Perioperative chemotherapy strategies in diffuse gastric cancer

Abstract

This study reviews the findings of a recent study by Li et al, which demonstrated that perioperative chemotherapy benefits patients with diffuse-type gastric cancer compared to surgery alone. Despite potential biases, the study supports the inclusion of perioperative chemotherapy in treatment guidelines. Neoadjuvant and adjuvant chemotherapy may also provide similar survival outcomes, allowing for flexible treatment planning.

Key Words: Gastric cancer; Neoadjuvant chemotherapy; Adjuvant chemotherapy; Gastric adenocarcinoma; Survival

Core Tip: Perioperative chemotherapy is potentially effective for treating diffuse-type gastric cancer, supporting its continued inclusion in treatment guidelines. However, further research is needed to define optimal therapeutic strategies and improve patient outcomes.

TO THE EDITOR

Gastric adenocarcinoma is an aggressive cancer with a 20% five-year survival rate in developed countries[1]. The main treatment involves surgical resection with lymphadenectomy, and accurate preoperative staging is crucial for successful outcomes. In medically fit patients with resectable tumors classified as locally advanced, perioperative chemotherapy is strongly recommended[2].

The Laurén classification system categorizes gastric adenocarcinomas into intestinal, diffuse, and mixed types[3]. Diffuse-type gastric adenocarcinoma (DGAC) has a poorer prognosis and shows lower response to chemotherapy compared to the intestinal type[4], which has raised questions about the effectiveness of perioperative chemotherapy for DGAC. Here we discuss a recent study by Li et al[5] in the World Journal of Gastrointestinal Surgery that explores the impact of perioperative chemotherapy on the survival of patients with locally advanced diffuse gastric cancer.

Is perioperative chemotherapy effective for diffuse-type gastric cancer?

Li et al[5] performed a United States population-based study on the surveillance, epidemiology, and end results (SEER) database and found that patients who received perioperative chemotherapy had higher overall survival and cancer-specific survival rates. These results were consistent with findings from the Netherlands Cancer Registry[6]; but, a separate study from France did not show a significant survival benefit from perioperative chemotherapy compared to surgery alone[7]. However, it is important to note that these studies are retrospective and rely on database analyses, which come with inherent limitations. For example, although the study by Li et al[5] demonstrated significant survival benefits, there is a potential for selection bias. Patients with better physical status and fewer comorbidities are more likely to be chosen for neoadjuvant chemotherapy, potentially leading to improved survival outcomes. Additionally, the absence of data on R0 resection rates introduces further bias, as patients receiving neoadjuvant chemotherapy are more likely to achieve an R0 resection, potentially affecting survival outcomes.

There is a lingering question about whether neoadjuvant chemotherapy provides consistent survival benefits across all stages of DGAC. The effectiveness of chemotherapy may vary depending on the stage, with more advanced DGACs potentially exhibiting greater resistance in comparison to early-stage disease. A study utilizing the SEER database discovered similar 5-year cancer-specific survival rates for patients with intestinal and diffuse-type early gastric cancer[8], suggesting that the benefits of perioperative chemotherapy might be comparable to those seen in intestinal-type cancers at earlier stages but may diminish as the disease progresses.

The tolerability and side effects of perioperative chemotherapy are critical factors influencing treatment decisions, especially in elderly patients or those with comorbidities. Common adverse effects include neutropenia, nausea, vomiting, and fatigue, which can lead to dose reductions or treatment discontinuation. Studies have shown that older patients often experience more severe toxicity, limiting their ability to complete the full regimen and potentially affecting survival outcomes[9]. Balancing the potential survival benefits with chemotherapy-related toxicity is essential, highlighting the importance of assessing patient fitness and tailoring treatment plans to individual needs. Emerging regimens, such as the FLOT protocol, have demonstrated improved efficacy but come with a higher side effect profile, necessitating careful patient selection.

The current evidence, along with ongoing debate in the literature, suggests that perioperative chemotherapy may be beneficial for DGAC, as indicated by studies such as that of Li et al[5]. There are insufficient grounds to exclude perioperative chemotherapy from the standard treatment guidelines for DGAC based on the available data. However, a prospective, controlled study is needed to provide a more definitive answer regarding the role of perioperative chemotherapy in this patient population.

Neoadjuvant or adjuvant chemotherapy?

Li et al[5] also found that among patients receiving perioperative chemotherapy, survival rates were similar between those who had neoadjuvant chemotherapy and those who received adjuvant chemotherapy. Although the study by Li et al[5] did not show significant survival differences between patients receiving neoadjuvant vs adjuvant chemotherapy, primary surgical resection followed by adjuvant chemotherapy alone is not common in Western countries. Moreover, clinical trials evaluating this approach have predominantly been conducted in Asian populations, where the presentation of gastric tumors often differs from Western populations. For example, the PRODIGY trial indicated that neoadjuvant chemotherapy leads to better survival outcomes compared to adjuvant therapy for gastric cancer[10]. However, gastric tumors in Asian populations are less likely to be proximal, a location associated with a worse prognosis but potentially better response to neoadjuvant chemotherapy[11]. This highlights the need for distinct studies in Western populations to understand the effectiveness of neoadjuvant chemotherapy vs adjuvant chemotherapy better. Li et al[5] found that survival rates were similar among patients receiving perioperative chemotherapy, regardless of whether they had neoadjuvant or adjuvant chemotherapy. However, primary surgical resection followed by adjuvant chemotherapy alone is uncommon in Western countries. Clinical trials showing the effectiveness of neoadjuvant chemotherapy were mainly conducted in Asian populations[10], where gastric tumor presentation differs from Western populations[11]. Separate studies in Western populations are needed to better understand the effectiveness of neoadjuvant vs adjuvant chemotherapy. The ongoing clinical trial in France, which began in 2012, aims to investigate differences in outcomes between neoadjuvant and adjuvant therapy specifically in patients with DGAC (NCT01717924).

Neoadjuvant chemotherapy is favored for its expedited preoperative treatment delivery, potentially downstaging tumor burden and improving surgical outcomes. This approach also provides valuable insight into the cancer's response to treatment before surgery, allowing for adjustments in the adjuvant setting if needed. It is important to note that a complete response to neoadjuvant chemotherapy doesn't guarantee survival. Studies have highlighted lymph node metastases as a crucial predictor of survival post-treatment. Thus, although patients with DGAC often exhibit poor pathologic response rates to chemotherapy, the potential for downstaging tumor burden, particularly in the lymph nodes, may still offer a survival advantage[12].

Li et al's study[5] indicates that adjuvant chemotherapy may still improve survival even if neoadjuvant chemotherapy is not feasible. However, the study's limitation lies in the variation of chemotherapy regimens over time. While the MAGIC trial established neoadjuvant chemotherapy for gastric adenocarcinoma[13], since 2019, the FLOT4 trial has refined this approach with a more effective regimen now considered the standard of care[2].

Additionally, the study has some limitations due to the lack of molecular data in the SEER database, which is crucial as tumor molecular characteristics significantly influence chemotherapy response. Advancements in sequencing technologies, including whole genome sequencing and RNA sequencing, have deepened our understanding of the molecular landscape of gastric cancer. Through these efforts, The Cancer Genome Atlas classified gastric cancer into four distinct molecular subtypes: Epstein-Barr virus (EBV) positive, microsatellite instability (MSI), chromosomal instability, and genomically stable (GS)[14]. Notably, DGAC are predominantly classified within the GS subtype, comprising 73% of cases. This subtype is characterized by frequent mutations in CDH1 (37%), RHOA (15%), and CLDN18-ARHGAP26 fusions (15%). Clinically, patients with GS gastric cancer often derive minimal benefit from adjuvant chemotherapy[15]. Additionally, while MSI and EBV-associated gastric cancers are less common in DGAC, they exhibit distinct chemotherapy responses, with MSI-positive tumors often showing limited survival benefits from neoadjuvant chemotherapy[12] and EBV-associated gastric cancers exhibiting variable responses to chemotherapy, with some studies indicating poorer survival following neoadjuvant chemotherapy[16]. These findings highlight the importance of molecular profiling to refine treatment strategies for diffuse gastric cancer.

CONCLUSION

In summary, Li et al's study[5] supports the use of perioperative chemotherapy in diffuse-type gastric cancer, demonstrating a survival advantage over surgery alone. The similar outcomes between neoadjuvant and adjuvant chemotherapy suggest the potential for personalized treatment plans. However, the retrospective nature of existing studies and limitations in current data underscore the need for more controlled, prospective trials to define optimal therapeutic approaches. Until then, perioperative chemotherapy should continue to be a cornerstone of treatment guidelines, tailored to each patient's unique presentation and prognosis.