Evaluation of Combined Modality Protons and Hepatic Transplantation for Hilar Cholangiocarcinoma

Liver and bile duct resection with lymphadenectomy is the standard of care for patients with hilar cholangiocarcinoma. Unfortunately, resection is only possible in a minority of patients for many reasons including, the extent of cancer or the presence of background primary sclerosing cholangitis (PSC). For patients with a background of PSC, liver transplantation is a potential treatment, and it was recently approved as an indication for a commissioned pilot service evaluation of liver transplantation in the UK.

Until recently, the use of liver transplantation for hilar cholangiocarcinoma was confined to a few centres in the United States. The initial publications from the Mayo Clinic and Nebraska, as well as more recent experience from other centres, support strict selection protocols to identify patients likely to benefit from liver transplantation. In 2000, the initial experience at the Mayo Clinic in which 19 patients enrolled in a pre-transplant neoadjuvant therapy protocol was published. 11 patients underwent subsequent liver transplantation. Of the 8 with long term follow up (median 44 months), only one patient developed cancer recurrence. Similarly, the long-term experience of patients in Nebraska, where 11 patients underwent liver transplantation after neoadjuvant chemoradiotherapy was published in 2002. 5 of the 11 patients were alive and disease free at a median follow up of 7.5 years .

Most recent experience is based on adopting the Mayo protocol. In general, the inclusion criteria define patients with early cancers, with a dominant stricture or tumour less than 3cm. Intra and extrahepatic disease including any site of nodal metastases precluded selection. Controversially, histology or cytology was not considered essential for diagnosis of cholangiocarcinoma by most centres. Elevated Ca 19.9 of \>100, Fluorescence In Situ Hybridization (FISH) polysomy 9p21 or tumour mass in the presence of a dominant stricture were considered sufficient for enrolment. Prior (attempts at) trans-peritoneal biopsy was another exclusion criterion based on concerns of increased risk of tumour dissemination. Neoadjuvant therapy involved external beam radiation therapy (EBRT) with concurrent chemotherapy (chemo sensitisation), followed by brachytherapy whenever possible. Patients were then re-staged and remain on systemic chemotherapy until the time of transplant.

A recent review looked at all studies from 2000 until 2019. 20 studies with 428 patients were eligible for analysis. The pooled 1, 3-, and 5-year overall survival rates following liver transplantation without neoadjuvant therapy (n=156) were 71.2%. In patients who had neoadjuvant therapy prior to transplantation (n=272), the survival improved to 82.8% at 1,3 and 5 years respectively.

The cancer recurrence rate was 51.7% in patients who did not receive neoadjuvant therapy compared to 24.1% for patients who had. Only 4 of the 20 studies reported pre-transplant histological confirmation of adenocarcinoma or malignant/suspicious cells on cytology. 98% of liver explants from studies not using neoadjuvant therapy confirmed malignancy, compared to 50.5% in those who had received neoadjuvant therapy. Patients in whom malignancy was not found are presumed to have had complete pathological response to neoadjuvant therapy (approximately 50% following neoadjuvant therapy). Patients with background PSC had better outcomes compared to patients with de novo cancers.

Study Design \& development of an evaluative commissioning study within ECIP:

It is not possible to design EMPHATIC, a study for patients with unresectable cholangiocarcinoma, as a randomised controlled trial (RCT), because there is no ethically acceptable control arm. In an RCT, patients in a theoretical control arm would be offered either no transplant, or no neoadjuvant therapy prior to the transplant. Based on the published literature summarised above, the adverse anticipated outcomes of patients in such a control arm would not be considered justified.

Neoadjuvant therapy is required to control the tumour prior to transplant. In the Mayo protocol described above, patients received external beam (chemo)radiotherapy followed by brachytherapy, and thereafter received chemotherapy until the time of transplant. Unfortunately, in the UK, brachytherapy services were not seen as a viable option, and hence the Mayo protocol is not feasible.

There is good scientific rationale that proton beam radiotherapy (PBT) offers the optimal technique for delivering neoadjuvant therapy as it is non-invasive, and spares as much functional liver as possible, compared with alternatives such as photon-EBRT techniques or invasive techniques (e.g. brachytherapy). Compared with photon-EBRT techniques, PBT delivers highly conformal radiotherapy, with a significantly reduced integral body dose, and no exit beam. It is expected to be associated with an improved toxicity profile.

All patients to be offered neoadjuvant proton beam therapy to a dose of 45 Gray (Gy) in 15 fractions over 3 weeks, with a tumour boost to 67.5 Gray (Gy), and alongside concurrent oral capecitabine 625mg/m2 twice daily on radiation days.

Radiation: Proton Beam Therapy · Drug: Concurrent oral capecitabine chemotherapy · Drug: Cisplatin & Gemcitabine intravenous chemotherapy · Procedure: Orthotropic Liver Transplant

All patients to be offered neoadjuvant proton beam therapy to a dose of 45 Gray (Gy) in 15 fractions over 3 weeks, with a tumour boost to 67.5 Gray (Gy)

All patients to be offered concurrent oral capecitabine 625mg/m2 twice daily on radiation days

Following chemoradiotherapy (PBT + capecitabine), and whilst on the liver transplant waiting list, patients will be offered up to 6 cycles of standard chemotherapy with cisplatin and gemcitabine.

If still eligible after neoadjuvant treatment (PBT + capecitabine), patients will be added to the liver transplant waiting list.

Plazo: Up to 90 days post neoadjuvant chemo-radiation.

Incidence of Grade ≥ 3 toxicity using CTCAE (grades 0-5) up to 90 days following completion of neoadjuvant (chemo)-PBT and liver transplant. Higher score indicates worse outcome.

Plazo: 90 days post transplant.

The proportion of patients who, following neoadjuvant (chemo)-PBT, undergo a successful liver transplant (measured at 90 days post-transplant).

Plazo: Up to 1 year

Number of patients completing planned radiotherapy

Plazo: Up to 2 years

Rate of Common Toxicity Criteria for recording Adverse Events (CTCAE) Grade 3 and above toxicity (Grades 0-5). Higher score may mean a worse outcome.

Plazo: At 1 year

Calculated from date of last PBT treatment and defined as time to death or censoring at 1 year.

Plazo: At 1 year

Calculated from date of liver transplant and defined as time to death or censoring at 1 year.

Plazo: At 1 year

Calculated from date of transplant and defined as time to death or censoring at 1 year.

Plazo: At 1 year

Calculated from the date the patient was added to the transplant waiting list and defined as time to death or censoring at 1 year.

Plazo: At 1 year

Calculated as time to cancer recurrence or death whichever is earliest, from date of transplant, with censoring at 1 year.

Plazo: Up to 6 months following transplant

Described as local, regional or metastatic disease

Plazo: Up to 2 years

Reported as time to loss of cancer control with censoring at time of transplant

Plazo: Up to 2 years

Reported as time to loss of cancer control with censoring at date of removal from transplant waiting list

Plazo: Within 3 months of surgery

Surgical complication rates according to Clavien Dindo scale, measured from grades 1-5, higher grade may mean worse outcome.

Plazo: Up to 2 years

Review of patient pathway deliverability defined as time interval from patient referral to the start of chemo-PBT treatment

Plazo: Up to 2 years

Measured in days from last day of PBT to date of transplant

Plazo: Up to 2 years

Measured in weeks from transplant listing date to liver transplant date

Plazo: At 6 months, 12 months, 18 months and 24 months following the opening of the study

Review annual referral rates to the study

Plazo: At 6 months, 12 months, 18 months and 24 months following the opening of the study

Number of patients participating in the study

Evaluation of Combined Modality Protons and Hepatic Transplantation for Hilar Cholangiocarcinoma (an Evaluative Commissioning in Protons Study)