Download Lecture 2: Treating lymphoma in the dog and cat

Lecture 2: Treating lymphoma in the dog and cat
What are the prognostic factors for lymphoma in the dog and cat?
The importance of thorough evaluation of the lymphoma patient and comprehensive clinical staging
is borne out when considering the prognostic factors for this group of diseases.
Clinical stage
In the dog, there is a moderate association between clinical stage and disease outcome.
In some studies there has been no correlation demonstrated between clinical stage and likelihood of
achieving a complete remission on treatment; in other studies, patients of stage I-III responded
more favourably to treatment than those of stage IV or V. Duration of remission and survival time
has been shown to be longer in patients of stage I-III disease versus higher stages; other studies
suggest that stage IV patients did best. Dogs with stage I or II disease are rarely encountered but
may perform best in terms of duration of disease remission compared to other stages. As previously
described however, the aggressiveness of clinical staging (e.g. whether a blood smear or bone
marrow cytology is performed) has been shown to result in stage migration in the dog.
Only small studies are available in cats regarding prognostic value of clinical stage. However one
study showed a significant survival advantage in cats with stage I or II disease compared to those
with more advanced disease. However the heterogeneity of anatomic forms of lymphoma in cats
makes specific prognostication more problematic.
Clinical substage
There is a strong association between clinical substage of disease and outcome in the dog. Dogs with
substage b disease (clinical signs present) have a shorter remission duration and survival time
compared to those in substage a.
In cats, one study showed that patients with substage a disease had a median survival time of 9.5
months versus 3.5 months for patients with substage b disease.
Histological type
Several histological grading systems have been developed in an attempt to sub-classify lymphoma in
the dog, similar to methods used for human patients (Rappaport System, NCI-Working Formulation,
and Kiel Classification). Canine lymphoma is morphologically heterogeneous, diffuse and usually
intermediate to high grade (diffuse large cell, centroblastic, immunoblastic) and the subclassification of the disease has unfortunately failed to have significant impact on clinical decision
making regarding treatment or prognosis. Overall however, high grade disease is associated with a
high proportion of ‘cycling’ cells in the tumour, enhancing chemotherapy sensitivity and response
rates to treatment. Low grade lymphomas are rare in the dog, accounting for 5-10% of cases.
Response rates to high dose treatments tend to be lower than for their higher grade counterparts
however survival times in patients responding to treatment may be long due to the associated
indolent clinical course.
Very little information is available for cats however patients with a high proliferative fraction of their
tumour cells had longer survival times than those with low proliferative fraction.
T cell immunophenotype
Only 20-25% of lymphomas in the dog are T-cell type. Dogs with T-cell lymphoma appear to have
reduced response rates, remission durations and survival times versus their B-cell counterparts.
Hypercalcaemia
Dogs with hypercalcaemia are by convention considered to be in clinical substage b. 43% of dogs
with hypercalcaemia will have a cranial mediastinal mass and the presence of a cranial mediastinal
mass is prognostic for survival (mass present = 3 months vs. no mass = 9.5 months). Dogs with
hypercalcaemia are much more likely to be affected by lymphoma of T-cell origin and it may be this
that is the most important prognostic factor rather than hypercalcaemia per se.
Gender
Small studies suggest that female dogs have a more favourable prognosis than male dogs.
Body size
Small dogs may have a more favourable prognosis than large dogs due to increased dose intensity.
Pre-treatment with corticosteroids
Glucocorticoids should not be given to dogs with lymphoma if future combination chemotherapy is
planned. In two studies, prior treatment with prednisolone resulted in reduced remission duration
and survival times however the critical length of exposure time is unknown. There is little
information about the effects of previous steroid exposure in cats on response to chemotherapy.
Steroids have been shown to be potent inducers of P-gp expression and activity.
P-glycoprotein expression
P-glycoprotein expression and drug resistance: P-glycoprotein (gp170) is transmembrane pump that removes
xenobiotics from the cell cytoplasm. This effectively extrudes drugs from cancer cells thereby limiting the
cytotoxicity of the drug at its cellular site of action. The protein is expressed on various normal tissues that
include the kidney, liver, selected bone marrow cells and the blood brain barrier. Ivermectin sensitivity and
neurotoxicity in Collie dogs can be accounted for by their expression of mutant P-gp. Expression of P-gp gives
rise to the MDR or multidrug resistance phenotype. As the name suggests, the MDR state confers simultaneous
resistance to many different structurally unrelated drugs, including vinca alkaloids, epipodophyllotoxins,
anthracyclines, dactinomyicn and taxanes. Such drugs are typically derived from natural sources and are
hydrophobic but otherwise have few similarities in their mechanisms of action or chemical structures.
Resistance to chemotherapeutic agents is therefore potentially associated with drug induced over-expression of
P-gp.
Other proteins that are expressed and may confer drug resistance in the absence of P-gp over expression
include the multi-drug resistance related protein (MRP), the lung resistance related protein (LRP), DNA
topoisomerase mutations, dihydrofolate reductase, O 6- alkylguanine DNA alkyltransferase and apoptosis
resistance-related multidrug resistance.
The basic structure of the feline MDR1 gene has been sequenced and is essentially the same as that of
multidrug- resistance genes of other species. In vitro research has shown that expression of P-gp appeared to
be one of the mechanisms responsible for the development of multidrug resistance in feline lymphoma cell lines
and therefore it is likely that this is a mechanism of drug resistance in vivo.
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Cat?
Anatomic location
Leukaemia, diffuse cutaneous and alimentary and hepato-splenic forms of lymphoma are associated
with reduced response rates, disease free remissions and median survival times. In addition, a
number of case reports have demonstrated that dogs with cranial mediastinal lymphadenopathy
have shorter remission durations and median survival times. Involvement of the CNS usually carries
a poor prognosis due to difficulty in achieving drug penetration to ‘privileged’ anatomical sites.
Cats with nasal lymphoma appear to have longer remission durations and survival times compared
to cats with other anatomical forms of the disease. In a paper in 2009, the median survival time was
536 days.
Anaemia
The presence of anaemia has been linked to shorter remission durations.
Hypoalbuminaemia
In one study the presence of hypoalbuminaemia prior to treatment was a poor prognostic indicator.
Tumour proliferation markers
Monoclonal antibodies have been raised against several cell surface proteins associated with
markers of cell proliferation.
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

Proliferating cell nuclear antigen (PCNA) is a non-histone protein detected 1st in the mid-G1
phase of the cellcycle, reaching a maximum in S and declining in G2. It is not expressed in
mitosis.
Ki-67 is a nonhistone nuclear protein that is expressed in early G1,S, G2, and M phases of the
cell cycle.Silver staining of proteins associated with AgNORs of interphase chromosomes
may be used on cytologic or histologic preparations for assessment of proliferation rates. In
canine lymphoma, a high Ki-67 index was associated with a prolonged first remission
duration.
In normal cells, silver staining nucleolar orginising regions (AgNORs) are usually tightly
organized in nucleoli, whereas in malignant cells, they desegregate from the nucleoli and
tend to disperse throughout the nucleus. Because AgNORs are related to DNA synthesis and
metabolic activities, their size and number are used to reflect nuclear activity. The amount
of AgNOR increases progressively in cells from G0 to S phase. AgNOR numbers have been
correlated with response to chemotherapy in canine lymphoma.
Unfortunately in feline lymphoma there has been no correlation between proliferation indices and
response to chemotherapy.
Response to therapy
Intuitively, response to therapy may influence survival times in canine lymphoma patients due to the
direct impact on the owner’s willingness to persevere with treatment for the disease.
In cats, response to treatment has been found to be one of the few reliable prognostic indicators. In
a large study (n=145 cats) those achieving a complete remission had a disease free interval of 7.5
months and survival time of 8.5 months compared to 3 weeks and 7 weeks respectively for cats
achieving a partial remission. In some studies, cats that received doxorubicin as part of their
treatment protocol had longer disease remissions than those that did not.
FeLV status (cats)
In cats that tested positive for FeLV, the remission duration and survival time were 4 weeks and 5
weeks respectively versus 5 months and 6 months for those that tested FeLV negative.
Prognostic Factor
Clinical Stage
Clinical substage (a) or (b)
Histological Type
T-cell immunophenotype
Hypercalcaemia
Prior steroid treatment
p-glycoprotein expression
Anatomic location
Anaemia
Hypoalbuminaemia
Prognostic Factors in Canine Lymphoma
Remission Duration
Survival Time
I-II (best); I-III > IV or V
I-III > IV or V
7-12 m (a) 3-5 months (b)
8-18 months (a) 4-6 months (b)
Immunoblastic > other high
Immunoblastic > other high
grade types
grade types
Low grade lymphomas
Low grade lymphomas
responding to treatment have a responding to treatment have a
long clinical course
long clinical course
50-67% achieve remission vs.
50d (T-cell type) vs. 200d (B-cell
81-84% for B-cell type
type); only long term survivals
associated with B-cell type
Neg prognostic factor due to
Neg prognostic factor due to
association with clinical
association with clinical
substage b, T-cell
substage b, T-cell
immunophenotype, presence
immunophenotype, presence
of a cranial mediastinal mass
of a cranial meditational mass
and altered organ function
and altered organ function
(renal effects)
(renal effects)
110d (prior treatment) vs. 180d
(no prior treatment)
7.4m (p-gp expressed) vs. 12m
(p-gp not expressed)
Gastrointestinal tract: 26d
Gastrointestinal tract: 77d
(partial response to treatment) Hepato-splenic: 7d
vs. 86 days (complete response) Diffuse splenic: 1m
Cutaneous/epitheliotrophic:
Cranial mediastinal lymph node
96d, 106d
involvement: 6.4m (cranial
mediastinal LN enlargement, Bcell type) vs. 10.8m (no cranial
mediastinal LN enlargement, Bcell type)
3.4m (cranial mediastinal LN
enlargement, T-cell type) vs.
6.4m (no cranial mediastinal LN
enlargement, T-cell type)
6.2m (anaemic) vs. 11.4m
(normal haematocrit)
3.5m (low serum albumin) vs.
7m (normal albumin)
How is lymphoma treated?
Chemotherapy is the cornerstone for the treatment of lymphoma in dogs and cats. Untreated, dogs
affected with malignant lymphoma live an average of only 6 weeks once a diagnosis has been made.
In the UK, a survey indicated that 87% of small animal practitioners treated more than half of the
cases of lymphoma that they diagnosed. Most used a protocol based on 3 drugs – vincristine,
cyclophosphamide and prednisolone (COP protocol) and the remainder used prednisolone alone
with the exception of 2% who used doxorubicin as a first line therapy.
What are the principles of chemotherapy?
Goals
The goal of chemotherapy is to control cancer and prolong survival while maintaining a good quality
of life for the patient.
Combination chemotherapy has three additional aims:
 To maximise tumour cell kill with minimal associated toxicity by using a combination of
drugs with different mechanisms of action used at dosages as close to the maximum
tolerated dose as possible
 To target a heterogeneous population of tumour cells
 To slow the onset of drug resistance in tumour cells
Chemotherapy combinations use drugs that have demonstrated activity as single agents and are
used on a schedule that minimises the risk of overlapping toxicities.
Factors that affect the efficacy of chemotherapy
 The duration of tumour exposure to an effective concentration of drug (equivalent to
[concentration]drug x exposure time to drug)
 Intrinsic or acquired drug resistance
 Up-regulation of drug inactivating enzymes
 Impaired transport of drug into the cells
 Upregulation of drug detoxification pathways
 Dysregulation of apoptotic or cell proliferation pathways
Phases of a multidrug protocol
Treatment
Induction
Description
Intense initial
anti-neoplastic
treatment
Toxicity
High risk
Response
Greatest chance
of response
Consolidation
Unrelated drugs
effective after
induction
Less intense
course, using
induction drugs
Moderate risk
Further reduces
surviving cancer
cells
Slows time to
relapse
Unrelated drugs
used upon
Moderate to high
risk
Maintenance
Rescue
Lower risk
Lower chance of
response
Example
First 9 weeks of
Madison
Wisconsin
Protocol; first 4
weeks of high
dose COP
protocol
Decreased
administration
frequency vs.
induction phase
Alkylating agents
often used or
relapse
other
combination
protocols
Commonly used terms in chemotherapy
Therapeutic Index: 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
Induction therapy: The goal of induction therapy is to dramatically reduce cancer cell numbers and
ideally induce a complete remission.
Consolidation therapy: The goal is to continue to reduce tumour cell numbers and hopefully to
achieve a complete remission in patients that did not achieve complete remission on induction
therapy.
Maintenance chemotherapy: The goal is to maintain remission and prevent disease relapse.
Rescue therapy: The goal is to achieve reinduction of remission after disease relapse
Complete remission (CR): complete resolution of measureable tumour burden based on physical
examination, haematological and biochemical monitoring or diagnostic imaging.
Partial remission (PR): >50% but <100% resolution of measureable tumour burden based on physical
examination, haematological and biochemical monitoring or diagnostic imaging.
Stable Disease (SD): <50% resolution of measureable tumour burden based on physical examination,
haematological and biochemical monitoring or diagnostic imaging and <25% increase of
measureable tumour burden based on physical examination, haematological and biochemical
monitoring or diagnostic imaging and no new lesions.
Progressive Disease (PD) : >25% increase of measureable tumour burden based on physical
examination, haematological and biochemical monitoring or diagnostic imaging or the appearance of
new lesions.
Disease free interval: describes the time to progression of local or systemic disease after induction of
a CR with treatment.
Median survival time: describes the point at which half the patients have relapsed or died and half
are still in remission or are alive
Which treatment protocols should you choose for managing lymphoma in the dog and cat?
Lymphoma is one of the most responsive forms of cancer presented to the practitioner and is
therefore very rewarding to treat. It is extremely important however to counsel the client in detail
about the range of treatment options that are available and their associated prognoses. In general,
clients want to know the likely chances of achieving a remission of disease in their pet, how long the
remission will last, what cost, time commitment and side effects are associated with treatment and
what options there are for follow up treatment when first line therapy fails. It is extremely important
to emphasise that the patient’s quality of life is central to all treatment considerations. If
chemotherapy is negatively impacting the quality of life of a pet then either a dose reduction,
treatment change or treatment cessation will be required. The clients should be aware of the
supportive care options that are available to minimise chemotherapy side effects (e.g. anti-nausea
medications, gut protectants) and how to distinguish mild side effects from those that are more
serious, so that medical attention can be sought promptly as required.
Once the client has been given all the options, the best option should be used first. As a general
rule, combination chemotherapy is superior to single-agent therapy. Each time an effective drug is
added to the protocol, the remission duration increases; however, so do the cost and the potential
for toxicity. It is also important that clients realize that a second or third remission is possible with
appropriate therapy but that these subsequent remissions are more difficult to attain and that their
duration is generally half the duration of the previous remission.
It is imperative that as a practitioner giving chemotherapy, you familiarise yourself with the
procedures for safe handling of chemotherapy agents and understand the drug specific dosing
schedules, considerations for safe administration of each agent and drug specific toxicities.
The treatment options below are tiered according to risk of toxicity, cost, and effi cacy.
First-level protocols provide a low risk of toxicity at low cost but have low effi cacy.
Prednisolone:
For clients who cannot afford or for whatever reason will not accept a combination chemotherapy
protocol due to the risks of toxicity, a protocol using prednisolone alone (2mg/kg PO daily for 7 days
then every other day) or in combination with chlorambucil (6 to 8 mg/m2 PO every other day) may
provide palliation with few risks of side effects. Approximately 50% of dogs will achieve a CR or PR
with average remission duration of 1-2 months.
In cats, single agent prednisolone is not considered to be an effective therapy for lymphoma.
Doxorubicin/Epirubicin
Doxorubicin is considered to be the most active single agent in the treatment of canine lymphoma
and therefore protocols that include doxorubicin appear to have superior efficacy to those that do
not. There are specific toxicities associated with the use and administration of doxorubicin and
epirubicin (see later). Cumulative cardiotoxicity (a primary dose limiting toxicity for the use of these
agents, may be less severe with epirubicin compared to doxorubicin.)
In cats, the use of doxorubicin as an induction agent found that fewer than 30% of patients achieved
a CR. However the inclusion of doxorubicin in multidrug protocols improved remission duration
significantly.
Second- level protocols
COP protocol: This is the most widely used chemotherapy protocol in practice and was the
foundation for the most currently advanced chemotherapy protocols. It is a relatively inexpensive
chemotherapy protocol with a low risk of toxicity Overall, COP chemotherapy causes CR in 70% of
dogs with lymphoma for a median of 4.3 months.
In cats, COP protocol has been found to be highly effective in treating lymphoma although the
results are quite variable most likely due to the heterogeneity of clinical presentation of the disease
in this species. In one study, 74% of cats had a CR lasting 2-42 months. There was 100% response
rate for multicentric lymphoma and 50% response rate for extranodal lymphoma. The median
duration of remission ranged from 4.5 months for alimentary lymphoma to 28 months for
multicentric disease however all anatomical groups had patients that lived longer than 1 year.
A more recent study from Europe described the results for 61 cats with malignant lymphomas in
various anatomical locations. 7.4% of cats were FeLV positive. CR was achieved in 75.4% of cats. The
estimated 1- and 2-year disease-free intervals in the cats with CR were 51.4 and 37.8%, respectively,
whereas the median duration of remission was 251 days. Response to treatment was predictive of
outcome; only long term survival was possible in cats that had a CR.
Third-level protocols
CHOP protocol: The addition of doxorubicin (or epirubicin) to a COP protocol, defines the acronym
CHOP. The best known CHOP based protocol was developed by the University of Wisconsin-Madison
and as a result is named after this institution. CR rates for dogs are greater than 90% with a median
survival time of 12 months. About 25% of dogs are long term survivors (longer than 2 years) and
some (perhaps 5%) are cured. Typically, L-asparaginase is incorporated into the CHOP protocol
during the induction phase however studies have failed to show that this increases the percentage
of dogs achieving a CR, the time to achieve a CR or the first remission duration. As a result, I
frequently elect to use L-asparaginase in the setting of rescue therapy. A number of different
prognostic factors have been discussed previously. In a study of 55 dogs treated with MadisonWisconsin protocol, CD3 +ve (T-cell immunophenotype) patients had a median survival time of 159
days vs. CD3 –ve patients with a median survival time of 389 days. Substage b animals had a median
survival time of 44 days versus substage a with a median survival time of 345 days.
When evaluating treatment outcomes for the Madison-Wisconsin protocol, researchers either
included a maintenance phase of treatment or discontinued the treatment after 6 months. Fiftythree dogs with multicentric lymphoma were treated with a 6-month modified version of the
University of Wisconsin (UW)-Madison chemotherapy protocol. Remission duration and survival
were compared to a historical control group of 55 dogs treated with a similar protocol with a
prolonged maintenance phase. Remission rate for the study dogs was 94.2%. The remission and
survival between the 2 groups did not differ significantly. Thus, we and others believe the 6-month
chemotherapy protocol based on CHOP with no maintenance phase provides is equal to a similar
protocol with a prolonged maintenance phase.
It is now customary to use discontinuous protocols in the referral setting. The chemotherapy break
allows a period of time to identify dogs that may have been cured of the disease, provides a time
commitment and financial break for the owner and a chemotherapy break for the patient. Relapse
typically occurs between 3-4 months after cessation of chemotherapy. Reinduction with the same
protocol has an approximately 80% success rate at achieving remission a second time.
In cats, the addition of doxorubicin to a COP protocol historically resulted in improved response
rates and remission durations however recent publications (see above) have shown impressive
results using COP protocol alone. A recent study evaluating the response to Madison-Wisconsin
protocol in cats showed a 47% CR rate and a 37% PR rate. For cats with a CR, the remission duration
was 654 days versus 114 days for cats with a PR. The overall duration of first remission was 156 days
and median survival time was 210 days. Initial response to treatment was the only significant
predictor of outcome again, age, stage and anatomical form of disease did not influence outcome.
Treatment outcomes for chemotherapy protocols in dogs
Drug/Protocol
#Dogs in CR
#dogs treated
% CR
Remission Duration
Prednisolone
26
57
46
Median 53 days
(range 0.5 -7 months)
Doxorubicin
Various
Various
Approx 70%
4-7 months
studies
studies
Epirubicin
26
37
70%
143 days
COP protocol
Various
Various
Various
Various studies
studies
studies
studies
4.3 months
70%
CHOP protocol
47
51
94%
9.1 months, survival 13.2
months
2006 World Congress WSAVA/FECAVA/CSAVA
What is the quality of life for patients receiving chemotherapy?
The owners of 25 dogs with multicentric lymphoma which were treated by multidrug chemotherapy
were interviewed to assess the quality of their pet's life during treatment. Sixty-eight per cent of the
owners considered their dog's quality of life to be the same as before the lymphoma occurred, and
the remaining 32 % felt that their pet's quality of life on chemotherapy treatment was acceptable
but poorer than before the lymphoma occurred. Treatment complications were reported by 52 % of
owners. Ninety-two per cent of owners had no regrets about treating their dog with multidrug
chemotherapy.
Questionnaires regarding the perceptions of chemotherapy and its impact on the quality of life (QoL)
of their cat were received from owners of 31 cats treated for lymphoma between 2002 and 2006
with COP (cyclophosphamide, vincristine, prednisolone) chemotherapy. The QoL scores prior to the
onset of cancer were significantly higher than the ratings given after the onset of cancer but before
commencement of chemotherapy. The QoL scores during were also significantly lower than prior to
the onset of cancer, but significantly higher during treatment than prior to starting treatment.
Adverse effects were experienced by 87% cats during the course of chemotherapy. Eighty three percent of clients were happy they treated their cat and 87% would treat another cat.