The primary objective of this project is to evaluate the primary and secondary technique effectiveness of IRE for centrally located colorectal liver metastases that are neither amenable for resection nor for other local ablation methods due to the…
ID
Source
Brief title
Condition
- Other condition
- Hepatobiliary neoplasms malignant and unspecified
- Hepatobiliary therapeutic procedures
Synonym
Health condition
colorectale levermetastasen
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is efficacy of IRE as expressed in primary technique
effectiveness (by perfoming imaging after 3, 6, 9 and 12 months) also expressed
by the local IRE site recurrence (LSR) on a per-lesion basis, and secondary
technique effectiveness on a per-lesion basis after repeat procedures for local
recurrences whenever indicated.
Secondary outcome
Secondary endpoints are (1) safety, derived from number and grade of (serious)
adverse events using the common terminology reporting criteria (CTCAE version
3.0) as recommended by the CIRSE quality approvement guidelines, (2) technical
success, defined as the ability to successfully administer all pulses and to
have complete tumor coverage on immediate post-IRE imaging (by IOUS or CT) (3)
feasibility of cross-sectional imaging modalities to detect local recurrences
after IRE, and (4) symptomatic response using specific quality of life
questionnaires.
Background summary
Colorectal carcinoma is one of the most common malignancies in the Western
world. 40-60% of the patients develop liver metastases in the course of the
disease. Surgical resection is still the treatment of choice but unfortunately
up to 70% of the patients are not eligible for resection. Selected patients are
offered other local treatment modalities like radiofrequency ablation (RFA),
microwave ablation and stereotactic ablative radiation therapy (SABR). A
shortcoming of these modalities is that they are not suitable for lesions close
to large vessels and/or bile ducts: the heat can destruct the bile ducts,
leading to biliary complications and the vicinity of large vessels can lead to
inadequate heating due to *heat-sink* (where tumor cells adjacent to a large
vessel are prevented from adequate heating due to flowing blood carrying away
the heat), which causes a higher percentage of local recurrences. Therefore,
the search for new local treatment therapies is ongoing.
Irreversible electroporation (IRE) is an ablation technique that takes
advantage of the electric potential gradient that exists across cell membranes.
The application of an electric field across a cell alters the transmembrane
potential. On reaching a sufficiently high voltage, the phospholipid bilayer
structure of the cell membrane is permanently disrupted, inducing apoptosis.
Recent findings resulting from animal studies using IRE on normal tissue show a
sharply demarcated treatment area, with preservation of the - acellular -
connective tissue architecture and major blood vessels in the ablated area.
This is in contrast to thermal ablation techniques, where denaturation of
proteins causes disruption of the connective tissue, destroying the anatomical
framework. IRE relies on electrical energy, not thermal energy, for achievement
of cell death and appears to be unaffected by heat-sink. This suggests a
potentially more effective treatment of an area with tumor cells in close
proximity to large vessels, such as centrally located liver lesions. In
addition, IRE has demonstrated the potential for real-time monitoring with
ultrasonography (US). Electroporation leaves supporting tissue largely
unaffected so the structure of large blood vessels, bile ducts, ureters and
nerves is preserved.
With these distinctive characteristics, IRE has the potential to become
a successful alternative ablation method for solid tumors, especially in areas
around large blood vessels and vulnerable structures such as centrally located
colorectal liver metastases (CRLM) that are not amenable for resection or
thermal ablation.
Study objective
The primary objective of this project is to evaluate the primary and secondary
technique effectiveness of IRE for centrally located colorectal liver
metastases that are neither amenable for resection nor for other local ablation
methods due to the proximity of vital structures. Imaging will be performed
respectively 2 weeks post-IRE and after 3, 6, 9 and 12 months Secondary
objectives are safety, technical success and characterization of CT-, MRI,
PET-CT and PET-MRI findings after IRE to determine the utility of these
findings in the accurate assessment of the ablation zone and early detection of
local site recurrence.
Study design: Multi-center combined phase I/II cohort study.
Study design
Multi-center phase II cohort study.
Intervention
Patients with CRLM who are considered candidates for local therapy, based on
their tumor load, medical history and general health status, but who are not
suitable for resection or thermal ablation due to the anatomical location of at
least one of the lesions, will be included after careful judgment in consensus
by our multidisciplinary liver team. Limited extrahepatic disease is not a
contra-indication whenever these lesions can be treated as well, during or
within 4 weeks after the IRE procedure. After study inclusion, patients will
undergo percutaneous or open IRE. Percutaneous procedures are performed under
CT-guidance with or without ultrasound (US) guidance. Open procedures are
performed with intra-operative ultrasound (IOUS). After correct placement of
the electrodes IRE will be performed under ECG monitoring (70 pulses; pulse
length 90µs per pulse; 1200-1500V/cm; 20-50Ampere; electrode distance 1.5-2.5
cm; active working length 2.0cm) between all electrode pairs (NanoKnife,
Angiodynamics, Latham, NY, USA). After the IRE procedure, additional CRLM can
be resected or treated with RFA or MWA within the same session. Follow-up will
be with PET-CT (including ceCT) (and PET-MRI including ceMRI in VUmc only).
Study burden and risks
Preclinical as well as clinical studies show a low complication profile in
comparison to other local treatment modalities in the liver. Because of the
high voltage used with IRE, the procedure carries a small risk of inducing
cardiac arrhythmias, although since the use of the Accusync ECG gating device,
which enables synchronized pulsing, no clinically significant arrhythmias have
been observed within the registry (now including >1400 patients including at
least 30 patients treated in our institution so far for heterogeneous salvage
indications such as participation in our COLDFIRE-1 ablate and resect study for
resectable CRLM). Because of the non-thermal treatment effect IRE is presumably
a safer option causing less collateral damage to adjacent or inlaying vital
structures. The NanoKnife IRE system is CE marked and FDA approved for
image-guided ablation of soft tissue in humans. Patients who agree to
participate in the study will undergo IRE of liver lesions not considered
treatable by resection or thermal ablation. They will undergo follow-up PET-CT
(including ceCT) (and PET-MRI including ceMRI in VUmc) performed on the same
day at 6 weeks, and after 3, 6, 9 and 12 months after IRE. Additionally PET-MRI
is used to investigate its feasibility in the follow-up to detect local
recurrences as compared to PET-CT and ceCT. In case of local site recurrence,
patients will be re-treated whenever feasible with the most suitable therapy.
De Boelelaan 1117
Amsterdam 1081 HZ
NL
De Boelelaan 1117
Amsterdam 1081 HZ
NL
Listed location countries
Age
Inclusion criteria
Screening must be performed no longer than 4 weeks prior to study inclusion. Subjects are eligible if they meet the following criteria:
• Histological or cytological documentation of primary colorectal tumor;
• Previous induction chemotherapy due to unresectability; no intra- or extrahepatic disease progression under induction chemotherapy; OR
• Previous chemotherapy for other CRLM, now presenting with renewed CRLM unsuitable for resection or thermal ablation;
• Liver metastases F-18-FDG PET avid and visible on ceCT, size <= 3,5 cm and not eligible for resection or thermal ablation due to location close to a vessel or bile duct;
• Age >= 18 years;
• ASA classification 0 - 3;
• Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to definite inclusion:
o Hemoglobin >= 5.6 mmol/L;
o Absolute neutrophil count (ANC) >= 1,500/mm3;
o Platelet count >= 100*109/l;
o Total bilirubin <= 1.5 times the upper limit of normal (ULN);
o ALT and AST <= 2.5 x ULN
o Serum creatinine <= 1.5 x ULN or a calculated creatinine clearance * 50 ml/min;
o Prothrombin time or INR < 1.5 x ULN;
o Activated partial thromboplastin time < 1.25 x ULN (therapeutic anticoagulation therapy is allowed if this treatment can be interrupted as judged by the treating physician)
• Written informed consent
Exclusion criteria
Subjects who meet the following criteria at the time of screening will be excluded:
• Lesion > 3,5 cm size;
• History of epilepsy;
• Extrahepatic metastases rendering local therapy unfeasible;
• History of cardiac disease:
o Congestive heart failure >NYHA class 2;
o Active Coronary Artery Disease (defined as myocardial infarction within 6 months prior to screening);
o Cardiac arrhythmias requiring anti-arrhythmic therapy or pacemaker/ICD (beta blockers are permitted);
• Uncontrolled hypertension. Blood pressure must be <=160/95 mmHg at the time of screening on a stable antihypertensive regimen;
• Compromised liver function (e.g. signs of portal hypertension, INR > 1,5 without use of anticoagulants, ascites);
• Pregnant or breast-feeding subjects;
• Immunotherapy <= 6 weeks prior to the procedure;
• Chemotherapy <= 6 weeks prior to the procedure;
• Use of anti-convulsives and anti-arrhythmic drugs other than beta blockers for antiepileptic or antiarrhythmic purpose;
• Allergy to contrast media which cannot be adequately prevented with the standard contrast allergy prevention regimen;
• Any condition that is unstable or that could jeopardize the safety of the subject and their compliance in the study
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 |
|---|---|
| CCMO | NL47818.029.14 |