Radiol Oncol 2025; 59(2): 233-243. doi: 10.2478/raon-2025-0040 233 research article Electrochemotherapy for basal cell carcinoma in the head and neck region: 5-year follow-up from the Insp-ECT registry Ales Groselj1, Giulia Bertino2, Marta Minuti2, Anthony James P Clover3, Camilla Kjaer Lonkvist4, Erika Kis5, Christian Kunte6,7, Tobian Muir8, Francesco Russano9, Francesca de Terlizzi10, Joy Odili11, Gregor Sersa12,13 1 Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Department of Otolaryngology-Head and Neck Surgery, IRCCS Policlinico San Matteo Foundation, Pavia, Italy 3 Department of Plastic Surgery, Cork University Hospital and Cancer Research@UCC, University College Cork 4 Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark 5 Department of Dermatology and Allergology, Medical University of Szeged, Szeged, Hungary 6 Department of Dermatologic surgery and Dermatology, Artemed Fachklinik München, Munich, Germany 7 Department of Dermatology and Allergology, Ludwig-Maximilian University Munich, Munich, Germany 8 Plastic and Reconstructive Surgery Department, James Cook University Hospital, Marton Road, Middlesbrough, United Kingdom 9 Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy 10 IGEA Biophysics Lab. Carpi, Modena, Italy 11 St George’s University Hospital NHS Foundation Trust, London, United Kingdom 12 Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 13 Faculty of Health Sciences, University of Ljubljana, Ljubljana, Slovenia Radiol Oncol 2025; 59(2): 233-243. Received 10 April 2025 Accepted 18 April 2025 Correspondence to: Prof. Gregor Serša, Ph.D., Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška c 2, SI-1000 Ljubljana, Slovenia. E-mail: gsersa@onko-i.si Ales Groselj and Giulia Bertino equally contributed to the paper and share the first authorship. Disclosure: No potential conflicts of interest were disclosed. Francesca de Terlizzi is an IGEA s.p.a. employee. This is an open-access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Basal cell carcinoma (BCC) is a cutaneous malignancy that typically appears in sun-exposed areas. We analyzed data from the Insp-ECT registry of all patients affected by BCC in the head and neck region. The aim of this study was to evaluate the safety and efficacy of electrochemotherapy (ECT) on a 5-year basis. Patients and methods. A cohort of 132 patients was included. They were treated by ECT according to the current Standard Operating Procedures. The median age was 74 years (range 41–93). There was a median of 1 nodule per patient (range 1–7), and the median size of the lesions was 1.4 cm (range 0.5–5.0 cm). Results. Patients tolerated ECT well, and 96% agreed to repeat it if needed. The side effects were mild and tempo- rary. All patients achieved a complete clinical response after 1 to 3 ECT sessions. During the first year of follow-up, 4 (3%) patients experienced recurrence, which was treated (2 with ECT, 1 with surgery, and 1 with a combination of ECT and surgery), after which they remained free of disease until the end of follow-up at 5 years. Five patients reported recurrence thereafter and were treated according to their condition. At the 5-year follow-up, the disease-free survival (DFS) rate was 92% (95% confidence interval [CI]: 87%–96%). At that time, 3 patients were alive with disease (2%), and 124 patients were free of disease (98%). Conclusions. This study shows the feasibility and efficacy of ECT treatment in elderly patients with BCC tumors in aes- thetically and functionally sensitive areas, with negligible toxicity. Comparable efficacy to other treatment modalities was demonstrated at 1 year and 5 years of follow-up in terms of DFS. Key words: basal cell carcinoma; electrochemotherapy, recurrence free survival; 5 years Radiol Oncol 2025; 59(2): 233-243. Groselj A et al. / Long term outcome of electrochemotherapy in BCC234 Introduction Basal cell carcinoma (BCC) is the most common malignant tumor among the white population, with a globally increasing incidence.1 Individuals with Fitzpatrick skin types I and II have a greater risk of developing BCC, with an estimated life- time risk of 30%. The likelihood of BCC is also increased in people with light eye color, freckles, and blonde or red hair.2 UV radiation exposure is the most significant environmental risk factor; thus, BCC typically appears on sun-exposed areas of the skin. Other risk factors include childhood sunburns, a family history of skin cancer, tanning bed use, chronic immunosuppression, photosen- sitizing drugs, ionizing radiation, and exposure to carcinogenic chemicals, particularly arsenic. Childhood sun exposure and intense, intermittent sun exposure are strongly linked to BCC develop- ment. This explains why approximately 80% of BCCs occur in the head and neck region.3 The standard treatments for BCC are surgical excision and Mohs micrographic surgery.4 Surgical excision is typically used for low-risk lesions lo- cated in easily accessible areas, whereas Mohs sur- gery is recommended for high-risk lesions.4 The five-year recurrence rate is lower for Mohs surgery than for standard excision for both primary and recurrent BCCs, at 1% and 6%, respectively.4 The destructive nature of BCC can result in significant physical and psychological morbidity after treat- ment, as many lesions develop in functionally and aesthetically important areas. Other local treat- ment options include cryosurgery, electrodesicca- tion and curettage, topical application of imiqui- mod or fluorouracil, photodynamic therapy, and radiation therapy.5 The choice of treatment de- pends on the patient’s condition, tumor location, and risk of recurrence.6 Radical surgical treatment or radiotherapy is not always the best treatment, especially for local- ly advanced BCC, which affects functionally and aesthetically important areas.7 Particularly in the elderly population, systemic targeted therapy or immunotherapy may not always be feasible due to comorbidities. In such cases, local treatments such as electrochemotherapy (ECT) may be consid- ered.8–10 ECT emerged in the late 1990s in Europe as a highly effective, minimally invasive local therapy for skin cancer treatment.11 Recent studies reported clearance rates ranging from 85% to 96% in BCCs treated with ECT.12–15 The technique involves intravenous (IV) or in- tratumoral (IT) administration of a cytotoxic agent, primary cisplatin or bleomycin, combined with electroporation. During electroporation, short high-voltage electric pulses transiently permea- bilize tumor cell membranes, allowing cytotoxic agents to diffuse into the cells more effectively, thereby increasing their cytotoxicity.16 ECT has been proven to be a safe and effective treatment for various types of solid skin tumors. Its application is well established for treating cu- taneous and subcutaneous nodules, regardless of the tumor’s histology.13,14,17,18 Most importantly, the mechanisms of its action are well understood. In addition to directly killing tumor cells, it also has local immunological effects due to immunogenic tumor cell death and shedding of tumor antigens.19 Furthermore, it exerts an indirect effect on the tu- mor vasculature. Electroporation itself triggers vasoconstriction, leading to transient ischemia. This is the so-called vascular lock effect, which in ECT delays the early washout of the cytotoxic drug from the tumor. However, bleomycin is also cytotoxic to endothelial cells, which later induces a vascular disrupting effect. The vascular disrupt- ing effect is selective for the tumor vasculature but preserves the adjacent normal tissue vasculature. Considering these effects, ECT represents an ef- fective ablative therapy because of its targeted and selective mechanisms.20,21 The recently published European guidelines on the diagnosis and treatment of BCC highlight the important role of ECT as a treatment option.6 It may be considered when surgery or radiotherapy is not feasible or contraindicated, in cases of lesions in critical areas (central face, eyelid, eyebrow, nose, lips, chin, ear, periauricular), poorly defined mar- gins, recurrent BCC, aggressive subtypes, peri- neural invasion, or multiple lesions.6 ECT may also be considered an appropriate treatment option for BCC recurrences following standard treatments.15 The primary aim of the present study was to analyze patients with BCC in the head and neck region treated with ECT from the Insp-ECT data- base and to elucidate long-term outcomes over 5 years. The secondary aim was to assess the safety and tolerability of ECT in the elderly population of patients. Patients and methods Patients and database The data for this study were obtained from the Insp-ECT database. The Insp-ECT registry is a pro- spective database established in 2008 to assess the Radiol Oncol 2025; 59(2): 233-243. Groselj A et al. / Long term outcome of electrochemotherapy in BCC 235 outcome of patients with skin cancers or cutane- ous metastases treated with ECT (https://insp-ect. eu) according to the published Standard Operating Procedure.22,23 The study was conducted in accordance with the principles of Good Clinical Practice and tenets of the Declaration of Helsinki. The collected infor- mation included patient demographics, ECT pa- rameters, tumor characteristics, tumor response, treatment toxicity and patient-reported outcomes, as well as potential later treatments. Written in- formed consent was obtained from each patient, and approval from the ethics committee and data protection authority was sought by each institu- tion. The inclusion and exclusion criteria followed the Standard Operating Procedures for ECT.22,23 The preoperative workup included a complete medical history, physical examination, radiologi- cal examination when necessary, and standard blood tests. For the data analysis, eligible patients were se- lected on the basis of the presence of primary or re- current BCC for which other treatment modalities had failed or were inapplicable. In particular, ECT treatment was considered for carefully selected patients affected by BCC located in critical areas (central face, eyelid, eyebrow, nose, lips, chin, ear, and periauricular regions) in the following cases: (a) primary lesions where all other treatment options, including surgery and radiotherapy, were contraindicated due to radically unresectable dis- ease, a high risk of functional organ damage or be- cause of a precarious physical condition resulting from age and comorbidities; b) persistent or recurrent primary BCC lesions when all other treatment options, including sur- gery and radiotherapy, failed or were not feasible; (c) when the patient, after being comprehensive- ly informed, declined all other treatment options. The primary aim of the present study was to analyze patients with BCC in the head and neck region treated with ECT from the Insp-ECT data- base and to elucidate long-term outcomes over 5 years. The secondary aim was to assess the safety and tolerability of ECT in the elderly population of patients. Procedure ECT was performed according to the European Standard Operating Procedures on Electrochemotherapy.22,23 Briefly, bleomycin was administered either intratumoral (IT) (max 1,000 IU/cm3 lesion volume) or intravenous (IV) (15,000 IU/m2 body surface area), depending on the num- ber and size of the tumors. The choice of electrode for ECT was based on the site and size of the lesion (Figure 1). Eight electrical pulses of 100 μs dura- tion were delivered using Cliniporator, a square- wave electric pulse generator (IGEA, Carpi, Italy). Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.0).24 The response of each target lesion was assessed at follow-up visits conducted at 1, 2, 6, and 12 months following ECT, with sub- sequent longitudinal monitoring of all patients to evaluate long-term outcomes. Pain intensity was evaluated using a visual nu- meric scale (VNS). Tumor-related symptoms were registered following the CTC 4.0 criteria. The spe- cific analysis considered ulcerations, hyperpig- mentation, bleeding and other local effects such as rash, itching and oedema of the treated area. Statistical analysis Descriptive analysis included the median and range and the mean and standard deviation for con- tinuous numeric variables. Comparisons between groups were performed by 2-tailed heteroscedastic uncoupled t test, whereas comparisons of repeated measurements in the same group over time were performed via a 2-tailed coupled Student’s t test for continuous variables. Categorical variables are reported as absolute counts and percentages. Comparisons between categorical variables were performed via contingency table analysis and the A B C D FIGURE 1. Types of electrodes used. (A) Type I: two plates with a 6 mm gap; (B) type IV: a wearable finger electrode with two parallel rows of needles; (C) type III: a hexagonal array with a 7.3 mm gap; or (D) type II: two parallel rows of needles with a 4 mm gap. Radiol Oncol 2025; 59(2): 233-243. Groselj A et al. / Long term outcome of electrochemotherapy in BCC236 Chi-square test with correction for repeated meas- urements. Disease-free survival (DFS) was defined as the time from the first ECT up to the date of re- lapse or the last follow-up. Survival curves for DFS were generated via the Kaplan–Meier method. NCSS 9 (NCSS, LLC. Kaysville, Utah, USA; www. ncss.com) software was used for the analysis. Results A total of 156 patients with BCC who were treated with ECT more than 5 years ago were identified in the Insp-ECT database. Patients were enrolled in 9 Insp-ECT centers: Pavia, Szeged, Ljubljana, Middlesbrough, London, Padova, München, Cork and Herlev. Among the entire patient cohort, 132 (85%) successfully completed at least 5 years of fol- low-up. The 24 remaining patients were excluded from the analysis, of whom 5 were lost to follow- up and 19 died due to causes unrelated to the study. The median follow-up time for the 132 in- cluded patients was 5.8 years (range 5.1–11.6 years). In this cohort, the median age was 74 years (range 41–93 years, mean 72.7 ± 10.8 years). Among them, 98 patients (74%) were older than 65 years, whereas 34 (26%) were younger than 65 years. The descrip- tive characteristics of the population are reported in Table 1. One or a few lesions up to 5 cm in diameter were treated with either local or systemic bleo- mycin administration. Most patients (77%) had a single nodule. The median number of nodules per patient was 1 (range 1–7, mean 2.1 ± 1.8), and the median size of the lesions was 1.4 cm (range 0.5– 5.0 cm, mean 1.5 ± 1.3 cm). A total of 158 target nod- ules from 132 patients were analyzed. The nodules were predominantly located in aesthetically and functionally sensitive areas, as shown in Table 2. ECT treatment was conducted under local an- esthesia and deep sedation in 100 patients (76%) and under general anesthesia in 32 patients (24%). Bleomycin was administered systemically (IV) in 76 patients (58%) and locally (IT) in 56 patients (42%). Among the 100 patients treated under local anesthesia, approximately half of them received IT and the other half IV bleomycin administra- tion (Table 3). Among the 32 patients treated under general anesthesia, dominated IV drug adminis- tration (Table 3). The treatment was equally effective wheth- er the drug was injected IT or IV (p = 0.0877). Nevertheless, the long-term follow-up with DFS suggested better treatment outcomes after IT bleo- mycin injection in ECT (Figure 2). Toxicity ECT treatment was well tolerated, and 127 patients (96%) expressed readiness to undergo repeated treatment if necessary. This finding indicates high patient satisfaction with the tolerability and effi- cacy of the therapy, along with the absence of sig- nificant disfigurement or dysfunction (Figure 3). Among 36 patients (27%) who presented with an ulcerated lesion prior to ECT, only 14 (11%) exhib- ited persistent ulceration at the first follow-up af- ter one month, which subsequently resolved com- pletely upon healing. In 10 patients (8%), light hy- perpigmentation remained after healing (Table 4). Pain assessment using VNS showed no statisti- cally significant difference between pre-ECT (0.4 ± 1.1, range 0 to 7) and immediately post-ECT (0.38 ± 1.17, range 0 to 8) evaluation (p = 0.586). However, a comparison of the pain scale at the first follow-up visit at 1 month (0.22 ± 1.12 range 0 to 9) with the pre-ECT evaluation revealed a statistically signifi- TABLE 1. Descriptive characteristics of the population N % GENDER Males Female 80 52 61% 39% LESIONS’ NUMEROSITY Single Multiple 102 30 77% 23% T STAGE T1 T2 T3 Tis 99 11 1 21 75% 8% 1% 16% TYPE OF TUMOR Primary Recurrent 72 60 55% 45% ULCERATED No Yes 96 36 73% 27% LESIONS’ PREIRRADIATION Yes 3 2% PREVIOUS TREATMENTS Surgery Radiotherapy Surgery, radiotherapy Surgery, other therapies Surgery, radiotherapy, other therapies No 52 2 6 1 2 69 39% 2% 5% 1% 2% 51% Radiol Oncol 2025; 59(2): 233-243. Groselj A et al. / Long term outcome of electrochemotherapy in BCC 237 cant decrease (p = 0.016) (Figure 4). Additionally, two cases of skin rash and one case of facial edema were reported at the first follow-up, both of which resolved completely at subsequent visits. Short-term response: first-year follow-up All patients achieved a complete response after 1 to 3 ECT sessions. In 127 patients (96%), a complete response was obtained after a single session. Due to a partial response, two sessions were required for four patients (3%), and three sessions were needed for one patient (1%). All retreatments were administered within 7 months of the initial session and were performed at 2, 4, 5, and 7 months (with two cases at 7 months). During the first year of follow-up, BCC recur- rence was observed in four patients (3%) between seven and eleven months after achieving a com- plete response to the initial treatment. Among them, two patients had recurrent BCC previously treated with surgical excision, while the remain- ing two had primary lesions. The tumor sizes ranged from 12 mm to 30 mm, with anatomical distribution located on the nose, temporal region, ear and multiple sites on the face. The recurrences were managed with further ECT in two patients, surgery in one patient and a combination of both ECT and surgery in one patient. Following the treatment of recurrence, all patients remained dis- ease free until the end of the five-year follow-up period (Table 5). Long-term results BCC recurrence was observed in 7 patients (5%) after the first year and throughout the subsequent four-year follow-up period. One patient had a re- currence at 2.9 years, while the remaining 6 devel- oped a recurrence at least 4 years after ECT (me- DISEASE FREE SURVIVAL YRS 0 1 2 3 4 5 0% 20% 40% 60% 80% 100% Local administration Systemic administration TABLE 2. Locations of nodules LOCALIZATION N % Nose 65 41% Ear 20 12% Forehead/temple 16 10% Eye 16 10% Cheek 6 4% Scalp 5 3% Lip 4 3% Chin 3 2% Neck 1 1% Other locations 22 14% TABLE 3. Distribution of patients according to drug delivery and type of anesthesia Local drug (IT) Systemic drug (IV) Local anesthesia 47 53 General anesthesia 9 23 IT = intratumoral; IV = intravenous TABLE 4. Symptoms and side effects per patient: comparison between pre-ECT values and 1-month post-ECT values Pre-ECT 1-month post-ECT Nausea 1 (1%) 0 (0%) Flu 0 (0%) 0 (0%) Suppuration 1 (1%) 2 (1%) Hyperpigmentation 1 (1%) 10 (8%) Ulceration 36 (27%) 14 (11%) Crust 0 (0%) 2 (1%) Edema/rush 0 (0%) 3 (2%) ECT = electrochemotherapy FIGURE 2. Disease-free survival (DFS) of nodules treated with local (intratumoral, IT) or systemic (intravenous, IV) drug administration. YRS = years Radiol Oncol 2025; 59(2): 233-243. Groselj A et al. / Long term outcome of electrochemotherapy in BCC238 dian 4.4 years, range 4.1–4.7 years). Among these patients, 2 patients underwent surgical interven- tion, 2 were retreated with ECT, 1 received radio- therapy, and 2 declined further treatment. By the end of follow-up, 4 patients who underwent sur- gery or ECT were disease free, whereas 3 patients remained alive with disease. The locations of the lesions included 5 cases in the nasal region, 1 in the scalp region and 1 in the temporal region. The mean age of patients with long-term recurrence A B C D E G HF FIGURE 3. Treatment outcomes of patients treated with intravenous and intratumoral electrochemotherapy (ECT). The outcome is good in larger and smaller basal cell carcinoma (BCC) tumors. Patient No.1 (A) Recurrent BCC after multiple surgeries in a male, 82 years old patient. ECT performed under sedation and local anesthesia. Intravenous bleomycin 18200 IU. Needle row electrode; 11 pulses. Three cycles of ECT were performed (2 for the first treatment; 1 for recurrence after 2 years). (B) Result after 5 years of follow-up. Patient No. 2 (C) Primary BCC in a female, 86 years old patient with multiple severe comorbidities and non-suitable to standard treatments. One ECT session was performed under sedation and local anesthesia. Intralesional Bleomycin 1.5 ml (concentration 1 mg/ml). Needle row electrode; 7 pulses. (D) Result after 5 years of follow-up. Patient No. 3 (E) Primary BCC in a female, 69 years old patient. Patient refused standard treatments. One ECT session was performed in general anesthesia with laryngeal mask. Intravenous bleomycin 18200 IU; Hexagonal electrode; 9 pulses. (F) Result after 5 years of follow-up. Patient No.4 (G) Primary BCC in a female, 88 years old patient with severe comorbidities, Alzheimer’s disease and non-suitable to standard treatments. One ECT session was performed in general anesthesia with laryngeal mask. Intralesional bleomycin 1.5 ml (concentration 1 mg/ml); Finger electrode; 10 pulses. (H) Result after 5 years of follow-up. Radiol Oncol 2025; 59(2): 233-243. Groselj A et al. / Long term outcome of electrochemotherapy in BCC 239 was 73 ± 10 years. A detailed summary of these pa- tients is provided in Table 6. Disease-free survival (DFS) Over the five-year period following ECT treat- ment, patients were monitored for recurrence and DFS. At three years, the DFS rate was 96% (confi- dence interval [C.I.] 95%: 93%–99%), whereas at five years, it was 92% (C.I. 95%: 87%–96%) (Figure 5). DFS was slightly greater in primary lesions than in recurrent lesions, as well as in nonulcerated and small lesions, as illustrated in the Kaplan‒Meier survival curves in Figure 6. Recurrences were managed according to clini- cal indications and/or patient preferences. By the end of the five-year follow-up period, three pa- tients (2%) were alive with disease, and 124 pa- tients (98%) were disease free. Discussion ECT has been established across various clinical settings as a highly effective treatment for cutane- ous and subcutaneous tumors, regardless of histo- logical type.13,17,25 Specifically, in the treatment of head and neck skin malignancies, ECT not only en- sures effective oncologic control but also preserves aesthetic and functional outcomes. Consequently, it may represent a feasible alternative to surgery, particularly in cases where surgery is contraindi- cated or considered inappropriate.14,15 Although there are extensive data on the efficacy of ECT in the treatment of skin cancer, evidence on long-term control remains limited, particularly for BCC, which can recur years after treatment, espe- cially in high-risk areas.4,26 Recently, a randomized control trial comparing the long-term outcomes of TABLE 5. Characteristics of the patients who experienced recurrence during the first year of follow-up Pt Age Primary Previous therapy Localization Size (cm) Time recurrence (months) Treatment of the recurrence Status at 5 years of follow-up 1 52 Recurrent Surgery Nasal ala 1.2 7 ECT NED 2 73 Primary No Temporal region 1.5 10 Surgery NED 3 65 Recurrent Surgery Ear 1.8 11 ECT, surgery NED 4 52 Primary No Multiple (face) 3.0 11 ECT NED ECT = electrochemotherapy; NED = no evidence of disease; Pt = patient TABLE 6. Characteristics of the recurrent patients Pt Age Primary Previous therapy Localization Size (cm) Time recurrence (years) Treatment of the recurrence Status at 5 years of follow-up 1 82 Recurrent Surgery Nasal ala 2.5 2.9 ECT NED 2 60 Primary No Temporal region 1.8 4.1 Surgery NED 3 89 Recurrent No Nasal ala 1.7 4.7 No AWD 4 84 Recurrent No Nasolabial fold 3.0 4.7 RT AWD 5 68 Primary Surgery Tip of the nose 1.0 4.5 ECT NED 6 74 Recurrent Surgery Nasolabial fold 1.6 4.2 No AWD 7 72 Recurrent Surgery +RT Scalp 1.5 4.2 Surgery NED AWD = alive with disease; ECT = electrochemotherapy; NED = no evidence of disease; PT = patient; RT = radiotherapy FIGURE 4. Pain intensity (visual numeric scale, VNS) pre- electrochemotherapy (pre-ECT), immediately post-ECT and 1 month after ECT (mean and standard error). Radiol Oncol 2025; 59(2): 233-243. Groselj A et al. / Long term outcome of electrochemotherapy in BCC240 primary BCCs treated with ECT and surgery was published.12 The results of this study showed that, at the five-year follow-up, the recurrence rate in the surgical arm (1.9%) was comparable to that in the ECT arm (7.5%), with no statistically significant difference between the two groups (p = 0.33). The study results suggest that ECT is a durable treat- ment option for primary BCC and achieves simi- lar long-term efficacy to surgery. These results are consistent with our findings, which demonstrated a five-year DFS rate of 92%. However, these data should be interpreted in the context of our cohort, which included patients with both primary and re- current BCC. Furthermore, the treatment was ad- ministered exclusively to patients with BCCs in the head and neck region, which is known to comprise high-risk areas for BCC recurrence.27 Importantly, 45% of the BCC patients treated in our study were recurrences, which is generally associated with a poorer response to any treat- FIGURE 5. Kaplan-Meier survival curves for the whole population. DFS = disease free survival FIGURE 6. Kaplan-Meier survival (A) of patients with small (< 3 cm) vs large (> 3 cm) lesions (B), patients with primary vs recurrent lesions (C), patients with single vs multiple lesions (D), and patients with ulcerated vs nonulcerated lesions. The differences were not significant. DFS = disease free survival; YRS = years A B C D Radiol Oncol 2025; 59(2): 233-243. Groselj A et al. / Long term outcome of electrochemotherapy in BCC 241 ment and presents a greater therapeutic challenge. Kaplan-Meier survival analysis showed that pa- tients with primary lesions had slightly better DFS than those with recurrent lesions. Nevertheless, the five-year DFS rates for recurrent and primary BCC patients were 90% and 93%, respectively. The favorable long-term response to ECT in both recur- rent and primary tumors can be attributed to the multifaceted mechanism of ECT. In addition to its direct antitumor effect, ECT also activates a local immune response, primarily through increased release of tumor antigens.19,28,29 This mechanism is particularly relevant in the treatment of BCCs, as these tumors have a high mutational burden.30 Consequently, the large amount of tumor antigens from necrotic BCCs following ECT stimulates the local immune response, which may further con- tribute to sustained disease control. The long-term responses of small, nonulcerated lesions and large, ulcerated lesions did not differ significantly. However, nonulcerated and smaller le- sions tend toward a greater likelihood of sustained disease control after ECT. This finding underscores the importance of patient and tumor selection when considering ECT and highlights its efficacy, particu- larly in well-defined, localized tumors. Similarly, there was no statistically signifi- cant difference in response to ECT depending on whether bleomycin was administered intratumor- ally or systemically. However, the slightly attenu- ated response observed after systemic adminis- tration raises important clinical considerations. According to standard operating procedures for ECT, the route of administration should not affect the efficacy of the treatment.17,22,23 Nevertheless, vascularization plays an important role in thera- peutic outcomes, as it affects the pharmacokinetics of bleomycin and thus the efficacy of ECT.31 The scarring process after previous treatments leads to vasculature remodeling within and around the tumor, which can influence the distribution of bleomycin by altering blood flow, perfusion and penetration of the drug into the tumor microen- vironment. Therefore, it is possible that systemic administration of bleomycin could lead to poorer disease control in the case of relapse. However, further studies in a larger cohort of patients with histologically diverse tumors are needed to sub- stantiate this hypothesis. In our study, the majority of tumors treated with ECT were located in the H-zone (central face, eyelid, eyebrow, nose, lips, chin, ear, and periau- ricular regions), an area associated not only with a higher risk of recurrence but also with significant esthetic and functional effects of treatment.26 As far as the subjective assessment of patients is con- cerned, the high acceptance of ECT is evident, as 96% of patients stated that they would be willing to undergo treatment again if necessary. This is con- sistent with previous studies highlighting the fa- vorable safety profile and low morbidity of ECT.13,17 The most common adverse effects were transient ulceration (11%) and mild hyperpigmentation (8%), both of which resolved over time without signifi- cant functional or aesthetic consequences. The minimal impact on pain perception, as shown by the stable VNS scores before and after treatment, also supports the tolerability of ECT. The safety and low morbidity profile are particularly impor- tant because 74% of our patients were over 65 years of age. This finding is in concordance with previ- ous studies that emphasized the suitability of ECT for older patients with comorbidities, as standard treatments may represent a greater therapeutic burden in an older population.9,10,32 Our results regarding long-term recurrence rates are comparable to those of Mohs micrograph- ic surgery, which is considered the gold standard for the treatment of high-risk facial BCCs, due to its high cure rate and tissue-sparing benefits. For example, a study that included 2,203 high-risk BCCs from the Danish Registry for Mohs Surgery reported a 5-year overall recurrence rate of 3.1% for primary BCCs and 5.3% for recurrent BCCs follow- ing Mohs micrographic surgery.33 However, one of the main advantages of ECT is that it can be re- peated safely and without significant side effects. In our study, ECT was repeated in 2 out of the 7 patients who experienced recurrence. Although our study supports the efficacy of ECT, it is important to recognize its limitations. A potential bias is that the response to treatment was evaluated solely by clinical assessment, with- out previous histologic or cytologic biopsies. This limitation is particularly relevant, as a previous biopsy might have identified a recurrence before it was clinically evident. Furthermore, the lack of direct comparisons with surgery or radiotherapy limits the assessment of the relative efficacy of ECT. Future prospective randomized trials with larger cohorts are needed to further clarify the role of ECT within the broader treatment algorithm for BCC, particularly in high-risk and recurrent cases. In conclusion, our results support the role of ECT as a valuable alternative for the treatment of BCC in challenging anatomical locations. The high DFS rates, favorable safety profile and patient ac- ceptance suggest that ECT can be integrated into Radiol Oncol 2025; 59(2): 233-243. Groselj A et al. / Long term outcome of electrochemotherapy in BCC242 clinical practice as a primary or adjunctive treat- ment modality. With advances in electroporation technology and drug delivery, further refinements in treatment protocols may enhance the therapeu- tic potential of ECT and solidify its position in the multidisciplinary treatment of BCC. Acknowledgments The protocol was approved by the National Medical Ethics Committee of the Republic of Slovenia (Permit No. 182/02/14, 0120-132/2015-2). This research was funded by Slovenian Research Agency grants (no. P3-0003, P3-0043, and J3-9269) and University Medical Center grant (no. 20230060). The manuscript has been proof- read using Rubriq, Academic Copy Editing and Automated Language Editing Tool. References 1. Levell NJ, Igali L, Wright KA, Greenberg DC. 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