Practical Oncology Principles of Chemotherapy

1. Practical Oncology Principles of Chemotherapy Wendy Blount, DVM

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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 dose Draw from the jugular vein

8. 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**

9. 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

10. 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 injection Have 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

11. 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)

12. 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

13. 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

14. Keep Refrigerated • Doxorubicin • Vincristine, Vinblastine • Elspar • Chlorambucil • Cytarabine once reconstituted • Dacarbazine None are damaged by refrigeration

15. MDR-1 Deletion White 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)

16. 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

17. 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

18. 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

19. 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 Longview for back ordered items

21. Alkylating Agents Orally or by IV injection or drip Efficacy not affected by route of administration • Cyclophosphamide (Cytoxan®, Neosar®) • Chlorambucil (Leukeran®) • Lomustine, aka CCNU (Ceenu®) • Melphalan (Alkeran®) • Mustargen (Mustine®) • Procarbazine (Matulane®) • Dacarbazine, (DTIC-Dome®)

22. 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: • 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 • Give with food to prevent stomach upset

23. 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)

24. 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

25. 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: • 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

26. 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 • Eliminated by the kidneys - Reduce dose in animals with kidney disease; possible renal toxicity • Give with food to reduce stomach upset • Rare stomatitis , corneal ulcers or pneumonitis

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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)

35. 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.

37. 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

38. 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

39. 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%

40. 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%)

41. 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

42. 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)

43. 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 days Doxorubicin is a double edged sword

44. 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

45. 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

46. 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

47. 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

48. Platinum Drugs by intravenous drip • Carboplatin (Paraplatin®) • Cisplatin

49. 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

50. 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