Gallbladder cancer

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Ari Seifter, MD
University of Illinois at Chicago
Chicago, IL
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Neeta K. Venepalli, MD, MBA
University of Illinois at Chicago
Chicago, IL
17 regimens on this page
22 variants on this page

Note: there is some overlap, especially in the earlier literature, between treatment regimens for gallbladder cancer and those for pancreatic adenocarcinoma, periampullary adenocarcinoma, and cholangiocarcinoma; please see those pages for additional regimens.

Contents


Guidelines

ESMO

NCCN

Adjuvant therapy

Capecitabine monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Primrose et al. 2019 (BILCAP) 2006-2014 Phase III (E-esc) Observation Might have superior OS

79 of 447 enrolled patients (17.7%) had primary gallbladder cancer. Note: Chemotherapy start date 8-16 weeks after surgery.

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles

References

  1. 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 May;20(5):663-673. Epub 2019 Mar 25. Erratum in: Lancet Oncol. 2019 Apr 2. link to original article PubMed

Capecitabine & Gemcitabine

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GemCap: Gemcitabine & Capecitabine

Regimen

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

25 of 79 enrolled patients (32%) had primary gallbladder cancer.

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

GemOx

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GemOx: Gemcitabine & Oxaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Edeline et al. 2019 (PRODIGE 12-ACCORD 18-UNICANCER GI) 2009-2014 Phase III (E-esc) Observation Did not meet primary endpoint of RFS

38 of 194 enrolled patients (20%) had primary gallbladder cancer.

Preceding treatment

Chemotherapy

14-day cycle for 12 cycles

References

  1. 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

Metastatic or unresectable disease, all lines of therapy

Capecitabine monotherapy

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Regimen

Study Evidence
Patt et al. 2004 Retrospective

3 of 37 patients (8%) had primary gallbladder cancer.

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 Years of enrollment Evidence Comparator Comparative Efficacy
Kornek et al. 2004 2000-2001 Randomized Phase II (E-switch-ic) Gemcitabine & Mitomycin Might have superior ORR

14 of 51 enrolled patients (27%) had primary gallbladder cancer.

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

CapeOx

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CapeOx: Capecitabine & Oxaliplatin
XELOX: XELoda (Capecitabine) & OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kim et al. 2019 (SMC 2011-05-070) 2011-2016 Phase III (E-switch-ic) GEMOX Non-inferior PFS

61 of 222 enrolled patients (22%) had primary gallbladder cancer.

Chemotherapy

21-day cycle for 8 cycles

References

  1. SMC 2011-05-070: Kim ST, Kang JH, Lee J, Lee HW, Oh SY, Jang JS, Lee MA, Sohn BS, Yoon SY, Choi HJ, Hong JH, Kim MJ, Kim S, Park YS, Park JO, Lim HY. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial. Ann Oncol. 2019 May 1;30(5):788-795. link to original article contains protocol PubMed

Cisplatin & Gemcitabine

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GC: Gemcitabine & Cisplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Valle et al. 2010 (ABC-02) 2002-2008 Phase III (E-esc) Gemcitabine Superior OS
Sharma et al. 2019 2011-2015 Phase III (C) mGemOx Inconclusive whether non-inferior OS
Morizane et al. 2019 (FUGA-BT) 2013-2016 Phase III (C) Gemcitabine & S-1 Seems to have non-inferior OS

In ABC-02, 149 of 410 enrolled patients (36%) had primary gallbladder cancer.

In FUGA-BT, 137 of 354 enrolled patients (39%) had primary gallbladder cancer.

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
  2. FUGA-BT: Morizane C, Okusaka T, Mizusawa J, Katayama H, Ueno M, Ikeda M, Ozaka M, Okano N, Sugimori K, Fukutomi A, Hara H, Mizuno N, Yanagimoto H, Wada K, Tobimatsu K, Yane K, Nakamori S, Yamaguchi H, Asagi A, Yukisawa S, Kojima Y, Kawabe K, Kawamoto Y, Sugimoto R, Iwai T, Nakamura K, Miyakawa H, Yamashita T, Hosokawa A, Ioka T, Kato N, Shioji K, Shimizu K, Nakagohri T, Kamata K, Ishii H, Furuse J. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann Oncol. 2019 Dec 1;30(12):1950-1958. link to original article PubMed
  3. Sharma A, Kalyan Mohanti B, Pal Chaudhary S, Sreenivas V, Kumar Sahoo R, Kumar Shukla N, Thulkar S, Pal S, Deo SV, Pathy S, Ranjan Dash N, Kumar S, Bhatnagar S, Kumar R, Mishra S, Sahni P, Iyer VK, Raina V. Modified gemcitabine and oxaliplatin or gemcitabine + cisplatin in unresectable gallbladder cancer: Results of a phase III randomised controlled trial. Eur J Cancer. 2019 Dec;123:162-170. Epub 2019 Nov 14. link to original article contains verified protocol PubMed CTRI/2010/091/001406

Cisplatin, Gemcitabine, nab-Paclitaxel

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Regimen

Study Evidence
Shroff et al. 2019 (MDACC 2014-0524) Phase II

Prolonged median PFS and OS vs reported for historical controls treated with gemcitabine-cisplatin alone.

13 of 60 patients (22%) had primary gallbladder cancer.

Chemotherapy

21-day cycle

References

  1. MDACC 2014-0524: Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff RA, Raghav KPS, Iwasaki M, Masci P, Ramanathan RK, Ahn DH, Bekaii-Saab TS, Borad MJ. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019 Apr 18. [Epub ahead of print] link to original article PubMed


ECF

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ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rao et al. 2005 1997-2003 Phase III (E-switch-ic) FELV Did not meet primary endpoint of OS

26 of 114 enrolled patients (23%) had primary gallbladder cancer.

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

10 of 54 patients (19%) included in endpoint analysis had primary gallbladder cancer.

Targeted therapy

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)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rao et al. 2005 1997-2003 Phase III (C) ECF Did not meet primary endpoint of OS

26 of 54 enrolled patients (48%) had primary gallbladder cancer.

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


FULV & Gemcitabine

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FULV & Gemcitabine: 5-FU, LeucoVorin (Folinic acid), Gemcitabine

Regimen

Study Evidence
Gebbia et al. 2001 Phase II

22 of 40 enrolled patients (55%) had primary gallbladder cancer.

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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Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Valle et al. 2010 (ABC-02) 2002-2008 Phase III (E-de-esc) Cisplatin & Gemcitabine Inferior OS

149 of 410 enrolled patients (36%) had primary gallbladder cancer.

Chemotherapy

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

Regimen variant #2

Study Evidence
Gebbia et al. 2001 Phase II

22 of 40 enrolled patients (55%) had primary gallbladder cancer.

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, Cisplatin, S-1

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GCS: Gemcitabine, Cisplatin, S-1

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sakai et al. 2018 (KHBO1401-MITSUBA) 2014-NR Phase III (E-esc) Cisplatin & Gemcitabine Seems to have superior OS

Although patients with primary gallbladder cancer met eligibility criteria, the relative number of patients enrolled was not reported in the presented abstract.

Chemotherapy

14-day cycles

References

  1. 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

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kornek et al. 2004 2000-2001 Randomized Phase II (E-switch-ic) Capecitabine & Mitomycin Might have inferior ORR

14 of 51 enrolled patients (27%) had primary gallbladder cancer.

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 & S-1

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GS: Gemcitabine & S-1

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Morizane et al. 2019 (FUGA-BT) 2013-2016 Phase III (E-switch-ic) Gemcitabine & Cisplatin Seems to have non-inferior OS

137 of 354 enrolled patients (39%) had primary gallbladder cancer.

Chemotherapy

References

  1. FUGA-BT: Morizane C, Okusaka T, Mizusawa J, Katayama H, Ueno M, Ikeda M, Ozaka M, Okano N, Sugimori K, Fukutomi A, Hara H, Mizuno N, Yanagimoto H, Wada K, Tobimatsu K, Yane K, Nakamori S, Yamaguchi H, Asagi A, Yukisawa S, Kojima Y, Kawabe K, Kawamoto Y, Sugimoto R, Iwai T, Nakamura K, Miyakawa H, Yamashita T, Hosokawa A, Ioka T, Kato N, Shioji K, Shimizu K, Nakagohri T, Kamata K, Ishii H, Furuse J. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann Oncol. 2019 Dec 1;30(12):1950-1958. link to original article PubMed

GemOx

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GemOx: Gemcitabine & Oxaliplatin
mGEMOX: modified GEMcitabine & OXaliplatin

Regimen variant #1, 900/80 ("mGEMOX")

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sharma et al. 2010 2006-2008 Randomized (E-esc) 1. Best supportive care Seems to have superior OS
2. FUFA Not reported
Sharma et al. 2019 2011-2015 Phase III (C) CisGem Inconclusive whether non-inferior OS

All patients enrolled in these studies had primary gallbladder cancer

Chemotherapy

21-day cycle for up to 6 cycles

Regimen variant #2, 1000/100, bi-weekly

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lee et al. 2011 (SMC 2008-12-024) 2009-2010 Phase III (C) E-GEMOX Might have inferior PFS

82 of 268 enrolled patients (31%) had primary gallbladder cancer

Chemotherapy

14-day cycles

Regimen variant #3, 1000/100, 2 weeks out of 3

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kim et al. 2019 (SMC 2011-05-070) 2011-2016 Phase III (C) XELOX Non-inferior PFS

61 of 222 enrolled patients (22%) had primary gallbladder cancer.

Chemotherapy

21-day cycle for 8 cycles

Regimen variant #4, 1000/85, bi-weekly

Study Evidence Efficacy
Halim et al. 2011 Phase II ORR: 27.5%

14 of 40 enrolled patients (35%) had primary gallbladder cancer

Chemotherapy

14-day cycles

Regimen variant #5, 1000/100 ("GEMOX-3")

Study Evidence Efficacy
Harder et al. 2006 Phase II ORR: 26% (95% CI 14–44)

GEMOX-3: GEMcitabine & OXaliplatin, 3 visits per month

10 of 31 enrolled patients (32%) had primary gallbladder cancer.

Chemotherapy

28-day cycles

References

  1. Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, Raina V, Shukla NK, Thulkar S, Garg P, Chaudhary SP. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol. 2010 Oct 20;28(30):4581-6. Epub 2010 Sep 20. link to original article contains protocol PubMed
  2. SMC 2008-12-024: Lee J, Park SH, Chang HM, Kim JS, Choi HJ, Lee MA, Jang JS, Jeung HC, Kang JH, Lee HW, Shin DB, Kang HJ, Sun JM, Park JO, Park YS, Kang WK, Lim HY. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012 Feb;13(2):181-8. Epub 2011 Dec 20. link to original article contains protocol PubMed
  3. SMC 2011-05-070: Kim ST, Kang JH, Lee J, Lee HW, Oh SY, Jang JS, Lee MA, Sohn BS, Yoon SY, Choi HJ, Hong JH, Kim MJ, Kim S, Park YS, Park JO, Lim HY. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial. Ann Oncol. 2019 May 1;30(5):788-795. link to original article contains protocol PubMed
  4. Halim A, Ebrahim MA, Saleh Y. A phase II study of outpatient biweekly gemcitabine-oxaliplatin in advanced biliary tract carcinomas. Jpn J Clin Oncol. 2011 Feb;41(2):217-24. link to original article contains verified protocol PubMed
  5. Harder J, Riecken B, Kummer O, Lohrmann C, Otto F, Usadel H, Geissler M, Opitz O, Henss H. Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer. 2006 Oct 9;95(7):848-52. link to PMC article contains verified protocol PubMed
  6. Sharma A, Kalyan Mohanti B, Pal Chaudhary S, Sreenivas V, Kumar Sahoo R, Kumar Shukla N, Thulkar S, Pal S, Deo SV, Pathy S, Ranjan Dash N, Kumar S, Bhatnagar S, Kumar R, Mishra S, Sahni P, Iyer VK, Raina V. Modified gemcitabine and oxaliplatin or gemcitabine + cisplatin in unresectable gallbladder cancer: Results of a phase III randomised controlled trial. Eur J Cancer. 2019 Dec;123:162-170. Epub 2019 Nov 14. link to original article contains verified protocol PubMed CTRI/2010/091/001406

GEMOX-B

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GEMOX-B: GEMcitabine, OXaliplatin, Bevacizumab

Regimen

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

10 of 35 enrolled patients (29%) had primary gallbladder cancer.

Chemotherapy

Targeted therapy

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

Regorafenib monotherapy

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Regimen

Study Evidence
Sun et al. 2019 Phase II

Only studied in patients with advanced biliary cancer who failed at least 1 line of systemic therapy.

5 of 43 enrolled patients (12%) had primary gallbladder cancer.

Targeted therapy

28-day cycles

References

  1. Sun W, 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 15;125(6):902-909. Epub 2018 Dec 18. link to original article link to PMC article PubMed