Common Chemotherapy

Medications and Side Effects

Jennifer Mahoney, DVM, DACVIM (Oncology)Upstate Veterinary Specialties

October 10, 2015

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

Chemotherapy Overview◦ Drugs target dividing cells and interfere with cell cycle

◦ S Phase (DNA replication)◦ M Phase (Mitosis)

G1

S

G2

M DNA SynthesisMitosis

Chemotherapy Overview◦ Rapidly-dividing cells are most susceptible

◦ Cancer Cells◦ Gastrointestinal epithelial cells◦ Bone marrow cells◦ Hair follicles of certain breeds

Gastrointestinal Side Effects◦ Nausea and Vomiting

◦ Decreased Appetite

◦ Diarrhea

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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

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

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

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

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

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

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◦ $$$

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

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/

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

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

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

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)

Acute Tumor Lysis Syndrome◦ Treatment

◦ Aggressive fluid therapy◦ Correct electrolyte imbalances◦ Allopurinol

◦ Prevention◦ Split or slow induction of chemotherapy◦ Pre-treatment with IV fluids

Drug Classes and Specific Side Effects

Vinca Alkaloids◦ Vincristine, Vinblastine

◦ Origin: ◦ Vinca rosea (periwinkle)

◦ Mechanism of Action:◦ Inhibit microtubule assembly◦ Metaphase arrest

commons.wikimedia.org

Vinca Alkaloids◦ Common Uses:

◦ Vincristine ◦ Lymphoma◦ Transmissible venereal tumor

◦ Vinblastine◦ Mast cell tumors◦ Transitional cell carcinoma◦ Lymphoma (vincristine substitute)

Webmd.com

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

Vinca Alkaloids◦ Cautions

◦ P-glycoprotein substrates

◦ Biliary excretion (vincristine)

◦ Dosing errors◦ Vincristine: 0.7 mg/m2◦ Vinblastine: 2 mg/m2

◦ ExtravasationWebmd.com

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

Alkylating Agents◦ Cyclophosphamide (Cytoxan)

◦ Common Uses:◦ Lymphoma◦ Oral metronomic chemotherapy

◦ Toxicity◦ GI (mild)◦ Bone marrow suppression (moderate)◦ Sterile hemorrhagic cystitis

◦ Acrolein

Alkylating Agents◦ Cyclophosphamide (Cytoxan)

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)

Alkylating Agents◦ Melphalan (Alkeran)

◦ Common Uses:◦ Multiple Myeloma◦ Anal sac adenocarcinoma

◦ Toxicity◦ GI (mild)◦ Bone marrow suppression (moderate; can be cumulative)

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

Alkylating Agents◦ Lomustine (CCNU)

◦ nitrosurea

◦ Common Uses:◦ Lymphoma rescue or single-agent use◦ Mast cell tumors◦ Histiocytic sarcoma◦ Crosses the blood-brain barrier

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

Platinum Agents◦ Carboplatin◦ Cisplatin

◦ Mechanism of Action:◦ Binding of platinum groups to DNA◦ Inter- or intrastrand cross-links◦ Inhibits DNA replication

Platinum Agents◦ Common Uses:

◦ Carboplatin◦ Osteosarcoma◦ Carcinomas: anal sac, transitional cell, mammary, etc

◦ Cisplatin◦ Osteosarcoma◦ Mesothelioma (intracavitary)

Platinum AgentsCARBOPLATIN

◦ 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

Anthracycline Antibiotics◦ Doxorubicin◦ Mitoxantrone

◦ Origin ◦ Doxorubicin: Streptomyces yeast

◦ Mechanisms of Action:◦ Topoisomerase II inhibition◦ DNA intercalation◦ Free radical generation (doxorubicin) oxidative damage

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

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)

Anthracycline Antibiotics◦ Cautions

◦ Doxorubicin: P-glycoprotein substrate

◦ Extravasation

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

Antimetabolites◦ Cytosar

◦ Crosses the blood brain barrier◦ Used in Lymphoma rescue protocols and Leukemia

◦ Gemcitabine◦ Liver and pancreatic tumors◦ Radiation sensitizer

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

Tyrosine Kinase Inhibitors◦ Toceranib (Palladia)◦ Masitinib (Kinavet)

◦ Mechanism of Action:◦ Small molecules that bind to tyrosine kinase receptors

◦ C-kit◦ VEGF

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

Tyrosine Kinase Inhibitors◦ Toxicity

◦ Gastrointestinal (moderate to severe)◦ Ulceration◦ Prophylactic treatment

◦ Bone Marrow Suppression

◦ Protein-losing nephropathy

◦ Muscle cramping

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• 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