J Vet Intern Med 2007;21:1355–1363

Comparison of COAP and UW-19 Protocols for Dogs with

Multicentric Lymphoma
Kenji Hosoya, William C. Kisseberth, Linda K. Lord, Francisco J. Alvarez, Ana Lara-Garcia,
Carrie E. Kosarek, Cheryl A. London, and C. Guillermo Couto

Background: Various chemotherapy protocols for treating lymphoma in dogs have been published; however, comparison of
protocols from different studies is difficult, especially when evaluating survival time and toxicoses.
Hypothesis: The choice of COAP (C, cyclophosphamide; O, vincristine; A, cytosine arabinoside; P, prednisone) and
a modified University of Wisconsin 19-week (UW-19) induction protocol has no influence on overall survival times in dogs
with lymphoma.
Animals: One hundred and one dogs with multicentric lymphoma.
Methods: Retrospective study (2001–2006). Dogs induced with either an 8-week COP-based protocol (C, cyclophospha-
mide; O, vincristine; and P, prednisone) with maintenance therapy (COAP group) or a 19-week CHOP (C, cyclophosphamide;
H, doxorubicin; O, vincristine; and P, prednisone) based protocol (UW-19 group) were compared in terms of the duration of
first remission, survival time, toxicoses, and cost.
Results: There were 71 dogs in the COAP group and 30 dogs in the UW-19 group. Various protocols were used after the
first relapse. The median duration of the first remission for the COAP and UW-19 groups were 94 days (range, 6–356 days)
and 174 days (28–438 days), respectively (P , .01). The median survival times for dogs in the COAP and UW-19 groups were
309 days (6–620 days) and 275 days (70–1102+ days), respectively (P 5 .09). Dogs in the COAP group had a hazard ratio of
1.9 (95% CI 1.1–3.4) for death relative to the UW-19 group (P 5 .03), after controlling for the confounders (World Health
Organization clinical stage, age, sex, use of doxorubicin during reinduction). The severity of neutropenia and gastrointestinal
toxicoses were significantly higher in the UW-19 group than in the COAP group (P 5 .01 and P , .01, respectively).
Conclusion and Clinical Importance: Use of a long-term doxorubicin-containing sequential combination chemotherapy
protocol is associated with a decreased risk of relapse and death relative to a non-doxorubicin-containing protocol.
Key words: Cancer; Chemotherapy; CHOP; COP; Cost.

ymphoma is the most common hematopoietic
L neoplasm in dogs, occurring in 13 to 24 per
100,000 dogs.1 The current standard of treatment for
dogs with lymphoma is sequential combination chemo-
therapy, and the results of treatment with various
chemotherapy protocols have been published.2–18 L-
asparaginase, cyclophosphamide, vincristine, predni-
sone, and doxorubicin are the most effective drugs,
and some or all of these agents are incorporated into
most induction chemotherapy protocols. During the
past 3 decades, the standard of care has shifted from so-
called COP-based protocols (C, cyclophosphamide; O,
vincristine; and P, prednisone) to CHOP-based proto-
cols (C, cyclophosphamide; H, doxorubicin; O, vincris-
tine; and P, prednisone). It is generally accepted that
CHOP-based protocols are associated with longer
From the Department of Veterinary Clinical Sciences and
Veterinary Teaching Hospital (Hosoya, Kisseberth, Alvarez, Lara-
Garcia, Kosarek, London, Couto); and Department of Veterinary
Preventive Medicine (Lord), College of Veterinary Medicine, The
Ohio State University, Columbus, OH. Dr Kosarek is presently
affiliated with the Department of Small Animal Medicine and Surgery,
College of Veterinary Medicine, University of Georgia, Athens, GA.
Presented in part at the 26th Annual Conference of the Veterinary
Cancer Society, Pine Mountain, GA, October 19–22, 2006.
Reprint requests: William C. Kisseberth, DVM, PhD, DACVIM
(Oncology), Department of Veterinary Clinical Sciences and
Veterinary Teaching Hospital, College of Veterinary Medicine, The
Ohio State University, Columbus, OH 43210; e-mail: kisseberth.2@
osu.edu.
Submitted November 28, 2006; Revised March 14, 2007, May 2,
2007, June 2, 2007; June 29, 2007.
Copyright E 2007 by the American College of Veterinary Internal
Medicine
0891-6640/07/2106-0027/$3.00/0
median duration of remission than COP-based proto-
cols. Median duration of remission that range from 3.3
to 6.0 months have been reported with COP-based
protocols, whereas the median duration of remission
that range from 5.0 to 10.9 months have been reported
with CHOP-based protocols.2–15,17–23 The role of mainte-
nance therapy after the initial induction period also has
been the subject of debate and investigation. The
addition of maintenance therapy immediately after
induction does not improve the duration of first
remission or overall survival for dogs induced with
different doxorubicin-based combination chemotherapy
protocols.11,13–15,18 The effect of maintenance or no
maintenance in COP-based protocols has not been
formally evaluated, although anecdotal experience
suggests that, without some form of maintenance
therapy, dogs treated with COP-based protocols often
relapse soon after induction.
Although the duration of remission is an objective
measurement and can be used to compare the initial
efficacy of induction protocols, it is less clear whether
a longer duration of first remission correlates with
longer overall survival in dogs with multicentric
lymphoma. Survival time, as opposed to the duration
of first remission, is influenced by many factors,
including the reinduction or rescue protocols used and
the owner’s willingness to continue treatment. Histori-
cally, longer survival times have been reported with
CHOP-based protocols, ranging from 5.8 to
17.0 months, compared with 7.3 to 9.7 months with
COP-based protocols.2–7,11,13–15,17 However, these reports
were published over a 30-year period, during which time
the quality of animal care and the average owner’s
commitment to their pet’s well being may have in-
1356 Hosoya et al
creased. Furthermore, in most instances, comparisons
between protocols have been made between studies done
at different institutions, by different oncologists, and
from different animal populations. Recently, a retrospec-
tive study by this group suggested that there was no
difference in survival times between dogs with lympho-
ma induced with COP- versus CHOP-based protocols.9
That study only included a small number of dogs who
received CHOP-based protocol, and the CHOP-based
protocol was selectively used for cases that were thought
to be less responsive to COP-based chemotherapy, such
as mediastinal form or gastrointestinal form.
Two protocols (COAP [C, cyclophosphamide; O,
vincristine; A, cytosine arabinoside; P, prednisone]
protocol and a modified University of Wisconsin-
Madison 19-week protocol [UW-19]) have been used
since 2001 as the initial induction protocols in dogs with
multicentric lymphoma treated at The Ohio State
University Veterinary Teaching Hospital (OSU-VTH),
where the choice of initial induction protocol largely was
dependent on the admitting clinician’s and owner’s
preferences. After choosing the induction protocol, dogs
were managed by the same group of clinicians, thus
potentially eliminating many of the biases inherent in
comparing dogs treated with different protocols at
different institutions. Several reinduction or rescue
protocols were equally available at the time of relapse
and also were chosen based on owner preference and the
judgment of the clinician who was assigned to the care of
the dog at the time of relapse.
The purpose of the study was to compare the
durations of first remission and survival in dogs with
multicentric lymphoma induced with either COAP with
maintenance therapy or UW-19 protocol without
maintenance therapy. We hypothesized that UW-19
protocol would be associated with longer duration of
first remission than COAP but that the choice of initial
induction protocol would have no significant influence
on overall survival time.
Materials and Methods
Dog Population and Selection
Medical records of dogs with multicentric lymphoma treated at
the OSU-VTH from January 1, 2001, to January 31, 2006, were
retrospectively reviewed. Inclusion criteria were (1) histologic or
cytologic diagnosis of lymphoma; (2) initiation of induction
chemotherapy during the study period; (3) clinical manifestation
of multicentric nodal involvement, that is, lymphomas that
primarily involve extranodal sites were excluded; (4) absence of
a previous history of chemotherapy other than corticosteroids.
The diagnosis of lymphoma was made on cytology of the
enlarged lymph nodes, histology of lymph-node biopsy, or both.
Immunophenotype (B or T cell) was determined by immunohisto-
chemistry by using antibodies to CD3 (T-cell markera) and CD 79a
and BLA 36 (B-cell markersb) flow cytometry by using multiple cell-
surface markers, or clonality assay by using polymerase chain
reaction.24–26 All dogs were retrospectively staged by using the World
Health Organization (WHO) clinical classification system for canine
lymphoma, on the basis of the available records of some or all of the
following: physical examination, CBC count, thoracic radiographs,
abdominal ultrasonography, and bone marrow aspiration cytolo-
gy.27 Bone marrow aspiration was not routinely performed if CBC
count changes indicated bone marrow involvement. Therefore, dogs
were considered to have bone marrow involvement when (1)
presence of neoplastic lymphocytes was demonstrated by bone
marrow cytology or (2) thrombocytopenia (,106 3 109 platelets/L;
reference range, 106–424 3 109 platelets/L) with or without
neutropenia (,3.0 3 106 cells/L; reference range, 3.0–10.4 3 106
cells/L), and the presence of circulating neoplastic lymphoid cells
were documented in the peripheral blood smear. Dogs also were
classified as substage a (absence of or mild clinical illness) or
substage b (moderate-to-severe lethargy or other systemic signs).
Clinical, hematologic, or biochemical abnormalities without sys-
temic illness, evidenced by ocular signs, cytopenias, hypercalcemia
were not by themselves considered as criteria for substage b.
Information extracted from the medical records included breed,
age, sex, hormonal status (intact versus neutered), weight, WHO
clinical stage (I–V), substage (a or b), immunophenotype (B versus
T), presence of extranodal involvement (eye/central nervous system
[CNS]/testicle, bone marrow, other), and presence of hypercalcemia
(.13.0 mg/dL; reference, 9.3–11.6 mg/dL).
Treatment Protocols
Two chemotherapy protocols, COAP (C, cyclophosphamide; O,
vincristine; A, cytosine arabinoside; P, prednisone) and a modified
University of Wisconsin 19-week (UW-19) protocols, were used
(Table 1).9,15 For dogs on the COAP protocol, LMP (L,
chlorambucil; M, methotrexate; P, prednisone) maintenance9 was
used at the conclusion of induction if the animal was in remission.
For dogs on the UW-19 protocol, chemotherapy was discontinued
after completion of the induction phase. In dogs who developed
hemorrhagic cystitis, chlorambucil was substituted for cyclophos-
phamide.
Reinduction or rescue protocols (Table 2) included vincristine-
based protocols (COP, CLOP, COAP, LMP/vincristine, and LMP/
vincristine/L-asparaginase protocols), doxorubicin-based protocols
(single agent doxorubicin, doxorubicin/cyclophosphamide [AC],
CHOP, UW-19, and modifications of UW-19), CCNU (lomustine)-
based protocols (single agent CCNU; CCNU/L-asparaginase;
CCNU/vincristine; and CVM: cyclophosphamide, vincristine, meth-
otrexate); DMAC (dexamethasone, melphalan, actinomycin D,
cytosine arabinoside); and others (single agent L-asparaginase,
cytosine arabinoside/mitoxantrone, and investigational agents).28
Tumor Response
Response was categorized as complete response (CR), evident
as complete resolution of disease; partial remission (PR), evident as
.50% but ,100% reduction of lymph node size; stable disease
(SD), evident as ,50% reduction or ,25% increase of lymph-node
size; progressive disease (PD), evident as .25% increase of lymph-
node size or development of a new extranodal lesion. Remission
duration of at least 3 weeks was required for classification of CR or
PR. Response rate (RR) was defined as the percentage of the dogs
who achieved CR or PR with a given protocol among all dogs who
received the same protocol. Duration of remission for a given
protocol was defined as the time, in days, from the start of the
protocol to development of progressive disease. Censored events
for the duration of remission analysis included death unrelated to
the disease and loss to follow-up with CR or PR. Survival time was
defined as the time, in days, from the initiation of chemotherapy to
the time of death. Censored events for the survival time analysis
included alive at the time of analysis (October 1, 2006), death
unrelated to the disease, loss to follow-up immediately after
initiation of the first or second reinduction protocol, and loss to
follow-up with CR or PR. Loss to follow-up while the disease was
in SD or PD was considered as a disease-related death, and counted
at the time of the last contact.
 Protocols for Canine Lymphoma 1357

Table 1. Induction protocols for dogs with multicentric lymphoma.

Week

Protocol 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 ˜
COAP
Cytosine arabinoside (300 mg/
N
m2 SC/IV drip)
Vincristine (0.5–0.75 mg/m2
N N N N N N N N
IV)
Cyclophosphamide (50 mg/m2
N N N N N N N N
PO EOD)
Prednisonea N N N N N N N N
LMP
Chlorambucil (20 mg/m2 PO) N N N N N N
Methotrexate (2.5–5 mg/m2
N N N N N N N N N N N
PO twice/wk)
Prednisone (20 mg/m2 PO
N N N N N N N N N N N
EOD)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
UW-19
L-asparaginase (400 mg/kg
N
IM)
2
Vincristine (0.5–0.7 mg/m IV) N N N N N N N N
Cyclophosphamide (200 mg/
N N N N
m2 IV)
Doxorubicin (30 mg/m2 or
N N N N
1 mg/kg IV)b
Prednisonec N N N N

a
40 mg/m2 PO q24h for 7 days, then 20 mg/m2 PO q48h thereafter.
b
30 mg/m2 for dogs .10 kg, 1 mg/kg for dogs ,10 kg.
c
2 mg/kg PO q24h for 7 days, 1.5 mg/kg PO q24h for 7 days, 1 mg/kg PO q24h for 7 days, then 0.5 mg/kg PO q24h for 7 days.

Toxicosis Co-operative Oncology Group-Common Terminology Criteria for

Adverse Events v. 1.0 (VCOG-CTCAE), with minor modification, in
Hematologic toxicoses were assessed by reviewing the CBC counts that sepsis was classified as grade 5 neutropenia and was distinguished
results and recorded at each treatment according to the Veterinary from grade 4 neutropenia without development of sepsis.29 Gastro-

Table 2. Reinduction protocols.

Vincristine-based protocols
COAP protocol See Table 1—induction protocols
COP protocol COAP without cytosine arabinoside
LMP/vincristine Add vincristine 0.5–0.75 mg/m2 IV q2 wk to LMP
Doxorubicin-based protocols
Single agent doxorubicin Doxorubicin 30 mg/m2 IV q3 wk
AC protocol Day 1: Doxorubicin 30 mg/m2 IV q3 wk
Day 10: Cyclophosphamide 200 mg/m2 PO
CHOP protocol Day 1: Doxorubicin 30 mg/m2 IV q3 wk
Day 8: Vincristine 0.75 mg/m2 IV
Day 10: Cyclophosphamide 200 mg/m2 PO
Day 15: Vincristine 0.75 mg/m2 IV
UW-19 protocol See Table 1—induction protocols
DMAC protocol Day 1: Actinomycin-D 0.75 mg/m2 IV
Cytosine arabinoside 300 mg/m2 SC
Dexamethasone 2.2 mg/kg SC
Day 14: Melphalan 20 mg/m2 PO
Dexamethasone 2.2 mg/kg PO
CCNU-based protocols
Single agent CCNU CCNU 60–80 mg/m2 PO q3 wk
CCNU/vincristine protocol Day 1: CCNU 60–80 mg/m2 PO q3 wk
Day 10: Vincristine 0.5–0.75 mg/m2 IV
CCNU/vincristine/methotrexate (CVM) Add methotrexate 2.5–5 mg/m2 PO twice/wk in CCNU/vincristine
protocol.
1358 Hosoya et al

intestinal toxicoses were assessed by reviewing the descriptions of the

Table 3. Distribution of WHO clinical stage, substage,
clinical signs and therapy instituted in the medical record. Gastroin-
testinal toxicoses were graded after each dose of chemotherapy
immunophenotype, and hypercalcemia.
according to VCOG-CTCAE. Toxicosis was scored as 0 if the dog had COAP Group, UW-19 Group,
abnormalities before treatments in the given parameter, unless it no. (%) no. (%)
progressed to the next grade after the treatment. Toxicosis grades for (n 5 71) (n 5 30) P Value
a given protocol were expressed as the highest grade during the period
from the first dose of the protocol to subsequent progression of the Staging methods
disease. Toxicoses recorded while dogs were in PD were not taken into CBC/ blood smear 71 (100) 30 (100) 1.00
consideration in the analysis, because it was difficult to assess whether Thoracic radiographs 37 (52) 24 (80) .01
abnormality related to therapy or disease. Abdominal ultrasound 34 (48) 22 (73) .03
Bone marrow 4 (6) 6 (20) .06
aspiration
Cost of the Treatment WHO stage .29
For dogs who received both treatment and management of I 1 (1) 0 (0)
adverse effects entirely at the OSU-VTH, the bill during the entire II 2 (3) 0 (0)
remission period (including the period during and after reinduc- III 26 (37) 7 (23)
tions until the ultimate progression of the disease) was extracted IV 22 (31) 13 (43)
from the OSU-VTH accounting database. Dogs who were V 20 (28) 10 (33)
presented with hypercalcemia were excluded from the analysis Substage .15
because of the cost associated with initial hospitalization. Although a 48 (68) 25 (83)
there were some minor changes in hospital charges during the study b 23 (32) 5 (17)
period (2001–2006; typically approximately a 5% increase per year), Extranodal involvement
this factor was not taken into account in the analysis. Bone marrow 8 (11) 1 (3) .27
Eye/CNS/testicle 10 (14) 1 (3) .17
Other sites 7 (10) 8 (27) .11
Statistical Analysis Immunophenotype ,.01
Comparisons were made between categorical variables by using B cell 34 (39) 27 (84)
the chi-square test. The Fisher exact test was used for categorical T cell 13 (15) 1 (3)
variables when the expected value of a given cell in the comparison Non-B/non-T/ 42 (47) 4 (13)
was less than 5. Comparisons between continuous variables were unknown
made by using the Student’s t-test. The severity of toxicoses was Hypercalcemia 10 (14) 0 (0) .03
compared by using the Mann-Whitney rank sum test and the
frequency of the toxicoses $grade 3 was compared between data COAP, cyclophosphamide, vincristine, cytosine arabinoside,
sets by using the chi-square test. The total cost during the entire prednisone; UW-19, University of Wisconsin 19-week induction
remission period were plotted against the time and compared by protocol; CNS, central nervous system.
the Student’s t-test after excluding the outliers.
The duration of remission and survival time curves were generated In all analyses, a P value ,.05 was considered statistically
by using the Kaplan-Meier product limit method, and median significant. Statistical analyses were performed by using Prism 4c
duration of first remission and survival time were calculated. and Stata version 9.1.d
Comparisons between treatment groups were made by using the
log-rank test. Cox proportional hazards models were used to compare
duration of first remission and survival time between the 2 treatment
Results
groups after adjusting for potential confounders. Potential confoun- Dogs
ders that were evaluated in the models included age (in years),
hormonal status (intact or neutered), sex, body weight, immunophe- One hundred and one dogs met the inclusion criteria: 71
notype (B cell, T cell, or unknown), WHO clinical stage (stage I–IV or dogs (70%) were induced with COAP protocol (COAP
V), substage (a or b), primary faculty clinician, presence of bone group), and 30 dogs (30%) with the UW-19 protocol (UW-
marrow involvement, presence of hypercalcemia, year of admission, 19 group). Breeds included were mixed breed (13), Golden
use of corticosteroid before initiation of chemotherapy, and use of Retriever (9), Labrador Retriever (6), Boxer (4), Rottweiler
doxorubicin during reinduction period. Because the primary com-
(4), Doberman Pinscher (4), and German Shepherd Dog (4)
parison focused on the difference between the 2 treatment groups, the
in the COAP group; and mixed breed (8), Golden Retriever
variable for treatment group was forced into the initial model.
Bivariate Cox proportional hazards regression model analyses were (4), Shih Tzu (3), Labrador Retriever (2), and Rottweiler (2)
performed to screen potential confounding variables for subsequent in the UW-19 group. Age was 8.0 6 2.6 years (mean 6 SD)
inclusion in the multivariate analysis. Variables with P values #.25 in and 8.4 6 2.7 years in the COAP and UW-19 groups,
these bivariate analyses were included in the multivariate analysis. respectively (P 5 .47). Body weight was 30.3 6 13.8 kg and
Variables were removed from the full multivariate model on the basis 29.7 6 16.2 kg in the COAP and UW-19 groups, re-
of results of the likelihood ratio test. Biologically meaningful spectively (P 5 .86). There were 37 males (6 intact) and 34
interactions between the main effect variables in the model were females (1 intact) in the COAP group, and 13 males (2
tested for inclusion in a similar manner. intact) and 17 females (1 intact) in the UW-19 group (P 5
Before the model building process, the proportional hazards
.51). There was no significant difference in the proportions
assumption was tested on each variable by means of Schoenfeld
residuals and graphical techniques to determine whether the log
of neutered animals between groups (P 5 1.00).
hazard ratio function was constant over time.30 After the model The methods of staging and the distribution of the
building process, the assumption of proportional hazards was WHO clinical stage, substage, immunophenotype, and
again tested for each variable included in the final model. presence of hypercalcemia are summarized in Table 3.
 Protocols for Canine Lymphoma 1359

Table 4. Distribution of reinduction protocols.

No. Reinduction Attempt (%)

Reinduction protocol 2nd 3rd 4th 5th 6th

COAP group
Vincristine based 32 (45) 2 (3) 0 (0) 0 (0) 0 (0)
Doxorubicin based 4 (6) 4 (6) 8 (11) 4 (6) 2 (3)
CCNU based 13 (18) 13 (18) 6 (8) 4 (6) 0 (0)
DMAC 4 (6) 16 (23) 5 (7) 2 (3) 0 (0)
Other 0 (0) 2 (3) 1 (1) 1 (1) 0 (0)
Total 53 (75) 37 (52) 20 (28) 11 (15) 2 (3)

UW-19 group
Vincristine-based 7 (23) 1 (3) 2 (7) 1 (3) 0 (0)
Doxorubicin-based 6 (20) 1 (3) 0 (0) 1 (3) 0 (0)
CCNU-based 6 (20) 4 (13) 1 (3) 1(3) 0 (0)
DMAC 4 (13) 7 (23) 1 (3) 0 (0) 0 (0)
Other 0 (0) 1 (3) 2 (7) 1 (3) 1 (3)
Total 23 (77) 15 (50) 6 (20) 4 (13) 1 (3)

COAP, cyclophosphamide, vincristine, cytosine arabinoside, prednisone; CCNU, lomustine; DMAC, dexamethasone, melphalan,
actinomycin D, cytosine arabinoside; UW-19, University of Wisconsin 19-week induction protocol.

Thoracic radiographs and abdominal ultrasonography RR between groups (P 5 .17 and .18, respectively).
were more frequently performed in the dogs in the UW- However, the median duration of first remission was
19 group than in the COAP group (P 5 .01, and .03, significantly shorter in the COAP group at 94 days (95%
respectively). There were no significant differences in CI 69–132 days) than the UW-19 group at 174 days
WHO clinical stage (P 5 .29), substage (P 5 .15), or (95% CI 120–265 days) (P , .01) (Fig 1). The WHO
extranodal involvement (bone marrow, P 5 .27; ocular/ clinical stage (I–IV versus V) was identified as a signif-
CNS, P 5 .17; other sites, P 5 .11) between the COAP icant confounder in the multivariate Cox proportional
and UW-19 groups. Hypercalcemia was more common hazards model (Table 5). After adjusting for the WHO
in dogs in the COAP group than in the UW-19 group (P clinical stage, dogs in the COAP group were found to
5 .03). Similarly, there were significantly more dogs have a 2.6 times higher risk for relapse than dogs in the
with T-cell lymphoma in the COAP group than in the UW-19 group (95% CI 1.6–4.4, P , .01).
UW-19 group (P , .01), although immunophenotype
was less frequently known in the COAP group than the Overall Survival Time
UW-19 group (P , .01). Six dogs received a short course
of corticosteroid for their lymphoma before presenta- The median survival times for dogs in the COAP and
tion (,2 weeks), and additional 2 dogs were chronically UW-19 groups were 309 days (95% CI 189–351 days)
on corticosteroid for reasons other than lymphoma. and 275 days (95% CI 179–502 days), respectively (P 5
.09) (Fig 2). The 1- and 2-year survival rate for the
Reinduction Protocols
Eighteen dogs (25%) in the COAP group and 7 dogs
(23%) in the UW-19 group did not receive reinduction
chemotherapy. The percentage of dogs that underwent the
2nd, 3rd, 4th, 5th, and 6th induction chemotherapy were
75, 52, 28, 15, and 3% in COAP group, respectively, and
77, 50, 20, 13, and 3% in UW-19 group, respectively
(Table 4). There was no difference in the proportion of
dogs who received these reinduction chemotherapy pro-
tocols between the COAP and UW-19 groups (P 5 .79).

Duration of First Remission

The initial response in the COAP group was CR in 43
dogs (61%), PR in 22 dogs (31%), SD in 2 dogs (3%),
and PD in 4 dogs (6%), resulting in a RR of 92%. The
initial response in the UW-19 group was CR in 23 dogs
(77%) and PR in 7 dogs (23%), resulting in a RR of
100%. There was no significant difference in CR rate or
Fig 1. Kaplan-Meier curves for the duration of first remission for
dogs with multicentric lymphoma. Dogs were treated with COAP
(n 5 71, solid line) or modified UW-19 protocol (n 5 30,
dashed line).
1360 Hosoya et al

Table 5. Final multivariate Cox proportional hazards

models for the analysis of duration of first remission and
survival time for comparison of COAP to UW-19
protocols for treatment of canine lymphoma.
Model for duration of first remission

Hazard
Variable Ratio (95% CI) P Value
Treatment (COAP versus referent 2.6 1.6–4.4 ,.01
group UW-19)
WHO clinical stage (stage V versus 1.1 1.0–1.2 .02
referent group I–IV)

Note: Other potential confounders that did not enter the final
model were age (in years), hormonal status (intact or neutered),
sex, body weight, immunophenotype (B cell, T cell, or unknown),
substage (a or b), primary faculty clinician, presence of bone Fig 2. Kaplan-Meier curves for the survival times for dogs with
marrow involvement, presence of hypercalcemia, year of admis- multicentric lymphoma. Dogs were induced with COAP (n 5 71,
sion, use of corticosteroid before initiation of chemotherapy, and solid line) or modified UW-19 protocol (n 5 30, dashed line).
use of doxorubicin during reinduction period. Various protocols were used after the first relapse.

reinduction phase favorable to dogs who did not) were

Model for survival time identified as significant confounders in the multivariate
Hazard Cox proportional hazards model (Table 5). After
Variable Ratio (95% CI) P Value adjusting for these confounders, dogs in the COAP
Treatment (COAP versus referent 1.9 1.1–3.4 .03
group were found to have a 1.9 times higher risk for
group UW-19) death compared with the dogs in the UW-19 group (95%
Sex (male versus referent group 2.4 1.4–4.3 ,.01 CI 1.1–3.4, P 5 .03).
female)
WHO clinical stage (stage V versus 1.1 1.0–1.3 .03 Toxicoses
referent group I–IV)
Age (in years) 1.1 1.0–1.2 .049 The mean neutropenia and gastrointestinal toxicosis
Use of doxorubicin during 0.5 0.3–0.8 .04 grades were significantly higher in the UW-19 group
reinduction (P 5 .01 and P , .01, respectively) (Table 6). Hema-
tologic toxicoses $grade 3 occurred in 7 dogs (10%) in
Note: Other potential confounders that did not enter the final
model were hormonal status (intact or neutered), body weight,
the COAP group and in 7 dogs (23%) in the UW-19
immunophenotype (B cell, T cell, or unknown), substage (a or b), group. Gastrointestinal toxicoses $grade 3 occurred in 9
primary faculty clinician, presence of bone marrow involvement, dogs (13%) in the COAP group and in 7 dogs (23%) in
presence of hypercalcemia, year of admission, and use of the UW-19 group. Other toxicoses included acute tumor
corticosteroid before initiation of chemotherapy. lysis syndrome (1 dog) in the COAP group, and
COAP, cyclophosphamide, vincristine, cytosine arabinoside, hemorrhagic cystitis (2 dogs) and acute tumor lysis
prednisone; UW-19, University of Wisconsin 19-week induction syndrome (1 dog) in the UW-19 group. The differences
protocol; WHO, World Health Organization. in frequency of $grade 3 neutropenia (P 5 .08),
thrombocytopenia (P 5 .15), and $grade 3 gastrointes-
tinal toxicoses (P 5 .23) between the 2 groups were not
COAP group was 32 and 0%, respectively. The 1- and 2- statistically significant.
year survival rate for the UW-19 group was 45 and 17%,
respectively. The results were similar when only dogs
Cost Analysis
with B-cell lymphoma were compared (data not shown).
When T- and B-cell lymphomas within the COAP group Thirty-four dogs in the COAP group and 22 dogs in
(n 5 11 and 24, respectively) were compared, there was the UW-19 group received all treatment and manage-
no significant difference in survival time between ment of toxicoses at the OSU-VTH from the initiation
immunophenotypes (B cell, 321 days; T cell, 378 days; of the induction protocol until the final disease pro-
P 5 .58). A comparison of survival times in dogs with B- gression or the loss to follow-up. Two dogs had
and T-cell lymphomas was not performed in UW-19 exceptionally long total durations of remission (794
group, because there was only 1 dog with T-cell and 1102 days) in the UW-19 group and were excluded
lymphoma in the group. from the cost comparison. For the remaining dogs, the
The WHO clinical stage (I–IV favorable to V), sex mean (6SD) duration of entire remission (or follow-up
(female favorable to male), age (younger dogs favorable time) for the COAP and UW-19 groups were 197 6
to older dogs), and use of doxorubicin during reinduc- 26 days and 243 6 37 days, respectively (P 5 .30). The
tion (dogs received doxorubicin at any time during mean (6SD) total cost during these period for the
 Protocols for Canine Lymphoma 1361

Table 6. Distribution of toxicosis grade during the during this time period, there was a clinical study in
initial induction (and maintenance in COAP progress that required induction with UW-19 for
group) period. enrollment and dogs with T-cell lymphomas or with
hypercalcemia were more commonly treated with
Hematologic COAP Group, no. UW-19 Group, no. COAP. Because, historically, dogs with the T-cell
toxicoses (%) (n 5 71) (%) (n 5 30) phenotype have been reported to have a poor prognosis,
Neutropenia this selection bias could have skewed the remission and
Grade 1 19 (27) 9 (30) survival data in favor of the UW-19 group; however, the
Grade 2 2 (3) 4 (13) duration of remission and the survival time curves were
Grade 3 2 (3) 3 (10) not different between phenotypes in the COAP group in
Grade 4 3 (4) 3 (10) animals where immunophenotyping was available.22,31–34
Grade 5 0 (0) 0 (0) Differences in staging methods may have influenced the
WHO clinical stage distribution in the 2 groups;
Thrombocytopenia
Grade 1 3 (4) 0 (0)
abdominal ultrasonography and thoracic radiographs
Grade 2 1 (1) 2 (7) were more commonly performed in dogs in the UW-19
Grade 3 1 (1) 1 (3) group, also reflecting individual clinician preferences.
Grade 4 0 (0) 0 (0) However, this difference is unlikely to have had any
impact on the remission and survival data, because dogs
Anemia with lymphoma in stages III and IV historically have the
Grade 1 30 (42) 16 (53) same prognosis, and only 1 dog in COAP group was
Grade 2 7 (10) 5 (17) classified as stage I, without results of thoracic radio-
Grade 3 1 (1) 0 (0)
graphs and abdominal ultrasonography.17,35 Because
Grade 4 0 (0) 0 (0)
many of stage V cases were classified as such because
Gastrointestinal toxicoses of extranodal involvement found in thoracic radio-
Grade 1 16 (23) 8 (27) graphs or abdominal ultrasonography, the Cox pro-
Grade 2 10 (14) 9 (30) portional hazards model was repeated by using only
Grade 3 8 (11) 5 (17) bone marrow involvement as the classification of stage
Grade 4 1 (1) 2 (7) V, and the results were similar (data not shown). Finally,
evaluating dogs at only one practice, particularly
COAP, cyclophosphamide, vincristine, cytosine arabinoside, a tertiary-referral practice, could mean that the types
prednisone; UW-19, University of Wisconsin 19-week induction
of cases included are not typical of dogs with lymphoma
protocol.
seen by a nonspecialty general practice.
Duration of first remissions and survival times for the
COAP and UW-19 groups were $3,515 6 $366 and COAP and UW-19 protocols in this study generally were
$3,581 6 $432, respectively (P 5 .91). consistent with previously published studies that used the
same protocols, although the duration of first remission
Discussion and survival time for the UW-19 protocol were somewhat
shorter than that reported for other versions of the
This study compared 2 groups of dogs with multi- Wisconsin protocol.4,9,14,15 In another retrospective study
centric lymphoma induced with either COAP and LMP where the UW-19 protocol was used, the first remission
maintenance chemotherapy or the UW-19 protocol duration and overall survival time were 206 and 310 days,
without maintenance for induction of remission at respectively, comparable with this study.15 Duration of
a single institution over the same time period. Use of first remission was calculated from the beginning of
the UW-19 protocol as the initial induction protocol was chemotherapy induction to relapse. Although duration of
associated with a longer duration of first remission and remissions were longer with the UW-19 protocol, because
a significant survival advantage compared with dogs it is considerably longer (19 weeks) than that of COAP
treated with the COAP protocol and LMP maintenance. protocol (8 weeks), the median duration of remission
However, the severity of neutropenia and gastrointesti- after completion of the induction protocol was similar
nal toxicoses with the UW-19 protocol were significantly (44 days in COAP protocol and 48 days in UW-19
higher than with the COAP protocol. protocol) in the 2 protocols.
The patient population was comparable in the 2 Comparison of survival time was complicated by the
groups in this study; however, although the choice of various reinduction protocols used, and, thus, care must
initial induction protocol was determined in part by be taken when interpreting these data. Because all dogs
clinician preference, there are several potential animal- were treated during the same time period by the same
selection biases. For example, owners with financial group of clinicians and there were no differences in the
limitations or those who were unsure about pursuing proportion of dogs who underwent reinduction or in the
chemotherapy for their pets may have tended to select type of reinduction protocols used, we believe this is a valid
the COAP protocol rather than the UW-19 protocol as comparison. The median survival times were not signif-
an induction. Furthermore, COAP protocol is preferred icantly different between the COAP and UW-19 groups in
by some clinicians in our practice for dogs with ocular, the univariate analysis. In fact, the survival curves were
CNS, or both involvement, or with hypercalcemia. Also, nearly identical up to approximately 300 days, although
1362 Hosoya et al
the 1- and 2-year survival rates were higher in the UW-19
group than the COAP group. Furthermore, when the data
were adjusted for significant confounders (age, sex, use of
doxorubicin during reinduction, and WHO clinical stage),
the dogs in the COAP group had a significantly higher risk
for death than the dogs in UW-19 group. Sex and WHO
clinical stage have also been reported to be prognostic
factors in other studies.3,4,19,20,36 These findings might
indicate that although the influence of the choice of initial
induction protocol on survival is relatively small for the
majority of dogs, there is a portion of dogs who have
a long-term survival advantage by being treated with the
UW-19 protocol for initial induction. Further studies are
warranted to test this hypothesis.
The frequency of $grade 3 hematologic or gastroin-
testinal toxicoses was not different between the 2
induction protocols, although the retrospective assess-
ment of gastrointestinal toxicosis requires a careful
interpretation. The frequency of toxicoses was expected
to be higher with UW-19 protocol, but the lack of
significance could be explained by the low frequency of
such toxicosis in both protocols. Although the difference
was not statistically significant between the 2 protocols
in the current study, the actual frequency was similar to
the previous studies (8.7% with COP- and 17% with
CHOP-based protocols).9,17 Although the frequency of
$grade 3 toxicoses did not differ significantly, the mean
grade of neutropenia and gastrointestinal toxicoses were
significantly greater in UW-19 protocol than COAP
protocol. This is expected, because the UW-19 protocol
contains doxorubicin and the treatment protocol is
considerably longer than the COAP protocol.
Although the COAP protocol initially was associated
with lower treatment costs and potentially lower
toxicosis management cost, most dogs treated with
COAP received subsequent reinduction protocols sooner
than dogs treated with UW-19, therefore, the total cost
became similar in the long term. In fact, dogs in both
groups received very similar treatment overall, differing
only in the order and timing of treatments.
As with any retrospective study for treatment of
lymphoma in dogs, biases may exist in this study
because of uncontrolled factors, such as factors influ-
encing protocol selection, owner’s commitment to treat
and financial considerations, animal selection based on
the presentation, and inconsistently used reinduction
protocols. Therefore, care must be taken not to over-
state the findings of the current study. It also is possible
that other confounders exist that were not controlled for
in our modeling. Nevertheless, our models suggest that
dogs treated with COAP were at approximately 2 times
higher risk for relapse and death than dogs induced with
the UW-19 protocol. Future, randomized prospective
studies are warranted to further assess the influence of
induction protocol and maintenance chemotherapy on
survival in dogs with lymphoma.
Footnotes
a
CD3 T-cell marker, DAKO Corp, Carpinteria, CA
b
CD 79a and BLA 36 B-cell markers, DAKO Corp, Carpinteria,
CA
c
Prism 4, GraphPad, Inc, San Diego, CA
d
Stata version 9.1 (StataCorp, College Station, TX
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