To evaluate the efficacy of SBRT as additional treatment after standard care chemotherapy regarding tumor local control, toxicity, progression-free survival, overall survival and quality of life. In addition, to explore the value of immunodynamics…
ID
Source
Brief title
Condition
- Bile duct disorders
- Hepatobiliary neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main endpoint with regards to the radiotherapy is local tumor control. With
regards to the translational part of the study the aim is to explore the value
of immunodynamics in peripheral blood for predicting progression-free survival
in patients undergoing chemotherapy.
Secondary outcome
Toxicity, biliary stent-related events (SRE) (*), progression-free survival,
overall survival, quality of life.
(*) The definition of SRE in this study is based on the definition used in the
study by Lamarca et al. [1], and includes the following:
*A SRE is defined as any one or more of the following: (1) any episode of
jaundice which is considered significant enough for new stenting or medical
treatment and is confirmed by radiological imaging to be associated with
biliary dilatation; (2) any episode of infection which is clinically in keeping
with cholangitis (bile duct infection) requiring antibiotic therapy; (3)
bacteraemia with isolation in blood cultures of bacteria suspected to have
originated in the biliary tract; and (4) any episode of cholecystitis or
gallbladder perforation. The following will not be considered SREs: (1)
jaundice related to high tumour burden liver disease with no significant change
in biliary dilatation compared with previous imaging; (2) episodes of
neutropenic or non-neutropenic fever with no identified biliary focus; and (3)
patients with non-clinically significant biliary occlusion or biliary
dilatation (i.e., radiological evidence only with no jaundice, increasing
bilirubin, increasing liver function tests (LFTs), fever or evidence of
infection) who require no action (no new stenting or no new antibiotic
therapy).*
Reference:
[1]: https://doi.org/10.3748/wjg.v22.i26.6065
Background summary
For patients with perihilar cholangiocarcinoma, surgery is the only treatment
modality that can result in cure. Unfortunately, in the majority of these
patients the tumors are found to be unresectable at presentation due to local
invasive tumor growth or the presence of distal metastases. For patients with
unresectable cholangiocarcinoma palliative chemotherapy is the standard
treatment yielding an estimated median overall survival of 12-15.2 months.
There is no evidence from randomized trials that support the routine use of
stereotactic body radiation therapy (SBRT) for cholangiocarcinoma. However, the
STRONG phase 1 feasibility study, showed favorable outcomes regarding safety,
and that the therapy was generally well tolerated.
Based upon these observations, we propose a phase 2 multi-center study with
SBRT after chemotherapy in patients with unresectable perihilar
cholangiocarcinoma in order to further research the efficacy of adding SBRT to
standard care chemotherapy.
We will add an explorative translational research component to the study in
which peripheral immunodynamics (NF-kB and IFN/ISG) may help to predict
survival after chemotherapy and may also help to predict the value of
additional treatment with radiotherapy.
Study objective
To evaluate the efficacy of SBRT as additional treatment after standard care
chemotherapy regarding tumor local control, toxicity, progression-free
survival, overall survival and quality of life. In addition, to explore the
value of immunodynamics in peripheral blood for predicting PFS in patients
undergoing chemotherapy.
Study design
Phase II multicenter study. 30 patients will be included.
Intervention
SBRT will be delivered in 15 fractions of 4 to 4.5Gy after 8 cycles of
chemotherapy. In case of toxicity causing premature termination of systemic
treatment, the patient can still proceed to SBRT.
Study burden and risks
The phase 1 STRONG study evaluating toxicity of SBRT delivered in 15 fractions
in perihilar cholangiocarcinoma provided evidence that SBRT is a relatively
safe treatment with acceptable complication risks.
Expected associated gastrointestinal grade >=3 toxicity such as stomach or bowel
perforation, is expected to be low (<5%). The risk of biliary grade >=4 toxicity
with the SBRT protocol used in this trial is also expected to be low (<5%).
However, biliary toxicity grade 3 (cholangitis) was observed in 5 of 6 patients
(83%) in the STRONG 1 trial, and it was reversed by improving the biliary
drainage (stent placement).
The burden associated with the participation in this study includes: 1-3 visits
related to the preparation of the treatment with radiotherapy, 15 daily visits
for the treatment itself, 8 times filling in QoL evaluation forms. The two
blood samples required for the immunodynamics will be collected during
scheduled appointments for blood collection regarding the standard of care
treatment with chemotherapy. Regarding the radiotherapy, a standard follow-up
protocol will be followed, with the 1st year after SBRT every 3 months a visit
and from the 2nd year a minimum of 2 follow-up moments each year.
No DSMB will be installed in the present study. No interim analysis is planned
for this study.
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
The initial translational part of the study will be performed in patients with
unresectable pCCA eligible for gemcitabine-based chemotherapy (*). After
chemotherapy, the patients will proceed to SBRT if they are still eligible
based on the following inclusion and exclusion criteria (see below). It may
happen that patients do not give consent for the translational part of the
study, but they may wish to participate in the SBRT part of the trial and vice
versa.
Inclusion criteria translational part of the study:
In order to be eligible to participate in the translational part of the study,
a subject must be discussed in a liver tumor board, should be eligible for
gemcitabine-based chemotherapy (and immunotherapy, if applicable), and should
meet all of the following criteria pre-chemotherapy:
- pCCA according to the criteria of the Mayo Clinic, Rochester (22):
o Positive or strongly suspicious intraluminal brush cytology or biopsy or,
o A radiographic malignant appearing stricture plus either:
* CA 19-9>100 U/ml in the absence of acute bacterial cholangitis, or
* polysomy on fluorescence in situ hybridization (FISH), or
* a well-defined mass on cross sectional imaging
- One tumor mass
- Unresectable tumor or patient deemed unfit for surgery
- T1-T4 (AJCC staging 8th edition), N0-N2-M0 (AJCC staging 8th edition),
radiologically or pathologically suspect
o N1 is defined as one to three affected lymph nodes typically involving the
hilar, cystic duct, common bile duct, hepatic artery, posterior
pancreatoduodenal, and portal vein lymph nodes. N2 is defined as four
or more affected lymph nodes from the sites described for
N1.
o Endoscopic ultrasound (EUS) is leading in identifying pathological lymph
nodes compared to CT.
- In case of (underlying) liver cirrhosis: Child-Pugh A
- Age >= 18 years
- ECOG performance status 0-1
- Written informed consent for the translational part of the study
Inclusion criteria SBRT part of the study:
Additionally, to the criteria mentioned above, patients should meet the
following criteria to be eligible for the treatment with SBRT:
- Measurable disease to be selected as a target on a computed tomography (CT)
or magnetic resonance imaging (MRI) scan, according to RECIST 1.1 criteria
- Finished gemcitabine-based chemotherapy treatment, preferably 8 cycles. If
less cycles are given, patients are still eligible for this study
- Bilirubin <=3.0 times normal value (**), aspartate aminotransferase
(AST)/alanine transami-nase (ALT) <=5 times ULN
- Platelets >= 50x10E9/ l, Leukocytes > 1.5x10E9/l, Hemoglobin (Hb) > 6 mmol/l
- Willing and able to comply to the follow-up schedule
- Able to start SBRT within 12 weeks after completion of chemotherapy and
immuno-therapy (if applicable)
- Written informed consent for the SBRT part of the study
(*) Gemcitabine-based chemotherapy will most frequently include a combination
of gemcitabine and cisplatin for this patient population. However, when deemed
necessary by a medical oncologist, variations of this chemotherapy regimen
regarding the cisplatin may be applied. Such variations in chemotherapy
regimens will be allowed in this study. Gemcitabine-based chemotherapy will be
administered according to local practice.
(**) This corresponds to the threshold beyond which gemcitabine-based
chemotherapy is no longer administered to patients in Erasmus MC, and also
closely resembles the threshold beyond which gemcitabine and cisplatin combined
with immunotherapy (durvalumab) is no longer administered to patients in a
study by Oh et al. (bilirubin <=2.5 times normal value) [1].
[1]: https://doi.org/10.1056/EVIDoa2200015
Exclusion criteria
Exclusion criteria translational part of the study
- Prior surgery or transplantation of the liver
- Tumor extension in stomach, colon, duodenum, pancreas or abdominal wall
- Ascites
- Prior radiotherapy to the liver
- Current pregnancy
- Affected lymph nodes outside the regions described in the inclusion
criteria (D4)
Exclusion criteria SBRT part of the study:
Progression (local or distant) during or after chemotherapy
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT06493734 |
| CCMO | NL86210.078.24 |