Oncology Flashcards
By treating the cancer like any other a chronic disease,
seeking only to slow its development and control clinical signs, we allow the
animal to?
Maintain their previous quality of life, rather than trying to annihilate
all the cancer cells and experiencing unacceptable side effects.
Cancer cells are cells that have escaped the body’s control and are?
Dividing and growing in an autonomous fashion.
Tumour development occurs in stages. List them?
Initiation
Promotion
Progression
What is the initiation stage of of tumour development?
The first step (due to one or more mutations) endows a somatic cell with
unlimited replication potential and/or other growth or survival advantages over
other cells
What is the promotion stage of of tumour development?
The second step gives the cell ability to out compete neighbouring cells leading to expansion into a tumour.
What is the Progression stage of of tumour development?
A third step provides the potential for malignancy by leading to invasion and
destruction of surrounding tissues and hence metastasis.
Discuss surgery for cancer?
Surgery has been the primary treatment modality for cancers for hundreds of
years, and is the keystone in the management in nearly all oral tumours.
Care has to be taken however to resect the tumour and all of its’ “root
network,” and a CT scan is very useful in identifying occult extension of the
tumour. When performing a tumour resection, the surgeon should first
consider the resection needed to remove all of the cancer tissue before
considering how to reconstruct the deficit. Any surgery planned first by the
possible reconstruction is much more likely to fail. I would encourage the
surgeon to mark or ink the margins, and to indicate (for example with the use
of a staple or suture) where areas of concern for incomplete excision lie, the
pathologist can inspect these areas for incomplete excision in some detail.
How does radiation therapy work?
Radiation Therapy
Radiation therapy (RT) is the second oldest treatment for cancer, and is also
a local therapy (treating one site in the body, rather than acting systemically).
RT seeks to damage cellular DNA, such that when the cell tries to divide it will
be unable to replicate its genetic material and undergo a “mitotic death.” The
sensitivity of a cancer to radiation depends on the tissue in question (some
tumours are much better able to repair radiation damage than others) and the
sheer bulk of the tumour. The simplest way of improving radiation sensitivity
is to surgically “debulk” the tumour since this will increase the proportion of
cells which are actively-dividing (and are therefore radio-sensitive), but
chemotherapy drugs (for example carboplatin) can also be used as “radiation sensitizers”) since these drugs will potentiate DNA damage and impede the
action of DNA-repair mechanisms.
What are the two types of radiation therapy?
Definitive
Palliative
What are definitive radiotherapy protocols?
Definitive protocols aim to cure the tumour, and involve hyperfractionation (giving lots of small doses of radiation;
typically 12-20 doses, often on at least three days a week for several weeks consecutively and reaching a total dose over 40Gy). Definitive treatments can cause acute side effects (for example mucositis of mucous membranes and
dry desquamation of skin). These adverse effects are related to the radiation
dose and dose interval. Although unpleasant, they are nearly always
manageable with appropriate supportive care and rapidly resolve when
treatment ceases.
What do palliative radiotherapy protocols aim to do?
Palliative radiation protocols aim to control pain and inflammation associated
with the tumour and involve hypofractionation (typically giving 2-4 large doses
of radiation). It is important to know whether a proposed radiation treatment
will be palliative or definitive, since palliative protocols will have negligible anticancer effect, instead they seek to control pain and inflammation only. Such
protocols rarely cause acute toxicity, and are cheaper and easier to perform,
however the hypofractionation of radiation poses a much greater risk of
delayed radiation toxicity, usually occurring at least 6 months after RT is
administered (often at least 1 year later). Delayed toxicities typically involve
necrosis of late-responding tissues (for example bone, or nervous tissue), or
fibrosis (for example strictures in the gastrointestinal tract); these adverse
events are usually catastrophic and often result in euthanasia of the animal
concerned. Despite the potentially-devastating nature of late toxicities
however, palliative radiation protocols are very effective means of pain
control, and can be very safely used in true “hospice-care” cases where the
life-expectancy of the animal is less than 6 months.
How do cytotoxic drugs work?
Cytotoxic drugs work similarly to RT in that they damage DNA such
that the cell is unable to replicate genetic material, or sometimes interfere with
the machinery of cell division directly.
What are the two groups cytotoxic drugs are divided in to?
The cell-cycle specific drugs (where the only susceptible cells are those at a
specific point in the cell cycle), or cell-cycle non-specific drugs (where all cells are susceptible but the lethal effect is only realised when the cell tries to divide).
Traditionally, cytotoxic drugs are given at the “maximum tolerated
dose” (MTD), and repeated as soon as possible after healthy tissues have
recovered. This kind of dosing works best where a large proportion of the
cancer cells are in the?
Cell cycle, thus is most effective in lymphoid
malignancies in dogs and cats.
Why are oral tumours more difficult to treat with cytotoxic drugs?
Oral tumours (mostly) have a much smaller
proportion of cells within the cell cycle and so their response is typically much
less dramatic. Similar to RT, the chemo-responsiveness of a tumour can be
improved by surgically debulking so that a greater proportion of remaining
cancer cells will enter the cell-cycle and become sensitive to drugs.
The most important example of anti-angiogenic therapy in
veterinary medicine is?
Metronomic chemotherapy and this has been shown to
be effective in some situations where MTD (maximum tolerated dose) chemotherapy is ineffective!
Metronomic chemotherapy has subsequently been shown to control the
activity of?
T-regulatory lymphocytes (thus allowing a stronger anti-cancer
immune response) as well as the anti-angiogenic effect.
Some of the tyrosine
kinase inhibitor drugs can also be used, off-license, to inhibit important cellsignalling pathways involved in angiogenesis. Give some examples?
For example:
toceranib, “Palladia” will inhibit the receptor for vascular endothelial growth factor, VEGF,
and masitinib, “Masivet” will inhibit the receptor for platelet-derived growth factor, PDGF, both important angiogenic ligands.
List small molecule inhibitors
(SMIs) chemotherapy drugs?
toceranib, masitinib and many others
All anticancer drugs affect cell division, aiming for greatest effect in the
tumour, but adverse effects are seen in tissues where cells are constantly
dividing, principally in the?
Gastrointestinal tract and in the bone marrow.
Thus, gastrointestinal upsets and bone marrow suppression can occur to a greater
or lesser degree with any medical anticancer treatment.
Discuss hair changes in dogs and cats undergoing cancer treatment?
Alopecia is also a
problem in people but at the doses used in veterinary medicine this is seldom
a problem; cats commonly lose whiskers however and long-haired breeds of
dog often experience a change in coat quality. Poodles and other breeds who
need to be “stripped” will often go temporarily bald.
How do nausea and vomiting happen with chemotherapy treatment?
First, certain drugs are
recognised by the brain’s chemoreceptor trigger zone as foreign poisons and trigger the vomit reflex while they are being given (for example carboplatin or
doxorubicin).
Secondly, all drugs will, to a less or greater degree, impede the
continuous replacement of the gastrointestinal lining, leading to malabsorption
and vomiting or diarrhoea 2-4 days after drug administration.
How is haematology effected during chemotherapy?
Myelosuppression is usually evident first in the neutrophils (fastest half-life of
all cells in the bone marrow) and secondly in the platelets (second fastest
half-life). Since red blood cells have a long-life (60-80 days in cats, 80-120
days in dogs) and are replaced slowly, an anaemic animal (with normal
platelets and neutrophils) is unlikely to have become anaemic due to the
chemotherapy! Frustratingly, adequate numbers of neutrophils and platelets
are needed to stop opportunistic infection of the body by bacteria and
spontaneous haemorrhage respectively. Thus, during a chemotherapy
treatment we pay close attention to these cell lines for two reasons; first as a
sentinel of the level of myelosuppression we are causing and secondly to
make sure we are not endangering the patient’s life!
What is cyclophosphamide?
Cyclophosphamide is an alkylating agent. Alkylating agents are oral oral
drugs (cyclophosphamide is also available as solution for injection) and are
cell cycle non-specific; they will alkylate the DNA of ALL cells, however the
lethal effect is only realised when the cells try to divide.
What can happen after being on alkylating agents (cyclophosphamide) for a long time?
After being
on any alkylating agent for a long time, permanent exhaustion of the bone
marrow can be seen (usually manifest as thrombocytopaenia or
neutropaenia). Cyclophosphamide is relatively sparing of platelets however,
in contrast to other drugs of it’s class. Myelosuppression with certain drugs
(for example melphalan and lomustine) can be particularly severe and
unpredictable in cats.
All alkylating agents cause minimal gastrointestinal effects and their oral
nature makes them popular with owners (though not necessarily
inexpensive!). Drug specific side-effects are important, for example:
cyclophosphamide can cause a debilititating sterile haemorrhagic cystitis; this
will occur in 15-20% of dogs receiving cyclophosphamide in a metronomic
fashion.
What is metronomic therapy?
Metronomic therapy is a new type of chemotherapy in which anti-cancer drugs are administered in a lower dose than the maximum tolerated dose repetitively over a long period to treat cancers with fewer side effects.
What is the only platinum agent in use?
Carboplatin is the only platinum agent in common use.
How does the platinum agent carboplatin work?
It shares much in
common with alkylating agents, having cell-cycle non-specific effects and
potentially cumulative toxicity.
What are the side effects of the platinum agent carboplatin?
It can cause acute nausea (mediated through
effects on the chemoreceptor trigger zone) and can cause cumulative renal
toxicity but is otherwise well tolerated.
How is carboplatin (platinum agent) commonly delivered?
It is given as an intravenous infusion
and is occasionally used as intracavitatory treatment for diffuse disease (for
example carcinomatosis or mesothelioma)
What is Doxorubicin and how does it work?
Doxorubicin has a number of mechanisms of action, both cell-cycle specific and non-specific. As such it is a broad-spectrum chemotherapy drug and used for a large number of cancers.
What are common and more dangerous side effects of Doxorubicin?
It can cause cumulative cardiotoxicity in
dogs, and cumulative nephrotoxicity in cats however it’s most important, dose limiting adverse effect is gastrointestinal toxicity. It is given by intravenous
infusion, is a substrate for the MDR1 mutation and can cause acute nausea
(as well as the devastating gastrointestinal toxicity resulting to the damage to
the gastrointestinal epithelium). Doxorubicin is also the most potent vesicant
of all chemotherapy drugs. If it is given subcutaneously then an antidote,
“dexrazoxane” exists; prompt administration of dexrazoxane after a
doxorubicin extravasation can often prevent amputation!
Doxorubicin & anthracyclines e.g.
Mitoxantrone
Epirubicin is a very similar drug to?
doxuribicin
Mitoxantrone is like doxorubicin but is not considered to have what?
The canine cardiotoxic effect or the
feline nephrotoxic effect. It is also not a vesicant drug and has even been used for intra-cavitatory chemotherapy. It is a much depleted range of
mechanisms of action compared with doxorubicin however and so it should be
considered much less hard-hitting
Metronomic chemotherapy therapy consists of?
An NSAID and a low dose alkylating agent (like cyclophosphamide) both given orally, every day, at home.
What does metronomic chemotherapy aim to do?
This type of treatment
aims to inhibit angiogenesis and has immunomodulatory effects (helps
promote anti-tumour immunity by depleting the T regulatory lymphocytes).
What are the most common oral tumours, starting with most common?
Melanoma is the commonest, followed by squamous cell carcinoma,
followed by fibrosarcoma and acanthomatous ameloblastoma.
Osteosarcomas and round cell tumours occur rarely.
What is the common diagnostic route for an oral tumour?
The diagnostic
investigation is reasonably stereotyped, and involves haematology, serum biochemistry, urinalysis, imaging of the oral cavity and thorax, fine needle
aspiration of the local lymph nodes (bilaterally) and biopsy of the mass. Record extent of lesion from physical
examination
Accurately record extent of mass on
dental charts
Take measurements for WHO Stage. The
use of 3-dimensional imaging like CT is very useful since conventional
radiography will not detect osteolysis unless 40% of the bone cortex has been
destroyed.
What are the the necessary margins and
suggestions of sensitivity to different therapies of different oral tumours?
Discuss oral melanomas?
Melanomas of the oral cavity in dogs are aggressive tumours, with a high rate
of metastasis.
What are the survival times for oral melanomas?
Survival times for oral melanomas treated with surgery alone
range from 5-17 months, with 1 year survival rates 21-35%. If the local
disease in the mouth is adequately addressed, most dogs with oral
melanomas are later euthanased because of metastatic disease.
What is the best treatment for oral melanomas?
As for all oral tumours, local therapy is the keystone in good melanoma
management. Surgery is usually the first consideration but for locations which
are not amenable to surgery melanomas respond well (80% response rate) to
hypofractionated radiation therapy; often responses are complete (tumours
almost disappearing). Following surgery there are two main options for systemic management of potential metastatic disease in canine melanoma:
immunotherapy (Merial Melanoma Vaccine) and systemic drug therapy.
Discuss the considerations/limitations of oral surgery of Canine Oral Squamous Cell Carcinomas?
Managing the
local disease in the jaw can be difficult as surgical excision with adequate
margins is extremely hard to achieve in the oral cavity. For this reason,
surgery may be followed with radiation therapy to try to sterilise the surgical
margins. If surgery is not possible, radiation therapy can be used in the gross
disease setting; many SCCs of the dental arcades will respond well to
radiation however not perhaps to the same extent as melanomas, and a
hyperfractionated protocol is required (with consequent greater expense).
Discuss squamous cell carcinoma behaviour in areas that aren’t the gingiva or buccal mucosa?
SCCs of the tonsil are much more aggressive than those associated with the
gingiva or buccal mucosa. They are typically much more resistant to radiation
therapy and have a very high metastatic rate (approximately 73%). This
difference in aggression may not be directly related to the anatomic location;
tonsillar SCCs have shown to be much more likely to be of higher grade than
the SCCs of other areas in the mouth. Tongue-based SCCs are reported to
be intermediate in their aggression between the gingival SCCs and the
tonsillar SCCs.
What is the behaviour of oral fibrosarcomas?
Oral fibrosarcomas are the most invasive oral tumour. Up to a third of cases
metastasize (to local lymph nodes or lungs) but local disease is nearly always
the cause of euthanasia. Complete resection of such a tumour will necessitate
a radical rostral maxillectomy or mandibulectomy procedure, involving
removal of the tumour and at least 3cm of healthy “margins.” Early reports of
recurrence after this surgery stated a 40-60% local recurrence rate, more
recent reports are of 20-25% recurrence. For this reason, surgery is best
followed by adjunctive radiation therapy, even in the cases that are resected
with clean margins.
What are the previous other names for Acanthomatous Ameloblastomas?
Acanthomatous Ameloblastomas (AAs) are the tumours formerly known as
acanthomatous epulides, adamantinomas, or basal cell carcinomas.
What is the behaviour of Acanthomatous Ameloblastomas (AAs)?
These are benign tumours (not considered to have a metastatic risk), derived
from the periodontal ligament. What sets them apart from the peripheral
odontogenic fibromas (“POFs” previously referred to as fibromatous or
ossifying epulides), is that AAs invade and destroy bone, POFs don’t.
What are most oral tumours in cats?
Most tumours are oral SCCs, with fibrosarcomas making up the remainder.
What are the acute adverse side effects of radiotherapy?
What are the late adverse side effects of radiotherapy?
What are the benefits of metronomic chemotherapy?
Summarise the 3 types of medical cancer treatment?
- Conventional “MTD” chemotherapy
*
Kills dividing cancer cells
*
Usually a discrete course of treatment
*
Dose intervals dictated by Eme for healthy Essues to recover - AnEangiogenic therapy e.g. metronomic chemotherapy
*
Alters the microenvironment of the tumour (metronomic
chemotherapy also alters the immune response to promote anE
tumour immunity)
*
No defined stopping point
*
Intervals between doses are rarely needed - Small molecule inhibiEon e.g. MasiEnib (Masivet) or Toceranib (Palladia)
*
Interrupt specific molecular interacEons which are occurring in an
uncontrolled way to cause uncontrolled cell growth and
proliferaEon.
*
No defined stopping point
*
Intervals between doses are rarely needed
Summarise treatment of cancer:
*Consider natural selection & survival of the fittest to understand cancer behaviour.
*Read the pathological descriptions in pathology reports to predict tumour behaviour from first
principles.
*Treat pathology reports like all other diagnostic tests!
*Onco-surgery is a specialised discipline; although neoadjunctive chemotherapy can shrink a
tumour, the most malignant cells are the most peripheral!
*Palliative & definitive RT protocols are available, and radiation response is dictated by the tissue
in question and the size of the mass.
*Medical therapy should be considered for metastatic or systemic disease; conventional MTD
chemotherapy may not be optimal for solid tumours and use of anti-angiogenic techniques and
small molecule inhibitors have found some support.
*The optimal medical treatment for a lot of solid tumours has yet to be established but it may
involve combination of MTD, antiangiogenic or small molecule treatments.
*Manage cancer as you would any chronic disease!
How do you WHO stage a mass?
What is a Canine Peripheral Odontogenic
Fibroma?
Surgical resection without bone
removal – 0-17% local recurrence
Radiation therapy: 3 year disease
control in 86%
What are the common side effects of medical anti-cancer therapy?
Summarise cyclophosphamide?
Summarise chlorambucil?
Summarise Doxorubicin?
Summarise carboplatin?
