small animal med- oncology objectives

what is an adjuvant treatment?

treatment with chemo agent after achieving control of the primary tumor with surgical resection or radiation therapy

what is neoadjuvant therapy?

chemo used prior to treatment with other modalities for local tumor control with intent of decreasing tumor size

what is induction therapy?

chemotherapy treatment with the intent of a cure. An initial chemotherapy protocol

what is rescue therapy?

use of chemotherapy after a tumor fails to respond to a previous therapy or after tumor recurrence

what are the different responses to treatment?

1. complete remission/response

2. partial remission/response

3. stable disease

4. progressive disease

5. progression free interval/survival

6. disease free interval/survival

what is complete remission/response?

complete disappearance of tumors and symptoms of disease

what is partial remission/response?

at least 30% reduction in the sum of diameters of target lesions

what is stable disease?

less than 30% reduction or 20% increase in the sum of diameters of target lesions

what is progressive disease?

either the appearance of one or more new lesions or at least a 20% increase in the sum of diameters of target lesions

what is progression free interval/survival?

the amount of time elapsed without evidence of progressive tumor growth or death

what is disease free interval/survival?

amount of time that elapses without disease recurrence

what are adverse events?

any unfavorable and unintended clinical sign or disease temporarily associated with the use of a medical treatment that may or may not be considered related to the medical event

are antibiotics/hospitalization indicated for prophylactic neutropenia?

no, neither are recommended

what is grade 2/mild toxicity neutropenia?

neutropenia= 1000/uL

does grade 2/mild toxicity neutropenia require antibiotics or hospitalization?

no, neither are recommended

what is a grade 3/moderate toxicity neutropenia?

neutropenia= 500-999u/L

does grade 3/moderate toxicity neutropenia require antibiotics or hospitalization?

oral broad spectrum antibiotics, recheck CBC in 2-3 days

do not hospitalize

SQ/IV fluids not done unless febrile

what is a grade 4/severe toxicity neutropenia?

neutropenia= <500/uL +/- fever

does grade 4/severe toxicity neutropenia require antibiotics or hospitalization?

oral broad spectrum antibiotics (IV if febrile)

-recheck CBC in 24 hours

hospitalize if febrile

what are the treatment options for pain management in cancer patients?

1. medications (NSAIDs, gabapentin, opioids, amantadine)

2. bisphosphanates

3. acupuncture

4. radiation

what nutritional support should cancer patients recieve?

supply a complete and balanced diet that meets the patients energy requirement

what support should you provide the the owners (clients) of cancer patients?

-Treat every client as an individual

-Avoid minimizing the feelings of burden

-Share power of knowledge

-Collaborative care plan (minimize or reduce burden)

-Help client problem solve

-Offer words of encouragement

what are the general causes of cancer?

1. ionizing or UV radiation

2. viruses, bacteria, parasites

3. environmental factors

4. lifestyle habits

5. genetics

6. chemical carcinogens

7. pesticides, herbicides, insecticides

8 hormonal

what cancers are seen from UV and ionizing radiation?

UV: nasal planum and cutaneous SCC

ionizing: sarcoma development in sites of previous radiation treatment

how can lifestyle habits cause cancer?

specific underlying cause unclear, but here is an example:

-rural vs urban environment: lymphoma, nasal carcinoma, tonsillar squamous cell carcinoma, etc.

how can pesticides, herbicides, and insecticides cause cancer?

bladder cancer increased with topical insecticides and dips, especially in overweight dogs (newer spot-on topical flea and tick treatments have not)

what are the 3 stages of carcinogenesis?

1. initiation

2. promotion

3. progression

what is initiation?

interaction of the carcinogen with cellular DNA

DNA damage may remain undetected (silent) for life unless further events stimulate tumor development

an initiated cell is not a cancer cell, yet (does not have autonomous growth ability)

is initiation reversible?

Initiation is reversible (DNA repair!)

what is promotion?

clonal expansion of the initiated cell

Mutated genes give cell selective growth advantage

Produces larger population of cells at risk of further genetic change

t or f: tumors cannot develop if only the promoter is applied, or if the promoter is applied before initiation occurs

true

what is progression?

tumor obtains ability to invade tissues and metastasize to distant locations

increased genetic instability and nuclear alterations are hallmarks of progression

what are the 6 functional hallmarks of cancer?

1. Evade apoptosis

2. Self-sufficiency in growth signals

3. Insensitivity to anti-growth signals

4. Sustained angiogenesis

5. Limitless replicative potential

6. Tissue invasion and metastasis

what are the recent 8 additional hallmarks of cancer?

1. Nonmutational epigenetic reprogramming

2. Unlocking phenotypic plasticity

3. Deregulating cellular metabolism

4. Avoiding immune destruction

5. Genome instability and mutation

6. Senescent cells

7. Polymorphic microbiomes

8. Tumor-promoting inflammation

what is the typical signalment of canine lymphoma?

6-9 years, certain breeds (boxers, bull mastiffs, bassets, bernies, bulldogs, retrievers)

what are the common anatomic sites of canine lymphoma?

Multicentric (multiple lymph nodes)= 80-84% of total cases

Gastrointestinal (5-7%)

Mediastinal (5%)

what are the clinical signs of multicentric canine lymphoma?

Lymphadenopathy is primary sign (with substage a, most patients have no symptoms)

substage b clinical signs: weight loss, anorexia, fever, lethargy

what are the clinical signs of canine GI lymphoma?

Malabsorption, vomiting, diarrhea, weight loss

what are the clinical signs of canine mediastinal lymphoma?

Hypercalcemia, PU/PD, respiratory signs, regurgitation, precaval syndrome

what are the clinical signs of lymphoma of other locations in dogs?

Reflect site involved: seizures, blindness, 37% have ocular involvement, nasal discharge, etc.

how is canine lymphoma classified?

histologic grade: low, mid, high

immunophenotype: t-cell or b-cell lymphocyte origin

how is canine lymphoma diagnosed?

LN sampling (FNA for cytology, biopsy for histopath)

staging diagnostics: CBC, chem, UA, chest rads, AUS, bone marrow aspirate

when are further diagnostics indicated to diagnose canine lymphoma?

-May help confirm diagnosis of lymphoma

-Subtype info

-Discern difference between reactive and neoplastic process

-Provide additional prognostic information

what are the general treatment options for canine lymphoma?

-No treatment (with high grade, multicentric lymphoma→ patient survival 4-6 weeks)

-Prednisone alone

-Chemotherapy

-Surgery (consider with obstructive or solitary lesions)

-Radiation (local treatment (nasal, mediastinal), or whole body)

what are the chemotherapy options for high grade canine lymphoma?

1. CHOP protocol

2. single agent doxorubicin (adriamycin)

3. single agent rabacfosadine (tanovea)

4. rabacfosadine + doxorubicin

what is the MST of the CHOP protocol for canine lymphoma?

10-14 months

what is the MST of single agent doxorubicin for canine lymphoma?

6-8 months

what are the chemotherapy options for low grade/indolent canine lymphoma?

tx may not be needed, but if so is often less aggressive:

-prednisone and chorambucil (leukeran)

-prednisone alone (50% ORR)

what are the drugs used in the CHOP protocol?

C: cyclophosphamide

H: doxorubicin (hydroxydaunorubicin)

O: vincristine (oncovin)

P: prednisone

what are the most common clinical manifestations of feline lymphoma?

1. alimentary/GI (most common form of lymphoma in cats)

2. mediastinal

3. nodal (1/3 are t-cell, FeLV+)

4. nasal (75% of nasal are b-cell)

5. CNS

6. renal

what are the clinical signs of low grade, small cell alimentary feline lymphoma?

Weight loss, vomiting/diarrhea, anorexia

Abnormal abdominal palpation in 70% of cases (50% have intestinal wall thickening, 33% have palpable mass)

what are the clinical signs of mediastinal feline lymphoma?

Dyspnea, tachypnea

Non-compressible anterior mediastinum, dull heart and lung sounds

Pleural effusion common

what are the clinical signs of nodal feline lymphoma?

Variable signs (peripheral lymphadenopathy alone is rare)

Systemic symptoms common (lethargy, decreased appetite)

what are the clinical signs of feline nasal lymphoma?

Discharge, epistaxis, sneezing, upper respiratory noise

what are the clinical signs of feline CNS lymphoma?

Gradual or sudden onset

Neurologic signs referring to intracranial lesions, spinal lesions or both

what are the clinical signs of feline renal lymphoma?

Renomegaly (often bilateral), renal insufficiency

how does retroviral status of FeLV impact the likelihood of lymphoma in cats?

FeLV with subgroup B associated with lymphoma, leukemia, and anemia

Direct role in tumorigenesis

T-cell more common

how does retroviral status of FIV impact the likelihood of lymphoma in cats?

Indirect role based on immunosuppressive effects of FIV

B-cell more common

how is large cell, high grade lymphoma in cats diagnosed?

Diagnosis typically obtained for PE, abdominal imaging, and cytologic or histologic evaluation of intestinal mass, enlarged LNs

--> generally less complicated than small cell

how is small cell, low grade feline lymphoma diagnosed?

More difficulty to distinguish from non-neoplastic diseases

Diagnosis typically needs abdominal imaging (U/S), tissue for histopath, and assessment of immunophenotype and clonality

what chemotherapy is used to treat small cell, low grade feline lymphoma?

1. prednisolone and chlorambucil (leukeran)

what is the overall response rate to chemo in cats with low grade, small cell lymphoma?

90-95% ORR

what is the MST of treating feline small cell, low grade lymphoma with prednisolone and chlorambucil?

2 years

-partial response MST= 400 days

-complete response MST= 900 days

what are the chemotherapy options for treating high grade, large cell feline lymphoma?

1. CHOP or COP based protocols (use vinblastine over vincristine)

2. single agent lomustine (CCNU)

what is the MST of treating feline high grade, large cell lymphoma with COP/CHOP based protocols?

MST= 2-3.5 months

-responder have MST of 6-8 months

what is the MST of treating feline high grade, large cell lymphoma with lomustine?

100 days

CCNU toxicity in cats can lead to prolonged, delayed nadir

what is the MST of treating feline nasal lymphoma with sterotactic body radiation (SBRT)?

MST=365 days

what is the MST of treating feline GI lymphoma with radiation therapy? (for local disease)

MST post-RT= 214 days

median OST= 355 days

what are the prognostic factors of feline lymphoma?

-complete response/remission with therapy

-FeLV status

-stage/anatomic location

-grade

-not based on immunophenotype alone

what toxicity may be anticipated when treating feline lymphoma with cyclophosphamide?

sterile hemorrhagic cystitis

bone marrow suppression

what toxicity may be anticipated when treating feline lymphoma with lomustine?

bone marrow suppression (up to 6 weeks post-administration), hepatotoxicity (especially with chronic use)

what toxicity may be anticipated when treating feline lymphoma with chlorambucil?

bone marrow suppression

what toxicity may be anticipated when treating feline lymphoma with vinblastine?

GI

bone marrow suppression

vesicant

peripheral neurotoxicity

what toxicity may be anticipated when treating feline lymphoma with doxorubicin?

renal toxicity

vesicant

bone marrow suppression

GI

what is flow cytometry?

Analyzes cells in single-cell suspension

Uses lasers to identify characteristics of the cells (size, cytoplasmic complexity, DNA or RNA content, proteins they express on surface)

what samples are needed for flow cytometry?

-Need fresh, live samples (to stain surface proteins)

-LN, mediastinal, or other organ aspirates

-Blood and bone marrow with concurrent CBC in EDTA tube

-Cavity fluid in EDTA and red top tube

what is PARR?

PCR for antigen receptor rearrangement

what does PARR do?

Detects regions of DNA of lymphocytes passed on to daughter cells (portion of gene that encodes antigen-binding region)

-Normal immune response (reactive): B and T cell activation, clonal expansion, majority die, memory cells

-Clonal population (neoplastic): expand significantly more, majority of cells have same gene sequence

what is the main application for PARR?

establish clonality in a sample that is cytologically or histologically ambiguous

what is another, secondary use for PARR?

immunophenotype, monitor response to treatment, detect recurrence of lymphoma

what samples are needed for PARR?

-Blood and bone marrow (EDTA tube)

-LN or other organ (aspirate on stained/unstained slide)

-Cavity fluid (EDTA or on slide)

-CSF (multiple cytospin samples, EDTA tube)

-Histopath slides

what cancers are flow cytometry and PARR used for diagnosing?

lymphoma

what cancer does the prognostic panel evaluate?

mast cell tumors

what are the components of the prognostic panel (for MCTs)?

1. Cell proliferation analysis (measures Ki67 and AgNOR)

2. C-kit PCR (analyzes mutation of c-kit)

3. C-kit IHC (identifies 3 patterns of KIT localization)

how can the cell proliferation analysis of the prognostic panel predict prognosis of MCT?

High amount/rate of proliferation (Ki67 and AgNOR) indicates more aggressive disease

how can the c-kit PCR component of the prognostic panel predict prognosis of MCT?

Presence of mutation linked to increased risk of local recurrence, metastasis, worse prognosis

how can the c-kit IHC component of the prognostic panel predict prognosis of MCT?

identifies 3 patterns of KIT localization:

I- membranous

II- cytoplasmic (focal/stippled)

III- cytoplasmic (perinuclear)

Patterns 2 and 3 associated with local recurrence and shorter survival

when should the MCT prognostic panel be performed?

not necessary for every tumor

Best for unclear clinical behavior (intermediate grade, or prognostic/clinical factors with ambiguous or unknown impact)

what cancers are cytochemical stains used for?

various tumor types

how are cytochemical stains used to help diagnose neoplasia?

-Can be applied to cytology or histology slides (ICC, IHC)

-Utilizes antibodies to identify proteins/peptides within or on the surface of cells

-Helps determine tumor type

-types of stains: ALP and different markers

what is the purpose of the malignancy profile panel?

helps determine the cause of hypercalcemia (hypercalcemia of malignancy)

what does the malignancy profile panel include?

1. Parathyroid hormone

2. Ionized calcium

3. PTHrp (remember, PTHrp is not the only cause of hypercalcemia of malignancy)

what are parathyroid-dependent causes of hypercalcemia?

parathryoid adenoma

primary hyperPTH

what are parathyroid independent causes of hypercalcemia?

malignancy

vitamin D toxicity

granulomatous disease

what is the MDR1 mutation?

Result of mutation in the ABC drug transport (ABC1 gene, encodes p-glycoprotein, a drug transport pump)

what breeds most commonly get the MDR1 mutation?

herding breeds (collies, aussies, GSDs)

border collies not as much

what are the dose reductions for homozygote/heterozygote carriers of the MDR1 mutation?

heterozygote: at least 30% dose reduction

homozygote: over 50% dose reduction, may dont treat at all

which drugs are affected by the MDR1 mutation?

-Doxorubicin (substitute with cyclophosphamide)

-vinca alkaloids (⅔ of the chop protocol drugs)

-Tyrosine kinase inhibitors

-Antimicrobial: doxycycline/tetracycline, ketoconazole

-Antiparasitic: ivermectin, milbemycin

-Cardiac drugs: digoxin, diltiezam

-Immunosuppressants: cyclosporine

-Opioids: butorphanol

-Others: acepromzaine, ondansetron

what are the common locations of canine appendicular osteosarcoma?

most commonly metaphyseal region of long bones:

Sites: distal radius, proximal humerus most common

Also pelvic limbs (prox/distal femur, prox/distal tibia)

Appendicular more common in dogs over 40kgs

what are the common locations of canine axial osteosarcoma?

Sites: mandible, maxilla, spine, cranium, ribs, nasal cavity, pelvis

Axial more common in dogs under 15kgs