Download A Primer on Oral Anti- Cancer Therapy

Kristi Hofer, B.Sc.Pharm
October 29, 2013
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1. Identify the class/category of and mechanism of action of
common oral anti-cancer agents.
2. Identify the types of cancers that these agents are used in,
and provide examples of drug names.
3. Recognize educate patients on common side effects of oral
anti-cancer therapies.
4. Understand safe handling of oral anti-cancer agents in the
pharmacy as well as in the home.
5. Identify strategies for promoting safety in
prescribing, educating and monitoring oral anti-cancer
therapies
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No conflicts of interest to disclose
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Way of the future
◦ About 45% of new cancer drugs in Phase 2/3 trials are oral
◦ Preferred choice of provider & patient
◦ Universal: used in all types and stages of cancer
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Unique challenges
◦ Lack of formal guidelines & education materials
◦ Informing & monitoring patients
◦ Shift of responsibility to patient and families
Barton, 2011;Birner, 2003; Moody &
Jakowski 2010; NCCN, 2008;
Winkljohn ,2007
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80+% of patients prefer oral chemotherapy, but
only provided this is not at the expense of efficacy
◦ given at home (cited by 57% of patients)
◦ avoidance of venepunctures (55%)
◦ greater sense of ‘control’ over their treatment (33%)
O’Neill, VJ., Twelves, CJ.,2002
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Patient convenience / preference
Flexibility in dosing and scheduling
Prolonging drug exposure
Decreased resource utilization
Altered toxicities
Improved quality of life
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Studies show that both patients and health care
providers underestimate the impact on safety and
patient tolerance
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Drug-Drug Interactions Drug
Food Interactions
Adherence
Patient Monitoring
Cost
CANO position statement 2013
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“Anti-Cancer” treatments include:
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Cytotoxic agents
Hormonal agents
Immunotherapies
Targeted Therapies
“Supportive Care” medications include:
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Anti-emetics
Colony stimulating factors (g-csf; filgrastim)
Bisphosphonates
Antihistamines
Anticoagulants
Steroids
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Neo-adjuvant: Shrink tumour before surgery
Adjuvant: Cancer is removed by surgery. Reduce
chance of cancer coming back (relapse)
Metastatic: Shrink or control cancer growth to
improve quality of life (palliative)
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Treatment plans are called regimens:
◦ combination of cancer meds (oral and IV) plus supportive
care meds
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Treatment Cycles
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time period in between regimens
counted in days
Most cycles are 14, 21 or 28 days long
Treatment day = day 1
May have multi-day treatments, such as day 1, 8, 15 OR
day 1, 2, 3
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May include oral cancer meds, IV cancer meds or
both.
May include radiation therapy
◦ Radiation may be given before, after or during systemic
therapy
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Mechanisms of Action
Adverse Effects
Examples
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Hormonal therapy:
◦ interferes with the production or action of specific
hormones and causes the cancer to stop or slow its growth.
◦ Usually have less severe side effects.
◦ Side Effects include: hot flashes, nausea, fatigue, increased
lipids, bone loss
◦ Anti-estrogens, anti-androgens
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Examples: anastrazole, letrozole,
medroxyprogesterone, tamoxifen, bicalutamide,
abiraterone, enzalutamide
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Immunotherapy:
◦ alter the body’s response to the tumour, or
◦ stimulate the immune system to fight the cancer
◦ may be a compound that is already produced in the body,
but given in much larger quantities than a human body
produces.
◦ Side effects include: nausea, headache, myelosupression,
liver dysfunction (dose limiting), fatigue, depression
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Example: Interferon alpha-2b (Intron A)
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Targeted Therapies
◦ newer agents that have been designed to bind to extracellular targets on cancer cells.
◦ Often less toxic because they don’t kill healthy cells.
◦ Associated with unique side effects that are not
traditionally associated with chemotherapy.
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Cytotoxic agents:
◦ interfere with DNA or RNA processes and prevent cell
replication and function.
◦ non-specific action; also kill healthy cells.
◦ associated with significant side effects such as nausea,
vomiting, diarrhea, alopecia, myelosupression
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Cell Phase Specific
Non-Cell Phase Specific
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Toxic to proportion of cells in the phase that the
agent is active in
Ideally given as a “continuous infusion” (oral dosing
or frequent dosing)
Kill proliferating cells (schedule dependant)
Pyrimidine antagonists
Antifolates
Purine analogues
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Inhibit thymidylate synthase
Capecitabine:
◦ a pro-drug selectively activated by tumor cells
◦ undergoes a 3-step conversion to 5-FU, the last step being
phosphorylation by thymidine phosphorylase (TP).
◦ TP levels are higher in tumor cells than normal tissues,
therefore the systemic exposure of active drug is
minimized.
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Side effects: diarrhea, hand-foot syndrome, rash,
nausea/vomiting,
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Inhibits dihydrofolate reductase
Methotrexate
◦ Used in childhood leukemias
◦ Once weekly dosing
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Side effects: nausea/vomiting, rash,
photosensitivity, alopecia, myelosuppression,
increased LFTs
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Resembles guanine and is incorporated into DNA
Mercaptopurine/Thioguanine
◦ Hepatotoxicity, stomatitis, myelosupression
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Fludarabine – unique immune supression of thelper cells
◦ require prophylactic antibiotics
◦ Opportunistic infections, viral reactivation
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Exert effect throughout entire cell cycle
Kill is proportional to dose (not schedule)
Alkylating Agents: prodrugs which form covalent
bonds with DNA and break the DNA strand
◦ Nitrogen Mustards
◦ Nitrosoureas
◦ Triazenes
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Cyclophosphamide
◦ Dose limiting toxicity is myelosupression
◦ Nausea/vomiting, alopecia, infertility, secondary leukemias,
hemorrhagic cystitis
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Counselling:
◦ Take in the morning
◦ Drink 3 L fluid/day
◦ Void frequently (q2h)
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Used in lymphoma, breast ca, small cell lung ca
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Chlorambucil
◦ SE: immunosupression, anorexia
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Used in: CLL (chronic lymphocytic leukemia),
lymphomas
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Lomustine
◦ Nausea/vomiting, pulmonary toxicity,
◦ Delayed myelosupression (nadir at 4 weeks)
◦ Q 6 week dosing
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Counselling:
◦ Empty stomach
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Used in brain tumours
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Temolozomide
◦ Crosses blood brain barrier
◦ SE: Nausea/vomiting, increased LFTs, myelosupression
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Used in brain tumours, melanoma
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Most cause myelosupression
◦ May be dose limiting
◦ May require rest period in between cycles
◦ Fever/infection is an emergency- recommend immediate
assessment
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Changes in liver or kidney function, as well as
thrombocytopenia, neutropenia, anemia can occur
◦ Frequent bloodwork required
◦ Dose adjustments
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Not all cause alopecia or nausea/vomiting
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Therapy that is directed at a specific target on the
cell that controls or signals cancer growth,
proliferation and angiogenesis
Targets are often over-expressed in cancer cells
(less effect on normal cells)
Main targets:
◦ Cell surface markers (e.g. CD20)
◦ EGFR-epidermal growth factor receptor
◦ VEGF- vascular endothelial growth factor
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Unique side effects: skin rashes, diarrhea,
hypertension, photosensitivity
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Monoclonal Antibodies (IV)
Tyrosine Kinase Inhibitors
Miscellaneous Agents
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Erlotinib and Gefitinib:
◦ inhibit the intracellular phosphorylation of several tyrosine
kinases associated with transmembrane cell surface
receptors
◦ epidermal growth factor receptor tyrosine kinase (EGFR-TK)
is overexpressed on the cell surface of 50-80% of NSCLC.
◦ Inhibition decreases the growth, invasion, metastasis,
angiogenesis, and resistance to apoptosis
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Side effects: diarrhea, rash (“acne-like”), dry skin,
nausea/vomiting
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Erolitinib/Gefitinib cont’d
Counselling:
◦ Rash may be indicative of efficacy
◦ Do not use acne products
◦ Use moisturizers, sun screen, topical steroids
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Drug interactions, including warfarin
Used for: lung cancer (2nd and 3rd line), pancreatic
cancer
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Lapatinib:
◦ Tyrosine kinase inhibitor of EGFR and Her-2.
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Side effects: diarrhea, cardiac toxicity, rash, hand
and food syndrome
Used in: metastatic breast cancer (with
capecitabine)
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Sorafenib and Sunitinib
◦ inhibitor of multiple receptor tyrosine kinases (plateletderived growth factor receptors, vascular endothelial
growth factor receptors, stem cell factor receptor)
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Side effects: diarrhea, dyspepsia, stomatitis, handand- foot syndrome, rash, hypertension
Used in: advanced renal cell carcinoma
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Everolimus:
◦ mTOR inhibitors
◦ Mammalian target of rapamycin (mTOR) is a intermediary
signalling pathway which signals other events in the cell
cycle that control growth and angiogenesis
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Side effects: rash, asthenia, mucositis, nausea,
edema, anemia, hyperglycemia, hyperlipidemia,
hypertriglyceridemia
Used in: metastatic renal cell carcinoma
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Vemurafenib
◦ Inhibits MAP kinase signaling pathway through inhibition of
ATP binding to mutated BRAF preventing phosphorylation
and activation of downstream pathways
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Side effects: arthralgia, rash, alopecia, fatigue,
photosensitivity reaction, nausea, pruritus, and
skin papilloma.
Used in: metastatic melanoma (with BRAF mutation)
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Thalidomide and Lenalidomide
◦ Immunomodulator
◦ MOA not fully known
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Dispensed through RevAid programs
Side effects: somnolence, dizziness, constipation,
hypotension, rash, increased chance of blood clots
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Unique side effects may require special
considerations
◦ Immune modulated diarrhea requires high dose
steroids
◦ Rashes may be indicative of efficacy
◦ Rashes should be treated according to protocols;
avoid products that dry the skin
◦ Severe sun sensitivity
◦ May affect lipids, blood pressure, blood sugar and
require meds to treat
Anna is a 58 year old woman who was diagnosed with HER-2 positive
breast cancer. She had a right lumpectomy and started adjuvant
chemotherapy followed by radiotherapy. Because her cancer type is
hormonesensitive, she takes an aromatase inhibitor.
Anna is a retired lawyer and lives with her 65 year old husband, who is
also a lawyer and is in good health. She looks after her 4 year old
granddaughter on weekdays from 8 am to 6 pm. She takes no other
medications, apart from a mild painkiller occasionally for headaches.
Anna had been receiving adjuvant trastuzumab when she came in for a
follow-up visit and was found to have liver metastasis. After taking
into account Anna’s preference to receive oral therapy, her
oncologist, prescribed the combination of two oral agents:
capecitabine and lapatinib.The new treatment plan is for Anna to
receive 2000 mg/m2 of capecitabine, so she needs to take four 500
mg pills in the morning and three 500 mg pills in the evening for 14
days on a 3 week cycle. She is also to take 5 lapatinib pills daily, and
to stop taking the aromatase inhibitor pills. In total, Anna has to
take 12 pills per day on her treatment days.
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Lacks built-in safeguards and processes
◦ Multiple checks and established process for IV treatment
◦ Multiple opportunities to educate when on IV
◦ Physician can hand Rx directly to patient
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Dispensing in Manitoba
◦ Most oral agents dispensed in community pharmacies
◦ Community pharmacist does not have access to pertinent
information such as height, weight, bloodwork, treatment
plan/goal
◦ Community pharmacist may assume complete education
provided at CCMB
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Shift in responsibility to patients and families
◦ Correctly administer
◦ Monitor and manage side effects
◦ Identify side effects vs symptoms of cancer
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Complicated regimens
◦ May be chronic or cyclical
◦ Complexity of dosing schedule
◦ May be used in combination with IV or other oral
medications
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Common misconception that oral treatments are
safer than IV
◦ Less rigorous checking processes, communication plans,
patient education
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Poor adherence
◦ Seems less serious if treatments are oral
◦ Complicated regimens
◦ Chronic side effects
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Twice Before
Starting
(Clinic visit + phone call or 2nd
visit)
• Know why taking oral chemo
• Know how to take
• Know what to expect
10 to 14 Days after • Assess educational needs
• Assess tolerance
starting
• Assess ability to adhere
chemotherapy
Before Repeat
Prescriptions
(next cycle or 4-6 weeks)
D
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• Assessment
• Lab work
• Nurse/physician
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Twice Before
Starting
(Clinic visit + phone call or
2nd visit)
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• Know why taking oral chemo
• Know how to take
• Know what to expect
Rationale for 2 encounters
o Information overload at initial visit
o Learning needs reinforcement
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o Instructions reviewed for clarity once filled
o Assess need for compliance aids
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Clear, specific directions
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When and how to take medications
Number of pills not known in clinic
Calendars? Diaries?
Recognizing and managing potential side-effects
Triggers for contacting clinic staff
Reinforce with written materials
◦ Drug-specific information sheets
◦ Safe-handling information
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Multinational Association of Supportive Care
in Cancer (www.mascc.org)
MOATT guides you through all aspects of the
education process
Available in 12 languages
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4 Key Elements:
1. Key assessment questions
2. Generic education discussion points
3. Drug specific education
4. Evaluation questions to help ensure patient
understanding
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KEY ASSESSMENT QUESTIONS
1) What have you been told about this treatment
plan with oral medications?
* Verify that the patient knows that these oral
agents are for cancer and are taken by mouth for
their cancer.
2) What other medications or pills do you take by
mouth?
* If you have a list of medicines, go over the list with
the patient.
* If you do not have a list, ask the patient what
medicines he/she is taking, (both prescription and
non-prescription), herbs, complementary, or other
treatments.
MASCC TEACHING TOOL FOR PATIENTS
RECEIVING ORAL AGENTS FOR CANCER
(MOATT)©
3) Are you able to swallow pills or tablets? If no,
explain.
4) Are you able to read the drug label/information?
5) Are you able to open your other medicine
bottles or packages?
6) Have you taken other pills for your cancer?
This teaching tool has been prepared to
assist health care providers in the
assessment and education of patients
receiving oral agents as treatment for their
cancer. The goal is to ensure that patients
know and understand their treatment and the
importance of taking the pills/tablets that are
prescribed.
* Find out if there were any problems, for example,
taking the medications or any adverse drug effects.
7) Are you experiencing any symptoms that would
affect your ability to keep down the pills, for
example nausea or vomiting?
8) How will you fill your prescription?
* Delays in obtaining the pills may affect when the
oral drugs are started
The following are aspects that impact the
9) Have you had any problems with your
insurance that has interfered with obtaining your
medications?
adherence to treatment with oral agents
(pills/tablets) for cancer
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Patient Characteristics
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Drug
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Disease
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Treatment Plan
Special Considerations when assessing
patients receiving oral agents for cancer:
When teaching the patient, you may need to
adapt your teaching to accommodate special
considerations such as, age, feeding tube, vision
problems/color blindness, dietary issues, mental
problems (dementia, depression, cognitive
impairments).
Include family member or other healthcare provider
in this information.
* Recommended information to assess is noted in italics
© 2008 Multinational Association of Supportive Care in Cancer
PATIENT EDUCATION
Generic Education for All Oral Drugs
Discuss the following items with the patient
and/or caretaker.
1) Inform any other doctors, dentists or healthcare
providers that you are taking pills/tablets for your
cancer.
2) Keep the pills/tablets away from children and pets
and in a childproof container.
3) Keep the pills/tablets in the original container,
unless otherwise directed. It could be dangerous
to mix with other pills.
4) Wash your hands before and after handling the
pills/tablets.
5) Do not crush, chew, cut or disrupt your
pills/tablets unless directed otherwise
6) Store your pills/tablets away from heat, sunlight,
or moisture as it may degrade the pills/tablets,
potentially making them less effective.
7) Have a system to make sure you take your
pills/tablets correctly.
* Give the patient some ideas, such as timer, clock or
calendar.
8) Make sure you have directions about what to do if
you miss a dose
9) If you accidentally take too many pills or if
someone else takes your pills/tablets, contact
your Doctor or nurse immediately.
10) Ask your nurse or pharmacist what you should do
with any pills/tablets you have not taken or are
out-dated.
* The patient may be asked to bring unused
pills/tablets back to the next visit.
11) Carry with you a list of medicines that you are
taking, including your cancer pills/tablets.
12) Let us know if you have a problem with paying for
or getting your pills.
13) Plan ahead for travel, refills and weekends.
TM
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DRUG-SPECIFIC INFORMATION
Drug name (generic and trade)
__________________________________________
What the drug looks like
__________________________________________
EVALUATE
Have the patient and/or caregiver answer
the following questions to ensure that
they understand what information you
have given them.
Dose and schedule
How many different pills?
__________________________________
You have received a lot of information today.
Let’s review key points.
How many times a day?
___________________________________
What is/are the name(s) of your cancer
pill(s)/tablet(s)?
For how long?
__________________________________________
Where the drug should be stored
* Be specific, for example, away from heat (not in the
kitchen), humidity (not in the bathroom), sun (not on the
window sill)
__________________________________________
__________________________________________
What are potential side effects and management of
them?
* Include lab evaluations or any medical tests that will
be used for drug monitoring.
__________________________________________
__________________________________________
__________________________________________
__________________________________________
Are there any precautions?
__________________________________________
__________________________________________
__________________________________________
Are there any drug and food interactions?
__________________________________________
__________________________________________
When and whom to call with questions
* Give names and phone numbers here
__________________________________________
__________________________________________
When will you take your cancer pill(s)/tablet(s)?
Does it matter if you take this pill/tablet with food
or not?
Where do you plan to keep it?
When should you call the Doctor or Nurse?
Do you have any other questions?
Your next appointment is?
______________________________________
For problems, contact
______________________________________
______________________________________
______________________________________
______________________________________
______________________________________
Drug-Specific Education –
The following information relates to topics and
references for the specific treatment that the
patient is receiving.
Refer to drug specific information to educate the patient on
his/her pills/tablets
References
 Product package insert or prescribing
information
 http://www.cancerbackup.org.uk/Treatments/Ch
emotherapy/Individualdrugs
 Micromedix
 AHFS Drug Info.
 http://www.cancersource.com/LibraryAndResou
rces/DrugGuide/
 http://www.naturaldatabase.com
Add website addresses, email links, internet sites
Whichever tool is used to educate the patient,
include the following drug-specific information. You
can complete the form provided below and give it to
the patients using reference material you have on
the specific pills/tablets.
Drug name (generic and trade)
What the drug looks like
Dose and schedule.
How many different pills?
How many times a day?
For how long?
Where to store the drug
* Be specific, for example, away from heat (not in the
kitchen), humidity (not in the bathroom), sun (not on
the window sill)
What are potential side effects and management of
them?
* Include lab evaluations or any medical tests that will
be used for drug monitoring.
Are there any precautions?
Are there any drug and food interactions?
When and whom to call with questions
* Give names and phone numbers here
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10 to 14 Days after • Assess educational needs
• Assess tolerance
starting
• Assess ability to adhere
chemotherapy
o Pre-plan encounter (e.g. schedule phone call)
o Focus on more than just side effects
o How is life being affected?
o Referrals needed?
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Before Repeat
Prescriptions
• Assessment
(next cycle or 4-6 weeks)
• Lab work
• Nurse/physician
o Physician and/or specialized oncology nurse
o Toxicities and side effect management
o Required lab and imaging
D
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o Adherence assessment
o Medication reconciliation
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World Health Organization definition of adherence:
“The extent to which a person’s behaviour corresponds with
agreed recommendations from a health care professional”
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Ability to follow timing, dosage, frequency
Persistence –ability to maintain behaviours over
time
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Provider & Treatment-Related
Patient & Disease-Related
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Literacy level
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Language
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Motivation
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Social support
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Belief in efficacy of regimen
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Mental and physical health
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Self- efficacy
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Understanding goals of
treatment
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Complexity of regimen
Clarity of instructions
Degree of behavior
change needed
Relationship with health
care providers
Degree of concordance
among members of
health care team
Availability of team to
respond to symptoms
Elliot, 2008; Hartigan, 2003;; Marin & Baxeos, 2010;
Verhoef et.al, 2009; Winklejohn, 2oo7
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Dexamethasone: days 1,2, 3 4, 9, 10, 11,12,17,18,
19, 20 of a 28 day cycle
Hydroxyurea 500 mg twice daily on Mon, Wed, Fri,
and three times daily on Tue, Thu, Sat, Sun.
Temozolomide (ondansetron 30 min pre) once daily
days 1-21 and celecoxib twice daily days 1-28 of a
28 day cycle. Plus Septra DS once daily Mon, Wed,
Fri.
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Explain significance of adherence
◦ Essential to efficacy + evaluating efficacy
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Consider provider assumptions
◦ Cancer a motivator?
◦ Taking as prescribed?
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Encourage successful self-administration
 Contact: regular and ongoing
 Tools: Calendars, alarms, diaries, blister packs
 Phone calls
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Pharmacists working together
◦ Communicate treatment plans
◦ Suggest strategies to improve adherence
◦ Don’t assume patient has received adequate education at
CCMB
◦ Electronic prescription vs. hand-written
◦ Blister pack chemo drugs separately to promote adherence
and allow for dose modifications
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Electronic Rx
No abbreviations
Include parameters used to calculate dose
No refills! 1 cycle or 4 to 6 weeks
◦ Ensures proper assessment of patient including relevant
bloodwork
◦ Prevents toxicity (e.g. week off in between cycles)
◦ Enables repeated evaluation of adherence
◦ Prevents errors when dose adjustments are made
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All staff who may come in to contact with oral
cytotoxic agents should have appropriate training
◦ Attend training specific to their roles
◦ Safe handling of hazardous drugs
◦ Written plan for spill or accidental exposure
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Store hazardous drugs separately from other drugs
◦ Consider manufacturer specifications eg: protect from
light
Goodin 2011
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Wear disposable gloves when dispensing
◦ Wash hands before and after glove application
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Use separate equipment for dispensing
◦ Use disposable materials if possible
◦ Wash equipment after use
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Do not use automatic dispensing machines
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Compounding, splitting, crushing should be done
in BSC wearing personal protective equipment
Goodin 2011
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Patients and their caregivers need to be educated
about safe-handling of chemotherapy medications
at home
◦ Safe handling of medication
◦ Safe handling of body wastes
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Wear gloves when handling tablets or capsules
(caregiver)
◦ Wash hands after removing gloves
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Do not split or crush cancer medications
Tell your pharmacist if you cannot swallow the
drugs whole
Store drugs in a secure place away from heat &
moisture
Store drugs out of reach of children and pets
Take unused medications to a pharmacy
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Body waste is contaminated for about 48 hours
after the last dose of cytotoxic medication is taken
(IV or oral)
Wear gloves when cleaning up waste
Wash soiled clothes or linens separately
Wash hands well
Close toilet lid and flush twice
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If a spill occurs:
◦ Use spill kit if provided
◦ Wear gloves when cleaning up
◦ Wash surfaces twice
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All patients with home infusions of IV
chemotherapy receive a home spill kit.
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Oral chemo is “huge” now and in the future
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Presents unique challenges
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Depends on successful self-administration including
monitoring and some self-management of side-effects
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Education essential– multidisciplinary, intentional includes
the patient
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BC Cancer Agency drug monographs (www.bccancer.bc.ca)

CANO position statements 2013 ((http://www.cano-acio.ca)

Given, B., Spoelstra, S. & Grant, M. (2011). The challenges of oral agents as
antineoplastic treatments. Seminars in Oncology Nursing, 27, (2), 93-103.

Goodin S, Griffith N, Chen, B et al (2011). Safe Handling of Oral Chemotherapeutic
Agents in Clinical Practice: Reccomendations from an International Pharmacy Panel.
Journal of Oncology Practice, 7 (1), 7-12
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MASCC tool for patient adherence:
http://data.memberclicks.com/site/mascc/MOATT_English_2010.pdf
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O’Neill, VJ., Twelves, CJ., British Journal of Cancer, (2002) REVIEW: Oral Cancer
Treatment: developments in chemotherapy and beyond, 933-937

Spoelstra, S., Given, B. Given, C. & Grant, M. (2011). Policy Implications of Oral Agents.
Seminars in Oncology Nursing, 27, (2) 161-165

Weingart SN, Brown E, Bach PB et al.(2008) NCCN Task Force Report: Oral Chemotherapy.
Journal of the National Comprehensive Cancer Network, 6 (suppl 3), S-1-14
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