Oncology Flashcards
What is the staging system for canine lymphoma?
Stages I: single LN, II: multiple LNs, III: regional LNs, IV: liver and/or spleen, V: distant metastasis.
Substaging: a - systemically well. b - systemically unwell.
Clinical staging system for feline LSA?
Stage I: single extranodal tumor or node. Primary intrathoracic tumor.
Stage 2: 2+ nodes on same side of diaphragm, single tumor with regional LN involvement, 2 tumors +/- LN on same side of diaphragm, resectable primary GI tumor (usually ICJ)
Stage 3: 2 single tumor on opp sides or above/below diaphragm, all primary resectable abdo tumors, all paraspinal/epidural tumors
Stage 4: 1-3 + liver/spleen involvment
Stage 5: 1-4 + CNS and/or BM involvement
Canine multicentric lymphoma - treatment options?
- Multiagent - CHOP. Remission rate >90%, DFI 12 months. 4-6 week cycles.
- Single agent - doxorubicin (+ steroid).
Chronic lymphocytic leukemia (CLL) - criteria for treatment?
Lymphocyte count >60K
Organomegaly (infiltrative disease)
Most common form - T cell, granular form.
Compare & contrast clinical features between ALL & CLL?
Signalment - ALL young-middle aged 6yo, CLL older 10-12yo
Cells - ALL resemble blasts, from BM. CLL small mature Lc, from peripheral blood +/- BM; can develop blast crisis / large cell LSA.
Immunophenotype - ALL B cell >90%. CLL T cell > B cell > atypical (B+T)
Lab - ALL leukopenia/leukocytosis, cytopenias (myelophthisis). CLL marked lymphocytosis, hyperglob (B cell > IgM > hyperviscosity syndrome + fLC/BJ proteinuria)
Similar - splenomegaly 70%, hepatomegaly 50%, mild generalised lymphadenopathy.
ALL +/- CNS, bone pain (infiltration)
BM aspirate - ALL blasts 30%+, CLL small mature Lc 30%+ (N <5-10%)
Workup - ddx stage V LSA (generally worse lymphadenopathy), hyperCa
CLL - treatment and prognostic factors?
Chlorambucil and prednisolone - long term.
2nd-line: cyclophosphamide instead of chlorambucil.
Refractory - as per ALL tx (CHOP, L-aspar, cytarabine)
Overall good prognosis
Negative - anemia, immunophenotype (B cell worse than T)
Cell surface markers for vascular neoplasia
CD31
Vimentin (spindle cell)
Factor 8
Cell cycle non-specific drugs?
Anti-tumor antibiotics (doxo, mitoxantrone)
Cell cycle specific drugs?
Alkylating agents (vinc-)
MDR-positive dogs - pathogenesis and considerations?
ABCB1 gene mutation (aka Multi Drug Resistance 1 gene) - deletion in 4 base pairs. Gene encodes for p-glycoprotein - affects drug efflux from cells. Most significant implication in epileptic control (often more refractory to conventional anti-epileptic drugs in Collies).
Overall <2% prevalence (UK, presumably Aus).
ABCB1/MDR1 - which drugs?
Alkylating agents (vincristine, vinblastine, vinorelbine), paclitaxel.
NOT cyclophosphamide, CCNU, doxorubicin.
MDR1 positive - Dose reduction by 25% if heterozygote, 50% if homozygous.
Chemotherapeutic drugs that cross the BBB
Lipophilic drugs:
Procarbazine
Alkylating agents - lomustine (CCNU), temozolomide
Cytarabine arabinoside (anti-metabolite)
Multiple myeloma - diagnostic criteria (list 4)
1) Neoplastic plasma cells in the BM/tissues
2) Lytic bone lesions
3) Monoclonal gammopathy (serum)
4) Bence Jones proteinuria (urine fLC)
3 & 4 - presence of clonal Ig paraproteins produced by neoplastic cells (M-proteins) - can be complete Ig (IgM predominantly as large) or free light chains (fLC).
Multiple myeloma - clinical manifestations & mechanisms?
Hyperviscosity syndrome
- Bleeding diathesis 40% (M component interferes with platelet aggregation & platelet factor 3 release, thrombocytopenia, abnormal fibrin polymerisation, functional decr Ca2+, absorption of minor clotting proteins)
Systemic hypertension - ocular TOD
Renal dysfunction (proteinuria, poor perfusion, neoplastic infiltrate)
Lameness/bone pain
Immunosuppression - 2’ infections (decreased functional Ig, myelopthisis)
Cytopenias (anemia, thrombocytopenia)
Hypercalcemia (D>C) - pdtn of osteoclastic-activating factors, bone infiltration
Multiple myeloma - treatment?
Melphalan and prednisolone
Pamidronate (if osteolytic lesions)
Lomustine (CCNU) + hepatoprotectant
Multiple myeloma - prognosis?
MST 540-930 days with PO chemotherapy
Soft tissue sarcoma (STS) grading system?
Grade I & II: low grade
Grade III: high grade
Histologic grade is PROGNOSTIC
Grading system for neutropenia?
Grade 1-4
Cyclophosphamide MOA?
Alkylating agent
Cyclophosphamide adverse effects and MOA?
Preventative measures for AE?
- Haemorrhagic cystitis (via renal excretion of its hepatic metabolite acrolein which is urotoxic - caustic to uroepithelium). Prevention - frusemide +/- pred concurrently, walk dog frequently after admin. TMS for UTI.
- Myelosuppression (neutropenia)
Canine cutaneous epitheliotropic LSA - predilection sites and presentation?
Mucocutaneous junctions (perianal, perioral, conjunctiva, paw pads)
GI epithelium - different disease entity
ICC/IHC markers - which?
B or T cell LSA
B cell - Pax5, CD79
T cell - CD4, CD8, CD3
Histiocytic sarcoma - Iba1 (macrophage origin)
MCT - prognostic factors?
Grading: high grade/grade III MCTs with a high mitotic rate (>5/10hpf) and/or prominent anisokaryosis and/or giant cell formation may have a poor outcome as a result of a high rate of local and distant metastasis or inoperable recurrence.
Oral SCC - dogs - prognostic indicators?
Tumor size
Tumor location (rostral more likely surgically resectable than caudal)
LN metastasis (uncommon, 10%) - good to do sentinel lymph node mapping
Hemangiosarcoma - staging system?
Stage I: Tumor confined to the spleen.
Stage II: Ruptured splenic tumor with or without regional lymph node involvement.
Stage III: Distant lymph node or other tissue metastases.
Canine HSA - common primary sites?
Spleen»_space; right atrium, cutaneous, SQ.
Canine HSA - prognostic factors?
Negative prognostic indicators -
Advanced stage - hemoperitoneum or splenic rupture.
Stage I tumors - MST >2yrs survival with sx alone, stage II & III - 6-10mths with sx alone.
Some forms of cutaneous/ subcutaneous HSA appear to have a lower metastatic potential and less aggressive biologic behavior.
Tigilanol tiglate (Stelfonta) - MOA and indications?
Intra-lesional injection for non-metastatic canine MCT.
Reported 75% with single injection, 87% with >1 injection.
Indications:
Non-metastatic subcutaneous mast cell tumors located at or distal to the elbow or the hock in dogs
Non-metastatic cutaneous mast cell tumors located all over the body
Tumors must be less than or equal to 10 cm3 in volume, and must be accessible to intratumoral injection
Do not exceed 5 mL per dog, regardless of tumor volume or body weight
The minimum dose of STELFONTA is 0.1 mL, regardless of tumor
Day 1: acute inflammatory response with swelling and erythema noted on the tumor margins and surrounding tissues.
Day 2: necrotic destruction –> blackening, shrinkage and thick discharge
See JVIM 2021 papers:
1) Jones et al. Recurrence-free interval 12 months after local treatment of mast cell tumors in dogs using intratumoral injection of tigilanol tiglate.
2) De Ridder et al. Randomized controlled clinical study evaluating the efficacy and safety of intratumoral treatment of canine mast cell tumors with tigilanol tiglate (EBC-46).
3) Reddell et al. Wound formation, wound size, and progression of wound healing after intratumoral treatment of mast cell tumors in dogs with tigilanol tiglate.
Bisphosphonates - MOA and indications?
Example drugs - pamidronate, zolendronate.
MOA: synthetic analogs of naturally occurring inorganic pyrophosphate compounds whose therapeutic effect inhibits osteoclasts, reducing pathologic bone resorption without inhibiting bone mineralization. Bind to hydroxyapatite particles in bone and are subsequently released and endocytosed during osteoclastic-mediated resorption, resulting in apoptosis of osteoclasts and inhibition of bone resorption.
Indications - hypercalcemia of malignancy, reduction of skeletal events in the management of bony metastases (humans)
Adverse effects - nephrotoxicity (4.5% for zolendronate in dogs in 1 study)
L-asparaginase - differences between native and pergylated (PEG) form?
Indications & disadvantages?
PEG L-aspar - prolonged circulation time –> requires less frequent administration. Pergylation also reduces immunogenicity of the enzyme
Rapid acting
Antibody development occurs quickly to enzyme, often after 1 injection - so limited efficacy with multiple injections
Modified Adam staging system for nasal tumors in dogs and cats?
Stage I - confined to 1 nasal passage, paranasal, and frontal sinus, no bone involvement.
Stage II - any bone involvement with no evidence of involvement of orbit, SQ/submucosal tissue.
Stage III - any involvement of the orbit and/or nasopharyngeal and/or SQ/submucosal tissues.
Stage IV - involvement of the cribriform plate/invasion of the brain
Doxorubicin adverse effects and MOA? Cats vs dogs?
1) Nephrotoxicity (cats)
2) Cardiotoxicity (dogs?): arrhythmias, DCM? Occurs via myocyte injury from generation of free radicals, which incorporate iron. Histo - loss of myofibrils, sarcoplasmic vacuolar degeneration, and decreasing number of myocytes.
3) Hypersensitivity
4) Extravasation injury
Methotrexate MOA, indications?
MOA: antifolate drug –> inhibits dihydrofolate reductase (DHFR) = key enzyme in folate synthesis. Folate is needed for production & maintenance of new cells, DNA replication (methyl donor for formation of thymidylate), RNA synthesis. Drug effects - folate accumulation in inactive form - depletes reduced folate substrates.
SE: rapidly proliferating cells most susceptible - neoplastic cells, BM, GI epithelium. Low doses - GI epithelial necrosis, myelosuppression. High doses - hepatocellular tox, nephrotox, CNS damage.
70% renal excretion.
Indications: OSA & LSA most common.
Tx for MTX tox (humans): leucovorin (folinic acid) = reduced active form of folate. Competes with MTX. Used as rescue therapy in high dose MTX therapy.
Which LNs can an oral melanoma or SCC metastasize to?
Mandibular, retropharyngeal. Can also go to contralateral LN.
What is the typical phenotype of CLL in cats?
CD4+ (T helper)
What is an example of a drug that could theoretically increase the risk of toxicity of some chemotherapeutics?
P-glycoprotein inhibiting medications can induce a risk similar to ABCB1 (MDR-1) mutants. E.g. ketoconazole, cyclosporine. Both drugs also inhibit cytochrome p450 metabolism —> thus can also increase vinblastine toxicity.
Protocols for which neoplasms may feature carboplatin?
What is its side effect profile?
OSA, UCC, AGASACA, Melanoma. Carcinomas in general.
Can be given intra-cavitary.
Platinum, like cisplatin - but not nephrotoxic and doesn’t cause fatal pulmonary oedema (cisplatin - ‘splat’ cats).
SE: GI, myelosuppression (14-28 days in).
Suggest dose adjustment for cats with renal disease, as renal excretion of drug means with reduced GFR > increased risk of myelosuppression.
Tx for doxorubicin extra-vasation?
What is a cat-specific doxorubicin adverse effect?
Dexrazoxane.
Nephrotoxicity.
Cell surface receptors associated with malignant histiocytiosis?
CD11c & CD18
Haemophagocytic: CD11d, CD18
Cell surface markers for:
- T cell
- B cell
- Haematopoietic stem cells
- CD3, CD5; subtypes CD4 (T helper) & CD8 (cytotoxic T cell)
- CD21, CD22, CD 25 (if activated)
- CD34
Cytarabine
- MOA
- Indications
- AE
Converted intracellularly to aracytidine triphosphate —> competes with deoxycytidine triphosphate to inhibit DNA polymerase —> inhibits DNA synthesis. S-phase specific - blocks cell progress from G1 to S phase.
Drug is incorporated into DNA.
Adjunct tx for:
- Lymphoreticular neoplasia (especially CNS lymphoma) - as rescue agent (poorly effective as single agent, limited data on efficacy as multi agent).
- Myeloproliferative disease (leukemia)
- MUO (dogs/cats) - combo with GCS
AE
- Hematologic - neutropenia (35%), thrombocytopenia (12%) most common. Myelosuppression worse with IV vs SQ.
- GI signs (including oral ulceration), neurotoxicity, hepatotoxicity (increased ALT in 15%), lethargy, pyrexia
- Alopecia, delayed hair regrowth, calcinosis cutis at injection sites reported
- Infiltrative lung disease (case report) following CRI
NB: drug resistance can develop (several mechanisms)
Which chemo drugs are contraindicated in MDR 1 (ABCB1) mutant dogs? What aspect of the drug PK is implicated?
Vincristine, Vinblastine, Doxorubicin, Paclitaxel.
Reduced biliary excretion so increased risk of SE.
Rare report of neurotoxicity (vincristine).
Vinca alkaloids
- Which drugs
- MOA (part of cell cycle affected)
- Vincristine, vinblastine, vinorelbine
- Inhibit microtubule assembly - so inhibit M phase.
Cyclophosphamide
- Drug class
- SE
- Contraindications
Alkylating agent
SE:
- Sterile hemorrhagic cystitis (acrolein metabolite) - dogs not cats
- Myelosuppression
-GI upset
Contraindications:
- Caution with hepatic or renal impairment
- Caution in TCC breeds (Scottish terrier)
Melphalan
- Drug class
- MOA
- SE
Alkylating agent
Effects DNA and RNA - so affects resting cells. Does not require hepatic activation, excreted in the urine unchanged.
SE
- Myelosuppression - onset & recovery from leukopenia can be delayed
- GI signs
- Pulmonary infiltrates/fibrosis.
- Neurotoxicity
- Skin HS (reported in people), dogs - minor hair coat changes (shaggy, lack lustre coat). Breeds with continuous growing hair coats (Poodles etc) more likely to have significant alopecia
- Secondary malignancies (reported in people)
Lomustine
- Drug class
- MOA
- AE
- Contraindications
Alkylating agent
Non-cell cycle phase specific
Crosses BBB - good for CNS neoplasia.
SE
Myelosuppression (nadir @1-3 weeks)
Hepatotoxicity (LE increase in 29% dogs, 6% clinical) - prophylactic SAME (hepatoadvanced) proven to reduce risk of this
GI upset
Pulmonary infiltrates
Nephrotoxicity
