The clinical significance of the PNI was investigated in 35 patients with metastatic AGC who underwent nivolumab mostly as second- or third-line therapy. As a result, the PNI was identified as an independent predictive factor of PFS and OS, suggesting that the PNI may be a useful biomarker to predict the response to ICIs in AGC patients with peritoneal metastases.
The molecular mechanisms by which AGC undergoes peritoneal metastases are not completely clear and considered as a multistep process, including the detachment of cancer cells from the primary tumor, survival in the free abdominal cavity, attachment to the distant peritoneum, invasion into the subperitoneal space and proliferation with angiogenesis . In particular, various molecules, such as E-cadherin, chemokines, growth factor receptors/ligands, immune cells, and extracellular matrix, broadly contribute during the invasion of the gastric wall and migration of the cancer cells . These factors all play an essential role in the progression and chemoresistance of peritoneal metastases . Although recent studies of AGC patients with peritoneal metastases have attempted to demonstrate improved survival with systemic chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC)/peritonectomy, the long-term outcomes remain dismal . In the present study, peritoneal metastases showed poor outcomes even after treatment with nivolumab, as consistent with previous study results. Subgroup analyses of the ATTRACTION-2 trial found no significant benefit from nivolumab in patients with peritoneal metastases. Similarly, Aarnink et al. reported that ICIs used in non-small cell lung cancer (NSCLC) patients with peritoneal metastasis were associated with poor PFS and OS . Recent studies also showed that diffuse and signet ring cell histologies had poor outcomes with nivolumab treatment, indicating that these types seemingly promote AGC cell migration, invasion, and enhanced peritoneal metastases [6, 21–23]. Therefore, since these findings and the current results suggest that peritoneal metastases have a relatively limited response to ICIs, the role of ICIs in AGC with peritoneal metastases requires further clarification.
Recent research has been focused on identifying robust predictive biomarkers for AGC treated with ICIs. The PNI, first reported by Onodera et al., is a well-known inflammatory prognostic marker for several solid tumors . The PNI includes the serum lymphocyte and albumin levels. There is increasing evidence that the lymphocyte ratio can be an effective predictive indicator related to ICIs for various solid tumors, having a favorable effect on their tumor inhibiting properties . Moreover, albumin is an acute-phase protein and decreases in response to inflammation . Thus, low levels of albumin may reflect cancer-induced malnutrition and have a negative impact on prognosis. Therefore, indicating a poor diet in the case of AGC with peritoneal metastases, these factors may help to determine the predictive value of ICIs including nivolumab in these patients. Several studies covering a variety of cancers: gastric cancer, colorectal cancer, NSCLC, and genitourinary cancer treated with ICIs found that a low PNI resulted in worse OS and PFS across various types of malignancies, which is consistent with the current study results [9, 12, 26, 27]. Plus, another recent study showed a statistically significant outcome with a large number of gastric cancer patients. Mohri et al. analyzed 365 CRC patients who underwent curative resection, and reported that a PNI < 45 independently affected OS . This particular parameter also has several advantages for daily clinical practice: ready to use, easily measurable, repeatable, and relatively economical to evaluate . Thus, considering its recognized influence on host nutritional status, immunity, and cancer, the PNI can be effectively used to predict the therapeutic effects of nivolumab in AGC patients with peritoneal metastases.
In summary, the PNI can be useful for predicting PFS and OS in AGC patients with peritoneal metastases. However, further studies are required to validate these results in AGC and new strategies are needed to improve the outcome for AGC patients with peritoneal metastases.