Gastric cancer is one of the prevalent tumors across the globe. It has the second-highest incidence and mortality in China [18]. Early gastric cancer has a 5-year survival rate of 95% when treated with surgery, adjuvant chemotherapy, and radiotherapy. However, the early symptoms of gastric cancer are unapparent and difficult to detect. Although chemotherapy is currently the primary treatment for advanced gastric cancer, advances in tumor molecular biology, particularly molecular targeted therapy and immunotherapy research have yielded new optimism for the comprehensive treatment of gastric cancer.
Prognosis of various cancers, including gastric cancer, is improved by Immune checkpoint inhibitors (ICIS), specifically, those targeting programmed cell death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) [8, 19–22]. Nonetheless, the number of elderly cancer patients is increasing due to the aging population [11]. Elderly patients are a unique population with multiple comorbidities at the time of diagnosis, which might inhibit their survival [23, 24]. Brenchley J M and colleagues discovered that the antitumor immunogenic response was attenuated due to upregulated expression of CD57 on the surface of cytotoxic T cells among the elderly [25, 26]. Thereafter, Henson SM and colleagues found that upregulated expression of PD-1 on elderly T cells, and its blockade did not achieve a similar degree of T cell activity as in young adults [27–29]. In addition, Elias R et al. in 2017 proposed that immune changes induced by aging could have an impact on the activity of checkpoint inhibitors, such as PD-1 and PD-L1 inhibitors [30]. Studies indicate that downregulated expression of CD28 on the surface of CD8 + T cells causes decreased immune activity among elderly people [31–34]. Although these quantitative and functional T cell abnormalities have gradually been characterized, the potential impact of aging on the efficacy and tolerance of immunotherapy in clinical practice remains unknown.
At present, specific studies on the efficacy evaluation of PD-1 inhibitors among elderly patients with advanced gastric cancer have not been published. ATTRACTION-2 study revealed that nivolumab prolongs the OS of elderly patients with gastric cancer > 65 years old (HR = 0.53, 95%). CI: 0.38 to 0.74) [8]. In cohort 1 of the KEYNOTE-059 study [6], an age-based subgroup analysis revealed that patients aged ≥ 65 years had an OS of 5.9 months, which was comparable to patients aged < 65 years (5.2 months). This study found that the ORR and DCR of all patients were 31.4% and 78.4%, respectively and the MOS for all patients was 14.4 months.
Additionally, we evaluated the safety of PD-1 inhibitors in the treatment of elderly patients with advanced gastric cancer. Consequently, 8 of 51 patients had immune-related adverse reactions, and 4 were liver damage (grade 2–3), 2 cases of hypothyroidism, 1 case of interstitial pneumonia, and 1 case of mild skin blisters. There were no immune-related deaths. Therefore, this study shows that the safety of PD-1 inhibitors in elderly patients with advanced gastric cancer is manageable.
Furthermore, studies have shown that the LIPI score can be used as a biomarker for immunotherapy in solid tumors, including lung cancer. Mikihiro Kano discovered that PMI could be a biomarker for advanced gastric cancer (17). Therefore, besides gender, ECOG score, chemotherapy regimen, and the number of metastases, PMI, LIPI were used for univariate and multivariate analyses. We found that the number of 2 or more distant metastatic organs was independently associated with low MPFS, whereas mPFS [9.3 months vs 4.4 months, P > 0.05] and mOS [18 months vs 12 months, p < 0.05] with patients on first-line PD-1 inhibitors showed a prolonged trend. At the same time, univariate analysis of ORR and DCR showed that the P values of first-line treatment, LDH, number of metastatic organs, and other influencing factors were less than 0.05; the difference was statistically significant. Furthermore, the first-line therapy was independently associated with ORR. That is, for the elderly, the first-line use of PD-1 inhibitors could greatly benefit patients; we speculate that this could be attributed to the physical status and tolerance of elderly patients with advanced gastric cancer. Nevertheless, this speculation remains to be validated in additional research. Because the association between first-line therapy and the efficacy of PD-1 inhibitors in elderly individuals with advanced gastric cancer has not been examined, comparing our findings to those of other trials to further establish their predictive value is difficult. Thus, larger-scale studies are necessary for validation.
Additionally, no correlation was found between PMI and the efficacy of elderly patients with advanced gastric cancer; this is inconsistent with the findings of Mikihiro Kano et al. Mikihiro Kano and colleagues discovered that PMI could help predict the response to PD-1 inhibitors in patients with advanced gastric cancer ( P = 0.004) [16]. However, we did not identify such a trend; this could be attributed to the fact that the cut-off value of PMI remained undefined. For the cut-off value, we referred to the research of Mikihiro Kano and colleagues, thus, the cut-off value of PMI warrants additional verification.
This work has several potential clinical implications; first, our findings for the first time show that the first-line use of PD-1 inhibitors prolongs the survival of elderly patients with advanced gastric cancer. Moreover, we found that the number of distant metastatic organs positively correlated with the efficacy and prognosis of elderly patients with advanced gastric cancer using PD-1 inhibitors.
This study has worth-mentioning limitations. First, it is a single-center retrospective study with a relatively small sample. Secondly, there exist inevitably certain biases and incompleteness in the process of data collection; this inevitably exerts an impact on the findings.