1. TOPICAL REVIEW
Lymphoma: Which Chemotherapy Protocol and Why?
Ruthanne Chun, DVM, Dipl. ACVIM (Oncology)
Lymphoma is the most common hematologic neoplasm of dogs. Although the order of drug administration and
duration of the maintenance portion of the protocol vary considerably, most oncologists agree that a doxoru-
bicin-based (eg, CHOP) combination chemotherapy protocol provides the longest period of disease control and
overall survival. The use of a prolonged maintenance phase is no longer recommended, but consolidation
therapy may prove to be of benefit. Further, combination of chemotherapy with half- or whole-body radiation
therapy or even bone marrow transplant is advocated by some institutions. The goal of this article is to
summarize the current literature regarding chemotherapy for dogs with high-grade lymphoma and provide
recommendations for therapy in a variety of different scenarios.
© 2009 Elsevier Inc. All rights reserved.
Keywords: CCNU, cyclophosphamide, doxorubicin, L-asparaginase, lomustine, lymphosarcoma, prednisone,
vincristine
L ymphoma is the most common hematopoietic tumor of
dogs. The most commonly encountered form of the dis-
ease is high-grade lymphoma, with indolent or small cell
protocols as opposed to combination chemotherapy proto-
cols.
lymphoma being a very different malignancy with different
treatment recommendations that are outside the scope of this
Single-agent Prednisone
article. Over the last 30 years, the standard of care for dogs For clients who have financial or logistic restrictions regard-
with high-grade lymphoma has gone from single-agent pro- ing treatment of their pets, single-agent therapy is a reason-
tocols to a combination chemotherapy protocol that contin- able option. Prednisone alone is commonly used; a reason-
ues indefinitely to one that is abbreviated to 6 months or less. able expected period of tumor control is 1 to 2 months.1
Sadly, even with multiple machinations, median overall sur- Advantages of this protocol include low cost and no risk of
vival times with aggressive therapy have not improved be- myelosuppression. Disadvantages of single-agent prednisone
yond 12 months. Thus, although the standard of care is rel- therapy include potentially severe side effects of polyuria,
atively easily defined, the treatment route opted for by polyphagia, and other less common issues of muscle wasting
oncology clients varies from inexpensive (and relatively inef- and personality change. In addition to prednisone toxicity,
fective) single-agent prednisone to the extreme measure of other disadvantages include induction of a chemotherapy-
aggressive chemotherapy, radiation therapy, and even bone resistant phenotype such that if clients want to pursue more
marrow transplantation. This article will cover the pros and aggressive chemotherapy when the tumor relapses, more ag-
cons of various treatments, from the bottom-of-the-barrel gressive drug therapy is not likely to be successful.
option to the current standard of care; it will also provide a
sneak preview at up-and-coming treatment options. Single-agent Doxorubicin
The following section will cover single-agent or relatively
easy to administer chemotherapy protocols (Table 1). Al- Doxorubicin as a single agent is an effective option for man-
though there are as many potential single-agent protocols as aging lymphoma.2-5 Doxorubicin is a relatively inexpensive
there are chemotherapy drugs, the focus will be on reported drug and is overall well tolerated by most dogs. Advantages
duration of disease control and overall survival. Unfortu- of single-agent doxorubicin include a short and relatively
nately, relatively little information is available on minimalist straightforward protocol with none of the prednisone-asso-
ciated side effects. Also, one study reports no difference in
median duration of remission or overall survival in dogs
From the University of Wisconsin–Madison School of Veterinary Medi- treated with single-agent doxorubicin compared directly
cine, Madison, WI, USA. with dogs treated with a doxorubicin-based combination
Address reprint requests to: Ruthanne Chun, DVM, Dipl. ACVIM (Oncol- chemotherapy protocol.5 Although it is tempting to take this
ogy), University of Wisconsin–Madison School of Veterinary Medicine, one study at face value, the specific advantages of multiagent
2015 Linden Dr, Madison, WI 53706. E-mail: chunr@svm.vetmed. protocols (eg, multiple mechanisms of tumor cell killing, de-
wisc.edu
© 2009 Elsevier Inc. All rights reserved. creased development of tumor resistance, and longer periods
1527-3369/06/0604-0171.00/0 of disease control and survival) still outweigh the ease of
doi:10.1053/j.tcam.2009.03.003 single-agent doxorubicin.
157

2. 158 Topics in Companion Animal Medicine
Table 1. Chemotherapy Protocols
Protocol Drug Dosage Follow-up
Single-agent prednisone 2 mg/kg/d ϫ 14 d, then 1.5 mg/kg/d ϫ 1- to 2-month median disease control
14 d, then 1 mg/kg/d ϫ 14 d, then 1 mg/kg
every other day indefinitely
Single agent doxorubicin2 30 mg/m2 IV every 21 days ϫ 5 treatments. ϳ7-month median disease control.
Dogs weighing Ͼ15 kg should be dosed at Median survival of 9 months.
1 mg/kg.
CCNU9 70 mg/m2 PO every 21 d ϫ 5 treatments ϳ3-month median survival, including
dogs treated with rescue therapies.
Prednisone 2 mg/kg/d ϫ 7 d, dose tapered over the Median duration of response: ϳ1 month
next 3 wk
COP (induction)16 6 weekly cycles of the following: Median survival not provided. Median
duration of response: ϳ3 months
Vincristine day 1: 0.7 mg/m2 IV
Cyclophosphamide days 4-7: 50 mg/m2 PO
Prednisone days 1-7: 20 mg/m2 PO every 12 h
COP (maintenance)16 Repeated weekly until relapse:
Methotrexate days 1 and 5: 5 mg/m2 PO
Cyclophosphamide day 3: 100 mg/m2 PO
Prednisone days 1, 3, 5, 7: 20 mg/m2 PO
Abbreviations: CCNU, cyclohexylchloroethylnitrosourea; COP, cyclophosphamide, Oncovin, and prednisone; IV, intravenously; PO, orally.
Disadvantages of this protocol include the potential for the veloped as a cardioprotective agent for individuals under-
common chemotherapy side effects of myelosuppression going doxorubicin therapy.6 With this goal, it may be admin-
and/or gastrointestinal upset, and the potential for the doxo- istered intravenously over 15 to 20 minutes immediately
rubicin-specific side effects of extravasation injury, anaphy- before doxorubicin. Another significant use of dexrazoxane
lactic reaction during or shortly after drug administration, is that, anecdotally, it completely abrogates doxorubicin-as-
and development of dilated cardiomyopathy and heart fail- sociated extravasation injury when administered within 3
ure. As mentioned previously, judicious administration of hours of extravasation.7,8 There is no set protocol for the use
antiemetics may circumvent nausea or vomiting, and use of a of dexrazoxane after doxorubicin extravasation. A conserva-
carefully placed intravenous catheter minimizes the risk of tive recommendation is to administer it within 3 hours of
extravasation injury. As with most chemotherapy protocols, doxorubicin extravasation and repeat the dose at 24 and 48
a blood count is measured the day of therapy as well as 7 days hours. Dexrazoxane itself is a vesicant, so caution is neces-
after each treatment. Dogs with a neutrophil count Ͼ2000 sary when administering this drug.
cells/␮L or a platelet count Ͼ75,000 cells/␮L should not be Some clients may shy away from treating their pets with
treated, and, if the 7-day blood count demonstrates a neutro- intravenous medications but are open to orally administered
phil count Ͼ1000 cells/␮L, fluoroquinolone antibiotics chemotherapy drugs. Further, some dogs may be fractious or
should be instituted for a minimum of 5 days. If the patient is difficult to restrain for IV treatments and oral therapy may be
actually febrile in addition to being neutropenic on day 7, an option. Although orally administered, it is still important
intravenous fluoroquinolones and ampicillin should be initi- to be sure that blood counts are measured before and at
ated. Anaphylactoid reactions are rarely associated with the indicated intervals after chemotherapy administration.
first treatment, but dogs should be carefully assessed for er-
ythema, urticaria, facial swelling, or even flatulence or nau- Cyclohexylchloroethylnitrosourea (CCNU);
sea (drooling or actual vomiting) during the 30 minutes after
doxorubicin administration. Should any of these signs arise,
(Lomustine) and Prednisone
2 mg/kg of diphenhydramine intramuscularly and 0.2 mg/kg This combination has been investigated as a treatment for
dexamethasone sodium phosphate (SP), also administered lymphoma.9 CCNU is a potent alkylating agent that may
intramuscularly, typically resolve the problem, and any re- cause profound neutropenia, cumulatively it may cause po-
maining dose can be administered once the reaction subsides. tentially irreversible thrombocytopenia, and it is associated
Animals that have had a reaction to doxorubicin should be with potentially fatal hepatotoxicity.10,11 Questions regard-
premedicated with both diphenhydramine and dexametha- ing the efficacy of hepato-supportive/protective agents (eg,
sone SP to minimize the risk of a second reaction. Finally, SAMe or milk thistle) in preventing or resolving CCNU-
dexrazoxane is a free-radical scavenging agent that was de- induced liver damage are unanswered as of the writing of this

3. Volume 24, Number 3, August 2009 159
Table 2. University of Wisconsin–Madison CHOP protocol18
Week and Drug Dose Follow-up
1: Vincristine 0.7 mg/m2 IV 2 mg/kg/d Median survival: ϳ13 months
Prednisone Median disease control: ϳ9 months
2: Cyclophosphamide 250 mg/m2 IV or PO
Prednisone 1.5 mg/kg/d
3: Vincristine 0.7 mg/m2 IV
Prednisone 1 mg/kg/d
4: Doxorubicin 30 mg/m2 IV (if Յ 15 kg: 1 mg/kg)
Prednisone 0.5 mg/kg/d
5: No drugs
6: Vincristine 0.7 mg/m2 IV
7: Cyclophosphamide 250 mg/m2 IV or PO
8: Vincristine 0.7 mg/m2 IV
9: Doxorubicin 30 mg/m2 IV (if Յ 15 kg: 1 mg/kg)
11: Vincristine 0.7 mg/m2 IV
13: Cyclophosphamide 250 mg/m2 IV or PO
15: Vincristine 0.7 mg/m2 IV
17: Doxorubicin 30 mg/m2 IV (if Յ 15 kg: 1 mg/kg)
19: Vincristine 0.7 mg/m2 IV
21: Cyclophosphamide 250 mg/m2 IV or PO
23: Vincristine 0.7 mg/m2 IV
25: Doxorubicin 30 mg/m2 IV (if Յ 15 kg: 1 mg/kg)
Abbreviations: CHOP, cyclophosphamide, hydroxyl-daunorubicin (doxorubicin; Adriamycin), Oncovin (vincristine), and prednisone; IV, intrave-
nously; PO, orally.
article. Thus, although it is an effective anticancer agent, care for the treatment of canine lymphoma. There are many
patients undergoing CCNU therapy must be carefully moni- variations of this particular combination of drugs, and all
tored. Because of the relatively poor median duration of tu- have similar median disease-free intervals and overall sur-
mor control (40 days) and overall survival (110 days), and vival times.17-23 Because of similarities in disease control and
because of the potentially significant toxicities, this protocol overall survival, only one CHOP protocol has been outlined
is not recommended as first-line therapy for dogs with lym- in this chapter (Table 2).18 Variations from this protocol
phoma. It is the opinion of this author that CCNU (combined include differences in the order of drug administration, addi-
with L-asparaginase and prednisone) is best reserved as a tion of L-asparaginase or methotrexate to the protocol, slight
rescue option for dogs with relapsed lymphoma.12 differences in drug doses, and increased or decreased protocol
duration. A 19-week CHOP protocol has been reported.19 The
Cyclophosphamide, Oncovin, and Prednisone 19-week protocol is essentially an accelerated version of
the University of Wisconsin-Madison protocol outlined in
The combination of cyclophosphamide, Oncovin (vincris-
Table 2. Instead of going to every-other-week treatments for
tine) and prednisone is a time-honored and effective way to
the last 8 doses of chemotherapy, weekly treatment intervals
treat lymphoma.2-16 The advantages include relatively few
are maintained. The median duration of first remission for
drugs in the protocol and relatively low expense associated
the 30 dogs treated with the 19-week protocol was reported
with each treatment. Disadvantages include the potential
as 174 days, compared with a median of 282 days for 53 dogs
specific side effects of sterile hemorrhagic cystitis from cyclo-
treated with the 25-week protocol. Because a “head to head”
phosphamide and perivascular irritation from vincristine ex-
travasation (see CHOP section for more discussion). Other comparison between the 25-week and 19-week protocols has
disadvantages include the prolonged maintenance portion of not been published, it is impossible to directly compare the
the protocol and the fact that some articles report shorter two. The main advantage to the 19-week protocol is that it is
median periods of disease control and overall survival.2 over sooner, perhaps making it logistically easier for some
clients.
According to 2 studies, the seemingly significant omission
CHOP Protocols and Beyond of L-asparaginase actually makes no apparent difference in
As mentioned earlier in this article, most veterinary oncolo- protocol efficacy.16,24 Thus, L-asparaginase can be saved for
gists consider CHOP protocols (consisting of cyclophospha- use as a rescue drug. Methotrexate, an antimetabolite that
mide, hydroxyl-daunorubicin [doxorubicin; Adriamycin], inhibits dihydrofolate reductase and depletes the body of
Oncovin [vincristine], and prednisone) as the standard of folates, was once a staple of combination chemotherapy pro-