Abstract
Aim
The influence of frailty on outcomes after hepatectomy for perihilar cholangiocarcinoma (PHCC) remains unclear. This study aimed to investigate the impact of frailty on the incidence of postoperative complications and survival after major hepatectomy for PHCC.
Methods
A total of 87 patients who had undergone surgery for PHCC between 2007 and 2020 were enrolled in this study. Frailty was scored retrospectively using the Clinical Frailty Scale (CFS). The survival and incidence of postoperative complications were compared based on the degree of frailty, and their risk factors were analyzed.
Results
The overall survival of the CFS score 1‐2 group was significantly higher than that of the CFS score 3‐7 group (P = .01). The survival benefit was especially observed in stage I or II PHCC. Furthermore, there were significant differences between the CFS score 1‐3 group and the CFS score 4‐7 group in the incidence of Clavien–Dindo classification grade ≥ IIIa (39.4% vs 70.6%; P = .03). Frailty was an independent risk factor for severe postoperative complications (odds ratio, 4.11; 95% confidence interval, 1.18‐15.20; P = .03) and the incidence of systemic complications (P < .01).
Conclusion
Frailty is a predictive factor for short‐ and long‐term outcomes in patients who have undergone major hepatectomy for PHCC.
Keywords: frailty, hepatectomy, perihilar cholangiocarcinoma, postoperative complications, survival analysis
In this study, multivariate analysis revealed that frailty was an independent risk factor for severe postoperative complications, and also an independent poor prognostic factor for OS. Frailty is a predictive factor for short‐ and long‐term outcomes in patients who have undergone major hepatectomy for perihilar cholangiocarcinoma.
1. INTRODUCTION
The proportion of elderly patients requiring surgery for gastrointestinal cancer has increased over the last few decades 1 and is expected to continue increasing. Although aging is a contributing factor for short‐ and long‐term outcomes, some patients have worse outcomes with age than expected. These patients are often associated with frailty—an impaired physiological condition resulting from aging that increases vulnerability to stress. 2 , 3 Recently, several studies have reported that frailty is a more significant risk factor than aging for postoperative complications or long‐term survival after surgery for various cancers, including gastrointestinal cancer. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11
Perihilar cholangiocarcinoma (PHCC) is the most common subtype of cholangiocarcinoma. This malignancy usually requires highly invasive surgical procedures with a relatively large volume of liver excision and biliary tract reconstruction. Therefore, it is generally not offered to the elderly population. 1 , 12 , 13 , 14 , 15 , 16 Several studies have evaluated surgery for PHCC in elderly patients. 1 , 12 Although these reports revealed that the rate of postoperative complications and long‐term survival were not significantly different between elderly and younger patients, a less invasive surgical procedure was more frequently selected in elderly patients. While some studies have reported an association between the increased risk of mortality, morbidity, and prognosis with aging or frailty, 5 , 6 , 7 , 8 , 9 , 11 the influence of frailty on outcomes after hepatectomy for PHCC remains unclear.
This study was designed to investigate the impact of frailty on the incidence of postoperative complications and survival after major hepatectomy for PHCC.
2. METHODS
2.1. Patients
A total of 87 patients who had undergone major hepatectomy for pathologically proven PHCC at the Division of Gastroenterological, Hepato‐Biliary‐Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University Hospital between January 2007 and December 2020 were enrolled in this study. Four patients who had undergone limited surgery were excluded. R2 resection and peri‐EQUATION operative deaths were also excluded from the survival analysis.
The study protocol was approved by the Shinshu University Hospital Ethics Committee (approval number: 4999), and the study conformed to the provisions of the Declaration of Helsinki. Informed consent was obtained in the form of an opt‐out on the website, and those who rejected were excluded.
2.2. Frailty assessment
Frailty was scored retrospectively using the Canadian Study of Health and Aging Clinical Frailty Scale (CFS). 3 CFS scoring is as follows: CFS 1 = very fit; CFS 2 = fit; CFS 3 = managing well; CFS 4 = living with very mild frailty; CFS 5 = living with mild frailty; CFS 6 = living with moderate frailty; CFS 7 = living with severe frailty; CFS 8 = living with very severe frailty; and CFS 9 = terminally ill. CFS scores were evaluated using medical records at the initial visit or on admission, a summary of medicines recorded by the pharmacist, and fall prevention scores recorded by nurses. The CFS score was assessed by at least two investigators, and the lower score was applied in case of differences. All patients were blinded to the medical records, except for those mentioned above.
2.3. Endpoint assessment and data collection
The survival and incidence of postoperative complications were compared between the frailty and nonfrailty groups, and their risk factors were analyzed.
Patient demographics, perioperative factors, postoperative outcomes, tumor characteristics, and survival were retrospectively collected from the medical records. The final pathologic stage was identified using the eighth edition of the TNM Classification of Malignant Tumors by the Union for International Cancer Control (UICC). 17 Postoperative complications were categorized according to the Clavien–Dindo classification (CD). 18 Posthepatectomy liver failure (PHLF) and posthepatectomy biliary leakage (PHBL) were defined according to the International Study Group of Liver Surgery standards in 2011. 19 , 20
2.4. Perioperative management and surgical procedure
Upon the development of obstructive jaundice, biliary drainage of the future liver remnant was initiated, and bile collected by the drainage catheter was taken orally until surgery. The indocyanine green (ICG) test has been routinely performed postoperatively along with general blood sampling. Indications for hepatectomy were determined according to Makuuchi's criteria, 21 ICG clearance of the remnant liver, 22 and the remnant hepatocellular uptake index. 23 Major hepatectomy with resection of the caudate lobe and extrahepatic bile duct has been routinely performed for PHCC. Drinking water was initiated on postoperative day (POD) 1 along with symbiotics, and no enteral tube was used. Postoperative rehabilitation was also initiated on POD 1.
Hematological examination was performed daily in the first week after hepatectomy, and the bilirubin concentration in the abdominal drainage fluid was routinely measured on postoperative d 1 and 3.
2.5. Statistical analysis
The results are presented as median values with ranges. Categorical variables were analyzed using the χ 2 test or Fisher's exact test, and quantitative variables were analyzed using the Mann–Whitney U test. Variables with P < .10 by univariate analysis were included in multivariate analyses using the multiple logistic regression model. Quantitative variables were categorized into two groups according to the cutoff value obtained from the receiver operating characteristic curve. Odds ratios (ORs) and 95% confidence intervals (CIs) for the incidence of postoperative complications were also calculated. Survival after surgery was estimated using the Kaplan–Meier method and compared using the log‐rank test. All statistical analyses were performed using JMP version 13.2.1 (SAS Institute, Inc.). P < .05 was considered statistically significance.
3. RESULTS
3.1. Baseline characteristics and survival after surgery
The distribution of CFS scores among the 87 surveyed patients is shown in Figure 1. Preoperative demographics, operative outcomes, and pathological characteristics of patients with a CFS score of 1‐2 and 3‐9 are summarized in Tables 1 and 2, respectively. The preoperative variables and surgical outcomes were similar between the two groups, except for the American Society of Anesthesiologists physical status score. Pathologically, the UICC T factor, N factor, and UICC TNM stage of the CFS score 3‐9 group were significantly higher than those of the CFS score 1‐2 group. The R0 resection rate or application rate of adjuvant chemotherapy was not significantly different between the two groups.
FIGURE 1.
The distribution of CFS scores among the 87 surveyed patients. CFS, Clinical Frailty Scale
TABLE 1.
Preoperative demographics and operative outcomes
|
CFS score 1‐2 n = 35 |
CFS score 3‐9 n = 44 |
P value | |||
|---|---|---|---|---|---|
| Age, median (range), year | 71 | (42‐81) | 72 | (59‐88) | .098 |
| Sex | |||||
| Male | 25 | (71.4) | 27 | (61.4) | .347 |
| Female | 10 | (28.6) | 17 | (38.7) | |
| Body mass index a , kg/m2 | 21.2 | (17.4‐31.7) | 21.9 | (16.7‐30.9) | .312 |
| ASA score | |||||
| 1 | 9 | (25.7) | 2 | (4.6) | .010 |
| 2 | 26 | (74.3) | 40 | (90.9) | |
| 3 | 0 | (0) | 2 | (4.6) | |
| Comobidity | |||||
| Hypertension | 16 | (45.7) | 25 | (56.8) | .326 |
| Diabetes mellitus | 6 | (17.1) | 9 | (20.5) | .708 |
| Previous operation | 11 | (31.4) | 19 | (43.2) | .283 |
| Preoperative cholangitis | 10 | (28.6) | 17 | (38.6) | .347 |
| Preoperative biliary drainage | 30 | (85.7) | 40 | (90.9) | .472 |
| Remnant liver volume a , % | 52.5 | (36.2‐87.8) | 46.5 | (31.0‐81.0) | .198 |
| Portal vein embolization | 15 | (42.9) | 14 | (31.8) | .312 |
| Lymphocyte a , /μL | 1420 | (610‐3000) | 1310 | (600‐3070) | .336 |
| Albumin a , g/dL | 3.7 | (2.7‐4.4) | 3.5 | (2.3‐4.6) | .109 |
| C‐reactive protein a , mg/dL | 0.18 | (0.02‐7.24) | 0.29 | (0.02‐5.02) | .604 |
| Total bilirubin a , mg/dL | 0.70 | (0.3‐1‐2.27) | 0.89 | (0.35‐2.15) | .145 |
| Indocyanine green test a , % | 8.2 | (3.5‐18.0) | 8.7 | (3.0‐21.0) | .914 |
| Operative procedure | |||||
| Right hemihepatectomy | 19 | (54.3) | 27 | (61.4) | .724 |
| Left hemihepatectomy | 15 | (42.9) | 15 | (34.1) | |
| Left trisectionectomy | 1 | (2.9) | 2 | (4.6) | |
| Concomitant resection | |||||
| Pancreaticoduodenectomy | 5 | (14.3) | 9 | (20.5) | .472 |
| Vascular resection (portal vein or artery) | 5 | (14.3) | 6 | (13.6) | .934 |
| Other organ resection | 1 | (2.9) | 2 | (4.6) | .693 |
| Stomach | 1 | (2.9) | 1 | (2.3) | |
| Kidney | 0 | (0) | 1 | (2.3) | |
| Operation time a , min | 674 | (443‐1330) | 656 | (490‐1153) | .650 |
| Blood loss a , mL | 550 | (120‐3500) | 675 | (130‐4000) | .441 |
| Blood transfusion | 12 | (34.3) | 22 | (50.0) | .159 |
| Postoperative hospital stay a , day | 29 | (14‐187) | 35 | (12‐198) | .242 |
Note: Figures in parentheses are percentage unless otherwise specified.
Abbreviations: ASA, American Society of Anesthesiologists; CFS, Clinical Frailty Scale.
Median (range).
TABLE 2.
Pathological characteristics
|
CFS score 1‐2 n = 35 |
CFS score 3‐9 n = 44 |
P value | |||
|---|---|---|---|---|---|
| UICC T factor, 8th edition | |||||
| 0 | 1 | (2.9) | 0 | (0) | .039 |
| 1 | 8 | (22.9) | 2 | (4.6) | |
| 2 | 19 | (54.3) | 31 | (70.5) | |
| 3 | 5 | (14.3) | 4 | (9.1) | |
| 4 | 2 | (5.7) | 7 | (15.9) | |
| UICC N factor, 8th edition | |||||
| 0 | 25 | (71.4) | 21 | (47.3) | .032 |
| 1 | 10 | (28.6) | 23 | (52.3) | |
| UICC stage, 8th edition | |||||
| 0 | 1 | (2.9) | 0 | (0) | .049 |
| I | 7 | (20.0) | 1 | (2.3) | |
| II | 13 | (37.1) | 16 | (36.4) | |
| III | 11 | (31.4) | 21 | (47.7) | |
| IV | 3 | (8.6) | 6 | (13.6) | |
| Microscopic residual disease | |||||
| R0 | 28 | (80.0) | 32 | (72.7) | .450 |
| R1 | 7 | (20.0) | 12 | (27.3) | |
| Adjuvant chemotherapy | |||||
| Yes | 25 | (71.4) | 31 | (70.5) | .925 |
| No | 10 | (28.6) | 13 | (71.4) | |
Note: Figures in parentheses are percentage unless otherwise specified.
Abbreviations: CFS, Clinical Frailty Scale; UICC, Union for International Cancer Control.
The overall survival (OS) of the CFS score 1‐2 group was significantly higher than that of the CFS score 3‐9 group (5‐year OS rate: 41.8% vs 10.2%, P = .01; Figure 2). This trend was also observed in disease‐specific survival (Figure S1). When patients in both groups were stratified into two subgroups according to TNM stage (0‐II or III/IV), the difference in OS was larger in stage 0‐II patients (5‐year OS rate: 44.5% vs 13.0%; P = .02; Figure 3A). Meanwhile, there was no significant difference in OS between the two groups in stage III/IV patients (5‐year OS rate: 40.0% vs 0%, P = .46; Figure 3B).
FIGURE 2.
Kaplan–Meier curve of OS in the CFS score 1‐2 group and the CFS score 3‐9 group. The OS of the CFS score 1‐2 group was significantly higher than that of the CFS score 3‐7 group (P = .01). CFS, Clinical Frailty Scale; OS, overall survival
FIGURE 3.
Kaplan–Meier curve of OS in the CFS score 1‐2 group and the CFS score 3‐9 group stratified according to TNM stage (0‐II or III/IV). (a) The OS of the CFS score 1‐2 group was significantly higher than that of CFS score 3‐9 group in stage 0‐II patients (P = .02). (b) A significant difference did not exist in stage III/IV patients (P = .46). CFS, Clinical Frailty Scale; OS, overall survival
3.2. Analysis of prognostic factors
Clinicopathological factors were assessed to identify prognostic factors in this population. Univariate analysis revealed that an operation time >663 mins (P = .04) and CFS score 3‐9 (P = .01) were significantly associated with OS. Although there was no significant difference, the OS of patients with stage III/IV UICC was longer than that of patients with UICC stage I/II (P = .09). Confounding factors with the above three factors (UICC T factor, UICC N factor, and the value of bilirubin) were excluded from the multivariate analysis of prognostic factors. Multivariate analysis using the Cox proportional hazards model revealed that a CFS score of 3‐9 was an independent prognostic factor for OS (hazard ratio, 2.31; 95% CI, 1.14‐4.87; P = .02; Table 3).
TABLE 3.
Univariate and multivariate analyses of prognostic factors for overall survival
| Variables | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | P value | Hazard ratio | 95% CI | P value | |
| CFS score | ||||||
| 1‐2 | Ref | Ref | ||||
| 3‐9 | 2.46 | 1.23‐5.13 | .011 | 2.31 | 1.14‐4.87 | .020 |
| Operation time, min | ||||||
| >663 | Ref | Ref | ||||
| ≤663 | 2.03 | 1.04‐4.22 | .038 | 1.93 | 0.96‐4.07 | .065 |
| UICC stage, 8th edition | ||||||
| 0‐II | Ref | Ref | ||||
| III/IV | 1.77 | 0.92‐3.56 | .087 | 1.29 | 0.64‐2.68 | .474 |
Abbreviations: CI, confidence interval; CFS, Clinical Frailty Scale; UICC, Union for International Cancer Control.
3.3. Incidence and risk factors of major postoperative complications
The incidence of postoperative complications of CD grade ≥IIIa and ≥IIIb were compared using a CFS score of 1‐2 and 3‐9 or a CFS score of 1‐3 and 4‐9 (Figure S2). There was a significant difference in the incidence of postoperative complications between the two groups. In the latter population, preoperative variables and outcomes were similar between the CFS score 1‐3 group and the CFS score 4‐9 group, except for the history of hypertension and the level of serum albumin (Table S1).
The incidence of mortality was 2.4% (n = 2 patients who died due to liver failure). The incidence of postoperative complications of CD all grade, grade ≥IIIa, and ≥IIIb were 81.9% (n = 68), 45.8% (n = 38), and 12.0% (n = 10 [intraabdominal abscesses formation after PHBL (n = 3), PHLF (grade C) (n = 2), intraabdominal bleeding (n = 1), intractable ascites (n = 1), anastomotic leakage (n = 1)]), respectively. The incidence of postoperative complications was significantly higher in the CFS score 4‐9 group than in the CFS score 1‐3 group both for CD grade ≥IIIa complications (CFS score 1‐3: 39.4% vs CFS score 4‐9: 70.6%, P = .03) and CD grade ≥IIIb complications (7.6% vs 29.4%, P = .03; Table 4).
TABLE 4.
Postoperative short‐term outcomes
|
CFS score 1‐3 n = 66 |
CFS score 4‐9 n = 17 |
P value | |||
|---|---|---|---|---|---|
| Mortality | 2 | (3.0) | 0 | (0) | 1.00 |
| Morbidity | |||||
| All grade | 50 | (75.8) | 17 | (100) | .004 |
| Clavien–Dindo classification grade ≥IIIa | 26 | (39.4) | 12 | (70.6) | .029 |
| Clavien–Dindo classification grade ≥IIIb | 5 | (7.6) | 5 | (29.4) | .025 |
| Surgery‐related postoperative complications | 45 | (68.2) | 11 | (64.7) | .695 |
| Posthepatectomy liver failure | 21 | (31.8) | 7 | (41.2) | .472 |
| Grade A | 11 | (16.7) | 2 | (11.8) | |
| Grade B | 8 | (12.1) | 5 | (29.4) | |
| Grade C | 2 | (3.0) | 0 | (0) | |
| Posthepatectomy bile leakage | 15 | (22.7) | 3 | (17.7) | .644 |
| Infectious complications | 37 | (56.1) | 12 | (70.6) | .517 |
| Incisional SSI | 27 | (40.9) | 6 | (35.3) | .672 |
| Infectious complications except for incisional SSI | 26 | (39.4) | 12 | (70.6) | .021 |
| Bleeding | 5 | (7.6) | 2 | (11.8) | .594 |
| Nonsurgery‐related postoperative complications | 11 | (16.7) | 13 | (76.5) | <.001 |
| Cardiovascular complications | 0 | (0) | 3 | (17.7) | .007 |
| Respiratory complications | 5 | (7.6) | 8 | (47.1) | <.001 |
| Delirium | 5 | (7.6) | 7 | (41.2) | <.001 |
| Postoperative hospital stay, median (range), day | 31.5 | (12‐287) | 44 | (17‐198) | .139 |
Note: Figures in parentheses are percentage unless otherwise specified.
Abbreviations: CFS, Clinical Frailty Scale; SSI, surgical site infection.
In multivariate analysis, frailty (CFS score 4‐9) was identified as an independent risk factor for CD grade ≥IIIa (severe) postoperative complications (OR, 4.11; 95% CI, 1.11‐15.20; P = .03), >10% ICG retention at 15 minutes (OR, 3.87; 95% CI, 1.36‐11.00; P = .01), and concomitant resection with pancreaticoduodenectomy (OR, 7.15; 95% CI, 1.67‐30.52; P = .01; Table 5).
TABLE 5.
Univariate and multivariate analyses of risk factors for postoperative complications of Clavien–Dindo classification IIIa or more
| Variables | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| Odds ratio | 95% CI | P value | Odds ratio | 95% CI | P value | |
| CFS score | ||||||
| 1‐3 | Ref | Ref | ||||
| 4‐9 | 3.69 | 1.16‐11.71 | .021 | 4.11 | 1.11‐15.20 | .034 |
| Indocyanine green test | ||||||
| <10.0% | Ref | Ref | ||||
| ≥10.0% | 3.50 | 1.38‐8.88 | .007 | 3.87 | 1.36‐11.00 | .011 |
| Concomitant resection with Pancreaticoduodenectomy | ||||||
| No | Ref | Ref | ||||
| Yes | 7.28 | 1.88‐28.07 | .001 | 7.15 | 1.67‐30.52 | .008 |
Abbreviations: CI, confidence interval; CFS, Clinical Frailty Scale.
3.4. Detailed assessment of postoperative complications
Postoperative complications were categorized into two groups: (a) surgery‐related complications (complications associated with the operative procedure), such as PHLF, PHBL, surgical site infection (SSI), and bleeding, and (b) nonsurgery‐related complications (systemic complications not associated directly with the operative procedure), such as pneumonia, arrhythmia, or delirium. The results of the statistical tests and descriptive information about postoperative complications are summarized in Table 4.
The incidence of surgery‐related postoperative complications did not differ between the CFS score 1‐3 group and the CFS score 4‐9 group. There was no significant difference in the incidence of PHLF, PHBL, SSI, or bleeding. In contrast, the incidence of nonsurgery‐related postoperative complications was significantly higher in the CFS score 4‐9 group (16.7% vs 76.5%; P < .01).
In contrast, there was a significant difference in the incidence of infectious complications except for incisional SSI (39.4% vs 70.6%, P = .02).
4. DISCUSSION
The present study demonstrated the relationship between frailty and the rate of severe postoperative complications of major hepatectomy for PHCC using CFS, which is a simple and useful measurement system for frailty. 3 , 4 , 5 , 11
Frailty is defined as a clinical state associated with impaired physiological conditions and vulnerability to stress. It results from aging‐related decline or disease, and various scores have been reported for its assessment. Several studies have revealed the association between poor outcomes and high frailty scores in patients with various disorders, such as cardiovascular diseases, 24 infectious diseases, 25 liver disease, 26 or malignant diseases including gastrointestinal cancer. 4 , 5 , 6 , 7 , 8 , 27 As for hepatic resection, 11 studies 5 , 6 , 7 , 8 , 9 , 10 , 11 , 13 , 14 , 15 , 16 are available to date, among which 10 showed the usefulness of frailty scoring in predicting mortality, morbidity, or prognosis after hepatectomy. Tanaka et al 7 conducted a prospective multicenter study using the Kihon checklist and demonstrated that high frailty was an independent risk factor for age‐related events (major respiratory complications, major cardiac events, delirium requiring medication, transfer to rehabilitation facility, and dependency). In addition, Gani et al, 6 McKechnie et al, 10 Chen et al, 13 van der Windt et al, 14 and Dauch et al 15 described that frailty measured using the revised frailty index, modified frailty index, or risk analysis index was a predictor of morbidity and/or mortality after liver surgery. Louwers et al 9 and Okabe et al 11 revealed a significant association between frailty and postoperative complications of CD grade III/IV. Moreover, Yamada et al 7 and Tokuda et al 16 described the usefulness of frailty assessed by CFS to estimate the prognosis of hepatocellular carcinoma (HCC) or colorectal liver metastasis after hepatectomy. Although Milliken et al 8 reported no significant difference with the degree of frailty in short‐ and long‐term outcomes after hepatectomy, it is reasonable to suggest—based on the findings of other previous studies—that frailty serves some degree of influence on outcomes after hepatectomy. However, the subjects of investigation in these studies were HCC, colorectal liver metastasis, and all types of liver cancer (HCC, PHCC, liver metastases), and, to the best of our knowledge, this is the first report to demonstrate the potency of frailty in predicting postoperative outcomes and prognosis for patients who have undergone surgery for PHCC.
In this study we used the CFS score to assess frailty. CFS is a nine‐point scale for assessing frailty, which is scored by evaluating comorbidity, function, and cognition. 3 Although the CFS is a semiquantitative scale that does not include preoperative test results, it provides a more detailed assessment, including cognitive function, than the ECOG‐PS, and various studies have reported an association between CFS and clinical outcomes. 4 , 5 , 11 , 16 , 28 The cutoff value of CFS varied among studies, 4 , 5 , 11 , 16 and even in this study, there is a difference in cutoffs for predicting prognosis and the development of complications. This may be due to differences in the impact of frailty on clinical outcomes, and we consider that a different cutoff value for each outcome may allow for a more rigorous evaluation.
Previous studies have suggested that frailty leads to increased postoperative complications, and some researchers have proposed various ideas for elucidating an accurate mechanism. Marcos‐Perez et al 29 reported that frailty is associated with inflammatory mediators, and Lu et al 30 clarified the relationship between frailty and immunosuppression. In the present study, although there was no significant difference, the platelet‐to‐lymphocyte ratio was higher and the prognostic nutrition factor was lower in the frailty group (Figures S3 and S4), which were in line with the findings of the two aforementioned reports. 30 The incidence of nonsurgery‐related postoperative complications was significantly higher in the frailty group, while the incidence of surgery‐related complications did not differ between the frailty and nonfrailty groups. These findings indicate that the impact of frailty on postoperative complications is not the outcome of local tissue vulnerability, but that of systemic inflammation or immunosuppression. The significant association between frailty and infection in our study further supports this theory.
In the present study frailty was a significant prognostic factor associated with survival, especially in the early stage group. In general, immunosuppression is known to adversely affect the progression of malignancy, which may be explained by the above theories regarding the association between frailty and immunosuppression. The reasons for the lack of difference in survival rates in advanced stages are unclear but include the possibilities of the number of nonfrailty patients being too small to make valid comparisons, or the immunosuppressive effect of the tumor itself exceeding the immune effect of frailty due to the large tumor volume.
The main limitations of this study are its single‐center, retrospective, nonrandomized design and its relatively small number of participants. Stage was not a prognostic factor in univariate and multivariate analysis, which might have occurred due to an insufficient sample size. However, the patients enrolled in this study showed considerable heterogeneity in characteristics, operative findings, and pathological outcomes. In addition, we used only CFS to assess frailty. A prospective study with a larger patient cohort is needed, and frailty should be assessed using other scoring systems. Hence, we have started assessing frailty using the Cardiovascular Health Study index, 2 Edmonton frail scale, 31 multidimensional frailty score, 32 and CFS to clarify the influence of frailty on postoperative outcomes after hepatobiliary and pancreatic surgery. To conclude, frailty is a predictive factor for short‐ and long‐term outcomes in patients who have undergone major hepatectomy for PHCC.
DISCLOSURE
Funding: The authors received no specific funding for this study.
Conflict of Interest: The authors declare no conflicts of interest for this article.
Author Contributions: KH, AS, KK, TN, and YS were involved in study design and data interpretation. KH and KF were involved in the drafting of the article. KH, HM, TY, HS, HH, and KY were involved in the data analysis. YS was involved in the study supervision. All authors critically revised the report, commented on drafts of the article, and approved the final report.
Ethics Statement: The protocol for this research project was approved by a suitably constituted Ethics Committee of the institution, and it conforms to the provisions of the Declaration of Helsinki. Committee of Shinshu University Hospital, Approval No. 4999. Informed consent was obtained from the subjects.
Supporting information
Figure S1
Figure S2
Figure S3
Figure S4
Table S1
Hosoda K, Shimizu A, Kubota K, Notake T, Masuo H, Yoshizawa T, et al. Usefulness of frailty to predict short‐ and long‐term outcomes in patients who have undergone major hepatectomy for perihilar cholangiocarcinoma. Ann Gastroenterol Surg. 2022;6:833–841. doi: 10.1002/ags3.12596
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Supplementary Materials
Figure S1
Figure S2
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Table S1