Which Drugs Are Used for Medical Management of Lymphoma in Dogs & Cats? Part 3
Christine Mullin, VMD, DACVIM (Oncology), BluePearl Pet Hospital, Malvern, Pennsylvania
Craig A. Clifford, DVM, MS, DACVIM (Oncology), BluePearl Pet Hospital, Malvern, Pennsylvania
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