Liver cancer or hepatobiliary cancer comprises cancers that arise within the liver and its hepatocytes (hepatocellular carcinoma) and the biliary tract cancers, which include bile duct cancer/cholangiocarcinoma and gallbladder cancer.
Guidelines
Adjuvant therapy
Capecitabine monotherapy
Regimen
Preceding treatment
Chemotherapy
21-day cycle for 8 cycles
References
- BILCAP: Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans JTR, Stocken D, Praseedom R, Ma YT, Davidson B, Neoptolemos JP, Iveson T, Raftery J, Zhu S, Cunningham D, Garden OJ, Stubbs C, Valle JW, Bridgewater J; BILCAP study group. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019 Mar 25. [Epub ahead of print] Erratum in: Lancet Oncol. 2019 Apr 2. link to original article PubMed
Capecitabine & Gemcitabine
GemCap: Gemcitabine & Capecitabine
Regimen
Preceding treatment
Chemotherapy
21-day cycle for 4 cycles
Subsequent treatment
References
- SWOG S0809: Ben-Josef E, Guthrie KA, El-Khoueiry AB, Corless CL, Zalupski MM, Lowy AM, Thomas CR Jr, Alberts SR, Dawson LA, Micetich KC, Thomas MB, Siegel AB, Blanke CD. SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma. J Clin Oncol. 2015 Aug 20;33(24):2617-22. Epub 2015 May 11. link to original article link to PMC article contains verified protocol PubMed
Gemcitabine monotherapy
Regimen
Preceding treatment
Chemotherapy
28-day cycle for 6 cycles
References
- BCAT: Ebata T, Hirano S, Konishi M, Uesaka K, Tsuchiya Y, Ohtsuka M, Kaneoka Y, Yamamoto M, Ambo Y, Shimizu Y, Ozawa F, Fukutomi A, Ando M, Nimura Y, Nagino M; Bile Duct Cancer Adjuvant Trial (BCAT) Study Group. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018 Feb;105(3):192-202. link to original article PubMed
Gemcitabine, then Fluorouracil & RT, then Gemcitabine
RT: Radiation Therapy
Regimen
Note: this study was in pancreatic cancer but in practice it is extrapolated to cholangiocarcinoma. Reported efficacy is based on the 2011 update.
Preceding treatment
Chemotherapy, part 1
21-day course, followed in 1 to 2 weeks by:
Chemoradiotherapy
- Fluorouracil (5-FU) 250 mg/m2/day IV continuous infusion throughout radiation therapy
- Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.
6-week course, followed in 3 to 5 weeks by:
Chemotherapy, part 2
28-day cycle for 3 cycles
References
- RTOG 9704: Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. link to original article contains verified protocol PubMed
- Update: Regine WF, Winter KA, Abrams R, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Rich TA, Willett CG. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the US Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011 May;18(5):1319-26. Epub 2011 Mar 10. link to original article link to PMC article PubMed
GemOx
GemOx: Gemcitabine & Oxaliplatin
Regimen
Preceding treatment
Chemotherapy
14-day cycle for 12 cycles
References
- PRODIGE 12-ACCORD 18-UNICANCER GI: Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P, Joly JP, Boudjema K, Fartoux L, Bouhier-Leporrier K, Jouve JL, Faroux R, Guerin-Meyer V, Kurtz JE, Assénat E, Seitz JF, Baumgaertner I, Tougeron D, de la Fouchardière C, Lombard-Bohas C, Boucher E, Stanbury T, Louvet C, Malka D, Phelip JM. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J Clin Oncol. 2019 Mar 10;37(8):658-667. Epub 2019 Feb 1. link to original article PubMed
Observation
Regimen
No antineoplastic treatment after surgery.
Preceding treatment
References
- BCAT: Ebata T, Hirano S, Konishi M, Uesaka K, Tsuchiya Y, Ohtsuka M, Kaneoka Y, Yamamoto M, Ambo Y, Shimizu Y, Ozawa F, Fukutomi A, Ando M, Nimura Y, Nagino M; Bile Duct Cancer Adjuvant Trial (BCAT) Study Group. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018 Feb;105(3):192-202. link to original article PubMed
- PRODIGE 12-ACCORD 18-UNICANCER GI: Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P, Joly JP, Boudjema K, Fartoux L, Bouhier-Leporrier K, Jouve JL, Faroux R, Guerin-Meyer V, Kurtz JE, Assénat E, Seitz JF, Baumgaertner I, Tougeron D, de la Fouchardière C, Lombard-Bohas C, Boucher E, Stanbury T, Louvet C, Malka D, Phelip JM. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J Clin Oncol. 2019 Mar 10;37(8):658-667. Epub 2019 Feb 1. link to original article PubMed
- BILCAP: Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans JTR, Stocken D, Praseedom R, Ma YT, Davidson B, Neoptolemos JP, Iveson T, Raftery J, Zhu S, Cunningham D, Garden OJ, Stubbs C, Valle JW, Bridgewater J; BILCAP study group. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019 Mar 25. [Epub ahead of print] Erratum in: Lancet Oncol. 2019 Apr 2. link to original article PubMed
Metastatic disease, all lines of therapy
Best supportive care
Regimen
No antineoplastic treatment. Included for reference purposes only.
References
- Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK, Linné T, Svensson C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996 Aug;7(6):593-600. link to original article contains verified protocol PubMed content property of HemOnc.org
Capecitabine monotherapy
Regimen
Chemotherapy
21-day cycles
References
- Retrospective: Patt YZ, Hassan MM, Aguayo A, Nooka AK, Lozano RD, Curley SA, Vauthey JN, Ellis LM, Schnirer II, Wolff RA, Charnsangavej C, Brown TD. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004 Aug 1;101(3):578-86. link to original article PubMed
Capecitabine & Mitomycin
Regimen
Chemotherapy
Supportive medications
28-day cycles
References
- Kornek GV, Schuell B, Laengle F, Gruenberger T, Penz M, Karall K, Depisch D, Lang F, Scheithauer W. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol. 2004 Mar;15(3):478-83. link to original article contains verified protocol PubMed
Cisplatin & Gemcitabine
Regimen
Chemotherapy
Supportive medications
- Cisplatin is mixed in a solution of 1 liter of normal saline with 20 mmol potassium chloride, 8 mmol magnesium sulfate
- After cisplatin, 500 mL normal saline given over 30 minutes
21-day cycle for 4 to 8 cycles depending on response
References
- ABC-02: Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. link to original article contains verified protocol PubMed
ECF
ECF: Epirubicin, Cisplatin, Fluorouracil
Regimen
Chemotherapy
21-day cycles
References
- Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, Ross PJ, Oates J, Norman AR. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer. 2005 May 9;92(9):1650-4. link to original article contains verified protocol link to PMC article PubMed
Erlotinib & Bevacizumab
Regimen
Chemotherapy
28-day cycles
References
- Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, Philip PA, Picus J, Yong WP, Horvath L, Van Hazel G, Erlichman CE, Holen KD. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol. 2010 Jul 20;28(21):3491-7. Epub 2010 Jun 7. link to original article contains verified protocol link to PMC article PubMed
FELV
FELV: Fluorouracil , Etoposide, LeucoVorin (Folinic acid)
Variant #1, 500/120/60
Chemotherapy
21-day cycles
Variant #2, 600/120/60
Chemotherapy
21-day cycles
References
- Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK, Linné T, Svensson C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996 Aug;7(6):593-600. link to original article contains verified protocol PubMed content property of HemOnc.org
- Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, Ross PJ, Oates J, Norman AR. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer. 2005 May 9;92(9):1650-4. link to original article contains verified protocol link to PMC article PubMed
Fluorouracil & Folinic acid
FUFA: 5-FU (Fluorouracil) & Folinic Acid
Regimen
Chemotherapy
14-day cycles
References
- Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK, Linné T, Svensson C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996 Aug;7(6):593-600. link to original article contains verified protocol PubMed
Fluorouracil, Folinic acid, Gemcitabine
Regimen
Chemotherapy
21-day cycles
References
- Gebbia V, Giuliani F, Maiello E, Colucci G, Verderame F, Borsellino N, Mauceri G, Caruso M, Tirrito ML, Valdesi M. Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. J Clin Oncol. 2001 Oct 15;19(20):4089-91. link to original article contains verified protocol PubMed
Gemcitabine monotherapy
Variant #1
Chemotherapy
28-day cycle for 3 to 6 cycles depending on response
Variant #2
Chemotherapy
30-day cycles
References
- Gebbia V, Giuliani F, Maiello E, Colucci G, Verderame F, Borsellino N, Mauceri G, Caruso M, Tirrito ML, Valdesi M. Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. J Clin Oncol. 2001 Oct 15;19(20):4089-91. link to original article contains verified protocol PubMed
- ABC-02: Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. link to original article contains verified protocol PubMed
Gemcitabine, Cisplatin, S-1
GCS: Gemcitabine, Cisplatin, S-1
Regimen
Chemotherapy
14-day cycles
References
- Abstract: Sakai D, Kanai M , Kobayashi S, Eguchi H, Baba H, Seo S, Taketomi A, Takayama T, Yamaue H, Ishioka C, Sho M, Takeyama Y, Fujimoto J, Toyoda M, Shimizu J, Goto T, Yoshimura K, Hatano E, Nagano H, Ioka T. Randomized phase III study of gemcitabine, cisplatin plus S-1 (GCS) versus gemcitabine, cisplatin (GC) for advanced biliary tract cancer (KHBO1401-MITSUBA). Annals of Oncology 29 (Supplement 8): viii205–viii270, 2018 link to abstract
Gemcitabine & Mitomycin
Regimen
Chemotherapy
Supportive medications
28-day cycles
References
- Kornek GV, Schuell B, Laengle F, Gruenberger T, Penz M, Karall K, Depisch D, Lang F, Scheithauer W. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol. 2004 Mar;15(3):478-83. link to original article contains verified protocol PubMed
Gemcitabine & nab-Paclitaxel
NG: Nab-Paclitaxel & Gemcitabine
Regimen
Note: this regimen was intended for ECOG PS 0 to 2, and Child-Pugh score less than 8.
Chemotherapy
28-day cycles
References
- Sahai V, Catalano PJ, Zalupski MM, Lubner SJ, Menge MR, Nimeiri HS, Munshi HG, Benson AB 3rd, O'Dwyer PJ. Nab-Paclitaxel and Gemcitabine as First-line Treatment of Advanced or Metastatic Cholangiocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):1707-1712. link to original article contains protocol PubMed
Gemcitabine, Cisplatin, nab-Paclitaxel
Regimen
Study
|
Evidence
|
Shroff et al. 2019
|
Phase II
|
Prolonged median PFS and OS vs reported for historical controls treated with gemcitabine-cisplatin alone.
21-day cycle
References
- Shross RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff RA, Raghav KPS, Iwasaki M, Masci P, Ramanathan RK, Ahn DH, Bekaii-Saab T, Borad MJ. Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial. JAMA Oncol. 2019 Apr. PMID: 30998813. DOI: 10.1001/jamaoncol.2019.0270.
GemOx
Gemcitabine & Oxaliplatin for biliary tract cancer
GEMOX-B
GEMOX-B: GEMcitabine, OXaliplatin, Bevacizumab
Regimen
Chemotherapy
28-day cycles
References
- MGH 05-349: Zhu AX, Meyerhardt JA, Blaszkowsky LS, Kambadakone AR, Muzikansky A, Zheng H, Clark JW, Abrams TA, Chan JA, Enzinger PC, Bhargava P, Kwak EL, Allen JN, Jain SR, Stuart K, Horgan K, Sheehan S, Fuchs CS, Ryan DP, Sahani DV. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol. 2010 Jan;11(1):48-54. Epub 2009 Nov 20. link to original article contains verified protocol PubMed
Gemcitabine, Cisplatin, nab-Paclitaxel
Regimen
Study
|
Evidence
|
Shroff et al. 2019
|
Phase II
|
References
- Weijing S, Patel A, Normolle A, Patel K, Ohr J, Lee JJ, Bahary N, Chu E, Streeter N, Drummond S. A phase 2 trial of regorafenib as a single agent in patients with chemotherapy‐refractory, advanced, and metastatic biliary tract adenocarcinoma. Cancer. 2019 Mar. 125(6):902-909. PMID: 30561756. DOI: 10.1002/cncr.31872.
Pembrolizumab monotherapy
Regimen
Note: KEYNOTE-016 was an expansion to a CRC-specific trial.
Immunotherapy
14-day cycle for up to 2 years
References
- KEYNOTE-016: Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. Epub 2017 Jun 8. link to original article link to PMC article contains verified protocol in supplement PubMed