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

2. 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.

3. 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.

4. 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

5. 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

6. 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

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

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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”)

16. 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

17. 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)

18. Hormonal Agents and Cytokines in Cancer Therapy: Host Response Modification

19. 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

20. 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

21. “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.

22. Virotherapy with Transductional Targeting
Scientific American, October 2003

23. Virotherapy with Transcriptional Targeting.
Scientific American

24. 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 ?

25. 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?

26. 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

27. 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?

28. 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 , David Malakoff

29. 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

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

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

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

34. Cancer Care Based on Ability to Pay
CxWorld_Sci pdf

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

36. 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)

37. Three Turning Point Questions

38. Response Counter

39. Response Counter

40. Response Counter