Ignite Creation Date:
2024-06-16 @ 11:49 AM
Last Modification Date:
2024-10-26 @ 3:30 PM
Study NCT ID:
NCT06434493
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-05-30
First Post:
2024-04-25
Brief Title:
Evaluation of Combined Modality Protons and Hepatic Transplantation for Hilar Cholangiocarcinoma
Sponsor:
The Christie NHS Foundation Trust
Organization:
The Christie NHS Foundation Trust
Study Overview
Official Title:
Evaluation of Combined Modality Protons and Hepatic Transplantation for Hilar Cholangiocarcinoma an Evaluative Commissioning in Protons Study
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
EMPHATIC
Brief 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 dont 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 cant 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
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 dont 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 cant 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 75 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 199 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 n156 were 712 In patients who had neoadjuvant therapy prior to transplantation n272 the survival improved to 828 at 13 and 5 years respectively
The cancer recurrence rate was 517 in patients who did not receive neoadjuvant therapy compared to 241 for patients who had Only 4 of the 20 studies reported pre-transplant histological confirmation of adenocarcinoma or malignantsuspicious cells on cytology 98 of liver explants from studies not using neoadjuvant therapy confirmed malignancy compared to 505 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 chemoradiotherapy 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 eg 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
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 75 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 199 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 n156 were 712 In patients who had neoadjuvant therapy prior to transplantation n272 the survival improved to 828 at 13 and 5 years respectively
The cancer recurrence rate was 517 in patients who did not receive neoadjuvant therapy compared to 241 for patients who had Only 4 of the 20 studies reported pre-transplant histological confirmation of adenocarcinoma or malignantsuspicious cells on cytology 98 of liver explants from studies not using neoadjuvant therapy confirmed malignancy compared to 505 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 chemoradiotherapy 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 eg 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None