Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multidisciplinary, multinational phase III trial

Alexander Stein, Dirk Arnold, John Bridgewater, David Goldstein, Lars Henrik Jensen, Heinz-Josef Klümpen, Ansgar W Lohse, Björn Nashan, John Primrose, Silke Schrum, Jenny Shannon, Eik Vettorazzi, Henning Wege, Alexander Stein, Dirk Arnold, John Bridgewater, David Goldstein, Lars Henrik Jensen, Heinz-Josef Klümpen, Ansgar W Lohse, Björn Nashan, John Primrose, Silke Schrum, Jenny Shannon, Eik Vettorazzi, Henning Wege

Abstract

Background: Despite complete resection, disease-free survival (DFS) of patients with cholangiocarcinoma (CCA) is less than 65 % after one year and not more than 35 % after three years. For muscle invasive gallbladder carcinoma (GBCA), prognosis is even worse, with an overall survival (OS) of only 30 % after three years. Thus, evaluation of adjuvant chemotherapy in biliary tract cancer in a large randomized trial is warranted.

Methods/design: ACTICCA-1 is a randomized, multidisciplinary, multinational phase III investigator initiated trial. With respect to data obtained in the ABC-02 trial, we selected the combination of gemcitabine and cisplatin for 24 weeks as investigational treatment. Based on adjuvant trials in pancreatic cancer with comparable postoperative recovery time, inclusion of patients within a maximum interval of 16 weeks between surgery and start of chemotherapy was stipulated. Due to the different prognosis and treatment susceptibility of muscle invasive carcinoma, two separate cohorts (CCA and GBCA) were included to capture the potentially different treatment effects. Randomization is stratified for lymph node status for both cohorts and localization for CCA. The primary endpoint is DFS and secondary endpoints include OS, safety and tolerability of chemotherapy, quality of life, and patterns of disease recurrence. For CCA, adjuvant chemotherapy should increase DFS 24 months post-surgery from 40 to 55 % to be considered relevant. With a power of 80 % and a significance level of 5 %, 271 evaluable study patients have to be followed for 24-28 months to observe 166 events. For GBCA, chemotherapy should increase DFS 24 months post-surgery from 35 to 55 % to be of relevance; thus, 154 evaluable study patients have to be monitored for 24-28 months to observe 90 events. In both cohorts, randomization will be 1:1 with chemotherapy for 24 weeks and imaging every twelve weeks. In 2014, the study was initiated in Germany and in The Netherlands (funded by the Deutsche Krebshilfe, the Dutch Cancer Society, and supported by medac GmbH). Sites in Australia, Denmark, and the United Kingdom (funded by Cancer Research UK) are joining 2015.

Trial registration: The study is registered with ClinicalTrials.gov ( NCT02170090 ) and the European Clinical Trials Database (2012-005078-70). Registration date is 06/18/2014.

Figures

Fig. 1
Fig. 1
ACTICCA-1 trial design. Legend: BTC, biliary tract cancer; CCA, cholangiocarcinoma; GBCA, gallbladder carcinoma; DFS, disease free survival; OS, overall survival; QoL, quality of life

References

    1. Seehofer D, Kamphues C, Neuhaus P. Management of bile duct tumors. Expert Opin Pharmacother. 2008;9:2843–56. doi: 10.1517/14656566.9.16.2843.
    1. Yang J, Yan LN. Current status of intrahepatic cholangiocarcinoma. World J Gastroenterol. 2008;14:6289–97. doi: 10.3748/wjg.14.6289.
    1. Ustundag Y, Bayraktar Y. Cholangiocarcinoma: a compact review of the literature. World J Gastroenterol. 2008;14:6458–66. doi: 10.3748/wjg.14.6458.
    1. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet. 2014;383:2168–79. doi: 10.1016/S0140-6736(13)61903-0.
    1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917. doi: 10.1002/ijc.25516.
    1. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99–109.
    1. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014;60:1268–89. doi: 10.1016/j.jhep.2014.01.021.
    1. Glimelius B, Hoffman K, Sjoden PO, Jacobsson G, Sellstrom H, Enander LK, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7:593–600. doi: 10.1093/oxfordjournals.annonc.a010676.
    1. Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol. 2010;28:4581–6. doi: 10.1200/JCO.2010.29.3605.
    1. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81. doi: 10.1056/NEJMoa0908721.
    1. Saxena A, Chua TC, Sarkar A, Chu F, Morris DL. Clinicopathologic and treatment-related factors influencing recurrence and survival after hepatic resection of intrahepatic cholangiocarcinoma: a 19-year experience from an established Australian hepatobiliary unit. J Gastrointest Surg. 2010;14:1128–38. doi: 10.1007/s11605-010-1203-1.
    1. Tamandl D, Herberger B, Gruenberger B, Puhalla H, Klinger M, Gruenberger T. Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2008;15:2787–94. doi: 10.1245/s10434-008-0081-1.
    1. Guglielmi A, Ruzzenente A, Campagnaro T, Pachera S, Valdegamberi A, Nicoli P, et al. Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection. World J Surg. 2009;33:1247–54. doi: 10.1007/s00268-009-9970-0.
    1. Nuzzo G, Giuliante F, Ardito F, De Rose AM, Vellone M, Clemente G, et al. Intrahepatic cholangiocarcinoma: prognostic factors after liver resection. Updates Surg. 2010;62:11–9. doi: 10.1007/s13304-010-0007-x.
    1. Murakami Y, Uemura K, Sudo T, Hashimoto Y, Nakashima A, Kondo N, et al. Prognostic factors after surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma. Ann Surg Oncol. 2011;18:651–8. doi: 10.1245/s10434-010-1325-4.
    1. Anderson C, Kim R. Adjuvant therapy for resected extrahepatic cholangiocarcinoma: a review of the literature and future directions. Cancer Treat Rev. 2009;35:322–7. doi: 10.1016/j.ctrv.2008.11.009.
    1. Choi SB, Kim KS, Choi JY, Park SW, Choi JS, Lee WJ, et al. The prognosis and survival outcome of intrahepatic cholangiocarcinoma following surgical resection: association of lymph node metastasis and lymph node dissection with survival. Ann Surg Oncol. 2009;16:3048–56. doi: 10.1245/s10434-009-0631-1.
    1. Li SQ, Liang LJ, Hua YP, Peng BG, He Q, Lu MD, et al. Long-term outcome and prognostic factors of intrahepatic cholangiocarcinoma. Chin Med J (Engl) 2009;122:2286–91.
    1. Ercolani G, Vetrone G, Grazi GL, Aramaki O, Cescon M, Ravaioli M, et al. Intrahepatic cholangiocarcinoma: primary liver resection and aggressive multimodal treatment of recurrence significantly prolong survival. Ann Surg. 2010;252:107–14. doi: 10.1097/SLA.0b013e3181e462e6.
    1. van der Gaag NA, Kloek JJ, de Bakker JK, Musters B, Geskus RB, Busch OR, et al. Survival analysis and prognostic nomogram for patients undergoing resection of extrahepatic cholangiocarcinoma. Ann Oncol. 2012;23:2642–9. doi: 10.1093/annonc/mds077.
    1. 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. Cancer. 2002;95:1685–95. doi: 10.1002/cncr.10831.
    1. Jarnagin WR, Ruo L, Little SA, Klimstra D, D’Angelica M, DeMatteo RP, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer. 2003;98:1689–700. doi: 10.1002/cncr.11699.
    1. Mayo SC, Shore AD, Nathan H, Edil B, Wolfgang CL, Hirose K, et al. National trends in the management and survival of surgically managed gallbladder adenocarcinoma over 15 years: a population-based analysis. J Gastrointest Surg. 2010;14:1578–91. doi: 10.1007/s11605-010-1335-3.
    1. Duffy A, Capanu M, Abou-Alfa GK, Huitzil D, Jarnagin W, Fong Y, et al. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC) J Surg Oncol. 2008;98:485–9. doi: 10.1002/jso.21141.
    1. Witjes CD, van den Akker SA, Visser O, Karim-Kos HE, de Vries E, Ijzermans JN, et al. Gallbladder cancer in the Netherlands: incidence, treatment and survival patterns since 1989. Dig Surg. 2012;29:92–8. doi: 10.1159/000336217.
    1. Koeberle D, Saletti P, Borner M, Gerber D, Dietrich D, Caspar CB, et al. Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine: a multicenter, phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2008;26:3702–8. doi: 10.1200/JCO.2008.16.5704.
    1. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer. 2007;96:896–902. doi: 10.1038/sj.bjc.6603648.
    1. Eckel F, Brunner T, Jelic S. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22(Suppl 6):vi40-4.
    1. Shinohara ET, Mitra N, Guo M, Metz JM. Radiation therapy is associated with improved survival in the adjuvant and definitive treatment of intrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 2008;72:1495–501. doi: 10.1016/j.ijrobp.2008.03.018.
    1. Hughes MA, Frassica DA, Yeo CJ, Riall TS, Lillemoe KD, Cameron JL, et al. Adjuvant concurrent chemoradiation for adenocarcinoma of the distal common bile duct. Int J Radiat Oncol Biol Phys. 2007;68:178–82. doi: 10.1016/j.ijrobp.2006.11.048.
    1. Gold DG, Miller RC, Haddock MG, Gunderson LL, Quevedo F, Donohue JH, et al. Adjuvant therapy for gallbladder carcinoma: the Mayo Clinic Experience. Int J Radiat Oncol Biol Phys. 2009;75:150–5. doi: 10.1016/j.ijrobp.2008.10.052.
    1. Wang SJ, Lemieux A, Kalpathy-Cramer J, Ord CB, Walker GV, Fuller CD, et al. Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol. 2011;29:4627–32. doi: 10.1200/JCO.2010.33.8020.
    1. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol. 2012;30:1934–40. doi: 10.1200/JCO.2011.40.5381.
    1. Bariani GM, Braghiroli MI, Riechelmann RP. Poor evidence to standardize adjuvant treatment for patients with biliary tract cancer. J Clin Oncol. 2012;30:4173. doi: 10.1200/JCO.2012.44.1634.
    1. de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, et al. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011;29:3140–5. doi: 10.1200/JCO.2011.35.6519.
    1. Goetze TO, Paolucci V. The prognostic impact of positive lymph nodes in stages T1 to T3 incidental gallbladder carcinoma: results of the German Registry. Surg Endosc. 2012;26:1382–9. doi: 10.1007/s00464-011-2044-z.
    1. Kriston L, Scholl I, Holzel L, Simon D, Loh A, Harter M. The 9-item Shared Decision Making Questionnaire (SDM-Q-9). Development and psychometric properties in a primary care sample. Patient Educ Couns. 2010;80:94–9. doi: 10.1016/j.pec.2009.09.034.
    1. Scholl I, Kriston L, Dirmaier J, Buchholz A, Harter M. Development and psychometric properties of the Shared Decision Making Questionnaire--physician version (SDM-Q-Doc) Patient Educ Couns. 2012;88:284–90. doi: 10.1016/j.pec.2012.03.005.

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