The Necessity of Guidance: Optimizing Adjuvant Therapy for Stage II/III MSI-H Gastric Cancer Through the Interplay of Evidence, Clinical Judgment, and Patient Preferences

Global variations in the prevalence and treatment of gastric cancer (GC) underscore the need for region-specific clinical guidelines. In response, the Korean Gastric Cancer Association (KGCA) published its first independent guidelines in 2019 and updated in 2023 [1,2]. This guideline is unique in that it prioritizes crucial clinical questions and uses systematic reviews and meta-analyses to establish evidence levels that guide clinical management. We are deeply thankful for these efforts.

Since their publication, these guidelines have been compared to contemporary international GC treatment guidelines [3]. After these comparisons, updates have been notably made to the European Society of Medical Oncology (ESMO) [4] and Chinese Society of Clinical Oncology (CSCO) guidelines [5]. Among these updates, the recommendations for adjuvant chemotherapy in stage II/III microsatellite instability-high (MSI-H) GC are particularly significant.

MSI-H is a unique and representative molecular subtype of GC caused by a deficiency in mismatch repair (dMMR), and accounts for approximately 10% of GC cases [6,7]. The clinical characteristics of dMMR/MSI-H GC have been reported to have a better prognosis than the microsatellite stable one and benefit from additional chemotherapy over surgery alone is questionable [8]. These results were confirmed in a multinational individual patient data meta-analysis [9] of retrospective biomarker studies from four randomized controlled trials (RCTs) (including Korean data, CLASSIC [10], and ARTIST trials [11]). Based on this meta-analysis of RCTs, recent ESMO guideline recommends “Adjuvant (postoperative) chemotherapy should be avoided in resected MSI-H GC” [4]. In addition, updated CSCO guideline recommends “Taking adverse reactions related to chemotherapy and patients’ financial implications into account, it is suggested that for dMMR/MSI-H patients, (neo)adjuvant treatments such as immunotherapy in clinical trial settings could be first considered, unless unwillingness from the patient’s side, after detailed discussion with the patient and families about the risk and benefits of different treatment strategies, postoperative observation or chemotherapy can be considered.” [5].

Globally, five major guidelines address GC treatment as follows: the KGCA (South Korea) [2], the National Comprehensive Cancer Network (NCCN) [12], ESMO (Europe) [4], Japanese Gastric Cancer Association (JGCA, Japan) [13], and CSCO (China) [5]. The updated ESMO and CSCO guidelines now advise against or at least reconsider adjuvant chemotherapy for patients with stage II/III MSI-H GC. However, others, including KGCA, have not commented on this issue. This discrepancy among the five GC guidelines underscores the complexity of this issue.

Adjuvant chemotherapy is critical for patients with stage II/III GC after curative resection. However, the prognosis of patients with MSI-H GC is comparatively favorable, with no discernible improvement in outcomes attributable to adjuvant chemotherapy. However, the decision-making process remains complex for clinicians as there is still a risk of recurrence among patients with MSI-H, which might be mitigated by adjuvant chemotherapy. While evidence [9] suggests that adjuvant chemotherapy may not be beneficial, the clinical dilemma persists owing to the potential for recurrence prevention. Although administering chemotherapy can reduce the risk of recurrence, subjecting patients to ineffective adjuvant chemotherapy may expose them to unnecessary risks and adverse effects. This dilemma lies between the academic and practical decisions for this patient subset. Thus, guidelines must address this issue and provide clinicians and patients with evidence-based recommendations to assist them in making informed decisions regarding adjuvant chemotherapy for patients with MSI-H GC.

As the KGCA guidelines are planned to be updated, we want to incorporate these findings to aid clinicians in navigating the evidence-based decision-making process while considering individual patient care. These guidelines will enable physicians and patients to discuss and decide on the best treatment strategy. We hope that these updates will allow patients and their doctors to make informed choices regarding adjuvant chemotherapy, based on the latest evidence and considering individual preferences and values.