type of cancer

stage of disease

general health (co-morbidity, physiologic status)

time commitment

cost (e.g. time off work)

tolerance for side effects

induction, consolidation, maintenance

adjuvant (after primary treatment) vs. neoadjuvant

radiation potentiation

single

less cost

less toxicity (in theory)

less time

increased drug resistance

less efficacy

multiple

more efficacious

less resistance

more cost

potential for greater toxicity

more time

• give maximal dose (kill cancer without killing patient cells)
• each drug should be effective alone
• avoid overlapping toxicities
• use drugs with different MOAs

pharmacokinetic

absorption

distribution (e.g. obesity alters distribution in protein-bound drugs)

metabolism

excretion

drug interactions

pharmacodynamic

dose-response

prior therapy

age, performance status, comorbidity

genetic

death of tumor vs. recovery of normal cells

efficacy=concentration x time

sustained release

intra-cavitary

intra-arterial (avoid first-pass metabolism)

decreased uptake (e.g. diseased GI tract)

decreased biotransformation/activation

increased inactivation (glutathione)

altered affinity of drug to target

increased repair of damage

increase in alternative pathways

increased concentration of drug target

apoptosis/cell death modulation

increased removal of drug from cells (p-glycoprotein)

• neutropenia, thombocytopenia, anemia
• (always check CBC before giving chemo drugs!!!)
• nadir:  low point of WBC depression post-chemo (usually 7-10 days after treatment)

blood work

radiograph lungs for pneumonia

urinalysis

blood culture (generally not in animals)

look for underlying infection (but may be difficult)

IV fluids

IV broad-spectrum antibiotics

colony stimulating factors (GCSF)

general supportive care (be aggressive)

• <2000 neuts, no fever, no clinical signs:  delay chemo
• <1000 neuts, no fever, no clinical signs:  delay chemo, prophylactic abx, monitor at home
• <2000 neuts, fever present, no clinical signs:  delay chemo, abx, monitor at home
• <1000 neuts, fever present, clinical signs present:  delay chemo, hospitalize, intensive care

nausea/vomiting

• usually delayed 2-3 days after chemo, occ. acute
• most common sign noticed by owners
• usually self-limiting
• treat with antiemetics, may need IV fluids if severe

diarrhea

• usually delayed 3-5 days post-chemo
• colitis
• treat with supportive care

urticaria, pruritis, head shaking, vomiting, diarrhea, collapse (possible anaphylaxis)

L asparagenase, doxorubicin

• most common with doxorubicin
• cumulative dose-dependent
• dilated cardiomyopathy/CHF
• predisposing factors:  age (young/old), previous chest radiation, breed (Boxers, Rotties, Dobs, Labs)

cytoxam metabolite acrolein causes irritation to bladder in <10% of patients

can give lasix at same time to prevent

if suspected, draw back and remove any residual drug if possible

doxorubicin:  cold pack, zenicard

vincristine:  warm pack

signs will occur in 1-10 days (tissue sloughing)

breed dependent (breeds with continually-growing hair)

cats lose their whiskers

drug-dependent

hair can come back a different color/texture

axonal degeneration, demyelization

peripheral (loss of sensory and motor)

pain, tingling, numbness

deafness

cross-link DNA

cell cycle non-specific

alkylating agent

IV, oral

must be metabolized in liver to be active

sterile hemorrhagic cystitis

LSA, sarcomas, MGT, MCT

alkylating agent

oral only

delayed onset of action

cerebellar toxicity?

CLL, LSA, MCT

alkylating agent

oral (IV in humans)

multiple myeloma

cytoxan

chlorambucil

melphalan

CCNU

alkylating agent

old drug

oral only

highly lipophilic, crosses BBB

passive diffusion into cells

myelosuppression, persistent thrombocytopenuia, possible liver toxicity

antimetabolite (inhibits DNA polymerase)

IV, SQ

crosses BBB

BAG side effects

Bone marrow suppression

Alopecia

Gastrointestinal

form stable complexes with DNA, inhibit DNA/RNA synthesis

cell cycle non-specific

BAG side-effects

intercalates DNA, free radical formation, topoisomerase II inhibitor

IV (heparin inactivates)

BAG

allergic reaction and colitis due to mast cell degranulation and histamine release

severe vessicant

dogs:  cardiac toxicity, arrhythmias

cats:  renal toxicity

dose reduction for smaller animals (<20kg)

Wide use in vet med:  LSA, OSA, HAS, MGT, thyroid, sarcomas

antibiotic

IV

BAG, no cardiac toxicity

LSA, TCC, SCC

antibiotic chemo

IV

BAG

LSA, sarcomas

doxorubicin

mitoxantrone

actinomycin D

vincristine

vinblastine

plant-derived chemo drug

interferes with tubulin formation/function

IV-vessicant

BAG

less neurotoxicity

LSA, MCT

plant-derived chemo drug

inhibits formation of mitotic spindle

cell cycle specific

IV-vessicant

AG, minimal bone marrow suppression

peripheral neuropathy, constipation

LSA, MCT, TVT (cures it), platelet release from bone marrow

chemo drug

inhibits asparagine synthetase and depletes asparagine in tumor cells

IM, IP, SQ

anaphylaxis, pancreatitis, DIC

LSA

chemo drug

intra and interstrand DNA cross-links

IV, polymer delivery systems

BAG (acute), neurotoxicity, ototoxicity, nephrotoxicity (must diurese before and after giving)

cats:  pulmonary toxicity (FATAL, DO NOT USE!!)

OSA, TCC, nasa, SCC, testicular, ovarian

chemo drug

intra and interstrand DNA cross-links

IV, IC

BAG, nephrotoxicity (rare), neurotoxicity

OSA, TCC, carcinomas

alternative delivery systems (polymers, inhaled, liposomes)

gene therapy

immunomodulation

anti-angiogenic compounds

targeted therapies (small molecules, signal transduction inhibitors)

metronomic therapy (non cytotoxic, targets tumor angiogenesis)