This document summarizes emerging electrical therapy using tumor treating fields (TTFields) for malignant gliomas. TTFields use alternating electric fields to inhibit tumor cell division. Clinical trials show TTFields improve progression-free and overall survival when added to chemotherapy for newly diagnosed and recurrent glioblastoma with relatively low toxicity. The role of the neuroradiologist includes imaging assessment of treatment response and potentially prescribing the TTFields device. Future applications may expand to other cancer types based on mechanisms of action targeting the cell division process.

1. Emerging Electrical Therapy
for Malignant Gliomas:
Impact of Tumor Treating Fields and the Role
of the Neuroradiologist
Aaron Skolnik, MD1
Harish Poptani, PhD1
Sanjeev Chawla, PhD1
Sumei Wang, MD1
Guarav Verma, PhD1
Steven Brem, MD2
Suyash Mohan, MD1
1Neuroradiology
2Neurosurgery
Hospital of the University of Pennsylvania
ASNR 2016
Abstract: eEdE-78
Submission: 2059

2. Disclosures
 Investigator-Sponsored Trial
 Evaluating Therapeutic Response to Novo-TTF
 NCT02441322
 Novocure
 Principal Investigator: Suyash Mohan, MD

3. Outline: Tumor Treating Fields

4. Scientific Basis
Tumor Treating Fields

5. Alternating Electric Fields in Medicine
Pless M et al. Tumor treating fields: concept, evidence and
future. Expert Opin Investig Drugs. 2011 Aug;20(8):1099-106
 Tumor Treating Fields (TTFields)
 Alternating Electric Fields within a specific range of frequency
(100-300 kHz) shown to inhibit tumor cell division
 Alternating electric fields are used in medicine
 Biologic effects vary by frequency
 Ranging from membrane depolarization to ablation

6. TTFields: Mechanism of action
 In static electric fields
 Charged particles move toward
opposite charge (A-B)
(electrophoresis)
 In alternating electric fields
 Dipoles oscillate or stay still (C)
 If field is non-uniform (D),
particles travel toward converging
side of field (dielectrophoresis)
Gutin PH et al. Noninvasive application of alternating electric
fields in glioblastoma: a fourth cancer treatment modality. Am
Soc Clin Oncol Educ Book. 2012:126-31.

7. TTFields: Mechanism of action
Gutin PH et al. Noninvasive application of alternating electric
fields in glioblastoma: a fourth cancer treatment modality. Am
Soc Clin Oncol Educ Book. 2012:126-31.
 These actions of alternating electric
fields interfere with cell division by two
major mechanisms:
1. Microtubule subunits (tubulin dimers) are
small dipoles (A)
 Oscillate or hold still in TTFields
 Can not polymerize to form mitotic
spindle
 Chromosomes are not separated
properly into daughter cells
2. Cleavage site of dividing cell induces
non-uniform electric field (B)
 Organelles and macromolecules
converge toward higher intensity
zone at cleavage site
(dielectrophoresis)
 Result  disordered cell division,
immunogenic cell death

8. TTFields: Mechanism of action
Pless M et al. Tumor treating fields: concept, evidence and
future. Expert Opin Investig Drugs. 2011 Aug;20(8):1099-106

9. In vitro and In vivo evidence
of tumor growth inhibition
Kirson ED et al. Disruption of cancer cell replication by alternating
electric fields. Cancer Res. 2004 May 1;64(9):3288-95.
 Tumors of various animal and
human tumor cell lines tested
(i.e. glioma, melanoma,
adenocarcinoma, etc.)
 With and without TTFields
 In vitro: culture dish (A)
 In vivo: mouse model (B)
 Result: All cell lines inhibited by
TTFields compared to control
 >0 on chart (C) means tumor growth
rate with TTFields less than controls
 Statistically significant in all cell
lines tested

10. Clinical Data
Tumor Treating Fields

11. EF-11 Trial: Eur J of Cancer Sep 2012
 TTFields show
equivalent survival
to physician's
choice
chemotherapy in
recurrent GBM
 Fewer adverse
effects (i.e.
gastrointestinal,
hematologic,
infectious) in
TTFields group
Stupp R et al. NovoTTF-100A versus physician's choice chemotherapy in recurrent
glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012
Sep;48(14):2192-202.

12. EF-14 Trial: JAMA Dec, 2015
Stupp R et al. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide
Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015 Dec 15;314(23):2535-43.
 In the newly
diagnosed GBM,
following surgery
and
chemoradiation:
 Patients treated
with TTFields +
maintenance
temozolomide
had longer
progression free
and overall
survival
compared to
temozolomide
alone

13. Major Clinical Trial Summary
 EF-11 Trial: TTFields show equivalent survival to physician's
choice chemotherapy in recurrent GBM, with less toxicity,
better quality of life
 EF-14 Trial: In the newly diagnosed GBM, TTFields extend:
 Progression free survival by ~3 months (from 4.0 to 7.1)
 Overall survival by ~5 months (from 15.6 to 20.5)
 Relatively low toxicity, most commonly skin irritation
 Dose dependent treatment efficacy observed with compliance
over 18 hours per day of treatment time
Stupp R et al. NovoTTF-100A versus physician's choice chemotherapy
in recurrent glioblastoma: a randomised phase III trial of a novel
treatment modality. Eur J Cancer. 2012 Sep;48(14):2192-202.
Stupp R et al. Maintenance Therapy With Tumor-Treating Fields Plus
Temozolomide vs Temozolomide Alone for Glioblastoma: A
Randomized Clinical Trial. JAMA. 2015 Dec 15;314(23):2535-43.

14. 0 5 10 15 20 25
No treatment
Surgery + Radiation
Surgery + Radiation + TMZ
Surgery + Radiation + TMZ + TTFields
Median Overall Survival (Months)
Natural History of Glioblastoma and
Impact of Available Therapies
Stupp R et al. Radiotherapy plus concomitant and adjuvant
temozolomide for glioblastoma. N Engl J Med. 2005 Mar
10;352(10):987-96.
Stupp R et al. Maintenance Therapy With Tumor-Treating Fields Plus
Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized
Clinical Trial. JAMA. 2015 Dec 15;314(23):2535-43.
< 3 months
12.1 months
20.5 months
14.6-16.7 months
TMZ: Temozolomide

15. New Treatment Paradigm:
From Triple to Quadruple Modality
Glioblastoma
Surgery
Radiation
Chemo-
therapy
Glioblastoma
Surgery
Radiation
Chemo-
therapy
TTFields
Prior Standard New Standard
Glioblastoma
Surgery
Radiation
Chemo-
therapy
Immuno-
therapy?
Under
investigation
TTFields

16. Historical Timeline
Tumor Treating Fields

17. Timeline of FDA - Approved
Therapies for Malignant Gliomas
October 5, 2015: TTFields for newly diagnosed glioblastoma
April 15, 2011: TTFields for recurrent glioblastoma

18. Historical Timeline of Tumor Treating Fields

19. Role of the Neuroradiologist
Tumor Treating Fields

20. Role of the Neuroradiologist
 Imaging assessment
 Conventional imaging
 Evaluate size, enhancement, edema, mass effect, etc.
 Advanced imaging
 Evaluate and define role of perfusion imaging, diffusion tensor
imaging (DTI), spectroscopy metrics, etc. to better understand
response to TTFields and guide management
 Prescription of the device
 Neuroradiologists can be certified to prescribe the device directly
 A new dimension to “Interventional” Neuroradiology?

21. Imaging Assessment
Tumor Treating Fields

22. Glioblastoma on TTFields: MRI
(a) (b)
MRI contrast-enhanced T1-weighted images of 51 year old woman with glioblastoma centered
in the left thalamus before TTFields therapy (a) and after approximately 2.5 months of
TTFields therapy (b) shows interval decrease in size of peripherally enhancing mass.

23. Glioblastoma on TTFields: MRI
(a) (b)
MRI contrast-enhanced T1-weighted images of 70 year old man with glioblastoma centered in
the right thalamus before TTFields therapy (a) and after approximately 1 month of TTFields
therapy (b) shows interval decrease in size and enhancement of mass.

24. TTFields:
Advanced Imaging Characterization
PC-T1 MD FA CBV Cho/Cr
Baseline
2 month follow-up
S Mohan et al. Response Assessment to Tumor Treating
Fields in newly diagnosed Glioblastoma using Physiologic
and Metabolic MR Imaging: Initial experience. CNS
Oncology. In Press.
 PC-T1: Post-Contrast T1-weighted, MD: Mean Diffusivity,
FA: Fractional Anisotropy, CBV: Cerebral Blood Volume,
Choline to Creatine ratio
 Early response to TTFields showed trends toward
 Increasing MD
 Decreasing tumor volume, FA, rCBV and Cho/Cr
 Potential for physiologic and metabolic MRI to
assess early treatment response to TTFields*

25. Patient and Family
Experience
Tumor Treating Fields

26. The Patient & Family Experience
 TTFields delivered by a portable external device
 Transducer arrays applied to shaved head by caregiver, wires
connected to backpack containing device and battery
 Arrays removed every 2-4 days to shave head and apply new arrays
 Worn as much as possible, goal treatment time >18 hours per day
 Device interrogated for monthly compliance rates
 Can be covered by hat, scarf, or wig

27. Transducer Array
Lacouture ME et al. Characterization and management of dermatologic adverse events with the NovoTTF-100A System, a novel
anti-mitotic electric field device for the treatment of recurrent glioblastoma. Semin Oncol. 2014 Jun;41 Suppl 4:S1-14.

28. TTFields Equipment
Lacouture ME et al. Characterization and management of
dermatologic adverse events with the NovoTTF-100A System, a
novel anti-mitotic electric field device for the treatment of recurrent
glioblastoma. Semin Oncol. 2014 Jun;41 Suppl 4:S1-14.

29. Future Projections
Tumor Treating Fields

30. In vitro & In vivo evidence:
Basis for use in other cancers
Kirson ED et al. Disruption of cancer cell replication by alternating
electric fields. Cancer Res. 2004 May 1;64(9):3288-95.
 Since mechanisms of action of
TTFields targets cell division
apparatus, relatively
independent of cell type
 Multiple cell lines inhibited by
TTFields compared to control
 Provides a basis for clinical
investigation in multiple tumor
types

31. TTFields Parameters
and Effect on Tumor Growth
Kirson ED et al. Disruption of cancer cell replication by alternating
electric fields. Cancer Res. 2004 May 1;64(9):3288-95.
Pless M et al. Tumor treating fields: concept, evidence and
future. Expert Opin Investig Drugs. 2011 Aug;20(8):1099-106
 Optimal treatment frequency
varies by cell type

32. Key cell line data & implications for
further investigation

33. Current Clinical Trials of TTFields in
Brain Metastases & Body Cancers (as of 4/2016)
 Brain metastases
 Small cell lung cancer: NCT02425072
 Non-small cell lung cancer: NCT01755624
 Body cancers
 Advanced non-small cell lung cancer: NCT00749346
 Mesothelioma: NCT02397928
 Pancreatic adenocarcinoma: NCT01971281
 Recurrent ovarian carcinoma: NCT02244502
ClinicalTrials.gov

34. Future Projections for TTFields

35. Summary:
Tumor Treating Fields in Glioblastoma
 TTFields are a novel mechanism and safe modality to treat cancer
 TTFields prolong survival in glioblastoma
 FDA approvals in 2011 and 2015
 The Neuroradiologist has the opportunity to add value to TTFields
patients by understanding the technology and associated imaging
evaluation for response assessment or even prescribing the device
 Expansion of this treatment modality is expected
 Laboratory data shows action in multiple tumor types
 Investigation underway in optimizing combination therapy for glioma
treatment, and for use in body cancers and brain metastases

36. References
1. Ammirati M, Vick N, Liao YL, Ciric I, Mikhael M. Effect of the extent of surgical resection on survival and quality of life in
patients with supratentorial glioblastomas and anaplastic astrocytomas. Neurosurgery. 1987 Aug;21(2):201-6.
2. Chaudhry A, Benson L, Varshaver M, Farber O, Weinberg U, Kirson E, Palti Y. NovoTTF(™)-100A System (Tumor Treating
Fields) transducer array layout planning for glioblastoma: a NovoTAL(™) system user study. World J Surg Oncol. 2015 Nov
11;13(1):316.
3. ClinicalTrials.gov
4. Gutin PH, Wong ET. Noninvasive application of alternating electric fields in glioblastoma: a fourth cancer treatment modality.
Am Soc Clin Oncol Educ Book. 2012:126-31.
5. Kirson ED, Dbalý V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z,
Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y. Alternating electric fields arrest cell
proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10152-7.
6. Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Disruption of cancer cell
replication by alternating electric fields. Cancer Res. 2004 May 1;64(9):3288-95.
7. Lacouture ME, Davis ME, Elzinga G, Butowski N, Tran D, Villano JL, DiMeglio L, Davies AM, Wong ET. Characterization and
management of dermatologic adverse events with the NovoTTF-100A System, a novel anti-mitotic electric field device for the
treatment of recurrent glioblastoma. Semin Oncol. 2014 Jun;41 Suppl 4:S1-14.
8. Lok E, Hua V, Wong ET. Computed modeling of alternating electric fields therapy for recurrent glioblastoma. Cancer Med.
2015 Aug 26.
9. Mohan S, S Chawla, S Wang, G Verma, A Skolnik, S Brem, K Peters, H Poptani. Response Assessment to Tumor Treating
Fields in newly diagnosed Glioblastoma using Physiologic and Metabolic MR Imaging: Initial experience. CNS Oncology. In
Press.
10. Novocure.com
11. Optune.com

37. References
12. Pless M, Weinberg U. Tumor treating fields: concept, evidence and future. Expert Opin Investig Drugs. 2011 Aug;20(8):1099-
106.
13. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn
U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96.
14. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH,
Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M,
Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance Therapy With Tumor-Treating
Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015 Dec
15;314(23):2535-43.
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Z, Villano JL,Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F,
Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous
N, Palti Y, Gutin PH. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase
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38. Acknowledgments
Radiology:
 Mitchell Schnall MD PhD
 Laurie Loevner, MD
 Ronald Wolf MD, PhD
Neurosurgery:
 Steven Brem MD
 Donald O’Rourke MD
Neuro-oncology/Radiation Oncology:
 Arati Desai MD
 Michelle A Basanta MD, PhD
 Robert Lustig MD
Neuropathology:
 Maria Martinez-Lage MD
Grants:
 Novocure
EPSI Development Group:
 Dr. Andrew Maudsley
 Dr. Albert Thomas
 Sulaiman Sheriff
 Dr. Mohammad Sabati
Research Personnel
 Lisa Desiderio
 Katelyn Reilly
 Lauren Karpf
 Krista Huff