Skip to main content

The Landmark Series: Gallbladder Cancer

Abstract

Given the rarity of gallbladder carcinoma, level I evidence to guide the multimodal treatment of this disease is lacking. Since 2010, four randomized phase III clinical trials including ABC-02, PRODIGE-12/ACCORD-18, BILCAP, and BCAT, and a single-arm phase II trial (SWOG0809) have been reported on the use of adjuvant strategies for biliary malignancies. These trials have led to the recommendation that patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy and those with R1 margins could be considered for chemoradiotherapy. Because there is no level I evidence to guide neoadjuvant therapy or surgical management, current consensus is based on strong retrospective data. The following review summarizes available trials and highlights the best available evidence that form the basis of consensus statements for the multimodal management of gallbladder carcinoma.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Reproduced from: N Engl J Med. 2010;362(14):1273–1281

Fig. 4
Fig. 5

Reproduced from: J Clin Oncol. 2019;37(8):658–667

Fig. 6
Fig. 7

Reproduced from: Lancet Oncol. 2019;20(5):663–673

Fig. 8
Fig. 9

Reproduced from: Br J Surg. 2018;105(3):192–202

Fig. 10

References

  1. 1.

    Henley SJ, Weir HK, Jim MA, et al. Gallbladder cancer incidence and mortality, United States 1999–2011. Cancer Epidemiol Biomark Prev. 2015;24:1319–26.

    Google Scholar 

  2. 2.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Google Scholar 

  3. 3.

    Diehl AK, Beral V. Cholecystectomy and changing mortality from gallbladder cancer. Lancet. 1981;2:187–9.

    CAS  PubMed  Google Scholar 

  4. 4.

    Saranga Bharathi R, Singh R, Gupta R, et al. Female sex hormone receptors in gallbladder cancer. J Gastrointest Cancer. 2015;46:143–8.

    CAS  PubMed  Google Scholar 

  5. 5.

    Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;118:1591–602.

    CAS  PubMed  Google Scholar 

  6. 6.

    Roa I, Araya JC, Villaseca M, et al. Gallbladder cancer in a high risk area: morphological features and spread patterns. Hepatogastroenterology. 1999;46:1540–6.

    CAS  PubMed  Google Scholar 

  7. 7.

    Diehl AK. Gallstone size and the risk of gallbladder cancer. JAMA. 1983;250:2323–6.

    CAS  PubMed  Google Scholar 

  8. 8.

    Lowenfels AB, Walker AM, Althaus DP, et al. Gallstone growth, size, and risk of gallbladder cancer: an interracial study. Int J Epidemiol. 1989;18:50–4.

    CAS  PubMed  Google Scholar 

  9. 9.

    Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut Liver. 2012;6:172–87.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99–109.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Global Cancer Observatory. [online] Available at: https://gco.iarc.fr/. Accessed 6 March 2020.

  12. 12.

    Akyurek N, Irkorucu O, Salman B, et al. Unexpected gallbladder cancer during laparoscopic cholecystectomy. J Hepatobiliary Pancreat Surg. 2004;11:357–61.

    PubMed  Google Scholar 

  13. 13.

    Ethun CG, Le N, Lopez-Aguiar AG, et al. Pathologic and prognostic implications of incidental versus nonincidental gallbladder cancer: a 10-institution study from the United States Extrahepatic Biliary Malignancy Consortium. Am Surg. 2017;83:679–86.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Zaidi MY, Maithel SK. Updates on gallbladder cancer management. Curr Oncol Rep. 2018;20:21.

    PubMed  Google Scholar 

  15. 15.

    Pawlik TM, Gleisner AL, Vigano L, et al. Incidence of finding residual disease for incidental gallbladder carcinoma: implications for re-resection. J Gastrointest Surg. 2007;11:1478–86 (discussion 1486-7).

    PubMed  Google Scholar 

  16. 16.

    Cubertafond P, Gainant A, Cucchiaro G. Surgical treatment of 724 carcinomas of the gallbladder. Results of the French Surgical Association Survey. Ann Surg. 1994;219:275–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Wilkinson DS. Carcinoma of the gall-bladder: an experience and review of the literature. Aust N Z J Surg. 1995;65:724–7.

    CAS  PubMed  Google Scholar 

  18. 18.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.

    PubMed  Google Scholar 

  19. 19.

    (U.S.) NCCN: Hepatobiliary cancer (version 4.2019).

  20. 20.

    Oikarinen H. Diagnostic imaging of carcinomas of the gallbladder and the bile ducts. Acta Radiol. 2006;47:345–58.

    CAS  PubMed  Google Scholar 

  21. 21.

    Bach AM, Loring LA, Hann LE, et al. Gallbladder cancer: can ultrasonography evaluate extent of disease? J Ultrasound Med. 1998;17:303–9.

    CAS  PubMed  Google Scholar 

  22. 22.

    Levy AD, Murakata LA, Rohrmann CA Jr. Gallbladder carcinoma: radiologic–pathologic correlation. Radiographics. 2001;21:295–314 (questionnaire, 549–55).

    CAS  PubMed  Google Scholar 

  23. 23.

    Cha SY, Kim YK, Min JH, et al. Usefulness of noncontrast MRI in differentiation between gallbladder carcinoma and benign conditions manifesting as focal mild wall thickening. Clin Imaging. 2019;54:63–70.

    PubMed  Google Scholar 

  24. 24.

    Rodriguez-Fernandez A, Gomez-Rio M, Medina-Benitez A, et al. Application of modern imaging methods in diagnosis of gallbladder cancer. J Surg Oncol. 2006;93:650–64.

    PubMed  Google Scholar 

  25. 25.

    Weber SM, DeMatteo RP, Fong Y, et al. Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg. 2002;235:392–9.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Aloia TA, Jarufe N, Javle M, et al. Gallbladder cancer: expert consensus statement. HPB (Oxford). 2015;17:681–90.

    PubMed Central  Google Scholar 

  27. 27.

    Vigano L, Ferrero A, Amisano M, et al. Comparison of laparoscopic and open intraoperative ultrasonography for staging liver tumours. Br J Surg. 2013;100:535–42.

    CAS  PubMed  Google Scholar 

  28. 28.

    Shindoh J, de Aretxabala X, Aloia TA, et al. Tumor location is a strong predictor of tumor progression and survival in T2 gallbladder cancer: an international multicenter study. Ann Surg. 2015;261:733–9.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Lee H, Choi DW, Park JY, et al. Surgical strategy for T2 gallbladder cancer according to tumor location. Ann Surg Oncol. 2015;22:2779–86.

    PubMed  Google Scholar 

  30. 30.

    Duffy A, Capanu M, Abou-Alfa GK, et al. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J Surg Oncol. 2008;98:485–9.

    CAS  PubMed  Google Scholar 

  31. 31.

    Foster JM, Hoshi H, Gibbs JF, et al. Gallbladder cancer: defining the indications for primary radical resection and radical re-resection. Ann Surg Oncol. 2007;14:833–40.

    PubMed  Google Scholar 

  32. 32.

    Fuks D, Regimbeau JM, Le Treut YP, et al. Incidental gallbladder cancer by the AFC-GBC-2009 Study Group. World J Surg. 2011;35:1887–97.

    PubMed  Google Scholar 

  33. 33.

    Hari DM, Howard JH, Leung AM, et al. A 21-year analysis of stage I gallbladder carcinoma: is cholecystectomy alone adequate? HPB (Oxford). 2013;15:40–8.

    PubMed  Google Scholar 

  34. 34.

    Principe A, Del Gaudio M, Ercolani G, et al. Radical surgery for gallbladder carcinoma: possibilities of survival. Hepatogastroenterology. 2006;53:660–4.

    PubMed  Google Scholar 

  35. 35.

    D’Angelica M, Dalal KM, DeMatteo RP, et al. Analysis of the extent of resection for adenocarcinoma of the gallbladder. Ann Surg Oncol. 2009;16:806–16.

    PubMed  Google Scholar 

  36. 36.

    Downing SR, Cadogan KA, Ortega G, et al. Early-stage gallbladder cancer in the surveillance, epidemiology, and end results database: effect of extended surgical resection. Arch Surg. 2011;146:734–8.

    PubMed  Google Scholar 

  37. 37.

    Shih SP, Schulick RD, Cameron JL, et al. Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg. 2007;245:893–901.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Gani F, Buettner S, Margonis GA, et al. Assessing the impact of common bile duct resection in the surgical management of gallbladder cancer. J Surg Oncol. 2016;114:176–80.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Jensen EH, Abraham A, Jarosek S, et al. Lymph node evaluation is associated with improved survival after surgery for early stage gallbladder cancer. Surgery. 2009;146:706–11 (discussion 711-3).

    PubMed  Google Scholar 

  40. 40.

    Ito H, Ito K, D’Angelica M, et al. Accurate staging for gallbladder cancer: implications for surgical therapy and pathological assessment. Ann Surg. 2011;254:320–5.

    PubMed  Google Scholar 

  41. 41.

    Kondo S, Nimura Y, Hayakawa N, et al. Regional and para-aortic lymphadenectomy in radical surgery for advanced gallbladder carcinoma. Br J Surg. 2000;87:418–22.

    CAS  PubMed  Google Scholar 

  42. 42.

    Hu J-B, Sun X-N, Xu J, et al. Port site and distant metastases of gallbladder cancer after laparoscopic cholecystectomy diagnosed by positron emission tomography. World J Gastroenterol. 2008;14:6428–31.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Z’Graggen K, Birrer S, Maurer CA, et al. Incidence of port site recurrence after laparoscopic cholecystectomy for preoperatively unsuspected gallbladder carcinoma. Surgery. 1998;124:831–8.

    PubMed  Google Scholar 

  44. 44.

    Maker AV, Butte JM, Oxenberg J, et al. Is port site resection necessary in the surgical management of gallbladder cancer? Ann Surg Oncol. 2012;19:409–17.

    PubMed  Google Scholar 

  45. 45.

    Fuks D, Regimbeau JM, Pessaux P, et al. Is port-site resection necessary in the surgical management of gallbladder cancer? J Visc Surg. 2013;150:277–84.

    CAS  PubMed  Google Scholar 

  46. 46.

    Ethun CG, Postlewait LM, Le N, et al. Routine port-site excision in incidentally discovered gallbladder cancer is not associated with improved survival: a multi-institution analysis from the US Extrahepatic Biliary Malignancy Consortium. J Surg Oncol. 2017;115:805–11.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Ethun CG, Postlewait LM, Le N, et al. Association of optimal time interval to re-resection for incidental gallbladder cancer with overall survival: a multi-institution analysis from the US Extrahepatic Biliary Malignancy Consortium. JAMA Surg. 2017;152:143–9.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Goere D, Wagholikar GD, Pessaux P, et al. Utility of staging laparoscopy in subsets of biliary cancers: laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder carcinoma. Surg Endosc. 2006;20:721–5.

    CAS  PubMed  Google Scholar 

  49. 49.

    Jarnagin WR, Ruo L, Little SA, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer. 2003;98:1689–700.

    PubMed  Google Scholar 

  50. 50.

    Nakachi K, Konishi M, Ikeda M, et al. A randomized Phase III trial of adjuvant S-1 therapy vs. observation alone in resected biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1202, ASCOT). Jpn J Clin Oncol. 2018;48:392–5.

    PubMed  Google Scholar 

  51. 51.

    Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81.

    CAS  PubMed  Google Scholar 

  52. 52.

    Edeline J, Benabdelghani M, Bertaut A, et al. 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;37:658–67.

    CAS  PubMed  Google Scholar 

  53. 53.

    Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20:663–73.

    CAS  PubMed  Google Scholar 

  54. 54.

    Malka D, Edeline J. Adjuvant capecitabine in biliary tract cancer: a standard option? Lancet Oncol. 2019;20:606–8.

    PubMed  Google Scholar 

  55. 55.

    Ebata T, Hirano S, Konishi M, et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018;105:192–202.

    CAS  PubMed  Google Scholar 

  56. 56.

    Ben-David MA, Griffith KA, Abu-Isa E, et al. External-beam radiotherapy for localized extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 2006;66:772–9.

    PubMed  Google Scholar 

  57. 57.

    Czito BG, Hurwitz HI, Clough RW, et al: Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience. Int J Radiat Oncol Biol Phys. 2005;62:1030–4.

    PubMed  Google Scholar 

  58. 58.

    Kresl JJ, Schild SE, Henning GT, et al. Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma. Int J Radiat Oncol Biol Phys. 2002;52:167–75.

    PubMed  Google Scholar 

  59. 59.

    Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. 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;33:2617–22.

    CAS  PubMed  Google Scholar 

  60. 60.

    Shroff RT, Kennedy EB, Bachini M, et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J Clin Oncol. 2019;37:1015–27.

    PubMed  Google Scholar 

  61. 61.

    Hakeem AR, Papoulas M, Menon KV. The role of neoadjuvant chemotherapy or chemoradiotherapy for advanced gallbladder cancer: a systematic review. Eur J Surg Oncol. 2019;45:83–91.

    PubMed  Google Scholar 

  62. 62.

    Javle M, Churi C, Kang HC, et al. HER2/neu-directed therapy for biliary tract cancer. J Hematol Oncol. 2015;8:58.

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Iyer P, Shrikhande SV, Ranjan M, et al. ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer. Int J Cancer. 2019;144:2008–19.

    CAS  PubMed  Google Scholar 

  64. 64.

    Lin J, Dong K, Bai Y, et al. Precision oncology for gallbladder cancer: insights from genetic alterations and clinical practice. Ann Transl Med. 2019;7:467.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Supported in part by the Katz Foundation.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Shishir K. Maithel MD.

Ethics declarations

Disclosure

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gamboa, A.C., Maithel, S.K. The Landmark Series: Gallbladder Cancer. Ann Surg Oncol 27, 2846–2858 (2020). https://doi.org/10.1245/s10434-020-08654-9

Download citation