Bile Duct Cancer (Cholangiocarcinoma)

Overview

The Bile Duct system transports bile from the liver, to the gall bladder, and then to the duodenum (small intestine). Bile duct cancers (cholangiocarcinoma) are a rare but highly lethal form of cancer. Although it has several risk factors (chronic bile duct inflammation, obesity, genetics, age, etc), bile duct cancer can happen to anyone.

Cholangiocarcinoma Treatment

Surgery

Surgery is the only treatment that reliably produces long-term survival for cholangiocarcinoma patients. The most important thing about cholangiocarcinoma surgery is whether the surgeon is able to remove all of the cancerous tissue. With respect to surgery, cholangiocarcinoma patients can be divided into 3 groups:

Resection – Negative Margins AND Negative Lymph Nodes.

When it appears the surgeon was able to remove all of the primary tumor, and there is no evidence of the cancer in your lymph nodes.
Average Survival Time: 25 to 50+ months.
Average 5-Year Survival Percent: 15% to 40%+.

Resection – Positive Margins OR Positive Lymph Nodes.

When the surgeon was NOT able to remove all of the primary tumor, and/or there are cancer cells in your lymph nodes.
Average Survival Time: 10 to 25+ months.
Average 5-Year Survival Percent: 5% to 20%+.

Not-Resectable

When you are not a candidate for surgery. This is often because the cancer has metastasized.
Average Survival Time: 5 to 15+ months.
Average 5-Year Survival Percent: 1% to 5%+

Orthotopic Liver Transplantation (OLT)

Some cholangiocarcinoma patients who are eligible for resection may also be eligible for a complete liver transplant. Liver transplantation is not an option for most cholangiocarcinoma patients because of the high risk of cancer recurrence. But their is some evidence that liver transplantation may improve the odds of long-term survival for patients with no evidence of cancer in their lymph nodes.
Average Survival Time: 35 to 60+ months.
Average 5-Year Survival Percent: 30% to 50+%

Chemotherapy

Capecitabine Only

Average Response Rate: 10% to 40%.
Average Extra Survival Time: 1 to 7 months.

Docetaxel

Average Response Rate: 0% to 30%.
Average Extra Survival Time: 0 to 6 months.

Fluorouracil (FU) Only

Average Response Rate: 10% to 40%.
Average Extra Survival Time: 1 to 7 months.

Fluorouracil + Bevacizumab

Average Response Rate: 40% to 70%.
Average Extra Survival Time:  5 to 11 months.

Fluorouracil + Cisplatin

Average Response Rate: 30%to 60%.
Average Extra Survival Time:  3 to 9 months.

Fluorouracil + Doxorubicin or Epirubicin

Average Response Rate: 35%-65% .
Average Extra Survival Time:  3 to 9 months.

Fluorouracil + Folinic Acid + Oxaliplatin (FOLFOX-4)

Average Response Rate: 35%-65% .
Average Extra Survival Time:  4 to 10 months.

Fluorouracil + Irinotecan (FOLFIRI)

Average Response Rate: 30%-60% .
Average Extra Survival Time:  3 to 9 months.

Fluorouracil + Irinotecan + Bevacizumab

Average Response Rate: 50%-80% .
Average Extra Survival Time:  6 to 12 months.

Fluorouracil + Irinotecan + Oxaliplatin (FOLFIRINOX)

Average Response Rate: 35% to 65%.
Average Extra Survival Time: 3-9 months.

Fluorouracil + Leucovorin + Etoposide

Average Response Rate: 30%-60% .
Average Extra Survival Time:  3 to 9 months.

Fluorouracil + Hydroxyurea

Average Response Rate: 25%-55% .
Average Extra Survival Time: 2 to 8 months.

Fluorouracil + Methotrexate

Average Response Rate: 10% to 40%.
Average Extra Survival Time: 1 to 7 months.

Fluorouracil + Mitomycin

Average Response Rate: 35% to 65%.
Average Extra Survival Time: 3-9 months.

Fluorouracil + Mitoxantrone + Cisplatin

Average Response Rate: 35% to 65%.
Average Extra Survival Time: 3-9 months.

Gemcitabine Only

Average Response Rate: 25% to 55%.
Average Extra Survival Time: 2-8 months.

Gemcitabine + Bevacizumab

Average Response Rate: 30% to 60%.
Average Extra Survival Time: 3-9 months.

Gemcitabine + Capecitabine

Average Response Rate: 25% to 55%.
Average Extra Survival Time:  3-9 months.

Gemcitabine + Capecitabine + Bevacizumab

Average Response Rate: 35% to 65%.
Average Extra Survival Time:  4-10 months.

Gemcitabine + Capecitabine + Cetuximab

Average Response Rate: 35% to 65%
Average Extra Survival Time: 4-10 months.

Gemcitabine + Cisplatin

Average Response Rate: 40% to 70%.
Average Extra Survival Time: 5-11 months.

Gemcitabine + Cisplatin + Sorafenib

Average Response Rate: 40% to 70%.
Average Extra Survival Time: 5-11 months.

Gemcitabine + Irinotecan + Panitumumab

Average Response Rate: 40% to 70%
Average Extra Survival Time: 5-11 months.

Gemcitabine + Oxaliplatin

Average Response Rate: 35% to 65%.
Average Extra Survival Time: 4-10 months.

Gemcitabine + Oxaliplatin + Bevacizumab

Average Response Rate: 40% to 70%.
Average Extra Survival Time: 5-11 months.

Gemcitabine + Oxaliplatin + Cetuximab

Average Response Rate: 50% to 80%.
Average Extra Survival Time: 6-12 months.

Gemcitabine + Oxaliplatin + Panitumumab

Average Response Rate: 45% to 75%.
Average Extra Survival Time: 5-11 months.

Gemcitabine + Oxaliplatin + Erlotinib

Average Response Rate: 35% to 65%.
Average Extra Survival Time: 4-10 months.

Targeted Therapy

Afatinib

Average Response Rate: 10% to 40%.
Average Extra Survival Time: 0-6 months.

Binimetinib

Average Response Rate: 5% to 35%.
Average Extra Survival Time: 1-7 months.

Bortezomib

Average Response Rate: 0% to 30%.
Average Extra Survival Time: 0-6 months.

Bosutinib

Average Response Rate: 0% to 30%.
Average Extra Survival Time: 0-6 months.

Cabozantinib

Average Response Rate: 0% to 30%.
Average Extra Survival Time: 0-6 months.

Erlotinib

Average Response Rate: 0% to 30%.
Average Extra Survival Time: 0-6 months.

Everolimus

Average Response Rate: 10% to 40%.
Average Extra Survival Time: 1-7 months.

Imatinib

Average Response Rate: 0% to 30%.
Average Extra Survival Time: 0-6 months.

Lapatinib

Average Response Rate: 0% to 30%.
Average Extra Survival Time: 0-6 months.

Lenvatinib

Average Response Rate: 15% to 45%.
Average Extra Survival Time: 2-8 months.

Pazopanib

Average Response Rate: 0% to 30%.
Average Extra Survival Time: 0-6 months.

Selumetinib

Average Response Rate: 25% to 55%.
Average Extra Survival Time: 3-9 months.

Sorafenib

Average Response Rate: 0% to 30%.
Average Extra Survival Time: 0-6 months.

Sorafenib + Erlotinib

Average Response Rate: 0% to 30%.
Average Extra Survival Time: 0-6 months.

Trametinib

Average Response Rate: 0% to 30%.
Average Extra Survival Time: 0-6 months.

Radiotherapy

External Beam Radio-Therapy (EBRT)

Average Response Rate: 50% to 80%.
Average Extra Survival Time: 2-8 months.

Stereotactic Body Radio-Therapy (SBRT)

Average Response Rate: 50% to 80%.
Average Extra Survival Time: 2-8 months.

Proton Beam Therapy

Average Response Rate: 60% to 90%.
Average Extra Survival Time: 3-9 months.

Intensity Modulated Radiation Therapy (IMRT)

Average Response Rate: 50% to 80%.
Average Extra Survival Time: 2-8 months.

Other

Trans-Arterial Chemo-Embolization (TACE)

Average Response Rate: 30% to 60%.
Average Extra Survival Time: 2-8 months.

Hepatic Artery Embolization (HAE)

Average Response Rate: 50% to 80%.
Average Extra Survival Time: 4-10 months.

Drug Eluting Bead TACE (DEB-TACE)

Average Response Rate: 30% to 60%.
Average Extra Survival Time: 2-8 months.

Selective Internal Radio-Therapy (SIRT) with 90-Y Microspheres

Average Response Rate: 40% to 70%.
Average Extra Survival Time: 3-9 months.

Photo-Dynamic Therapy (PDT)

Average Response Rate: 40% to 70%.
Average Extra Survival Time: 3-9 months.

Brachytherapy

Average Response Rate: 25% to 55%.
Average Extra Survival Time: 1-7 months.

Immunotherapy and Monoclonal Antibodies

Immunotherapies are a class of treatment that enlist the patient’s own immune system to fight their cancer. There are many different subsets of medications that are used in cancer immunotherapy. An important subset of this class are Monoclonal Antibodies (mAbs), which are a highly target-specific group of medications. This section is organized by the drug target rather than the drug itself. This section only contains cancer immunotherapy medications that have received FDA or European approval. There are many more cancer immunotherapies being evaluated in clinical trials.

Epidermal Growth Factor Receptor 1 (EGFR, HER1)

Drug Names: Cetuximab (Erbitux), Panitumumab (Vectibix), Necitumumab (Portrazza).
Summary: EGFR mAbs can block EGFR signaling, which may slow tumor growth. They may also help the immune system identify the tumor as “foreign” via antibody binding.
When To Consider This Medication: If your tumor has high EGFR expression. EGFR expression should be confirmed by IHC prior to treatment.
Current Role In CC Treatment: Both Cetuximab and Panitumumab have been shown to provide a therapeutic benefit for a subset of CC patients. Can be used in combination with standard chemotherapy regimens. Although not studied in CC, Necitumumab is expected to have similar effect. Preliminary evidence suggest that Cetuximab (and Necitumumab) may be slightly more effective than Panitumumab due to antibody isotype (IgG1 vs IgG2).
Future Role in CC Treatment: These medications are likely to synergize with many other cancer immunotherapies by enhancing a tumor-specific immune response. In particular, they may enhance the activity of systemic checkpoint inhibitors (PD-1, PD-L1, CTLA-4) for patients with EGFR+ tumors.
Gene Expression Profile: EGFR is consistently expressed at biologically relevant levels in cholangiocarcinoma tumors, and is often significantly up-regulated relative to healthy tissue.

Epidermal Growth Factor Receptor 2 (ERBB2, HER2)

Drug Names: Trastuzumab (Herceptin), Ado-Trastuzumab Emtansine (Kadcyla) .
Summary: HER2 mAbs can block HER2 signaling, which may slow tumor growth. They may also help the immune system identify the tumor as “foreign” via antibody binding.
When To Consider This Medication: If your tumor has high HER2 expression. HER2 expression should be confirmed by IHC or FISH prior to treatment.
Current Role In CC Treatment: Only a small subset of cholangiocarcinoma tumors express high levels of HER2. Preliminary evidence suggests that Trastuzumab may have a therapeutic benefit for patients with HER2+ tumors.  Can be used in combination with standard chemotherapy regimens.
Future Role in CC Treatment: These medications are likely to synergize with many other cancer immunotherapies by enhancing a tumor-specific immune response. In particular, they may enhance the activity of systemic checkpoint inhibitors (PD-1, PD-L1, CTLA-4) for patients with HER2+ tumors.
Gene Expression Profile: HER2 is consistently expressed at biologically relevant levels in cholangiocarcinoma tumors, but it is not is often up-regulated relative to healthy tissue.

Vascular Endothelial Growth Factor Alpha (VEGF-A)

Drug Names: Bevacizumab (Avastin).
Summary: VEGF-A mAbs can block VEGF-A signaling, which may slow tumor growth. They may also help the immune system identify the tumor as “foreign” via antibody binding.
When To Consider This Medication: If your tumor has high VEGF-A or VEGFR2 expression. VEGF-A expression should be confirmed by IHC prior to treatment.
Current Role In CC Treatment: Bevacizumab has been shown to provide a therapeutic benefit for a subset of CC patients. Can be used in combination with standard chemotherapy regimens.
Future Role in CC Treatment: These medications are likely to synergize with many other cancer immunotherapies by enhancing a tumor-specific immune response. In particular, they may enhance the activity of systemic checkpoint inhibitors (PD-1, PD-L1, CTLA-4) for patients with VEGF-A+ tumors.
Gene Expression Profile: VEGF-A is consistently expressed at high levels both in cholangiocarcinoma tumors and healthy tissue.

Vascular Endothelial Growth Factor Receptor 2 (VEGFR2, KDR)

Drug Names: Ramucirumab (Cyramza).
Summary: VEGFR2 mAbs can block VEGFR2 signaling, which may slow tumor growth. They may also help the immune system identify the tumor as “foreign” via antibody binding.
When To Consider This Medication: If your tumor has high VEGFR2 or VEGF-A/B/C expression.
Current Role In CC Treatment: The efficacy of Ramucirumab as a treatment for cholangiocarcinoma has not been established, but clinical trials are ongoing. Based on the observed efficacy of Bevacizumab (VEGF-A inhibitor), it is likely that Ramucirumab will provide some therapeutic benefit to a subset of cholangiocarcinoma patients.
Future Role in CC Treatment: These medications are likely to synergize with many other cancer immunotherapies by enhancing a tumor-specific immune response. In particular, they may enhance the activity of systemic checkpoint inhibitors (PD-1, PD-L1, CTLA-4) for patients with VEGFR2+ and VEGF-A/B/C+ tumors.
Gene Expression Profile: VEGFR2+ does not appear to be expressed at high levels in either cholangiocarcinoma tumors or healthy bile duct tissue. However, it is consistently up-regulated in cholangiocarcinoma, relative to healthy tissue. Overall, the gene expression data suggests VEGFR2 is a promising but uncertain therapeutic target for the treatment of cholangiocarcinomas.

Programmed Cell Death Protein 1 (PD-1)

Drug Names: Nivolumab (Opdivo), Pembrolizumab (Keytruda).
Summary: PD-1 mAbs are in a class of cancer immunotherapies called “Checkpoint Inhibitors”. PD-1 mAbs work by blocking PD-1/PD-L1 signaling, which is a system that inhibits T cell activity. Treatment with PD-1 inhibitors can increase Cytotoxic “Killer” T cells ability to attack cancer cells.
Note: PD-1 and PD-L1 inhibitors target the same immune signaling system. Preliminary evidence suggests they may be used interchangeably in many circumstances.
When To Consider This Medication: If your tumor has high expression of PD-L1 and/or has a high tumor mutational burden (TMB) and/or has high micro-satellite instability (MSI) and/or has high T cell infiltration.
Current Role In CC Treatment: PD-1 inhibitors are a sub-class of immunotherapies called “immune checkpoint inhibitors”. Immune checkpoint inhibitors are becoming an increasingly important modality of cancer treatment. Although they do not work for many patients, PD-1 inhibitors can produce durable, complete remission in some patients. PD-1 inhibitors are not currently part of the standard-of-care for cholangiocarcinoma, but there are numerous clinical trials investigating these medications for the treatment of bile duct cancers. Based on compelling preliminary results demonstrating complete remission in some CC patients, checkpoint inhibitors (and PD-1 inhibitors in particular), are likely to play an expanded role in cholangiocarcinoma treatment in the near future.
Future Role in CC Treatment: Because PD-1 inhibitors can yield durable complete remissions in some cholangiocarcinoma patients (unlike conventional chemotherapy, where remission is almost always temporary), these checkpoint inhibitors will become increasingly important for
cholangiocarcinoma treatment. Combinations of PD-1 inhibitors with other treatments that make tumors more immunogenic (easier for the immune system to recognize as foreign) are especially promising. Complementary immunotherapies (eg. antibodies against EGFR, VEGF-A, VEGFR, HER2), radiotherapy and certain targeted therapies are all likely to synergize with checkpoint inhibitors. PD-1 inhibitors may be interchangeable with PD-L1 inhibitors because they target the same signalling system.
Gene Expression Profile: Cholangiocarcinomas tend to have low-to-moderate expression of PD-1, PD-L1 and CD3 (T cell marker). Cholangiocarcinomas also tend to have low tumor mutational burden (TMB-LOW) and are genetically stable (MSI-STABLE). Patients with all of the above characteristics are unlikely to respond to monotherapy with PD-1 inhibitors. However, the addition of radiotherapy or intratumoral adjuvants to systemic PD-1 inhibition may improve response rates.

Programmed Cell Death Ligand 1 (PD-L1, CD274)

Drug Names: Atezolizumab (Tecentriq), Avelumab (Bavencio), Durvalumab (Imfinzi).
Summary: Same conditions as PD-1 inhibitors. See above.
Note: PD-1 and PD-L1 inhibitors target the same immune signaling system. Preliminary evidence suggests they may be used interchangeably in many circumstances.
When To Consider This Medication: Same conditions as PD-1 inhibitors. See above.
Current Role In CC Treatment: Same as PD-1 inhibitors. See above.
Gene Expression Profile: Same as PD-1 inhibitors. See above.

Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4)

Drug Names: Ipilimumab (Yervoy).
Summary: CTLA-4 mAbs are in a class of cancer immunotherapies called “Checkpoint Inhibitors”. CTLA-4 mAbs work by CTLA-4 signaling, which is a system that inhibits T cell activity. Treatment with CTLA-4 inhibitors can increase Cytotoxic “Killer” T cells ability to attack cancer cells.
When To Consider This Medication: Same conditions as PD-1 inhibitors. See above.
Current Role In CC Treatment: Same as PD-1 inhibitors. See above.
Gene Expression Profile: Same as PD-1 inhibitors. See above.

Interleukin 2 (IL-2)

Drug Names: Interleukin 2 (Proleukin).
Summary: Interleukin 2 is an immune stimulant. It works by increasing the proliferation and activity of lymphocytes (eg. T cells).
When To Consider This Medication: Undefined for Cholangiocarcinoma.
Current Role In CC Treatment: Not generally used in Cholangiocarcinoma. New generations of this medication (eg. Pegylated IL-2) may play an important in future combination immunotherapies for cholangiocarcinoma.
Gene Expression Profile: Same as PD-1 inhibitors. See above.

Interferon Alpha 2B (IFNa-2b)

Drug Names: Interferon Alpha 2B (Intron-A, Others).
Summary: Interferon Alpha 2B is an immune stimulant. It works by inducing an immune response that is similar to the response to viral infections.
When To Consider This Medication: Undefined for Cholangiocarcinoma.
Current Role In CC Treatment: Not generally used in Cholangiocarcinoma. Was tested in the 1990’s and showed moderate efficacy, but was also associated with significant toxicity and adverse events. May be useful as an intratumoral adjuvant in the context of combination immunotherapy.
Gene Expression Profile: Unknown.

Interferon Gamma (IFNy)

Drug Names: Interferon Gamma (ACTIMMUNE).
Summary: Interferon Gamma is an immune stimulant. It works by enhancing the activity of cytotoxic “Killer” T cells, increasing antigen presentation and other mechanisms.
When To Consider This Medication: Undefined for Cholangiocarcinoma.
Current Role In CC Treatment: Not currently used in Cholangiocarcinoma. Short half-life in blood and high toxicity make Interferon Gamma an unattractive candidate for use as systemic immunotherapy. May be useful as an intratumoral adjuvant in the context of combination immunotherapy.
Gene Expression Profile: Bile duct cancers tend to express physiologically relevant levels of the Interferon Gamma Receptor. This makes it feasible that intratumoral administration of this medication could modulate the tumor microenvironment to make it more permissive of anti-tumor immune responses.

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