Modalities in Cancer Therapy Folder Title: Therapy(NoTP) Updated: April 24, 2017

Why We Do Cancer Therapy Research Read: “In the Elevator at the Princess Margaret Hospital” See tpfondy.mysite.syr.edu Also on course web-site.

Therapeutic Modality Options Surgery Radiation or Local Thermal Effects: X-Ray; Photodynamic Therapy; Thermal Ablation; Microwave; Hyperthermia Chemotherapy (Including Hormonal Therapy) See Chapter 16: Rational Treatment of Cancer Immunotherapy See Chapter 15: Crowd Control – Tumor Immunology and Immunotherapy Host Response Modification Gene Therapy (and “Virotherapy”?) “Specific-Targeted” Therapies: Monoclonal antibodies or pharmaceuticals directed to errors in signaling pathways, to signal receptors, or to other key oncoproteins or suppressor proteins.

Features of Surgical Intervention Highly Tumor-specific and Effective Technically Sophisticated and of Limited Applicability Access depends on economic status of country* *See Cancer in the Developing World (later) Useless for Extensive Systemic Disease or for Unrecognized Metastases Depends on Pathological Identification and Understanding: Must know where the cancer is Need to know whether the cancer will spread Will intervention do any good? Will intervention actually be harmful and reduce survival time? Will intervention serve only to extend the terminal suffering? Traumatic, Immunosuppressive, & Dangerous Can Induce Systemic Spread Patient Refusal and Opting for Alternative Medicine Physical Modality - Emergence of Cellular Resistance is not Likely

Therapies Involving Electromagnetic Radiation: Part 1: X-Ray External physical intervention with a chemical target (DNA) Not Especially Tumor-specific; Damage to Normal Tissue Can Limit Utility Limited Utility Against Extensive, Systemic Disease Can be Valuable for Debulking Large Local Tumor or Reducing Tumor Size to Permit Surgery Second Malignancies Can Be Induced Combination with Radio-sensitizers Can Improve Anti-tumor Specificity Limited by Tumor Heterogeneity and Selection for Radiation-resistant Variants

Therapies Involving Electromagnetic Radiation: Part 2: Photodynamic Therapy, Hyperthermia, Neutron Capture, Microwave or Radiowave Therapy External physical intervention with a physical target: (the cancer cell or cancer mass) Must know where the cancer mass is Must be able to direct the physical intervention e.g. Laser-directed microwave Can be useful against cancers not accessible to surgery May use antibody to bind metal to tumor target for microwave destruction Damage to normal tissue must be circumvented Emergence of resistance is unlikely

Ideas About Leukemia Cell Size Cytoskeletal and Membrane Modifications Cell Disruption with Pulsed Low-frequency Ultra-sound

Possibilities with Ultra-sonic Radiation: Part 1 External physical intervention with a physical target: the size and sonic sensitivity of the cell. Emergence of cellular resistance based on cancer cell biochemistry is not possible. Target is a necessary physical state (enlarged cell size at mitosis) through which the dividing cancer cell must pass, no matter how it got to that state. May not have to know where the cancer cells are. Possibility of Whole-Body Ultra-sound Should be applicable to metastasizing cells including carcinomas and sarcomas in the circulation or in the lymphatic drainage. Treatment of circulating blood in extra-corporeal shunt or in appendages: Sonication of flowing leukemia cells in a glass-coil.

Possibilities with Ultra-sonic Radiation: Part 2 Possible to magnify the differences in sonic sensitivity between normal and cancer cells by treatment with cytoskeletal-directed agents or other agents that preferentially affect leukemia cell size. Chemotherapeutic agents produce cell enlargement in cells that are damaged that may still remain viable. Possible to link ultra-sonic therapy with cell cycle-directed chemotherapy. Resistance of red blood cells to low frequency ultra-sound is key to the concept.

Modulation of Ultra-sonic Treatment Can vary the sonic frequency (wavelength). Can vary the intensity. Can vary the timing to correspond with cell cycle and cell treatment responses. Opportunity for multiple ultra-sonic treatments repeated at minutes, hours, or days. Host toxicity is likely to be manageable.

Application of Ultra-sound to Attached Cells: In Situ or Metastatic Cell must detach and round up in order to divide. Attached cells can be made to detach by treatment with cytoskeletal-directed agents. Ultra-sound may be applicable to disseminated attached metastatic cells, not just to leukemia-lymphoma.

Therapeutic Modality Options Surgery Radiation or Local Thermal Effects: X-Ray; Photodynamic Therapy; Thermal Ablation; Microwave; Hyperthermia Chemotherapy (Including Hormonal Therapy) See Chapter 16: Rational Treatment of Cancer Immunotherapy See Chapter 15: Crowd Control – Tumor Immunology and Immunotherapy Host Response Modification Gene Therapy (and “Virotherapy”?) “Specific-Targeted” Therapies: Monoclonal antibodies or pharmaceuticals directed to errors in signaling pathways, to signal receptors, or to other key oncoproteins or suppressor proteins.

Chemical agents as tumor-specific or tumor selective anti-neoplastic agents: Cancer Chemotherapy Requires specific or selective targets Involves Side Reactions and Host Toxicities Affected by Host Metabolism of Drug Requires Transport to Target and Maintenance of Effective Drug Concentration Generates the Emergence of Drug Resistance Immunotherapy Involving Tumor-specific or Tumor-directed Antibodies, Lymphocytes, or Other Cytotoxic Cells, Innate Immunity, and Cytokines and Complement is Considered Separately from Chemotherapy (See Chapter 15: “Crowd Control”)

Immunotherapy of Cancer Potentially Highly Tumor-Specific Can be Effective Against Disseminated Disease Including Unrecognized Micro-metastases Probably of Limited Value Against Extensive Advanced Disease Can Involve Severe, Sudden Onset Life-threatening Treatment-limiting Side-Reactions Limited by Tumor Heterogeneity, Selection for Unresponsive Variants, and Emergence of Immune-Escape

Host-Response Modification in Cancer Management (“Biotherapies”) Potentially Less Intrusive than Other More-Aggressive Modalities Treating Host Supporting Cells to Reduce their ability to promote tumor growth (e.g. anti-angiogenesis) Host stromal cell interactions supporting tumor growth: “Respect Thy Neighbor!” Science, Feb. 6, 2004 (BIO 501 Web-Site: Password-protected Link)

Hormonal Agents and Cytokines in Cancer Therapy: Host Response Modification

Biotherapies Currently Approved by the FDA for Treating Cancer Common Name Commercial Product Indicated Use Interferon A2a Inferon A Hairy Cell Leukemia Interferon A2b Intron A AIDS-related Kaposi’s Sarcoma Interleukin 2 Proleukin Metastatic renal cell carcinoma BCG Extract TICE Bladder carcinoma in situ Granulocyte Colony-stimulating Fact Neupogen Chemotherapy-induced neutropenia; Supports hematopoietic stem cell transplants Granulocyte-Macrophage Colony-stimulating Factor Leukine Supports Bone-marrow transplants Erythropoietin Epogen; Procrit Anemia

Gene Therapy for Cancer Potentially Highly Tumor-Specific Accessibility of Cell Targets Is a Major Obstacle for General Application May Have Great Value in Combined Modality Approaches Potentially Dangerous Side-Reactions from Viral Vector Delivery Agents

“Viro-Therapy” Using Viruses to Treat Cancers (See Scientific American, October 2003, pp 69 to 75 Virotherapy with Transductional Targeting: Adenovirus engineered to bind to and infect only cancer cells Does not infect normal cells Adenovirus multiplies in cancer cells. Cancer cell burst and disperse virus to infect other cancer cells. Virotherapy with Transcriptional Targeting: Adenovirus engineered to replicate under control of tumor promoter genes. Virus replicates only in cancer cells that have the tumor-specific promoter. Cancer cell bursts and disperse virus particles to infect other cancer cells. Lethal immune-responses in persons sensitized to adenovirus vector.

Virotherapy with Transductional Targeting Scientific American, October 2003

Virotherapy with Transcriptional Targeting. Scientific American

Individual Therapeutic Modality Options: Surgery Radiation Chemotherapy (Including Hormonal Therapy) See Chapter 16: Rational Treatment of Cancer Immunotherapy See Chapter 15: Crowd Control – Tumor Immunology and Immunotherapy Host Response Modification Gene Therapy (and Virotherapy?) “Specific-Targeted” Therapies: Monoclonal antibodies or pharmaceuticals directed to errors in signaling pathways, to signal receptors, or to other key oncoproteins or suppressor proteins. What if we use these in combination with each other ?

Combined Modality Therapies for Cancer Surgery and Radiation Adjuvant Chemotherapy: Surgery and Chemotherapy Radio-sensitizers: Chemotherapy and Radiation Chemotherapy and Host-Response Modification Induction of Differentiation by Chemotherapeutic Agents Induction of Apoptosis by Chemotherapeutic Agents Immunotherapy and Gene Therapy Genetically Engineered T-Cells Chemotherapy with Ultra-sonic Disruption?

Adjuvant Chemotherapy: Combined Chemotherapy and Surgery Surgically reduce tumor burden by 11-fold. Tolerated chemotherapy may become curative Surgery alone not curative Chemotherapy alone at host-tolerated levels not curative

Cancer Treatment Problems Diagnosis and Prognosis: Will This Cancer be a Problem? How do we know what to expect? What are the side effects of treatment likely to be? Is treatment worth it for the patient? What are the costs to the patient and to society? How do we make treatment options fairly available? Within the United States Around the World?

Costs of Cancer Treatment vs Efficacy Non-small-cell Lung Cancer Treatment with Erbitux (cetuximab) 18 Week course of treatment, $40,000 Average Life Span Increase vs Standard Therapy: 1.2 Months Avastin (bevacizumab) $30,000 to $62,000 per patient per course of treatment. Efficacy marginal Costs of non-curative treatments Off-Label use of approved medications See Science, March 25, 2011, p. 1545-7, David Malakoff

Cancer in the U.S. Population 1.7 million new cases per year 1 in 2 for Males 1 in 3 for Females 1.7 million new cases per year 700,000 deaths per year

Age of US Population: 65 Years of Age and Older 2060 This is you!!!!

Costs of Cancer Treatment in the US Science 2011 CxCosts_Sci331_2011.pdf

Science, Vol 331, March 25, 2011, p. 1547. Average Costs for a single patient. 1st year after diagnosis vs continuing care vs terminal year care

Cancer Care Based on Ability to Pay CxWorld_Sci3312011.pdf

Ratio of Mortality to Incidence. If the ratio is large the prospects for survival are bleak. 25 Mar p. 1548

And You Questions for Society and the Health-Care System Do We Treat Everyone? Regardless of Condition, Age, or Life Expectancy? Whether the treatments are clearly beneficial or not? Do we pay for off-label drug treatments (using an agent approved for one cancer to treat another cancer for which efficacy has not been tested)

Three Turning Point Questions

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