104 Seminars in Oncology Nursing, Vol 27, No 2 (May), 2011: pp 104-115

ORAL AGENTS IN CANCER

TREATMENT: THE CONTEXT

FOR ADHERENCE

DEBRA BARTON

Debra BarProfessor, On

Address co

AOCN�, FAA

ton 6-133, Ro

mayo.edu

� 2011 Els

0749-2081/27

doi:10.1016/j

OBJECTIVES: To review oral agents approved for cancer, discuss their

mechanism of action and/or molecular targets, and outline side effects and

challenges that impact adherence.

DATA SOURCES: Peer reviewed literature and on-line drug information.

CONCLUSION: Oral agents to treat cancer, although not new, are common and

increasing dramatically. The context of adherence to oral agents is complicated

by increased knowledge of food-drug interactions and combinations of agents

with overlapping or synergistic toxicity profiles.

IMPLICATIONS FOR NURSING PRACTICE: The role of nursing in the

administration and education of oral cancer treatments is critical to optimal

treatment outcomes.

KEY WORDS: Oral agents, oral adherence, side effects, small molecules,

chemotherapy

MANYmay remember when oral cancertreatment was the exception, pertain-ing to patients with select hemato-logic malignancies, such as the use of

chlorambucil for chronic lymphocytic leukemia.Later, oral equivalents for several injectable drugsbecame available, and the standard treatment for

ton, RN, PhD, AOCN�, FAAN: Associate

cology, Mayo Clinic, Rochester, MN.

rrespondence to Debra Barton, RN, PhD,

N, Mayo Clinic, 200 First Street SW, Charl-

chester, MN 55905. e-mail: barton.debra@

evier Inc. All rights reserved.

02-$36.00/0.

.soncn.2011.02.002

breast cancer often incorporated oral cyclophos-phamide.1 In such cases, for drugs with injectableequivalents, patients could receive their medica-tion intravenously if the oral medication was notwell tolerated or feasible.This paradigm has changed. Advances in molec-

ular biology have led to the discovery of newmolecular targets for cancer treatment, as well asto a better understanding about novel strategiesfor getting drugs successfully to their cellulartargets. Because many newer drugs are smallmolecules, this has led to a considerable increasein the number of oral agents coming into use.Oral agents, while becoming more common, arenot merely an option for convenient administra-tion, but oral administration is sometimes theonly route available.

ORAL AGENTS IN CANCER TREATMENT 105

There are many challenges related to oral agentsas treatment for cancer, not the least of these isadherence to taking the drugs. Moreover, atten-tion to numerous issues such as safety (rightdrug, right dose, right time), drug interactions,optimal pharmacodynamics and kinetics, andhandling and disposal is needed. This article willprovide an overview of the types of oral agentsthat are currently approved for use in patientswith cancer, briefly discussing their mechanismof action, indications, and side effects. Challengesrelated to the management of those side effects,including overlapping toxicities and combinationsof agents, will be addressed. Both traditionalchemotherapy agents and US Food and DrugAdministration (FDA)-approved targeted agentswill be discussed. Hormonal agents will not beincluded because they are well covered elsewherein the literature.2-4

TRADITIONAL CHEMOTHERAPY

Although the oral administration of chemo-therapy is not a new phenomenon, there is oneimportant change that can impact adherence. Asmore is known about the life and death of cancercells, living with cancer, rather than succumbingto the disease, is more common. Consequently,there is a growing trend for the need to take oralagents on maintenance schedules, requiringlonger term use. The use of long-term oral anti-cancer treatments is challenging because of thepossibility of cumulative toxicities and a decreasedability to cope with and/or tolerate side effectsover time.

Careful, ongoing monitoring for the occurrenceof side effects, and the ability to manage or dose-reduce early to avoid worse, irreversible toxicityis imperative. Patients need to understand underwhat circumstances they need to call theirproviders, as well as what strategies they need toincorporate to prevent and manage toxicities asthey manifest. Finally, as more is known aboutthe individual bioavailability of a medication andthe various genotypic and phenotypic issues thatcan impact this, more education on drug andfood effects is needed.

Agents that are typically given orally are listed inTable 1,5,6 along with their mechanism of action,oral use/indication, special considerations, andmost common side effect profile. By and large,

most of the oral chemotherapeutic agents are alky-lating agents that are not specific to the cell cycle.Alkylating agents exert their anticancer effects

by interfering with a cell’s process of alkylation,often by substituting a different molecule thanwhat is needed and also by cross-linking strandsof DNA.6 Alkylating agents, as well as other tradi-tional chemotherapy, are cytotoxic to most prolif-erating cells, not just cancer cells, because theseagents target cell division and growth processesused by all cells. Additionally, chlorambucil, inparticular, is cytotoxic to cells that are not in theprocess of proliferation.6

Side effects of traditional chemotherapy relate totheir effect on healthy cells that are more activelygoing through the cell cycle, such as the bonemarrow, gastrointestinal (GI) tract, skin, and hairfollicles.5More recently, there is acknowledgementthat nerve cell function can also be disrupted,resulting in neurotoxicities such as peripheralneuropathy, cognitive changes, mental status,andmoodalterations.7,8Neurotoxicities are partic-ularly challenging because the severity tends to becumulative, can be irreversible, and may notappear until after the nerve damage has alreadyoccurred; in other words, there are often no earlywarning signs.GI alterations can be a strong aversion for

patients needing to take chemotherapy on botha short- and longer-term basis. Although greatstrides have been made in the control of nauseaand vomiting in general,9 most of the data on anti-emetics reveal great control of vomiting, with lessattention paid to the efficacy related to nausea. Itis not known how well our current antiemeticstrategies prevent or manage nausea10 because ofthe frequent omission of this endpoint in past anti-emetic clinical trials. The assessment of daily,bothersome nausea and subsequent treatment,when needed, is an important factor in maintain-ing patients on oral chemotherapy.Fatigue is a common side effect of all cancer

treatment, including chemotherapy, and may bea major deterrent to staying on an oral regi-men.11,12 Other than an overwhelming sense ofbeing tired, important components of fatigueinclude pep, motivation, and energy.13 Being defi-cient in energy/motivation can impact a patient’sability to remember to take medications properly,decrease their appetite and/or ability to preparefood, thus affecting the bioavailability of somedrugs and, overall, negatively impact quality of

TABLE 1.Oral Chemotherapy Agents5,6

Agent Mechanism of Action

Oncology Oral Indication FDA-

Approved Special Considerations Side Effects - Common or Serious

Cyclophosphamide Alkylating agent-cell cycle

nonspecific

Very broad range of solid and

hematologic malignancies

Oral dosing is in range of 1-5 mg/

kg/day; can be used for

maintenance therapy; ongoing

hydration is critical to avoid

hemorrhagic cystitis, watch for

cardiomyopathy

Nausea, vomiting, leukopenia,

amenorrhea, alopecia,

cardiomyopathy, hemorrhagic

cystitis, infertility

Melphalan Alkylating agent-cell cycle

nonspecific

Palliative treatment for multiple

myeloma and epithelial tumors

of the ovary

Food decreases absorption, bone

marrow suppression/organ

failure can occur – assess risk/

benefit throughout treatment

Stomatitis, secondary

malignancies, bone marrow

suppression, acute renal failure

Temozolomide Alkylating agent-cell cycle

nonspecific

Refractory anaplastic

astrocytoma, glioblastoma

multiforme

Recommended to take on empty

stomach or at bedtime with

whole glass of water; used with

radiation therapy in glioblastoma

multiforme, maintenance

therapy used

Constipation, nausea, vomiting,

headache, seizures, fatigue,

secondary malignancies

Chlorambucil Alkylating agent-cell cycle

nonspecific

Hodgkin’s, non-Hodgkin’s

lymphoma, chronic lymphocytic

leukemia

Assess for infection risk, refer for

fertility options

Bone marrow suppression,

peripheral neuropathy, seizure,

drug fever, secondary

malignancy, infertility

Busulfan Alkylating agent-cell cycle

nonspecific

Palliative and chronic myeloid

leukemia, stem cell transplant

conditioning

Can be used as maintenance

(long-term), take on a regular

schedule, monitor complete

blood count, liver function, refer

for fertility options

Bone marrow suppression, rash,

nausea, vomiting, stomatitis,

insomnia, dizziness,

depression, anxiety, cough,

dyspnea, rhinitis, epistaxis,

hyperglycemia,

hypomagnesemia,

hypophosphatemia

Procarbazine Alkylating agent-cell cycle

nonspecific

Hodgkin’s disease, stages III/IV Alcohol use can cause negative

reaction, tyramine containing

foods can contribute to

hypertension, fertility consult,

pregnancy concerns

Nausea, vomiting,

myelosuppression, peripheral

neuropathy, depression,

nervousness, nightmares,

hallucinations, second

malignancies

Lomustine Alkylating agent-cell cycle

nonspecific

Intracranial tumors, Hodgkin’s

–secondary therapy

Myelosuppression is cumulative Myelosuppression, nausea,

vomiting, stomatitis, ataxia,

lethargy, confusion,

neurotoxicity

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Hexamethylmelamine Unknown; resembles but is not

alkylating agent; blocks

thymidine/uridine into DNA/RNA

synthesis

Ovarian cancer; persistent/

recurrent

Recommended to take after meals

and at bedtime; avoid vitamin

B6, cimetidine, monoamine

oxidase inhibitors,

antidepressants

Nausea, vomiting, diarrhea,

peripheral neuropathy,

myelosuppression

Methotrexate Antimetabolite-S phase in cell

cycle

Very wide range of indications in

solid tumors, non-Hodgkin’s

lymphoma and acute

lymphocytic leukemia

Food delays absorption and

decreases peak concentration;

attention to hydration,

gastrointestinal toxicity may be

exacerbated with NSAID use

Photosensitivity, rash, alopecia,

diarrhea, anorexia, nausea,

vomiting, stomatitis, bone

marrow suppression, liver/

kidney/lung dysfunction

Capecitabine Antimetabolite-interferes with both

DNA and RNA synthesis (5-FU

precursor)

Colon cancer, adjuvant and

metastatic; metastatic breast

cancer

Can be added to docetaxel,

bevacizumab, and oxaliplatin,

more recently sorafenib.

Needs to be taken twice a day.

Recommended to take within 30

minutes after a meal, to

decrease stomach irritation,

frequent INR checks if on

warfarin

Bone marrow suppression,

dermatitis, hand and foot

syndrome, stomatitis, nausea,

vomiting, diarrhea or

constipation, fatigue, loss of

appetite, abdominal pain

Etoposide Mitotic inhibitor-late S/early G2

phase in cell cycle, inhibits

topoisomerase II

Small cell lung cancer, refractory

testicular cancer

Pills need to be stored in

refrigerator, concomitant alcohol

not recommended; grapefruit

juice decreases absorption

Myelosuppression, alopecia,

diarrhea, anorexia, nausea,

vomiting, asthenia, malaise,

fever, shivering, inflammation of

mucous membranes

Abbreviations: FDA, United States Food and Drug Administration; NSAID, nonsteroidal anti-inflammatory drug; 5-FU, 5-fluorouracil; INR, international normalized ratio.

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108 D. BARTON

life. This negative sequelae can compromisea patient’s willingness to continue with treatment.

Various types of oral chemotherapy are ab-sorbed differentially based on the presence orabsence of food (as well as other drugs); andrecommendations vary regarding food and fluidintake.14 Capecitabine should be taken within 30minutes after a meal; while chlorambucil andmelphalan should be taken 30 to 60 minutesbefore eating.6 Cyclophosphamide, methotrexate,and procarbazine should be taken with a full glassof water.6 The variability in these types of instruc-tions can be confusing, difficult to implement(especially if patients are on yet other oralprescription drugs that require different butequally specific administration), and are anotherimportant issue to address when helping patientsadhere to their treatment regimen.

Behaviors that comprise a person’s normal dailyroutine may also be impacted by oral regimens.For those living in more temperate/southernclimates, sun exposure can be a daily occurrencewith outside hobbies being common, such asgardening, golfing, or hiking. Attention to agentsthat present the risk of photosensitivity, such asmethotrexate,6 providing counseling about life-style modification is needed.

Asmore is known about themetabolismof drugs,particularly related to cytochrome P450 metabo-lism, identification of drug interactions isincreasing. Cytochrome P450 is often referred toas CYP and is simply a process involving enzymesor proteins within the cells that allows them tometabolize, use, and discard various chemicals,including drugs. Cytochrome P450 varies in indi-viduals based on both genetic and phenotypicdetails. Age, liver function, and even heart failure,resulting in decreased organ perfusion, can impacthow drugs are metabolized.15 In addition, dietarysupplements, herbs, and foods can affect the wayan individual can use or discard drugs from theirsystem.14,16 The CYP enzymes can result inincreased drug toxicity, decrease drug efficacy, orcan increase or decrease other enzymes that cancause changes in how other drugs are metabo-lized.17 Almost monthly, new information aboutdrug interactions is discovered. It is critical thathealthcare providers assess what over-the-counter products patients are consuming andcheck the latest known interactions.

Important interactions related to traditionalchemotherapy involve primarily CYP3A4 andCYP2D6, with the latter enzyme being important

in the metabolism of tamoxifen. CYP3A4 is impor-tant in several chemotherapeutic agents; forexample, cyclophosphamide, etoposide, pacli-taxel, docetaxel, and vinca alkaloids.17 Therefore,drugs or herbal agents that inhibit or induceCYP3A4 can impact the efficacy or toxicity associ-ated with these agents. Aprepitant (an importantdrug for managing chemotherapy induced nauseaand vomiting) has been shown to be a moderateinhibitor of CYP3A4, and can, therefore,negatively interact with some chemotherapyagents.18 Grapefruit juice, and some otherfruit juices containing furocoumarins, inhibitCYP3A4 and CYP2C9.19,20 By inhibiting theenzyme responsible for metabolizing drugs, serumconcentrations can be increased, causingincreased toxicities. St. John’s wort, a popularherb taken for mild to moderate depression, canaffect a couple of different enzymes in the cyto-chrome P450 system and is therefore particularlyunwise to use with oral prescription agents.16

TARGETED ORAL AGENTS

Much of the knowledge about molecular biologyhas led to the identification of targets that areamenable to drugs that are small molecules. Bydefinition, small molecules are able to be givenorally, as opposed to large molecules that mustbe given by injection.21 There are several oralagents that have recently been FDA approvedand that are being incorporated into clinical prac-tice, but dozens more are in various phases of clin-ical trials and will likely be approved in the comingyears.22

Targeted therapies are directed toward a specifictarget that is believed to be preferentially ex-hibited by cancer cells, as opposed to healthycells. The targets can be cell surface markers orreceptors for proteins that cause the cell to prolif-erate, called ‘‘growth factors.’’21 These agents wereinitially thought to have fewer systemic sideeffects than traditional chemotherapy, becauseof their selectivity.23 However, as in all of humanbiology, there is now a realization that it is difficultto impact isolated cellular mechanisms. There isnow an understanding of cross talk and interac-tions between various cellular targets and molec-ular pathways. This has implications for thebreadth of side effects that are possible with theuse of these agents. Side effects associated withtargeted therapy can be difficult to manage with

ORAL AGENTS IN CANCER TREATMENT 109

standard medical approaches, and they can alsoexacerbate problems from pre-existing comorbid-ities. There can be a fairly high discontinuationrate with many of these agents, particularlywhen trying to combine them, because of overlap-ping and dose limiting toxicities.23

One of the important aspects of helping patientsadhere to oral treatment is to educate them aboutthe role of the therapy in the control of theirdisease, and by assertively helping patients eval-uate their personal risk versus benefit of the treat-ment. Despite the side effect profile of targetedagents, at least one review article highlights thefact that patients in several trials receiving treat-ment for renal cell carcinoma found the neweragents more tolerable and were more satisfiedwith their treatment than those on the older, stan-dard immunotherapy.24

The two most commonly used classes of oraltargeted agents are kinase inhibitors and antian-giogenic factors. Kinase inhibitors are agents thatblock the action of enzymes/proteins involved incell communication and growth. They can inter-fere with the receptors or inhibit the enzyme,and can be directed at multiple enzymes/proteinsor a single one. Kinase inhibitors can be in twoforms, one as monoclonal antibodies which arelarger molecules administered intravenously(often with the suffix ‘‘mab’’) or small moleculesthat are administered orally (often with the suffix‘‘nib’’). Antiangiogenic agents, and drugs thatinhibit vascular endothelial growth factor(VEGF), stop the ability of the cell to developand maintain their blood supply by blocking thevarious growth factors involved in generating thenew branches of blood vessels.21,23,25

VEGF is important in the development of newblood vessels from the existing network ofvessels.25,26 The specific functionof VEGF includesendothelial cell proliferation, movement, andsurvival when physiologic stressors are present,maintaining the permeability of capillaries andproducing nitric oxide which enhances vascularsmoothmuscle relaxation.Whenconsidering thesefunctions, it is easier to understand why the sideeffects associated with these agents include hyper-tension, cardiac effects, and bleeding.

Many of the newer agents are eliminated throughthe feces (as opposed to renal elimination); there-fore, dosing for renal function is not as much ofa concern as hepatic function. Many of the neweragents are highly protein bound, so patients withpoor nutrition who have low albumin concentra-

tions may have higher systemic concentrations,which will result in increased toxicity. Addition-ally, with drugs that have high protein binding,foods high in fat may compete for the same bindingsites on the albumin, so patients who eat high-fatfoods in conjunction with their drugs may experi-ence higher drug concentrations and may be atrisk for increased toxicity.14 An awareness ofpatients with a history of gastric surgery is alsohelpful, as these patients may have inadequateabsorption of drugs, vitamins, and minerals thatmay impact the toxicity profile. Food and smokingmay impact absorption of various agent, puttingpatients at risk for inadequate disease outcomes(if reduced concentrations) or increased toxicity(if increased concentrations). These issues are ad-dressed in Table 2, listing molecularly targetedagents that are approved,5,6 highlighting theirapproved indications, mechanism of action, andside effect profile.Nearly all of these agents are associated with

fatigue and/or asthenia and GI side effects of diar-rhea or constipation, nausea, vomiting, andanorexia.23,27 Both fatigue and GI side effectscan be very taxing on a patient and their family’scoping skills, impacting numerous activities ofdaily living and role functioning. The inability tofunction and have a decent quality of life becauseof extreme fatigue and the inability to eat, drink,or have GI regularity can easily be reasons forearly discontinuation of therapy. Hypothyroidismis a particular concern with sunitinib and pazopa-nib, and is at least one cause of fatigue that can beevaluated and managed medically.28-30

The management of cardiovascular changes, inparticular hypertension, is a newer problem incancer treatment. Cardiac toxicities have beenknown to occur with traditional chemotherapy,such as doxorubicin, and knowledge about cardiacchanges was brought even more to the forefrontwhen trastuzumab began to be used to treat breastcancer along with doxorubicin. However, severalcardiovascular changes, some perhapsmore subtle,have been identified with molecular therapy.23,25

QT interval prolongation and reduced left ventric-ular systolic dysfunction, myocardial ischemia,and heart failure are more rare, but are seriousadverse effects of agents that inhibit VEGF. Thereis a growingneed to collaboratewithproviders expe-rienced in cardiac management and health. Hyper-tension in patients receiving VEGF inhibitors isa particular problem that is described in a paperrecently published by the Cardiovascular Toxicities

TABLE 2.Oral Targeted Agents5,6

Agent Target

Most Common FDA-Approved Oncology

Indications Special Considerations Important Side Effects

Sunitinib PDGFR, VEGFR,

KIT, FLT3, RET,

CSF-1R

Advanced renal cell carcinoma,

gastrointestinal stromal tumors

(intolerable to imatinib)

Avoid St. John’s wort, monitor for adrenal

insufficiency after stress (ie, surgery),

no food effect, 1/2 life 40 to 60 hours,

monitor blood pressure, thyroid effects

Hypertension, skin changes, bone

marrow suppression, hypothyroid,

asthenia/fatigue, abdominal pain,

constipation, diarrhea, anorexia,

nausea/vomiting, taste changes,

inflammation of mucous membranes,

prolonged QT interval, left ventricular

dysfunction, gastrointestinal

perforation, pulmonary embolism

Sorafenib VEGFR, PDGFR,

FLT3, c-Kit, p-38

alpha, Raf - anti-

angiogenesis

Liver cancer- unresectable, advanced

renal cell cancer

Bleeding risk with concomitant warfarin;

high-fat foods decrease bioavailability,

take on empty stomach, monitor blood

pressure

Alopecia, hand-foot skin reaction, rash,

weight loss, abdominal pain, diarrhea,

anorexia, nausea, fatigue, increased

amylase/lipase, hypertension, pain,

headache, congestive heart failure,

hemorrhage, decreased phosphate

Pazopanib VEGFR, PDGFR,

FGFR, c-Kit, Ltk,

Lck, c-Fms

Advanced renal cell cancer Avoid grapefruit juice, food increases area

under the curve, take 1 hour before or 2

hours after a meal, do not crush

Hypertension, hyperglycemia, decreases

in magnesium, phosphate, mental

changes, diarrhea, nausea, vomiting,

fatigue, bone marrow suppression,

hypothyroid, prolonged QT interval

Lapatinib EGFR, HER1/HER2 Adjuvant and metastatic breast cancer;

inflammatory breast cancer

Avoid grapefruit juice, beware of CYP3A4

inhibitors, food increases systemic

exposure, take 1 hour before/after

meals: note that if prescribed with

capecitabine, capecitabine is takenwith

food, educate regarding schedule

Hand-foot skin reaction, rash, diarrhea,

nausea/vomiting, anemia, fatigue,

indigestion, pain in extremities, back

pain, headache, decreased left

ventricular function

Erlotinib EGFR Pancreatic cancer, non-small cell lung

cancer

Smoking decreases concentrations, food

increases absorption, take on empty

stomach, avoid grapefruit juice

Rash, edema, abdominal pain, fatigue,

diarrhea, bone pain, myalgias,

alopecia, anxiety, depression,

cerebrovascular accident, deep vein

thrombosis, gastrointestinal perforation

Gefitinib EGFR Non-small cell lung cancer Evaluate patients with new onset eye

symptoms (pain, corneal ulcer), no

impact of food, can dissolve in 1/2 glass

water if unable to swallow, do not crush

Acne, dry skin, rash, diarrhea, nausea/

vomiting, anorexia, asthenia, weight

loss

Nilotinib Bcr-Abl, PDGFR,

c-Kit

Chronic myelogenous leukemia, new

Philadelphia chromosome positive or

resistant to prior therapy

Avoid St. John’s wort, grapefruit juice,

food increases absorption, take 1 hour

before or 2 hours after meals, black box

warning regarding QT interval

prolongation, taking with food or in

Peripheral edema, rash, fatigue, bone

marrow suppression, dry skin,

constipation, diarrhea, nausea/

vomiting, arthralgias, myalgias, bone

110

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presence of low potassium,

magnesium, may increase this risk

pain, muscle spasms, hepatic toxicities,

prolonged QT interval

Dasatinib Bcr-Abl, SRC,

c-Kit, PDGFR

Resistant or intolerant Philadelphia

chromosome positive acute

lymphocytic leukemia, chronic, blastic,

accelerated chronic myelogenous

leukemia (resistant to imatinib)

Avoid St. John’s wort, little effect of food,

do not crush or cut tablets, no antacids

within 2 hours of taking agent

Fluid retention, rash, diarrhea, nausea/

vomiting, dyspnea, fatigue,

musculoskeletal pain, headache,

decreased calcium/phosphate, bone

marrow suppression, congestive heart

failure, prolonged QT interval,

gastrointestinal/cerebral hemorrhage,

liver function changes

Imatinib Bcr-Abl, c-Kit,

PDGFR

Refractory or relapsed Philadelphia

chromosome positive acute

lymphocytic leukemia, chronic

myelogenous leukemia,

gastrointestinal stromal tumor,

myelodysplastic syndrome (PDGFR

rearranged)

Watch CYP2D6 inhibitors (paroxetine,

fluoxetine), do not crush, can disperse

in 50 to 100 mL apple juice or water,

avoid grapefruit juice, take with meal

and full glass of water, contraception

required

Rash, edema, diarrhea, nausea/vomiting,

fatigue, bone marrow suppression,

arthralgias/myalgias, cramps,

musculoskeletal pain, headache,

dizziness, insomnia, cough, rigors

Lenalidomide Anti-angiogenic Multiple myeloma, myelodysplastic

syndrome

Contraception, no sperm donation 4

weeks post treatment, take with water,

do not crush, chew, or open tablets,

renal excretion, less protein binding

Peripheral edema, rash/pruritus,

constipation/diarrhea, nausea,

arthralgias, cramps, fatigue, dizziness,

insomnia, headache, pneumonia,

thrombosis, bone marrow suppression,

atrial fibrillation

Thalidomide Anti-apoptotic,

anti-angiogenic

Multiple myeloma Take with water 1 hour or more after

evening meal, renal excretion, birth

defect precautions

Edema, peripheral neuropathy, rash,

hypocalcemia, constipation, nausea,

leucopenia, confusion, somnolence,

tremor, thrombosis

Everolimus mTor Advanced renal cell cancer Use SPF 30 in sun, avoid grapefruit juice

and St. John’s wort, contraception up to

2 months post treatment, food

decreases absorption, do not crush or

chew, take with glass of water

Hyperglycemia, increased cholesterol

and triglycerides, rash, fatigue/

asthenia, fever, bowel movement

suppression, diarrhea, nausea/

vomiting, anorexia, stomatitis,

increased creatinine and liver function

tests, peripheral edema, hypertension,

pleural effusion

Abbreviations: KIT or c-KIT, proto-oncogenic receptor tyrosine kinase (CD117); c-Fms, proto-oncogene originally isolated from feline sarcoma virus; SRC, sarcoma proto-oncogene

tyrosine kinase; Bcr-Abl, oncogene fusion protein of BCR and ABL; CSF-1R, colony stimulating factor receptor; CYP, cytochrome-P; EGFR, epidermal growth factor receptor; FGFR,

fibroblast growth factor receptor; FLT3, FMS-related tyrosine kinase 3 ligand; HER1, human epidermal growth factor receptor 1; HER2, human epidermal growth factor receptor 2;

Lck, lymphocyte receptor kinase; Ltk, leukocyte receptor kinase; mTor, mammalian target of rapamycin; PDGFR, platelet derived growth factor receptor; RET, rearranged during

transection; SPF, sun protective factor; VEGFR, vascular endothelial growth factor receptor.

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112 D. BARTON

Panel of the Investigational Drug SteeringCommittee of the National Cancer Institute, alongwith monitoring and management recommenda-tions.25 Education and assessment regarding homeblood pressure monitoring is an important compo-nent of patient management on these agents; onethat can impact adherence if patients react to bloodpressure readings with the withholding of theircancer treatment.

Dermatologic toxicities including rash andhand-foot skin reactions are another group ofside effects that can dissuade patients from adher-ence to treatment.23 These side effects are moreseverely disfiguring than drug rashes seen withmore traditional agents.31 The rash induced byepidermal growth factor inhibitors, for example,can be associated with not only itching, but ispainful and physically bothersome, as well asemotionally distressing.31 Many review articleshave been written to describe the clinical practicefor managing this rash.31,33,34 However, despitebeing a focus of recent research, definitive preven-tion and treatment is not yet clear.

In addition to rash, a host of dermatologic effectscan result from kinase inhibitors. Hand-foot skinreaction (HFSR) is one of these, possibly becauseof the role of vascular epidermal growth factor inmaintaining adequate vascular function to repairthe results of trauma to the hands and feet.35 Otherdermatologic effects include xerosis of the skin,inflammation of mucous membranes, includingthose of the nose, oral cavity, vagina and perineum,overgrowth of eyelashes, and changes in thetexture, color, and growth of body hair.

Endocrine-metabolic effects of hypothyroidism,hyperglycemia, and other electrolyte changes arealso relatively new side effects, often requiringmedical management.23 Metabolic changes canbe difficult to monitor because the symptomscan overlap with other problems. For example,decreased magnesium and phosphate can mani-fest as muscle cramps, weakness, irritability,confusion, and depression. However, these arealso symptoms that can be associated with fatigue,nausea, use of pain medication, directly relate tothe drugs themselves, or result from coping withthe disease and treatment. Furthermore, hypo-phosphatemia can also impact calcium andvitamin D concentrations. Regular patient contactwith the same provider can provide the context toenable a good assessment of any changes, as wellas be the foundation for effective communicationand symptom management.

Interactions with food and other drugs are alsoa consideration with targeted agents. Food candecrease or increase the concentration of severalof the agents, including sorafenib, erlotinib, niloti-nib, everolimus, and pazopanib.6 Consequently,these drugs should be taken either 1 hour beforeor 2 hours after a meal. Food has no effect on su-nitinib, gefitinib, or dasatinib. A full glass of wateris important when taking imatinib, thalidomide,lenalidomide, and pazopanib. In addition, manyof these agents also interact with drugs that induceand inhibit CYP3A4, namely imatinib, dasatinib,gefitinib, erlotinib, pazopanib, sorafenib, andsunitinib.

COMPLEX ISSUES IN SIDE EFFECT MANAGEMENT

Overlapping ToxicitiesToxicities from oral agents can manifest as the

same side effect, but have very different etiologies.One example of this is fatigue. Sunitinib can causechanges in thyroid function, resulting in hypothy-roidism. It can also result in cardiac impairment,particularly left ventricular dysfunction. Both ofthese toxicities contribute to fatigue, but wouldbe managed differently. Another example pertainsto sorafenib. This agent causes hand and foot skinreaction, which can cause extensive, painful ulcer-ations or blisters on the feet and hands. Activity islikely to be curtailed because of this side effect, re-sulting in deconditioning, contributing to fatigue.Sorafenib can also cause a decrease in appetite,nausea, and diarrhea, all of which could impactnutritional status and hydration, further addingto fatigue. Finally, the drug itself is directly associ-ated with fatigue. Therefore, fatigue related to thisone agent, sorafenib, can have a three-prongedetiology, intensifying the experience of thesymptom but also compromising the ability tomanage it.

Lack of KnowledgeFor many side effects, the exact physiology is

not known. Therefore, research to evaluatemanagement strategies is often based on serendip-itous findings or extrapolation from related areas.Consequently, guidelines for the treatment ofvarious side effects, such as chemotherapy-induced neuropathy and skin rash, are based onbest practice and not on large, randomized clinicaltrials. The lack of insight about the physiologicprocesses that result in side effects is a particular

ORAL AGENTS IN CANCER TREATMENT 113

barrier to developing effective management strate-gies. In fact, research on the prevention of sideeffects is complicated by the fact that, in someinstances, the incidence of the side effect is anindicator of the therapy’s ability to hit the targetand efforts to prevent the side effect carry therisk of altering the efficacy of therapy. Oneexample of this is the rash associated with EGFRtherapy. Studies in various populations haveshown that the advent of a rash, as well as itsseverity, is associated with both tumor responseand survival.36

Combination TherapiesJust as it was discovered that combining tradi-

tional chemotherapy and hitting the cell cyclefrom more than one perspective was more effec-tive against cancer than single-agent therapy, sois the current thinking in the new molecular age.There will likely be increased efforts in the nextseveral years to combine small molecule tyrosinekinase inhibitors targeting the VEGF pathwaywith traditional chemotherapy agents, both oraland intravenous. The VEGF pathway is importantin both the development of blood vessels to helptumor growth (angiogenesis), as well as chemo-therapy resistance by increasing substances thatprotect cells from cell death (apoptosis).37 Recentproof of principle studies have been completedand reviewed by Boere et al.37 Trials are gettingunderway to seek FDA approval with such combi-nations as sorafenib and doxorubicin, gemcita-bine, or oxaliplatin.37 However, toxicity to thehands and feet with combination regimens canbe increased. For example, in one study, boththe incidence and severity of HFSR was signifi-cantly increased in patients receiving bevacizu-

TABLEResources for Oral Agent Sympt

Knowledge Need Agency or Institution

Drug interactions Indiana University School of Medicine,

Division of Clinical Pharmacology

Medscape

Side-effect

management

Oncology Nursing Society

Multinational Association of the

Supportive Care in Cancer

Physician Data Query

National Comprehensive Cancer Netwo

Patient education

resources

Oncology Nursing Society

American Society of Clinical Oncologis

mab and sorafenib compared with sorafenibalone.35 HFSR has some characteristics similarto hand and foot syndrome (HFS), namely, tender-ness and pain on the palms of the hands and solesof the feet. These are generally reversible whentreatment is stopped. However, HFSR and HFSare different side effects with unique characteris-tics and histopathology. HFSR begins 2 to 4 weeksafter treatment and presents as redness that mayor may not include blisters.32,35,38 This progressesto lesions that result from constant or too muchfriction or pressure.38 They can also be accompa-nied by numbness and/or tingling. As the use ofnewer agents in combination grows, being alertto situations where agents have overlapping orsimilar toxicities (such as capecitabine withhand-foot syndrome and rash and EGFR-inhibitors such as lapatinib with hand-foot skinreaction and rash) is warranted. Cumulative andoverlapping toxicities are major concerns forproviders and patients and need to be addressedearly and assertively so that patients can get theintended benefit from combination therapies.

CONCLUSION

Oncology is a rewarding but sometimes over-whelming field because of the rapid pace of scien-tific milestones achieved that may impact practiceand our patients. Keeping up with all of the newinformation in a timely fashion is difficult. Asnew therapy combinations emerge and side effectsand toxicities result, there are some resourcesavailable to help providers keep up with the infor-mation. A list of resources are listed in Table 3.

3.om Management/Interactions

Website

http://medicine.iupui.edu/clinpharm/ddis/

http://www.drugs.com/drug_interactions.php

http://www.ons.org/ClinicalResources/Symptom

www.mascc.org

www.cancer.gov/cancertopics/pdq/supportivecare

rk www.nccn.org

www.thecancerjourney.org

ts http://www.cancer.net/patient/

114 D. BARTON

Challenges in keeping current with side effects/toxicities and needed management strategies fornewer agents are compounded by a lack of cleardirection in the emerging literature. Papers aboutseminal clinical trials often do not provide thedata needed to understand what education ourpatients need or what side effects we need to beprepared to manage and when. This is becausemuch of the toxicity information is based onCommon Terminology Criteria (CTC) gradingand not patient-reported experience. Therefore,the severity, frequency, distress, and pattern ofside effects is not always well known, particularlywhen drugs are new on the market. These issuescan impact adherence. However, efforts to remedythis, including a revised version of the CTC(recently launched), as well as the developmentof a patient-reported version of the CTC, will behelpful in better understanding the toxicities thatresult from approved treatments that are experi-encing a broader use, as well as new treatments.It is important to assess the patient’s experienceof side effects and the success/satisfaction of theirmanagement strategies often and intervene early,when needed.

Another important consideration is that clinicaltrials for approved agents are generally conductedin very select populations with few to no comor-bidities. For example, studies with agents thatcan result in hyperglycemia often did not includediabetics, and studies with drugs that can causecardiovascular changes often did not includepatients with pre-existing cardiovascular symp-toms. Therefore, in concert with lessons previ-ously learned, the incidence and expression ofside effects with targeted agents and combinationsof drugs as they are used in our general oncologypopulation are, perhaps, likely to reveal anincreased prevalence and severity.Understanding the toxicities and nuances of oral

agents, including optimal pharmacodynamics, andbeing well versed in the information patients willneed to adhere to treatments they choose totake, will likely result in the best disease manage-ment and optimal patient outcomes. Successfullyhelping patients and their family members toprevent or treat side effects and counselingpatients in the practical aspects of oral drugtherapy is a critical nursing role.

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