Title:

Method and device for treating cancer with electrical therapy in conjunction with chemotherapeutic agents and radiation therapy

Document Type and Number:

United States Patent 7412285

Abstract:

This invention relates generally to the electrical treatment of malignant tumors and neoplasms by applying a voltage to affected tissue. Devices and various adaptations therein are described for use in electrical therapy. Additionally, various chemotherapeutic agent and radiation therapies are described which may be advantageously used in conjunction with electrical therapy to ameliorate cancer.

Inventors:

Schroeppel, Edward A. (Sugar Land, TX, US)
Kroll, Mark W. (Simi Valley, CA, US)
Kroll, Kai (Minneapolis, MN, US)

Plaque It!

Sponsored by:
Flash of Genius

Application Number:

10/434400

Publication Date:

08/12/2008

Filing Date:

05/07/2003

View Patent Images:

Images are available in PDF form when logged in. To view PDFs, Login or Create Account (Free!)

Export Citation:

Click for automatic bibliography generation

Assignee:

OncoStim, Inc. (Maple Grove, MN, US)

Primary Class:

607/2

International Classes:

A61N1/00

Field of Search:

604/20, 607/2, 607/3, 604/21

US Patent References:

4003379	Apparatus and method for implanted self-powered medication dispensing	January, 1977	Ellinwood, Jr.
4026304	Bone generating method and device	May, 1977	Levy
4289135	Apparatus for destroying a selected part of biological tissue	September, 1981	Nordenstrom et al.
4572214	Electrode device	February, 1986	Nordenstrom et al.
4639244	Implantable electrophoretic pump for ionic drugs and associated methods	January, 1987	Rizk
4679561	Implantable apparatus for localized heating of tissue	July, 1987	Doss
4919138	Method and apparatus for supplying electric energy to biological tissue for simulating the physiological healing process	April, 1990	Nordenstrom
4974595	Electrode device intended to be introduced into the body of a living being	December, 1990	Nordenstrom
5058605	Method and device for the controlled local, non-invasive application of DC pulses to human and animal tissues	October, 1991	Slovak
5098843	Apparatus for the high efficiency transformation of living cells	March, 1992	Calvin
5314451	Replaceable battery for implantable medical device	May, 1994	Mulier	607/33
5458627	Electrochemically controlled faradic stimulation of osteogenesis	October, 1995	Baranowski
5501662	Implantable electroporation method and apparatus for drug and gene delivery	March, 1996	Hofmann
5584872	Electrophysiology energy treatment devices and methods of use	December, 1996	LaFontaine et al.
5611350	Method and apparatus for facilitating recovery of patients in deep coma	March, 1997	John
5630426	Apparatus and method for characterization and treatment of tumors	May, 1997	Eggers et al.
5674267	Electric pulse applicator using pairs of needle electrodes for the treatment of biological tissue	October, 1997	Mir et al.
5701895	Subcutaneous electrical data port	December, 1997	Prutchi et al.
5820548	Apparatus for treating malignant tissue changes	October, 1998	Sieben et al.
5919187	Method and apparatus for endovascular thermal thrombosis and thermal cancer treatment	July, 1999	Guglielmi et al.
5985305	Sustained delivery of an active agent using an implantable system	November, 1999	Peery et al.	424/422
5993434	Method of treatment using electroporation mediated delivery of drugs and genes	November, 1999	Dev et al.
6021347	Electrochemical treatment of malignant tumors	February, 2000	Herbst et al.
6051017	Implantable microstimulator and systems employing the same	April, 2000	Loeb et al.
6169924	Spinal cord stimulation	January, 2001	Meloy et al.
6171787	Member of the TNF family useful for treatment and diagnosis of disease	January, 2001	Wiley	435/6
6269270	Apparatus and method for adjunct (add-on) therapy of Dementia and Alzheimer's disease utilizing an implantable lead and external stimulator	July, 2001	Boveja
6278895	Electrodes and electrode arrays for generating electroporation inducing electrical fields	August, 2001	Bernard	604/20
6366808	Implantable device and method for the electrical treatment of cancer	April, 2002	Schroeppel
6391026	Methods and systems for treating breast tissue	May, 2002	Hung et al.
6591133	Apparatus and methods for fluid delivery using electroactive needles and implantable electrochemical delivery devices	July, 2003	Joshi
6638273	Expandable catheter having improved electrode design, and method for applying energy	October, 2003	Farley et al.
6708066	Electrochemical treatment of tissues, especially tumors	March, 2004	Herbst et al.
6713291	Electrodes coated with treating agent and uses thereof	March, 2004	King
6733485	Microstimulator-based electrochemotherapy methods and systems	May, 2004	Whitehurst et al.
6738663	Implantable device and method for the electrical treatment of cancer	May, 2004	Schroeppel et al.
6901296	Methods and systems for direct electrical current stimulation as a therapy for cancer and other neoplastic diseases	May, 2005	Whitehurst et al.
20010021868	Electrochemical treatment of tissues, especially tumors	September, 2001	Herbst et al.
20040254618	Implantable device and method for the electrical treatment of cancer	December, 2004	Schroeppel et al.
20050004507	Method and device for treating cancer with electrical therapy in conjunction with chemotherapeutic agents and radiation therapy	January, 2005	Schroeppel et al.	604/20
20050222623	Partially implantable system for the electrical treatment of cancer	October, 2005	Kroll et al.	607/2
20050222646	Method and device for treating cancer with modified output electrical therapy	October, 2005	Kroll et al.	607/72

Other References:

PCT/US03/14104. International Search Report. Nov. 18, 2004.
www.genetronics.com, retrieved Jul. 29, 2003.
Electro-Cancer Treatment, http://www.st-georg.com/ect.html, retrieved Oct. 25, 1999.
J. Belehradek, Jr., S. Orlowski, L.H. Ramirez, G. Pron, B. Poddevin, L.M. Mir. Electropermeabilization of Cells in Tissues Assessed By the Qualitative and Quantitative Electroloading of Bleomycin, Biochimica et Biophysica Acta 1190 (1994): 155-163.
M. Belehradek, C. Domenge, B. Luboinski, S. Orlowski, J. Belehradek, Jr., L.M. Mir. Abstract of Electrochemotherapy, a New Antitumor Treatment. First Clinical Phase I-II Trial, Cancer Dec. 1993 15:72(12):3694-700.
J. Berendson and D. Simonsson. Electrochemical Aspects of Treatment of Tissue with Direct Current, European Journal of Surgery 1994; Suppl 574: 111-115.
K. Brandisky, I. Daskalov. Abstract of Electrical Field and Current Distributions in Electrochemotherapy, Biolectrochemistry and Bioenergetics Feb. 1999: 48(1):201-8.
H. Buchwald and T.D. Rohde. Implantable Pumps: Recent Progress and Anticipated Future Advances, ASAIO Journal 1992, p. 772-778.
M. Cemazar, G. Sersa and D. Miklavcic. Electrochemotherapy with Cisplatin in the Treatment of Tumor Cells Resistant to Cisplatin, Anticancer Research 18: 4463-4466 (1998).
B. Chen, Z. Xie, F. Zhu. Experimental Study on Electrochemical Treatment of Cancer in Mice, European Journal of Surgery, 1994; Suppl. 574: 75-77.
C.K. Chou, J.A. McDougall, C. Ahn, N. Vora. Abstract of Electrochemical Treatment of Mouse and Rat Fibrosarcomas with Direct Current, Bioelectromagnetics 1997; 18(1):14-24.
B. Damascelli, G. Patelli, L.R. Frigerio, R. Lanocita, G. Di Tolla, A. Marchiano, C. Spreafico, F. Garbagnati, M.G. Bonalumi, L. Monfardini, V. Ticha, A. Prino. First Clinical Experience with a High-Capacity Implantable Infusion Pump for Continuous Intravenous Chemotherapy, CardioVascular and Interventional Radiology (1999) 22:37-43.
S. L. David, D.R. Absolom, C.R. Smith, J. Gams, and M.A. Herbert. Effect of Low Level Direct Current on In Vivo Tumor Growth in Hamsters, Cancer Research 45, 5625-5631, Nov. 1985.
R.A. Gatenby. Abstract of Mathmatical Models of Tumour Invasion Mediated by Transformation-Induced Alteration of Microenvironment pH, Symposium 240: The Tumour Microenvironment: Causes and Consequences of Hypoxia and Acidity, p. 23, held at the Novartis Foundation, London, 240 10-12, Oct. 2000.
L.F. Glass, N.A. Fenske, M. Jaroszeski, R. Perrott, D.T. Harvey, D.S. Reintgen, R. Heller. Abstract of Bleomycin-Mediated Electrochemotherapy of Basal Cell Carcinoma, Journal of the American Academy of Dermatology Jan. 1996; 34(1):82-6.
H. Y. Gong, G.Z. Liu. Effect of Electrochemical Therapy on Immune Functions of Normal and Tumour-Bearing Mice, European Journal of Surgery, Suppl. 1994; (574): 73-74.
S.A. Grossman, P.S. Staats. Abstract of Current management of pain in patients with cancer. Oncology (Huntingt) Mar. 1994; 8(3):93-107.
M.B. Habal, M.D., M.K. Schauble, M.D. Clinical Device Note: An Implantable DC Power Unit for Experimental Tumor Growth in Hamsters, Journal of the Association for the Advancement of Medical Instrumentation, vol. 7, No. 5, Nov.-Dec. 1973, p. 305-306.
M.B. Habal. Effect of Applied DC Currents on Experimental Tumor Growth in Rats, Journal of Biomedical Material Research, vol. 14, 789-801 (1980).
M.A. Hamza, P.F. White, H.E. Ahmed, E.A. Ghoname. Abstract of Effect of the Frequency of Transcutaneous Electrical Nerve Stimulation on the Postoperative Opioid Analgesic Requirement and Recovery Profile. Anesthesiology Nov. 1999;91(5):1232-8.
C. Hauton, M. Charbonnier, L. Cara and J.P. Salles. A New Type of Liposome for Electrochemical Treatment of Cancer; The Lipogelosomes, European Journal of Surgery 1994; Suppl 574: 117-119.
K.T. Heruth. Medtronic SynchroMed Drug Administration System. Ann NY Acad Sci 1988: 531: 72-75.
G.A. Hofmann, S.B. Dev, S. Dimmer and G.S. Nanda. Electroporation Therapy: A New Approach for the Treatment of Head and Neck Cancer, IEEE Transactions on Biomedical Engineering, vol. 46, No. 6, Jun. 1999.
G.A. Hofmann, S.B. Dev, G.S. Nanda and D. Rabussay. Electroporation Therapy of Solid Tumors, Critical Reviews in Therapeutic Drug Carrier Systems, 16(6):523-569 (1999).
C.E. Humphrey, E.H. Seal. Biophysical Approach Toward Tumor Regression in Mice, Science, vol. 130, 1959.
D.L. Kirsch, F.N. Lerner. Electromedicine: The Other Side of Physiology. In: “Innovations in Pain Management: A Practical Guide for Clinicians”, selections of Chapter 23, 1995, GR Press, Winter Park, FL.
M. Kraus and B. Wolf. Implications of Acidic Tumor Microenvironment for Neoplastice Growth and Cancer: A Computer Analysis, Tumor Biology 1996; 17: 133-154.
M. Kraus and B. Wolf. Physicochemical Microenvironment as Key Regulator for Tumor Microevolution, Invasion, and Immune Response: Targets for Endocytotechnological Approaches in Cancer Treatment, Endocytobiosis & Cell Research, 12, 133-156 (1998).
Y.H. Lao, T.G. GE, X.L. Zheng, J.Z. Zhang, Y.W. Hua, S.M. Mao and X. Feng. Electrochemical Therapy for Intermediate and Advanced Liver Cancer: A Report of 50 Cases, European Journal of Surgery 1994; Suppl 574: 51-53.
K.H. Li, Y.L. Xin, Y.N. Gu, B.L. Xu, D.J. Fan and B.F. Ni. Effects of Direct Current on Dog Liver: Possible Mechanisms for Tumor Electrochemical Treatment, Bioelectromagnetics 18:2-7 (1997).
X.Z. Lin, C.M. Jen, C.K. Choud, D.S. Chou, M.J. Sung, T.C. Chou. Saturated Saline Enhances the Effect of Electrochemical Therapy. Digestive Diseases and Sciences 2000; 45(3): 509-514.
D. Liu, Y.L. Xin, B. Ge, F. Zhao, H.C. Zhso. Experimental Studies on Electrolytic Dosage of ECT for Dog's Oesophageal Injury and Clinical Effects of ECT for Oesophageal Anastomotic Opening Stenosis and Oesophageal Carcinoma, European Journal of Surgery Suppl 1994; (574):71-72.
Y. Matsushima, E. Takahashi, K. Hagiwara, C. Konaka, H. Miura, H. Kato and Y. Koshiishi. Clinical and Experimental Studies of Anti-Tumoural Effects of Electrochemical Therapy (ECT) Alone or in Combination with Chemotherapy, European Journal of Surgery 1994; Suppl 574: 59-67.
D. Miklavcic, D. An, J. Belehradek, Jr., L.M. Mir. Abstract of Host's Immune Response in Electrotherapy of Murine Tumors by Direct Current, European Cytokine Network Sep. 1997;8(3):275-9.
L.M. Mir, S. Orlowski, J. Belehradek Jr., and C. Paoletti. Electrochemotherapy Potentiation of Antitumour Effect of Bleomycin by Local Electric Pulses, European Journal of Cancer, vol. 27, No. 1, pp. 68-72, 1991.
D.M. Morris, M.D., A.A. Marino, Ph. D., and E. Gonzalez, M.D. Electrochemical Modification of Tumor Growth in Mice, Journal of Surgical Research 53, 306-309 (1992).
E. Nilsson. Modelling of the Electrochemical Treatment of Tumours, Dissertation, Department of Chemical Engineering and Technology, Applied Electrochemistry, Royal Institute of Technology, Stockholm 2000.
T. Nishi, S.B. Dev., K. Yoshizato, J. Kuratsu, Y. Ushio. Abstract of Treatment of Cancer Using Pulsed Electric Field in Combination With Chemotherapeutic Agents or Genes, Human Cell Mar. 1997;10(1):81-6.
B. Nordenstrom. Preliminary Clinical Trials of Electrophoretic Ionization in the Treatment of Malignant Tumors, IRCS Medical Science: Biomedical Technology; Cancer; Cell and Membrane Biology; Clinical Medicine; Respiratory System; Pathology, 6, 537 (1978).
B. Nordenstrom. Biologically Closed Electric Circuits: Clinical, Experimental and Theoretical Evidence for an Additional Circulatory Systems, XVI., Tissue transformations over BCEC in cancer of the breast, p. 203-268; XVII., Application of the principle of BCEC for treatment of cancer, p. 269-317, 1983, Karolinska Institutet, Stockholm Sweden Nordic Medical Publications.
B. Nordenstrom, M.D. Biologically Closed Electric Circuits: Activation of Vascular Interstitial Closed Electric Circuits for Treatment of Inoperable Cancers, Journal of Bioelectricity, 3 (1&2), 137-153 (1984).
B.E.W. Nordenstrom, M.D. Electrochemical Treatment of Cancer. I: Variable Response. American Journal of Clinical Oncology (CCT) 12(6): 530-536, 1989.
B.E.W. Nordenstrom, M.D., S. Eksborg, Ph. D., and H. Beving, Ph. D. Electrochemical Treatment of Cancer. II: Effect of Electrophoretic Influence on Adriamycin, American Journal of Clinical Oncology (CCT) 13(1): 75-88, 1990.
B.E.W. Nordenstrom, M.D. Survey of Mechanisms in Electrochemical Treatment (ECT) of Cancer, European Journal of Surgery 1994; Suppl 574: 93-109.
G.D. O'Clock, Ph. D. (E.E.), P.E. The Effects of In Vitro Electrical Stimulation on Eukaryotic Cells: Suppression of Malignant Cell Proliferation, Journal of Orthomolecular Medicine, vol. 12, No. 3, 1997.
M. Okino and H. Mohri. Effects of a High-Voltage Electrical Impulse and an Anticancer Drug on In Vivo Growing Tumors, Japan Journal of Cancer Research, (Gann) 78, 1319-1321; Dec. 1987.
S. Orlowski, J. Belehradek, Jr., C. Paoletti and L.M. Mir. Transient Electropermeablization of Cells in Culture; Increase of Cytotoxicity of Anticancer Drugs, Biochemical Pharmacology, vol. 37, No. 24, pp. 4727-4733, 1988.
W.R. Panje, M.P. Hier, G.R. Garman, E. Harrell, A. Goldman, I. Bloch. Abstract of Electroporation Therapy of Head and Neck Cancer, Annals of Otology, Rhinology and Laryngology Sep. 1998; 107(9 Pt 1): 779-85.
A. Plesnicar, G. Sersa, L. Vodovnik, J. Jancar, L. Zaletel-Kragelj and S. Plesnicar. Electric Treatment of Human Melanoma Skin Lesions with Low Level Direct Electric Current: An Assessment of Clinical Experience Following a Preliminary Study in Five Patients, European Journal of Surgery 1994; Suppl 574: 45-49.
K.H. Quan. Analysis of the Clinical Effectiveness of 144 Cases of Soft Tissue and Superficial Malignant Tumours Treated with Electrochemical Therapy, European Journal of Surgery 1994; Suppl 574: 37-40.
N. Raghunand. pH and Chemotherapy, Symposium 240: The Tumour Microenvironment: Causes and Consequences of Hypoxia and Acidity, p. 5-6, held at the Novartis Foundation, London, 10-12, Oct. 2000.
L.H. Ramirez, S. Orlowski, D. An, G. Bindoula, R. Dzodic, P. Ardouin, C. Bognel, J. Belehradek Jr., J-N Munck, and L.M. Mir. Electrochemotherapy on Liver Tumours in Rabbits, British Journal of Cancer (1998) 77(12). 2104-2111.
V.V. Ranade, Ph. D. Drug Delivery Systems 4, Implants in Drug Delivery, Journal of Clinical Pharmacology 1990;30:871-889.
A. Reis, T. Henninger. Zerstorung maligner Wachstumsenergie durch anodische Oxydation, Klin Wochenschrift 1951; —:39.
L. Samuelsson, J. Harnek, S.B. Ewers and L. Jonsson. Electrochemical and Megavolt Treatment of Rat Tumours, European Journal of Surgery 1994; Suppl 574: 69-70.
M.K. Schauble, M.B. Habal. Electropotentials of Tumor Tissues. Journal of Surgical Research 9: 9, 1969.
M.K. Schauble, M.B. Habal, H.D. Gullick. Inhibition of Experimental Tumor Growth in Hamsters by Small Direct Currents, Archives of Pathology and Laboratory Medicine vol. 101. p. 294, Jun. 1977.
D.C. Schechter. Flashbacks: Containment of Tumors Through Electricity, Pacing and Clinical Electrophysiology, vol. 2, Jan.-Feb. 1979.
K. Seguchi, S. Kawauchi, Y. Morimoto, T. Arai, H. Asanuma, M. Hayakawa, M. Kikuchi. Abstract of Critical Parameters in the Cytotoxicity of Photodynamic Therapy Using a Pulsed Laser. Lasers Med Sci 2002;17(4):265-71.
D. Semrov, D. Miklavcic. Calculation of the Electrical Parameters in Electrochemotherapy of Solid Tumours in Mice, Computers in Biology and Medicine 28 (1998) 439-448.
G. Sersa, M. Cemazar, D. Miklavcic and D. J. Chaplin. Tumor Blood Flow Modifying Effect of Electrochemotherapy with Bleomycin, Anticancer Research 19: 4017-4022 (1999).
G. Sersa, Ph. D., S. Kranjc, B. Sc., and M. Cemazar, Ph. D. Improvement of Combined Modality Therapy with Cisplatin and Radiation Using Electroporation of Tumors, International Journal of Radiation-Oncology- Biology and Physics., vol. 46, No. 4, pp. 1037-1041, 2000.
B.N. Singh and C. Dwivedi. Antitumor Drug Delivery by Tissue Electroporation, Anti-Cancer Drugs 1999, 10, pp. 139-146.
Y. Song, C. Li, Y. Li, Q. Song, B. Chang, L. Song, C. Liu and T. Wang. Electrochemical Therapy in the Treatment of Malignant Tumours on the Body Surface, European Journal of Surgery 1994; Suppl 574: 41-43.
L.C. Song, C.Y. Liu, B.P. Zhang, T. Wang, Y.Q. Song and Y.W. Li. Electrochemical Therapy (ECT) for Thyroid Adenoma During Acupuncture Anaesthesia: Analysis of 46 Patients, European Journal of Surgery 1994; Suppl 574: 79-81.
S. Srinivasan, G.L. Gahen Jr., G.E. Stoner. Electrochemistry in The Biomedical Sciences. In: Bloom H, Gumann F (eds): Electrochemistry The Last Thirty and The Next Thirty Years. New York: Plenum Press, 1977.
T.V. Taylor, P. Engler, B.R. Pullan and S. Holt. Ablation of Neoplasia by Direct Current, British Journal of Cancer (1994), 70, 342-345.
A. Turler, H. Schaeer, N. Schaefer, D. Maintz, M. Wagner, J.C. Qiao and A.H. Hoelscher. Local Treatment of Hepatic Metastases with Low-Level Direct Electric Current: Experimental Results, Scandinavian Journal of Gastroenterology Mar. 2000; 35(3):322-328.
A.L. Vandenbogaerde, E.M. Delaey, A.M. Vantieghem, B.E. Himpens, W.J. Merlevede P.A. de Witte. Abstract of Cytotoxicity and Antiproliferative Effect of Hypericin and Derivatives After Photosensitization. Photochem Photobiol Jan 1998;67(1):119-25.
P. Vaupel, D.K. Kelleher, M. Hockel. Abstract of Oxygen Status of Malignant Tumors: Pathogenesis of Hypoxia and Significance for Tumor Therapy. Semin Oncol Apr. 2001; 28(2 Suppl 8);29-35.
L. Vodovnik, D. Moklavcic, G. Sersa. Modified Cell Proliferation Due to Electrical Currents, Medical and Biological Engineering and Computing, 1992, 30, CE21-CE28.
N.J. Vogelzang, M. Ruane, and T.R. DeMeester. Phase 1 Trial of an Implanted Battery-Powered, Programmable Drug Delivery System for Continuous Doxorubicin Administration, Journal of Clinical Oncology, vol. 3, No. 3 (March) 1985.
H. von Euler. Electrochemical Treatment of Tumours, Doctoral Thesis, Uppsala 2002, Swedish University of Agricultural Sciences.
H.L. Wang. Electrochemical Therapy of 74 Cases of Liver Cancer, European Journal of Surgery 1994; Suppl 574: 55-57.
J.C. Weaver. Electroporation: A General Phenomenom for Manipulating Cells and Tissues. J Cell Biochem 1993; 51 No. 4: 426-435.
B.D. Wigness, F.D. Dorman, H.J. Robinson, E.A. Arendt, T.R. Oegema Jr., T.D. Rohde, and H. Buchwald. Catheter with an Anchroring Tip for Chronic Joint Capsule Perfusion, ASAIO Trans. Jul.-Sep. 1991; 37(3): M290-2.
M. Wojcicki, R. Kostyrka, B. Kaczmarek, J. Kordowski, M. Romanowski, M. Kaminski, J. Klonek, S. Zielinski. Abstract of Electrochemical Therapy in Palliative Treatment of Malignant Dysphagia: A Pilot Study, Hepatogastroenterology Jan.-Feb. 1999;46(25):278-84.
B. Wolf, M. Kraus and U. Sieben. Potential of Microsensor-Based Feedback Bioactuators for Biophysical Cancer Treatment, Biosensors & Bioelectronics vol. 12, No. 4, pp. 301-309, 1997.
B. Wolf, M. Brischwein, W. Baumann, R. Ehret, T. Henning, M. Lehmann, A. Schwinde. Microsensor-Aided Measurements of Cellular Signalling and Metabolism on Tumor Cells, Tumor Biology 1998; 19:374-383.
Y.L. Xin, D. Liu. Electrostatic Therapy (EST) of Lung Cancer and Pulmonary Metastais: Report of 15 Cases, European Journal of Surgery 1994; Suppl 574: 91-92.
Y.L. Xin. Organisation and Spread of Electrochemical Therapy (ECT) in China, Honorary Lecture. European Journal of Surgery 1994; Suppl 577: 25-30.
Y.L. Xin, F.Z. Xue, B.S. Ge, F.R. Zhao, B. Shi and W. Zhang. Electrochemical Treatment of Lung Cancer, Bioelectromagnetics 18:8-13 (1997).
Y.L. Xin, F.Z. Xue, F.G. Zhao. Effectiveness of Electrochemical Therapy in the Treatment of Lung Cancers of Middle and Late Stage, Chinese Medical Journal 1997; 110(5): 379-383.
Y. Yen, J.R. Li, B.S. Zhou, F. Rojas, J. Yu and C.K. Chou. Electrochemical Treatment of Human KB Cells In Vitro, Bioelectromagnetics 20:34-41 (1999).
M. Yokoyama, T. Itaoka, H. Nakajima, T. Ikeda, T. Ishikura, S. Nitta. Abstract of The Use of Direct Current in the Local Destruction of Cancer Tissues, Gan to Kagaku Ryoho Apr. 1989:16(4 Pt 2-2):1412-1417.
PCT International Preliminary Report in Patentability, PCT/US2005/011430, date mailed Oct. 19, 2006.
Notice of Allowance from U.S. Appl. No. 09/524,405 dated Sep. 26, 2001.
Office Action from U.S. Appl. No. 09/524,405 dated May 21, 2001.
Notice of Allowance from U.S. Appl. No. 09/974,474 dated Dec. 22, 2002.
Office Action from U.S. Appl. No. 09/974,474 dated Jul. 11, 2003.
International Search Report, PCT/US2005/011430.
Office Action from U.S. Appl. No. 10/881,375 dated Apr. 11, 2007.
Office Action from U.S. Appl. No. 10/881,375 dated Sep. 13, 2006.
Office Action from U.S. Appl. No. 10/792,256 dated Jun. 25, 2007.
Office Action from U.S. Appl. No. 10/841,205 dated Nov. 6, 2006.
Office Action U.S. Appl. No. 09/974,474 dated Apr. 29, 2003.
Office Action from U.S. Appl. No. 10/841,205 dated Oct. 23 2007.
Office Action from U.S. Appl. No. 10/841,205 dated Jul. 27 2007.
Office Action from U.S. Appl. No. 10/819,641 dated Apr. 13, 2007.
Office Action from U.S. Appl. No. 10/819,641 dated Nov. 3, 2006.
Office Action from U.S. Appl. No. 10/819,641 dated Aug. 29, 2006.
Office Action from U.S. Appl. No. 10/841,205 dated Sep. 13, 2006.
Office Action from U.S. Appl. No. 10/841,205 dated Nov. 21, 2007.

Primary Examiner:

Manuel, George

Attorney, Agent or Firm:

Lebens, Thomas F.
Sinsheimer Juhnke Lebens & Mclvor, LLP

Parent Case Data:

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part (CIP) of U.S. Ser. No. 09/974,474 for “IMPLANTABLE DEVICE AND METHOD FOR THE ELECTRICAL TREATMENT OF CANCER” filed Dec. 14, 2001 under 35 U.S.C. § 120, which is a non-provisional application claiming priority under 35 U.S.C. § 119(e) to provisional U.S. Ser. No. 60/238,609 for “IMPLANTABLE THERAPEUTIC DEVICE” filed Feb. 13, 2001 and also is a continuation-in-part (CIP) under 35 U.S.C. § 120 of U.S. Ser. No. 09/524,405 for “IMPLANTABLE DEVICE AND METHOD FOR THE ELECTRICAL TREATMENT OF CANCER” filed Mar. 12, 2000 under 35 U.S.C. § 120, now U.S. Pat. No. 6,366,808. This application is also related to U.S. Ser. No. 60/238,612 for “ELECTROPHORETIC DRUG INFUSION DEVICE” filed Oct. 10, 2000; Ser. No. 60/255,184 for “METHOD FOR ELIMINATING POSSIBLE CORROSION OF ELECTRODES IN ELECTROCHEMICAL THERAPY AND ELECTROCHEMOTHERAPY” filed Dec. 12, 2000; and Ser. No. 60/128,505 for “IMPLANTABLE DEVICE AND METHOD FOR THE ELECTRICAL TREATMENT OF CANCER” filed Apr. 9, 1999 all of which are herein incorporated by reference.

This application also claims priority under 35 U.S.C. § 119(e) to provisional U.S. Ser. No. 60/377,840 for “PROGRAMMER AND INSTRUMENT FOR ELECTROCHEMICAL CANCER TREATMENT” filed May 7, 2002; Ser. No. 60/377,841 for “METHOD OF ELECTRICAL TREATMENT FOR CANCER IN CONJUNCTION WITH CHEMOTHERAPY AND RADIOTHERPAY filed May 7, 2002; Ser. No. 60/378,209 for “LEAD CONDUIT METHOD FOR ECT THERAPY” filed May 7, 2002; Ser. No. 60/378,210 for “DIELECTRIC SENSOR FOR ELECTROCHEMICAL CANCER THERAPY” filed May 7, 2002; Ser. No. 60/378,211 “INDIVIDUALLY IDENTIFIABLE ELECTROES FOR ELECTROCHEMICAL CANCER THERAPY” filed May 7, 2002; Ser. No. 60/378,212 for “MULTIPLE TUMOR TREATMENT FOR CANCER BY ELECTRICAL THERAPY” filed May 7, 2002; Ser. No. 60/378,213 for “PATIENT CONTROL FOR ELECTROCHEMICAL CANCER THERAPY” filed May 7, 2002; 60/378,214 for “OPTICAL FIBER ECT SYSTEM FOR PHOTOACTIVATED CYTOTOXIC DRUGS” filed May 7, 2002; Ser. No. 60/378,215 for “SPECIALIZED LEAD FOR ELECTROCHEMICAL CANCER TREATMENT” filed May 7, 2002; Ser. No. 60/378,216 “THREE-AXIS ELECTRODE SYSTEM TO CHASE THE CENTER OF TUMOR MASS” filed May 7, 2002; Ser. No. 60/378,629 for “CLOSED LOOP OPERATION OF ELECTROCHEMICAL TREATMENT FOR CANCER” filed May 9, 2002; Ser. No. 60/378,824 for “METHOD OF IMAGING BEFORE AND AFTER ELECTROCHEMICAL TREATMENT” filed May 9, 2002; Ser. No. 60/379,793 for “ECT AND ELECTROPORATION ELECTRODE SYSTEM” filed May 13, 2002; and Ser. No. 60/379,797 for “FIXATION MEANS LOCATED OUTSIDE TUMOR MASS FOR ECT FOR CANCER” filed May 13, 2002 all of which are herein incorporated by reference.

Claims:

What is claimed is:

1. A medical device for the treatment of cancer comprising: an implantable portion comprising: a device housing; circuitry contained within said device housing; at least one electrode operably coupled to said circuitry wherein said circuitry delivers electrical therapy to said at least one electrode for the treatment of cancerous tumors; an external portion comprising: a means for providing power to said implantable portion; and a communication means for communicating between said implantable portion and said external portion; wherein said external portion receives data from said implantable portion by way of said communication means; and wherein said data is formatted into an oncogram.

2. The medical device of claim 1 wherein said implantable portion further comprises a power source.

3. The medical device of claim 2 wherein said power source is a battery.

4. The medical device of claim 2 wherein said power source is rechargeable.

5. The medical device of claim 2 wherein said external portion recharges said implantable power source.

6. The medical device of claim 1 wherein said means for providing power to said implantable portion is any of the group consisting of a hardwire connection and a wireless connection.

7. A medical device for the treatment of cancer comprising: an implantable portion comprising: a device housing; a port for receiving power; circuitry contained within said device housing wherein said circuitry is coupled to said port for receiving power; and at least one electrode operably coupled to said circuitry wherein said circuitry delivers electrical therapy to said at least one electrode for the treatment of cancerous tumors; an external portion comprising: a power source; and circuitry contained within said external portion wherein said circuitry is coupled to said power source; a wire operably coupled to said circuitry of said external portion and said port for receiving power wherein said wire transports power from said external portion to said implantable portion; and a communication means for communicating between said implanted portion and said external portion; wherein said external portion receives data from said implantable portion by way of said communication means; wherein said data is formatted into an oncogram.

8. The medical device of claim 7 wherein said power source is a battery.

9. The medical device of claim 7 wherein said implantable portion further comprises a power source.

10. The medical device of claim 9 wherein said power source is a battery.

11. The medical device of claim 10 wherein said power source is rechargeable.

12. The medical device of claim 9 wherein said external portion recharges said power source of said implantable portion.

13. The medical device of claim 7 wherein said implantable portion further comprises a drug port.

Description:

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to the electrical treatment of malignant tumors and neoplasms by applying a voltage to affected tissue. Devices and various adaptations therein are described for use in electrical therapy. Additionally, various chemotherapeutic agents and radiation therapies are described which may be advantageously used in conjunction with electrical therapy to ameliorate cancer.

2. Discussion of the Related Art

Cancer is one of the major causes of hospitalization and death worldwide. However, many of the therapies applied to cancer treatment are either ineffective or not well-tolerated by patients.

Cancer malignancies result in approximately 6,000,000 deaths worldwide each year. In 1995, 538,000 cancer related deaths were reported in the United States, representing over 23% of the total deaths in the United States. This number has increased since 1970 when 331,000 deaths occurred. The estimated number of new cases in the United States in 1997 was 1,382,000. An astounding 40% of Americans will eventually be stricken with the disease and more than 1 in 5 will die from it. The percentage is increasing at about 1% per year and cancer deaths will soon outstrip deaths from heart disease.

Much of the medical care cost associated with cancer results from hospitalization. In 1994 there were 1,226,000 hospital discharges in the United States related to cancer treatment. The cost of cancer in terms of both human suffering and monetary expenditures is staggering. Effective treatment methods, which result in fewer days of hospital care, are desperately needed.

Primary treatment methods currently used in cancer therapy include surgery, radiation therapy, chemotherapy, hormone therapy and many others including bone marrow replacement, biological response modifiers, gene therapy, and diet. Therapy often consists of combinations of these treatment methods. It is well known that these methods may result in sickness, pain, disfigurement, depression, spread of the cancer, and ineffectiveness. Despite recent announcements of potential pharmaceutical “cures”, which may work well in animals and in humans in certain cases, researchers are cautious in overstating their effectiveness. In the case of radiation treatment, rapid decreases in the size of poorly differentiated tumors after treatment may be experienced; however, shortly thereafter the tumor often experiences re-growth. Unfortunately, following re-growth the tumor is generally more insensitive to future radiation treatment attempts.

The approaches previously described, as well as other prior approaches, are not sufficient to meet the needs of real patients. The present invention addresses the above and other needs.

SUMMARY OF THE INVENTION

This invention relates generally to a method of treating cancer. It involves a device, either partially or totally implanted, consisting of a generator and one or more wires (or leads) containing one or more electrodes. The electrodes are implanted in or near the tumor and the generator may be implanted subcutaneously as close to the tumor as practical. The device is powered either by an implantable generator or via an external electrical source. The implantation is typically performed under local anesthesia and the device is generally left implanted for a period of months. With implantation, the device permits electric current to be applied at low levels for long periods of time. In another embodiment, the implanted device may be connected to an external device for energy input, data input, and/or therapy regimen modifications. While the internal generator is useful for applying low levels of electrical current for long periods of time, the external electrical source may be advantageously used to generate high levels of electrical current over shorter periods of time. In a preferred embodiment the external generator may produce currents and pulses useful in electroporation therapy. Additionally, methods and devices directed to chemotherapy and radiation therapy are described for use in conjunction with electrical therapy. In a preferred embodiment, electricity is provided in the form of direct current.

BRIEF DESCRIPTION OF THE DRAWINGS

The above mentioned and other objects and features of this invention and the manner of attaining them will become apparent, and the invention itself will be best understood by reference to the following description of the embodiments of the invention in conjunction with the accompanying drawings, wherein:

FIG. 1 is a diagram depicting an overall system in accordance with one embodiment;

FIGS. 2 a - 2 d are diagrams illustrating examples of unipolar and multipolar lead placements suitable for use in an electrical therapy system;

FIGS. 2 e - 2 f are schematic diagrams showing examples of circuitry for switching electrode polarity, such as for use with an electrical therapy system;

FIG. 2 g is a drawing illustrating an example of a multipolar lead placement with an adapter, such as for use with an electrical therapy system;

FIGS. 3 a - 3 c are drawings in front perspective, top view, and side perspective illustrating an example of an array of multiple electrodes on a lead comprising a ring of electrodes, a separate top electrode, and a plurality of fixation needles that may be used with an electrical therapy system;

FIG. 4 is a drawing in top view illustrating an example of an array of multiple electrodes on a lead comprising a ring of electrodes and a fixation needle unattached to any electrode such as may be employed in an electrical therapy system;

FIGS. 5 a - 5 b are drawings in top view and side perspective illustrating an example of an array of multiple electrodes on a lead comprising a ring of electrodes, a separate top electrode, and a single fixation needle such as may be employed in an electrical therapy system;

FIGS. 6 a - 6 b are drawings in top view and side perspective illustrating an example of an array of multiple electrodes on a lead comprising a ring of electrodes such as may be employed in an electrical therapy system;

FIGS. 7 a - 7 b are diagrams shown in top view and side perspective illustrating an example of an array of multiple electrodes on a lead comprising a ring of electrodes and an anchoring hook such as may be used with an electrical therapy system;

FIGS. 8 a - 8 b are illustrations in top view and side perspective depicting an example of an array of multiple electrodes on a lead comprising a segment of electrodes not in closed ring formation and a plurality of fixation needles such as may be employed in an electrical therapy system;

FIG. 9 is a diagram representing an example of an array of multiple electrodes on a lead comprising adapters that may be used with an electrical therapy system;

FIGS. 10 a - 10 b is an illustration depicting an example of an electrode arrangement which accommodates electrical therapy and electroporation such as may be employed in an electrical therapy system;

FIG. 11 is a drawing illustrating an example of three-axis electrode system such as may be employed in an electrical therapy system;

FIGS. 12 a - 12 b is a drawing depicting an example of a set of leads with unique identification markings that may be utilized with an electrical therapy system;

FIGS. 13 a - 13 e are drawings showing examples of lead anchoring systems such as may be used with any of the leads described in FIGS. 2 a - 2 d , FIG. 2 g , FIGS. 3 a - 3 c , FIG. 4, FIGS. 5 a - 5 b , FIGS. 6 a - 6 b , FIGS. 7 a - 7 b , FIGS. 8 a - 8 b , FIG. 9, FIG. 11, and FIGS. 12 a - 12 b;

FIG. 14 is an illustration depicting an example of a fixation means for directly anchoring a lead to healthy tissue that may be used with any of the leads described in FIGS. 2 a - 2 d , FIG. 2 g , FIGS. 3 a - 3 c , FIG. 4, FIGS. 5 a - 5 b , FIGS. 6 a - 6 b , FIGS. 7 a - 7 b , FIGS. 8 a - 8 b , FIG. 9, FIG. 11, and FIGS. 12 a - 12 b;

FIG. 15 is an illustration depicting an example of a fixation means for indirectly anchoring a lead to healthy tissue that may be used with any of the leads described in FIGS. 2 a - 2 d , FIG. 2 g , FIGS. 3 a - 3 c , FIG. 4, FIGS. 5 a - 5 b , FIGS. 6 a - 6 b , FIGS. 7 a - 7 b , FIGS. 8 a - 8 b , FIG. 9, FIG. 11, and FIGS. 12 a - 12 b;

FIG. 16 is an illustration depicting an example of a lead with various options including a lumen, non-stick surface, and an inflatable balloon that may be used with any of the leads described in FIGS. 2 a - 2 d , FIG. 2 g , FIGS. 3 a - 3 c , FIG. 4, FIGS. 5 a - 5 b , FIGS. 6 a - 6 b , FIGS. 7 a - 7 b , FIGS. 8 a - 8 b , FIG. 9, FIG. 11, and FIGS. 12 a - 12 b;

FIG. 17 is a drawing illustrating an example of a lead with various options including optical fibers and thermocouples that may be used with any of the leads described in FIGS. 2 a - 2 d , FIG. 2 g , FIGS. 3 a - 3 c , FIG. 4, FIGS. 5 a - 5 b , FIGS. 6 a - 6 b , FIGS. 7 a - 7 b , FIGS. 8 a - 8 b , FIG. 9, FIG. 11, and FIGS. 12 a - 12 b;

FIG. 18 is a drawing illustrating a side view of an example of a lead with thermocouples that may be used with any of the leads described in FIGS. 2 a - 2 d , FIG. 2 g , FIGS. 3 a - 3 c , FIG. 4, FIGS. 5 a - 5 b , FIGS. 6 a - 6 b , FIGS. 7 a - 7 b , FIGS. 8 a - 8 b , FIG. 9, FIG. 11, and FIGS. 12 a - 12 b;

FIGS. 19 a - 19 c is a drawing showing several examples of a lead modified for measuring capacitance and resistance that may be used with any of the leads described in FIGS. 2 a - 2 d , FIG. 2 g , FIGS. 3 a - 3 c , FIG. 4, FIGS. 5 a - 5 b , FIGS. 6 a - 6 b , FIGS. 7 a - 7 b , FIGS. 8 a - 8 b , FIG. 9, FIG. 11, and FIGS. 12 a - 12 b;

FIGS. 20-21 are representations of an example of a method and device for creating a conduit for leads to pass through to a tumor for use in electrical therapy systems;

FIG. 22 is a block representation of an exemplary basic generator such as may be utilized in an electrical therapy system;

FIG. 23 is a block representation of an exemplary advanced generator such as may be utilized in an electrical therapy system;

FIG. 24 is a block representation of an exemplary generator comprising a port such as may be utilized in an electrical therapy system;

FIG. 25 is an illustration depicting an example of a port for use in an electrical therapy system;

FIG. 26 is an up close diagram of a needle inserted into a port during electrical therapy;

FIGS. 27 a - 27 f are flow charts representing exemplary methods of the preferred embodiment;

FIGS. 28 a - 28 b are graphs representing exemplary current levels for use in electrical therapy;

FIGS. 29 a - 29 b are graphs representing exemplary current levels for use in electrical therapy;

FIG. 30 is a diagram representing exemplary therapeutic pathways in a human body during electrical therapy;

FIG. 31 is an illustration depicting an example of a generator/infusion device that infuses chemotherapeutic agents to a tumor such as may be employed with an electrical therapy system;

FIG. 32 is an illustration depicting an example of a generator/infusion device that infuses chemotherapeutic agents to the circulatory system such as may be employed in an electrical therapy system;

FIG. 33 is an illustration depicting an example of a drug infusion device that is physically separated from a generator such as may be utilized in electrical therapy systems;

FIG. 34 is a diagram representing an exemplary method of passive synchronization which may be employed with an electrical therapy system;

FIGS. 35 a - 35 f are illustrations depicting several examples of catheters used to infuse drugs at a target site such as may be employed with an electrical therapy system;

FIGS. 36 a - 36 c are illustrations depicting examples of catheters comprising porous drug-absorbing material, which can be laid out over a tumor and may be employed with an electrical therapy system;

FIGS. 37 a - 37 c is a drawing illustrating an example of an electrode array that can be used to steer or spread charged drugs in electrical therapy systems;

FIGS. 38 a - 38 b is a drawing depicting an application of the electrode array/catheter design of FIGS. 37 a - 37 c;

FIG. 39 is an illustration of an example electrophoretic drug pump such as may be used with any of the catheters described in FIGS. 35 a - 35 f and FIGS. 36 a - 36 c;

FIG. 40 is an a illustration depicting an application of the electrophoretic drug pump of FIG. 39 into an electrical therapy system;

FIGS. 41 a - 41 b is an illustration representing an application of FIG. 40, whereby the electrodes are in the form of bands arranged around the circumference of a cylindrical implantable device for use in an electrical therapy system;

FIGS. 42 a - 42 b is an illustration of a device for infusing a solid ionized substance for increased conductivity and reduced impedance in a tumor for use in an electrical therapy system;

FIG. 43 is an illustration depicting an example of a device for treatment of tumors with an optical fiber such as may be employed in an electrical therapy system;

FIG. 44 is side-view illustration depicting an example of a generator useful for providing power to a light source that activates photosensitive drugs in an electrical therapy system;

FIG. 45 is a graph depicting examples of time-varying characteristics of an electrical pulse for use in an electrical therapy system;

FIG. 46 is a graph representing an exemplary method for use with an electrical therapy system

FIGS. 47 a - 47 b is a drawing showing examples of redundant electrodes used to prevent adverse effects of corrosion in electrical therapy;

FIG. 48 is an illustration representing an example of a basic form of an external device for use with electrical therapy; and

FIG. 49 is an example of a user friendly data chart that can be used to display current information and to input changes to the controller of an external device used in electrical therapy.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description is of the best mode presently contemplated for practicing the invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of describing the general principles of the invention. The scope of the invention should be ascertained with reference to the claims.

The devices and methods of the present embodiment are contemplated for use in patients afflicted with cancer or other non-cancerous (benign) growths. These growths may manifest themselves as any of a lesion, polyp, neoplasm (e.g. papillary urothelial neoplasm), papilloma, malignancy, tumor (e.g. Klatskin tumor, hilar tumor, noninvasive papillary urothelial tumor, germ cell tumor, Ewing's tumor, Askin's tumor, primitive neuroectodermal tumor, Leydig cell tumor, Wilms'tumor, Sertoli cell tumor), sarcoma, carcinoma (e.g. squamous cell carcinoma, cloacogenic carcinoma, adenocarcinoma, adenosquamous carcinoma, cholangiocarcinoma, hepatocellular carcinoma, invasive papillary urothelial carcinoma, flat urothelial carcinoma), lump, or any other type of cancerous or non-cancerous growth. Tumors treated with the devices and methods of the present embodiment may be any of noninvasive, invasive, superficial, papillary, flat, metastatic, localized, unicentric, multicentric, low grade, and high grade.

The devices and methods of the present embodiment are contemplated for use in numerous types of malignant tumors (i.e. cancer) and benign tumors. For example, the devices and methods described herein are contemplated for use in adrenal cortical cancer, anal cancer, bile duct cancer (e.g. periphilar cancer, distal bile duct cancer, intrahepatic bile duct cancer), bladder cancer, benign and cancerous bone cancer (e.g. osteoma, osteoid osteoma, osteoblastoma, osteochrondroma, hemangioma, chondromyxoid fibroma, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma, giant cell tumor of the bone, chordoma, lymphoma, multiple myeloma), brain and central nervous system cancer (e.g. meningioma, astocytoma, oligodendrogliomas, ependymoma, gliomas, medulloblastoma, ganglioglioma, Schwannoma, germinoma, craniopharyngioma) breast cancer (e.g. ductal carcinoma in situ, infiltrating ductal carcinoma, infiltrating lobular carcinoma, lobular carcinoma in situ, gynecomastia), Castleman disease (e.g. giant lymph node hyperplasia, angiofollicular lymph node hyperplasia), cervical cancer, colorectal cancer, endometrial cancer (e.g. endometrial adenocarcinoma, adenocanthoma, papillary serous adnocarcinoma, clear cell), esophagus cancer, gallbladder cancer (mucinous adenocarcinoma, small cell carcinoma), gastrointestinal carcinoid tumors (e.g. choriocarcinoma, chorioadenoma destruens), Hodgkin's disease, non-Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer (e.g. renal cell cancer), laryngeal and hypopharyngeal cancer, liver cancer (e.g. hemangioma, hepatic adenoma, focal nodular hyperplasia, hepatocellular carcinoma), lung cancer (e.g. small cell lung cancer, non-small cell lung cancer), mesothelioma, plasmacytoma, nasal cavity and paranasal sinus cancer (e.g. esthesioneuroblastoma, midline granuloma), nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g. embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma), salivary gland cancer, skin cancer (e.g. melanoma, nonmelanoma skin caner), stomach cancer, testicular cancer (e.g. seminoma, nonseminoma germ cell cancer), thymus cancer, thyroid cancer (e.g. follicular carcinoma, anaplastic carcinoma, poorly differentiated carcinoma, medullary thyroid carcinoma, thyroid lymphoma), vaginal cancer, vulvar cancer, and uterine cancer (e.g. uterine leiomyosarcoma)

Patients treated with the devices and methods of the present embodiment may be any living thing, but preferably a mammal such as, but not limited to, humans, monkeys, chimps, rabbits, rats, horses, dogs, and cats. Patients treated with the devices and methods of the present embodiment may be of any age (e.g. infant, child, juvenile, adolescent, adult, and even pregnant women and their unborn fetus, such as in the case of gestational trophoblastic disease).

The devices and methods of the present embodiment work to treat cancerous tumors by delivering electrical therapy continuously and/or in pulses for a period of time ranging from a fraction of a second to several days, weeks, and/or months to tumors. In a preferred embodiment, electrical therapy is direct current electrical therapy. For the purposes of discussion herein, the term “direct current (DC) electrical therapy” may be used interchangeably with “direct current (DC) ablation”. Additionally, for the purposes of discussion herein, the term “electrical therapy” may refer to any amount of coulombs, voltage, and/or current delivered to a patient in any period of time. For example, coulombs, voltage, and/or current used at levels sufficient for DC ablation (which are generally lower coulombs, voltage, and/or current and longer periods of time) and coulombs, voltage, and/or current used at levels sufficient for electroporation (which are generally higher coulombs, voltage, and/or current and shorter periods of time) are both included in “electrical therapy”. Furthermore, “electroporation” (i.e. rendering cellular membranes permeable) as used herein may be caused by any amount of coulombs, voltage, and/or current delivered to a patient in any period of time sufficient to open holes in cellular membranes (e.g. to allow diffusion of molecules such as pharmaceuticals, solutions, genes, and other agents into a viable cell).

Delivering electrical therapy to tissue causes a series of biological and electrochemical reactions. At a high enough voltage, cellular structures and cellular metabolism are severely disturbed by the application of electrical therapy. Although both cancerous and noncancerous cells are destroyed at certain levels of electrical therapy, tumor cells are more sensitive to changes in their microenvironment than are non-cancerous cells. Distributions of macroelements and microelements are changed as a result of electrical therapy.

Electrical therapy produces various byproducts including hydrogen, oxygen, chlorine, and hydrogen peroxide. Hydrogen peroxide is known to destroy living tissues whereas the effect of the other reaction products on living tissues varies. The byproducts and changes in tissue that result from electrical therapy are differentially experienced throughout the tissue based on the positioning of the anode and cathode. For example, chlorine, which is a strong oxidant, is liberated at the anode, whereas hydrogen is liberated at the cathode. Additionally, the concentration of chlorine ions is high around the anode while the concentration of sodium and potassium ions is found to be higher around the cathode. pH changes due to electrical therapy cause the tissue around the anode to become strongly acidic, down to 2.1, while the tissue around the cathode becomes strongly basic, up to 12.9. Water migrates from the anode to the cathode while fat moves from the cathode to the anode, causing local hydration around the cathode and dehydration around the anode. Proteins may be denatured in electrical therapy. For example, hemoglobin is transformed into acidic hemoglobin around the anode and alkaline hemoglobin around the cathode.

Electrochemical reactions as a function of pH and electrode potential can be predicted by means of a Pourbaix diagram in Aqueous Solutions -Pergamon Press, 1986-by Pourbaix, which is herein incorporated by reference.

As is readily understood by those of ordinary skill in the art, the coulomb (C) is the basic unit of charge (e.g. the magnitude of the charge on an electron or a proton is 1.6×10 ⁻¹⁹coulombs—where the charge on an electron is negative and the charge on a proton is positive). Electrical therapy may be described as the application of voltage in volts (V), current in amperes (A), and/or total coulombs (C) delivered. Voltage is a measure of force per unit of charge. Voltage causes charge (i.e. current) to flow in a particular direction. Current, is the rate that charge passes through a medium. Moreover, charge delivered in coulombs is equal to the current level in amperes multiplied by the time in seconds (i.e. charge (C)=current (A)*time (s)). In a wire (or lead) current is carried by electrons. In extracellular fluid (such as in a tumor), current may be carried by an ion in solution.

Although electrical therapy examples described hereinbelow may be expressed in voltage (i.e. volts) and/or current (i.e. amperes), it should be understood that by applying Ohm's law, which states that voltage and current are proportional (i.e. V=IR), the equivalent voltage to current or current to voltage may be calculated. The proportionality constant is the resistance (R) in the electrode/tissue system. Resistance is measured in Ohms (Ω) and is equal to one volt per ampere. Resistance is the property of a material to resist current flow. In the electrical therapy system described herein, resistance may be caused by any number of factors including tumor density, tumor consistency, tumor volume, tumor location, pharmaceuticals utilized, wire(s) (or lead) utilized, electrode(s) utilized, and patient characteristics such as weight, age, gender, and diet. Because resistances may change with long-term electrical therapy, it may be advantageous to program the devices of the present embodiment in terms of current instead of voltage. For example in DC ablation, if 10 mA are applied to a tumor with a resistance of 100 Ω the corresponding voltage is 1 V. However, if 10 mA are applied to a tumor with a resistance of 25 Ω the corresponding voltage is 0.25 V. In another example consistent with electroporation, if 500 V are applied to a tumor with a resistance of 25 Ω the corresponding current is 20 A. However, if 500 V are applied to a tumor with a resistance of 100 Ω the corresponding current is 5 A.

Electrical therapy may also be described as total coulombs (C) delivered. As will be appreciated by those of ordinary skill in the art, describing electrical therapy in terms of total coulombs (C) delivered can apply to numerous ranges of volts and amperes dependent on the resistance of the system and the rate of delivery. Therefore, because resistance may vary widely from one tumor to another, each of the examples of the preferred embodiments described herein are merely examples and are not limiting. In each situation resistance of a tumor may be measured prior to application of electrical therapy to determine the appropriate voltage, current, and/or coulombs to be delivered.

For example, if a dose of 0.5 C is applied to a tumor the resulting voltage and current varies dependent on the rate at which the charge is delivered and the resistance of the system. If, for example, the resistance of the system is 100 Ω and the rate of delivery is over 10 seconds then the resulting current is 0.05 A (50 mA) and the resulting voltage is 5 V. In some circumstances it may be advantageous to deliver the charge over a longer time period such as in DC ablation. For example, if a dose of 25 C is applied to a tumor over 1 hour and the resistance is 100 Ω then the resulting current is 0.007 A (7 mA) and the resulting voltage is 0.7 V. In electroporation, electrical therapy is delivered over a short time period. For example, if 1 mC is applied to a tumor over 1 ms and the resistance is 1000 Ω then the resulting voltage is 1000 V and the resulting current is 1 A.

With regard to the preferred methods of the embodiment, single electrode and/or multi-electrode configurations of the preferred embodiment may be used in conjunction with electrical therapy regimens.

In the case of a single electrode configuration, high voltage may be applied for minutes to hours between a lead electrode and the generator housing, which generates a pH change of at least 2 in either direction to begin destruction of cancerous tissue. Following application of high voltage, a rest period, marked by idling of the device, is optionally entered. Later, low voltage is applied for hours to days, which may attract white blood cells to the tumor site. In this way, the cell mediated immune system may remove dead tumor cells and may develop antibodies against tumor cells. Furthermore, the stimulated immune system may attack borderline tumor cells and metastases. Molecular chlorine generated at the anode may kill additional local tumor cells.

Various adjuvants may be used to increase any immunological response, depending on the host species, including but not limited to Freund's adjuvant (complete and incomplete), mineral salts such as aluminum hydroxide or aluminum phosphate, various cytokines, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and Corynebacterium parvum. Alternatively, the immune response could be enhanced by combination and or coupling with molecules such as keyhole limpet hemocyanin, tetanus toxoid, diptheria toxoid, ovalbumin, cholera toxin or fragments thereof.

In the case of a multi-electrode configuration, high voltage may be applied for minutes to hours between a first set of one or more electrodes and either a second set of one or more other electrodes, or the generator housing.

In any case, high voltage may be applied for minutes to hours between at least one anode and at least one cathode.

Any number and configuration of electrodes comprising either anodes or cathodes, or anodes and cathodes may be used.

In some embodiments the generator housing serves as either an anode or a cathode.

As with the single electrode configuration, the high voltage applied between at least one anode and at least one cathode generates a pH change of at least 2 in either direction to begin necrosis. Following application of high voltage, a rest period, marked by idling of the device, is optionally entered. Later, low voltage is applied for hours to days, which may attract white blood cells to the tumor site. In this way, the cell mediated immune system may remove dead tumor cells and may develop antibodies against tumor cells. Furthermore, the stimulated immune system may attack borderline tumor cells and metastases.

As previously described, various adjuvants may be used to increase any immunological response.

Additionally, electrical therapy may be used in conjunction with chemotherapy and radiation therapy. Steps relating to single electrode and/or multi-electrode therapies may be followed by steps specifically designed for chemotherapy and radiation therapy.

In the case of electrical therapy used in conjunction with chemotherapy, at least one remote cathode may be implanted near a chemotherapy administration site, or other site if the chemotherapy agent is administered systemically. Next, a chemotherapy agent is administered. Following administration of a (positively charged) chemotherapeutic agent, medium voltage is applied between at least one anode (e.g. the generator housing or first electrode coupled to the generator housing by a first lead) and at least one remote cathode (e.g. an electrode coupled to the generator by a lead or second electrode coupled to the generator by a second lead) to direct a chemotherapeutic agent to the tumor site. Alternatively, medium voltage may be applied between at least one cathode and at least one remote anode to direct a chemotherapeutic agent to the tumor site. Following the medium voltage step, the polarity of the generator housing (or first electrode) may switch with the polarity of the electrode (or second electrode) such that the generator housing (or first electrode) becomes cathodic and the electrode (or second electrode) becomes anodic. By reversing polarity of the generator housing (or first electrode) and electrode (or second electrode), the chemotherapeutic agent is dispersed throughout the peripheral tumor mass. Following polarity reversal, electroporation electrical therapy may be optionally administered to the tumor site in order to increase permeability of the cells to allow enhanced uptake of a chemotherapeutic agent. As is described hereinbelow, the devices and methods of the present embodiment may be adjusted for other variations, such as in the case of a negatively charged chemotherapy agent.

In the case of electrical therapy used in conjunction with radiation therapy, following the electrical therapy regimen as described for single electrode and/or multi-electrode configurations of the preferred embodiment, high voltage is applied to all electrodes, thereby forcing all electrodes anodic, for minutes to generate molecular oxygen. Alternatively, various substances may be administered to oxygenate tissue, as described hereinbelow. In this embodiment, localized hyperoxia significantly increases brachytherapy effectiveness. As such, brachytherapy may be applied concomitantly to enhance the effects of electrical therapy.

Each of the previously described methods and method steps therein may be used in conjunction with each other for increased effectiveness. For example, chemotherapy and radiation therapy may be used in conjunction with the methods for unipolar and/or bipolar treatments.

Complexity of the device and therapeutic regimen can vary considerably, depending upon its desired flexibility of use. The device in its simplest form may consist of a single lead permanently connected to a generator encapsulated in plastic or potting compound (with an embedded generator housing electrode) with a fixed DC output voltage. Alternatively, a complicated device may have numerous options and configurations ideal for any particular situation. Examples of the numerous options and configurations suitable for implementing various embodiments are described in full detail hereinbelow. A therapeutic regimen in its simplest form may consist of a single voltage applied to a single electrode for an amount of time. However, many complicated therapeutic regimens are also contemplated. Examples of the types of complex therapeutic regimens suitable for implementing various embodiments are apparent in the following description.

The cancer therapy system of several embodiments differs from implantable pacemaker systems in various ways. For example, pacemakers are generally implanted for years while the device of such embodiments is typically implanted for months, until the cancerous condition has been ameliorated. The cancer therapy system described herein is not life-supporting as opposed to pacemakers, which are relied on by patients to stimulate their heartbeat. The generator housing of cancer therapy systems may have lower hermeticity requirements (i.e. higher leak rate tolerance) in comparison to hermeticity requirements of housings used with pacemaker generators because the device of the present embodiment is designed to be implanted for months not years. The leads of the present embodiment may have less stringent mechanical requirements since they are not stressed by movement (such as by the movement created by a beating heart) to the degree of pacemakers and are required for shorter periods of time, again months not years. Additionally, in most cases electromagnetic interference is not a concern with the cancer therapy system of the present embodiment as it is with pacemaker systems. However, electromagnetic interference may be a concern in the case of highly specialized systems wherein certain sensors are employed.

Referring now to the drawings, further features and embodiments are now described.

1. Overview of Device

In FIG. 1, a system 1000 of the present embodiment for treating cancer is depicted. The system 1000 comprises a generator 1 , one or more implanted wires or leads 2 and 1616 , an anode electrode 3 , a cathode electrode 4 , and an external instrument 5 . The generator 1 and the leads 2 and 1616 are implanted into a body 7 in a subcutaneous area as near as practical to a tumor 6 , but out of a path of any potentially planned ionizing radiation. The leads 2 and 1616 may terminate with either an anode electrode 3 or a cathode electrode 4 . The anode electrode 3 and the cathode electrode 4 are implanted inside or outside of the tumor 6 . In a preferred embodiment, the anode electrode 3 is implanted in the center of the tumor 6 and the cathode electrode 4 is implanted outside the tumor 6 as shown, or in the tumor's internal periphery (i.e. in the vicinity of a cancerous tumor). The leads 2 and 1616 are tunneled subcutaneously from the generator 1 to the tumor 6 . The lead 1616 terminating with the cathode electrode 4 may be alternatively placed into a blood vessel (not shown) near tumor 6 . The system 1000 may also comprise an external instrument 5 used to communicate with the generator 1 . The external instrument 5 is operably coupled to the generator 1 via coupling means, which coupling means may be physical and/or telemetric and may include any of a universal serial bus (USB), a serial port, a Personal Computer Memory Card International Association (PCMCIA) card, and a radio frequency (RF). The external instrument 5 may alter various parameters including rate, intensity, and duration of therapy. The external device 5 of the embodiment allows for inputting of data or manipulating of therapy non-invasively.

2. Leads

FIGS. 2 a - 2 d and FIG. 2 g depict various options for leads to be used with the cancer therapy system of the present embodiment. Shown in FIGS. 2 a - 2 d and FIG. 2 g are the generator 1 ; the tumor 6 ; a unipolar lead 8 ; a single electrode 9 ; a multipolar lead 10 ; two or more electrodes 11 and 12 ; multiple unipolar leads 13 and 14 ; multiple multipolar leads 15 , 16 , 17 , and 25 ; multiple electrodes 18 , 19 , 20 , 21 , 22 , and 23 ; an adapter 24 ; lead extensions 26 and 27 ; a same electrical connection 28 ; a common lead segment 1001 ; and a different electrical connection 1002 .

In FIG. 2 a , the unipolar lead 8 is depicted. The unipolar lead 8 of FIG. 2 a may be permanently coupled to a generator 1 such as with a hermetic feedthrough or may, alternatively, be coupled with a detachable coupling means such as a hermetically sealed and/or biocompatible plug and socket connector. In any case, the unipolar lead B is operably coupled to the generator 1 such that the unipolar lead 8 is energized when the generator 1 is activated, thereby energizing electrode 9 as well. The end of the unipolar lead 8 , opposite the generator 1 , terminates with the single electrode 9 . The single electrode 9 may be implanted in or adjacent to a tumor 6 . In this case, the electrode 9 is shown implanted inside the tumor 6 . In a preferred embodiment, the unipolar lead 8 terminates with an anode electrode while the generator housing serves as the cathode electrode. Alternatively, the unipolar lead 8 may terminate with a cathode electrode while the generator housing serves as the anode electrode. In a preferred embodiment, the generator 1 contains internal circuitry so that the polarity of the single electrode 9 and the polarity of the generator 1 may switch. For example, in the case that therapy begins with the single electrode 9 serving as an anode and the generator housing 1 serving as a cathode, later, after a time period, internal circuitry may switch the polarity so that the single electrode 9 serves as the cathode and the generator housing 1 serves as the anode.

FIG. 2 b shows a multipolar lead 10 . The multipolar lead 10 of FIG. 2 b is operably coupled, either permanently or detachably, at one end with the generator 1 and terminates with the two or more electrodes 11 and 12 , which may be implanted in or adjacent to (i.e. in the vicinity of) the tumor 6 such that when the generator 1 is activated, energy flows from the generator 1 through the multipolar lead 10 and to the two or more electrodes 11 and 12 which are then consequently energized. The electrodes 11 and 12 may interchangeably serve as the anode and the cathode. For example, at the beginning of treatment, the electrode 11 may be designated as the anode while the electrode 12 may be designated as the cathode, or vice versa. Then, during therapy, the polarity of the electrodes may change (reverse), such that the electrode 11 becomes the cathode and the electrode 12 becomes the anode. In another embodiment, both electrodes 11 and 12 of the lead may simultaneously serve as anodes while the generator housing serves as the cathode, or vice versa, and their polarities may change.

In FIG. 2 c , multiple unipolar leads 13 and 14 are operably coupled, either permanently or detachably, at one end to the generator 1 and terminate at the end opposite the generator 1 with one or more electrodes 11 and 12 . In this embodiment, the electrodes 11 and 12 are implanted adjacent to the tumor 6 . However, in another embodiment, the electrodes 11 and 12 may be implanted into the tumor 6 . The electrodes 11 and 12 each may serve as either an anode or a cathode (and may change polarity as described above). In another embodiment, both electrodes 11 and 12 may simultaneously serve as anodes while the generator housing serves as the cathode, or vice versa, and their polarities may change.

Referring now to FIG. 2 d , three multipolar leads 15 , 16 , and 17 are shown. Each of the multipolar leads 15 , 16 , and 17 are operably coupled at one end to the generator 1 . The multipolar leads 15 , 16 , and 17 may be permanently coupled to the generator 1 or may, alternatively, be coupled with a detachable means, such as described hereinabove. At the end of the multipolar leads 15 , 16 , and 17 , opposite the generator 1 , the multipolar leads 15 , 16 , and 17 terminate with multiple electrodes 18 , 19 , 20 , 21 , 22 , and 23 (including tip electrodes 19 , 21 , 23 and ring electrodes 18 , 20 , 22 ). In one embodiment, the multiple electrodes 20 and 21 are anode electrodes and the multiple electrodes 18 , 19 , 22 , and 23 are cathode electrodes. In another embodiment, the ring electrodes 20 , 18 , and 22 may each serve as an anode while the tip electrodes 21 , 19 , and 23 may each serve as a cathode, or vice versa. However, the multiple electrodes 18 , 19 , 20 , 21 , 22 , and 23 may function in any combination of anodes and cathodes.

Internal circuitry permits electrode switching as previously described. Turning now to FIGS. 2 e - 2 f , a hex bridge 300 which may be advantageously used in conjunction with the embodiments described herein is illustrated. Shown are a hex bridge 300 ; current source 249 with the positive output shown on top; switches 240 , 241 , 242 , 243 , 244 , and 245 ; electrodes 246 and 247 ; and a generator housing 248 . By opening and closing switches 240 , 241 , 242 , 243 , 244 , and 245 , electrodes 246 , 247 , and the generator housing 248 may be switched from an anode to a cathode or vice versa. For example, by closing switch 240 and switch 243 , current flows from the current source 249 through the switch 240 to the electrode 246 then passes through tissue (not shown) to the electrode 247 , through the switch 243 and back to the current source 249 . In this example, the electrode 246 serves as an anode while the electrode 247 serves as a cathode. In another example, by opening the switch 240 , and the switch 243 , and by closing switch 242 and switch 241 , electricity flows from the current source 249 through the switch 242 to the electrode 247 , then passes through the tissue to the electrode 246 through the switch 241 and back to the current source 249 . In this example, the electrode 247 serves as the anode and the electrode 246 serves as the cathode.

As illustrated by the previous two examples, the electrode 246 may serve as either the anode or the cathode and the electrode 247 may serve as an anode or a cathode. The electrodes 246 , 247 may be electrodes of separate unipolar leads, or may be tip and ring electrodes of a bipolar electrode.

As will be appreciated by those of ordinary skill in the art, numerous configurations of anode(s) and cathode(s) based on these principles may be achieved by the type of circuit illustrated in FIGS. 2 e - 2 f . For example, both of the electrodes 246 , 247 may be configured as the anode or both of the electrodes 246 , 247 may be configured as the cathode. And, in a similar manner, the generator housing 248 can be selectively configured as the anode or the cathode, either in addition to or instead of one of the electrodes 246 , 247 . Importantly, the circuit as illustrated in FIGS. 2 e - 2 f may have any number of switches and any combination of such switches may be closed or opened to treat tumors with electrical therapy. The switches described hereinabove may be discrete, or solid state and/or software controlled or electronically controlled. Furthermore, any number of electrodes and configurations are contemplated by the inventors. For example, as shown in FIG. 2 f , any number of electrodes may be coupled to the hex bridge 300 electrically between switch 242 and switch 244 and electrically between switch 243 and switch 245 , as is indicated by dashed lines. The electrodes of FIG. 2 f , like the electrodes of FIG. 2 e , may be of any configuration, especially such as those described herein.

Looking now to FIG. 2 g , a common lead segment 1001 of the present embodiment comprising a lead adapter 24 is shown. The lead adapter 24 of this embodiment allows the lead extensions 26 and 27 to enter the generator 1 via the common lead segment 1001 at the same electric connection 28 . The lead 25 enters the generator 1 in a different electric connection 1002 than lead extensions 26 and 27 . The lead adapter 24 permits the use of additional leads such as lead extensions 26 and 27 under certain circumstances. The lead adapter 24 may be advantageously used when a large tumor and/or multiple tumors are being treated by a single generator 1 . Importantly, the lead adapter 24 allows for adaptation during implantation or treatment. If, for example, an additional tumor is formed or found at a later date than at initial implant of the device of the preferred embodiment, use of the lead adapter 24 (or multiple lead adapters) allows flexibility in the implanted device. Adjusting the number of leads via a lead adapter may be preferable to extricating and replacing the entire implanted device or adding an additional implanted device. Leads used in conjunction with the lead adapter 24 may be unipolar and multipolar, anode and cathode, may contain any number of electrodes, and may be placed internally and externally relative to a tumor or both internally and externally. The lead adapter 24 may take on any form useful to electrically couple current from two or more leads to the same electric connection 28 . However, in a preferred embodiment, the adapter may be shaped like a “Y.”

Many variations of lead configurations are possible and, likewise, possibilities of electrode placement are equally numerous. The above are but a few examples of the types of lead configurations and electrode placements possible. As shown above, the leads of the present embodiment may be multipolar and unipolar and of various lengths, sizes, and shapes. Furthermore, the leads may terminate with electrodes that are anode and/or cathode, and be implanted into, adjacent to, and/or in the internal periphery of a tumor. In any event, the electrodes and leads of the preferred embodiment should be configured so that an electric field encompasses as much of the tumor as possible (or alternatively a target portion of the tumor) while excluding the majority of the surrounding tissue.

Depicted in FIG. 3 a - 3 c is an electrode array 310 . Shown are the electrode array 310 ; a tumor 6 ; a wire bundle 29 ; insulated wire segment 30 ; electrodes 31 , 32 , 33 , 34 , and 35 ; needles 36 ; and insulated wire ring 1003 . FIG. 3 a is a front perspective of the electrode array 310 wherein the entire mass of the tumor 6 is surrounded by the electrodes 31 , 32 , 33 , 34 , 35 . The electrode 31 is placed at the top of the tumor 6 via insulated wire segment 30 , while electrodes 32 , 33 , 34 , and 35 surround the tumor 6 via insulated wire ring 1003 . The electrode 35 is depicted behind the tumor 6 and is therefore not visible from the perspective of FIG. 3 a . The electrodes 32 , 33 , 34 , and 35 are coupled together in a ring via insulated wire ring 1003 . The electrode 34 is coupled to a distal end of the wire bundle 29 . The electrode 31 is electrically coupled to the wire bundle 29 via the insulated wire segment 30 through the electrode 34 . A proximal end of the wire bundle 29 is coupled to a generator (such as in FIG. 1) which provides electrical therapy to the electrodes 31 , 32 , 33 , 34 , and 35 . Current paths can be switched by the generator (not shown), such as by using circuitry similar to that depicted in FIG. 2 e - 2 f , so that a current pulse can flow from the electrode 35 to the electrode 31 , then from the electrode 34 to the electrode 31 , then from the electrode 33 to the electrode 31 , then from the electrode 32 to the electrode 31 , and so on in any sequence by delivering pulses of current between successive pairs of the electrode 31 and a remaining one of the electrodes 32 , 33 , 34 , and 35 . Each electrode is fixed to tissue via the needles 36 , which may or may not serve as part of the electrode. The electrodes 31 , 32 , 33 , 34 , and 35 may selectively comprise any combination of anodes and cathodes. In another embodiment, all of the electrodes 31 , 32 , 33 , 34 , and 35 may simultaneously serve as anodes while the generator housing (not shown) serves as the cathode, or vice versa.

FIG. 3 b is a top view of the electrode array 310 comprising electrodes 31 , 32 , 33 , 34 , and 35 ; wire bundle 29 ; insulated wire segment 30 ; and insulated wire ring 1003 of FIG. 3 a . The electrode 35 , hidden in FIG. 3 a is seen on FIG. 3 b . FIG. 3 c is a side perspective of the electrode array 310 comprising electrodes 31 , 32 , 33 , 34 , and 35 ; wire bundle 29 ; insulated wire segment 30 ; and insulated wire ring 1003 of FIG. 3 a . The needles 36 are coupled to the electrodes 31 , 32 , 33 , 34 , and 35 . Two or more electrodes may simultaneously be used as anodes or cathodes for electrical therapy. The electrodes 31 , 32 , 33 , 34 , and 35 comprise an electrode array 310 that can be used to increase the effectiveness of electrical therapy by establishing an electric field pattern that encompasses all of the tumor volume. In a preferred embodiment, this type of electrode array 310 can be used for electrochemical therapy and/or electroporation.

Turning now to FIG. 4 a top view of an electrode array 311 is depicted. The electrode array 311 of FIG. 4 has been modified from the electrode array 310 of FIGS. 3 a - 3 c by including four electrodes 32 , 33 , 34 , and 35 instead of five electrodes 31 , 32 , 33 , 34 , and 35 and coupling a single needle 36 for fixation to a central non-electrical connection 37 . Shown are a wire bundle 29 ; the electrodes 32 , 33 , 34 , and 35 ; the needle 36 ; the central non-electrical connection 37 ; and the insulated wire ring 1003 . The electrodes 32 , 33 , 34 , and 35 are anchored to a tissue via the needle 36 , which is not directly associated with any one of the electrodes 32 , 33 , 34 , and 35 . Needle 36 is mechanically coupled to the electrode array 311 via the central non-electrical connection 37 but, as depicted, is electrically isolated from the electrodes 32 , 33 , 34 , and 35 .

Illustrated in FIGS. 5 a - 5 b is an electrode array 312 . The electrode array 312 of FIGS. 5 a - 5 b has been modified from the electrode array of FIGS. 3 a - 3 c 310 by utilizing a single needle 36 to anchor the electrode array 312 . Shown are the electrode array 312 ; a wire bundle 29 ; an insulated wire segment 30 ; electrodes 31 , 32 , 33 , 34 , and 35 ; the needle 36 ; and an insulated wire ring 1003 . FIG. 5 a is a top view and FIG. 5 b is a side perspective view. In FIG. 5 a each of the electrodes 31 , 32 , 33 , 34 , and 35 is coupled to the wire bundle 29 via the insulated wire ring 1003 . The electrodes 32 , 33 , 34 , and 35 are coupled to the insulated wire ring 1003 , while the electrode 31 is coupled independently to the wire bundle 29 via the insulated wire segment 30 . Only the electrode 31 is mechanically coupled to the needle 36 as an anchoring means. The needle 36 may or may not serve as part of the electrode 31 . FIG. 5 b is a side perspective of FIG. 5 a.

Shown in FIGS. 6 a - 6 b is an electrode array 314 . The electrode array 314 of FIGS. 6 a - 6 b has been modified from the electrode array 310 of FIGS. 3 a - 3 c by including four electrodes 32 , 33 , 34 , and 35 instead of five and by removing all fixation needles. Shown are the electrode array 314 ; the wire bundle 29 ; the electrodes 32 , 33 , 34 , and 35 ; and an insulated wire ring 1003 . FIG. 6 a is a top view and FIG. 6 b is a side perspective view. In FIG. 6 a each of the electrodes 32 , 33 , 34 , and 35 is coupled to the wire bundle 29 via the insulated wire ring 1003 . No electrode is coupled to a needle for fixation means. In this case, the electrode array is placed on top of or around a tumor. In FIG. 6 b , the electrodes 32 , 33 , 34 , and 35 are shown coupled together via the insulated wire ring 1003 to the wire bundle 29 . No electrode is coupled to a needle for placement or anchoring means.

FIGS. 7 a - 7 b are illustrations of an electrode array 316 . The electrode array 316 of FIGS. 7 a - 7 b has been modified from the electrode array 310 of FIGS. 3 a - 3 c by including four electrodes 32 , 33 , 34 , and 35 instead of five and by using an anchoring hook in lieu of a fixation needle or needles. Shown are the electrode array 316 ; a wire bundle 29 ; electrodes 32 , 33 , 34 , and 35 ; an anchoring hook 38 ; and an insulated wire ring 1003 . FIG. 7 a is a top view and FIG. 7 b is a side perspective view. In FIG. 7 a each of the electrodes 32 , 33 , 34 , and 35 is coupled to the wire bundle 29 via the insulated wire ring 1003 . No electrode is directly coupled to a needle for fixation. Instead, an anchoring hook 38 is coupled to the wire bundle 29 ; however, the anchoring hook 38 can be placed at any place on the electrode array 316 . The anchoring hook 38 secures placement of the electrode array 316 by hooking into tissue. In one variation, the anchoring hook 38 may be secured to healthy tissue to increase stability. In FIG. 7 b the electrodes 32 , 33 , 34 , and 35 are shown coupled together via insulated wire ring 1003 to wire bundle 29 . The anchoring hook 38 is shown coupled to wire bundle 29 .

In accordance with further variations, the anchoring hook 38 or several anchoring hooks may be used either alone or in combination with a fixation needle or needles.

Looking now at FIGS. 8 a - 8 b , a non-continuous electrode array 318 is depicted. The non-continuous electrode array 318 of FIGS. 8 a - 8 b has been modified from the electrode array 310 of FIGS. 3 a - 3 c by not attaching electrodes in a complete circle, i.e. by substituting the insulated wire ring 10003 for a curved structure, or insulated wire “C” 1005 . Shown are the electrode array 318 ; a wire bundle 29 ; the electrodes 32 , 33 , 34 , and 35 ; fixation needles 36 ; and an insulated wire “C” 1005 . The electrodes 32 , 33 , 34 , and 35 are coupled together via the insulated wire “C” 1005 . The fixation needles 36 are coupled to the electrodes 32 , 33 , 34 , and 35 . The needles 36 may or may not serve as part of the electrodes 32 , 33 , 34 , and 35 . The insulated wire may be flexible to allow any conformation of the insulated wire “C” 1005 and any relative position of the electrodes 32 , 33 , 34 , and 35 . For example, the electrodes 32 , 33 , 34 , and 35 may be arranged in a partial circle or three-quarter circle (or “C”), as shown, a straight line or a line with a bend, such as a 90° bend, or the like, a complex curve, or the like. The non-continuous electrode array 318 of FIGS. 8 a - 8 b may be advantageously used when a tumor is awkwardly located or shaped, or difficult to surround with a ring of electrodes for any other reason. It is generally accepted that cancerous tumors should not be broken apart and, as such, a non-continuous electrode array 318 will allow flexibility in positioning.

Referring now to FIG. 9, an electrode array 39 with lead adapters 24 and 1620 (such as shown above in FIG. 2 f ) is shown in connection with a tumor. Shown are a generator 1 , a lead 2 , a tumor 6 , the lead adapters 24 and 1620 , and a multiple electrode array 39 . The electrode array 39 is electrically coupled to the generator 1 . The multiple electrode array 39 may be placed on top of, around, and/or adjacent to the tumor 6 . The multiple electrode array 39 may be anchored to the tumor 6 by any fixation means such as a needle, hook, barbed hook, “corkscrew”, or any other suitable suture for mechanically securing the multiple electrode array 39 to the tumor 6 or to nearby tissue. Because the lead 2 and the multiple electrode array 39 together may be larger or bulkier than a single electrode lead, tunneling the lead to the tumor 6 may be problematic. To overcome this difficulty, the lead adapters 24 and 1620 may be used. The lead adapters 24 and 1620 are located at both ends of the lead 2 with lead adapter 24 lying closest to the generator 1 and the lead adapter 1620 lying closest to the electrode array 39 . In this way, the multiple electrode array 39 can be placed on or proximate to the tumor 6 and connected to the generator 1 by way of the lead 2 , which can be tunneled through tissue that may be interposed between a suitable implantation site for the generator 1 and the tumor 6 , where the multiple electrode array 39 must be located.

As will be appreciated by one of ordinary skill in the art, many variations of electrode arrays may be used in electrical therapy. The examples described herein are by way of example and in no way limit the scope of the invention. Any combination of the numerous options described herein or otherwise suitable variations can be used to deliver electrical therapy.

For example, a non-continuous ring of electrodes may be used with an anchoring hook. In addition, two electrode arrays may branch from the same electrical connection on the generator 1 by way of, for example, a lead adapter. Therefore, any of a virtually infinite number of combinations of options, configurations, and features described herein are contemplated by the inventors.

Shown in FIGS. 10 a - 10 b is an example of an electrode arrangement that accommodates electrical therapy and electroporation. Shown are a tumor 6 ; electrodes 40 , 41 , and 42 ; a DC ablation current 43 ; and an electroporation current 44 . In this arrangement, three electrodes 40 , 41 , and 42 are placed in and around the tumor 6 . The electrodes 40 and 42 lie at a periphery of the tumor 6 and the electrode 41 is placed at a center of, on top of, or below the tumor 6 . By utilizing three electrodes, both DC ablation and electroporation can be performed. In a preferred embodiment, DC ablation current 43 occurs between the electrodes 40 and 42 , as shown in FIG. 10 a , and electroporation occurs between the electrodes 40 and 41 , or between 41 and 42 , as shown in FIG. 10 b . Typically a set of electrode pairings having a greater interelectrode distance, such as between the electrodes 40 and 42 , in comparison to electrodes 40 and 41 , or 41 and 42 , are used in electrical therapy to create the maximum electric field for encompassing large portions of a tumor, as shown in FIG. 10 a . However, any combination of electrodes may be used for electrical therapy. Shown in FIG. 10 b , two sets of electrode pairings with a smaller interelectrode distance may be optimally used for electroporation in order to increase the electric field intensity for a given pulse voltage amplitude. In a preferred embodiment, a chemotherapeutic agent may enter the electroporated area faster than cells in the surrounding area. The area between electrodes 40 and 41 and/or 41 and 42 will preferably consist of a large portion of the primary tumor whereas the area between the electrodes 40 and 42 might include metastases as well as the border of the primary tumor.

A three-axis electrode system 350 is shown in FIG. 11 and comprises a configuration of three leads 45 , 46 , and 47 ; multiple electrodes 48 ; and the three-axis system 350 for electrical therapy. The three-axis system 350 is electrically coupled to an internal and/or external power source (not shown). Each of the three leads 45 , 46 , and 47 , which have a plurality of spaced apart electrodes 48 along a portion of their distal ends are implanted into a tumor 6 orthogonally and intersect near the center of the tumor 6 . As the size, shape, density, and other characteristics of the tumor 6 change during application of electrical therapy, the central vector of current flow can be altered through selectively activating multiple electrodes 48 on the x, y, and z coordinates. In this way, the system can target the center of the tumor's mass. Additionally the system can selectively designate electrodes 48 as anodes or cathodes, or both anodes and cathodes in any sequence (such as using the hex bridge 300 , such as shown in FIGS. 2 e - 2 f ) and alter the 3-dimensional distribution of currents. The system can also pulse for more energy efficiency, such as by delivering one or more pulses of current between one or more pairs (or more) of the electrodes 48 . In some cases it is more energy efficient to pulse at a low duty cycle than to maintain a steady current, even when the pulses may be at a higher voltage.

Turning now to FIGS. 12 a - 12 b leads 49 , 50 , 51 , and 52 with unique identification marks 53 , 54 , 55 , and 56 are illustrated. Shown are four leads 49 , 50 , 51 , and 52 ; the unique markings 53 , 54 , 55 , and 56 ; and a tumor 6 . The leads 49 , 50 , 51 , and 52 are electrically coupled to an internal and/or external power source (not shown). The leads 49 , 50 , 51 , and 52 are coupled with any number and configuration of electrodes (not shown).

Each lead 49 , 50 , 51 , and 52 is shown with its unique marking 53 , 54 , 55 , and 56 respectively. The unique marking 53 , 54 , 55 , and 56 is individually identifiable under imaging. The unique marking may be of a different material distinguishable from the lead material under imaging. By visually tracking the tumor 6 in relation to the leads 49 , 50 , 51 , and 52 , via their unique markings 53 , 54 , 55 , and 56 , during treatment, therapy can be reprogrammed, such as through transcutaneous telemetry, to deliver electrical therapy tailored to any changes in the tumor 6 . For example, the leads and/or electrodes (not shown) may be shifted over time as the size, shape, or position of the tumor 6 changes. Referring to FIG. 12 a , a set of four uniquely marked leads 49 , 50 , 51 , and 52 surround the tumor 6 . Then, in FIG. 12 b , the same tumor 6 has changed size, shape, and position. In this case, based on the unique markings 53 , 54 , 55 , and 56 of the leads 49 , 50 , 51 , and 52 , the leads 49 , 50 , 51 , and 52 and/or electrodes (not shown) may be appropriately repositioned to target the center of the altered tumor. The markings may be a different number of stripes near the tip of each lead, such as shown in FIGS. 12 a - 12 b . However, any other type of unique marking that distinguishes one lead from another in the local tumor area may be used.

In another embodiment, imaging may also be accomplished by magnetic resonance imaging (MRI), computed tomography scan (CT), and ultrasound (echo imaging). The leads of the device may be adapted to withstand the radiation associated with MRI imaging by the addition of shunting and opening protection circuitry to prevent the induction of high currents through Faraday's law acting on the current loop of the electrodes. Alternatively, current loops may be generated from one wire and a return path through the tissue.

To enhance MRI and CT scanning, a contrast agent may be administered directly into the core of the tumor to be scanned. Alternatively, depending on the desired outcome of the MRI or CT scan, the contrast agent may be administered to the periphery of the tumor (i.e. in the vicinity of the tumor). The contrast agent may be injected with a needle or syringe, or it may be administered via any of the internal reservoirs and drug pumps described hereinbelow. The contrast agents may be for example, iodine compounds and solutions and charged micro spheres. Micro spheres are particularly advantageous in ultrasound imaging.

In another embodiment, the electrical therapy system may enhance imaging by applying current to increase the concentration of certain chemicals, such as oxygen. Oxygen concentration may be increased by forcing all electrodes anodal and/or by administering certain oxygenating substances, such as perfluorocarbons and/or any other oxygenators, such as, for example, any of the oxygenating substances described hereinbelow. Using this technique, the imaging device can read current distributions by back calculations from the oxygen and hydrogen concentrations, thereby rendering the tumor more visible.

Referring now to FIGS. 13 a - 13 e various types of lead anchoring mechanisms are illustrated. Shown are a tumor 6 , a screw-in lead 57 , a screw 58 , pronged lead 59 , two or more prongs 60 , a telescoping lead 360 , telescoping cylindrical electrode section 61 , stationary electrode section 62 , adjustable screw-in lead 1111 , adjustable screw-in electrode 1113 , adjusting means 1115 , and rotatable coupling means 1117 . Each of the leads 57 , 59 , 360 , and 1111 is coupled to an internal and/or external power source (not shown).

FIG. 13 a shows the screw-in lead 57 . Adapted with the screw 58 , the screw-in lead 57 is designed to be left within a tumor 6 during therapy. Shown in FIG. 13 b is the pronged lead 59 ending with two or more prongs 60 , which are expanded into the tumor 6 during implantation and are left expanded throughout therapy. Depicted in FIG. 13 c , is the telescoping lead 360 . Shown are the telescoping lead 360 and one or more overlapping telescoping cylindrical electrode sections 61 and stationary electrode section 62 , the telescoping cylindrical electrode section 61 has been extended from the stationary electrode section 62 . The telescoping cylindrical electrode section 61 may be adjusted either pre- or post-implantation to an optimum length in order to anchor to the tumor 6 and create electrical contact therewith.

FIG. 13 d depicts an adjustable screw-in lead 1111 . The adjustable screw-in lead 1111 may be repositioned during electrical therapy as needed to “chase” a tumor. The adjustable screw-in lead 1111 is coupled at one end to a power source (not shown) such that the power source delivers electrical therapy to the adjustable screw-in lead 1111 . At the other end, the adjustable screw-in lead 1111 is coupled with a rotatable coupling means 1117 . The rotatable coupling means 1117 is electrically and mechanically coupled to an adjustable screw-in electrode 1113 such that the electrical therapy delivered by the power source (not shown), and carried by the adjustable screw-in lead 1111 , is delivered to the screw-in electrode 1113 via the rotatable coupling means 1117 . Rotatable coupling means 1117 may be, in one embodiment, a washer. The adjustable screw-in electrode 1113 may be in various sizes and lengths depending on the tumor characteristics (e.g. size, location, density, and composition). In a preferred embodiment, the adjustable fixation screw may be in the range of 0.2 to 2 inches in length and 0.1 to 1 inch in diameter. Coupled to the top of the adjustable screw-in electrode 1113 is an adjusting means 1115 . Adjusting means 1115 allows the adjustable screw-in electrode 1113 to be easily inserted and removed from a tumor. Additionally, the adjusting means 1115 allows for easy repositioning during electrical therapy. Adjusting means 1115 may be designed with an elevated curve as shown. Alternatively, adjusting means 1115 may be shaped like a screw head or a bolt head. FIG. 13 e is a top view of the adjusting means 1115 .

Shown in FIG. 14 is a means for directly anchoring a lead to healthy tissue. Illustrated are a tumor 6 , a lead 63 , a fixation means 64 , and healthy tissue 65 . The lead 63 is coupled to an internal and/or external power source. The lead 63 may be coupled with any number and configuration of electrodes (not shown).

The lead 63 is shown inserted into the tumor 6 . The lead 63 is held in position by means of a fixation device 64 , which is directly anchored into the healthy tissue 65 , which is peripheral to the tumor 6 . Because tumor tissue may be soft and/or watery, a means for fixing a lead to nearby healthy, solid tissue, as shown, may be advantageous. In this case, the lead 63 remains fixed in place with no regard to any characteristics of the tumor 6 . Additionally, as electrical therapy is applied, the tumor 6 may change size, shape, and density, thus anchoring the lead to healthy tissue may render readjusting the lead unnecessary. Fixation means may be a hook, needle, prongs, screw and any other device capable of anchoring a lead to healthy peripheral tissue.

Turning now to FIG. 15 a means for indirectly anchoring a lead to healthy tissue is illustrated. Shown are a tumor 6 , a lead 63 , healthy tissue 65 , a suture 66 , and a suture sleeve 67 . The lead 63 is coupled with an internal and/or external source of power (not shown). The lead 63 may be coupled with any number and configuration of electrodes.

The lead 63 is shown inserted into a tumor 6 . The lead 63 is held in position by means of the suture 66 in the suture sleeve 67 . The suture 66 indirectly anchors the lead 63 into healthy tissue 65 peripheral to the tumor 6 . Again, because tumor tissue may be soft and/or watery, a means for fixing a lead, either directly or indirectly, to nearby healthy solid tissue may be advantageous. In this case, despite any changes in size or composition occurring in the tumor 6 , the lead 63 remains fixed in place. The lead 63 will remain in place regardless of changes occurring within the tumor 6 .

The above illustrates only a few of the types of anchoring mechanisms possible for anchoring a lead to a tumor. The anchoring mechanisms may be of numerous shapes and sizes. Ideally, the anchoring mechanism is selected relative to the size, density, and location of the tumor in each circumstance. Importantly, tumor tissue, such as the tissue to which a lead of the present embodiment is anchored proximately, is quite different from heart muscle to which a pacemaker is anchored. Tumor tissue tends to be soft and retracting and, therefore, the anchoring device should permit penetration of this type of cancerous tissue while allowing safe removal. Anchoring leads of the present embodiment are akin to active fixation pacing leads rather than passive fixation leads. The anchoring mechanism may or may not also act as one or more of the electrodes. For example, in one embodiment, the anchoring means may double as the electrodes; both anode and cathode configurations are contemplated. Alternatively, the anchoring mechanism may not serve as an electrode, in which case the electrode may be at the end of the lead distal to the anchoring mechanism.

The lead depicted in FIG. 16 has additional features and options that may be advantageous in certain circumstances. Shown are lead 68 , a non-stick coating 69 , a lumen 70 , and an inflatable balloon 71 . The lead 68 is coupled to an internal and/or external source of power (not shown). The lead 68 may be coupled with any number and configuration of electrodes (not shown).

The lead 68 of FIG. 16 features the non-stick coating 69 on an external surface of the lead 68 . Additionally, the lumen 70 runs lengthwise along a distance of the lead 68 . The inflatable balloon 71 is coupled to a distal end of the lead 68 . The lumen 70 , running the entire length of the lead 68 , is useful for insertion, extraction, gas removal, and liquid removal. Because metabolic changes in a tumor may cause gas and liquid production, the lead 68 , comprising the lumen 70 configured to remove both gases and liquids may be advantageous. During periods of high current injection, when gas and liquid production are likely to be greatest, gas and liquid removal may be particularly advantageous because excess gas and/or excess liquid may interfere with electrical therapy and/or cause bloating and/or pain.

In another embodiment, the lumen 70 may be completely open from end to end for a so-called “over the wire” insertion technique. Alternatively, the lumen 70 may be partially closed at a distal end, opposite the inflatable balloon 71 , to block a stylet. The non-stick coating 69 , which is applied to the outer surface of the lead 68 , renders insertion and removal of the lead 68 easier. The inflatable balloon 71 is optionally coupled with the distal end of the lead 68 for securing the distal end of the lead 68 in a tumor. Additionally, the inflatable balloon 71 may be conductive such that by controlling the radius (through inflation or deflation) current density can also be regulated. Holes of any number, but preferentially two, may be associated with the distal end of the lumen 68 comprising the inflatable balloon 71 to allow for gas and liquid removal. However, the holes should be small enough to prevent a stylet from escaping. Any of the variations described herei