Download adverse effects of chemotherapy

Lecture 3 : Complications of chemotherapy in the dog and cat
The primary target for most anticancer agents is DNA, preventing production of RNA and
proteins coded by the DNA. The effect is decreased ability of tumor cells to replicate, and
ideally, cell death. Unfortunately, rapidly proliferating normal cells such as bone marrow
progenitor cells, gastrointestinal epithelial cells, hair follicles and germ cells can also be
adversely affected by chemotherapy drugs. Toxicities to normal tissues limit the dose of
drugs which can be given to patients. Therapeutic index is the dose of a drug required to
produce a given level of damage to normal tissues divided by the dose of the drug required
to produce anticancer effects. Optimizing the therapeutic index is the goal of modern clinical
chemotherapy.
Therapeutic Index = Dose of drug required to produce a given level of damage to normal tissues
Dose of drug required to produce anti-cancer effects
The main problems encountered in chemotherapy of lymphoma patients are adverse effects
of therapy or emergence of resistance and relapse.
Avoiding chemotherapy complications relies on predicting what might go wrong. As
chemotherapy drugs affect dividing cells, many agents have adverse effects on the normal
tissues where a high proportion of cells are dividing: the most important of these are the
gastrointestinal tract (GI) and the bone marrow (BM) as described above. In addition to
these commonly affected tissues, individual drugs have individual toxicities. Drugs in the
same class, as defined by their mode of action, may have different toxicities. The toxicity
profiles of agents differ in cats and dogs, and some breeds are at risk of increased toxicity
from certain agents. The dosage of drugs given, the route of administration and the timing
of dosages (relative to previous drug administration) may also affect toxicity. Poorly planned
or executed chemotherapy can also result in treatment failure and early development of
drug resistance, particularly in lymphoma.
Established protocols provide the best basis for chemotherapy treatment, and should be
followed whenever possible. Continuing to administer ineffective drugs after relapse and
tumour progression places the patient at risk of toxicity with little potential benefit and
should be avoided, especially when drugs with potentially cumulative toxicities are used.
The consequences of dose alterations (increases or decreases) should also be carefully
considered.
Myelosuppressive potential of common anti-neoplastic agents
(neutrophil count at nadir)
Severe
Moderate
Mild-none
(<1,000 neutrophils/L)
(1-2,000 neutrophils/L)
(>2,000 neutrophils/L)
Carboplatin
Actinomycin-D
Chlorambucil (Leukeran)
CCNU (Lomustine)
Cisplatin
Corticosteroids
Cyclophosphamide
Cytosine Arabinoside
L-asparaginase
Doxorubicin
Hydroxyurea
Vincristine
Mitoxantrone
Melphalan (Alkeran)
Vinblastine
Emetic potential of common anti-neoplastic agents
High
Medium
Low
Cisplatin
Actinomycin
Chlorambucil
Streptozotocin
Carboplatin
Lomustine
Vincristine
L-asparaginase
Vinblastine
Cyclophosphamide
Cytosine arabinoside
Melphalan
Methotrexate
Mitoxantrone
ADVERSE EFFECTS OF CHEMOTHERAPY
Cytotoxic drugs have a lower therapeutic index than most other drugs used in veterinary
medicine. As cytotoxic drugs kill dividing cells, the normal tissues which are affected by
these drugs tend to be those which are rapidly dividing. Thus the normal tissues which are
most affected by cytotoxics are the bone marrow and the gastrointestinal tract. Some
agents have other adverse effects on specific organs. In addition to these specific toxic
effects some drugs are associated with immediate adverse reactions which are a result of
their biochemical nature rather than their action against tumours. Both you and the client
must be aware of the potential side effects of the drugs you are using.
The most commonly used drugs in lymphoma patients are vincristine, cyclophosphamide
and prednisolone in COP regimens; and, in addition to these drugs, doxorubicin/epirubicin,
(L-asparaginase) and antimetabolites in multidrug regimens like the Madison Wisconsin
protocols. The drugs in the D-MAC and LMP protocols are also mentioned.
Vincristine: vincristine is a severe perivascular irritant, and should be administered through
a cleanly placed intravenous catheter which is flushed with saline prior to withdrawal.
Strenuous efforts should be made to avoid extravasation. In the event of suspected
extravasation, a hot compress should be applied immediately. Hyaluronidase (300units
diluted in 6ml of 0.9% saline, administered circumferentially to extravasations site,
immediately then weekly) may limit tissue necrosis and promote recovery. Topical DMSO
may also then be applied by the owner at home.
Vincristine is generally not very myelosuppressive, though dogs receiving the higher end of
the dose range (0.7-0.75mg/m2) may occasionally become neutropenic 4-7 days after
administration. Gastrointestinal side effects are generally uncommon, though some animals
may not eat their food on the evening of drug administration.
Vincristine has its effects against tubulin, and neuropathies (mainly sensory) are reported in
people. In dogs, the autonomic nervous system may be affected and constipation or ileus is
occasionally seen.
Some Collies, Collie crosses and other individuals have mutations of the MDR1 (multidrug
resistance 1) gene and may show toxicity with vincristine (and some other drugs) at lower
than standard doses, and severe toxicity at standard doses, necessitating dose modification.
It is sensible to start at the lower end of the dose range in Collies and establish the maximum
tolerated dose on an individual basis. A screening test is available at Washington State
University: however, other genes may also be involved in sensitivity so a normal result does
not preclude toxicity.
Cyclophosphamide can cause gastrointestinal side effects such as vomiting or diarrhoea 1-3
days after treatment, particularly after bolus dosing. It may cause myelosuppression
(neutrophil nadir 5-7 days after bolus administration). Haematology must be checked
immediately prior to every bolus dose of cyclophosphamide, and at appropriate intervals on
low dose regimens. A particularly troublesome side effect of cyclophosphamide is
haemorrhagic cystitis: in dogs, this affects 10-15% of patients. Acrolein, a metabolite of
cyclophosphamide, causes haemorrhagic cystitis. Urinalysis (dipstick analysis of a voided
sample for evidence of haemorrhage) should be carried out every 2-3 weeks on low dose
regimes, and prior to every bolus on high dose COP/multidrug regimens. Detection of a
subclinical problem and cessation of therapy can avoid clinical signs, so urine monitoring is
mandatory. When bolus doses are used, risk may be reduced by administering furosemide
or MESNA. On low dose regimes, give the drug in the morning and, where possible, pair this
with corticosteroid administration. With either regime, patients should have access to ad lib
water and be encouraged to drink and given frequent opportunities to urinate after drug
administration. If blood is detected in the urine or the dog develops any signs of cystitis,
cyclophosphamide should be stopped (and replaced with melphalan or chlorambucil).
Haemorrhagic cystitis is debilitating for patients and frustrating for owners, and may take
weeks to resolve. In slow to resolve cases, DMSO flush is of benefit: 10ml of medical grade
50% DMSO is diluted with 10ml of water for injection. The bladder is emptied and the
diluted DMSO instilled. After 20 minutes, the DMSO is withdrawn. DMSO treatment can be
repeated after a week. Anti-inflammatories are of benefit. The role of n-acetyl glucosamine
in treatment of haemorrhagic cystitis is unproven. It is rare in cats.
Prevention may be associated with treatment with furosemide at a dose of 2.2 mg/kg IV
once, at the time of cyclophosphamide administration. This causes a forced diuresis and
forced voiding of the toxic metabolites. The same effect may occur if an animal is already on
a prednisolone containing protocol. Cyclophophosphamide can also be given early in
morning and the pet allowed to drink and urinate often over 24h.
In cats, cyclophosphamide can cause reduced appetite, thought to be due to altered taste
and/or subclinical stomatitis. It is also associated with whisker loss, though this tends to
occur gradually and patients adapt. Haemorrhagic cystitis is rare in cats and is not generally
closely monitored for, but owners should be aware and monitor for clinical signs.
Prednisolone has a number of problematic effects in lymphoma patients. Iatrogenic
hyperadrenocorticism is potentially very problematic. Dogs with marked polyphagia may
cause problems by raiding bins, stealing food from children and so on. In addition, obesity is
a problem and must be counselled against overfeeding the patient. Polyuric dogs may get
owners up during the night, which is intolerable long term. Owners must be warned about
polyphagia and polyuria. Prednisolone can also cause gastrointestinal ulceration, and has
rarely been associated with pancreatitis. Multidrug regimens tend to cease steroid therapy
after the first few weeks.
L-asparaginase is used inconsistently during induction in multidrug regimens. As an enzyme,
it is a foreign protein. To reduce the risk of an anaphylactic reaction, the drug is given
intramuscularly rather than intravenously. PEGylated L-asparaginase has reduced
immunogenicity but the pharmacokinetics are also altered and it is not readily available.
Repeated administration of L-asparaginase is thought to be associated with a higher risk. L-
asparaginase has also been associated with diverse effects on protein synthesis including
coagulation disturbances in humans. It has rarely been associated with pancreatitis.
Doxorubicin or epirubicin are used interchangeably in treatment of lymphoma. Epirubicin is
a structural analogue of doxorubicin, but is much less cardiotoxic in dogs. Both are very
severe perivascular irritants, and the complications of extravasation can be disastrous (limb
amputation or euthanasia). Drugs should be administered through a cleanly placed, first
stick catheter. Patients should be supervised throughout infusions, and injection/infusion
stopped immediately if there is any local swelling, or if there are signs of discomfort, or
changes in resistance to injection or rate of infusion. The catheter must be flushed through
with saline prior to withdrawal to ensure no drug is dragged through the tissues on
withdrawal. In the event of suspected extravasation, a cold compress should be applied
immediately. Hyaluronidase may reduce the risk of severe tissue injury as above, and topical
DMSO may then be applied by the owner at home. Dexrazoxane is used for anthracycline
extravasations in humans under strict guidelines.
Anaphylaxis/hypersensitivity is also occasionally seen after administration of doxorubicin
and other anthracyclines, using within a few hours of administration. Premedication with
chorpheniramine (0.5mg/kg i.m.) is recommended prior to doxorubicin (but not epirubicin).
Hypersensitivity reactions have been rarely reported and it is recommended that patients
receiving doxorubicin are premedicated with an antihistamine (usually chlorpheniramine).
Another potential problem during drug administration is cardiac dysrythmias: pulse should
be monitored throughout infusion and ECG must be available. The risk is reduced if the drug
is infused over approximately 30 minutes.
These agents are more emetic than the other commonly used drugs, and animals that have
vomiting or are off their food post treatment should be treated with antiemetics
(maropitant or metoclopramide: see below) ideally on the day of treatment and for three
further days. Myelosuppression may occur and the nadir is generally 5-10 days after
administration.
Doxorubicin and epirubicin may cause an irreversible dose dependent chronic/cumulative
cardiotoxicity in dogs. The cause is multifactorial but mostly related to free radical damage
to myocardiocytes and high peak serum concentrations of drug. The maximum cumulative
dose of doxorubicin for dogs is 240mg/m2 (8 standard doses) but many dogs will show
changes in myocardial function at much lower doses. Echocardiographic evaluation prior to
the first treatment and then at the third and each alternate treatment is recommended as a
minimum. As a broad rule, avoid these drugs if the left ventricular fractional shortening is
less than 27%, or the ejection fraction is <50%. Epirubicin is less cardiotoxic: patients are still
monitored in the same stringent manner. Dogs that develop cardiomyopathy do not
respond to traditional medical management and invariably die rapidly of irreversible cardiac
failure.
Cytosine arabinoside/methotrexate: as expected, the main adverse effects of these S phase
specific agents are on the rapidly dividing cells in the gastrointestinal tract and bone
marrow. Gastrointestinal side effects and/or myelosuppression are relatively common.
Occasional animals develop severe GI toxicity after methotrexate administration. Cytosine
arabinoside is rarely reported to cause anaphylaxis.
COMMON SIDE EFFECTS
1. Gastrointestinal (GI) toxicity
The mechanism of GI toxicity is multifactorial and includes direct damage to GI mucosal
epithelial cells and stimulation of the chemoreceptor trigger zone (CRTZ - floor of 4th
ventricle) via neurotransmitters. Stimulation of the medullary emetic center via
neurotransmitters (especially neurokinins (NK1) can also occur. Abolishing vomiting at the
level of the emetic center likely has a role in controlling emesis due to a variety of causes.
Local GI tract irritation can also stimulate GI neurotransmitter receptors and subsequent
activation of the vomiting center via vagus and sympathetic nerves. The neurotransmitters
include serotonin, neurokinin 1 (substance P like), dopamine, histamine and noradrenaline.
Serotonin released from enterochromaffin cells of the GI tract can lead to acute vomiting.
Neurokinins (substance P) found in nuclei of vomiting center plays a central role as a
neurotransmitter in sensory neurons and also in the afferent pathway of the vomiting reflex.
Nausea and anorexia
Some agents can cause nausea during or soon after administration, due to central effects on
the chemoreceptor trigger zone. Later nausea and vomiting may be due to direct GI tract
toxicity. Nausea may be reduced/prevented by pre-treating patients with maropitant orally
(2mg/kg p.o.) the night before or by injection prior to chemotherapy (1mg/kg s.c.), and by
continuing with treatment orally once daily for up to 4 days if the patient is off his/her food
or there is vomiting. (Metoclopramide is unlicensed in the UK, but has a prokinetic effect
and useful as a constant rate infusion for animals with GI toxicity). In cats, cyproheptadine
(Periactin®, 2-4mg/cat q12-24h) can be fairly effective to treat anorexia and mirtazapine
(alpha-2 antagonist, nonselective serotonin antagonist – cats 1/8 to 1/4 of 15-mg tab q 3d) is
a new treatment for which more information is needed before recommending its general
use.
Gastrointestinal Toxicity
The direct effects of cytotoxic drugs on the dividing cells of the oral basal epithelium, gastric
mucosa and intestinal crypt cells may cause clinical signs, usually 1-5d after treatment
(uncommonly up to 10d after treatment). The pattern is most often anorexia on day 1 after
treatment, then vomiting or diarrhoea at day 2-3. Symptomatic treatment is required:
(intravenous fluids, electrolytes, antiemetics, gut protectants, acidity regulators and
antibiotics) and should be aggressive. If GI toxicity results in epithelial damage then there is
a greater risk of sepsis should neutropenia develop, as the gut mucosa is a less effective
barrier to bacterial translocation. GI signs are also seen as a sequelum to myelosuppression.
Vomiting – mild, self-limiting
 Withold food for 12-24h and perform water only trial; introduce bland foods/small
meals.
Diarrhoea – mild, self-limiting
 No food x 12h, introduce bland food
 Metronidazole (Flaygl®, 15 mg/kg q12h PO), effective for hemorrhagic colitis
associated with doxorubicin, epirubicin
Severe Vomiting or Diarrhoea
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Hospitalisation for fluid, antiemetic, prophylactic antibiotics and possibly nutritional
support.
GI symptoms assoc with a fever may be more serious and can be the first signs of
sepsis.
Fluid support
Antiemetics
o Metoclopramide – 1-2mg/kg IV as a CRI over 24h is preferable.
o Maropitant (Cerenia®) 1 mg/kg SQ q 24h x 5d or 2.2 mg/kg PO q24h x 5d
o Chlorpromazine (Thorazine®) – 0.5 mg/kg q6h SQ if persistent vomiting.
o Serotonin antagonists (Ondansetron, Zofran®, 0.1 -1mg/kg q12-24 IV, PO;
o Dolasetron, Anzemet®, 0.6-1 mg/kg q24h IV).
o Butorphanol (Torbugesic®) – 0.4 mg/kg IM administered once
H2-antagonists – ranitidine (2mg/kg BID IV, PO) has prokinetic activity and might
have a role for ileus secondary to vinca alkaloids.
Antidiarrhoeals
o Loperamide (Imodium®, 0.08 mg/kg q6-8h)
o Consider opportunistic infections secondary to altered GI flora in patients
with prolonged diarrhea or diarrhea nonresponsive to therapy- colitis –
metronidazole (Flaygl®, 15 mg/kg q12h PO), sulfasalazine
Small bowel diarrhea – rarely r/o salmonella, campylobacter
Pancreatitis is reported as an idiosyncratic toxicity with many drugs, including L-asparaginase
and prednisone/prednisolone.
2. Myelosuppression
Haematology should be carried out at appropriate intervals depending on any low dose
regime and prior to every bolus dose of myelosuppressive agents.
Bone Marrow Toxicity
In healthy adults there are many myeloid stem cells in a quiescent state, which are
protected from cytotoxic drugs, but they are triggered into active proliferation when there is
any increased demand. Marrow transit time for neutrophil is about 4 days, and in marrow in
healthy animals there is a storage pool with about 5 days worth of neutrophils. If neutrophil
production ceases, the patient runs out in about 5 days. After a bolus dose of most drugs,
the neutrophil nadir occurs 5-7 days later. Some drugs have a delayed effect (melphalan,
lomustine) and this effect may also be cumulative. Patients that have problems with
particular drugs after bolus doses sometimes cope better with low dose metronomic
therapy (e.g. giving low dose cyclophosphamide every other day instead of using a bolus
dose every 21 days) , though this may also impact on tumour cell kill and predispose to
resistance. Neutropenia is usually the most important bone marrow toxicity, but
thrombocytopenia is seen due to melphalan, actinomycin, and lomustine and cytosine
arabinoside. BM toxicity will be worsened if there are inadequate recovery periods between
myelosuppressive drugs (usually 21 days is allowed). For patients with delayed
myelosuppression (e.g. after carboplatin administration) a 4 week dosing interval may be
required to allow marrow recovery and prevent cumulative toxicity.
Some considerations:
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The combination of vincristine and L- asparaginase when given within 24 hours of
each other will often cause significant myelosuppression (reduction in neutrophil
count).
Carboplatin: variable nadir (dogs, 7-28 days; cats, 14-21days).
Lomustine (CCNU): cats, variable nadir (7-28 days).
Prior therapy can influence neutrophil nadir and recovery
Lomustine and Melphalan (especially when given sequentially), can also affect
platelet production, sometimes leading to prolonged or permanent
thrombocytopenia
Carboplatin: dogs, severe thrombocytopenia can occur
Life span of erythrocytes in circulation is 110-120 days (dog) and 70 days (cat)
Mild anemia during chemotherapy is common – consider treatment associated
gastrointestinal blood loss or anaemia of chronic disease
Anemia is rarely severe and rarely of clinical significance
Individual patient variation
Regular haematological monitoring (at least prior to every bolus dose and strategically in
metronomic therapy) and monitoring of trends is essential.
The clinically significant effects of myelosuppression are:
•
Neutropenia (a neutrophil count of less than 3x109/l in a dog, 2.5x109/l in a cat)
•
Thrombocytopenia (a platelet count of less than 70x109/l)
Anaemia is rarely clinically significant and is often indistinguishable from anaemia associated
with the neoplasm itself (chronic disease). Chronic GI haemorrhage is a potential
complication in patients on long term steroid therapy.
Haematological monitoring is vital in all cases receiving potentially myelosuppressive drugs.
Thrombocytopenic patients should be kept quiet until platelet count recovers. It is relatively
unusual to see thrombocytopenia without neutropenia.
Neutropenic Patients
There is no need to panic, particularly if the neutropenia is picked up on haematological
evaluation prior to the next scheduled treatment and the animal is well.
Asymptomatic, Afebrile Neutropenic Animals
If the neutrophil count is less than 1x109/l, the animal may be treated as follows:
•
Trimethoprim sulphonamide (TMPS) or another broad spectrum antibiotic
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Sulphadiazine-trimethoprim (Tribrissen®, 15 mg/kg q12h PO x 5-7d)
Clavulanate potentiated amoxicillin (Synulox® 13.75mg/kg PO BID)
Discontinuation of the offending drug until neutrophil numbers recover
•
If possible, the owner should check the animal's temperature 2 or 3 times a day
If the neutrophil count is 2 to 3x109/l then discontinuation of the drug until the count
recovers will suffice. If it is 1 to 2x109/l then antibiotics may be given at the discretion of the
clinician e.g. if there is a pre-existing focus of infection, but should not be given routinely.
TMPS combinations are recommended for prophylaxis as although they affect the aerobic
intestinal flora, the anaerobes remain, and these bacteria are involved in local defence in the
intestines. TMPS combinations also have broad spectrum bactericidal activity, and do not
have the resistance issues associated with enrofloxacin. Some oncologists prefer to use
clavulanate-potentiated amoxicillin as their first line drug because of the potential toxicities
associated with TMPS combinations.
Pyrexic, Neutropenic Patients
These patients are a medical emergency, but in most cases, pyrexia resolves within hours
and circulating neutrophil numbers normalise within 24-48 hours. Patients must be
supported aggressively as well as treated with antibiotics. Chemotherapy-induced mucosal
damage allows invasion by opportunistic gram negative bacteria (Escherichia coli, Klebsiella,
Pseudomonas). Infections with gram-positive cocci and anaerobes are less common but can
occur e.g. associated with staphylococci. The clinical signs of neutropenic sepsis include
fever, weakness, shaking/shivering, brick-red mucus membranes, tachycardia, tachypnoea,
coughing, vomiting and diarrhea. Interestingly, the cardinal signs of inflammation may be
absent due to insufficient numbers of neutrophils to participate in the inflammatory
process; however it is most common for patients despite extremely low neutrophil numbers
to be febrile at presentation. Neutropenic sepsis represents a medical emergency.
The following steps should be taken:
•
All cytotoxic drugs except corticosteroids should be immediately discontinued
▪
The patient should be barrier nursed ideally in isolation, and all sampling, catheter
placements etc carried out aseptically
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Supportive therapy: intravenous fluids, electrolytes, glucose as indicated
•
Bactericidal antibiotics: TMPS, fluoroquinolones (enrofloxacin) (can alter later based
on sensitivity). Enrofloxacin is preferable to gentamicin (historically recommended)
due to the nephrotoxicity of gentamicin
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5-7 days of antibiotic therapy after clinical recovery and restoration of neutrophil
numbers.
What about the use of Granulocyte Colony-Stimulating Factor?
G-CSF (Filgrastim, Neupogen®) regulates production, maturation and function of neutrophils.
Its primary use in human chemotherapy patients is to administer G-CSF 24-48h after highly
myelosuppressive chemotherapy to decrease the duration and depth of neutropenia. This
allows dose intense chemotherapy of human patients, particularly if they are elderly by
providing support to the bone marrow. The neutropenic state causes upregulation and
production of endogenous G-CSF so serum concentrations are actually higher than before
neutropenia, however, dogs with cancer will have lower G-CSF concentrations at their nadir
than a healthy dog that was given chemotherapy. Evidence suggests that G-CSF can actually
improve neutrophil function therefore giving G-CSF to neutropenic patients that are already
febrile might speed neutrophil recovery and reduce hospitalization. Unfortunately data from
the human literature does not show consistent clinical benefit and G-CSF is not always
recommended as an adjunct to empirical antibiotic therapy. Also, currently only human GCSF is available and dogs and cats might develop neutralizing antibodies if prolonged courses
are given (i.e. > 2-3 weeks). The dose for dogs and cats is 5 μg/kg SQ q24h for up to 5 days.
What Happens the Next Time?
When re-introducing a previously myelosuppressive drug a reduced dose rate is often
required. Remember all drug dose reductions reduce tumour cell kill. A 20% reduction in
drug dosage can result in a 50% reduction in tumour cell kill in some situations. Dose
reduction should be discussed with the owner: approaches include trying a 10% reduction in
the first instance, or reducing by 20% or 25% then increasing to 90% of initial dose if there is
no toxicity. In some cases the original planned dose will be tolerated by the patient once in
remission.
When drugs associated with previous GI toxicity are given again, supportive therapy should
be increased. Where there has been vomiting, should be treated with antiemetics
(metoclopramide or maropitant) ideally on the day of treatment and for three further days.
Where there has been severe GI upset, a dose reduction might be required.
Some individual animals do not cope well with particular drugs or dosage regimens, and
protocols should be tailored to suit. A dog on high dose COP that has problems after bolus
doses of cyclophosphamide may do better on low dose oral treatment at home, and a cat
that is inappetent after cyclophosphamide treatment may do better on chlorambucil or
melphalan.
3. Hair loss
Complete hair loss is very uncommon but can be seen in certain dog breeds. Typically
affected breeds have continually growing coats and include Poodles, Old English Sheepdogs
and some terrier breeds. More commonly slow hair regrowth and alteration in coat quality
in cats and dogs and whisker loss in cats are seen.
SPECIFIC TOXICITIES
Cardiac toxicity
Chronic cardiac toxicity has been associated with treatment with anthracycline drugs:
doxorubicin and epirubicin. See above.
Acute toxicity occurs during or shortly after treatment and is uncommon. It is non-dose
dependent. It occurs due to histamine-mediated catecholamine release from mast cells
during rapid drug infusion. The signs are acute arrhythmias, hypotension, collapse and other
signs of hypersensitivity reaction. This acute toxicity is almost completely eliminated if drug
is given slowly (1mg per min). In the event of an acute reaction occurring, discontinue the
infusion, administer dexamethasone (0.2mg/kg IV) and chlorpheniramine (4-8mg per dog
IM); wait 20 minutes and then restart the infusion at a slower rate.
To prevent cardiotoxicity being a problem, avoid use of doxorubicin if there is underlying
cardiac disease (myocardial disease, arrhythmias). A baseline echocardiogram is indicated
and essential in at risk breeds (Doberman, Boxer, giant breeds). Limit the cumulative dose to
150-180 mg/m2.Cardiac monitoring during infusion can be carried out using a stethoscope
and continuous ECG monitor. Cardiac troponin (cTnt) is a protein that mediates interaction
between actin and myosin. Measurements of troponin may allow for early detection of
myocardial injury caused by doxorubicin. More information is needed however based on
clinical research.
Dexrazoxane (Zinecard®) is an iron chelator (iron needs to be present for free radical
generation to occur that results in myocardial damage). This drug effectively reduces the
cardiotoxicity of doxorubicin however there is no benefit once cardiac damage has occurred
and the drug is expensive.
If a patient appears to have significant systolic dysfunction prior to commencing treatment
with potentially cardiotoxic drugs, the owner must be counseled on the risk-benefit ratio of
giving the medication and an alternative medication such as mitoxantrone or actinomycin D
may be indicated in place of doxorubicin or epirubicin.
Hepatic Toxicity
Lomustine may cause hepatotoxicity and liver enzymes should be monitored. This toxicity
may be idiosyncratic and can be fatal. Care should be taken with agents that undergo
hepatic metabolism (e.g. vincristine, doxorubicin, epirubicin) in patients with significantly
impaired liver function: these drugs will be metabolised less effectively and toxicity may be
increased, rather than there being a direct hepatotoxicity.
Nephrotoxicity
Anthracyclines (doxorubicin, epirubicin etc) are potentially nephrotoxic.
Hypersensitivity reactions
There are a number of different mechanisms for development of hypersensitivity reactions
due to chemotherapy administration. For L-asparaginase, a polypeptide of bacterial origin
(E.coli), the mechanism is stimulated production of IgE and other immunoglobulins that
mediate an acute type I anaphylactic reaction. Delayed reactions a few hours to several days
can occur. As the mechanism of the hypersensitivity reaction usually requires prior exposure
of the immune system to the protein, this rarely occurs on the first administration of the
drug. Cases however have been reported and this may be due to previous gastrointestinal
disease allowing translocation of small peptide sequences from E. coli in the gut. The risk of
reaction increases on second and subsequent administrations of the drug. For
doxorubicin/epirubicin, the reaction is not immunologically-mediated. Hypersensitivity
reaction is related to direct mast cell degranulation and histamine release if the drug is given
too quickly (see above).
Clinical signs of hypersensitivity reactions include pruritis, urticaria, cutaneous erythema,
agitation, head shaking, facial edema, vocalization, injection-site discomfort, vomiting,
diarrhea, hypotension and collapse. Treatment is outlined above. Premedication with
chlorpheniramine and dexamethasone 20minutes prior to drug administration may reduce
the risk of anaphylactic reactions developing.
RESISTANCE AND RELAPSE
It is imperative that you check that the animal achieves and maintains remission.
Complete remission (CR) means that there is no detectable disease. Lymph nodes should be
normal or subnormal in size, and of normal texture. Extranodal disease should be
undetectable. Even in complete remission many tumour cells remain.
Partial remission (PR) refers to a reduction in tumour volume of more than 50%. In PR there
is a huge population of resistant cells.
IF YOUR PATIENT IS NOT IN CR YOU MUST DECIDE HOW TO DEAL WITH YOUR RESISTANT
POPULATION OF CELLS: YOUR CHEMO IS NOT WORKING.
When relapse occurs, it is often possible to achieve a second remission. However, this
remission is invariably shorter than the first.
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Re-induction: for modern non-continuous regimens (e.g. Madison Wisconsin 24
week), simply starting at the beginning again is the usual approach.
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Re-induction plus additional drugs cytosine arabinoside, L-asparaginase (taking care
to avoid additive toxicities)
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Alter regime completely using drugs which have not been used before e.g.
doxorubicin/epirubicin instead of COP, D-MAC (dexamethasone, melphalan,
actinomycin D), lomustine after other protocols etc.
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Radiation therapy
Eventually, most dogs and cats develop multidrug resistance and will cease to respond to
any drugs.
OTHER PROBLEMS IN CHEMOTHERAPY OF LYMPHOMA
Alimentary Lymphoma
Lysis of GI tract tumours can result in perforation and peritonitis. Where there is a mass
lesion that is amenable to surgery this should be resected. Where there is extensive
intestinal infiltrate, chemotherapy should be initiated in a staggered manner to reduce the
risk of tumour lysis resulting in intestinal perforation. One method of doing this with e.g.
COP is to initiate vincristine therapy, then give cyclophosphamide on the third day and start
prednisolone therapy on the fifth. Remember absorption of orally administered drugs may
be poor.
Cutaneous Lymphoma
Standard chemotherapy regimens generally have poor response rates in cutaneous
lymphoma, and recent studies suggest lomustine is more effective. The role of retinoids
(isotretinoin/etretinate) in the treatment of cutaneous lymphoma remains controversial.
These agents have significant side effects in some patients, and are very teratogenic and
must not be handled by women of child bearing age. They may ameliorate clinical signs
(pruritus) but do not seem to produce true remission. Alpha interferons show promise for
cutaneous lymphomas, but only human recombinants are available.
Tumour Lysis Syndrome
Rarely, where there is a large tumour burden, sudden lysis of the neoplastic lymphoid cells
produces a hyperkalaemia and hyperphosphataemia (with resultant hypocalcaemia) which
can cause cardiac dysrythmias, or renal failure. Aggressive supportive care is required, with
frequent monitoring of electrolytes.
CNS/Renal lymphoma
It may be beneficial to include cytosine arabinoside in induction.