Identification of publication characteristics and research trends in the management of gallbladder cancer

Abstract

Background

To date, no comprehensive analysis of gallbladder cancer (GBC) management has been reported. We aimed to identify the publication characteristics and research trends in managing GBC over the past three decades.

Methods

We selected the 100 most cited articles and performed a bibliometric analysis to summarize the publication characteristics, explore research hotspots, and identify research trends in the management of GBC.

Results

The total citations of the included articles ranged from 123 to 1822. Period II (2001–2010) yielded the highest number of included articles, whereas the lowest was in Period III (2011–2020). The United States and Japan published the most papers, in which the Memorial Sloan–Kettering Cancer Center and Nagoya University were the leading institutions, respectively. The most influential authors were Blumgart LH and Fong YM from the United States. Cooperation among countries, institutions, and authors was weak. The Annals of Surgery contributed the most articles with the highest number of total citations. The most researched topic was surgery, followed by systemic therapy and adjuvant therapy. Since Period I, the percentage of surgery-related publications continuously decreased (Periods II and III versus Period I, both p < 0.001), with a concomitant increase in those of adjuvant therapy (Period III versus Period I, p = 0.004) and systemic therapy (Period II versus Period I, p = 0.004; Period III versus Period I, p = 0.002).

Conclusions

Surgery remains the preferred treatment, while there is a tendency toward adjuvant and systemic therapy in GBC management. An increase in local and international collaboration for managing GBC is required.

Highlights

• •The 100 most cited papers in gallbladder cancer management were identified based on the total citations.
• •A bibliometric analysis was performed, identifying publication characteristics and research trends in gallbladder cancer management.
• •Surgery remained the primary treatment, while there was a research trend to adjuvant and systemic therapy in gallbladder cancer management.

1. Introduction

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract system and it has a unique geographical distribution pattern worldwide. GBC has a poor prognosis with a 5-year overall survival (OS) of < 5% [1,2]. The surgical management of GBC is the most effective strategy for resected GBC and subsequent postoperative adjuvant therapy may improve its prognosis [3,4]. Unfortunately, in patients with atypical clinical symptoms at the early stages of GBC, most of them are diagnosed with advanced GBC and have to undergo non-surgical treatment [5]. Non-surgical treatment has developed from chemotherapy and radiotherapy to systemic therapy, such as targeted therapy and immunotherapy [6]. With the rapid advancement of medical equipment and technologies, evaluating publication characteristics and identifying research trends in GBC treatment based on previous studies are difficult because of an overload of publications of varying academic quality.

Bibliometric citation analysis is a convenient method to evaluate the quality of the research output [7]. This analysis enables the exploration of various publication characteristics within a certain field, including total citations (TCs), journal distribution, research hotspots, and the cooperative relationships among countries, institutions, and authors. The TCs of a study directly correlate with their significance and are used as a grading criterion for identifying influential studies. Bibliometric analysis based on TCs has been extensively conducted to serve as a reference for clinicians and researchers in various diseases, such as gastric cancer [8], hepatocellular carcinoma [9], and colorectal cancer [10]. However, no bibliometric analysis has been conducted for the management of GBC.

This study aimed to conduct a bibliometric analysis of the top 100 cited papers to ascertain publication characteristics and research trends in the field of GBC management. This study will provide clinicians and researchers with a broad vision of the progress of GBC care and relevant insights into future investigations.

2. Materials and methods

2.1. Literature search and screening

We performed a systematic literature search from January 1981 to December 2020 in the Clarivate Analytics Web of Science Core Collection (WOSCC) database in December 2021. A summary of the search terms and search strategy is shown in Table 1. Original articles, reviews, consensus statements, and guidelines in which the main topics were relevant to GBC management were included in the study. Commentaries, case reports, and editorials were excluded. Two authors independently identified the 100 most cited papers based on TCs, and then, a third author was involved in the discussion until any disagreement was resolved.

Table 1.

Search strategy with a summary of keywords to identify the top 100 papers from the Clarivate Analytics Web of Science Core Collection database.

Search Sequence	Search Query	Result
Search #1	TOPIC: (gallbladder cancer) OR TOPIC: (gallbladder carcinoma) OR TOPIC: (GBC) OR TOPIC: (gallbladder malignancy) OR TOPIC: (gallbladder malignant tumor) OR TOPIC: (incidental gallbladder cancer) OR TOPIC: (IGBC)	6036
Search #2	TOPIC: (treatment) OR TOPIC: (therapy) OR TOPIC: (management) OR TOPIC: (surgery) OR TOPIC: (resection) OR TOPIC: (cholecystectomy) OR TOPIC: (radical cholecystectomy) OR TOPIC: (completion surgery) OR TOPIC: (curative resection) OR TOPIC: (hepatic resection) OR TOPIC: (liver resection) OR TOPIC: (portal lymphadenectomy) OR TOPIC: (lymph node dissection) OR TOPIC: (bile duct resection) OR TOPIC: (adjuvant therapy) OR TOPIC: (chemotherapy) OR TOPIC: (systemic chemotherapy) OR TOPIC: (locoregional therapy) OR TOPIC: (transarterial chemoembolization) OR TOPIC: (TACE) OR TOPIC: (hepatic arterial infusion) OR TOPIC: (HAI) OR TOPIC: (intraductal ablative procedures) OR TOPIC: (radiofrequency ablation) OR TOPIC: (photodynamic therapy) OR TOPIC: (PDT) OR TOPIC: (radiotherapy) OR TOPIC: (fractionated radiotherapy) OR TOPIC: (intensity-modulated radiation therapy) OR TOPIC: (stereotactic body radiation therapy) OR TOPIC: (stereotactic body radiotherapy) OR TOPIC: (SBRT) OR TOPIC: (targeted therapy) OR TOPIC: (immunotherapy)	8,195,236
Search #3	#1 AND #2	3519

Note: Indexes = SCI-EXPANDED, CPCI–S. Timespan = From January 1981 to December 2020.

SCI-EXPANDED, Science Citation Index Expanded; CPCI–S, Conference Proceedings Citation Index-Science.

2.2. Bibliometric analysis and visualization

The top 100 most cited papers that matched the search criteria were identified, and all available information was downloaded from the WOSCC database. We then converted and analyzed the bibliographic information of the top 100 most cited articles by R Studio Version 4.0.4 (R Foundation for Statistical Computing, Vienna, Austria) with the “bibliometrix” package [11]. The publication characteristics, such as TCs, country, institution, author, journal, impact factor, publication year, title, and keywords, were further extracted and analyzed using the “bibliometrix” package. We also determined the main topics, subtopics, and article type of the included studies after reading the titles, abstracts, and keywords.

We inserted all collected information and data into a spreadsheet and manipulated them using Microsoft Excel 2019 (Microsoft Corp., Redmond, WA, USA). Graphs and figures were mainly created by R Studio Version 4.0.4 (R Foundation for Statistical Computing) and Prism Version 8.4.0 (GraphPad Software, Inc., La Jolla, CA). Microsoft Excel 2019 Power Map (Microsoft Corp.) was applied for a global map of countries’ contributions to the 100 most cited articles. Finally, the cooperation relationship among all countries, institutions, and authors, and a keywords clustering map were created and visualized on an online bibliometric platform (https://bibliometric.com/) and VOS viewer Version 1.6.10 (Leiden University, Leiden, The Netherlands). This work has been reported in line with the STROCSS criteria [12].

2.3. Statistical analysis

Categorical variables were reported as the frequency and percentage and were assessed between two groups by the Pearson χ² test. No continuous variables were reported in the study. Statistical analyses were performed using IBM SPSS Version 20.0 (IBM Corp., Armonk, NY, USA). p < 0.05 was considered statistically significant.

3. Results

3.1. Top-cited publications and publication periods

A total of 3519 publications that focused on GBC management were identified from the WOSCC database from January 1981 to December 2020. Because there were limited publications before 1990 (n = 18) and no publications (n = 0) ranked in the top 100 (Fig. 1), we excluded 18 initial publications and considered publications over the past three decades. The 100 most cited papers were shown in Table 2 according to the descending sequence of the TCs. The TCs ranged from 1822 [13], of which the TCs far exceeded the rest, to 123 [14]. The earliest notable articles were two studies published in 1991 that focused on the surgical treatment for GBC [15,16]. The latest article was published in 2019, which received 302 TCs, and it focused on adjuvant therapy and compared capecitabine with observation in resected GBC in a phase 3 trial [17]. Period II (2001–2010, n = 49) yielded the highest number of most cited articles with the most dramatic growth, followed by Period I (1991–2000, n = 28) and Period III (2011–2020, n = 23) (Fig. 2). Notably, 2008 and 2015 showed the peak of the most cited articles (n = 8), while there were no publications for several years in Period III, namely 2013, 2016, 2018, and 2020.

Fig. 1.

Annual and cumulative number of publications on GBC management over the past four decades. GBC, gallbladder cancer.

Table 2.

Top 100 papers in gallbladder cancer management.

Rank	Paper	TC
1	Valle J et al. Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. New England Journal of Medicine. 2010; 362:1273–1281.	1822
2	Schnitzbauer AA et al. Right Portal Vein Ligation Combined With In Situ Splitting Induces Rapid Left Lateral Liver Lobe Hypertrophy Enabling 2-Staged Extended Right Hepatic Resection in Small-for-Size Settings. Annals of Surgery. 2012; 255:405–414.	749
3	Lazcano-Ponce EC et al. Epidemiology and molecular pathology of gallbladder cancer. Ca-a Cancer Journal for Clinicians. 2001; 51:349–364.	538
4	Nakamura H et al. Genomic spectra of biliary tract cancer. Nature Genetics. 2015; 47:1003-+.	509
5	Hundal R et al. Gallbladder cancer: epidemiology and outcome. Clinical Epidemiology. 2014; 6:99–109.	490
6	Randi G et al. Gallbladder cancer worldwide: Geographical distribution and risk factors. International Journal of Cancer. 2006; 118:1591–1602.	486
7	Stinton LM et al. Epidemiology of Gallbladder Disease: Cholelithiasis and Cancer. Gut and Liver. 2012; 6:172–187.	480
8	Misra S et al. Carcinoma of the gallbladder. Lancet Oncology. 2003; 4:167–176.	476
9	Takada T et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer. 2002; 95:1685–1695.	431
10	Okusaka T et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. British Journal of Cancer. 2010; 103:469–474.	401
11	Horgan AM et al. Adjuvant Therapy in the Treatment of Biliary Tract Cancer: A Systematic Review and Meta-Analysis. Journal of Clinical Oncology. 2012; 30:1934–1940.	394
12	Nagino M et al. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer - Surgical outcome and long-term follow-up. Annals of Surgery. 2006; 243:364–372.	361
13	Eckel F et al. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. British Journal of Cancer. 2007; 96:896–902.	355
14	Shibata T et al. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology. 2008; 135:1358–1368.	344
15	Benson AB et al. Hepatobiliary Cancers. Journal of the National Comprehensive Cancer Network. 2009; 7:350–391.	342
16	Nduka CC et al. Abdominal-Wall Metastases Following Laparoscopy. British Journal of Surgery. 1994; 81:648–652.	339
17	Jarnagin WR et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma - Implications for adjuvant therapeutic strategies. Cancer. 2003; 98:1689–1700.	308
18	Bartlett DL et al. Long-term results after resection for gallbladder cancer - Implications for staging and management. Annals of Surgery. 1996; 224:639–646.	306
19	Henson DE et al. Carcinoma of the Gallbladder - Histologic Types, Stage of Disease, Grade, and Survival Rates. Cancer. 1992; 70:1493–1497.	305
20	Primrose JN et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomized, controlled, multicentre, phase 3 study. Lancet Oncology. 2019; 20:663–673.	302
21	Fong Y et al. Gallbladder cancer: Comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Annals of Surgery. 2000; 232:557–566.	297
22	Lee J et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary tract cancer: a multicentre, open-label, randomized, phase 3 study. Lancet Oncology. 2012; 13:181–188.	294
23	Cubertafond P et al. Surgical Treatment of 724 Carcinomas of the Gallbladder - Results of the French-Surgical-Association Survey. Annals of Surgery. 1994; 219:275–280.	275
24	De Palma GD et al. Unilateral versus bilateral endoscopic hepatic duct drainage in patients with malignant hilar biliary obstruction: results of a prospective, randomized, and controlled study. Gastrointestinal Endoscopy. 2001; 53:547–553.	269
25	Malka D et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary tract cancer (BINGO): a randomized, open-label, non-comparative phase 2 trial. Lancet Oncology. 2014; 15:819–828.	243
26	Knox JJ et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: A phase II trial. Journal of Clinical Oncology. 2005; 23:2332–2338.	242
27	Nimura Y et al. Hepatopancreatoduodenectomy for Advanced-Carcinoma of the Biliary Tract. Hepato-Gastroenterology. 1991; 38:170–175.	242
28	Ben-Josef E et al. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. Journal of Clinical Oncology. 2005; 23:8739–8747.	236
29	Reilly WT et al. Wound recurrence following conventional treatment of colorectal cancer - A rare but perhaps underestimated problem. Diseases of the Colon & Rectum. 1996; 39:200–207.	233
30	Paolucci V et al. Tumor seeding following laparoscopy: International survey. World Journal of Surgery. 1999; 23:989–997.	231
31	Ogura Y et al. Radical Operations for Carcinoma of the Gallbladder - Present Status in Japan. World Journal of Surgery. 1991; 15:337–343.	227
32	Anderson CD et al. Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma. Journal of Gastrointestinal Surgery. 2004; 8:90–97.	226
33	Valle JW et al. New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discovery. 2017; 7:943–962.	219
34	Duffy A et al. Gallbladder Cancer (GBC): 10-Year Experience at Memorial Sloan–Kettering Cancer Center (MSKCC). Journal of Surgical Oncology. 2008; 98:485–489.	219
35	Zhu AX et al. Current Management of Gallbladder Carcinoma. Oncologist. 2010; 15:168–181.	206
36	Valle JW et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomized trials. Annals of Oncology. 2014; 25:391–398.	199
37	Weber SM et al. Intrahepatic Cholangiocarcinoma: expert consensus statement. Hpb. 2015; 17:669–680.	191
38	Zatonski WA et al. Epidemiologic aspects of gallbladder cancer: A case–control study of the SEARCH Program of the International Agency for Research on Cancer. Jnci-Journal of the National Cancer Institute. 1997; 89:1132–1138.	191
39	Aloia TA et al. Gallbladder Cancer: expert consensus statement. Hpb. 2015; 17:681–690.	190
40	Cuschieri A. Whither Minimal Access Surgery - Tribulations and Expectations. American Journal of Surgery. 1995; 169:9–19.	190
41	Petrowsky H et al. Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. Journal of Hepatology. 2006; 45:43–50.	189
42	Nakazawa K et al. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. Journal of Pathology. 2005; 206:356–365.	187
43	Levy AD et al. Gallbladder carcinoma: Radiologic-pathologic correlation. Radiographics. 2001; 21:295–314.	187
44	Bergquist A et al. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: A case–control study. Hepatology. 1998; 27:311–316.	185
45	Valle JW et al. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumors: a multicentre randomized phase II study - The UK ABC-01 Study. British Journal of Cancer. 2009; 101:621–627.	184
46	Sharma A et al. Best Supportive Care Compared With Chemotherapy for Unresectable Gall Bladder Cancer: A Randomized Controlled Study. Journal of Clinical Oncology. 2010; 28:4581–4586.	181
47	Hezel AF et al. Systemic therapy for biliary tract cancers. Oncologist. 2008; 13:415–423.	178
48	Shirai Y et al. Radical Surgery for Gallbladder Carcinoma - Long-Term Results. Annals of Surgery. 1992; 216:565–568.	178
49	Pawlik TM et al. Incidence of finding residual disease for incidental gallbladder carcinoma: Implications for re-resection. Journal of Gastrointestinal Surgery. 2007; 11:1478–1486.	171
50	Lubner SJ et al. Report of a Multicenter Phase II Trial Testing a Combination of Biweekly Bevacizumab and Daily Erlotinib in Patients With Unresectable Biliary Cancer: A Phase II Consortium Study. Journal of Clinical Oncology. 2010; 28:3491–3497.	170
51	Mansour JC et al. Hilar Cholangiocarcinoma: expert consensus statement. Hpb. 2015; 17:691–699.	169
52	Randi G et al. Epidemiology of biliary tract cancers: an update. Annals of Oncology. 2009; 20:146–159.	168
53	Kondo S et al. Regional and para-aortic lymphadenectomy in radical surgery for advanced gallbladder carcinoma. British Journal of Surgery. 2000; 87:418–422.	167
54	Johnstone PAS et al. Port site recurrences after laparoscopic and thoracoscopic procedures in malignancy. Journal of Clinical Oncology. 1996; 14:1950–1956.	167
55	Ben-Josef E et al. SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma. Journal of Clinical Oncology. 2015; 33:2617-U2657.	166
56	Dixon E et al. An aggressive surgical approach leads to improved survival in patients with gallbladder cancer - A 12-year study at a North American center. Annals of Surgery. 2005; 241:385–394.	166
57	Mager DL. Bacteria and cancer: cause, coincidence or cure? A review. Journal of Translational Medicine. 2006; 4.	163
58	Weber SM et al. Staging laparoscopy in patients with extrahepatic biliary carcinoma - Analysis of 100 patients. Annals of Surgery. 2002; 235:392–399.	160
59	Shimada H et al. The role of lymph node dissection in the treatment of gallbladder carcinoma. Cancer. 1997; 79:892–899.	157
60	Corvera CU et al. F-18-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. Journal of the American College of Surgeons. 2008; 206:57–65.	157
61	Shih SP et al. Gallbladder cancer: The role of laparoscopy and radical resection. Annals of Surgery. 2007; 245:893–901.	156
62	Cheng JLS et al. Endoscopic palliation of patients with biliary obstruction caused by nonresectable hilar cholangiocarcinoma: efficacy of self-expandable metallic Wallstents. Gastrointestinal Endoscopy. 2002; 56:33–39.	156
63	Razumilava N et al. Cancer Surveillance in Patients With Primary Sclerosing Cholangitis. Hepatology. 2011; 54:1842–1852.	155
64	Donohue JH et al. The National Cancer Data Base Report on Carcinoma of the Gallbladder, 1989–1995. Cancer. 1998; 83:2618–2628.	154
65	Hezel AF et al. Genetics of Biliary Tract Cancers and Emerging Targeted Therapies. Journal of Clinical Oncology. 2010; 28:3531–3540.	153
66	Tsukada K et al. Outcome of radical surgery for carcinoma of the gallbladder according to the TNM stage. Surgery. 1996; 120:816–821.	153
67	Fong YM et al. Gallbladder Cancer Discovered during Laparoscopic Surgery - Potential for Iatrogenic Tumor Dissemination. Archives of Surgery. 1993; 128:1054–1056.	152
68	Benoist S et al. Long-term results after curative resection for carcinoma of the gallbladder. American Journal of Surgery. 1998; 175:118–122.	151
69	Attili AF et al. The Natural-History of Gallstones - the Grepco Experience. Hepatology. 1995; 21:656–660.	151
70	Cirocco WC et al. Abdominal-Wall Recurrence after Laparoscopic Colectomy for Colon-Cancer. Surgery. 1994; 116:842–846.	151
71	Patt YZ et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004; 101:578–586.	150
72	Clair DG et al. Rapid Development of Umbilical Metastases after Laparoscopic Cholecystectomy for Unsuspected Gallbladder Carcinoma. Surgery. 1993; 113:355–358.	150
73	Drouard F et al. Cutaneous Seeding of Gallbladder Cancer after Laparoscopic Cholecystectomy. New England Journal of Medicine. ;325:1316–1316.	149
74	Murakami Y et al. Prognostic Factors After Surgical Resection for Intrahepatic, Hilar, and Distal Cholangiocarcinoma. Annals of Surgical Oncology. 2011; 18:651–658.	145
75	Kondo S et al. Guidelines for the management of biliary tract and ampullary carcinomas: surgical treatment. Journal of Hepato-Biliary-Pancreatic Surgery. 2008; 15:41–54.	145
76	Overby DW et al. SAGES guidelines for the clinical application of laparoscopic biliary tract surgery. Surgical Endoscopy and Other Interventional Techniques. 2010; 24:2368–2386.	144
77	Sharma A et al. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World Journal of Gastroenterology. 2017; 23:3978–3998.	142
78	Reid KM et al. Diagnosis and surgical management of gallbladder cancer: A review. Journal of Gastrointestinal Surgery. 2007; 11:671–681.	142
79	Strom BL et al. Risk Factors for Gallbladder Cancer - an International Collaborative Case - Control Study. Cancer. 1995; 76:1747–1756.	141
80	Miller G et al. Gallbladder carcinoma. Ejso. 2008; 34:306–312.	139
81	Schaeff B et al. Port site recurrences after laparoscopic surgery - A review. Digestive Surgery. 1998; 15:124–134.	139
82	Naitoh I et al. Unilateral versus bilateral endoscopic metal stenting for malignant hilar biliary obstruction. Journal of Gastroenterology and Hepatology. 2009; 24:552–557.	133
83	Miyakawa S et al. Biliary tract cancer treatment: 5584 results from the Biliary Tract Cancer Statistics Registry from 1998 to 2004 in Japan. Journal of Hepato-Biliary-Pancreatic Surgery. 2009; 16:1–7.	133
84	Ransohoff DF et al. Treatment of Gallstones. Annals of Internal Medicine. 1993; 119:606–619.	132
85	Fernandez E et al. Hormone replacement therapy and cancer risk: A systematic analysis from a network of case–control studies. International Journal of Cancer. 2003; 105:408–412.	130
86	Madoff DC et al. Portal vein embolization with polyvinyl alcohol particles and coils in preparation for major liver resection for major liver resection for hepatobiliary malignancy: Safety and effectiveness - Study in 26 patients. Radiology. 2003; 227:251–260.	130
87	Ito H et al. Accurate Staging for Gallbladder Cancer Implications for Surgical Therapy and Pathological Assessment. Annals of Surgery. 2011; 254:320–325.	129
88	Tsukada K et al. Lymph node spread from carcinoma of the gallbladder. Cancer. 1997; 80:661–667.	129
89	Javle M et al. HER2/neu-directed therapy for biliary tract cancer. Journal of Hematology & Oncology. 2015; 8.	128
90	D'Angelica M et al. Analysis of the Extent of Resection for Adenocarcinoma of the Gallbladder. Annals of Surgical Oncology. 2009; 16:806–816.	128
91	Hawkins WG et al. Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Annals of Surgical Oncology. 2004; 11:310–315.	128
92	Wang SJ et al. Nomogram for Predicting the Benefit of Adjuvant Chemoradiotherapy for Resected Gallbladder Cancer. Journal of Clinical Oncology. 2011; 29:4627–4632.	125
93	DeWitt J et al. EUS-guided FNA of proximal biliary strictures after negative ERCP brush cytology results. Gastrointestinal Endoscopy. 2006; 64:325–333.	125
94	Wakai T et al. Early gallbladder carcinoma does not warrant radical resection. British Journal of Surgery. 2001; 88:675–678.	125
95	Liu TY et al. Baicalein Inhibits Progression of Gallbladder Cancer Cells by Downregulating ZFX. Plos One. 2015; 10.	124
96	Kim JY et al. Clinical role of (18)F-FDG PET-CT in suspected and potentially operable cholangiocarcinoma: A prospective study compared with conventional imaging. American Journal of Gastroenterology. 2008; 103:1145–1151.	124
97	Leone F et al. Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma. Clinical Cancer Research. 2006; 12:1680–1685.	124
98	Chijiiwa K et al. Surgical treatment of patients with T2 gallbladder carcinoma invading the subserosal layer. Journal of the American College of Surgeons. 2001; 192:600–607.	124
99	Kanthan R et al. Gallbladder Cancer in the 21st Century. Journal of Oncology. 2015; 2015.	123
100	Gourgiotis S et al. Gallbladder cancer. American Journal of Surgery. 2008; 196:252–264.	123

TC, Total citations.

Fig. 2.

Annual and cumulative number of the 100 most cited papers over the past three decades.

3.2. Countries and cooperation

According to the analysis of the corresponding authors' countries, the 100 most cited articles originated from 16 countries spanning three continents (Fig. 3). Compared with the distribution of countries’ publications in Europe (n = 25), the United States and Japan contributed the most to the Americas (n = 50) and Asia (n = 25), respectively. Five countries published more than five articles, and seven countries contributed one article each. The top 10 countries with the most influential articles were shown in Table 3. Among them, the United States (n = 43) published the most papers, followed by Japan (n = 19), the United Kingdom (n = 7), Canada (n = 6), Italy (n = 5), Germany (n = 4), France (n = 4), India (n = 3), South Korea (n = 2), and Mexico (n = 1). The ratio of TCs to publications (TC/publication) indicated the average influence of each study. Although the United States contributed 43 articles with the highest number of TCs (7,682), it had the lowest TC/publication of 179. Unexpectedly, Mexico (n = 1) ranked 10th in the number of articles with the highest TC/publication of 538. With regard to the cooperation relationships among countries, the United States, Italy, France, and Mexico were involved in a relatively close partnership, while there was weak cooperation in other countries (Fig. 4).

Fig. 3.

National distribution of the 100 most cited papers.

Table 3.

Top 10 countries with the most publications.

Country	Publication	TC	TC/Publication
USA	43	7682	179
Japan	19	4291	226
United Kingdom	7	3255	465
Canada	6	1895	316
Italy	5	1198	240
Germany	4	1474	369
France	4	818	205
India	3	799	266
South Korea	2	418	209
Mexico	1	538	538

TC, Total citations.

Fig. 4.

Cooperation relationships among countries that published the 100 most cited papers.

3.3. Institutions and authors

The leading institutions in the field were shown in Table 4. These institutions included the Memorial Sloan–Kettering Cancer Center in the United States, Nagoya University in Japan, and the Mayo Clinic in the United States with 14, 9, and 9 papers, which received 2627, 2248, and 1453 citations, respectively. Among the top 10 institutions, more than half were located in the United States (n = 6), three were in Japan (n = 3), and one was a French institution (n = 1). Notably, the French institution, called the International Agency for Research on Cancer, ranked seventh in the publications and had the highest TC/publication of 346, followed by three institutions from Japan (National Cancer Center Hospital: 320, Nagoya University: 250, and Chiba University: 246). The top 10 authors were shown in Table 5, and these included Blumgart LH, Fong YM, and Jarnagin WR in the United States with 10, 10, and 8 papers, which received TCs of 1984, 1984, and 1339, respectively. Both British researchers achieved the highest TC/publication of 627 with only four papers. While collaboration across institutions and authors was crucial for the development of treatment, there was a lack of collaboration based on more than two clusters (Fig. 5).

Table 4.

Top 10 institutions with the most publications.

Institution	Country	Publication	TC	TC/Publication
Memorial Sloan–Kettering Cancer Center	USA	14	2627	188
Nagoya University	Japan	9	2248	250
Mayo Clinic	USA	9	1453	161
University of Texas MD Anderson Cancer Center	USA	7	1232	176
Harvard University	USA	6	1097	183
National Cancer Center Hospital	Japan	5	1598	320
International Agency for Research on Cancer	France	4	1383	346
Emory University	USA	4	690	173
Chiba University	Japan	3	737	246
University of Texas	USA	3	571	190

TC, Total citations.

Table 5.

Top 10 authors with the most publications.

Author	Country	Publication	TC	TC/Publication
Blumgart LH	USA	10	1984	198
Fong YM	USA	10	1984	198
Jarnagin WR	USA	8	1339	167
Dematteo RP	USA	7	1229	176
Nimura Y	Japan	5	1602	320
Nagino M	Japan	5	1243	249
Bridgewater J	United Kingdom	4	2507	627
Wasan H	United Kingdom	4	2507	627
Kondo S	Japan	4	955	239
Valle JW	United Kingdom	4	904	226

TC, Total citations.

Fig. 5.

Cooperation relationships of (A) institutions and (B) authors who have co-published more than two top-cited articles.

3.4. Top-cited journals

According to the descending order of publications, the top 10 journals were shown in Table 6. The Annals of Surgery (IF = 12.969) and the Journal of Clinical Oncology (IF = 44.544) published the most articles on GBC management, among which 10 publications had the highest number of TCs (2777) and 10 publications had 1957 TCs, respectively. Two journals had a TC/publication exceeding 300, among which Lancet Oncology (IF = 41.316) had the highest TC/publication of 329 with four articles, and the British Journal of Cancer (IF = 7.640) generated a TC/publication of 313 with three articles.

Table 6.

Top 10 journals with the most publications.

Journal	Publication	2020 IF	TC	TC/Publication
Annals of Surgery	10	12.969	2777	278
Journal of Clinical Oncology	10	44.544	1957	196
Cancer	7	6.860	1467	210
Lancet Oncology	4	41.316	1315	329
British Journal of Cancer	3	7.640	940	313
British Journal of Surgery	3	6.939	631	210
Gastrointestinal Endoscopy	3	9.427	550	183
HPB	3	3.647	550	183
Journal of Gastrointestinal Surgery	3	3.452	539	180
Hepatology	3	17.425	491	164

TC, Total citations; IF, Impact factor.

3.5. Keywords, main topic, subtopic, and article type

After the cluster analysis of keywords appeared more than five times, the research hotspots were identified as surgery, chemotherapy, and emerging growth factor receptor-related therapy for GBC (Fig. 6). A timeline chart showing the tendency of these research hotspots was shown in Fig. 7. The publications of surgery remained stable in Period I (n = 22, 60.6%) and they decreased in Period II (n = 12, 36.4%), with only one article in Period III (n = 1, 3.0%). In contrast, the research hotspots of chemotherapy and growth factor receptor appeared in Period II (n = 9, 60.0%; n = 5, 55.6%) and remained popular in Period III (n = 6, 40.0%; n = 4, 44.4%). The main topic, subtopic, and article type of the 100 most cited papers were defined, and the relationships among them were shown in Fig. 8. Surgery (n = 33) was the most studied main topic, followed by systemic therapy (n = 19), epidemiology (n = 15), and adjuvant therapy (n = 9). Additionally, chemotherapy (n = 15) was considered as the most studied subtopic, followed by targeted therapy (n = 9) and radical resection (n = 8). Among the included research, there were 57 retrospective studies, 19 reviews, 12 clinical trials (8 phase II trials and 4 phase III trials), 8 prospective studies, 3 practice guidelines, and 1 basic study. Notably, most surgery-related and adjuvant therapy-related studies were performed retrospectively. Interestingly, chemotherapy was primarily evaluated in clinical trials in systemic therapy, whereas targeted therapy-related studies were a mixture of retrospective and prospective studies.

Fig. 6.

Cluster analysis of keywords of the 100 most cited papers.

Fig. 7.

Timeline chart showing the tendency of research hotspots of GBC management. GBC, gallbladder cancer.

Fig. 8.

Main topic, subtopic, and article type of the 100 most cited papers. EUS-FNA, endoscopic ultrasound-guided fine-needle aspiration; PET, positron emission tomography; PVE, portal vein embolization; HAI, hepatic arterial infusion; HRT, hormone replacement therapy.

3.6. Research trends of different main topics

Table 7 and Fig. 9 showed the research trends for various main topics. The top 100 most cited articles that focused on surgery appeared in Period I (n = 20, 71.4%), declined in Period II (n = 12, 24.5%, versus Period I, p < 0.001), and reached a nadir in Period III (n = 1, 4.3%, versus Period I, p < 0.001). The publication percentages of adjuvant therapy and systemic therapy grew rapidly in Period II, (6.1% versus 0, versus Period I, p = 0.182; 24.5% versus 0, versus Period I, p = 0.004, respectively) and constantly increased in Period III (26.1% versus 0, versus Period I, p = 0.004; 30.4% versus 0, versus Period I, p = 0.002, respectively).

Table 7.

Publication of different main topics over time.

Main topic	Period I (1991–2000) (n = 28)	Period II (2001–2010) (n = 49)	p- value	Period III (2011–2020) (n = 23)	p- value
Epidemiology	5 (17.9)	6 (12.2)	0.498	4 (17.4)	0.965
Non-operative diagnosis	0 (0)	1 (2.0)	0.447	0 (0)	–
Preoperative evaluation	0 (0)	6 (12.2)	0.054	0 (0)	–
Outcomes prediction	2 (7.1)	2 (4.1)	0.560	2 (8.7)	0.837
Surgery	20 (71.4)	12 (24.5)	<0.001∗	1 (4.3)	<0.001∗
Locoregional treatment	0 (0)	5 (10.2)	0.080	0 (0)	–
Adjuvant therapy	0 (0)	3 (6.1)	0.182	6 (26.1)	0.004∗
Systemic therapy	0 (0)	12 (24.5)	0.004∗	7 (30.4)	0.002∗
Management	1 (3.6)	2 (4.1)	0.911	3 (13.0)	0.211

∗p < 0.05.

Fig. 9.

Research trends of different main topics over the past three decades.

4. Discussion

Clinicians and researchers have struggled to identify publishing characteristics and research trends in GBC management during the past three decades because of the many articles of varying academic quality. Using a bibliometric analysis, we selected the 100 most cited papers by TCs and summarized the characteristics of these articles, such as publication periods, journals, countries, institutions, authors, and keywords. We also identified research hotspots and research trends of different main topics in the field of GBC management.

With the rising global prevalence and poor prognosis of GBC [18], clinicians and researchers have focused on its management, which has contributed to a growing number of influential articles since Period I (1991–2000). There was an increase in publications in Period II (2001–2010), particularly in clinical trials because adjuvant and systemic therapy for GBC was experimental in the absence of an established standard. During Period II, a pooled analysis of phase 2 clinical trials showed that gemcitabine combined with platinum compounds was the provisional standard of chemotherapy for GBC [19]. Somatic mutations of epidermal growth factor receptor (EGFR) were identified and evaluated for small-molecule inhibitor treatment, namely targeted therapy [20]. Nevertheless, fewer highly cited papers were published in Period III (2011–2020) than Period II (2001–2010). A probable explanation for this finding is that the TCs of recently published articles accumulated in a time-dependent manner and were unable to exceed the threshold of the top 100 papers in the short term [21].

In this study, we identified the contributions of countries, institutions, and authors to the management of GBC. There was a substantial variation by geographical region globally in the epidemiology of GBC, and Chile suffered the most in developing GBC, followed by Poland, Pakistan, and Japan [22]. Paradoxically, as a low-risk country, the United States produced the majority of papers, and the majority of institutions and authors were based in the United States, which may have been due to developed countries’ scientific accomplishments. Additionally, a similar publication status existed in Japan. Notably, local and international collaboration should be strengthened in the future to facilitate the development of more effective large-scale trials that would provide evidence for the management of GBC.

Surgery is widely regarded as the most effective method of treating GBC. According to the 8th American Joint Committee on Cancer Staging Manual [23], the surgical resection principle is dependent on the depth of tumor invasion, with simple cholecystectomy being preferred for patients with Tis or T1a. Additionally, extensive surgery is preferred for individuals with a histological stage of ≥ T1b. The majority of surgery-related research was performed in Period I because of the non-mainstream status of adjuvant and systemic therapy [24,25]. Although the prognosis of GBC is ameliorated after surgery, the specific methods for GBC are still controversial, such as surgical approaches (laparoscopic/open), hepatectomy strategy (wedge resection/segment resection), and lymphadenectomy (predicting patients with GBC who have benefits postoperatively). In a previous study, the perioperative and survival outcomes were compared after laparoscopic versus the open approach for T1b/T2 GBC [26]. Furthermore, Chen et al. [27] concluded that patients with T2 GBC undergoing IVb/V segment resection instead of wedge resection achieved an improved disease-free survival. Moreover, the survival benefits of lymphadenectomy (≥6 lymph nodes) were confirmed in GBC [28], and extrahepatic bile duct resection to achieve an R0 margin had the potential to improve GBC survival with acceptable postoperative morbidity [29]. Specifically, a decision model was developed to predict which patients with GBC may benefit from lymphadenectomy (≥4 lymph nodes) [30]. Despite the improvement in surgical techniques, GBC continues to have a poor prognosis compared with other gastrointestinal malignancies [22]. The advent and popularity of adjuvant and systemic therapy for survival advantages undermine the predominant status of surgery.

In this study, adjuvant therapy, such as chemotherapy and radiotherapy, was based on the evidence of high-quality retrospective studies and several phase 2 studies, which increased in Period II and continued to increase in Period III. Adjuvant chemotherapy was advised for patients with GBC who had positive lymph nodes, while adjuvant radiation was recommended for those who had a positive resection margin [31]. Because of the lack of a standard regimen and the explicit survival benefits of adjuvant therapy at the time [32], there was a trend to investigate the optimal treatment for GBC, and the publication percentage exceeded that of surgery since Period II. Chemotherapy was the subject of the majority of research. A meta-analysis comprising 10 retrospective studies and 3191 patients with GBC showed a significant improvement in OS, and the use of chemotherapy as adjuvant therapy was justified [33]. However, several randomized, controlled trials did not meet either of their primary endpoints, such as OS, relapse-free survival, and health-related quality of life [17,34,35]. Similarly, adjuvant radiotherapy prolonged OS and lowered the local recurrence rate in selected patients with GBC, especially those with lymph node (+) disease and R1 disease [36,37]. However, no phase 3 studies were conducted to evaluate the role of adjuvant radiotherapy. As a result, a lot of research into the optimum adjuvant therapy has provided convincing data for the treatment of patients with GBC.

Although the predominance of highly cited papers on systemic therapy may reflect a shift in research priorities over the previous three decades, the survival benefits of comprehensive treatment for patients with advanced GBC remain unknown. In 2010, the ABC-02 study (first phase 3 trial) suggested that cisplatin with gemcitabine should be the standard of care for biliary tract cancer considering the improved OS without considerable toxicity [13]. Nonetheless, a lack of the specificity of chemotherapy on advanced GBC promoted the development of subsequent randomized, controlled trials [38,39]. The feasibility and benefits of the combination of radiotherapy were demonstrated in a Southwest Oncology Group study [40], which was further confirmed by phase 3 studies. Fortunately, the advent of next-generation sequencing technology showed specific molecular abnormalities and associated pathways in GBC, which are consistent with the hotspot (growth factor receptor) discovered in our study. The notable mutations in signaling pathways include EGFR/HER1 [[41], [42], [43]] and EGFR2/HER2 [43,44] in the PI3K/AKT/mTOR and RAS/BRAF/MEK/MAK pathways, and vascular endothelial growth factor receptor [45] in the PI3K/AKT/mTOR pathway. Multiple inhibitors of EGFR have shown activity in advanced GBC, such as erdafitinib [46], infigratinib [47], and pemigatinib [48]. Additionally, as a representative type of immunotherapy, programmed cell death protein 1/programmed cell death 1 ligand 1 inhibitors have emerged as a promising strategy for advanced GBC, and this was confirmed by multiple randomized, controlled trials, such as the KEYNOTE-028 and KEYNOTE-158 studies [49]. Immune-mediated complications and infusion reactions, such as hypothyroidism and pneumonitis, should not be ignored. The current research trend is combination therapy involving chemotherapy, targeted therapy, and immunotherapy. While many clinical trials of systemic therapy are currently underway and awaiting results, combination therapy has the potential to provide further benefits for individuals with GBC.

This study had several limitations. First, while only 100 articles were included, they were the most influential and representative based on the TCs, which are potentially meaningful for conducting a bibliometric analysis for the management of GBC. Second, because of the non-universal calculation of TCs among different databases, we only included the 100 most cited papers from the WOSCC database to avoid bias without considering the CNKI database and other non-English databases. Third, all influential publications in the field may not have been included in the current study because of the limited time of TC accumulation. Moreover, although TCs were the most appropriate criteria to evaluate the scientific quality of articles, potential citation biases, such as self-citations, institutional biases, and influential author biases, were unavoidable and might inevitably have altered the results. Additionally, the exact regimens of adjuvant therapy and systemic therapy, such as drug names and dosages, were not provided in the study because we aimed to identify research trends in GBC management instead of the specific regimens. With the rapid development and increasing number of TCs of adjuvant therapy and systemic therapy, the above-mentioned factors should be taken into account and a further analysis should be performed based on a comprehensive search in GBC management.

In conclusion, we identified publication characteristics and research trends in the management of GBC based on the 100 most cited articles. While surgery remained the primary treatment for GBC, there was a research trend toward adjuvant and systemic therapy, which should be reinforced by increased local and international collaboration. This study provides insight into the surgical and non-surgical management of GBC for clinicians and researchers.

Funding

This work was supported by the Scientific Research Fund of Zhejiang Provincial Education Department (grant number: Y202148325); and the National Natural Science Foundation of China (grant numbers: 81800540, 81827804).

Author contributions

Cao JS, Hu JH, Shen JL, and Chen MY designed the study and collected the data; Cao JS, Zhang B, Topatana W, Chen TE, and Cai XJ analyzed and interpreted the data; Cao JS, Li SJ, Jeungpanich S, Tian YT, and Lu ZY wrote the manuscript; Peng SY, Cai XJ, and Chen MY revised the manuscript; all authors made final approval of the version of the manuscript.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data available statement

All original data are available upon reasonable request to the corresponding authors.

Ethics statement

Ethical review and approval were waived for this study because no patients’ data were reported.

Informed consent

Not applicable.