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Neoadjuvant chemotherapy for high-risk intrahepatic cholangiocarcinoma – does pathologic response mean better outcomes?

Published:January 23, 2023DOI:https://doi.org/10.1016/j.hpb.2023.01.011

      Abstract

      Background

      The role of neoadjuvant chemotherapy (NAC) in the management of intrahepatic cholangiocarcinoma (ICC) remains unknown. We sought to evaluate our experience treating high-risk ICC with NAC and to determine the prognostic significance of pathologic response.

      Methods

      Patients with ICC treated with NAC and surgery were analyzed using a prospectively maintained database. Pathologic response was graded by a blinded pathologist. Clinicopathologic/treatment variables were evaluated for associations with survival.

      Results

      Onsidered stage III, and 6(13%) were considered stage IV at time of diagnosis. Major response was identified in 39% of cases, including 2 with pathologic complete response. Patients with major response had a longer median NAC duration than patients with minor response (6 vs 4cycles, P=0.02). Regimen (gemcitabine/cisplatin vs gemcitabine/cisplatin/nab-paclitaxel) was not associated with response rate. Median recurrence-free (RFS) and overall survival (OS) were 11 and 45 months. Pathologic response was not associated with improved survival.

      Discussion

      Pathologic response to NAC was not associated with survival in this highly selected cohort. Nonetheless, the extended OS experienced by these high-risk patients is encouraging and suggests that NAC may help select patients who stand to benefit from aggressive resection.
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      References

        • Khan S.A.
        • Emadossadaty S.
        • Ladep N.G.
        • Thomas H.C.
        • Elliott P.
        • Taylor-Robinson S.D.
        • et al.
        Rising trends in cholangiocarcinoma: is the ICD classification system misleading us?.
        J Hepatol. 2012; 56: 848-854
        • Saha S.K.
        • Zhu A.X.
        • Fuchs C.S.
        • Brooks G.A.
        Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise.
        Oncologist. 2016; 21: 594-599
        • Florio A.A.
        • Ferlay J.
        • Znaor A.
        • Ruggieri D.
        • Alvarez C.S.
        • Laversanne M.
        • et al.
        Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012.
        Cancer. 2020; 126: 2666-2678
        • Zhu A.X.
        • Macarulla T.
        • Javle M.M.
        • Kelley R.K.
        • Lubner S.J.
        • Adeva J.
        • et al.
        Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial.
        JAMA Oncol. 2021;
      1. Meric-Bernstam F, Bahleda R, Hierro C, Sanson M, Bridgewater J, Arkenau HT, et al. Futibatinib, an irreversible FGFR1-4 inhibitor, in patients with advanced solid tumors harboring FGF/FGFR aberrations: a phase I dose-expansion study. Cancer Discov. 2021.

      2. NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers (Version 3.2021) 2021 [Available from: https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf.

        • Fong Z.V.
        • Brownlee S.A.
        • Qadan M.
        • Tanabe K.K.
        The Clinical Management of Cholangiocarcinoma in the United States and Europe: A Comprehensive and Evidence-Based Comparison of Guidelines.
        Ann Surg Oncol. 2021; 28: 2660-2674
        • Kato A.
        • Shimizu H.
        • Ohtsuka M.
        • Yoshitomi H.
        • Furukawa K.
        • Takayashiki T.
        • et al.
        Downsizing Chemotherapy for Initially Unresectable Locally Advanced Biliary Tract Cancer Patients Treated with Gemcitabine Plus Cisplatin Combination Therapy Followed by Radical Surgery.
        Ann Surg Oncol. 2015; 22: S1093-S1099
        • Kato A.
        • Shimizu H.
        • Ohtsuka M.
        • Yoshidome H.
        • Yoshitomi H.
        • Furukawa K.
        • et al.
        Surgical resection after downsizing chemotherapy for initially unresectable locally advanced biliary tract cancer: a retrospective single-center study.
        Ann Surg Oncol. 2013; 20: 318-324
        • Fruscione M.
        • Pickens R.C.
        • Baker E.H.
        • Martinie J.B.
        • Iannitti D.A.
        • Hwang J.J.
        • et al.
        Conversion therapy for intrahepatic cholangiocarcinoma and tumor downsizing to increase resection rates: A systematic review.
        Curr Probl Cancer. 2021; 45100614
        • Le Roy B.
        • Gelli M.
        • Pittau G.
        • Allard M.A.
        • Pereira B.
        • Serji B.
        • et al.
        Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma.
        Br J Surg. 2018; 105: 839-847
        • Mason M.C.
        • Massarweh N.N.
        • Tzeng C.D.
        • Chiang Y.J.
        • Chun Y.S.
        • Aloia T.A.
        • et al.
        Time to Rethink Upfront Surgery for Resectable Intrahepatic Cholangiocarcinoma? Implications from the Neoadjuvant Experience.
        Ann Surg Oncol. 2021; 28: 6725-6735
        • Sutton T.L.
        • Billingsley K.G.
        • Walker B.S.
        • Enestvedt C.K.
        • Dewey E.N.
        • Orloff S.L.
        • et al.
        Neoadjuvant chemotherapy is associated with improved survival in patients undergoing hepatic resection for intrahepatic cholangiocarcinoma.
        Am J Surg. 2021; 221: 1182-1187
        • Utuama O.
        • Permuth J.B.
        • Dagne G.
        • Sanchez-Anguiano A.
        • Alman A.
        • Kumar A.
        • et al.
        Neoadjuvant Chemotherapy for Intrahepatic Cholangiocarcinoma: A Propensity Score Survival Analysis Supporting Use in Patients with High-Risk Disease.
        Ann Surg Oncol. 2021; 28: 1939-1949
        • Yadav S.
        • Xie H.
        • Bin-Riaz I.
        • Sharma P.
        • Durani U.
        • Goyal G.
        • et al.
        Neoadjuvant vs. adjuvant chemotherapy for cholangiocarcinoma: A propensity score matched analysis.
        Eur J Surg Oncol. 2019; 45: 1432-1438
        • Karagkounis G.
        • Thai L.
        • Mace A.G.
        • Wiland H.
        • Pai R.K.
        • Steele S.R.
        • et al.
        Prognostic Implications of Pathological Response to Neoadjuvant Chemoradiation in Pathologic Stage III Rectal Cancer.
        Ann Surg. 2019; 269: 1117-1123
        • Groth S.S.
        • Burt B.M.
        • Farjah F.
        • Smaglo B.G.
        • Sada Y.H.
        • Sugarbaker D.J.
        • et al.
        Prognostic value of neoadjuvant treatment response in locally advanced esophageal adenocarcinoma.
        J Thorac Cardiovasc Surg. 2019; 157: 1682-16893 e1
        • Symmans W.F.
        • Peintinger F.
        • Hatzis C.
        • Rajan R.
        • Kuerer H.
        • Valero V.
        • et al.
        Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy.
        J Clin Oncol. 2007; 25: 4414-4422
        • Badgwell B.
        • Blum M.
        • Estrella J.
        • Chiang Y.J.
        • Das P.
        • Matamoros A.
        • et al.
        Predictors of Survival in Patients with Resectable Gastric Cancer Treated with Preoperative Chemoradiation Therapy and Gastrectomy.
        J Am Coll Surg. 2015; 221: 83-90
      3. Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, et al. AJCC Cancer Staging Manual (8th edition). 8th ed. Chicago, IL: Springer International Publishing AG; 2018.

        • Blazer 3rd, D.G.
        • Kishi Y.
        • Maru D.M.
        • Kopetz S.
        • Chun Y.S.
        • Overman M.J.
        • et al.
        Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases.
        J Clin Oncol. 2008; 26: 5344-5351
        • Tsilimigras D.I.
        • Ejaz A.
        • Cloyd J.
        • Guglielmi A.
        • Aldrighetti L.
        • Weiss M.
        • et al.
        Tumor Necrosis Impacts Prognosis of Patients Undergoing Resection for T1 Intrahepatic Cholangiocarcinoma.
        Ann Surg Oncol. 2022;
        • Hyder O.
        • Marques H.
        • Pulitano C.
        • Marsh J.W.
        • Alexandrescu S.
        • Bauer T.W.
        • et al.
        A nomogram to predict long-term survival after resection for intrahepatic cholangiocarcinoma: an Eastern and Western experience.
        JAMA Surg. 2014; 149: 432-438
        • Wang Y.
        • Li J.
        • Xia Y.
        • Gong R.
        • Wang K.
        • Yan Z.
        • et al.
        Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
        J Clin Oncol. 2013; 31: 1188-1195
        • Raoof M.
        • Dumitra S.
        • Ituarte P.H.G.
        • Melstrom L.
        • Warner S.G.
        • Fong Y.
        • et al.
        Development and Validation of a Prognostic Score for Intrahepatic Cholangiocarcinoma.
        JAMA Surg. 2017; 152e170117
        • Denbo J.W.
        • Fleming J.B.
        Definition and Management of Borderline Resectable Pancreatic Cancer.
        Surg Clin North Am. 2016; 96: 1337-1350
        • Isaji S.
        • Mizuno S.
        • Windsor J.A.
        • Bassi C.
        • Fernandez-Del Castillo C.
        • Hackert T.
        • et al.
        International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017.
        Pancreatology. 2018; 18: 2-11
        • Hennessy B.T.
        • Hortobagyi G.N.
        • Rouzier R.
        • Kuerer H.
        • Sneige N.
        • Buzdar A.U.
        • et al.
        Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy.
        J Clin Oncol. 2005; 23: 9304-9311
        • Wei T.
        • Zhang X.F.
        • Bagante F.
        • Ratti F.
        • Marques H.P.
        • Silva S.
        • et al.
        Tumor Necrosis Impacts Prognosis of Patients Undergoing Curative-Intent Hepatocellular Carcinoma.
        Ann Surg Oncol. 2021; 28: 797-805
        • Valle J.
        • Wasan H.
        • Palmer D.H.
        • Cunningham D.
        • Anthoney A.
        • Maraveyas A.
        • et al.
        Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.
        N Engl J Med. 2010; 362: 1273-1281
        • Malka D.
        • Cervera P.
        • Foulon S.
        • Trarbach T.
        • de la Fouchardiere C.
        • Boucher E.
        • et al.
        Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial.
        Lancet Oncol. 2014; 15: 819-828
        • 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.
        JAMA Oncol. 2019; 5: 824-830
        • Moeini A.
        • Sia D.
        • Bardeesy N.
        • Mazzaferro V.
        • Llovet J.M.
        Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma.
        Clin Cancer Res. 2016; 22: 291-300