January 2017
Peer Reviewed

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The following drugs can be used in the management of lymphoma in dogs and cats. Part 3 will discuss dacarbazine, actinomycin D, melphalan, and mitoxantrone.

  • Asparaginase
  • Doxorubicin
  • Vincristine
  • Cyclophosphamide
  • Lomustine
  • Chlorambucil
  • Corticosteroids (prednisone and derivatives)
  • Cytarabine
  • Mechlorethamine
  • Procarbazine
  • Dacarbazine
  • Actinomycin D
  • Melphalan
  • Mitoxantrone

Dacarbazine

Dacarbazine, a methylating agent (alkylator) also known as DTIC, is most often used as a single agent or as part of a combination chemotherapy protocol (eg, doxorubicin+DTIC, CCNU [lomustine] +DTIC, temozolomide+DTIC) in the rescue setting for dogs with intermediate- to high-grade lymphoma.1-7 

Mechanism of action → The exact mechanism underlying the antitumor activity of dacarbazine remains unknown.4

  • However, it is thought that the active metabolites bind methyl groups to specific DNA sites, which leads to DNA strand breaks, inhibition of DNA synthesis, and subsequent cell death.4 

Dose (dogs only, as single agent) → 800-1000 mg/m2 IV as slow infusion over 6 to 8 hours5

Dose (dogs only, in combination with CCNU or anthracycline) → 600 mg/m2 IV via similar infusion protocol7

  • Frequency and duration can vary, depending on whether the drug is used as a single agent (q3wk) or as part of a multiagent protocol.5,6

Monitoring during therapy → Serial CBC evaluations, assessment of hepatic function

Adverse Events

  • GI upset, specifically acute emesis during infusion1,2,4
    • Injectable antiemetics recommended before infusion1,2,4
  • Myelosuppression, particularly thrombocytopenia1,2,4-6
    • Neutropenia typically occurs 7 to 10 days postadministration.
    • Thrombocytopenia typically occurs between 10 and 21 days postadministration.
  • Rare but severe hepatotoxicity reported in humans; unclear whether clinically significant in dogs4
  • Hypotension can occur if the IV dose is administered rapidly.4
  • Moderate-to-severe vesicant; extravasation injury can be severe.8 

Key Points

  • Dacarbazine is a prodrug that requires bioactivation to active metabolites.4 
  • Dose adjustments are indicated in patients with hepatic dysfunction.
  • Has not been effectively evaluated in cats
    • Unknown whether cats can metabolize parent drug into active metabolites 

Actinomycin D

Actinomycin D, also known as dactinomycin, is an antitumor antibiotic of the mitomycin class of chemotherapy agents (ie, derivatives of the soil bacteria of the Streptomyces genus). This drug is most commonly used as a single agent or part of the multiagent rescue DMAC protocol for canine lymphoma.1,2,9-13 

Mechanism of action → Binds DNA at the transcription initiation complex and prevents RNA chain elongation by RNA polymerase, which leads to inhibition of RNA transcription or protein synthesis and altered cell metabolism1,10  

Dose (dogs only) → 0.5-0.7 mg/m2 IV slowly over 15 to 20 minutes

  • Frequency and duration can vary, depending on whether the drug is used as a single agent (q3wk) or incorporated in a multidrug protocol (eg, CHOP, DMAC).9,11-13

Monitoring during therapy → Serial CBC evaluations 

Adverse Events

  • Myelosuppression, including neutropenia 7 to 10 days post-administration and thrombocytopenia ≥14 days postadministration1,2,10,13 
  • GI upset1,2,10,13
  • Tissue damage if perivascular extravasation occurs10

Key Points

  • First antibiotic shown to have anticancer activity10 
  • Mutation in the multidrug resistance MDR1 gene (also known as ABCB1-1∆) can lead to increased risk for severe side effects.14
    • Numerous breeds are affected with the MDR1 mutation, including various herding breeds, the silken windhound, and the long-haired whippet.14
    • Perform MDR1 testing.15
    • If mutation (heterozygous) is present, major dose reduction is indicated; if patient is homozygous mutant, consider drug omission or substitution.2,14
  • DMAC protocol has not been evaluated in cats, but anecdotal experience suggests it is well-tolerated. 
  • Although actinomycin D is less cardiotoxic than doxorubicin, a randomized controlled trial of doxorubicin vs actinomycin D in a multiagent protocol for canine lymphoma documented decreased efficacy of a actinomycin D-based protocol.11
  • Another study evaluated actinomycin D as part of maintenance therapy following a standard CHOP protocol for canine lymphoma and documented a higher complete response rate (97%) as compared with historical control studies.12 

Melphalan

Melphalan, an alkylating agent of the nitrogen mustard family, is most commonly used to treat canine lymphoma as part of the multiagent DMAC rescue protocol.1,2,9,16 

Mechanism of action → Binds alkyl groups directly to specific DNA sites, which leads to interstrand and intrastrand cross-links, DNA strand breakage, disruption of DNA synthesis, and subsequent cell death16

Dose (dogs only, for DMAC protocol) → 20 mg/m2 PO on day 7 of a 14-day cycle of the DMAC protocol

Monitoring during therapy → Serial CBC evaluations, assessment of renal function

Adverse Events

  • Myelosuppression, particularly thrombocytopenia16 
    • Neutrophil nadir typically occurs around 7 to 10 days postadministration.
    • Platelet nadir can occur between 10 and 21 days post-administration.
    • Thrombocytopenia can be cumulative and irreversible because of cytotoxicity against slowly cycling and/or noncycling hematopoietic stem cells.16 
  • Increased toxicity seen with renal insufficiency1,16

Key Points

  • Active drug that does not require metabolic activation16

Mitoxantrone 

Mitoxantrone is a synthetic anthracenedione compound most commonly used as a rescue agent for intermediate- to high-grade canine lymphoma or as a substitute for doxorubicin in multiagent protocols.1,2,17-19 

Mechanism of action → Has multiple anticancer mechanisms of action, including DNA intercalation, inhibition of DNA and RNA polymerases, and inhibition of type II topoisomerase17

  • These various actions ultimately lead to halted DNA and RNA synthesis, DNA strand breakage, and cell death.17

Dose (dogs only) → 5-6 mg/m2 IV q3wk (slow bolus)

  • Many clinicians start at low end of dose range and escalate if the drug is well-tolerated.

Monitoring during therapy → Serial CBC evaluations

Mitoxantrone causes less free-radical formation and oxidative damage as compared with doxorubicin.

Adverse Events

  • Myelosuppression17,19
    • Neutropenia and, to a lesser degree, thrombocytopenia typically occur between 7 and 10 days postadministration.20
  • GI upset, typically mild17,19

Key Points

  • Causes less free-radical formation and oxidative damage as compared with doxorubicin and thus is not associated with cardiac toxicity in dogs2,17 
    • Therefore, mitoxantrone can be used as a substitute for doxorubicin in dogs with cardiac disease and possible doxorubicin-induced cardiotoxicity.2,17,21 
  • Not associated with renal toxicity, so can be used as a substitute for doxorubicin in patients with significant renal disease17
  • One study evaluated mitoxantrone as part of maintenance therapy following a standard CHOP protocol for canine lymphoma and documented longer remission and survival times as compared with historical controls.18

Common Chemotherapy Protocols

  • CHOP = cyclophosphamide, H daunorubicin/doxorubicin, vincristine (Oncovin), prednisone 
  • COP = cyclophosphamide, vincristine (Oncovin), prednisone
  • DMAC = dexamethasone, melphalan, actinomycin, cytarabine
  • MOPP = mechlorethamine, vincristine (Oncovin), procarbazine, prednisone
  • MPP = mechlorethamine, procarbazine, prednisone 
References and author information Show
References
  1. Chen EX. Pharmacology of anticancer drugs. In: Tannock I, Hill R, Bristow R, Harrington L, eds. The Basic Science of Oncology. 5th ed. Toronto, Ontario: McGraw-Hill; 2013:419-442.
  2. Gustafson DL, Page RL. Cancer chemotherapy. In: Withrow SW, Vail DM, eds. Small Animal Clinical Oncology. 5th ed. St Louis, MO: Saunders Elsevier; 2013:157-179.
  3. Flory AB, Rassnick KM, Al-Sarraf R, et al. Combination of CCNU and DTIC chemotherapy for treatment of resistant lymphoma in dogs. J Vet Intern Med. 2008;22(1):164-171.
  4. Friedman HS, Averbuch SD, Kurtzberg J. Alkylating agents. Part B: methylating agents. In: Chabner BA, Longo DL, eds. Cancer Chemotherapy and Biotherapy: Principles and Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:293-309. 
  5. Griessmayr PC, Payne SE, Winter JE, Barber LG, Shofer FS. Dacarbazine as a single-agent therapy for relapsed lymphoma in dogs. J Vet Intern Med. 2009;23(6):1227-1231.
  6. Dervisis NG, Dominguez PA, Sarbu L, et al. Efficacy of temozolomide or dacarbazine in combination with an anthracycline for rescue chemotherapy in dogs with lymphoma. J Am Vet Med Assoc. 2007;231(4):563-569.
  7. Van Vechten M, Helfand SC, Jeglum KA. Treatment of relapsed canine lymphoma with doxorubicin and dacarbazine. J Vet Intern Med. 1990;4(4): 187-191.
  8. Plumb DC, ed. Plumb’s Veterinary Drug Handbook. 8th ed. Stockholm, WI: John Wiley & Sons; 2015.
  9. Alvarez FJ, Kisseberth WC, Gallant SL, Couto CG. Dexamethasone, melphalan, actinomycin D, cytosine arabinoside (DMAC) protocol for dogs with relapsed lymphoma. J Vet Intern Med. 2006;20(5):1178-1183.
  10. Chabner BA. Bleomycin and other antitumor antibiotics. In: Chabner BA, Longo DL, eds. Cancer Chemotherapy and Biotherapy: Principles and Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:323-341. 
  11. Khanna C, Lund EM, Redic KA, et al. Randomized controlled trial of doxorubicin versus dactinomycin in a multiagent protocol for treatment of dogs with malignant lymphoma. J Am Vet Med Assoc. 1998;213(7):985-990.
  12. Siedlecki CT, Kass PH, Jakubiak MJ, Dank G, Lyons J, Kent MS. Evaluation of an actinomycin-D-containing combination chemotherapy protocol with extended maintenance therapy for canine lymphoma. Can Vet J. 2006;47(1):52-59.
  13. Bannick EO, Sauerbrey ML, Mullins MN, Hauptman JG, Obradovich JE. Actinomycin D as rescue therapy in dogs with relapsed or resistant lymphoma: 49 cases (1999-2006). J Am Vet Med Assoc. 2008;233(3):446-451.
  14. Mealey KL, Meurs KM. Breed distribution of the ABCB1-1Δ (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. J Am Vet Med Assoc. 2008;233(6):921-924.
  15. Frequently asked questions. Washington State University College of Veterinary Medicine Veterinary Clinical Pharmacology Lab website. http://vcpl.vetmed.wsu.edu/faqs. Accessed November 29, 2016.
  16. Gerson SL, Friedman H. Alkylating agents. Part A: classical alkylating agents. In: Chabner BA, Longo DL, eds. Cancer Chemotherapy and Biotherapy: Principles and Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:267-292.
  17. Doroshow JH. Topoisomerase II inhibitors: anthracyclines. In: Chabner BA, Longo DL, eds. Cancer Chemotherapy and Biotherapy: Principles and Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:356-374.
  18. Daters AT, Mauldin GE, Mauldin GN, Brodsky EM, Post GS. Evaluation of a multidrug chemotherapy protocol with mitoxantrone based maintenance (CHOP-MA) for the treatment of canine lymphoma. Vet Comp Oncol. 2009; 8(1):11-22.
  19. Lucroy MD, Phillips BS, Kraegel SA, Simonson ER, Maewell BR. Evaluation of single-agent mitoxantrone as chemotherapy for relapsing canine lymphoma. J Vet Intern Med. 1998;12(5):325-329.
  20. Ogilvie GK, Obradovich JE, Cooper MF, Walters LM, Salman MD, Boone TC. Use of recombinant canine granulocyte colony-stimulating factor to decrease myelosuppression associated with the administration of mitoxantrone in the dog. J Vet Intern Med. 1992;6(1):44-47. 
  21. Tham P, Dougherty W, Iatropoulos MJ, et al. The effect of mitoxantrone treatment in beagle dogs previously treated with minimally cardiotoxic doses of doxorubicin. Am J Pathol. 1987;128(1):121-130.
Authors

Christine Mullin

VMD, DACVIM (Oncology) Hope Veterinary Specialists, Malvern, Pennsylvania

Christine Mullin, VMD, DACVIM (Oncology), is a medical oncologist at Hope Veterinary Specialists in Malvern, Pennsylvania. She completed a 1-year internship in small animal medicine and surgery at Red Bank Veterinary Hospital in New Jersey and a 3-year residency in medical oncology at The Oncology Service in the Washington, DC, metro area. Dr. Mullin serves on the Northeast Veterinary Cooperative Oncology Group committee. Dr. Mullin received the Most Outstanding Resident Basic Science Research award at the annual Veterinary Cancer Society meeting in 2014.

Craig A. Clifford

DVM, MS, DACVIM (Oncology) Hope Veterinary Specialists, Malvern, Pennsylvania

Craig A. Clifford, DVM, MS, DACVIM (Oncology), is the director of clinical studies at Hope Veterinary Specialists in Malvern, Pennsylvania, where he also serves as a medical oncologist. Dr. Clifford earned his DVM from Mississippi State University and his MS in animal science/virology from University of Delaware, then completed an internship and a medical oncology residency at University of Pennsylvania. He has authored and coauthored more than 50 papers and book chapters. Dr. Clifford created the Veterinary Cancer Society’s resident review session and the Northeast Veterinary Cooperative Oncology Group and has served on the VCS executive board, ACVIM Examination Rating Committee, Residency Training and Credentials Committee, Oncology Pathology Working Group, Standards of Excellence in Residency Education Task Force, and Australian Scientist’s Oncology Specialty Examination. Dr. Clifford also serves on the Scientific Advisory Boards for Industry. 

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