Biliary Tract Cancer Treatment Protocols

Updated: Jan 03, 2023

Author: Tomislav Dragovich, MD, PhD; Chief Editor: N Joseph Espat, MD, MS, FACS

Treatment Protocols

Treatment protocols for biliary tract cancer are provided below, including the following:

Surgery
Neoadjuvant therapies
Liver transplantation
Locoregional therapies
Hepatic arterial infusion
Adjuvant therapy after resection
Palliative systemic therapies
Targeted therapies

Surgical resection

Surgery is the only curative modality for biliary tract cancers; surgical resectability of disease should be established by care teams who are experts in the field and should be performed following multidisciplinary discussion when possible.

Surgical cures are most often accomplished with incidentalomas discovered on pathologic review after laparoscopic cholecystectomy performed for other indications.[1] Simple cholecystectomy is possible for stage I and II disease (without nodal involvement).

Criteria for resectability include absence of all of the following: retropancreatic and paraceliac nodal metastases or distant liver metastases, invasion of the portal vein or main hepatic artery (although some centers can offer vascular reconstruction), extrahepatic adjacent organ invasion, and disseminated disease. If initial exploration reveals positive nodes in the celiac axis or aorto-caval groove, further surgical management is contraindicated.

Surgical resection includes cholecystectomy, en bloc hepatic resection (typically of segments IVb and V), and lymphadenectomy with or without bile duct excision, depending on the location of the tumor. Extended hepatectomy may be required.[2]

Adequate lymphadenectomy to confer survival benefit includes assessment of any suspicious regional nodes, evaluation of the aortocaval nodal basin, and a goal of harvesting at least 6 nodes.[3]

Current consensus guidelines from the Americas Hepato-Pancreato-Biliary Association recommend re-resection for patients with T1b, T2 or T3 gallbladder cancer that is incidentally identified in a cholecystectomy specimen, unless this surgery is contraindicated because of advanced disease or poor performance status. Re-resection should include complete portal lymphadenectomy and segmental/non-anatomic hepatectomy of segments IVb/V. Bile duct resection should be attempted only to achieve negative margin (R0) resection.[2]

Patients with preoperatively staged T3 or T4 N1 disease should be considered for clinical trials of neoadjuvant chemotherapy. Following R0 resection of T2-4 disease in N1 gallbladder cancer, patients should be considered for adjuvant systemic chemotherapy and/or chemoradiotherapy.

Patients with confirmed metastasis to N2 nodal stations (para-aortic, celiac, or superior mesenteric artery) do not benefit from radical resection and should receive systemic and/or palliative treatment. The role of extended re-operation in patients with stage III (serosal or nodal involvement) disease is questionable.

Preoperative jaundice is considered a relative contraindication to radical resection.

Neoadjuvant therapy

Neoadjuvant chemoradiotherapy

Neoadjuvant chemoradiotherapy is not currently a standard option for patients with biliary tract cancer. National Comprehensive Cancer Network (NCCN) guidelines do not currently recommend neoadjuvant chemoradiation.[4] Small, mostly retrospective, reports describe preoperative chemoradiation resulting in downstaging, or permitting R0 radical resection of initially unresectable locally advanced cholangiocarcinoma. However, there is no consensus on the optimal regimen.[5, 6, 7, 8, 9, 10]

Neoadjuvant chemotherapy

The decision to use neoadjuvant chemotherapy needs to be individualized, with close consultation of a multidisciplinary team. There is a dearth of clinical data to define a standard regimen.[11, 12, 13, 14]

NCCN guidelines recommend consideration of a course of neoadjuvant chemotherapy for patients with jaundice.[4]

Liver transplantation

For highly selected patients with early stage (≤3 cm), unresectable hilar cholangiocarcinoma or cholangiocarcinoma arising in the setting of primary sclerosing cholangitis, the sequential combination of high-dose neoadjuvant radiotherapy with chemosensitization, brachytherapy, maintenance chemotherapy, and orthotopic liver transplantation achieves excellent outcomes, with a 65% rate of recurrence-free survival after 5 years.[15] Based on these outcomes and a low 11.5% dropout rate at 3 months, the United Network of Organ Sharing (UNOS) has offered a standardized Model for End-stage Liver Disease (MELD) exception for this disease in the setting of liver transplantation since 2010.[16] The Mayo Clinic protocol is as follows:

External beam radiation therapy plus continuous 5-fluorouracil (5-FU) for 3 weeks, then
Brachytherapy for 2 weeks, then
Maintenance capecitabine until transplantation (held perioperatively during staging), then
Abdominal exploration for staging, then
Liver transplantation

UNOS has largely excluded patients with intrahepatic cholangiocarcinoma from transplant lists. Data have shown that highly selected patients with locally advanced intrahepatic cholangiocarcinoma who demonstrated pre-transplant disease stability on neoadjuvant therapy might benefit from liver transplantation with encouraging survival rates.[17, 18] Prospective definitive evidence for the intrahepatic indication for transplant remains lacking.

Locoregional therapies

Local therapies that enable directed treatment of hepatic disease include the following:

Radioembolization (SIRT) ^[19]
Transarterial chemo-embolization (TACE)
Hepatic artery infusion chemotherapy (HAIC)
Microwave/radiofrequency ablation

Combining SIRT and chemotherapy in locally advanced intrahepatic cholangiocarcinoma may permit downstaging.[20]

HAIC may result in better survival outcomes than TACE.[21] and may have better outcomes when used in the first line and in combination with systemic chemotherapy[22, 23] (eg, hepatic arterial infusion of floxuridine with systemic gemcitabine and oxaliplatin or cisplatin.[24, 25]

Multifocality, nodal status and genomic alterations are further refining selection of patient who benefit from resection and hepatic artery infusion.[26, 27, 28]

No randomized trials have guided when to best sequence HAIC in metastatic therapy and whether it achieves sufficient downstaging rates for neoadjuvant use.[29]

Adjuvant therapy following curative-intent resection

Adjuvant therapy is the standard of care following R0 or R1 resection. Microscopic positive margins can be managed with concurrent chemoradiation.[30] Patients should be offered a clinical trial when possible.

Stage IB-III (T1-3, N0-1, M0):

Capecitabine 1250 mg/m ² BID on treatment days 1 to 14 of a 3-week cycle for 24 weeks, for eight cycles) ^{[31, 32]}Western patients may need to be started at a dose of 1500 mg BID because of lower tolerance.

Adjuvant chemoradiation for patients with extrahepatic cholangiocarcinoma or gallbladder cancer with microscopically positive surgical margins (R1) includes the following:

Gemcitabine 1000 mg/m ² IV on days 1 and 8 plus capecitabine (1500 mg/m ² per day on days 1 to 14) every 21 days then
Capecitabine 1330 mg/m ² per day) plus radiotherapy (45 Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed) ^[33]

For periampullary tumors, the following regimens have been used for adjuvant therapy[34] :

Gemcitabine 1000 mg/m ² IV once a week for 3 of every 4 weeks for 6 months.
Leucovorin 20 mg/m ² IV bolus then 5-FU 425 mg/m ² IV bolus on days 1- 5 every 28 days

Adjuvant chemoradiotherapy regimens for stage IB-III:

5-FU 225 mg/m ² IV daily during radiation ^[35] or
5-FU 500 mg/m ² IV bolus on days 1-3 and days 29-31 during radiation or
Capecitabine 825 mg/m ² PO twice daily during radiation ^[36]; following radiation, consider an additional 4 months of therapy ^[37] or
Capecitabine 1000 mg/m ² PO twice daily for 14 of every 21d ^[38] or
Capecitabine 800-900 mg/m ² PO BID on days of radiation or
Four cycles of capecitabine plus gemcitabine followed by concurrent RT plus oral capecitabine (1330 mg/m ² per day divided into two daily doses) ^[33]

Systemic therapy for biomarker-agnostic nonresectable or metastatic disease

Selected stage III-IV (T3-4, Any N, M0-1):

Any patient with a stage IV, unresectable biliary cancer should be considered for clinical trial participation.
Cisplatin 25 mg/m ² IV on days 1 and 8 plus gemcitabine 1000 mg/m ² IV on days 1 and 8 every 21 days. ^[39]
Cisplatin 25 mg/m ² IV on days 1 and 8 plus gemcitabine 1000 mg/m ² IV on days 1 and 8 every 21 days plus durvalumab (1500 mg) on day 1 every 21d; chemotherapy is given up to 24wk or until disease progression; patients without disease progression at 24 weeks (8 cycles) receive durvalumab 1500 mg every 28 days until progression or unacceptable toxicity as maintenance therapy. ^[40]
Historically, when the gemcitabine/cisplatin doublet was used, gemcitabine was continued as maintenance therapy until progression or unacceptable toxicity. No prospective data are currently available on maintenance with both gemcitabine and durvalumab.
In countries where the fourth-generation oral fluoropyrimidine S-1 is available, a viable first-line regimen is gemcitabine 1000 mg/m ² IV on days 1 and 8 plus S-1 orally twice daily: 60 mg/day for body surface area [BSA] < 1.25 m ², 80 mg/day for BSA 1.25-1.50 m ², and 100 mg/day for BSA ≥1.50 m ² on days 1–14; regimen repeated every 3 weeks. ^[41]

Other active first-line therapies in the metastatic or unresectable setting include:

Modified GEMOX (gallbladder cancer): Gemcitabine 900 mg/m ²IV on days 1 and 8 plus oxaliplatin 80 mg/m ² on day 1; regimen repeated every 3 weeks for a maximum of six cycles ^[42]
Capecitabine 650 mg/m ² orally twice a day for 14 days plus gemcitabine 1000 mg/m ² IV over 30 minutes on days 1 and 8 ^[43]
CAPOX: Oxaliplatin 130 mg/m ² on day 1 plus capecitabine 1000 mg/m ² BID on days 1-14 every 3 weeks ^[44]

Therapy after the first line

In patients with unresectable or metastatic disease, next-generation sequencing combined with RNA sequencing and immunohistochemistry is standard of care to guide further treatment options for biomarker-selected therapy after front-line gemcitabine/cisplatin therapy. Testing should include the following[4] :

HER2 IHC/ERBB2 amplification
dMMR/MSI-H
IDH1 mutations
FGFR fusions/rearrangements
BRAF V600E mutation
NTRK fusions

Selected targeted therapies are as follows:

IDH1 mutations: Ivosidenib 500 mg orally once daily in 28-day cycles; continue until disease progression or unacceptable toxicity ^[45]
FGFR2 fusion or rearrangement: Pemigatinib 13.5 mg PO qDay for 14 consecutive days followed by 7 days off therapy; continue until disease progression or unacceptable toxicity ^[46] or
FGFR2 fusion or rearrangement: Infigratinib 125 mg PO qDay for 21 consecutive days followed by 7 days off therapy; continue until disease progression or unacceptable toxicity ^[47] or
FGFR2 fusion or rearrangement: Futibatinib 20 mg orally once daily until disease progression or unacceptable toxicity ^[48]
BRAF V600E: Dabrafenib 150 mg PO BID plus trametinib 2 mg PO qDay; continue until disease recurrence or unacceptable toxicity ^[49]
NTRK fusion: Larotrectinib 100 mg PO BID; continue until disease progression or until unacceptable toxicity ^[50] or
NTRK fusion: Entrectinib 600 mg PO qDay; continue until disease progression or unacceptable toxicity ^[51]
HER2 amplification/overexpression (off label): Pertuzumab 840 mg IV infusion over 60 min, then 420 mg IV infusion over 30-60 min q3Weeks thereafter plus trastuzumab 8 mg/kg IV infusion over 90 min initially, then 6 mg/kg IV infusion over 30-90 min q3Weeks thereafter ^[52]
dMMR/MSI-H/TMB-H: Pembrolizumab 200 mg IV q3Weeks or 400 mg q6Weeks until disease progression or unacceptable toxicity, or up to 24 months without disease progression ^[53]
RET fusion (off label): Pralsetinib 400 mg PO qDay; continue until disease progression or until unacceptable toxicity ^[54]

If no targetable biomarkers are found, second-line therapy in unselected patients is modified FOLFOX:

Oxaliplatin 85 mg/m ² IV, folinic acid (leucovorin) 175 mg IV, 5-FU 400 mg/m ² IV bolus on day 1, followed by 2400 mg/m ² IV infused over 46h; every 14 days for up to 12 cycles or progression/limiting toxicity then maintenance therapy with 5-FU plus leucovorin after the discontinuation of the oxaliplatin is conventional. ^[55]

Alternative treatment options after gemcitabine/cisplatin that for biliary cancer patients with good performance status include the following:

5-FU plus liposomal irinotecan ^[56]
Gemcitabine 1000 mg/m ² IV on day 1 plus oxaliplatin 100 mg/m ² IV on day 2; then every 14d until progression or toxicity ^[57] or
Gemcitabine 1000 mg/m ² IV on days 1 and 8 plus capecitabine 650 mg/m ² PO on days 1-14; then every 21d until progression or toxicity ^[43] or
Capecitabine 1000 mg/m ² PO twice daily on days 1-14 plus oxaliplatin 130 mg/m ² IV on day1; then every 21d until progression or toxicity ^[44] or
Leucovorin 400 mg/m ² IV infused over 2h prior to 5-FU plus 5-FU 400 mg/m ² IV bolus on day 1, followed by 2400 mg/m ² IV infused over 46h plus oxaliplatin 100 mg/m ² IV on day 1; then every 14d until progression or toxicity ^[58] ^[59] or
Capecitabine 1250 mg/m ² PO twice daily on days 1-14 plus cisplatin 60 mg/m ² IV on day 1; then every 21d until progression or toxicity ^[60] or
5-FU 1000 mg/m ²/day via continuous IV infusion on days 1-5 plus cisplatin 100 mg/m ² IV on day 2; then every 4wk until progression or toxicity ^[61]

Persistent biliary obstruction but good performance status:

5-FU–based regimens with or without oxaliplatin are preferred in the setting of biliary obstruction, but gemcitabine/cisplatin has preserved overall survival benefit if luminal obstruction is from cancer and liver function is intact. ^[39] ^[62] ^[63]

Single-agent regimens for patients with poorer performance status (ECOG score > 2):

Gemcitabine 1000 mg/m ² IV on days 1 and 8; then every 21d until progression or toxicity ^[64] or
Capecitabine 1000 mg/m ² PO twice daily for 14d; then every 21d until progression or toxicity or
5-FU 425 mg/m ² IV bolus plus folinic acid 20 mg/m ² IV; then weekly until progression or toxicity or
Docetaxel 100 mg/m ² IV; then every 21d until progression or toxicity ^[65]

Special considerations

Consider the following:

Chemotherapy should generally be reserved for patients with good performance status.
Palliative biliary drainage is often necessary in patients with advanced unresectable biliary tract carcinoma.
Percutaneous biliary drainage is usually more successful and has a lower complication rate than endoscopic stenting. ^[66]

Author

Tomislav Dragovich, MD, PhD Chief, Section of Hematology and Oncology, Banner MD Anderson Cancer Center

Tomislav Dragovich, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, SWOG

Disclosure: Nothing to disclose.

Coauthor(s)

Zachary Yeung, MD Physician, GI Medical Oncology, Banner MD Anderson Cancer Center

Zachary Yeung, MD is a member of the following medical societies: American Society of Clinical Oncology, Phi Lambda Upsilon

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee

Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

N Joseph Espat, MD, MS, FACS Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center

N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral Nutrition, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Association for Academic Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas Club, Sigma Xi, The Scientific Research Honor Society, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress, Southern Medical Association, Surgical Infection Society

Disclosure: Nothing to disclose.

Additional Contributors

Jeffrey B VanDeusen, MD, PhD Assistant Clinical Professor of Internal Medicine, Medical Director, James Cancer Network, Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center

Disclosure: Nothing to disclose.

Rumaisa Hameed, MD Fellow in Hematology/Oncology, MedStar Georgetown University Hospital

Rumaisa Hameed, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, International Society on Thrombosis and Haemostasis, Pakistan Medical and Dental Council

Disclosure: Nothing to disclose.

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