In this pilot-study we investigate the safety, feasibility and efficacy of IRE in locally advanced pancreatic carcinoma. We hypothesize that IRE of the pancreas is a safe treatment that will cause few complications. Moreover, we expect the treatment…
ID
Source
Brief title
Condition
- Exocrine pancreas conditions
- Appetite and general nutritional disorders
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome of the study is the safety of IRE for the treatment of locally
advanced pancreatic carcinoma, By registration and analysis of adverse events
and serious adverse events, incidence and severity of complications within 90
days after the intervention are investigated and morbidity and mortality will
be determined. Late complications that might be related to the intervention
(listed in the study protocol under paragraph 12.1), will always be registered
and reported if necessary (in case of SAE's). These results will be compared to
patients that have undergone radio- and or chemotherapy alone.
Secondary outcome
Secondary parameters are (see paragraph 2.1.2. from the project protocol):
- Feasibility: parameters are willingness of patients to participate, number of
eligible patients, total procedure time, ablation time, number of tme of
replacement of the electrodes (expressed in learning curve)
-Efficacy, as expressed in:
1. Symptomatic response: Quality of life, pain registration and pain medication
and general performance status
2. Tumor evaluation: Size and shape of the ablation area, ablation success and
local recurrence rate (by CT and MRI)
- Immunologic response: by investigating the T-cell specific immune reaction,
before, 2 weeks and 3 months after IRE.
- Exocrine pancreatic function, smaal bowel absorption capacity and body fat
composition
Background summary
Cancer of the exocrine pancreas is the fourth leading cause of cancer-related
death in Western-Europe and the US and is second only to colorectal cancer as a
cause of digestive cancer-related death. The majority of these tumors (85
percent) are adenocarcinomas arising from the ductal epithelium.
Surgical resection is the only potentially curative treatment. Unfortunately,
because of the generally late presentation of the disease, only 15 to 20
percent of patients are candidates for operation with curative intent. Forty
percent of patients have locally advanced pancreatic carcinoma (LAPC) at the
time of diagnosis and another forty percent have concurrent metastatic disease.
The prognosis of pancreatic cancer is poor, even in those resected with
curative intent. The median survival after resection for pancreatic
adenocarcinoma is only 12.6 months, with a five-year survival of 3 to 31
percent (stage IA, 31.4%; IB, 27.2%; IIA, 15.7%; IIB, 7.7%; III, 6.8%; IV,
2.8%). In these patients, tumor size, nodal status and distant metastases all
affect the likelihood of death.
The primary goals of treatment for LAPC are palliation of intractable pain and
obstruction and improved overall survival. Observational and phase II studies
of patients with borderline and locally advanced tumors suggest a *downstaging
effect* of chemotherapy, with main agents gemcitabine, 5-FU, and cisplatinum,
in some rare cases allowing future resection. For patients with locally
advanced, nonmetastatic disease (typically a T4 lesion) and patients with
metastatic disease, chemoradiation (with gemcitabine or 5-fluorouracil (5-FU))
has proven to prolong survival and to improve quality of life (QoL). However,
median survival remains extremely poor at 6 to 11 months.
In the past years, non-surgical local treatment therapies for tumors in
different organs have broadly developed, such as cryoablation, and
heat-mediated ablation methods such as radiofrequency ablation (RFA), high
intensity focused ultrasound (HIFU), laser-ablation and microwave ablation
(MWA). These ablative therapies have also been studied in patients with LAPC to
achieve better palliation through cytoreduction. However, the use of thermal
tumor ablative techniques in the pancreas is limited due to the high risks
involved. Denaturation of proteins due to the heat causes disruption of
connective tissue and destroys the anatomical framework, leading to
pancreatitis and damaging major vascular structures in LAPC. A complete
ablation in LAPC is therefore not realistic.The so called *heat-sink* effect,
in which tumor cells adjacent to a large vessel are prevented from adequate
heating due to flowing blood, which cools adjacent tissue can lead to
incomplete ablation. This effect is another drawback in the performance of RFA
in LAPC, since the tumor is surrounded typically by major vessels.
Therefore, the search for new local ablative methods is ongoing, particularly
for pancreatic cancer. 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. Also, since IRE relies on electrical energy, and not on thermal
energy, its effectiveness appears to be unaffected by the *heat-sink* effect.
This suggests a potentially more effective treatment of an area with tumor
cells in close proximity to large vessels. Moreover, there are indications that
IRE induces a cellular immune response in the lymph nodes draining the area of
ablation. If this immune reaction can be harnessed, it could result in the
destruction of micro-metastases in the affected lymph nodes which could affect
survival. In addition, the procedure time will be much shorter compared to
thermal ablation methods and surgical resection.
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 the pancreas.
Early clinical data on IRE in the pancreas for treatment of pancreatic
carcinoma are promising, with good local palliation and local control and even
improved overall survival.
To investigate the safety, feasibility and efficacy of IRE in the treatment of
LAPC, we designed a pilot study. We hypothesize that IRE in the pancreas will
induce good symptom palliation and local control.
Study objective
In this pilot-study we investigate the safety, feasibility and efficacy of IRE
in locally advanced pancreatic carcinoma. We hypothesize that IRE of the
pancreas is a safe treatment that will cause few complications. Moreover, we
expect the treatment to lead to good local tumor control and better symptom
palliation. This will hopefully lead to an improvement of quality of life.
Also, the immunologic response that is induced by IRE will be investigated.
Furthermore, the influence of IRE on the exacrine pancreatic function and the
small bowel absorption capacity is investigated, which is important to guide
adequate adminitration of nutrition supplements and advice with respect to
intake.
Study design
Multi center pilot study
Intervention
Criteria for LAPC are based on the guidelines of the National Comprehensive
Cancer Network. For each individual patient, these criteria will be judged in
consensus by a multidisciplinary hepatobiliary team. A contrast enhanced
computed tomography scan (ceCT) of the chest and abdomen will be performed to
exclude metastatic disease. Baseline tumor marker CA 19-9 will be measured. To
investigate the cellular immune response, baseline mesothelin will be measured
and cultured in vitro, after which T-cell response will be examined. Quality of
life questionnaires will be filled in. A day before the procedure, pancreatic
MRI will be performed. Percutaneous IRE will be performed under CT-guidance.
After satisfactory electrode placement, tumor ablation with the NanoKnife will
be performed according to protocol under careful ECG-monitoring. Also, during
the procedure, possible epileptic activity will be recorded by
EEG-registration. Postprocedurally, pancreatic and hepatic enzymes will be
monitored. One day after the procedure, pancreatic MRI will be performed to
investigate the imaging after the procedure. Two weeks later, mesothelin will
be measured again to compare the immune response to mesothelin to baseline.
Follow-up will consist of regular assessment of performance status by the
physician, ceCT- and MRI -scanning and serum marker CA 19.9. To assess the
effect of the treatment on the quality of life, questionnaires will be filled
in. Furthermore, before and after the procedure, the exocrine pancreatic
function and smaal bowel absorption capacity is investigated by means of fecal
sampling and blood sampling, and the resting metabolism and body fat percentage
are measured.
Study burden and risks
Preclinical as well as clinical studies using IRE show a favorable complication
profile for local tumor treatment in comparison to other local treatment
modalities in distinct cases. IRE is a potentially useful technique to treat
tumors near vital structures, as is the case in pancreatic cancer. However, the
number of treated patients is still relatively small. Therefore, more
prospective studies are needed to evaluate the safety, feasibility,
effectiveness and potential benefits of this technique.
Patients with LAPC are confronted with a grave prognosis with a short life
expectancy and severe complications to be expected due to local tumor ingrowth
and metastatic disease. Treatment with the NanoKnife might be the only
potentially successful treatment with respect to local symptom palliation and
to achieve local tumor control. The first reports of patients with LAPC treated
with IRE are promising. In one study in which open IRE was performed on 54
patients, the results were compared to a control group that received standard
(radio)chemotherapy. The authors demonstrated that even in the patients who did
not undergo IRE, after 4 months of induction therapy, there remains significant
morbidity in those patients, which in some instances is as severe as in
surgical patients, or even worse. The authors state that the rationale that
patients with LAPC are spared surgical or interventional radiological therapy
is unsubstained and should continue to be evaluated even after initial
diagnosis.
In this study, we offer patients a potential method to prevent, delay and/or
decrease the expected complications or their severity from happening. We
hypothesize that treatment with the NanoKnife will lead to a drop in morbidity,
by achieving tumor size reduction without the necessity of performing extensive
surgery. Hopefully, tumor size reduction will decrease and delay pain and
obstructive complaints. In conclusion, the participants will undergo a new and
relatively experimental procedure that is regarded to be safe but carries a
certain risk, but if our hypothesis will prove to be right participants will
profit from better symptom palliation and have a better QoL and possibly better
OS. From this perspective, we believe the additional risk of treatment with the
NanoKnife is justified, for the best interest of the patient.
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 2 weeks prior to study inclusion. Subjects are eligible if they meet the following criteria:;* Histologic or cytologic confirmation of primary pancreatic carcinoma;
* Radiologic confirmation of unresectable pancreatic carcinoma without distant metastases by at least ceCT of chest and abdomen, performed maximum 2 weeks prior to the procedure;
* Maximum tumor diameter * 5 cm;
* Age * 18 years;
* ASA-classificaton 0 * 3;
* Life expectancy of at least 12 weeks;
* Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to definite inclusion;
- Hemoglobin * 5.6 mmol/L;
- Absolute neutrophil count (ANC) * 1,500/mm3;
- Platelet count * 100*109/l;
- Total bilirubine * 1.5 times the upper limit of normal (ULN);
- ALT and AST * 2.5 x ULN;
- Serum creatinine * 1.5 x ULN or a calculated creatinine clearance * 50 ml/min;
- Prothrombin time or INR < 1.5 x ULN;
- 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:
* Resectable pancreatic adenocarcinoma as discussed by our multidisciplinary hepatobiliary team;
* Extrapancreatic metastases;
* Successful downstaging after (radio)chemotherapy from previous unresectable/borderline tumor to resectable tumor;
* History of epilepsy;
* History of cardiac disease:
- Congestive heart failure >NYHA class 2;
- Active Coronary Artery Disease (defined as myocardial infarction within 6 months prior to
screening);
- Ventricular cardiac arrhythmias requiring anti-arrhythmic therapy or pacemaker (beta blockers for antihypertensive regimen 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);
* Uncontrolled infections (> grade 2 NCI-CTC version 3.0);
* Pregnant or breast-feeding subjects. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment;
* Immunotherapy * 6 weeks prior to the procedure;
* Chemotherapy * 6 weeks prior to the procedure;
* Radiotherapy * 6 weeks prior to the procedure;
* Concomitant use of anti-convulsive and anti-arrhythmic drugs (other than beta blockers for hypertension);
* Allergy to contrast media;
* Any implanted stimulation device;
* 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 | NL42888.029.13 |