Trial Design for Treatment of Cutaneous Metastases:
The current study is a randomized double blinded phase II study comparing the effect of calcium electroporation with ECT with bleomycin on patients with cutaneous metastases of any histology. As calcium and bleomycin are administered intratumoral, only small metastases from 0.5-3 cm will be treated. The treatments will be compared in tumor response and adverse events. Treatment will be done in a palliative purpose.
Cancer patients with cutaneous involvement have often several metastases. A maximum of ten metastases will be included per patient. One to six metastases (depending on the patient's number of metastases) will be numbered 1-6 and randomized into one of two treatment arms
1. Intratumoral calcium followed by electroporation
2. Intratumoral bleomycin followed by electroporation Randomization will be performed separately on each metastasis, so the patient may receive both treatments. Calcium and bleomycin will be mixed into syringes labeled with numbers according to the metastases and both treating doctor and patient will be blinded to the content of the syringes.
If the patient has more than six metastases, then one to four metastases will be used for biopsy. The treatment of these metastases will be known, and biopsies will be performed before and after treatment.
Biopsies will only be performed if the patient has more than six metastases. The metastases used for biopsy will not be evaluated on response.
The treatment will be performed in local or general anesthesia depending on location and number of metastases. Bleomycin/calcium will be administered intratumorally and immediately after the electrode will be placed on the metastasis. The electric pulses are generated using a cliniporator according to ESOPE (European Standard Operating Procedure of Electrochemotherapy). The therapy is a once only treatment and the patients will be followed up with regular clinical controls for six months. At follow up six months after treatment, the randomization code for the one patient will be revealed. If the patient agrees, biopsies will then be taken from an area treated with calcium and an area treated with bleomycin. Last visit will be one year after treatment.
To identify the metastases at follow up visits, the metastases will be marked with a pen, numbered and documented with clinical photos at baseline.
Randomization The metastases are randomized by block randomization and are done separately in each patient. The randomization is performed by an extern unit, using the computer program nQuery Adviser 7.0. The bleomycin and calcium are mixed and labeled by an extern unit, and since both calcium and bleomycin are transparent and identical in volume, it is possible to label the syringes in a manner to blind the treating doctor. The syringes are labeled with numbers according to the metastases so syringe number "1" goes to metastasis number "1" and so on. The randomization code is kept behind locked doors, and is not accessible to the treating doctor. The randomization code is revealed for each patient after follow up, 6 months after treatment.
The randomization code can be revealed before completion of the investigation, if the investigator believes that the treatment causes so serious unexpected events or reactions, that a continuation of treatment is unacceptable.
As the randomization is done separately in each patient, code-break is possible for the individual patient, without breaking the code of the other participants.
Dose In the preclinical study, the tumors were treated with isotonic calcium chloride solution 168 mmol/L and with a volume equivalent to 0.5 x tumor volume, and this with good effect. In another preclinical study the investigators have tested the effect of this dose in different tumor types and saw variable results of the response rate. Some tumor types showed slightly lower response at this dose (own data, manuscript in preparation). Because of this experience the investigators have decided to increase the dose of calcium chloride, in this trial, to 220 mmol/L.
Volume of calcium chloride is dependent on tumor volume. Smaller tumors should have bigger volume per cm³, as smaller tumors are expected to have a bigger loss of injected medicine into the surrounding tissue. The dose volume is calculated according to the "European Standard Operating Procedure of the Electrochemotherapy (ESOPE)".
Calcium
Calcium chloride 220 mmol/L (9 mg/ml):
* Tumor \< 0.5 cm³ - 1 ml/cm³ tumor volume
* Tumor \> 0.5 cm³ - 0.5 ml/cm³ tumor volume Tumor volume = ab2π/6 (a = longest diameter, b = longest diameter perpendicular to "a")
Bleomycin Both dose and volume of bleomycin is standard according to ESOPE
Bleomycin 1000 IU/ml:
* Tumor \< 0.5 cm³ - 1 ml/cm³ tumor volume
* Tumor \> 0.5 cm³ - 0,5 ml/cm³ tumor volume Tumor volume = ab²π/6 (a = longest diameter, b= longest diameter perpendicular to "a")
Maximum of injected bleomycin per tumor will be 1500 IU and total dose per treatment 7500 IU. Normal maximum limit for bleomycin is 15.000 IU/m² body surface area.
Bleomycin and calcium chloride are mixed and labeled according to current guidelines. The mixtures will be used in a maximum of 6 hours after mixing.
