Download Targeted drugs for cancer treatment

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continuing education lesson
Targeted drugs for cancer treatment
1.25
CEUs
■ Jennifer Spencer, B.Sc., B.Sc.Pharm., BCOP
Sept 2006
Learning objectives
Upon successful completion of this lesson, you should be able to:
1. describe new targets for drug therapy in cancer patients
2. manage side effects with these new targeted drugs
3. prevent toxicity or lack of efficacy by anticipating potential drug interactions with these therapies
To successfully complete the post-test for this lesson, you may need access to the
Compendium of Pharmaceuticals and Specialties (CPS).
n 2006, an estimated 153,100 Canadians
will be diagnosed with cancer. Approximately
791,400 Canadians are living with some form
of cancer.1 Depending on the type of malignancy, traditional treatment options have
included surgery, radiation, hormonal therapy
and chemotherapy. The promise of increased
survival has made undergoing these treatments
worth the risk of their adverse effects.2 With the
advent of molecular biology, a new era in cancer
treatment has begun. Targeted drug therapy has
created a completely novel approach to treatment. This lesson will provide pharmacists with
the mechanistic background behind these
newer agents and information on the management of their side effects and drug interactions.
I
Targeted drug therapy
Traditional cytotoxic chemotherapy was developed to take advantage of the fact that tumour
cells divide more rapidly than other cells.
Unfortunately, many other healthy cells in the
body turn over rapidly, such as the lining of the
gastrointestinal tract, white blood cells and
hair. This lack of specificity results in many of
the side effects associated with chemotherapy,
such as the development of mouth ulcers,
potential for infection and hair loss.
Molecular biology has allowed us to identify
specific targets within tumour tissues. The
ideal molecular target is one that functions differently in tumour than in nontumour tissues.
In addition, through epidemiologic study, it is
important that this molecular target has been
identified as a predictor of poor disease outcome.3
Generally, these targets are found in cellular pathways that lead to tumour growth, survival and metastasis. Due to their specificity,
drugs that target these cellular pathways do
not exhibit the same toxicity profile as traditionally seen with conventional chemotherapy
treatments. Three such targets include transmembrane proteins called tyrosine kinases,
Instructions
1. After carefully reading this lesson, study each question and select the one answer you
believe to be correct. Circle the appropriate letter on the attached reply card.
2. To pass this lesson, a grade of at least 70% (14 out of 20) is required. If you pass, your
CEU(s) will be recorded with the relevant provincial authority(ies). (Note: some provinces
require individual pharmacists to notify them.)
Answering options
A. For immediate results, answer online at www.pharmacygateway.ca.
B. Mail or fax the printed answer card to (416) 764-3937. Your reply card will be marked
and you will be advised of your results within six to eight weeks in a letter from
Pharmacy Practice.
antibody-directed therapies against cell suface
proteins and antibodies directed against new
vessel formation (angiogenesis).
Receptor tyrosine kinases
Tyrosine kinases are transmembrane proteins
that have an extracellular ligand binding
domain, transmembrane domain and catalytic
intracellular domain (Figure 1).4-7 Normally,
ligands or molecules bind to these receptors.
Binding causes auto-phosphorylation of key
tyrosine kinase residues found inside the cell.
This then leads to activation of a series of
downstream signalling events that mediate cellular proliferation, survival, differentiation,
function and motility.5 In certain situations,
these tyrosine kinase receptors can be overexpressed or mutated in cells. This results in the
cells constantly receiving signals to proliferate.
Several tyrosine kinases have been targeted. The epidermal growth factor receptor
(EGFR) is a tyrosine kinase receptor that is
normally activated by epidermal growth factor
(EGF). It is found to be abnormal or overexpressed in many malignancies including
head and neck, colorectal, breast, pancreatic,
lung and brain cancer.5.8
The EGFR tyrosine kinase is an ideal target
because it is involved in cell signalling, induces
cancer when it is aberrant, and elevated levels
have been found in cancer specimens compared to normal tissue. Overexpression of EGFR
is directly related to chemotherapy resistance
Supported by an unrestricted grant from
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and poor prognosis.8 Specifically, > 50% of
non-small cell lung cancers overexpress EGFR
and it is a negative prognostic factor.9 Pre-clinical studies demonstrated that inhibition of
EGFR could impair tumour growth.10 This has
lead to the development of the currently marketed tyrosine kinase inhibitor, erlotinib.
A different tyrosine kinase has also been
targeted. In a type of hematological malignancy called chronic myeloid leukemia (CML),
a translocation occurs between chromosomes
9:22. This translocation results in a new gene
called BCR-ABL, or the Philadelphia chromosome.11 The new gene produces a BCR-ABL
tyrosine kinase that is abnormal and constitutively active. When it is always turned on, the
leukemia cells multiply in an uncontrolled
manner.12 Imatinib is a specific inhibitor of the
BCR-ABL tyrosine kinase.13
Targeted drugs for cancer treatment
FIGURE 1
Tyrosine kinase receptor6,7
growth factor
(e.g.: epidermal growth factor, EGF)
extracellular
transmembrane
cell membrane
intracellular
tyrosine kinase domain
(becomes activated)
Antibody-directed therapies
against cell surface proteins
Specific targets on the extracellular surface of
cancer cells have been identified. Through biological engineering, antibodies have been
developed that specifically bind to these extracellular surface proteins. When this antibody
binds to the receptor, five different possible
actions are thought to occur, which result in
targeted elimination of the cancer cell. The
suggested actions include down-regulation of
the receptor, down-regulation of the growth
signalling properties, initiation of antibody
dependent cellular toxicity, complement
dependent cytotoxicity and apoptosis (Figure
2).14-16 This strategy has been used in different
malignancies including breast cancer and lymphoma.
In breast cancer, 15–25% of patients overexpress the human epidermal growth factor
receptor protein-2 (HER2) protein.17 HER2
downstream signalling
cellular proliferation
overexpression is correlated with higher-grade
tumours, relative resistance to certain types of
chemotherapy and poorer prognosis.18 A monoclonal antibody called trastuzumab was developed that specifically targets the HER2 receptor.19 The treatment of certain lymphomas has
also included the use of antibody-directed
therapies. Malignant and nonmalignant B lymphocytes express a cell surface protein called
the CD20 antigen.20 Rituximab is a monoclonal
antibody that specifically binds to the CD20
positive lymphoma cells.
survival
cell migration
Angiogenesis and vascular
endothelial growth factor
Angiogenesis is the formation of new blood
vessels.21 Tumours are unable to grow beyond
two to three millimetres unless they create
their own vascular supply.22 Angiogenesis is a
multistep process that occurs through the
stimulus of many cytokines including vascular
endothelial growth factor (VEGF). Angiogenesis
is needed for tumours to grow, invade and
metastasize. Normal blood vessels are ordered
and regulated, while tumour vessels are chaotic and irregular. This irregularity appears to
CE Faculty
This month
Reviewers
Targeted drugs for cancer treatment
All lessons are reviewed by a minimum of
six pharmacists for accuracy, currency and
relevance to current pharmacy practice.
Author
Jennifer Spencer, B.Sc., B.Sc.Pharm, BCOP,
is a board certified oncology pharmacist.
She works as a clinical pharmacist in the
medical oncology department of the Ottawa
Hospital and teaches the oncology section of
the nursing pharmacology course at the
University of Ottawa.
2
Answer online at www.pharmacygateway.ca
CE Co-ordinator
Brenda McBean Cochran, B.S.P., M.Sc.(Phm)
Pharmacist consultant, Bedford, N.S.
This lesson (CCCEP file # 428-0606)
has been approved for 1.25 CEUs by
the Canadian Council on Continuing
Education in Pharmacy. Approved for
1.25 CEUs by l’Ordre des pharmaciens
du Québec. Accreditation of this program
will be recognized by CCCEP until
June 16, 2009.
This lesson is published by Rogers Publishing
Limited, One Mount Pleasant Rd., Toronto,
ON M4Y 2Y5. Editorial office: Tel: (416)
764-3927 Fax: (416) 764-3931. CE queries:
Tel: (416) 764-3879 Fax: (416) 764-3937
[email protected].
No part of this CE lesson may be reproduced, in whole or in part, without the written permission of the publisher.
The authors, expert reviewers and
provider state that they have no real or
potential conflict to disclose. This lesson is
supported by an unrestricted grant from
Genpharm Inc.
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FIGURE 2
Targeted drugs for cancer treatment
Monoclonal antibody targeting a cancer cell14,16
antibody dependent
cellular toxicity
(phagocytosis)
macrophage
Erlotinib
monoclonal antibody
complement binding
resulting in cell lysis
antigen receptor
(i.e., HER-2 protein or CD20)
cancer cell
intracellular events
• down regulation of growth signals
• down regulation of receptor
• apoptosis
FIGURE 3
A. Normal tumour growth. When a growing tumour reaches a certain critical size
(0.5–2 mm), it can no longer supply itself with nutrients and oxygen from nearby
small blood vessels. In response, the tumour secretes vascular endothelial growth
factor (VEGF), which attaches to nearby blood vessels and stimulates growth toward
the tumour, allowing it to thrive.
B. Effect of bevacizumab on tumour growth. Possible mechanism of action of antibody to
vascular endothelial growth factor (VEGF). Antibody to VEGF blocks the signals from the
tumour that prompt blood vessel growth. Without nutrients and oxygen, the tumour stops growing.
*Reprinted with permission from Hoffmann-La Roche.
decrease the ability of chemotherapy to be
effectively delivered to the entire tumour.23
Several cancers overexpress VEGF. Elevated
levels are associated with a poorer prognosis
and higher risk of metastatic disease.23
Bevacizumab is a monoclonal antibody that
specifically binds to VEGF (Figure 3). When
Pharmacy Practice | September 2006
Specific targeted drug therapies
Many targeted therapies are currently available
on the Canadian market. The more commonly
administered drugs are reviewed in this section.
bound to VEGF, it prevents binding of VEGF to
the receptor on the endothelial cells, and thus
blocks the stimulus for endothelial cell growth
and angiogenesis.24 VEGF is an excellent target
as angiogenesis is usually dormant in adults
except during wound healing, inflammation
and female reproductive cycles.25
Erlotinib is approved in Canada for patients
with non-small cell lung cancer who have
failed at least one prior chemotherapy regimen. It inhibits the EGFR tyrosine kinase
(Figure 1). Most patients with non-small cell
lung cancer are diagnosed with advanced disease. Median survival is eight to 10 months.
There has been little progress in improving the
efficacy of treatment options in the last 20
years.26 Second-line chemotherapy provides a
response rate of 20% and prolongs survival by
two to four months.27 Newer treatment options
were desperately needed.
Erlotinib was studied as a second- or thirdline treatment. The BR-21 trial included 731
patients randomized in a 2:1 ratio to erlotinib
150 mg po daily or placebo.28 Overall response
rates were nine per cent in the erlotinib group
and < 1% in the placebo arm. Erlotinib provided a significantly longer overall survival of
two months as compared to placebo (6.7 vs.
4.7 months). This was the first trial showing a
survival advantage of a tyrosine kinase inhibitor
after second- or third-line chemotherapy in
non-small cell lung cancer.28 Of interest, higher
response rates were correlated with female, nonsmoker and Asian groups, and those tumours
with adenocarcinoma histology (a subset of
non-small cell cancer patients).
Erlotinib is also being studied in other
malignancies including colorectal cancer, cancer of the pancreas and renal carcinoma.
Dosing
Erlotinib is given as a 150 mg tablet orally
daily on an empty stomach. Food increases the
bioavailability from 59% to 100%. The higher
bioavailability when taken with food may result
in more side effects without an increase in efficacy.27
Metabolism of erlotinib is primarily through
the cytochrome P450 CYP3A4. Potent inducers
(i.e., rifampin, phenobarbital, carbamazepine,
phenytoin, St John’s wort) may decrease
erlotinib levels and may compromise its efficacy. Inhibitors (i.e., itraconazole, ketoconazole,
fluconazole, diltiazem, verapamil, erythromycin,
clarithromycin, grapefruit juice) may increase
levels, which could result in increased side
effects. Erlotinib can also interact with warfarin.
Patients who are being initiated on erlotinib
should have their INRs followed closely.29
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Adverse effects
Common side effects with erlotinib include
rash (43–85%) and low-grade diarrhea (55%).
Of interest, rash has been highly correlated
with response.10,30,31 Most cases of rash are
mild. It is described as acneiform-like and
appears as inflammatory follicular papules and
pustules. Acneiform rash is not usually associated with comedones and therefore is not like
true acne. The T zone of the facial area, labial
folds, forehead and chin are often first
affected. The rash can also develop on the
upper chest and back. The onset is usually
within seven to 10 days of starting therapy.
The intensity and severity fluctuates and many
lesions will improve on their own, even while
continuing on erlotinib.30
If the rash is mild, treatment may not be
necessary. If bothersome, anti-acne or antirosacea agents can be tried such as topical
metronidazole, erythromycin or clindamycin.
Drying agents such as benzoyl peroxide should
be avoided. If the lesions become symptomatic
and cover < 50% of the body, the topical antiacne treatments, such as those just mentioned
above, can be used, as well as an oral antihistamine if the lesions are itchy.10 An oral tetracycline, such as minocycline or doxycyline
100 mg orally daily, can be attempted. Topical
steroids can be offered, but should be used
sparingly.30
If the rash progresses to > 50% of the body
surface and is painful, ulcerative or desquamating, interruption of erlotinib should be seriously considered.10 All previously mentioned
treatments can be used, as well as increasing
the minocycline or doxycycline dose to 200 mg
per day, and then tapered when the acute
inflammation has subsided.10 Total treatment
duration of the minocycline/doxycycline is
three to six weeks.30
Mild diarrhea occurs in 48% of patients,
with only six per cent experiencing severe diarrhea.3 Most patients are well-controlled with
loperamide. If severe, or the patient develops
nausea, anorexia or vomiting associated with
dehydration, therapy should be dose reduced
or temporarily interrupted.29
Finally, interstitial lung disease can be a rare
(0.8%) but serious complication from erlotinib.
Therapy should be interrupted at any signs of
acute onset or worsening of dyspnea/cough.3,29
Imatinib
Imatinib revolutionized the treatment of chronic
myelogenous leukemia (CML). It is currently
approved for the treatment of adults with
Philadelphia chromosome positive CML and a
rare tumour called gastrointestinal stromal
4
Answer online at www.pharmacygateway.ca
Targeted drugs for cancer treatment
tumour (GIST). In CML, imatinib inhibits the
abnormal tyrosine kinase that is produced by
the genetic translocation that results in the
Philadelphia chromosome.32 In a multicentre
trial, 1,106 patients with chronic phase CML
were randomized to imatinib or to interferon
alpha (INF α) and low-dose cytarabine. A major
cytogenetic response was seen in 85.2% of
patients on imatinib compared to 22.1% in the
INF α and cytarabine group (p < 0.001).11 A
major cytogenetic response is both a complete
or partial response, where 0– < 35% of
Philadelphia positive cells are found in the bone
marrow.12 Normal bone would not contain any
Philadelphia positive cells. Imatinib has also
been studied in the accelerated form of CML
and provided significant response rates.13 In
GIST tumours, a gain of function mutation
occurs at the KIT or platelet-derived growth factor alpha (PDGFRA) gene. Imatinib inhibits the
resultant abnormal KIT and PDGRFA tyrosine
kinases produced from these abnormal genes.33
Dosing
Dosing of imatinib for CML is 400 mg orally in
the chronic phase and 600 mg orally daily in
the accelerated and blast phases. Doses can
be increased in both situations by 200 mg, if
inadequate response is seen with the initial
dose. In GIST, most patients receive 400 mg
per day. To decrease the incidence of nausea,
imatinib should be taken after a meal with a
large glass of water.34
Significant drug interactions can occur
with imatinib. A major metabolic pathway for
its clearance is through CYP3A4, and it is an
inhibitor of CYP2D6.
Elevated imatinib levels, due to enzyme
inhibition, could result in a higher incidence of
adverse effects, including rash. Imatinib levels
could be increased by the following substances
that inhibit CYP3A4: ketoconazole, erythromycin, clarithromycin, itraconazole, voriconazole
and grapefruit juice.34,35
Enzyme induction could lead to decreased
imatinib blood concentrations and possibly
result in decreased effectiveness. Medications
that may decrease imatinib levels are inducers
of CYP3A4 including dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital
and St John’s wort.34
Imatinib has also been shown in vitro to
inhibit CYP2D6. Substrates for 2D6 include
beta-blockers, serotonin H3 antagonists, morphine, oxycodone and cyclophosphamide.
Caution is also advised when co-administering medications that are metabolized by
CYP2C9, including warfarin. Careful monitoring of INRs is recommended when imatinib is
initiated, or with any dose adjustments.
Changing to a low-molecular weight heparin or
unfractionated heparin should be considered.34
Adverse effects
Imatinib is generally well-tolerated. The more
frequently reported adverse effects include
mild nausea, vomiting, diarrhea, myalgias and
muscle cramps. Superficial edema primarily
evident as periorbital edema and lower limb
edema, is commonly seen (> 50% of
patients).34 It is rarely severe and can be
managed with diuretics or lowering the dose of
imatinib. Pleural effusions, ascites, pulmonary
edema and rapid weight gain are usually
managed by temporarily withholding the dose
and treating with a diuretic. Patients should be
weighed regularly and monitored for weight
gain. The likelihood of edema is more likely in
patients on a higher dose or who are over the
age of 65. Only 0.9% of newly diagnosed CML
patients and 1–2% of other CML patients had
severe fluid retention.34
Hepatotoxicity can occur and occasionally
can be severe (< 4% of patients). Liver function tests should be done before starting treatment and then monthly, as clinically indicated.
In patients in the accelerated or blast phases
of CML, neutropenia or thrombocytopenia can
commonly occur. Complete blood counts should
be monitored weekly for the first month, then
every second week for the second month, and
every two to three months thereafter.34
Trastuzumab
The epidermal growth factor receptor, HER2, is
overexpressed in 15–25% of breast cancers.
Trastuzumab is a monoclonal antibody that
binds specifically to the HER2 receptor and is
indicated for the treatment of metastatic breast
cancer patients whose tumours significantly
overexpress the HER2 protein.36 As a single
agent, objective response rates of 15% have
been seen in extensively pre-treated metastatic
breast cancer patients who are positive for
HER2 overexpression.19 In untreated metastatic
breast cancer patients, objective response rates
of up to 26% have been seen. When trastuzumab is added to chemotherapy, objective
response rates climb to 50%, compared to
32%, when chemotherapy is given alone.19
Recently, trastuzumab has demonstrated
significant reduction in the risk of disease progression when given as adjuvant therapy for
early breast cancer. When the treatment is
labelled adjuvant, the goal is cure.37 Three
groundbreaking trials, HERA, NSABP B-31
and NCCTG-N9831, assessed trastuzumab in
the adjuvant setting. In the HERA trial, after
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their initial chemotherapy treatment, 3,387
women were randomized to receive either
trastuzumab every three weeks for one year or
just observation.17 All the women overexpressed the HER2 protein or had amplification
of the HER2 gene. Disease-free survival was
the primary end point. With a median followup
of one year post-trastuzumab or post-observation, disease-free survival was less in the
women who had received trastuzumab (127
disease-free survival events compared to 220
in the observation group). This represents an
unadjusted hazard ratio of 0.54 (95% confidence interval [CI] 0.43–0.61, p < 0.001). Of
note, more cardiac dysfunction was seen in the
trastuzumab group.17
Similar results were replicated in the
NSABP B31 and NCCTG-N9831 trials. The
results of these two trials were pooled in a joint
analysis approved by the FDA. The combination
trial had 3,351 HER2 positive women receiving
their initial chemotherapy, who were then randomized to either one year of trastuzumab
given on a weekly basis or to observation only.38
The primary end point was again disease-free
survival. At the first planned interim analysis,
the study was terminated early due to a significant difference in disease-free survival between
the two groups. The median followup was two
years. There were only 133 events (recurrent,
second primary cancer or death before recurrence) in the trastuzumab arm compared to
261 events in the observation group. The
hazard ratio was 0.48 (95% CI 0.39–0.55,
p < 0.0001). At three years, 87.1% of patients
were alive in the trastuzumab group versus
75.4% in the control group. This was an
absolute difference of 11.7%, which is highly
significant. Of note, grades III and IV (patients
experiencing symptoms of congestive heart failure [CHF] with less than ordinary activity or at
rest) New York Heart Association CHF, or death
was higher in the trastuzumab group (4.1%
compared to 0.8% in the control group in the
B31 trial and in the N9831 trial; 2.9% in the
trastuzumab group and 0% in the N9831
group).39,40 These three trials have revolutionized the treatment of early breast cancer for
HER2 positive women.
Dosing
Trastuzumab is given intravenously (IV), either
weekly as a loading dose of 4 mg/kg over 90
minutes followed by a maintenance dosing of
2 mg/kg over 30 minutes, or every three weeks
as a loading dose of 8 mg/kg over 90 minutes,
followed by maintenance dosing of 6 mg/kg
also over 90 minutes. Trastuzumab should not
be given concurrently with an anthracycline
Pharmacy Practice | September 2006
Targeted drugs for cancer treatment
(e.g., doxorubicin or epirubicin) due to
increased risk of cardiotoxicity.36
Adverse effects
Generally, trastuzumab is very well-tolerated.
The most significant side effect is infusionrelated reactions, which occur in 40% of
patients.19 Most reactions are mild to moderate
in severity and are associated with fever and
chills. In some centres, patients are premedicated with acetaminophen to prevent
these reactions, although this is not generally
recommended by the manufacturer. Usually,
the reactions will occur during the first infusion or up to six hours afterwards and respond
to acetaminophen or diphenhydramine; occasionally meperidine is required.36 Less than
three per cent of patients have further problems with future infusions.19
The other potentially significant side effect
is symptomatic or asymptomatic cardiac dysfunction, the cause of which is unclear. It has
been suggested that there is uptake of
trastuzumab in the myocardium and it may
cross-react with an antigen in the myocardium.39,41,42 It is known that myocardial cells
express the HER2 antigen. Significant cardiotoxicity is seen when trastuzumab is given
concurrently with an anthracycline (e.g., doxorubicin or epirubicin). Quantified lowering of
ejection fraction of at least 10% was seen in
27% of patients who had received trastuzumab and chemotherapy (doxorubicin and
cyclophosphamide) versus eight per cent who
received chemotherapy alone. On its own,
trastuzumab has an incidence of cardiac dysfunction of 4.7%.19 Careful monitoring of left
ventricular function should be done prior to,
and during treatment. If there is clinically significant cardiac failure, trastuzumab should be
stopped and medication should be initiated to
treat the cardiac failure. Signs and symptoms
to monitor include dyspnea, increased cough,
peripheral edema and nocturnal dyspnea.37
Patients who experienced cardiotoxicity while
on trastuzumab will generally regain cardiac
function once the trastuzumab is stopped.
Improvement is usually seen within a few
months.39,41
Rituximab
Lymphoma is a malignancy that originates in
the lymphoid tissue. Of all types of lymphomas, 90% are B-cell in origin. Both malignant and nonmalignant B-cells have a CD20
antigen found on their cell surface.20
Rituximab is a monoclonal antibody that
specifically binds to this CD20 receptor.
Indolent lymphomas, which express CD20,
have a median survival of approximately 10
years, and response to initial therapy is excellent (80–90%). Unfortunately, this response is
usually not maintained. Initially, patients can
be followed through watchful waiting or they
can be treated with chemotherapy. For patients
who relapse after initial therapy, there is no
standard treatment. Rituximab, given as 375
mg/m2 IV weekly for four weeks, provided a
median time-to-progression of 13 months,
which is comparable to chemotherapy with significantly fewer side effects.20 In Canada,
rituximab is officially indicated for relapsed or
refractory low grade or follicular CD20 positive
B-cell non-Hodgkin’s lymphoma (NHL).
For more aggressive forms of NHL, rituximab has been studied as initial treatment. In
patients who are > 60 years old, the addition
of rituximab to chemotherapy increased the
event-free survival at five years from 28%, in
patients who only received chemotherapy, to
47.5%, in those who received both chemotherapy and rituximab. Benefit was seen in
younger populations, as well.43 For this reason,
rituximab is also indicated for CD20 positive
diffuse large B-cell NHL in combination with
cyclophosphamide-doxorubicin-vincristineprednisone (CHOP) chemotherapy.
Dosing
The dosing of rituximab depends on the
indication. As a single agent, the dose is
375 mg/m2 IV weekly for four weeks. If it is
being given in combination with chemotherapy, it is 375 mg/m2 IV with chemotherapy
every three weeks. This combination is given
for six to eight cycles.
Adverse effects
Rituximab is generally well-tolerated. Infusionrelated reactions are usually mild to moderate
in severity, but approximately 10% of patients
will experience severe reactions. Mild to moderate reactions are typically seen within one to
two hours after starting the rituximab infusion
and are brief in duration. Patients may experience fever, chills and rigors. The incidence of
reactions decreases with subsequent infusions. Severe infusion-related reactions involve
fever, chills and rigors, but also bronchospasm, hypotension, angioedema and hypoxia.
The infusion should be stopped immediately
and corticosteroids, diphenhydramine, acetaminophen, IV fluids, oxygen and/or bronchodilators should be added. Fatalities are rare
and are reported in 0.04–0.07% of patients.
Close monitoring during the infusion is critical,
as well as premedicating with acetaminophen
and diphenhydramine. In most situations,
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rituximab can be resumed using a slower infusion rate (50%) when symptoms have completely resolved.20,44
Pulmonary events such as hypoxia, pulmonary infiltrates and acute respiratory failure
have occurred and are usually preceded by
severe bronchospasm and dyspnea. Patients at
risk are those with pulmonary insufficiency or
with pulmonary tumour infiltration, and rituximab should be used with caution in these
patients. Transient hypotension may occur with
rituximab infusion, and withholding antihypertensive medications 12 hours prior to,
and throughout the rituximab infusion, should
be considered.44
Other serious side effects include tumour
lysis syndrome, where significant cell death
can result in hyperuricemia leading to acute
renal failure and, in rare cases, death. Those at
most risk of tumour lysis syndrome are persons
with high tumour burden.44
Bevacizumab
Bevacizumab is the first anti-angiogenesis
inhibitor marketed in Canada. It is a recombinant humanized monoclonal antibody that
specifically binds to vascular endothelial
growth factor (VEGF).
In a multicentre trial, 813 patients with
metastatic colorectal cancer were randomized
to receive either irinotecan-fluorouracil-leucovorin (IFL) chemotherapy or IFL with bevacizumab. This was first-line therapy for these
patients. The usual first-line therapy in this
population is a combination of irinotecan,
fluorouracil and leucovorin. The primary end
point was duration of overall survival.
Response rates were 34.8% in the IFL group
compared to 44.8% in the IFL/bevacizumab
patients (p = 0.004). Median progression-free
survival increased from 6.2 months to 10.6
months (hazard ratio for progression 0.54,
p < 0.001).45 Impressively, the overall median
survival increased from 15.4 months to
20.3 months (hazard ratio for death 0.55,
p < 0.001). Results such as these have not
previously been seen in the metastatic colorectal setting.45
Bevacizumab is indicated for the first-line
treatment of patients with metastatic colon and
rectal cancer in combination with fluoropyrimidine-based (e.g. fluorouracil) chemotherapy.46
Dosing
The dose is 5 mg/kg IV every two weeks in
combination with chemotherapy. Pre-medication is not specifically recommended before
the infusion.47 It is contraindicated in patients
with untreated brain metastases due to its
6
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Targeted drugs for cancer treatment
potential for developing a central nervous system (CNS) hemorrhage. There are no known
drug interactions with bevacizumab.47
Adverse effects
Twenty-two to 32% of patients will develop
hypertension and 11–16% of patients will
have grades III–IV hypertension. Most will have
grade III hypertension, which is defined as an
increase in blood pressure that will require the
initiation of oral antihypertensive therapy.48
Angiotensin converting enzyme (ACE)
inhibitors or calcium channel blockers are
effective. Only 0.7% of patients develop grade
IV hypertension where bevacizumab needs to
be discontinued. Onset can occur at any time.
It is believed the elevation in blood pressure
is due to VEGF inhibition. When VEGF is
inhibited, less nitric oxide is produced. Nitric
oxide is a vasodilator and when inhibited by
anti-VEGF agents (e.g., bevacizumab), would
result in vasoconstriction and elevations in blood
pressure. Hypertension will resolve in most
patients when bevacizumab is discontinued.48
Arterial thrombosis is rare (3.8% in bevacizumab vs. 1.7% in placebo group). It can
manifest as a stroke, transient ischemic
attack, subarachnoid hemorrhage, myocardial
infarction and angina. Patients at increased
risk for arterial thrombosis from bevacizumab
therapy are those who have a prior history of an
arterial thromboembolic event and are older
than 65.
Wound healing complications can also
occur. Angiogenesis is critical in this normally
occurring process. In trials, the risk of wound
complications increased from 0 to 10% in the
bevacizumab group.48 The manufacturer
recommends that bevacizumab should not be
initiated in any patient until at least 28 days
post-surgery to prevent wound dehiscence.46
Bleeding is also a possible side effect.
Most hemorrhagic complications have been
minor nosebleeds and occur in 20–40% of
patients. Duration is usually less than five
minutes and resolves without medical treatment.48 Concomitant use of low-dose aspirin
TABLE 1
does not appear to increase bleeding risk, nor
does the use of warfarin in patients who have
developed a thrombosis. The risk of bleeding
with known CNS metastases has not been
studied and bevacizumab is contraindicated in
this patient population.
A small risk of gastrointestinal perforation
also exists; 1.6% of 1,367 patients in the
metastatic colorectal cancer trials developed
gastrointestinal perforations. More than half of
these patients had some risk factor including
acute diverticulitis, tumour at the site of perforation, obstruction, abdominal carcinomatosis or radiation in the area. Patients should be
warned to report any signs of abdominal pain
associated with constipation or vomiting.48
Cost considerations
Targeted therapies provide a novel approach in
the fight against cancer. They have increased
overall survival and time-to-disease progression in many different tumour types. In some
situations, these targeted agents are the only
available treatment option. Their additional
benefit is that they have fewer side effects and
are better tolerated by patients. Certain
patients are not candidates for traditional therapy, but would be able to tolerate these targeted therapies.
As these are relatively newly marketed therapies, the cost of these agents is substantial
(Table 1). However, it is important to place
their cost into perspective. There is the cost of
managing the side effects of conventional therapies, which includes hospital admissions,
and short- and long-term toxicities. As an
example, docetaxel is second-line therapy in
non-small cell lung cancer and costs approximately $1,690 to $1,950 for three weeks of
treatment. The side effects are significant
including myelosuppression (which may
require hospital admission), neuropathies, hair
loss and mucositis. Erlotinib, which can also
be used as second-line therapy, is approximately $2,464 per month (not including pharmacy fees). The main side effects of erlotinib
are rash and mild diarrhea.
Approximate cost of the targeted agents49
Targeted agent
Cost (treating a 70 kg patient for one month-acquisition drug)
erlotinib
$ 2,464
imatinib
$ 4,442 (600 mg po daily x 30 days)
trastuzumab
$ 3,433 (price normalized to 28 days)
rituximab
$ 2,887 (for 1 infusion that would be given every 3 weeks along with
chemotherapy)
bevacizumab
$ 2,757 (2 infusions, as dosing is q2weeks)
Pharmacy Practice | September 2006
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continuing education lesson
With the rising cost of pharmaceutical
agents in the healthcare system, difficult decisions need to be made by hospital pharmacy
and therapeutic committees, as well as
governments. Traditional therapies and these
newer targeted agents need to be compared for
both their efficacy and toxicity. Although there
is a scattering of pharmacoeconomic studies
done for some of these agents, more of these
studies will be necessary to make informed
decisions in this very difficult and emotionally
charged setting.50-52
Targeted drugs for cancer treatment
References
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Canada. Canadian Cancer Statistics 2006. Toronto, Canada,
2006.
2. Green MR. Targeting targeted therapy. N Engl J Med
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5. Krause DS, Van Etten RA. Tyrosine kinases as targets for
cancer therapy. N Engl J Med 2005;353:172-87.
6. Sridhar SS, Seymour L, Shepherd FA. Inhibitors of epi-
Future directions
Currently, many new targeted agents are being
developed and evaluated in clinical trials. The
hypothesis is that a single pathway is unlikely
to be solely responsible for the uncontrolled
cell division that occurs in cancer cells. By targeting multiple pathways within the cell, a
higher likelihood of response might be possible. Trials combining targeted agents with different mechanisms of action are being conducted.17 Newer agents that inhibit more than
one receptor, such as sunitinib, are being
developed. This drug inhibits KIT, PDGFRA
and VEGF and fms-related tyrosine kinase 3.
Sunitinib has been studied in metastatic renal
cell carcinoma and in GIST after failure with
imatinib.17,33 The potential in this field is
unlimited and exciting.
dermal-growth-factor receptors: a review of clinical research with
a focus on non-small-cell lung cancer. Lancet Oncol 2003;4:
397-406.
7. Hamid O. Emerging treatments in oncology: focus on
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3238-47.
As treatment regimens become more complex, our patients will require counselling on
the nontraditional side effects of these novel
agents. Some side effects are rare, but potentially life threatening. Patients will need to
know what to do in the event that they do
arise. Traditional chemotherapeutic agents
generally do not have many drug interactions,
but these newer agents do. Prescribers may
not always be aware of these interactions and
may not have access to the patient’s complete list of medications. The pharmacist will
play a key role intercepting these potential
interactions.
The cure for cancer is complex and ever
evolving. We have reached somewhat of a
plateau with our conventional therapies and
newer options are needed. Targeted therapies
offer us a completely novel approach to
cancer treatment, with the benefits of fewer
side effects. The challenge will be to determine how our healthcare system will be able
to incorporate these new therapies into
patient care.
Pharmacy Practice | September 2006
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previously treated non-small-cell lung cancer. N Engl J Med
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Oncol 2005;6:491-500.
31. Perez-Soler R, Saltz L. Cutaneous adverse effects with
HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol
2005;23:5235-46.
32. Cortes J, Kantarjian H. New targeted approaches in
chronic myeloid leukemia. J Clin Oncol 2005;23:6316-24.
33. Van der Zwan SM, De Matteo RP. Gastrointestinal stromal tumour: 5 years later. Cancer 2005;104:1781-8.
34. Novartis. Gleevec product monograph. April 27, 2005.
New monograph for February 27, 2006.
35. Gambillara E, Laffitte E, Widmer N, et al. Severe pustular eruption associated with imatinib and voriconazole in a
patient with chronic myeloid leukemia. Dermatology 2005;211:
363-5.
36. Hoffmann-La Roche Ltd. Herceptin product monograph. Mississauga, Ont.;July 20, 2005.
9. Giaccone G. Epidermal growth factor receptor inhibitors
37. Devita VT, Rosenberg SA, eds. Cancer: principles and
practice of oncology. Baltimore, MD: Lippincott, Williams &
2005;23:3235-42.
Wilkins; 2005.
10. Segaert S, Van Cutsem E. Clinical signs, pathophysiology
38. Romond EH, Perez EA, Bryant J, et al. Trastuzumab
and management of skin toxicity during therapy with epidermal
plus adjuvant chemotherapy for operable HER2-positive breast
growth factor receptor inhibitors. Ann Oncol 2005;16:1425-33.
cancer. N Engl J Med 2005;353:1673-84.
11. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib com-
39. Tan-Chiu E, Yothers, G, Romond E, et al. Assessment of
pared with interferon and low-dose cytarabine for newly diag-
cardiac dysfunction in a randomized trial comparing doxorubicin
nosed chronic-phase chronic myeloid leukemia. N Engl J Med
and cyclophosphamide as adjuvant therapy in node-positive,
2003;348:994-1004.
human epidermal growth factor receptor 2-overexpressing
12. Lyseng-Williamson K, Jarvis B. Imatinib. Drugs 2001;61:
1765-74.
13. AHFS First Fax. New drug overview, imatinib. Am J
14. Harris M. Monoclonal antibodies as therapeutic agents
for cancer. Lancet Oncol 2004;5:292-302.
15. Leyland-Jones B. Trastuzumab: hopes and realities.
Lancet Oncol 2002;3:137-44.
16. Hennessy BT, O Hanrahan EO, Daly PA. Non-Hodgkin
lymphoma: an update. Lancet Oncol 2004;5:341-53.
17. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.
Trastuzumab after adjuvant chemotherapy in HER2-positive
breast cancer. N Engl J Med 2005;353:1659-72.
18. Burnstein MJ. The distinctive nature of HER2-positive
breast cancers. N Engl J Med 2005;353:1652-4.
breast cancer: NSABP B-31. J Clin Oncol 2005;23:7811-9.
40. Arnold JMO, Liu P, Demers C, et al. Canadian
Cardiovascular Society consensus conference recommendations
on heart failure 2006: diagnosis and management. Can J Cardiol
2006;22:23-45.
41. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility
of trastuzumab-related cardiotoxicity: new insights based on
clinical course and response to medical treatment. J Clin Oncol
2005;23:7820-6.
42. Levine MN. Trastuzumab cardiac side effects: only time
will tell. J Clin Oncol 2005;31:7775-6.
43. Coiffier B. State-of-the-art therapeutics: diffuse large Bcell lymphoma. J Clin Oncol 2005;23:6387-93.
44. Genentech Inc. Rituxan product monograph. South San
Francisco, CA; March 9, 2006.
19. McKeage K, Perry CM. Trastuzumab: a review of its use
45. Hurwitz H, Fehrenbacher L, Novotny W, et al.
in the treatment of metastatic breast cancer overexpressing
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for
HER2. Drugs 2002;62:209-43.
metastatic colorectal cancer. N Engl J Med 2004;350:2335-42.
20. Plosker GL, Figgitt DP. Rituximab: a review of its use in
non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia.
Drugs 2003;63:803-43.
21. Marshall J. The role of bevacizumab as first-line therapy
for colon cancer. Semin Oncol 2005;32 Suppl 9:S43-S47.
22. Zakarija A, Soff G. Update on angiogenesis inhibitors.
Conclusion
2005;65:7525-9.
in the treatment of non-small-cell lung cancer. J Clin Oncol
Health-Syst Pharm 2001;58:2241-2.
The pharmacist’s role
27. Johnson BE, Janne PA. Epidermal growth factor receptor mutations in patients with non-small cell cancer. Cancer Res
Curr Opin Oncol 2005;17:578-83.
23. Zondor SD, Medina PJ. Bevacizumab: an angiogenesis
inhibitor with efficacy in colorectal and other malignancies. Ann
Pharmacother 2004;38:1258-64.
46. Hoffmann-La Roche Ltd. Avastin product monograph.
Mississauga, Ont.; April 12, 2006.
47. Motl S. Bevacizumab in combination chemotherapy for
colorectal and other cancers. Am J Health-Syst Pharm
2005;62:1021-32.
48. Gordon MS, Cunningham D. Managing patients treated
with bevacizumab combination therapy. Oncology 2005;69
Suppl 3:25-33.
49. http://www.cancercare.on.ca/index_chemoRegimensby
Disease.htm (accessed February 27, 2006).
24. Ignoffo RJ. Overview of bevacizumab: a new cancer
50. Neyt M, Albrecht J, Cocquyt V. An economic evaluation
therapeutic strategy targeting vascular endothelial growth factor.
of Herceptin in adjuvant setting: the Breast Cancer International
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Research Group 006 trial. Ann Oncol 2006;17:381-90.
25. Bergsland EK. Vascular endothelial growth factor as a
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against HER-2 (trastuzumab) for metastatic breast cancer: a
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model-based cost-effectiveness analysis. Ann Oncol 2005;16:
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factor receptor mutations in non-small-cell lung cancer: implica-
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Answer online at www.pharmacygateway.ca
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continuing education lesson
Targeted drugs for cancer treatment
Questions
1 Which one of the following statements is true
about targeted therapy?
a) Preferably the target functions exactly the
same in tumour and healthy tissue.
b) The target has been validated as a negative
prognostic factor.
c) Generally they are less expensive treatment
options than other therapies.
d) Hair loss is a common side effect.
2 Which of the following is true regarding tyrosine kinases?
a) They are usually found on the extracellular
surface of cells.
b) The BCR-ABL tyrosine kinase is usually in its
inactive form.
c) EGFR overexpression is common in non-small
cell lung cancer.
d) The EGFR and BCR-ABL tyrosine kinase are
the same tyrosine kinase.
3 Antibody-derived therapy is best described by:
a) It requires the use of a specific antibody for a
selected target.
b) Rituximab and trastuzumab have the potential to cause infusion-related reactions.
c) It has specificity for intracellular targets.
d) a and b are correct
e) a, b and c are correct
4 Which of the following statements are false
regarding angiogenesis?
a) It is stimulated by VEGF.
b) It typically produces irregular and convoluted
vessels in tumour tissue.
c) It is a process that is usually very active in
adults on a daily basis.
d) It is necessary for tumours to grow greater
than two millimetres.
CASE A
CM is a 68-year-old women with non-small cell
lung cancer and a nonsmoker.
5 Which one of the following statements about
erlotinib is true?
a) She will likely receive it as first-line therapy.
b) Drowsiness is its main side effect.
c) Her likelihood of a response is lower because
she is a woman and a nonsmoker.
d) Survival benefit has been demonstrated
when it was compared to placebo.
6 It will be important to counsel CM on her new
erlotinib prescription. Which of the following is a
side effect common to erlotinib?
a) There is a significant risk of nosebleeds.
b) It is preferable to take the dose with food.
c) There is a potential for rash.
d) Significant hair loss is likely.
7 CM also has a prescription for the following
medications. Which one would not be a problem,
if taken concurrently with erlotinib?
8
Answer online at www.pharmacygateway.ca
a)
b)
c)
d)
St. John’s wort
trimethoprim/sulfamethoxazole
itraconazole
warfarin
8 Eight days after starting her erlotinib, CM
notices an acne-like, nonpruritic rash on her
forehead and chin. What is the best management
option?
a) Stop therapy immediately.
b) Apply some benzoyl peroxide acne gel to the
lesions.
c) Use doxycycline 200 mg po daily x 6 weeks.
d) No treatment—rash may improve on its own.
9 Three weeks after starting therapy, CM
notices that her rash is now found on more than
50% of her body, and is itchy. Which approach to
treatment is inappropriate?
a) doxycycline 200 mg po daily
b) topical steroids to cover all of the rash
c) diphenhydramine prn
d) interruption in therapy should be considered
10 Rash with erlotinib is often a predictor of positive response.
a) true
b) false
11 Regarding the diarrhea that can develop
while a patient is on erlotinib, which answer is
the most correct?
a) Loperamide is rarely potent enough to treat
this type of diarrhea.
b) Dose reductions can be attempted if the diarrhea is significant.
c) Erlotinib must be abandoned.
d) Diarrhea is correlated with response to
erlotinib.
CASE B
BN is a 56-year-old male with a diagnosis of
chronic phase CML who will be starting therapy
with imatinib.
12 Which of the following is true?
a) He can continue to take the St. John’s wort
that he has been using for mild depression.
b) He should take imatinib on an empty stomach.
c) The risk of developing thrombocytopenia in
his case is very high.
d) Liver function tests should be done before
starting therapy.
13 After a few weeks of treatment, BN notices his
ankles and lower legs are swollen, but not red or
warm. What is the best treatment approach?
a) Lowering his dose would be helpful.
b) He was at a high risk of developing peripheral
edema due to his age.
c) Symptomatic relief may be obtained with a
diuretic.
d) a and c are correct
e) a, b and c are correct
14 BN has returned from a trip to Australia and
developed a deep vein thrombosis during the
flight. Warfarin treatment will be easily managed
while on imatinib.
a) true
b) false
15 When speaking to a patient before her first
trastuzumab infusion, which risk is it important
she be aware of?
a) Hair loss may occur.
b) Cardiac dysfunction occurs in > 50% of
patients.
c) She might develop a fever and chills that are
easily treated with acetaminophen and
diphenhydramine.
d) The risk of developing an infusion-related reaction is just as likely with the second infusion.
16 Which of the following is false regarding
cardiotoxicity with trastuzumab?
a) It is irreversible in most cases.
b) It is exacerbated when trastuzumab is given
concurrently with a chemotherapy in the
anthracycline family (e.g., doxorubicin).
c) Nocturnal dyspnea and peripheral edema
are potential symptoms of cardiac dysfunction.
d) It can be managed with medications used to
treat congestive heart failure.
17 Which is true regarding infusion-related reactions with rituximab?
a) Severe infusion-related reactions are common.
b) The risk is higher on the second infusion.
c) Fatalities are common.
d) Premedication with acetaminophen and
diphenhydramine are essential.
18 Angiogenesis is only stimulated by VEGF.
a) true
b) false
19 Which of the following statements is true
regarding bevacizumab?
a) It can cause significant nausea.
b) Nosebleeds are common and can be treated
conservatively.
c) Hair loss is common.
d) > 50% of patients develop sore ulcerated
mouths.
20 When counselling a patient on bevacizumab,
it is important to mention all of the following
except :
a) Blood pressure monitoring is important.
b) Any signs of abdominal pain with constipation
or vomiting should be reported to a physician.
c) Regular heart scans are required during
therapy.
d) It is important to let the oncologist know if
there are any surgical procedures pending.
Pharmacy Practice | September 2006