Gallbladder cancer

Overview

Gallbladder cancer (GBC) is a rare but aggressive malignancy arising from the epithelial lining of the gallbladder. It represents the most common malignancy of the biliary tract and the fifth most common gastrointestinal cancer globally. Despite its rarity in Western populations, it carries a disproportionately poor prognosis, largely due to its asymptomatic nature in early stages, aggressive biological behavior, and advanced stage at diagnosis.

The gallbladder is a small, pear-shaped organ located beneath the liver in the right upper quadrant of the abdomen. Its primary function is to store and concentrate bile—a digestive fluid produced by the liver—releasing it into the duodenum via the common bile duct to facilitate fat digestion. Because the gallbladder lacks a serosal layer on its hepatic surface and has a thin muscular wall, malignant cells easily invade the liver and surrounding structures, facilitating early metastasis.

Epidemiology and Risk Factors

Global Incidence and Demographics

Gallbladder cancer exhibits striking geographic, ethnic, and gender variations.

• High-incidence regions: Chile, Bolivia, India, Pakistan, Japan, Korea, and Eastern Europe.
• Low-incidence regions: North America, Western Europe, Australia.
• Gender: Women are affected 2 to 3 times more frequently than men.
• Age: Median age at diagnosis is typically 65–75 years; it is exceedingly rare before age 40.

Established Risk Factors

While gallstones are present in the vast majority of GBC patients, the absolute risk of developing cancer in a patient with asymptomatic gallstones is low (<0.5–1% lifetime). Prophylactic cholecystectomy for asymptomatic stones is not routinely recommended solely for cancer prevention, except in specific high-risk groups (e.g., porcelain gallbladder, stones >3 cm, APBDJ, Native American/Chilean ethnicity, or polyps >1 cm).

Pathology and Molecular Biology

Histological Classification

Over 90% of gallbladder cancers are adenocarcinomas. The World Health Organization (WHO) classifies them based on architectural pattern and cellular morphology:

1. Conventional Adenocarcinoma: Most common. Subtypes include:

• Papillary: Finger-like projections; least aggressive; better prognosis; rarely invades liver/lymph nodes early.
• Nodular: Mass-forming; intermediate prognosis.
• Tubular: Gland-forming; common.
• Poorly differentiated / Signet-ring cell / Mucinous: Aggressive; high metastatic potential; worse prognosis.

1. Adenosquamous Carcinoma: Contains both glandular and squamous components; aggressive.
2. Squamous Cell Carcinoma: Rare (<1%); very poor prognosis.
3. Neuroendocrine Carcinoma: Rare; high-grade (small/large cell) behave aggressively.
4. Undifferentiated Carcinoma: No discernible differentiation.

Molecular Pathogenesis: Two Distinct Pathways

Modern genomics has defined two major molecular pathways leading to GBC, explaining geographic variance:

Actionable Targets: ERBB2 (HER2) amplification (10–15%), FGFR2 fusions (3–5%), IDH1 mutations (2–5%), BRAF V600E (1–3%), MSI-H/dMMR (2–5%), NTRK fusions (rare). These guide targeted therapy in advanced disease.

Staging Systems

Accurate staging dictates management. Two systems are used concurrently:

1. TNM Classification (AJCC 8th Edition / UICC 8th Edition)

• T (Primary Tumor):
• Tis: Carcinoma in situ (high-grade dysplasia).
• T1a: Invades lamina propria.
• T1b: Invades muscularis propria.
• T2: Invades perimuscular connective tissue (Subclassified: T2a = peritoneal side; T2b = hepatic side — critical prognostic distinction).
• T3: Perforates serosa (visceral peritoneum) and/or directly invades liver and/or one adjacent organ (colon, duodenum, stomach, abdominal wall).
• T4: Invades main portal vein/hepatic artery or invades two or more extrahepatic organs.
• N (Regional Lymph Nodes):
• N0: No regional metastasis.
• N1: Metastasis in nodes along cystic duct, common bile duct, hepatic artery, portal vein (pericholedochal nodes).
• N2: Metastasis in periaortic, pericaval, superior mesenteric artery, celiac artery nodes (distant nodal mets = M1 in some contexts, but N2 in AJCC 8th).
• M (Distant Metastasis): M0 / M1 (liver parenchyma mets beyond direct invasion, peritoneal carcinomatosis, distant nodes, lung, bone).

2. Stage Grouping (Prognostic Groups)

How Does It Look? (Gross & Radiological Appearance)

Understanding the visual phenotype of gallbladder cancer is essential for radiologists, surgeons, and pathologists to distinguish it from benign mimics (chronic cholecystitis, adenomyomatosis, cholesterol polyps).

1. Gross Pathological Appearance (Macroscopic)

Upon surgical resection or autopsy, GBC typically manifests in three classic growth patterns (often overlapping):

Key Gross Findings for Pathologists:

• Wall Thickness: Normal < 3mm. Malignant infiltration usually > 1cm (often 2–4cm in infiltrative type).
• Mucosal Surface: Irregular, ulcerated, granular, or velvety (papillary).
• Liver Invasion: Direct extension into the gallbladder fossa (Segments IVb/V) appears as firm, white-tan tumor nodules replacing liver parenchyma at the gallbladder bed.
• Metastases: Lymph nodes in Calot’s triangle, hepatoduodenal ligament, and peripancreatic region are firm, matted, and white.

2. Radiological Appearance (Imaging Phenotypes)

Imaging is the cornerstone of diagnosis, staging, and resectability assessment. Contrast-enhanced Multidetector CT (MDCT) and MRI/MRCP are the primary modalities. Ultrasound (US) is the initial screening tool.

A. Transabdominal Ultrasound (US) – First Line

• Focal Wall Thickening: Asymmetric, eccentric thickening > 3–4 mm (often > 10 mm). Loss of the normal trilaminar wall signature (mucosa-muscle-serosa).
• Mass: Hypoechoic or heterogeneous mass replacing the gallbladder fossa, invading liver.
• “Strawberry” / “Cauliflower” Appearance: Papillary tumors projecting into lumen.
• Loss of Interface: Obliteration of the echogenic line between gallbladder wall and liver parenchyma = T2b/T3 invasion.
• Limitations: Operator dependent; obscured by bowel gas/obesity; poor nodal assessment.

B. Contrast-Enhanced CT (Triple Phase: Arterial, Portal Venous, Delayed) – Staging Workhorse

• Infiltrative Type: Circumferential or segmental wall thickening (>10–15 mm) with heterogeneous enhancement. Delayed phase often shows progressive enhancement (fibrotic stroma retains contrast).
• Nodular Type: Enhancing soft-tissue mass. Arterial hyperenhancement with washout on portal venous/delayed phases mimics HCC but arises from GB fossa.
• Papillary Type: Intraluminal papillary projections enhancing vividly on arterial phase; stalk feeding vessels may be seen.
• Critical Signs of Advanced Disease:
• Loss of Fat Plane: Between GB and liver (T2b), duodenum, colon, or anterior abdominal wall.
• Vascular Encasing: Encasement >180° of Portal Vein (PV), Hepatic Artery (HA), or Common Hepatic Duct (CHD) = T4 / Unresectable.
• Lymphadenopathy: Short axis > 10 mm (pericholedochal, porta hepatis, retropancreatic, celiac). Necrotic centers suggest metastasis.
• Distant Mets: Liver metastases (hypovascular, “target sign” on portal phase), peritoneal nodules, ascites, lung nodules.

C. MRI / MRCP – Problem Solving & Biliary Mapping

• Superior Soft Tissue Contrast: T2-weighted imaging distinguishes tumor (intermediate-high signal) from fibrosis (low signal) and edema.
• Diffusion Weighted Imaging (DWI): High sensitivity for tumor detection (restricted diffusion = high cellularity), nodal mets, and peritoneal deposits.
• MRCP (Magnetic Resonance Cholangiopancreatography): Gold standard for biliary anatomy. Defines level of bile duct obstruction (T3/T4), presence of APBDJ, and relationship of tumor to hepatic ducts (critical for surgical planning—need for hepaticojejunostomy vs. CBD stump closure).
• Hepatobiliary Contrast Agents (Gd-EOB-DTPA): Functional imaging; tumor lacks hepatocyte transporters → appears as “cold” defect on hepatobiliary phase, improving detection of small liver mets.

D. PET-CT (FDG) – Staging & Occult Mets

• Not routine for initial diagnosis (inflammatory cholecystitis = false positive).
• Indicated for: Staging locally advanced (T3/T4) or node-positive disease to rule out occult M1 disease before major surgery; restaging post-neoadjuvant therapy.
• High SUVmax correlates with grade and poor prognosis.

E. Endoscopic Ultrasound (EUS) – T-Staging & Tissue Acquisition

• Best modality for T-staging (accuracy 80–90%). High-frequency probe (12 MHz) visualizes 5-layer wall architecture.
• T1a: Hyperechoic mucosa intact.
• T1b: Hypoechoic muscularis propria disrupted.
• T2: Hyperechoic subserosa/adventitia disrupted.
• T3: Tumor breaches serosa into perimuscular fat/liver.
• EUS-FNA/FNB: Safe and accurate for cytology/histology only if unresectable or neoadjuvant therapy planned. Contraindicated in potentially resectable disease due to risk of peritoneal seeding (needle tract implantation).

Symptoms and Clinical Presentation

Gallbladder cancer is notorious for its prolonged silent phase. Symptoms typically appear only when the tumor has invaded surrounding structures or caused biliary obstruction. The clinical picture often mimics benign biliary disease, leading to diagnostic delays.

1. Early / Non-Specific Symptoms (Often Months Before Diagnosis)

These symptoms are indistinguishable from symptomatic cholelithiasis or chronic cholecystitis.

• Right Upper Quadrant (RUQ) Pain / Discomfort: Dull, aching, constant or intermittent. Often postprandial (fatty meals). May radiate to right scapula or shoulder (phrenic nerve irritation).
• Dyspepsia / Bloating / Early Satiety: Vague upper GI symptoms.
• Nausea / Vomiting: Non-specific.
• Food Intolerance: Particularly fatty/fried foods.
• Chronic “Indigestion”: Patients often self-medicate with antacids/PPIs for months.

Clinical Pitfall:** A patient with known gallstones presenting with worsening or changing character of pain (constant vs. colicky), new onset weight loss, or a palpable mass should trigger high suspicion for malignancy.

2. Symptoms of Local Invasion (Locally Advanced Disease – T3/T4)

As the tumor breaches the gallbladder serosa and invades adjacent organs:

• Persistent, Severe RUQ Pain: Unrelieved by analgesics; indicates liver capsule invasion (Seg IVb/V) or direct invasion of the hepatic flexure of colon/duodenum.
• Gastric Outlet Obstruction: Nausea, vomiting undigested food (invades duodenum/pylorus).
• Large Bowel Obstruction / Change in Bowel Habits: Invasion of hepatic flexure / transverse colon.
• Hemobilia (Triad of Quincke): Rare but pathognomonic. 1) Upper GI bleeding (hematemesis/melena), 2) RUQ pain, 3) Obstructive jaundice. Caused by tumor erosion into cystic duct/common hepatic duct with bleeding into biliary tree.
• Biliary-Cutaneous / Biliary-Enteric Fistula: Spontaneous drainage of bile/b pus through skin or into duodenum/colon.

3. Symptoms of Biliary Obstruction (Cholestasis)

Occurs when tumor compresses or invades the Common Hepatic Duct (CHD) or Common Bile Duct (CBD) – Mirizzi Syndrome Type II-IV or direct invasion.

• Jaundice: Progressive, painless (or painful), dark urine, pale stools (acholic), pruritus (itching).
• Cholangitis (Charcot’s Triad / Reynolds’ Pentad): Fever + Jaundice + RUQ Pain (± Hypotension ± Altered Mental Status). Medical emergency requiring urgent biliary decompression (ERCP/PTBD).
• Pruritus: Often precedes visible jaundice; due to bile salt deposition in skin.

4. Constitutional / Systemic Symptoms (Advanced / Metastatic Disease)

• Unintentional Weight Loss: >10% body weight over 3–6 months (cancer cachexia).
• Anorexia: Loss of appetite.
• Fatigue / Weakness: Anemia (chronic disease, occult bleeding), metabolic derangements.
• Malaise: General feeling of unwellness.
• Ascites / Abdominal Distension: Peritoneal carcinomatosis or portal vein thrombosis/obstruction.
• Palpable Masses:
• RUQ Mass: Enlarged gallbladder (Courvoisier’s Law: Palpable, non-tender gallbladder with jaundice suggests malignant obstruction, not stones—though in GBC, the GB is often fibrotic/shrunken; a palpable mass usually represents liver invasion or nodal conglomerate).
• Supraclavicular Node (Virchow’s Node / Troisier’s Sign): Left supraclavicular lymphadenopathy = metastatic spread via thoracic duct (Stage IVB).
• Periumbilical Node (Sister Mary Joseph Nodule): Metastatic peritoneal deposit.
• Ovarian Mass (Krukenberg Tumor): Bilateral ovarian metastases (signet ring cell type).

5. Incidental Diagnosis (“Incidentaloma”)

10–25% of cases are diagnosed incidentally on imaging (CT/MRI) performed for unrelated reasons, or histologically after cholecystectomy for presumed benign disease (cholelithiasis/polyps).

• Scenario: Laparoscopic cholecystectomy for “symptomatic stones” → Pathology returns “Adenocarcinoma T1b”.
• Implication: Requires immediate multidisciplinary review for re-resection (radical surgery).

Diagnostic Workup Algorithm

1. Clinical Suspicion / Incidental Finding: RUQ pain, jaundice, weight loss, or incidental mass on imaging.
2. Laboratory Studies:

• LFTs: Elevated ALP, GGT, Bilirubin (obstructive pattern). Transaminases (AST/ALT) normal or mildly elevated unless liver invasion/hepatitis.
• Tumor Markers: CA 19-9 (Sensitivity 70–80%, Specificity ~80%; elevated in cholangitis/benign obstruction too). CEA (complementary). Not diagnostic alone.
• CBC, Coagulation, Renal Function: Baseline for surgery/chemo fitness.

1. Imaging (Staging Laparotomy is obsolete):

• Triple-Phase CT Abdomen/Pelvis + Chest CT: Primary staging.
• MRI/MRCP: If CT equivocal, for biliary anatomy, or renal impairment (no iodinated contrast).
• PET-CT: For locally advanced (T3/T4/N+) to exclude occult mets.

1. Tissue Diagnosis (Context Dependent):

• Resectable on Imaging: NO BIOPSY. Proceed directly to surgery (risk of seeding). Diagnosis confirmed on final pathology.
• Unresectable / Metastatic / Neoadjuvant Candidate: EUS-FNA/FNB or Percutaneous Biopsy (if EUS unavailable) for molecular profiling (HER2, MSI, FGFR, etc.) and histology confirmation.
• ERCP/PTBD: For biliary drainage (stenting) before neoadjuvant chemo or palliation. Brush cytology low yield (<50%).

Treatment Modalities

Treatment is strictly stage-dependent and requires a Multidisciplinary Team (MDT) (Hepatobiliary Surgeon, Medical Oncologist, Radiation Oncologist, Radiologist, Pathologist, Palliative Care).

1. Surgical Treatment (Only Curative Intent)

Surgical Principles: R0 Resection (Microscopically negative margins) is the single most important prognostic factor. Open approach preferred for T2+ due to tumor fragility, need for lymphadenectomy, and avoidance of port-site recurrence. Laparoscopic radical resection only in high-volume centers for selected T1b/T2a.

2. Adjuvant Therapy (Post-Surgery)

• Standard of Care (Based on BILCAP & ACTICCA-1 Trials): Adjuvant Capecitabine (1000–1250 mg/m² BID Days 1–14 q21d x 8 cycles) for all resected T1b or higher / Node-positive (Stage IB–IIIB).
• BILCAP: Improved OS (median 53 vs 36 mo) for biliary cancers (incl GBC).
• ACTICCA-1: Confirmed DFS/OS benefit for GBC/CCA.
• Adjuvant Chemoradiation (CRT): Considered for R1 (microscopically positive) margins or N2 disease (SWOG S0809 / PRODIGE 12-ACCORD 18 trial designs). Controversial for R0/N0-1.
• Timing: Start within 8–12 weeks post-op.

3. Neoadjuvant Therapy (Pre-Surgery)

• Indications: Borderline resectable (T4 vascular involvement without mets), Locally advanced N+ (clinically), or to downstage for R0.
• Regimens: Gemcitabine + Cisplatin (GemCis) ± Nab-paclitaxel; FOLFOX; CapeOx.
• Goal: Conversion to resectability. Re-staging with CT/PET-CT after 2–4 months. Response assessment difficult due to fibrosis.

4. Systemic Therapy for Advanced / Metastatic Disease (Stage IVB / Unresectable)

First-Line (Standard of Care)

Second-Line & Beyond

• FOLFOX (5-FU/Oxaliplatin): Standard 2nd line post-GemCis failure (ABC-06 trial showed OS benefit vs Active Symptom Control).
• Targeted Therapy (Biomarker-Driven):
• HER2+ (IHC 3+ or FISH+): Trastuzumab + Deruxtecan (T-DXd) or Trastuzumab + Pertuzumab + Chemo (HERBIL / KYPHOS trials).
• FGFR2 Fusions: Pemigatinib / Infigratinib / Futibatinib (Phase II data ~30–40% ORR).
• IDH1 Mutations: Ivosidenib (ClarIDHy trial – PFS benefit).
• MSI-H / dMMR / TMB-H: Pembrolizumab / Dostarlimab (High response rates).
• NTRK Fusions: Larotrectinib / Entrectinib.
• BRAF V600E: Dabrafenib + Trametinib.
• Clinical Trials: Strongly encouraged at all lines.

5. Palliative Care & Symptom Management

Integral from diagnosis for advanced disease.

• Biliary Drainage: ERCP with Stenting (Plastic vs Self-Expanding Metal Stent – SEMS) is first line for obstructive jaundice. PTBD (Percutaneous Transhepatic Biliary Drainage) if ERCP failed/altered anatomy. Relieves pruritus, cholangitis, improves liver function for chemo eligibility.
• Pain Management: WHO Analgesic Ladder. Celiac Plexus Neurolysis (EUS-guided or percutaneous) for refractory visceral pain.
• Gastric Outlet Obstruction: Endoscopic stenting (duodenal SEMS) or surgical bypass (gastrojejunostomy).
• Ascites: Paracentesis, diuretics (if portal hypertension), intraperitoneal chemo (experimental).
• Nutrition: Pancreatic enzyme replacement (if pancreatic duct obstructed), dietary counseling.

Prognosis and Survival

Prognosis is heavily dependent on T-stage, N-stage, Margin Status (R0 vs R1), and Grade.

5-Year Overall Survival by Stage (Post-Curative Resection)

Recurrence Patterns: Even after R0 resection, recurrence rates are high (50–65%).

• Locoregional: Liver bed, porta hepatis nodes, port sites (laparoscopic).
• Distant: Liver (hematogenous), Peritoneum, Lungs.
• Surveillance: CT Chest/Abdomen/Pelvis + CA 19-9 every 3–6 months x 2 years, then 6–12 months x 3 years, then annually.

Prevention and Screening

Primary Prevention

• Cholecystectomy for High-Risk Benign Conditions:
• Porcelain Gallbladder: Prophylactic cholecystectomy recommended.
• Gallbladder Polyps > 1 cm: Cholecystectomy recommended.
• Polyps 6–9 mm: Surveillance US (6–12 months) or cholecystectomy if risk factors (age >50, stones, sessile, growth).
• APBDJ / Choledochal Cyst: Prophylactic excision (hepaticojejunostomy) recommended in childhood/early adulthood.
• Gallstones > 3 cm: Consider prophylactic cholecystectomy (especially in high-incidence areas/ethnicities).
• Lifestyle: Weight management, control of metabolic syndrome (reduces stone formation).

Screening

• No general population screening recommended (low prevalence, lack of validated test).
• High-Risk Surveillance: Not standardized. Some guidelines suggest annual US for:
• Porcelain GB (if not resected).
• PSC patients (annual MRI/MRCP + CA 19-9).
• Indigenous populations in high-incidence regions (e.g., Chilean Mapuche, Native Americans) – policy varies by country.

Living with Gallbladder Cancer: Survivorship & Quality of Life

• Post-Cholecystectomy Syndrome: Diarrhea, bile acid malabsorption (treated with cholestyramine), dyspepsia.
• Post-Hepatectomy Liver Function: Future Liver Remnant (FLR) hypertrophy critical pre-op (Portal Vein Embolization – PVE if FLR <20-30%).
• Nutritional Support: Medium-chain triglycerides (MCT) oil, fat-soluble vitamin supplementation (A, D, E, K) if biliary drainage compromised or extensive resection.
• Psychosocial Support: High distress due to poor prognosis statistics; early palliative care integration improves mood and survival.
• Genetic Counseling: Consider for young patients (<50) or strong family history (Lynch syndrome, BRCA, FAP associations rare but reported).

Frequently Asked Questions (FAQ)

Q: Is gallbladder cancer hereditary?

A: Most cases are sporadic. However, a family history of GBC or biliary tract cancer increases risk 2-5 fold. Rarely associated with Lynch Syndrome (MMR genes), BRCA1/2, or Familial Adenomatous Polyposis (FAP). Genetic counseling is advised if diagnosed <50 years or strong family history.

Q: Can I live without a gallbladder?

A: Yes, completely normally. Bile flows directly from the liver into the intestine. ~10-20% experience transient diarrhea or bloating (bile acid malabsorption), manageable with diet/bile binders.

Q: My gallbladder was removed for stones, and cancer was found incidentally. What now?

A: Do not panic. This is a common scenario. You need an urgent referral to a High-Volume Hepatobiliary Center for multidisciplinary review. Further surgery (re-resection: liver bed resection + lymphadenectomy) is standard for T1b or deeper. Outcomes are excellent for T1a/T1b if re-resection is R0.

Q: Does a “porcelain gallbladder” always mean cancer?

A: No. The risk is historically cited as 10-20%, but modern imaging suggests lower risk for complete mucosal calcification. Incomplete calcification carries higher risk. Current guidelines recommend cholecystectomy for all porcelain gallbladders found incidentally.

Q: Is immunotherapy a cure for gallbladder cancer?

A: Not a cure alone in advanced stages, but GemCis + Immunotherapy (Durvalumab/Pembrolizumab) is now the standard First-Line treatment, extending median survival by ~1.5–2 months over chemo alone with durable responses in a subset. It is not curative for metastatic disease but transforms it into a chronic manageable condition for some.

Q: What is the difference between Gallbladder Cancer and Cholangiocarcinoma (Bile Duct Cancer)?

A: They are distinct primary sites.

• GBC: Arises in the gallbladder. Spreads early to liver bed, cystic node, peritoneum.
• Cholangiocarcinoma (CCA): Arises in the bile ducts (Intrahepatic, Perihilar/Klatskin, Distal).
• Staging/Treatment differ. However, systemic chemo regimens (GemCis + Immuno) are similar for advanced disease. Distinction is critical for surgery (hepatectomy vs radical cholecystectomy).

Summary of Key Takeaways

1. GBC is aggressive but curable if caught early (T1/T2).
2. Gallstones are the #1 risk factor, but absolute risk is low; prophylactic surgery only for high-risk features.
3. Imaging (CT/MRI) defines resectability; Biopsy is avoided if surgery is planned.
4. T1b and above require Radical Resection (Liver bed + Lymphadenectomy), not simple cholecystectomy.
5. Adjuvant Capecitabine is standard for Stage IB-IIIB.
6. First-line Advanced: GemCis + Durvalumab / Pembrolizumab.
7. Molecular Profiling (HER2, FGFR, IDH1, MSI) is mandatory in advanced disease for targeted options.
8. Palliative biliary drainage and early palliative care integration are essential for quality of life.

References

1. American Joint Committee on Cancer (AJCC) (2017) AJCC Cancer Staging Manual. 8th edn. Chicago: Springer.
2. Valle, J.W. et al. (2010) ‘Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer’, New England Journal of Medicine, 362(14), pp. 1273–1281. Available at: https://doi.org/10.1056/NEJMoa0908721.
3. Primrose, J.N. et al. (2019) ‘Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study’, The Lancet Oncology, 20(5), pp. 663–673. Available at: https://doi.org/10.1016/S1470-2045(19)30119-0.
4. Edeline, J. et al. (2023) ‘Adjuvant gemcitabine plus oxaliplatin or capecitabine plus oxaliplatin after gemcitabine plus cisplatin in resected biliary tract cancer (PRODIGE-12-ACCORD-18 and ACTICCA-1): two randomised, phase 3 trials’, The Lancet Oncology, 24(8), pp. 859–872. Available at: https://doi.org/10.1016/S1470-2045(23)00226-8.
5. Oh, D-Y. et al. (2022) ‘Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1): a randomised, double-blind, placebo-controlled, phase 3 trial’, The Lancet Oncology, 23(10), pp. 1310–1320. Available at: https://doi.org/10.1016/S1470-2045(22)00465-5.
6. Kelley, R.K. et al. (2023) ‘Pembrolizumab plus gemcitabine and cisplatin for advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial’, The Lancet, 402(10401), pp. 569–582. Available at: https://doi.org/10.1016/S0140-6736(23)01113-8.
7. Lamarca, A. et al. (2021) ‘FOLFOX for previously treated advanced biliary tract cancer (ABC-06): a randomised, open-label, phase 3 trial’, The Lancet Oncology, 22(5), pp. 690–701. Available at: https://doi.org/10.1016/S1470-2045(21)00091-2.
8. Javle, M. et al. (2023) ‘Treatment of biliary tract cancer: a review’, JAMA Oncology, 9(5), pp. 687–695. Available at: https://doi.org/10.1001/jamaoncol.2022.7654.
9. National Comprehensive Cancer Network (NCCN) (2024) NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. Version 2.2024. Plymouth Meeting, PA: NCCN. Available at: https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf (Accessed: [Current Date]).
10. European Society for Medical Oncology (ESMO) (2023) ‘Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up’, Annals of Oncology, 34(12), pp. 1087–1104. Available at: https://doi.org/10.1016/j.annonc.2023.09.004.
11. Hundal, R. and Shaffer, E.A. (2014) ‘Gallbladder cancer: epidemiology, outcome and clinical implications’, Canadian Journal of Gastroenterology and Hepatology, 28(1), pp. 1–6. Available at: https://doi.org/10.1155/2014/736463.
12. Shirai, Y. et al. (2020) ‘Surgical treatment of gallbladder cancer: current status and future perspectives’, Journal of Hepato-Biliary-Pancreatic Sciences, 27(2), pp. 74–85. Available at: https://doi.org/10.1002/jhbp.745.
13. Zhang, X.F. et al. (2017) ‘Identification of distinct molecular subtypes of gallbladder cancer with prognostic and therapeutic relevance’, Nature Communications, 8, p. 14675. Available at: https://doi.org/10.1038/ncomms14675.
14. Goetze, T.O. (2019) ‘Gallbladder carcinoma: Prognostic factors and therapeutic options’, World Journal of Gastrointestinal Oncology, 11(4), pp. 283–294. Available at: https://doi.org/10.4251/wjgo.v11.i4.283.
15. Roa, J.C. et al. (2021) ‘Gallbladder cancer: A review of the literature’, Journal of Clinical and Translational Hepatology, 9(2), pp. 272–281. Available at: https://doi.org/10.14218/JCTH.2020.00045.