
Electrochemotherapy
Electrochemotherapy is one of the most efficient, cost-effective, and non-invasive oncological procedures. It is a method to introduce cytostatics into cancer cells, combining the injection of these drugs into the tumor or bloodstream with an electric pulse. This process, known as electroporation, targets the drugs specifically into cancer cells. A special probe transmits an electric impulse to the malignant tumor, altering the cancer cell membrane and forming pores that allow the medication to enter and intensify its action solely on the cancer cells.
Among the clinically approved drugs tested in preclinical studies, bleomycin and cisplatin have proven to be the most suitable for clinical use in electrochemotherapy. Exposing cells to electric pulses increases the cytotoxicity of bleomycin (by nearly 10,000 times). The application of electric pulses to tumors can be done either through plate electrodes placed on the skin above the tumor or through needle electrodes inserted into it. The application of electric pulses, delivered by either type of electrode, has minimal or no effect on tumor growth.
Electrochemotherapy Protocol
Drug Administration
Initially, a chemotherapeutic drug, usually bleomycin or cisplatin, is administered to the patient. These chemotherapeutic substances are known to be more effective when cells are exposed to electric fields.
Electroporation
Eight minutes after the drug administration, special electrodes are placed around or directly into the tumor tissue. The impulse is transmitted by the CLINIPORATOR device through a pen-shaped probe equipped with an electrode. The physician inserts the electrode into the tumor to discharge the electric pulse onto the tumor. The duration of the emitted pulse is 100 microseconds (µs). The number of pulses varies from 1 to 20, and their amplitude from 100 to 1000 volts. The frequency used ranges between 1 and 5000 Hz. During implementation, both the applied voltage and the current profile are displayed in real-time on the screen, allowing for the monitoring of the efficiency of each individual electroporation directly on the monitor [1].
These pulses temporarily create pores in the cellular membranes, a process called electroporation. This phenomenon allows the drug to penetrate more efficiently into the tumor cells, leading to tumor apoptosis. The treatment can last between 30-60 minutes, depending on the number of tumors.
Advantages of Using Electrochemotherapy
Through this method, the concentration of the chemotherapeutic drug in the tumor tissue is significantly increased, which is why the cytostatic is administered in much smaller doses. This leads to a reduction in side effects. Thus, the main advantage of this procedure is that it preserves healthy tissue unaffected, compared to other options for classical oncological treatment. Electrochemotherapy can reduce tumor masses to disappearance, can lead to the reduction in the size of affected lymph nodes, diminish or even eliminate local pain, and thus improves the quality of life. Also, it can treat tumors that do not respond well to other forms of treatment and can be used in combination with other therapies. Is This Therapy Approved in Europe?
This technique, which has been used for over 25 years in Europe, benefits from many clinical studies and even includes a European treatment guideline. Electrochemotherapy currently uses bleomycin and cisplatin to treat cutaneous metastases of various tumors, as well as inoperable primary tumors.
Effects of Electroporation
- Selective destruction of tumor tissues.
- Major and irreversible damage to the blood vessels that nourish the tumor with nutrients and oxygen, leading to the death of tumor cells [2].
- Immunogenic effect in destroying distant metastases through the abscopal effect.
How Many Sessions Are Needed?
Generally, a single session is sufficient. This can trigger an abscopal immunogenic effect whereby the immune system destroys other metastases. However, in cases of larger tumors, a second session may be necessary.
Through the courtesy of Dr. Gregor Sersa
What are the cancers where electrochemotherapy is indicated?
- Melanoma [3], especially recurrent or metastatic.
- Skin cancer, such as basal cell carcinoma [4] and squamous cell carcinoma [5].
- Breast cancer [6], particularly in cases that have proven resistant to other treatments recommended by guidelines. Studies show a complete response in 50% of cases, partial response in 21%, stable disease in 18%, and progression in only 8% of cases [7].
- Recurrence at the chest wall in breast cancer, where a complete cure
rate of 59% is recorded and an objective response rate of 89% is even
higher than on primary tumors in breast cancer.
- Bone metastases [8], where studies have recorded a response rate of 29%, stable disease in 59%, and progression in only 16%. The mineral structure of the bone and its regenerative capacity are not affected.
- Sarcoma [9] can be treated by electrochemotherapy, especially when located in the skin or soft tissues.
- Squamous cell carcinoma of the oral cavity and oropharynx [10].
- Head and neck tumors [11], or those located at this level.
- Rectal cancer [12].
- Cutaneous metastases [13], of any histology, which are symptomatic due to bleeding, ulceration, breathing, smell, or pain.
- Primary mucosal cancers [14], including recurrent tumors, where other treatment modalities (surgery, radiotherapy, systemic therapies) have failed or are not possible.
- Primary unresectable pancreatic cancer [15].
- Liver metastases [16] from solid tumors.
- Cholangiocellular carcinoma [17] at the hepatic hilum.
- Hepatocellular carcinoma [18].
- Salivary gland cancer [19].
- Esophageal cancer [20].
Contraindications for electrochemotherapy
- Allergy or hypersensitivity to bleomycin or Cisplatin.
- Cumulative dose of bleomycin of 400,000 IU.
- Peripheral neuropathy > grade 2.
- History of pulmonary fibrosis will prevent intravenous administration of bleomycin.
- Infection and/or heart failure and/or liver failure and/or other serious systemic diseases.
- Severe uncorrectable coagulation disorders.
- Pregnancy, breastfeeding: potentially fertile patients must use appropriate contraceptive methods.
Clinical Benefit of Electrochemotherapy
Disease Control
- Objective response rate greater than 80%.
- High percentage (53-86%) of long-lasting complete responses
Symptoms to be mitigated by ECT
- Bleeding
- Discharge
- Pain
- Smell
Other advantage
- Safe, easy, and extremely effective treatment.
- Improvement in the patient's quality of life, regardless of life expectancy.
- Positive cosmetic and functional results.
- Electrochemotherapy is independent of histology.
- Small doses of medication.
- No significant side effects.
- Can be safely repeated multiple times, and patients are willing to undergo repeat treatments.
- Cost-effectiveness
Immunogenic Effect of Electrochemotherapy
Electrochemotherapy not only possesses intrinsic cytotoxic capacity
against cancer cells but also generates a systemic anticancer immune
response by activating immunogenic cell death. Thus, electrochemotherapy
can be considered to trigger a local immune response and act as an
in-situ vaccination with immunogenic effects throughout the body. This
results in a more effective and long-lasting antitumor effect even in
metastases that have not been electroporated.
Therefore, a strong immune response is essential in this therapy to
amplify the immunogenic effects of electrochemotherapy. This should mean
both a sufficient number of immune cells, T, NK, and Dendritic cells,
and subsequent support of the therapy with specific immune-strengthening
therapies. In this regard, studies show a strong synergy of
electrochemotherapy with immunotherapy [22], especially in immunogenic
tumors such as melanoma [23], breast cancer [24], liver cancer [25],
etc.
ImunoMedica Clinic is the only place in Roumania where
electrochemotherapy is used in the treatment of cancer. The equipment we
use is the latest generation, the most efficient in the field of
electroporation. Most of the clinical and preclinical studies in the
field of electrochemotherapy have been conducted using this equipment -
IGEA.
To find out if you are eligible for electrochemotherapy treatment for
the cancer you are suffering from, you can schedule an appointment at
our clinic with Dr. Valentin Popescu, one of the few specialists in this
field in Romania.
Bibliography
1. Schmidt, G., et al. "Electrochemotherapy in breast cancer: a review of references." Geburtshilfe und Frauenheilkunde 74.06 (2014): 557-562.2. Jarm, Tomaz, et al. "Antivascular effects of electrochemotherapy: implications in treatment of bleeding metastases." Expert review of anticancer therapy 10.5 (2010): 729-746.
3. Sersa, Gregor. "The state-of-the-art of electrochemotherapy before the ESOPE study; advantages and clinical uses." European Journal of Cancer Supplements 4.11 (2006): 52-59.
4. Clover, A. J. P., et al. "Electrochemotherapy for the treatment of primary basal cell carcinoma; A randomised control trial comparing electrochemotherapy and surgery with five year follow up." European Journal of Surgical Oncology 46.5 (2020): 847-854.
5. Tokmakçı, Mahmut. "A high-voltage pulse generation instrument for electrochemotherapy method." Journal of medical systems 30 (2006): 145-151.
6. Wichtowski, Mateusz, et al. "Electrochemotherapy in breast cancer-discussion of the method and literature review." Breast Care 12.6 (2017): 409-414.
7. Matthiessen, Louise Wichmann, et al. "Electrochemotherapy for breast cancer—results from the INSPECT database." Clinical Breast Cancer 18.5 (2018): e909-e917; Sersa, Gregor, et al. "Electrochemotherapy of chest wall breast cancer recurrence." Cancer Treatment Reviews 38.5 (2012): 379-386.
8. Bianchi, Giuseppe, et al. "Electrochemotherapy in the treatment of bone metastases: a phase II trial." World Journal of surgery 40 (2016): 3088-3094; Campanacci, Laura, et al. "Electrochemotherapy is effective in the treatment of bone metastases." Current Oncology 29.3 (2022): 1672-1682; Bocchi, Maria Beatrice, et al. "Electrochemotherapy in the Treatment of Bone Metastases: A Systematic Review." Journal of Clinical Medicine 12.19 (2023): 6150.
9. Campana, Luca G., et al. "Electrochemotherapy treatment of locally advanced and metastatic soft tissue sarcomas: results of a non-comparative phase II study." World journal of surgery 38 (2014): 813-822.
10. Prospective randomised trial with control group ‘Electrochemotherapy as first-line treatment of squamous cell carcinoma recurrences of the oral cavity and oropharynx: a randomised controlled trial’.EudraCT 2018-003589-15. Lead researcher: Dr Franco Ionna, G. Pascale Foundation National Institute of Tumours IRCCS, Naples.
11. De Virgilio, Armando, et al. "Electrochemotherapy in head and neck cancer: A review of an emerging cancer treatment." Oncology letters 16.3 (2018): 3415-3423; Strojan, Primož, et al. "Electrochemotherapy in mucosal cancer of the head and neck: a systematic review." Cancers 13.6 (2021): 1254.
12. Prospective randomised trial with control group ‘Organ sparing for locally advanced rectal cancer after neoadjuvant therapy followed by electrochemotherapy’. EudraCT number: 2018-004166-33. Lead Researcher: Dr Paolo Delrio, G. Pascale Foundation National Institute of Tumours IRCCS, Naples.
13. Matthiessen, Louise Wichmann, et al. "Management of cutaneous metastases using electrochemotherapy." Acta Oncologica 50.5 (2011): 621-629; Ferioli, Martina, et al. "Electrochemotherapy of skin metastases from breast cancer: a systematic review." Clinical & Experimental Metastasis 38 (2021): 1-10.
14. Strojan, Primož, et al. "Electrochemotherapy in mucosal cancer of the head and neck: a systematic review." Cancers 13.6 (2021): 1254.
15. Prospective randomised trial with control group ‘Phase IIb trial to evaluate the efficacy of laparoscopic electrochemotherapy in the treatment of locally advanced pancreatic cancer’. EudraCT: 2018-003925-27; Phase I/II trial - feasibility and safety of a new surgical technology: electrochemotherapy in locally advanced pancreatic adenocarcinoma. Lead Researcher: Dr Francesco Izzo, G. Pascale Foundation National Institute of Tumours IRCCS, Naples.
16. Edhemovic, Ibrahim, et al. "Intraoperative electrochemotherapy of colorectal liver metastases." Journal of surgical oncology 110.3 (2014): 320-327; Edhemovic, Ibrahim, et al. "Intraoperative electrochemotherapy of colorectal liver metastases: a prospective phase II study." European Journal of Surgical Oncology 46.9 (2020): 1628-1633.
17. Tarantino, Luciano, et al. "Electrochemotherapy of cholangiocellular carcinoma at hepatic hilum: a feasibility study." European Journal of Surgical Oncology 44.10 (2018): 1603-1609; Granata, V., et al. "Electrochemotherapy of cholangiocellular carcinoma at hepatic hilum: a case report." European Review for Medical & Pharmacological Sciences 24.12 (2020).
18. Djokic, Mihajlo, et al. "Electrochemotherapy as treatment option for hepatocellular carcinoma, a prospective pilot study." European Journal of Surgical Oncology 44.5 (2018): 651-657.
19. Strojan, Primož, et al. "Electrochemotherapy in mucosal cancer of the head and neck: a systematic review." Cancers 13.6 (2021): 1254.
20. Egeland, Charlotte, et al. "Endoscopic electrochemotherapy for esophageal cancer: a phase I clinical study." Endoscopy International Open 6.06 (2018): E727-E734.
21. Calvet, Christophe Y., et al. "Electrochemotherapy with bleomycin induces hallmarks of immunogenic cell death in murine colon cancer cells." Oncoimmunology 3.4 (2014): e28131.
22. Calvet, Christophe Y., and Lluis M. Mir. "The promising alliance of anti-cancer electrochemotherapy with immunotherapy." Cancer and Metastasis Reviews 35 (2016): 165-177.
23. Goggins, Clare A., and Amor Khachemoune. "The use of electrochemotherapy in combination with immunotherapy in the treatment of metastatic melanoma: A focused review." International Journal of Dermatology 58.8 (2019): 865-870.
24. Denkert, Carsten. "The immunogenicity
of breast cancer—molecular subtypes matter." Annals of Oncology 25.8
(2014): 1453-1455; Loizides, Sotiris, and Anastasia Constantinidou.
"Triple negative breast cancer: Immunogenicity, tumor microenvironment,
and immunotherapy." Frontiers in Genetics 13 (2023): 1095839.
25. Trotovšek,
Blaž, et al. "New era of electrochemotherapy in treatment of liver
tumors in conjunction with immunotherapies." World Journal of
Gastroenterology 27.48 (2021): 8216; Trotovsek, Blaz, et al.
"Laparoscopic electrochemotherapy for the treatment of hepatocellular
carcinoma: Technological advancement." Frontiers in Oncology 12 (2022):
996269.
Therapies
- Hormone therapy
- Metronomic chemotherapy
- Electrochemotherapy
- Insulin potentiation therapy (IPT)
- Whole body hyperthermia
- Loco-regional Hyperthermia
- Bevacizumab
- Non-flavonoid phenols
- Flavonoid phenols
- Mistletoe in cancer
- Hyperbaric oxygen in cancer
- Ozone therapy in cancer
- Vitamin C in cancer
- Photodynamic Therapy (PDT)
- Lymphatic drainage in cancer
- Molecular hydrogen therapy
- Psychotherapy in cancer
- Breathing exercises in cancer
- Physical activity and exercise
- Sauna Detox in cancer
- Amygdalin in cancer
- Selenium in cancer
- Curcumin
- Quercetinul