Neoplasms

Symptoms and General Pathology

All Conditions

Digestive System Diseases

Neoplasm Metastasis

Liver Diseases

Liver Neoplasms

Neoplastic Processes

Gastrointestinal Diseases

Gastrointestinal Neoplasms

Digestive System Neoplasms

Hematinics

All Drugs and Chemicals

Liver Extracts

Single arm study: Irreversible electroporation of colorectal liver metastasis

Tumor ablation with irreversible electroporation with the NanoKnife

Irreversible electroporation (IRE)

Martijn R Meijerink, MD, PhD

Petrousjka M van den Tol, MD, PhD

C van Kuijk, Prof. Dr.

Irreversible electroporation is a new, minimal-invasive image-guided treatment to treat tumors near or around vulnerable structures, such as central liver tumors.

To investigate the safety and efficacy of IRE in the treatment of colorectal liver metastases, patients with resectable colorectal liver metastases undergo IRE and resection of the metastases in the same session. After resection, the specimen is examined macroscopically to determine vitality using a specific vitality staining (triphenyl-tetrazoliumchloride) and to visualize the exact ablation zone. Subsequently, histopathologic examination is used to determine type of cell death and the microscopic ablation zone.

The investigators hypothesize that IRE is a safe effective method to treat colorectal liver metastasis and that cell damage and cell death is demonstrated as soon as 1 hour after the procedure.

This pilot-study is designed to determine the safety of IRE using the NanoKnife on colorectal liver metastases. Secondary, feasibility, histological effect on the ablated cells and exact shape and size of the ablated area will be determined.

Study design:

Patients with resectable CRLM (1 lesion or more) undergoing surgical resection of the metastases will receive study information to participate in this pilot-study. Limited extrahepatic disease is not contra-indicated.

Patients will undergo a general pre-procedural work-up: total body FDG PET-CT, ceCT of the abdomen, anesthetic review with special attention to cardiac history, baseline full blood examination, urea and electrolytes, renal function tests, liver enzymes and coagulation profile test.

The procedure is conducted under general anaesthesia with muscle relaxants to prevent patient motion and epidural analgesia. A laparotomy will be performed at the surgeon's discretion for optimal liver exposure. Intraoperative ultrasonography (IOUS) will be carried out by an experienced interventional radiologist for exact evaluation of maximum diameter, number and location of all lesions and to confirm resectability (if lesions prove not to be resectable, only RFA will be performed according to standard of care). All lesions will be biopsied. The electrodes will be placed under ultrasound guidance according to manufacturer's guidelines in the lesions that are eligible for resection. After correct placement of the electrodes the lesions will be ablated according to protocol with ECG synchronization and the ablation zone is determined by US.

During the procedure the cardiac rhythm will be closely monitored and a defibrillator will be present at all times.

After IOUS confirmation of complete ablation (at least 30 minutes after ablation of the lesion) the surgeon will perform a partial liver resection / metastasectomy including the ablated lesions and the surgical procedure is ended as usual. After the treatment of all lesions with the NanoKnife and before resection (and RFA of unresectable CRLM if indicated), blood samples will be drawn to determine renal function and liver enzymes since cell destruction may cause biochemical abnormalities.

The resected specimen will be transported to the department of pathology. After sectioning, the specimen will be photographed extensively to determine exact shape and size of the ablated area. One slice is stained in vitality-staining (TTC), to macroscopically distinguish viable from nonviable tissue.

After formalin fixation, the specimen is stained and examined under light microscopy according to standard protocol to determine radicality of the resection margins. Additionally, special attention will be given to indications for cellular damage, vessel wall damage and size and shape of the ablation zone. Caspase-3 and BAX/BCL-2 analysis will be performed to investigate the induction of apoptosis. The results will be compared to the result of the biopsy taken prior to ablation.

On day one and day three post-operatively regular blood samples will be drawn, including liver enzymes and renal function tests. After discharge, out of hospital follow-up will be according to liver surgery protocol. The investigators aim to include 10 patients in this pilot study.

Monitoring:

An independent monitor (quality officer) will monitor all study data according to Good Clinical Practice (GCP). The informed consent of selected individual participants will be checked. Source Data verification will be performed during onsite monitoring (to verify if all data on the Case Report Form are in accordance with the source data). The intensity of this verification is in relation to the risk associated with the intervention investigated. Data that by all means will be checked are the informed consent form, in- and exclusion criteria and the primary outcome. The monitor will also verify if all (S)AE's and SUSAR's are reported adequately and within the time that is determined by legal rules and regulations.

Prospective ablate and resect trial where 10 patients with resecatble colorectal liver metastases were treated with irrevrsible electroporation approximately 2 hours before the tumors were resected.

Pilot-study: Non-thermal Ablation Using Irreversible Electroporation to Treat Colorectal Liver Metastases

Pilot-study: Non-thermal Ablation Using Irreversible Electroporation (IRE) to Treat Colorectal Liver Metastases - "Ablate and Resect"

The investigators hypothesize that it will initially take several replacements before adequate positioning is obtained. It is suspected that placement of the electrodes will become easier in the course of the study and that procedure time will decrease (expressed in learning curve).

Safety using Common terminology Criteria for Adverse Events (CTCAE). Since the ablated tissue will be resected we expect procedure-related complications to occur mainly during the procedure.

Cell death of CRLM after IRE is demonstrated macroscopically by using vitality-staining with triphenyl-tetrazoliumchloride (TTC). Since and shape of the ablation zone is assessed. Immunohistologic examination is used to more specifically assess microscopic cell damage and vessel wall damage. Apoptotic markers are used.

Amsterdam UMC, location VUmc

Dr. M.R. Meijerink

Colorectal Neoplasms

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

Micronutrients

Oxaliplatin

Leucovorin

Fluorouracil

Irinotecan

Floxuridine

Antimetabolites

Patients with potentially resectable colorectal liver metastases will undergo hepatic artery infusion pump placement. Subsequent hepatic artery infusion of floxuridine via the HAIP as well as standard of care Dutch systemic chemotherapy (FOLFOX or FOLRIRI) will be administered in a combined chemotherapy schedule.

Administration of intra-arterial floxuridine via the HAIP (HAIP chemotherapy) to the liver with concomitant Dutch standard of care systemic FOLFOX (5-FU, leucovorin and oxaliplatin) or FOLFIRI (5-FU, leucovorin and irinotecan).

Surgical implantation of hepatic artery infusion pump (HAIP) followed by administration of the combined chemotherapy (HAIP and systemic).

Tricumed IP2000V infusion pump

Myrtle F Krul, MD

Roos Steenhuis, MSc

Koert FD Kuhlmann, MD, PhD

The PUMP-IT study is designed to prove the feasibility of HAIP chemotherapy with concomitant standard systemic chemotherapy (FOLFOX and FOLFIRI) in the Netherlands. This study will include patients with both unresectable CRLM and resectable CRLM with an indication for upfront systemic therapy (further referred to as potentially resectable CRLM), without extrahepatic metastases. The study will be performed in two tertiary referral centers in the Netherlands.

RATIONALE - Colorectal cancer (CRC) is the third most common cancer with an annual incidence of 14.000 patients in the Netherlands. Of all patients with metastases, 32% have isolated colorectal liver metastases (CRLM). Local treatment of CRLM, i.e. resection, ablation and/or stereotactic radiotherapy, is the only potentially curative option. Unfortunately over 75% of these patients have CRLM which are (initially) not suitable for such local treatment.

Current treatment of unresectable CRLM includes subsequent lines of systemic (chemo)therapy aiming to convert the CRLM from an unresectable to a resectable or local treatable state in order to prolong survival. Conversion rates of modern first line systemic chemotherapeutic regimens, as described in multiple retrospective studies with highly selected patients, are observed in 10-76% of patients, resulting in a 5-year survival of 33-43% after conversion. Patients with progressive disease on first line therapy are offered second line systemic therapy. Conversion during second line systemic therapy is rare and described in only 7-13.5% of patients. These patients have a poor prognosis with a median OS of approximately 10-15 months. However, overall survival (OS) of patients undergoing local treatment after conversion on second line systemic therapy is comparable to what is observed after conversion on first line systemic therapy.

Hepatic arterial infusion pump (HAIP) can deliver high-dose regional chemotherapy to the CRLM using their unique arterial blood supply. Floxuridine is used for HAIP chemotherapy because of the advantages of having a half-life of ten minutes, a 95% first-pass effect and allowing high intrahepatic dosing resulting in increased hepatic exposure by a factor 400, with minimal systemic exposure (e.g. complications). These specific properties of HAIP chemotherapy make it possible to combine high-dose local HAIP therapy with standard of care systemic therapy.

Several single center studies from Memorial Sloan Kettering Cancer Center (MSKCC) (New York, USA) have shown high response rates with HAIP chemotherapy in combination with systemic therapy for unresectable CRLM. Conversion to resection of the initially unresectable CRLM have been observed in up to 57% of chemo-naïve patients and in 20%-38% of patients with prior systemic therapy treated with the combination of HAIP and systemic therapy. Irrespective of conversion, the combined therapy resulted in a median OS of 50.8-76.6 months and a 5-year OS of 51.9% for chemo-naïve patients. The median and 5-year OS was 27.7-35 months and 27.9%, respectively, for patients who have been treated with systemic therapy before.

Although these results are impressive, they come from a single center and have not yet been confirmed elsewhere. Most important reasons were the technically challenging surgical procedure of HAIP implantation and the need for stringent monitoring and specific management of HAIP chemotherapy requiring a highly skilled multidisciplinary treatment team.

A study investigating combined treatment is required to prove feasibility in a multicenter setting outside MSKCC before a multicenter randomized phase III trial can be initiated in the Netherlands.

STUDY DESIGN - All eligible patients who signed informed consent (registration) and meet all inclusion criteria (inclusion) will undergo surgical HAIP implantation. HAIP function is evaluated with a perfusion test during surgery and postoperatively before starting drug treatment. Start of combined HAIP chemotherapy and systemic chemotherapy is aimed within 6 weeks postoperatively. Clinical and laboratory evaluations and chemotherapy administration are scheduled every two weeks. Response evaluations will be conducted with CT thorax/abdomen and CEA measurement every 2 HAIP cycles (every 4 systemic chemotherapy cycles) during combined therapy.

The combined therapy cycles are continued until disease progression, severe toxicity, CRLM conversion to surgical local treatment or patients withdrawal. After HAIP chemotherapy discontinuation, treatment and/or follow-up are according to standard clinical practice.

Patients with potentially resectable (i.e. unresectable or upfront resectable with an indication for upfront systemic therapy) will receive hepatic artery infusion pump chemotherapy, consisting of floxuridine (FUDR), combined with standard of care systemic therapy (FOLFOX or FOLFIRI).

Hepatic Arterial Infusion Pump Chemotherapy Combined With Systemic Chemotherapy (PUMP-IT)

Hepatic Arterial Infusion PUMP Chemotherapy Combined With systemIc chemoTherapy for Potentially Resectable Colorectal Liver Metastases: The PUMP-IT Study.

The quality of life will be examined with validated questionnaires (EORTC QLQ-C30 \& EQ-5D-3L).

The percentage of patients that complete two cycles of combined chemotherapy (HAIP chemotherapy and systemic therapy) after being scheduled for surgical implantation.

Surgical complications will be defined according to Clavien-Dindo surgical complications score. Complications of Clavien-Dindo grade 3 or higher are recorded for the first 90 days after surgery. Postoperative complications include those related to the HAIP implantation. Postoperative mortality is defined as any death during hospitalization or within 90 days from surgery.

Toxicity grade 3 or higher will be recorded from the time of study inclusion according to the CTCAE criteria.

Treatment related serious adverse events (SAE) and adverse events (AE) of grade 3 or higher will be collected continuously from the time of study inclusion until the end of combined chemotherapy. AE are followed up until the event is either resolved or adequately explained, even after the patient has completed his/her study treatment. Nature and duration of any hospitalization, treatment of any AE, and nature and duration of any outpatient care will be recorded.

Response rates of CRLM will be measured according to RECIST criteria

PFS will be defined from inclusion date until disease progression.

OS will be defined from inclusion date until death.

Conversion rate is defined as the percentage of patients in whom CRLM convert from an unresectable to a resectable state and undergo surgical treatment with curative intent. Possibility of local treatment is at the discretion of the multidisciplinary liver panel.

Erasmus Medical Center

The Netherlands Cancer Institute

Neoplasms, Second Primary

R0 Resection of Liver Metastases after Planning with preoperative imaging data and comparison with intraoperative contrast enhanced ultrasound

Liver Surgery

The contrast enhanced Ultrasound imaging is performed before and during the operation using Sonovue contrast agent (2.5ml iv preop, 4.5ml iv intraop)

Contrast Enhanced Ultrasound

A staging CT of the liver/abdomen with the minimal possible dosage for aquiring sufficent triphasic data in a 64-line helical scan

CT Scan (standard)

an MRI scan of the liver with Primovist contrast agent including late phase as addition to the preop staging according to the protocol

Primovist MRI (3 Tesla)

Gregor A Stavrou, Dr.med

The study compares the established imaging techniques (CT, MRT, Contrast Ultrasound) with the new method of intraoperative contrast enhanced ultrasound to compare all methods for their rate of detection of colorectal liver metastasis.

1. Introduction: The surgical resection of colorectal liver metastases is the only curative therapy for those patients (1). Because a major part of those patients become diagnosed in a technical irresectable stadium, most patients primary get a chemotherapy to reach a secondary resection (2). Especially for this group of patients an effective preoperative staging is necessary to know the exact number and location of the liver metastases. Standard imaging is abdominal CT with a contrast medium, lately it is also possible to create a 3D analysis based on vasculatory territories out of the 2D data (3) (4). Alternatively MRI imaging can be used as well, but because of its defiency in the imaging of vascular anatomy it is only partly suited for the surgical planning and resection. By now the contrast enhanced sonography has been further developed and can be used for dignity evaluation of leasions. Depending on the examiner it can provide very useful informations (5). Because of the intraoperative ultrasound is the most sensitive and specific diagnosic procedure (6), the intraoperative use of contrast medium ultrasound seems to suggest itself. As the necessary ultrasonic probes weren't avaiable until now, only a few experiences have been made yet (7).

Aim of the study is to compare the value of all described methods considering the detection rate of colorectal metastases, including the by now available intraoperative cm-ultrasound. From the comparison of all modern methods (64-line doublehelix CT, 3D virtual operation planning, 3 tesla Primovist-MRI, pre- and intraoperative contrast enhanced sonography) we aim to get a reliable recommendation for the preoperative necessary staging.

1. Background: state of research/ scientific arguementation/ leading question In the last 20 years, the surgery of colorectal liver metastases has developed a lot (8,9,10,11). In centers even complex surgeries can be done with a mortality of 0,1% and with a morbidity of 15%. Today, neither the number, nor the localisation of metastases or an extrahepatic tumour growth is decisive for a resection, but the fact, if there is a possibilty for a complete tumor excision (12). Especially because of the further developement of neoadjuvant (13) and adjuvant (14) chemotherapeutics on the one hand and the technical developement (portal embolisation (15), two-time resection (16), virtual operation planning (4), navigated surgery (17)) on the other hand enlarged the number of patients becoming resectable secondarily.

The demand on preoperative imaging increased with the technical and therapeutical developements. In surgical and technical prospect the abdomen CT imaging is still standard in surgery planning, because besides the tumor imaging, the good vascular anatomy imaging enables a surgical strategy (5). Today, 2D CT data can be used to create a 3D imaging of the liver and its vascularisation to plan a virtual surgery beneffiting especially the most complex surgeries (18). Because of the distinct better resolution of a lesion, MRI imaging of the liver has a high significance in literature and allows radiologists a higher quality of their diagnosis (19), but does not obligatory ease the surgery planning for the surgeon (20). A comparing study in a surgeons point of view could show a equal validity of both modalities (21). Interestingly, the mentionend studies showed that the detection of metastases in altered liver tissue (fatty degeneration/ status post chemotherapy) is reduced. In these difficult cases the CE-sonography gives the decisive informations (22). The practical disadvantage is the dependence on the examiner.

Intraoperative sonography is the gold standard procedure during the operation, additional leasions can be detected which may change the resection strategy (6). Even if there are only a few experiences with intraoperative ultrasonic probes that are able to do contrast enhancment, we assume an advantage of the use of contrast medium sonography (23) in the operation room. The yet published data is not enough for a ensured evidence.

In our point of view it is necessary to carry out a prospective study comparing all available state of the art imaging methods and adding the intraoperative contrast enhanced ultrasound to validate it´s effect.

In times of limited resources it becomes more and more important with a lot of difference in the costs for the imaging modalities to define an optimal staging for these complex patients that at the same time has enough value for the surgeon to go forward with an operation.

3. Design The Study is concepted as a prospective, monocentric and controlled observational study.

4. Primary Endpoints: the detection of the liver metastases intraoperative and the comparison with the preoperative information. Secondary endpoints : comparison of the detection-rates of all the imaging methods, comparison of the sensitivity of all the imaging methods and comparison of the specificity of all imaging methods.

5. Caseload discussion and statistical Analysis: As the primary target figure the number of metastases detected during the operation using ultrasound and CT/MRI are taken into consideration.

It has to be shown that the average number of the liver metastases that have been detected using the two procedures CE-IOUS and CT/MRI are different. On average using the CE-IOUS method for the patient sample detects 1.95 metastases, the pre surgery detects 1.54 metastases using CT/MRI.

The standard deviation between the detected metastasis is 1.10.

The null- and alternative hypothesis of the key question is:

H0: the two procedures CE-IOUS and CT/MRI detect the same number of metastases, H1: CE-IOUS and CT/MRI detect unequal numbers of metastases. It has been presumed that the CE-IOUS method is more successful in detection of the metastases . To test the two-sided question a paired T-test with an average difference of 0 regarding the absolute detection-number on a significance level of 5% with a stastistical power of 90% will be used.

To be able to prove the difference between the two methods a number of 78 patients must be evaluated. With respect to the 20% rate of drop-outs 98 patients were recruited.

6. Patient population: 98 patient are supposed to be included in this study. Operation and execution: in the first contact we will explain to our patients the research plan. The case will be discussed at our interdisciplinary tumor conference. The next step is imaging with CT abdomen and contrast medium sonography. Data of the CT will be finished of for a 3D surgery planning.

In the next step we carry out a MRI of the liver. Preoperative all imaging methods will be compared. Thus we plan an operative strategy. Intraoperative the regular sonography will be supplemented by contrast media (this leads to an extention of the 4 hour surgery by 10 minutes. Afterwards we carry out the liver resection.

Data of all the imaging techniques with regard to detection of metastases, species delineation of the leasion, preoperative resection strategies as well as intraoperative changes of the resection strategies will be collected in a data base. Patients will be provided with care immediately after they are discharged. Therefore, every six months they will be send to our special consultation. The data we gain will subsequently be tested for statistical significance and will then be evaluated (MS Excel, SPSS). The results will be published in medical literature.

For the trail, we plan to use the data of patients in a period of 18 months. Our hospital carries out about 80 liver resections every year hence we should be able to collect 98 patients with colorectal metastases. With this amount we can gain a meaningful analysis.

7. There are risks and additional strain for patients by the additional administration of contrast media during MRI imaging. There is a possibility that it leads to severe reaction of the body (\<1:100.000) which can be treated medicinal.

In our opinion, there is no risk due to the elongation of the about 4 hour enduring surgery for 10 minutes because of the contrast media sonography. This is because of the surgical morbidity by liver resection not because of the procedure of the sonography.

8. Possible benefit for the patient: With the possibility of having an optimal staging sequence with high reliability using todays imaging methods not only can more and more patients benefit from therapeutic measures with high chances of cure but many might also be spared from unnecessary surgeries.

In medical literature there is still a controversary discussion about the ideal imaging modality in liver surgery. Here, different angles of view encounter the same problem (surgical/radiological view) both availability of methods (CT/MRI) and their costs. For the advancement of the always more complex and interdisciplinary stamped treatment strategies of colorectal liver metastases it is vital to use a reliable imaging method and respectively for a high significance a combination of methods. The intraoperative contrast media sonography promises a significant benefit in the detection of leasions which have not been detected so far. In the future patients may benefit a lot from it and thus get a better prognosis. The up to now existing data are not sufficient. Therefore, from our point of view, it is very important to consider the comparative consideration of all modalities.

9. Abruption criteria revocation of accordance of attendance of a trail through the patient and factors, which do not allow a surgical intervention.

10. Voluntary attendance and countermand of the accordance The patient's attendance on this project is voluntary. The decision of taking part or not, does not interfere with the right to sanitary protection or other attainments. The decision of taking part or not does not intervene with the Health protection claim or other services to which the patients are entitled. The patients in no way denounce their legal claims or rights by taking part in this study. When the patients make a decision to take part they are granted the power to withdraw or revoke their consent and abort their participation.

11. Ethical basis of this study is carried out according to the declaration of the 18th world medical association of Helsinki, Finland 1964 and the later revisions. The study will be presented to the Ethic committee of Hamburg for careerlegal counceling. Possible subsequent changes will be presented to the Ethic committee for assessment.

12. Data privacy that have been collected according to the patients consent, particularly results, underlie discretion and the data privacy assignation. They will be recorded and saved in paper format and data medium in the Asklepios clinic Barmbek, department of general and visceral surgery. The use of these Data is carried out pseudonymously. A transmission of the data for research purposes will also be done pseudonymously. The same rule applies to publication of the study- and scientific results.

These patients have the right to demand information regarding their personal data and possible personal results. Where appropriate the head of the study or the scientific manager will make the decision.

(The recording and saving of the data will take place for a period of ten years.) In case of revocation of the consent the already collected data will be further used in this format.

The Literature is found under Citations

Detection Rate of Liver Metastases With Contrast Enhanced Intraoperative Ultrasound Compared to Regular Imaging

Value of Contrast Enhanced Intraoperative Ultrasound Compared to Preoperative CEUS, CT and MRT in the Treatment of Colorectal Liver Metastases.

Intraoperative Rate of Detection of Liver Metastasis compared to preoperative Imaging Analysis

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pilot-study: Non-thermal Ablation Using Irreversible Electroporation to Treat Colorectal Liver Metastases	NCT01799044	Colorectal Live... Metastatic Live...	Irreversible el...	18 Years -	Amsterdam UMC, location VUmc
Hepatic Arterial Infusion Pump Chemotherapy Combined With Systemic Chemotherapy (PUMP-IT)	NCT04552093	Colorectal Neop...	Floxuridine Tricumed IP2000...	18 Years - 115 Years	The Netherlands Cancer Institute
Pilot-study: Non-thermal Ablation Using Irreversible Electroporation to Treat Colorectal Liver Metastases	NCT01799044	Colorectal Live... Metastatic Live...	Irreversible el...	18 Years -	Amsterdam UMC, location VUmc
Detection Rate of Liver Metastases With Contrast Enhanced Intraoperative Ultrasound Compared to Regular Imaging	NCT01522209	Colon Cancer Li... Contrast Enhanc... Imaging for Liv... Imaging for Liv...	Liver Surgery Contrast Enhanc... CT Scan (standa... Primovist MRI (...	18 Years -	Asklepios Kliniken Hamburg GmbH
Pilot-study: Non-thermal Ablation Using Irreversible Electroporation to Treat Colorectal Liver Metastases	NCT01799044	Colorectal Live... Metastatic Live...	Irreversible el...	18 Years -	Amsterdam UMC, location VUmc

Spots Global Cancer Trial Database for crlm

Every month we try and update this database with for crlm cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for crlm

Every month we try and update this database with for crlm cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for crlm cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.