veterinary, chemotherapy, medicine

1. Common Chemotherapy
Medications and Side
Effects
Jennifer Mahoney, DVM, DACVIM (Oncology)
Upstate Veterinary Specialties
October 10, 2015

2. Presentation Outline
◦General Chemotherapy Side Effects and Complications
◦Gastrointestinal
◦Bone Marrow Suppression
◦Extravasation
◦Acute Tumor Lysis Syndrome
◦Drug Classes and Specific Side Effects
◦Vinca Alkaloids
◦Alkylating Agents
◦Platinum Agents
◦Anthracycline Antibiotics
◦Antimetabolites
◦Tyrosine Kinase Inhibitors

3. Chemotherapy Overview
◦Drugs target dividing cells and interfere with cell cycle
◦S Phase (DNA replication)
◦M Phase (Mitosis)
G1
S
G2
M DNA SynthesisMitosis

4. Chemotherapy Overview
◦Rapidly-dividing cells are most susceptible
◦Cancer Cells
◦Gastrointestinal epithelial cells
◦Bone marrow cells
◦Hair follicles of certain breeds

5. Gastrointestinal Side Effects
◦Nausea and Vomiting
◦Decreased Appetite
◦Diarrhea
www.clipartsheep.com

6. Gastrointestinal Side Effects
◦Direct Damage
◦Rapidly-dividing GI mucosal cells
◦2-5 days post-treatment
◦Stimulation of the CRTZ
◦Acute nausea
◦Cisplatin
◦DTIC
◦Streptozotocin
◦Ileus
◦Vincristine
library.med.utah.edu

7. Gastrointestinal Side Effects
◦Veterinary Cooperative Oncology Group Grading Scheme for Vomiting

8. Gastrointestinal Side Effects
◦Treatment
◦ Cerenia (Maropitant)
◦ NK1 inhibitor
◦ Reglan (Metoclopramide)
◦ Stimulates GI motility
◦ Useful for Vincristine-related Ileus
◦ Zofran (Ondansetron) and Dolasetron (Anzemet)
◦ 5-HT3 receptor antagonists
◦ Appetite stimulants: Mirtazapine or Cyproheptadine
◦ Metronidazole
◦ Fluids

9. Bone Marrow Suppression
◦Damage to Bone Marrow Stem Cells
◦Cells with shortest circulating lifespan = most susceptible
◦Neutrophils: 10 hours
◦Reserve: 5 days
◦Nadir: ~7 days
◦Platelets: 5-9 days
◦RBCs: 4 months
◦Sepsis: <5% of patients

10. Bone Marrow Suppression
◦Treatment Parameters (General)
◦Neutrophils: at least 2000
◦Platelets: at least 80,000
◦CBC monitoring at expected Nadir
◦Indications for Prophylactic Antibiotics
◦Neutrophils < 1000
◦Febrile
◦Sick

11. Bone Marrow Suppression
◦Neutropenia: to hospitalize or not?
◦Increased exposure to pathogens in the hospital
◦If clinically well: home with antibiotics, supportive care
◦If febrile, not eating, signs of sepsis
◦Hospitalize
◦Reverse Isolation
◦Sterile IV catheter
◦IV fluids, antibiotics
◦Supportive care as indicated

12. Bone Marrow Suppression
◦Neutrophil Recovery
◦Usually within 5-7 days
◦May see “rebound” neutrophilia
◦Neupogen (GCSF)
◦Granulocyte Colony Stimulating Factor
◦Only human factor available
◦Reserve for septic patients whose neutrophil count is not recovering properly
◦$$$

13. Bone Marrow Suppression
◦VCOG Grading Scheme for Bone Marrow Toxicity
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Neutropenia 1500 -
<LLN
1000-1499 500-999 <500 Death
Thrombocytopenia 100,000 -
<LLN
50,000-
99,000
25,000-
49,000
<25,000 Death

14. MDR Mutation
◦Certain breeds at increased risk for chemotherapy toxicity
◦Collies: 70%
◦Long-haired Whippet: 65%
◦Australian Shepherd: 50%
◦Silken Windhound & McNab: 30%
◦Shetland Sheepdogs: 15%
◦Border Collies: <5%
◦MDR1 (ABCB1) Allele Mutation
◦Washington State University PCR Test (cheek swab)
◦http://www.vetmed.wsu.edu/depts-vcpl/

15. MDR Mutation
◦MDR1 encodes the P-glycoprotein pump
◦Active transport of chemotherapy drugs out of cell
◦“Natural Product” Drugs
◦Vinca alkaloids (periwinkle)
◦Anthracyclines (Doxorubicin: Streptomyces yeast)
◦Taxanes (Pacific yew tree bark)
◦Treatment
◦Substitute non-P-glycoprotein substrate drugs in suspect patients pending test results
◦Alkylators
◦Dose reduction by 25-50% pending test results
howmed.net

16. Extravasation
◦General
◦ Always need a clean stick!
◦ Keep catheter in place, aspirate back as much drug as possible
◦Doxorubicin
◦ Cold compress to minimize tissue diffusion
◦ Potential surgical debridement or amputation
◦ Dexrazoxane (Zinecard)
◦Vincristine
◦ “Dilution is the Solution”
◦ Warm compress
◦ Saline
avmajournals.avma.org

17. Acute Tumor Lysis Syndrome
◦Cause
◦Rapid lysis of tumor cells after initiation of chemo or RT
◦Most common with lymphoblastic lymphoma or leukemia
◦Risk factors
◦Large tumor burden
◦Dehydrated, sick patients
◦Pre-existing renal failure
◦Rapid remission

18. Acute Tumor Lysis Syndrome
◦Clinical Signs: within 24-48 hours
◦Depression
◦Vomiting, Diarrhea
◦Acute collapse, CV shock
◦Laboratory findings
◦Hyperphosphatemia
◦Hyperkalemia
◦Hypocalcemia
◦+/- Azotemia
◦ Metabolic acidosis (uric acid release)

19. Acute Tumor Lysis Syndrome
◦Treatment
◦Aggressive fluid therapy
◦Correct electrolyte imbalances
◦Allopurinol
◦Prevention
◦Split or slow induction of chemotherapy
◦Pre-treatment with IV fluids

20. Drug Classes and
Specific Side Effects

21. Vinca Alkaloids
◦Vincristine, Vinblastine
◦Origin:
◦Vinca rosea (periwinkle)
◦Mechanism of Action:
◦Inhibit microtubule assembly
◦Metaphase arrest
commons.wikimedia.org

22. Vinca Alkaloids
◦Common Uses:
◦Vincristine
◦Lymphoma
◦Transmissible venereal tumor
◦Vinblastine
◦Mast cell tumors
◦Transitional cell carcinoma
◦Lymphoma (vincristine substitute)
Webmd.com

23. Vinca Alkaloids
◦Toxicity
◦Vincristine
◦GI (mild to moderate)
◦Nausea
◦Ileus
◦Diarrhea
◦Bone marrow suppression (mild)
◦Vinblastine
◦GI (mild)
◦Bone marrow suppression (neuts: moderate to severe)
Webmd.com

24. Vinca Alkaloids
◦Cautions
◦P-glycoprotein substrates
◦Biliary excretion (vincristine)
◦Dosing errors
◦Vincristine: 0.7 mg/m2
◦Vinblastine: 2 mg/m2
◦Extravasation
Webmd.com

25. Alkylating Agents
◦Cyclophosphamide (Cytoxan)
◦Chlorambucil (Leukeran)
◦Melphalan (Alkeran)
◦Mechlorethamine (Mustargen)
◦Lomustine (CCNU or CeeNu)
◦Mechanism of Action:
◦Binding of alkyl groups to DNA
◦Inter- or intrastrand cross-links
◦Inhibits DNA replication

26. Alkylating Agents
◦Cyclophosphamide (Cytoxan)
◦Common Uses:
◦Lymphoma
◦Oral metronomic chemotherapy
◦Toxicity
◦GI (mild)
◦Bone marrow suppression (moderate)
◦Sterile hemorrhagic cystitis
◦Acrolein

27. Alkylating Agents
◦Cyclophosphamide (Cytoxan)

28. Alkylating Agents
◦Chlorambucil (Leukeran)
◦Common Uses:
◦Chronic Lymphocytic Leukemia
◦Low grade (small cell) Lymphoma
◦Oral metronomic chemotherapy
◦Toxicity
◦GI (mild)
◦Bone marrow suppression (mild but can be cumulative)

29. Alkylating Agents
◦Melphalan (Alkeran)
◦Common Uses:
◦Multiple Myeloma
◦Anal sac adenocarcinoma
◦Toxicity
◦GI (mild)
◦Bone marrow suppression (moderate; can be cumulative)

30. Alkylating Agents
◦Mechlorethamine (Mustargen)
◦Common Uses:
◦Lymphoma rescue (MOPP protocol)
◦Toxicity
◦GI (mild to moderate)
◦Bone marrow suppression (mild to moderate)
◦Staff exposure
en.wikipedia.org

31. Alkylating Agents
◦Lomustine (CCNU)
◦nitrosurea
◦Common Uses:
◦Lymphoma rescue or single-agent use
◦Mast cell tumors
◦Histiocytic sarcoma
◦Crosses the blood-brain barrier

32. Alkylating Agents
◦Lomustine (CCNU)
◦Toxicity:
◦GI: none to mild
◦Bone marrow suppression: severe
◦Double neutrophil nadir
◦Cumulative thrombocytopenia
◦Hepatotoxicity
◦Liver failure is rare
◦Monitor ALT
◦Consider supplementation
En.wikipedia.org

33. Platinum Agents
◦Carboplatin
◦Cisplatin
◦Mechanism of Action:
◦Binding of platinum groups to DNA
◦Inter- or intrastrand cross-links
◦Inhibits DNA replication

34. Platinum Agents
◦Common Uses:
◦Carboplatin
◦Osteosarcoma
◦Carcinomas: anal sac, transitional cell, mammary, etc
◦Cisplatin
◦Osteosarcoma
◦Mesothelioma (intracavitary)

35. Platinum Agents
CARBOPLATIN
◦GI (mild)
◦Bone marrow suppression (severe)
◦Double neutrophil nadir
◦Thrombocytopenia
◦Renal elimination
CISPLATIN
◦GI (moderate to severe; acute nausea)
◦Bone marrow suppression (moderate)
◦Severe nephrotoxicity
◦CATS: contraindicated
◦Fulminant pulmonary edema
◦FATAL

36. Anthracycline Antibiotics
◦Doxorubicin
◦Mitoxantrone
◦Origin
◦Doxorubicin: Streptomyces yeast
◦Mechanisms of Action:
◦Topoisomerase II inhibition
◦DNA intercalation
◦Free radical generation (doxorubicin)  oxidative damage

37. Anthracycline Antibiotics
◦Common Uses:
◦Doxorubicin
◦Lymphoma
◦Sarcomas: Hemangiosarcoma, Osteosarcoma, Fibrosarcoma, others
◦Histiocytic sarcoma
◦Carcinomas: Mammary, Transitional Cell, etc
◦Mitoxantrone
◦Transitional Cell Carcinoma
◦Anal sac adenocarcinoma
◦Doxorubicin substitute

38. Anthracycline Antibiotics
◦Toxicity
◦Doxorubicin
◦GI (moderate to severe)
◦Bone marrow suppression (moderate to severe)
◦Cardiac
◦Anaphylaxis
◦Mitoxantrone
◦GI (mild)
◦Bone marrow suppression (moderate to severe)

39. Anthracycline Antibiotics
◦Cautions
◦Doxorubicin: P-glycoprotein substrate
◦Extravasation

40. Antimetabolites
◦Cytosine arabinoside (Cytosar)
◦Gemcitabine (Gemzar)
◦5-fluorouracil
◦Mechanisms of Action:
◦Analogs of normal cell metabolism compounds
◦Inhibit the use of cell metabolites in growth and division
◦Incorporation into DNA and prevention of replication

41. Antimetabolites
◦Cytosar
◦Crosses the blood brain barrier
◦Used in Lymphoma rescue protocols and Leukemia
◦Gemcitabine
◦Liver and pancreatic tumors
◦Radiation sensitizer

42. Antimetabolites
◦5-FU
◦Accidental ingestion of owner’s skin cream
◦Overdose in dogs
◦Severe neurotoxicity
◦Severe GI signs
◦>20 mg/kg = toxic
◦> 43 mg/kg = fatal
◦Cats
◦Neurotoxicity = fatal

43. Tyrosine Kinase Inhibitors
◦Toceranib (Palladia)
◦Masitinib (Kinavet)
◦Mechanism of Action:
◦Small molecules that bind to tyrosine kinase receptors
◦C-kit
◦VEGF

44. Tyrosine Kinase Inhibitors
◦Common Uses:
◦Palladia
◦Mast Cell Tumors
◦Carcinomas
◦Neuroendocrine tumors
◦Kinavet
◦Conditional license
◦Grade II or Grade III cutaneous Mast Cell Tumors
◦No previous RT or chemo, except steroids

45. Tyrosine Kinase Inhibitors
◦Toxicity
◦Gastrointestinal (moderate to severe)
◦Ulceration
◦Prophylactic treatment
◦Bone Marrow Suppression
◦Protein-losing nephropathy
◦Muscle cramping

46. References
• Chabner, BA and DL Longo. Cancer Chemotherapy and Biotherapy:
Principles and Practice. 5th
ed. Philadelphia: Lippincott, 2011.
• Fan, TM and LP deLorimier. Treating lymphoma in dogs and cats. Veterinary Medicine, April 1,2005.
• Latimer, KS, EA Mahaffey, and KW Prasse. Duncan and Prasse’s Veterinary Laboratory Medicine Clinical Pathology. 4th
ed. Ames:
Blackwell, 2003.
• Venable RO, Saba CF, Endicott MM, Northrup NC. Dexrazoxane treatment of doxorubicin extravasation injury in four dogs. JAVMA
240(3):304-7
• Veterinary Cooperative Oncology Group: Common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or
biologic antineoplastic therapy in dogs and cats v1.1. Veterinary and Comparative Oncology 20 July 2011.
• Withrow, SJ and EG MacEwen. Small Animal Clinical Oncology. 3rd
ed. Philadelphia: Saunders, 2001.
• Withrow, SJ, DM Vail, and RL Page. Withrow and MacEwen’s Small Animal Clinical Oncology. 5th
ed. St. Louis: Elsevier, 2013