• Call: 7506942069
  • Mumbai, India
  • Mon - Fri: 9.00am - 04.00pm

Freely Accessible Healthcare Knowledge

Immunotherapy for advanced intrahepatic bile duct cancer - Understanding the tumor microenvironment

In this video, Dr. Gunjan Desai, a liver surgeon in Mumbai, provides a detailed discussion on the management of unresectable intrahepatic bile duct cancer (iCCA). Unlike resectable cases where surgery offers a potential cure, unresectable iCCA requires a multidisciplinary approach, integrating systemic therapy, locoregional treatments, and emerging targeted therapies.

Understanding Unresectability in iCCA

Dr. Desai explains the criteria defining unresectable intrahepatic cholangiocarcinoma, which include:

  • Extensive vascular invasion involving major hepatic arteries or both branches of the portal vein
  • Insufficient future liver remnant (FLR) making curative resection impossible
  • Multifocal or bilobar disease not amenable to segmental or lobar resection
  • Distant metastases, including spread to peritoneum, lungs, or distant lymph nodes
  • Severe underlying liver dysfunction, such as cirrhosis or portal hypertension, precluding major surgery

Tumor Microenvironment-Based Classification of iCCA

Dr. Desai highlights the importance of the tumor microenvironment (TME) in guiding treatment decisions. The latest research categorizes iCCA into distinct molecular and immune subtypes based on its TME, influencing therapeutic response:

Inflamed Tumor Microenvironment (Hot Tumors)

  • Characterized by high immune cell infiltration, particularly T-cells and macrophages
  • Responds well to immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 therapies
  • Often associated with mismatch repair deficiency (dMMR) or high tumor mutational burden (TMB)

Immune-Excluded Tumors

  • The immune cells are present but restricted to the tumor stroma, preventing effective anti-tumor response
  • May benefit from combination therapy with VEGF inhibitors (bevacizumab) and immune checkpoint inhibitors

Immune Desert Tumors (Cold Tumors)

  • Minimal immune cell infiltration, leading to resistance to immunotherapy
  • Targeted therapies and chemotherapy are the primary treatment options

Systemic Therapy: First-Line and Second-Line Treatment Options

For patients with unresectable iCCA, systemic therapy is the mainstay of treatment. Dr. Desai reviews the latest evidence-based options:

First-line chemotherapy

  • Gemcitabine + Cisplatin (GemCis) – Standard of care based on the ABC-02 trial, improving survival
  • GemCis + Durvalumab (TOPAZ-1 trial) – The addition of immunotherapy (anti-PD-L1) showed a significant improvement in overall survival in patients with iCCA
  • FOLFIRINOX (5-FU, Leucovorin, Irinotecan, Oxaliplatin) – Considered in patients with good performance status as an alternative regimen

Second-line chemotherapy

  • FOLFOX (fluorouracil + oxaliplatin) based on the ABC-06 trial
  • Irinotecan-based regimens in select cases

Actionable Molecular Targets in iCCA

With advances in molecular profiling, personalized treatment strategies are emerging for unresectable iCCA. Dr. Desai discusses key actionable targets and their corresponding targeted therapies:

  • FGFR2 Fusions or Rearrangements (~10-15% of iCCA cases) – Pemigatinib (FIGHT-201 trial) and Futibatinib have shown clinical benefit
  • IDH1 Mutations (~15-20% of iCCA cases) – Ivosidenib (ClarIDHy trial) has demonstrated improved progression-free survival
  • BRAF V600E Mutations (~5% of iCCA cases) – Dabrafenib + Trametinib (BRAF/MEK inhibitors) are effective
  • HER2 Amplification (~5% of cases) – Trastuzumab + Pertuzumab or HER2-directed TKIs are promising options
  • KRAS G12C Mutations (~1-2% of iCCA cases) – KRAS inhibitors (Sotorasib, Adagrasib) are currently being explored
  • MSI-High/dMMR Tumors (~2-3% of iCCA cases) – Pembrolizumab (anti-PD-1 therapy) is FDA-approved

Locoregional Therapies for Unresectable iCCA

For select patients, liver-directed therapies may help control tumor progression or act as a bridge to transplant or resection.

Liver Transplantation in Unresectable iCCA

Dr. Desai also touches upon emerging evidence supporting liver transplantation for highly selected patients with unresectable iCCA.

Whether you are a liver surgeon, medical oncologist, gastroenterologist, or researcher, this discussion will help you stay updated on the latest advancements in treating unresectable intrahepatic bile duct cancer. Watch till the end for expert recommendations and future perspectives in the management of this complex disease.