German Shorthaired Pointer National Specialty Show-2013

1. German Shorthaired Pointer National Specialty Show-2013 What Happens to Your GSP with a Diagnosis of Cancer? K. Ann Jeglum, V.M.D., ACVIM, Oncology

2. Oncology: Diagnostics and Therapies in Today’s Times K. Ann Jeglum, V.M.D. Diplomate, ACVIM, Oncology Adjunct Associate Professor The Wistar Institute, Philadelphia Veterinary Oncology Services and Research Center Veterinary Oncology Services’ Radiation Center

9. Diagnostics in Today’s Times • Important to obtain a definitive diagnosis as practically as possible • Costly diagnosis leaves no funds to treat • Clinical staging based on needs to prognosticate for owners • Ex. Abdominal ultrasound in lymphoma does not change prognosis nor protocol unless GI signs • Ex. Role of abdominal US in mast cell tumors • Ex. Role of thoracic US vs. radiographs

10. Advanced Imaging: MRI and CT Scans • Significant role in staging for treatment of head and neck tumors, ie, nasal, oral, brain • Pulmonary tumors: CT • Recognize potential of costly treatment, ie, radiation, after imaging • Critical for diagnosis and treatment planning of brain tumors- surgical biopsies rare • Prognosis based on anatomic site and MRI appearance

11. Role of Ultrasound as Medical Oncologist • Diagnosis and staging of intraabdominal disease with US-guided needle aspirate • Evaluation and cytology of thoracic masses • Treatment follow-up of bladder, prostate, liver, adrenal, GI tumors- course of treatment based on results • Surgical planning extemitiy, soft tissue and thyroid masses

12. Definition of “Effective” Treatment in Today’s Times • Quality of life not quantity- palliative vs. therapeutic treatment • Cost effectiveness • “Reasonable” prognosis based on owner expectations and outcome • Treating the disease and not the client- therapeutic doses vs. subtherapeutic causing more harm than good • Ex. Low dose, infrequent chemotherapy enhances MDR- q 3 week chemo in lymphoma not treating the disease

13. Cancer Therapy in Today’s Times • Chemotherapy • Nucleus: kills by breaking DNA • Molecular Targeted Therapy • Cytoplasma: inhibits signal transduction allowing programmed cell death or apoptossis • Anti-Angiogenesis Therapy • Tumor microenvironment: inhibits growth factors that promote tumor vasculature

14. Canine Mammary Tumors • Higher incidence in purebreed- breeding • Overall 50:50% Benign to Malignant • Of the 50% malignant half are surgically cured • Therefore 25% overall life threatening • Size does not predict malignancy • Early detection and early resection • Surgical Approach: Radical vs. Simple mastectomy- en bloc lymph node resectionl

15. Soft Tissue Sarcomas • Histopathology: fibrosarcoma, spindle cell sarcoma, histiocytic sarcoma, peripheral nerve sheath, hemangiopericytoma • Surgery initial treatment of choice • Local control: radiation therapy • Anaplastic pathology: doxorubicin/DTIC • Histiocytic sarcoma/malignant histiocytosis- breed related prognosis • Young dogs <5 yrs.- very aggressive- neoadjuvant chemotherapy

16. Malignant Histiocytosis/Histiocytic Sarcoma • Genetic predisposition: Bernese Mountain dogs, Flat-coated Retrievers, Golden Retrievers (reported VOSRC, 2008) • Increasing incidence • Differentiate systemic disease (MH) from localized • Sites of Involvement: soft tissue, spleen, liver, lymph nodes, lung, bone marrow • Classification/Nomenclature changes- P. Moore (UCDavis)

17. Histiocytic Diseases • Histiocytes: subset of leukocytes including monocytes, macrophage, dendritic antigen presenting cells (DAPCs) • Cutaneous Histiocytoma • Benign, proliferation of CD 1+, CD 11 c+, Thy-1, CD 4- Langerhans cells

18. Histiocytic Diseases • Reactive Histiocytosis • Cutaneous and systemic forms • Angiocentric, CD 1, CD 11 c+, Thy 1+, CD 4 + DAPCs • Considered an immunoregulatory disorder and repsonds to immunosuppressive therapy

19. Histiocytic Sarcoma • Localized and dissminated • Large round cells with spindiloid cells with increased cytoplasmic:nuclear ratio- diagnosed on cytology or histo • Immuophenotype of DAPCs • Clinically aggressive with high rate of metastases • Systemic therapy generally indicated

20. Therapy of Histiocytic Sarcoma • Chemotherapy • VOSRC gold standard: Doxorubicin/DTIC • Bone marrow involvement- poor prognosis • CCNU +/- cyclophosphamide • ECOG trial- dismal results

21. Alternative Therapies for Histiocytic Sarcoma • Radiation therapy for local and/or regional disease- 19 daily @ 3 Gy fractions to 57 Gy • TALL-104 Cell Line Therapy • Wistar Intitute • Effective but not available- internet question • Biphosphanates- Pamidronate • Based on responsed in human Langerhan’s cell histiocytosis • B. Kitchell- responses in individual cases

22. Management of Mast Cell Tumors K. Ann Jeglum, V.M.D. The Wistar Institute Philadelphia, Pennsylvania West Chester, Pennsylvania

24. Radiation Therapy and Chemosensitization • Hypoxic cells are resistant to radiation • Low dose of chemotherapy drugs will sensitize hypoxic cells in bulky tumors to radiation kill • Several drugs inhibit DNA repair or sublethal radiation damage • Drugs used: cisplatin, carboplatin, dactinomycin d, doxorubicin, gemcitabine

25. Canine Osteosarcoma • A cancer of large and giant breeds • Median age of 10 years but an aggressive subset in young (18-24 mos) • Occur at metaphysis of rapidly growing bones- predisposition- also trauma sites, ie, fractures, internal fixation devices- different biological behavior • 75% in long bones, ie, “away from the elbow and around the knee” and hock • Radiographic appearance: lytic, osteoblastic and mixed- cortical lysis, periosteal reaction (“sunburst”) • Differential Diagnoses: fungal disease, infection, other primary bone tumors (fibrosarcoma, chondrosarcoma, hemangiosarcoma), hemopoietic tumors (LSA, myeloma)

26. Canine Osteosarcoma- Diagnosis • “Pathognomonic” diagnosis of history, clinical signs, anatomic site and radiographic appearance • Dilemmas with biopsy- non-diagnostic with reactive bone using an invasive procedure that may result in vascular release, increase pain and lameness and increase risk for pathologic fracture • Characteristic appearance of other bone tumors • Geographic predisposition for mycotic diseases • Not indicated if amputation is definitive treatment

27. Canine Osteosarcoma-Staging and Prognosis Thoracic Radiographs: negative in >90% cases at initial diagnosis Evidence of micrometastases at time of diagnosis- disputed by anticoagulation data during amputation Favorable Prognostic Factors: low serum alkaline phophatase, intracompartmental lesions, small primary tumor, parosteal osteosarcomas, axial and mandibular sites, tumor necrosis following chemotherapy- role of neoadjuvant chemo?

29. Canine Osteosarcoma: Where Are We? • No significant change in survival or disease free interval in the 15+ years since advent of platnum compounds Amputation + 4 cycles of cisplatin=median survivals=260-400 days with 1 year survival of 30-62%- not all disease free at 1 yr. • 2 year survival rates 6-21% • Doxorubicin alone < 1 yr. median survival • Surgical limb salvage procedures • Amputation vs. palliative radiation followed by chemotherapy

30. Canine Osteosarcoma- con’t. • Protocol changes to improve prognosis: • Combine cisplatin and doxorubicin in alternating cycles • Increase number of cycles to 6 • Introduce additonal chemotherapeutic agents such as ifosfamide • No new cytotoxic agents- high dose methotrexate problematic in dogs • Maintenance metronomic chemotherapy • No effective treatment for metastatic disease

31. Canine Osteosarcoma- con’t. • Current VOSRC protocol post amuputation or palliative radiation • Cisplatin (60mg/M2) alternating with Doxorubicin (30 mg/M2every 3 weeks-3 cycles each • Historically cisplatin first- recently doxorubicin before platum compound may be more effective

32. Canine Osteosarcoma- Palliative Radiation and Biphosphonates • Weekly radiation therapy to primary tumor (9 Gy weekly X 4=36 Gy) • Biphosphonate- Pamidronate 1 mg/kg intravenous infusion over min. 2 hours every 3 weeks • Increase calcification of tumor, decrease bone pain and now antitumor effects • Controversy of value of chemotherapy in such a model

33. Biphosphonate Therapy in Bone Tumors • Osteosarcoma and metastatic malignant tumors induce and stimulate osteoclasts to invade bone • Can be osteolytic or osteoblastic and osteoclasts has important role in both patterns • Tumors produce many factors that stimulate osteolysis, osteosclerosis and aggressive tumor growth • Osteoclastic targeted therapies: biphophonates- induction osteoclast apoptosis

34. Metronomic Chemotherapy • Chronic administration of chemotherapy at low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks • Could less be more? Origins in pediatric oncology- similarities to vet onco • Antiangiogenic by targeting endothelial cells- more sensitive to continuous exposure of chemotherapy drugs without undergoing genetic mutations like tumor cells that develop drug resistance

35. Metronomic Chemotherapy- con’t. • Major mechanism is inhibition of mobilization of endothelial cells that develop in bone marrow and seeds tissue • Bone marrow-derived endothelial cells are major source on new blood vessels to tumor cells • Also stimulates production of thrombospondin-1, a potent angiogenesis endogenous inhibitor • Low dose cyclophosphamide also depletes regulatory T-cells which are immunosuppressive on effector T-cells and antigen presenting cells

36. Metronomic Chemotherapy + COX-2 Inhibitors • Cyclooxygenase-2 is over expressed in tumors cells and stromal cells and promotes tumor growth by stimulation angiogenesis • Overexpression of COX-2 stimulates growth factors (VEFG) • COX also plays role in generation of T-reg cells • Synergism of two approaches- metronomics plus COX-2 inhibitors

37. Metronomic Protocol • Piroxicam 0.3 mg/kg po sid- Cox-2 inhibitor as antiangiogenic • Chlorambucil 0.1 mg/kg po EOD or Cyclophosphamide 10-15 mg/M2 EOD but hemorhagic cystitis a problem • Doxycycline 5 mg/kg bid • Methotrexate 0.05-0.1 mg/kg once weekly- no piroxicam

38. Metronomic Chemotherapy + COX-2 Inhibitors • Piroxicam only NSAID in dogs with proven in vitro and in vivo antitumor activity • Low-dose cyclophosphamide plus piroxicam • Increased DFI in dogs with completely resected splenic hemangiosarcoma compared to doxorubicin alone- small nos. (Lana,JVIM, 2007) • Delay tumor recurrences in soft tissues recurrences in incompletely excised soft tissue sarcomas (peripheral nerve sheath) (Elmslie, JVIM, 2008)- retrospective

39. Canine Hemangiosarcoma • Tumor of vascular endothelium • Prevalent sites: spleen, liver, right atrium, lung, subcutaneous, bone • Clinical presentations include abdominal bleed, pericardial effusion-cardiac tamponade • Proven inherited in GRs! (Jeglum) GSHPs? • Not a death sentence

40. Canine Hemangiosarcoma • Soft tissue vs. splenic HSA- different diseases- long term survival with chemotherapy of soft tissue • Do we change biological behavior of splenic with adjuvant chemotherapy? • Doxorubicin/dacarbazine- objective tumor responses in measurable metastatic disease- not seen with doxo alone or with addition of cyclophosphamide • However, after 4 cycles A/DTIC still develop metastases but not during- delay of mets? • Improvement? More chemotherapy vs. maintenance metronomics

41. Doxorubicin (Adriamycin) and Dacarbazine (DTIC) • Day 1 : Doxorubicin 30 mg/M2 slow IV • Days 1-5 DTIC 200/mg2 IV bolus • Days 4-5 Complete Blood Count (CBC) • Day 10 CBC • Day 21 Start 2nd cycle X 4 cycles • Prophylactic antiemetics (Cernia, Centrine, Zofran) and antibiotics

42. Oral Tumors • Diagnostics • Cytology vs. surgical biopsy • Staging: lymph node aspirate, thoracic radiographs • MRI for treatment planning: surgical resection, radiation therapy

43. Oral Tumors- con’t. • Squamous Cell Carcinoma • Treatment based on anatomic site and size of tumor • Rostral: segmental mandibulectomy or maxillectomy • Caudal: neoadjuvant chemotherapy vs. radiation therapy +/- chemosensitization • Role of systemic chemotherapy with local therapy dependent on histopathology • Cats: BAC- doxorubicin, cyclophophamide, bleomycin • Dogs: Cisplatin, 5-FU

44. Oral Tumor- con’t • Sarcomas • Changes in histopathology: spindle cell sarcoma, fibrosarcoma • Surgical approach similar to SCC • Radiation therapy +/- chemosensitization with dactinomycin • Systemic chemotherapy: dactinomycin, doxorubicin/dtic • Application dependent on pathology/cytology

45. Tyrosinase- Melanoma Antigen • Tyrosinase- a protein present on normal canine cutaneous melanocytes and overexpressed on melanoma cells • Not normally targeted by the immune system- CMV trains the immune system to recognize tumor-associated protein or antigen

46. Canine Melanoma • Two malignant sites: oral cavity (gingiva, palate, tongue) and subungal (digit) • Locally invasive and metastatic to regional lymph nodes and distant sites, primarily lung also liver, kidney and brain • Dermal melanomas historically considered benign but recently increase in malignant cutaneous melanoma- can be multicentric

47. Xenogeneic Plasmid DNA Vaccine Technology • A non-canine (human) tyrosinase is inserted in a ring of canine DNA= xenogeneic plasmid DNA containing canine DNA for human tyrosinase • Foreign tyrosinase breaks through the dog’s tolerance of a self tumor thereby inducing a strong and active immunity • Results in production of human antigen that is homologous to canine tyrosinase but recognized as foreign

48. Xenogeneic Plasmid DNA Vaccine Technology- con’t • The antigen is transcribed in the host and actively presented by the immune system during malignant transformation targeting melanoma cells as foreign • The immune response appears tumor-specific targeting tumor producing cells not normal melanocytes

49. Canine Melanoma Vaccine- ONCEPT • Historically dogs with WHO stage II or III oral melanoma treated with surgery alone have survival times <5-6 mos. • WHO Stage II: approximately 150-180 days • WHO Stage III: approximately 60-90 days

50. Canine Melanoma Vaccine- ONCEPT- con’t • Local disease control achieved through surgery (negative local lymph nodes or positive lymph nodes that were surgically removed or irradiated • 58 dogs with stage II or III COM treated by vaccination with ONCEPT following local disease control • Follow-up survival data 6 mos. after conclusion of the study, <50% have died of melanoma (median survival time not attained)