For dogs treated with 15-week CHOP protocol in this study, comparable time to progression and overall survival time with 25-week modified UW-Madison protocol were showed. However, the result may be different if longer follow-up time is allowed, especially for dogs treated with 15-week protocol here, in the future. Adverse events were well-tolerated and the incidence and severity were similar between two groups.
Experiencing toxicity such as neutropenia might imply a more effective drug exposure and resulted in a longer survival in the study. Dogs able to attain complete remission as best response during the treatment were expected to have longer remission duration and potentially overall survival time.
Figures
Fig. 1. The Kaplan-Meier curve for time to progression (TTP) of the two groups The median TTP was 242 days for the 25-week group (solid line, n=42) and 217 days for the 15-week group (dashed line, n=22). No significant difference was observed (P=0.503).
Fig. 2. The Kaplan-Meier curve for overall survival time (OST) of the two groups The median OST was 354 days for the 25-week group (solid line, n=42) and 326 days for the 15-week group (dashed line, n=22). No significant difference was observed (P=0.999).
Fig. 3. The Kaplan-Meier curve of time to progression (TTP) for body weight (< and ≥ median body weight) from all patients
The median TTP was 273 days for dogs < 16.15 kg (solid line, n=32) and 156 days for dogs ≥ 16.15 kg (dashed line, n=32). Significant difference between two groups was observed (P=0.01).
Fig. 4. The Kaplan-Meier curve of time to progression (TTP) for breed (Non-GR and GR) from all patients
The median TTP was 244 days for non-GR (solid line, n=48) and 126 days for GR (dashed line, n=16). Significant difference between two groups was observed (P=0.024).
Fig. 5. The Kaplan-Meier curve of time to progression (TTP) for response to treatment (CR and Non-CR) from all patients
The median TTP was 244 days for CR (solid line, n=56) and 56 days for non-CR (dashed line, n=8). Significant difference between two groups was observed (P=0.000).
Fig. 6. The Kaplan-Meier curve of time to progression (TTP) for substage (a and b) from all patients
The median TTP was 273 days for substage a (solid line, n=35) and 209 days for substage b (dashed line, n=29). No significant difference between two groups was observed (P=0.069).
Fig. 7. The Kaplan-Meier curve of overall survival time (OST) for body weight (< and ≥ median body weight) from all patients
The median OST was 555 days for dogs < 16.15 kg (solid line, n=32) and 307 days for dogs ≥ 16.15 kg (dashed line, n=32). Significant difference between two groups was observed (P=0.002).
Fig. 8. The Kaplan-Meier curve of overall survival time (OST) for breed (Non-GR and GR) from all patients
The median TTP was 496 days for non-GR (solid line, n=48) and 245 days for GR (dashed line, n=16). Significant difference between two groups was observed (P=0.007).
Fig. 9. The Kaplan-Meier curve of overall survival time (OST) for the presence of neutropenia during treatment from all patients
The median OST was 514 days for dogs experiencing neutropenia (absolute neutrophil count <3000 /uL) during treatment (solid line, n=34) and 313 days for dogs who hadn’t experienced neutropenia (dashed line, n=30). Significant difference between two groups was observed (P=0.029).
Fig. 10. The Kaplan-Meier curve of overall survival time (OST) for response to treatment (CR and Non-CR) from all patients
The median OST was 392 days for CR (solid line, n=56) and 189 days for non-CR (dashed line, n=8). Significant difference between two groups was observed (P=0.016).
Tables
Table 1. World Health Organization’s clinical staging system for lymphoma in domestic animals
Stage Criteria
I Involvement limited to a single node or lymphoid tissue in a single organ a II Involvement of many lymph nodes in a regional area (± tonsils)
III Generalized lymph node involvement
IV Liver and/or spleen involvement (± stage III)
V Manifestation in the blood and involvement of bone marrow and/or other organ systems, e.g. intestine, lung, neoplastic effusion (± stage I-IV) Each stage is subclassified into:
a Without systemic signs b With systemic signs
a Excluding bone marrow.
Table 2. 15-week CHOP protocol dosing schedule
Chemotherapy agents
Week
1 2 3 4 5 6 7 9 10 11 13 14 15
Vincristine 0.7 mg/m2 IV Cyclophosphamide 250 mg/m2 PO
Doxorubicin 30 mg/m2 IV a
Prednisolone (mg/kg) Q24H PO 2.0 1.5 1.0 0.5
a Patients with body weight <15 kg could receive doxorubicin at 1 mg/kg either
Table 3. Modified University of Wisconsin-Madison protocol without maintenance (25-week protocol dosing schedule)
Chemotherapy agents Week
1 2 3 4 5 6 7 8 9 11 13 15 17 19 21 23 25
Vincristine 0.7 mg/m2 IV Cyclophosphamide 250 mg/m2 PO
Doxorubicin 30 mg/m2 IV a or Mitoxantrone 6 mg/m2 IV
Prednisolone (mg/kg) Q24H PO 2.0 1.5 1.0 0.5
a Patients with body weight <15 kg could receive doxorubicin at 1 mg/kg either
Table 4. Veterinary Cooperative Oncology Group Common Terminology Criteria for nutrition; PPN, partial parental nutrition; ADL, activities of daily living (eating, sleeping, defecating and urinating)
Table 5. Comparison of characteristics between two groups
There was no significant difference in the distribution of patient and disease characteristics between two groups.
25-week (n=42) 15-week (n=22) P value 25-week (n=42) 15-week (n=22) P value
Gender 0.583 Steroid pretreatment 0.257
Female spayed 17 (40.5%) 8 (36.4%) Yes 5 (11.9%) 5 (22.7%)
Hypercalcemia b 0.449 Baseline neutrophil (/uL) 0.661
Yes 1 (2.6%) 0 (0%) Mean (range) 9293 (3139-29211) 8976 (3542-28576)
No 38 (97.4%) 22 (100%)
a 8 dogs in 25-week group were lack of information of abdominal image to determine liver/spleen involvement.
Table 6. Distribution of findings in laboratory examination at diagnosis between two groups
There was no significant difference in the distribution of abnormal laboratory findings between two groups.
25-week (n=42) 15-week (n=22) P value 25-week (n=42) 15-week (n=22) P value
Anemia 0.730 Lymphocytosis 2 (4.8%) 3 (13.6%) 0.329
WNRa 21 (50%) 12 (54.5%) Leukocytosis 9 (21.4%) 4 (18.2%) 1.000
Grade 1 16 (38.1%) 6 (27.3%) Hypercalcemia c 1 (2.6%) 0 (0%) 0.449
Grade 2 4 (9.5%) 3 (13.6%) Neutrophil (/µL) 0.661
Grade 3 1 (2.4%) 1 (4.5%) Mean±SD 10881±5948 10388±6089
Grade 4 0 (0%) 0
(0%) Median (range) 9293
(3139-29211)
8976 (3542-28576)
Thrombocytopenia b 0.469 Globulin (/µL) d 0.508
WNRa 29 (72.5%) 14 (63.6%) Mean±SD 3.3±0.59 3.2±0.42
Grade 1 9 (22.5%) 4 (18.2%) Median (range) 3.2 (2.2-4.7) 3.3 (2.4-3.8)
Grade 2 2 (5%) 4 (18.2%)
Grade 3 0 (0%) 0 (0%)
Grade 4 0 (0%) 0 (0%)
a WNR: within normal range
b 2 dogs from 25-week group were unable to be graded due to clotting sample.
c Serum calcium concentration > 12 mg/dL. 3 dogs in 25-week group were lack of information of serum calcium concentration.
d 3 dog were lack of information of globulin at diagnosis
Table 7. Summary of response to treatment in two groups
There was no significant difference in objective response rate and distribution of each response between two groups.
25-week (n=42) 15-week (n=22) P value
Objective response rate a 41 (97.6%) 22 (100%) 0.466
Complete remission 35 (83.3%) 21 (95.5%) 0.364
Partial remission 6 (14.3%) 1 (4.5%)
Stable disease 1 (2.4%) 0 (0%)
Progressive disease 0 (0%) 0 (0%)
a The percentage of complete and partial remission
Table 8. Summary of median time to progression (TTP) and overall survival time (OST) for two groups There was no significant difference in median TTP and OST between two groups.
25-week (n=42) 15-week (n=22) P value
Median TTP 242 days 217 days 0.503
Median OST 354 days 326 days 0.999
Table 9. Summary of adverse events and dose adjustment for two groups
There was no significant difference in the rate of occurrence for each adverse event between two groups. Most episodes from each event were grade 1 to 2. For dose adjustment, significantly more patients in 15-week group received dose reduction for ATLS prevention (P=0.000).
Adverse events 25-week (n=42) 15-week (n=22) P value Adverse events 25-week (n=42) 15-week (n=22) P value
Neutropenia a Vomiting
Table 10. Univariate analysis of factors associated with demographics of patients in the whole population for attaining CR or not
The rate of complete remission was significantly lower in dogs with body weight higher than median value and Golden retrievers (P=0.002 and 0.000, respectively).
Factor Number % of complete remission P value Factor Number % of complete remission P value
Age (years) 0.635 Stage 0.911
< 8 (median) 29 89.7 5 15 86.7
≥ 8 (median) 35 85.7 < 5 49 87.8
Body weight (kg) 0.002 Substage 0.296
< 16.15 (median) 32 100 a 35 91.4
≥ 16.15 (median) 32 75 b 29 82.8
Breed 0.000* Immunophenotype a 0.628
Golden retriever 16 62.5 B 42 92.9
Other breeds 48 95.8 T 3 100
Sex 0.341 Null 6 83.3
Female spayed 25 84 Steroid pretreatment 0.795
Female intact 9 88.9 No 54 87.0
Male castrated 23 95.7 Yes 10 90.0
Male intact 7 71.4
a 13 dogs were lack of information of immunophenotype.
* The exact P value was 0.00048
Table 11. Univariate analysis of factors associated with clinical findings in the whole population for attaining CR or not
The rate of complete remission was significantly different between dogs with thoracic involvement and those without (P=0.018). Dogs with thoracic involvement had significantly lower rate of complete remission.
Factor Number % of complete remission P value Factor Number % of complete remission P value Thoracic
a 17 dogs were lack of information of thoracic radiography.
b .
Table 12. Univariate analysis of factors associated with adverse events and treatment in the whole population for attaining CR or not No factors associated with adverse events and treatment resulted in significant difference for attaining CR or not.
Factor Number % of complete remission P value Factor Number % of complete remission P value
Neutropenia a Diarrhea
a Neutropenia was defined as absolute neutrophil count <3000 /uL; thrombocytopenia was defined as platelet count <100,000 /uL.
b Factors only evaluated in 25-week group. Three dogs experiencing drug switch between doxorubicin and mitoxantrone were not purely CHOP or CMOP and thus not included.
Table 13. Univariate analysis of factors associated with demographics of patients in the whole population for time to progression (TTP) Time to progression was significantly shorter in dogs with body weight higher than median value and Golden retrievers (P=0.010 and 0.024, respectively).
Factor Number Median TTP (days) P value Factor Number Median TTP (days) P value
Age (years) 0.872 Stage 0.591
< 8 (median) 29 231 5 15 231
≥ 8 (median) 35 209 < 5 49 242
Body weight (kg) 0.010 Substage 0.069
< 16.15 (median) 32 273 a 35 273
≥ 16.15 (median) 32 156 b 29 209
Breed 0.024 Immunophenotype a 0.675
Golden retriever 16 126 B 42 244
Other breeds 48 244 T 3 202
Sex 0.149* Null 6 104
Female spayed 25 237 Steroid pretreatment 0.347
Female intact 9 231 No 54 237
Male castrated 23 259 Yes 10 202
Male intact 7 165
Table 14. Univariate analysis of factors associated with clinical findings in the whole population for time to progression (TTP) No factors associated with clinical findings resulted in significant difference in median TTP.
Factor Number Median TTP (days) P value Factor Number Median TTP (days) P value
a 17 dogs were lack of information of thoracic radiography.
b 2 dogs were unable to be assessed due to clotting sample.
c 3 dog were lack of information of globulin at diagnosis.
Table 15. Univariate analysis of factors associated with adverse events and treatment in the whole population for time to progression (TTP) Dogs with complete remission had significantly longer TTP than dogs who failed to attain complete remission (P=0.000).
Factor Number Median TTP (days) P value Factor Number Median TTP (days) P value
Table 16. Multivariate analysis of univariate factors with significance in the whole population for time to progression (TTP)
Dogs who failed to attain CR had significantly higher hazards ratio than those able to attain CR as their best response.
Factor Number Hazards ratio 95% CI P value
Body weight (kg) 1.625 0.804-3.282 0.176
< Median 32
≥ Median 32
Breed 1.000 0.440-2.273 0.999
Other breeds 48
Golden retriever 16
Response to treatment 3.560 1.433-8.842 0.006
CR 56
Non-CR 8
Table 17. Univariate analysis of factors associated with demographics of patients in the whole population for overall survival time (OST) Overall survival time was significantly shorter in dogs with body weight higher than median value and Golden retrievers (P=0.002 and 0.007, respectively).
Factor Number Median OST (days) P value Factor Number Median OST (days) P value
Age (years) 0.223 Stage 0.906
< 8 (median) 29 392 5 15 392
≥ 8 (median) 35 309 < 5 49 326
Body weight (kg) 0.002 Substage 0.237
< 16.15 (median) 32 555 a 35 501
≥ 16.15 (median) 32 307 b 29 309
Breed 0.007 Immunophenotype a 0.365
Golden retriever 16 245 B 42 392
Other breeds 48 496 T 3 309
Sex 0.529 Null 6 189
Female spayed 25 469 Steroid pretreatment 0.231
Female intact 9 572 No 54 379
Male castrated 23 392 Yes 10 311
Table 18. Univariate analysis of factors associated with clinical findings in the whole population for overall survival time (OST) No factors associated with clinical findings resulted in significant difference for median OST.
Factor Number Median OST (days) P value Factor Number Median OST (days) P value
a 17 dogs were lack of information of thoracic radiography.
b 2 dogs were unable to be assessed due to clotting sample.
c 3 dog were lack of information of globulin at diagnosis.
Table 19. Univariate analysis of factors associated with adverse events and treatment in the whole population for overall survival time (OST) No factors associated with adverse events and treatment resulted in significant difference for median OST.
Factor Number Median OST (days) P value Factor Number Median OST (days) P value
Anorexia Dose reduction for ATLS
No 26 496 0.179 No 53 379 0.516
Table 20. Multivariate analysis of univariate factors with significance for overall survival time (OST) in all patients
Although dogs experiencing neutropenia had lower hazards ratio than those who didn’t, significance was not observed (P=0.092). No factors remained significant in multivariate analysis for OST.
Factor Number Hazards ratio 95% CI P value
Body weight (kg) 1.804 0.784-4.150 0.165
< Median 32
≥ Median 32
Breed 1.366 0.579-3.225 0.476
Other breeds 48
Golden retriever 16
Neutropenia 0.573 0.300-1.096 0.092
No 30
Yes 34
Response to treatment 1.385 0.574-3.340 0.469
CR 56
Non-CR 8
Table 21. Body weight distribution in large-sized dogs (≥ 20 kg)
Number Golden retriever (kg) Large-sized non-GR (kg)
1 24.2 20.6
2 26.9 20.6
3 27 23.3
4 27.8 24.5
5 28.3 24.9
6 28.3 25.3
7 29.2 29.4
8 30 30.6
9 31.3 33.4
10 33.9 44.6
11 34.2 54.4
12 34.8
13 35
14 40
15 46
16 47.4
Table 22. Comparison of rate of complete remission, time to progression (TTP) and overall survival time (OST) in three subgroups
Only the rate of complete remission was significantly lower in non-GR dogs whose body weight ≥ 20 kg than those whose body weight
< 20kg (P=0.049). Other comparison didn’t reveal statistical significance.
Non-Golden retriever (non-GR) Golden retriever Dogs < 20 kg Dogs ≥ 20 kg
Case number 37 11 16
Body weight (kg)
Median (range) 10.6 (1.46-22.5) 25.3 (20.6-54.4) 30.65 (24.2-47.4) P value Not compared 0.126
% of complete remission 100 81.8 62.5
P value 0.049 0.405
Median TTP (days) 265 187 126
P value 0.171 0.413
Median OST (days) 537 313 245
P value 0.100 0.370
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