Introduction

Primary skin malignancies are a global public health threat with a significant impact on mortality and morbidity, particularly amongst the older population [1]. Surgical resection with or without reconstruction remains the gold-standard curative treatment option [2,3]. The incidence of skin malignancies is higher in the clinically frail patient, in whom elevated rates of postoperative complications are seen [4,5]. In some patients, there are factors which preclude excision as the treatment of choice. Tumour size, location, plurality and co-morbidity all influence the feasibility of curative surgical intervention. Radiotherapy is a well-established treatment modality which can be offered with palliative intent in the management of a number of cutaneous carcinomas and sarcomas [6–8]. Electrochemotherapy is an alternative treatment which has been gaining international traction in specialist centres since the publication of standard operating procedures for its use [9,10]. The treatment relies on the principle of electroporation—the use of electrical current to increase the permeability of cells to cytotoxic agents—and has been shown to have greater efficacy than the administration of chemotherapy agents alone [11]. Previous systematic reviews have demonstrated the efficacy of electrochemotherapy in the treatment of primary cutaneous malignancies [11–13], and in the treatment of cutaneous metastases from other primary solid organ malignancies [14–16]. The National Institution for Health and Clinical Excellence have issued guidance for the use of electrochemotherapy in specialist settings, though treatment selection is still deferred to the opinion of the loco-regional multi-disciplinary team [17,18].

A systematic review and meta-analysis by Spratt et al. examined non-comparative trials to estimate the efficacy of different skin-directed therapies in the treatment of cutaneous metastases [14]. They synthesised independent estimates of the efficacy of electrochemotherapy and radiotherapy, inferring conclusions from low-level evidence. To date, there has been no level 5 evidence evaluating directly or indirectly comparative studies of electrochemotherapy and radiotherapy in the treatment of primary cutaneous malignancies or cutaneous metastases from primary solid organ malignancies.

The objective of this study, therefore, was to systematically examine the published literature directly and indirectly comparing electrochemotherapy and radiotherapy in the treatment of patients with primary cutaneous malignancies unsuitable for curative surgical resection or cutaneous metastases from primary solid organ malignancies.

Materials and methods

The protocol for this review was registered on the PROSPERO International Prospective Register of Systematic Reviews [19] with the protocol ID CRD42021285415 and has been published in a peer-reviewed journal [20]. A copy of the protocol registered on PROSPERO is provided in the supporting information. The review has been conducted in line with the Cochrane Handbook for Systematic Reviews of Interventions [21] and the manuscript prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and checklist [22]. A completed PRISMA flow diagram is provided in the supporting information. Ethical approval was not required for this study as it extracted data from previous studies in which informed consent had been obtained by the primary researches.

Results

In total 577 records were identified by the search strategy after removal of duplicates. After title and abstract screening, the full text for 17 records were sought for retrieval. The study selection procedure adapted from the PRISMA 2020 Statement is shown in Fig 1 [22]. After full-text screening, two studies were identified that compared electrochemotherapy and radiotherapy [27,28]. A summary of these can be seen in Table 1. There were insufficient studies for meta-analysis. Results are therefore provided as a narrative synthesis.

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Fig 1. The selection process for studies included in the review.

https://doi.org/10.1371/journal.pone.0288251.g001

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Table 1. A summary of included the studies.

https://doi.org/10.1371/journal.pone.0288251.t001

Risk of bias in included studies

The ROBINS-I tool was used to assess risk of bias in the included studies [25]. Overall risk of bias was judged to be serious for both studies. The risk of bias in each domain is summarised in Table 2. As the included studies are both case series, an important source of bias was bias due to confounding as patients were treated with different interventions according to factors related to their disease.

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Table 2. The risk of bias assessment for included the studies using the ROBINS-I tool.

https://doi.org/10.1371/journal.pone.0288251.t002

Discussion

Despite a thorough search strategy and robust methodology, our results were limited by the paucity of the literature. We identified just two studies which contained indirectly comparative data for electrochemotherapy and radiotherapy in the treatment of cutaneous malignancy [27,28]. These two case series contained only a small number of relevant patients treated with electrochemotherapy or radiotherapy. Whilst both studies examined patients with cutaneous squamous cell carcinoma, they were clinically heterogenous demographics. Amaral et al. examined patients who were predominantly elderly with advanced cutaneous squamous cell carcinoma lesions mostly presenting in the head/neck region [27], whereas the cases examined by Robertson et al. were relatively young patients with cutaneous squamous cell carcinoma lesions presenting mostly on the limbs and directly attributable to a rare skin condition (severe recessive dystrophic epidermolysis bullosa). Both case series were judged to be at serious risk of bias. One significant source of bias was through treatment allocation; in both studies, participants were allocated treatment based on disease-related factors. This is evidenced in the study by Robertson et al. where patients with locally aggressive disease were treated with electrochemotherapy whereas patients with ulcerated cutaneous metastases were treated with radiotherapy. Though individually, these two case series may be of interest to specialists involved in the treatment of either demographic, they are too clinically heterogenous to be meaningfully combined and their inherent risk of bias means these results are unlikely to be externally valid and should not be used to inform decision making about the use of electrochemotherapy or radiotherapy in the treatment of cutaneous malignancies in the general population.

Through searching, additional data sets which included groups of patients treated with electrochemotherapy and with radiotherapy were identified, but due to the how the outcomes for these patients were grouped, no data could be extracted to allow indirect comparison [33,34]. Notably, there was no published data from any directly comparative trials between electrochemotherapy and radiotherapy. Though we did identify a previously withdrawn and an ongoing randomised controlled trial comparing these two therapies [37,38]. This review highlights a marked deficit of comparative data between electrochemotherapy and radiotherapy in the published literature.

Previous systematic reviews of the literature have demonstrated that electrochemotherapy is a safe and effective tool in the treatment of metastases from primary solid organ malignancies [14–16] and in the treatment of primary cutaneous malignancies such as basal cell carcinoma [12] and melanoma [13]. A review by Mali et al. examined the effect of electrochemotherapy on multiple cutaneous and subcutaneous tumour types and found squamous cell carcinoma to have the lowest complete response rate (49.5%) and objective response rate (69.7%) in comparison to basal cell carcinoma which had the highest complete response rate (88.6%) and objective response rate (100.0%) of all tumour types [11]. The two studies identified by our review examined patients with squamous cell carcinomae treated with electrochemotherapy or radiotherapy [27,28]. In the small number of these patients who were treated with electrochemotherapy, the tumour response was generally not favourable. The literature suggests that electrochemotherapy may be less efficacious in this particular cohort of patients.

In their review of skin-directed therapies for cutaneous metastases, Spratt et al. estimated the complete response rate of electrochemotherapy to be 47.5% (95% CI 30.3%–65.3%) and the objective response rate to be 75.4% (95% CI 57.7%–87.3%) [14]. They also estimated the complete response rate for radiotherapy to be 62.7% (95% CI 22.8%–90.5%) and the objective response rate to be 83.8% (95% CI 37.9%–97.8%). These estimates were synthesised independently from non-comparative sources. Where this sits within the wider treatment landscape is unknown, and our review demonstrates there is little comparative data for these two treatment modalities.

The primary aim of this review was to compare electrochemotherapy with radiotherapy. Although there are other treatment modalities available for cutaneous malignancies and metastases from solid organ malignancies, such as systemic chemotherapy, immunotherapy, isolated limb perfusion, and intralesional therapies like interferon and interleukin-2, an extensive examination of the literature on these modalities was beyond the scope of this review. Each therapy has its distinct merits and flaws, which, in addition to clinical efficacy, need to be considered when determining the appropriate treatment for each patient. Therapies such as electrochemotherapy and isolated limb perfusion can induce a sustained response after just one or two treatment sessions a few weeks apart [39,40]. In contrast, radiotherapy and intralesional therapy require regular administration over several weeks [41,42]. Despite the time efficiency of electrochemotherapy and isolated limb perfusion, these therapies often necessitate the patient to undergo general anaesthesia in order to be tolerated [39,43]. In cases were patients are too high risk for general anaesthetia, radiotherapy, which can be delivered without anaesthesia, may be an suitable alternative [42]. Additionally, electrochemotherapy and radiotherapy have been recognised as highly cost-effective therapies, proving significantly more affordable than isolated limb perfusion and interferon treatment [32]. Moreover, the substantial costs associated with emerging treatments such as systemic immunotherapy, can limit their delivery to selected groups of patients [44,45]. Therefore, it is important not to disregard economical therapies such as electrochemotherapy and radiotherapy.

There is a clear need for further directly comparative data in the form of clinical trials (such as the ongoing trial in patients with basal cell carcinoma [38]) and observational studies to provide evidence for guidelines for the use of electrochemotherapy in the treatment of primary cutaneous malignancies and cutaneous metastases from other primary solid organ malignancies. Future clinical trials should not only investigate the comparative efficacy of these therapies but should also consider their convenience for patients, effect on quality of life, associated adverse events, and cost effectiveness. This comprehensive approach will allow clinicians to make well-informed decisions to tailor patient-specific management. Despite being limited by the paucity of literature, this review was undertaken with a robust methodology and should be repeated in the future when more directly comparative data is published.

Conclusion

Despite electrochemotherapy showing promising efficacy in a variety of tumour types, there is an almost complete lack of literature containing comparative data for electrochemotherapy and radiotherapy in the treatment of primary cutaneous malignancies and metastases from other primary solid organ malignancies. The two studies identified by this review differ significantly in study population and outcomes, as such, their heterogeneity precludes synthesis of a consolidated comparison of electrochemotherapy and radiotherapy. Recommendations from NICE suggest it is suitable for use in select patient cohorts under the guidance of specialist skin cancer multi-disciplinary teams. Further research is required in this domain in the form of clinical trials and observational studies to inform patient selection guidelines for the use of electrochemotherapy.

Supporting information

Acknowledgments

We would like to thank Tim Staniland, librarian at Hull University Teaching Hospitals NHS Trust, for his help with designing the search strategy.