Gallbladder cancer

Page editor		Section editor
	Emily Mann, MD Boston University Boston, MA, USA		Eric I. Marks, MD Boston University Boston, MA, USA

21 regimens on this page 26 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.
Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO

• 2022: Vogel et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up PubMed

• 2016: Valle et al. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Biliary Tract Cancers.

Adjuvant therapy

Capecitabine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Primrose et al. 2019 (BILCAP)	2006-2014	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of OS1 Median OS: 49.6 vs 36.1 mo (aHR 0.84, 95% CI 0.67-1.06)

¹Reported efficacy is based on the 2022 update.
79 of 447 enrolled patients (17.7%) had primary gallbladder cancer. Note: Chemotherapy start date 8-16 weeks after surgery.

Preceding treatment

• Surgical resection with macroscopically curative resection

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycle for 8 cycles

References

1. BILCAP: Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthoney 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 NCT00363584
   1. Update: Bridgewater J, Fletcher P, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthoney A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans TR, Stocken D, Stubbs C, Praseedom R, Ma YT, Davidson B, Neoptolemos J, Iveson T, Cunningham D, Garden OJ, Valle JW, Primrose J; BILCAP study group. Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study. J Clin Oncol. 2022 Jun 20;40(18):2048-2057. Epub 2022 Mar 22. link to original article PubMed

Capecitabine & Gemcitabine

GemCap: Gemcitabine & Capecitabine

Regimen

Study	Dates of enrollment	Evidence
Ben-Josef et al. 2015 (SWOG S0809)	2008-2012	Phase 2

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

Preceding treatment

• Surgical resection

Chemotherapy

• Capecitabine (Xeloda) 750 mg/m² PO twice per day on days 1 to 14
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Subsequent treatment

• Adjuvant 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 dosing details in manuscript PubMed NCT00789958

Capecitabine & RT

Regimen

Study	Dates of enrollment	Evidence
Ben-Josef et al. 2015 (SWOG S0809)	2008-2012	Phase 2

Preceding treatment

• Adjuvant GemCap x 4

Chemotherapy

• Capecitabine (Xeloda) 665 mg/m² PO twice per day on days 1 to 14

Radiotherapy

• Concurrent radiation therapy 5400 cGy in 30 fractions, given 5 times per week

40-day course

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 dosing details in manuscript PubMed NCT00789958

GemOx

GemOx: Gemcitabine & Oxaliplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Edeline et al. 2019 (PRODIGE 12-ACCORD 18-UNICANCER GI)	2009-2014	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of RFS

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

Preceding treatment

• Surgical resection with macroscopically curative resection

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 2

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 NCT01313377

S-1 monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Nakachi et al 2023 (ASCOT)	2013-09-09 to 2018-06-22	Phase 3 (E-esc)	Observation	Superior OS (primary endpoint) OS36: 77.1% vs 67.6% (HR 0.69, 95% CI 0.51-0.94)

Preceding treatment

• Surgical resection

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
  • Less than 1.25 m²: 40 mg PO twice per day on days 1 to 28
  • 1.25 m² up to 1.5 m²: 50 mg PO twice per day on days 1 to 28
  • 1.5 m² or more: 60 mg PO twice per day on days 1 to 28

42-day cycle for up to 4 cycles

References

1. ASCOT: Nakachi K, Ikeda M, Konishi M, Nomura S, Katayama H, Kataoka T, Todaka A, Yanagimoto H, Morinaga S, Kobayashi S, Shimada K, Takahashi Y, Nakagohri T, Gotoh K, Kamata K, Shimizu Y, Ueno M, Ishii H, Okusaka T, Furuse J; Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group (JCOG-HBPOG). Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. 2023 Jan 21;401(10372):195-203. PMID: 36681415. link to original article contains dosing details in abstract PubMed UMIN000011688

Metastatic or unresectable disease, all lines of therapy

Capecitabine monotherapy

Regimen

Study	Evidence
Patt et al. 2004	Retrospective

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

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

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

CAPIRI

CAPIRI: CAPecitabine & IRInotecan

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ramaswami et al. 2020 (GB-SELECT)	2018-2020	Randomized Phase 2 (E-esc)	Irinotecan	Did not meet primary endpoint of OS6

Prior treatment criteria

• Progression after prior gemcitabine-based chemotherapy

Chemotherapy

• Capecitabine (Xeloda) 1700 mg/m²/day PO on days 1 to 14
• Irinotecan (Camptosar) 200 mg/m² IV bolus once on day 1

21-day cycles

References

1. GB-SELECT: Ramaswamy A, Ostwal V, Sharma A, Bhargava P, Srinivas S, Goel M, Patkar S, Mandavkar S, Jadhav P, Parulekar M, Choudhari A, Gupta S. Efficacy of Capecitabine Plus Irinotecan vs Irinotecan Monotherapy as Second-line Treatment in Patients With Advanced Gallbladder Cancer: A Multicenter Phase 2 Randomized Clinical Trial (GB-SELECT). JAMA Oncol. 2021 Mar 1;7(3):436-439. Epub 2020 Dec 3. link to original article contains dosing details in manuscript link to PMC article PubMed CTRI/2017/10/010112

Capecitabine & Mitomycin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kornek et al. 2004	2000-2001	Randomized Phase 2 (E-switch-ic)	Gemcitabine & Mitomycin	Might have superior ORR (primary endpoint)

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

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
• Mitomycin (Mutamycin) 8 mg/m² IV bolus once on day 1

Supportive therapy

• Dexamethasone (Decadron) and 5-HT3 antagonists on the day of IV chemotherapy

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 dosing details in manuscript PubMed

CapeOx

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kim et al. 2019 (SMC 2011-05-070)	2011-2016	Phase 3 (E-switch-ic)	GEMOX	Non-inferior PFS6 PFS6: 46.7% vs 44.5%

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

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

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 dosing details in abstract PubMed NCT01470443

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Valle et al. 2010 (ABC-02)	2002-2008	Phase 3 (E-esc)	Gemcitabine	Superior OS (primary endpoint)
Sharma et al. 2019	2011-2015	Phase 3 (E-switch-ic)	mGemOx	Inconclusive whether non-inferior OS
Morizane et al. 2019 (FUGA-BT)	2013-2016	Phase 3 (C)	Gemcitabine & S-1	Seems to have non-inferior OS

Note: 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

• Cisplatin (Platinol) 25 mg/m² IV over 60 minutes once per day on days 1 & 8, given first
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 8, given second

Supportive therapy

• 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 dosing details in manuscript PubMed NCT00262769
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; JCOG. 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 UMIN000010667
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 dosing details in manuscript PubMed CTRI/2010/091/001406

Cisplatin & Gemcitabine (GC) & nab-Paclitaxel

Regimen

Study	Dates of enrollment	Evidence
Shroff et al. 2019 (MDACC 2014-0524)	2015-2017	Phase 2

Note: 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

• Cisplatin (Platinol) 25 mg/m² IV over 60 minutes once per day on days 1 & 8
• Gemcitabine (Gemzar) 800 mg/m² IV once per day on days 1 & 8
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1 & 8

21-day cycles

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 Jun 1;5(6):824-830. Epub 2019 Apr 18. link to original article link to PMC article contains dosing details in abstract PubMed NCT02392637

ECF

ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rao et al. 2005	1997-2003	Phase 3 (E-switch-ic)	FELV	Did not meet primary endpoint of OS

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

Chemotherapy

• Epirubicin (Ellence) 50 mg/m² IV once on day 1
• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Fluorouracil (5-FU) 200 mg/m²/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m²)

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 dosing details in manuscript link to PMC article PubMed

Erlotinib & Bevacizumab

Regimen

Study	Dates of enrollment	Evidence
Lubner et al. 2010 (MC044G)	2006-08 to 2008-04	Phase 2

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

Targeted therapy

• Erlotinib (Tarceva) 150 mg PO once per day on days 1 to 28
• Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1 & 15

28-day cycles

References

1. MC044G: 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 dosing details in manuscript link to PMC article PubMed NCT00356889

FELV

FELV: Fluorouracil , Etoposide, LeucoVorin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rao et al. 2005	1997-2003	Phase 3 (C)	ECF	Did not meet primary endpoint of OS

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

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m² IV bolus once per day on days 1 to 3, given first
• Etoposide (Vepesid) 120 mg/m² IV over 40 minutes once per day on days 1 to 3, given second
• Leucovorin (Folinic acid) 60 mg/m² IV bolus once per day on days 1 to 3, given third

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 dosing details in manuscript link to PMC article PubMed

FULV & Gemcitabine

FULV & Gemcitabine: 5-FU, LeucoVorin, Gemcitabine

Regimen

Study	Evidence
Gebbia et al. 2001	Phase 2

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

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 600 mg/m² IV continuous infusion over 22 hours (total dose per cycle: 1000 mg/m²)
• Leucovorin (Folinic acid) 100 mg/m² IV over 2 hours once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

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 dosing details in manuscript PubMed

Gemcitabine monotherapy

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Valle et al. 2010 (ABC-02)	2002-2008	Phase 3 (C)	GC	Inferior OS

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

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

Regimen variant #2

Study	Evidence
Gebbia et al. 2001	Phase 2

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15

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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00262769

Gemcitabine, Cisplatin, S-1

GCS: Gemcitabine, Cisplatin, S-1

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ioka et al. 2022 (KHBO1401-MITSUBA)	2014-2016	Phase 3 (E-esc)	Cisplatin & Gemcitabine	Might have superior OS (primary endpoint) Median OS: 13.5 vs 12.6 mo (HR 0.79, 90% CI 0.63-0.996)

Note: Approximately 1/3 of the patients enrolled had gallbladder cancer.

Chemotherapy

• Cisplatin (Platinol) 25 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once on day 1
• Tegafur, gimeracil, oteracil (S-1) 80 mg/m² PO once per day on days 1 to 7

14-day cycles

References

1. KHBO1401-MITSUBA: Ioka T, Kanai M, Kobayashi S, Sakai D, Eguchi H, Baba H, Seo S, Taketomi A, Takayama T, Yamaue H, Takahashi M, Sho M, Kamei K, Fujimoto J, Toyoda M, Shimizu J, Goto T, Shindo Y, Yoshimura K, Hatano E, Nagano H; Kansai Hepatobiliary Oncology Group (KHBO). Randomized phase III study of gemcitabine, cisplatin plus S-1 versus gemcitabine, cisplatin for advanced biliary tract cancer (KHBO1401- MITSUBA). J Hepatobiliary Pancreat Sci. 2023 Jan;30(1):102-110. Epub 2022 Aug 9. link to original article contains dosing details in abstract link to PMC article PubMed NCT02182778

Gemcitabine & Mitomycin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kornek et al. 2004	2000-2001	Randomized Phase 2 (E-switch-ic)	Capecitabine & Mitomycin	Might have inferior ORR (primary endpoint)

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

Chemotherapy

• Gemcitabine (Gemzar) 2000 mg/m² IV over 30 minutes once per day on days 1 & 15
• Mitomycin (Mutamycin) 8 mg/m² IV bolus once on day 1

Supportive therapy

• Dexamethasone (Decadron) and 5-HT3 antagonists on the day of IV chemotherapy

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 dosing details in manuscript PubMed

Gemcitabine & S-1

GS: Gemcitabine & S-1

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Morizane et al. 2019 (FUGA-BT)	2013-2016	Phase 3 (E-switch-ic)	Gemcitabine & Cisplatin	Seems to have non-inferior OS (primary endpoint) Median OS: 15.1 vs 13.4 mo (HR 0.945, 90% CI 0.78-1.15)

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
  • Less than 1.25 m²: 30 mg PO twice per day on days 1 to 14
  • 1.25 m² up to 1.5 m²: 40 mg PO twice per day on days 1 to 14
  • 1.5 m² or more: 50 mg PO twice per day on days 1 to 14

21-day cycles

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; JCOG. 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 contains dosing details in manuscript PubMed UMIN000010667

GemOx

GemOx: Gemcitabine & Oxaliplatin
mGEMOX: modified GEMcitabine & OXaliplatin

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sharma et al. 2010	2006-2008	Randomized (E-esc)	1. Best supportive care	Superior OS (co-primary endpoint) Median OS: 9.5 vs 4.5 mo (HR 0.44, 95% CI 0.22-0.86)
			2. FUFA	Not reported
Sharma et al. 2019	2011-2015	Phase 3 (E-switch-ic)	CisGem	Inconclusive whether non-inferior OS

Note: All patients enrolled in these studies had primary gallbladder cancer

Chemotherapy

• Gemcitabine (Gemzar) 900 mg/m² IV once per day on days 1 & 8
• Oxaliplatin (Eloxatin) 80 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lee et al. 2011 (SMC 2008-12-024)	2009-02-16 to 2010-08-01	Phase 3 (C)	E-GEMOX	Might have inferior PFS Median PFS: 4.2 vs 5.8 mo (HR 1.25, 95% CI 0.97-1.64)

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 100 mg/m² IV once on day 2

14-day cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kim et al. 2019 (SMC 2011-05-070)	2011-2016	Phase 3 (C)	XELOX	Non-inferior PFS

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Oxaliplatin (Eloxatin) 100 mg/m² IV once on day 1

21-day cycle for 8 cycles

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

Study	Dates of enrollment	Evidence	Efficacy
Halim et al. 2010	2005-12 to 2009-11	Phase 2	ORR: 27.5%

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once on day 1, given first
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1, given second

14-day cycles

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

Study	Evidence	Efficacy
Harder et al. 2006	Phase 2	ORR: 26% (95% CI 14–44)

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

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, given first
• Oxaliplatin (Eloxatin) 100 mg/m² IV over 2 hours once per day on days 1 & 15, given second

28-day cycles

References

1. 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. Epub 2006 Sep 12. link to original article link to PMC article contains dosing details in manuscript PubMed
2. 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 dosing details in abstract PubMed
3. 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. Epub 2010 Nov 8. link to original article contains dosing details in manuscript PubMed
4. 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 dosing details in abstract PubMed NCT01149122
5. 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 dosing details in abstract PubMed NCT01470443
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 dosing details in manuscript PubMed CTRI/2010/091/001406

GEMOX-B

GEMOX-B: GEMcitabine, OXaliplatin, Bevacizumab

Regimen

Study	Evidence
Zhu et al. 2009 (MGH 05-349)	Phase 2

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV over 100 minutes once per day on days 1 & 15, given second
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once per day on days 1 & 15, given third

Targeted therapy

• Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15, given first

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 dosing details in manuscript PubMed

Irinotecan monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ramaswami et al. 2020 (GB-SELECT)	2018-2020	Randomized Phase 2 (C)	Capecitabine & Irinotecan	Did not meet primary endpoint of OS6

Prior treatment criteria

• Progression after prior gemcitabine-based chemotherapy

Chemotherapy

• Irinotecan (Camptosar) 240 mg/m² IV bolus once on day 1

21-day cycles

References

1. GB-SELECT: Ramaswamy A, Ostwal V, Sharma A, Bhargava P, Srinivas S, Goel M, Patkar S, Mandavkar S, Jadhav P, Parulekar M, Choudhari A, Gupta S. Efficacy of Capecitabine Plus Irinotecan vs Irinotecan Monotherapy as Second-line Treatment in Patients With Advanced Gallbladder Cancer: A Multicenter Phase 2 Randomized Clinical Trial (GB-SELECT). JAMA Oncol. 2021 Mar 1;7(3):436-439. Epub 2020 Dec 3. link to original article contains dosing details in manuscript link to PMC article PubMed CTRI/2017/10/010112

Regorafenib monotherapy

Regimen

Study	Evidence
Sun et al. 2019 (UPMC 13-100)	Phase 2

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

Prior treatment criteria

• Failure of at least 1 line of systemic therapy

Targeted therapy

• Regorafenib (Stivarga) 120 mg PO once per day on days 1 to 21

28-day cycles

References

1. UPMC 13-100: 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 contains dosing details in manuscript PubMed NCT02053376