Skip to main content
Log in

Neoadjuvant calcium electroporation for potentially curable colorectal cancer

  • Published:
Surgical Endoscopy Aims and scope Submit manuscript

Abstract

Background

The development of new perioperative treatment modalities to activate the immune system in colorectal cancer might have a beneficial effect on reducing the risk of recurrence after surgery. Calcium electroporation is a promising treatment modality that potentially modulates the tumor microenvironment. The aim of this study was to evaluate the safety of the procedure in the neoadjuvant setting in localized left-sided colorectal cancer (CRC).

Methods

The study included patients with potentially curable sigmoid or rectal cancer with no indication for other neoadjuvant treatment. Patients were offered calcium electroporation as a neoadjuvant treatment before elective surgery. Follow-up visits were conducted on the preoperative day before elective surgery, POD2, POD14, and POD30, with an evaluation of adverse events, impact on elective surgery, clinical examination, and quality of recovery.

Results

Endoscopic calcium electroporation was performed as an outpatient procedure in all 21 cases, with no procedure-related complications reported. At follow-up, five adverse events were registered, two of which were classified as serious adverse events. Surgery was performed as planned in 19 patients (median time to surgery, 8 days), and the final two patients underwent surgery with a delay due to adverse events (14 and 33 days). No significant impact on the quality of recovery scores nor inflammatory markers were seen before and after calcium electroporation, nor baseline and POD30.

Conclusions

Endoscopic calcium electroporation is a safe and feasible procedure in patients with potentially curable CRC. The study showed limited side effects and limited impact on the following elective surgical resection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    Article  PubMed  Google Scholar 

  2. Osterman E, Glimelius B (2018) Recurrence risk after up-to-date colon cancer staging, surgery, and pathology: analysis of the entire swedish population. Dis Colon Rectum 61(9):1016–1025

    Article  PubMed  Google Scholar 

  3. Van Der Bij GJ, Oosterling SJ, Beelen RHJ, Meijer S, Coffey JC, Van Egmond M (2009) The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer. Ann Surg 249(5):727–734

    Article  PubMed  Google Scholar 

  4. Raskov H, Orhan A, Salanti A, Gögenur I (2020) Premetastatic niches, exosomes and circulating tumor cells: early mechanisms of tumor dissemination and the relation to surgery. Int J Cancer 146(12):3244–3255

    Article  CAS  PubMed  Google Scholar 

  5. Horowitz M, Neeman E, Sharon E, Ben-Eliyahu S (2015) Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat Rev Clin Oncol 12(4):213–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K et al (2020) Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 26(4):566–576

    Article  CAS  PubMed  Google Scholar 

  7. Teissie J, Tsong TY (1981) Electric field induced transient pores in phospholipid bilayer vesicles. Biochemistry 20(6):1548–1554

    Article  CAS  PubMed  Google Scholar 

  8. Zimmermann U, Schulz J, Pilwat G (1973) Transcellular ion flow in Escherichia coli B and electrical sizing of bacterias. Biophys J 13(10):1005–1013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Neumann E, Rosenheck K (1972) Permeability changes induced by electric impulses in vesicular membranes. J Membr Biol 10(1):279–290

    Article  CAS  PubMed  Google Scholar 

  10. Frandsen SK, Gissel H, Hojman P, Tramm T, Eriksen J, Gehl J (2012) Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis. Cancer Res 72(6):1336–1341

    Article  CAS  PubMed  Google Scholar 

  11. Frandsen SK, Vissing M, Gehl J (2020) A comprehensive review of calcium electroporation: a novel cancer treatment modality. Cancers (Basel) 12(2):78

    Article  Google Scholar 

  12. Egeland C, Baeksgaard L, Gehl J, Gögenur I, Achiam MP (2022) Palliative treatment of esophageal cancer using calcium electroporation. Cancers (Basel) 14(21):5283

    Article  CAS  PubMed  Google Scholar 

  13. Justesen TF, Orhan A, Raskov H, Nolsoe C, Gögenur I (2022) Electroporation and immunotherapy-unleashing the abscopal effect. Cancers (Basel). 14(12):7

    Article  Google Scholar 

  14. Falk H, Forde PF, Bay ML, Mangalanathan UM, Hojman P, Soden DM et al (2017) Calcium electroporation induces tumor eradication, long-lasting immunity and cytokine responses in the CT26 colon cancer mouse model. Oncoimmunology 6(5):e1301332

    Article  PubMed  PubMed Central  Google Scholar 

  15. Falk H, Lambaa S, Johannesen HH, Wooler G, Venzo A, Gehl J (2017) 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 (Stockholm, Sweden) 56:1126–1131

    Article  Google Scholar 

  16. Broholm M, Vogelsang R, Bulut M, Stigaard T, Falk H, Frandsen S (2023) Endoscopic calcium electroporation for colorectal cancer: a phase i study. Endosc Int Open. 11(5):E451–E459

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kleif J, Waage J, Christensen KB, Gögenur I (2018) Systematic review of the QoR-15 score, a patient- reported outcome measure measuring quality of recovery after surgery and anaesthesia. Br J Anaesth 120(1):28–36

    Article  CAS  PubMed  Google Scholar 

  18. Whittaker TM, Abdelrazek MEG, Fitzpatrick AJ, Froud JLJ, Kelly JR, Williamson JS et al (2021) Delay to elective colorectal cancer surgery and implications for survival: a systematic review and meta-analysis. Colorectal Dis 23(7):1699–1711

    Article  PubMed  PubMed Central  Google Scholar 

  19. Staresinic B, Jesenko T, Kamensek U, Krog Frandsen S, Sersa G, Gehl J et al (2018) Effect of calcium electroporation on tumour vasculature. Sci Rep 8(1):9412

    Article  PubMed  PubMed Central  Google Scholar 

  20. Pagès F, Galon J, Fridman WH (2008) The essential role of the in situ immune reaction in human colorectal cancer. J Leukoc Biol 84(4):981–987

    Article  PubMed  Google Scholar 

  21. Angell HK, Bruni D, Barrett JC, Herbst R, Galon J (2020) The immunoscore: colon cancer and beyond. Clin Cancer Res 26(2):332–339

    Article  CAS  PubMed  Google Scholar 

  22. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964

    Article  CAS  PubMed  Google Scholar 

  23. Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C et al (2014) Towards the introduction of the “Immunoscore” in the classification of malignant tumours. J Pathol 232(2):199–209

    Article  CAS  PubMed  Google Scholar 

  24. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  25. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Terzić J, Grivennikov S, Karin E, Karin M (2010) Inflammation and colon cancer. Gastroenterology 138(6):2101-2114.e5

    Article  PubMed  Google Scholar 

  27. Frandsen SK, Gehl J (2018) 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 17:1533033818788077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Frandsen SK, Krüger MB, Mangalanathan UM, Tramm T, Mahmood F, Novak I et al (2017) Normal and Malignant cells exhibit differential responses to calcium electroporation. Cancer Res 77(16):4389–4401

    Article  CAS  PubMed  Google Scholar 

  29. Szewczyk A, Gehl J, Daczewska M, Saczko J, Frandsen SK, Kulbacka J (2018) Calcium electroporation for treatment of sarcoma in preclinical studies. Oncotarget 9(14):11604–11618

    Article  PubMed  PubMed Central  Google Scholar 

  30. Falk H, Matthiessen LW, Wooler G, Gehl J (2018) Calcium electroporation for treatment of cutaneous metastases; a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy. Acta Oncol 57(3):311–319

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Ditte Scofield for the linguistic review of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Broholm.

Ethics declarations

Disclosures

Malene Broholm, Rasmus Vogelsang, Mustafa Bulut, Mikail Göegnur, Trine Stigaard, Adile Orhan, Xenia Schefte, Anne Marie Kanstrup Fiehn, Julie Gehl and Ismail Gögenur have no conflicts of interest or financial ties to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Broholm, M., Vogelsang, R., Bulut, M. et al. Neoadjuvant calcium electroporation for potentially curable colorectal cancer. Surg Endosc 38, 697–705 (2024). https://doi.org/10.1007/s00464-023-10557-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00464-023-10557-1

Keywords

Navigation