Practical Oncology Principles of Chemotherapy

Wendy Blount, DVM

Indications for Chemotherapy

Systemic or metastatic disease that is chemo responsive• local control (surgery, radiation therapy) isn’t adequate • Cure is rare (TVT is an exception)• Remission or prolonged stable disease is likely

• Months to years• Prepare owners for relapse that will ultimately be unmanageable

Neo-adjuvant therapy• Reducing size of large, localized tumor prior to surgery

Dirty borders on localized tumor Increased survival time without decreasing quality of life

Metronomic Therapy

Fewer side effects than high dose treatment Cyclophosphamide and piroxicam to prevent recurrence of

sarcomas• Cyclophosphamide 10 mg/m2 PO SID or QOD• Piroxicam 0.3 mg/kg PO SID or QOD

Take care that the pet is not also on prednisone

Low dose chlorambucil is also considered metronomic

Side Effects Make sure clients understand that chemo protocols for

animals are much less aggressive than for people• Side effects are assumed to be present and possibly severe for

people• Many pets who undergo chemotherapy have infrequent side

effects that are often mild Chemo drugs kill or harm cells that divide rapidly

• Gastrointestinal tract, bone marrow, skin and hair The most common side effects are gastrointestinal,

pancytopenias (mostly WBC) and changes in fur Dogs may be unable to reproduce after chemotherapy

Side Effects

GI Toxicity Direct damage to epithelial cells

• 3-5 days after chemo Direct stimulation of the chemoreceptor trigger zone

• 24-48 hours after chemo Both - inappetance, nausea, vomiting, diarrhea

• Can vary from a few soft stools to parvovirus-like disease Dispense Cerenia and Metronidazole at the first treatment

if you anticipate a problem with getting the meds on the day needed

Side Effects

Bone Marrow Toxicity Direct damage to stem cells Neutrophils have shortest life, so they are affected first Then other WBC, platelets and RBC Delay chemo if Neutrophils <2,000/ul

• recheck CBC 3-7 days Antibiotic therapy if fever or neutrophils <1,000/ul GCSF (Neupogen®) if neutrophils <500/ul IV fluids and IV antibiotics only if septic

• Placing an IV catheter in an asymptomatic neutropenic dog can result in infection or sepsis

Side Effects

Bone Marrow Toxicity Delay chemo if platelets <50,000, unless Tpenia is thought

to be caused by neoplasia If cytopenia, delay treatment by 3-7 days and reduce dose

by 20-25% when resumed• Most chemo delay by 3-7 days• Lomustine*, doxorubicin, cyclophosphamide*, chlorambucil

delay at least 7 days

CBC the day of and prior to every chemo doseDraw from the jugular vein

Side Effects

Bone Marrow Toxicity Nadirs – recovery usually within 7 days (*these drugs longer)

Not usually myelosuppressive – L-asparaginase 4-6 days - methotrexate 5-7 days - cytarabine 7-10 days – doxorubicin*, mustargen, procarbazine 10 days – mitoxantrone 7-14 days – chlorambucil*, cyclophosphamide** 14 days – carboplatin (cats 17-21 days) 7-21 days – lomustine**

Side Effects

Hair Loss Fur might thin or change color, but complete hair loss is

rare Fur loss is more common with non-shedding dogs such as

poodles and terriers• Their fur continuously grows

Cats may lose guard hairs or whiskers

Overdose

Be very careful to use kg not lb when converting body weight to Body Surface Area.

Using lb will result in 2x chemotherapy dose If given PO, induce vomiting immediately This mistake is almost always fatal if given by injectionHave 2 staff members calculate the dose, and compare

A 60 lb dog is about 1m2 = 0.6cc vincristine, 15cc doxorubicin, 40mg prednisone, 60mg CCNU, 200-250mg cyclophosphamide (8-10 small tablets, 4-5 large tablets)

1 vial Elspar

Patient Care

Chemotherapy patients should never be given MLV vaccines (risk of post-vaccinal infection)

Vaccinations with killed vaccines (rabies) should be fine Clients should be furnished with gloves to wear

• For administering chemo pills• for cleaning up pet eliminations• When sitting with animals during IV drips

Always provide a written educational handout for each drug given (http://wendybount.com)

Safe Handling

Order liquid injectables rather than those that must be reconstituted• Doxorubicin, vincristine, vinblastine, carboplatin, mitoxantrone

Have oral chemo doses professionally compounded ALWAYS WEAR GLOVES!!

• Chemo gloves or double latex gloves Wear a respirator mask if you must reconstitute powders

• Cytosar-U, Actinomycin-D, dacarbazine (not Elspar) Inject bubbles out of the syringe prior to removing the

needle from the vial Put anything that touched the drug in biohazard disposal

Safe Handling

Reconstitute drugs in a biological safety cabinet• Have your local pharmacist do it for you

Use venting devices or drug filters to avoid aerosolization when withdrawing needle from the vial

Wear an isolation gown, buttoned lab coat, etc. Wear eye protection Oncology nurses have higher incidence of

• headaches and nausea• Skin irritation• Chromosomal, bone marrow and liver damage• Miscarriage and cancer

Keep Refrigerated

Doxorubicin Vincristine, Vinblastine Elspar Chlorambucil Cytarabine once reconstituted Dacarbazine

None are damaged by refrigeration

MDR-1 DeletionWhite Feet – Don’t Treat Test for MDR1 deletion before giving these drugs to

collies: (form)• Doxorubicin, D-actinomycin• Vincristine, Vinblastine

Do not give drugs that inhibit p-glycoprotein concurrently• Comfortis or Trifexis• Ca++ channel blockers (amioderone, diltiazem, verapamil,

carvedilol)• Azole antifungals• Cyclosporin• Lincosamides (azithromycin, clarithromycin, erythromycin)

IV Push Chemotherapy For drugs that are given IV quickly -

• Vincristine, mitoxantrone Flush butterfly catheter (19-22 gauge) with sterile fluid compatible

with the drug• Place it on the glove envelope used as sterile field

Predraw syringes – two 4-6cc fluid for flush, plus drug; remove needles and place on sterile field

Clip and gently clean the skin Assistant occludes and rolls the vein, to release when instructed Place butterfly catheter on clean stick, do not tape Flush/test, inject drug, flush/test Remove butterfly catheter and bandage leg

IV Drip Chemotherapy

For drugs that are given IV slowly – more than a minute or two• Doxorubicin, mustargen, actinomycinD, carboplatin, (vinblastine)

Attach buretrol and IV line to compatible IV fluid bag and hang

Draw up chemo to be given Clip and gently clean the skin Place and secure IV catheter on clean stick

IV Drip Chemotherapy

Trained trusted assistant sits with dog during drip• If any problems, stop drip and then get help

Run 20-50cc fluids into Buretrol and run into patient to test line patency• If problems, place another catheter

Add chemo drug to Buretrol and qs to 2ml/minute• e.g., vinblastine given over 10 minutes, qs to 20 ml

Run 2-3 aliquots of 10-20cc IV fluids into the buretrol and then into the patient, until fluid runs clear when drug is colored

Remove IV catheter and bandage

Wicked Expensive Drugs

Mustargen (<$700 for a 4-pack) Palladia and Kinavet (>$500 a month for medium dog) Gleevex ($100 a pill) Procarbazine (>$1000 last time I checked) Doxil – liposomal doxorubicin – 20x cost of doxorubicin

Try Diamondback Pharmacy for all but TKIs

Try Medshoppe Pharmacy in Longviewfor back ordered items

Alkylating Agents

Orally or by IV injection or dripEfficacy not affected by route of

administration Cyclophosphamide (Cytoxan®, Neosar®) Chlorambucil (Leukeran®) Lomustine, aka CCNU (Ceenu®) Melphalan (Alkeran®) Mustargen (Mustine®) Procarbazine (Matulane®) Dacarbazine, (DTIC-Dome®)

Cyclophosphamide

Dose: 200-250 mg/m2 PO or IV• Can give in one dose, or divide into 3-5 daily doses

Indications: LSA, leukemias, carcinomas, sarcomas Unique side effects:

1. Can cause sterile hemorrhagic cystitis (CIC)• Can predispose to transitional cell carcinoma• If not on prednisone, add furosemide 1 mg/lb given with each

cyclophosphamide dose• Negative urine culture diagnoses CIC• If cystitis, discontinue and replace with chlorambucil • Give in the morning & encourage frequent bladder emptying

2. Give with food to prevent stomach upset

Cyclophosphamide

Unique side effects:• Rarely can cause pneumonitis• Cleared by liver and kidneys – use with caution in pets with liver

or kidney disease Drug Interactions:

• Allopurinol an increase bone marrow toxicity• Doxorubicin can increase cardiotoxicity• Chloramphenicol, imipramine, phenobarbital, phenothiazines, KI,

thiazide diuretics and vitamin A can enhance toxicity Handling: Injectable is good for 14 days if refrigerated,

once mixed (label says 6 days)

Chlorambucil

Dose: 15-20 mg/m2 PO SID or QOD x 4 days, repeat q3 weeks• If sterile cystitis in response to cyclophosphamide occurs,

substitute chlorambucil 15 mg/m2 PO SID x 4 days• 6-8 mg/m2 PO QOD for chronic therapy in dogs & cats

Indications: leukemias, myeloma, indolent lymphomas Unique Side Effects: Liver toxicity, Pneumonitis Handling:

• Keep refrigerated• Exterior coating is sweet – keep away from pets and children

Lomustine Dose: 60-70 mg/m2 PO, q3-4 weeks

• Doses of 90 mg/m2 are published, but Barton says she has never given this high dose without sepsis

• Kevin Hahn uses 40 mg/m2 every 2 weeks• Premedicate with diphenhydramine

Indications: MCT, LSA Rescue, histiocytic sarcoma, CNS tumors, canine skin lymphoma

Unique Side effects: 1. Prolonged and cumulative myelosuppression

• No other chemo for 3-4 weeks• First dose should have a 4 week treatment interval• If subsequent doses show recovery by 3 weeks, interval can be reduced

to 3 weeks

Lomustine

Unique Side effects:2. Can cause hepatotoxicity

• Serum panel prior to the first dose• Bile acids if significant liver disease is suspected• Choose another drug if bile acids significantly elevated• Check panel prior to third dose and every other dose thereafter• Discontinue if and when ALT climbs or albumin falls significantly• Often discontinued after 6-12 doses• SAMe and silymarin may mediate hepatotoxicity

3. Eliminated by the kidneys - Reduce dose in animals with kidney disease; possible renal toxicity

4. Give with food to reduce stomach upset5. Rare stomatitis , corneal ulcers or pneumonitis

Melphalan

Indications: LSA rescue (DMAC), myeloma, sarcoma, carcinoma, FIP

Unique Side Effects: • Pneumonitis, pulmonary fibrosis• Use with caution with kidney disease – reduce dose by 50%• neurotoxicity

Drug Interactions:• Kidney toxicity when used with cyclosporine

Melphalan

Multiple Myeloma Protocol, with prednisone• 0.1 mg/kg PO SID x 10 days, then 0.05 mg/kg PO QOD

thereafter• Prednisone 0.5 mg/kg PO SID x 10d, then QOD

Or Pulse Therapy• 7 mg/m2 PO SID x 5 days, repeat every 3 weeks

Some add single dose cyclophosphamide – • 200 mg/m2 IV

Monitor globulins for response to therapy• Also resolution of symptoms

• Lameness, bleeding diathesis, retinal lesions

Melphalan

CLL for cats – 2 mg/m2 PO QOD + prednisone 20 mg/m2 QOD

Any chronic melphalan therapy• CBC q2 weeks x 2 times• Then once a month

Also comes as an injectable – different protocol

Mustargen

Dose: 3 mg/m2 IV over 10 minutes Indications: LSA Rescue, intracavitary injections for

neoplastic effusions Unique Side Effects:

• Urate stone formation in Dalmations• Hearing loss with • Liver toxicity• Peripheral neuropathy – weakness, ileus, constipation• GI ulceration• Sloughing if extravasated

Mustargen

Drug Interactions: allopurinol dose may need to be increased

Handling: • Mix and administer immediately – it is inactive within an hour• Draw up dose and dilute to 12 ml with saline• Then give IV over 10 minutes

Procarbazine

Dose: 50 mg/m2 PO SID x 14 days Indications: LSA Rescue, GME, Brain tumors Unique Side Effects:

• Use with caution with liver disease, kidney disease, heart disease, urate stones

• Nausea – give concurrently with Cerenia• Neurotoxicity – seizures, ataxia• Peripheral neuropathy – ileus, constipation, stumbling• stomatitis

Procarbazine

Drug Interactions: • Potentiates activity of CNS depressants

• anticonvulsants, opiates, sedatives, antihistamines, antihypertensives, tricyclic antidepressants

• Serious hypertension if given with sympathomimetics• Phenylpropanolamine

• Avoid foods high in tyramine – aged cheese, yogurt, bananas Contraindications: any of the above drugs Handling: OK to compound into capsules, but liquids

must be oil based

Dacarbazine

Dose: 800-1000 mg/m2 IV over 5-8 hours q2-3 weeks• Pretreat with Cerenia• Pretreat with dexamethasone to prevent phlebitis• Pretreat with opiate to prevent pain on IV infusion

Indications: LSA Rescue, ST sarcoma, melanoma Unique Side Effects:

• Serious extravasation injury, like Actinomycin D• Hepatoxicity and nephrotoxicity - use with caution with hepatic

or renal disease• Photosensitivity• Dilute to prevent pain on IV infusion (D5W or saline)

Dacarbazine

Contraindications: not for use in cats, as there is no evidence cats can metabolize it in the liver

Handling: • Keep refrigerated• Use within 8 hours of reconstituting at room temperature and 72

hours if refrigerated• I do not use this drug, as it is causes severe injury on

extravasation and I can not have a tech sit with a dog for 5-8 hours to manage an IV drip. It may work well in a practice with ICU supervision.

Antitumor Antibiotics

by intravenous drip Doxorubicin (Adriamycin®) Mitoxantrone (Novantrone®) Actinomycin-D, dactinomycin (Cosmegen®) Bleomycin (Doxycycline)

• Decreases metalloproteinases, which break down intracellular matrix allowing tumor invasion

• Antioangiogenic effects

Doxorubicin – “Red Death” Dose: 20-30 mg/m2 IV over 20 minutes, q2-3 weeks

• Premedicate with diphenhydramine and Cerenia• 1 mg/kg if less than 15 kg

Indications: LSA, leukemia, carcinomas, sarcomas Unique Side Effects:

• Severe necrosis leading to amputation or death due to cardiotoxicity if extravasated

• More likely to cause GI signs and malaise than the other drugs in CHOP protocols• Often the last drug to lose effectiveness in CHOP

• Toxicity can be somewhat cumulative – may need to reduce dose with time

• Prolonged myelosuppression – check CBC at 10 days post Tx

Doxorubicin – “Red Death” Unique Side Effects:

• Hypersensitivity – allergy to one brand may not be to others• Cardiotoxicity

• Acute cardiotoxicity – cardiac arrest during or several hours after chemotherapy

• Cumulative cardiotoxicity precludes further use of doxorubicin• can occur as low as 90 mg/m2 total dose• 6% of dogs with 5+ doses

• Nephrotoxicity in cats• monitor BUN, creat, phos• Urinalysis - casts

• Increased toxicity in dogs with MDR-1 Deletion• Reduce dose by 30%

Doxorubicin – “Red Death” Drug Interactions:

• Actinomycin-D and Ca channel blockers increase cardiotoxicity• Diltiazem• Verapamil

• Cyclophosphamide, cyclosporine increase doxorubicin levels• Phenobarbital & glucosamine may reduce doxorubicin levels

Contraindications: • Myocardial failure

• echocardiogram prior to giving doxorubicin to Dobermans, Great Danes and Boxers or if heart murmur

• Dogs and Cats with renal failure• Dogs with MDR-1 deletion (reduce dose by 30%)

Doxorubicin – “Red Death” Handling:

• refrigerate and protect from light• Irritating to the skin – wash well if exposed

Special Client Communications: • Prior permission to take immediately to surgery if extravasated• Warn of cardiotoxicity – acute and cumulative• GET PERMISSION TO USE THIS DANGEROUS DRUG

Doxorubicin – “Red Death”

Lifetime Total Dose: • should not exceed 180-200 mg/m2, unless cardioprotective

drugs are given• Check echocardiogram prior to each dose >150 mg/m2

• Should never exceed 240 mg/m2, or cardiotoxicity is likely Liposomal doxorubicin (Doxil)

• Reduces cumulative cardiotoxicity• Can be used after total lifetime doxorubicin dose has been

reached• Cost is 20x that of native doxorubicin

Overcoming resistance with dacarbazine (see LSA Rescue Handout)

Doxorubicin Extravasation

Some believe you should take the dog right to surgery and cut out the red stuff

Give Zinecard (dexrazoxane) 150-300 mg/m2 IV within 2-3 hrs of extravasation through a different IV catheter

Repeat at 24 and 48 hours Zinecard can near 100% protection from slough and acute

fatal cardiotoxicity Ice pack 15 minutes every 6 hours for 48 hours Apply DMSO 99% to area 2x extravasation q6hrs x 14

daysDoxorubicin is a double edged sword

Mitoxantrone – “Blue Thunder”

Dose: 5-6.5 mg/m2 IV every 2-3 weeks Indications: LSA, carcinomas, hemangiopericytoma

• Safer for cats with renal failure than doxorubicin• Combining with dacarbazine (DTIC) may increase effectiveness

for rescue therapy Unique Side Effects:

• Use with caution in hepatic disease• Conjunctivitis• Jaundice, renal failure• Irritation if extravasated• Green-blue urine for up to 5 days

Mitoxantrone – “Blue Thunder”

Drug Interactions:• Increased dose of allopurinol may be needed• Enhanced cardiotoxicity if previous doxorubicin, daunorubicin or

radiation therapy• Precipitates in contact with heparin

Contraindications: myocardial failure, though cardiotoxicity not yet reported in dogs as in people

Actinomycin-D

Dose: 0.5-1 mg/m2 IV over 20 minutes, q2-3 weeks• Premedicate with diphenhydramine and Cerenia

Indications: LSA Rescue, OSA Unique Side Effects:

• Necrosis if extravasated • GI ulceration or stomatitis• Increases uric acid – avoid in urate stone formers• Possible hepatotoxicity – monitor liver enzymes every 2-3 doses• Cardiotoxicity – echo after 4-6 doses

Actinomycin-D

Drug Interactions: • Additive cardiotoxicity with doxorubicin

Contraindications: • hepatic dysfunction• Dogs with MDR-1 deletion (reduce dose by 30%)

Handling: use immediately and discard unused portion

Platinum Drugs

by intravenous drip Carboplatin (Paraplatin®) Cisplatin

Carboplatin

Dose: • 300-350 mg/m2 IV over 15 minutes q3 weeks in dogs• 180-260 mg/m2 IV over 15 minutes q3-4 weeks in cats• Has been given intratumorally for nasal planum SCC in cats• Intracavitary for mesothelioma

Indications: carcinomas (not TCC), sarcomas, OK for cats

Unique Side Effects:• Anorexia or vomiting at 2-4 days• Used cautiously if hepatic or renal disease• Hearing impairment

Carboplatin

Drug Interactions: • increased nephrotoxicity and ototoxicity of aminoglycosides• Increased likelihood of MLV vaccine induced disease

Handling: • dilute in D5W, saline or sterile water• Once reconstituted, use within 8 hours• Black precipitate will form if it comes into contact with aluminum

Vinca Alkaloids

by intravenous injection or drip Vincristine (Oncovin®) Vinblastine (Velban®)

Vincristine

Dose: 0.5-0.75 mg/m2 IV push Indications: LSA, leukemias, thrombocytopenia, TVT Unique Side Effects:

• Peripheral neuropathy - ileus, constipation, dropped hocks• Slough if extravasated (not as severe as doxorubicin)

• Infiltrate with dexamethasone or DMSO• Rare severe GI side effects in cats• Reduce dose by 50% if icteric (cats with LSA can be)• Use with caution with liver or musculoskeletal disease• Reduce dose by 25-30% in MDR1 deletion dogs

Vincristine

Drug Interactions: • Toxicities increased by drugs that inhibit p-glycoprotein• Comfortis or Trifexis• Ca++ channel blockers (amioderone, diltiazem, verapamil,

carvedilol)• Azole antifungals• Cyclosporin• Lincosamides (azithromycin, clarithromycin, erythromycin)

Contraindications: severe liver disease Handling: keep refrigerated

Vinblastine

Dose: 2-2.2 mg/m2 IV over 10 minutes• Nausea, pallor, vomiting if given too fast

Indications: LSA, MCT, carcinomas• Developed to avoid vincristine associated neuropathy (dogs)

Unique Side Effects: • More myelosuppressive than vincristine• The rest like vincristine• Nausea, vomiting for 24 hours

Drug Interactions/Contraindications: same as vincristine

Handling: keep refrigerated

Antimetabolites Cytarabine, cytosine arabinoside (Cytosar-U®) Methotrexate 5-Fluouracil

Cytarabine

Dose: 200 - 300 mg/m2 IV drip over 4 hours or SQ divided q1 hour x 4• Premedicate with Cerenia

Indications: leukemias, CNS LSA, feline renal LSA Unique Side Effects:

• More myelosuppression with IV administration• stomatitis, conjunctivitis• Rare liver toxicity

Cytarabine

Drug Interactions: • May decrease absorption of digoxin for several days• May decrease efficacy of gentocin

Handling: • good for 17 days after reconstituting if refrigerated• hazy solution should be discarded.

Serum panel/lytes and urinalysisevery 3 months minimum on chemo patients

Tyrosine Kinase Inhibitors

by mouth – covered under lymphoma Palladia® Kinavet® Gleevex®

Corticosteroids

by mouth or by injection Prednisone Dexamethasone

NSAIDs

by mouth or by injection Piroxicam (Feldene®)

• Cancer cells express cyclo-oxygenases that form prostaglandins

• Prostaglandins of the E2 series inhibit NK cells• NK cells kill cancer cells• COX-2 inhibitors and other COX inhibitors inhibit

formation of the PGE2 series• They remove inhibition of NK cells by cancer cells

Deramaxx® Previcox®

Piroxicam – COX inhibitors

Dose: 0.3 mg/kg PO SID to QOD• Little data, but some believe any COX inhibitor is just as good• Carprofen (Rimadyl®), meloxicam (Metacam®), Zubrin®,

Oncior®, etc.• No studies of antineoplastic effects in cats

Indications: • carcinomas, sarcomas• Generally not LSA or MCT because those are on pred

Unique Side Effects: • Positive side effects – antipyretic, anti-inflammatory, analgesic

effects• Inhibits platelet aggregation like aspirin

Piroxicam – COX inhibitors

Unique Side Effects:• GI ulceration• Renal papillary necrosis – monitor especially in cats• peritonitis

Drug Interactions:• do not give with corticosteroids or furosemide• Displaces protein bound drugs to increase toxicity –

aminoglycosides, anticoagulants, sulfas, phenytoin Contraindications: serious toxicity when NSAIDs used

with methotrexate

Enzymes L-Asparaginase (Elspar®)

L-Asparaginase MOA:

• To make a cancer drug, some fundamental difference between cancer cells and normal cells must be defined and exploited

• Lymphoproliferative tumors require huge amounts of asparagine to support tumor growth, and lack L-asparaginase synthetase

• Asparaginase is an enzyme that breaks down asparagine• Tumor cells become depleted and rapidly die

Dose: 10,000 U/m2 SC, IM, IV (max dose 1 vial)• Pretreat with diphenhydramine

Indications: Lymphoma, MCT• When bone marrow is compromised , bulky disease or ALL• Works only 2-3 times in most cases

L-Asparaginase

Unique Side Effects:• IV administration increases risk of anaphylaxis• Induction of hepatic encephalitis in patients with liver failure• Rare coagulopathy or hepatotoxicity• Hyperglycemia and dysregulation in diabetics• Thyroid suppression for 4 weeks

Drug Interactions: • Reduced efficacy of methotrexate (wait 48 hours)• Occasional marrow suppression when given with vincristine

Contraindications: history of pancreatitis

L-Asparaginase

Handling: • no special handling is necessary as other chemo drugs• Keep refrigerated• Once reconstituted, good for 8 hours – 14 days• Discard turbid solutions• Dilute with D5W or sodium chloride – volume not crucial• Avoid shaking vigorously – becomes foamy and difficult to inject

Acknowledgements

Ruthanne Chun, BS, DVM, DACVIM(Oncology) UW Madison School of Vet Med, Madison, WI

Plumb Veterinary Drug Handbook, 7th edition