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Current standards and future perspectives in adjuvant treatment for biliary tract cancers

  • Angela Lamarca
    Correspondence
    Corresponding authors at: Medical Oncology Department, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom.
    Affiliations
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

    Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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  • Julien Edeline
    Affiliations
    Department of Medical Oncology, Centre Eugene Marquis, Rennes, France
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  • Mairéad G McNamara
    Affiliations
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

    Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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  • Richard A Hubner
    Affiliations
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

    Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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  • Masato Nagino
    Affiliations
    Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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  • John Bridgewater
    Affiliations
    Department of Medical Oncology, UCL Cancer Institute, London, United Kingdom
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  • John Primrose
    Affiliations
    Department of Surgery, University of Southampton, Southampton, United Kingdom
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  • Juan W Valle
    Correspondence
    Corresponding authors at: Medical Oncology Department, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom.
    Affiliations
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

    Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Published:December 03, 2019DOI:https://doi.org/10.1016/j.ctrv.2019.101936

      Highlights

      • Capecitabine is the new standard of care for resected CCA and GBC.
      • Relapse rate remains high and not all patients benefit from such adjuvant therapy.
      • There is an urgent need for further adequately-designed and properly powered studies.
      • Role of targeted therapies, other chemotherapy and radiotherapy requires further research in this setting.

      Abstract

      Biliary tract cancer, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC) are rare tumours with a rising incidence. Prognosis is poor, since most patients are diagnosed with advanced disease. Only ~20% of patients are diagnosed with early-stage disease, suitable for curative surgery. Despite surgery performed with potentially-curative intent, relapse rates are high, with around 60–70% of patients expected to have disease recurrence. Most relapses occur in the form of distant metastases, with a predominance of liver spread. In view of high tumour recurrence, adjuvant strategies have been explored for many years, in the form of radiotherapy, chemo-radiotherapy and chemotherapy. Historically, few randomised trials were available, which included a variety of additional tumours (e.g. pancreatic and ampullary tumours); most evidence relied on phase II and retrospective studies, with no high-quality evidence available to define the real benefit derived from adjuvant strategies.
      Since 2017, three randomised phase III clinical trials have been reported; all recruited patients with resected biliary tract cancer (CCA and GBC) who were randomised to observation alone, or chemotherapy in the form of gemcitabine (BCAT study; included patients diagnosed with extrahepatic CCA only), gemcitabine and oxaliplatin (PRODIGE-12/ACCORD-18; included patients diagnosed with CCA and GBC) or capecitabine (BILCAP; included patients diagnosed with CCA and GBC). While gemcitabine-based chemotherapy failed to show an impact on patient outcome (relapse-free survival (RFS) or overall survival (OS)), the BILCAP study showed a benefit from adjuvant capecitabine in terms of OS (pre-planned sensitivity analysis in the intention-to-treat population and in the per-protocol analysis), with confirmed benefit in terms of RFS. Based on the BILCAP trial, international guidelines recommend adjuvant capecitabine for a period of six months following potentially curative resection of CCA as the current standard of care for resected CCA and GBC. However, BILCAP failed to show OS benefit in the intention-to-treat (non-sensitivity analysis) population (primary end-point), and this finding, as well as some inconsistencies between studies has been criticised and has led to confusion in the biliary tract cancer medical community.
      This review summarises the adjuvant field in biliary tract cancer, with evidence before and after 2017, and comparison between the latest randomised phase III studies. Potential explanations are presented for differential findings, and future steps are explored.

      Graphic abstract

      Keywords

      Introduction

      The term “biliary tract cancer” (BTC) includes tumours of the gallbladder (GBC), cholangiocarcinoma (CCA) and ampullary tumours. Cholangiocarcinomas are subdivided according to location into intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA) [eCCA are further divided in hilar cholangiocarcinoma (hCCA) and distal cholangiocarcinoma (dCCA)].
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      Fig. 1Reported 5-year overall survival rate for patients with resected CCA and GBC during the last 15 years are shown in the figure below. Adapted and updated from
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      ]. For many years, cisplatin and gemcitabine has been the standard of care first-line chemotherapy schedule for patients with inoperable disease [
      • Valle J.
      • Wasan H.
      • Palmer D.H.
      • Cunningham D.
      • Anthoney A.
      • Maraveyas A.
      • et al.
      Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.
      ,
      • Okusaka T.
      • Nakachi K.
      • Fukutomi A.
      • Mizuno N.
      • Ohkawa S.
      • Funakoshi A.
      • et al.
      Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan.
      ]. Triple-chemotherapy combinations are also being explored with promising results in the first-line setting [
      • Shroff R.T.
      • Javle M.M.
      • Xiao L.
      • Kaseb A.O.
      • Varadhachary G.R.
      • Wolff R.A.
      • et al.
      Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial.
      ,
      • Sakai
      • et al.
      Randomized phase III study of Gemcitabine, Cisplatin plus S-1 (GCS) versus Gemcitabine.
      ] and the combination of oxaliplatin and 5-fluorouracil (FOLFOX) has been recently established as a new second-line strategy [

      Angela Lamarca et al: ABC-06 | A randomised phase III, multi-centre, open-label study of Active Symptom Control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J Clin Oncol 37, 2019 (suppl; abstr 4003), 2019 (abstr).

      ]. Development of new agents [

      McNamara et al: A new ProTide, NUC-1031, combined with cisplatin for the first-line treatment of advanced biliary tract cancer (ABC-08). Presented at the ESMO Annual Meeting 2018; Annals of Oncology (2018) 29 (suppl_8): viii205-viii270. 10.1093/annonc/mdy282, 2018.

      ], liver-directed therapies [
      • Al-Adra D.P.
      • Gill R.S.
      • Axford S.J.
      • Shi X.
      • Kneteman N.
      • Liau S.S.
      Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis.
      ,
      • Burger I.
      • Hong K.
      • Schulick R.
      • Georgiades C.
      • Thuluvath P.
      • Choti M.
      • et al.
      Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: initial experience in a single institution.
      ,
      • Ibrahim S.M.
      • Mulcahy M.F.
      • Lewandowski R.J.
      • Sato K.T.
      • Ryu R.K.
      • Masterson E.J.
      • et al.
      Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study.
      ,
      • Edeline J.
      • et al.
      Radioembolisation plus chemotherapy for first-line treatment of locally-advanced intrahepatic cholangiocarcinoma:a phase 2 clinical trial.
      ], external beam radiotherapy [
      • Hong T.S.
      • Wo J.Y.
      • Yeap B.Y.
      • Ben-Josef E.
      • McDonnell E.I.
      • Blaszkowsky L.S.
      • et al.
      Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma.
      ] and targeted therapies, with inhibition of fibroblast growth factor receptor (FGFR) fusion rearrangements and isocitrate dehydrogenase (IDH)-1 and −2 mutations [

      Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX: New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discov:10-8290, 2017.

      ] are rapidly changing the treatment paradigm in metastatic disease [

      G.K.Abou-Alfa TMMMJRKKSLea: ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Annals of Oncology (2019) 30 (suppl_5): v851-v934 10 1093/annonc/mdz394, 2019 (abstr).

      ,
      • Javle M.
      • Lowery M.
      • Shroff R.T.
      • Weiss K.H.
      • Springfeld C.
      • Borad M.J.
      • et al.
      Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma.
      ].
      Until recently, the evidence supporting the role of adjuvant chemotherapy in CCA and GBC was scarce and adjuvant therapy was not considered standard practice in many countries [
      • Lamarca A.
      VJ: Should patients with resected bile duct cancer receive an adjuvant treatment?.
      ]. Since 2017, data from phase III randomised studies have been reported and have challenged the role of adjuvant therapy in resected BTC [
      • Ebata T.
      • Hirano S.
      • Konishi M.
      • Uesaka K.
      • Tsuchiya Y.
      • Ohtsuka M.
      • et al.
      Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.
      ,

      John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019.

      ,
      • Edeline J.
      • Benabdelghani M.
      • Bertaut A.
      • Watelet J.
      • Hammel P.
      • Joly J.P.
      • et al.
      Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.
      ]. Even though interpretation of the outcomes of these studies, specifically due to discrepant findings, has not been straight forward [

      Lamarca A, Gambardella V, Cejalvo JM, Fleitas-Kanonnikoff T, Cervantes A: In the literature: June 2019. ESMO Open %20;4:e000547, 2019.

      ], current practice has changed based on these results [
      • Shroff R.T.
      • Kennedy E.B.
      • Bachini M.
      • Bekaii-Saab T.
      • Crane C.
      • Edeline J.
      • et al.
      Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline.
      ]. This review summarises and provides an overview of the latest data in the field of adjuvant therapy in CCA and GBC.

      Patterns of relapse

      Despite potentially curative surgery, frequent relapse is the rule for CCA and GBC [
      • Lamarca A.
      VJ: Should patients with resected bile duct cancer receive an adjuvant treatment?.
      ]. There is a predominance for distant metastases for GBC [
      • Ebata T.
      • Hirano S.
      • Konishi M.
      • Uesaka K.
      • Tsuchiya Y.
      • Ohtsuka M.
      • et al.
      Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.
      ,
      • Jarnagin W.R.
      • Ruo L.
      • Little S.A.
      • Klimstra D.
      • D'Angelica M.
      • Dematteo R.P.
      • et al.
      Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies.
      ], while reported relapse patterns vary between studies for CCA, with some studies supporting a predominance of distant (liver) metastases [
      • Ebata T.
      • Hirano S.
      • Konishi M.
      • Uesaka K.
      • Tsuchiya Y.
      • Ohtsuka M.
      • et al.
      Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.
      ], while others report a higher rate of loco-regional relapse [
      • Jarnagin W.R.
      • Ruo L.
      • Little S.A.
      • Klimstra D.
      • D'Angelica M.
      • Dematteo R.P.
      • et al.
      Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies.
      ]. The fact that distant metastases seem to be predominant over local recurrence supports the use of systemic chemotherapy strategies in the adjuvant setting for GBC and CCA. However, radiotherapy is still an option for patients with R1 (microscopically-involved resection margins) disease due to risk of local recurrence; even though level of evidence is low [
      • Shroff R.T.
      • Kennedy E.B.
      • Bachini M.
      • Bekaii-Saab T.
      • Crane C.
      • Edeline J.
      • et al.
      Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline.
      ].

      Factors associated with poor outcome

      Some of the factors associated with increased risk of relapse include the presence of R1, high serum carbohydrate antigen (CA) 19–9 and the presence of lymph node metastases [
      • DeOliveira M.L.
      • Cunningham S.C.
      • Cameron J.L.
      • Kamangar F.
      • Winter J.M.
      • Lillemoe K.D.
      • et al.
      Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution.
      ,
      • Kim B.H.
      • Kim E.
      • Kim K.
      • Jang J.Y.
      • Kim S.W.
      • Oh D.Y.
      • et al.
      The impact of perioperative CA19-9 change on the survival and recurrence patterns after adjuvant chemoradiotherapy in resectable extrahepatic cholangiocarcinoma.
      ,
      • Weber S.M.
      • Dematteo R.P.
      • Fong Y.
      • Blumgart L.H.
      • Jarnagin W.R.
      Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients.
      ,
      • Madariaga J.R.
      • Iwatsuki S.
      • Todo S.
      • Lee R.G.
      • Irish W.
      • Starzl T.E.
      Liver resection for hilar and peripheral cholangiocarcinomas: a study of 62 cases.
      ,
      • Hanazaki K.
      • Kajikawa S.
      • Shimozawa N.
      • Shimada K.
      • Hiraguri M.
      • Koide N.
      • et al.
      Prognostic factors of intrahepatic cholangiocarcinoma after hepatic resection: univariate and multivariate analysis.
      ,
      • Tanaka S.
      • Hirohashi K.
      • Tanaka H.
      • Yamamoto T.
      • Kubo S.
      • Shuto T.
      • et al.
      Prognostic factors in patients with carcinoma of the papilla of Vater.
      ,
      • Miwa S.
      • Miyagawa S.
      • Kobayashi A.
      • Akahane Y.
      • Nakata T.
      • Mihara M.
      • et al.
      Predictive factors for intrahepatic cholangiocarcinoma recurrence in the liver following surgery.
      ,
      • Jan Y.Y.
      • Yeh C.N.
      • Yeh T.S.
      • Hwang T.L.
      • Chen M.F.
      Clinicopathological factors predicting long-term overall survival after hepatectomy for peripheral cholangiocarcinoma.
      ,
      • Riall T.S.
      • Cameron J.L.
      • Lillemoe K.D.
      • Campbell K.A.
      • Sauter P.K.
      • Coleman J.
      • et al.
      Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma–part 3: update on 5-year survival.
      ,
      • Wade T.P.
      • Prasad C.N.
      • Virgo K.S.
      • Johnson F.E.
      Experience with distal bile duct cancers in U.S. Veterans Affairs hospitals: 1987–1991.
      ,
      • Horgan A.M.
      • Amir E.
      • Walter T.
      • Knox J.J.
      Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis.
      ]. Some evidence does also support that patients with eCCA have increased risk of tumour recurrence [

      John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019.

      ].
      In a recent series of patients with resected eCCA, the presence of post-operative CA19-9 (Hazard Ratio (HR) 2.26) and presence of lymph node infiltration (HR 2.33) were associated with worse outcomes (overall survival (OS)). Patients with resected eCCA with high pre-and post-operative CA19-9 were shown to have a higher distant metastasis rate and shorter disease-free interval [
      • Kim B.H.
      • Kim E.
      • Kim K.
      • Jang J.Y.
      • Kim S.W.
      • Oh D.Y.
      • et al.
      The impact of perioperative CA19-9 change on the survival and recurrence patterns after adjuvant chemoradiotherapy in resectable extrahepatic cholangiocarcinoma.
      ]. Involvement of adjacent structures, perineural invasion, and poorly-differentiated histology have also been associated with poor outcomes for resected eCCA [
      • DeOliveira M.L.
      • Cunningham S.C.
      • Cameron J.L.
      • Kamangar F.
      • Winter J.M.
      • Lillemoe K.D.
      • et al.
      Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution.
      ,
      • Riall T.S.
      • Cameron J.L.
      • Lillemoe K.D.
      • Campbell K.A.
      • Sauter P.K.
      • Coleman J.
      • et al.
      Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma–part 3: update on 5-year survival.
      ,
      • Wade T.P.
      • Prasad C.N.
      • Virgo K.S.
      • Johnson F.E.
      Experience with distal bile duct cancers in U.S. Veterans Affairs hospitals: 1987–1991.
      ,
      • Aljiffry M.
      • Walsh M.J.
      • Molinari M.
      Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990–2009.
      ,
      • Seiler C.A.
      • Wagner M.
      • Bachmann T.
      • Redaelli C.A.
      • Schmied B.
      • Uhl W.
      • et al.
      Randomized clinical trial of pylorus-preserving duodenopancreatectomy versus classical Whipple resection-long term results.
      ,
      • Seiler C.A.
      • Wagner M.
      • Sadowski C.
      • Kulli C.
      • Buchler M.W.
      Randomized prospective trial of pylorus-preserving vs. Classic duodenopancreatectomy (Whipple procedure): initial clinical results.
      ,
      • Fong Y.
      • Blumgart L.H.
      • Lin E.
      • Fortner J.G.
      • Brennan M.F.
      Outcome of treatment for distal bile duct cancer.
      ,
      • Chen C.Y.
      • Shiesh S.C.
      • Tsao H.C.
      • Lin X.Z.
      The assessment of biliary CA 125, CA 19–9 and CEA in diagnosing cholangiocarcinoma–the influence of sampling time and hepatolithiasis.
      ].
      Factors associated with increased relapse rate and poor prognosis for resected iCCA include R1, lymphatic invasion, vascular invasion and periductal infiltrating disease [
      • DeOliveira M.L.
      • Cunningham S.C.
      • Cameron J.L.
      • Kamangar F.
      • Winter J.M.
      • Lillemoe K.D.
      • et al.
      Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution.
      ,
      • Madariaga J.R.
      • Iwatsuki S.
      • Todo S.
      • Lee R.G.
      • Irish W.
      • Starzl T.E.
      Liver resection for hilar and peripheral cholangiocarcinomas: a study of 62 cases.
      ,
      • Hanazaki K.
      • Kajikawa S.
      • Shimozawa N.
      • Shimada K.
      • Hiraguri M.
      • Koide N.
      • et al.
      Prognostic factors of intrahepatic cholangiocarcinoma after hepatic resection: univariate and multivariate analysis.
      ,
      • Miwa S.
      • Miyagawa S.
      • Kobayashi A.
      • Akahane Y.
      • Nakata T.
      • Mihara M.
      • et al.
      Predictive factors for intrahepatic cholangiocarcinoma recurrence in the liver following surgery.
      ,
      • Jan Y.Y.
      • Yeh C.N.
      • Yeh T.S.
      • Hwang T.L.
      • Chen M.F.
      Clinicopathological factors predicting long-term overall survival after hepatectomy for peripheral cholangiocarcinoma.
      ,
      • Aljiffry M.
      • Walsh M.J.
      • Molinari M.
      Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990–2009.
      ,
      • Hirohashi K.
      • Uenishi T.
      • Kubo S.
      • Yamamoto T.
      • Tanaka H.
      • Shuto T.
      • et al.
      Macroscopic types of intrahepatic cholangiocarcinoma: clinicopathologic features and surgical outcomes.
      ]. Prognostic nomograms have been designed for patients with a resected iCCA [
      • Wang Y.
      • Li J.
      • Xia Y.
      • Gong R.
      • Wang K.
      • Yan Z.
      • et al.
      Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
      ]; this nomogram included serum carcinoembryonic antigen (CEA), CA19-9), tumour diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extra-hepatic metastasis, and was superior in prognostic discrimination to five other staging systems for iCCA (p < 0.001).
      R1-resection, depth of mural invasion, lymph node metastasis, extramural extension and perineural invasion have been proposed as factors of poor outcome for GBC [
      • Weber S.M.
      • Dematteo R.P.
      • Fong Y.
      • Blumgart L.H.
      • Jarnagin W.R.
      Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients.
      ,

      AJCC Cancer Staging Manual, Seventh Edition, in, 2010.

      ,
      • Kondo N.
      • Furuya H.
      • Yamamoto S.
      • Nakano A.
      • Sakashita Y.
      Diffuse large B-cell lymphoma in the ampulla of vater causing obstructive jaundice: report of a case.
      ,
      • Eckel F.
      • Brunner T.
      • Jelic S.
      Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ].

      Adjuvant scenario prior to 2017

      Prior to 2017, there was a lack of dedicated randomised studies exploring adjuvant therapy in patients with CCA and GBC [
      • Horgan A.M.
      • Amir E.
      • Walter T.
      • Knox J.J.
      Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis.
      ,
      • Zhu A.X.
      • Knox J.J.
      Adjuvant therapy for intrahepatic cholangiocarcinoma: the debate continues.
      ]. The use of adjuvant therapy (both in the form of chemotherapy or chemoradiotherapy) was supported by a meta-analysis published in 2012 by Horgan and colleagues [
      • Horgan A.M.
      • Amir E.
      • Walter T.
      • Knox J.J.
      Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis.
      ]. This systematic review and meta-analysis included 20 trials; one randomised study, two Surveillance, Epidemiology, and End Results (SEER) registry studies and 17 retrospective series with a total of 6,712 patients (of whom 1787 received adjuvant treatment). Of the 20 studies included, 9, 3 and 8 included data on adjuvant radiotherapy alone, chemotherapy alone and chemo-radiotherapy, respectively.
      When all studies were included (including SEER registry data), adjuvant treatment did not improve survival in the pooled analysis compared to surgery alone (odds ratio (OR) 0.74, 95%CI 0.55–1.0); moreover, no benefit was identified when gallbladder and cholangiocarcinoma were analysed separately. When the SEER registry data were excluded, there was a benefit in favour of adjuvant treatment in the pooled analysis (OR 0.53, 95%CI 0.39–0.72); with benefit for chemotherapy alone (OR 0.39, 95%CI 0.23–0.66) and for chemo-radiotherapy (OR 0.61, 95%CI 0.38–0.99), while no benefit was shown for radiotherapy alone (OR 0.98, 95%CI 0.67–1.43) [
      • Horgan A.M.
      • Amir E.
      • Walter T.
      • Knox J.J.
      Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis.
      ]. Horgan and colleagues analysed the benefit of adjuvant therapy in two high risk populations (R1 and presence of lymph node metastases (N1), and showed a benefit of adjuvant therapy in both groups with OR of 0.36 (95%CI 0.19–0.68) and 0.49 (95%CI 0.30–0.80), respectively.
      One of the main criticisms of this meta-analysis was the fact that only one randomised study was available at the time, therefore relying on retrospective (with major risk of selection bias) and small phase II studies employing multiple different chemotherapy schedules. It was clear that further prospective studies to define the benefit of adjuvant treatment were required [
      • Lamarca A.
      VJ: Should patients with resected bile duct cancer receive an adjuvant treatment?.
      ,
      • Bariani G.M.
      • Braghiroli M.I.
      • Riechelmann R.P.
      Poor evidence to standardize adjuvant treatment for patients with biliary tract cancer.
      ] as adjuvant strategies were used variably worldwide.

      Previously available randomised clinical trials exploring the role of adjuvant therapy

      Only two randomised studies were available prior to 2017 [
      • Takada T.
      • Amano H.
      • Yasuda H.
      • Nimura Y.
      • Matsushiro T.
      • Kato H.
      • et al.
      Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma.
      ,
      • Neoptolemos J.P.
      • Moore M.J.
      • Cox T.F.
      • Valle J.W.
      • Palmer D.H.
      • McDonald A.C.
      • et al.
      Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial.
      ], but none were exclusively dedicated to CCA and GBC and did, instead, include a variety of pancreato-biliary tumours.
      The first randomised study by Takada and colleagues in 2002 [
      • Takada T.
      • Amano H.
      • Yasuda H.
      • Nimura Y.
      • Matsushiro T.
      • Kato H.
      • et al.
      Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma.
      ] evaluated adjuvant therapy with mitomycin-C and 5-fluorouracil (MF arm) versus surgery alone (control arm). The study recruited a total of 508 patients with resected pancreato-biliary tumours (including fully-resected CCA (n = 118; 58 in the MF group and 60 in the control group, but including less than half with curative-intent resection) and GBC (n = 112; 69 in the MF group and 43 in the control group). The study showed evidence of benefit for the GBC group only, both in terms of OS (5-year OS rate was 26.0% (MF group) vs 14.4% (control group); p-value 0.0367) and disease-free survival (RFS) (5-year OS rate was 20.3% (MF group) vs 11.6% (control group); p-value 0.0210). No benefit was identified for patients with CCA, either in terms of OS (5-year OS rate was 26.7% (MF group) vs 24.1% (control group); p-value > 0.05) or RFS (5-year RFS rate was 20.7% (MF group) vs 15.8% (control group); p-value 0.8892) [
      • Takada T.
      • Amano H.
      • Yasuda H.
      • Nimura Y.
      • Matsushiro T.
      • Kato H.
      • et al.
      Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma.
      ]. Based on these findings, there was evidence supporting the role of adjuvant chemotherapy for GBC, even though its role remained unclear for CCA.
      The ESPAC-3 trial explored the role of adjuvant chemotherapy for resected pancreato-biliary tumours [
      • Neoptolemos J.P.
      • Moore M.J.
      • Cox T.F.
      • Valle J.W.
      • Palmer D.H.
      • McDonald A.C.
      • et al.
      Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial.
      ]. In this trial, 428 patients with periampullary malignancies (a heterogeneous group including 297 ampullary cancers, 96 bile duct cancers and 35 “other” subtypes) were randomised after curative surgery to observation alone, adjuvant 5-FU or adjuvant gemcitabine chemotherapy. In the 96 patients with CCA, adjuvant chemotherapy did not improve OS (27.2 months (95% CI 15.4–31.9) vs 18.3 months (95% CI 12.9–28.7) vs 19.5 months (95% CI 16.2–36.1) for the observation, 5-FU and gemcitabine groups, respectively) [
      • Neoptolemos J.P.
      • Moore M.J.
      • Cox T.F.
      • Valle J.W.
      • Palmer D.H.
      • McDonald A.C.
      • et al.
      Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial.
      ].

      Other non-randomised studies focused on CCA

      The role of adjuvant radiotherapy and chemotherapy has been explored in small phase II and retrospective studies. The available data for adjuvant chemotherapy was based on retrospective studies only [
      • Akahoshi K.
      • Ban D.
      • Kuboki R.
      • Oba A.
      • Ono H.
      • Mitsunori Y.
      • et al.
      Orotate phosphoribosyltransferase as a predictor of benefit from S-1 adjuvant chemotherapy for cholangiocarcinoma patients.
      ,
      • Hester C.
      • Nassour I.
      • Adams-Huet B.
      • Augustine M.
      • Choti M.A.
      • Minter R.M.
      • et al.
      Improved survival in surgically resected distal cholangiocarcinoma treated with adjuvant therapy: a propensity score matched analysis.
      ,
      • Reames B.N.
      • Bagante F.
      • Ejaz A.
      • Spolverato G.
      • Ruzzenente A.
      • Weiss M.
      • et al.
      Impact of adjuvant chemotherapy on survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      ,
      • Kelley S.T.
      • Bloomston M.
      • Serafini F.
      • Carey L.C.
      • Karl R.C.
      • Zervos E.
      • et al.
      Cholangiocarcinoma: advocate an aggressive operative approach with adjuvant chemotherapy.
      ,
      • Todoroki T.
      • Ohara K.
      • Kawamoto T.
      • Koike N.
      • Yoshida S.
      • Kashiwagi H.
      • et al.
      Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma.
      ,
      • Murakami Y.
      • Uemura K.
      • Sudo T.
      • Hayashidani Y.
      • Hashimoto Y.
      • Nakamura H.
      • et al.
      Gemcitabine-based adjuvant chemotherapy improves survival after aggressive surgery for hilar cholangiocarcinoma.
      ,
      • Murakami Y.
      • Uemura K.
      • Sudo T.
      • Hashimoto Y.
      • Nakashima A.
      • Sakabe R.
      • et al.
      Adjuvant chemotherapy with gemcitabine and S-1 after surgical resection for advanced biliary carcinoma: outcomes and prognostic factors.
      ,
      • Yubin L.
      • Chihua F.
      • Zhixiang J.
      • Jinrui O.
      • Zixian L.
      • Jianghua Z.
      • et al.
      Surgical management and prognostic factors of hilar cholangiocarcinoma: experience with 115 cases in China.
      ], most of which employed gemcitabine-based regimens with inconsistent findings. Adjuvant radiotherapy, either alone or with radio-sensitising chemotherapy, after resection of CCA had not shown a clear benefit [
      • Anderson C.
      • Kim R.
      Adjuvant therapy for resected extrahepatic cholangiocarcinoma: a review of the literature and future directions.
      ,
      • Nakeeb A.
      • Pitt H.A.
      • Sohn T.A.
      • Coleman J.
      • Abrams R.A.
      • Piantadosi S.
      • et al.
      Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors.
      ,
      • Gonzalez G.D.
      • Gouma D.J.
      • Rauws E.A.
      • van Gulik T.M.
      • Bosma A.
      • Koedooder C.
      Role of radiotherapy, in particular intraluminal brachytherapy, in the treatment of proximal bile duct carcinoma.
      ,
      • Pitt H.A.
      • Nakeeb A.
      • Abrams R.A.
      • Coleman J.
      • Piantadosi S.
      • Yeo C.J.
      • et al.
      Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival.
      ,
      • Vern-Gross T.Z.
      • Shivnani A.T.
      • Chen K.
      • Lee C.M.
      • Tward J.D.
      • MacDonald O.K.
      • et al.
      Survival outcomes in resected extrahepatic cholangiocarcinoma: effect of adjuvant radiotherapy in a surveillance, epidemiology, and end results analysis.
      ]. Some retrospective and phase II trials appeared to show a benefit compared to surgery alone [
      • Todoroki T.
      • Ohara K.
      • Kawamoto T.
      • Koike N.
      • Yoshida S.
      • Kashiwagi H.
      • et al.
      Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma.
      ,
      • Kraybill W.G.
      • Lee H.
      • Picus J.
      • Ramachandran G.
      • Lopez M.J.
      • Kucik N.
      • et al.
      Multidisciplinary treatment of biliary tract cancers.
      ,
      • Borghero Y.
      • Crane C.H.
      • Szklaruk J.
      • Oyarzo M.
      • Curley S.
      • Pisters P.W.
      • et al.
      Extrahepatic bile duct adenocarcinoma: patients at high-risk for local recurrence treated with surgery and adjuvant chemoradiation have an equivalent overall survival to patients with standard-risk treated with surgery alone.
      ,
      • Kim S.
      • Kim S.W.
      • Bang Y.J.
      • Heo D.S.
      • Ha S.W.
      Role of postoperative radiotherapy in the management of extrahepatic bile duct cancer.
      ,
      • Nakeeb A.
      • Tran K.Q.
      • Black M.J.
      • Erickson B.A.
      • Ritch P.S.
      • Quebbeman E.J.
      • et al.
      Improved survival in resected biliary malignancies.
      ,
      • Nelson J.W.
      • Ghafoori A.P.
      • Willett C.G.
      • Tyler D.S.
      • Pappas T.N.
      • Clary B.M.
      • et al.
      Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma.
      ], predominantly for incompletely-resected patients (e.g. R1-resection). A meta-analysis summarising adjuvant radiotherapy or chemo-radiotherapy studies in eCCA reported that radiotherapy significantly improved OS compared with surgery alone (HR 0.62; 95%CI 0.48–0.78, p < 0.001) [
      • Bonet B.M.
      • Allal A.S.
      • Gich I.
      • Sole J.M.
      • Carrio I.
      Is adjuvant radiotherapy needed after curative resection of extrahepatic biliary tract cancers? A systematic review with a meta-analysis of observational studies.
      ]. One of the largest retrospective series exploring the role of adjuvant radiotherapy included a total of 3,839 patients with iCCA from the SEER database [
      • Shinohara E.T.
      • Mitra N.
      • Guo M.
      • Metz J.M.
      Radiotherapy is associated with improved survival in adjuvant and palliative treatment of extrahepatic cholangiocarcinomas.
      ]. The median overall survival was 11 months (95% CI 9–13) for patients treated with surgery followed by adjuvant radiotherapy, versus 6 months (95% CI 5–6) for the group receiving surgery alone; p-value 0.014. Differences were significant when adjusted for other prognostic factors in the multivariable analysis (HR, 0.82 (95% CI, 0.70–0.96)).

      Other non-randomised studies focused on GBC

      In addition to the randomised phase III study by Takada and colleagues, [
      • Takada T.
      • Amano H.
      • Yasuda H.
      • Nimura Y.
      • Matsushiro T.
      • Kato H.
      • et al.
      Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma.
      ], adjuvant radiotherapy [
      • Wang J.
      • Narang A.K.
      • Sugar E.A.
      • Luber B.
      • Rosati L.M.
      • Hsu C.C.
      • et al.
      Evaluation of adjuvant radiation therapy for resected gallbladder carcinoma: a multi-institutional experience.
      ,
      • Bosset J.F.
      • Mantion G.
      • Gillet M.
      • Pelissier E.
      • Boulenger M.
      • Maingon P.
      • et al.
      Primary carcinoma of the gallbladder.
      ,
      • Mojica P.
      • Smith D.
      • Ellenhorn J.
      Adjuvant radiation therapy is associated with improved survival for gallbladder carcinoma with regional metastatic disease.
      ,
      • Mehta A.
      • Bahadur A.K.
      • Aranya R.C.
      • Jain A.K.
      Role of radiation therapy in carcinoma of the gall bladder–a preliminary indian experience.
      ] and chemo-radiotherapy [
      • Kresl J.J.
      • Schild S.E.
      • Henning G.T.
      • Gunderson L.L.
      • Donohue J.
      • Pitot H.
      • et al.
      Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma.
      ,
      • Gu B.
      • Qian L.
      • Yu H.
      • Hu J.
      • Wang Q.
      • Shan J.
      • et al.
      Concurrent chemoradiotherapy in curatively resected gallbladder carcinoma: a propensity score-matched analysis.
      ,
      • Agrawal S.
      • Gupta P.K.
      • Rastogi N.
      • Lawrence A.
      • Kumari N.
      • Das K.J.
      • et al.
      Outcomes of adjuvant chemoradiation and predictors of survival after extended cholecystectomy in gall bladder carcinoma: a single institution experience from an endemic region.
      ,
      • Cho S.Y.
      • Kim S.H.
      • Park S.J.
      • Han S.S.
      • Kim Y.K.
      • Lee K.W.
      • et al.
      Adjuvant chemoradiation therapy in gallbladder cancer.
      ,
      • Gold D.G.
      • Miller R.C.
      • Haddock M.G.
      • Gunderson L.L.
      • Quevedo F.
      • Donohue J.H.
      • et al.
      Adjuvant therapy for gallbladder carcinoma: the Mayo Clinic Experience.
      ,
      • Czito B.G.
      • Hurwitz H.I.
      • Clough R.W.
      • Tyler D.S.
      • Morse M.A.
      • Clary B.M.
      • et al.
      Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience.
      ] for resected GBC have been explored in multiple phase II and retrospective studies. The largest series was from SEER including 3,187 patients with GBC which showed that adjuvant radiotherapy was associated with improved OS (14 vs 8 months; p ≤ 0.001) [
      • Mojica P.
      • Smith D.
      • Ellenhorn J.
      Adjuvant radiation therapy is associated with improved survival for gallbladder carcinoma with regional metastatic disease.
      ]. There was also evidence suggesting that those patients with lymph node-positive disease and T2-T3 tumours, appeared to benefit the most from radiotherapy [
      • Wang S.J.
      • Fuller C.D.
      • Kim J.S.
      • Sittig D.F.
      • Thomas Jr., C.R.
      • Ravdin P.M.
      Prediction model for estimating the survival benefit of adjuvant radiotherapy for gallbladder cancer.
      ] and chemo-radiotherapy [
      • Wang S.J.
      • Lemieux A.
      • Kalpathy-Cramer J.
      • Ord C.B.
      • Walker G.V.
      • Fuller C.D.
      • et al.
      Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer.
      ,
      • Cho S.Y.
      • Kim S.H.
      • Park S.J.
      • Han S.S.
      • Kim Y.K.
      • Lee K.W.
      • et al.
      Adjuvant chemoradiation therapy in gallbladder cancer.
      ].

      The urgent need for further randomised studies

      The two randomised studies available prior to 2017 recruited a wide spectrum of pancreato-biliary malignancies [
      • Takada T.
      • Amano H.
      • Yasuda H.
      • Nimura Y.
      • Matsushiro T.
      • Kato H.
      • et al.
      Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma.
      ,
      • Neoptolemos J.P.
      • Moore M.J.
      • Cox T.F.
      • Valle J.W.
      • Palmer D.H.
      • McDonald A.C.
      • et al.
      Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial.
      ], and even though multiple phase II and retrospective studies had been reported, these were heavily influenced by selection bias; and contained a heterogeneous component of radiotherapy and chemotherapy schedules with discrepant findings. Some evidence suggested that those patients with poor prognostic factors such as R1 and N1 were the ones deriving the most benefit from adjuvant therapy but this had not been confirmed in prospective randomised studies [
      • Horgan A.M.
      • Amir E.
      • Walter T.
      • Knox J.J.
      Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis.
      ,
      • McNamara M.G.
      • Walter T.
      • Horgan A.M.
      • Amir E.
      • Cleary S.
      • McKeever E.L.
      • et al.
      Outcome of adjuvant therapy in biliary tract cancers.
      ]. Thus, there was an urgent need for dedicated and appropriately powered randomised clinical trials exploring the role of adjuvant strategies following curative resection for patients diagnosed with CCA and GBC [
      • Valle J.W.
      • Borbath I.
      • Khan S.A.
      • Huguet F.
      • Gruenberger T.
      • Arnold D.
      Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,
      • Lamarca A.
      VJ: Should patients with resected bile duct cancer receive an adjuvant treatment?.
      ].

      2017–2019: Paradigm shift

      The era of dedicated randomised trials for patients with CCA and GBC

      Three phase III randomised clinical trials were reported and published between 2017 and 2019, all focused on patients with resected BTC (including CCA and GBC) and exploring the role of chemotherapy compared to observation alone after curative surgery [
      • Ebata T.
      • Hirano S.
      • Konishi M.
      • Uesaka K.
      • Tsuchiya Y.
      • Ohtsuka M.
      • et al.
      Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.
      ,

      John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019.

      ,
      • Edeline J.
      • Benabdelghani M.
      • Bertaut A.
      • Watelet J.
      • Hammel P.
      • Joly J.P.
      • et al.
      Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.
      ]. Table 1 and Fig. 2 provide a summary of the design and main findings of these clinical trials.
      Table 1Main characteristics of available phase III studies exploring the role of adjuvant treatment for GBC and CCA. iv: intravenously; CCA: cholangiocarcinoma, GBC, gallbladder cancer; dCCA: distal cholangiocarcinoma; hCCA: hilar cholangiocarcinoma; eCCA: extrahepatic cholangiocarcinoma; iCCA: intrahepatic cholangiocarinoma; OS: overall survival; RFS: relapse-free survival; TTD: time to definitive deterioration; HRQOL: health-related quality of life; ITT: intention-to-treat; IDMC: independent data monitoring committee; Mod dif: moderately differentiated; Poorly dif: poorly differentiated; Gem: gemcitabine, GemOx: gemcitabine and oxaliplatin; Cap: capecitabine; IQR: interquartile range; Obs: observation; n: number of patients; %: percentage; R1: positive resection margins; R0: clear resection margins: N0: negative lymph nodes; N1: presence of metastatic regional lymph nodes.
      Figure thumbnail gr2
      Fig. 2Summary of main findings and differences within the ecent phase III trial exploring the role of adjuvant chemotherapy in biliary tract cancer. Three phase III trials have been recently published exploring the role of adjuvant chemotherapy in resected cholangiocarcinoma and gallbladder cancer. The trials differ in some of the baseline characteristics which may explain why only the BILCAP trial (capecitabine vs observation) was the only study showing benefit in favour of adjuvant chemotherapy in resected biliary tract cancer. .A shows main differences in study characteristics. .B provides a graphic representation of HR for Relapse-free and Overall survival, with further details summarised in .C. iCCA: intrahepatic cholangiocarcinoma; eCCA: extrahepatic cholangiocarcinoma; GBC: gallbladder cancer; N0: no evidence of lymph node metastases; N1: presence of lymph node metastases; R0: clear resection margins; R1: affected resection margins (including tumour within 1 mm for the BILCAP trial); Cap: capecitabine, Gem: gemcitabine; GemOc: gemcitabine and oxaliplatin; HR: Hazard Ratio; CI: confidence interval. *Hazard Ratio in the ITT (intention-to-treat) population (sensitivity analysis) is presented for the BILCAP trial (Overall Survival).
      The BCAT trial randomised patients to gemcitabine (Gem) or observation alone [
      • Ebata T.
      • Hirano S.
      • Konishi M.
      • Uesaka K.
      • Tsuchiya Y.
      • Ohtsuka M.
      • et al.
      Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.
      ]. A total of 226 patients were randomised to Gem (n = 117 patients) or observation alone (109 patients; 1 patient was not eligible and therefore excluded from the analysis). Patient demographics were well balanced between study groups. Only patients with eCCA were included in the BCAT trial, including perihilar and distal CCAs only. Around 35.9% (Gem arm) and 33.3% (observation arm) of patients had N1 disease, and the rate of R1-resection was 9.4% in the Gem arm and 13.0% in the observation arm. Chemotherapy was well tolerated, with 52.1% of patients completing the full course of adjuvant Gem. The primary end-point was OS; the study identified no significant differences in OS (median 62.3 months (Gem) vs 63.8 months (observation); HR 1.01 (95% CI 0.70–1.45; p-value 0.964). There was no evidence of benefit in RFS (median 36.0 months (Gem) vs 39.9 months (observation arm); HR 0.93 (95% CI 0.66–1.32); p-value 0.693). Based on these findings, the BCAT study failed to show a benefit from Gem chemotherapy in patients with resected eCCA.
      The PRODIGE-12/ACCORD-18 trial randomised patients to gemcitabine and oxaliplatin (GemOx) versus observation alone [
      • Edeline J.
      • Benabdelghani M.
      • Bertaut A.
      • Watelet J.
      • Hammel P.
      • Joly J.P.
      • et al.
      Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.
      ]. A total of 196 patients were randomised, and 95 and 99 were included in the intention-to-treat (ITT) population in the GemOx and the observation arm, respectively. A high proportion of patients included in the PRODIGE-12/ACCORD-18 trial were diagnosed with iCCA (44%) or had N1 disease (36%) and only 13% had R1 resection; these characteristics were balanced between the study arms. The study was powered to identify differences in terms of RFS, with a pre-specified HR of 0.6. The study failed to show a benefit from GemOx chemotherapy in terms of RFS (HR 0.83 (95% CI 0.58–1.19); p-value 0.31); lack of benefit was confirmed in the per-protocol population. There was also no trend towards improved OS (HR 1.08 (95% CI 0.70–1.66; p-value 0.74). Interestingly, most patients with recurrent disease developed presence of distant metastases and were treated with gemcitabine-based chemotherapy. The authors also described a trend towards worse post-relapse survival in the GemOx arm (median OS 8.0 months) versus patients in the observation arm (median OS 15.2 months); HR 1.55 (95% CI 0.98–2.47); p-value 0.06. The median number of chemotherapy cycles delivered were 12, including 10 with oxaliplatin.
      The BILCAP trial randomised 447 patients to capecitabine (Cap) (223 patients) and observation alone (224 patients) and recruited patients with both CCA and GBC [

      John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019.

      ]. Within the BILCAP trial, dCCA were the largest subgroup (34% in the Cap arm, 36% in the observation arm), followed by hCCA (29% in the Cap arm, 28% in the observation arm); only 19% in the Cap arm and 18% in the observation arm were iCCA. Regarding prognostic factors, 38% of the patients in each arm were R1 and 48% in the Cap arm and 46% in the observation arm were N1. The BILCAP trial was powered to identify differences in terms of OS in the ITT population adjusted to stratification factors [institution, primary site (iCCA vs hCCA vs dCCA vs GBC), resection margin, and performance status], with a target HR of 0.69. In addition to the OS analysis in the ITT population, the study had pre-planned a sensitivity analysis of OS in the ITT population adjusting the treatment effect for identified prognostic factors and a separate analysis of OS in the per-protocol population. The median OS (ITT population) was 51.1 months (95% CI 34.6–59.1) and 36.4 months (95% CI 29.7–44.5) in the capecitabine and observation arms, respectively. Even though the BILCAP study did not meet its primary end-point in terms of OS in the ITT population (HR 0.81 (95% CI 0.63–1.04); p-value 0.097), adjuvant capecitabine was beneficial, both in terms of OS in the pre-specified ITT sensitivity analysis adjusted for nodal status, grade of disease and gender (HR 0.71 (95% CI 0.55–0.92); p-value 0.010) and in the per protocol population (HR 0.75 (95% CI 0.58–0.97); p-value 0.028). There was also benefit in terms of RFS (median 24.4 months (95% CI 18.6–35.9) vs 17.5 months (95% CI 12.0–23.8); HR 0.75 (95% CI 0.58–0.98); p-value 0.033). In the BILCAP study, capecitabine was well tolerated with an expected toxicity profile and no chemotherapy-related death; 55% of the patients who started capecitabine completed the full 8 cycles of adjuvant therapy and 46% required at least one dose reduction. Median capecitabine dose was 1,250 mg/kg twice daily (inter-quartile range (IQR) 1,061–1250).

      Potential reasons for discrepant results

      There was variability within study design between the most relevant phase III studies discussed above, some of which are relevant and deserve detailed discussion [
      • Ebata T.
      • Hirano S.
      • Konishi M.
      • Uesaka K.
      • Tsuchiya Y.
      • Ohtsuka M.
      • et al.
      Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.
      ,

      John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019.

      ,
      • Edeline J.
      • Benabdelghani M.
      • Bertaut A.
      • Watelet J.
      • Hammel P.
      • Joly J.P.
      • et al.
      Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.
      ]. In addition, it is also appropriate to compare these new studies with the prior Japanese phase III study [
      • Takada T.
      • Amano H.
      • Yasuda H.
      • Nimura Y.
      • Matsushiro T.
      • Kato H.
      • et al.
      Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma.
      ] to put study designs into context and highlight changes in practice over time (Table 1). Studies can be grouped according to the chemotherapy backbone employed: fluoropyrimidine-based (Takada and BILCAP) and gemcitabine-based (BCAT and PRODIGE-12/ACCORD-18). Only one of the studies tested doublet chemotherapy (PRODIGE-12/ACCORD-18). Overall, the largest study dedicated to CCA/GBC was the BILCAP study, which also recruited patients over a longer time period (total of 11 years).
      There are two main differences identified regarding study design when comparing the modern studies [
      • Ebata T.
      • Hirano S.
      • Konishi M.
      • Uesaka K.
      • Tsuchiya Y.
      • Ohtsuka M.
      • et al.
      Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.
      ,

      John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019.

      ,
      • Edeline J.
      • Benabdelghani M.
      • Bertaut A.
      • Watelet J.
      • Hammel P.
      • Joly J.P.
      • et al.
      Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.
      ], with the older Takada study [
      • Takada T.
      • Amano H.
      • Yasuda H.
      • Nimura Y.
      • Matsushiro T.
      • Kato H.
      • et al.
      Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma.
      ]. The first is that current study designs allowed time for adequate recovery from surgery before starting adjuvant chemotherapy (maximum 12–16 weeks), whereas Takada et al. administered adjuvant chemotherapy at the time of surgery and continued 1 week after. Such recovery time may confer significant benefit by improving tolerance of adjuvant therapy, as has been shown in another disease group [
      • Valle J.W.
      • Palmer D.
      • Jackson R.
      • Cox T.
      • Neoptolemos J.P.
      • Ghaneh P.
      • et al.
      Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study.
      ]. A second difference is the current preference for administering adjuvant therapy for a pre-defined period of time (typically 6 months [
      • Ebata T.
      • Hirano S.
      • Konishi M.
      • Uesaka K.
      • Tsuchiya Y.
      • Ohtsuka M.
      • et al.
      Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.
      ,

      John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019.

      ,
      • Edeline J.
      • Benabdelghani M.
      • Bertaut A.
      • Watelet J.
      • Hammel P.
      • Joly J.P.
      • et al.
      Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.
      ]), rather than continuing chemotherapy until disease progression [
      • Takada T.
      • Amano H.
      • Yasuda H.
      • Nimura Y.
      • Matsushiro T.
      • Kato H.
      • et al.
      Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma.
      ].
      The study design included 1:1 randomisation for all studies, with stratification factors, which included main prognostic factors such as the primary site (all studies), resection margins (BCAT, PRODIGE-12/ACCORD-18) and lymph node metastases (BCAT and PRODIGE-12/ACCORD-18). Even though the BILCAP study did not stratify according to lymph node metastases, such characteristics were well balanced between study arms, and it is unlikely that this had any impact on findings. Similarly, BCAT and PRODIGE-12/ACCORD-18, did not stratify according to performance status but the rate of Eastern Cooperative Oncology Group (ECOG) performance status 2 patients (the group most likely to impact prognosis) was well balanced between study arms. It is worth highlighting that all the studies stratified according to the institution, an important factor to take into account at the time of evaluating treatment strategies that include any form of surgery. In fact, the BILCAP trial required patients to undergo surgery in “specialist hepato-pancreato-biliary centres” which is mandated practice in the United Kingdom; such information in other studies was not specified. This may be of relevance, especially because the number of study sites involved was similar for all the studies, with the corresponding heterogeneity in surgical expertise. Finally, if resection margins are to be used as a stratification factor, it is important to understand its definition, which varies between countries. The College of American Pathologists defines R1 as tumour cells present at the margin, while the Royal College of Pathologists (United Kingdom) also includes tumour cells within 1 mm of the margin as R1 [
      • Hermanek P.
      • Wittekind C.
      Residual tumor (R) classification and prognosis.
      ,
      • Deeter M.
      • Dorer R.
      • Kuppusamy M.K.
      • Koehler R.P.
      • Low D.E.
      Assessment of criteria and clinical significance of circumferential resection margins in esophageal cancer.
      ,
      • O'Neill J.R.
      • Stephens N.A.
      • Save V.
      • Kamel H.M.
      • Phillips H.A.
      • Driscoll P.J.
      • et al.
      Defining a positive circumferential resection margin in oesophageal cancer and its implications for adjuvant treatment.
      ]; the latter definition was used in the BILCAP trial only.
      The primary end-point selected for each study, associated sample size calculations and planned statistical analyses require careful discussion. The majority of studies chose OS as a primary end-point, with the exception of PRODIGE-12/ACCORD-18, which selected RFS. Analysis of primary end-point in the ITT population was selected for both PRODIGE-12/ACCORD-18 and BILCAP. Even though the BCAT study analysed the primary and secondary end-points excluding the non-eligible randomised patients (likely to represent the per-protocol population), the study population only varied by 1 patient in the control arm, and therefore it is unlikely that this impacted on study findings. BILCAP was the only study that pre-specified that the primary end-point would be analysed adjusted for stratification factors, and which also pre-defined a sensitivity analysis adjusting the analysis for additional prognostic factors. For both, PRODIGE-12/ACCORD-18 and BILCAP, there was a plan for analysis of primary and secondary end-points in the per-protocol populations. Definition of such populations vary slightly between both studies, but there was a component of meeting eligibility criteria and receiving a minimum pre-set amount of adjuvant therapy in both. Interestingly, the percentage of patients excluded from the ITT population at the time of defining the per-protocol population was 3.8% in BILCAP but much higher in PRODIGE-12/ACCORD-18 (20.9%). If a proportion of these were due to early post-operative recurrence, it may highlight the need for better selection of patients for resection. Some recent work has been done in this area, and additional imaging prior to surgery in the form of 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18FDG-PET) may have a role, especially for identification of occult metastatic disease [
      • Lamarca A.
      • Barriuso J.
      • Chander A.
      • McNamara M.G.
      • Hubner R.A.
      • O'Reilly D.
      • et al.
      18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) for patients with biliary tract cancer: systematic review and meta-analysis.
      ].
      Regarding the sample size and assumptions related to these sample size calculations, it is worth highlighting that some of the studies aimed for a very ambitious benefit, such as the PRODIGE-12/ACCORD-18 (study powered for HR of 0.6 for RFS) or the study by Takada study (aimed to identify an absolute difference in 5-year OS rate of 20%). This resulted in studies underpowered to identify small but perhaps still clinically meaningful differences, which would require larger, longer duration, and more costly studies to reliably confirm of refute.
      In addition to the sample size, the maturity of the data is of relevance. Only two of these studies had actually reached the maturity of the data for analysis of the pre-defined primary end-point: PRODIGE-12/ACCORD-18 and BILCAP. Therefore, the other two studies are underpowered for any further conclusions, including the primary end-point for which the study was theoretically powered.
      When analysing RFS and comparing between studies, one wonders why capecitabine showed a benefit in term of RFS while GemOx did not. As mentioned above, the PRODIGE-12/ACCORD-18 study was adequately-powered and data maturity in terms of RFS events was appropriate. In addition, median RFS in the control arms are similar (18.5 (PRODIGE-12/ACCORD-18) vs 17.5 (BILCAP) months), suggesting that both study populations were comparable, at least with respect to RFS time. Despite this, one of the potential explanations for the discrepant results in terms of RFS benefit may rely on in the length of follow-up. When reporting HRs, the separation of the respective curves in the Kaplan-Meier graph is relevant. In the BILCAP trial, the separation of the curves for RFS initiated at the beginning of follow-up and runs in parallel throughout (HR 0.75 in the ITT population). In contrast, in the PRODIGE-12/ACCORD-18 study, the curves converge at month 48. This may reflect the fact that the median follow-up for PRODIGE-12/ACCORD-18 trials was shorter (median 46.5 months) than BILCAP (median follow-up 60 months). This could also explain why the median RFS for the GemOx arm in this study was longer than for capecitabine in the BILCAP study (30.4 (PRODIGE-12/ACCORD-18) vs 24.4 (BILCAP) months), which, despite overlapping 95% CIs, may represent overoptimistic estimations due to shorter follow-up for censored patients in PRODIGE-12/ACCORD-18. The fact that median RFS in PRODIGE-12/ACCORD-18 was “achieved at a plateau with the largest separation between the curves” could also make the median RFS less representative of the true difference [
      • Edeline J.
      • Benabdelghani M.
      • Bertaut A.
      • Watelet J.
      • Hammel P.
      • Joly J.P.
      • et al.
      Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.
      ]. The fact that radiological assessment was more frequently performed for the PRODIGE-12/ACCORD-18 trial (3-monthly during the first 2 years, 6-monthly thereafter) than for the BILCAP trial (6-monthly during the first 2 years, annually thereafter) is unlikely to have impacted on the above-mentioned differences, since it would have skewed the findings in the contrary direction.
      In terms of OS, both the control and the experimental median OS were longer in the PRODIGE-12/ACCORD-18 study when compared to BILCAP. Once again, it is unlikely that this represents a real effect or any differences between study populations, and is more likely to be a reflection of overoptimistic estimations due to limitations derived from shorter follow-up and lack of OS data maturity. In addition to differences in follow-up time, power and data maturity, there are some imbalances in the subpopulations of BTCs recruited between studies. The BCAT study limited recruitment to eCCA alone, with almost half split between hCCA and dCCA; this was also the most prevalent population in BILCAP. The PRODIGE-12/ACCORD-18 had a predominance of iCCA. Whether this impacts on findings cannot be fully excluded, since there is some evidence suggesting that iCCA may have a more favourable natural history [
      • Lamarca A.
      • Ross P.
      • Wasan H.S.
      • Hubner R.A.
      • McNamara M.G.
      • Lopes A.
      • et al.
      Advanced intrahepatic cholangiocarcinoma: post-hoc analysis of the ABC-01, -02 and -03 clinical trials.
      ], likely reflective of different molecular biology [

      Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX: New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discov:10-8290, 2017.

      ]. It has also been suggested that in view of worse response to GemOx in previous studies for the GBC population [
      • Andre T.
      • Reyes-Vidal J.M.
      • Fartoux L.
      • Ross P.
      • Leslie M.
      • Rosmorduc O.
      • et al.
      Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study.
      ], the fact that resected GBC were included in PRODIGE-12/ACCORD-18 could have negatively affected the findings [
      • Edeline J.
      • Benabdelghani M.
      • Bertaut A.
      • Watelet J.
      • Hammel P.
      • Joly J.P.
      • et al.
      Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.
      ]. In addition to the differences in the subtypes of BTC recruited into the different studies, there was also a higher proportion of patients harbouring poor prognosis factors (such as R1 and N1 disease, previously reported to be the subgroups benefiting the most from chemotherapy [
      • Horgan A.M.
      • Amir E.
      • Walter T.
      • Knox J.J.
      Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis.
      ,
      • McNamara M.G.
      • Walter T.
      • Horgan A.M.
      • Amir E.
      • Cleary S.
      • McKeever E.L.
      • et al.
      Outcome of adjuvant therapy in biliary tract cancers.
      ]) in the BILCAP study and could maybe also explain the positive findings of this study [
      • Edeline J.
      • Benabdelghani M.
      • Bertaut A.
      • Watelet J.
      • Hammel P.
      • Joly J.P.
      • et al.
      Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.
      ].
      One of the main criticisms of the BILCAP study is the limited absolute reduction in relapse rate (65% vs 60%) and also the fact that the study did not show a benefit in RFS beyond the 24 month period from randomisation (HR 1.48 (95% CI 0.80–2.77); p-value 0.21), raising the possibility “that capecitabine only defers recurrence” [
      • Malka JE D.
      Adjuvant capecitabine in biliary tract cancer: a standard option?.
      ]. Relapse rate reported in all studies was similar, highlighting that this is an ongoing issue to resolve. The 5-year survival data from the BILCAP trial is awaited; if 5-year OS benefit is confirmed, a potential real effect of capecitabine increasing the rate of cure and not only delaying recurrence may then be confirmed.
      The fact that recurrent disease is mainly in the form of distant metastases was already known and is the rationale for adjuvant strategies with systemic chemotherapy. However, at the time of recurrence, clinicians and patients are facing among others, two main issues. Firstly, the majority of patients will have recurrent disease which is not amenable to surgical options, therefore entering a palliative pathway with the implications on prognosis that this implies. Secondly, the selection of the first-line palliative chemotherapy is often influenced by which adjuvant therapy the patient previously received, and the time between the adjuvant therapy and recurrence. Data on palliative treatment were not recorded in the BILCAP study but were reported in the PRODIGE-12/ACCORD-18 study and highlight an important message. Choice of first-line chemotherapy was most frequently gemcitabine-based regimens in the observation arm and fluoropyrimidine-based regimens in the GemOx arm; interestingly, post-relapse OS tended to be worse in the GemOx arm (median OS 8.0 months) vs observation arm (median OS 15.2 months); HR 1.55 (95% CI 0.98–2.47); p-value 0.06. Current evidence supports use of cisplatin and gemcitabine as the standard of care in the first-line setting for advanced disease. However, the evidence for fluoropyrimidine-based chemotherapy is reserved for the second line setting. Patients who received adjuvant GemOx potentially did not receive the most effective first-choice palliative treatment. Additional questions include: are adjuvant strategies that potentially compromise first-line advanced disease chemotherapy adequate? Are we selecting clones of cells resistant to gemcitabine and oxaliplatin when these patients recur? These will require further research and need to be taken into account in further study design.

      Summary of current guidelines and recommendations

      ESMO guidelines (last updated in 2016) have not yet been updated and adjusted to include the latest evidence [
      • Ebata T.
      • Hirano S.
      • Konishi M.
      • Uesaka K.
      • Tsuchiya Y.
      • Ohtsuka M.
      • et al.
      Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.
      ,

      John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019.

      ,
      • Edeline J.
      • Benabdelghani M.
      • Bertaut A.
      • Watelet J.
      • Hammel P.
      • Joly J.P.
      • et al.
      Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.
      ]. Therefore, statements regarding adjuvant recommendations do not provide strong recommendations in favour of a specific strategy and do, in fact, highlight the lack of quality evidence at the time of these being issued. Authors concluded that “adjuvant therapy (radiotherapy, chemo-radiotherapy or chemotherapy alone) may be offered to patients on the understanding that the evidence base is weak, and only after risk–benefit assessment; participation in clinical trials should be encouraged” [
      • Valle J.W.
      • Borbath I.
      • Khan S.A.
      • Huguet F.
      • Gruenberger T.
      • Arnold D.
      Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ].
      National Comprehensive Cancer Network (NCCN) guidelines were updated January 2019 [

      NCCN (National Comprehensive Cancer Network): NCCN Guidelines.

      ], prior to the publication of the BILCAP study [

      John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019.

      ]. Current NCCN guidelines support the use of adjuvant chemotherapy and chemo-radiotherapy for CCA and GBC, regardless of R0/1 and N0/1 status for GBC and eCCA. The only exception is for patients with completely resected (R0) iCCA, for whom chemo-radiotherapy is not recommended. However, the NCCN guidelines do not specify a recommended chemotherapy schedule and do suggest that schedules active in the metastatic setting could be employed: “There are phase II trials that support the following combinations: gemcitabine/cisplatin, gemcitabine/capecitabine, capecitabine/cisplatin, capecitabine/oxaliplatin, 5-fluorouracil/oxaliplatin, 5-fluorouracil/cisplatin and the single agents gemcitabine, capecitabine, and 5-fluorouracil in the unresectable or metastatic setting. The phase III BILCAP study shows improved overall survival for adjuvant capecitabine in the per-protocol analysis, but the study is not yet published, and the overall survival did not reach statistical significance in the intent-to-treat analysis”.
      Following the latest evidence published, an urgent need for updated guidelines was recognised. Based on this, the ASCO guidelines were updated [
      • Shroff R.T.
      • Kennedy E.B.
      • Bachini M.
      • Bekaii-Saab T.
      • Crane C.
      • Edeline J.
      • et al.
      Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline.
      ] and, based on the BILCAP trial results, recommended adjuvant capecitabine for a period of six months following curative resection of BTCs (CCA and GBC) as a new standard of care [
      • Shroff R.T.
      • Kennedy E.B.
      • Bachini M.
      • Bekaii-Saab T.
      • Crane C.
      • Edeline J.
      • et al.
      Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline.
      ]. Authors stated that the role of chemo-radiotherapy remained unclear and suggested its use for patients with eCCA with R1 resection [
      • Shroff R.T.
      • Kennedy E.B.
      • Bachini M.
      • Bekaii-Saab T.
      • Crane C.
      • Edeline J.
      • et al.
      Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline.
      ,
      • Ben-Josef E.
      • Guthrie K.A.
      • El-Khoueiry A.B.
      • Corless C.L.
      • Zalupski M.M.
      • Lowy A.M.
      • 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.
      ] or other high-risk factors.

      Current caveats and future perspectives

      We have learned multiple lessons from past clinical trials. Researchers agree on the fact that a recovery time period is required post-surgery prior to starting adjuvant therapy; based on findings from the BILCAP trial, it does seem that a maximum period of 12–16 weeks is sufficient, without adversely impacting on patient outcomes. In addition, administration of chemotherapy during a limited period of time (rather than until disease recurrence) is accepted as standard practice in the adjuvant setting and has been shown to be safe, with very limited long-term toxicity. Finally, based on the data available, chemotherapy based on fluoropyrimidines seems to be preferable, since this was used in the only two positive studies to date [
      • Takada T.
      • Amano H.
      • Yasuda H.
      • Nimura Y.
      • Matsushiro T.
      • Kato H.
      • et al.
      Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma.
      ,

      John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019.

      ]. However, emerging data on molecular targets in BTC may result in novel future adjuvant designs incorporating these findings.
      There are multiple clinical trials ongoing to further explore the role of adjuvant chemotherapy for BTC (Table 2). However, multiple questions remain unanswered (Fig. 3).
      Table 2Ongoing trials studying the efficacy of adjuvant treatment in cholangiocarcinoma and gallbladder cancer (www.clinicaltrials.gov; last accessed October 2019).
      Study/Country (registration number)Patient numberPopulationArmsPrimary endpointExpected completion
      Germany - ACTICCA-1 NCT02170090781Cholangiocarcinoma and gallbladderCapecitabine vs Cisplatin-Gemcitabine Phase IIIRelapse-free survivalApril 2023
      South Korea NCT03079427100Extrahepatic cholangiocarcinomaCapecitabine vs Cisplatin-Gemcitabine Phase II2-year disease-free survivalApril 2022
      China NCT02548195286Intrahepatic cholangiocarcinomaCapecitabine vs Gemcitabine-Oxaliplatin Phase IIIRelapse-free survivalDecember 2018
      China NCT0407798340Intrahepatic cholangiocarcinomaGemcitabine-Nab-paclitaxel Phase IIRelapse-free survivalSeptember 2022
      China - AdBTC-1 NCT03779035460Cholangiocarcinoma and gallbladderGemcitabine vs Capecitabine Phase IIIRelapse-free survivalDecember 2023
      China NCT03702491138Gallbaldder cancerApatinib with SOX (Tegafur, Oxaliplatin) vs SOX aloneProgression-free survivalAugust 2020
      Figure thumbnail gr3
      Fig. 3Future perspectives and unanswered questions. N1: lymph node positivity; R1: positive resection margins; CCA: cholangiocarcinoma; GBC: gallbladder cancer; 18FDG-PET: 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography; RT: radiotherapy.
      There is a need to standardise the definition of some of the risk factors (such as R1), and also an urgent need to include these as stratification factors and to pre-plan adjusted statistical analysis. Typical risk factors such as primary tumour site, resection margins and lymph node metastases are the most important ones, but have not, yet, resulted in design alteration. Should these be used as stratification to enrich for patients at risk of relapse in future studies? Is adjuvant therapy a “one size fits all”, as it seems at the moment? The institution should also be included as a stratification factor in studies exploring an experience-dependent intervention, such as surgery.
      Similar to the need for identification and use of risk factors for tailored treatment strategies, we are in urgent need of biomarkers to better select which patients are more likely to benefit from specific adjuvant strategies. In addition, there is a need for in-depth translational research to understand mechanisms of resistance and disease recurrence. In order for researchers to learn from every patient and every trial (even if negative), it is crucial to include tissue banking and translational research questions in future studies.
      In addition, adequate patient selection is key, not only for adjuvant therapy but also for surgery. There is evidence supporting the use of 18FDG-PET for identification of occult metastases in BTC and this is of huge relevance in this setting [
      • Lamarca A.
      • Barriuso J.
      • Chander A.
      • McNamara M.G.
      • Hubner R.A.
      • O'Reilly D.
      • et al.
      18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) for patients with biliary tract cancer: systematic review and meta-analysis.
      ]; to reduce the number of patients undergoing unnecessary surgery and to avoid delays in initiating systemic therapy in patients with “occult” metastatic disease.
      Adequate study design is crucial. The time for small phase II studies has passed and the community is now in need of further phase III randomised studies, comparing experimental arms with an active (non-observational) control arm (currently: capecitabine). Clinically-meaningful but achievable assumptions are required at time of sample size calculations; to design adequately-powered studies able to provide mature and quality data to answer the question that is being asked. Sample size calculations may require revision during the study period to ensure that assumptions made at the time of study design are still accurate and relevant. Over the years, there has been some discrepancy regarding the most adequate primary end-point for adjuvant studies (RFS vs OS). The caveats of these two are to be taken into account, since we probably need power to show benefit in both of them; unfortunately, RFS may not be a good surrogate for OS due to the impact of subsequent lines of therapy on OS. Related to the study design, we have reached a point in which the feasibility of performing dedicated adjuvant trials in BTCs has been shown, despite their infrequency. However, long study durations cannot be ignored. Length of studies does not only depend on required follow-up per patient (directly related to primary end-point selected), but also the fact that all studies until now have been performed in single countries. The rationale for this approach has been related to funding and the fact that they were all investigator-led studies. Securing funding for performing multi-national studies is challenging, if not impossible. As a research community, we need to re-think how we collaborate in future studies. Biliary tract researchers have been successful at recruiting to randomised phase III trials in the advanced setting, when performed with adequate funding, to allow sites to open in multiple countries, even when small subpopulations of a rare cancer have been targeted [

      G.K.Abou-Alfa TMMMJRKKSLea: ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Annals of Oncology (2019) 30 (suppl_5): v851-v934 10 1093/annonc/mdz394, 2019 (abstr).

      ]. It is likely that researchers have to be imaginative and find ways around these issues, since it is unlikely that third-parties (e.g. industry) will be interested in adjuvant trials exploring well-known chemotherapy agents and radiotherapy.
      Relapse rate remains high, with 60% reported with capecitabine in the BILCAP study [

      John N Primrose et al: Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol March 25, 2019, 2019.

      ]. New chemotherapy agents and novel combinations are probably required to overcome this issue, together with the additional challenge of how to implement some of the emerging targeted therapies in the adjuvant scenario. In addition, the role of radiotherapy is still to be elucidated, and randomised phase III studies adequately powered to answer these questions are urgently required. It is likely that patients with a higher risk of local recurrence (R1 disease) are likely to benefit more from these approaches. Emerging strategies such as peri-operative treatment and neo-adjuvant strategies are also to be explored. As previously mentioned, the schedule chosen in the adjuvant setting may impact on the first-line palliative chemotherapy that patients are exposed to, and on occasions there has been an apparent detrimental effect [
      • Edeline J.
      • Benabdelghani M.
      • Bertaut A.
      • Watelet J.
      • Hammel P.
      • Joly J.P.
      • et al.
      Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.
      ]. It will be interesting to see whether a similar effect will be demonstrated in the ongoing ACTICCA-1 clinical trial (cisplatin and gemcitabine versus capecitabine; NCT02170090) and if so, this will need to be addressed in future study design, to ensure that first-line palliative treatment choice is not compromised.

      Conclusion

      Despite the reservations regarding the findings of the BILCAP trial, this study has changed the paradigm of adjuvant therapy, establishing capecitabine as the new standard of care for resected CCA and GBC. Unfortunately, the relapse rate remains high and it is clear that not all patients benefit from such adjuvant therapy, necessitating further randomised studies exploring the role of novel strategies. Adequately-designed and properly powered studies with sufficient follow-up are required for development of adjuvant tools which will increase the cure rate for patients with CCA and GBC.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgement

      Dr Angela Lamarca has received funding from The Christie Charity .

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