Abstract
Background. We aimed to verify the clinical efficacy and safety of the electrochemotherapy in melanoma metastases and in cases of rare non-melanoma tumors that were difficult to treat for the specific anatomical site or for patient comorbidities. Patients and Methods: We treated 68 patients (699 cutaneous nodules), 44 patients with metastatic melanomas and 24 patients with non-melanoma tumors, at the Melanoma & Skin Cancer Unit, Florence, Italy. Results: We obtained an objective response of 89.7% (88.6% in melanomas and 91.7% in non-melanoma tumors), complete response 54.4% and partial response 35.3%. Conclusion: This study showed that electrochemotherapy is effective in the treatment of melanoma metastases and in rare types of non-melanoma tumors. In particular, we successfully treated rare tumors as angiosarcoma, pleomorphic sarcoma, myxofibrosarcoma, sarcoma di Kaposi, porocarcinoma, sebaceous carcinoma, Merkel cell carcinoma, malignant blue nevus, undifferentiated epitheliomorphic cell neoplasia and metastases from thyroid carcinoma. No serious adverse events were observed.
Electrochemotherapy (ECT) is a non-thermal tumor ablation modality introduced in oncology for local control of cutaneous and subcutaneous nodules of melanoma or other primary and metastatic tumors (1-4). This technique combines the use of short and intense electric pulses to create of pores and transient permeabilization of the cell membrane (reversible electroporation), with the administration of cytotoxic drugs, i.e. bleomycin and less frequently cisplatin, that can thus freely permeate the cytosol and achieve an optimal intracellular concentration and a homogeneous intra-tumoral distribution (1, 2, 5, 6). Although the technique was first developed in 1990, it gained attention in clinical practice only after the European Standard Operating Procedures for Electrochemotherapy (ESOPE) study in 2006 (1, 7).
ECT is performed in a single session as a local tumor treatment when surgery is not recommended. It is also efficient against chemotherapy- and radiotherapy-resistant lesions (4). ECT is well tolerated, it allows for immediate recovery, and it can be repeated in the case of large tumor nodules (3, 8, 9) or partial response. The cost of the treatment is acceptable and the required technology is relatively inexpensive, which makes it ideal in terms of budget constraints for all health systems (1, 3).
ECT has been mainly used in the treatment of selected cases of cutaneous and subcutaneous melanoma metastases (8, 10-12). However, this technique is not tumor-specific and it has been shown in preclinical and clinical studies to be effective for other cutaneous tumor histotypes, including squamous cell and basal cell carcinomas, Kaposi sarcoma and breast cancer (13-15). More recently, ECT has also been introduced into the treatment of deep-seated and endoluminal tumors (16-18).
In this study, we evaluated the efficacy of ECT for cutaneous and subcutaneous melanoma metastases unresponsive to previous therapies and in cases of primary and secondary rare neoplasms (incidence <6 cases/100,000/year) (19). The aim of the study was to verify the clinical efficacy and safety of the ECT in melanoma metastases and in cases of rare non-melanoma tumors that were difficult to treat due to the specific anatomical site of the tumor or that were poor candidates for other treatment based on patient comorbidities.
Patients and Methods
A total of 68 patients were treated with ECT at the Melanoma and Skin Cancer Unit, Department of Plastic and Reconstructive Surgery, Tuscan Regional Melanoma Referral Center, Florence, Italy, and evaluated in a prospective study (Prot.0003615/67). Treated tumors included cutaneous and subcutaneous metastases from melanoma and primary and secondary tumors of different histogenesis.
Included patients were at least 18 years old and signed an informed consent form, had measurable tumor nodules suitable for electrode application, were ineligible for surgery or other therapies or had already been treated with unsuccessful results with surgery, isolated limb infusion/perfusion, chemotherapy, immunotherapy, target therapy and radiotherapy. The final decision about eligible therapy was taken by a Multidisciplinary Oncology Group, which included surgeons, oncologists, dermatologists, radiotherapists, pathologists, radiologists, etc. Treated patients were permitted to have a performance status up to a maximum of 2 according to the Eastern Cooperative Oncology Group scale and a life expectancy of at least 3 months.
Data were recorded in relation to primary tumor histology and nodule size (<3 cm or ≥3 cm) in order to correlate these characteristics to clinical response. For each patient with multiple lesions, all nodules were treated, however, one to seven nodules were selected and registered as target lesions and the largest lesions were always recorded, according to the ESOPE study (1). Before and after the treatment, target lesion diameters were measured and photo-documented. ECT was performed according to the ESOPE study and Standard Operating Procedure (1, 7, 20). The only deviation from that protocol was the inclusion of tumor nodules ≥3 cm in size. This cut-off was chosen because the ESOPE study provided information for lesions <3 cm in diameter but no data are available for larger nodules.
Bleomycin was administered intravenously [15,000 IU/m2 body surface area (BSA), with an injected solution concentration of 1,000 IU/ml, dissolved in sterile water] in a time frame of 60 s (65 patients) or intratumorally (three patients) at a dose dependent on size of the nodule (1,000 IU/cm3 for tumors <0.5 cm3, 500 IU/cm3 for tumors between 0.5 and 1 cm3, and 250 IU/cm3 for tumors >1 cm3). The procedure was performed under local or general anesthesia according to the dimensions and site of tumors. General anesthesia was performed in 10 patients, deep sedation in 17 patients, and locoregional anesthesia was administered in 41 patients with lesions in the lower limbs. The entire lesion with perilesional margin was treated with ECT. The electrical impulses (variable amplitude with 1-5,000 Hz delivery frequencies) were delivered to the tumoral lesion by means of Cliniporator™ device (IGEA Ltd, Modena, Italy) using electrodes (IGEA Ltd) in a time window between 8 and 28 min after bleomycin infusion.
According to the ECT-SOP (1), nodules up to 1-2 cm were treated with plate or needle row electrodes, while larger nodules were treated with hexagonal needle electrodes.
Follow-up visits were planned at 2 weeks, and 1, 2, 3 and 6 months after the treatment and subsequently according to the tumor type. At each visit, data on local response, treatment failure, toxicity and patient outcomes were collected. Target lesion diameters were measured using calipers and using ultrasonography in cases of subcutaneous nodules. Digital photographs were taken at each visit. In order to have objective evaluation of ECT efficacy and comparable results, tumor assessment was performed accordingly to ESOPE (1) and RECIST (21) criteria 8 weeks after the treatment. Complete response (CR) was defined as disappearance of the target lesions; partial response (PR) was a decrease of at least 30% in the sum of diameters of target lesions; progressive disease (PD) was an increase of at least 20% in the sum of diameters of target lesions; whilst stable disease (SD) was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (21, 22).
Patients whose disease was judged to be non-responsive or partially responsive to therapy at the 8-week visit were scheduled for re-treatment. The appearance of metastases in previously unaffected anatomical areas outside the treatment field were considered as new lesions.
Adverse events were evaluated using Common terminology criteria for adverse events (CTCAE) Skin and subcutaneous tissue disorders (23). Pain of the skin, a disorder characterized by a sensation of marked discomfort in the skin, was considered in grade 1: mild pain; grade 2: moderate pain, limiting instrumental activities of daily living; grade 3: severe pain, limiting self-care activities of daily living. Skin ulceration, a disorder characterized by a circumscribed, erosive lesion on the skin, was considered as grade 1 when combined area of ulcers was <1 cm, non-blanchable erythema of intact skin with associated warmth or edema; grade 2 when combined area of ulcers was 1-2 cm, partial thickness skin loss involving skin or subcutaneous fat; grade 3 when combined area of ulcers was >2 cm, full-thickness skin loss involving damage to or necrosis of subcutaneous tissue that may extend down to fascia; grade 4 was any size ulcer with extensive destruction, tissue necrosis, or damage to muscle, bone, or supporting structures with or without full thickness skin loss; grade 5 was that resulting in death. Skin hyperpigmentation, a disorder characterized by darkening of the skin due to excessive melanin deposition, was graduated as: Grade 1: hyperpigmentation covering <10% BSA, no psychosocial impact; grade 2: hyperpigmentation covering >10% BSA, associated with psychosocial impact. Skin hypopigmentation, a disorder characterized by loss of skin pigment (e.g. vitiligo), was graduated as: Grade 1: hypopigmentation or depigmentation covering <10% BSA, no psychosocial impact; grade 2 hypopigmentation or depigmentation covering >10% BSA, with associated psychosocial impact. Patients were asked if they would potentially agree to another session as a measure of how they felt about the treatment procedure.
Results
Sixty-eight patients were treated (23 males, 45 females), and the mean age was 73 years (range=31-100 years). Forty-four patients had cutaneous metastases from melanoma and 24 patients had tumors of different histotype. Patient and tumors characteristics are listed in Table I.
Ninety-three ECT sessions were performed on 68 patients: 48 patients received only one treatment, 15 patients had two treatments and five patients were treated three times. An objective response (OR) was obtained in 61/68 patients (89.7%), 54.4% with a CR and 35.3% with a PR. In particular, an OR was obtained in 39/44 patients with melanoma (88.6%), 59.1% with a CR and 29.5% with a PR. Considering 24 patients with non-melanoma tumor, an OR was obtained in 22 (91.7%), 50% with a CR and 41.7% with a PR. Notably an OR was achieved in all 13 patients bearing rare neoplasia (Table II).
A second ECT session was performed on 15 patients due to PR (seven cases), SD (two cases), PD (one case) or development of new cutaneous metastases. A third ECT session was performed on newly developed nodules in five patients. Among the 10 patients with lesions re-treated, an OR was obtained in nine, in particular, a CR was reached in five and PR was observed in four.
Six hundred and ninety-nine cutaneous nodules, including 303 target lesions, were treated during the first ECT treatment; 86 cutaneous nodules and 35 target lesions were treated during the second ECT treatment; and 30 cutaneous nodules and 25 target lesions were treated during the third ECT treatment.
Distribution of the 303 target nodules of the first ECT treatment according to size and histotype is shown in Table III. An OR was obtained in 258/303 lesions (85.2%), 59.1% (179/303) with a CR and 26.1% (79/303) with a PR. Among 270 ECT-treated target nodules <3 cm in diameter, an OR was obtained in 234 (86.7%) lesions, 62.2% with a CR and 24.5% with a PR. In contrast, among 33 treated nodules ≥3 cm, an OR was obtained in 24 (72.7%) lesions, 33.3% with a CR and 39.4% with a PR. Table IV shows a description of the included target lesions response according to the type of response, primary tumor histology and size of metastases after first ECT application.
Among the 303 target nodules, 244 were melanomas and 59 were non-melanoma tumors.
Melanoma. All 44 patients with melanoma had stage IIIB, IIIC, IIID or IV disease, according to the eighth edition of the American Joint Committee on Cancer staging system (24, 25). Among patients with advanced melanoma (visceral and cutaneous metastases), 10 received novel systemic therapies (four patients underwent target therapy and six immunotherapy). In these patients, significant regression of internal lesions but not of cutaneous metastases was obtained.
Melanoma ECT-treated target lesions (n=244) had an OR in 82% of nodules (200/244), 58.6% (143/244) with a CR and 23.4% (57/244) with a PR. Among 222 ECT-treated melanoma nodules <3 cm in diameter, an OR was obtained in 83.8% of lesions, 61.3% with a CR and 22.5% with a PR (Table IV). Among 22 ECT-treated melanoma nodules ≥3 cm, an OR was obtained in 63.6%, 31.8% with a CR and 31.8% with a PR (Table IV).
Non-melanoma tumors. Among 24 patients with non-melanoma tumors, 10 had primary tumors, including locally advanced squamous cell carcinoma involving the head and neck region in six and the trunk in one, anal porocarcinoma in one, sebaceous carcinoma in one, and angiosarcoma in one. Patients with locoregional disease included local recurrence of soft-tissue sarcomas in five, in-transit metastases from porocarcinoma in one, Merkel cell carcinoma in one, malignant blue nevus in one and undifferentiated epitheliomorphic cell neoplasia in one. Four patients with chest wall recurrence from breast carcinoma had visceral metastatic disease and had received chemo- and radiotherapy. One patient had skin metastasis from thyroid carcinoma.
Non-melanoma ECT-treated target lesions (n= 59) had an OR in 98.3% of nodules (58/59), 61% (36/59) with a CR and 37.3% (22/59) with a PR. Forty-eight non-melanoma target lesions had a diameter <3 cm and 11 lesions were ≥3 cm. Among 48 ECT-treated non-melanoma nodules <3 cm in diameter, an OR was obtained in 100%, 66.7% with a CR and 33.3% with a PR (Table IV). Among 11 treated non-melanoma nodules ≥3 cm, an OR was obtained in 90.9% of nodules, 36.4% with a CR and 54.5% with a PR (Table IV).
Rare primary and secondary non-melanoma tumors. CR was reached in an elderly patient with an angiosarcoma of the leg (Figure 1). The patient suffered from serious comorbidities and refused radical surgery and reconstruction with flap. ECT was proposed instead of radiotherapy due to the abundant bleeding for which the patients had required blood transfusions. The first ECT treatment (Figure 2) induced an immediate interruption of bleeding and a partial regression of the lesion. The patient well accepted a second ECT treatment after 3 months and a complete regression of the lesion was obtained. The patient is disease free after 1 year of follow up (Figure 3).
An 87-year-old woman with a history of thyroid carcinoma developed a subcutaneous nodule of the glabellar region. This nodule stretched to the upper left eyelid, compromising her sight. An incisional biopsy revealed a metastasis from thyroid carcinoma. A single treatment with ECT significantly reduced the lesion, with reduction of the discomfort for the patient.
Two porocarcinomas were successfully treated, one perianal primary lesion in an elderly woman previously reported (26) and one in-transit metastasis in a 67-year-old woman, with a PR of the lesions.
Among sarcomatous lesions, one patient with pleomorphic sarcoma and another with myxofibrosarcoma which had relapsed after surgery were successfully treated. Both patients refused a further surgical approach, which would have led to a large demolition of the involved anatomical site.
Notably, good local tumor control was observed in the treatment of rare multiple in-transit metastases from a malignant blue nevus unresponsive to immunotherapy. Similarly, good local tumor control was achieved in a case of undifferentiated epitheliomorphic cell neoplasia with multiple in-transit metastases of the left leg unresponsive to chemotherapy.
No serious adverse events were observed in our case series. Reported adverse events were all low grade (grade 1) and easily manageable. Twelve patients experienced local pain 1-2 days after ECT requiring minor analgesics and 23 patients developed fever which resolved 2 days after the treatment. Eight patients presented ulcerations in some treated nodules and 3 patients experienced delayed wound-healing, resolved with topical treatments.
Treated lesions developed an inflammatory reaction, which resulted in a post-procedural hyper- or hypo-pigmentation in 61 out of 68 patients (89.7%). Treatment was considered tolerable by all patients and all said they would have agreed to undergo another treatment if necessary having reported subjective clinical benefit.
None of the target lesions that achieved a CR relapsed after 6 months of follow-up. At a median follow-up of 14 months (range=4-65 months; mean=20.8 months), 36 patients were alive and 32 patients had died due to systemic disease progression.
Discussion
This study showed that ECT was effective in melanoma and non-melanoma cutaneous metastases and in the treatment of rare different types of primary non-melanoma skin cancer, with an OR in 89.7% of patients. In particular, we reported here for the first time the efficacy of ECT in the case of cutaneous metastasis from thyroid carcinoma, in a rare case of in-transit malignant blue nevus metastases, in cutaneous-subcutaneous metastases from undifferentiated epitheliomorphic cell neoplasia and in the treatment of recurrent myxofibrosarcoma. ECT was equally effective for other rare tumors such as porocarcinoma, sebaceous carcinoma, Merkel cell carcinoma, pleomorphic sarcoma, Kaposi sarcoma and angiosarcoma. Since there are no standard therapies available for rare skin tumors, these results highlight the importance of ECT as a further new therapeutic option in such cases.
We treated a total of 699 nodules from 68 patients during the first ECT session. The procedure was repeated twice in 15 patients and three times in five patients. The advantage of having all lesions treated at a single center is that the criteria for selecting patients and evaluating responses are homogeneous.
We recorded an OR in 89.7% of patients, with CR in 54.4% and PR in 35.3% of cases. The OR was 88.6% in patients with melanoma (CR=59.1%, and PR=29.5%) and 91.7% in those with non-melanoma (CR=50%, and PR=41.7%).
Regarding the evaluation of target lesions, OR was observed in 85.2% of nodules, with CR of 59.1% and a PR of 26.1% of lesions after one single ECT session. The ESOPE study reported a higher CR rate (74%) (1), however this difference migh be due to the enrolment in our study of patients bearing lesions with greater dimensions. Considering lesions ≥3 cm in diameter, our CR and PR were of 33.3% and 39.4%, respectively. These findings are in accordance with recent meta-analyses based on data from tumors of any histotype that showed significantly lower effectiveness of ECT on tumors with maximal diameter of 3 cm or more (CR of 33.3%) (27, 28).
In our study non-melanoma tumors had a better overall response than melanomas. In particular, melanoma lesions had a CR of 58.6% and a PR of 23.4%, whilst the other histotypes had a CR of 61% and a PR of 37.3%, in line with a meta-analysis showing a melanoma CR of 56.8% and non-melanoma CR of 67% (2). The lower CR observed in our series for non-melanoma tumors may reflect, at least in part, the larger dimensions of these tumors. Indeed, all cutaneous breast carcinoma metastases exceeded 5 cm in diameter. However, the possibility of repeating the treatment overcomes the dimensional limit of the lesions to be treated. Importantly, the CR was 66.7% for non-melanoma nodules <3 cm.
Moreover, in this study we reported the efficacy of ECT in the treatment of rare and aggressive cases of non-melanoma skin cancer. We obtained CR of a massive and bleeding angiosarcoma of the leg after two ECT treatments in an elderly patient with serious comorbidities. Interestingly, the treatment induced an immediate interruption of bleeding. In fact, ECT induces a reduction in tumor blood flow, which contributes to the antitumor effect. The ‘vascular lock’ effect of ECT (29) was of extreme importance in clinical practice and for patient quality of life.
We also obtained good results in cases of recurrent myxofibrosarcoma and pleomorphic sarcoma.
Among other particular cases, we successfully treated a 87-year-old woman with a skin metastasis from thyroid carcinoma of the glabella with ECT, which avoided severe facial scarring which would have resulted from surgery; a diffuse anal porocarcinoma that would have required demolition surgery; an in-transit melanoma metastases of the leg in a 100-year-old woman without visceral metastases which had CR after a single ECT treatment.
Interestingly, ECT was particularly useful in elderly patients which were approximately half of the patients treated. Elderly patients represented a challenge in the decision making of therapy because of the presence of comorbidities which significantly influenced the choice of major treatment. ECT was an excellent therapeutic approach, well accepted by patients, inducing a good clinical response, with few side-effects and improvement in the quality of life (30). Since ECT was well tolerated, it was possible to repeat it, leading to a better likelihood of obtaining a high clinical response. The possibility to re-treat patients was essential in cases of wide tumors. Thus, in the complexity of the approach to the elderly patient affected by skin tumors, the efficacy of ECT offers an additional weapon in personalized treatment.
ECT is at present considered a successful local palliative treatment and was recently recognized by the UK National Institute for Health and Care Excellence as an integral part of the multidisciplinary treatment for patients with skin metastases of non-skin origin and melanoma (31). The next step will be to combine ECT with the new effective systemic therapies in order to potentiate the antitumor effects. Preliminary studies in mouse models (32) and in patients with melanoma suggested that ECT induces a local immune response, dendritic cell recruitment and partial activation (33, 34), which was enhanced by systemic immunotherapy (35, 36). Recently, it has been reported that among immunotherapeutic agents, the association of antibody to cytotoxic T-lymphocyte associated protein-4 and antibody to programmed cell death protein-1 with ECT were efficient approaches for the management of advanced melanoma (37, 38).
In conclusion, ECT is a safe and effective local treatment in selected patients with cutaneous and subcutaneous melanoma metastases and in patients with different primary and secondary skin tumors, even rare and aggressive ones. The combination of ECT with other treatment modalities, surgical and possibly immunological, might extend the field of application of ECT as a new useful tool to be taken into account in an integrated treatment strategy for different types of cutaneous neoplasms.
Footnotes
Authors' Contributions
Concept and design of the study: LB, LP, SS; data collection: LB, LP, SS; additional data and writing: LB, SS; additional writing: LP, GG, FB; writing and supervision: LB, SS, PP, RG, VG.
Conflicts of Interest
None of the Authors has any potential financial conflict of interest related to this article.
- Received July 12, 2020.
- Revision received September 6, 2020.
- Accepted September 7, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved