Abstract
Background/Aim: Electrochemotherapy (ECT) is a predominately palliative treatment for cutaneous metastases where an electric field is used to increase the intracellular accumulation of a chemotherapeutic drug (bleomycin or cisplatin). ECT induces a strong anti-vascular effect and endothelial cells seem especially vulnerable. To date, almost no neurological and/or cerebrovascular complications after ECT treatment have been published. In this paper two such cases are reported. Case report: A seizure in a man treated with ECT for a basal cell carcinoma in the temporal region and a fatal ischemic stroke in a woman treated for cutaneous metastases in the neck are reported. In both cases a causal relationship to ECT treatment was strongly suspected. Conclusion: ECT in the head and neck can potentially cause severe neurological complications. Ultrasound is recommended for ECT treatment in the neck.
Electrochemotherapy (ECT) is a cancer treatment modality that uses a strong locally applied electrical field to enhance the intracellular accumulation of hydrophilic chemotherapeutic molecules through the mechanism of electroporation (1). Bleomycin and cisplatin are the drugs currently approved for use in clinical ECT (2, 3). The electrical field used in ECT is eight 0.1 ms square wave pulses with approximately 1.000 V/cm field strength with minor variations depending on which electroporation system that is used. The field induces strong muscular contractions in both the upper and lower limbs when applied in the face and neck areas, but usually only mild muscle contractions when applied to the limbs, back or scalp. Treatment in the face and neck area thus usually requires treatment in general anesthesia with muscle relaxation, whereas treatment of the limbs, back or scalp can be performed with local anesthesia.
There is an inverse relationship between the electrical field that causes electroporation and the diameter of the cell (E=ΔVm/f r cosθ, where E is the external electrical field, ΔVm is the induced membrane potential, f is a form factor of the cell, r is the cell radius and θ is the angle of the electrical field E) (4). This means that cells with a smaller radius r will need a stronger electrical field E to reach electroporation. Typically, axons are much smaller than the average cancer cell and neurons could be selectively spared relative to cancer cells, if the electrical field is strong enough to cause electroporation in cancer cells, but lower than the threshold for electroporation in axons.
One of the mechanisms behind the clinical effects of ECT is its anti-vascular effect (5). This effect leads to vasoconstriction and hypo-perfusion in the treated area, especially in the tumor tissue. In vitro studies have shown that endothelial cells seem to be vulnerable to ECT with both bleomycin and cisplatin (6). In fact, endothelial cells seem to be vulnerable to electroporation by itself (without the drug) with the potential risk of thrombus formation. The anti-vascular effect could therefore possibly lead to unintended side effects such as hypo-perfusion of vital tissues. Electroporation has also been a suspected mechanism in delayed neurological damage seen in high voltage and lightning injuries (7, 8).
Here, two cases of neurological complications, a seizure and a fatal stroke after ECT using two different electroporation systems are reported. To date no reports of neurological or neurovascular complications related to ECT treatment have been published except for a brief mention of one of the patients in a previous publication (9). In this paper new information that increase the suspicion of a relationship between treatment and complication is reported.
Case Report
Patient 1. A 65-year-old man with mild hypertension was treated with ECT with intratumoral bleomycin injection with curative intention for a Glas type IA basal cell carcinoma in the left temporal region (Figure 1). The bleomycin dose was 1.000 IU per cm3 of tumor volume. The Medpulser (Inovio, San Diego, CA, USA) electroporation system with a hexagonal-needle applicator was used. ECT treatment was performed under general anesthesia with muscle relaxation using mivacurium chloride. The postoperative period was unremarkable and the patient was discharged the day after treatment. Five and a half months after treatment the patient developed an epileptic seizure at home. At the emergency room a bite trauma to the tongue was found. The patient was initially aggressive but after being admitted to a neurology ward he quickly recovered and could be discharged the next day. A CT-scan performed the same day showed no pathological findings. A subsequent EEG performed 4 weeks after the seizure was pathological with delta waves in the left fronto-temporal F7 and T3 leads without epileptiform activity. The F7 and T3 leads directly corresponded to the skin treatment area (Figure 1) (10). The patient was told to abstain from driving for nine months. No additional seizures have been recorded and he remains tumor free.
ECT treatment of a basal cell carcinoma in the left temporal area (patient 1). A: Photo taken two weeks after treatment. B: The treatment area directly corresponds to the F7 and T3 leads where the EEG recorded delta waves.
Patient 2. An 80-year-old woman with no previous history of cardiovascular incidents, but with a history of mild hypertension and hyperlipidemia, was referred for treatment of recurrent cutaneous squamous cell carcinoma of the right temporal region. She had developed parotid gland metastases and was treated with surgery and postoperative radiotherapy (68 Gy), but developed a regional recurrence ten months after initial treatment. She presented with an ulcerating wound in the right side of the neck. A biopsy confirmed squamous cell carcinoma. There was concern that the carotid artery could become involved and at a multidisciplinary tumor board it was decided to recommend ECT with local bleomycin injection (1,000 IU/cm3). The treatment was successful without clinical signs of local recurrence but an eschar formation occurred. However, she developed cutaneous metastases, predominantly in the right side of the neck, within a month after the first treatment. Again, palliative treatment with ECT was recommended. Several cutaneous metastases were treated using the Cliniporator (IGEA, Modena, Italy), this time with intratumoral cisplatin administration. The total cisplatin dose was 0.25 ml of 2 mg/ml per cm3 of tumor volume, in accordance with the ESOPE (European Standard Operating Procedures of Electrochemotherapy) treatment protocol (2, 3). The treatment was performed in general anesthesia with mivocurium chloride used for muscle relaxation (Figure 2). The first post-operative hours were unremarkable, she was sent to the ward and could be discharged the next day. Subsequently, approximately 20 h after treatment, she developed dysphasia and a near complete paralysis of her left side. A CT-scan performed within hours of the symptoms debut showed no signs of an intracranial hemorrhage and no cerebral infarction. The clinical diagnosis was an ischemic stroke originating in the right carotid artery. Because of the patient’s advanced palliative stage, no intervention was performed and she was admitted to the neurology ward. Her condition worsened, and she died two days later.
ECT treatment of cutaneous metastases in the neck of cutaneous squamous cell carcinoma in patient 2. A: Before treatment. B: During ECT treatment. Note the length of needle insertion to ensure a sufficient margin. The needle length is 4 cm.
Discussion
Electrochemotherapy is still a relatively new treatment modality. It is a safe and efficient procedure for the treatment of small cutaneous and subcutaneous tumors of different origin (11, 12). However, in tumors that involve tissues with large blood vessels and nerves, both the feasibility and the safety of treatment should be of concern to the treating physician. To our knowledge this is the first time that clinically significant neurological complications after ECT have been reported. In neither of the cases, other causes of these complications can be ruled out definitely. There are, however, many circumstances that suggest a relationship to the treatment.
The patient that developed a seizure some months after ECT treatment had a normal CT-scan but the EEG was pathological in the leads that exactly corresponded to the treatment area. Electroporation has been proposed as a mechanism with delayed neurological complications due to the high voltage and lightning injury and can be outside the “line of direct injury” due to the structure and resistance of the blood vessels (7, 8). In the second patient, there was an initial suspicion that possible pressure on the carotid artery during treatment could have led to the release of a plaque leading to ischemia. However, due to the delay in the symptoms debut a more plausible cause seems to be that the ECT treatment caused damage to the endothelial cells in the carotid artery leading to a thromboembolic event.
This case has led to a mandatory use of ultrasound during ECT-treatment of the neck in the ENT department at the Örebro University Hospital, both for intratumoral injection and electroporation. Since then, there have been no additional cases of stroke in patients treated with ECT in the department.
Electrochemotherapy is a welcome treatment alternative for many patients with advanced stage disease. In several studies, ECT seems to be an efficient and safe palliative treatment of cutaneous metastases. However, with the treatment of larger tumors situated in the vicinity of large blood vessels, the safety assessment before treatment should be vigorous. The authors also urge physicians involved with ECT treatment to continue to report adverse events with potential relationships to the treatment.
Footnotes
Authors’ Contributions
Stefan Kristiansson and Fredrik Landström have collected the data. Peter Appelros has contributed valuable insight. All three have collaborated in writing the paper.
Conflicts of Interest
Fredrik Landström and Stefan Kristiansson have been paid by OnMed Oncology Medical Devices for education of future users of the Sennex electrochemotherapy system.
- Received May 20, 2021.
- Revision received June 2, 2021.
- Accepted June 5, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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