Background
The average life expectancy has increased all over the world. Japanese individuals showed the longest life expectancy worldwide in recent years. Treatment of cancer in older individuals has been a clinical problem owing to this increase in life expectancy [
1]. Pancreatic ductal adenocarcinoma (PDAC), a type of lethal malignant tumor, has a poor prognosis, and more than half of patients are diagnosed after the age of 70 years [
2]. With advances in perioperative management and surgical techniques, surgery offers a potential cure for PDAC, but surgery in older populations remains controversial [
3]. Although recent studies insisted that most older patients can receive curative therapy, including surgery, older patients selected for surgery may be among the fittest and are less likely to have comorbidities [
4]. In a recent meta-analysis, the overall survival of older patients with PDAC who underwent pancreatic resection was shorter compared with younger patients [
5]. Thus, the best way to decide the indications of pancreatic surgery for older patients should be investigated.
Frailty is a multidimensional and heterogeneous syndrome associated with instability that can be discriminated from aging or disability [
6]. Frailty is commonly assessed using summative impairment lists and algorithms based on clinical assessment [
7‐
9]. As the number of elderly patients undergoing surgery has recently increased with developments in surgery and anesthesia, reliable methods to preoperatively assess the risks of surgery in such patients are necessary, and frailty is of great importance in predicting postoperative outcomes [
9]. Although many methods can be used to assess frailty, such as the Fried frailty phenotype [
10], the study of osteoporotic fracture index [
11], the FRAIL scale (fatigue, resistance, ambulation, illness, loss of weight) [
12], and the modified Fried index [
13], few studies have compared these methods in terms of feasibility and acceptability for evaluating frailty. It was recently reported that the clinical frailty scale (CFS) was useful for predicting death or new disability after elective non-cardiac surgery [
14]. CFS is a nine-point global frailty scale based on clinical evaluation in the domains of mobility, energy, physical activity, and function [
15]. The CFS is reportedly a highly feasible, acceptable, and convenient instrument for clinical use in the perioperative period. We previously reported that frailty assessed using the CFS could predict the prognosis of older patients with hepatocellular carcinoma undergoing hepatic resection [
1]. However, there are no reports of the CFS in patients with PDAC who underwent surgery.
Herein, we aimed to investigate whether frailty, as determined by the CFS, could be a prognostic factor in patients with PDAC undergoing pancreatic resection.
Discussion
In the present study, the relationship between clinicopathological factors and frailty was investigated in patients with PDAC and the usefulness of frailty as a prognostic factor. Frailty showed correlation with (1) a low serum albumin concentration and PNI, (2) a high NLR and mGPS, (3) a large tumor diameter and a high rate of lymph node metastasis, and (4) worse cancer-specific and disease-free survival. Furthermore, aging itself was not an independent prognostic factor for survival. To our knowledge, the present study is the first to use the CFS to show a significant association between frailty and post-surgical prognosis in patients with PDAC.
Frailty is an aggregate expression of susceptibility to adverse health outcomes because of age- and disease-related deficits that accumulate across multiple domains [
15]. Some reports in geriatric patients show that frailty correlates with functional decline, hospitalization, and death [
9,
14]. In our study, the CFS was used to assess frailty. Many methods can be used to assess frailty [
10‐
13]; however, these methods require multiple questionnaires. The CFS is less quantitative compared with other methods that use clinical questionnaires, but the CFS correlates with other established assessment methods [
7]. Furthermore, the CFS can easily assess the general appearance and frailty of patients at the first check-up.
Recently, it has emerged that frailty is associated with cancer-specific survival in patients with some malignancies [
1]. In our study, frailty correlated with poor survival rate after surgery and advanced tumor state, such as larger tumor diameter and higher rate of lymph node metastasis. Although the mechanism by which frailty influences cancer malignancy and recurrence has not yet been determined, frailty is associated with inflammatory markers, such as a high mGPS. mGPS was reported to represent the presence of inflammatory response and correlated with decreased muscle mass, lower functional level, and inflammatory and angiogenic cytokines [
20]. It has also been reported that patients with frailty and various solid malignancies show a high mGPS, a more advanced tumor stage, and a poor prognosis [
21]. Hypoalbuminemia, which mainly causes a high mGPS, partially reflect an immunosuppressed status and weak systemic defense; thus, it may be related with poor survival outcomes [
22]. This can affect overall and disease-free survival in patients with various cancers. In the present study, the frailty group showed significantly lower albumin level and tendency of higher mGPS compared with the non-frailty group. Furthermore, longitudinal aging studies of Singapore [
23] showed that frailty was associated with low ɤ/δ T cells and exhausted B cell. These findings, which indicate systemic inflammation and immunosuppression, might be related to tumor progression such as large tumor diameter and higher rate of lymph node metastasis, and poor survival in our study.
Although frailty was an independent prognostic factor for cancer-specific survival, it was not a prognostic factor for disease-free survival. One reason for this discrepancy is the induction rate of adjuvant chemotherapy. The frailty group showed a significantly lower rate of induction compared with the non-frailty group. In pancreatic cancer, induction of adjuvant chemotherapy is a prognostic factor [
24]. Regarding the relationship between frailty and chemotherapy, frailty is associated with a low adjuvant chemotherapy induction rate in patients with stage III colon cancer [
25]. In our study, a low induction rate of adjuvant chemotherapy may have led to worse cancer-specific survival.
In this study, aging itself was not an independent prognostic factor, and the non-frail elderly group showed comparable outcomes compared with the non-elderly group. Recently, the number of reports insisting that pancreatic resection of PDAC can be performed safely on older patients with acceptable risks is increasing [
26]. However, frailty is a prognostic factor in several cancers [
1], as shown in the present study. For older patients with frailty, preoperative rehabilitation improves postoperative motor function, quality of life, and possibly surgical outcomes. Perioperative intervention seems important during pancreatic resection for postoperative outcomes and good induction of adjuvant chemotherapy.
The present study has several limitations. First, it was a single-center study, and the study cohort was relatively small. Larger prospective studies are necessary to confirm our findings. Second, we only used CFS scores to assess frailty in this study. In the future, we plan to assess other variables associated with frailty and cancer, such as sarcopenia and dynapenia.
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