342 Journal of Pain and Symptom Management Vol. 42 No. 3 September 2011

Original Article

Adverse Drug Reactions and DrugInteractions as Causes of Hospital Admissionin OncologyVanessa Miranda, MD, Angelo Fede, MD, Melissa Nobuo, BS, Veronica Ayres, BS,Auro Giglio, MD, PhD, Michele Miranda, MD, andRachel P. Riechelmann, MD, PhDABC School of Medicine (V.M., A.F., M.N., V.A., A.G., M.M.); and Medical Oncology Department

(R.P.R.), Instituto do Cancer do Estado de S~ao Paulo, Faculdade de Medicina da Universidade de S~ao

Paulo, S~ao Paulo, Brazil.

Abstract

Context. Although several studies have evaluated the frequency of adverse drug

reactions (ADRs) and drug-drug interactions (DDIs) in general medicine, fewstudies have looked at the epidemiology of adverse drug events (ADEs) in oncology.

Objectives. We sought to investigate how many hospital admissions in oncologyare related to a DDI or an ADR.

Methods. All cancer patients admitted to an oncology ward during aneight-month period had their charts retrospectively evaluated for reasons ofhospitalization, using a 4-point scale (definitely, probably, possibly, or unlikelyassociated) to classify admissions by their probability of being associated witheither a DDI or an ADR.

Results. From September 2007 to May 2008, there were 550 hospital admissionsand 458 were eligible. Among unplanned admissions (n¼ 298), 39 (13.0%, 95%confidence interval [CI] 9.4%e17.4%) were considered to be associated with anADE, 33 (11.0%, 95% CI 7.7%e15.2%) with an ADR, and six (2.0%, 95% CI 0.7%e4.3%) with a DDI. The most common DDIs involved warfarin, captopril, andanti-inflammatory agents, and the most frequent ADR was neutropenic feverpost-chemotherapy. Most patients were discharged completely recovered, buttwo patients died.

Conclusion. Approximately one in 10 unplanned hospitalizations of cancerpatients is associated with an ADE. Prospective and population-based studies arewarranted to evaluate their magnitude in oncology. J Pain Symptom Manage2011;42:342e353. � 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc.All rights reserved.

Key Words

Supportive care, toxicity, adverse drug reactions, oncology, drug interactions

Address correspondence to: Rachel P. Riechelmann,MD, PhD, Medical Oncology Department, Institutodo Cancer do Estado de S~ao Paulo, Faculdade deMedicina da Universidade de S~ao Paulo, Av. Dr.

Arnaldo 251, 5th Floor, S~ao Paulo, SP, 01246-000,Brazil. E-mail: rachelri2005@gmail.com

Accepted for publication: November 23, 2010.

� 2011 U.S. Cancer Pain Relief CommitteePublished by Elsevier Inc. All rights reserved.

0885-3924/$ - see front matterdoi:10.1016/j.jpainsymman.2010.11.014

Vol. 42 No. 3 September 2011 343Drug Interactions and Adverse Drug Reactions in Oncology

Introduction Patients and Methods

Adverse drug events (ADEs) relate to any

clinical or laboratory alteration incurred bya patient that is directly or indirectly associ-ated with an administered medication.1 AnADE can be either a drug-induced side effect(or adverse drug reaction [ADR]) or a drug-drug, drug-food, or drug-herb interaction.The World Health Organization defines anADR as ‘‘. one that is noxious, unintended,and occurs at doses normally used in man.’’1

With respect to drug-drug interactions(DDIs), pharmacology texts define them as in-stances in which a medication interferes withthe pharmacokinetic, pharmacodynamic, orpharmaceutical properties of another drug,resulting in an altered net effect of one orboth drugs.2

ADEs are a major concern in health care.3

Although several studies have evaluated thefrequency of ADRs and DDIs in general med-icine, few studies have looked at the epidemi-ology of ADEs in oncology. Because cancerpatients receive numerous medications, theyare at particular risk for an ADE, such asa DDI.4 Studies of ambulatory cancer patientshave shown that approximately one-third ofthem were at risk for DDIs, with most involv-ing medications to treat comorbidities, suchas anticoagulants and antihypertensives.4,5 Aretrospective evaluation of 100 hospitalizedcancer patients found that two-thirds hadbeen prescribed one or more drug combina-tions with the potential to interact duringhospitalization.6

Several studies have analyzed ADRs for pa-tients with generalmedical conditions. A recentsystematic review showed that approximately5%e6% of patients with different medical con-ditions present with an ADR as a contributingfactor to hospital admission.7 Information onfrequency of ADRs as a cause of hospitalizationin oncology is scarce. An evaluation of causes ofdeath in a Norwegian hospital identified 18%of more than 700 deaths to be associated withan ADE and 4% of all cancer-related deathswere likely to be associated with a seriousinteraction.8

Given the lack of information on the epide-miology of ADEs in oncology, we sought to as-sess how many hospital admissions in oncologyare associated with a DDI or an ADR.

Study DesignThis was a retrospective cohort study of all

consecutive cancer patients admitted to theoncology ward of a teaching hospital (MarioCovas) located in the greater Sao Paulo areain Brazil, during an eight-month period. Thehospital is a 300-bed public and teaching in-stitution that serves more than three millionpeople. The local ethics board reviewed andapproved the study.

We reviewed the medical records of consec-utive adult cancer patients admitted at our in-stitution to identify hospital admissions thatwere possibly associated with an ADE. Patientsreceiving treatment within a clinical trial wereexcluded. ADEs involving food-related interac-tions, multivitamins, and herbs were notconsidered.

Each hospital admission was evaluated by twoindependent and blinded investigators whoevaluated the cause(s) of admission and classi-fied it by its probability of being associatedwith either a DDI or an ADR. After classifyingthe admission, the investigators thoroughlyreviewed the medical records to gather infor-mation about patient demographics, tumorcharacteristics, and type of treatment receivedwithin four weeks of admission, comorbid ill-ness(es), andmedications used before hospital-ization. A comorbid condition was defined asa clinical situation that required pharmacologi-cal intervention, and its severity was gradedusing the Charlson Comorbidity Index.9 TheCharlson Comorbidity Index was initially devel-oped to score the risk of death among hospital-ized noncancer patients. Although it has notbeen validated in the oncology population, weconsidered it acceptable to use as a measureof comorbidity severity in this study. Thenumber of medications for each subject was cal-culated by summing all pharmacological com-pounds, and each one was considered anindividual medication for analysis, regardlessof drug schedule; for example, commercialcombinations of oxycodone/acetaminophenwere counted as two drugs, oxycodone and acet-aminophen, and short- and sustained-releasemorphine was counted as one drug. Multivita-mins, as described above, were not considered.

For admissions suspected to involve an ADE,additional information was gathered on patient

Table 2Patient Characteristics

Characteristics n (%)

All patients 264 (100)

Median age, range 58 (18e91)

SexMale 142 (54)Female 122 (46)

Cancer typeGastrointestinal 76 (28.8)

344 Vol. 42 No. 3 September 2011Miranda et al.

outcomes (stable outcome: when the patientwas kept on the ward and had no life-threatening complications; unstable outcome:when the patient was transferred to an intensivecare unit and/or had life-threatening complica-tions; or fatal outcome), clinical status atdischarge (completely recovered, partially re-covered, or death), need for invasive procedureto treat ADE complications, andneedof special-ist consultation.

Hematologic 48 (18.2)Breast 33 (12.5)Genitourinary 29 (11)Lung 25 (9.5)Gynecologic 14 (5.3)Other 39 (14.7)

Comorbid illnessesYes/no 116 (44)/148 (56)Median Charlson Index (range) 2 (0e7)

Receipt of systemic chemotherapy within four weeks ofadmissiona

Yes 152 (58)No 112 (42)

Note: For patients with more than one admission during the studyperiod, only the first hospitalization was evaluated.aIf the patient had received chemotherapy within four weeks ofhospitalization.

Classification of Reasons for HospitalAdmission

Causes of admission were examined inde-pendently by two blinded investigators (MCM,MNF), using a 4-point scale (Table 1) devel-oped by the authors. They agreed on all butseven classifications, when a third investigator(RPR) was consulted, and consensus wasachieved. The scale was adapted from theWorld Health Organization causality criteria(probable, possible, and unlikely) and pilotedin the first 30 hospital admissions.10 Afterminor fine-tuning, the scale classified admis-sions into four different categories: definitelyassociated with an ADE, probably associatedwith an ADE, possibly associated with an ADE,or unlikely associated with an ADE.

The classification of causes of hospital admis-sionwas basedonmedical record review anddis-cussion with medical oncologists. To classifyeach admission, the authors reviewed the com-pletemedical history that led to hospitalization,including the medications used by patients im-mediately before and at the time of admission,symptomatology, tumor type and stage, and on-cology treatment. In addition, patient medica-tion lists at the time of admission were enteredinto the Drug Interaction Facts software version4.0 (available from www.factsandcomparisons.com, Lippincott Williams & Wilkins, St. Louis,

Table 1Classification of Causes of Hospital Admission

Type of HospitalAdmission

Probability of an ADEa BeingAssociated with Hospitalization

1 Definitely associated. ADE was thesole cause of hospital admission.

2 Probably associated. ADE significantlycontributed to hospital admission.

3 Possibly associated. ADE somewhatcontributed to hospital admission.

4 Unlikely associated.

aAn ADE includes both ADR and DDI.

MO), which contains a comprehensive databaseof drug monographs and DDI lists, and whichhas been used in other studies.4,5 Subsequently,the information about drugs was put in the con-text of medical history at admission and dis-cussed among the authors, followed bydiscussionwithmedical oncologists.Whenobvi-ous drug-unrelated causes of admission wereidentified, the admission was regarded as un-likely associated. Examples of such admissionsinclude the following: disease progression, ad-missions to treat patients with continuousinfusion chemotherapy, or elective colostomyreversal. The authors agreed on all classi-fications except for one case for which theadmission was considered as a drug interaction-related hospitalization, but the actual druginteraction occurred during hospitalization andnot as the primary cause of admission. The pa-tient was admitted for breast cancer surgeryand developed postoperative hemorrhage sec-ondary to a drug interaction between enoxapar-in and aspirin. Details are presented in Table 4.After the initial classification, the investiga-

tors evaluated the cause of each admission inan attempt to enhance the internal validity ofthis study, that is, to focus on the admissionsthat were not elective hospitalizations and do

Table 3Admissions Associated with DDIs or ADRs

Characteristics DDI, n¼ 6 ADR, n¼ 33 (100%)

Median age (range) 58 (39e72) 54 (18e75)

Cancer typeBreast 2 1 (3)Lung 1 4 (12.1)Gastrointestinal 0 9 (27.3)Gynecologic 0 1 (3)Hematologic 1 14 (42.5)Genitourinary 1 0Other 1 4 (12.1)

Presence of comorbid illnessYes 6 9 (27.3)No 0 24 (72.7)

Receipt of chemotherapya

Yes 0 29 (87.9)No 6 4 (12.1)

Median lengthof admission(days, range)

7 (6e37) 6 (1e18)

aReceipt of systemic chemotherapy within four weeks before hospi-tal admission.

Vol. 42 No. 3 September 2011 345Drug Interactions and Adverse Drug Reactions in Oncology

not reflect the scenario of admissions secondaryto cancer-related complications. The admis-sions were then considered either planned(elective scheduled interventions, such as portinsertion, continuous infusion chemotherapy,and elective biopsies) or unplanned (when itwas an urgent situation, mostly clinical com-plications from cancer or its treatment). Thefocus of this study was the unplanned hospitaladmissions (UHAs).

Statistical ConsiderationsTwo previous studies4,5 with nearly 400 pa-

tients found a 30% frequency of potentialDDIs with a 10% variance for the 95% confi-dence interval (CI). Based on these results,we determined that 400 hospital admissionswould be sufficient to evaluate how many ad-missions were caused by ADEs among cancerpatients. We used summary statistics to de-scribe patient characteristics and frequencyand types of hospital admissions associatedwith an ADE, separately for ADRs and DDIs.The unit of analysis was hospital admission;therefore, the same patient could be includedmore than once. Logistic regression was usedto identify factors associated with being hos-pitalized for an ADR (admission definitely,probably, or possibly associated with an ADEvs. unlikely), considering planned hospitaladmissions and UHAs. The small number of

admissions associated with a DDI preventedany exploratory analysis. Independent vari-ables tested included the following: age (me-dian age: 57 years, <57 years, or $57 years),cancer type (solid or hematological), severityof comorbid conditions (median Charlson Co-morbidity Index: 2, score <2, or $2), receiptof chemotherapy within four weeks of hospitaladmission (yes or no), and number of medica-tions taken by patients at hospital admission(median number of drugs taken by patient:3, <3, or $3). For binary variables, the groupat lower risk of the outcome was chosen asthe referent. Variables with univariate P-values<0.1 were entered into the multivariablemodel. In the multivariable model, predictorswere considered statistically significant if theP-value was <0.05. The Statistical Packagefor the Social Sciences version 13 (SPSS, Inc.,Chicago, IL) was used for all analyses.

ResultsFrom September 2007 to April 2008, there

were 550 admissions and 458 were eligible;92 were excluded because they were participat-ing in clinical trials. Many patients were admit-ted more than once during the study period:39 patients were admitted twice, and 41 wereadmitted more than twice. Table 2 summarizespatient characteristics considering only oneadmission (the first admission) per patient(n¼ 294). The median age was 58 (range15e91), more than half were male, the mostcommon tumor type was gastrointestinal, andthe median number of drugs per patient wastwo (range 1e8).

Among all 458 hospital admissions, 160 wereplanned and 298 were UHA. The most fre-quent reasons for planned hospitalizationwere scheduled intravenous chemotherapyadministered by continuous infusion (36%),surgical intervention (12%), and diagnosticworkup (9%). The most common causes ofUHA were clinical deterioration requiring sup-portive care and/or pain control (30%). Con-sidering only UHA, 39 admissions (13.0%,95% CI 9.4%e17.4%) were considered to beconsequent to an ADE: six because of a DDI(2.0%, 95% CI 0.7%e4.3%) and 33 (11.0%,95% CI 7.7%e15.2%) because of an ADR(Table 3). The DDIs involved warfarin,

Table 4Description of Hospital Admissions Associated with Drug Interactions

Drug Combination

Probability of anADE to be Associatedwith Hospitalization

Medical History atAdmission

Cause ofAdmission Mechanism

Length of Admission(Days)/Evolution/Clinical

Status at Discharge

Phenyoinþ warfarin(Nappi, 1979)14

Definitely associated. 54-year-old female with advancedbreast cancer who was takinglong-term warfarin presentedwith deep venous thrombosisafter starting phenytoin formultiple brain metastasis.

Deep venousthrombosis

Phenytoin induces warfarinhepatic metabolism withconsequent reduction inits anticoagulant effect.

Six/stable/completelyrecovered.

Captoprilþhydrochlorothiazide(Clarke et al., 1991)25

Probably associated. 54-year-old female with advancedbladder cancer on exclusivesupportive care, type II diabetes,and high blood pressure treatedwith hydrochlorothiazidepresented with asthenia andsymptoms of arterialhypotension after startingcaptopril. Captopril wasstopped and blood pressurenormalized.

The additive effect of the twoantihypertensive agents coupledwith the frail clinical conditionof the patient may have led tohospital admission.

Arterialhypotension

Additive hypotensive effects. Seven/stable/completelyrecovered.

Captoprilþdexamethasonea

Probably associated. 80-year-old male withnon-Hodgkin’s lymphoma,receiving supportive careexclusively, had chronicrenal failure and arterialhypertension controlledwith captopril andhydrochlorothiazide for thepast four months, presentedwith high blood pressure afterstarted on high-dosedexamethasone. Blood pressuredecreased after the patient wasgiven antihypertensive agents.

Arterialhypertension

Dexamethasone inducessodium retention, whichantagonizes hypotensiveeffects of captopril.

12/stable/completelyrecovered.

Warfarinþomeprazole(Unge et al., 1992)26

Definitely associated. 71-year-old female with advancedthymic carcinoma not receivingcancer-directed therapy, withhistory of arterial hypertensionand chronic atrial fibrillation,

Upper digestivehemorrhage

Omeprazole inhibitshepatic metabolismof warfarin, enhancingits anticoagulanteffect.

37/short-term unstable/completely recovered.

346

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daetal.

was admitted for upperdigestive hemorrhage andINR¼ 6. The dose ofomeprazole was increased to40 mg/day po a few daysbefore admission.

Warfarin was discontinued untilINR was 3, and a low molecularweight heparin was started.

Aspirinþ enoxaparin(Macie et al., 2004)15

Definitely associated. 63-year-old female with localizedbreast cancer, arterialhypertension controlledwith captopril andhydrochlorothiazide, hadrecent breast surgery and wasstarted on prophylactic lowmolecular weight heparin.Presented with surgical scarbleeding after restartedon aspirin.

72-year-old male with extensivesmall-cell lung cancer, not onchemotherapy, known history ofarterial hypertension and whowas taking long-term aspirinand omeprazole, presented withmelena a few days after startingdexamethasone for bone pain.He was admitted, and a gastricbleeding ulcer was diagnosed byupper endoscopy. Red bloodcell transfusion was required.

Post-surgicalbleedingand melena

Hemorrhage from thecombination of ananticoagulant and anantiaggregation agent

Seven to 18 days/short-termunstable/completelyrecovered

INR¼ international normalized ratio.aThe interaction between captopril and dexamethasone is considered theoretical, with no clinical case reported in the literature. We considered it clinically significant because the patient had arterial bloodpressure under control before admission.

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348 Vol. 42 No. 3 September 2011Miranda et al.

captopril, and anti-inflammatory agents andanticonvulsants (Table 4). The most frequentADRs were neutropenic fever (20 instances)caused by cytotoxic chemotherapy (Table 5).

Most patients admitted for an ADE wereclinically stable (n¼ 33/39, 84.6%) and recov-ered completely by the time of discharge(n¼ 34, 87.2%). Two of 20 patients whowere admitted for febrile neutropenia diedof sepsis (mortality rate¼ 10%, 95%CI¼ 1.2%e31.6%). A 60-year-old male withadvanced non-small cell lung cancer whohad received carboplatin and paclitaxel twoweeks before admission was admitted to treatfebrile neutropenia; he developed hemody-namic instability and died on the ward afterthree days. The other patient was a 32-year-old female with localized breast cancer whowas being treated with adjuvant cyclophospha-mide, methotrexate, and leucovorin. She wasadmitted because of febrile neutropenia andhemodynamic instability. She died after 14days. Both patients received standard carewith broad-spectrum antibiotics, blood trans-fusion, and granulocyte-colony stimulatingfactors (G-CSF).

Univariable analysis (n¼ 458) identifiedthe number of medications taken by patients,receipt of systemic chemotherapy within fourweeks of admission, and cancer type as riskfactors for patients to be hospitalized for anADR (Table 6). In adjusted analysis, cancertype and receipt of chemotherapy remainedsignificant. Patients with hematologic malig-nancies were 12 times more likely to be admit-ted for an ADR than were those with solidtumors (odds ratio [OR]: 12.1, 95% CI5.9e25.0; P< 0.0001). Patients who receivedchemotherapy within four weeks before hos-pitalization had a tenfold risk of being admit-ted for an ADR than were those who did notreceive chemotherapy within this time frame(OR: 10.8, 95% CI 5.3e22.1; P< 0.0001).

DiscussionThe present study showed that one in 10

cancer patients was hospitalized to treat anADR. Although febrile neutropenia was obvi-ously common, other ADEs, including DDIsand ADRs, also were identified. Althoughmost patients recovered and were discharged

from hospital in good clinical condition, twopatients admitted for febrile neutropeniadied despite receiving standard treatment.We are unaware of studies on the frequency

of ADEs as causes of hospitalization in oncol-ogy. A recent systematic review of 25 studiesin general medicine conducted over the last19 years demonstrated that approximately 6%of adult patients and 11% of the elderly wereadmitted to treat complications from ADRs,with the drugs most commonly involved beingcardiovascular medications, nonsteroidal anti-inflammatory drugs (NSAIDs), and centralnervous system drugs.7 A Dutch retrospectivecohort of more than 3500 patients with differ-ent illnesses also found a similar prevalence ofhospitalization for ADRs (5%), and in 0.3% ofpatients, the outcome was fatal.11 In that study,neutropenic fever was among the most com-mon causes of admission.Because cancer patients often receive che-

motherapy with a substantial risk of side ef-fects,12 their chance of being hospitalizedfor ADEs is expected to be higher than thatfor patients without cancer. Moreover, drugpharmacokinetics may be altered in cancerpatients because of malnourishment, organdysfunction, and edema. Indeed, we foundthat 12.7% of hospital admissions were associ-ated with an ADE, roughly triple the 5% ratereported for adult noncancer patients.7 Thisis likely caused by cytotoxic chemotherapy,which is known to be highly toxic. Our multi-variable analysis showed that cancer patientswho received chemotherapy close to admis-sion were at risk of being hospitalized for anADR in comparison with those who did not.Similar to the Dutch cohort,11 we identifiedfebrile neutropenia as a common ADR lead-ing to hospitalization.Presence of hematological malignancies was

a risk factor for an ADR-associated hospitaliza-tion. Febrile neutropenia was responsible forhospital admission for one in 29 U.S. cancer pa-tients receiving cytotoxic chemotherapy from1999 to 2005 and for one death for every 14 hos-pitalized patients.13 Themortality rate of febrileneutropenia among our patients was 10%,which does not differ significantly from that re-ported for the U.S. patients, despite probabledifferences in socioeconomic status. The U.S.study also found that hospitalization for neutro-penia was more common in patients with a

Table 5Description of Hospital Admissions Associated with ADR

ADRNumber ofInstances

Probability of anADE to be Associatedwith Hospitalization Medical History at Admission

Length of Admissions (Days)/Evolution/Clinical Status at Discharge

Febrile neutropeniapost systemicchemotherapy

20 Definitely associated. Patients with various tumor types (nine hadhematological cancers) presented with feverand neutropenia seven to 20 days after receiptof cytotoxic chemotherapy. Patients did notreceive prophylactic colony stimulatingfactors but all received it while in hospital totreat febrile neutropenia.

Median of seven days (range 2e14)/17 patientshad a stable clinical course, one patient wastaken to the intensive care unit; all 18 weredischarged completely recovered. Twopatients died in hospital.

Mucositis after systemicchemotherapy

6 Definitely associated. Four patients with non-Hodgkin’s lymphomasand two with gastric cancer developed oraland/or intestinal mucositis after receivingchemotherapy (methotrexate orfluoropirimidines). Patients received localoral mouthwash, painkillers, hydration, andsometimes, antibiotics.

Median of seven days (range 5e8)/all patientsexcept one had a stable clinical course andwere discharged completely recovered. Onepatient had hemodynamic instability becauseof dehydration but recovered later after IVfluids.

Chemotherapy-inducednausea and vomiting

1 Definitely associated. 34-year-old male with colorectal cancer treatedwith Folfox regimen. He took steroids forchemotherapy-induced nausea and vomitingprophylaxis, but four days after treatment, hedeveloped severe nausea and vomiting andwas admitted to receive IV fluids and IVantiemetics.

10 days/stable clinical course/completelyrecovered.

Constipation andabdominal pain(Becouarn andRougier, 1998)27

3 Definitely associated. Two patients (36 and 56 years old) withadvanced colorectal cancer were treated withFolfox and a 70-year-old male also withcolorectal cancer not receiving chemotherapybut tramadol 40 mg/daily po developedsevere constipation and abdominal pain. Theywere treated with stool softeners, laxatives,fluids, nonopioid analgesics; the dose oftramadol was decreased to 300 mg/day po,and stool softeners were given prophylatically.

Seven to 15 days/stable clinical course/discharged in good clinical condition.

ATRA syndrome(De Bottonet al., 1998)28

1 Definitely associated. 75-year-old male with acute promyelocyticleukemia who was receiving ATRA developedATRA syndrome with dyspnea, prolongedfever, and asthenia. He was admitted andtreated with dexamethasone.

Spent seven days in hospital/stable clinicalcourse/discharged completely recovered.

Arterial hypertensionand seizures(Chu et al., 2007)16

1 Definitely associated. 63-year-old male with advanced non-small celllung cancer, with no evidence of brainmetastasis and no known comorbid conditionsstarted treatment with platin-basedchemotherapy combined with bevacizumab.After onemonth, the patient was admittedwithhypertensive crisis and seizures. He received

Spent four days in hospital/good clinical coursebut was discharged with high blood pressure.

(Continued)

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Table5

Continued

ADR

Number

of

Instan

ces

Probab

ilityofan

ADEto

beAssociated

withHospitalization

Med

ical

History

atAdmission

Len

gthofAdmissions(D

ays)/Evolution/

Clinical

Statusat

Disch

arge

antihypertensive

agen

tsan

dan

tico

nvulsan

ts,

andbevacizumab

was

stopped

.Cereb

rovascularisch

emia

(Czaykowskiet

al.,1998;29

Numicoet

al.,20

05)3

0

1Probab

lyassociated

.61

-year-old

malewithad

vancednon-smallcell

lungcancer,typeII

diabetes

(taking

metform

in),

andarterial

hypertension

controlled

withaten

ololan

den

alap

ril.

Developed

cerebralvascularisch

emia

during

infusionofcisplatin60

mg/

m2.

Cisplatinwas

stopped

,an

dthepatientwas

admittedan

dtake

ncare

ofbyaneu

rologist.

Thevasculartoxicity

inducedbycisplatin

coupledwithch

ronic

highbloodpressure

anddiabetes

mighthaveco

ntributedto

the

cerebralisch

emia.

Spen

tfive

daysin

hospital

andwas

disch

arge

dpartially

reco

vereddaneu

rologicalmotor

defi

citremained

.

Folfox¼fluorouracil,leuco

vorin,an

doxaliplatin;ATRA¼alltran

s-retinoic

acid;IV

¼intraven

ous.

350 Vol. 42 No. 3 September 2011Miranda et al.

hematological malignancy than for those withsolid tumors.13 These findings reflect the in-tense anticancer regimens coupled with the un-derlying aggressive nature of these diseases.Cancer patients usually receive many medi-

cations to treat comorbid illness and/or assupportive care. Two studies by Riechelmannet al.4,5 showed that each additional drugtaken by patients increases the risk of DDIs,although the number of medications takenby patients was not a significant risk factorfor an ADR in the adjusted analysis. It is pos-sible that type of drug is more importantthan the number of medications in predispos-ing patients to experience ADRs.The proportion of DDIs leading to hospital

admission of cancer patients is unknown.Among our patients, six patients were hospi-talized to treat the clinical consequences ofDDIs, such as thromboembolism resultingfrom phenytoin-induced reduction in hepaticmetabolism of warfarin14 and hemorrhagefrom the additive effects of NSAIDs and lowmolecular weight heparin.15 Studies of poten-tial DDIs showed that one-third of ambulatoryCanadian cancer patients take drug doubletswith the potential to interact,4,5 mostly notinvolving chemotherapy but medications totreat comorbid illnesses, such as warfarin, cap-topril, and phenytoin, the same drugs associ-ated with hospitalization for a DDI in thepresent analysis. Screening of cancer patients’medications to identify those taking theseagents could identify potentially dangerousdrug combinations and avoid hazardous clin-ical outcomes.Our study has limitations. The study popu-

lation came from a single institution, and al-though it is representative of the generalcancer patients seen in the public setting, se-lection bias was possible. Brazil is a developingcountry, with heterogeneous access to healthcare, such that 80% of the population, oursincluded, does not have access to expensivecancer treatments, including most moleculartargeted agents. Molecular targeted agentsare being prescribed increasingly in cancertreatment, and although their side effectsare different from those of cytotoxic chemo-therapy, they may lead to serious adverseevents. Clinically significant cardiotoxicityhas been reported in up to 15% of patientstreated with sunitinib, an agent that targets

Table 6Factors Associated with Hospital Admission Involving ADRs Among Cancer Patients

Variable

Univariable Multivariable

OR (95% CI) P-value OR (95% CI) P-value

Age 0.7 (0.4e1.3) 0.26 d dNumber of medications taken by patient at admission 3.3 (1.7e6.4) 0.001 2.0 (1.0e4.3) 0.065Receipt of chemotherapy 12.2 (6.1e24.6) 0.0001 10.8 (5.3e22.1) 0.0001Type of cancer (hematologic vs. solid tumor) 4.4 (2.3e8.6) 0.0001 12.1 (5.9e25.0) 0.0001Severity of comorbid illness (Charlson Comorbidity Index $2) 1.2 (0.5e3.0) 0.632 d d

Vol. 42 No. 3 September 2011 351Drug Interactions and Adverse Drug Reactions in Oncology

tyrosine kinase receptors, including the vas-cular endothelial growth factor receptor,16

and about 4% of breast cancer patientstreated with trastuzumab, a HER2/neu-targetmonoclonal antibody, develop symptomaticcardiac dysfunction.17 Although we identifieda patient who developed severe high bloodpressure after receiving bevacizumab, theprevalence of hospitalizations associatedwith ADEs from molecular targeted canceragents could not be evaluated. Another limi-tation was the lack of involvement from a clin-ical pharmacist, which might have hamperedthe identification of ADRs and DDIs.

There is no established method to iden-tify clinically significant ADEs, and chart re-views and/or patient interviews have beenused often; we identified ADEs by medicalrecord review. Also, although it has been es-timated that 60%e70% of ADEs reported ingeneral medicine and about 20% of hospitaladmissions of cancer patients for ADEs arepreventable,18,19 we did not evaluate pre-ventability of ADEs. This is because criteriaused to define an ADE as avoidable includepatient compliance and a detailed medicalhistory20 (such as allergy history), whichcould not be captured reliably in a retrospec-tive study. Here, we focused on ADEs thatresulted in hospitalization, although we rec-ognize the potentially large number of mi-nor ADEs misdiagnosed because of cancersymptomatology and comorbidities.

Cost analysis was not performed, but thecost of morbidity and mortality associatedwith hospitalizations for ADEs is substantial.A U.S. study showed that the mean cost of hos-pitalization to treat febrile neutropenia was$13,372 per admission.21

Cancer brings great physical and psychologi-cal burdens to patients and their caregivers.Ways to minimize patient suffering include

the avoidance of futile interventions, such asunnecessary prescriptions. Prevention of ADEsin cancer patients requires increasing aware-ness by physicians of the pharmacology ofagents commonly prescribed. Because manyDDIs found here were the same ones found ina study of potential DDIs, screening tools, suchas flyers listing the most dangerous combina-tions, or electronic programs, could help toidentify risky doublets and prevent their conse-quences. Avoidance of polypharmacy and med-ication reconciliation also can help to decreasethe risk of an ADE. Improved patient reportingof ADEs is also pivotal. Studies that comparepatient self-reporting with physician capturingADEs have shown that patients do not always ex-press their concerns about ADEs unless theirdoctors inquire about them.22 Use of electronicpatient self-report tools to identify possibleADEs seems useful,23 although not applicableto many patients (illiterate and functionally im-paired individuals); strengthening patient-doctor relationships may help cancer patientsto better report their symptoms. Cultural back-ground also plays a role in determining how of-ten patients report their symptoms.

Despite the strategies described above to re-duce clinically significant ADEs, it is impossi-ble to avoid all cancer therapy-induced ADEs.There must be a balance between an ‘‘accept-able’’ rate of ADEs and dose-intensity of anti-cancer agents. For chemotherapy regimensfrom which a 20% rate of febrile neutropeniais anticipated, oncology guidelines advise onthe use of prophylactic G-CSF, when the costof such agents is not an issue.24 In our setting,dose reductions and cycle delays of anticanceragents are used as an alternative to prophylac-tic G-CSF because of reimbursement issues, al-though they may compromise drug efficacy,especially in the adjuvant setting. Therefore,the acceptable tradeoff between the risks of

352 Vol. 42 No. 3 September 2011Miranda et al.

a serious ADE vs. the dose-intensity deliveredhas not yet been established. Recognizingthis limitation, we suggest more attention bepaid to patients with hematological malignan-cies and those receiving anticancer therapy. Ahospitalization for an ADE may decrease treat-ment efficacy because of treatment interrup-tion, lead to life-threatening complicationsand/or long term disability, and ultimatelyhave a fatal outcome.

Disclosures and AcknowledgmentsNo funding was received for this study, and

the authors have no conflicts of interest todeclare.

References1. World Health Organization. International drugmonitoring: the role of national centres. Report ofa WHO meeting. World Health Organ Tech RepSer 1972;498:1e25.

2. Hardman JG, Limbird LE, Gilman AG, eds.Goodman and Gilman’s the pharmacological basisof therapeutics. Cedro, NM: McGraw-Hill Compa-nies, Inc., 2001:903e952.

3. Lazarou J, Pomeranz BH, Corey PN. Incidenceof adverse drug reactions in hospitalized patients:a meta-analysis of prospective studies. JAMA 1998;279:1200e1205.

4. Riechelmann RP, Zimmermann C, Chin SN,et al. Potential drug interactions in cancer patientsreceiving supportive care exclusively. J Pain Symp-tom Manage 2008;35:535e543.

5. Riechelmann RP, Tannock IF, Wang L, et al. Po-tential drug interactions and duplicate prescriptionsamong cancer patients. J Natl Cancer Inst 2007;99:592e600.

6. Riechelmann RP, Moreira F, Smaletz O,Saad ED. Potential for drug interactions in hospital-ized cancer patients. Cancer Chemother Pharmacol2005;56:286e290.

7. Kongkaew C, Noyce PR, Ashcroft DM. Hospitaladmissions associated with adverse drug reactions:a systematic review of prospective observationalstudies. Ann Pharmacother 2008;42:1017e1025.

8. Ebbesen J, Buajordet I, Erikssen J, et al. Drug-related deaths in a department of internal medi-cine. Arch Intern Med 2001;161:2317e2323.

9. CharlsonME, Pompei P, Ales KL, MacKenzie CR.A new method of classifying prognostic comorbidityin longitudinal studies: development and validation.J Chronic Dis 1987;40:373e383.

10. World Health Organization. International drugmonitoring. The role of the hospital. World HealthOrgan Tech Rep Ser 1969;425:5e24.

11. van der Hooft CS, Dieleman JP, Siemes C, et al.Adverse drug reaction-related hospitalisations:a population-based cohort study. Pharmacoepide-miol Drug Saf 2008;17:365e371.

12. RiechelmannRP, KrzyzanowskaMK,O’Carroll A,Zimmermann C. Symptom and medication profilesamong cancer patients attending a palliative careclinic. Support Care Cancer 2007;15:1407e1412.

13. Caggiano V, Weiss RV, Rickert TS, Linde-ZwirbleWT. Incidence, cost, andmortality of neutro-penia hospitalization associated with chemotherapy.Cancer 2005;103:1916e1924.

14. Nappi JM. Warfarin and phenytoin interaction[letter]. Ann Intern Med 1979;90:852.

15. Macie C, Forbes L, Foster GA, Douketis JD.Dosing practices and risk factors for bleeding inpatients receiving enoxaparin for the treatmentof an acute coronary syndrome. Chest 2004;125:1616e1621.

16. Chu TF, Rupnick MA, Kerkela R, et al. Cardio-toxicity associated with tyrosine kinase inhibitor su-nitinib. Lancet 2007;370:2011e2019.

17. Ewer SM, Ewer MS. Cardiotoxicity profile oftrastuzumab. Drug Saf 2008;31:459e467.

18. Franceschi M, Scarcelli C, Niro V, et al. Preva-lence, clinical features and avoidability of adversedrug reactions as cause of admission to a geriatricunit: a prospective study of 1756 patients. DrugSaf 2008;31:545e556.

19. McDonnell PJ, Jacobs MR. Hospital admissionsresulting from preventable adverse drug reactions.Ann Pharmacother 2002;36:1331e1336.

20. Schumock GT, Thornton JP. Focusing on thepreventability of adverse drug reactions [letter].Hosp Pharm 1992;27:538.

21. Bennett CL, Calhoun EA. Evaluating the totalcosts of chemotherapy-induced febrile neutropenia:results from a pilot study with community oncologycancer patients. Oncologist 2007;12:478e483.

22. Basch E, Iasonos A, McDonough T, et al. Pa-tient versus clinician symptom reporting using theNational Cancer Institute Common TerminologyCriteria for Adverse Events: results of a question-naire-based study. Lancet Oncol 2006;7:903e909.

23. Basch E, Iasonos A, Barz A, et al. Long-term tox-icity monitoring via electronic patient-reported out-comes in patients receiving chemotherapy. J ClinOncol 2007;25:5374e5380.

24. Smith TJ, Khatcheressian J, Lyman GH, et al.2006 update of recommendations for the use of whiteblood cell growth factors: an evidence-based clinicalpractice guideline. J Clin Oncol 2006;24(19):3187e3205.

Vol. 42 No. 3 September 2011 353Drug Interactions and Adverse Drug Reactions in Oncology

25. Clarke PF, Kendall R, Hornby R, Kendall MJ.Captopril and hydrochlorthiazideea safe antihyper-tensive for use in general practice? J Clin PharmTher 1991;16(5):361e366.

26. Unge P, Svedberg LE, Nordgren A, et al. A studyof the interaction of omeprazole andwarfarin in anti-coagulated patients. Br J Clin Pharmacol 1992;34(6):509e512.

27. Becouarn Y, Rougier P. Clinical efficacy ofoxaliplatin monotherapy: phase II trials in advancedcolorectal cancer. Semin Oncol 1998;25(2 Suppl 5):23e31.

28. De Botton S, Dombret H, Sanz M, et al. Inci-dence, clinical features, and outcome of all trans-

retinoic acid syndrome in 413 cases of newlydiagnosed acute promyelocytic leukemia. TheEuropean APL Group. Blood 1998;92(8):2712e2718.

29. Czaykowski PM, Moore MJ, Tannock IF. Highrisk of vascular events in patients with urothelialtransitional cell carcinoma treated with cisplatinbased chemotherapy. J Urol 1998;160(6 Pt 1):2021e2024.

30. Numico G, Garrone O, Dongiovanni V, et al.Prospective evaluation of major vascular events inpatients with nonsmall cell lung carcinoma treatedwith cisplatin and gemcitabine. Cancer 2005;103(5):994e999.