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