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Center for Experimental Drug and Gene Electrotransfer (C∗EDGE), Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Roskilde and Næstved, Ringstedgade 61, 4700, Næstved, DenmarkDepartment of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
Center for Experimental Drug and Gene Electrotransfer (C∗EDGE), Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Roskilde and Næstved, Ringstedgade 61, 4700, Næstved, DenmarkDepartment of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
Cutaneous metastases can cause distressing symptoms and be challenging to treat. Local therapies are essential in management. Calcium electroporation uses calcium and electrical pulses to selectively kill cancer cells. This multicentre study aimed to define response in cutaneous metastases across different cancer types.
Methods
Patients with tumours ≤3 cm of any histology were included (stable or progressing on current therapy ≥2 months), at three centres. Tumours were treated with 220 mM calcium chloride injection and manual application of eight 0.1 ms pulses with 1 kV/cm and 1Hz with a handheld electrode, in local or general anaesthesia. Clinical response was evaluated after 1, 2, 3, 4, 5, 6, and 12 months. Primary endpoint was response at two months. The overall response rate (ORR) was partial- and complete responses of treated tumours. MR-imaging and qualitative interviews were performed in respective subsets.
Results
Nineteen patients with disseminated cancer (breast n = 4, lung n = 5, pancreatic n = 1, colorectal n = 2, gastric n = 1, and endometrial cancer n = 1) were enrolled, and 58 metastases were treated (50 once, 8 retreated). The ORR was 36% (95% CI 22-53) after two months. Best ORR was 51% (CR 42%; PR 9%). Previous irradiation improved outcomes (p = 0.0004). Adverse events were minimal. Median pain score was reduced after two months (p = 0.017). Treatment may relieve symptoms according to qualitative interviews. MRI showed restriction in treated tissue.
Conclusion
The majority of tumours were treated only once with calcium electroporation, achieving an ORR of 36% after two months and best ORR of 51%. Efficacy, symptom-relief and safety support calcium electroporation as a palliative treatment option for cutaneous metastases.
1. Introduction
1.1 Cutaneous metastases
Cutaneous metastasis (CM) is an under-reported condition, which can have a devastating impact on patients physical and emotional well-being [
]. As such, the condition often presents in the last months of life, but may be present for longer. Symptoms such as pain, bleeding, malodour or infection are frequent complications, as tumours may evolve into ulcerated or fungating wounds [
]. Poor responses to standard therapies (e.g. radiation-, chemo-, immuno- or endocrine therapy) are a common challenge, and surgical management is not always possible [
Calcium electroporation (CaEP) is a novel treatment that combines intratumoural injection of calcium and subsequent manual application of electric pulses directly to tumour tissue [
]. CaEP applies the electroporation (EP) technique used in electrochemotherapy (bleomycin and EP), and has been explored for management of CM and mucosal cancers [
Calcium electroporation for treatment of cutaneous metastases; a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy.
Dose-dependent ATP depletion and cancer cell death following calcium electroporation, relative effect of calcium concentration and electric field strength.
Calcium electroporation and electrochemotherapy for cancer treatment: importance of cell membrane composition investigated by lipidomics, calorimetry and in vitro efficacy.
Electrochemotherapy and calcium electroporation inducing a systemic immune response with local and distant remission of tumors in a patient with malignant melanoma - a case report.
Two smaller randomised clinical trials have investigated CaEP for CM. The first by Falk et al. showed an ORR of 72% (CR = 66%; PR = 5%) for breast- and melanoma metastases (6 and 1 patient, respectively), with best response after two months [
Calcium electroporation for treatment of cutaneous metastases; a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy.
]. The second trial by Ágoston et al. showed an ORR of 33% (CR = 22%; PR = 11%) in a cohort of six patients with melanoma-metastases and one with breast cancer metastases [
]. CaEP has also shown promise in recurrent head-and-neck cancer, cutaneous lymphoma, gynaecological-, colorectal- and oesophageal cancer, but larger studies are needed to confirm results and determine which patients benefit most [
Calcium electroporation for treatment of cutaneous metastases; a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy.
This exploratory, non-randomised study aimed to investigate tumour response to CaEP in a multicentre phase II clinical trial, including a larger number of patients with CM of multiple entities, and investigate experience with qualitative interviews, and MRI for visualization of treatment areas.
2. Methods
2.1 Study design
The study design is thoroughly described in the related protocol article [
Study protocol designed to investigate tumour response to calcium electroporation in cancers affecting the skin: a non-randomised phase II clinical trial.
]. Briefly, the study was designed as an international, multi-centre, prospective, non-randomized, non-blinded Phase II trial. Three cancer centres (The Department of Oncology and Palliative Care Zealand University Hospital, Denmark; the Department of Oncology University Hospital of Southern Denmark, Vejle, Denmark; Clinic for Gynaecology and Obstetrics University Medical Centre Schleswig-Holstein Campus Lübeck Germany) enrolled patients. The study is registered on ClinicalTrials.gov (NCT04225767), EudraCT (2019-004314-34), and approved by the German Data Conformity and Danish Data Protection Agency (REG-115-2019). The study was monitored for Good Clinical Practice (GCP) compliant with the Declaration of Helsinki.
2.2 Primary endpoint
Based on time of best response in the first clinical trial [
Calcium electroporation for treatment of cutaneous metastases; a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy.
], the primary endpoint was ORR after 2 months, defined as the number of partially (≥30% decrease in largest diameter) or completely responding (no clinical sign of malignancy) tumours, relative to all treated tumours. Up to seven tumours were treated per patient.
2.3 Secondary endpoints
Secondary objectives were: Treatment response at months 1, 3, 4, 5, 6 and 12; Histological changes in biopsies after 1 year; DW-MRI assessment using the apparent diffusion coefficient (ADC) in a patient-subset; Quality-of-life (QoL) evaluated using EORTC QLQ-C15-PAL questionnaires at baseline, 2 months and 1 year; Abscopal response from routine scans; Response and duration according to histology; Best response at tumour level; Response at patient level; Response depending on previous radiation; Pulse parameters; and qualitative interviews on experience and QoL before, 2 and 12 months after treatment.
2.4 Participants
Eligible patients were ≥18 years old, understood participant information, had histologically verified cutaneous or subcutaneous cancer 0.5–3 cm in diameter, were deemed inoperable, had been offered standard treatment, had progressive or stable disease ≥2 months, did not receive radiation in target area, ECOG/WHO performance status ≤2, used contraception if sexually active, provided signed informed consent. Pregnant or lactating patients were excluded. Patients could be withdrawn if they retracted consent, their disease progressed, or it was considered in their best interest. Systemic treatments for disease control in other areas could continue.
2.5 Procedure
Tumours were measured using Vernier calliper and photographed before CaEP. Tumour volume was calculated with ESOPE formula V = ab 2 π/6 [
]. In local or general anaesthesia, 220 mM CaCl2 in saline (half tumour volume, max 20 ml) was injected into both tumour and margin. Eight 0.1 ms pulses with 1 kV/cm amplitude and 1Hz frequency were applied with a linear needle-electrode and Cliniporator (model EPS02, IGEA, Carpi, Italy). Adjacent fields were repeated until the entire target was treated. Adverse events (AEs) were recorded using CTCAE v.4.0 (Fig. 1).
Fig. 1Calcium electroporation treatment of cutaneous metastasis on the back. The patient had multiple metastasis from breast cancer, and the aim of treatment was to treat the most symptomatic lesions once with calcium EP. A: Injection of local anaesthesia with epinephrine around the target area (palpable tumour with a 3 mm margin) B: Intratumoural injection of calcium chloride 220 mM with visible distribution (paling). C: Insertion of the needle electrode. Note that the skin is manually elevated from underlying muscle to minimize muscle contraction when delivering the electrical pulses. D: Photograph after the procedure. Visible bruising in the target area, central paleness, needle marks with minimal bleeding, and peripheral paleness due to local anaesthesia containing epinephrine.
Noncontrast-enhanced 3-Tesla MRI using surface coil as a complementary test for assessment of distribution and depth of locoregional cutaneous metastases of malignant melanoma.
]. A subset of patients at the Vejle site underwent diffusion weighted (DW)-MRI using the ADC to monitor water diffusion changes in the treatment area, before and just after CaEP, and after 2 months [
]. Patients were positioned prone using body coils and sequences of axial T1, axial STIR, and DW-MRI using a Big Bore Ingenia 3 T MRI unit (Philips Medical Systems, Best, The Netherlands) with 70 cm aperture, with b 0 and b 1000, to generate an ADC map.
2.7 QoL assessment and reporting of adverse events
QoL was evaluated before treatment, after two months and one year using the EORTC (European Organisation for Research and Treatment of Cancer) certified QLQ-C15-PAL Core Questionnaire. Qualitative interviews were conducted with a subset of patients at the Næstved centre before treatment, and after 2 and 12 months, by an independent team [
Adverse events were reported according to CTCAE v. 4.0.
2.8 Evaluation of response
Response was clinically evaluated 1, 2, 3, 4, 5, 6 and 12 months after CaEP using a Vernier calliper, documented by digital photography. Responses were defined using modified RECIST: Complete Response (CR) (disappearance of the lesion), Partial Response (PR) (≥30% decrease in largest diameter), Progressive Disease (PD) (≥20% increase in largest diameter), and Stable Disease (SD) (neither 30% decrease nor 20% increase) [
]. Wounds were measured level with surrounding skin, including erythema if suspect of malignancy. Punch biopsies from the treatment area were assessed after one year for histopathological regressive changes. Systemic abscopal response was investigated from routine scans.
2.9 Statistical methods
Statistical considerations for sample size are described in the protocol paper [
Study protocol designed to investigate tumour response to calcium electroporation in cancers affecting the skin: a non-randomised phase II clinical trial.
]. Descriptive statistics were applied to describe primary and secondary endpoints. Fisher's exact test was used to analyse pain after treatment and correlation to response. The analysis population includes all tumours treated as the Intention-To-Treat (ITT) Analysis Set.
3. Results
3.1 Participants
A modified consort diagram is depicted in Fig. 2. An overview of the patient demographic is presented in Table 1. Nineteen patients were included (6 male, 13 female) of which 13 were evaluated at day 60. The median age at inclusion was 63 years (44-92). Breast cancer metastases represented the largest group (n = 8). Other entities included lung- (n = 5), colorectal- (n = 2), gastric- (n = 1), oesophageal- (n = 1), endometrial- (n = 1) and pancreatic cancer (n = 1). Three centres included patients: Næstved (n = 13), Vejle (n = 4) and Lübeck (n = 2).
Fig. 2Consort diagram (modified for a non-randomised trial design). The diagram shows the number of patients screened, included and followed at each of three sites: Zealand University Hospital, Næstved, Denmark; University Hospital Schleswig-Holstein, Lübeck, Germany and University Hospital of Southern Denmark, Vejle, Denmark.
Tumour characteristics are shown in Supplementary Table S1. Fifty-eight tumours were treated with median largest diameter of 14 mm (5-30). A mean of three lesions were treated per patient (1-7). Breast cancer metastases represented 55.2% of treated tumours (32/58). The majority of treated tumours were located on the trunk (69%). Eighteen tumours were in previously irradiated areas (31%).
3.3 Response
3.3.1 Primary endpoint – response at two months across all treated tumours
Response classification is represented in Fig. 3. Six of 39 treated tumours had CR after two months (15.4%, 95% CI 6.4–31.2%). Eight had PR (20.5%, 95% CI 9.9–36.9), yielding an ORR of 35.9% (95% CI 21.7–52.8). Eighteen tumours showed SD (46.2%, 95% CI 30.4–62.6) and seven tumours progressed (17.9%, 95% CI 8.1–34.1). The response at tumour level from month 1–12 is shown in Fig. 4.
Fig. 3Representation of response classification. A: Complete response (CR) in a patient with breast cancer metastases (Pt 6), with development of a crusted wound one month after treatment and disappearance of tumour tissue after two months with slight hyperpigmentation of the skin; B: Partial Response (PR) in a patient with breast cancer metastasis (Pt 1). Note full remission of all treated tumours at one-month follow-up with relapse at two months; C: Stable Disease (SD) in a patient with lung cancer metastases (Pt 5); D: Progressive Disease (PD) in a patient with pancreatic cancer skin metastases (Pt 2). An increase of the largest diameter of the lesion and new lesions were observed at one-month follow up. The patient deceased due to primary disease progression.
Fig. 4Response across all treated tumours. The highest ORR was observed at 3 months with response in 23 of 58 treated tumours (37.9%). At last follow-up (12 months), 11 tumours had CR (18%) and three had PR (3%). Note the decline in number of evaluable tumours due to off-study participants, because of primary disease progression (15 of 19 patients).
At the patient level, two patients had CR (10.5%), four had PR (21%), four had PD (21%) and seven had SD (36.8%). Five patients were deceased and one referred to radiotherapy.
3.3.3 Response depending on whether tumours were in a previously irradiated area
Tumours in a previously irradiated area showed a 61.1% (95% CI 34.1–88.2) increased response compared to non-irradiated tumours (p = 0.0004) with a mean diameter reduction of 53% (8.6 mm) in irradiated tumours and a mean increase in diameter of 8.6% (2.9 mm) in non-irradiated tumours (p = 0.0003, 95% CI 5.6–17.3) (see sup. Fig. S1).
3.3.4 According to tumour size
Responses seemed independent of tumour size (0–30 mm). The best ORR was 50.9% (CR 41.5%; PR 9.4%), see sup. Fig. S2.
3.3.5 Response according to diagnosis at patient level
Eight patients with breast cancer were treated with an ORR of 77.4% (CR 67.7%; PR 9.7%) (Fig. 5). Patient one had CR in six of seven tumours and was successfully retreated for recurrence after 2 and 7.5 months. The five patients with lung cancer metastases had lower ORR of 14.3% (CR 14.3%; PR 0%), however CR was achieved in one patient (Pt 7). This patient was retreated for recurrence after 11 months with histologically verified response (sup. Fig. S3). Two of three tumours in the patient with endometrial cancer metastasis showed CR, with suppuration relief. The patient with oesophageal cancer metastasis had SD in treated areas and rapid progression in untreated areas and was referred to radiotherapy. The patient with gastric cancer metastasis showed both CR and progression, while the patient with pancreatic cancer metastasis showed PD only. No response was seen in patients with colorectal cancer metastasis, who along with patients with endometrial-, gastric-, pancreatic-, and oesophageal cancer metastases, had a short follow-up period due to death from primary disease progression.
Fig. 5Swimmer's plot of different cancer metastases histotypes and response to calcium electroporation (CaEP). Two patients were retreated with CaEP (Pt 1 and Pt 7). Four patients were assessed after one year of which two had been retreated. After one year, response was histologically confirmed in Patient 7 at 12 months.
Tumours were treated with a median injected dose of 1.07 ml CaCl2 220 mM. A median current of 7.0–10.0 A was delivered (Supplementary Table S1). The procedure was performed in general anaesthesia at the Lübeck site, according to local practice.
3.5 Post-treatment interventions
Wounds were dressed with silicone-border adhesive bandages. One patient had local infection treated with oral antibiotics. Wound escars were left in situ. Two patients with responsive lesions had recurrence during follow-up and were re-treated with CaEP. Three patients with rapidly progressive new lesions were referred to other treatments (Fig. 5).
3.6 CTCAE and AEs
Treatment was well tolerated in local anaesthesia, with patient account of moderate discomfort during injection of anaesthesia and muscle contractions in relation to pulse application. In some cases, minimal bleeding or oozing occurred post-treatment manageable with simple wound dressings. Post-treatment AEs included ulceration and pain. At two months, AEs related to skin symptoms were minimal. AEs according to CTCAE V. 4.0 are shown in sup. Fig. S4. CTCAE scores at baseline were minor. Three patients reported local pain two months after treatment compared to 12 at baseline (p = 0.017). There was no correlation between response and pain at two months (p > 0.99). There was a subtle trend towards increased suppuration at two months related to non-healed wounds. Crusted wounds were observed in six patients after two months (Fig. 3A). Some target areas did not present ulceration following treatment, mainly observed in subcutaneous tumours (Fig. 3 and sup. Fig. S3.B).
Pain of treated areas declined by first follow-up and was related to post-treatment swelling. Across all treated areas, most were transiently darker (hyperpigmentation in five patients at two months). Local infection occurred in one patient. One SAE was reported, deemed not related to CaEP treatment.
3.7 Impact on QoL
Change in cancer-related symptoms two months after calcium electroporation was analysed from the EORTC QLQ-C15-PAL questionnaire data. CaEP led to a non-significant increase in QoL score two months after treatment, where the median was 75% (IQR = 62.5–87.5) compared to 58.3% (IQR = 50-83) at baseline (n = 12). Five (42%) reported higher QoL, and two (17%) reported lower QoL. There was indication of a trend of improvement in global health status, physical and emotional functioning, fatigue, and pain (sup. Fig. S5).
The results of the independent qualitative interview sub-study were recently published [
A total of 11 tumours were MR-scanned before and after treatment at baseline. Seven tumours were evaluated by MRI again after 2 months. MRI scans performed just after treatment showed a demarcated area where CaEP caused restriction in all tumours. Supplementary Fig. S6 shows acute tumour reduction. MRI scans at two months provided supplementary assessment of depth and distribution of tumour tissue.
4. Discussion
CM is a challenging condition that currently needs more effective treatment options. CaEP is a promising new treatment-modality, with efficacy and few side effects observed in the first randomized controlled trials [
Calcium electroporation for treatment of cutaneous metastases; a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy.
]. This study aimed to further define ORR of CaEP for CM in patients who have exhausted other options. Although the number of patients treated in this study is limited, the study does increase the knowledge base by including more treatment centres and patients with diagnoses for which data were not previously published. Using response at two months as the primary endpoint based on the aforementioned studies, 19 patients with different types of metastases were included, with an ORR of 36% at two months. Interestingly, we observed best response after three months, with CR in all previously irradiated tumours at four months. As lengthy wound healing is common following EP, future studies could consider best response as endpoint for CM. Best ORR was 50.9%, Few AEs were reported. Only ulceration was registered as grade 3, where all other AEs were grade 1-2. Long-term response was seen in three of four patients assessed one year after treatment. Two of these patients were successfully retreated, supporting treatment repeatability. The median size of the included tumours (14 mm) was larger than previous studies using CaEP for CM [
Calcium electroporation for treatment of cutaneous metastases; a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy.
] and responses seemed independent of size. Falk et al. had a median tumour size of 9.5 mm and ORR of 72%, while Ágoston et al. had a median size of 6.5 mm and an ORR of 22%. The dose equation from the ESOPE guidelines may result in a low dose for small tumours, which could explain poorer outcomes than expected [
Electrochemotherapy in the treatment of cutaneous malignancy: outcomes and subgroup analysis from the cumulative results from the pan-European International Network for Sharing Practice in Electrochemotherapy database for 2482 lesions in 987 patients (2008-2019).
Electrochemotherapy in the treatment of cutaneous malignancy: outcomes and subgroup analysis from the cumulative results from the pan-European International Network for Sharing Practice in Electrochemotherapy database for 2482 lesions in 987 patients (2008-2019).
]. An independent qualitative analysis from this study showed improved QoL two months after treatment, with reduced pain and fatigue and increased social inclination [
], and indication of a trend that these symptoms decreased was found in our EORTC analysis. CTCAE analysis showed decrease in pain at two months follow-up (p = 0.017). Moderate symptoms at baseline may be related to included tumour size (≤3 cm) [
Calcium electroporation for treatment of cutaneous metastases; a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy.
]. To our knowledge, this is the first report of successful CaEP treatment of lung cancer metastasis. We also report CaEP for less common types of metastases, including various types of visceral adenocarcinomas [
]. We observed different response-types in the same patient in several cases, also with aggressive histotypes. The patient with gastric cancer metastasis displayed both CR and PD. In addition, CR was achieved in two of three tumours in the patient with endometrial cancer metastasis, which could inspire further investigation of CaEP for gynaecological indications.
To our knowledge, this study attempted the first use of diffusion-weighted MRI to visualize skin tumours treated with CaEP. CaEP causes constriction of blood vessels in vivo, which may explain restriction observed with MRI [
]. The results support MRI for mapping treated tissue, in particular larger areas or areas difficult to assess clinically.
A multidisciplinary approach is often key for optimal management of CM by addressing the diverse medical, surgical, and supportive requirements. ECT is standard therapy for inoperable CM [
], however, calcium is readily accessible and easier to handle compared to chemotherapy drugs, and could offer a low-cost and non-toxic alternative to bleomycin. These properties make calcium compelling to investigate for benign lesions, such as keloids [
]. Interestingly, as clinical research into CaEP has increased in recent years, reports of long-term disease control in treated individuals are emerging [
Electrochemotherapy and calcium electroporation inducing a systemic immune response with local and distant remission of tumors in a patient with malignant melanoma - a case report.
]. In future studies, it would be valuable to investigate the efficacy of CaEP in larger cohorts of patients to better understand potential benefits for a wider population of individuals with CM.
5. Conclusion
This phase II trial supports CaEP as a safe and effective palliative treatment for a variety of skin malignancies, with high efficacy in previously irradiated tumours. We found an ORR of 36% (95% CI 22-53) after two months and best ORR of 51% (CR 41%; PR 9%). CaEP is a promising new therapy option for CM, which may improve QoL for a growing patient group with debilitating symptoms.
Funding
This project was supported by The Interreg consortium Changing Cancer Care (CCC) 094-1.1-18 funded by Interreg Deutschland Danmark.
Data availability
De-identified participant data are available from the corresponding author upon reasonable request. Reuse of data requires approval from the pertinent ethics committee.
CRediT authorship contribution statement
Mille Vissing: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Visualization, Preparation, Project administration. Mascha Pervan: Investigation, Resources, Data curation, Writing – review & editing, Project administration. John Pløen: Investigation, Resources, Data curation, Writing – review & editing. Mazen Schnefeldt: Methodology, Resources, Data curation, Writing – review & editing. Søren Rafael Rafaelsen: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Writing – review & editing, Visualization, preparation. Lars Henrik Jensen: Supervision, Funding acquisition. Achim Rody: Supervision, Funding acquisition. Julie Gehl: Conceptualization, Methodology, Investigation, Resources, Data curation, Writing – review & editing, Supervision, Project administration, Funding acquisition.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JG is co-inventor of a patent regarding calcium electroporation: Therapeutic applications of calcium electroporation to effectively induce tumour necrosis. Granted. PCT/DK2012/050496. No other authors have conflict of interest to declare.
Acknowledgements
The authors would like to thank research nurses Lars Much Larsen and Monica Tronhjem for contributing to collection and registration of data, and correspondence with GCP authorities. This work did not employ writing assistance.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Fig. S1Tumour size at follow up depending on whether tumours were in a previously irradiated area. The median tumour size declined over time in both groups. All irradiated lesions measured at 4, 5 and 6 months follow-up had complete response.
Fig. S2Best response across all treated tumours. All types of responses seem evenly distributed among larger and smaller tumours (0–30 mm). The ORR was 50.9%: CR was observed in 22 of 58 tumours (41.5%), 95% CI 28.4–55.8; PR was observed in five tumours (9.4%); SD in 19 tumours (35.8% 95% CI 23.5–50.3) and PD in seven tumours (13.2%).
Fig. S3Response and histological analyses in a retreated subcutaneous lung cancer metastasis. Iatrogenic, post-needle biopsy, subcutaneous lung cancer metastasis. Retreated with calcium electroporation after 11 months due to recurrence. A biopsy from post-treatment ulceration shows no sign of residual tumour tissue.
Fig. S5Change in cancer-related symptoms two months after calcium electroporation (EORTC QLQ-C15-PAL questionnaire). Positive values for Global health status/QoL, physical and emotional functioning equal improvement. For the remaining symptoms, negative values (e.g. less symptoms) equal improvement.
Fig. S6DW-MRI of target area on chest wall before and after calcium electroporation. Short-T1 inverion recovery (STIR) sequences. The target area was a 30 mm breast cancer cutaneous recurrence with a 3 mm margin (Patient 14). A: Imaged tumour site before calcium electroporation at baseline (day 0). Marking capsule (arrow). B: After calcium electroporation (day 0). Note reduction in tumour mass with resulting cavity.
Calcium electroporation for treatment of cutaneous metastases; a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy.
Dose-dependent ATP depletion and cancer cell death following calcium electroporation, relative effect of calcium concentration and electric field strength.
Calcium electroporation and electrochemotherapy for cancer treatment: importance of cell membrane composition investigated by lipidomics, calorimetry and in vitro efficacy.
Electrochemotherapy and calcium electroporation inducing a systemic immune response with local and distant remission of tumors in a patient with malignant melanoma - a case report.
Study protocol designed to investigate tumour response to calcium electroporation in cancers affecting the skin: a non-randomised phase II clinical trial.
Noncontrast-enhanced 3-Tesla MRI using surface coil as a complementary test for assessment of distribution and depth of locoregional cutaneous metastases of malignant melanoma.
Electrochemotherapy in the treatment of cutaneous malignancy: outcomes and subgroup analysis from the cumulative results from the pan-European International Network for Sharing Practice in Electrochemotherapy database for 2482 lesions in 987 patients (2008-2019).
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