Introduction
Gallbladder carcinoma (GBC) is the most common malignant tumor of the biliary system, ranking sixth among all digestive tract cancers; GBC is characterized by a low early diagnosis rate, a high degree of malignancy, and a poor prognosis.[1,2] The incidence of GBC, which has increased worldwide in recent years, stands at 1.00–1.30 per 100,000 in China.[3–5] Numerous studies are currently being conducted to determine the influence of clinicopathological features (such as carbohydrate antigen 19-9[CA19-9], the degree of tumor differentiation, and tumor node metastasis [TNM] stage), surgical procedures, and other variables on prognosis.[6–8] Nevertheless, individual outcome and single indicator cannot accurately reflect or evaluate the disease extent or treatment outcomes.
Textbook outcome (TO) is a multi-dimensional composite indicator, including intraoperative and postoperative outcomes such as negative surgical margins (R0), no perioperative blood transfusion, no postoperative complications, short hospital stay, no death within 30 days after surgery, and no readmission within 30 days after discharge; these outcomes represent an ideal short-term postoperative prognosis.[9] Currently, TO is utilized to assess the surgical effect in hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and pancreatic carcinoma, leading to quality improvement efforts.[9–12] Additionally, TO can be used to measure hospital performance and variation, promoting fairness in healthcare.[13–15] Nevertheless, the factors associated with a TO for GBC after resection have not been evaluated. In this study, we explored the factors associated with a TO for GBC after resection and determined the effect of adjuvant chemotherapy (ACT) on patients who achieved TO and those who did not to assist with clinical decision-making.
Methods
Ethical approval
The study was approved by the Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University (No. XJTU1AF2022LSK-089), Xi'an, China. Written informed consent was obtained from all included patients and their families before study enrollment.
Patients and design
This study included all histologically confirmed GBC patients treated between 2011 and 2020 at the First Affiliated Hospital of Xi'an Jiaotong University. The inclusion criteria were as follows: (1) patients underwent the curative-intent resection for GBC; (2) postoperative pathologically confirmed GBC; (3) clinicopathological characteristics and follow-up data were available; and (4) patients who did not receive anti-tumor treatment, such as chemotherapy, radiotherapy, and radiochemotherapy before surgery and within 30 days after surgery. The exclusion criteria were as follows: (1) patients completely lost to follow-up after discharge; (2) patients with severe organ insufficiency; and (3) patients with other systemic malignant tumors. A total of 540 patients were included in the study based on the inclusion and exclusion criteria. Through January 2022, all included patients were evaluated using the 8th edition American Joint Committee on Cancer (AJCC) staging system.
Definition of TO
The TO, as a composite endpoint, adopts the "all or none" principle, only when patients meet all of the following criteria they were defined TO: (1) negative surgical margins (R0); (2) no perioperative blood transfusion; (3) no prolonged hospital stay (a hospital stay below the 50th percentile of the total cohort); (4) no severe postoperative complications (Clavien–Dindo grade ≥grade III); (5) no 30-d readmission after discharge; and (6) no 30-d mortality after operation.[9,16–18]
Follow-up
Each patient included in the study was followed up via clinic or telephone call on a routine basis. During the first year after surgery, liver function and tumor biomarkers (carcinoembryonic antigen [CEA], CA19-9, carbohydrate antigen 125[CA125]) were assessed and ultrasound, contrast-enhanced computed tomography (CT), or magnetic resonance imaging (MRI) examinations were performed every 2–3 months; over the 1-year period, follow-ups were conducted once every 3–6 months. We calculated the overall survival duration from the date of radical resection to the date of most recent follow-up or death. The follow-up period ended in January 2022.
Propensity score matching (PSM)
We used PSM to mitigate the baseline differences affecting long-term outcomes between the ACT and non-ACT groups, evaluating the intervention effects using non-randomized controlled data in SPSS version 25 (IBM, Armonk, NY, USA).[19] An analysis of propensity scores with 1:1 matching was conducted within a standard deviation range of 0.02.
The regimens of postoperative ACT
The following protocols were strictly followed by postoperative ACT patients. The regimens included gemcitabine (1000 mg/m2 on days 1 and 8) + tegafur (40–60 mg twice daily on days 1–14) on a 3-week cycle; gemcitabine (1000 mg/m2 on days 1 and 8) + oxaliplatin (100 mg/m2 on day 1) on a 3-week cycle; gemcitabine (1000 mg/m2 on days 1 and 8) + cisplatin (30 mg/m2 on days 1 and 8)on a 3-week cycle; gemcitabine (1000 mg/m2 on days 1 and 8) + capecitabine (1250 mg/m2 twice daily on days 1–14) on a 3-week cycle, and oxaliplatin (100 mg/m2 on day 1) + tegafur (40–60 mg twice daily on days 1–14) on a 3-week cycle.
In this study, the inclusion criteria for ACT were advanced T stage, or N1–2 stage, or positive surgical margins combined with major vascular or perineural invasion associated with high postoperative recurrence risk. The selection of the chemotherapy regimen was mainly based on the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines.[20] 62 patients with GBC received ACT. Among the 26 patients in the TO group, 11 (42.3%) received gemcitabine + tegafur, ten (38.5%) received gemcitabine + oxaliplatin, and five (19.2%) received gemcitabine + cisplatin. Among the 36 patients in the non-TO group, 18 (50.0%) received gemcitabine + tegafur, seven (19.4%) received gemcitabine + oxaliplatin, six (16.7%) received gemcitabine + cisplatin, three (8.3%) received gemcitabine + capecitabine, and two (5.6%) received oxaliplatin + tegafur.
Statistical analysis
All statistical analyses were performed using SPSS version 25(IBM). Categorical variables were expressed as number and percentages and compared by chi-squared test, ordinal categorical variables were compared by Mann–Whitney U test. The median survival was estimated by Kaplan–Meier method and the log-rank test was used to assess differences in overall survival. Factors associated with overall survival were identified using Cox proportional hazard regression model, whereas TO was investigated using univariate and multivariable logistic regression model. Hazard ratio (HR) and odds ratio (OR) with corresponding 95% confidence interval (CI) were estimated. The Kaplan–Meier curves and bar, line, and forest plots were generated by GraphPad Prism (version 8.0, San Diego, CA, USA). Variables with P <0.05 were considered statistically significant.
Nomogram development and assessment
The nomogram prediction model was developed using R software version 3.6.1 (http://www.r-project.org/) based on the independent variables associated with a TO in GBC patients after curative-intent resection. The concordance index (C-index), calibration curve, and Hosmer–Lemeshow test were used to evaluate the performance of the nomogram model.[21]
Results
Baseline data and TO rates
Among 540 patients with GBC after curative-intent resection, 223 patients (41.3%) achieved a TO. The incidence of TO ranged from 19.0% to 51.0%, with a slightly increasing trend over the study period [Figure 1A]. An increasing proportion of GBC patients achieved a TO after resection during 2016–2020 when compared with that during 2011–2015 (46.4% [170/366] vs. 30.5% [53/174], P <0.001).
;)
Figure 1: Trends in the proportion of textbook outcome and the TO distribution by definition over the study period. (A) Trends in the proportion of TO over the study period. (B) TO distribution by definition over the study period. TO: Textbook outcome.
We calculated the individual rate of each outcome variable comprising the TO in order to determine which variables were more likely to be realized. In detail, the rates were 94.6% (511/540) for negative surgical margins, 60.2% (325/540) for no perioperative blood transfusion, 57.6% (311/540) for no prolonged hospital stay, 95.2% (514/540) for no severe postoperative complications, 98.7% (533/540) for no 30-d readmission after discharge, and 98.7% (533/540) for no 30-d mortality after surgery [Figure 1B]. Therefore, among the outcome variables required to achieve a TO, no 30-d readmission after discharge and no 30-d mortality after operation were the easiest to achieve, and no prolonged hospital stay was the hardest to achieve.
Prognosis analysis of TO in GBC after resection
The survival analysis showed that the 1-, 3-, and 5-year survival rates of the TO group were 83.5%, 61.2%, and 54.7%, respectively, and the 1-, 3-, and 5-year survival rates of the non-TO group were 64.1%, 38.9%, and 29.1%, respectively (P <0.001) [Figure 2]. The univariate analysis confirmed that non-TO was a prognostic risk factor associated with GBC after resection. Further, the multivariate analysis showed that non-TO was an independent risk factor (HR: 1.524, 95% CI: 1.155–2.011, P = 0.003). Detailed results of the univariate and multivariate analyses are shown in Table 1.
Figure 2: Survival analysis curves of the TO and non-TO groups among patients with GBC after curative-intent resection. GBC: Gallbladder carcinoma; TO: Textbook outcome.
Table 1 -
Univariate and multivariate analysis of
prognosis for GBC after
curative-intent resection.
|
Variables
|
Univariate analysis
|
|
Multivariate analysis
|
|
HR (95% CI)
|
P-value
|
HR (95% CI)
|
P-value
|
| Sex |
|
|
|
|
|
| Female vs. male |
0.825 (0.646–1.054) |
0.124 |
|
|
|
| Age |
|
|
|
|
|
| >60 vs. ≤60 (years) |
1.346 (1.043–1.737) |
0.022 |
|
|
|
| CEA |
|
|
|
|
|
| >5.0 vs. ≤5.0 (ng/mL) |
2.797 (2.182–3.585) |
<0.001 |
|
1.506 (1.139–1.992) |
0.004 |
| CA19–9 |
|
|
|
|
|
| >39.0 vs. ≤39.0 (U/mL) |
2.505 (1.978–3.171) |
<0.001 |
|
|
|
| CA125 |
|
|
|
|
|
| >35.0 vs. ≤35.0 (U/mL) |
2.069 (1.622–2.639) |
<0.001 |
|
|
|
| TBIL |
|
|
|
|
|
| >34.1 vs. ≤34.1 (μmol/L) |
2.031 (1.495–2.760) |
<0.001 |
|
|
|
| Unexpected GBC |
|
|
|
|
|
| Yes vs. no |
0.746 (0.571–0.975) |
0.032 |
|
|
|
| Gallstones |
|
|
|
|
|
| Yes vs. no |
1.435 (1.122–1.835) |
0.004 |
|
1.490 (1.153–1.925) |
0.002 |
| Gallbladder polyps |
|
|
|
|
|
| Yes vs. no |
0.111 (0.036–0.347) |
<0.001 |
|
|
|
| Lymph node dissection |
|
|
|
|
|
| ≥6 vs. <6 |
1.164 (0.914–1.482) |
0.219 |
|
|
|
| Tumor location |
|
|
|
|
|
| Body and bottom vs. neck |
0.657 (0.486–0.888) |
0.006 |
|
|
|
| All gallbladder vs. neck |
0.803 (0.567–1.137) |
0.217 |
|
|
|
| Tumor morphology |
|
|
|
|
|
| Infiltrating type vs. massive type |
2.259 (1.710–2.983) |
<0.001 |
|
|
|
| Hybrid type vs. massive type |
1.062 (0.677–1.668) |
0.793 |
|
|
|
| Pathological type of tumor |
|
|
|
|
|
| Non-adenocarcinoma vs. adenocarcinoma |
0.950 (0.707–1.276) |
0.732 |
|
|
|
| Tumor differentiation |
|
|
|
|
|
| Moderate vs. well |
2.766 (1.635–4.677) |
<0.001 |
|
1.508 (0.872–2.610) |
0.142 |
| Poor vs. well |
7.013 (4.176–11.778) |
<0.001 |
|
3.046 (1.764–5.262) |
<0.001 |
| Liver involvement |
|
|
|
|
|
| Yes vs. no |
2.824 (2.228–3.579) |
<0.001 |
|
1.368 (1.047–1.786) |
0.021 |
| Major vascular invasion |
|
|
|
|
|
| Yes vs. no |
3.454 (2.294–5.201) |
<0.001 |
|
|
|
| Perineural invasion |
|
|
|
|
|
| Yes vs. no |
2.478 (1.814–3.385) |
<0.001 |
|
|
|
| Microvascular invasion |
|
|
|
|
|
| Yes vs. no |
1.684 (1.079–2.629) |
0.022 |
|
|
|
| AJCC 8th edition T stage |
|
|
|
|
|
| T3 vs. T1–2 |
3.536 (2.186–5.719) |
<0.001 |
|
|
|
| T4 vs. T1–2 |
12.253 (7.015–21.404) |
<0.001 |
|
|
|
| AJCC 8th edition N stage |
|
|
|
|
|
| N1 vs. N0 |
2.820 (2.165–3.673) |
<0.001 |
|
1.918 (1.453–2.530) |
<0.001 |
| N2 vs. N0 |
6.469 (4.628–9.041) |
<0.001 |
|
2.300 (1.437–3.682) |
0.001 |
| AJCC 8th edition TNM stage |
|
|
|
|
|
| III vs. I–II |
3.668 (2.129–6.319) |
<0.001 |
|
1.807 (1.015–3.214) |
0.044 |
| IVA–B vs. I–II |
15.865 (8.950–28.122) |
<0.001 |
|
4.243 (2.139–8.416) |
<0.001 |
| TO |
|
|
|
|
|
| No vs. yes |
2.060 (1.595–2.661) |
<0.001 |
|
1.524 (1.155–2.011) |
0.003 |
| ACT |
|
|
|
|
|
| Yes vs. no |
0.743 (0.489–1.130) |
0.165 |
|
|
|
ACT: Adjuvant chemotherapy; AJCC: American Joint Committee on Cancer; CA19-9: Carbohydrate antigen 19-9; CA125: Carbohydrate antigen 125; CEA: Carcinoembryonic antigen; CI: Confidence interval; GBC: Gallbladder carcinoma; HR: Hazard ratio; TBIL: Total bilirubin; TO: Textbook outcome.
Risk factors associated with TO
An univariate analysis was performed to compare the clinicopathological characteristics of the TO and non-TO subgroups, revealing that age ≤60 years, CEA ≤5.0 ng/mL, CA19-9 ≤39.0 U/mL, CA125 ≤35.0 U/mL, total bilirubin (TBIL) level ≤34.1 μmol/L, unexpected GBC, gallbladder polyps, massive-type tumor morphology, well-differentiated tumor, no liver involvement, no major vascular invasion, no perineural invasion, T1–2 stage disease, and TNM I–II stage disease were associated with achieving a TO for GBC after resection (P <0.050) [Tables 2 and 3].
Table 2 -
Baseline characteristics of GBC patients after
curative-intent resection.
|
Variables
|
TO
|
χ
2/Z
|
P-value
|
|
No (n = 317)
|
Yes (n = 223)
|
| Sex |
|
|
|
|
| Male |
98 (30.9) |
75 (33.6) |
0.444*
|
0.505 |
| Female |
219 (69.1) |
148 (66.4) |
| Age |
|
|
|
|
| ≤60 (years) |
98 (30.9) |
91 (40.8) |
5.631*
|
0.018 |
| >60 (years) |
219 (69.1) |
132 (59.2) |
| CEA |
|
|
|
|
| ≤5.0 (ng/mL) |
229 (72.2) |
184 (82.5) |
7.678*
|
0.006 |
| >5.0 (ng/mL) |
88 (27.8) |
39 (17.5) |
| CA19-9 |
|
|
|
|
| ≤39.0 (U/mL) |
185 (58.4) |
174 (78.0) |
22.723*
|
<0.001 |
| >39.0 (U/mL) |
132 (41.6) |
49 (22.0) |
| CA125 |
|
|
|
|
| ≤35.0 (U/mL) |
213 (67.2) |
172 (77.1) |
6.317*
|
0.012 |
| >35.0 (U/mL) |
104 (32.8) |
51 (22.9) |
| TBIL |
|
|
|
|
| ≤34.1 (μmol/L) |
260 (82.0) |
214 (96.0) |
23.729*
|
<0.001 |
| >34.1 (μmol/L) |
57 (18.0) |
9 (4.0) |
| Unexpected GBC |
|
|
|
|
| No |
249 (78.5) |
134 (60.1) |
21.631*
|
<0.001 |
| Yes |
68 (21.5) |
89 (39.9) |
| Gallstones |
|
|
|
0.236 |
| No |
119 (37.5) |
95 (42.6) |
1.402*
|
| Yes |
198 (62.5) |
128 (57.4) |
| Gallbladder polyps |
|
|
|
| No |
304 (95.9) |
200 (89.7) |
8.121*
|
0.004 |
| Yes |
13 (4.1) |
23 (10.3) |
| Lymph node dissection |
| <6 |
131 (41.3) |
81 (36.3) |
1.374*
|
0.241 |
| ≥6 |
186 (58.7) |
142 (63.7) |
| Tumor location |
|
|
|
|
| Neck |
63 (19.9) |
30 (13.5) |
3.895*
|
0.143 |
| Body and bottom |
182 (57.4) |
141 (63.2) |
| All gallbladder |
72 (22.7) |
52 (23.3) |
| Tumor morphology |
|
|
|
|
| Massive type |
99 (31.2) |
80 (35.9) |
13.706*
|
0.001 |
| Infiltrating type |
193 (60.9) |
106 (47.5) |
| Hybrid type |
25 (7.9) |
37 (16.6) |
| Pathological type of tumor |
|
|
|
|
| Adenocarcinoma |
249 (78.5) |
180 (80.7) |
0.377*
|
0.539 |
| Non-adenocarcinoma |
68 (21.5) |
43 (19.3) |
| Tumor differentiation |
|
|
|
|
| Well |
32 (10.1) |
45 (20.2) |
-4.666†
|
<0.001 |
| Moderate |
137 (43.2) |
114 (51.1) |
| Poor |
148 (46.7) |
64 (28.7) |
| Liver involvement |
|
|
|
|
| No |
181 (57.1) |
185 (83.0) |
40.091*
|
<0.001 |
| Yes |
136 (42.9) |
38 (17.0) |
| Major vascular invasion |
|
|
|
|
| No |
288 (90.9) |
222 (99.6) |
18.884*
|
<0.001 |
| Yes |
29 (9.1) |
1 (0.4) |
| Perineural invasion |
|
|
|
|
| No |
274 (86.4) |
205 (91.9) |
3.942*
|
0.047 |
| Yes |
43 (13.6) |
18 (8.1) |
| Microvascular invasion |
|
|
|
|
| No |
298 (94.0) |
212 (95.1) |
0.281*
|
0.596 |
| Yes |
19 (6.0) |
11 (4.9) |
| AJCC 8th edition T stage |
|
|
|
|
| T1–2 |
43 (13.6) |
54 (24.2) |
-5.374†
|
<0.001 |
| T3 |
227 (71.6) |
167 (74.9) |
| T4 |
47 (14.8) |
2 (0.9) |
| AJCC 8th edition N stage |
|
|
|
|
| N0 |
199 (62.8) |
157 (70.4) |
-1.790†
|
0.073 |
| N1 |
83 (26.2) |
46 (20.6) |
| N2 |
35 (11.0) |
20 (9.0) |
| AJCC 8th edition TNM stage |
|
|
|
|
| I–II |
39 (12.3) |
50 (22.4) |
-4.614†
|
<0.001 |
| III |
204 (64.4) |
151 (67.7) |
| IVA-B |
74 (23.3) |
22 (9.9) |
Data are presented as n (%). *:Chi-squared test. †:Mann-Whitney U test. AJCC: American Joint Committee on Cancer; CA19-9: Carbohydrate antigen 19-9; CA125: Carbohydrate antigen 125; CEA: Carcinoembryonic antigen; CI: Confidence interval; GBC: Gallbladder carcinoma; TBIL: Total bilirubin; TO: Textbook outcome.
Table 3 -
Univariate and multivariate analysis of TO for GBC after
curative-intent resection.
|
Variables
|
Univariate analysis
|
|
Multivariate analysis
|
|
OR (95% CI)
|
P-value
|
OR (95% CI)
|
P-value
|
| Sex |
|
|
|
|
|
| Female vs. male |
0.883 (0.612–1.273) |
0.505 |
|
|
|
| Age |
|
|
|
|
|
| >60 vs. ≤60 (years) |
0.649 (0.454–0.928) |
0.018 |
|
0.617 (0.417–0.913) |
0.016 |
| CEA |
|
|
|
|
|
| >5.0 vs. ≤5.0 (ng/mL) |
0.552 (0.361–0.843) |
0.006 |
|
|
|
| CA19-9 |
|
|
|
|
|
| >39.0 vs. ≤39.0 (U/mL) |
0.395 (0.268–0.582) |
<0.001 |
|
|
|
| CA125 |
|
|
|
|
|
| >35.0 vs. ≤35.0 (U/mL) |
0.607 (0.411–0.898) |
0.012 |
|
|
|
| TBIL |
|
|
|
|
|
| >34.1 vs. ≤34.1 (μmol/L) |
0.192 (0.093–0.396) |
<0.001 |
|
0.238 (0.110–0.512) |
<0.001 |
| Unexpected GBC |
|
|
|
|
|
| Yes vs. no |
2.432 (1.665–3.553) |
<0.001 |
|
|
|
| Gallstones |
|
|
|
|
|
| Yes vs. no |
0.810 (0.571–1.149) |
0.237 |
|
|
|
| Gallbladder polyps |
|
|
|
|
|
| Yes vs. no |
2.689 (1.331–5.432) |
0.006 |
|
|
|
| Intraoperative and postoperative pathological data |
| Lymph node dissection |
|
|
|
|
|
| ≥6 vs. <6 |
1.235 (0.868–1.757) |
0.541 |
|
|
|
| Tumor location |
|
|
|
|
|
| Body and bottom vs. neck |
1.627 (0.999–2.648) |
0.050 |
|
|
|
| All gallbladder vs. neck |
1.517 (0.864–2.661) |
0.147 |
|
|
|
| Tumor morphology |
|
|
|
|
|
| Infiltrating type vs. massive type |
0.680 (0.466–0.992) |
0.045 |
|
|
|
| Hybrid type vs. massive type |
1.831 (1.019–3.293) |
0.043 |
|
|
|
| Pathological type of tumor |
|
|
|
|
|
| Non-adenocarcinoma vs. adenocarcinoma |
0.875 (0.571–1.341) |
0.539 |
|
|
|
| Tumor differentiation |
|
|
|
|
|
| Moderate vs. well |
0.592 (0.353–0.992) |
0.047 |
|
0.693 (0.395–1.218) |
0.202 |
| Poor vs. well |
0.308 (0.179–0.528) |
<0.001 |
|
0.444 (0.244–0.812) |
0.008 |
| Liver involvement |
|
|
|
|
|
| Yes vs. no |
0.273 (0.181–0.414) |
<0.001 |
|
0.387 (0.244–0.615) |
<0.001 |
| Major vascular invasion |
|
|
|
|
|
| Yes vs. no |
0.045 (0.006–0.331) |
0.002 |
|
|
|
| Perineural invasion |
|
|
|
|
|
| Yes vs. no |
0.560 (0.314–0.999) |
0.049 |
|
|
|
| Microvascular invasion |
|
|
|
|
|
| Yes vs. no |
0.814 (0.379–1.746) |
0.597 |
|
|
|
| AJCC 8th edition T stage |
|
|
|
|
|
| T3 vs. T1–2 |
0.586 (0.374–0.917) |
0.019 |
|
0.984 (0.593–1.633) |
0.951 |
| T4 vs. T1–2 |
0.034 (0.008–0.147) |
<0.001 |
|
0.113 (0.024–0.528) |
0.006 |
| AJCC 8th edition N stage |
|
|
|
|
|
| N1 vs. N0 |
0.702 (0.463–1.006) |
0.097 |
|
|
|
| N2 vs. N0 |
0.724 (0.402–1.304) |
0.282 |
|
|
|
| AJCC 8th edition TNM stage |
|
|
|
|
|
| III vs. I–II |
0.577 (0.361–0.922) |
0.022 |
|
|
|
| IVA–B vs. I–II |
0.232 (0.123–0.437) |
<0.001 |
|
|
|
AJCC: American Joint Committee on Cancer; CA19-9: Carbohydrate antigen 19-9; CA125: Carbohydrate antigen 125; CEA: Carcinoembryonic antigen; CI: Confidence interval; GBC: Gallbladder carcinoma; OR: Odds ratio; TBIL: Total bilirubin; TNM: Tumor node metastasis; TO: Textbook outcome.
The multivariate analysis showed that age ≤60 years (OR: 0.617, 95% CI: 0.417–0.913, P = 0.016), TBIL level ≤34.1 μmol/L (OR: 0.238, 95% CI: 0.110–0.512, P <0.001), well-differentiated tumor (OR: 0.444, 95% CI: 0.244–0.812, P = 0.008), no liver involvement (OR: 0.387, 95% CI: 0.244–0.615, P <0.001), and T1–2 stage disease (OR: 0.113, 95% CI: 0.024–0.528, P = 0.006) were independently associated with GBC patients achieving a TO after resection [Table 3].
Subgroup analysis for the TO and non-TO groups
Prognostic analyses were performed for the TO and non-TO subgroups to examine how TO affects treatment decisions among GBC patients. The stratified analysis confirmed that the number of lymph nodes dissected ≥6 was associated with a worse prognosis in the TO group (HR: 1.708, 95% CI: 1.507–2.762, P <0.050), and ACT could improve non-TO group patient prognosis (HR: 0.552, 95% CI: 0.314–0.969, P <0.050). T stage, N stage, and TNM stage had a good prognostic discrimination ability in both the TO and non-TO groups. Detailed results of the subgroup prognosis analysis are shown in Figure 3.
Figure 3: Forest plots of the subgroup prognostic analysis in patients with GBC after curative-intent resection. (A) Forest plots for the non-TO group. (B) Forest plots for the TO group. AJCC: American Joint Committee on Cancer; CA19-9: Carbohydrate antigen 19-9; CA125: Carbohydrate antigen 125; CEA: Carcinoembryonic antigen; CI: Confidence interval; GBC: Gallbladder carcinoma; HR: Hazard ratio; TBIL: Total bilirubin; TNM: Tumor node metastasis; TO: Textbook outcome.
Comparison of overall survival between ACT and non-ACT
We used PSM to mitigate the differences of baseline clinicopathological characteristics in the non-TO and TO groups (age in the TO group and sex and CA19-9 in the non-TO group, respectively) to further confirm the effect of ACT on the prognosis of GBC patients. After PSM, all baseline data were then comparable (P >0.05).
Finally, a 1:1 PSM was utilized to identify 26 pairs of patients in the TO group and 36 pairs in the non-TO group. Before and after PSM, the overall survival outcomes of GBC patients who achieved TO after resection were not significantly different between the ACT and non-ACT groups (P >0.05) [Figures 4A, 4C]; conversely, the overall survival outcomes of GBC patients in the non-TO group after resection demonstrated significantly different outcomes between the ACT and non-ACT groups (P <0.05) [Figures 4B, 4D]. ACT prolonged the survival time of non-TO GBC patients after resection.
Figure 4: Comparison of overall survival among TO and non-TO GBC patients after curative-intent resection with or without ACT. (A,B) TO and non-TO groups before PSM. (C,D) TO and non-TO groups after PSM. ACT: adjuvant chemotherapy; GBC: Gallbladder carcinoma; PSM: propensity score matching; TO: Textbook outcome.
Nomogram development and assessment
A nomogram model was developed using the independent associated variables, including age, TBIL levels, tumor differentiation status, liver involvement, and T stage. The nomogram demonstrated good predictive ability, with a C-index of 0.728 in the whole cohort [Figure 5A]. The calibration plots and Hosmer–Lemeshowtest (χ2 = 2.916, P = 0.893) illustrated that the nomogram model performed better in the whole cohort [Figure 5B].
Figure 5: Nomogram and calibration plot for the chances of achieving a TO for GBC after curative-intent resection. (A) Nomogram for predicting a TO for GBC after curative-intent resection. (B) Calibration plot for assessing the nomogram. GBC: Gallbladder carcinoma; TBIL: Total bilirubin; TO: Textbook outcome.
Discussion
Surgical resection was the only potentially curative therapy for GBC. However, the postoperative recurrence rate was high (approximately 50%), and recurrence can occur as soon as several weeks after surgery in some cases.[22] Thus, it is critical to assess both short-term and long-term prognoses. The TO is an ideal short-term postoperative prognosis and refers to a composite outcome measure covering the surgical care process. The TO was achieved by 41.3% of GBC patients, and the trend of achieving a TO increased over the study period, indicating an improvement in the surgical treatment of GBC at our medical center. Among the outcome variables associated with achieving a TO, no prolonged hospital stay and no perioperative blood transfusion had lower proportions, consistent with previous findings.[9,10,17] Although blood transfusion can cause immunosuppression and affect the long and short term prognosis of patients, the adverse effect on intraoperative blood loss is more important than that of blood transfusion on the prognosis of patients[23–25] Therefore, delicate surgical operations can effectively reduce blood loss and prevent blood transfusions by reducing intraoperative bleeding and coagulation disorders. Furthermore, shortening hospital stayduring perioperative surgery and care should be a priority to help GBC patients achieve a TO.
In the study, the results showed that the 1-, 3-, and 5-year overall survival rates of the TO group were better than those of the non-TO group, and the multivariate analysis showed that non-TO was an independent risk factor for GBC prognosis after resection. In addition, age, TBIL level, tumor differentiation status, liver involvement, and T stage were independently associated with achieving a TO among GBC patients after resection. Therefore, achieving a TO was associated with age ≤60 years, TBIL level ≤34.1 μmol/L, well-differentiated tumor, no liver involvement, and T1–2 stage disease. These factors associated with TO facilitate the overall survival benefit and reduce the chance of GBC recurrence. Therefore, TO in GBC can be used to evaluate the surgery and perioperative care quality and to predict the long-term prognosis of patients after radical resection, similar to its use in hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and gastric cancer.[10,26]
According to the 8th edition AJCC staging system, a minimum of six lymph nodes should be evaluated to adequately assess lymph node status intraoperatively.[27] In our study, the lymph nodes dissected ≥6 did not improve the long-term prognosis of GBC patients. However, a recent study confirmed that lymph nodes dissected ≥6 can demonstrate the N stage and improve the prognosis of patients with N0 and N1–2 stage disease.[28] Unfortunately, the prognosis of patients in the TO group with ≥6 lymph nodes dissected was significantly worse than that of patients with <6. In addition, we found that patients with ≥6 lymph nodes dissected often considered lymph node metastasis before resection or identified positive lymph nodes by intraoperative frozen examination; it has been established that lymph node metastasis is an independent risk factor for the prognosis of GBC patient after resection.[6,29]
The in-depth study of ACT for GBC revealed that gemcitabine combined with platinum-based chemotherapy drugs can improve the prognosis of GBC patients.[30] Eckel and Schmid[31] showed that gemcitabine combined with cisplatin or oxaliplatin, recommended as the standard chemotherapy regimen, was the most effective regimen for patients with advanced biliary tract malignancies. In this study, we found that postoperative ACT could effectively improve the overall survival outcome of GBC patients in the non-TO group. This effect observed with ACT is likely due to its common application in patients with elevated N1–2 stages and positive surgical margins. Numerous studies have confirmed that ACT can significantly improve overall survival outcomes in patients with biliary tract malignancies with lymph node metastasis and positive surgical margins, consistent with our results.[32,33] However, ACT did not significantly improve the prognosis of patients who achieved a TO in this study. Ostwal et al[34] found that gemcitabine combined with cisplatin could improve the prognosis of stage II–III GBC after radical resection without serious side effects, and patients tolerated this regimen well. Unfortunately, a prospective randomized controlled trial also confirmed that gemcitabine combined with cisplatin did not improve the overall survival outcomes for GBC patients after radical resection.[35] Whether ACT can improve the prognosis of patients who achieve a TO requires further research.
Although some outcome variables were available to assess whether GBC patients achieved a TO after resection, it was still unclear whether GBC patients experienced no 30-d readmission after discharge or no 30-d mortality after operation. The nomogram, as a predictive statistical model for individual patients, has been shown to have advantages in predicting tumor recurrence, and a TO after resection has been proposed as a practical tool to guide cancer treatment.[9,36] In this study, a nomogram model was developed using factors independently associated with achieving a TO, including age, TBIL level, tumor differentiation status, liver involvement, and T stage. The nomogram demonstrated good predictive ability, with a C-index of 0.728; thus, the nomogram can help predict a TO and provide a reference for effective perioperative management. Therefore, TO can be used as a quality control standard for surgical treatment among GBC patients in the future.
Several limitations should be considered when interpreting the results of our study. It was difficult to avoid selection bias in the retrospective approach and the definitions of TO. Additionally, the whole patient cohort was recruited from one medical center in China, with poor generalizability; additionally, surgical-related variables, such as the extent of surgical resection and whether vascular resection and reconstruction were performed, were not included. Moreover, there has been no further analysis as to why non-TO patients can benefit from ACT, and the sample size between TO patients and non-TO patients after PSM for ACT on prognosis impact analysis was limited. An analysis of TO in a multicenter, prospective, and large-scale study is required in the near future to guide the clinical diagnosis and treatment of GBC.
In conclusion, this study confirmed that achieving a TO is associated with a better long-term prognosis among GBC patients after curative-intent resection. Age, TBIL level, tumor differentiation status, liver involvement, and T stage were independently associated with achieving a TO among GBC patients after resection. In addition, ACT can improve the prognosis of non-TO patients.
Funding
This study was supported by grants from the National Natural Science Foundation of China (No. 62076194), the Key Research and Development Program of Shaanxi Province (Nos. 2021-SF-016, 2022-SF-410, and 2022-SF-606), the Central University Basic Research Business Fund (No. xzy012020113), and the Clinical Research Fund of the First Affiliated Hospital of Xi'an Jiaotong University (No. XJTU1AF-CRF-2018-022).
Conflicts of interest
None.
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