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

A prospective multicentre pilot study which includes patients ≤ 70 years-old diagnosed of unresectable perihilar cholangiocarcinoma (pCCA) ≤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

Neoadjuvant treatment consisting of:

1. External beam radiotherapy at a total dose of 50-54 Gy, delivered in 25-27 fractions of 1.8-2 Gy per day over 5 weeks. Dose reduction may be considered if necessary, or stereotactic body radiotherapy (SBRT), to be agreed according to the center's clinical practice. 2. Capecitabine will be given concurrently with radiotherapy at a dose of 825 mg/m² orally twice daily, seven days a week. 3. Cisplatin 25 mg/m² on days 1 and 8 of each 21-day cycle + gemcitabine 1000 mg/m² on days 1 and 8 of each 21-day cycle until the time of transplantation (minimum 4 cycles).

As an alternative, neoadjuvant treatment without radiotherapy is proposed:

a. Cisplatin 25 mg/m² on days 1 and 8 of each 21-day cycle + gemcitabine 1000 mg/m² on days 1 and 8 of each 21-day cycle + durvalumab 1500 mg on day 1 of each 21-day cycle for 6 cycles (18 weeks).

Continue treatment for at least eight weeks without durvalumab (minimum 60-day wash-out period), while maintaining gemcitabine-cisplatin. During this period, pre-transplant evaluation is proposed to begin if there is no progression and/or to assess inclusion on the transplant waiting list, depending on the estimated waiting time.

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

NGS 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 the context of standard clinical care, to detect any recurrence.

• Recurrence free survival at 1, 3 and 5 years post-transplant [Time frame: 5 years]
• Intention-to-treat survival of overall patients included in the study at 1,3 and 5 year [Time frame: 5 years]
• The rate of patients included in the study who are finally transplanted. [Time frame: 5 years]