13/12/26	

The 3rd Asian Meetings Animal Medicine Specialties 2013	

Febrile Neutropenia (FN)	
Febrile Neutropenia in 523 Dogs
with Various Malignant Tumors•

Fever and neutropenia caused by chemotherapy•

One of the severe side effects of chemotherapeuticagents•

Caused by Vincristine and Doxorubicin mostcommonly

Fukiko Oshima 1) , Tetsuya Kobayashi 1) , Eri Fukazawa 1)
Yuko Nakano 1) , Kei Harada 1) , Yozo Shiraishi 2)

Sorenmo KU, JAVMA, 2010	

1)Japan Small Animal Cancer Center (JSACC)
2)Japan Small Animal Center (JSAMC)

Britton BM, Vet Comp Oncol, 2013		

Our study objective	Methods	

•Inclusion criteria

To evaluate FN that occurred after administration of
the following chemotherapeutic agents• Carboplatin (CBDCA)• Cyclophosphamide (CPM)• Doxorubicin (DOX)• Vincristine (VCR)• Mitoxantorone (MIT)• Lomustine (CCNU)	

• Dogs that received chemotherapy at JSACC between Jan/2005
and June/2012

Exclusion criteria• Dogs that could not be followed more than 6 days afterchemotherapy• Dogs that received more than one agent at the same time 		

Definition of FN	

Data analyses	•Neutrophil count < 2500 cells/µL

Overall incidence rate of FN•Body temperature > 39.2℃ or < 36.0℃• Incidence of FN / Total number of chemotherapy ×100	

Overall mortality of FN• Total number of all deaths / Total number of all dogs×100
Sorenmo KU, JAVMA, 2010	
Britton BM, Vet Comp Oncol, 2013	
VCOG-CTCAE ver1.1 Vet Comp Oncol. 2011	

Mortality rate of FN• Total number of all deaths / Total number of FN ×1001	

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Analysis of risk factors	
Factors• Age (< 8y vs. ≧ 8y)• Sex (male vs. female)Results• Body weight (<10kg vs. ≧10kg)

Statistical analysis• Logistic model (p<0.05)	

Dogs characteristics	

Numbers of dogs / Dosed of drugs	

Median age: 9 years old (1-17)

Drug	

Median BW: 10.6 kg (1.9-63.3)
Sex :• Female 258 (neutered 162), Male 265 (neutered 121)

Tumor type :• Lymphoma or Leukemia : 327• Solid tumors : 196• Histiocytic sarcoma：44• Mast cell tumor：19• Hemangiosarcoma：19• Others：114	

Number (chemo)	

Dosage (range)	

Dose (mode)	

CBDCA	

59 (168)	

150 – 300 mg/m2 	

250 mg/m2	CPM	

90 (241)	

150 – 250 mg/m2	

250 mg/m2	

DOX	

135 (425)	

1 mg/kg – 30mg/m2	

1mg/kg	

VCR	

104 (484)	

0.35 – 0.7mg/m2	

0.7 mg/m2	

MIT	41 (118)	

3.75 –5.5 mg/m2	

5 mg/m2	

CCNU	

94 (334)	

44 – 87.7 mg/m2	

70.0 mg/m2*	
※ median	

Overall Incidence of FN = 5.5% (97/1770)	

Incidence rate of > Grade 3 neutropenia 	

Incidence of FN 	
1270

10.2

Grade4(0-500/µl)

60

107.7

8%68.1	Grade3(500-1000/µl)

506.2

640.7	

％	 405.4

38.5	
31.7	
24.4	

304

2.5
1.4

20CCNUCBDCA

CPM

VCR

MIT

DOX

13.3	

20100
CCNU

CBDCA

VCR

MIT

CPM

DOX

VCOG-CTCAE ver1.1. Vet Comp Oncol. 2011	2	

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Summary of dogs that died	
Mortality rate 	•Overall mortality rate = 0.95% (5/523)•

Mortality rate of FN = 5.88% (5/85)

Dogs	 BW(kg)		

Drug	

Tumor	

Region	Lung GISeg
lesion	 sign	 (µ/L)	

W.Corgie	

15.4	

CCNU
70.9 mg/m2	

HS	

Liver
LN	+	+	

57	

Shih tzu	

5.54	

CCNU
63.3 mg/m2	

LSA	skin	-	-	43	

Shelty	

14.3	

CBDCA
250 mg/m2	

LSA	

Multicentric
LN	+	+	1223	

M.Dachs	5.68	

CBDCA
250 mg/m2	

TCC	

Bladder	+	+	71	

W.Corgie	

15.08	

CPM
250 mg/m2	

LSA	

Multicentric
LN (CR)	

-	-	672	

Analysis of risk factors	
•Age : p=0.700•

Sex : p=0.194•BW : p=0.401	

Discussion

Comparison with the previous study 	

Comparison with the previous study 	

Drugs	

Previous report(n=70)	

Our study(n=85)	

Drugs	

Previous report(n=70)	

Our study(n=85)	

DOX	

37.1 % (26)	

7.0 % (6)	DOX	37.1 % (26)	

7.0 % (6)↓	VCR	

32.9 % (23)	

28.2 % (24)	

VCR	

32.9 % (23)	

28.2 % (24)	

CPM	22.8 % (16)	

15.2 % (13)	

CPM	

22.8 % (16)	

15.2 % (13)	

CCNU	

12.8 % (9)	30.5 % (26) 	

CCNU	

12.8 % (9)	30.5 % (26) ↑	

CBDCA	

5.7 % (4)	15.2 % (13)	

CBDCA	

5.7 % (4)	15.2 % (13) ↑	MIT	-	

3.5 % (3)	MIT	-	

Britton BM, Vet Comp Oncol, 2013	

3.5 % (3)	Britton BM, Vet Comp Oncol, 2013	3	

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Relationship between dose of DOX and BW	

Relationship between dose of DOX and BW	< 5 kg< 5 kg: 1mg/kg: 1mg/kg → 20% (27/135)

5 – 10 kg : 20 〜 25mg/m25 – 10 kg : 20 〜 25mg/m2 → 35.5% (48/135)

10 –15 kg : 25 〜 30mg/m2

10 –15 kg : 25 〜 30mg/m2 → 17.7% (24/135)> 15 kg: 30mg/m2> 15 kg: 30mg/m2 → 26.6% (36/135)

		Comparison with mortality rate in two studies 	

Risk factors of FN in human	• Previous study = 8.57%

Rate of severe FN < 5%

• Our study =5.88%	

Risk factors (high risk)• Pulmonary infiltration or chronic lung disease• GI signs (abdominal pain, nausea, vomiting and diarrhea)• GI mucosal disorder with dysphasia or diarrhea• Severe neutropenia (<100cells/µL) for more than 7 days
• Intravascular catheter infection• New or worsening neurological disorders	American Society of clinical oncology / European society for medical Oncology 	

Britton BM, Vet Comp Oncol, 2013	

Summary of dogs who died	Dogs	 BW(kg)	

Summary of dogs who died	

Lung GISeg
lesion	 sign	 (µ/L)	

Drug	

Tumor	Region	

15.4	

CCNU
70.9 mg/m2	

HS	LiverLN	

Shih tzu	

5.54	

CCNU
63.3 mg/m2	

LSA	skin	-	-	43	

Shelty	

14.3	

CBDCA
250 mg/m2	

LSA	

Multicentric
LN	+	+	

M.Dachs	5.68	

CBDCA
250 mg/m2	

TCC	

Bladder	+	+	15.08	

CPM
250 mg/m2	

W.Corgie	

W.Corgie	LSA	

None(CR)	+	-	+	-	Lung GISeg
lesion	 sign	 (µ/L)	

Drug	

Tumor	Region	

15.4	

CCNU
70.9 mg/m2	

HS	

Liver
LN	+	+	

57	

Shih tzu	

5.54	

CCNU
63.3 mg/m2	

LSA	

skin	

-	-	43	1223	

Shelty	

14.3	

CBDCA
250 mg/m2	

LSA	

Multicentric
LN	+	+	1223	

71	

M.Dachs	

5.68	

CBDCA
250 mg/m2	

TCC	

Bladder	+	+	71	

15.08	

CPM
250 mg/m2	

LSA	

None(CR)	

-	-	672	

57	

672	

Dogs	 BW(kg)	
W.Corgie	

W.Corgie	4	

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Our future directions	• To investigate the risk factors that could cause side
effects in each agent• To investigate the appropriate dosage for small breeds	5