Protocol for a phase III randomized trial of chemoradiation and systemic chemotherapy vs. systemic chemotherapy alone in patients with unresectable nonmetastatic cholangiocarcinoma
Background: Systemic doublet chemotherapy constitutes the current standard of care for patients with unresectable non-metastatic cholangiocarcinoma. The use of doublet chemotherapy is associated with median survival of 11.7 months. Concurrent chemo-radiation in this cohort is associated with similar overall survival however the impact of combination of chemoradiation and systemic chemotherapy on overall survival has not been investigated. The present phase III randomized study investigates the impact of chemoradiation in addition to systemic chemotherapy on overall survival.
Methods: Patients older than 18 years of age with diagnosis of unresectable non-metastatic cholangiocarcinoma with performance status 0-2and preserved liver function (Child Pugh score up to B7) will be eligible for study participation. The trial is designed such that patients will undergo stratified randomization (extra-hepatic vs. intrahepatic) either into systemic chemotherapy (standard arm) or chemo-radiation and systemic chemotherapy arm (experimental arm). The primary aim of the study is to compare difference in overall survival. The secondary aims of the study will focus on loco regional progression free survival and cause specific survival. The study will also report on the acute and late toxicity, quality of life and resectability rates in both the study arms. To demonstrate 7-month improvement in overall survival from 11 to 18 months a sample size of 142 is needed. Accounting for attrition a total of 155 patients will be accrued. All study subjects will be accrued after written informed consent. The trial is approved by the institutional ethics review board.
This trial is registered with ClinicalTrials.gov as NCT02773485
Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, et al. Cholangiocarcinoma, A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463–75.
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(14):1273-81.
Chopra S, Mathew AS, Engineer R, Shrivastava SK. Positioning high-dose radiation in multidisciplinary management of unresectable cholangiocarcinomas: review of current evidence. Indian J Gastroenterol. 2014;33(5):401-7.
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 cholangio-carcinoma: Implications for adjuvant therapeutic strategies. Cancer. 2003;98:1689–700.
Kim JK, Ha HK, Han DJ, Auh YH. CT analysis of postoperative tumor recurrence patterns in periampullary cancer. Abdom Imaging. 2003;28:384–91.
de Castro SM, Kuhlmann KF, van Heek NT, Busch OR, Offerhaus GJ, van Gulik TM, et al. Recurrent disease after microscopically radical (R0) resection of periampullary adenocarcinoma in patients without adjuvant therapy. J Gastrointest Surg. 2004;8:775–84.
Crane CH, Macdonald KO, Vauthey JN, Yehuda P, Brown T, Curley S, et al. Limitations of conventional doses of chemoradiation for unresectable biliary cancer; Int J Radiation Oncology Biol Phys. 2002:53(4):969–74.
Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangio-carcinoma. Ann Surg. 2005;242(3):451-61.
Alden ME, Mohiuddin M. The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer. Int J Radiat Oncol Biol Phys. 1994;28:945–51.
Polistina FA, Guglielmi R, Baiocchi C, Francescon P, Scalchi P, Febbraro A, et al. Chemoradiation treatment with gemcitabine plus stereotactic body radiotherapy for unresectable, non-metastatic, locally advanced hilar cholangiocarcinoma. Results of a five year experience. Radiother and Oncol. 2011;99:120–3.
Zeng ZC, Tang ZY, Fan J, Zhou J, Qin LX, Ye SL, et al. Consideration of the role of radiotherapy for unresectable intrahepatic cholangiocarcinoma: A retrospective analysis of 75 patients. Cancer J. 2006;12(2):113–22.
Chen YX, Zeng ZC, Tang ZY, Fan J, Zhou J, Jiang W, et al. Determining the role of external beam radiotherapy in unresectable intrahepatic cholangio-carcinoma: a retrospective analysis of 84 patients. BMC Cancer. 2010;10:492.
Ben-Josef E, Normolle D, Ensminger WD, Walker S, Tatro D, Ten Haken RK, et al. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol. 2005;23:8739–47.
Ibarra RA, Rojas D, Snyder L, Yao M, Fabien J, Milano M, et al. Multicenter results of stereotactic body radiotherapy (SBRT) for non-resectable primary liver tumors. Acta Oncol. 2012;51(5):575-83.
Tse RV, Hawkin M, Lockwood G, Kim JJ, Cummings B, Knox J, et al. Phase I Study of Individualized Stereotactic Body Radiotherapy for Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. J Clin Oncol. 2008;26:657-64.
Baisden JM, Kahaleh M, Weiss GR, Sanfey H, Moskaluk CA, Yeaton P, et al. Multimodality Treatment with Helical Tomotherapy Intensity Modulated Radiotherapy, Capecitabine, and Photodynamic Therapy is Feasible and Well Tolerated in Patients with Hilar Cholangio-carcinoma. Gastrointest Cancer Res. 2008;2(5):219-24.
Golfieri R, Giampalma E, Renzulli M, Galuppi A, Vicenzi L, Galaverni MC, et al. Unresectable hilar cholangiocarcinoma: multimodality approach with percutaneous treatment associated with radiotherapy and chemotherapy. In Vivo. 2006;20(6):757-60.
Habermehl D, Lindel K, Rieken S, Haase K, Goeppert B, Büchler MW, et al. Chemoradiation in patients with unresectable extrahepatic and hilar cholangiocarcinoma or at high risk for disease recurrence after resection : Analysis of treatment efficacy and failure in patients receiving postoperative or primary chemoradiation. Strahlenther Onkol. 2012;188(9):795-801.
Mosconi C, Renzulli M, Giampalma E, Galuppi A, Balacchi C, Brandi G, et al. Unresectableperihilar cholangiocarcinoma: multimodal palliative treatment. Anticancer Res. 2013;33(6):2747-53.
Kalyani ND, Engineer R, Chaudhari S, Dharia T, Shetty N, Chopra S, et al. Efficacy and clinical outcomes of radiotherapy with or without chemotherapy in inoperable or post-operative high-risk cholangiocarcinoma [Abstract]. ASCO Meeting Abstracts. 2013;31(4):273.
Ede RJ, Williams SJ, Hatfield AR, McIntyre S, Mair G. Endoscopic management of inoperable cholangiocarcinoma using iridium-192. Br J Surg. 1989;76(8):867-9.
Ohnishi H, Asada M, Shichijo Y, Iijima N, Itobayashi E, Shimura K, et al. External radiotherapy for biliary decompression of hilar cholangiocarcinoma. Hepatogastroenterology. 1995;42(3):265-8.
Bruha R, Petrtyl J, Kubecova M, Marecek Z, Dufek V, Urbanek P, et al. Intraluminal brachytherapy and self-expandable stents in nonresectable biliary malignancies--the question of long-term palliation. Hepatogastroenterology. 2001;48(39):631-7.
Schleicher UM, Staatz G, Alzen G, Andreopoulos D. Combined external beam and intraluminal radiotherapy for irresectable Klatskin tumors. Strahlenther Onkol. 2002;178(12):682-7.
Kopek N, Holt MI, Hansen AT, Høyer M. Stereotactic body radiotherapy for unresectable Cholangiocarcinoma. Radiotherapy and Oncology. 2010;94:47–52.
Momm F, Schubert E, Henne K, Hodapp N, Frommhold H, Harder J, et al. Stereotactic fractionated radiotherapy for Klatskin tumors. Radiother and Oncol. 2010;95:99–102.
Foo ML, Gunderson LL, Bender CE, Buskirk SJ. External radiation therapy and transcatheter iridium in the treatment of extra hepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys. 1997;39:929–35.
Flickinger JC, Epstein A, Iwatzuki S, Carr B, Starzl T. Radiation therapy for primary carcinoma of the extra hepatic biliary system. Cancer. 1991;68:289–94.
Deodato F, Clemente G, Mattiucci GC, Macchia G, Costamagna G, Giuliante F, et al. Chemoradiation and brachytherapy in biliary tract carcinoma: long-term results. Int J Radiat Oncol Biol Phys. 2006;64:483–8.
Ben-David MA, Griffith KA, Abu-Isa E, Lawrence TS, Knol J, Zalupski M, et al. External-Beam Radiotherapy for Localized Extra hepatic Cholangiocarcinoma. Int J Radiat Oncol Biol Phys, 2006;66(3):772–9.
Buskirk SJ, Gunderson LL, Schild SE, Bender CE, Williams HJ Jr, McIlrath DC, et al. Analysis of failure after curative irradiation of extra hepatic bile duct carcinoma. Ann Surg. 1992;215:125–31.
Jackson MW, Amini A, Jones BL, Rusthoven CG, Schefter TE, Goodman KA. Treatment Selection and Survival Outcomes With and Without Radiation for Unresectable, Localized Intrahepatic Cholangiocarcinoma. Cancer J. 2016;22(4):237-42.
Tao R, Krishnan S, Bhosale PR, Javle MM, Aloia TA, Shroff RT, Kaseb AO, et al. Ablative Radiotherapy Doses Lead to a Substantial Prolongation of Survival in Patients With Inoperable Intrahepatic Cholangiocarcinoma: A Retrospective Dose Response Analysis. J Clin Oncol. 2016;34(3):219-26.
Autorino R, Mattiucci GC, Ardito F, Balducci M, Deodato F, Macchia G, et al. Radiochemotherapy with Gemcitabine in Unresectable Extrahepatic Cholangiocarcinoma: Long-term Results of a Phase II Study. Anticancer Res. 2016;36(2):737-40.