Safety of irreversible electroporation treatment for metastatic disease in humans

Silk Mikhail; Wimmer, Thomas; Getrajdman, George; Durack, Jeremy; Sofocleous, Constantinos T.; Solomon, Stephen B.

Interventional Radiology & Image Guided TherapiesMemorial Sloan Kettering Cancer Center. New York, NY

Email:sofoclec@mskcc.org

Agenda Agenda

• Background on Ablation Devices

• Physics (RFA, MWA, IRE)

• Pre-Clinical Data

• Clinical Applications

  

300GHZ

3HZ

Thermal ablation uses Electromagnetic Spectrum

300 MHz

RFA

MWA

Thermal ablation uses the EM frequencies of 3 Hz and 300 GHz.

Irreversible ElectroporationIrreversible Electroporation

• Electroporation– Electric pulses create

tiny holes in the cell – Temporary as long as

the energy is low• 360 V/cm

– Chemotherapy and Genetic therapy delivery

• “Irreversible”– Higher energy

• 680 V/cm1

• Create permanent holes in the cell

• Cell loses essential molecules and internal signals tell the cell to die

ElectroporationElectroporation

• Reversible electroporation is used to allow genes and drugs to enter cells (300-600 V/cm)

• Direct current pulse leads to elevation of transmembrane potentials creating permanent cell membrane pores: ~1,500 V/cm

• Strong electric fields applied across a cell can cause:

Irreversible permeabilizationof the cell membrane: “IRE”

How IRE kills cellsHow IRE kills cells

Advantages of IREAdvantages of IRE

• IRE is non-thermal

– Little to no scar tissue formation– Structural Protein Sparing

• Nerves and bile ducts in the area of ablation have the potential to heal after treatment

– No heat sink effect• Compared to thermal techniques where blood flow dissipates

heat. Electric pulses are not effected by blow flow.

Patient DemographicsPatient Demographics

Table 1. Patient Demographics

Variable Data

Total number of patients included 29

Age range: 42y-81y

Sex:

Male 16

Female 13

Treated tumor lesions 43

Table 2. Tumor characteristics

Variable Data

Total Tumors 43

Tumor Size 2.3cm

<1 cm 6

1-2 cm 13

2.1-3 cm 12

>3 cm 12

Tumor location

Liver 29

Soft Tissue 12

Lung 1

Tumor type (%)

Metastatic Colorectal 26

Metastatic Pancreatic 6

Metastatic Endometrial 3

Metastatic Prostatic 3

Metastatic Leiomyosarcoma 2

Metastatic Hemangiopericytoma 1

Metastatic Ovarian 1

Metastatic Thyroid 1

Multiple IRE electrodes to treat larger Multiple IRE electrodes to treat larger lesions minimum: lesions minimum: 2 parallel electrodes spaced 1.5-2 cm2 parallel electrodes spaced 1.5-2 cm

NO Heat Sink Effect NO Heat Sink Effect

Case close to bile duct and major veinCase close to bile duct and major vein

• Pre-Tx • Tx • Post-Tx• 3 mo. f/u MRI

No tumor for +778 daysNo tumor for +778 days

Perivascular/periductal Liver MetastasesPerivascular/periductal Liver Metastases

28 patients/ 65 tumors: 1 arrhythmia; 1 PV thrombosis (3%) 6 months: 92% Complete Ablation

Kingham P et al: IRE for Perivascular Hepatic Malignant Tumors. J Am Coll Surg 2012; 215(3): 379-87

Applicators

Animal Lung IRE

Post IRE: GGO

1 week 3 weeks

LUNG close to bronchus

Tumor near airway Tumor near airway

• Pre-Tx • Tx • Post-Tx• 3 mo. PET scan

IRE as an Ablation Tool: Potential AdvantagesIRE as an Ablation Tool: Potential Advantages

• Non-Thermal:

-Application in Locations non eligible for Thermal Ablation

-Limit recurrences near vessels by avoiding the “heat sink”

effect

• Cellular Kill Mechanism Avoids Damage to:

- Extracellular Matrix. This may result in fewer complications:

Near Bile Ducts, Intestines, Ureters, Bronchi, Vital structures.

51 year old with rectal cancer recurrence near 51 year old with rectal cancer recurrence near rectumrectum

NO tumor for +565 days NO tumor for +565 days

Transmural Necrosis; No Perforation at 14 days

IRE Rectal Wall

Applications: IREWhere Thermal ablation is NOT feasible

• Pancreas: Locally advanced adenocarcinoma 100% success at 90 days. Martin RC e al J Am Coll Surg 2012; 215(3): 361-9

• Perivascular Liver Tumors. Kingham P et al: IRE for Perivascular Hepatic Malignant Tumors. J Am

Coll Surg 2012; 215(3): 379-87

• Prostate: A potential Therapeutic Paradigm Shift. Ward JF Curr Opin Urol

2012; (2): 104-108

• Intracranial: Canine brain Surgery. Garcia PA Conf Proc IEEE Eng Med Biol Soc 2009:

6513-6. and Technol Cancer Res Treat 2011; 10(1): 73-83

• Blood Brain barrier Disruption: Rat Hjoui M et al. MRI study on reversible and irreversible

electroporation induced blood brain barrier disruption. Plos One. 2012;7(8)

• Small Intenstine: Rat: Complete ablation but recovery of Epithelium in 3 weeks. Phillips MA. Br J Cancer 2012; 31; 106(3): 490-5

Enhancing Irreversible Electroporation

A zone of Reversible electroporation Surrounds the Area of IRE

A lethal agent can be targeted to the reversible zone:

ElectrochemotherapyGene Electrotransfer

Electrochemotherapy : A new technological approach in treatment of Liver Metastases. Edhemovic et al Technol Cancer Res Treat 2011 Oct; 10(5):475-85

Treatment Planning of Electroporation-Based medical Interventions: electrochemotherapy, gene electrotransfer and IRE Phys Med Biol 2012; 7;57(17)5425-40

Model assumes 360 V/cm threshold for reversible and 680 V/cm threshold for irreversible

Reversible

Irreversible

ConclusionConclusion

• Unlike Thermal Ablation, IRE, can be performed in close proximity to bile ducts, major vessels, bladder, rectum, and nerves, with an acceptable safety profile.

• Longer term follow up is performed to determine efficacy.

• Further research will determine the potential of this new ablation technology

sofoclec@mskcc.org