Treatment of Liver Metastases With Electrochemotherapy

Study Overview
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Brief Summary
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The aim of the study is to evaluate toxicity and effectiveness of electrochemotherapy with bleomycin in treatment of liver metastases of colorectal cancer in clinical study phase I and II. The study will include 10-15 patients with colorectal cancer with synchronous or metachronous liver metastases, but electrochemotherapy will be performed on metastasis not more than 3 cm in the largest diameter. Treatment effectiveness will be evaluated by magnetic resonance imaging (MRI) and ultrasonography (US) in a monthly interval. Two or three month after the first operation the treated and untreated metastases will be resected and through histological analyses performed. The secondary objectives of the trial are to quantify the impact of the treatment on the patient's quality of life, tolerance to the therapy and suitability for larger study to be conducted.

Detailed Description
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The study will be conducted on patients with colorectal cancer with synchronous or metachronous liver metastases. Included will be 10-15 patients. Predominantly, patients with synchronous metastases will be included into the study. These patients present liver metastases at the time of primary tumor resection. Electrochemotherapy will be performed on one metastasis not more than 3 cm in largest diameter at the time of the primary tumor operation, but patients have to have at least 2 to 8 metastases. These metastases will be aimed to be resected in the following operation. It is a standard procedure that liver metastases are resected 2-3 months after the primary tumor resection, in the meantime they are on standard chemotherapeutic protocol (FOLFOX, FOLFIRI, Capecitabine). Only in the case of solitary metastasis smaller than 3 cm in diameter, it is resected during the resection of the primary tumor. In the study additional antitumor effectiveness of electrochemotherapy to other treatment (chemotherapy) will be evaluated, compared to non-electrochemotherapy treated metastases. Treatment effectiveness will be evaluated by magnetic resonance imaging (MRI) and ultrasonography (US), in a monthly interval. Two to three month after the first operation the treated and untreated metastases will be resected and thorough histological analysis performed. The second group of patients will be with metachronous liver metastases not larger than 3 cm in diameter, that location is in the vicinity of hollow liver structures and would not be possible to resect them without extensive and potentially jeopardizing liver resection. One of them will be treated by electrochemotherapy. In a month interval treatment effectiveness will be evaluated by MRI. In the case that metastases will decrease in size and to the situation that metastases are resectable, second operation will be performed, metastases resected and thorough histopathological evaluation performed. Otherwise standard treatment procedure will be performed (chemotherapy). All patients will be treated after the procedure is thoroughly described to them, and have signed informed consent.

Official Title
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Treatment of Liver Metastases With Electrochemotherapy

Conditions
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Liver Metastases

Intervention / Treatment
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* Procedure: Electrochemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with measurable liver metastases, presented simultaneously with primary tumor, aimed at primary tumor resection and in a 2-3 month interval resection of liver metastases. One metastasis will be treated by electrochemotherapy, not larger than 3 cm in diameter. Metastasis has to be accessible for application of electrochemotherapy during the operation, without major liver manipulation or mobilization in order not to create situation that would hamper feasibility of the second operation; resection of metastases. Patients with metachronous liver metastases, that are positioned in unresectable liver area, near blood vessels, but inoperable patients. Recurrent liver metastases, not more than 3, that are not larger than 3 cm in diameter. Histologically and cytologically confirmed cancer, any histological differentiation. Life expectancy more than 3 month. Performance status Karnofsky ≥ 70 or (World Health Organization) WHO ≥ 2. Age more than 18. The patient must be offered standard treatment. Electrochemotherapy is offered to the patients in the case of the disease progression during the standard treatment, in the case or metastases recurrence, or when they refuse standard treatment. Treatment free interval 2-5 weeks, depending on the drugs used. Patient must be mentally capable of understanding the information given. Patient must give informed consent. Exclusion Criteria: Metastases more than 3 cm in diameter. Synchronous unresectable metastases. Metachronous unresectable metastases or bigger than 3 cm in diameter. Visceral, bone or diffuse metastases. Coagulation disturbances. Allergic reaction to bleomycin, or cumulative dose of 250 mg/m2 bleomycin received. Impaired kidney function (creatinin > 150 µmol/l). Patients with hearth failure or pace maker. Patients with epilepsy. Secondary primary tumor, except surgically treated noninvasive cancer of cervix, or surgically or irradiated basal cell carcinoma. Pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Procedure: Electrochemotherapy|Treatment procedure: anesthesia, positioning of electrodes, intravenous in bolus administration of bleomycin (15 mg/m2), within 5-30 min after administration of bleomycin application of electric pulses (8 pulses, duration 100 microseconds, frequency 4 Hz with amplitude adequate to cover the whole treated lesion with electric field necessary for reversible plasma membrane permeabilization), removal of electrodes. The maximum duration of procedure is 90 minutes.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Toxicity Related to Electrochemotherapy (Toxicity, Symptoms) |  | After operation on day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Non-Serious Adverse Events |  | After operation on tha days 2, 7, 30, monthly | 
| Treatment Evaluation of Tumor Response - Measurements of Tumor Lesions by Contrast Enhanced Ultrasonography (US-Doppler), Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Histology | Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | After operation or 1st day after operation, 7th day, 30th day, monthly | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver metastases of colorectal cancer, Bleomycin, Electrochemotherapy