
==== Front
Ann Med
Ann Med
Annals of Medicine
0785-3890
1365-2060
Taylor & Francis

39262385
10.1080/07853890.2024.2402072
2402072
Version of Record
Research Article
Oncology
What eliminates the chance for cure: a multi-center evaluation on 10-year follow-up of gallbladder cancer after surgical resection
Z. Ma et al.
Evaluation on 10-Year Follow-Up of GC
Ma Zuyi a*
Li Zhenchong b*
Cao Jiasheng c*
Sun Jia a
Huang Shanzhou de
Zhou Qi fg
https://orcid.org/0000-0002-9142-0793
Li Binglu a
a Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
b Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
c Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
d Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
e Southern Medical University, Guangzhou, China
f Department of General Surgery, Hui Ya Hospital of The First Affiliated Hospital, Sun Yat-sen University, Huizhou, China
g Department of hepatic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
* Zuyi Ma, Zhenchong Li and Jiasheng Cao contributed equally to this work and should be considered co-frst authors.

Supplemental data for this article can be accessed online at https://doi.org/10.1080/07853890.2024.2402072.

CONTACT Qi Zhou hnzhouqi@163.com Department of General Surgery, Hui Ya Hospital of The First Affiliated Hospital, Sun Yat-sen University, Huizhou, Guangdong 516081, China
Binglu Li PUMCHLBL@163.com Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100005, China
12 9 2024
2024
12 9 2024
56 1 240207221 5 2024
27 8 2024
29 8 2024
KnowledgeWorks Global Ltd.11 9 2024
published online in a building issue11 9 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

Curative resection stands as the sole potential cure for gallbladder cancer (GBC); nevertheless, a dearth of knowledge persists regarding long-term follow-up data and prognostic factors that hinder achieving a cure post-surgery. A retrospective cohort study was conducted by analyzing pathologically confirmed initial resections for GBC between 2000 and 2013 across three Chinese medical centers. The concept of observed cure refers to a 10-year survival period devoid of any disease recurrence. Employing a semiparametric proportional hazards mixture cure model enabled the identification of clinicopathological factors impeding a cure for GBC post-surgery. In our current study, a total of 331 patients were included, with a follow-up period exceeding a decade. The median overall survival (OS) was recorded at 31.6 months, with 39 patients (11.78%) achieving a 10-year OS, classified as 10-year survivors. Within this subset, 36 patients reached a 10-year relapse-free survival, denoting cure, and yielding an observed cure rate of 10.88%. Notably, factors such as combined surgical resection involving invaded organs, positive lymph node metastasis, and R1 resection (below 1%) were identified as virtually precluding a cure. Additionally, patients with T3–4 stage, hepatic invasion, advanced AJCC stage or poor tumor differentiation exhibited a low likelihood of achieving cure (below 5%). The discovery of these prognostic factors holds significant value in tailoring individualized treatment strategies and enhancing clinical decision-making processes.

Keywords

Gallbladder cancer
survival
prognosis
surgical resection
cure
Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences 2022-I2M-C&T-A-004 National High Level Hospital Clinical Research Funding 2022-PUMCH-B-005 National Natural Science Foundation of China 10.13039/501100001809 82102961 82173149 Science and Technology Program of Guangzhou 2024A04J10016 Young Talent Support Project of Guangzhou Association for Science and Technology QT2024-037 This study was supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences [2022-I2M-C&T-A-004], National High Level Hospital Clinical Research Funding [2022-PUMCH-B-005], National Natural Science Foundation of China [82102961 and 82173149], the Science and Technology Program of Guangzhou [2024A04J10016] and Young Talent Support Project of Guangzhou Association for Science and Technology [QT2024-037].
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pmcIntroduction

Gallbladder cancer (GBC) is recognized as the most prevalent primary biliary malignancy, with adenocarcinoma constituting approximately 90% of GBC cases, making it the predominant histological type [1]. Other less common subtypes include squamous carcinoma, undifferentiated carcinoma, carcinosarcoma, and neuroendocrine carcinoma [2,3]. Global incidence rates of GBC vary significantly, with notably high rates observed in Southeast Asia and South America, exceeding 20 cases per 100,000 [4]. The development of GBC is thought to result from a combination of individual genetic susceptibility and chronic local or systemic inflammation synergistically promoting carcinogenesis. Recognized risk factors for GBC include female gender, high body mass index (BMI), cholecystolithiasis, gallbladder polyps, and a family history of the disease [1,5]. Radical surgical intervention remains the sole potential cure for early-stage GBC patients; however, treatment options for unresectable or metastatic cases are severely limited. The combination of gemcitabine and cisplatin, established by the ABC-02 trial, represents the standard first-line systemic therapy for advanced biliary tract cancer (BTC), encompassing GBC [6]. While innovative targeted therapies like pemigatinib, infigratinib, and ivosidenib have been approved to improve outcomes in BTC patients, mutations of these targets are infrequent in GBC, resulting in persistently disappointing long-term survival rates for patients with advanced GBC [7–10].

GBC is recognized as one of the most lethal digestive tumors, chiefly attributable to its aggressive nature and high tendency for early tumor recurrence. While radical resection remains the sole curative option, the recurrence rate post-resection is alarmingly high in GBC patients, with a 5-year overall survival (OS) rate ranging from 10% to 32% [11–13]. Previous research has indicated that elevated preoperative levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in GBC patients correlate with poorer post-surgical survival [14,15]. Additional adverse prognostic factors for resected GBC outcomes include hepatic invasion, lympho-vascular invasion, positive surgical margins, and perineural invasion [16–18]. Despite the simplicity and efficacy of the American Joint Committee on Cancer (AJCC-8) staging system in clinical prediction [19], investigators have recently made efforts to explore various clinicopathologic factors for developing novel prognostic models to predict GBC survival [20,21]. In a previous study focusing on GBC patients from a single center, a novel nomogram was devised, and superior risk stratification capabilities were demonstrated, aiding in the differentiation of high-risk GBC cases and outcome prediction [11]. However, achieving a cure for GBC after resection remains uncertain, with existing risk models often overlooking factors crucial for long-term survival and cure in GBC. As such, an updated assessment of long-term prognosis and cure rates post-surgical resection in GBC is imperative to inform contemporary clinical decision-making among healthcare professionals.

Our present study collected demographic, laboratory, and pathological data from 331 GBC patients across three Chinese medical centers. Following a 10-year follow-up period, the research aimed to establish the cure rate, defined as a 10-year survival without recurrence post-surgical resection in GBC patients, and to investigate the perioperative clinicopathologic profiles of these verified 10-year survivors. Employing a semi-parametric mixture cure model, the study successfully identified clinicopathologic factors that impede cure within this multi-center GBC cohort.

Methods

Data collection

Patients diagnosed with GBC who underwent cholecystectomy or radical resection were retrospectively gathered from three medical centers in China – Peking Union Medical College Hospital (PUMCH) in Beijing, Sir Run Run Shaw Hospital in Hangzhou, and Guangdong Provincial People’s Hospital in Guangzhou, post-2000. The study aimed for a 10-year follow-up duration by selecting patients who had surgery between January 2000 and December 2013. Inclusion criteria were: (1) primary GBC confirmed via preoperative imaging and postoperative pathology; (2) cholecystectomy or radical resection performed; (3) an American Society of Anesthesiologists (ASA) Score ≤ II; (4) ≥ 18 years old and ≤ 70 years old. Exclusion criteria included: (1) distal metastasis or secondary primary malignancy; (2) only explorative laparotomy or palliative surgery performed; (3) receipt of neoadjuvant therapy; (4) incomplete clinical records; (5) loss to follow-up within 10 years; (6) death within three months post-surgery. The enrolled patients’ demographic, laboratory, and pathological data were collected, focusing on preoperative factors (age, gender, BMI, diabetes, cholecystolithiasis, jaundice, CA19-9, and CEA), operative details (surgical margin, hepatic resection, surgery type, combined resection of invaded organs), and postoperative characteristics (tumor size, infiltration, location, hepatic invasion, differentiation, lymph node metastasis, AJCC stage and adjuvant therapy). Tumor infiltration and AJCC stage was assessed using the AJCC-8 T staging system [19]. Data collection was independently performed by two reviewers. The study was ethically approved by the medical research ethics committees of the participating institutions with approval number I-22PJ1007 and complied with the Declaration of Helsinki. Due to its retrospective nature, the requirement for informed consent was waived, which was approved by the Ethics Committees of PUMCH.

Treatment and follow‑up

The perioperative management of patients, including the choice of surgery type (laparoscopic or open) and hepatic resection strategy (segment IVb and V or wedge resection), varied among the collaborating medical centers. Essentially, the surgical approach was individualized based on patient health status, imaging studies, and pathological findings. Simple cholecystectomy was the standard for patients at the T1a stage, while those at the T1b to T2 stages underwent radical resection involving gallbladder removal with adjacent hepatic tissue and lymph node dissection. Advanced tumors (T3–T4) often necessitate more extensive procedures like right hemi-hepatectomy or combined resection of other affected organs, excluding the liver. The term ‘combined organ resection’ refers to the partial or complete removal of invaded organs, such as the colon, stomach, and pancreas, beyond hepatic involvement. Each surgical specimen was meticulously examined and conclusively diagnosed as GBC by two independent pathologists. Follow-ups were conducted through various means, including telephone calls, outpatient consultations, and electronic communication platforms like WeChat and emails. The primary study endpoints focused on overall survival (OS) and relapse-free survival (RFS), defined as the duration from surgical resection until death or disease recurrence. If patients neither died nor experienced relapse, the cut-off point was the date of the last follow-up. Adjuvant therapy encompassed any radiotherapy or chemotherapy administered within six months post-surgery. The concept of observed cure entailed a 10-year OS without any indication of disease recurrence. During the final clinical assessment, patients with no documented recurrence or with resected recurrent disease sites were considered free of disease recurrence. Differences in demographic and perioperative clinicopathologic characteristics were compared across distinct OS groups (<5 years, 5–10 years, and >10 years).

Cure model and statistical analysis

Quantitative data, including age, CA19-9, tumor size, and CEA, were transformed into qualitative variables based on optimal cutoff values identified using X-tile software (New Haven, USA) to enhance outcome-based optimization. The qualitative variables were summarized as frequencies and assessed using the χ2 test or Fisher’s exact test. The prognostic significance of perioperative clinicopathologic features in GBC patients was evaluated through Kaplan-Meier survival analyses. After a prolonged follow-up period, the assumption of Cox proportional hazards was invalidated due to survival curve plateaus at the tails, necessitating the creation of a semi-parametric mixture cure model [22–26]. This model was designed to explore heterogeneity between long-term survivors and non-survivors and determine the likelihood of cure in GBC. Logistic regression was employed to simulate and predict survival probabilities in the model, while the proportional hazards model was used to estimate cure probabilities in high-risk patients or those with significant events. Statistical analyses and graphical presentations were conducted utilizing R software version 4.3.2 and GraphPad Prism version 8.3.0. A p-value less than 0.05 was considered statistically significant unless otherwise specified.

Results

Patient characteristics

The study cohort comprised 390 patients with GBC who underwent surgical resection between 2000 and 2013. Following the established criteria, 331 GBC patients were included in the analysis (Figure 1). A summary of baseline and perioperative clinicopathologic characteristics across distinct survival groups is presented in Table 1. Cholecystolithiasis was present in the majority of patients (n = 232, 70.10%), while jaundice was observed in 48 patients (14.50%). Most patients underwent hepatic resections, including segment IVb and V resection or wedge resection (n = 267, 80.66%), and 90 patients (27.19%) showed hepatic tumor invasion. The majority of surgeries were open procedures (n = 236, 80.66%), with 35 patients (10.57%) having an R1 surgical margin. Twenty patients underwent combined resections of invaded organs, involving areas such as the transverse colon, stomach, and pancreaticoduodenum. According to the AJCC-8 staging system, 157 patients (47.43%) were classified as T3 or T4 and 129 patients (38.97%) were in AJCC IIIB–IVA stage. Positive lymph node metastases were detected in 104 patients (31.42%), while 102 patients (30.82%) exhibited poor tumor differentiation. Postoperative adjuvant therapy was administered to 89 patients (26.8%), with 36 patients undergoing chemotherapy, 31 receiving radiotherapy, and 22 patients undergoing chemoradiotherapy.

Figure 1. The flow diagram of the inclusion and exclusion for gallbladder cancer patients.

Table 1. A summary of baseline and characteristics of GC patients across different survival groups.

Patient characteristics	n	<5 Year	%	5–10 Year	%	>10 Year	%	
n	331	213	64.35%	79	23.87%	39	11.78%	
Preoperative characteristics	
Age (years)	<60	137	85	62.04%	30	21.90%	22	16.06%	
≥60	194	128	65.98%	49	25.26%	17	8.76%	
Gender	Male	100	64	64.00%	21	21.00%	15	15.00%	
Female	231	149	64.50%	58	25.11%	24	10.39%	
BMI (kg/m2)	≥18.5	290	184	63.45%	72	24.83%	34	11.72%	
<18.5	41	29	70.73%	7	17.07%	5	12.20%	
Diabetes	Absent	270	173	64.07%	69	25.56%	28	10.37%	
Present	61	40	65.58%	10	16.39%	11	18.03%	
Cholecystolithiasis	Absent	99	62	62.63%	26	26.26%	11	11.11%	
Present	232	155	66.81%	50	21.55%	27	11.64%	
Jaundice	Absent	283	187	66.08%	65	22.97%	31	10.95%	
Present	48	26	54.17%	14	29.17%	8	16.66%	
CA19-9 (U/ml)	<58	227	127	55.95%	66	29.07%	34	14.98%	
≥58	104	86	82.69%	13	12.50%	5	4.81%	
CEA (ng/ml)	<4.5	251	156	62.15%	65	25.90%	30	11.95%	
≥4.5	80	57	71.25%	14	17.50%	9	11.25%	
Operative characteristics	
Surgical margin	R0	296	184	62.16%	74	25.00%	38	12.84%	
R1	35	29	82.86%	5	14.28%	1	2.86%	
Hepatic resection	Absent	64	36	56.25%	15	23.44%	13	20.31%	
Present	267	177	66.29%	64	23.97%	26	9.74%	
Surgery type	Laparoscopic	95	50	52.63%	27	28.42%	18	18.95%	
Open	236	163	69.07%	52	22.03%	21	8.90%	
Combined resection of invaded organs	Absent	311	195	62.70%	77	24.76%	39	12.54%	
Present	20	18	90.00%	2	10.00%	0	0.00%	
Postoperative characteristics	
Tumor size	<3.5	199	122	61.31%	47	23.62%	30	15.07%	
≥3.5	132	91	68.94%	32	24.24%	9	6.82%	
T stage	T1–2	174	84	48.28%	58	33.33%	32	18.39%	
T3–4	157	129	82.16%	21	13.38%	7	4.46%	
Location	Hepatic-sided	150	113	75.33%	23	15.33%	14	9.34%	
Peritoneal-sided	181	100	55.25%	56	30.94%	25	13.81%	
Hepatic invasion	Absent	241	138	57.26%	68	28.22%	35	14.52%	
Present	90	75	83.33%	11	12.22%	4	4.45%	
Differentiation	Well and moderately	229	128	55.90%	65	28.38%	36	15.72%	
Poor	102	85	83.33%	14	13.73%	3	2.94%	
Lymphnode metastasis	Absent	227	121	53.30%	69	30.40%	37	16.30%	
Present	104	92	88.46%	10	9.62%	2	1.92%	
AJCC stage	I–IIIA	202	106	52.47%	63	31.19%	33	16.34%	
IIIB–IVA	129	107	82.95%	16	12.40%	6	4.65%	
Adjuvant therapy	Absent	242	147	60.74%	65	26.86%	30	12.40%	
Present	89	66	74.16%	14	15.73%	9	10.11%	

Patient survival

Figure 2A illustrates the overall survival outcomes of the entire cohort. All participants were followed for over 10 years, with a median OS of 31.6 months. The 2-, 5-, and 10-year OS rates stood at 68.89%, 35.65%, and 11.78%, respectively. Subsequent Kaplan-Meier analyses highlighted that GBC patients with elevated CA19-9 levels, positive surgical margins (R1 resection), advanced T stage (T3–4), and poor tumor differentiation displayed significantly poorer OS. Conversely, patients without hepatic invasion, lymph node metastasis, or combined organ resections showed improved survival outcomes (Figure 2B–H). The 10-year OS rates were notably higher in the following comparisons: CA19-9 < 58 U/ml (n = 34, 14.98%) versus CA19-9 ≥ 58 U/ml (n = 5, 4.81%), R0 resection (n = 38, 12.84%) versus R1 resection (n = 1, 2.86%), T1–2 stage (n = 32, 18.39%) versus T3–4 stage (n = 7, 4.46%), well or moderately tumor differentiation (n = 36, 15.72%) versus poor differentiation (n = 3, 2.94%), negative lymph node status (n = 37, 16.30%) versus positive lymph node metastasis (n = 2, 1.92%), and the absence of hepatic invasion (n = 35, 14.52%) versus presence of hepatic invasion (n = 4, 4.45%).

Figure 2. Kaplan-Meier Analyses for all enrolled gallbladder cancer patients (A) and patients stratified by the predictors: CA19-9 index (B), surgical margin (C), combined resection of invaded organs (D), T stage (E), hepatic invasion (F), lymphnode metastasis (G) and tumor differentiation (H).

Actual 10-year survivors

A total of 39 patients achieved a noteworthy 10-year survival milestone, qualifying them as 10-year survivors. Among this group, the majority (n = 31, 79.49%) remained alive without any signs of tumor recurrence or metastasis. Five patients (12.82%) passed away after 10 years post-surgery without recurring tumors. Additionally, three patients (7.69%) were still alive but had experienced disease recurrence or metastasis. Key clinicopathologic traits of the 10-year survivors are detailed in Supplementary Table 1. Notably, none of these survivors underwent combined organ resections. Within the subset of three recurrent cases, none had undergone R1 resections or had positive lymph node involvement. Two survivors displayed hepatic invasion and poor tumor differentiation, while all three were categorized as T3–4 stages.

Observed cure and cure model

A total of 36 patients achieving a 10-year recurrence-free survival (RFS) mark were deemed cured, resulting in an observed cure rate (OCR) of 10.88% (Table 2). The OCR analysis revealed that only combined resections of invaded organs prevented a cure for GBC patients (0/20, 0.00%). The next lowest OCR rate was seen in cases of R1 resections (1/35, 2.86%). The most favorable OCR for preoperative characteristics was observed in patients with CA19-9 levels ≥58 U/ml (5/104, 4.81%). Additionally, very low OCR rates were noted for postoperative characteristics, including poor tumor differentiation (2/102, 1.96%), positive lymph node metastasis (2/104, 1.92%), and hepatic invasion (2/90, 2.22%). Furthermore, the correlation between clinicopathologic characteristics and cure probability was investigated through semiparametric mixture cure models. The calculated cure probability was 0.79% for patients with positive lymph node metastasis and 0.93% for those with R1 resections. Characteristics associated with cure probabilities below 5% included the T3–4 stage (2.71%), hepatic invasion (1.01%), AJCC IIIB–IVA Stage (2.66%) and poor tumor differentiation (3.25%). Notably, no patient survived beyond 10 years following combined organ resections.

Table 2. The overview of characteristics of GC patients with observed cure and probability of cure.

Patient characteristics	All patients	Observed cure* %	Probability of cure#	
n	331	36	10.88%	 	
Preoperative characteristics	
Age (years)	<60	137	21	15.33%	17.53%	
≥60	194	15	7.73%	9.78%	
Gender	Male	100	14	14.00%	18.53%	
Female	231	22	9.52%	13.56%	
BMI (kg/m2)	≥18.5	290	31	10.69%	13.27%	
<18.5	41	5	12.20%	16.34%	
Diabetes	Absent	270	26	9.63%	14.64%	
Present	61	10	16.39%	19.11%	
Cholecystolithiasis	Absent	99	10	10.10%	14.76%	
Present	232	25	10.76%	13.44%	
Jaundice	Absent	283	28	9.89%	11.43%	
Present	48	8	16.67%	14.95%	
CA19-9 (U/ml)	<58	227	31	13.66%	14.56%	
≥58	104	5	4.81%	6.53%	
CEA (ng/ml)	<4.5	251	29	11.55%	13.54%	
≥4.5	80	7	8.75%	9.45%	
Operative characteristics	
Surgical margin	R0	296	35	11.82%	13.52%	
R1	35	1	2.86%	0.93%	
Hepatic resection	Absent	64	13	20.31%	23.93%	
Present	267	23	8.61%	9.45%	
Surgery type	Laparoscopic	95	18	18.95%	19.42%	
Open	236	18	7.63%	9.93%	
Combined resection of invaded organs	Absent	311	36	11.58%	13.53%	
Present	20	0	0.00%	0.00%	
Postoperative characteristics	
Tumor size	<3.5	199	30	15.08%	18.34%	
≥3.5	132	5	3.79%	7.43%	
T stage	T1-2	174	32	18.39%	20.56%	
T3-4	157	7	4.46%	2.71%	
Tumor location	Hepatic-sided	150	12	8.00%	10.53%	
Peritoneal-sided	181	24	13.26%	16.45%	
Hepatic invasion	Absent	241	34	14.11%	17.74%	
Present	90	2	2.22%	1.01%	
Differentiation	Well and moderately	229	34	14.85%	16.82%	
Poor	102	2	1.96%	3.25%	
Lymphnode metastasis	Absent	227	34	14.98%	17.64%	
Present	104	2	1.92%	0.79%	
AJCC Stage	I–IIIA	202	32	15.84%	16.72%	
IIIB–IVA	129	4	3.10%	2.66%	
Adjuvant therapy	Absent	242	28	11.57%	13.98%	
Present	89	8	8.99%	11.42%	
The significance of bold values are clinical characteristics associated with cure probabilities below 5%.

Discussion

A comprehensive study on the demographic profile of cured GBC patients following surgery and the determinants impacting long-term survival has been lacking in recent investigations. In this study, we presented the extended outcomes of a substantial multi-center GBC cohort, focusing on actual 10-year survival and cure rates post-surgical resection. Notably, a cure rate of 10.88% was observed among resected GBC patients in this cohort. Through semiparametric mixture cure analysis, clinicopathologic factors that significantly hindered cure were identified, including combined surgical resections of invaded organs, positive lymph node metastasis, and R1 resections, all below a 1% cure rate probability. Patients with T3–4 stage disease, hepatic invasion, advanced AJCC stage or poor tumor differentiation exhibited a limited likelihood of being cured, below a 5% cure rate probability.

Radical resection remains the sole potential curative strategy for GBC patients, with the primary objective of achieving a negative resection margin and providing oncologic benefits. An earlier publication identified the surgical margin as a key predictive factor and utilized it to develop a nomogram for predicting OS in GBC patients [11]. Notably, individuals undergoing R0 resection from the National Cancer Database exhibited a significantly longer median OS compared to those with R1 resections (34.6 months vs. 16.3 months) [27]. Consistent with established findings, the present study reaffirmed the critical importance of R0 resection for potential cure, as indicated by a mere 2.86% observed and a predicted 0.93% 10-year DFS in patients with R1 resections [16]. The involvement of the cystic duct margin emerged as a crucial variable impacting prognosis, with GBC patients having a positive cystic duct margin demonstrating lower 5-year OS rates than those with negative margins [16,28]. However, the contentious issue of an extended common bile duct resection in GBC patients with a positive cystic duct margin persists [29]. Previous reports indicated that combined resections of the common bile duct did not enhance lymph node sampling or improve OS in GBC patients with positive cystic duct margins [16,30,31]. While neoadjuvant therapy has shown benefits in reducing tumor size and aiding R0 resections in various digestive cancers, there is insufficient data supporting its application in advanced GBC. Notably, given a 35.4% R0 rate reported in a systematic review of 8 study cohorts [32], our study excluded a subgroup of patients who received neoadjuvant therapy due to their limited number (n = 5). Future randomized controlled trials are critical for assessing the potential advantages of neoadjuvant therapy in advanced GBC.

In addition to the surgical margin, tumor infiltration depth plays a crucial role in GBC prognosis. Within the current study, three clinical factors related to tumor infiltration – T3–4 stage, hepatic invasion, and combined resection of invaded organs – significantly impeded cure for GBC patients. The selection of the surgical approach for GBC is heavily influenced by tumor infiltration depth, particularly the T stage. Although hepatic resection is considered essential for optimal radical resection of GBC at the T1b stage or higher, the choice of hepatectomy strategies remains subject to recent debate. While hepatic wedge resection aims to secure a negative surgical margin, formal segment IVb and V resections anatomically eliminate occult liver metastases to achieve a cure [33]. Previous studies suggest that, despite no significant differences in survival or recurrence rates between the approaches [34–37], hepatic wedge resection is associated with notably fewer postoperative complications (Clavien-Dindo grade ≥ III) [34]. Reducing postoperative complications is pivotal for improving long-term survival outcomes.

Additional clinical factors that hinder cure in GBC, as discovered in our analysis, encompass positive lymph node metastasis and poor tumor differentiation, extensively documented in prior literature. Beyond these clinical manifestations, the emergence of aggressive GBC phenotypes stems from somatic mutations and pathway dysregulation, driven by genetic and epigenetic mechanisms [1]. Notably, TP53 mutation is prevalent in 40% of GBC cases, alongside detrimental mutations documented in SMAD4, KRAS, CDKN2A, ARID1A, and ERBB2 [1,38,39]. These driver mutations play essential roles in various cancer-related processes and pathways, including apoptosis, cell cycle regulation, DNA repair, and chromatin remodeling [9,40]. Characterized by activated TGF-β signaling and epithelial-mesenchymal transition, a poor prognosis subtype of GBC has been identified in earlier studies [9,41]. This GBC subtype reveals an immunosuppressive tumor microenvironment rich in lymphocytes, enhanced immune checkpoints, and heightened immunological signaling pathways such as tumor necrosis factor and interferon-γ responses [9]. The reshaping of the TME during GBC progression signifies extensive tumor heterogeneity and remodeling, paving the way for innovative treatment avenues in GBC.

This study is not the first to investigate the definition and clinical factors associated with a cure for digestive malignancies. The semiparametric proportional hazards mixture cure model offers the advantage of determining the relationship between clinicopathological characteristics and long-term outcomes. This relationship has been validated in cohorts of perihilar cholangiocarcinoma and colorectal cancer with liver metastases [22–24]. The cure model utilizes time-dependent hazard ratio estimation to address complex long-term survival patterns, outperforming the conventional Cox regression model in providing information [24]. Despite our study representing one of the largest GBC cohorts with a 10-year follow-up, there are limitations to consider. Sample sizes among different survival subgroups are limited, and controlling data heterogeneity is challenging due to the study’s duration. Additionally, the lack of available data on causes of death in this multi-center cohort necessitates the use of OS instead of disease-specific survival to define cure, potentially introducing bias in our analyses on the cure rate. Another limitation is the omission of somatic mutations or molecular phenotypes of GBC in our study. Future analyses should explore the impact of genetic information or molecular characteristics on the long-term survival and cure of GBC.

Conclusion

In a multi-center cohort, patients with GBC who undergo surgical resection exhibit an observed cure rate of 10.88%. Poor prognostic factors, such as combined surgical resection of invaded organs, positive lymph node metastasis, R1 resection, T3–4 stage, hepatic invasion, advanced AJCC stage and poor tumor differentiation, greatly diminish the chance of cure (with a probability of cure below 5%). The identification of informative combinations of clinicopathologic prognostic factors holds significant importance for personalized treatment approaches. Insights gained from the mixture cure model will aid in evaluating new factors to define clinical subtypes of GBC and streamline clinical decision-making processes.

Ethical approval

The study protocol was approved and under the supervision by the Medical Research Ethics Committee of Peking Union Medical College Hospital, Sir Run Run Shaw Hospital and Guangdong Provincial People’s Hospital and the approval number was I-22PJ1007. This study was carried out according to the Declaration of Helsinki of the World Medical Association.

Supplementary Material

Supplementary Tables.docx

Authors contributions

Conceptualization, Zuyi Ma, Zhenchong Li, Jiasheng Cao and Binglu Li; Data curation, Zuyi Ma, Zhenchong Li and Jiasheng Cao; Funding acquisition, Shanzhou Huang, Qi Zhou and Binglu Li; Investigation, Jia Sun; Methodology, Zuyi Ma, Zhenchong Li, Jiasheng Cao and Jia Sun; Project administration, Binglu Li; Writing – original draft, Zuyi Ma, Zhenchong Li and Jiasheng Cao; Writing – review and editing, Zuyi Ma, Zhenchong Li, Jiasheng Cao, Shanzhou Huang, Qi Zhou and Binglu Li. All authors have read and approved the final work.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The original contributions presented in the study are included in the article or the supplementary material. Other data that support the findings are available from the corresponding author upon reasonable request.
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