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Small Animal Medicine II > Cancer Treatments > Flashcards

Cancer Treatments Flashcards

1
Q

What to considerations do you need to consider prior to treatment?

A

Histologic type and biologic behavior
Grade of tumor
Stage of disease

Morbidity/mortality of therapy (toxicity)
Survival for this tumor type with the treatment regime
Cost of therapy

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2
Q

Surgery

Benifit

A

Only way to actually remove cancer; cures more patients than any other modality

How to get appropriate staging

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3
Q

Surgery

Common mistake

A

Not taking large enough margins on first surgery (need wide margins; 3 cm of normal tissue)

Not submitting all tissues removed and marking margins

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4
Q

Surgery

What happens if tumor not completely excised?

A

Tumor will recur

Alters vascularity, immune system, and tissue planes => recurring tumors are more aggressive, subsequent surgeries more difficult

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5
Q

Surgery

Limitations

A

Localized tumor, not useful if tumor has or will metastasize (grade and staging important); usually still have to do chemo

Some areas there is only so much you can remove

Cats are not as amendable to removal

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6
Q

Radiation Therapy

A

Deposition of energy on or near DNA (breakage of DNA)

Cells die when they try to divide

Kills a constant proportion of cells

Damages normal and cancer cells

Iodine 131 is the only direct radiation; will kill only cancer cells

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7
Q

Direct DNA Damage

A

Radiation therapy

Direct ionization
Chemical bonds broken through DNA; lethal damage and double stranded break

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8
Q

Indirect DNA Damage

A

Radiation therapy

Bonds broken through the ionization of water and the formation of damaging reactive radicals

Oxygen required to perpetuate damage

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9
Q

Radiation therapy

Limitations

A

Local disease only (tumor size)
Surrounding normal tissue must tolerate radiation
Radiation sensitive tumor type (oxygen must be able to get to the location)
Anesthesia requirement because patient needs to be completely still

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10
Q

What are the four R’s of Radiation Therapy

A

Repair
Repopulation
Re-oxygenation
Redistribution

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11
Q

Radiation Therapy

Repair

A

Save normal cells

Damaging cells but cells with normal DNA repair will fix themselves (6 hours)
Cancer cells do not have correct repair mechanisms; DNA is wonky anyway

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12
Q

Radiation Therapy

Repopulation

A

Number of clonogenic tumor cells

Rely on epithelial cells; wound healing mechanisms

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13
Q

Radiation Therapy

Reoxygenation

A

Kills cancer cells

Oxic and hypoxic

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14
Q

Radiation Therapy

Redistribution

A

Given time post one dose of radiation all remaining cells move towards mitosis, and towards increased sensitivity

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15
Q

Radiation Therapy

Goal

A

Time period allowing reoxygen and redistribution in tumor, repopulation and repair in normal cells

Large total dose (tumor control)

Small fraction (less late effects)

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16
Q

Radiation Therapy

What are late effects?

A

Necrosis of tissues:
Bone, brain, etc.
Skin fibrosis

Alopecia, hyperpigmentation, cataracts

May not live long enough to get the late side effects

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17
Q

Radiation Therapy

Size of Tumor

A

Larger tumor is difficult to treat mechanistically
Radiation kills only a portion each time
Larger size, more hypoxia

Gompertizian growth; exponential growth of cancer cells (tumor not palpable until it is 1 gram; 10^10 cells!)

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18
Q

Radiation Therapy

Acute effects

A 
Fast dividing cells:
Hair loss
Moist dermatitis
Mucositis (conjunctiva, oral cavity, nasal passages)
Intestine or bladder inflammation
Nervous tissue inflammation/edema
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19
Q

Radiation Therapy

Skin

A

No longer than 2-3 weeks
Hair loss, mild erythema of skin (no treatment needed)

Custing oozing skin; aloe vera, aquaphor, NSAIDs, pain medication

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20
Q

Radiation Therapy

Conjunctivitis

A

1-2 weeks

Antibacterial opthalmic ointment, NO steroids

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21
Q

Stereotactic Radiation Therapy

A

Few very large doses of radiation versus many small ones

May kill cells not rapidly dividing better than traditional

May damage blood supply more than tumor

Must be done close to tumor

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22
Q

Chemotherapy

Mechanism

A

Act on rapidly dividing cell populations by interfering with DNA synthesis or cell division

Highly non-specific; exploits a macro difference in cells

Only therapy for metastatic disease

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23
Q

Chemotherapy

Alkylating Agents

A

Chlorambucil
Cyclophosphamide
Lomustine
Melphalan

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24
Q

Chemotherapy

Antimetabolites

A

Cystosine Arabinoside
Methotrexate
Elspar
Azothioprine

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25
Q

Chemotherapy

Antitumor Antibiotics

A

Bleomycin
Anthracyclines
Doxorubicin

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26
Q

Chemotherapy

Spindle Cell Poisons

A

Vinblastine
Vincristine
Taxols

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27
Q

Chemotherapy

Platinum drugs

A

Carboplatin

Cisplatin

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28
Q

Chemotherapy

Limitations

A

Resistance/Multiple drug resistance (multiplies fast)

Drug may not be able to make it to tumor site

Side effects to normal tissues: 
bone marrow
alopecia
allergic reactions
GI
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29
Q

Chemotherapy

Rx: Kidney side effects

A

Cisplatin
Doxorubicin (cat)
Lomustine (chronic)

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30
Q

Chemotherapy

Rx: Heart side effects

A

Doxorubicin

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31
Q

Chemotherapy

Rx: Bladder side effects

A

Cyclophosphamide

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32
Q

Chemotherapy

Rx: Pancreas side effects

A

Elspar

Doxorubicin

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33
Q

Chemotherapy

Rx: Nervous system side effects

A 
Vincristine
5 FU (cats!)
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34
Q

Chemotherapy

Rx: Hepatic side effects

A

Lomustine

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35
Q

Chemotherapy

Rx: Lung side effects

A

Cisplatin (cat)
Bleomycin
Lomustine

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36
Q

Chemotherapy Protocols

Multiple Drugs

A

Single drugs are unlikely to cure bulky disease
Multiple drugs may help fight development of resistance
Toxicity may be less with low doses of multiple drugs vs. large doses of single drugs

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37
Q

Chemotherapy Protocols

Single Agent

A

Common because not much is known about efficacy of individual drugs

38
Q

What neoplasias do soly using chemotherapy work for?

A

Lymphoma
Germ cell tumors
Transmissible venereal tumors

39
Q

Neoplasia treatment recommendation

A

Surgery and Chemotherapy

40
Q

Chemotherapy

Dose

A

BSA (m^2)

Too much can kill the patient

41
Q

Chemotherapy

Monitoring

A

Timing
CBC
Chem

Careful venipuncture

42
Q

Chemotherapy

Quick IV

A

Lateral saphenous or cephalic (dogs)

Medial saphenous (cats)

Butterfly or indwelling catheter

43
Q

Chemotherapy

Slow administration

A

Infusion to decrease cardiac toxicity
Severe tissue reactions if extravasated (Doxorubicin)
Must clearly see vein
Flush with saline
Constant monitoring; someone sits with patient

44
Q

Cyrotherapy

A

Only successful with tumor is small and superficial

SCC sometimes

45
Q

Evaluation of Treatment Results

A

Survival: length of time post diagnosis an animal will live (average)

Time to recurrence or relapse; end of treatment to tumor reappearance

Time to tumor progression/recurrence

Prognostic indicator

46
Q

What are “macro” differences between cancer and normal cells?

A

Proliferative rates
DNA synthesis rates
Ineffecient repair of damage

47
Q

Signal Transduction Therapy

What is it?

A

Aberrant signal transduction elements present in most cancers

Mutated signal proteins often oncogenic
Consitutive activation of signaling elements (is cell itself secreting the factor to keep it alive?)

48
Q

Signal Transduction

Cancer Physiology

A

Expression of growth receptors and/or mutated signal transduction elements related to:
Increase in potential for proliferation, invasion, metastasis
Increased angiogenesis

Cancer can support self
Shortened survival of patients
Poor response to chemo
Poor prognosis

49
Q

Signal Transduction Therapy

Example

A

Receptor tyrosine kinases (RTKs)
Main mediators of the signaling network that transmit extracellular signals to the cell

Controls cellular differentiation and proliferation

50
Q

RTKs

Mechanism

A

Signal Transduction: Receptor tyrosine kinases

RTK signaling -> dysregulated cell growth -> cancer

Overexpression of RTK proteins
Functional alterations caused by mutations in corresponding genes (gain of function)
Abnormal stimulation by autocrine growth factor loops (increased stimulation)

Once started are on for life until effect is gone

51
Q

RTKs

Primary targets

A

EGFR-HER-2
c-Kit
VEGFR

52
Q

What is EGFR-HER-2

A

RTK

Epidermal growth factor receptor

53
Q

What is c-Kit

A

RTK

Proto-oncogene coding for RTK

54
Q

What is VEGFR

A

RTK
Vascular endothelial growth factor receptor

Angiogenesis

55
Q

c-Kit

Mutations

A

9-33% of MCTs have c-Kit mutations

Higher tumor grades associated with more frequent c-Kit mutations

56
Q

Toceranib
What is it?
Response to Grade II

A

RTK Inhibitor: Palladia

Response to grade II: 42.8%

57
Q

What neoplasias have RTKs been used in?

A 
Thyroid carcinoma
Anal gland adenocarcinomas
Hemangiosarcoma
Soft tissue sarcomas
Lymphoma
Histiocytic sarcoma
Vaccine associated sarcomas
58
Q

Angiogenesis

Background

A

Tumor growth is dependent on vascular growth: neovascularization required for growth

Delivery of nutrients, growth factors, hormones, oxygen
Removal of wastes and toxins
Immune surveliance

Is different than normal vasculature

59
Q

Targeting tumor blood vessels

How?

A

Vascular disrupting agents (VDAs):
Given only intermittently
Designed to induce rapid and selective vascular shutdown in tumors

Suppression of endothelial cell growth and recruitment from bone marrow (only good in small tumors)

60
Q

Targeting tumor blood vessels

What treatment modality cannot be used then?

A

Radiation because it needs the vascular oxygen supply to cause damage and to help normal cells develop

61
Q

Targeting tumor blood vessels

Biologics

A

Antibodies or peptides that deliver toxins and procoagulant and pro-apoptotic effectors to tumor endothelium

VEGF = target

Avastin in humans
Not available for vet med

62
Q

Targeting tumor blood vessels

Two categories

A

Biologics

Small molecules

63
Q

Targeting tumor blood vessels

Small molecules

A

Agents that exploit known differences between tumor and normal endothelium to induce severe vascular dysfunction (blocking receptors)

Examples:
Thalidomide (not allowed; very teratogenic)
Toceranib (c-Kit) - direct inhibitor of VEGF

64
Q

What is metronomic chemotherapy?

A

Low daily dosing of traditional drugs

Stop endothelial cells from multiplying in, and homing to neoplastic tissues

Most effective in prevention of metastasis or tumor regrowth

Not effective for large tumors

65
Q 
Metronomic chemotherapy
Drugs used (4)
A

Chlorambucil
Cyclophosphamide
Lomustine
Satraplatin

66
Q

Chlorambucil

Uses

A

TCC
MCT
Thyroid

67
Q

Cyclophosphamide

Uses

A

Soft tissue sarcomas

MUST let animal outside often; will have to pee frequently or will cause bladder damage

68
Q

Apoptosis

Two Pathways

A

Intrinsic (mitochondrial)

Extrinsic (receptors)

69
Q

Apoptosis

Intrinsic Pathway

A

Affected by conventional therapies (Radiation and other traditional Chemos)

Mutations commonly occur rendering tumors resistant to conventional therapies

70
Q

Apoptosis

Extrinsic Pathway

A

Novel therapies targeting here may circumvent resistance

Caution; could cause all cells to apoptose

71
Q

Immune Tolerance
Tumors
Target Idea

A

Tumors avoid immune system via variety of mechanisms; main one being recognized as “self”

Immune therapy; attempt to get immune system to recognize a tumor as something to destroy

72
Q

Immune Therapy

3 Kinds

A

Active Nonspecific - Immune Stimulation

Active Specific - Tumor Vaccines

Passive - Antibody Administration

73
Q

Immune Therapy

Active Nonspecific

A

Goal: immune stimulation

Intact bacteria (potent) of cell components

Chemical agents (COX-2 inhibitors, Levamisole)

Vitamins/minerals

Growth factors (activate lymphatics)

IL-2, IFN-alpha

74
Q

Immune Therapy

Active Specific

A

Vaccines

Genetically engineered antigen source designed to stimulate an immune response against established tumor

Increase immune reactivity to tumor antigens:
Cytokines
Molecules
Adjuvants

75
Q

Immune Therapy

Tumor Vaccine

A

Activate T-cells (increase MHC on cell surface)

Activate antigen presenting cells

Get the destruction stimulated!

76
Q

Melanoma Vaccine

A

Immune Therapy-Tumor Vaccine

Murine (mouse) Tyrosinase DNA: source of melanoma differentiated antigen

Licensed only for dogs with oral melanomas

77
Q

Immune Therapy
Passive Immunotherapy
Examples (2)

A

Monoclonal antibodies specific for tumor

Target specific antibodies: VEGF (ostesarcoma; HER-2)
RTK (Herceptin; breast cancer in humans)

More research needed

78
Q

Immune Therapy

Target T-regulatory Cells

A

Destroy immunosuppressive environment around tumor

May use conventional drugs (metronomic chemo, Cimetidine)

Cancer has made the immune system their b!tch and we are trying to stop that

79
Q

COX-2 Inhibitors
Piroxicam
Use

A

Osteosarcoma

Seen to shrink tumors

80
Q

Cyclooxygenase

What is it?

A

Key enzyme in conversion of arachidonic acid to prostanoids

COX-1 and COX-2

81
Q

COX-2

Where do you see this?

A 
Pro-inflammatory
Growth factors
Mitogenic substances
Oncogenes
Hypoxia
82
Q

COX-2 and Cancer
Specific target
Drug that targets this

A

Tumor promoting activities-PGE2

PGE2 Function:
Conversion of pro-carcinogens to carcinogens
Stimulation of tumor cell growth
Prevention of apoptotic cell death
Promotion of angiogenesis
Immune suppression

Note: Galliprant targets PGE2!

83
Q

COX-2 Expression in what tumors

A 
TCC
Renal cell carcinoma
Oral SCC
GI tumors
Mammary tumors
Nasal tumors
Ovarian Carcinomas
Prostatic Carcinomas
Canine intracranial meningiomas 
Canine melanoma (ocular and oral)
84
Q

Piroxicam Alone
What does it have?
What tumors?

A

COX-1 and COX-2

SCC oral cavity dogs and cats
Nasal tumors
Inflammatory mammary carcinoma (better than chemotherapy)

85
Q

Piroxicam plus Chemotherapy

What tumors?

A

Cisplatin for Oral SCC

Carboplatin for Oral non-tonsilar SCC

Metronomic cyclophosphamide for soft tissue sarcomas

86
Q

NSAIDs and Cancer Prevention?

A

71% tumor reduction in dogs receiving long term NSAID therapy

Carcinomas: 91% reduced
MCT: 94% reduced

Note: the higher the MCT grade the more COX-2 present

87
Q

COX-2 in Cats

Drug Examples

A

Meloxicam or Piroxicam

Note meloxicam could cause kidney issues so monitor this

88
Q

COX-2 in Cats

Tumor Examples

A

TCC
Oral/Cutaneous SCC
Mammary carcinoma
GI carcinomas

89
Q

COX-2 in Dogs

Drug Examples

A

Deracoxib

Fibrocoxib (Previcox)

90
Q

NSAID overall response to Cancer

A

Not curative but can help suppress growth

Small Animal Medicine II (17 decks)

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