german shorthaired pointer national specialty show-2013 what happens to your gsp with a diagnosis of...
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German Shorthaired German Shorthaired Pointer National Pointer National Specialty Show-2013Specialty Show-2013
What Happens to Your GSP What Happens to Your GSP with a Diagnosis of Cancer?with a Diagnosis of Cancer?
K. Ann Jeglum, V.M.D., ACVIM, K. Ann Jeglum, V.M.D., ACVIM, OncologyOncology
Oncology: Diagnostics Oncology: Diagnostics and Therapies in and Therapies in TodayToday’’s Timess Times
K. Ann Jeglum, V.M.D.K. Ann Jeglum, V.M.D.Diplomate, ACVIM, OncologyDiplomate, ACVIM, OncologyAdjunct Associate ProfessorAdjunct Associate ProfessorThe Wistar Institute, PhiladelphiaThe Wistar Institute, PhiladelphiaVeterinary Oncology Services and Research Center Veterinary Oncology Services and Research Center Veterinary Oncology ServicesVeterinary Oncology Services’’ Radiation Center Radiation Center
Diagnostics in TodayDiagnostics in Today’’s s TimesTimes Important to obtain a definitive diagnosis Important to obtain a definitive diagnosis
as practically as possibleas practically as possible Costly diagnosis leaves no funds to treatCostly diagnosis leaves no funds to treat Clinical staging based on needs to Clinical staging based on needs to
prognosticate for ownersprognosticate for owners– Ex. Abdominal ultrasound in lymphoma does Ex. Abdominal ultrasound in lymphoma does
not change prognosis nor protocol unless GI not change prognosis nor protocol unless GI signssigns
– Ex. Role of abdominal US in mast cell tumorsEx. Role of abdominal US in mast cell tumors– Ex. Role of thoracic US vs. radiographsEx. Role of thoracic US vs. radiographs
Advanced Imaging: Advanced Imaging: MRI and CT ScansMRI and CT Scans Significant role in staging for treatment of Significant role in staging for treatment of
head and neck tumors, ie, nasal, oral, head and neck tumors, ie, nasal, oral, brainbrain
Pulmonary tumors: CTPulmonary tumors: CT Recognize potential of costly treatment, Recognize potential of costly treatment,
ie, radiation, after imagingie, radiation, after imaging Critical for diagnosis and treatment Critical for diagnosis and treatment
planning of brain tumors- surgical biopsies planning of brain tumors- surgical biopsies rarerare– Prognosis based on anatomic site and MRI Prognosis based on anatomic site and MRI
appearanceappearance
Role of Ultrasound as Role of Ultrasound as Medical OncologistMedical Oncologist Diagnosis and staging of intraabdominal Diagnosis and staging of intraabdominal
disease with US-guided needle aspiratedisease with US-guided needle aspirate Evaluation and cytology of thoracic Evaluation and cytology of thoracic
massesmasses Treatment follow-up of bladder, Treatment follow-up of bladder,
prostate, liver, adrenal, GI tumors- prostate, liver, adrenal, GI tumors- course of treatment based on resultscourse of treatment based on results
Surgical planning extemitiy, soft tissue Surgical planning extemitiy, soft tissue and thyroid massesand thyroid masses
Definition of Definition of ““EffectiveEffective”” Treatment in TodayTreatment in Today’’s s TimesTimes Quality of life not quantity- palliative Quality of life not quantity- palliative
vs. therapeutic treatmentvs. therapeutic treatment Cost effectiveness Cost effectiveness ““ReasonableReasonable”” prognosis based on prognosis based on
owner expectations and outcomeowner expectations and outcome Treating the disease and not the client- Treating the disease and not the client-
therapeutic doses vs. subtherapeutic therapeutic doses vs. subtherapeutic causing more harm than goodcausing more harm than good– Ex. Low dose, infrequent chemotherapy Ex. Low dose, infrequent chemotherapy
enhances MDR- q 3 week chemo in enhances MDR- q 3 week chemo in lymphoma not treating the diseaselymphoma not treating the disease
Cancer Therapy in Cancer Therapy in TodayToday’’s Timess Times ChemotherapyChemotherapy
– Nucleus: kills by breaking DNANucleus: kills by breaking DNA Molecular Targeted TherapyMolecular Targeted Therapy
– Cytoplasma: inhibits signal transduction Cytoplasma: inhibits signal transduction allowing programmed cell death or allowing programmed cell death or apoptossisapoptossis
Anti-Angiogenesis TherapyAnti-Angiogenesis Therapy– Tumor microenvironment: inhibits growth Tumor microenvironment: inhibits growth
factors that promote tumor vasculaturefactors that promote tumor vasculature
Canine Mammary Canine Mammary TumorsTumors Higher incidence in purebreed- breedingHigher incidence in purebreed- breeding
Overall 50:50% Benign to MalignantOverall 50:50% Benign to Malignant Of the 50% malignant half are surgically Of the 50% malignant half are surgically
curedcured Therefore 25% overall life threateningTherefore 25% overall life threatening Size does not predict malignancySize does not predict malignancy Early detection and early resectionEarly detection and early resection Surgical Approach: Radical vs. Simple Surgical Approach: Radical vs. Simple
mastectomy- en bloc lymph node resectionlmastectomy- en bloc lymph node resectionl
Soft Tissue SarcomasSoft Tissue Sarcomas
Histopathology: fibrosarcoma, spindle Histopathology: fibrosarcoma, spindle cell sarcoma, histiocytic sarcoma, cell sarcoma, histiocytic sarcoma, peripheral nerve sheath, peripheral nerve sheath, hemangiopericytoma hemangiopericytoma
Surgery initial treatment of choiceSurgery initial treatment of choice Local control: radiation therapyLocal control: radiation therapy Anaplastic pathology: doxorubicin/DTICAnaplastic pathology: doxorubicin/DTIC Histiocytic sarcoma/malignant Histiocytic sarcoma/malignant
histiocytosis- breed related prognosishistiocytosis- breed related prognosis Young dogs <5 yrs.- very aggressive- Young dogs <5 yrs.- very aggressive-
neoadjuvant chemotherapyneoadjuvant chemotherapy
Malignant Malignant Histiocytosis/Histiocytosis/Histiocytic SarcomaHistiocytic Sarcoma Genetic predisposition: Bernese Genetic predisposition: Bernese
Mountain dogs, Flat-coated Retrievers, Mountain dogs, Flat-coated Retrievers, Golden Retrievers (reported VOSRC, Golden Retrievers (reported VOSRC, 2008)2008)
Increasing incidenceIncreasing incidence Differentiate systemic disease (MH) Differentiate systemic disease (MH)
from localizedfrom localized Sites of Involvement: soft tissue, spleen, Sites of Involvement: soft tissue, spleen,
liver, lymph nodes, lung, bone marrowliver, lymph nodes, lung, bone marrow Classification/Nomenclature changes- P. Classification/Nomenclature changes- P.
Moore (UCDavis)Moore (UCDavis)
Histiocytic DiseasesHistiocytic Diseases
Histiocytes: subset of leukocytes Histiocytes: subset of leukocytes including monocytes, including monocytes, macrophage, dendritic antigen macrophage, dendritic antigen presenting cells (DAPCs)presenting cells (DAPCs)
Cutaneous HistiocytomaCutaneous Histiocytoma– Benign, proliferation of CD 1+, CD Benign, proliferation of CD 1+, CD
11 c+, Thy-1, CD 4- Langerhans cells11 c+, Thy-1, CD 4- Langerhans cells
Histiocytic DiseasesHistiocytic Diseases
Reactive HistiocytosisReactive Histiocytosis– Cutaneous and systemic formsCutaneous and systemic forms– Angiocentric, CD 1, CD 11 c+, Thy Angiocentric, CD 1, CD 11 c+, Thy
1+, CD 4 + DAPCs1+, CD 4 + DAPCs– Considered an immunoregulatory Considered an immunoregulatory
disorder and repsonds to disorder and repsonds to immunosuppressive therapy immunosuppressive therapy
Histiocytic SarcomaHistiocytic Sarcoma
Localized and dissminated Localized and dissminated Large round cells with spindiloid cells Large round cells with spindiloid cells
with increased cytoplasmic:nuclear with increased cytoplasmic:nuclear ratio- diagnosed on cytology or historatio- diagnosed on cytology or histo
Immuophenotype of DAPCsImmuophenotype of DAPCs Clinically aggressive with high rate of Clinically aggressive with high rate of
metastasesmetastases Systemic therapy generally indicatedSystemic therapy generally indicated
Therapy of Histiocytic Therapy of Histiocytic SarcomaSarcoma ChemotherapyChemotherapy
– VOSRC gold standard: VOSRC gold standard: Doxorubicin/DTICDoxorubicin/DTIC Bone marrow involvement- poor Bone marrow involvement- poor
prognosisprognosis
– CCNU +/- cyclophosphamideCCNU +/- cyclophosphamide ECOG trial- dismal resultsECOG trial- dismal results
Alternative Therapies Alternative Therapies for Histiocytic Sarcomafor Histiocytic Sarcoma Radiation therapy for local and/or regional Radiation therapy for local and/or regional
disease- 19 daily @ 3 Gy fractions to 57 disease- 19 daily @ 3 Gy fractions to 57 GyGy
TALL-104 Cell Line TherapyTALL-104 Cell Line Therapy– Wistar IntituteWistar Intitute– Effective but not available- internet questionEffective but not available- internet question
Biphosphanates- PamidronateBiphosphanates- Pamidronate– Based on responsed in human LangerhanBased on responsed in human Langerhan’’s s
cell histiocytosiscell histiocytosis– B. Kitchell- responses in individual casesB. Kitchell- responses in individual cases
Management of Mast Management of Mast Cell TumorsCell Tumors
K. Ann Jeglum, V.M.D.K. Ann Jeglum, V.M.D.
The Wistar InstituteThe Wistar Institute
Philadelphia, PennsylvaniaPhiladelphia, Pennsylvania
West Chester, PennsylvaniaWest Chester, Pennsylvania
Radiation Therapy and Radiation Therapy and ChemosensitizationChemosensitization Hypoxic cells are resistant to radiationHypoxic cells are resistant to radiation Low dose of chemotherapy drugs will Low dose of chemotherapy drugs will
sensitize hypoxic cells in bulky tumors sensitize hypoxic cells in bulky tumors to radiation killto radiation kill
Several drugs inhibit DNA repair or Several drugs inhibit DNA repair or sublethal radiation damagesublethal radiation damage
Drugs used: cisplatin, carboplatin, Drugs used: cisplatin, carboplatin, dactinomycin d, doxorubicin, dactinomycin d, doxorubicin, gemcitabine gemcitabine
Canine OsteosarcomaCanine Osteosarcoma
A cancer of large and giant breedsA cancer of large and giant breeds Median age of 10 years but an aggressive subset in Median age of 10 years but an aggressive subset in
young (18-24 mos)young (18-24 mos) Occur at metaphysis of rapidly growing bones- Occur at metaphysis of rapidly growing bones-
predisposition- also trauma sites, ie, fractures, internal predisposition- also trauma sites, ie, fractures, internal fixation devices- different biological behaviorfixation devices- different biological behavior
75% in long bones, ie, 75% in long bones, ie, ““away from the elbow and away from the elbow and around the kneearound the knee”” and hock and hock
Radiographic appearance: lytic, osteoblastic and Radiographic appearance: lytic, osteoblastic and mixed- cortical lysis, periosteal reaction (mixed- cortical lysis, periosteal reaction (““sunburstsunburst””))
Differential Diagnoses: fungal disease, infection, other Differential Diagnoses: fungal disease, infection, other primary bone tumors (fibrosarcoma, chondrosarcoma, primary bone tumors (fibrosarcoma, chondrosarcoma, hemangiosarcoma), hemopoietic tumors (LSA, hemangiosarcoma), hemopoietic tumors (LSA, myeloma)myeloma)
Canine Osteosarcoma- Canine Osteosarcoma- DiagnosisDiagnosis ““PathognomonicPathognomonic”” diagnosis of history, clinical diagnosis of history, clinical
signs, anatomic site and radiographic appearancesigns, anatomic site and radiographic appearance Dilemmas with biopsy- non-diagnostic with Dilemmas with biopsy- non-diagnostic with
reactive bone using an invasive procedure that reactive bone using an invasive procedure that may result in vascular release, increase pain and may result in vascular release, increase pain and lameness and increase risk for pathologic fracturelameness and increase risk for pathologic fracture
Characteristic appearance of other bone tumors Characteristic appearance of other bone tumors Geographic predisposition for mycotic diseasesGeographic predisposition for mycotic diseases Not indicated if amputation is definitive treatment Not indicated if amputation is definitive treatment
Canine Osteosarcoma-Canine Osteosarcoma-Staging and PrognosisStaging and PrognosisThoracic Radiographs: negative in >90% cases Thoracic Radiographs: negative in >90% cases
at initial diagnosisat initial diagnosisEvidence of micrometastases at time of Evidence of micrometastases at time of
diagnosis- disputed by anticoagulation data diagnosis- disputed by anticoagulation data during amputationduring amputation
Favorable Prognostic Factors: low serum Favorable Prognostic Factors: low serum alkaline phophatase, intracompartmental alkaline phophatase, intracompartmental lesions, small primary tumor, parosteal lesions, small primary tumor, parosteal osteosarcomas, axial and mandibular sites, osteosarcomas, axial and mandibular sites, tumor necrosis following chemotherapy- role tumor necrosis following chemotherapy- role of neoadjuvant chemo? of neoadjuvant chemo?
Canine Osteosarcoma: Canine Osteosarcoma: Where Are We?Where Are We? No significant change in survival or disease No significant change in survival or disease
free interval in the 15+ years since advent of free interval in the 15+ years since advent of platnum compoundsplatnum compoundsAmputation + 4 cycles of cisplatin=median Amputation + 4 cycles of cisplatin=median survivals=260-400 days with 1 year survival survivals=260-400 days with 1 year survival of 30-62%- not all disease free at 1 yr.of 30-62%- not all disease free at 1 yr.– 2 year survival rates 6-21% 2 year survival rates 6-21%
Doxorubicin alone < 1 yr. median survivalDoxorubicin alone < 1 yr. median survival Surgical limb salvage proceduresSurgical limb salvage procedures Amputation vs. palliative radiation followed Amputation vs. palliative radiation followed
by chemotherapyby chemotherapy
Canine Osteosarcoma- Canine Osteosarcoma- concon’’t.t. Protocol changes to improve prognosis:Protocol changes to improve prognosis:
– Combine cisplatin and doxorubicin in Combine cisplatin and doxorubicin in alternating cycles alternating cycles
– Increase number of cycles to 6Increase number of cycles to 6– Introduce additonal chemotherapeutic agents Introduce additonal chemotherapeutic agents
such as ifosfamidesuch as ifosfamide– No new cytotoxic agents- high dose No new cytotoxic agents- high dose
methotrexate problematic in dogsmethotrexate problematic in dogs– Maintenance metronomic chemotherapyMaintenance metronomic chemotherapy– No effective treatment for metastatic diseaseNo effective treatment for metastatic disease
Canine Osteosarcoma- Canine Osteosarcoma- concon’’t.t. Current VOSRC protocol post Current VOSRC protocol post
amuputation or palliative amuputation or palliative radiationradiation
Cisplatin (60mg/MCisplatin (60mg/M22) alternating ) alternating with Doxorubicin (30 mg/Mwith Doxorubicin (30 mg/M22every every 3 weeks-3 cycles each3 weeks-3 cycles each
Historically cisplatin first- recently Historically cisplatin first- recently doxorubicin before platum doxorubicin before platum compound may be more effectivecompound may be more effective
Canine Osteosarcoma- Canine Osteosarcoma- Palliative Radiation and Palliative Radiation and BiphosphonatesBiphosphonates Weekly radiation therapy to primary Weekly radiation therapy to primary
tumor (9 Gy weekly X 4=36 Gy)tumor (9 Gy weekly X 4=36 Gy) Biphosphonate- Pamidronate 1 mg/kg Biphosphonate- Pamidronate 1 mg/kg
intravenous infusion over min. 2 hours intravenous infusion over min. 2 hours every 3 weeksevery 3 weeks
Increase calcification of tumor, Increase calcification of tumor, decrease bone pain and now antitumor decrease bone pain and now antitumor effectseffects
Controversy of value of chemotherapy Controversy of value of chemotherapy in such a model in such a model
Biphosphonate Biphosphonate Therapy in Bone Therapy in Bone TumorsTumors Osteosarcoma and metastatic malignant Osteosarcoma and metastatic malignant
tumors induce and stimulate osteoclasts to tumors induce and stimulate osteoclasts to invade boneinvade bone
Can be osteolytic or osteoblastic and Can be osteolytic or osteoblastic and osteoclasts has important role in both osteoclasts has important role in both patternspatterns
Tumors produce many factors that stimulate Tumors produce many factors that stimulate osteolysis, osteosclerosis and aggressive osteolysis, osteosclerosis and aggressive tumor growthtumor growth
Osteoclastic targeted therapies: Osteoclastic targeted therapies: biphophonates- induction osteoclast biphophonates- induction osteoclast apoptosisapoptosis
Metronomic Metronomic ChemotherapyChemotherapy Chronic administration of chemotherapy Chronic administration of chemotherapy
at low, minimally toxic doses on a at low, minimally toxic doses on a frequent schedule of administration at frequent schedule of administration at close regular intervals, with no prolonged close regular intervals, with no prolonged drug-free breaksdrug-free breaks
Could less be more? Origins in pediatric Could less be more? Origins in pediatric oncology- similarities to vet oncooncology- similarities to vet onco
Antiangiogenic by targeting endothelial Antiangiogenic by targeting endothelial cells- more sensitive to continuous cells- more sensitive to continuous exposure of chemotherapy drugs without exposure of chemotherapy drugs without undergoing genetic mutations like tumor undergoing genetic mutations like tumor cells that develop drug resistance cells that develop drug resistance
Metronomic Metronomic Chemotherapy- conChemotherapy- con’’t.t. Major mechanism is inhibition of mobilization of Major mechanism is inhibition of mobilization of
endothelial cells that develop in bone marrow endothelial cells that develop in bone marrow and seeds tissueand seeds tissue
Bone marrow-derived endothelial cells are Bone marrow-derived endothelial cells are major source on new blood vessels to tumor major source on new blood vessels to tumor cellscells
Also stimulates production of thrombospondin-Also stimulates production of thrombospondin-1, a potent angiogenesis endogenous inhibitor1, a potent angiogenesis endogenous inhibitor
Low dose cyclophosphamide also depletes Low dose cyclophosphamide also depletes regulatory T-cells which are immunosuppressive regulatory T-cells which are immunosuppressive on effector T-cells and antigen presenting cells on effector T-cells and antigen presenting cells
Metronomic Metronomic Chemotherapy + COX-2 Chemotherapy + COX-2 InhibitorsInhibitors Cyclooxygenase-2 is over expressed in Cyclooxygenase-2 is over expressed in
tumors cells and stromal cells and tumors cells and stromal cells and promotes tumor growth by stimulation promotes tumor growth by stimulation angiogenesisangiogenesis
Overexpression of COX-2 stimulates Overexpression of COX-2 stimulates growth factors (VEFG)growth factors (VEFG)
COX also plays role in generation of T-COX also plays role in generation of T-reg cellsreg cells
Synergism of two approaches- Synergism of two approaches- metronomics plus COX-2 inhibitorsmetronomics plus COX-2 inhibitors
Metronomic Protocol Metronomic Protocol
Piroxicam 0.3 mg/kg po sid- Cox-2 Piroxicam 0.3 mg/kg po sid- Cox-2 inhibitor as antiangiogenicinhibitor as antiangiogenic
Chlorambucil 0.1 mg/kg po EOD or Chlorambucil 0.1 mg/kg po EOD or Cyclophosphamide 10-15 mg/M2 Cyclophosphamide 10-15 mg/M2 EOD but hemorhagic cystitis a EOD but hemorhagic cystitis a problemproblem
Doxycycline 5 mg/kg bidDoxycycline 5 mg/kg bid Methotrexate 0.05-0.1 mg/kg once Methotrexate 0.05-0.1 mg/kg once
weekly- no piroxicamweekly- no piroxicam
Metronomic Metronomic Chemotherapy + COX-2 Chemotherapy + COX-2 InhibitorsInhibitors Piroxicam only NSAID in dogs with proven Piroxicam only NSAID in dogs with proven
in vitro and in vivo antitumor activityin vitro and in vivo antitumor activity Low-dose cyclophosphamide plus Low-dose cyclophosphamide plus
piroxicam piroxicam – Increased DFI in dogs with completely resected Increased DFI in dogs with completely resected
splenic hemangiosarcoma compared to splenic hemangiosarcoma compared to doxorubicin alone- small nos. (Lana,JVIM, 2007)doxorubicin alone- small nos. (Lana,JVIM, 2007)
– Delay tumor recurrences in soft tissues Delay tumor recurrences in soft tissues recurrences in incompletely excised soft tissue recurrences in incompletely excised soft tissue sarcomas (peripheral nerve sheath) (Elmslie, sarcomas (peripheral nerve sheath) (Elmslie, JVIM, 2008)- retrospective JVIM, 2008)- retrospective
Canine Canine HemangiosarcomaHemangiosarcoma Tumor of vascular endotheliumTumor of vascular endothelium Prevalent sites: spleen, liver, right Prevalent sites: spleen, liver, right
atrium, lung, subcutaneous, boneatrium, lung, subcutaneous, bone Clinical presentations include Clinical presentations include
abdominal bleed, pericardial effusion-abdominal bleed, pericardial effusion-cardiac tamponadecardiac tamponade
Proven inherited in GRs! (Jeglum) Proven inherited in GRs! (Jeglum) GSHPs?GSHPs?
Not a death sentenceNot a death sentence
Canine Canine HemangiosarcomaHemangiosarcoma Soft tissue vs. splenic HSA- different Soft tissue vs. splenic HSA- different
diseases- long term survival with diseases- long term survival with chemotherapy of soft tissuechemotherapy of soft tissue
Do we change biological behavior of splenic Do we change biological behavior of splenic with adjuvant chemotherapy?with adjuvant chemotherapy?
Doxorubicin/dacarbazine- objective tumor Doxorubicin/dacarbazine- objective tumor responses in measurable metastatic disease- responses in measurable metastatic disease- not seen with doxo alone or with addition of not seen with doxo alone or with addition of cyclophosphamidecyclophosphamide
However, after 4 cycles A/DTIC still develop However, after 4 cycles A/DTIC still develop metastases but not during- delay of mets?metastases but not during- delay of mets?
Improvement? More chemotherapy vs. Improvement? More chemotherapy vs. maintenance metronomicsmaintenance metronomics
Doxorubicin Doxorubicin (Adriamycin) and (Adriamycin) and Dacarbazine (DTIC) Dacarbazine (DTIC) Day 1 : Doxorubicin 30 mg/M2 slow IVDay 1 : Doxorubicin 30 mg/M2 slow IV Days 1-5 DTIC 200/mg2 IV bolusDays 1-5 DTIC 200/mg2 IV bolus Days 4-5 Complete Blood Count Days 4-5 Complete Blood Count
(CBC)(CBC) Day 10 CBCDay 10 CBC Day 21 Start 2Day 21 Start 2ndnd cycle X 4 cycles cycle X 4 cycles Prophylactic antiemetics (Cernia, Prophylactic antiemetics (Cernia,
Centrine, Zofran) and antibioticsCentrine, Zofran) and antibiotics
Oral TumorsOral Tumors
DiagnosticsDiagnostics– Cytology vs. surgical biopsyCytology vs. surgical biopsy– Staging: lymph node aspirate, Staging: lymph node aspirate,
thoracic radiographsthoracic radiographs– MRI for treatment planning: surgical MRI for treatment planning: surgical
resection, radiation therapyresection, radiation therapy
Oral Tumors- conOral Tumors- con’’t.t.
Squamous Cell CarcinomaSquamous Cell Carcinoma– Treatment based on anatomic site and Treatment based on anatomic site and
size of tumorsize of tumor– Rostral: segmental mandibulectomy or Rostral: segmental mandibulectomy or
maxillectomymaxillectomy– Caudal: neoadjuvant chemotherapy vs. Caudal: neoadjuvant chemotherapy vs.
radiation therapy +/- chemosensitizationradiation therapy +/- chemosensitization– Role of systemic chemotherapy with local Role of systemic chemotherapy with local
therapy dependent on histopathologytherapy dependent on histopathology– Cats: BAC- doxorubicin, cyclophophamide, Cats: BAC- doxorubicin, cyclophophamide,
bleomycinbleomycin– Dogs: Cisplatin, 5-FUDogs: Cisplatin, 5-FU
Oral Tumor- conOral Tumor- con’’tt
SarcomasSarcomas– Changes in histopathology: spindle cell Changes in histopathology: spindle cell
sarcoma, fibrosarcomasarcoma, fibrosarcoma– Surgical approach similar to SCCSurgical approach similar to SCC– Radiation therapy +/- chemosensitization Radiation therapy +/- chemosensitization
with dactinomycinwith dactinomycin– Systemic chemotherapy: dactinomycin, Systemic chemotherapy: dactinomycin,
doxorubicin/dticdoxorubicin/dtic– Application dependent on Application dependent on
pathology/cytologypathology/cytology
Tyrosinase- Melanoma Tyrosinase- Melanoma AntigenAntigen Tyrosinase- a protein present on Tyrosinase- a protein present on
normal canine cutaneous normal canine cutaneous melanocytes and overexpressed on melanocytes and overexpressed on melanoma cellsmelanoma cells
Not normally targeted by the Not normally targeted by the immune system- CMV trains the immune system- CMV trains the immune system to recognize tumor-immune system to recognize tumor-associated protein or antigen associated protein or antigen
Canine MelanomaCanine Melanoma
Two malignant sites: oral cavity (gingiva, Two malignant sites: oral cavity (gingiva, palate, tongue) and subungal (digit)palate, tongue) and subungal (digit)
Locally invasive and metastatic to regional Locally invasive and metastatic to regional lymph nodes and distant sites, primarily lymph nodes and distant sites, primarily lung also liver, kidney and brainlung also liver, kidney and brain
Dermal melanomas historically considered Dermal melanomas historically considered benign but recently increase in malignant benign but recently increase in malignant cutaneous melanoma- can be multicentriccutaneous melanoma- can be multicentric
Xenogeneic Plasmid Xenogeneic Plasmid DNA Vaccine DNA Vaccine TechnologyTechnology A non-canine (human) tyrosinase is A non-canine (human) tyrosinase is
inserted in a ring of canine DNA= inserted in a ring of canine DNA= xenogeneic plasmid DNA containing xenogeneic plasmid DNA containing canine DNA for human tyrosinasecanine DNA for human tyrosinase
Foreign tyrosinase breaks through the Foreign tyrosinase breaks through the dogdog’’s tolerance of a self tumor thereby s tolerance of a self tumor thereby inducing a strong and active immunityinducing a strong and active immunity
Results in production of human Results in production of human antigen that is homologous to canine antigen that is homologous to canine tyrosinase but recognized as foreigntyrosinase but recognized as foreign
Xenogeneic Plasmid Xenogeneic Plasmid DNA Vaccine DNA Vaccine Technology- conTechnology- con’’tt The antigen is transcribed in the host The antigen is transcribed in the host
and actively presented by the and actively presented by the immune system during malignant immune system during malignant transformation targeting melanoma transformation targeting melanoma cells as foreigncells as foreign
The immune response appears The immune response appears tumor-specific targeting tumor tumor-specific targeting tumor producing cells not normal producing cells not normal melanocytesmelanocytes
Canine Melanoma Canine Melanoma Vaccine- ONCEPTVaccine- ONCEPT
Historically dogs with WHO stage II Historically dogs with WHO stage II or III oral melanoma treated with or III oral melanoma treated with surgery alone have survival times surgery alone have survival times <5-6 mos. <5-6 mos. – WHO Stage II: approximately 150-180 WHO Stage II: approximately 150-180
daysdays– WHO Stage III: approximately 60-90 WHO Stage III: approximately 60-90
daysdays
Canine Melanoma Canine Melanoma Vaccine- ONCEPT- conVaccine- ONCEPT- con’’tt Local disease control achieved through Local disease control achieved through
surgery (negative local lymph nodes or surgery (negative local lymph nodes or positive lymph nodes that were positive lymph nodes that were surgically removed or irradiatedsurgically removed or irradiated
58 dogs with stage II or III COM treated 58 dogs with stage II or III COM treated by vaccination with ONCEPT following by vaccination with ONCEPT following local disease controllocal disease control
Follow-up survival data 6 mos. after Follow-up survival data 6 mos. after conclusion of the study, <50% have conclusion of the study, <50% have died of melanoma (median survival died of melanoma (median survival time not attained) time not attained)
Canine Melanoma Canine Melanoma Vaccine-ONCEPTVaccine-ONCEPT Quantile estimates of survival time for Quantile estimates of survival time for
vaccinates (25% mortality {95% confidence vaccinates (25% mortality {95% confidence intervals was 464 daysintervals was 464 days
Significant difference between historical Significant difference between historical stage-matched controls and vaccinates with stage-matched controls and vaccinates with better survival times with vaccinates better survival times with vaccinates (p<0.0001)(p<0.0001)
No significant association in response No significant association in response between stage II and III (p=0.58)between stage II and III (p=0.58)
No difference in survival in dogs with post-No difference in survival in dogs with post-surgical histological clean surgical boarders surgical histological clean surgical boarders vs. narrow or dirty marginsvs. narrow or dirty margins
Canine Melanoma Canine Melanoma Vaccine- ONCEPTVaccine- ONCEPT Phil Bergman: 20% response in Phil Bergman: 20% response in
gross diseasegross disease Radiation and vaccine- administer Radiation and vaccine- administer
in conjunction to achieve immune in conjunction to achieve immune response to ag release at tumor response to ag release at tumor deathdeath
VOSRC experience: local and VOSRC experience: local and regional control essentialregional control essential
Canine Malignant Canine Malignant MelanomaMelanoma Advanced stage diseaseAdvanced stage disease
– Cisplatin/dacarbazineCisplatin/dacarbazine– Vs. Carboplatin- 15-20% loss of Vs. Carboplatin- 15-20% loss of
efficacy with chemotherapy efficacy with chemotherapy analoguesanalogues
Genitourinary Tract Genitourinary Tract TumorsTumors Increased incidence of prostate tumors Increased incidence of prostate tumors
especially prostate in neutered malesespecially prostate in neutered males Chemotherapy of Prostate: MitoxantroneChemotherapy of Prostate: Mitoxantrone Transitional Cell Carcinoma:Transitional Cell Carcinoma:
– Diagnosis with ultrasound and urine cytologyDiagnosis with ultrasound and urine cytology– Piroxicam alone: 20-25% ORRPiroxicam alone: 20-25% ORR– Chemotherapy: doxorubicin/cyclophophamide, Chemotherapy: doxorubicin/cyclophophamide,
mitoxantrone, gemcitabinemitoxantrone, gemcitabine
Anal Sac CarcinomasAnal Sac Carcinomas
Surgery based on size and invasiveness of Surgery based on size and invasiveness of local tumorlocal tumor
Regional lymph node metastases common on Regional lymph node metastases common on US stagingUS staging
““BarrierBarrier”” effect of lymph node- prolonged effect of lymph node- prolonged survival without distant metastasessurvival without distant metastases
Role of chemotherapy to prevent clinical Role of chemotherapy to prevent clinical signssigns
Protocols: FAC- doxorubicin, 5-FU, Protocols: FAC- doxorubicin, 5-FU, cyclophosphamide alternating with cyclophosphamide alternating with carboplatincarboplatin
Palladia (toceranib Palladia (toceranib phosphate)phosphate) FDA approved for the FDA approved for the ““treatment treatment
of grade II or III, recurrent, of grade II or III, recurrent, cutaneous mast cell tumors with cutaneous mast cell tumors with or without regional lymph node or without regional lymph node involvement in doginvolvement in dog
Palladia- conPalladia- con’’t.t.
““Mult-center, Placebo-controlled, Mult-center, Placebo-controlled, Double-blind, Randomized Study of Double-blind, Randomized Study of Oral Toceranib Phosphate Oral Toceranib Phosphate (SU11654), a Receptor Tyrosine (SU11654), a Receptor Tyrosine Kinase Inhibitor, for the Treatment Kinase Inhibitor, for the Treatment of Dogs with Recurrent (Either Local of Dogs with Recurrent (Either Local or Distant) Mast Cell Tumor or Distant) Mast Cell Tumor Following Surgical ExicisionFollowing Surgical Exicision”” London CA, Clin Cancer Res London CA, Clin Cancer Res 2009:15(11)3856-3865.2009:15(11)3856-3865.
Palladia-conPalladia-con’’t.t.
Blinded Phase: 6 weeks- 3.25 mg/kg Blinded Phase: 6 weeks- 3.25 mg/kg EOD- thereafter, eligible dogs received EOD- thereafter, eligible dogs received open-label Palladiaopen-label Palladia
Blinded phase ORR in Palladia-treated Blinded phase ORR in Palladia-treated dogs (n=86)=37.2% (7 CR and 25 PR) dogs (n=86)=37.2% (7 CR and 25 PR) vs. 7.9% (5 PR) in placebo-treated vs. 7.9% (5 PR) in placebo-treated (n=63; p=0.0004)(n=63; p=0.0004)
Of 58 dogs that received Palladia Of 58 dogs that received Palladia following placebo-escape, 41.4% (8 CR, following placebo-escape, 41.4% (8 CR, 16 PR) had ORR16 PR) had ORR
ORR in 145 dogs receiving Palladia was ORR in 145 dogs receiving Palladia was 42.8% (21 CR, 41 PR)42.8% (21 CR, 41 PR)
Palladia- conPalladia- con’’t.t.
62 Responders: Median duration of 62 Responders: Median duration of objective response= 12 weeks and objective response= 12 weeks and median time to progression= 18.1 weeksmedian time to progression= 18.1 weeks
Survival time was not an end point and Survival time was not an end point and not reportednot reported
Dogs with positive c-kit ITD were more Dogs with positive c-kit ITD were more likely to have an objective response likely to have an objective response compared to those negative (44.8% vs. compared to those negative (44.8% vs. 20.3%)20.3%)
Palladia- conPalladia- con’’t.t.
Most common adverse events- Most common adverse events- majority grade 1 or 2majority grade 1 or 2– Diarrhea 46%Diarrhea 46%– Vomiting 32.2%Vomiting 32.2%– Blood in stool 12.6%Blood in stool 12.6%– Anorexia 39.1%Anorexia 39.1%– Neutropenia 46%Neutropenia 46%– Weight loss14.9%Weight loss14.9%– Musculoskeletal 25%Musculoskeletal 25%
Palladia- conPalladia- con’’t.t.
Grade 3 or 4 adverse were 20.7% Grade 3 or 4 adverse were 20.7% in Pallladia treated vs. 15.6% of in Pallladia treated vs. 15.6% of placebo (p=0.527)placebo (p=0.527)
Toxicities secondary to mast cell Toxicities secondary to mast cell disease and degranulationdisease and degranulation
Canine LymphomaCanine Lymphoma
VCAA: L-asparaginase, vincristine, VCAA: L-asparaginase, vincristine, cyclophosphamide, doxorubicin- single cyclophosphamide, doxorubicin- single agent, weekly for 4 weeks X 2 cyclesagent, weekly for 4 weeks X 2 cycles
UW (KirkUW (Kirk’’s CT) Protocol Standard of s CT) Protocol Standard of Care but long term maintenance not Care but long term maintenance not necessary- decreased to 12 wk. necessary- decreased to 12 wk. without significant differenceswithout significant differences
Quality of life, cost effectiveness and Quality of life, cost effectiveness and avoidance of multi-drug resistanceavoidance of multi-drug resistance
Canine Lymphoma-Canine Lymphoma-cont. cont. Importance of bone marrow aspirate as Importance of bone marrow aspirate as
15-20% involvement without 15-20% involvement without hematological changeshematological changes
Mechanism of early relapseMechanism of early relapse Referral disease or not?Referral disease or not? ““Tricks of the tradeTricks of the trade””- when to cross over - when to cross over
to rescue protocolsto rescue protocols Combined treatment to determine MDRCombined treatment to determine MDR Importance of doxorubicin/DTICImportance of doxorubicin/DTIC
Veterinary Oncology Veterinary Oncology Services and Research Services and Research Center Center West Chester, PAWest Chester, PA
K. Ann Jeglum, V.M.D., Diplomate, ACVIM, K. Ann Jeglum, V.M.D., Diplomate, ACVIM, OncologyOncology
Donna L. Lindner, D.V.M., Board eligible Donna L. Lindner, D.V.M., Board eligible surgery, 9 years medical oncologysurgery, 9 years medical oncology
Vicky Nelson, D.V.M., Board eligible Vicky Nelson, D.V.M., Board eligible internal medicine, 8 years medical internal medicine, 8 years medical oncologyoncology
Lisa Suslack-Brown, V.M.D., Diplomate, Lisa Suslack-Brown, V.M.D., Diplomate, ACVRACVR
Kenneth Sadanaga, D.V.M. Diplomate, Kenneth Sadanaga, D.V.M. Diplomate, ACVSACVS
Michael Miller, V.M.D., cardiologyMichael Miller, V.M.D., cardiology
Veterinary Oncology Veterinary Oncology ServicesServices’’ Radiation Radiation CenterCenterChalfont, PAChalfont, PA Drs. Jeglum, Lindner, NelsonDrs. Jeglum, Lindner, Nelson Dr. Patrick Gavin, Diplomate, ACVR, Dr. Patrick Gavin, Diplomate, ACVR,
ACVRO- radiation planningACVRO- radiation planning Sue Chipollini, Board Certified Sue Chipollini, Board Certified
Radiation Therapist- 25 yrs. ExperienceRadiation Therapist- 25 yrs. Experience Tracey Murphy, Board Certified Tracey Murphy, Board Certified
Radiation Therapist- 20 yrs. ExperienceRadiation Therapist- 20 yrs. Experience Linear accelerator 6Mv with photons Linear accelerator 6Mv with photons
and electrons and simulatorand electrons and simulator Full capacity medical oncology facilityFull capacity medical oncology facility
Canine Mast Cell Tumor: Canine Mast Cell Tumor: ClinicianClinician’’s Dilemma s Dilemma Heterogeneous Biological Heterogeneous Biological BehaviorBehaviorPrognostic Factors in Management of Mast Cell TumorsPrognostic Factors in Management of Mast Cell Tumors
1.1. Is this a first time occurrence of the MCT of is it recurrent? Is Is this a first time occurrence of the MCT of is it recurrent? Is the tumor in the same site or different site?the tumor in the same site or different site?
Recurrent disease requires adjuvant therapy following re-Recurrent disease requires adjuvant therapy following re-excisionexcision
2.2. What is the anatomical site of the tumor? Is it solitary or What is the anatomical site of the tumor? Is it solitary or multicentric?multicentric?
Anatomic sites with a more malignant behavior despite Anatomic sites with a more malignant behavior despite histological grade include:histological grade include:
Genitalia (male) and inguinal(?)/ perineal Genitalia (male) and inguinal(?)/ perineal areaarea
Mammary gland in femaleMammary gland in femaleOral cavityOral cavityDigit or dorsum of pawDigit or dorsum of paw
Canine Mast Cell Tumors: Canine Mast Cell Tumors: Heterogeneous Biological Behavior Heterogeneous Biological Behavior (cont.)(cont.)
3. 3. What is the growth rate?What is the growth rate?
Slow growing and indolent (benign), slow growing with a Slow growing and indolent (benign), slow growing with a rapid growth spurt (becoming malignant), rapid growth rapid growth spurt (becoming malignant), rapid growth and invasion from onset (malignant).and invasion from onset (malignant).
4.4. What does the biopsy report tell about the grade of What does the biopsy report tell about the grade of malignancy of the mast cells?malignancy of the mast cells?
Despite which numerical system may be used, a Despite which numerical system may be used, a description of the cells is critical. Are the surgical description of the cells is critical. Are the surgical boarders devoid of tumor cells?boarders devoid of tumor cells?
Biology of Mast CellsBiology of Mast Cells
Normal cells of connective tissue- most numerous Normal cells of connective tissue- most numerous underlying serosal surfaces, mucous membranes underlying serosal surfaces, mucous membranes and dermisand dermis
Most Common site of tumor formation is skin and Most Common site of tumor formation is skin and subcutaneoussubcutaneous
Spleen, liver, GI, oral cavitySpleen, liver, GI, oral cavity
Characteristically have metochromatic granules Characteristically have metochromatic granules containing vasoactive substances including containing vasoactive substances including histamine, heparin.histamine, heparin.
Prognostic Factors in Prognostic Factors in Canine Mast Cell Tumors Canine Mast Cell Tumors
1.1. Grade- I, II, IIIGrade- I, II, III• Well-differentiatedWell-differentiated anaplastic anaplastic
2.2. Solitary vs. multicentric tumorsSolitary vs. multicentric tumors
3.3. Completeness of tumor excisionCompleteness of tumor excision
4.4. Tumor siteTumor site
Prognostic Factors in Prognostic Factors in Canine Mast Cell Tumors Canine Mast Cell Tumors (con(con’’t)t)5.5. Regional and distant metastasis, Regional and distant metastasis,
i.e. lymph node, liver, spleen i.e. lymph node, liver, spleen (methods of evaluation?)(methods of evaluation?)
VCS Study: >100 cases buffy coats, VCS Study: >100 cases buffy coats, ultrasound liver and spleen, bone ultrasound liver and spleen, bone marrows yielded <2% positive resultsmarrows yielded <2% positive results
6.6. Recurrence in stage II tumors has Recurrence in stage II tumors has negative impact on survival timenegative impact on survival time
Prognostic Factors in Prognostic Factors in Canine Mast Cell Tumors- Canine Mast Cell Tumors- concon’’t.t.6. Mitotic Index: <5> MI/ 10 HPF- Median 6. Mitotic Index: <5> MI/ 10 HPF- Median
Survival Time (MST)Survival Time (MST)Grade II: <5 MST=70 mos.Grade II: <5 MST=70 mos.
>5 MST= 5 mos. >5 MST= 5 mos. (p<.001)(p<.001)Grade III: <5= no MST attained Grade III: <5= no MST attained
>5 MST =<2 mos.>5 MST =<2 mos.(p<.001)(p<.001)
Vet Path 2007:44(3)335-41Vet Path 2007:44(3)335-41
Prognostic Factors in Prognostic Factors in Canine Mast Cell Tumors- Canine Mast Cell Tumors- concon’’t.t. 7. Cellular Proliferative Indices- 7. Cellular Proliferative Indices-
results from the number of cycling results from the number of cycling cells (growth fraction) and rate of cell cells (growth fraction) and rate of cell cycle progression (generation time)cycle progression (generation time)– Increased Ki67 (growth fraction) and Increased Ki67 (growth fraction) and
AgNOR (generation time) counts predict AgNOR (generation time) counts predict significantly recurrence at original site, significantly recurrence at original site, distant metastases, MCT-related distant metastases, MCT-related mortality rates, decreased survival timesmortality rates, decreased survival times
– Vet Path 2007:44(3):298-308 Vet Path 2007:44(3):298-308
Prognostic Factors in Prognostic Factors in Canine Mast Cell Tumors- Canine Mast Cell Tumors- concon’’t.t. 8.8. cc-kit-kit Mutations Mutations
– c-c-kit kit proto-oncogene encodes the proto-oncogene encodes the receptor tyrosine kinase KIT- important receptor tyrosine kinase KIT- important in normal mast cell survival, in normal mast cell survival, proliferation, differentiation, migration proliferation, differentiation, migration and cell deathand cell death
– Mutations result in increased cellular Mutations result in increased cellular proliferation, higher histological grade, proliferation, higher histological grade, decreased disease-free and overall decreased disease-free and overall survival timessurvival times
Medical Work-Up for Medical Work-Up for Mast Cell TumorsMast Cell Tumors
1.1. Complete Blood Count +/- Buffy CoatComplete Blood Count +/- Buffy Coat
2.2. Biochemical ProfileBiochemical Profile
3.3. Thoracic and Abdominal RadiographsThoracic and Abdominal Radiographs
4.4. Needle Aspirate of Regional Lymph Needle Aspirate of Regional Lymph NodeNode
5.5. Abdominal Ultrasound?Abdominal Ultrasound?
6.6. Bone Marrow?Bone Marrow?
WHO Clinical Staging System WHO Clinical Staging System for Mast Cell Tumorsfor Mast Cell Tumors
Stage I: One tumor confined to the dermis Stage I: One tumor confined to the dermis without regional lymph node involvement.without regional lymph node involvement.
a)a) Without systemic signsWithout systemic signsb)b) With systemic signsWith systemic signs
Stage II: One tumor confined to the dermis Stage II: One tumor confined to the dermis with regional lymph node involvement.with regional lymph node involvement.
a)a) Without systemic signsWithout systemic signsb)b) With systemic signsWith systemic signs
WHO Clinical Staging WHO Clinical Staging System for Mast Cell System for Mast Cell Tumors (conTumors (con’’t)t)Stage III: Multiple dermal tumors; large Stage III: Multiple dermal tumors; large
infiltrating tumors with or without infiltrating tumors with or without regional lymph node involvement.regional lymph node involvement.
a)a) Without systemic signsWithout systemic signs
b)b) With systemic signsWith systemic signs
Stage IV: Any tumor with distant Stage IV: Any tumor with distant
metastasis or recurrence with metastasis or recurrence with
metastasis.metastasis.
Histologic Classification of Histologic Classification of Mast Cell TumorMast Cell Tumor
Grade Bostock Patnaik Microscopic DescriptionAnaplastic, Undifferentiated
1 3 Pleomorphic size and of cells and nuclei, high mitotic rate, few to no granules. Invasive into deep tissue
Moderately Differentiated
2 2 Moderate pleomorphism with round to avoid cells, fine granules, decreased nuclear to cytoplasmic ratio, few mitotic figures, infiltrate deep dermis and subcutaneous
Wall Differentiated 3 1 Round monomorphic cells with distinct boarders, round nuclei with many distinct granules, n mitotic figures, confined to dermis
Survival Times of Dogs Based Survival Times of Dogs Based on Histologic Gradeon Histologic Grade
No. of Dogs % AliveMonths Post-
Surgery
Bostock, 1973
Well-differentiated 39 77 6
Differentiated 30 45 6
Undifferentiated 45 13 6
Patnaik, et. al, 1984
Well-differentiated 30 83 15
Differentiated 36 44 15
Undifferentiated 17 6 15
Adjuvant Treatment of Canine Mast Adjuvant Treatment of Canine Mast Cell TumorsCell Tumors
Clinical IndicationsClinical Indications
1. Recurrent and/or multiplicity of tumors1. Recurrent and/or multiplicity of tumors
2. Dirty surgical boarders2. Dirty surgical boarders
3. Malignant anatomic site, i.e. , inguinal area/ genitalia of male 3. Malignant anatomic site, i.e. , inguinal area/ genitalia of male
dog, mammary gland, digit or oral cavity.dog, mammary gland, digit or oral cavity.
4. Histological Grading - dependent on numerical classification 4. Histological Grading - dependent on numerical classification
used (Misdorp vs. Patnaik) Most important is the description of used (Misdorp vs. Patnaik) Most important is the description of
the morphology of the tumor cells ( well differentiated vs. the morphology of the tumor cells ( well differentiated vs.
anaplastic - granular vs. agranular).anaplastic - granular vs. agranular).
5. Lymph node metastases5. Lymph node metastases
6. Increased mitotic index6. Increased mitotic index
33% 66%
Surgery Alone
SurgerySteroidsCimetidine+/- Radiation
Stage I
Stage II
Stage I
Stage II
SurgerySteriods+/- Radiation
SurgerySteroidsCimetidine+/- RadiationChemotherapy
Stage III, IV
Surgery+/- ChemotherapyCimetidine
Well-Differentiated Intermediate and Undifferentiated
Mast Cell Tumor
Management of Mast Cell Management of Mast Cell TumorsTumors
1.1. Surgical Excision- Cut Early, Wide and DeepSurgical Excision- Cut Early, Wide and Deep
2.2. Radiation Therapy- An extension of the Scapel Radiation Therapy- An extension of the Scapel for Local and Regional Diseasefor Local and Regional Disease
3.3. Corticosteriods- Use Early in High Risk DiseaseCorticosteriods- Use Early in High Risk DiseasePalliative in Advanced DiseasePalliative in Advanced Disease
Level I Level I Protocol:Protocol:
Prednisone or PrednisolonePrednisone or Prednisolone
40mg/m40mg/m22/day for 3 weeks, then/day for 3 weeks, then
20mg/m20mg/m22/day for 3 weeks and /day for 3 weeks and wean offwean off
Recommend H2 and Recommend H2 and H1AntagonistsH1Antagonists
Management of Mast Cell Management of Mast Cell Tumor (Cont.)Tumor (Cont.)
4. Chemotherapy- Heterogeneous 4. Chemotherapy- Heterogeneous ResponseResponse
a)a) Level II: Chlorambucil 0.2 mg/kg po sid X 6 mos +/- Level II: Chlorambucil 0.2 mg/kg po sid X 6 mos +/- PrednisonePrednisone
b)b) Level III: Vinblastine 2 mg/M2 IV bolus weekly to Level III: Vinblastine 2 mg/M2 IV bolus weekly to responseresponse
c)c) Level IV: Lomustine 70 mg/M2 po q 3- 4 wksLevel IV: Lomustine 70 mg/M2 po q 3- 4 wks
5. Immunotherapy- Observation Supporting 5. Immunotherapy- Observation Supporting ApplicationApplication
a)a) Evidence of immunological defect- decreased Evidence of immunological defect- decreased antibody production- Howard, 1967antibody production- Howard, 1967
b)b) Adminstration of BCG resulting in fever and Adminstration of BCG resulting in fever and regression of MCTs- Jeglum, 1977regression of MCTs- Jeglum, 1977
c)c) rhTNF + rhIL-2: Partial to complete necrosis in rhTNF + rhIL-2: Partial to complete necrosis in 6/6 dogs- Moore, et. Al, 19916/6 dogs- Moore, et. Al, 1991
Molecular Targeted Molecular Targeted Therapeutics Therapeutics
Signal Transduction TargetsSignal Transduction Targets– IntracytoplasmicIntracytoplasmic– Mutations of genes resulting in Mutations of genes resulting in
uncontrolled growthuncontrolled growth– Assays for presence of such mutationsAssays for presence of such mutations– C-kit mutation in canine mast cell C-kit mutation in canine mast cell
tumorstumors– Therapeutic: Gleevac- iminatinibTherapeutic: Gleevac- iminatinib
Palladia (toceranib Palladia (toceranib phosphate)phosphate) FDA approved for the FDA approved for the ““treatment treatment
of grade II or III, recurrent, of grade II or III, recurrent, cutaneous mast cell tumors with cutaneous mast cell tumors with or without regional lymph node or without regional lymph node involvement in doginvolvement in dog
Palladia- conPalladia- con’’t.t.
““Mult-center, Placebo-controlled, Mult-center, Placebo-controlled, Double-blind, Randomized Study of Double-blind, Randomized Study of Oral Toceranib Phosphate (SU11654), Oral Toceranib Phosphate (SU11654), a Receptor Tyrosine Kinase Inhibitor, a Receptor Tyrosine Kinase Inhibitor, for the Treatment of Dogs with for the Treatment of Dogs with Recurrent (Either Local or Distant) Recurrent (Either Local or Distant) Mast Cell Tumor Following Surgical Mast Cell Tumor Following Surgical ExicisionExicision”” London CA, Clin Cancer London CA, Clin Cancer Res 2009:15(11)3856-3865.Res 2009:15(11)3856-3865.
Palladia- conPalladia- con’’t.t.
62 Responders: Median duration of 62 Responders: Median duration of objective response= 12 weeks and objective response= 12 weeks and median time to progression= 18.1 median time to progression= 18.1 weeksweeks
Survival time was not an end point Survival time was not an end point and not reportedand not reported
Dogs with positive c-kit ITD were Dogs with positive c-kit ITD were more likely to have an objective more likely to have an objective response compared to those negative response compared to those negative (44.8% vs. 20.3%)(44.8% vs. 20.3%)
Palladia-conPalladia-con’’t.t.
Blinded Phase: 6 weeks- 3.25 mg/kg EOD- Blinded Phase: 6 weeks- 3.25 mg/kg EOD- thereafter, eligible dogs received open-thereafter, eligible dogs received open-label Palladialabel Palladia
Blinded phase ORR in Palladia-treated dogs Blinded phase ORR in Palladia-treated dogs (n=86)=37.2% (7 CR and 25 PR) vs. 7.9% (n=86)=37.2% (7 CR and 25 PR) vs. 7.9% (5 PR) in placebo-treated (n=63; p=0.0004)(5 PR) in placebo-treated (n=63; p=0.0004)
Of 58 dogs that received Palladia following Of 58 dogs that received Palladia following placebo-escape, 41.4% (8 CR, 16 PR) had placebo-escape, 41.4% (8 CR, 16 PR) had ORRORR
ORR in 145 dogs receiving Palladia was ORR in 145 dogs receiving Palladia was 42.8% (21 CR, 41 PR)42.8% (21 CR, 41 PR)
Palladia- conPalladia- con’’t.t.
Most common adverse events- Most common adverse events- majority grade 1 or 2majority grade 1 or 2– Diarrhea 46%Diarrhea 46%– Vomiting 32.2%Vomiting 32.2%– Blood in stool 12.6%Blood in stool 12.6%– Anorexia 39.1%Anorexia 39.1%– Neutropenia 46%Neutropenia 46%– Weight loss14.9%Weight loss14.9%– Musculoskeletal 25%Musculoskeletal 25%
Palladia- conPalladia- con’’tt
DO NOT USE THE CLINICAL INSERT DO NOT USE THE CLINICAL INSERT DOSING CHART (same for PfizerDOSING CHART (same for Pfizer’’s s Cerenia)Cerenia)
Current Recommendation per C. Current Recommendation per C. LondonLondon– Start dosing at 2.75 mg/kg every other dayStart dosing at 2.75 mg/kg every other day– Use prophylactic antiemetics (Centrine, Use prophylactic antiemetics (Centrine,
CereniaCerenia– Dose escalate to 3.25 mg/kg EOD based on Dose escalate to 3.25 mg/kg EOD based on
toxicity profiletoxicity profile
Masitinib- Inhibitor of Masitinib- Inhibitor of KIT, A Receptor KIT, A Receptor Tyrosinase KinasTyrosinase Kinas Licensed by AB Science in Europe for Licensed by AB Science in Europe for
veterinary use in November 2008veterinary use in November 2008 Phase III Study- multicenter, Phase III Study- multicenter,
randomized, placebo-controlled with randomized, placebo-controlled with measurable grade II or III mast cell measurable grade II or III mast cell tumors without regional or distant tumors without regional or distant metastases- 202 dogsmetastases- 202 dogs
6 month treatment at dose of 16 month treatment at dose of 1
2.5 mg/kg/day2.5 mg/kg/day
Masitinib Phase III- Masitinib Phase III- concon’’t.t. Prolonged time to tumor progression Prolonged time to tumor progression
(TTP) compared with placebo (75 to (TTP) compared with placebo (75 to 118 days; p=.038)118 days; p=.038)
Effect more pronounced with first-line Effect more pronounced with first-line therapy – increase TTP from 75 to 253 therapy – increase TTP from 75 to 253 days (p=.001) regardless of days (p=.001) regardless of expression of mutant vs. wild type KITexpression of mutant vs. wild type KIT
Overall response assessed at 4 and 6 Overall response assessed at 4 and 6 mos. not significantly increase by mos. not significantly increase by masitinibmasitinib
Masitinib Phase III- Masitinib Phase III- concon’’t.t. No significant differences with masitinib vs. No significant differences with masitinib vs.
placebo in proportion with CR (11.2 vs placebo in proportion with CR (11.2 vs 4.9%) or PR (4.6 vs 9.8%)4.9%) or PR (4.6 vs 9.8%)
ToxicityToxicity– Significantly more diarrhea and vomiting with Significantly more diarrhea and vomiting with
masitinib- 96.2 % grade I or II- tolerable and masitinib- 96.2 % grade I or II- tolerable and transient and without sequeleatransient and without sequelea
– Neutropenia 6.2%Neutropenia 6.2%– Renal 7.5%Renal 7.5%
J Vet Intern Med 2008;22:1301-1309J Vet Intern Med 2008;22:1301-1309
Clinical Consequences of Clinical Consequences of Degranulation of Mast CellsDegranulation of Mast Cells
1.1. Vomiting and/or Diarrhea- Not related to Vomiting and/or Diarrhea- Not related to GI ulcerGI ulcer
2.2. Gastrodoudenal Ulcers- Mechanisms:Gastrodoudenal Ulcers- Mechanisms:a)a) Histamine stimulates H2 receptors resulting Histamine stimulates H2 receptors resulting
in excessive acid secretion and hypermotilityin excessive acid secretion and hypermotilityb)b) Histamine causes vacular dilation that Histamine causes vacular dilation that
increases endothelial permeability leading to increases endothelial permeability leading to intravascular thrombosis and ischemic intravascular thrombosis and ischemic necrosisnecrosis
c)c) Clinical Signs: asymptomatic to anorexia, Clinical Signs: asymptomatic to anorexia, vomiting/ diarrhea +/- blood, anemiavomiting/ diarrhea +/- blood, anemia
d)d) Perforated Ulcer- peritonitis, deathPerforated Ulcer- peritonitis, death
Clinical Management of Clinical Management of Gastrointestinal SignsGastrointestinal Signs
1.1. H2 blockersH2 blockersa)a) Cimetidine (Tagamet): 2-4/mg/kg PO QIDCimetidine (Tagamet): 2-4/mg/kg PO QIDb)b) Ranitidine (Zantec): Dog: 2mg/kg TID IV, PORanitidine (Zantec): Dog: 2mg/kg TID IV, POc)c) Famotidine (Pepcid): 1 mg/kg SID, POFamotidine (Pepcid): 1 mg/kg SID, PO
2.2. Coating Agent: Sucralfate: 250mg/15kg Coating Agent: Sucralfate: 250mg/15kg PO QIDPO QID
Give 2 hours apart from other medsGive 2 hours apart from other meds
3.3. Diphenhydramine (Benadryl): 2-4 mg/kg Diphenhydramine (Benadryl): 2-4 mg/kg q6-8h PO, IM. If used IV, give very slowly q6-8h PO, IM. If used IV, give very slowly due to hypotension.due to hypotension.
Canine MCT TreatmentsCanine 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)
Mullins et al. 2006 Surgery +/- treatment 54 1,917 days (mean)
Controversies in the Controversies in the Management of Canine Management of Canine Mast Cell TumorsMast Cell Tumors1.1. Heterogenous disease Heterogenous disease
≠Homogeous treatment≠Homogeous treatment2.2. Cohort studies vs. Individual casesCohort studies vs. Individual cases
• Mean DFI & Survival vs. MedianMean DFI & Survival vs. Median
3.3. Lack of controlled, prospective Lack of controlled, prospective studies, compare treatment studies, compare treatment methodsmethods
4.4. Extent of medical work-up: Extent of medical work-up: cytology, buffy coat, ultrasoundcytology, buffy coat, ultrasound
Controversies in the Controversies in the Management of Canine Management of Canine Mast Cell Tumors (conMast Cell Tumors (con’’t)t)5.5. To treat or not treat solitary grade To treat or not treat solitary grade
II tumorsII tumors6.6. Multicentric vs. metastatic diseaseMulticentric vs. metastatic disease7.7. Significance of prognostic factorsSignificance of prognostic factors8.8. Defining end pointsDefining end points
• Ex: definition of reccurence, local at Ex: definition of reccurence, local at site vs. new MCT at distant sitesite vs. new MCT at distant site
• Time to tumor progression (Masitinib) Time to tumor progression (Masitinib) vs response rate (Palladia)vs response rate (Palladia)
Adjuvant Treatment of Canine Mast Adjuvant Treatment of Canine Mast Cell TumorsCell Tumors
Clinical IndicationsClinical Indications
1. Recurrent and/or multiplicity of tumors1. Recurrent and/or multiplicity of tumors
2. Dirty surgical boarders2. Dirty surgical boarders
3. Malignant anatomic site, i.e. , inguinal area/ genitalia of 3. Malignant anatomic site, i.e. , inguinal area/ genitalia of
male dog, mammary gland, digit or oral cavity.male dog, mammary gland, digit or oral cavity.
4. Histological Grading - dependent on numerical 4. Histological Grading - dependent on numerical
classification used (Misdorp vs. Patnaik) Most classification used (Misdorp vs. Patnaik) Most
important is the description of the morphology of the tumor important is the description of the morphology of the tumor
cells ( well differentiated vs. anaplastic - granular vs. cells ( well differentiated vs. anaplastic - granular vs.
agranular).agranular).
5. Lymph node metastases5. Lymph node metastases