immunotherapy, reaching 61.6 percent versus 37.8 percent with chemotherapy, suggesting that immune-related toxicities documented in trials have not prevented patients in routine practice from moving on to subsequent therapy when needed.

The study also captured demographic undercurrents reshaping the treated population. The proportion of patients aged 75 or older rose from 19.4 percent in 2012–2013 to 36.7 percent in 2022–2023, mirroring Japan’s aging population and likely facilitated by the shift from cisplatin to the better-tolerated oxaliplatin backbone. Older patients adopted SOX particularly rapidly, and although per-line treatment durations were similar across age groups, those 75 and older transitioned to later lines less often, producing shorter overall durations. Treatment at designated cancer hospitals was likewise associated with faster uptake of new regimens, higher transition rates, and longer overall treatment, a gap the authors attribute to the multidisciplinary care management systems concentrated in those centers, and one that persisted across every era of the analysis.

The authors are candid about the limits of claims-based research. The database captures mainly acute-care hospitals using Japan’s Diagnostic Procedure Combination system, lacks race and ethnicity data, and cannot track patients across hospitals, so some later-line treatments may have gone unrecorded; a lack of reliable death information also meant the team measured duration of therapy rather than overall survival. Missing PD-L1 expression and performance status data mean the benefits of first-line nivolumab may be somewhat overestimated, since fitter patients with higher PD-L1 expression may preferentially have received it, and the data stop before the most recent approvals such as zolbetuximab. Even so, the message is unambiguous: newly recommended regimens for HER2-negative advanced gastric cancer have been steadily and successfully woven into Japanese clinical practice, and patients today remain on active treatment roughly four months longer than their counterparts a decade ago. The authors hope these real-world benchmarks will guide the next round of research into the optimal sequencing of therapies for this hard-to-treat population.

Subject of Research: Real-world evolution of treatment patterns and duration of therapy in HER2-negative advanced gastric cancer in Japan from 2012 to 2023

Article Title: Evolution of Real-World Treatment Patterns over Time in Patients with HER2-Negative Advanced Gastric Cancer: A Retrospective Database Cohort Study from Japan

Article References: Hironaka, S., Kimijima, Y., Shinno, Y., Nishiyama, E., Kikko, Y., Matsuda, Y., Yamamoto, T., Teixeira, B. C., & Yoshikawa, T. (2026). Evolution of Real-World Treatment Patterns over Time in Patients with HER2-Negative Advanced Gastric Cancer: A Retrospective Database Cohort Study from Japan. Advances in Therapy. https://doi.org/10.1007/s12325-026-03763-5

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03763-5

Keywords: gastric cancer, HER2-negative, nivolumab, immunotherapy, chemotherapy, treatment patterns, duration of therapy, real-world data, S-1, oxaliplatin, Japan, administrative claims database

GEA’s global burden continues to rise, yet patterns of incidence and response to treatment diverge sharply between regions, particularly when contrasting Asia with Western countries. This geographic variability has underscored the complexity of the disease, driving a need for region-specific clinical trials that respect these epidemiologic subtleties. For instance, Asian populations show a higher prevalence of distal gastric tumors and a greater responsiveness to certain chemotherapy regimens, while Western cohorts often experience proximal or gastro-oesophageal junction tumors with differing molecular characteristics. These disparities have important implications for designing perioperative treatment strategies that can be tailored to both patient population and tumor biology.

The integration of immune checkpoint inhibitors (ICIs) into the perioperative management of GEA represents one of the most significant strides forward in recent years. Previously confined largely to metastatic or refractory disease settings, immunotherapy now encroaches on the curative-intent landscape, offering hope for enhanced pathological response rates and survival benefits when combined with chemotherapy or chemoradiotherapy. Randomized controlled trials employing PD-1/PD-L1 blockade in the neoadjuvant or adjuvant setting have demonstrated encouraging activity, fundamentally altering the standard of care and prompting ongoing investigations into optimal sequencing and combination strategies.

Despite these advances, setbacks have tempered some of the initial enthusiasm, particularly concerning radiotherapy’s evolving role. While radiotherapy has been a cornerstone of multimodal perioperative therapy for GEA, burgeoning data from recent trials have questioned its universal applicability. In some contexts, radiotherapy’s incremental benefit appears marginal or associated with increased toxicity, weighing against its use without precise patient selection criteria. Consequently, researchers are now focusing on identifying biomarkers capable of predicting radiotherapy sensitivity, aiming to balance efficacy with safety while preserving organ function where feasible.

Targeted therapies continue to expand the therapeutic armamentarium in GEA, with agents directed against HER2, VEGF, and MET pathways exemplifying precision medicine’s potential. The successful integration of HER2-targeting agents, particularly trastuzumab, into perioperative regimens for HER2-positive tumors represents a paradigm shift, transforming historically dismal prognoses. Beyond HER2, emerging targets and novel agents—either as monotherapy or combined with immunotherapy—are under intense scrutiny in clinical trials, reflecting a vigorous effort to intercept tumor progression through molecular vulnerabilities specific to each patient’s cancer.

Advances in circulating tumor DNA (ctDNA) analysis herald a new era in personalized therapy for GEA, enabling dynamic monitoring of tumor burden and minimal residual disease during the perioperative period. By quantifying ctDNA, clinicians can identify molecular residual disease post-surgery or during systemic therapy, predicting relapse risk with unprecedented precision. This liquid biopsy approach is poised to revolutionize risk stratification, influence treatment escalation or de-escalation decisions, and expedite the design of individualized therapeutic schedules, ultimately enhancing survival outcomes and minimizing overtreatment.

In line with these molecular advances, organ-preserving strategies are garnering increasing attention as alternatives to radical surgery in highly selected patients exhibiting excellent response to neoadjuvant therapies. The potential to maintain quality of life and reduce morbidity without compromising oncological outcomes challenges traditional paradigms centered on total gastrectomy or oesophagectomy. Clinical trials exploring active surveillance and local ablative treatments in patients with complete clinical response are underway, reflecting a patient-centered approach that prioritizes functional preservation alongside disease control.

The elucidation of tumor microenvironment dynamics has further enriched our understanding of GEA biology, revealing complex interactions between cancer cells, immune infiltrates, stromal components, and the extracellular matrix. This intricate ecology influences tumor progression, metastasis, and treatment resistance, highlighting opportunities for combinatorial therapies that target not only the malignant cells but also their supportive niche. Agents modulating the immune milieu, stromal reprogramming drugs, and vasculature-targeting molecules represent promising adjuncts to enhance perioperative therapeutic efficacy.

The reliance on robust, well-structured clinical trials has been pivotal in shaping current perioperative paradigms. Landmark studies such as FLOT4, CheckMate 577, and others have established chemotherapy regimes that improve survival, introduced immunotherapy in the adjuvant context, and explored novel therapeutics. Additionally, negative or equivocal trial results have been equally instructive, refining patient selection and guiding hypothesis-driven research to overcome previous limitations. These iterative cycles of success and setback underscore the importance of rigorous evidence generation to translate molecular discoveries into clinical benefit.

Future horizons for GEA perioperative management emphasize multi-modal, multi-disciplinary strategies intricately informed by tumor genomics and immunoprofiling. The convergence of big data analytics, artificial intelligence, and machine learning promises to further elevate treatment personalization, enabling clinicians to predict therapeutic responses and adapt regimens dynamically in real time. Additionally, the integration of patient-reported outcomes and quality of life metrics into clinical decision-making will promote holistic care models that address physical, psychological, and social dimensions of cancer survivorship.

International collaboration has emerged as a cornerstone of progress against GEA, given the disease’s global heterogeneity and the necessity for large patient cohorts to validate novel interventions. Consortia and networks spanning continents are facilitating harmonized protocols, shared biobanking, and pooled data analysis, accelerating discovery and dissemination of best practices. This global approach ensures that advances made in one region can be adapted, validated, and implemented worldwide, bridging gaps in access and equity that have historically hampered cancer care.

On the technological front, advances in surgical techniques including minimally invasive and robotic-assisted procedures have complemented systemic therapy improvements, promoting faster recovery and reduced perioperative morbidity. Enhanced imaging modalities allow improved staging accuracy and intraoperative guidance, crucial for tailoring surgical extent and integrating adjunct therapies. The synergy between surgical innovation and systemic treatment optimization epitomizes the multi-pronged attack necessary for tackling GEA effectively.

At the molecular level, increased understanding of genetic instability, epigenetic alterations, and metabolic reprogramming in GEA cells continues to unearth novel targets. Future therapies may exploit synthetic lethality approaches, epigenetic modifiers, and metabolic inhibitors, potentially combined with existing immuno- and chemo-therapeutics to overcome resistance mechanisms. The identification of new biomarkers capable of predicting these interactions will be essential, accelerating bench-to-bedside translation and continuous refinement of treatment algorithms.

Ultimately, the evolving paradigm for perioperative management in gastro-oesophageal adenocarcinoma reflects a dynamic interplay of epidemiologic insights, clinical trial innovation, biological understanding, and technological advances. While significant challenges remain—such as overcoming tumor heterogeneity, managing toxicity, and translating research into equitable global care—the steady accumulation of knowledge and therapeutic options offers unprecedented hope. The future for GEA patients lies in personalized, precisely targeted, and biologically informed approaches that maximize cure rates while preserving quality of life in an increasingly patient-centric oncology era.

Subject of Research:
Perioperative treatment strategies and therapeutic innovation in gastro-oesophageal adenocarcinoma (GEA).

Article Title:
Transforming perioperative treatment of gastro-oesophageal adenocarcinoma: triumphs, setbacks and future horizons.

Article References:
Zhu, H., Lordick, F., Janjigian, Y.Y. et al. Transforming perioperative treatment of gastro-oesophageal adenocarcinoma: triumphs, setbacks and future horizons. Nat Rev Clin Oncol (2026). https://doi.org/10.1038/s41571-026-01156-9

Image Credits: AI Generated