Defining cancer to client
group of abnormal cells grow uncontrollably by disregarding normal rules of cell division
What causes cancer?
Multifactorial
Genetic - DNA mutations result in deficits in the regulatory circuits of a cell; individual cell behaviour not autonomous
Environmental - diet, exposure, viruses, age
Mechanisms of cancer - multistep carcinogenesis
Initiation - rapid - carcinogens induce DNA damage but not enough to induce neoplastic transformation
Promotion - original carcinogens or normal growth promoters/hormones cause reversible tissue and cellular changes
Progression - slow - progressing agents are able to irreversibly convert an initiated cell into a cell exhibiting malignancy
6 hallmarks of cancer cell
- Evading apoptosis
- self-sufficiency in growth signals
- insensitivity to anti-growth signals
- tissue invasion and metastasis
- limitless replicative potential
- sustained angiogenesis
Establishment of tissue diagnosis
diagnostic cytology - needle biopsy
3 cell type origins of cancer
- round cell
- mesenchymal
- epithelial
Round cell tumors
individualized round cells arranged in a mono layer
5 Ddx of round cell tumors
Please Help Me Learn This
Plasmacytoma, Histiocytoma, Mast cell tumor, Lymphoma, TVT
Mesenchymal tumors
spindle-shaped, arranged individually or in non cohesive aggregates
SARCOMAS
Epithelial tumors
round, cuboidal, columnar or polygonal cells arranged in cohesive sheets or clusters
CARCINOMAS
Characteristics of malignancy
homogenous vs. heterogenous
monomorphic vs pleomorphic
cellular/cytoplasmic cluster
nuclear criteria - anisokaryosis, multiple nucleoli, increased mitosis
Advantages and Disadvantages of cytology
Advantages - low risk, low cost, non-invasive - rapid turnover of results - ability to evaluate morphologic appearance of individual cells - HIGHLY SPECIFIC Disadvantages - low sensitivity - poor sample quality - small sample size - inability to evaluate tissue architecture
When will cytopathology fail you?
oral tumors (don’t exfoliate well), mammary tumors (most are carcinomas which have inflammation = false -), splenic tumors (often very bloody)
In which tumors do cells spill out causing tumor cell growth along the needle tact when you take a cytopathology sample?
Urogenital neoplasms (carcinomas) *remember he said you wouldn't do a FNA on a TCC because risk of seeding
Clinical technique preferred for FNA
Needle off (coring) - grasp mass, advance needle in mass and redirect several times to dislodge cells and drive them into hollow shaft of needle
Cytology of liver, splenic, GI and bone tumors
Liver - <50% accuracy, interpret with caution
Splenic - non-aspiration techniques superior because produce samples of > cellularity and less blood contamination
GI - high specificity
Bone - ALP staining - very good, differentiates OSA from other sarcomas
cytology of bone tumors with ALP staining
differentiates OSA from other sarcomas
Staging vs. Grading
Staging
- answers Q is tumor localized, spread regionally or diffusely
- requires series of noninvasive testing
- based on WHO TNM (tumor, node, metastasis system)
Grading
- requires a block of tissue
- estimates inherent aggressiveness of tumor using systematic approaches
- allow definitive prognostication
Regional LN cytology
Sentinel LN = LN cancer cell is most likely to spread to from primary tumor, not always nearest LN downstream
SLN - unique to each patient
- don’t assume normal sized LN are not metastatic
- 3 view thoracic metastasis check (rads) - can detect >7-9mm nodules
- CT detects greater # nodules and greater Dx confidence and accuracy
- abdominal US +/- image guided FNA
- cross sectional imaging (CT/MRI)
Which organ is most common receptacle of blood born metastasis?
Liver
Paraneoplastic syndrome
tumor associated alterations in body structure or function, occur distant to tumor, often first signs of malignancy
Paraneoplastic causes of hypercalcemia
Anal sac adenocarcinoma
Lymphoma
Mammary tumors
Multiple Myeloma
Paraneoplastic cause of hypoglycemia
Intestinal leiomyosarcoma
2 Goals of conventional chemotherapy
- enhane or maintain QOL and family bond
- stabilize, diminish or eliminate neoplastic process
T/F: chemotherapy drugs only target cancer cells
false, target ALL rapidly dividing cells
- cancer cells, gut, bone marrow, hair
Fractionation
allows recovery of normal tissue between treatment intervals
Adjuvant chemotherapy
used after Sx as adjunct to local therapy
Neoadjuvant chemotherapy
used prior to definitive Tx (Sx) in attempt to shrink tumor
Induction/Maintenance chemotherapy
the sole Tx for measurable dz
Palliateive chemotherapy
improve QOL by helping to alleviate signs, but won’t cure
Chemotherapy dosing
- based on maximum tolerated dose (toxicity) rather than efficacy
- dose response curves very steep in most cancers
- BSA body surface area -though to be better estimate vs BW, but doesn’t predict drug metabolism and absorption/excretion
- smaller patients receive higher dose based on mg/m basis
Which drugs are risky to give small animal patients based off of BSA dosing calculations?
doxorubicin, melphalan, cis- and carboplatin
how many people should do dosing calculations for chemo drugs?
2
important when writing chemo doses
no trailing zeros or naked decimals
4 Rs of chemo Tx
right drug, right dose, right route, right patient
MDR-1 gene/ABCB gene
Collie, Australian shepherds, long haired whippet
- gene encodes production of pgp pumps which remove drugs from individual cells
- increased risk in drugs that are substrates for pumps
Vincristine, vinblastine, paclitaxel, doxorubracin
Which drugs should you probably not give to Collies, Aussies, or long haired whippets?
they have ABCB gene
Vincristine, vinblastine, paclitaxel, doxorubicin
Common adverse effects of cytotoxic chemotherapy
BAG Bone marrow suppression Alopecia - non-shedding breeds only Gastrointestinal - crypt cells destroyed = V/D - only in 3-5%
Monitoring chemo patient
On day of Tx - do a CBC, neuts >3000/ul and Plt >100000/ul. if too low, NO TX THAT DAY, recheck 3-7d later
After 1st chemo, check weekly after 1st dose to establish nadir (expected low point of bone marrow insult)
If neut at nadir <1500/ul or PLT <60000/ul, subsequent dose should be decreased by 20-25%
Management of chemo side effects: myelosupression
risk of systemic infection - prophylactic antibiotics warranted (neutropenia)
- clavamox or baytril
- infection from opportunistic pathogens
- severe cases may need ICU
*MAY NOT HAVE FEVER (lack fever producing cells)
WBCs make IL-1 and TNF but levels are too low to yield a fever
Nupogen - granulocyte colony stimulating factor, stems WBC prod from BM, rarely used because tolerance built after 1st use (human origin)
Management of chemo side effects: thrombocytopenia
exercise restriction, close monitoring for bleeding, careful w/ lomustine and melphalan (cumulative effect)
Management of chemo side effects: GI effects
MOA for GI toxicity: (1)direct stim of CRTZ and (2)damage to crypt cells
- 1 causes V <24h of tx
- 2 causes anorexia, V or D w/in 2-5d of Tx
- key drug players: cisplatin, streptozocin, dacarbazine, mustargen, doxorubracin
- Tx symptoms (anti-emetics, anti-diarrheals, palatable food)
4 main classes of chemo drugs
1) antimitotics
2) alkylating agents
3) antibiotic agents
4) Antimetabolites
also platinum agents
Antimitotics/microtubule toxins
Disrupt or immobilize mitotic spindle, cell-cycle-phase-specific (mitosis)
VINCRISTINE (vinca alkaloids) - used for LSA or TVT
- Toxicity: BAG, GI signs, Vesicant (if outside vessel causes necrosis, Tx w/ hyaluronidase + heat), ileus (nausea), neuropathy (peripheral, pelvic limbs)
Vinblastine - used for MCT in dogs
- Toxicity: BAG
Alkylating agents
Bind DNA, insert alkyl group and change DNA structure to interfere w/ transcription, replication and repair machinery, cell-cycle-phase- non-specific
Melphan - Multiple myeloma
- Toxicity: BAG
Cyclophosphamide - LSA, Metronomica
- Toxicity: BAG, Sterile hemorrhagic cystitis - metabolite toxic to bladder epithelium
Lomustine - LSA, MCT, Histiocytic sarcoma
- Toxicity: BAG, Liver toxicity (give w/ Denamarin, hepatoprotectant)
Chlorambucil - CLL, low grade LSA (cats)
- Toxicity: BAG
Antibiotic agents
several mechanisms of action, cell-cycle phase non-specific
Doxorubricin (red death, adriamycin) - LSA, OSA, mesenchymal + epithelial tumors
- Toxicity: BAG, dose related cardiotoxicity (prescreen Boxers + Dobes w/ echo) and give w/ Dexrazoxane to decrease cardiotoxicity, Tinnitus (ear ringing), Vesicant (ice ASAP and give w/ dexrazoxane to localize + neutralize)
Mitoxantrone (blue thunder) - TCC, LSA
- Toxicity: BAG, cardiac sparing
Antimetabolites
nucleotide analogs or substrates of active metabolic processes within the cell = S phase, cell-cycle-phase-specific (S phase)
Cytosine arabinoside (Cytosar) - CNS tumors, +/- LSA - Toxicity = *B*AG
Platinum agents
covalent binding to DNA strands, forming interstrand crosslinks which are cytotoxic (cell-cycle phase non-specific)
L-Asparaginase (Elspar) - LSA relapse
- inhibit protein synth by hydrolysis of L-asparginase to L-aspartic acid
- Toxicity: hypersensitivity rxn, pancreatitis, DIC
Cisplatin - OSA DOGS ONLY, SPLATS CATS
- Toxicity: BAG, nephrotoxic (diuresis during Tx)
Carboplatin - OSA and other sarcomas, ok in cats
- Toxicity: BAG, NO nephrotoxicty
Novel Agents (Tanovea - CA1)
inhibits proliferation of lymphocytes and LSA cell lines by inhibiting DNA synthesis
1st FDA approved Tx for lymphoma in dogs
Used as RESCUE - once patient fails after standard chemo Tx
Metronomic chemotherapy (MC)
revolves around concept of eliminating break period by giving low dose continuous chemotherapy
not designed to cure, meant for palliative care
MOA
- angiogenesis - up regulation of endogenous angiogenesis inhibitor thrombospondin - 1, blockade of COX and circulating endothelial precursor cells
- immunomodulation - tumor cells up regulate Treg to decrease host immune response (and host defence), MC combats tumor Treg proliferation
- Direct targeting - despite low dose has some direct cytotoxic effect on cancer cells
cyclophosphamide
Cyclophosphamide
alkylating agent commonly used in metronomic chemotherapy
- inexpensive, low GI/hematologic toxicity and PO route
Unique SE: sterile hemorrhagic cystitis due to metabolite acrolein - incidence = 7-32% in MC protocols
- prevent w/ environmental control (give w/ water access), concurrent GC or furosemide to promote diuresis
Toceranib phosphate
blocks receptor tyrosine kinases on cell surface
approved for use on MAST CELL TUMORS in dogs
- a lot of off label use
Immunotherapy
non specific tumor IT, monoclonal antibiotics, T cell therapy (cytotoxic T cells NOT Treg), tumor vaccines
Tumor vaccine - Oncept canine melanoma vaccine
DNA based vaccine, uses tyrosinase in a small DNA ring, labelled for dogs with stage II or III oral melanoma
C vesicolor mushroom (turkey tail)
most commonly prescribed integrative medicine
- cell-cycle arrest at G1/S checkpoint = a reduction in proliferation and an increase in apoptosis in cancer cells
Yunnan Baiyao
Chinese herbal formula - improves clotting and platelet function
- prolong survival in HSA dogs
- dose and time dependent HSA cell death
Tissue effects of radiation therapy
Early responding tissue - epithelial layers of skin/mucosa and bone marrow - looks like massive sunburn, effects seen within weeks of exposure
Late responding tissue - nervous tissue and bone, severe, late effects seen within months or years, blindness, nerve death
Fractioning of radiation
Tx better tolerated and more effective if dose is delivered in multiple small Tx as opposed to delivering dose all at once (fractions)
Big 3 - variables that dictate response of tissues to radiation
- Total dose - related to both tumor response and toxicity
- Fraction size - larger fraction size = higher probability of late effect
- Duration of Tx - longer protocol =. fewer/milder acute effects but increased chance for tumor to repopulate during Tx
Teletherapy
external beam radiation
- orthovoltage = obsolete
- protons/particle therapy = not used in vet med
Megavoltage - most common teletherapy
- used for abdominal or deep tumors
- cobalt machine and linear accelerators produce high energy x-rays for even, predictable distribution and deep penetration
Brachytherapy
radioactive beads sealed source
Nuclear medicine
radioactive iodine
Standard radiation therapy
40Gy over 20 daily fractions = 2Gy/fraction
Hypofractional dosing
total dose divided into larger doses in shorter period of time - good for rapidly. growing tumors
3D CRT (conformational radiation therapy)
Intensity-modulated RT (IMRT)
Stereotactic RT (SRT)
- radiation beams from different direction to match shape of tumor
Measuring response to radiation therapy
RECIST
- response, evaluation, criteria, in solid tumors
Complete response: 100% resolution of tumor
Partial response: >30% reduction in overall tumor size
Progressive disease: >20% increase in overall tumor size
Stable disease: <30% reduction, <20% increase in tumor size
Nasal planum tumors signalment
common in cats (15% of skin tumors)
older, lightly pigmented, outdoor cats
Hx of crusting/erythema progressing to superficial ulcers then deep erosive lesions
SCC - variations dictate Tx plan
Staging of nasal planum tumors
cytology NOT effective bc lesions are flat and ulcerated
wedge or punch biopsy for tissue dx - take tiny sample from center of lesion, NOT under sedation
- low metastatic rate - goes late
- LN staging w/ FNA - sentinel LN with H&N tumors unpredictable, check prescaps too (check ALL LNs)
Tx of nasal planum tumors
- prevention and client education
- if superficial lesion, many options but preferred is cryoablation (minimally invasive, cheap, available)
Infiltrative lesions = nasal planectomy (nosectomy)
Prognosis of nasal planum
Aggressive surgical therapy yields improved prognosis
- combination of intra-lesional carboplatin with orthovoltage
ECT - combined use of chemo drugs (bleomycin or cisplatin) in combo with high-voltage electric pulses
Signalment of ear canal tumors
recurrent signs of infection with visible mass effect in canal
- pruritus, bleeding, pain or reluctance to open mouth
- cocker spaniels, poodles, GSD
- more likely benign in younger cats
Ddx of ear canal tumors
ceruminous glad adenocarcinoma
cats develop more malignant disease than benign, more split in dogs
- other carcinomas (SCC/undifferentiated), round cell tumors (plasmacytomas), sarcomas
Staging of ear canal tumors
sedated or anesthetized, shave or pinch biopsy - small alligator or clamp shell forceps to fit through otoscope cone
FNA usually unrewarding
stage LNs w/ cytology, 3 view rads for metastasis check (low yield but should do)
CT if suspect invasion through canal, jaw pain and swelling could mean deep infiltration
Tx of ear canal tumors
Aggressive Sx - total ear canal ablation with bulla osteotomy (TECA-BO)
- likely also have otitis media, need to remove epithelial lining and flush + Tx with antibiotics
Negative prognostic factors of ear canal tumors
Extension beyond ear canal - ruptures outside cartilage of canal
Dx of SCC or undifferentiated carcinoma - increased predilection for metastasis and local invasion
Neuro signs at Dx - muscle paralysis, seizures, etc
PO histo criteria
Feline sinonasal tumor signalment
malignancies 90% of the time, need good biopsy to ddx LSA from lymphoplasmocytic rhinitis
Canine sinonasal tumor signalment
older dog, median 10y
medium to large breed, focilocephalic (long snout)
environmental exposure - kerosene indoor heaters
2-3m of unilateral epistaxis, facial deformity = advanced
Ddx of sinonasal tumors
2/3 are carcinomas, must do work up to determine cause of epistaxis
Dogs - sarcoma, fungal disease
Cats - LSA LSA LSA
Staging of Sinonasal tumors
x-rays - open mouth DV oblique view to show caudal nasal cavity/cribiform, ipsilateral turbinate loss, bone invasion, sinus infiltration = neoplasia likely
- cross sectional imaging preferred
Biopsy - blind trans-nostril using cup forceps, if no blood on floor not good enough biopsy, measure to medial canthus and place tape for max safe insertion
regional LN - 10-24% incidence, 46% have late metastasis
Tx of sinonasal tumors
Palliative only, not curative
NSAIDs - COX2 over expression - a must for dogs
low dose 6-9Gy week radiation tx
Palladia
hemorrhage control
Curative intent. - radiation therapy external bean, course fractioned, can do image guided IMRT or SRT; SE profile better in SRT
Negative prognostic factors of sinonasal tumors
age - older is worse
presence of epistaxis
longer duration of CS
tumor stage; cribriform involvement = BAD
presence of metastatic dz
Histological subtype - SCC/undifferentiated carcinomas are worse
failure to achieve resolution of CS after tx
Salivary tumors
older dogs (spaniels) and cats (siamese) - more aggressive in cats
most commonly mandibular/parotid SG
locally invasive - cause local effects, regional LN mets common
Staging: FNA/cytology, biopsy but don’t risk compromising 2nd sx
Tx: Sx alone rarely curative, need adjuvant RT for margins
Thyroid tumor dog signalment
older (9-11y), golden, huskies, beagles, boxers
chief complaint = palpable cervical mass
signs of hyperthyroidism if functional
if invasive - coughing, dysphagia, dyspnea, horners
Thyroid tumor cat signalment
older (12-15y), think hyper T4
siamese/himalayan have reduced risk
weight loss despite good appetite, PU/PD, palpable nodule, GI signs
What is the 90:10 rule for thyroid tumors?
Dog are 90% malignant, 10% benign
Cats are 10% malignant and 90% benign
Dog thyroid tumor DDx
CARCINOMAs
r/o abscesses or granuloma, ectopic salivary mucocele, carotid body tumor or medial retropharyngeal LN enlargment
Cat thyroid tumor DDx
ADENOMAS
Staging of thyroid tumors
Metastasis to regional LNs and lungs
unique phenomenon: some dogs w/ thyroid tumors have multiple malignancy
FNA/cytology is ok - needle off, use US to guide bc can be very vascular
fixed vs not fixed - use hands to feel for slip
Tx of thyroid tumors
thyroidectomy, I131 therapy
Prognosis of thyroid tumors
Best: Sx>RT
fractioned RT better than hypofractioned
issue with RRT is it can take time before tumor shrinks so if sick cannot be feasible
Px of animals w/ bilateral thyroid tumor
do fine if resectable, careful w/ PO management = hypoCa (parathyroids gone)
MST = +3y
Negative prognostic factors of thyroid tumors
size - tumor volume
movability - invasion into neighbour tissue = poor prognostic factor
bilateral = greater risk of metastasis
non-medullary thyroid carcinomas = more likely to develop metastatic dz