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Application of electrochemotherapy in the management of primary and metastatic cutaneous malignant tumours: a systematic review and meta-analysis Volume 28, numéro 3, May-June 2018

Illustrations


  • Figure 1

  • Figure 2

Tableaux

Melanoma and non-melanoma skin cancer are now the most common types of cancer in Caucasian populations [1]. Surgery or radiotherapy is the elective treatment for most of the primary skin cancers, which provide high rates of local control and survival [2, 3]. However, despite significant advances in treatment guidelines, recurrence or metastases in the skin are often difficult to manage. As a result, the patients receive multimodal treatment including surgery, radiotherapy, and systemic chemotherapy. The poor response to these treatments could be due to the relative impermeability of the cell membrane to the therapeutic agents [2, 4, 5].

In the 1980s, it was discovered that the delivery of intense electric pulses can transiently and reversibly result in permeabilization of the cell membrane to a large variety of molecules, which are otherwise unable to enter into the cell [2, 6-10]. Therefore, application of a combination of short intense electric pulses and chemotherapy, termed “electrochemotherapy”, has been proposed as a new treatment modality for cutaneous involvement of different malignancies [11-16], in which a local increase in plasma membrane permeability, i.e. exposure of the tumour nodule to electric pulses (electroporation), results in increased uptake of chemotherapeutics into the tumour cells [17-19]. Hence, by using this method, the intracellular concentration, and thereby the toxicity, of bleomycin and cisplatin (as the effective drugs for the treatment of different cutaneous tumours [20-22]) can be increased up to 10,000 times and 80 times, respectively [14, 23], which significantly potentiates their antitumour effectiveness, with lower doses required [15, 18, 24-26].

In order to shed more light on the clinical applications of electrochemotherapy in dermatology, the current review aimed to clarify current knowledge on the administration of this method in the management of primary and metastatic skin malignancies.

Material and methods

This review was conducted based on the PRISMA group statement [27]. A systematic literature search was performed in the PubMed Library and Cochrane electronic databases, up to the end of 2016, taking all electroporation synonyms and skin tumours into account, using the following search terms or respective combinations: electroporation, electrochemotherapy, electropermeabilization, skin cancer, skin metastasis, melanoma, Kaposi's sarcoma, Merkel-cell carcinoma, and basal cell carcinoma.

In some cases, the same article could be found in both databases, however, the evaluation for each database was performed separately and reported in the table of results of the search.

Additionally, no geographical restrictions were imposed in this study. Both qualitative and quantitative studies were chosen. From these manuscripts, those that fulfilled the following inclusion and exclusion criteria were considered in the current review:

  • Studies focused on the clinical application of electroporation in the management of primary and metastatic skin tumours.
  • Studies restricted to English language and limited to humans. As a result, in vitro treatments and veterinary studies were excluded from full-text assessment.
  • Scientific letters, review articles, and meta-analysis were not considered for this study.

After evaluation of the selected studies, these were then summarised in a table and subclassified under publication year, authors, patient number, tumour number, type/dose/route of chemotherapy, settings of electroporation, outcome, and side effects. The studies were then ordered chronologically to reveal any changes and particularly advances made over time (table 1). Finally, the main emerging themes from the papers were discussed in more detail.

Statistical analysis

Pooled analysis was conducted using MetaXL Version 5.3 (EpiGear International Pty Ltd, Australia). The presence of heterogeneity among these studies was evaluated with Cochran's Q test, and inconsistency was assessed with I2 test that describes the percentage of the variability in effect estimates that is due to heterogeneity, where p < 0.05 indicates significant heterogeneity. Pooled estimates of mean objective (complete) responses, with 95% confidence intervals (CIs), were calculated to assess the overall efficacy. In order to calculate the pooled estimate of mean objective (complete) response for each tumour or specific administration route, only the relevant papers were considered for the analysis. The random-effects model was defined as the preferred method due to diversity and heterogeneity of the studies, patients, and treated tumours [28].

Results

A total of 465 articles were identified. All abstracts were examined and screened, excluding 308 articles regarding in vitro or veterinary treatments, or non-English papers. Full-text assessment of the remaining 128 articles resulted in 70 eligible articles (figure 1).

Considering objective responses, significant heterogeneity was detected among all studies (I2 = 68%; p-heterogeneity<0.001). After a pooled analysis, the estimate for mean objective response was 84.02% (95% CI: 80.08-87.61%), which suggests efficacy of electrochemotherapy in the management of primary and metastatic cutaneous malignant tumours (figure 2).

Choice of chemotherapeutic agent for electroporation

Bleomycin and cisplatin are the most commonly administered drugs for the treatment of skin tumours with electrochemotherapy [29], which can be given systemically or locally [30].

Bleomycin is a water-soluble antibiotic with toxicity to mammalian cells due to the capability to induce DNA breaks [7, 13, 31]. Electropermeabilization of cells allows bleomycin to enter the cytosol and exert its cytotoxic potential. Therefore, bleomycin is an ideal candidate for combining with electric pulses because it is non-permeant, but highly cytotoxic once inside the cell [7, 21, 31-35]. It can therefore be used at lower doses than those needed for classic chemotherapies [7, 13, 31]. In previous studies, electrochemotherapy with bleomycin was found to be effective for primary and metastatic malignant melanoma [2, 5, 17, 20, 30, 36-49], primary and metastaticbasal cell carcinoma [2, 21, 38, 44, 50-52], primary and metastatic squamous cell carcinoma [44, 47, 49, 53], Kaposi's sarcoma [41, 43, 49, 54-59], Merkel cell carcinoma [41, 60, 61], cutaneous primary and metastatic lesions of breast cancer [49, 62-68], soft tissue sarcoma [49, 69], cutaneous B-cell lymphoma [70], superficial angiosarcoma [71], metastatic cutaneous nodules and transitional cell carcinoma (bladder cancer) [72], locally advanced and metastatic angiosarcoma [71], and as a palliative therapy for tumour complications [12, 36, 73-75].

Cisplatin is a nuclear DNA-damaging agent with the capability to form DNA crosslinks. Cisplatin transport through the plasma membrane is also limited [76]. Nevertheless, exposure of cutaneous tumours to electric pulses after intravenous or intratumoural non-toxic cisplatin doses potentiates its antitumor effectiveness several-fold [24, 77, 78]. Electrochemotherapy with cisplatin was first introduced by Sersa et al. in 1998 [78]. Subsequently, further studies showed its treatment efficacy for malignant melanoma [17, 78, 79], squamous cell carcinoma [78], basal cell carcinoma [78], cutaneous lesions of breast cancer [80], and as a palliative therapy [79]. Efficacy of electrochemotherapy with cisplatin was proven to be dependent on the cisplatin dose, the amplitude of the electric pulses, and the sequence and interval of cisplatin administration [24, 78].

Route of drug administration

According to the findings of the previous trials, either bleomycin or cisplatin can be used as treatment due to their good antitumour effectiveness. Clinical data have proven antitumour effectiveness of bleomycin and cisplatin when given intratumourally, however, intravenous injection is only recommended for bleomycin [24, 37, 77, 78, 81]. The estimates for objective response following electrochemotherapy with intravenous bleomycin, intra-lesional bleomycin, and intra-lesional cisplatin were 83.46% (95% CI: 73.42-91.57%), 89.61% (95% CI: 83.87-94.24%), and 80.82% (95% CI: 66.00-92.36%), respectively (complete response: 49.53% [95% CI: 36.57-62.52%], 60.32% [95% CI: 51.91-68.43%], and 63.06% [95% CI: 36.32-86.44%], respectively). However, the choice of the drug and its administration route should be made based on tumour size and number of tumour nodules [15]. In general, the intravenous route is recommended in the presence of extensive disease, lymphedema, and any other conditions that could predict an irregular distribution of the drug within the tumour, whereas the intratumoural route is preferable for poorly perfused nodules [82].

Dosage of chemotherapeutic agent

The amount of drug administered into cells is a crucial factor, which is proportional to the drug concentration around the tumour. During growth, vascularization notably decreases with the size of the tumour. In addition, following an increase in pressure, diffusion and convection processes decrease [13].

The required drug dosage is based on tumour size. For direct administration into the tumour, the dose of injected drug is smaller than the normal intravenous dose unless the tumour volume is very large. As a result, if the tumour is very large or a large number of tumours are going to be electroporated, intravenous administration seems to be more convenient than intratumoural injection [14, 83]. In previous studies, intravenous bleomycin was mostly given at a dose of 10 or 15 mg/m2 (10-20 mg/m2 of body surface), and when administered as an intratumoural injection, the dose was usually dependent on tumour volume and varied between 0.5 and 4 mg/cm3 (of tumour size) [14]. The dose of cisplatin by intratumoural route was 1 mg/cm3 of tumour size [2, 37, 81].

Timing of drug administration

As tumours are inhomogeneous, in terms of drug distribution and electrical conductivity, the only way to ensure that the drug has reached the target tissue is by performing pulse delivery after injection of the drug [84], when an appropriate drug concentration is available in the interstitial fluid around the tumour cells [85]. With intravenous administration, electric pulse delivery to the treated area needs to be timed to the pharmacokinetic peak of the drug, which in humans is between 8 and 28 minutes after its administration [37, 85]. However, the intratumoural drug administration requires electric pulse delivery between 1 and 10 minutes after the injection [25, 26, 37].

Selection of appropriate electrodes

The distribution of the electric field in the target tissue depends on the geometry and configuration of the electrodes [37]. Therefore, electrodes should be carefully selected according to shape and size of the tumour [37, 86]. The increasing number of electrode applications and electrochemotherapy cycles were shown to be predictors of superficial tumour control. This finding justifies the insertion of multiple electrodes during a single procedure and the application of more electrochemotherapy courses for the patients with large and/or diffuse metastases [5]. Electric pulses for electroporation of tissue were delivered by different sets of electrodes, such as plate electrodes (type I) [15, 85], row needle electrodes (type II) [15, 87], hexagonal-centred electrodes (type III) [15, 88], and finger electrodes (type IV) [82]. The plate and row needle electrodes were limited to treatment of superficial and small tumour nodules (<2 cm diameter), whereas hexagonal-centred electrodes allowed the treatment of bigger (2-3-cm diameter), thicker, and deeper-seated tumour nodules [15, 82, 88]. No difference was observed in objective response rate of the treated tumour nodules regarding the electrodes used [15]. However, the least amount of muscle contraction was detected when hexagonal-centred electrodes (type III) were used and the strongest muscle contractions were reported with plate electrodes (type I) [15].

Characteristics of electric pulses

Depending on the electrodes, four, six, or eight electric pulses were delivered per application. Pulses were delivered by placing appropriate stainless electrodes on the skin adjacent to or around the tumour. Skin contact was ensured using electrocardiography paste and shaving when necessary [22]. For electrochemotherapy of small tumours, one series of electric pulses was recommended. [22]. However, for the treatment of large tumours, sequential electrical treatments were applied at adjacent positions in order to cover the entire tumour volume [22]. The electric pulses delivered in most reported cases were consecutive square waves with duration of 100 μs, voltage and current amplitudes of up to 3,000 V and 50 A, respectively, and frequency of between 1 to 5,000 Hz [84]. The comparison of electrochemotherapy at 1 and 5,000 Hz demonstrated similar antitumour effectiveness [4, 15, 62, 89-91]. Therefore, 5,000-Hz frequency was selected for patients with multiple nodules, because this exceeds the frequency of tetanic contraction. As a result, delivering the electric pulses at a repetitive frequency of 5,000 Hz not only shortens treatment duration for each nodule to just 1.5 mseconds, but also makes the electrochemotherapy treatment more comfortable, because the multiple delivered pulses are perceived by the patients as a single stimulus, producing an unpleasant sensation only once [4, 15, 62, 89-91].

Clinical responses to electrochemotherapy for malignant cutaneous tumours

The estimate for mean objective treatment response of evaluated studies was 83.91% (95% CI: 79.15-88.17%) for bleomycin and 80.82% (95% CI: 66.00-92.36%) for cisplatin. Efficacy of electrochemotherapy has been reported to be independent of the treated tumour types [14, 15, 42, 49, 82, 92]. Similarly, in the current review, electrochemotherapy was found to be effective for basal cell carcinoma [2, 21, 50, 78, 93], malignant melanoma [2, 5, 12, 13,17, 21, 23, 36, 40, 73, 74, 79, 92, 94-97], cutaneous lesions of breast cancer [2, 63, 64, 80], squamous cell carcinoma [2, 21, 96, 98-100], Kaposi's sarcoma [55-57], Merkel cell carcinoma [41, 60, 61, 96, 101], and other tumours. The efficacy of this method is presented in more detail in table 2.

Correlation between electroporation efficacy and tumour size is one of the controversial aspects. In some studies, no statistical difference was observed among the responses when tumours were grouped according to their size [15, 41, 95]. However, other studies showed that the size of lesion was associated with a different response rate [4, 11, 44, 62]. In fact, authors stated that local response was inversely correlated with the maximum diameter of the target lesion [102]. However, based on multivariable analysis, a tumour size equal to or less than 3 was associated with better response to treatment [5, 44]. Another prognostic variable for local control was the number of lesions, and 20 or fewer lesions showed better response [5]. The correlation between response and the number of tumour nodules might raise the possibility that some lesions could have been electroporated beyond the recommended bleomycin washout time [5, 81].

Side effects of electrochemotherapy

In the reviewed studies, electroporation delivery was shown to be safe, without any major local or general adverse effects [11, 13, 21, 30, 85, 98, 101]. In particular, no significant modification of haemodynamic or cardiological parameters was noticed even when the treated tumours were located in the chest above the cardiac region. A painless contraction of the underlying muscles was regularly observed at the end of each pulse. However, most of the patients had no residual pain or discomfort from the electrical pulses, either immediately after the treatment or in the following hours or days [11, 13, 21, 30, 85, 98, 101]. Furthermore, after a number of hours following treatment, the only noticeable effects were the occurrence of erythema and slight oedema at the treated area, which soon disappeared. Therefore, all of the observed minor adverse effects seem to be reversible [11, 13, 21, 30, 85, 98].

Discussion

Several reviews have reported on the effectiveness of electrochemotherapy, but no recent comprehensive summary of the effectiveness of electrochemotherapy on skin tumours has been published. In this systematic review, the mean objective response of electrochemotherapy across all eligible studies was estimated at 84.02% (95%CI: 80.08-87.61%).

Systemic chemotherapy has only a palliative role, with response rates below 25% as monotherapy [11, 103]. More aggressive polichemo- or chemoimmunotherapeutic schedules have been recommended to increase response rates, but these are associated with high toxicity and many trials failed to show a significant survival improvement in patients [11, 103]. There are also other issues associated with the management of skin metastases, such as the detrimental impact on quality of life of the patients and the need for significant time-consuming and costly resources, such as nursing support and intensive dressing schedules [11].

In order to cope with these issues, enhanced delivery of chemotherapeutic drugs to tumour cells by electroporation was first introduced by Okino and Mohri [6], and used as a new antitumour treatment strategy by Belehradek et al. in 1993 for permeation nodules [98]. Following this study, several clinical studies on electrochemotherapy using bleomycin and cisplatin were initiated to treat cutaneous metastases of different tumours, such as malignant melanoma, basal cell carcinoma, head and neck squamous cell carcinoma, Kaposi's sarcoma, adenocarcinoma of the breast and salivary gland, hypernephroma, and transitional cell carcinoma of the bladder [14, 29, 30, 81, 92]. The basic mechanism of electrochemotherapy accounts for the high response rate regardless of histological type. Electroporation is a physical phenomenon that can be applied to all types of living cells [22]. This is due to the fact that, besides membrane permeabilization and magnification of drug cytotoxicity, the application of electric pulses to targeted tissues induces a reversible and transient decrease of tumour blood flow (around 80% reduction) [5, 36, 76, 104, 105]. This transient vasoconstriction at the arteriolar level, called “vascular lock”, leads to drug entrapment in the targeted tissue [5, 36, 76, 104, 106]. As a consequence, the uptake of chemotherapeutic drugs into the tumour vascular endothelial cells leads to unrepairable damage to tumour vessels and to a further decrease in tumour blood flow within hours after electrical treatment [76], which breaks down the nutrient supply and causes death of tumour cells [76]. The synergism of these mechanisms accounts for the notable results for the treatment of all histological types of tumours [5, 14, 15, 42, 92], in which a mean objective treatment response of 83.91% and 80.82%% was shown after electrochemotherapy with bleomycin and cisplatin, respectively. Similar to the previous reviews [107], in general, basal cell carcinomas showed highest objective and complete response among all types of tumours. The differences in effectiveness of electrochemotherapy in various clinical studies might be due to heterogeneous treatment conditions (i.e. tumour characteristics, patients’ features, drug type, route of drug administration, and electroporation settings) [107].

In order to resolve various controversies regarding the clinical application of this method, a guideline for standard operating procedures for electrochemotherapy was provided in 2006 to unify application strategies in order to conveniently treat patients with cutaneous and subcutaneous nodules by electrochemotherapy [81]. The guideline recommended that all patients should undergo full history-taking, clinical examination, ECG, and the following laboratory tests, before the therapy: full blood count, INR and sodium measurements, potassium, chlorine, phosphate, magnesium, urea, creatinine, bilirubin, AST, ALT, AF, γ-GT, LDH, and creatinine clearance [80, 81].

The adverse effects of electrochemotherapy seem to be mild and transient. In most of the studies, complications such as erythema, oedema, and pain appeared immediately and resolved after a few days [108]. Late side effects and systemic toxicity were also mild due to low chemotherapy drug doses [108].

Post-procedure pain seems to be associated with moderate or severe pain before treatment, size of the largest treated lesion, previous irradiation, and a high level of current [15, 22, 85, 101]. Patients at risk of post-procedure pain could be identified at the pre-treatment visit, and/or at the time of treatment, to provide a pain management strategy for them [101], because the unpleasant sensation can be totally managed by local or general anaesthesia [15, 22, 85]. Whether electrochemotherapy is administered during general anaesthesia or only with local anaesthetics depends on the patient and physician as well as the location, condition, number, and size of the tumours [14, 81]. Additionally, epinephrine is often administered to provide a vasoconstrictive effect, which is beneficial as it would prevent washout of the injected drug prior to electroporation [12, 14, 42, 81, 109].

According to the studies, the main technical pitfalls and difficulties for optimal tumour electroporation are based on the following [81, 102]:

  • (1)Electrochemotherapy is contraindicated in patients with known allergy to the drug, interstitial lung fibrosis, cumulative bleomycin dose of ≥400,000 UI/m2, and chest wall location of lesions and pacemakers [81, 82].
  • (2)Electrochemotherapy of a large tumour might be difficult due to the required repeated time-consuming electrode applications, considering the available window after drug injection [102, 110].
  • (3)Electrochemotherapy of large tumour size (>3 cm) might be an issue due to the technical impossibility of reaching the inner portion of the tumour at first application [102].
  • (4)Electrochemotherapy of previously irradiated fields could be problematic, due to partial electrode needle penetration and suboptimal electrical current delivery in fibrotic tissue [102, 111].

However, the results of the studies demonstrate that electrochemotherapy is a feasible, inexpensive, and easy-to-operate local treatment with no significant adverse effects or patient discomfort [12, 15, 21, 30]. Electrochemotherapy using low doses of chemotherapeutic agents is very specific to tumour cells and causes no damage to healthy peripheral tissue [112, 113]. This method is not only effective for therapy and local control of primary skin cancers [2, 114], but can also be used in patients with only in-transit metastases or regional diseases, or as a complement to other modalities in patients with distant metastases [95, 114]. The method may also be used as a first-line treatment, for example, for the treatment of non-operable primary [79] or recurrent melanoma [74] in which organs are spared, for alleviation of pain or reduction of tumour bleeding in the palliative setting [12, 112], as well as a neoadjuvant treatment before conventional treatment [15, 79].

From the technological point of view, new pulse generators and different electrode types have been provided for the treatment of deep-seated tumours or those located in more challenging anatomical sites, such as the oral cavity or the anal canal [84, 90]. Furthermore, administration of new drugs, such as calcium or a combination of electrochemotherapy and immunotherapeutic compounds (such as Dabrafenib or Ipilimumab) and biological response modifiers, such as IL-2 [42, 45, 115-123], in order to target distant and non-electroporated lesions, could broaden the therapeutic indications of electrochemotherapy [90, 122]. This might be a strategy to obtain better long-term local and systemic control of skin tumours, which may hopefully lead to an increase in overall survival and improvement of patient's quality of life, within a multidisciplinary oncological approach [29, 122]. However, further new randomised controlled trials are warranted to compare the efficacy and safety of electroporation-mediated skin cancer therapies with current approved management guidelines.

Disclosure

Financial support: none. Conflict of interest: none.