Cancer Treatments Flashcards
What to considerations do you need to consider prior to treatment?
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
Surgery
Benifit
Only way to actually remove cancer; cures more patients than any other modality
How to get appropriate staging
Surgery
Common mistake
Not taking large enough margins on first surgery (need wide margins; 3 cm of normal tissue)
Not submitting all tissues removed and marking margins
Surgery
What happens if tumor not completely excised?
Tumor will recur
Alters vascularity, immune system, and tissue planes => recurring tumors are more aggressive, subsequent surgeries more difficult
Surgery
Limitations
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
Radiation Therapy
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
Direct DNA Damage
Radiation therapy
Direct ionization
Chemical bonds broken through DNA; lethal damage and double stranded break
Indirect DNA Damage
Radiation therapy
Bonds broken through the ionization of water and the formation of damaging reactive radicals
Oxygen required to perpetuate damage
Radiation therapy
Limitations
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
What are the four R’s of Radiation Therapy
Repair
Repopulation
Re-oxygenation
Redistribution
Radiation Therapy
Repair
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
Radiation Therapy
Repopulation
Number of clonogenic tumor cells
Rely on epithelial cells; wound healing mechanisms
Radiation Therapy
Reoxygenation
Kills cancer cells
Oxic and hypoxic
Radiation Therapy
Redistribution
Given time post one dose of radiation all remaining cells move towards mitosis, and towards increased sensitivity
Radiation Therapy
Goal
Time period allowing reoxygen and redistribution in tumor, repopulation and repair in normal cells
Large total dose (tumor control)
Small fraction (less late effects)
Radiation Therapy
What are late effects?
Necrosis of tissues:
Bone, brain, etc.
Skin fibrosis
Alopecia, hyperpigmentation, cataracts
May not live long enough to get the late side effects
Radiation Therapy
Size of Tumor
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!)
Radiation Therapy
Acute effects
Fast dividing cells: Hair loss Moist dermatitis Mucositis (conjunctiva, oral cavity, nasal passages) Intestine or bladder inflammation Nervous tissue inflammation/edema
Radiation Therapy
Skin
No longer than 2-3 weeks
Hair loss, mild erythema of skin (no treatment needed)
Custing oozing skin; aloe vera, aquaphor, NSAIDs, pain medication
Radiation Therapy
Conjunctivitis
1-2 weeks
Antibacterial opthalmic ointment, NO steroids
Stereotactic Radiation Therapy
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
Chemotherapy
Mechanism
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
Chemotherapy
Alkylating Agents
Chlorambucil
Cyclophosphamide
Lomustine
Melphalan
Chemotherapy
Antimetabolites
Cystosine Arabinoside
Methotrexate
Elspar
Azothioprine
Chemotherapy
Antitumor Antibiotics
Bleomycin
Anthracyclines
Doxorubicin
Chemotherapy
Spindle Cell Poisons
Vinblastine
Vincristine
Taxols
Chemotherapy
Platinum drugs
Carboplatin
Cisplatin
Chemotherapy
Limitations
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
Chemotherapy
Rx: Kidney side effects
Cisplatin
Doxorubicin (cat)
Lomustine (chronic)
Chemotherapy
Rx: Heart side effects
Doxorubicin
Chemotherapy
Rx: Bladder side effects
Cyclophosphamide
Chemotherapy
Rx: Pancreas side effects
Elspar
Doxorubicin
Chemotherapy
Rx: Nervous system side effects
Vincristine 5 FU (cats!)
Chemotherapy
Rx: Hepatic side effects
Lomustine
Chemotherapy
Rx: Lung side effects
Cisplatin (cat)
Bleomycin
Lomustine
Chemotherapy Protocols
Multiple Drugs
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
Chemotherapy Protocols
Single Agent
Common because not much is known about efficacy of individual drugs
What neoplasias do soly using chemotherapy work for?
Lymphoma
Germ cell tumors
Transmissible venereal tumors
Neoplasia treatment recommendation
Surgery and Chemotherapy
Chemotherapy
Dose
BSA (m^2)
Too much can kill the patient
Chemotherapy
Monitoring
Timing
CBC
Chem
Careful venipuncture
Chemotherapy
Quick IV
Lateral saphenous or cephalic (dogs)
Medial saphenous (cats)
Butterfly or indwelling catheter
Chemotherapy
Slow administration
Infusion to decrease cardiac toxicity
Severe tissue reactions if extravasated (Doxorubicin)
Must clearly see vein
Flush with saline
Constant monitoring; someone sits with patient
Cyrotherapy
Only successful with tumor is small and superficial
SCC sometimes
Evaluation of Treatment Results
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
What are “macro” differences between cancer and normal cells?
Proliferative rates
DNA synthesis rates
Ineffecient repair of damage
Signal Transduction Therapy
What is it?
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?)
Signal Transduction
Cancer Physiology
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
Signal Transduction Therapy
Example
Receptor tyrosine kinases (RTKs)
Main mediators of the signaling network that transmit extracellular signals to the cell
Controls cellular differentiation and proliferation
RTKs
Mechanism
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
RTKs
Primary targets
EGFR-HER-2
c-Kit
VEGFR
What is EGFR-HER-2
RTK
Epidermal growth factor receptor
What is c-Kit
RTK
Proto-oncogene coding for RTK
What is VEGFR
RTK
Vascular endothelial growth factor receptor
Angiogenesis
c-Kit
Mutations
9-33% of MCTs have c-Kit mutations
Higher tumor grades associated with more frequent c-Kit mutations
Toceranib
What is it?
Response to Grade II
RTK Inhibitor: Palladia
Response to grade II: 42.8%
What neoplasias have RTKs been used in?
Thyroid carcinoma Anal gland adenocarcinomas Hemangiosarcoma Soft tissue sarcomas Lymphoma Histiocytic sarcoma Vaccine associated sarcomas
Angiogenesis
Background
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
Targeting tumor blood vessels
How?
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)
Targeting tumor blood vessels
What treatment modality cannot be used then?
Radiation because it needs the vascular oxygen supply to cause damage and to help normal cells develop
Targeting tumor blood vessels
Biologics
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
Targeting tumor blood vessels
Two categories
Biologics
Small molecules
Targeting tumor blood vessels
Small molecules
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
What is metronomic chemotherapy?
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
Metronomic chemotherapy Drugs used (4)
Chlorambucil
Cyclophosphamide
Lomustine
Satraplatin
Chlorambucil
Uses
TCC
MCT
Thyroid
Cyclophosphamide
Uses
Soft tissue sarcomas
MUST let animal outside often; will have to pee frequently or will cause bladder damage
Apoptosis
Two Pathways
Intrinsic (mitochondrial)
Extrinsic (receptors)
Apoptosis
Intrinsic Pathway
Affected by conventional therapies (Radiation and other traditional Chemos)
Mutations commonly occur rendering tumors resistant to conventional therapies
Apoptosis
Extrinsic Pathway
Novel therapies targeting here may circumvent resistance
Caution; could cause all cells to apoptose
Immune Tolerance
Tumors
Target Idea
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
Immune Therapy
3 Kinds
Active Nonspecific - Immune Stimulation
Active Specific - Tumor Vaccines
Passive - Antibody Administration
Immune Therapy
Active Nonspecific
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
Immune Therapy
Active Specific
Vaccines
Genetically engineered antigen source designed to stimulate an immune response against established tumor
Increase immune reactivity to tumor antigens:
Cytokines
Molecules
Adjuvants
Immune Therapy
Tumor Vaccine
Activate T-cells (increase MHC on cell surface)
Activate antigen presenting cells
Get the destruction stimulated!
Melanoma Vaccine
Immune Therapy-Tumor Vaccine
Murine (mouse) Tyrosinase DNA: source of melanoma differentiated antigen
Licensed only for dogs with oral melanomas
Immune Therapy
Passive Immunotherapy
Examples (2)
Monoclonal antibodies specific for tumor
Target specific antibodies: VEGF (ostesarcoma; HER-2)
RTK (Herceptin; breast cancer in humans)
More research needed
Immune Therapy
Target T-regulatory Cells
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
COX-2 Inhibitors
Piroxicam
Use
Osteosarcoma
Seen to shrink tumors
Cyclooxygenase
What is it?
Key enzyme in conversion of arachidonic acid to prostanoids
COX-1 and COX-2
COX-2
Where do you see this?
Pro-inflammatory Growth factors Mitogenic substances Oncogenes Hypoxia
COX-2 and Cancer
Specific target
Drug that targets this
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!
COX-2 Expression in what tumors
TCC Renal cell carcinoma Oral SCC GI tumors Mammary tumors Nasal tumors Ovarian Carcinomas Prostatic Carcinomas Canine intracranial meningiomas Canine melanoma (ocular and oral)
Piroxicam Alone
What does it have?
What tumors?
COX-1 and COX-2
SCC oral cavity dogs and cats
Nasal tumors
Inflammatory mammary carcinoma (better than chemotherapy)
Piroxicam plus Chemotherapy
What tumors?
Cisplatin for Oral SCC
Carboplatin for Oral non-tonsilar SCC
Metronomic cyclophosphamide for soft tissue sarcomas
NSAIDs and Cancer Prevention?
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
COX-2 in Cats
Drug Examples
Meloxicam or Piroxicam
Note meloxicam could cause kidney issues so monitor this
COX-2 in Cats
Tumor Examples
TCC
Oral/Cutaneous SCC
Mammary carcinoma
GI carcinomas
COX-2 in Dogs
Drug Examples
Deracoxib
Fibrocoxib (Previcox)
NSAID overall response to Cancer
Not curative but can help suppress growth
