In conclusion, when comparing the efficacy in treating measurable high-risk canine cutaneous MCT, only CBR was significantly higher for dogs treated with VBL-based chemotherapy than with imatinib, a significant difference was not observed in ORR and median PFI. The incidence of toxicity was significantly higher for dogs treated with VBL-based chemotherapy, especially for neutropenia and lethargy. Hence, imatinib could be advocated when adverse events are of great concern to the patient. Younger age and stage 2 compared to stage 4 were associated with a longer PFI in the study.
Figures
The median PFI for the VBL group (solid line, n = 21) and the imatinib group (dashed line, n = 20) was 83 days and 51 days, respectively. There was no significant difference in PFI between 2 groups (P = 0.885).
Figure 1. The Kaplan-Meier curve for the progression-free interval (PFI) of the two groups.
Figure 2. The Kaplan-Meier curve for the progression-free interval (PFI) for dogs achieved an objective response in two groups.
For dogs achieved an objective response, the median PFI for the VBL group (solid line, n = 9) and the imatinib group (dashed line, n = 7) was 55 days and not reached, respectively. The difference was not significant (P = 0.080).
Figure 3. The Kaplan-Meier curve for the progression-free interval (PFI) for dogs achieved clinical benefit in two groups.
For dogs achieved clinical benefit, the median PFI for the VBL group (solid line, n = 21) and the imatinib group (dashed line, n = 16) was 83 days and 189 days, respectively. The difference was not significant (P = 0.387).
Figure 4. The Kaplan-Meier curve for the progression-free interval (PFI) for dogs grouped by the age.
The median PFI was 189 days for dogs younger than 11 years-old (solid line, n = 19) and 51 days for dogs older than 11 years-old (dashed line, n = 22) (P = 0.048).
Figure 5. The Kaplan-Meier curve for the progression-free interval (PFI) for dogs classified as stage 2 and stage 4.
The median PFI was not reached for dogs classified as stage 2 (solid line, n = 10) and 35 days for dogs classified as stage 4 (dashed line, n = 15) (P = 0.005).
Figure 6. The Kaplan-Meier curve for the progression-free interval (PFI) for dogs classified as stage 3 and stage 4.
The median PFI was 189 days for dogs classified as stage 3 (solid line, n = 15) and 35 days for dogs classified as stage 4 (dashed line, n = 15) (P = 0.015).
Figure 7. The Kaplan-Meier curve for the progression-free interval (PFI) for responders and non-responders.
The median PFI was 160 days for responders (solid line, n = 16) and 40 days for non-responders (dashed line, n = 25) (P = 0.025).
Tables
Table 1. World Health Organization clinical staging system for mast cell tumors Stage Description
0 One tumor incompletely excised from the dermis, identified histologically, without regional LN involvement
1 One tumor confined to the dermis without regional LN involvement 2 One tumor confined to the dermis, with regional LN involvement 3 Multiple dermal tumors; large, infiltrating tumors with or without
regional LN involvement
4 Any tumor with distant metastasis, including blood or bone marrow involvement
Substage
a Without systemic signs b With systemic signs
Note. Adapted from London et al., 2013. LN, lymph node.
Table 2. Comparison of characteristics of vinblastine and imatinib
Note. VBL, vinblastine; GI, gastrointestinal.
VBL Imatinib
Classification Vinca alkaloid antineoplastic Tyrosine kinase inhibitor Mechanism Interfere with the polymerization
of microtubules
Inhibiting the phosphorylation of dysregulated tyrosine kinases
Organ of metabolism Liver (Not evaluated)
Organ of elimination Bile (Not evaluated)
Adverse events
• Myelosuppression
• GI toxicity
• Extravasation
• Neurotoxicity
• Hepatotoxicity
• Myelosuppression
• GI toxicity
Table 3. Veterinary cooperative oncology group – common terminology criteria for adverse events version 1.1
Grade
1 2 3 4 5
Neutropenia 1500 /uL to <
LNN 1000-1499 /uL 500-999 /uL < 500 /uL Death
Note. Adapted from Veterinary Cooperative Oncology Group, 2016. LNN, lower limit of normal; ADL, activities of daily living (eating, sleeping, defecating and urinating); GI, gastrointestinal; IV, intravenous;
SC, subcutaneous; ALT, alanine transaminase; TPN, total parenteral nutrition; PPN, partial parenteral
Table 4. Comparison of patient characteristics between the two groups
Note. VBL, vinblastine.
VBL group (n = 21)
Imatinib group (n = 20)
P-value
Age (years) 0.609
Median (range) 11 (6-15) 10 (4-17)
Bodyweight (kg) 0.003
Median (range) 17.6 (4.9-36.8) 10.9 (2.6-34.5)
Breed 0.146
Pure breed 10 (47.6%) 14 (70.0%)
Mixed breed 11 (52.4%) 6 (30.0%)
Sex 0.437
Female 12 (57.1%) 9 (45.0%)
Male 9 (42.9%) 11 (55.0%)
Table 5. Comparison of tumor features and previous treatments between two groups
The diameter of target lesions (cm)
a. Abdominal ultrasound was not performed in 1 dog in VBL group and one dog in imatinib group b. Abdominal ultrasound was not performed in 2 dogs in VBL group and four dogs in imatinib group
Table 6. Response to treatment in two groups
Note. Responses were defined according to “Response Evaluation Criteria in Solid Tumors” by Eisenhauer et al., 2009. VBL, vinblastine.
a. The clinical benefit included complete remission, partial remission and stable disease.
VBL group (n = 21)
Imatinib group (n = 20)
P-value
Objective response rate 0.606
Complete remission 1 (4.8%) 3 (15.0%)
Partial remission 8 (38.1%) 4 (20.0%)
Stable disease 12 (57.1%) 9 (45.0%)
Progressive disease 0 (0.0%) 4 (20.0%)
Clinical benefit rate 0.048
Clinical benefit a 21 (100.0%) 16 (80.0%)
Progressive disease 0 (0.0%) 4 (20.0%)
Table 7. Progression-free interval in two groups
VBL group Imatinib group P-value Median PFI (days)
All dogs 83 (7-239) 51 (7-415) 0.885
Dogs achieved objective response 55 (21-239) NR (51-415) 0.080 Dogs achieved clinical benefit a 83 (7-239) 189 (7-415) 0.387 Note. Responses were defined according to “Response Evaluation Criteria in Solid Tumors” by Eisenhauer et al., 2009. PFI, progression-free interval; VBL, vinblastine; NR, not reached.
a. The clinical benefit included complete remission, partial remission and stable disease.
Table 8. Episodes of toxicities classified according to the severity in two groups
VBL group Imatinib group
Grade 1 2 3 1 2 3
Neutropenia 5
Lethargy 8
Anorexia 2 3 3
GI signs 11 2
Elevation of ALT 6 5 1 2 4
Grand total (%) 32 (78.1%)
8 (19.5%)
1 (2.4%)
7 (63.6%)
4 (36.4%)
0 (0.0%) Note: The severity of toxicities was graded based on “Veterinary Cooperative Oncology Group- Common Terminology Criteria for Adverse Events” by Veterinary Cooperative Oncology Group, 2016. VBL, vinblastine; GI, gastrointestinal; ALT, alanine transaminase.
Table 9. Incidence of toxicity in two groups VBL group
(n = 21)
Imatinib group
(n = 20) P-value
Neutropenia 5 (23.8%) 0 (0.0%) 0.048
Lethargy 6 (28.6%) 0 (0.0%) 0.021
Anorexia 5 (23.8%) 2 (10.0%) 0.410
GI signs 6 (28.6%) 2 (10.0%) 0.238
Elevation of ALT 9 (42.9%) 4 (20.0%) 0.116
Grand total 15 (71.4%) 7 (35.0%) 0.019
Note. VBL, vinblastine; GI, gastrointestinal; ALT, alanine transaminase.
Table 10. Incidence of toxicity in two subgroups VCP subgroup
(n = 11)
VP subgroup (n = 10)
P-value
Neutropenia 4 (36.4%) 1 (10.0%) 0.311
Lethargy 5 (45.5%) 1 (10.0%) 0.149
Anorexia 4 (36.4%) 1 (10.0%) 0.311
GI signs 5 (45.5%) 1 (10.0%) 0.149
Elevation of ALT 7 (63.6%) 2 (20.0%) 0.080
Grand total 10 (90.9%) 5 (50.0%) 0.063
Note. VCP, cyclophosphamide-prednisone/ prednisolone; VP, vinblastine-prednisone/ prednisolone; GI, gastrointestinal; ALT, alanine transaminase.
Table 11. Univariate analysis of progression-free interval regarding patient characteristics
Factor n Median PFI (days) P-value
Age (years) 0.048
< 11 19 189 (7-415)
≥ 11 22 51 (7-168)
Bodyweight (kg) 0.990
< 13.5 20 51 (7-415)
≥ 13.5 21 83 (7-239)
Breed 0.782
Pure breed 24 56 (7-415)
Mixed breed 17 83 (7-121)
Sex 0.898
Female 21 112 (7-239)
Male 20 56 (7-415)
Note. PFI, progression-free interval.
Table 12. Univariate analysis of progression-free interval regarding tumor features and previous treatments
Note. PFI, progression-free interval; NR, not reached.
a. Stage 1 was not included due to the small sample size (n = 1).
b. Abdominal ultrasound was not performed in 1 dog in VBL group and 1 dog in imatinib group.
c. Abdominal ultrasound was not performed in 2 dogs in VBL group and 4 dogs in imatinib group.
d. Stage 2 compared to stage 4.
The diameter of target lesions (cm) 0.327
< 5.9 19 121 (7-415)
Multiple cutaneous 19 51 (7-415)
LN only 4 73 (14-73)
Median dosage of prednisolone
(mg/kg) 0.059
Table 13. Multivariate analysis of possible prognostic factors for progression-free interval
n Hazards ratio 95% CI P-value
Age (years)
< 11 19
≥ 11 22 3.710 1.110-12.408 0.033
Stage a
2 b 10 0.223 d 0.050-0.996 d 0.049 d
3 c 15 0.453 e 0.140-1.468 e 0.187 e
4 15
Objective response
Yes 16
No 25 2.051 0.632-6.650 0.231
Note. PFI, progression-free interval.
a. Stage 1 was not included due to the small sample size (n = 1).
b. Abdominal ultrasound was not performed in 1 dog in VBL group and 1 dog in imatinib group.
c. Abdominal ultrasound was not performed in 2 dogs in VBL group and 4 dogs in imatinib group.
d. Stage 2 compared to stage 4.
e. Stage 3 compared to stage 4.
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