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.

References

Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. Bridgewater, et al. 2014.
Treatment and Prognosis for Patients With Intrahepatic Cholangiocarcinoma
Systematic Review and Meta-analysis. Mavros, et al. 2014.
Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database. Jutric, et al. 2016.
Evolution of Surgical Treatment for Perihilar Cholangiocarcinoma A Single-Center 34-Year Review of 574 Consecutive Resections. Nagino, et al. 2012.
Adjuvant Therapy in the Treatment of Biliary Tract Cancer: A Systematic Review and Meta-Analysis. Horgan, et al. 2012.
Systemic therapy for unresectable, mixed hepatocellular-cholangiocarcinoma: treatment of a rare malignancy. Rogers, et al. 2017.
Cancer review: Cholangiocarcinoma. Ghouri, et al. 2015.
Locoregional therapies in cholangiocarcinoma. Labib, et al. 2017.
SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma. Ben-Josef, et al. 2015.
Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study – The UK ABC-01 Study. Valle, et al. 2009.
Adjuvant therapy for resected extrahepatic cholangiocarcinoma: A review of the literature and future directions. Anderson, et al. 2009.
Gemcitabine Plus Cisplatin for Advanced Biliary Tract Cancer: A Systematic Review. Park, et al. 2015.
Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: A systematic review and pooled analysis. Al-Adra, et al. 2015.
Unresectable intrahepatic cholangiocarcinoma: Systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone. Konstantinidis, et al. 2015.
Ablative Radiotherapy Doses Lead to a Substantial Prolongation of Survival in Patients With Inoperable Intrahepatic Cholangiocarcinoma: A Retrospective Dose Response Analysis. Tao, et al. 2016.
Emerging therapies for the treatment of cholangiocarcinoma. Turbeville, et al. 2017.
Gene expression analysis for predicting gemcitabine resistance in human cholangiocarcinoma. Sato, et al. 2011.
Celecoxib Acts in a Cyclooxygenase-2-independent Manner and in Synergy with Emodin to Suppress Rat Cholangiocarcinoma Growth in Vitro through a Mechanism Involving Enhanced Akt Inactivation and Increased Activation of Caspases-9 and -3. Lai, et al. 2003.
Sensitivity of Human Intrahepatic Cholangiocarcinoma Subtypes to Chemotherapeutics and Molecular Targeted Agents: A Study on Primary Cell Cultures. Fraveto, et al. 2015.
Efficacy and safety of FOLFIRINOX in advanced cholangiocarcinoma. Kim, et al. 2017.
Comparison of FOLFIRINOX Chemotherapy with Other Regimens in Patients with Biliary Tract Cancers: a Retrospective Study. Kus, et al. 2017.
FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma. Guion-Dusserre, et al. 2015.
Pathogenesis and management of cholangiocarcinoma in the future. Gores. 2017.
The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma. Shroff, et al. 2017.
Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion–Positive Cholangiocarcinoma. Goyal, et al. 2017.
A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma. Goyal, et al. 2017.
Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Banales, et al. 2016.
Phase II trial of docetaxel for cholangiocarcinoma. Pazdur, et al. 1999.
Hepatic artery infusion of 5-fluorouracil and mitomycin C in cholangiocarcinoma and gallbladder carcinoma. Smith, et al. 1988.
The role of chemotherapy in biliary tract carcinoma. Verslype, et al. 2008.
HER2/neu-directed therapy for biliary tract cancer. Javie, et al. 2015.
Cost-effectiveness of HER2 testing and 1-year adjuvant trastuzumab therapy for early breast cancer. Lidgren, et al. 2008.
Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications. Ahn, et al. 2017.
A phase II FOLFOX-4 regimen as second-line treatment in advanced biliary tract cancer refractory to gemcitabine/cisplatin. He, et al. 2014.
Cetuximab plus gemcitabine-oxaliplatin (GEMOX) in patients with refractory advanced intrahepatic cholangiocarcinomas. Paule, et al. 2007.
Fluoropyrimidines plus cisplatin versus gemcitabine/gemcitabine plus cisplatin in locally advanced and metastatic biliary tract carcinoma – a retrospective study. Criotoru, et al. 2012.
Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. Bekaii-Saab, et al. 2011.
Targeted Therapy in Biliary Tract Cancers. Merla, et al. 2015.
Phase II study of erlotinib in patients with advanced biliary cancer. Philip, et al. 2006.
Cyclooxygenase-2 Promotes Human Cholangiocarcinoma Growth. Han, et al. 2004.
The PD‐1/PD‐L1 axis may be aberrantly activated in occupational cholangiocarcinoma. Sato, et al. 2017.
Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): Preliminary data and correlation with next-generation sequencing. Lin, et al. 2018.
Program Death 1 Immune Checkpoint and Tumor Microenvironment: Implications for Patients With Intrahepatic Cholangiocarcinoma. Gani, et al. 2016.
PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma. Fontugne, et al. 2017.
PD-L1 and HLA class I antigen expression and clinical course of the disease in intrahepatic cholangiocarcinoma. Sabbatino, et al. 2016.
Viral infection of tumors overcomes resistance to PD-1-immunotherapy by broadening neoantigenome-directed T-cell responses. Woller, et al. 2015.
Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer. Patt, et al. 1996.
Phase II Trial of Cisplatin, Interferon α-2b, Doxorubicin, and 5-Fluorouracil for Biliary Tract Cancer. Patt, et al. 2001.
Phase I trial of recombinant human γ-interferon and recombinant human tumor necrosis factor in patients with advanced gastrointestinal cancer. Abbruzzese, et al. 1989.
Determining the role of external beam radiotherapy in unresectable intrahepatic cholangiocarcinoma: a retrospective analysis of 84 patients. Chen, et al. 2010.
Phase I Study of Individualized Stereotactic Body Radiotherapy for Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. Tse, et al. 2008.
Clinical outcomes and toxicity using Stereotactic Body Radiotherapy (SBRT) for advanced cholangiocarcinoma. Barney, et al. 2012.
Stereotactic body radiotherapy (SBRT) for locally advanced intrahepatic and extrahepatic cholangiocarcinoma. Gkika, et al. 2017.
Efficacy and Safety of Stereotactic Body Radiation Therapy for Treatment of Inoperable Intrahepatic and Perihilar Cholangiocarcinoma. Toesca, et al. 2017.
Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. Hong, et al. 2016.
Proton beam therapy for unresectable intrahepatic cholangiocarcinoma. Ohkawa, et al. 2015.
Clinical outcomes and toxicity of proton beam therapy for advanced cholangiocarcinoma. Makita, et al. 2014.
Proton beam therapy as a rising option in treating intrahepatic cholangiocarcinoma. Lee, et al. 2017.
Intensity-modulated radiotherapy following null-margin resection is associated with improved survival in the treatment of intrahepatic cholangiocarcinoma. Jia, et al. 2015.
High dose chemoradiation for unresectable hilar cholangiocarcinomas using intensity modulated external beam radiotherapy: a single tertiary care centre experience. Engineer, et al. 2017.
Phase I dose-escalation study of helical intensity-modulated radiotherapy-based stereotactic body radiotherapy for hepatocellular carcinoma. Kim, et al. 2016.
Chemoembolization (TACE) of unresectable intrahepatic cholangiocarcinoma with slow-release doxorubicin-eluting beads: preliminary results. Aliberti, et al. 2008.
Treatment of unresectable cholangiocarcinoma: conventional transarterial chemoembolization compared with drug eluting bead-transarterial chemoembolization and systemic chemotherapy. Kuhlmann, et al. 2012.
Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. Boehm, et al. 2014.
Comparison of Triple-Drug Transcatheter Arterial Chemoembolization (TACE) With Single-Drug TACE Using Doxorubicin-Eluting Beads: Long-Term Survival in 313 Patients. Gomes, et al. 2017.
THU-174 – Combined photodynamic therapy with systemic chemotherapy improves survival of patients with irresectable cholangiocarcinoma. Gonzalez-Carmona, et al. 2018.
Neoadjuvant Down-Sizing of Hilar Cholangiocarcinoma with Photodynamic Therapy—Long-Term Outcome of a Phase II Pilot Study. Wagner, et al. 2015.
Combined Photodynamic Therapy with Systemic Chemotherapy Compared to Chemotherapy or Photodynamic Therapy Alone in Patients with Non-Resectable Extrahepatic Cholangiocarcinoma: a Retrospective Study. Gonzalez-Carmona, et al. 2016.
Photodynamic Therapy Plus Chemotherapy Compared with Photodynamic Therapy Alone in Hilar Nonresectable Cholangiocarcinoma. Wentrup, et al. 2016.
Endoscopically inserted nasobiliary catheters for high dose-rate brachytherapy as part of neoadjuvant therapy for perihilar cholangiocarcinoma. Mukewar, et al. 2015.
Comparison of external beam radiation and brachytherapy to external beam radiation alone for unresectable extrahepatic cholangiocarcinoma. Boothe, et al. 2016.
Intraluminal Brachytherapy: An Effective Palliation for Cholangiocarcinoma Causing Bile Duct Obstruction?. Nguyen, et al. 2015.
Selective internal radiation therapy (SIRT) with yttrium-90 microspheres for unresectable intrahepatic cholangiocarcinoma. Abeysinghe, et al. 2018.
Comparison of Choi criteria and Response Evaluation Criteria in Solid Tumors (RECIST) for intrahepatic cholangiocarcinoma treated with glass-microspheres Yttrium-90 selective internal radiation therapy (SIRT). Beuzit, et al. 2016.
Selective internal radiation therapy with SIR-Spheres in hepatocellular carcinoma and cholangiocarcinoma. Wang, et al. 2017.
Safety of selective internal radiation therapy (SIRT) with yttrium-90 microspheres combined with systemic anticancer agents: expert consensus. Kennedy, et al. 2017.

The Genetic Landscape of Cancer

Cancer is a genetic disease. Some cancers are inherited and other cancers arise from genetic mutations or viral infections that occur during your life. But every cancer is driven by a dysfunctional genetic operating system.

Tumor Gene Expression Data (Transcriptome)

The analyses from cure-hub.org are based on the genetic profile of each cancer type. In order define these profiles, we are aggregating genetic data from the repository at NCBI GEO (National Center for Biotech Info – Gene Expression Omnibus). Specifically, we are aggregating expression data generated using the Affymetrix GPL570 microarray. This section contains the master files with all of the cancer types together. If you want to compare the genetic profiles of 2 different cancer types, this is the section for you.

Genetic Profile Explorer

The link below will open a program that allows you to explore and compare the gene expression profiles of the cancer types we have analyzed. This program includes the average gene expression profile for every cancer subset we have analyzed. For more info on how to use and interpret the data from this program, read our Guide to Using the Gene Expression Spider Plot. Note: This link works best when opened with Google Chrome.

Tumor Genetic Profile Explorer – All Tumor Types

Tumor Genetic Profile Explorer Screen Grab
Tumor Genetic Profile Explorer Screen Grab

Tumor Sample List

The link below will take you to a Google Sheet that lists all of the tumor samples included in the analysis. This list will be updated as the profiles for new tumor types are added.

Access the Tumor Sample List

Summarized Data Files

Would you like to do your own analysis of the gene expression profiles generated by cure-hub.org? Feel free to download the raw data (averaged at the tumor-type level) by following the link below.

Raw Data for Tumor-Type Gene Expression Averages

Have Questions?

If you have questions, or need help using any of these resources, feel free to email the cure-hub.org team: help (at) cure-hub.org.

Specific Types of Cancer

Overview

There are many types of cancer and they are all unique. This section is intended to provide in-depth analyses of specific cancers and their treatment options. That is an immense task so we are going to start with two of the most lethal classes of cancer: Hepatobiliary (bile duct, liver, pancreas) and Brain (glioblastoma).

The Genetic Landscape of Cancer

Cancer is a genetic disease. Some cancers are inherited and other cancers arise from genetic mutations or viral infections that occur during your life. But every cancer is driven by a dysfunctional genetic operating system.

The analyses from cure-hub.org are based on the genetic profile of each cancer type. In order define these profiles, we are aggregating genetic data from hundreds of studies and thousands of tumor samples. This section contains the master files, with all of the genetic profiles from different cancers in one place.

Cancer Types

Bile Duct

Brain (Glioblastoma)

Liver

Pancreas

 

Why You Need to Be Your Own Healthcare Advocate & How To Do It

 

Why Do I Need to Be My Own Advocate?

You and your family care more about your health than anyone else. Nobody else has the same amount of skin in the game or enough time to focus exclusively on you.  That is just a fact. Healthcare workers are compassionate and care deeply about providing great care, but they just don’t have the bandwidth to spend endless hours thinking about your problem.

You have time to think deeply about your health condition. The physician who you are about to see? They probably didn’t know you were on their schedule until that morning. Most of the time they had to ask a nurse or medical assistant for your name right before they walk in the door (it’s happened to us).

So how much time do you think they really spend thinking about the nuance of your health problem? Not much, and because they don’t have time they must operate under the law of averages. Guess who isn’t average though…YOU!

Physican-Patient Time Is Limited

Physicians have limited time to spend with each patient because they are under pressure to see as many patients as possible. This is why the typical patient-physician encounter is only scheduled for 15 minutes. If you have cancer you might get a 45-minute consult.

The physician will look at your chart for a few minutes before the appointment. If you are lucky they will present your cancer history at a tumor board meeting, where multiple physicians sit at a table and discuss your case for… 5-10 minutes. That isn’t much time but they have many other patients to see, after all.

Cancer Doesn’t Care If Your Physician Is Helpful

Your physicians, nurses and the rest of your medical staff want to provide you with great care, that is the reason they are in the medical field. With that said, there are exceptions to every rule and some physicians do not develop positive, give-and-take relationships with their patients.

If you EVER get the impression that your physician is uncooperative and doesn’t appreciate your insight, then you need to find a new doctor. This is very important and we will repeat – Find a new physician if your current physician is not 100% cooperative with you.  Cancer doesn’t wait for physicians to come around and a physician’s recalcitrance is a red flag for decision making that could adversely affect your health – and survival.

A good doctor is a doctor who welcomes your input, questions and research. This indicates a certain amount of humility, which is necessary for a physician to provide exceptional medical care. Humility indicates that your physician is open to a point of view and information they hadn’t considered. A single piece of new information could be the difference maker that helps cure your tumor.

You Need To Form A Team With Your Health Care Providers

Teammates share information, work towards the same goal and most importantly they don’t emphasize who is responsible for team wins. This is because when the team wins, everyone has their own success to show for it. In order for you and your healthcare team to beat your tumor, there must be open channels of communication. You must be willing to consider all of their input, and they must be willing to consider yours.

Humility and openness by your physician shows that they have a commitment to team approaches to healthcare. Your physician may captain the team, but you are also an important player who can provide valuable information. Believe in yourself – you can and will productively add to your healthcare team.

Make Use of Open Source Information

Many people call our current era, “The information age,” due to the abundance of, and access to information. We recommend using the internet to research your health problems. At first it might be difficult to understand technical jargon, but if you stay determined you will soon be prepared to engage your healthcare team in meaningful discussions.

With a serious health condition like cancer it might be useful to make your own health records. You can make an electronic log of medications, supplements, diet, activities and symptoms. Record what makes you feel better or worse. Maybe some of your symptoms are connected, or a specific activity is really helping. It will be difficult to keep everything straight in your mind if you don’t record that stuff. If you review those records before your appointments, then you will ask your healthcare provider more meaningful questions.

Be Empowered: Be Your Own Healthcare Advocate

First off, you can do this.  We believe you can take control of your own healthcare and most importantly, we believe you should take control. Like we said earlier, nobody cares about your health more than you and your family.

“You can learn the basic elements of your advisor’s trade. You don’t have to learn very much, because if you learn just a little, you can make them explain why they are right.” – Charlie Munger

Charlie Munger is a brilliant thinker and you can apply his advice to healthcare. You are empowering yourself when you learn about your health problem and the various treatment options. Empowered patients have better outcomes because they take responsibility and add scrutiny to their healthcare.

Questions Worth Asking Your Physician

Here are some questions that you might consider asking your health care provider:

What is causing my symptoms and what treatment are you recommending? Are there any alternatives?

Why do you recommend this treatment over the other options? 

Is there a chance for short or long-term side effects and what are they?

When might I start to see improvement in my symptoms?

What tests do I need?

What is the reason for those tests?

Will the test results change my treatment plan?

What are my follow-up plans and what symptoms should I report before my next appointment? 

When can I resume my normal activities?

Cure-Hub Will Help You And Your Physician

Our clinical trial finder is very comprehensive and it is specifically designed to find treatments with an intent to cure your tumor. There are about 6,500 clinical trials around the world that fall under this criteria and our website is updated on a regular basis.

For many cancer types the number of clinical trial options is quite high. In fact, the number is so high and updates are so frequent that no human could keep track of each of them. But with some effort you can use the power of Cure-Hub to take control of your healthcare. It starts by creating a profile and searching for trials on the clinical trial finder.

We recommend saving several trials to your profile and then sharing them with your physician. Or you can ask your physician to help you search for trials. Once you have a list of trials, ask your physician, “If you were in my position, which trial would you enroll in and why?”

Resources

Here is a list of web resources that we find helpful when we do our own cancer research:

  1. https://www.cancer.gov/ – Comprehensive resource from the National Cancer institute (NCI).
  2. https://dailymed.nlm.nih.gov/dailymed/ – ‘Daily Med’ is the National Institute of Health’s database with detailed information on all clinically approved drugs.
  3. NCCN.org – National Comprehensive Cancer Network, used by physicians to help make treatment decisions. Free to register and use.
  4. https://scholar.google.com/ – Google search engine designed to find research publications.

This list is just a start and there are many other sites that might be useful. Feel free to send us other web resources to review and add to the list.

How To Interpret Your Foundation One Test Results

 

One of the most common questions people ask is, “How do I interpret Foundation One test results?” We want to help you understand the test itself, as well as the report generated from its results. As always, we recommend consulting your physician when making any medical decisions.

What Does Foundation One Test?

The purpose of the Foundation One test is to identify changes in tumor cell DNA. Each cell in your body has a complete copy of your DNA and tumor cells are no different. Generally speaking, DNA is made up of functional units which are known as genes.

Your DNA is sometimes referred to as your genetic code because it instructs cellular processes. This is similar to the way that computer code instructs computer processes. When there are errors in your DNA code, cells can start malfunctioning. Just like an error in computer code can cause problems in a software program.

Tumors are composed of malfunctioning cells and unsurprisingly tumor cell DNA is full of errors. Damaged or altered versions of your DNA are often referred to as mutations. Sometimes a DNA mutation occurs in a harmless gene. Other times a mutation can causes a serious glitch that results in unrestrained cell division. Cell division is when one cell divides and becomes two cells.

Click to See What Cell Division Looks Like: Cell Division Gif

Gene Mutations And The Foundation One Test

If an error in DNA leads to a glitch in the functions of a cell, then division might occur more frequently than normal. Increased rates of cell division can lead to the growth of a tumor. Many different types of errors can occur in DNA and each error has the potential to negatively mutate the affected gene.

Depending on which gene is mutated, normal processes like cell division, metabolism or even tumor suppression can be negatively impacted. If a cell does not correct the error, the DNA will become permanently mutated. Each cell division will create a sister cell harboring that same mutation. Sometimes those mutations compound and lead to errors in other important genes. This can speed up tumor growth.

Over several decades scientists have cataloged common DNA errors and mutated genes found in tumors. The Foundation One test is designed to detect the types of errors and the specific genes that are mutated. In total this test assesses changes in over 300 genes that have been found to influence tumor growth.


Each patient will receive a detailed report with a table that looks similar to this:

This table has four sections and they are:

Column 1: Genomic Findings Detected

The first column, “Genomic Findings Detected,” displays mutated genes in your tumor’s DNA. The bold text is the name of the mutated gene and the lighter text is the specific type of mutation. There are many mutations that occur in DNA. Sometimes the type of mutation can confer treatment decisions. However, not all mutations can be targeted by existing therapies.

The first row in the above table displays a mutation in the ERBB2 gene. The mutation was a gene amplification. Amplification means that the gene was copied multiple times in tumor-cell DNA. In a gene like ERRB2 this could result in much more rapid cell division. Foundation One includes the word, “Equivocal,” when they believe a result needs secondary testing.

Other information such as, “Splice site…” , “Loss of exons…” , or a string of letters and numbers with, “*”,  refer to specific changes to the coding sequence of the gene.

Tumor Mutation Burden

“Tumor Mutation Burden,” is also reported in this section. This doesn’t explain a specific gene mutation but it can be useful information. The burden is characterized as high, low or intermediate. Research suggests that a high tumor mutation burden may predict response to immunotherapy.

Microsatellite Status

You might also see, “Microsatellite status,” in your report. This analyzes specific regions of DNA that are important but do not code for a gene. Sometimes errors occur in those microsatellite regions and the report will state if your microsatellite instability is, ‘high’, ‘low’, ‘stable’, or ‘unknown.’ If your report says you have high microsatellite instability, then you might have a genetic disease in mismatch repair genes (MMR). Some research suggests that immunotherapy is more effective against tumors with high microsatellite instability status.

Column 2: FDA Approved Therapies In Your Tumor Type

The second column, “FDA Approved Therapies In Your Tumor Type,” tells you therapies that are FDA approved for both your tumor type and your specific DNA mutation in that row.

In the first row, the table displays the drug, Afatinib. Afatinib is approved for use in the patient’s Lung Adenocarcinoma tumor (tumor type will be written at top right of the chart) and Afatinib targets the ERBB2 gene mutation detected by Foundation One testing. When a drug is approved to treat a mutation found in your tumor type, it is referred to as, “On-label use,” which means drug costs will likely be covered by your health insurance.

Column 3: FDA Approved Therapies In Other Tumor Types

The third column, “FDA Approved Therapies In Other Tumor Types,” tells you therapies that are FDA approved for other tumor types, but target DNA mutations found in your tumor.

In the table we see that the drugs Ado-trastuzumab emtansine, Lapatinib, Pertuzumab and Trastuzumab are all approved to target the ERBB2 gene. Those drugs are approved for use in at least one tumor type; however, they haven’t been approved for use in Lung Adenocarcinoma, the example patient’s tumor type.

Using drugs that are approved in other tumor types but not your own is referred to as, “Off-label use,” which is not usually covered by health insurance. Off-label drugs can be prescribed by your physician then legally purchased at full price. Note that off-label drugs may work in tumor types that have not yet been approved.

Column 4: Potential Clinical Trials

Rows in the last column, “Potential Clinical Trials,” will either say, “None,” or, “Yes, see clinical trials section.” The clinical trials section lists ongoing trials for investigational drugs that target mutations found in your tumor’s DNA.

Each patient’s Foundation One report will include a clinical trial section that looks similar to this:

How to interpret the clinical trials section of your Foundation One report:

Trial Phase

If you are considering clinical trials, there are a couple important pieces of information in this table. First, consider the trial, “Phase.” Phase 1 trials involve dose escalation to determine the drug’s biologically active and safe dosage.

The first patient cohorts receive very low dosages, which means some patients in phase 1 trials will not receive a biologically active dosage. That isn’t good if you need to cure your tumor.

Phase 2 trials use a dosage that has already shown biological activity. Phase 2 trials also attempt to show some efficacy which – differentiates them from Phase 1 trials. Keep in mind that a hint of efficacy isn’t known until the end of the trial. At this stage there is continued investigation to determine the best and safest dosage.

Phase 3 trials are the most important trials because they’re randomized, blinded and controlled. Blinded means the investigators (meaning clinical staff and researchers) don’t know which patients are receiving the study drug. Controlled means some patients will not receive the study drug, they’ll receive existing standard-of-care treatments. Randomized means that the patients who receive the study drug are randomly selected to prevent ‘gaming’ the patient cohort.

Targets

The column labeled, “Targets,” also has useful information. This section tells you the specific gene(s) targeted by the drug. A drug targeting multiple mutated genes in your tumor may be a better choice than drugs that hit only one target. Oftentimes the more ways you can hit your tumor the better.

How To Use The Cure-Hub Clinical Trial Finder

You can use Cure-Hub to find any phase 2 or 3 therapeutic cancer trials. The best way to search for a specific trial is to use the NCT ID – the trial’s unique identifier. This is in the last column of Foundation One’s clinical trial table. To do this, plug the NCT ID into the keyword section on the Cure-Hub Clinical Trial Finder.

If you login to Cure-Hub, you can save the trial to your profile. This makes it easy for you to read about, compare trials and share information with your physician. In our, “How To Enroll In a Trial,” section we have detailed instructions for contacting and enrolling in a trial.

You can also use drug or gene names to search for other clinical trials that might help treat your tumor. As always we are available to answer questions regarding Foundation One testing or finding the right clinical trial for you.

Here is a link to Foundation One’s guide to interpreting their test results: Link