TV4001/4002 Small Animal Oncology

Cluster of molecular disturbances causing abnormal growth regulation

Cells no longer respond to stimuli that regulate growth & differentiation

They also hijack cellular support mechanisms and evade inflam/immune defences

What is cancer?

Smoking, asbestos, radiation exposure.

Most cause: Inflammation, damage to DNA, ROS damage

What are some risk factor for cancer and what do these risk factors for cancer all cause?

Sustaining proliferative signalling

Evading growth suppressors

Activating invasion and metastasis

Enabling replicative immortality

Inducing angiogenesis

Resisting cell death

What are the hallmarks of cancer?

Epithelial, mesenchymal, round cell (based on embryogenic progenitors

What are the 3 broad categories of cancer?

Tumour arising from cell linings/glandular structures. e.g., SCC, ACA

Carcinoma

Tumour arising from connective tissue. e.g., HSA, OSA

Sarcoma

Rate of growth

Manner of growth

Effects in adjacent tissue

Metastasis

Effect on host

What are the features that differentiate benign tumours from malignant ones?

Relatively slow

Expansive

Usually well-defined boundary btw neoplastic and normal tissues. May become encapsulated

What is the rate & manner of growth for benign tumours?

Often rapid. Rarely ceases growing

Invasive

Poorly defined borders, tumour cells extend into and may be scattered throughout adjacent normal tissues

What is the rate & manner of growth for malignant tumours?

Often minimal

May cause pressure necrosis and anatomical deformity

What is the effects in adjacent tissue for benign tumours?

Often serious

Tumour growth and invasion results in destruction of adjacent normal tissues, manifests as ulceration of superficial tissues, or lysis of bone

What is the effects in adjacent tissue for malignant tumours?

does not occur

Does metastasis occur with benign tumours?

Metastasize by lymphatic and haematogenous routes and transcoelomic spread

Does metastasis occur with malignant tumours?

Minimal (can be life threatening if tumour develops in a vital organ e.g. brain)

Outline the effect on host of benign tumours

Life-threatening by virtue of destructive nature of growth and metastatic dissemination to other vital organs

Outline the effect on host of malignant tumours

Anatomical perturbations, i.e., lameness, dyspnoea, seizures, GIT obstruction

What are the local effects of cancer?

General: Weight-loss, pain, malaise, inflammation

Paraneoplastic syndromes

What are the systemic effects of cancer?

Often older pets

Breed predispositions: Rottweiler (OsteoSarcomA - OSA), Golden Retriever (LymphoSarcomA -LSA), GSD (hemangiosarcoma)

Presentations: Sick animal, visible mass/lump

Outline the typical cancer presentations/signalment

BIOPSY!

FNA

Trucut biopsy

Incisional biopsy

Excisional biopsy

What is the diagnostic approach to cancer?

Cells are spread (swash or slide)

Can offer definitive dx in some cases

Adv: Quick, cheap, fairly sensitive. 66% sensitivity for cytology

Outline the use of FNA for diagnosing cancer

Mast cell tumour, lymphosarcoma, melanoma.

Which tumours can FNA offer a diagnostic for?

Small samples (18-14g core)

Easy to sample non-representative area, cannot grade lesion

Not much more sensitive than FNA

Not recommended

Outline the use of a tru-cut biopsy for diagnosing cancer

Cutting a portion of the mass off

Allows to develop a diagnostic approach before intervention

May improves outcome: Histological grade prior to SX

May not add value: No histo grade, risk of seeding tumour into adjacent areas, risk of getting a non-representative region

Outline the use of a incisionial biopsy for diagnosing cancer

Take the whole mass off and send off

Advantage: Diagnostic and potentially curative, less cost, most dx

Disadvantage: May irreparably compromise long term prognosis (take out with two small of margins, and in future to hard to get the rest out

Should always do a pre-excisional biopsy check

Outline the use of an excisional biopsy for diagnosing cancer

Stick a needle in first (FNA)

Full physical (lymph node check, lump-hunt, co-morbidities)

Get a minimal database

Thoracic rads or abdominal U/S

Explain to owner the risks. Get them to sign something indicating you have explained these things

Consider consult with specialist

What is involved in a pre-excisional biopsy check

Never cut off a lump without sending for histopathology

If adamant they cant send ensure that you always place a lump into formalin

What's involved in a post-excisional biopsy check?

Done by a histopathologist

Refers to the histological appearance of a tumour

Categorised in some way (1-4, low, moderate, high)

Associated with biological aggression and likelihood to metastasise

What is cancer grading

Understanding of the level of aggression: How much tissue is required to remove, where can it spread to

PX of the animal: Likelihood of metastasis/ recurrence, median survival time, median disease free interval

TX: Post OP chemo/ radiation. More extensive sx

What does grading allow?

For general clinician

TMN System

Classified according to the nature of the mass, whether it has extended beyond the limits of the mass

What is cancer staging

Local vs systemic

Prognosis according to stage

Establish TX plan: Multimodal approach, lymph node excision, chemo/radiation

What does staging allow?

T0 - Primary neoplasm is not evident

T1 - Less than 1cm, mobile

T2 - 1-3cm in diameter, not deeply attached

T3 - 3-5cm, partially fixed to underlying structures

T4 - >5cm, invading deeper structures

Outline the use of the TNM system to describe: Tumours

N0 - palpably normal size and consistency

N1 - Enlarged, firm (ipsilateral)

N2 - Fixed to surrounding tissue

N3 - Involvement of lymph nodes beyond the first station

Outline the use of the TNM system to describe: Nodes

M0 - No evidence of metastasis

M1 - Single visceral metastasis

M2 - Multiple visceral metastases

Outline the use of the TNM system to describe: Metastasis

Disruption to physiology and homeostasis that occur systemically or distant to the tumour and are not directly related to the mass effect of the tumour

Define paraneoplastic syndromes

Cachexia, fever

Hyperhistaminaemia

Hypercalcaemia

Hypoglycaemia

Hyper(gamma)globulinaemia

Extreme neutrophilia

Erythrocytosis

Hypertrophic osteopathy (Marie's diseases)

Myasthenia gravis

Alopecia

What are some paraneoplastic syndromes?

Mast cell tumours

Results in ulcers

Which tumours can cause Hyperhistaminaemia?

Anal sac adenocarcinoma

Lymphoma

Which tumours can cause hypercalcaemia?

Ca has many roles (heart beat, metabolism, nerve function, blood clotting)

Maintained within range of 1.1-1.5nMol/L (ionised calcium)

What is calcium important for in the body?

Parathyroid and kidneys most important in keeping this so tightly regulated

Thyroid produces calcitonin which decreases calcium in the blood and parathyroid produced PTH which increases calcium in the blood.

How is calcium regulated?

Activates D3 to promote intestinal and kidney resorption and works with D3 to mobilise calcium from the bone.

How does parathyroid hormone increase calcium in the blood?

Humoral

Tumours produce parathyroid hormone related peptides (PTHrP)

E.g. Lymphoma, anal gland adenocarcinoma, multiple myeloma

Cell mediated

Bone mets, osteoclastic activity

Unlikely to be marked hyper-Ca

What are the two forms of hypercalcaemia?

PU/PD (before irreversible kidney damage). Later get irreversible renal failure

Anorexia, V+, constipation

Bradycardia and hypertension

Skeletal muscle weakness

Depression

Stupor, coma, seizures

What are the signs of hypercalcaemia?

Error

Young animal

Lymphoma, apocrine gland adenocarcinoma of anal sac (most common cause in dogs)

Multiple myeloma, lymphoid leukaemia

Primary hyperthyroidism

Bone metastases

Chronic, severe granulomatous disease

Cholecalciferol intoxication

Hypoadrenocorticism (Addison's disease)

What are some differentials causing hypercalcaemia?

Insulinoma, secreting insulin

Large liver tumours (hepatomas, hepatocellular carcinomas)

Leukaemia's

Salivary adenocarcinoma

Non-islet solid tumours (make insulin-like growth factors)

Leukaemia cells may consume blood glucose

What are some causes of Hypoglycaemia?

Oesophageal and large abdominal tumours

What can cause Hypertrophic osteopathy (Marie's diseases)

Hypertrophic osteopathy (Marie's diseases)

Malignant spirocerca lupi cancer in the distal oesophagus

What is depicted in the following image?

Multiple myeloma (most common), often make a monoclonal Ig (most often A)

Lymphoma

What are some causes of Hyper(gamma)globulinaemia

Causes a hyperviscocity syndrome

Bleeding

Retinopathy

Seizures

Renal disease

Heart disease

What are the signs of hypergammaglobulinaemia?

Involves identifying and treating underlying cause (e.g. Melphalan and prednisone if multiple myeloma)

+/- phelbotomy/ crystalloid fluid replacement

What is your approach to Hypergammaglobulinaemia

Several, esp. kidney/renal tumours

Others include mesothelioma

What can cause erythrocytosis

Multifocal causes

Hard to correct nutritionally (and often not achieved)

Large reason owners put animals down

Cachexia, fever

Thymoma

What can cause myasthenia gravis

Anorexia, weight loss, fatigue, impaired immunity

Cytokines (produced by some tumours) mobilise nutrition for white cells.

What are the signs of cancer cachexia

Cholangiocarcinoma

What can cause paraneoplastic alopecia?

Systemic (PO or IV)

Intralesional/ intracavitary

Neoadjuvant (before sx)

Adjuvant (during or after sx)

What are the types of chemotherapy administration?

Induce a complete & durable remission

Delay development of multiple drug resistance

Minimise morbidity associated with TX and with DZ itself

± Induce a second remission following relapse after primary treatment course

What are the goals of chemotherapy?

Use drugs that are effective as single agents

Combine drugs with different MOA

Use drugs with different toxicities

Use an intermittent TX schedule

TX aggressively

What are the principles of chemotherapy?

Chemotherapy kills a known fraction of the cancerous cells. e.g log 4 - will reduce 10^12 to 10^8

Chemo drugs action work via fractional killing. What is fractional killing?

10^9 cells

What is the detection limit of cancer?

Low dose given constantly over long period of time -> Rate isn't lethal to cancer, isn't given at a cytotoxic conc means body isn't as effected

Goal is to prevent progression, anti-angiogenic and anti-T reg effects.

What is metronomic chemotherapy?

When owners decline conventional therapy or there is incomplete excision of a tumour that can't be fixed.

When would you use metronomic chemotherapy?

Achieve a definitive diagnosis

± Stage tumour

Explain carefully to the owner

Understand the drugs and their potential toxic effects

Understand how to handle the drug safely

What are the prerequisites for chemotherapy?

Some chemo agents are carcinogenic & teratogenic

Adverse effects dependent on dose & exposure time

Some agents are powerful irritants/ vesicants

Why do you need to understand how to handle the drug sefely?

Any excrement are considered cytotoxic -> should be handled only with gloves for 24-72hrs post TX

What are some risks to owners?

Keep separate from other drugs

Never break tablets

Check DOSE and ROUTE before admin

Have everything ready

Owners - provide with gloves & well labelled drugs

All the PPE and equipment used must go into a separate cytotoxic bin (Purple bin)

Outline some considerations regarding drug safety

Good restraint +/- sedation

Start IV catheter placement as distally on each limb as possible

Flush with 5-10ml saline afterwards, before catheter removal

Vein protection: Drawing blood use jugulars, record keeping of which veins used for what drugs & when

Outline some considerations regarding patient safety

Body surface area (BSA) mg/m2

In small dogs -> mg/kg

How are antineoplastic drugs dosed?

Bind and disrupt DNA, interfere with DNA synthesis by intercalating with DNA

Cyclophosphamide, Chlorambucil, Melphalan

What is the MOA of alkylating agents and provide some examples

Alkylating agents

Anthracyclines - anti-tumour antibiotics

Platinum drugs

Antimetabolites

Antimicrotubule agents

Misc: L-asparaginase / Procarbazine

What classes of drugs are commonly used for chemotherapy?

Alkylating agent

IV or oral

Lymphoma, sarcoma, carcinoma

Side effects: Haemorrhagic cystitis, GI signs, Myelosuppressive

Outline the use of Cyclophosphamide

More so dogs

Due to metabolisation in blood stream into number of compounds

Hemorrhagic cyst due to acrolein that enters and sits in the bladder

TX: mesna (antidote), regular walking and diuretics

Cyclophosphamide causing hemorrhagic cystitis

Oral

Nitrogen mustard alkylating agent

For chronic lymphocytic leukemia (CLL) or Multiple myeloma

Possible replacement for cyclophosphamide

Side effects: Myelosuppressive (use it to suppress bone marrow cancers)

Chlorambucil

Alkylating agent

Oral or IV

Myelosuppressive

Used for MM, CLL

Melphalan

Anti-tumour antibiotics

Doxorubicin, Dactrinomycin, Mitoxantrone

What is the MOA of anthracyclines and provide some examples?

Anthracyclines: Anti-tumour antibiotics

Cornerstone drug, lymphoma, sarcoma, carcinoma

Only IV

Best single use drug (go to if tight budget).

Side effects: Severe vesicant, perivascular sloughing, myelosuppression, cumulative cardio toxicosis, cardiomyopathy (dogs), renal failure (cats)

Doxorubicin

Anthracyclines: Anti-tumour antibiotics

Myelosuppression, extravasation reaction, diarrhoea, vomiting

Dactrinomycin

Anthracyclines: Anti-tumour antibiotics

Used for lymphoma, carcinoma

IV

Myelosuppression, GI effects

Mitoxantrone

Cross-link DNA, inhibiting DNA synthesis and function

Carboplatin, Cisplatin

What is the MOA of platinum drugs and provide some examples?

2nd gen platinum drug, like an alkylating agent

Admin via IV, IP (intra-perioneal), Itu (intra-tumour)

Used for OS, M.Mel, CAs

Side-effect: Myelosuppression

Carboplatin

Sarcoma, carcinoma

Renal toxicosis, V+ & D+, Mild myelosuppressive

Not in cats: Fatal pulmonary oedema in cats

Cisplatin

Similar to nucleotides, get incorporated into DNA causing damage

Methotrexate, Cytosine arabinoside, Gemcitabine, 5-Fluorouracil (not in cats)

What is the MOA of antimetabolites and provide some examples?

Antimetabolites

Oral or IV, used for lymphoma

Myelosuppressive, GI toxicity

Methotrexate

Anti-metabolite, interferes with DNA synthesis

Admin via SC, IV, IP, Intrathecal

Myelosuppressive, good blood brain barrier penetration

Indications: Lymphoma

Cytosine arabinoside

Inhibit spindle formation during mitosis

Vincristine, Vinblastine SO4

What is the MOA of antimicrotubule agents and provide some examples?

Antimicrotubule - mitotic spindle inhibitor

Cornerstone Drug; Esp. Mast cell tumours, Lymphoma, and TVT in dogs

Only IV

Side effects: vesicant, mild myelosuppression, anorexia in cats, +/- neuropathy and constipation

Vincristine

Antimicrotubule - mitotic spindle inhibitor

Only IV, For mast cell tumours

Vesicant, myelosuppression, peripherally neuropathy

Vinblastine SO4

Cornerstone drug, many actions, usually orally

Side effects: PU/PD, polyphagia, panting

Is protective against haemorrhagic cystitis

Prednisolone

Enzyme that destroys asparagine (needed by lymphoma cells)

Not cytotoxic

SC or IM

Good early-stage drug (esp. for early stage presumption dx)

Side effect: Anaphylaxis (quite rare), may increase toxicity of vincristine

L-asparaginase

Generally work on rapidly dividing cells

Susceptible tissue: Rapidly dividing tumour, bone marrow, gastrointestinal mucosa (crypts)

How does anti-neoplastic drugs react to normal tissues?

Most common and important form of toxicity

Bone marrow progenitor cells have a high proportion of dividing cells

Cats more commonly affected than dogs

Myelosuppression

Doxorubicin (Highly myelosuppressive)

Cyclophosphamide

Cytosine arabinoside

Melphalan

Vinblastine

Azathioprine

Hydroxyurea

What are some drugs that cause myelosuppression?

Peripheral blood cytopenia's; First granulocytopenia, then thrombocytopenia, and then anaemia.

How does myelosuppression present clinically?

Look at neutrophils (stop chemo and give AB if gets too low), Measure rectal temp regularly (>40 degrees go to vet).

How can you monitor myelosuppression?

Lowest cell count after chemo

Generally 7-10d post-drug admin

Cell counts usually rebound within 1-2d

Nadir

Risk of sepsis is of major concern

Owners to check rectal temp of patient on regular basis; If pyrexia (>40C) or other illness would prompt immediate medical tx

WBCC and differential counts and platelet should be checked regularly

CBC should always be checked 10-14d after doxorubicin therapy

Monitoring the cancer patient during treatment

Nausea and vomiting

Gastroenteritis (seen if sufficient mucosal cells die and slough off)

Constipation (occasionally seen with vincristine)

GI toxicity signs

May be seen with doxorubicin, cyclophosphamide, high dose vincristine

May be due to stimulation of CNS centre, starts at the time of admin and may last for 1-2days

May be due to GI mucosal damage

What can cause GI toxicity?

Metoclopramide, prochlorperazine, ondansetron, maropitant

Cyproheptadine and mirtazipine in cats

What antiemetics are given to treat GIT toxicity?

Leukaemias: Acute & chronic lymphoblastic leukaemia

Plasma cell tumours: Multiple myeloma & solitary lymphoma

Lymphoma

What are the types of lymphoproliferative diseases?

Idiopathic

Some associations with genetic predisposition, familial, retorival, magnetic fields, herbicides

Outline the aetiology of lymphoma