Immunotherapy for gastric cancer and liver metastasis: Is it time to bid farewell

Abstract

Patients with metastatic gastric cancer have a grim prognosis. Palliative chemotherapy offers a limited survival improvement, but recent advancements in immunotherapy have sparked hope. However, the effectiveness of immunotherapy in patients with liver metastases remains debated. This article reviews a recent study by Liu et al and evaluates conflicting evidence on the impact of liver metastases on response to immunotherapy in metastatic gastric cancer. While some studies suggest no significant difference in treatment response based on liver involvement, others report varied response rates. The present study, a retrospective analysis of 48 patients by Liu et al, examines this issue and concludes that immunotherapy is less effective in patients with liver metastases. Despite methodological limitations and a small sample size, the study contributes to the ongoing discourse. The nuanced response to immunotherapy in certain patients underscores the importance of understanding the tumor microenvironment, immune cell infiltration, and the expression of immune checkpoints. Rather than dismissing immunotherapy for patients with gastric cancer and liver metastases, a shift towards personalized treatment strategies and a more profound understanding of tumor-specific biomarkers is essential. By unraveling the molecular intricacies of individual cases, clinicians may tailor more effective and customized treatments, offering a glimmer of hope for this challenging patient group.

Key Words: Immunotherapy; Gastric cancer; Liver metastasis; Efficacy; Prognosis

Core Tip: The prognosis of patients with gastric cancer and liver metastasis is abysmal. Palliative chemotherapy is associated with a limited survival benefit yet is very toxic. Immunotherapy is considered an emerging promising therapy with some remarkable results. There has been a growing body of literature from animal and human studies that question the efficacy of immunotherapy in these patients. In this article, we discuss this issue and provide a balanced appraisal of the literature.

INTRODUCTION

The median survival of patients with metastatic gastric cancer is only 3 to 5 months without treatment. Palliative chemotherapy may prolong survival to approximately 9-11 months in patients with Her2-negative disease[1]. Recently, immunotherapy has emerged as a promising therapy after a remarkable response in various malignancies. Results from several randomized trials, including the Checkmate-649[2] trial and the KEYNOTE-158[3] trial, which showed improved survival compared to chemotherapy, led to the approval of drugs such as Nivolumab and Pembrolizumab, respectively.

Current recommendations for the management of patients with HER2-negative metastatic gastric cancer include Fluoropyrimidine, oxaliplatin, or Cisplatin, with or without nivolumab or pembrolizumab as first-line therapy, followed by Ramucirumab and paclitaxel, Docetaxel, Paclitaxel, Irinotecan, Fluorouracil, or irinotecan as a second line therapy[4]. However, several pre-clinical[5] and clinical studies[6-8] have suggested reduced efficacy of immunotherapy in patients with liver metastases in melanoma and non-small cell lung cancer. Scientific observation from animal studies nicely described the mechanisms for this phenomenon. Liver metastases induce a systemic loss of antigen-specific T cells, siphon activated CD8+ T cells from the systemic circulation, reduce peripheral T cell numbers, and diminish tumoral T cell diversity and function. Liver metastases alter the hepatic immune microenvironment by inducing activated T cell apoptosis via the Fas-FasL pathway. Consequently, liver metastases create a systemic immune desert[5].

CURRENT EVIDENCE

In gastric cancer, previous studies evaluating the efficacy of immunotherapy in the setting of liver metastases have shown conflicting results. In a subgroup analysis with a 2-year follow-up from the CheckMate-649, the presence of liver metastases did not impact the rate of response in patients with metastatic gastric cancer treated with immunotherapy[9]. Similarly, findings from the ATTRACTION-2 trial and the ATTRACTION-4 trial demonstrated that the survival benefit of Nivolumab did exist regardless of the status of the liver metastases[10,11]. Contrarily, in the REGONIVO trial, patients with liver metastases had a response rate of approximately 42%, whereas patients without liver involvement had a response rate of 80%[12]. Retrospective studies examining the role of immunotherapy in patients with gastric cancer and liver metastases have yielded mixed results as well. Some studies demonstrated that liver metastasis was associated with a decreased response rate and rapid disease progression, compared to other metastases[13,14], whereas other studies showed no such impact[15].

In the study by Liu et al[16] published in this issue of the World Journal of Gastrointestinal Surgery, the authors challenged the efficacy of immunotherapy in this group of patients. This study is a small (n = 48) retrospective evaluation of patients with HER2-negative metastatic gastric cancer treated with immunotherapy at a Chinese hospital. The methodology is a simple comparison of two groups of patients (metastatic gastric cancer with or without liver metastasis) across the study outcomes: Objective response rate, disease control rate, progression-free survival (PFS), and overall survival. Although clinical differences were noted between the two groups in all measured outcomes favoring the group without liver metastasis, apart from the PFS, none of the other outcomes showed statistical significance. The study concluded that immunotherapy is less effective in patients with liver metastases than those without.

I commend the authors for their efforts to expand our understanding of the role of immunotherapy for this disease and improve patient selection for this costly and potentially risky treatment. Several issues are worth discussing. Paclitaxel is not a first-line chemotherapy for patients with metastatic gastric cancer. Tirellizumab, an investigational, humanized PD-1 inhibitor, has demonstrated preliminary antitumor activity in hepatocellular carcinoma. It is unclear how this agent was selected as part of the combination regimen as it has not been approved for treating metastatic gastric cancer patients. The study's retrospective design, with its inherited selection bias, especially given the significant difference in baseline performance status and, finally, the small sample size, are additional issues that should be considered when evaluating the study.

While some studies suggest a limited efficacy of immunotherapy in patients with gastric cancer and liver metastases, a broader examination of the literature revealed diverse findings. Other studies counter this notion, demonstrating that the mere presence of liver metastases does not definitively predict poor response to immunotherapy; instead, it underscores the importance of delving into the underlying tumor biology as variation in molecular characteristics and genetic makeup may play a pivotal role in determining the responsiveness of these patients.

CONCLUSION

Throughout history, surgeons have always understood with much clarity that the biology of the tumor dictates prognosis. No better than the late Dr. Blake Clady's famous quotation, "Biology is King," who eloquently illustrated this understanding. However, as another surgical giant, the late Dean Lutin, once said, "We are only at the foothills of understanding cancer, and the biological mountain still lies in the clouds ahead," we are yet to fully understand the biology of tumors. The diverse response to immunotherapy in patients with gastric cancer and liver metastases may be attributed to several underlying tumor biological characteristics such as a tumor microenvironment, immune cell infiltration, and expression of immune checkpoint. Tumors with high levels of immune cell infiltration and increased expression of PD L1 may exhibit an enhanced response to immunotherapy[17].

Additionally, genomic instability, tumor mutational burden, and specific molecular subtypes of gastric cancer can influence treatment outcomes[18-20]. Even more interesting is the revolutionary cutting-edge single-cell omics and spatial transcriptomics technologies, which enabled the exploration of cellular heterogeneity and molecular landscapes of gastric cancer at the single-cell level and revolutionized our understanding of cellular function and tissue organization. These technologies have a promising potential for even more personalized treatment for patients with gastric cancer[21-23]. Therefore, it is not time yet to bid farewell to immunotherapy in this unfortunate group of patients whose prognosis is otherwise dismal. Instead, we need to shift focus toward comprehensive tumor profiling to identify these biomarkers and understand the molecular intricacies of individual cases to tailor more personalized and effective treatment strategies.