Biliary Tract Cancer

Intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer, FGFR2 fusions, IDH1 mutations, and the evolving landscape of targeted therapy and immunotherapy

Key Points

Epidemiology & Classification

Biliary tract cancers are a heterogeneous group of malignancies arising from the epithelium of the bile ducts and gallbladder. In the United States, approximately 12,000 new cases of cholangiocarcinoma and 12,000 new gallbladder cancer cases are diagnosed annually. Worldwide, incidence is substantially higher in Southeast Asia (particularly Thailand and China) due to liver fluke infection (Opisthorchis viverrini, Clonorchis sinensis). Anatomic classification: • Intrahepatic CCA (iCCA): Arises from bile ducts proximal to the second-order bile ducts within the liver parenchyma. Accounts for…

Molecular Biology & Actionable Alterations

Comprehensive molecular profiling is essential for all advanced BTC patients at diagnosis, as targetable alterations are common and several have approved therapies: FGFR2 fusions/rearrangements (~10–15% of iCCA, rare in eCCA/GBC): • FGFR2 is fused to a partner gene (most commonly BICC1, AHCYL1, TACC3, and others) through chromosomal rearrangements, resulting in constitutive FGFR2 kinase activation. • Detected by FISH, RNA-based NGS (most sensitive), or DNA-based NGS. RNA sequencing is preferred as DNA-based panels may miss novel fusion partners. • Approved targeted therapies: Pemigatinib…

Clinical Presentation & Diagnosis

Clinical presentation varies significantly by tumor location: Intrahepatic CCA: • Typically presents late as a hepatic mass incidentally found on imaging or causing abdominal pain, weight loss, fatigue, and malaise. • Jaundice is absent until late-stage (peripheral location); abnormal liver function tests (elevated alkaline phosphatase, GGT, mild transaminases) may be the only early finding. • CA 19-9 elevated in ~60–70%; CEA elevated in ~30%; neither is diagnostic. Perihilar CCA (Klatskin tumor): • Presents with painless obstructive jaundice (pruritus, dark urine, acholic stools), weight…

Surgical Treatment & Resectability

Surgery remains the only potentially curative treatment for BTC, but fewer than 20–30% of patients present with resectable disease: Intrahepatic CCA: • Hepatic resection with R0 margins is the goal; typically requires major hepatectomy (≥3 Couinaud segments). Vascular involvement (hepatic veins, IVC), bilobar disease, or inadequate future liver remnant (FLR <30–40%) contraindicate resection. • 5-year survival after R0 resection: ~25–35%; R1/R2 resection significantly worsens prognosis. Adjuvant capecitabine (BILCAP trial — OS HR 0.75 favoring capecitabine in per-protocol analysis) is the…

First-Line Advanced / Metastatic Treatment

For patients with unresectable locally advanced or metastatic BTC, systemic therapy is the standard of care: Gemcitabine + Cisplatin (GemCis) — historical standard: • ABC-02 trial (Valle 2010): GemCis vs. gemcitabine alone — mOS 11.7 vs. 8.1 months (HR 0.64); established GemCis as the backbone of first-line BTC treatment. • GemCis remains the cytotoxic backbone for all BTC combination regimens. Gemcitabine + Cisplatin + Durvalumab (preferred first-line): • TOPAZ-1 trial (Oh 2022, N=685): Durvalumab 1500 mg q3w + GemCis vs. GemCis alone. • mOS 12.9 vs. 11.3 months (HR 0.76, p=0.021); 24-month…

Second-Line and Targeted Therapy

Second-line and beyond therapy for advanced BTC is guided primarily by molecular profiling results: FGFR2-altered iCCA (second-line after GemCis-based therapy): • Pemigatinib (Pemazyre): FDA approved 2020 based on FIGHT-202 (N=107, FGFR2 fusion/rearrangement cohort): ORR 36%, mPFS 6.9 months, mOS 17.5 months. Toxicities: hyperphosphatemia (dietary phosphate restriction, phosphate binders), stomatitis, dry eye (FGFR-mediated), alopecia, palmar-plantar erythrodysesthesia. Ophthalmology exam before treatment and q2 months during treatment. • Futibatinib (Lytgobi): FDA approved 2023 based on…