TO THE EDITOR
Pancreatic cancer (PC) is one of the leading causes of cancer-related deaths worldwide, and its incidence increases significantly with age. Most patients are diagnosed at an advanced stage, with a 5-year survival rate < 10%[1]. The majority of PC patients are elderly, with an average age of 70 years at the time of diagnosis, and 24.7% of these patients fall within the age range of 75-84 years[2]. While several chemotherapy-based clinical trials have been conducted in elderly patients with PC, robust evidence from pivotal studies remains limited[2,3].
Immunotherapy, represented by programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors, plays an important role in the treatment of various solid tumors by blocking T-cell inhibitory signals and restoring their anti-tumor activity. However, PC has a highly immunosuppressive tumor microenvironment, characterized by an “immune desert” or “immune exclusion” phenotype, which is considered the main reason for PD-1/PD-L1 inhibitor resistance[4]. Therefore, it is crucial to explore the precise use and safety of PD-1/PD-L1 inhibitors in elderly patients with PC. The recent retrospective study by Lu et al[5] published in the World Journal of Gastrointestinal Oncology, identified clinical predictors in elderly patients with advanced PC treated with PD-1 inhibitors. The results revealed that an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-1, prognostic nutritional index (PNI) ≥ 45.6, and triglyceride (TG) levels < 1.315 mmol/L can serve as independent predictors of progression-free survival (PFS) and overall survival (OS). Elderly patients with these biomarkers may benefit clinically from PD-1 inhibitors. The above results provide clues for identifying the clinical benefit of PD-1/PD-L1 inhibitors for elderly patients with advanced PC.
Although this study identified important prognostic factors, based on the study design and the basic characteristics of the included patients, some important issues need to be discussed. The study included 99 elderly patients with advanced PC, analyzed clinical characteristics such as sex, age, and ECOG PS, etc. in relation to PFS and OS, and recorded adverse events related to PD-1 inhibitors. ECOG PS, PNI, and TG levels independently influenced the patients’ PFS and OS. The overall incidence of immune-related adverse reactions was low, and safety was good.
Based on the distribution of clinical characteristics in the included population, the following points need to be noted: The majority of patients were under 75 years old; the number of hepatitis B virus infection cases was small; 70.7% of the patients were receiving first-line treatment; most patients did not receive radiotherapy, but combined chemotherapy; and the distribution of these clinical characteristics was relatively uniform. For patients with advanced PC, whether first or second-line treatment, and whether radiotherapy or chemotherapy are used, significantly affects PFS and OS. Therefore, these clinical variables were not identified as independent prognostic factors for the patients; a finding that warrants further investigation.
Notably, the single-center design and limited sample size represent the study’s primary limitations. Furthermore, the inclusion criteria did not rigorously control for variations in patients’ treatment regimens, potentially introducing confounding effects in the analysis of the associations between treatment stage, treatment modality, and survival outcomes, especially in relation to the minimum cycle of PD-1 treatment or chemotherapy. Adding information about biomarkers for PD-1 treatment efficacy [mismatch repair (MMR)/microsatellite instability (MSI) status, PD-L1 expression level, and tumor mutation burden] would further improve the quality of the study. Biomarker data collection is often problematic in the context of unresectable PC, as there is insufficient high-level evidence to support routine testing of PD-L1 and other biomarkers in tissue samples.
Regarding adverse reactions, this study should provide more comprehensive results. The majority of the included patients were receiving combined treatment, so the overall incidence of adverse reactions, including immune treatment-related adverse reactions, should be analyzed. Given that elderly patients are generally characterized by reduced treatment tolerance, safety considerations assume heightened priority in clinical decision-making. A meta-analysis showed that the overall incidence of immune-related adverse events in elderly patients may be similar to or slightly lower than that in young patients, but the risk of certain organ toxicity (such as pneumonia or nephritis) may increase[6]. Another study demonstrated that treatment interruptions or dose adjustments resulting from immune-related adverse events or non-immune complications were more frequent in elderly patients, potentially having indirect effects on therapeutic efficacy[7]. Therefore, accurate and comprehensive adverse reaction data could can further enhance the clinical value of this study. In terms of specific adverse reaction types, colitis/diarrhea occurred frequently, with a total incidence of 10%-20%. The incidence of grade 3 or above adverse reaction was 1%-3%, but this was not mentioned in the results, which is also a deficiency[8].
Progress in anti-PD-1/PD-L1 therapy for PC
Previous studies have demonstrated that the efficacy of anti-PD-1/PD-L1 therapy in patients with advanced PC is highly limited. Even when combined with chemotherapy, the 1-year survival rate remains approximately only 50%[9]. MSI-high/deficient MMR patients benefit most, but accounts for only 1%-2% of the total PC population. Based on the results of KEYNOTE-158, pembrolizumab has been approved for advanced solid tumors in MSI-high/deficient MMR patients, including some patients with PC, and the efficacy is not significantly correlated with age[10].
However, for elderly PC patients with microsatellite stable, immune checkpoint inhibitor (ICI) monotherapy is not the standard choice. In combination therapy for the first-line treatment of metastatic PC, adding ICI to standard chemotherapy regimens (such as AG or FOLFIRINOX) does not significantly improve OS[11]. On the contrary, some small-sample phase I/II clinical trials have found that combined treatment with anti-PD-1/PD-L1 therapy can provide survival benefits[12-14]. More innovative combined treatment models are gradually being developed, such as those combining CXCR4 antagonists and PD-1 inhibitor, or stereotactic body radiotherapy and PD-1 inhibitor[15,16]. The clinical value of anti-PD-1/PD-L1 therapy in the comprehensive treatment of PC still has many ambiguities and controversies. How to secure the beneficial effect of ICIs in combined therapy remains a hot topic.
Particularities of elderly patients receiving anti-PD-1/PD-L1 therapy
The immune system undergoes remodeling during aging, as a result of the combined effects of cellular and tissue physiological aging, environmental factors, and chronic antigen exposure[17]. ICIs rely on a sustained immune response to exert their anti-tumor effects. It is not clear whether the decline in immune function associated with aging negatively impacts the anti-tumor response and thereby reduces the efficacy of ICIs in elderly patients. A meta-analysis including 5265 patients from nine randomized controlled trials compared the efficacy of ICIs between young and elderly patients. Patients were divided into an elderly group aged 65-70 years and a young group. An improvement in PFS was observed in both the young group [hazard ratio (HR) = 0.58; 95% confidence interval (CI): 0.40-0.84] and the elderly group (HR = 0.77; 95%CI: 0.58-1.01). Subgroup analysis revealed consistent survival benefits in both the young and elderly groups (HR = 0.86; 95%CI: 0.41-1.83)[6]. In most cases, elderly patients (typically defined as ≥ 65 years old or ≥ 70 years old) benefit from immune therapies such as ICIs, CAR-T cells, and bispecific antibodies, to the same extent as younger patients. Some scholars have suggested that, based on the epidemiological characteristics of tumor occurrence, the majority of patients in the future may be aged over 60 years. Therefore, the evaluation of immune system aging should be based on biomarkers rather than age alone, which may precisely reflect the actual physiological status of the body[18].
Conclusion
Lu et al[5] showed that ECOG PS, PNI, and TG levels independently influence the PFS and OS of elderly patients with advanced PC receiving PD-1 inhibitors. This provides clues for accurately predicting the benefit from anti-PD-1 treatment for elderly patients. However, this study is limited by its modest sample size, and lack of basic clinical information, and safety data. The results need to be verified in higher-level evidence-based clinical trials. For elderly individuals with PC, future research should focus on designing stratified clinical trials, establishing clinical databases and biological sample banks, exploring new biomarkers, and developing safe combination treatment strategies.
