Management of cutaneous metastases using electrochemotherapy

Figures & data

Figure 1. The electroporation procedure: A. Electroporation occurs when an applied external field exceeds the capacity of the cell membrane. The formation of permeable areas happens in the frame of less than a second whereas resealing happens over minutes. As the resting transmembrane potential is negative on the inside respective to the outside, the first part of the membrane that will be permeabilised is the pole facing the positive electrode. The positive electrode should be imagined in the left of the picture and the negative electrode on the right. Pulses were delivered to a cell suspended in medium containing propidium iodide and after the pulses propidium iodide is trapped within the cells [9]. B. The application of pulses to skin tumours must be preceded by local or general anaesthesia, in local anaesthesia the lidocain is injected around the metastasis. C. The cliniporator equipment allows monitoring of voltage and current during the pulse. D. A treatment situation is shown where a patient is receiving local injection of bleomycin followed by application of pulses under local anaesthesia. The application of pulses lasts only a few minutes in total.

Figure 2. Electrochemotherapy. In the right panel, bleomycin is injected at the tumour site, at a concentration of 1000 IU/ml (1 U/ml). In the middle panel the electric pulses are subsequently applied, cells are permeabilised and the drug enters. In the left panel the cells reseal after a few minutes and the extracellular drug is washed out while the internalised molecules remain trapped intracellularly.

Figure 3. Results. Top: ECT treatment of a 75-year-old woman with metastatic breast cancer. Previously the patient underwent surgery and received endocrine therapy, chemotherapy and radiotherapy. The patient was treated with one single treatment of ECT in local anaesthesia with intratumoural injection of bleomycin. A. before treatment, B. two weeks after treatment, C. four weeks after treatment. A crust formed and after four weeks showed signs of falling of. The patient was very satisfied with the treatment and had no side-effects. Middle: ECT treatment of an 82-year-old woman with malignant melanoma. The patient was diagnosed in 2007, since had local spread on the lower limb and metastasis to the lungs. The patient was not suited for temozolamide, immunotherapy or isolated limb perfusion. The patient was treated with ECT in general anaesthesia and intravenous injection of bleomycin. A. before treatment, B. 24 days after treatment and C. three months after treatment. After three months the metastasis is in partial response. Bottom: ECT treatment of a 38-year-old woman with metastatic breast cancer. Previously the patient underwent mastectomy, radiotherapy and chemotherapy. The patient was treated with one single treatment of ECT in general anaesthesia with i.v. injection of bleomycin. A. before treatment, B. 10 weeks after treatment, C. two years and two months after treatment with complete resolution despite ongoing systemic disease.

Table I. Patients’ characteristics at baseline.

	Patients Total (N = 52)	Patients (%)	Patients Herlev, N = 30	Patients Middlesbrough N = 22
Median age in years (range)	69.6 (38.9–94.7)		72.1 (53–89.8)	68.3 (38.9–94.7)
Age distribution^1
80+	11	11%
70+	25	48%
60+	44	85%
50+	48	92%
Sex
Female	35	67%	24	13
Male	17	33%	6	8
ECOG^2 performance status
0	35	67%	58%	84%
1	12	23%	33%	5%
2	5	10%	9%	11%
Previous Treatment
Surgery	42	81%	71%	95%
Radiotherapy	20	38%	42%	21%
Chemotherapy	21	40%	42%	37%
No previous treatment	8	15%	21%	0%
Number of metastases treated pr. patient^3
Median (range)	3 (1–7)		3 (1–7)	4 (1–7)
Diagnosis^4
Malignant Melanoma	21	40%	36%	47%
Breast Cancer	15	29%	33%	21%
Adenocarcinoma (other than breast)	5	10%	15%	0%
Basocellular Carcinoma	5	10%	9%	11%
Squamous Cell Carcinoma	3	6%	6%	5%
Other	3	5%	0%	16%
Location of metastasis
Chest	79	40	40	41
Lower limbs	54	28	22	36
Head and Neck	30	15	22	6
Scalp	21	11	12	9
Upper limbs	6	3	4	1
Abdomen	5	3	1	5
Back	1	1	0	1
Size of metastases
Median diameter in mm (range)	12 (1–200)		15 (2–200)	5 (1–140)
≤3 cm	138
>3 cm	24

¹Number of patients at or above a given age.

²ECOG = Eastern Cooperative Oncology Group.

³Maximum seven metastases per patient registered, for 51 patients.

⁴No significant differences among distribution of diagnosis of primary tumour among centres could be observed (p = 0).

Table II. Treatment data and response.

TREATMENT DATA	All Patients (n = 51)	All Patients (%)	Herlev	Middlesbrough
Chemotherapy
Bleomycin I.T.	21	41%	41%	42%
Bleomycin I.V.	30	59%	59%	58%
Anaesthesia
Local	23	45%	50%	37%
General	28	55%	50%	63%
ECT session duration^1, hours:minutes
Median (range) (hh-mm)	00:16 (00:05–01:27)		00:29 (00:08–01:27)	00:18 (00:05–00:35)
Would agree for another session
yes	46	90%	87%	90%
no	4	8%	13%	5%
no answer	1	2%	0	5%
RESPONSE	All Metastases (n = 97)^2	Metastases (%)	Herlev	Middlesbrough
Response for registered metastases^3
CR	58	60%	54%	68%
PR	18	19%	20%	17%
SD	11	11%	18%	2%
PD	7	7%	4%	12%
Not evaluable	3	3%	5%	0%
Time from treatment to CR (days)
Median (range) (days	47 (16–110)		41 (16–110)	63 (38–100)
Size of metastases ≤30 mm (n = 84)
CR	57	68%
PR	15	18%
SD	5	6%
PD	5	6%
Not evaluable	2	2%
Size of metastases >30 mm (n = 13)
CR	1	8%
PR	3	23%
SD	6	46%
PD	2	15%
Not evaluable	1	8%

¹Data available for 42 patients, the time is from start of chemotherapy administration till the last pulse was given. This means it does not include time anaesthesia. One patient with the procedure lasting 1 hour and 9 min was treated in local anaesthesia with i.t. injection of bleomycin had three nodules where treatment of the first nodule was finished before the anaesthesia of the next nodule began. One patient with the procedure lasting 1 hour and 27 min was treated in general anaesthesia with i.t. injection of bleomycin had seven nodules where treatment of the first nodule was finished before injection of bleomycin in the next nodule. This explains why some procedures lasted longer than one would expect.

²24 patients with 97 metastases with a follow-up > 60 days.

³Maximum seven metastases per patient registered.

Table III. Choice of anaesthesia according to location of metastases and size.

	Local anaesthesia		General anaesthesia
Location of metastases
Chest	23	32%	56	46%
Lower limbs	31	42%	23	19%
Head and Neck	11	15%	19	15%
Scalp	4	5%	17	14%
Upper limbs	3	4%	3	2%
Abdomen	1	1%	4	3%
Back	0	0	1	1%
Size of metastases
Median (range) (mm)	7.5 (1–60)		10 (1–200)
Number of metastases per patient
Median (range)	3		4

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