227.431 - Oncology

(Medical and surgical procedures)

What is cancer?

Cells that have lost the normal controls that balance cell death with cell proliferation

Steps to success - what, where, when

What - locate, describe and identify the mass

Where - locate any spread

When - determine whether it is likely to spread in the future

List 5 things used to describe the mass (5)

• fixed vs moveable

• ulcerated vs non-ulcerated

• size

• subcut vs dermal vs intracavitary

• soft vs hard

What methods can you use to identify the mass? (2)

fine needle aspirate or biopsy with histopathology

Why should you be cautious about performing an FNA?

Carcinomas have a tendency to spread along the needle line and can result in cells being deposited into a body wall and become incurable

What can a FNA tell us about a mass?

If the mass is cellular or acellular and whether or not the cells are ones we would expect to see or not

Criteria of malignancy (6)

• Anisokaryosis 

• Anisocytosis 

• Abnormal Nucleoli

• Multinucleation 

• Mitotic figures 

• Altered/Variable nucelus to cytoplasm ratio (N:C ratio)

What are 2 types of biopsies we can do to identify a potential cancer?

Incisional and excisional

What are the pros and cons to an incisional biopsy?

Pros: Does not compromise the field of surgery + is more diagnostic than an FNA

Cons: You have to go back to properly remove the tumour + may give lower grades due to variability in heterogeneity in big tumours (STS and MCT)

What are the pros and cons to an excisional biopsy for a mass?

Pros: May give you a treatment and diagnosis all at once

Cons: Don't know the tumour identity therefore getting accurate margins can be difficult + if any tumour is left behind the prognosis goes down

FIRST chance to cut is the BEST chance to

Cure

If it is important enough to take off, it is important enough to submit

Histology

Giving the cancer an origin -

(hint: 3 common cancer types and 3-4 examples each)

Carcinoma: urothelial carcinomas, squamous cell carcinoma, mammary carcinoma, anal sac adenocarcinoma

Sarcoma: osteosarcoma, fibrosarcoma, soft tissue sarcoma

Round cell tumour: lymphoma, melanoma, mast cell tumour

Describe the differentiation of cells for a malignant vs benign cancer

• Malignant: Undifferentiated, lacks organisation

• Benign: Well differentiated, organised tissue

Describe the boundaries for a malignant vs benign cancer

• Malignant: Poorly defined, invasive

• Benign: Defined, can be encapsulated

Describe the mitosis and rate of growth for a malignant vs benign cancer

• Malignant: Mitosis common, fast growth

• Benign: Mitosis rare, slow growth

Describe the clinical results for a malignant vs benign cancer

• Malignant: Local destruction and compression +tumour necrosis, hormone production, disfigurement, mets into vital organs

• Benign: Local compression + hormone production & disfigurement

Describe the likelihood for mets for a malignant vs benign cancer

• Malignant: Common

• Benign: None

Describe grading (3 points)

(hint: description + when + how)

A way of predicting likelihood of spread in future by describing appearance of neoplastic cells and tissue on histopath

If tumour is malignant, we will provide a grade (higher numbers are typically more aggressive)

Grading is done by pathologists

Important info from histopath (4)

• Cell description 

• Margins 

• Mitotic index (mitoses per 10 HPF) = helps to predict likelihood of spread 

• Invasiveness (through basement membrane, into lymphatics or blood vessels = worse prog)

Describe staging (2 points)

(hint: description + measurement)

• Performed after intial diagnosis to assess extent of a tumour throughtout the body

• Look at size (T), regional lymph node involvement (N), distant metastasis (M)

Diagnostic testing for staging (9)

• history + physical exam

• FNA

• CBC/biochem/urinalysis

• radiographs

• U/S

• echocardiogram

• CT

• MRI

• bone marrow aspirate

When staging cancer we want to do it with intention. What does this mean?

Guide the owners to tests we need to do and not additional things the owner wants
- e.g.

• Carcinomas typically spread via lymphatics +/- lungs therefore don't require blood tests

• Sarcomas typically spread via blood

• Round cells can do either or both

Which lymph nodes can normally be felt and how big would you expect them to be? (3 LN + measurement)

submandibular, prescapular and popliteal

0.5-1cm

When should you stage?

always unless it wont change what you would do

Paraneoplastic syndromes

Alterations in bodily structure or function due to cancer that are not directly due to the physical effect of the primary or metastatic lesion i.e. distant effects due to what the cancer is secreting

Paraneoplastic syndromes examples (7)

• cancer cachexia (cancer eats glucose → weight loss)

• gastric ulcers (secondary to MCT b/c histamine release)

• hypercalcaemia (secondary to excessive PTHrP)

• hypoglycaemia (secondary to insulinoma)

• hypertrophic osteopathy (secondary to lung tumour or mets to lungs → tumour tells bone to proliferate and cause an issue → lung-digit-syndrome)

• monoclonal gammopathy w/ multiple myeloma (blood cancer of antibody-secreting plasma cells → produce antibodies and ignoring body’s restraint systems → globulins out in circulation affect coagulation)

• myasthenia gavis  (secondary to thymomas)

Treatment options for paraneoplastic syndromes (3)

surgery, radiation, chemothapy

Things to consider when carrying out treatment of neoplasia (4)

• Histologic type and biologic behaviour

• grade and stage

• morbidity/mortality of tumour

• treatment cost and owners choice

  • Just because we can, doesn’t mean we should

Describe Neoadjuvant

Treatment before surgical treatment (to shrink tumor for better excision success)

Describe Adjuvant

Treated after surgical treatment (to destroy residual microscopic disease)

Describe Palliative

Treatment to improve quality of life without aiming to prolong lifespan

Describe Curative intent

Treatment to prolong lifespan which is generally surgical treatment

With few exceptions, the only treatment for cancer that will CURE a pet is

surgery

What should you NEVER place in a surgery field for cancer?

a drain

if you didn't get it all, you will spread the cells

If you try to resect a scar from a previous incomplete surgery, you must assume the entire scarline is now full of

cancer cells

When would you use radiation as a method of cancer treatment? (2)

• Local disease or for improving quality of life from local disease

• Often useful for sites that are hard to reach for surgery or if surgery is declined

Radiation tx needs (2)

• Cells to be dividing

• Multiple treatments/anaesthesia events

What can cause radiation tx to fail? (3)

• not well oxygenated 

• Poor penetration/large tumour 

• Geographic miss - even a single tendril

When would we use chemotherapy to treat cancer?

widespread disease or when other options aren't available due to location

Chemo tx needs: (1)

actively dividing cells in the G1 or greater stage of the mitotic cycle

Following treatment and with regards to staging, when might we want to recheck a tumour? (4)

1. A few days if lymphoma
2. A few weeks if chemotherapy for fast growing tumour
3. A few months if radiation
4. variable timeframe if surgical, depends on goals and margin

Describe Complete response

no evidence of tumor at this time

Describe Partial response

tumor burden shrank by at least 30%

Describe Stable disease

tumor less than 20% larger or shrank by less than 30%

Describe Progressive disease

tumor is at least 20% larger or new lesions are noted

When to change treatment: based on owner goals and where patients is in protocol

Lymphoma that has never been treated previously:

Typically switch chemotherapy if there is not a complete response

When to change treatment: based on owner goals and where patients is in protocol

Lymphoma that has been through multiple chemotherapy options

we usually keep treating with the same protocol if there is stable disease

Cancer treatments are not benign - so you should?

Think before you use and consider if the benefits are worth the risks? Is it helping?

Chemotherapy

A treatment (not cure) for systemic neoplastic disease

What’re the 3 main types of chemotherapy?

• Maximum-tolerated chemotherapy: A few large doses (highest dose level that the animal can tolerate) given over a set period of time and then stopped → kill cancer w/ max dose

• Metronomic chemotherapy: Multiple small doses given over long-term (often life-long) → modifes the tumour to allow the immune system to better penetration and decrease blood vessel formation = tumour growth stops

• Electrochemotherapy: Local doses of chemotherapy (Bleomycin) given and then electrical shocks administrered over the area → forces the cells to open their pores and allow the drug to enter, when the electrical shocks stop and the pores close they are left with the drug inside them. Typically it is given a few times and then stopped.

Chemotherapy - how does it work?

non-specifically attacks actively dividing cells - most work in the S phase (DNA replication) with some in the M phase (mitosis)

Side effects of chemotherapy: due to

normal body cells that are also actively dividing and therefore damaged by chemotherapy

Side effects of chemotherapy: BAAGi

• Bone marrow suppression

• Alopecia

• Allergic reaction

• Gastrointestinal upset

• (+I for infertility)

When might we see bone marrow toxicity following chemotherapy?

7-10 days after chemotherapy

When do we want to give antibiotics for a bone marrow toxicity case caused by chemotherapy?

When we have a sick animal with < 1.0 x 10⁹/L Neutrophils

• Neutrophils have the shortest circulating half-life (life-span) so are typically the first haematologic toxicity observed in chemo → often the dose-limiting toxicity

When chemotherapy causes bone marrow toxicity, what might this manifest in (and would be seen on biochem/cbc ...)? (3)

Neutropenia, Thrombocytopenia and Anaemia

Describe the alopecia seen by chemotherapy

Generally uncommon, but would cause temporary alopecia during chemotherapy and only seen with breeds with continuously growing hair. Cats may lose whiskers but not the rest of their hair.

What animals are affected and what drug tends to cause allergic reactions when it comes to chemotherapy?

Horses and doxorubicin

How can chemotherapy cause GIT issues and how do we manage it?

Direct stimulation of the chemoreceptor trigger zone - treat with antinausea medications (ondansetron, maropitant)

GI mucosa cell death and risk of bacterial translocation - treat with GI support +/- antibiotics (pumpkin, yogurt +/- metronidazole)

With regards to chemotherapy, what is the issue with the MDR-1 mutation?

It is a mutation where drugs are not effluxed out of cells properly

• upregulation makes the patient chemo-resistant

• down regulation makes the patient more likely to experience toxicity

• Certain breed predispositions so important to test dogs before treatment

MDR-1 breeds

Collies (+ huntaways, beardies, smithfields), aussies, mini aussies, long-haired whippet, McNab, silken windhound, chinook, shelties

How do you test for the MDR-1 gene? Why is it important to test?

Cheek swab test - doesn't cost much

Do swabs of all these breeds as a normal dose could kill them

Chemotherapy protocols

When to use a Single agent (4)

• use if cost is a concern

• no benefits when combining (use one drug for as long as it works before switching e.g. urothelial carcinoma)

• only one is shown to be highly effective (e.g. lomustine for histiocytic sarcoma)

• palliative care (to avoid side effects of multi-agent)

Chemotherapy protocols

When to use Multiple agents (4)

• use if non-overlapping toxicity

• drugs have non-overlapping mechanisms of action

• each individual drug known efficacy against tumour

• significant concern about development of drug resistance

List the 6 major types of chemotherapy drugs

(hint: AAAAP ; 3.5 antis + 2 agents + misc)

1. Antimicrotubule

2. Antineoplastic antibiotics

3. Antimetabolites

4. Alkylating agents

5. Platinum agents

6. Misc drugs

Which drugs are "M"s - mitosis

Antimicrotubule

Which drugs are "S"s (DNA replication)

Alkylating agents, Antineoplastic antibiotics, Platinum agents, Antimetabolites

Antimicrotubule agents (3)

(hint: 3 Vin sisters)

Vincristine (lymphoma or immune-mediated thrombocytopenia (ICT)) ← hint: Cristine limps to avoid plates?

Vinblastine (mast-cell tumours & transitional cell carcinoma) ← hint: ‘blast the mast’ (and the bladder?)

Vinorelbine (lung tumours) ← hint: pleur-elbine?

What is the mechanism for antimicrotubule agents which are used for chemotherapy?

Crossbinds to tubulin to inhibit mitotic spindle → prevents the chromosomes from dividing

Alkylating Agents (5)

(hint: Cy-chlo-must + 2 Ms mel & mec)

• Cyclophosphamide

• Chlorambucil

• Lomustine (histiocytic sarcoma, MCT and cancers in the brain b/c crosses BBB)

• Mechlorethamine

• Melphalan (multiple myeloma)

What is the mechanism of action for alkylatic agents (chemotherapy)?

covalent binding of alkyl groups to cellular macromolecules resutling in DNA interstrand and intrastrand cross-links → DNA apoptosis

Antineoplastic antibiotics (7)

• doxorubicin (anthracycline) - (sarcoma, lymphoma & bladder tumours)

• dactinomycin (Paul’s pharma)

• mitoxantrone (doxorubicin subsitute)

• bleomycin

What are the several different mechanisms for antineoplastic antibiotics? (5)

1. DNA Intercalation
2. DNA Alkylation
3. Calcium homeostasis alterations (doxo only)
4. Reactive oxygen generation (doxo only)
5. Topoisomerase II inhibition

What are some side effects to antineoplastic antibiotics?

• Doxorubicin can cause cumulative (and sometimes acute) cardiotoxicity and nephrotoxicity

• Doxorubicin can cause allergic reaction esp. in horses

• Doxorubicin can cause severe extravasation reactions if not given directly into the bloodstream

  • If it gets outside the blood stream the wound will continuously enlarge until you have to amputate the limb 

Antimetabolites (4 + 3 cancers)

• Cytosine Arabinoside/Cytarabine

• 5-Fluorouracil

• Azathioprine/mercaptopurine (Paul’s pharma)

• Methotrexate (Paul’s pharma)

• Used in meningioencephalitis, lymphomas or carcinomas

What is the mechanisms of action for antimetabolites (chemotherapy)? (2)

• competitive inhibition of DNA polymerase alpha (Cytosine arabinoside)

• incorporated into DNA and interferes with DNA synthesis and function (5-fluorouracil)

What are some side effects to antimetabolites?

5-fluorouracil causes neurotoxicity, especially in cats

Platinum agents (2 + 2 cancers)

(hint: platin)

• Carboplatin

• Cisplatin

• Used in osteosarcoma or carcinomas

What is the mechanism of action for platinum agent chemotherapies?

covalently binds to DNA to cause inter-strand and intra-strand cross-linkages

What are some side effects to Platinum agents?

Cisplatin in cats causes fatal pulmonary oedema

Misc chemo drugs (2)

• prednisone (lymphoma or MCT)

• L-asparaginase (lymphoma)

What is the mechanism of action for Misc chemo drugs?

• Pred - direct killing effects

• L-asp - breaks down asparagine and deprives lymphocytes of it

What are some side effects to Misc drugs

Pred: PU/PD, panting, and polyphagia

L-asp - anaphylaxis b/c its an enzyme

What are some chemo specific toxicities?

Hints: 7 organs/body systems
Nervous (3)
Heart: doxo kinda sounds like digoxin? (1)
Lungs (3)
Liver (1)
Pancreas ??? (2)
Kidney: CoLD kidneys? (3)
Bladder: cystitis caused by cyclophosphamise (1)

• Nervous System: Vincristine (+/- vinblastine), 5-Fluorouracil (especially cats)

• Heart: Doxorubicin

  • Cumulative & acute toxicity in dogs

  • normal cut-off of 6 doses to avoid DCM + give over 20-60 min

• Lungs: Cisplatin (cat), Bleomycin, Lomustine

• Liver: Lomustine

  • Occurs frequently! - Give liver support meds at the same time (milk thistle?) 

  • Monitor liver values! 

• Pancreas: L-asparaginase, Doxorubicin 

• Kidney: Cisplatin, Doxorubicin, Lomustine

• Bladder: Cyclophosphamide

  • Sterile haemorrhagic cystitis

    • Make sure pets are peeing the metabolite out

    • give pre/furosemide concurrently to encourage urination 

    • if develop SHC stop and never give again 

What is important to remember when it comes to handling chemotherapy agents?

• Teratogenic (cause birth defects)

• Mutagenic (cause DNA mutations)

• Carcinogenic (cause cancer)

What are the 4 R's to remember for chemotherapy safe handling?

(hint: Dr. Dop)

• right drug

• right route

• right dose

• right patient

How are some more chemo safe handling protocols? (5)

• Careful drug calculation

• Careful timing and monitoring

• "Single-poke" IV access (save those peripheral vessels)

• Limit exposure to staff and self by using closed system for administration

• Wear gloves while handling body fluids after administration

How to prevent aerosolisation of chemo drugs? (4)

1. Don't crush or split tablets
2. Do not open capsules
3. Do not compound liquid versions
4. Do not use powdered versions

How to educate owners? (3)

Explain and advise on:

• Side effects and risks of the chemotherapy for the pet

• Safe handling for the owner (typically 3 days but can be longer - assess owner risks and know the drug)

• Drug elimination routes

Lymphocytes include

B cells, T cells, natural killer cells, plasma cells memory B cells

What is the role of lymphocytes?

part of the adaptive immune system which recognise and respond to specific foreign antigens

B cells

become palsma cells and make antibodies

T cells

regulate adaptive immunity and cell mediated

Typical canine multicentric large cell lymphoma present as

multicentric LN enlargement as lymphocytes proliferate

Other presentations of lymphoma

mediastinal mass, nasal bleeding, vomiting or weight loss, external mass, honeycomb spleen, hypercalcaemia, anything - variable, most large cell lymphomas are aggressive

How to sort lymphoma

size (large cell vs small cell), location and immunophenocyte (B vs T cell)

Is B or T cell lymphoma better for dogs?

B is better, T is terrible

Canine lymphoma locations

Most common is multicentric with lymph nodes affected

What is more common in dogs - B or T cell lymphoma?

B cell