Palliative Care with Electrochemotherapy Targets Drug Delivery for Cancers in the Skin

Dr Brian Bisase Outlines how Electrochemotherapy is Used in Palliative Care, and Examines Issues Around Access to Treatment, Staff Training, and Side Effects

Introduction

Electrochemotherapy (ECT) is a NICE-approved treatment available to patients with skin metastases of cancers of non-skin origin and melanoma,¹ primary basal cell carcinoma (BCC), and primary squamous cell carcinoma (SCC).² It combines the treatment of cancer lesions in the skin via chemotherapy with the introduction of a small electrical field to the lesions.^1–3 This causes pores in the membranes of the cancer cells to open, allowing more of the anticancer drug to enter, and dramatically increasing the effectiveness of the treatment.^1–3

Although clinical experience is limited, ECT can be used for the treatment of inaccessible or otherwise difficult-to-treat primary BCC and SCC in carefully selected patients.² NICE recommends the use of ECT in the context of palliative treatment for skin metastases of cancers of non-skin origin and melanoma.¹ The mean survival of patients with cancers unsuitable for, or resistant to, other forms of treatment is generally short, but palliative treatment is usually necessary to reduce pain and suffering, control odour or bleeding lesions, and prevent the obstruction of other vital functions. In most cases, these cancers require surgical excision and/or radiotherapy and/or chemotherapy. 

More recent uses of ECT that are not currently approved by NICE include treatment for keloids and hypertrophic scars.⁴

There is also a growing body of evidence that ECT represents a useful palliative treatment option for the control of cancers that are unsuitable for surgery and resistant to radiotherapy or chemotherapy.¹

How Does ECT Work?

ECT involves the intravenous or local administration of a single dose of a chemotherapeutic agent under local or general anaesthesia with or without sedation.^1–3 Drug dose is individualised based upon either body surface area or tumour volume.^1–3 This is followed by the local application of electrical pulses (electroporation) around or directly into the tumour, using either surface plates or needle electrodes, to enhance selective permeation of the chemotherapeutic agent through the cell membranes of dividing tumour cells.^1–3 

This facilitates and magnifies drug delivery to these cells, increasing the cytotoxic effect of chemotherapy drugs.^1–3 The therapy causes local vascular disruption, has a cytotoxic effect on tumour endothelial cells, and stimulates a host immune response—all of which enhance the overall antitumour effect.^1–3

Once the drug permeates the cell and the electric pulse stops, it is ‘locked in’ to the electroporated area by local vascular hypoperfusion, therefore avoiding systemic toxicity.³ The chemotherapeutic agents cisplatin or, more commonly, bleomycin, can be used for head and neck cancers, subcutaneous metastases of melanoma, and non-melanoma skin cancers.^5,6 

Clinicians are expected to submit data on all patients undergoing ECT (including details of case selection, methods of follow up, and outcomes) to the InspECT register (www.insp-ect.org), an international register dedicated to ECT, and review clinical outcomes locally.¹

Who is Eligible to Receive ECT?

Those eligible to receive ECT include patients requiring palliative care with:^1–3

• cutaneous and subcutaneous skin metastases of head and neck neoplasms
• BCC and SCC of the head and neck
• metastatic skin lesions of melanoma (stage IIIB, IIIC, and higher)
• cutaneous and subcutaneous metastatic breast cancer lesions (stage IIIA, IIIB, IIIC, and higher)
• chronic lymphocytic leukaemia infiltration
• Merkel cell carcinoma and Kaposi’s sarcoma
• major salivary gland cancers extending to the skin that are deemed inoperable and not amenable to curative or palliative radiotherapy
• tumours of the above types that either cannot have, or have already had, conventional treatments (surgery, radiotherapy, or chemotherapy).

Eligible patients must have an estimated life expectancy of greater than 3 months.⁷ Previously irradiated areas are not a contraindication, and ECT can be repeated if the response to treatment is good.^1–3 

What are the Advantages and Disadvantages of ECT? 

The advantages of ECT compared with the current standards of care (surgical excision and/or radiotherapy and/or chemotherapy) include:^1–3,7,8 

• high and durable objective response rates 
• minimal toxicity and unwanted side effects 
• a good tissue-sparing profile 
• avoidance of wounds that are hard to heal and expensive to manage 
• improved quality of life for patients 
• avoidance of surgery (including amputation and long inpatient admissions)
• no limit on the number of treatments (unlike radiotherapy)
• safety and efficacy in previously irradiated tissues (unlike surgery)
• suitability for elderly patients because it can be performed under local anaesthesia for small lesions or very short general anaesthesia for larger lesions. 

Cautions and relative contraindications include:^1,2,7,8 

• presence of a pacemaker in close proximity to the treatment area, or implantable defibrillators and cardiac resynchronisation therapy devices 
• pre-existing pulmonary disease or very poor lung function (requiring high-flow oxygen at a concentration greater than 28%)—high-dose oxygen exposure should be avoided 
• previous treatment with bleomycin with a cumulative dose greater than 60,000 IU/m²—the total cumulative bleomycin dose must not exceed 400,000 IU/m² 
• other uncontrolled symptomatic lesions 
• symptomatic and/or rapidly progressing non-cutaneous metastasis (for example, large vessel infiltration) 
• allergic reaction to bleomycin or cisplatin
• chronic renal dysfunction and severe renal failure (glomerular filtration rate less than 10 ml/min), although dose reduction is possible
• epilepsy 
• pregnancy and breastfeeding.

Notable adverse effects include:^1–3,7–9 

• involuntary muscle contraction during treatment 
• changes in pigmentation and tattooing of the skin (avoid adhesive use to minimise this effect) 
• neutropenic sepsis, although this is very rare with single-dose chemotherapy—bleomycin is a neutral cytotoxic drug, and is therefore unlikely to cause problems if extravasation occurs 
• an inflammatory reaction, leading to superficial necrosis and an eschar, which occurs in most tumours treated with ECT 
• electrode marks and superficial erosions in some patients; these usually heal within 1 month
• in most patients, some erythema and oedema at the treated sites; this usually resolves within a few days.

Access to ECT, and Potential Barriers

Referral for ECT comes from a variety of sources, including: 

• secondary care surgeons—head and neck, breast, and skin (melanoma) 
• secondary care oncologists—head and neck, breast, and skin (melanoma) 
• secondary care palliative care teams 
• primary care—GPs, practice nurses, and district nurses 
• hospices—doctors and nurse specialists. 

The patient pathway from referral to post-treatment follow up is demonstrated in Figure 1.

Because ECT treatment for cancers in the skin requires multidisciplinary team (MDT) approval and the involvement of two specialists per patient (an oncologist for the prescription of chemotherapy, and a surgical team for the administration of chemotherapy and electroporation), referral for treatment can sometimes take longer than desired. The surgical team should include clinicians or nurses trained to administer chemotherapy intravenously and intratumourally.

COVID-Related Changes

During the pandemic, prioritisation of treatments and patient access to primary and secondary care was significantly limited for those who were seeking help that would result in referral for ECT. Referral from secondary care to secondary care or to tertiary care continued, although internal triaging did not always result in eligible palliative patients receiving ECT. The post-COVID era has seen a recovery in the levels of access and treatment, and clinicians with a special interest in ECT have been able to meet and reach consensus, and deliver research.

However, a lack of chemotherapy-trained nurses as part of the ECT MDT in some trusts has become apparent in the post-COVID era. Surgical hospitals that do not routinely offer chemotherapy, for example, require the presence of a nurse or clinician trained in the administration of chemotherapy within the team. When the ECT team is unchanged from pre-pandemic, this does not pose a problem; however, if key members left during COVID, or services have expanded, there is insufficient nurse training available, and financial restrictions have limited the ability of trusts to set up service-level agreements with chemotherapy-trained nurses from neighbouring oncology trusts.

Does ECT Offer any Savings Compared with Other Treatments? 

When most trusts first began to use ECT, there were no national tariffs for the treatment; thus, there was a requirement to agree prices for ECT services locally. In future, specialised commissioning is likely to take this up; however, the average tariffs and HRGs have not yet been agreed. 

The use of ECT in eligible patients may represent a considerable reduction in the cost of treatment compared with the current standard of care. Cost implications for the service include: 

• traditional electroporator console and power unit: £100,000¹⁰
• consumables and single-dose chemotherapy per patient: £3100–£3250. Intra oral and long finger probes have become available in the past few years and are generally a little more expensive than the original probes, but are less frequently used. Depending on the purchase—single, bulk, or as part of a trust agreement—the cost may vary.¹⁰

Although not restricted to specialist cancer trusts, in my experience, most units delivering ECT are cancer centres or hospitals that have a strong presence of plastic, head, and neck surgery. The learning curve for use of the console is reasonably straightforward and this is evident in trusts that have been delivering ECT over the past 7–8 years or more. When starting up, most units rely on an IGEA company representative being present, but this is not feasible in the long term as the volume of cases rises. A greater challenge is the link between timely oncology prescribing of bleomycin, delivery by the pharmacy, and administration by an appropriately trained person.

What Does the Future Hold for ECT?

In future, ECT could be used more widely to treat melanoma in combination with immunotherapy. A number of trials have been set up,¹¹ most of which have shown similar benefit to immunotherapy alone. There remains a group of melanomas that are non-responsive to immunotherapy alone. Responsiveness to immunotherapy is usually judged after 3 months of treatment or, in some cases, after a 2-year immunotherapy course. In cases where the MDT determines a patient is not responding to immunotherapy, ECT should commence within 2–3 weeks, and no longer than 4 weeks. In my clinical experience, prompt commencement of ECT at this point allows less time for the tumour to grow significantly.

A growing body of evidence suggests some cases of recurrent oral SCC that are no longer responsive to conventional treatments may benefit from ECT.³ The relative paucity of reports or papers to support this reflects the infrequent use of ECT in this anatomical site. Coupled with reports of gross oedema risking the airway, the use of ECT for oral SCC is restricted to selected cases. In my opinion, it is most applicable to oral SCC involving the lip, buccal mucosa, and the thin tumours of the hard palate, as these selected cases are distant from the immediate airway and the risk of compromising oedema.

Other potential uses include:

• intra-abdominal open or laparoscopic ECT for visceral organ cancers. This is used in some European countries; however, it is still in its infancy, and in most cases occurs under experimental conditions¹² 
• electroporation with calcium—supraphysiological doses of which cause cell death—rather than chemotherapy is also currently under investigation.¹³ However, recent reports of pigmentation with the use of calcium have hampered its adoption. In a double-blind, randomised, controlled phase 2 trial, hyperpigmentation and ulceration were observed more frequently after bleomycin-based ECT than calcium electroporation,¹⁴ with one study observing no hyperpigmentation from calcium electroporation.¹⁵ However, it is important to consider factors such as racial variation and response to electroporation; in addition, some may have had bleomycin treatment in advance of calcium electroporation, possibly compounding any side effects. Electroporation with calcium is currently limited to intratumoural use only, and is not used intravenously; therefore, only a selection of tumours is suitable for this technique—for example, small, solid tumours, ideally less than 1 cm³
• electroporation consoles using higher frequencies (250 kHz) are also emerging onto the market, which have the benefit of causing less pain and muscle contracture on delivering pulses; as such, procedures can be performed without general anaesthesia, with less local anaesthetic, and potentially in the outpatient setting¹⁶
• ECT with bleomycin for keloid and hyperplastic scars.⁴

Conclusion

ECT is better known today than when it was first approved for use in palliative care in the UK in 2013.^1,17 Referral sources have increased and most units providing treatment have become more familiar with the processes. Although COVID-19 has altered practice and prioritisation—as in many areas of medicine—there is increased recognition of the importance of quality of life in palliative care, and service recovery after the pandemic witnessed a swift return of providers offering ECT. Even though ECT techniques have not really changed in the past 5 years, attempts have been made to introduce new anatomical sites, cancer types, and applications, although not all of these have been successful. Research into this area has also increased significantly, an effort that I applaud.¹⁸ The newer, most recent challenge for this essentially tertiary service in most of the UK is the impact of cost of living on the ability for patients to seek referral or travel long distances. Coupled with time off work for relatives to support patients psychosocially or for transportation, limitations to access are evident in most, if not all, groups subject to health inequality and deprivation.

This is an update of an article first published in Specialised Medicine (Bisase B. May 2020; 4 (2): 12–15).