Small Animal/Exotics
PHARM PROFILE
LOMUSTINE
Timothy M. Fan, DVM, Diplomate ACVIM
Barbara E. Kitchell, DVM, PhD,
Diplomate ACVIM
University of Illinois
L
omustine is classified as an anti-
tumor alkylating agent in the
nitrosourea family. Unlike ni-
trogen mustard alkylating agents, the
nitrosoureas are highly lipid soluble.
This allows for rapid transport across
the blood–brain barrier and effective
treatment of primary and metastatic
brain tumors.
PHARMACOLOGY
Alkylating agents can be divided
into five chemical groups: nitrogen
mustards (melphalan, chlorambucil,
cyclophosphamide, ifosfamide), ni-
trosoureas (lomustine, carmustine,
streptozotocin), sulfonates (busulfan),
triazines (dacarbazine), and ethylen-
imines (thiotepa).1 Although struc-
turally distinct, all alkylators have or
generate reactive functional groups
that are electron deficient and thus
capable of forming covalent bonds
with electron-rich (nucleophilic)
groups in nucleic acids, proteins, and
most importantly, DNA.
Alkylation of DNA produces a va-
riety of defects—including double-
and single-stranded breaks and inter-
and intrastrand cross-links—that dis-
rupt normal DNA replication and
transcription. Cell death occurs when
Pharm Profile introduces drugs that are new to the veterinary market as well as new indications for existing drugs. If you would like
Pharm Profile to cover a particular agent, please contact column editor Gigi Davidson, BS, RPh, North Carolina State University,
4700 Hillsborough Street, Raleigh, NC 27606; phone 919-821-9500 • fax 919-829-4225 • email gigi_davidson@ncsu.edu.
these fundamental DNA alterations
cannot be repaired efficiently. Ni-
trosoureas specifically induce in-
trastrand DNA cross-linking via the
transfer of a chloroethyl group from
the chloroethyl–nitrosourea to the O-
6 position of guanine in DNA.2
The half-life of lomustine in dogs is
less than 15 minutes. 3 Like other
alkylating agents, lomustine is rapidly
hydroxylated by liver microsomes.
This occurs by a cytochrome P-
450–dependent process that produces
highly reactive intermediates, which
in turn damage DNA by creating in-
trastrand cross-linkages.3 The primary
route of elimination of lomustine and
its biotransformation products is
through the kidneys, with biliary ex-
cretion and reabsorption from the gut
also playing a major role.3 In dogs,
approximately 37% of lomustine is
excreted unchanged in the urine with-
in 24 hours after intravenous admin-
istration.3
INDICATIONS
In humans, lomustine has been ap-
proved for the treatment of refractory
Hodgkin’s lymphoma and primary
and metastatic brain tumors. In dogs,
lomustine has been reported to be a
Compendium October 2000
useful rescue agent for multicentric
lymphosarcoma.4 The drug has also
shown efficacy in the treatment of
metastatic mast cell tumors and cuta-
neous lymphosarcoma in dogs.5,6 In a
pilot study, lomustine had question-
able efficacy against a variety of histo-
logically distinct intracranial neo-
plasms in dogs7 (Table I4–7).
CAUTIONS
Because lomustine requires hepatic
microsomal enzyme hydroxylation for
drug activation and is primarily ex-
creted by the kidneys, the drug should
be used cautiously in patients with
significant renal or hepatic dysfunc-
tion. Like all alkylating agents, lomus-
tine has the potential to be embryo-
toxic and teratogenic; thus pregnant
women should have minimal contact
with the drug itself as well as with
urine from animals being treated with
lomustine.
ACUTE TOXICITY
An animal study8 revealed that lo-
mustine is toxic to bone marrow, lym-
phoid tissue, liver, kidneys, and gas-
trointestinal epithelium. Most notably,
lomustine is capable of causing hema-
topoietic toxicity in dogs.8 Toxicity
Compendium October 2000 Small Animal/Exotics

monary infiltrates and/or fibrosis;

Client Counseling Information nausea and vomiting; reversible hepa-
■ Lomustine capsules must not be crushed or opened before being totoxicity; and nephrotoxicity.11 Dose
administered because of the risk for accidental human dermal intensity appears to play an important
absorption or inhalation. role in the development of toxicity in
■ Observe your pet for anorexia, vomiting, diarrhea, and depression humans. Humans treated with 130
following drug administration; contact your veterinarian if any of these mg/m2 every 6 to 8 weeks are more
signs persist for more than 24 hours. likely to develop myelotoxicity than
■ Contact your veterinarian immediately if your pet develops a fever, are those treated with a weekly dose of
experiences unexplainable hemorrhage, or becomes icteric. 30 mg/m2.12
■ Inform your veterinarian about all medications you are giving to your
animal.
■ Avoid contact with eyes and skin. If contact occurs, flush eyes with DRUG INTERACTIONS
copious amounts of water and wash exposed skin thoroughly. Contact Lomustine requires microsomal en-
your local poison control center for further recommendations. zyme hydroxylation for the produc-
tion of antineoplastic metabolites.
The dominant metabolite in rats is a
was evaluated in beagles given various ministration.6 Thrombocytopenia was cis-3-hydroxy compound; lesser
single oral doses of lomustine (5, 10, not observed in any of the dogs in ei- amounts of cis-4-hydroxy compound
15, 20, and 30 mg/kg).8 All dogs re- ther of these two clinical trials 7 days are also produced.3 The quantitative
ceiving the 5-mg/kg dose survived the after lomustine administration.4,6 distribution of hydroxylated metabo-
toxicity trial but suffered grade III or In addition to inducing myelotoxi- lites appears to change in rats treated
IV (of IV) neutropenia (nadir, 7 days; city, lomustine has been found to long-term with phenobarbital, and
recovery by day 20). Platelet and lym- cause delayed liver damage in research the cis-4-hydroxy compound is domi-
phocyte counts remained normal. dogs. Dogs receiving a single oral dose nant.3 Changes in antineoplastic effi-
Dogs receiving 10-, 15-, and 20- of 4 mg/kg had histologic changes cacy associated with altered distribu-
mg/kg doses experienced grade IV consistent with periportal fibrosis and tion of hydroxylated metabolites has
neutropenia, lymphopenia, and Kupffer cell hyperplasia.9 Reversible not been investigated in dogs. Because
thrombocytopenia (nadir, days 7 to biochemical abnormalities (e.g., eleva- of potential changes in antineoplastic
10) and subsequently died of either tions in serum alanine aminotrans- efficacy, lomustine should be used
bacterial infection or intractable ferase, alkaline phosphatase, and lac- with caution in dogs being treated
bleeding. 8 Dogs receiving the 30- tate dehydrogenase; increases in concurrently with medications requir-
mg/kg dose died of severe gastroin- sulfobromophthalein retention) were ing microsomal enzyme induction
testinal toxicity within 7 days of drug seen 14 days after oral lomustine ad- (e.g., phenobarbital). Owing to lo-
administration.8 ministration.9 mustine’s potential myelotoxicity,
Myelotoxicity has been reported In one large clinical study of 228 precautions should be taken when us-
with oral lomustine in tumor-bearing dogs treated with oral lomustine, 9 ing lomustine in combination with
dogs.4 Thirty-five dogs with multicen- dogs were identified with hepatotoxi- other myelosuppressive agents to
tric lymphosarcoma were treated with city presumptively associated with avoid additive bone marrow toxicity.
lomustine (90 mg/m2); 7 days after chronic oral administration of the
drug administration, the median neu- drug; 6 of the 9 dogs eventually died DOSAGE AND ADMINISTRATION
trophil count was 1400 cells/µl of hepatic failure.10 Whether to initi- In dogs, lomustine has been admin-
(range, 104 to 11,200 cells/µl).4 Six ate lomustine in dogs with preexisting istered orally at a dose of 50 to 90
dogs receiving lomustine at a dose of nonneoplastic hepatic diseases should mg/m2 every 21 days.4–6 Minimal cu-
100 mg/m2 had a median neutrophil be carefully evaluated. Discontinua- mulative side effects, including bone
count of 792 cells/µl (range, 104 to tion of lomustine should be consid- marrow toxicity, are associated with
2394 cells/µl).4 Rare nonhematologic ered in dogs that develop acute or un- the low dose (50 mg/m 2 every 21
toxicity included fever and gastroin- explained elevations in serum liver days).6 At the high end of the dose
testinal signs. 4 Seven (41%) of 17 enzyme activities. range (90 mg/m2 every 21 days), lo-
dogs with grade II or III mast cell tu- Toxicities associated with long- mustine may induce severe and life-
mors that were treated with lomustine term lomustine administration in hu- threatening neutropenia in some
(90 mg/m2) developed grade III or IV mans include a delayed, cumulative dogs.4,5,7
neutropenia (neutrophil count below myelotoxicity (thrombocytopenia is The use of lomustine to treat cats
1000 cells/µl) 7 days after drug ad- more severe than is leukopenia); pul- with malignant neoplasms has recent-
Small Animal/Exotics
TABLE I
Documented Uses for Lomustine in Dogs4–7
Indication
Multicentric lymphoma rescue therapy4 (n = 43)
Cutaneous lymphoma5 (n = 7)
6
Cutaneous mast cell tumor (n = 23)
Various intracranial neoplasms7 (n = 7)
ly been reported.13 Preliminary results
suggest that cats can tolerate oral lo-
mustine at a dose of 60 mg/m2 every
21 days. Dose-limiting toxicity from
oral lomustine appears to be neu-
tropenia, which can develop after one
dose, with a variable time to nadir (7
to 21 days).13 Potential adverse effects
associated with chronic lomustine ad-
ministration in cats have not been
evaluated.
PREPARATIONS
Lomustine (CeeNU®, Bristol-My-
ers Squibb, Princeton, NJ) is a yellow
powder. Lomustine is sold only in
capsule form. Capsules are available
in 10-, 40-, and 100-mg preparations;
the costs for a bottle of 20 are $100,
$300, and $575, respectively.
STORAGE AND HANDLING
Procedures for proper handling and
disposal of anticancer drugs should be
followed. Clients handling capsules at
home should wear gloves when ad-
ministering the agent to their animals.
A licensed pharmacist should refor-
mulate lomustine capsules only under
appropriate hood and ventilation sys-
tems to minimize inadvertent expo-
sure from aerosolization of contents.
Capsules should be stored at tempera-
tures below 40˚C.
RECOMMENDATIONS
Lomustine is a potent drug that can
cause severe neutropenia 7 days after
drug administration. In general, lo-
Dose (mg/m2)
90 every 3 wk
50 every 3 wk
90 every 3 wk
60–80 every 6–8 wk
mustine should be reserved as a rescue
drug for patients with multicentric
lymphosarcoma that have failed stan-
dard chemotherapy protocols; it can
also be used when therapeutic options
are limited by financial constraints.
Lomustine should be considered a
first-line therapeutic choice when
treating systemic or metastatic mast
cell tumors. It can also be used in the
treatment of cutaneous lymphoma
and brain tumors, although data re-
garding its effectiveness are limited.
A complete blood count should be
performed 7 days after initiation of
treatment to monitor for hematologic
changes. If severe neutropenia (fewer
than 1000 cells/µl) develops, adminis-
tration of broad-spectrum antibiotics
is recommended until neutrophil
counts exceed 2500 cells/µl. The use
of granulocyte colony-stimulating fac-
tor (Neupogen®, Amgen, Thousand
Oaks, CA; 5 µg/kg/day subcutaneous-
ly for 3 to 5 days) may be implement-
ed if myelosuppression secondary to
lomustine is prolonged.
REFERENCES
1. Cooper MR: Principles of medical oncol-
ogy, in Holleb AI, Fink DJ, Murphy GP
(eds): American Cancer Society Textbook
of Clinical Oncology. Atlanta, American
Cancer Society, 1991, pp 47–68.
2. Teicher BA: Antitumor alkylating agents,
in DeVita VT, Rosenberg SA, Hellman S
(eds): Cancer: Principles and Practice of
Oncology, ed 5. Philadelphia, JB Lippin-
cott, 1997, pp 405–414.
3. Oliverio VT: Pharmacology of the ni-
trosoureas: An overview. Cancer Treat
Compendium October 2000
Toxicity
Neutropenia, thrombocytopenia
None reported
Neutropenia, thrombocytopenia
Neutropenia, thrombocytopenia
Rep 60(6):703–707, 1976.
4. Moore AS, London CA, Wood CA, et al:
Lomustine (CCNU) for the treatment of
resistant lymphoma in dogs. J Vet Intern
Med 13:395–398, 1999.
5. Graham JC, Myers RK: Pilot study on the
use of lomustine (CCNU) for the treat-
ment of cutaneous lymphoma in dogs.
Proc 17th ACVIM Forum:723, 1999.
6. Rassnick KM, Moore AS, Williams LE, et
al: Treatment of canine mast cell tumors
with CCNU (lomustine). J Vet Intern
Med 13:601–605, 1999.
7. Fulton LM, Steinberg SH: Preliminary
study of lomustine in the treatment of in-
tracranial masses in dogs following local-
ization by imaging techniques. Semin Vet
Med Surg Small Anim 5:241–245, 1990.
8. Abb J, Netzel B, Rodt HV, Thierfelder S:
Autologous bone marrow grafts in dogs
treated with lethal doses of 1-(2-chloro-
ethyl)-3-cyclohexyl-1-nitrosourea. Cancer
Res 38(7):2157–2159, 1978.
9. Henry MC, Davis RD, Schein PS: Hepa-
totoxicity of 1-(2-chloroethyl)-3-cyclo-
hexyl-1-nitrosourea (CCNU) in dogs: The
use of serial percutaneous liver biopsies.
Toxicol Appl Pharmacol 25:410–417, 1973.
10. Kristal O, Rassnick KM, Gliatto J, et al:
Hepatotoxicity associated with CCNU
chemotherapy in dogs. 19th Annu Vet Can-
cer Soc Conf :15, 1999.
11. Weiss RB, Issell BF: The nitrosoureas:
Carmustine (BCNU) and lomustine
(CCNU). Cancer Treat Rev 9(4):313–
330, 1982.
12. Koller CA, Gorski CC, Benjamin RS, et
al: A phase I trial of weekly lomustine in
patients with advanced cancer. Cancer
73(1):236–239, 1994.
13. Rassnick KM, Northrup NC, Kristal O,
et al: Phase I/II evaluation of CCNU (lo-
mustine) in tumor bearing cats: Preliminary
report. 19th Annu Vet Cancer Soc Conf :65,
1999.