CC BY-NC-ND 4.0 · Endosc Int Open 2023; 11(05): E451-E459
DOI: 10.1055/a-2033-9831
Original article

Endoscopic calcium electroporation for colorectal cancer: a phase I study

Malene Broholm
1   Center for Surgical Science, Department of Surgery, Zealand University Hospital, Denmark
,
Rasmus Vogelsang
1   Center for Surgical Science, Department of Surgery, Zealand University Hospital, Denmark
,
Mustafa Bulut
1   Center for Surgical Science, Department of Surgery, Zealand University Hospital, Denmark
2   Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
,
Trine Stigaard
1   Center for Surgical Science, Department of Surgery, Zealand University Hospital, Denmark
,
Hanne Falk
3   Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
,
Stine Frandsen
4   Center for Experimental Drug and Gene Electrotransfer (C*EDGE), Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Roskilde, Denmark
,
Dorte Levin Pedersen
5   Department of Radiology, Zealand University Hospital, Denmark
,
Trine Perner
5   Department of Radiology, Zealand University Hospital, Denmark
,
Anne-Marie Kanstrup Fiehn
1   Center for Surgical Science, Department of Surgery, Zealand University Hospital, Denmark
2   Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
6   Department of Pathology, Zealand University Hospital, Denmark
,
Ida Mølholm
7   Visiopharm, Hoersholm, Denmark
,
Michael Bzorek
6   Department of Pathology, Zealand University Hospital, Denmark
,
Andreas Weinberger Rosen
1   Center for Surgical Science, Department of Surgery, Zealand University Hospital, Denmark
,
Christina Søs Auður Andersen
6   Department of Pathology, Zealand University Hospital, Denmark
,
Niels Pallisgaard
6   Department of Pathology, Zealand University Hospital, Denmark
,
Ismail Gögenur
1   Center for Surgical Science, Department of Surgery, Zealand University Hospital, Denmark
2   Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
,
Julie Gehl
2   Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
3   Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
4   Center for Experimental Drug and Gene Electrotransfer (C*EDGE), Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Roskilde, Denmark
› Author AffiliationsSupported by: Enhanced perioperative oncology (EPEONC) consortium
Supported by: Kræftens Bekæmpelse http://dx.doi.org/10.13039/100008363 R110-A6996

TRIAL REGISTRATION: Prospective trial NCT03542214 at ClinicalTrials.gov (http://www.clinicaltrials.gov/)
› Further Information
Also available at
   Permissions and Reprints

Abstract

Background and study aims Colorectal cancer is one of the most common malignancies, with approximately 20 % of patients having metastatic disease. Local symptoms from the tumor remain a common issue and affect quality of life. Electroporation is a method to permeabilize cell membranes with high-voltage pulses, allowing increased passage of otherwise poorly permeating substances such as calcium. The aim of this study was to determine the safety of calcium electroporation for advanced colorectal cancer.

Patients and methods Six patients with inoperable rectal and sigmoid colon cancer were included, all presenting with local symptoms. Patients were offered endoscopic calcium electroporation and were followed up with endoscopy and computed tomography/magnetic resonance scans. Biopsies and blood samples were collected at baseline and at follow-up, 4, 8, and 12 weeks after treatment. Biopsies were examined for histological changes and immunohistochemically with CD3/CD8 and PD-L1. In addition, blood samples were examined for circulating cell-free DNA (cfDNA).

Results A total of 10 procedures were performed and no serious adverse events occurred. Prior to inclusion, patients reported local symptoms, such as bleeding (N = 3), pain (N = 2), and stenosis (N = 5). Five of six patients reported symptom relief. In one patient, also receiving systemic chemotherapy, clinical complete response of primary tumor was seen. Immunohistochemistry found no significant changes in CD3 /CD8 levels or cfDNA levels after treatment.

Conclusions This first study of calcium electroporation for colorectal tumors shows that calcium electroporation is a safe and feasible treatment modality for colorectal cancer. It can be performed as an outpatient treatment and may potentially be of great value for fragile patients with limited treatment options.

Supplementary material



Publication History

Received: 23 September 2022

Accepted after revision: 09 February 2023

Accepted Manuscript online:
13 February 2023

Article published online:
09 May 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Gehl J. Electroporation: theory and methods, perspectives for drug delivery, gene therapy and research. Acta Physiol Scand 2003; 177: 437-447
    CrossrefPubMedSearch in Google Scholar
  • 2 Frandsen SK, Vissing M, Gehl J. A comprehensive review of calcium electroporation - a novel cancer treatment modality. Cancers 2020; 12: 290
    CrossrefPubMedSearch in Google Scholar
  • 3 Frandsen SK, Gissel H, Hojman P. et al. Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis. Cancer Res 2012; 72: 1336-1341
    CrossrefPubMedSearch in Google Scholar
  • 4 Frandsen SK, Krüger MB, Mangalanathan UM. et al. Normal and malignant cells exhibit differential responses to calcium electroporation. Cancer Res 2017; 77: 4389-4401
    CrossrefPubMedSearch in Google Scholar
  • 5 Falk H, Forde PF, Bay ML. et al. Calcium electroporation induces tumor eradication, long-lasting immunity and cytokine responses in the CT26 colon cancer mouse model. Oncoimmunology 2017; 6: e1301332
    CrossrefPubMedSearch in Google Scholar
  • 6 Frandsen SK, Gehl J. A Review on differences in effects on normal and malignant cells and tissues to electroporation-based therapies: a focus on calcium electroporation. Technol Cancer Res Treat 2018; 17
    CrossrefPubMedSearch in Google Scholar
  • 7 Hoejholt KL, Mužić T, Jensen SD. et al. Calcium electroporation and electrochemotherapy for cancer treatment: Importance of cell membrane composition investigated by lipidomics, calorimetry and in vitro efficacy. Sci Rep 2019; 9: 4758
    CrossrefPubMedSearch in Google Scholar
  • 8 Frandsen SK, Gissel H, Hojman P. et al. Calcium electroporation in three cell lines: a comparison of bleomycin and calcium, calcium compounds, and pulsing conditions. Biochim Biophys Acta 2014; 1840: 1204-1208
    CrossrefPubMedSearch in Google Scholar
  • 9 Hansen EL, Sozer EB, Romeo S. et al. Dose-Dependent ATP depletion and cancer cell death following calcium electroporation, relative effect of calcium concentration and electric field strength. PLoS One 2015; 10: e0122973
    CrossrefPubMedSearch in Google Scholar
  • 10 Szewczyk A, Gehl J, Daczewska M. et al. Calcium electroporation for treatment of sarcoma in preclinical studies. Oncotarget 2018; 9: 11604-11618
    CrossrefPubMedSearch in Google Scholar
  • 11 Falk H, Matthiessen LW, Wooler G. et al. Calcium electroporation for treatment of cutaneous metastases; a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy. Acta Oncol 2018; 57: 311-319
    CrossrefPubMedSearch in Google Scholar
  • 12 Falk H, Lambaa S, Johannesen HH. et al. 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. Acta Oncol 2017; 56: 1126-1131
    CrossrefPubMedSearch in Google Scholar
  • 13 Ágoston D, Baltás E, Ócsai H. et al. Evaluation of calcium electroporation for the treatment of cutaneous metastases: a double blinded randomised controlled phase II trial. Cancers (Basel) 2020; 12: 179
    CrossrefPubMedSearch in Google Scholar
  • 14 Plaschke CC, Gehl J, Johannesen HH. et al. Calcium electroporation for recurrent head and neck cancer: A clinical phase I study. Laryngoscope Investig Otolaryngol 2019; 4: 49-56
    CrossrefPubMedSearch in Google Scholar
  • 15 Frandsen SK, Gibot L, Madi M. et al. Calcium electroporation: evidence for differential effects in normal and malignant cell lines, evaluated in a 3D spheroid model. PLoS One 2015; 10: e0144028
    CrossrefPubMedSearch in Google Scholar
  • 16 Røge R, Vyberg M, Nielsen S. Accurate PD-L1 protocols for non-small cell lung cancer can be developed for automated staining platforms with clone 22C3. Appl Immunohistochem Mol Morphol 2017; 25: 381-385
    CrossrefPubMedSearch in Google Scholar
  • 17 Pallisgaard N, Spindler KLG, Andersen RF. et al. Controls to validate plasma samples for cell free DNA quantification. Clin Chim Acta 2015; 446: 141-146
    CrossrefPubMedSearch in Google Scholar
  • 18 Lefèvre AC, Pallisgaard N, Kronborg C. et al. The clinical value of measuring circulating HPV DNA during chemo-radiotherapy in squamous cell carcinoma of the anus. Cancers (Basel) 2021; 13: 2451
    CrossrefPubMedSearch in Google Scholar
  • 19 Lalchandani UR, Sahai V, Hersberger K. et al. A Radiologist’s Guide to Response Evaluation Criteria in Solid Tumors. Curr Probl Diagn Radiol 2019; 48: 576-585
    CrossrefPubMedSearch in Google Scholar
  • 20 Falk Hansen H, Bourke M, Stigaard T. et al. Electrochemotherapy for colorectal cancer using endoscopic electroporation: a phase 1 clinical study. Endosc Int Open 2020; 8: E124-E132
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Egeland C, Baeksgaard L, Johannesen HH. et al. Endoscopic electrochemotherapy for esophageal cancer: a phase I clinical study. Endosc Int Open 2018; 6: E727-E34
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Schipilliti FM, Onorato M, Arrivi G. et al. Electrochemotherapy for solid tumors: literature review and presentation of a novel endoscopic approach. Radiol Oncol 2022; 56: 285-291
    CrossrefPubMedSearch in Google Scholar
  • 23 Egeland C, Baeksgaard L, Gehl J. et al. Palliative treatment of esophageal cancer using calcium electroporation. Cancers (Basel) 2022; 14: 5283
    CrossrefPubMedSearch in Google Scholar
  • 24 Staresinic B, Jesenko T, Kamensek U. et al. Effect of calcium electroporation on tumour vasculature. Sci Rep 2018; 8: 9412
    CrossrefPubMedSearch in Google Scholar