Trial Title:
Evaluation of Combined Modality Protons and Hepatic Transplantation for Hilar Cholangiocarcinoma
NCT ID:
NCT06434493
Condition:
Cholangiocarcinoma
Conditions: Official terms:
Cholangiocarcinoma
Klatskin Tumor
Gemcitabine
Capecitabine
Conditions: Keywords:
proton beam therapy
protons
evaluative commissioning
liver transplant
Study type:
Interventional
Study phase:
N/A
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Radiation
Intervention name:
Proton Beam Therapy
Description:
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)
Arm group label:
Proton Beam Therapy
Intervention type:
Drug
Intervention name:
Concurrent oral capecitabine chemotherapy
Description:
All patients to be offered concurrent oral capecitabine 625mg/m2 twice daily on radiation
days
Arm group label:
Proton Beam Therapy
Intervention type:
Drug
Intervention name:
Cisplatin & Gemcitabine intravenous chemotherapy
Description:
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.
Arm group label:
Proton Beam Therapy
Intervention type:
Procedure
Intervention name:
Orthotropic Liver Transplant
Description:
If still eligible after neoadjuvant treatment (PBT + capecitabine), patients will be
added to the liver transplant waiting list.
Arm group label:
Proton Beam Therapy
Summary:
Proton Beam Therapy (PBT) is an advanced radiotherapy technique. There are two National
Health Service (NHS) PBT treatment centres in the United Kingdom (UK), in Manchester and
London. The NHS is committed to ensuring the best use of this limited resource by
investigating which patients will benefit from PBT.
Evaluative Commissioning in Protons (ECIP) is a programme of studies exploring the role
of PBT in different types of cancer. The studies are funded by NHS England. ECIP studies
are not randomised studies, which means that all eligible patients will be offered PBT.
Any eligible patient in the UK can be referred, and accommodation is available for
patients who don't live close to a PBT centre.
The main benefit of PBT, compared with standard photon radiotherapy, is the predicted
reduction in radiation dose to surrounding healthy tissues. With photon radiotherapy,
some radiation passes beyond the target area, affecting healthy tissues and causing
side-effects. With PBT, the radiation dose stops within the target area, causing less
damage to surrounding tissues, and limiting side effects.
EMPHATIC is a study within the ECIP programme. In EMPHATIC, the investigators are looking
to see whether a combination of treatments, including PBT, chemotherapy and a liver
transplant, can be used to treat patients with cholangiocarcinoma (bile duct cancer).
EMPHATIC offers patients whose cancer can't be removed with surgery (unresectable) a
potentially curative treatment option. There is evidence that liver transplant is a
curative treatment option in patients with cholangiocarcinoma. There is a risk that the
cancer may grow or spread whilst waiting for a transplant, potentially making patients
ineligible. PBT and chemotherapy is thought to be the best way to control the cancer,
until a liver transplant can be performed. EMPHATIC will look at how a combination of PBT
and chemotherapy, followed by a liver transplant, can be used to curatively treat
patients with unresectable cholangiocarcinomas.
Detailed description:
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
General criteria
- Age 17 years and over
- Performance status 0 or 1 (Eastern Cooperative Oncology Group)
- Suitable for liver transplantation as determined by Multi Disciplinary Team (MDT)
- Able to tolerate neoadjuvant therapy.
- A history of primary sclerosing cholangitis (PSC) will be a necessary eligibility
criterion at the start of the study. Part-way through recruitment to the study, the
eligibility criteria may be broadened, allowing patients with sporadic / non-PSC
unresectable cholangiocarcinoma to also be considered. The decision to do this will
be taken by the Study Management Group, who will be monitor results closely,
following an interim analysis after the first 10 patients. Suitability for
Orthotropic Liver Transplant will continue to be confirmed in the regional Hepato
Biliary cancer MDT.
Specific criteria
- Presence of a dominant hilar stricture or mass <3cm on cross-sectional imaging
- Histologically proven cholangiocarcinoma by brush cytology or biopsy via Endoscopic
Retrograde Cholangiopancreatography (ERCP) or Percutaneous Transhepatic
Cholangiography (PTC)
- No metastatic disease, including to regional lymph nodes.
Exclusion Criteria:
General criteria
- Inability to consent
- Poor performance status
- Failed fitness assessment
- Extrahepatic disease at any stage of presentation, assessment and treatment
- Prior biliary resection or hilar dissection for attempted resection within the past
12 months
- Prior malignancy in the last 5 years (excluding early breast, prostate, cervix and
non melanoma skin cancers)
Specific criteria
- Estimated Glomerular Filtration Rate (eGFR) <30
- Prior radiation to the upper abdomen
- Uncontrolled infection
- Duodenal invasion
Gender:
All
Minimum age:
17 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
November 1, 2024
Completion date:
June 1, 2029
Lead sponsor:
Agency:
The Christie NHS Foundation Trust
Agency class:
Other
Collaborator:
Agency:
University College London Hospitals
Agency class:
Other
Collaborator:
Agency:
University College, London
Agency class:
Other
Collaborator:
Agency:
Royal Free Hospital NHS Foundation Trust
Agency class:
Other
Source:
The Christie NHS Foundation Trust
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06434493
