German Shorthaired
Pointer National
Specialty Show-2013
What Happens to Your GSP with a
Diagnosis of Cancer?
K. Ann Jeglum, V.M.D., ACVIM,
Oncology
Oncology: Diagnostics and
Therapies in Today’s
Times
K. Ann Jeglum, V.M.D.
Diplomate, ACVIM, Oncology
Adjunct Associate Professor
The Wistar Institute, Philadelphia
Veterinary Oncology Services and Research Center
Veterinary Oncology Services’ Radiation Center
Diagnostics in Today’s
Times



Important to obtain a definitive diagnosis as
practically as possible
Costly diagnosis leaves no funds to treat
Clinical staging based on needs to
prognosticate for owners
– Ex. Abdominal ultrasound in lymphoma does not
change prognosis nor protocol unless GI signs
– Ex. Role of abdominal US in mast cell tumors
– Ex. Role of thoracic US vs. radiographs
Advanced Imaging:
MRI and CT Scans




Significant role in staging for treatment of
head and neck tumors, ie, nasal, oral, brain
Pulmonary tumors: CT
Recognize potential of costly treatment, ie,
radiation, after imaging
Critical for diagnosis and treatment planning
of brain tumors- surgical biopsies rare
– Prognosis based on anatomic site and MRI
appearance
Role of Ultrasound as
Medical Oncologist




Diagnosis and staging of intraabdominal
disease with US-guided needle aspirate
Evaluation and cytology of thoracic masses
Treatment follow-up of bladder, prostate,
liver, adrenal, GI tumors- course of
treatment based on results
Surgical planning extemitiy, soft tissue and
thyroid masses
Definition of “Effective”
Treatment in Today’s Times




Quality of life not quantity- palliative vs.
therapeutic treatment
Cost effectiveness
“Reasonable” prognosis based on owner
expectations and outcome
Treating the disease and not the clienttherapeutic doses vs. subtherapeutic
causing more harm than good
– Ex. Low dose, infrequent chemotherapy
enhances MDR- q 3 week chemo in lymphoma
not treating the disease
Cancer Therapy in
Today’s Times

Chemotherapy
– Nucleus: kills by breaking DNA

Molecular Targeted Therapy
– Cytoplasma: inhibits signal transduction allowing
programmed cell death or apoptossis

Anti-Angiogenesis Therapy
– Tumor microenvironment: inhibits growth factors
that promote tumor vasculature
Canine Mammary Tumors







Higher incidence in purebreed- breeding
Overall 50:50% Benign to Malignant
Of the 50% malignant half are surgically
cured
Therefore 25% overall life threatening
Size does not predict malignancy
Early detection and early resection
Surgical Approach: Radical vs. Simple
mastectomy- en bloc lymph node
resectionl
Soft Tissue Sarcomas






Histopathology: fibrosarcoma, spindle cell
sarcoma, histiocytic sarcoma, peripheral
nerve sheath, hemangiopericytoma
Surgery initial treatment of choice
Local control: radiation therapy
Anaplastic pathology: doxorubicin/DTIC
Histiocytic sarcoma/malignant histiocytosisbreed related prognosis
Young dogs <5 yrs.- very aggressiveneoadjuvant chemotherapy
Malignant Histiocytosis/
Histiocytic Sarcoma





Genetic predisposition: Bernese Mountain
dogs, Flat-coated Retrievers, Golden
Retrievers (reported VOSRC, 2008)
Increasing incidence
Differentiate systemic disease (MH) from
localized
Sites of Involvement: soft tissue, spleen,
liver, lymph nodes, lung, bone marrow
Classification/Nomenclature changes- P.
Moore (UCDavis)
Histiocytic Diseases


Histiocytes: subset of leukocytes
including monocytes, macrophage,
dendritic antigen presenting cells
(DAPCs)
Cutaneous Histiocytoma
– Benign, proliferation of CD 1+, CD 11 c+,
Thy-1, CD 4- Langerhans cells
Histiocytic Diseases

Reactive Histiocytosis
– Cutaneous and systemic forms
– Angiocentric, CD 1, CD 11 c+, Thy 1+,
CD 4 + DAPCs
– Considered an immunoregulatory disorder
and repsonds to immunosuppressive
therapy
Histiocytic Sarcoma





Localized and dissminated
Large round cells with spindiloid cells
with increased cytoplasmic:nuclear
ratio- diagnosed on cytology or histo
Immuophenotype of DAPCs
Clinically aggressive with high rate of
metastases
Systemic therapy generally indicated
Therapy of Histiocytic
Sarcoma

Chemotherapy
– VOSRC gold standard: Doxorubicin/DTIC

Bone marrow involvement- poor prognosis
– CCNU +/- cyclophosphamide

ECOG trial- dismal results
Alternative Therapies for
Histiocytic Sarcoma


Radiation therapy for local and/or regional
disease- 19 daily @ 3 Gy fractions to 57 Gy
TALL-104 Cell Line Therapy
– Wistar Intitute
– Effective but not available- internet question

Biphosphanates- Pamidronate
– Based on responsed in human Langerhan’s cell
histiocytosis
– B. Kitchell- responses in individual cases
Management of Mast Cell
Tumors
K. Ann Jeglum, V.M.D.
The Wistar Institute
Philadelphia, Pennsylvania
West Chester, Pennsylvania
Radiation Therapy and
Chemosensitization




Hypoxic cells are resistant to radiation
Low dose of chemotherapy drugs will
sensitize hypoxic cells in bulky tumors to
radiation kill
Several drugs inhibit DNA repair or sublethal
radiation damage
Drugs used: cisplatin, carboplatin,
dactinomycin d, doxorubicin, gemcitabine
Canine Osteosarcoma






A cancer of large and giant breeds
Median age of 10 years but an aggressive subset in young
(18-24 mos)
Occur at metaphysis of rapidly growing bones- predispositionalso trauma sites, ie, fractures, internal fixation devicesdifferent biological behavior
75% in long bones, ie, “away from the elbow and around the
knee” and hock
Radiographic appearance: lytic, osteoblastic and mixedcortical lysis, periosteal reaction (“sunburst”)
Differential Diagnoses: fungal disease, infection, other primary
bone tumors (fibrosarcoma, chondrosarcoma,
hemangiosarcoma), hemopoietic tumors (LSA, myeloma)
Canine OsteosarcomaDiagnosis





“Pathognomonic” diagnosis of history, clinical signs,
anatomic site and radiographic appearance
Dilemmas with biopsy- non-diagnostic with reactive
bone using an invasive procedure that may result in
vascular release, increase pain and lameness and
increase risk for pathologic fracture
Characteristic appearance of other bone tumors
Geographic predisposition for mycotic diseases
Not indicated if amputation is definitive treatment
Canine OsteosarcomaStaging and Prognosis
Thoracic Radiographs: negative in >90% cases at
initial diagnosis
Evidence of micrometastases at time of diagnosisdisputed by anticoagulation data during amputation
Favorable Prognostic Factors: low serum alkaline
phophatase, intracompartmental lesions, small
primary tumor, parosteal osteosarcomas, axial and
mandibular sites, tumor necrosis following
chemotherapy- role of neoadjuvant chemo?
Canine Osteosarcoma:
Where Are We?

No significant change in survival or disease free
interval in the 15+ years since advent of platnum
compounds
Amputation + 4 cycles of cisplatin=median
survivals=260-400 days with 1 year survival of 3062%- not all disease free at 1 yr.
– 2 year survival rates 6-21%



Doxorubicin alone < 1 yr. median survival
Surgical limb salvage procedures
Amputation vs. palliative radiation followed by
chemotherapy
Canine Osteosarcomacon’t.

Protocol changes to improve prognosis:
– Combine cisplatin and doxorubicin in alternating
cycles
– Increase number of cycles to 6
– Introduce additonal chemotherapeutic agents
such as ifosfamide
– No new cytotoxic agents- high dose
methotrexate problematic in dogs
– Maintenance metronomic chemotherapy
– No effective treatment for metastatic disease
Canine Osteosarcomacon’t.



Current VOSRC protocol post
amuputation or palliative radiation
Cisplatin (60mg/M2) alternating with
Doxorubicin (30 mg/M2every 3 weeks3 cycles each
Historically cisplatin first- recently
doxorubicin before platum compound
may be more effective
Canine OsteosarcomaPalliative Radiation and
Biphosphonates




Weekly radiation therapy to primary tumor
(9 Gy weekly X 4=36 Gy)
Biphosphonate- Pamidronate 1 mg/kg
intravenous infusion over min. 2 hours
every 3 weeks
Increase calcification of tumor, decrease
bone pain and now antitumor effects
Controversy of value of chemotherapy in
such a model
Biphosphonate Therapy in
Bone Tumors




Osteosarcoma and metastatic malignant tumors
induce and stimulate osteoclasts to invade bone
Can be osteolytic or osteoblastic and osteoclasts
has important role in both patterns
Tumors produce many factors that stimulate
osteolysis, osteosclerosis and aggressive tumor
growth
Osteoclastic targeted therapies: biphophonatesinduction osteoclast apoptosis
Metronomic
Chemotherapy



Chronic administration of chemotherapy at
low, minimally toxic doses on a frequent
schedule of administration at close regular
intervals, with no prolonged drug-free
breaks
Could less be more? Origins in pediatric
oncology- similarities to vet onco
Antiangiogenic by targeting endothelial
cells- more sensitive to continuous exposure
of chemotherapy drugs without undergoing
genetic mutations like tumor cells that
develop drug resistance
Metronomic
Chemotherapy- con’t.




Major mechanism is inhibition of mobilization of
endothelial cells that develop in bone marrow and
seeds tissue
Bone marrow-derived endothelial cells are major
source on new blood vessels to tumor cells
Also stimulates production of thrombospondin-1, a
potent angiogenesis endogenous inhibitor
Low dose cyclophosphamide also depletes
regulatory T-cells which are immunosuppressive on
effector T-cells and antigen presenting cells
Metronomic Chemotherapy
+ COX-2 Inhibitors




Cyclooxygenase-2 is over expressed in
tumors cells and stromal cells and promotes
tumor growth by stimulation angiogenesis
Overexpression of COX-2 stimulates growth
factors (VEFG)
COX also plays role in generation of T-reg
cells
Synergism of two approaches- metronomics
plus COX-2 inhibitors
Metronomic Protocol




Piroxicam 0.3 mg/kg po sid- Cox-2
inhibitor as antiangiogenic
Chlorambucil 0.1 mg/kg po EOD or
Cyclophosphamide 10-15 mg/M2 EOD
but hemorhagic cystitis a problem
Doxycycline 5 mg/kg bid
Methotrexate 0.05-0.1 mg/kg once
weekly- no piroxicam
Metronomic Chemotherapy
+ COX-2 Inhibitors


Piroxicam only NSAID in dogs with proven in
vitro and in vivo antitumor activity
Low-dose cyclophosphamide plus piroxicam
– Increased DFI in dogs with completely resected
splenic hemangiosarcoma compared to
doxorubicin alone- small nos. (Lana,JVIM, 2007)
– Delay tumor recurrences in soft tissues
recurrences in incompletely excised soft tissue
sarcomas (peripheral nerve sheath) (Elmslie,
JVIM, 2008)- retrospective
Canine Hemangiosarcoma





Tumor of vascular endothelium
Prevalent sites: spleen, liver, right
atrium, lung, subcutaneous, bone
Clinical presentations include
abdominal bleed, pericardial effusioncardiac tamponade
Proven inherited in GRs! (Jeglum)
GSHPs?
Not a death sentence
Canine Hemangiosarcoma





Soft tissue vs. splenic HSA- different diseases- long
term survival with chemotherapy of soft tissue
Do we change biological behavior of splenic with
adjuvant chemotherapy?
Doxorubicin/dacarbazine- objective tumor
responses in measurable metastatic disease- not
seen with doxo alone or with addition of
cyclophosphamide
However, after 4 cycles A/DTIC still develop
metastases but not during- delay of mets?
Improvement? More chemotherapy vs.
maintenance metronomics
Doxorubicin (Adriamycin)
and Dacarbazine (DTIC)






Day 1 : Doxorubicin 30 mg/M2 slow IV
Days 1-5 DTIC 200/mg2 IV bolus
Days 4-5 Complete Blood Count (CBC)
Day 10 CBC
Day 21 Start 2nd cycle X 4 cycles
Prophylactic antiemetics (Cernia,
Centrine, Zofran) and antibiotics
Oral Tumors

Diagnostics
– Cytology vs. surgical biopsy
– Staging: lymph node aspirate, thoracic
radiographs
– MRI for treatment planning: surgical
resection, radiation therapy
Oral Tumors- con’t.

Squamous Cell Carcinoma
– Treatment based on anatomic site and size of
tumor
– Rostral: segmental mandibulectomy or
maxillectomy
– Caudal: neoadjuvant chemotherapy vs. radiation
therapy +/- chemosensitization
– Role of systemic chemotherapy with local
therapy dependent on histopathology
– Cats: BAC- doxorubicin, cyclophophamide,
bleomycin
– Dogs: Cisplatin, 5-FU
Oral Tumor- con’t

Sarcomas
– Changes in histopathology: spindle cell sarcoma,
fibrosarcoma
– Surgical approach similar to SCC
– Radiation therapy +/- chemosensitization with
dactinomycin
– Systemic chemotherapy: dactinomycin,
doxorubicin/dtic
– Application dependent on pathology/cytology
Tyrosinase- Melanoma
Antigen


Tyrosinase- a protein present on
normal canine cutaneous melanocytes
and overexpressed on melanoma cells
Not normally targeted by the immune
system- CMV trains the immune
system to recognize tumor-associated
protein or antigen
Canine Melanoma



Two malignant sites: oral cavity (gingiva,
palate, tongue) and subungal (digit)
Locally invasive and metastatic to regional
lymph nodes and distant sites, primarily
lung also liver, kidney and brain
Dermal melanomas historically considered
benign but recently increase in malignant
cutaneous melanoma- can be multicentric
Xenogeneic Plasmid DNA
Vaccine Technology



A non-canine (human) tyrosinase is inserted
in a ring of canine DNA= xenogeneic
plasmid DNA containing canine DNA for
human tyrosinase
Foreign tyrosinase breaks through the dog’s
tolerance of a self tumor thereby inducing a
strong and active immunity
Results in production of human antigen that
is homologous to canine tyrosinase but
recognized as foreign
Xenogeneic Plasmid DNA
Vaccine Technologycon’t


The antigen is transcribed in the host
and actively presented by the immune
system during malignant
transformation targeting melanoma
cells as foreign
The immune response appears tumorspecific targeting tumor producing
cells not normal melanocytes
Canine Melanoma
Vaccine- ONCEPT

Historically dogs with WHO stage II or
III oral melanoma treated with surgery
alone have survival times <5-6 mos.
– WHO Stage II: approximately 150-180
days
– WHO Stage III: approximately 60-90 days
Canine Melanoma
Vaccine- ONCEPT- con’t



Local disease control achieved through
surgery (negative local lymph nodes or
positive lymph nodes that were surgically
removed or irradiated
58 dogs with stage II or III COM treated by
vaccination with ONCEPT following local
disease control
Follow-up survival data 6 mos. after
conclusion of the study, <50% have died of
melanoma (median survival time not
attained)
Canine Melanoma
Vaccine-ONCEPT




Quantile estimates of survival time for vaccinates
(25% mortality {95% confidence intervals was 464
days
Significant difference between historical stagematched controls and vaccinates with better
survival times with vaccinates (p<0.0001)
No significant association in response between
stage II and III (p=0.58)
No difference in survival in dogs with post-surgical
histological clean surgical boarders vs. narrow or
dirty margins
Canine Melanoma
Vaccine- ONCEPT



Phil Bergman: 20% response in gross
disease
Radiation and vaccine- administer in
conjunction to achieve immune
response to ag release at tumor death
VOSRC experience: local and regional
control essential
Canine Malignant
Melanoma

Advanced stage disease
– Cisplatin/dacarbazine
– Vs. Carboplatin- 15-20% loss of efficacy
with chemotherapy analogues
Genitourinary Tract
Tumors



Increased incidence of prostate tumors
especially prostate in neutered males
Chemotherapy of Prostate: Mitoxantrone
Transitional Cell Carcinoma:
– Diagnosis with ultrasound and urine cytology
– Piroxicam alone: 20-25% ORR
– Chemotherapy: doxorubicin/cyclophophamide,
mitoxantrone, gemcitabine
Anal Sac Carcinomas





Surgery based on size and invasiveness of local
tumor
Regional lymph node metastases common on US
staging
“Barrier” effect of lymph node- prolonged survival
without distant metastases
Role of chemotherapy to prevent clinical signs
Protocols: FAC- doxorubicin, 5-FU,
cyclophosphamide alternating with carboplatin
Palladia (toceranib
phosphate)

FDA approved for the “treatment of
grade II or III, recurrent, cutaneous
mast cell tumors with or without
regional lymph node involvement in
dog
Palladia- con’t.

“Mult-center, Placebo-controlled,
Double-blind, Randomized Study of
Oral Toceranib Phosphate (SU11654),
a Receptor Tyrosine Kinase Inhibitor,
for the Treatment of Dogs with
Recurrent (Either Local or Distant)
Mast Cell Tumor Following Surgical
Exicision” London CA, Clin Cancer
Res 2009:15(11)3856-3865.
Palladia-con’t.




Blinded Phase: 6 weeks- 3.25 mg/kg EODthereafter, eligible dogs received open-label
Palladia
Blinded phase ORR in Palladia-treated dogs
(n=86)=37.2% (7 CR and 25 PR) vs. 7.9%
(5 PR) in placebo-treated (n=63; p=0.0004)
Of 58 dogs that received Palladia following
placebo-escape, 41.4% (8 CR, 16 PR) had
ORR
ORR in 145 dogs receiving Palladia was
42.8% (21 CR, 41 PR)
Palladia- con’t.



62 Responders: Median duration of
objective response= 12 weeks and median
time to progression= 18.1 weeks
Survival time was not an end point and not
reported
Dogs with positive c-kit ITD were more
likely to have an objective response
compared to those negative (44.8% vs.
20.3%)
Palladia- con’t.

Most common adverse events- majority
grade 1 or 2
–
–
–
–
–
–
–
Diarrhea 46%
Vomiting 32.2%
Blood in stool 12.6%
Anorexia 39.1%
Neutropenia 46%
Weight loss14.9%
Musculoskeletal 25%
Palladia- con’t.


Grade 3 or 4 adverse were 20.7% in
Pallladia treated vs. 15.6% of placebo
(p=0.527)
Toxicities secondary to mast cell
disease and degranulation
Canine Lymphoma



VCAA: L-asparaginase, vincristine,
cyclophosphamide, doxorubicin- single
agent, weekly for 4 weeks X 2 cycles
UW (Kirk’s CT) Protocol Standard of Care
but long term maintenance not necessarydecreased to 12 wk. without significant
differences
Quality of life, cost effectiveness and
avoidance of multi-drug resistance
Canine Lymphoma-cont.






Importance of bone marrow aspirate as 1520% involvement without hematological
changes
Mechanism of early relapse
Referral disease or not?
“Tricks of the trade”- when to cross over to
rescue protocols
Combined treatment to determine MDR
Importance of doxorubicin/DTIC
Veterinary Oncology
Services and Research
Center
West Chester, PA






K. Ann Jeglum, V.M.D., Diplomate, ACVIM,
Oncology
Donna L. Lindner, D.V.M., Board eligible
surgery, 9 years medical oncology
Vicky Nelson, D.V.M., Board eligible internal
medicine, 8 years medical oncology
Lisa Suslack-Brown, V.M.D., Diplomate,
ACVR
Kenneth Sadanaga, D.V.M. Diplomate, ACVS
Michael Miller, V.M.D., cardiology
Veterinary Oncology
Services’ Radiation Center
Chalfont, PA






Drs. Jeglum, Lindner, Nelson
Dr. Patrick Gavin, Diplomate, ACVR, ACVROradiation planning
Sue Chipollini, Board Certified Radiation
Therapist- 25 yrs. Experience
Tracey Murphy, Board Certified Radiation
Therapist- 20 yrs. Experience
Linear accelerator 6Mv with photons and
electrons and simulator
Full capacity medical oncology facility
Canine Mast Cell Tumor: Clinician’s
Dilemma Heterogeneous Biological
Behavior
Prognostic Factors in Management of Mast Cell Tumors
1.
Is this a first time occurrence of the MCT of is it recurrent? Is the
tumor in the same site or different site?
Recurrent disease requires adjuvant therapy following re-excision
2.
What is the anatomical site of the tumor? Is it solitary or
multicentric?
Anatomic sites with a more malignant behavior despite histological
grade include:
Genitalia (male) and inguinal(?)/ perineal area
Mammary gland in female
Oral cavity
Digit or dorsum of paw
Canine Mast Cell Tumors: Heterogeneous
Biological Behavior (cont.)
3.
What is the growth rate?
Slow growing and indolent (benign), slow growing with a rapid
growth spurt (becoming malignant), rapid growth and invasion
from onset (malignant).
4.
What does the biopsy report tell about the grade of malignancy of
the mast cells?
Despite which numerical system may be used, a description of the
cells is critical. Are the surgical boarders devoid of tumor cells?
Biology of Mast Cells
Normal cells of connective tissue- most numerous
underlying serosal surfaces, mucous membranes and
dermis
Most Common site of tumor formation is skin and
subcutaneous
Spleen, liver, GI, oral cavity
Characteristically have metochromatic granules
containing vasoactive substances including histamine,
heparin.
Prognostic Factors in Canine
Mast Cell Tumors
Grade- I, II, III
1.
•
2.
3.
4.
Well-differentiated anaplastic
Solitary vs. multicentric tumors
Completeness of tumor excision
Tumor site
Prognostic Factors in Canine
Mast Cell Tumors (con’t)
5.
Regional and distant metastasis, i.e.
lymph node, liver, spleen (methods
of evaluation?)
VCS Study: >100 cases buffy coats,
ultrasound liver and spleen, bone
marrows yielded <2% positive results
6.
Recurrence in stage II tumors has
negative impact on survival time
Prognostic Factors in Canine
Mast Cell Tumors- con’t.
6. Mitotic Index: <5> MI/ 10 HPFMedian Survival Time (MST)
Grade II: <5 MST=70 mos.
>5 MST= 5 mos.
(p<.001)
Grade III: <5= no MST attained
>5 MST =<2 mos.
(p<.001)
Vet Path 2007:44(3)33541
Prognostic Factors in Canine
Mast Cell Tumors- con’t.

7. Cellular Proliferative Indices- results
from the number of cycling cells
(growth fraction) and rate of cell cycle
progression (generation time)
– Increased Ki67 (growth fraction) and
AgNOR (generation time) counts predict
significantly recurrence at original site,
distant metastases, MCT-related mortality
rates, decreased survival times
– Vet Path 2007:44(3):298-308
Prognostic Factors in Canine
Mast Cell Tumors- con’t.

8. c-kit Mutations
– c-kit proto-oncogene encodes the
receptor tyrosine kinase KIT- important in
normal mast cell survival, proliferation,
differentiation, migration and cell death
– Mutations result in increased cellular
proliferation, higher histological grade,
decreased disease-free and overall
survival times
Medical Work-Up for Mast
Cell Tumors
1.
2.
3.
4.
5.
6.
Complete Blood Count +/- Buffy Coat
Biochemical Profile
Thoracic and Abdominal Radiographs
Needle Aspirate of Regional Lymph Node
Abdominal Ultrasound?
Bone Marrow?
WHO Clinical Staging System for
Mast Cell Tumors
Stage I: One tumor confined to the dermis without
regional lymph node involvement.
a)
b)
Without systemic signs
With systemic signs
Stage II: One tumor confined to the dermis with
regional lymph node involvement.
a)
b)
Without systemic signs
With systemic signs
WHO Clinical Staging System
for Mast Cell Tumors (con’t)
Stage III: Multiple dermal tumors; large
infiltrating tumors with or without regional
lymph node involvement.
a)
b)
Without systemic signs
With systemic signs
Stage IV: Any tumor with distant metastasis
or recurrence with metastasis.
Histologic Classification of Mast
Cell Tumor
Grade
Anaplastic,
Undifferentiated
Bostock
1
Patnaik
3
Moderately
Differentiated
2
2
Wall Differentiated
3
1
Microscopic Description
Pleomorphic size and of cells and
nuclei, high mitotic rate, few to
no granules. Invasive into deep
tissue
Moderate pleomorphism with
round to avoid cells, fine
granules, decreased nuclear to
cytoplasmic ratio, few mitotic
figures, infiltrate deep dermis and
subcutaneous
Round monomorphic cells with
distinct boarders, round nuclei
with many distinct granules, n
mitotic figures, confined to
dermis
Survival Times of Dogs Based on
Histologic Grade
No. of Dogs
% Alive
Months PostSurgery
Well-differentiated
39
77
6
Differentiated
30
45
6
Undifferentiated
45
13
6
Well-differentiated
30
83
15
Differentiated
36
44
15
Undifferentiated
17
6
15
Bostock, 1973
Patnaik, et. al, 1984
Adjuvant Treatment of Canine Mast Cell
Tumors
Clinical Indications
1. Recurrent and/or multiplicity of tumors
2. Dirty surgical boarders
3. Malignant anatomic site, i.e. , inguinal area/ genitalia of male
dog, mammary gland, digit or oral cavity.
4. Histological Grading - dependent on numerical classification
used (Misdorp vs. Patnaik) Most important is the description of the
morphology of the tumor cells ( well differentiated vs. anaplastic granular vs. agranular).
5. Lymph node metastases
6. Increased mitotic index
Mast Cell Tumor
66%
33%
Well-Differentiated
Intermediate and Undifferentiated
Stage I
Surgery Alone
Stage I
Surgery
Steriods
+/- Radiation
Stage II
Surgery
Steroids
Cimetidine
+/- Radiation
Stage II
Surgery
Steroids
Cimetidine
+/- Radiation
Chemotherapy
Stage III, IV
Surgery
+/- Chemotherapy
Cimetidine
Management of Mast Cell
Tumors
1.
2.
3.
Surgical Excision- Cut Early, Wide and Deep
Radiation Therapy- An extension of the Scapel for
Local and Regional Disease
Corticosteriods- Use Early in High Risk Disease
Palliative in Advanced Disease
Level I
Protocol:
Prednisone or Prednisolone
40mg/m2/day for 3 weeks, then
20mg/m2/day for 3 weeks and wean off
Recommend H2 and H1Antagonists
Management of Mast Cell
Tumor (Cont.)
4. Chemotherapy- Heterogeneous Response
a)
b)
c)
Level II: Chlorambucil 0.2 mg/kg po sid X 6 mos +/Prednisone
Level III: Vinblastine 2 mg/M2 IV bolus weekly to
response
Level IV: Lomustine 70 mg/M2 po q 3- 4 wks
5. Immunotherapy- Observation Supporting
Application
a)
Evidence of immunological defect- decreased
antibody production- Howard, 1967
b) Adminstration of BCG resulting in fever and
regression of MCTs- Jeglum, 1977
c) rhTNF + rhIL-2: Partial to complete necrosis in 6/6
dogs- Moore, et. Al, 1991
Molecular Targeted
Therapeutics

Signal Transduction Targets
– Intracytoplasmic
– Mutations of genes resulting in
uncontrolled growth
– Assays for presence of such mutations
– C-kit mutation in canine mast cell tumors
– Therapeutic: Gleevac- iminatinib
Palladia (toceranib
phosphate)

FDA approved for the “treatment of
grade II or III, recurrent, cutaneous
mast cell tumors with or without
regional lymph node involvement in
dog
Palladia- con’t.

“Mult-center, Placebo-controlled,
Double-blind, Randomized Study of
Oral Toceranib Phosphate (SU11654),
a Receptor Tyrosine Kinase Inhibitor,
for the Treatment of Dogs with
Recurrent (Either Local or Distant)
Mast Cell Tumor Following Surgical
Exicision” London CA, Clin Cancer
Res 2009:15(11)3856-3865.
Palladia- con’t.



62 Responders: Median duration of
objective response= 12 weeks and
median time to progression= 18.1
weeks
Survival time was not an end point
and not reported
Dogs with positive c-kit ITD were
more likely to have an objective
response compared to those negative
(44.8% vs. 20.3%)
Palladia-con’t.




Blinded Phase: 6 weeks- 3.25 mg/kg EODthereafter, eligible dogs received open-label
Palladia
Blinded phase ORR in Palladia-treated dogs
(n=86)=37.2% (7 CR and 25 PR) vs. 7.9%
(5 PR) in placebo-treated (n=63; p=0.0004)
Of 58 dogs that received Palladia following
placebo-escape, 41.4% (8 CR, 16 PR) had
ORR
ORR in 145 dogs receiving Palladia was
42.8% (21 CR, 41 PR)
Palladia- con’t.

Most common adverse eventsmajority grade 1 or 2
– Diarrhea 46%
– Vomiting 32.2%
– Blood in stool 12.6%
– Anorexia 39.1%
– Neutropenia 46%
– Weight loss14.9%
– Musculoskeletal 25%
Palladia- con’t


DO NOT USE THE CLINICAL INSERT
DOSING CHART (same for Pfizer’s
Cerenia)
Current Recommendation per C.
London
– Start dosing at 2.75 mg/kg every other
day
– Use prophylactic antiemetics (Centrine,
Cerenia
– Dose escalate to 3.25 mg/kg EOD based
on toxicity profile
Masitinib- Inhibitor of KIT, A
Receptor Tyrosinase Kinas



Licensed by AB Science in Europe for
veterinary use in November 2008
Phase III Study- multicenter,
randomized, placebo-controlled with
measurable grade II or III mast cell
tumors without regional or distant
metastases- 202 dogs
6 month treatment at dose of 1
2.5 mg/kg/day
Masitinib Phase IIIcon’t.



Prolonged time to tumor progression
(TTP) compared with placebo (75 to
118 days; p=.038)
Effect more pronounced with first-line
therapy – increase TTP from 75 to 253
days (p=.001) regardless of
expression of mutant vs. wild type KIT
Overall response assessed at 4 and 6
mos. not significantly increase by
masitinib
Masitinib Phase IIIcon’t.


No significant differences with masitinib vs.
placebo in proportion with CR (11.2 vs
4.9%) or PR (4.6 vs 9.8%)
Toxicity
– Significantly more diarrhea and vomiting with
masitinib- 96.2 % grade I or II- tolerable and
transient and without sequelea
– Neutropenia 6.2%
– Renal 7.5%
J Vet Intern Med 2008;22:1301-1309
Clinical Consequences of
Degranulation of Mast Cells
1.
2.
Vomiting and/or Diarrhea- Not related to GI
ulcer
Gastrodoudenal Ulcers- Mechanisms:
a) Histamine stimulates H2 receptors resulting in
excessive acid secretion and hypermotility
b) Histamine causes vacular dilation that increases
endothelial permeability leading to intravascular
thrombosis and ischemic necrosis
c) Clinical Signs: asymptomatic to anorexia, vomiting/
diarrhea +/- blood, anemia
d) Perforated Ulcer- peritonitis, death
Clinical Management of
Gastrointestinal Signs
1.
H2 blockers
a) Cimetidine (Tagamet): 2-4/mg/kg PO QID
b) Ranitidine (Zantec): Dog: 2mg/kg TID IV, PO
c) Famotidine (Pepcid): 1 mg/kg SID, PO
2.
Coating Agent: Sucralfate: 250mg/15kg
PO QID
Give 2 hours apart from other meds
3.
Diphenhydramine (Benadryl): 2-4 mg/kg
q6-8h PO, IM. If used IV, give very slowly
due to hypotension.
Canine MCT Treatments
Protocol
# Dogs
Survival rate
Al-Sarraf et al. 1996
Cobalt Radiation
32
1 yr (100%), 2-5 yrs (96%)
Hahn et al. 2004
Alt day radiation
31
28 months (median)
Surgery +/- treatment
54
1,917 days (mean)
Mullins et al. 2006
Controversies in the
Management of Canine Mast
Cell Tumors
Heterogenous disease ≠Homogeous
treatment
Cohort studies vs. Individual cases
1.
2.
•
3.
4.
Mean DFI & Survival vs. Median
Lack of controlled, prospective
studies, compare treatment methods
Extent of medical work-up: cytology,
buffy coat, ultrasound
Controversies in the
Management of Canine Mast
Cell Tumors (con’t)
To treat or not treat solitary grade II
tumors
Multicentric vs. metastatic disease
Significance of prognostic factors
Defining end points
5.
6.
7.
8.
•
•
Ex: definition of reccurence, local at site
vs. new MCT at distant site
Time to tumor progression (Masitinib)
vs response rate (Palladia)
Adjuvant Treatment of Canine Mast Cell
Tumors
Clinical Indications
1. Recurrent and/or multiplicity of tumors
2. Dirty surgical boarders
3. Malignant anatomic site, i.e. , inguinal area/ genitalia of
dog, mammary gland, digit or oral cavity.
male
4. Histological Grading - dependent on numerical
classification used (Misdorp vs. Patnaik) Most important is
the description of the morphology of the tumor cells ( well
differentiated vs. anaplastic - granular vs. agranular).
5. Lymph node metastases