Clinical trial NCT04378023: Liver Transplant Combined With Neoadjuvant Chemo-radiotherapy in the Treatment of Unresectable Hilar Cholangiocarcinoma. A Prospective Multicenter Study.
Official title: Liver Transplant Combined With Neoadjuvant Chemo-radiotherapy in the Treatment of Unresectable Hilar Cholangiocarcinoma. A Prospective Multicenter Study.
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Unresectable Cholangiocarcinoma
Lead sponsor: Hospital Vall d'Hebron
Sponsor class: OTHER
First posted: 2020-05-07
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Those patients with unresectable malignant appearing hilar stricture and at least one of the following:

* Malignant cytology or histology
* CA 19.9\>130U/mL without cholangits or/and jaundice
* Mass on cross-sectional imaging

Brief summary: A prospective multicentre study which includes patients ≤ 70 years-old diagnosed of unresectable hilar cholangiocarcinoma (hCCA) ≤3cm in radial diameter, without evidence of lymph node or distant metastases. Liver transplantation preceded by neoadjuvant radio-chemotherapy will be performed in this selected group.

The primary endpoint will be overall survival at 1, 3, and 5 years post-transplant. The secondary endpoints will be: 1) recurrence free survival at 1, 3 and 5 years post-transplant; 2) intention-to-treat survival of overall patients included in the study at 1,3 and 5 year; 3) the rate of patients included in the study who are finally transplanted.

Detailed description: A prospective multicentre pilot study which includes patients ≤ 70 years-old diagnosed of unresectable hilar cholangiocarcinoma (hCCA) ≤3cm in radial diameter, without evidence of lymph node or distant metastases.

The number of subjects necessary is 34 patients to achieve a power of 82% with a significance level of 0.05 to detect a 40% difference between the estimated 50% survival of those patients who are transplanted and 10% of those patients with hCCA unresectable who are not transplanted. This corresponds to a hazard ratio of 3.3219. Estimated loss to follow-up of 10% of patients.

RADIOLOGICAL EVALUATION

It will be considered unresectable those lesions Bismuth IV with the following criteria (Jarnagin WR, et al. Ann Surg 2001; 234:507; Memorial Sloan Kettering Cancer Center Hilar Cholangiocarcinoma Classification):

* Bilateral extension to second order biliary
* Unilateral extension to second-order biliary radicals AND contralateral portal vein involvement OR contralateral hepatic lobar atrophy
* Main or bilateral portal vein involvement
* Insufficient future liver remnant even after portal embolization

It will be performed the tumoral marker (CA 19.9), multiphase chest-abdomen CT scan, magnetic resonance cholangiopancreatography (MRCP) as well as positon emission tomography (PET)-scan if there is doubts of distant disease and upper endoscopic ultrasound (EUS) in order to rule out any obvious lymph node metastases. A biliary drainage will be placed by percutaneous transhepatic biliary drainage (PTBD) or endoscopic biliary drainage (EBD).

NEOADJUVANT TREATMENT

Patients will receive neoadjuvant radiotherapy (External - 50-54 grays) following by concomitant oral capecitabine (1,330mg/m2).Thereafter, gemcitabine iv (1000mg/m2) plus cisplatin iv will be administered the day 1 and 8 every 21 days until transplant.

A staging laparotomy/laparoscopy is recommended before including the patient in waiting list for transplant to confirm the abscence of extra-hepatic disease, especially peritoneal seeding and lymph nodes involvement.

A score exception will be allowed to optimized the treatment received and to be transplanted during the first 6 months.

LIVER TRANSPLANT AND FOLLOW UP

Regarding liver transplant technique, hepatic artery should be avoided for arterial reconstruction using the splenic artery or an iliac conduit.

Biomarker analyses in the explant specimen will be performed.

The patient will be monitored post-operatively at the clinical, biological and morphological levels every 3 months during the first 2 years and every 6 months thereafter in order to detect any recurrence and in the context of standard clinical care.

Eligibility criteria: Inclusion Criteria:

* Willing and able to provide written consent form
* Age ≤ 70 years-old
* ECOG 0 or 1
* Unresectable hCCA ≤3cm in radial diameter

Exclusion Criteria:

* Those patients who have received chemotherapy or radiotherapy previously out of protocol
* Liver, extrahepatic or lymph node metastases
* Previous intent of surgical resection or percutaneous biopsy
* Previous or concurrent cancer that is different in primary site or histology from adenocarcinoma, except cervical carcinoma in situ, localized prostate cancer, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, T1). Any cancer curatively treated 5 years prior to entry is permitted.
* Infection no controlled

Primary outcomes:
measure: Overall survival at 1, 3, and 5 years post-transplant
timeFrame: 5 years
Secondary outcomes:
measure: Recurrence free survival at 1, 3 and 5 years post-transplant
timeFrame: 5 years
measure: Intention-to-treat survival of overall patients included in the study at 1,3 and 5 year
timeFrame: 5 years
measure: The rate of patients included in the study who are finally transplanted.
timeFrame: 5 years
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Department of HPB Surgery and Transplants, Hospital Vall d´Hebron
Study officials:
affiliation: HOSPITAL UNIVERSITARIO VALL D´HEBRON, UNIVERSIDAD AUTONOMA, BARCELONA
name: Cristina Dopazo
role: PRINCIPAL_INVESTIGATOR
affiliation: HOSPITAL UNIVERSITARIO VALL D´HEBRON, UNIVERSIDAD AUTONOMA, BARCELONA
name: Ramón Charco-Torra
role: PRINCIPAL_INVESTIGATOR
affiliation: HOSPITAL GENERAL UNIVERSITARIO, ALICANTE
name: Sonia Pascual-Bartolomé
role: STUDY_CHAIR
affiliation: HOSPITAL UNIVERSITARIO 12 DE OCTUBRE, MADRID
name: Carmelo Loinaz-Segurola
role: STUDY_CHAIR
affiliation: HOSPITAL UNIVERSITARIO VIRGEN DEL ROCIO, SEVILLA
name: José María Álamo-Martinez
role: STUDY_CHAIR
affiliation: HOSPITAL UNIVERSITARIO PUERTA DE HIERRO, MAJADAHONDA
name: José Luis Lucena de la Poza
role: STUDY_CHAIR
affiliation: HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARANON, MADRID
name: Arturo Colon-Rodríguez
role: STUDY_CHAIR
affiliation: COMPLEJO HOSPITALARIO UNIVERSITARIO, BADAJOZ
name: Diego López-Segarra
role: STUDY_CHAIR
affiliation: Hospital Clinic of Barcelona
name: Yilliam Fundora-Suárez
role: STUDY_CHAIR
affiliation: Hospital Universitario La Fe
name: Andrea Bosca-Robledo
role: STUDY_CHAIR
affiliation: HOSPITAL UNIVERSITARIO MARQUES DE VALDECILLA, SANTANDER
name: Juan Andrés Echeverri-Cifuentes
role: STUDY_CHAIR
affiliation: HOSPITAL UNIVERSITARIO DE BELLVITGE, BARCELONA
name: Josefina López-Domínguez
role: STUDY_CHAIR
affiliation: HOSPITAL UNIVERSITARIO VALL D´HEBRON, UNIVERSIDAD AUTONOMA, BARCELONA
name: Xavier Merino-Casabiel
role: STUDY_CHAIR
affiliation: HOSPITAL UNIVERSITARIO DE BELLVITGE, BARCELONA
name: David Leiva-Pedraza
role: STUDY_CHAIR
affiliation: HOSPITAL UNIVERSITARIO VALL D´HEBRON, UNIVERSIDAD AUTONOMA, BARCELONA
name: María Teresa Salcedo-Allende
role: STUDY_CHAIR
affiliation: HOSPITAL CLÍNICO UNIVERSITARIO LOZANO BLESA, ZARAGOZA
name: José Antonio Gracia Solanas
role: STUDY_CHAIR
affiliation: HOSPITAL UNIVERSITARIO NUESTRA SEÑORA DE LA CANDELARIA, TENERIFE
name: Manuel Angel Barrera-Gómez
role: STUDY_CHAIR
affiliation: Hospital Universitario Virgen de la Arrixaca
name: Ricardo Robles-Campos
role: STUDY_CHAIR
affiliation: HOSPITAL UNIVERSITARIO DE BELLVITGE, BARCELONA
name: Laura Lladó-Garrida
role: STUDY_DIRECTOR
affiliation: HOSPITAL UNIVERSITARIO VALL D´HEBRON, UNIVERSIDAD AUTONOMA DE BARCELONA
name: María Teresa Macarulla-Mercadé
role: STUDY_DIRECTOR
affiliation: HOSPITAL UNIVERSITARIO VALL D´HEBRON, UNIVERSIDAD AUTONOMA DE BARCELONA
name: Begoña Navalpotro-Yagüe
role: STUDY_DIRECTOR
affiliation: HOSPITAL UNIVERSITARIO VALL D´HEBRON, UNIVERSIDAD AUTONOMA DE BARCELONA
name: Florian Castet
role: STUDY_CHAIR
affiliation: HOSPITAL REGIONAL UNIVERSITARIO DE MALAGA
name: Julio Santoyo
role: STUDY_CHAIR
affiliation: HOSPITAL UNIVERSITARIO REINA SOFIA DE CÓRDOBA
name: Manuel Durán Martínez
role: STUDY_CHAIR
affiliation: Hospital Virgen de las Nieves (Granada)
name: Natalia Zambudio
role: STUDY_CHAIR
References:
citation: Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BS J, Youssef BA M, Klimstra D, Blumgart LH. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001 Oct;234(4):507-17; discussion 517-9. doi: 10.1097/00000658-200110000-00010.
citation: Heimbach JK, Gores GJ, Haddock MG, Alberts SR, Nyberg SL, Ishitani MB, Rosen CB. Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis. 2004 May;24(2):201-7. doi: 10.1055/s-2004-828896.
citation: Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, Gores GJ, Nagorney DM. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 2005 Sep;242(3):451-8; discussion 458-61. doi: 10.1097/01.sla.0000179678.13285.fa.
citation: Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM, Botha JF, Mezrich JD, Chapman WC, Schwartz JJ, Hong JC, Emond JC, Jeon H, Rosen CB, Gores GJ, Heimbach JK. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012 Jul;143(1):88-98.e3; quiz e14. doi: 10.1053/j.gastro.2012.04.008. Epub 2012 Apr 12.
citation: Ethun CG, Lopez-Aguiar AG, Anderson DJ, Adams AB, Fields RC, Doyle MB, Chapman WC, Krasnick BA, Weber SM, Mezrich JD, Salem A, Pawlik TM, Poultsides G, Tran TB, Idrees K, Isom CA, Martin RCG, Scoggins CR, Shen P, Mogal HD, Schmidt C, Beal E, Hatzaras I, Shenoy R, Cardona K, Maithel SK. Transplantation Versus Resection for Hilar Cholangiocarcinoma: An Argument for Shifting Treatment Paradigms for Resectable Disease. Ann Surg. 2018 May;267(5):797-805. doi: 10.1097/SLA.0000000000002574.