Practical Oncology Principles of Chemotherapy

Transcription

1 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 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 1

2 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 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 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 injection Have 2 staff members calculate the dose, and compare A 60 lb dog is about 1m 2 = 0.6cc vincristine, 15cc doxorubicin, 40mg prednisone, 60mg CCNU, mg 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 ( 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 2

3 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 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) 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 3

4 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 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 ) Cyclophosphamide Dose: mg/m 2 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 Allopurinol an increase bone marrow toxicity Doxorubicin can increase cardiotoxicity Chloramphenicol, imipramine, phenobarbital, phenothiazines, KI, thiazide diuretics and vitamin A can enhance toxicity Injectable is good for 14 days if refrigerated, once mixed (label says 6 days) Chlorambucil Dose: mg/m 2 PO SID or QOD x 4 days, repeat q3 weeks If sterile cystitis in response to cyclophosphamide occurs, substitute chlorambucil 15 mg/m 2 PO SID x 4 days 6-8 mg/m2 PO QOD for chronic therapy in dogs & cats Indications: leukemias, myeloma, indolent lymphomas Liver toxicity, Pneumonitis Keep refrigerated Exterior coating is sweet keep away from pets and children 4

5 Lomustine Dose: mg/m 2 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/m 2 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 upset 5. Rare stomatitis, corneal ulcers or pneumonitis Melphalan Indications: LSA rescue (DMAC), myeloma, sarcoma, carcinoma, FIP Pneumonitis, pulmonary fibrosis Use with caution with kidney disease reduce dose by 50% neurotoxicity 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/m 2 PO SID x 5 days, repeat every 3 weeks Some add single dose cyclophosphamide 200 mg/m 2 IV Monitor globulins for response to therapy Also resolution of symptoms Lameness, bleeding diathesis, retinal lesions Melphalan CLL for cats 2 mg/m 2 PO QOD + prednisone 20 mg/m 2 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/m 2 IV over 10 minutes Indications: LSA Rescue, intracavitary injections for neoplastic effusions Urate stone formation in Dalmations Hearing loss with Liver toxicity Peripheral neuropathy weakness, ileus, constipation GI ulceration Sloughing if extravasated 5

6 Mustargen allopurinol dose may need to be increased 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/m 2 PO SID x 14 days Indications: LSA Rescue, GME, Brain tumors 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 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 OK to compound into capsules, but liquids must be oil based Dacarbazine Dose: 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 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 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. 6

7 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: mg/m 2 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 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 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/m 2 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 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 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 mg/m 2, unless cardioprotective drugs are given Check echocardiogram prior to each dose >150 mg/m 2 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) 7

8 Doxorubicin Extravasation Some believe you should take the dog right to surgery and cut out the red stuff Give Zinecard (dexrazoxane) mg/m 2 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 Mitoxantrone Blue Thunder Dose: mg/m 2 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 Use with caution in hepatic disease Conjunctivitis Jaundice, renal failure Irritation if extravasated Green-blue urine for up to 5 days Mitoxantrone Blue Thunder 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: mg/m 2 IV over 20 minutes, q2-3 weeks Premedicate with diphenhydramine and Cerenia Indications: LSA Rescue, OSA 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 Additive cardiotoxicity with doxorubicin Contraindications: hepatic dysfunction Dogs with MDR-1 deletion (reduce dose by 30%) use immediately and discard unused portion Platinum Drugs by intravenous drip Carboplatin (Paraplatin ) Cisplatin 8

9 Carboplatin Dose: mg/m 2 IV over 15 minutes q3 weeks in dogs mg/m 2 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 Anorexia or vomiting at 2-4 days Used cautiously if hepatic or renal disease Hearing impairment Carboplatin increased nephrotoxicity and ototoxicity of aminoglycosides Increased likelihood of MLV vaccine induced disease 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: mg/m 2 IV push Indications: LSA, leukemias, thrombocytopenia, TVT 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 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 keep refrigerated Vinblastine Dose: mg/m2 IV over 10 minutes Nausea, pallor, vomiting if given too fast Indications: LSA, MCT, carcinomas Developed to avoid vincristine associated neuropathy (dogs) More myelosuppressive than vincristine The rest like vincristine Nausea, vomiting for 24 hours Drug Interactions/Contraindications: same as vincristine keep refrigerated 9

10 Antimetabolites Cytarabine, cytosine arabinoside (Cytosar-U ) Methotrexate 5-Fluouracil Cytarabine Dose: mg/m 2 IV drip over 4 hours or SQ divided q1 hour x 4 Premedicate with Cerenia Indications: leukemias, CNS LSA, feline renal LSA More myelosuppression with IV administration stomatitis, conjunctivitis Rare liver toxicity Cytarabine May decrease absorption of digoxin for several days May decrease efficacy of gentocin good for 17 days after reconstituting if refrigerated hazy solution should be discarded. Tyrosine Kinase Inhibitors by mouth covered under lymphoma Palladia Kinavet Gleevex Serum panel/lytes and urinalysis every 3 months minimum on chemo patients Corticosteroids by mouth or by injection Prednisone Dexamethasone 10

11 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 Positive side effects antipyretic, anti-inflammatory, analgesic effects Inhibits platelet aggregation like aspirin Piroxicam COX inhibitors GI ulceration Renal papillary necrosis monitor especially in cats peritonitis 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/m 2 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 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 Reduced efficacy of methotrexate (wait 48 hours) Occasional marrow suppression when given with vincristine Contraindications: history of pancreatitis 11

12 L-Asparaginase 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, 7 th edition 12