Liver Transplant Combined With Neoadjuvant Chemo-radiotherapy in the Treatment of Unresectable Hilar Cholangiocarcinoma. A Prospective Multicenter Study.

Unresectable Cholangiocarcinoma Clinical Trial

Official title:

Liver Transplant Combined With Neoadjuvant Chemo-radiotherapy in the Treatment of Unresectable Hilar Cholangiocarcinoma. A Prospective Multicenter Study.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04378023
• Other study ID #: hCCA-LT
• Status: Recruiting
• Start date: April 24, 2020
• Est. completion date: June 1, 2025

Study information

• Verified date: September 2023
• Source: Hospital Vall d'Hebron
• Contact: CRISTINA DOPAZO, MD/PhD
• Phone: +34932746113
• Email: cristina.dopazo[@]vallhebron.cat
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 34
• Est. completion date: June 1, 2025
• Est. primary completion date: June 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Cholangiocarcinoma
• Klatskin Tumor
• Unresectable Cholangiocarcinoma

Intervention

Drug:
• Neoadjuvant Chemo-radiotherapy
Patients will receive neoadjuvant radiotherapy (External - 50-54 grays) following by concomitant oral capecitabine (825mg/m2 bid).Thereafter, gemcitabine iv (1000mg/m2) plus cisplatin iv (25mg/m2) will be administered the day 1 and 8 every 21 days until transplant.

Procedure:
• Liver Transplantation
If no spread disease is discovered after neoadjuvant treatment, the patient will be listed for liver transplantation.

Locations

Country	Name	City	State
Spain	Department of HPB Surgery and Transplants, Hospital Vall d´Hebron	Barcelona

Sponsors (1)

Lead Sponsor	Collaborator
Hospital Vall d'Hebron

Country where clinical trial is conducted

Spain, 

References & Publications (5)

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 — View 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, S — View 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. — View 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: 10.109 — View 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- — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival at 1, 3, and 5 years post-transplant		5 years
Secondary	Recurrence free survival at 1, 3 and 5 years post-transplant		5 years
Secondary	Intention-to-treat survival of overall patients included in the study at 1,3 and 5 year		5 years
Secondary	The rate of patients included in the study who are finally transplanted.		5 years