Cholangiocarcinoma

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 Candice Schwartz, MD
University of Illinois at Chicago
Chicago, IL
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 Neeta K. Venepalli, MD, MBA
University of Illinois at Chicago
Chicago, IL
29 regimens on this page
35 variants on this page


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

ESMO

NCCN

Adjuvant therapy

Capecitabine & Gemcitabine

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GemCap: Gemcitabine & Capecitabine

Regimen

Study Evidence
Ben-Josef et al. 2015 (SWOG S0809) Phase II

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

  • Capecitabine & RT

References

  1. 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, then Fluorouracil & RT, then Gemcitabine

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Regine et al. 2008 (RTOG 9704) Phase III (E) Fluorouracil & RT Seems not superior (*)

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

  1. 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
    1. 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

Gemcitabine and Oxaliplatin

Regimen

Study Evidence Comparator Efficacy
Edeline et al. (PRODIGE 12-ACCORD 18-UNICANCER GI) Phase III (C) Observation Inferior RFS

Chemotherapy

·        Gemcitabine 1,000 mg/m2 on day 1

·        Oxaliplatin 85 mg/m2 infused on day 2

2-week cycle for 12 cycles

Preceding treatment

·        Surgical resection with macroscopically curative resection

References

  1. PRODIGE 12-ACCORD 18-UNICANCER GI: Edeline, J, Benabdelghani M, Bertaut , Watelet J, Hammel P, Joly JP, Boudjema K, Fartoux L,  Bouhier-Leporrier K, Jouve JL, Faroux R, Guerin-Meyer V, Kurtz JE, Assenat E, François Seitz JF, Baumgaertner I, Tougeron D, de la Fouchardiere C, Lombard-Bohas 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. Journal of Clinical Oncology.  2019 Feb 1. 37 (8):658-667. https://doi. org/10.1200/JCO.18. 00050.

Capecitabine

Regimen

Study Evidence Comparator Efficacy
Primrose et al (BILCAP) Phase III (E) Observation Superior OS

Chemotherapy

·        Capecitabine (Xeloda) 1250 mg/m² twice daily on days 1–14

21-day cycles x 8 cycles

Preceding treatment

·        Surgical resection with macroscopically curative resection

References

  1. BILCAP: Primrose JN, Fox RP, Palmer DH, Malik HZ, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wason H, Ross P, Wall L, Wadsley J, Evans JTR, Stocken D, Praseedom R, Ma TY, Davidson B, Neoptolemos JP, Iveson T, Raftery J, Zhu S, Cunningham D, Garden OJ, Stubbs C, Valle JW, Bridgewater J. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre,phase 3 study. Lancet. 2019 Mar 25. http://dx.doi.org/10.1016/ S1470-2045(18)30915-X

Gemcitabine

Regimen

Study Evidence Comparator Efficacy
Ebata et al. 2018 (BCAT) Phase III (C) Observation Seems not superior

Chemotherapy

·        Gemcitabine 1000 mg/m2, administered on days 1, 8 and 15

Every 28 days for six cycles

Preceding treatment[edit | edit source]

·        Surgical resection with macroscopically curative resection

References

1.    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. DOI: 10.1002/bjs.10776

Observation

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Regimen

Study Evidence Comparator Efficacy
Ebata et al. 2018 (BCAT) Phase III (C) Gemcitabine Seems not superior

No antineoplastic treatment after surgery.

Preceding treatment

References

  1. 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

Metastatic disease, all lines of therapy

Best supportive care

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Regimen

Study Evidence Comparator Efficacy
Glimelius et al. 1996 Phase III (C) 1. FELV Inferior OS
2. Fluorouracil & Folinic acid Inferior OS

No antineoplastic treatment. Included for reference purposes only.

References

  1. 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

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Regimen

Study Evidence
Patt et al. 2004 Retrospective

Chemotherapy

21-day cycles

References

  1. 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

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Regimen

Study Evidence Comparator Efficacy
Kornek et al. 2004 Randomized Phase II (E) Gemcitabine & Mitomycin Might have superior ORR

Chemotherapy

Supportive medications

28-day cycles

References

  1. 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

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Regimen

Study Evidence Comparator Efficacy
Valle et al. 2010 (ABC-02) Phase III (E) Gemcitabine Superior OS

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

  1. 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

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study Evidence Comparator Efficacy
Rao et al. 2005 Phase III (E) FELV Seems not superior

Chemotherapy

21-day cycles

References

  1. 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

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Regimen

Study Evidence
Lubner et al. 2010 Phase II

Chemotherapy

28-day cycles

References

  1. 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

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FELV: Fluorouracil , Etoposide, LeucoVorin (Folinic acid)

Variant #1, 500/120/60

Study Evidence Comparator Efficacy
Glimelius et al. 1996 Phase III (E) Best supportive care Superior OS

Chemotherapy

21-day cycles

Variant #2, 600/120/60

Study Evidence Comparator Efficacy
Rao et al. 2005 Phase III (C) ECF Seems not superior

Chemotherapy

21-day cycles

References

  1. 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
  2. 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

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FUFA: 5-FU (Fluorouracil) & Folinic Acid

Regimen

Study Evidence Comparator Efficacy
Glimelius et al. 1996 Phase III (E) Best supportive care Superior OS

Chemotherapy

14-day cycles

References

  1. 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

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Regimen

Study Evidence
Gebbia et al. 2001 Phase II

Chemotherapy

21-day cycles

References

  1. 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

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Variant #1

Study Evidence Comparator Efficacy
Valle et al. 2010 (ABC-02) Phase III (E) Cisplatin & Gemcitabine Inferior OS

Chemotherapy

28-day cycle for 3 to 6 cycles depending on response

Variant #2

Study Evidence
Gebbia et al. 2001 Phase II

Chemotherapy

30-day cycles

References

  1. 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
  2. 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 & Mitomycin

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Regimen

Study Evidence Comparator Efficacy
Kornek et al. 2004 Randomized Phase II (E) Capecitabine & Mitomycin Might have inferior ORR

Chemotherapy

Supportive medications

28-day cycles

References

  1. 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

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NG: Nab-Paclitaxel & Gemcitabine

Regimen

Study Evidence
Sahai et al. 2018 Phase II

Note: this regimen was intended for ECOG PS 0 to 2, and Child-Pugh score less than 8.

Chemotherapy

28-day cycles

References

  1. 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

GemOx

Gemcitabine & Oxaliplatin for biliary tract cancer

GEMOX-B

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GEMOX-B: GEMcitabine, OXaliplatin, Bevacizumab

Regimen

Study Evidence
Zhu et al. 2009 (MGH 05-349) Phase II

Chemotherapy

28-day cycles

References

  1. 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

Pembrolizumab monotherapy

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Regimen

Study Evidence
Le et al. 2017 (KEYNOTE-016) Phase II, <20 pts of this subtype

Note: KEYNOTE-016 was an expansion to a CRC-specific trial.

Immunotherapy

14-day cycle for up to 2 years

References

  1. 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

BGJ (FGFR kinase inhibitor)

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Regimen

Study Evidence
Jayne et al Phase II

Note: studied in advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy

Targeted therapy

·        BGJ398 125 mg once daily for 21 days, then 7 days off 

28 day cycle

References

  1. Javle M, Lowery M, Shroff RT, Heinz Weiss K, Springfeld C, Borad MJ, Ramanathan RK, Goyal L, Sadeghi S, Macarulla T, El-Khoueiry A, Kelley RK, Borbath I,  Choo SP, Oh DY, Philip PA, Chen LT, Reungwetwattana T, Cutsem EV, Yeh KH, Ciombor K, Finn RS, Patel A, Sen S, Porter D, Isaacs R,  Zhu AX,  Abou-Alfa GK, Bekaii-Saab, TB. Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma. 2018 Jan 20. 36 (2); 276-282. DOI: https://doi.org/10.1200/JCO.2017. 75.5009. 

Gemcitabine, Cisplatin, S-1

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Regimen

Study Evidence Comparator Efficacy
Sakai et al (KHBO1401-MITSUBA) Phase III Gemcitabine and Cisplatin Seems to have superior OS

 Chemotherapy

·        Gemcitabine 1,000 mg/m2 IV on day 1

·        Cisplatin 25 mg/m2 IV on day 1

·        S-1 80 mg/m2 PO on days 1-7

Every 2 weeks

References

  1. 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 doi:10.1093/annonc/mdy282. 
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