342

Journal of Pain and Symptom Management

Vol. 42 No. 3 September 2011

Original Article

Adverse Drug Reactions and Drug

Interactions as Causes of Hospital Admission
in Oncology
Vanessa Miranda, MD, Angelo Fede, MD, Melissa Nobuo, BS, Veronica Ayres, BS,
Auro Giglio, MD, PhD, Michele Miranda, MD, and
Rachel P. Riechelmann, MD, PhD
ABC School of Medicine (V.M., A.F., M.N., V.A., A.G., M.M.); and Medical Oncology Department
(R.P.R.), Instituto do C^
a ncer do Estado de S~
a o Paulo, Faculdade de Medicina da Universidade de S~
ao
Paulo, S~
a o Paulo, Brazil.

Abstract
Context. Although several studies have evaluated the frequency of adverse drug
reactions (ADRs) and drug-drug interactions (DDIs) in general medicine, few
studies have looked at the epidemiology of adverse drug events (ADEs) in oncology.
Objectives. We sought to investigate how many hospital admissions in oncology
are related to a DDI or an ADR.
Methods. All cancer patients admitted to an oncology ward during an
eight-month period had their charts retrospectively evaluated for reasons of
hospitalization, using a 4-point scale (definitely, probably, possibly, or unlikely
associated) to classify admissions by their probability of being associated with
either a DDI or an ADR.
Results. From September 2007 to May 2008, there were 550 hospital admissions
and 458 were eligible. Among unplanned admissions (n 298), 39 (13.0%, 95%
confidence interval [CI] 9.4%e17.4%) were considered to be associated with an
ADE, 33 (11.0%, 95% CI 7.7%e15.2%) with an ADR, and six (2.0%, 95% CI 0.7%e
4.3%) with a DDI. The most common DDIs involved warfarin, captopril, and
anti-inflammatory agents, and the most frequent ADR was neutropenic fever
post-chemotherapy. Most patients were discharged completely recovered, but
two patients died.
Conclusion. Approximately one in 10 unplanned hospitalizations of cancer
patients is associated with an ADE. Prospective and population-based studies are
warranted to evaluate their magnitude in oncology. J Pain Symptom Manage
2011;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, Instituto
do C^ancer do Estado de S~ao Paulo, Faculdade de
Medicina da Universidade de S~ao Paulo, Av. Dr.
2011 U.S. Cancer Pain Relief Committee
Published by Elsevier Inc. All rights reserved.

Arnaldo 251, 5th Floor, S~ao Paulo, SP, 01246-000,

Brazil. E-mail: rachelri2005@gmail.com
Accepted for publication: November 23, 2010.
0885-3924/$ - see front matter
doi:10.1016/j.jpainsymman.2010.11.014

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

Introduction

Patients and Methods

Adverse drug events (ADEs) relate to any

clinical or laboratory alteration incurred by
a patient that is directly or indirectly associated with an administered medication.1 An
ADE can be either a drug-induced side effect
(or adverse drug reaction [ADR]) or a drugdrug, drug-food, or drug-herb interaction.
The World Health Organization defines an
ADR 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 instances in which a medication interferes with
the pharmacokinetic, pharmacodynamic, or
pharmaceutical properties of another drug,
resulting in an altered net effect of one or
both drugs.2
ADEs are a major concern in health care.3
Although several studies have evaluated the
frequency of ADRs and DDIs in general medicine, few studies have looked at the epidemiology of ADEs in oncology. Because cancer
patients receive numerous medications, they
are at particular risk for an ADE, such as
a DDI.4 Studies of ambulatory cancer patients
have shown that approximately one-third of
them were at risk for DDIs, with most involving medications to treat comorbidities, such
as anticoagulants and antihypertensives.4,5 A
retrospective evaluation of 100 hospitalized
cancer patients found that two-thirds had
been prescribed one or more drug combinations with the potential to interact during
hospitalization.6
Several studies have analyzed ADRs for patients with general medical conditions. A recent
systematic review showed that approximately
5%e6% of patients with different medical conditions present with an ADR as a contributing
factor to hospital admission.7 Information on
frequency of ADRs as a cause of hospitalization
in oncology is scarce. An evaluation of causes of
death in a Norwegian hospital identified 18%
of more than 700 deaths to be associated with
an ADE and 4% of all cancer-related deaths
were likely to be associated with a serious
interaction.8
Given the lack of information on the epidemiology of ADEs in oncology, we sought to assess how many hospital admissions in oncology
are associated with a DDI or an ADR.

Study Design

343

This was a retrospective cohort study of all

consecutive cancer patients admitted to the
oncology ward of a teaching hospital (Mario
Covas) located in the greater Sao Paulo area
in Brazil, during an eight-month period. The
hospital is a 300-bed public and teaching institution that serves more than three million
people. The local ethics board reviewed and
approved the study.
We reviewed the medical records of consecutive adult cancer patients admitted at our institution to identify hospital admissions that
were possibly associated with an ADE. Patients
receiving treatment within a clinical trial were
excluded. ADEs involving food-related interactions, multivitamins, and herbs were not
considered.
Each hospital admission was evaluated by two
independent and blinded investigators who
evaluated the cause(s) of admission and classified it by its probability of being associated
with either a DDI or an ADR. After classifying
the admission, the investigators thoroughly
reviewed the medical records to gather information about patient demographics, tumor
characteristics, and type of treatment received
within four weeks of admission, comorbid illness(es), and medications used before hospitalization. A comorbid condition was defined as
a clinical situation that required pharmacological intervention, and its severity was graded
using the Charlson Comorbidity Index.9 The
Charlson Comorbidity Index was initially developed to score the risk of death among hospitalized noncancer patients. Although it has not
been validated in the oncology population, we
considered it acceptable to use as a measure
of comorbidity severity in this study. The
number of medications for each subject was calculated by summing all pharmacological compounds, and each one was considered an
individual medication for analysis, regardless
of drug schedule; for example, commercial
combinations of oxycodone/acetaminophen
were counted as two drugs, oxycodone and acetaminophen, and short- and sustained-release
morphine was counted as one drug. Multivitamins, as described above, were not considered.
For admissions suspected to involve an ADE,
additional information was gathered on patient

344

Miranda et al.

outcomes (stable outcome: when the patient

was kept on the ward and had no lifethreatening complications; unstable outcome:
when the patient was transferred to an intensive
care unit and/or had life-threatening complications; or fatal outcome), clinical status at
discharge (completely recovered, partially recovered, or death), need for invasive procedure
to treat ADE complications, and need of specialist consultation.

Classification of Reasons for Hospital

Admission
Causes of admission were examined independently by two blinded investigators (MCM,
MNF), using a 4-point scale (Table 1) developed by the authors. They agreed on all but
seven classifications, when a third investigator
(RPR) was consulted, and consensus was
achieved. The scale was adapted from the
World Health Organization causality criteria
(probable, possible, and unlikely) and piloted
in the first 30 hospital admissions.10 After
minor fine-tuning, the scale classified admissions into four different categories: definitely
associated with an ADE, probably associated
with an ADE, possibly associated with an ADE,
or unlikely associated with an ADE.
The classification of causes of hospital admission was based on medical record review and discussion with medical oncologists. To classify
each admission, the authors reviewed the complete medical history that led to hospitalization,
including the medications used by patients immediately before and at the time of admission,
symptomatology, tumor type and stage, and oncology treatment. In addition, patient medication lists at the time of admission were entered
into the Drug Interaction Facts software version
4.0 (available from www.factsandcomparisons.
com, Lippincott Williams & Wilkins, St. Louis,
Table 1
Classification of Causes of Hospital Admission
Type of Hospital
Admission
1
2
3
4
a

Probability of an ADEa Being

Associated with Hospitalization
Definitely associated. ADE was the
sole cause of hospital admission.
Probably associated. ADE significantly
contributed to hospital admission.
Possibly associated. ADE somewhat
contributed to hospital admission.
Unlikely associated.

An ADE includes both ADR and DDI.

Vol. 42 No. 3 September 2011

Table 2
Patient Characteristics
Characteristics
All patients
Median age, range
Sex
Male
Female
Cancer type
Gastrointestinal
Hematologic
Breast
Genitourinary
Lung
Gynecologic
Other
Comorbid illnesses
Yes/no
Median Charlson Index (range)

n (%)
264 (100)
58 (18e91)
142 (54)
122 (46)
76
48
33
29
25
14
39

(28.8)
(18.2)
(12.5)
(11)
(9.5)
(5.3)
(14.7)

116 (44)/148 (56)

2 (0e7)

Receipt of systemic chemotherapy within four weeks of

admissiona
Yes
152 (58)
No
112 (42)
Note: For patients with more than one admission during the study
period, only the first hospitalization was evaluated.
a
If the patient had received chemotherapy within four weeks of
hospitalization.

MO), which contains a comprehensive database

of drug monographs and DDI lists, and which
has been used in other studies.4,5 Subsequently,
the information about drugs was put in the context of medical history at admission and discussed among the authors, followed by
discussion with medical oncologists. When obvious drug-unrelated causes of admission were
identified, the admission was regarded as unlikely associated. Examples of such admissions
include the following: disease progression, admissions to treat patients with continuous
infusion chemotherapy, or elective colostomy
reversal. The authors agreed on all classifications except for one case for which the
admission was considered as a drug interactionrelated hospitalization, but the actual drug
interaction occurred during hospitalization and
not as the primary cause of admission. The patient was admitted for breast cancer surgery
and developed postoperative hemorrhage secondary to a drug interaction between enoxaparin and aspirin. Details are presented in Table 4.
After the initial classification, the investigators evaluated the cause of each admission in
an attempt to enhance the internal validity of
this study, that is, to focus on the admissions
that were not elective hospitalizations and do

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

Table 3
Admissions Associated with DDIs or ADRs
Characteristics

DDI, n 6

ADR, n 33 (100%)

Median age (range)

58 (39e72)

54 (18e75)

Cancer type
Breast
Lung
Gastrointestinal
Gynecologic
Hematologic
Genitourinary
Other

2
1
0
0
1
1
1

1
4
9
1
14

(3)
(12.1)
(27.3)
(3)
(42.5)
0
4 (12.1)

Presence of comorbid illness

Yes
6
No
0

9 (27.3)
24 (72.7)

Receipt of chemotherapya
Yes
0
No
6

29 (87.9)
4 (12.1)

Median length
of admission
(days, range)

7 (6e37)

6 (1e18)

a
Receipt of systemic chemotherapy within four weeks before hospital admission.

not reflect the scenario of admissions secondary

to cancer-related complications. The admissions were then considered either planned
(elective scheduled interventions, such as port
insertion, continuous infusion chemotherapy,
and elective biopsies) or unplanned (when it
was an urgent situation, mostly clinical complications from cancer or its treatment). The
focus of this study was the unplanned hospital
admissions (UHAs).

Statistical Considerations
Two previous studies4,5 with nearly 400 patients found a 30% frequency of potential
DDIs with a 10% variance for the 95% confidence interval (CI). Based on these results,
we determined that 400 hospital admissions
would be sufficient to evaluate how many admissions were caused by ADEs among cancer
patients. We used summary statistics to describe patient characteristics and frequency
and types of hospital admissions associated
with an ADE, separately for ADRs and DDIs.
The unit of analysis was hospital admission;
therefore, the same patient could be included
more than once. Logistic regression was used
to identify factors associated with being hospitalized for an ADR (admission definitely,
probably, or possibly associated with an ADE
vs. unlikely), considering planned hospital
admissions and UHAs. The small number of

345

admissions associated with a DDI prevented

any exploratory analysis. Independent variables tested included the following: age (median age: 57 years, <57 years, or $57 years),
cancer type (solid or hematological), severity
of comorbid conditions (median Charlson Comorbidity Index: 2, score <2, or $2), receipt
of chemotherapy within four weeks of hospital
admission (yes or no), and number of medications taken by patients at hospital admission
(median number of drugs taken by patient:
3, <3, or $3). For binary variables, the group
at lower risk of the outcome was chosen as
the referent. Variables with univariate P-values
<0.1 were entered into the multivariable
model. In the multivariable model, predictors
were considered statistically significant if the
P-value was <0.05. The Statistical Package
for the Social Sciences version 13 (SPSS, Inc.,
Chicago, IL) was used for all analyses.

Results
From September 2007 to April 2008, there
were 550 admissions and 458 were eligible;
92 were excluded because they were participating in clinical trials. Many patients were admitted more than once during the study period:
39 patients were admitted twice, and 41 were
admitted more than twice. Table 2 summarizes
patient characteristics considering only one
admission (the first admission) per patient
(n 294). The median age was 58 (range
15e91), more than half were male, the most
common tumor type was gastrointestinal, and
the median number of drugs per patient was
two (range 1e8).
Among all 458 hospital admissions, 160 were
planned and 298 were UHA. The most frequent reasons for planned hospitalization
were scheduled intravenous chemotherapy
administered by continuous infusion (36%),
surgical intervention (12%), and diagnostic
workup (9%). The most common causes of
UHA were clinical deterioration requiring supportive care and/or pain control (30%). Considering only UHA, 39 admissions (13.0%,
95% CI 9.4%e17.4%) were considered to be
consequent 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,

346

Table 4
Description of Hospital Admissions Associated with Drug Interactions

Drug Combination

Probability of an
ADE to be Associated
with Hospitalization

Captopril
hydrochlorothiazide
(Clarke et al., 1991)25

Probably associated.

Captopril
dexamethasonea

Probably associated.

Warfarin
omeprazole
(Unge et al., 1992)26

Definitely associated.

54-year-old female with advanced

breast cancer who was taking
long-term warfarin presented
with deep venous thrombosis
after starting phenytoin for
multiple brain metastasis.
54-year-old female with advanced
bladder cancer on exclusive
supportive care, type II diabetes,
and high blood pressure treated
with hydrochlorothiazide
presented with asthenia and
symptoms of arterial
hypotension after starting
captopril. Captopril was
stopped and blood pressure
normalized.
The additive effect of the two
antihypertensive agents coupled
with the frail clinical condition
of the patient may have led to
hospital admission.
80-year-old male with
non-Hodgkins lymphoma,
receiving supportive care
exclusively, had chronic
renal failure and arterial
hypertension controlled
with captopril and
hydrochlorothiazide for the
past four months, presented
with high blood pressure after
started on high-dose
dexamethasone. Blood pressure
decreased after the patient was
given antihypertensive agents.
71-year-old female with advanced
thymic carcinoma not receiving
cancer-directed therapy, with
history of arterial hypertension
and chronic atrial fibrillation,

Mechanism

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

Deep venous
thrombosis

Phenytoin induces warfarin

hepatic metabolism with
consequent reduction in
its anticoagulant effect.

Six/stable/completely
recovered.

Arterial
hypotension

Additive hypotensive effects.

Seven/stable/completely
recovered.

Arterial
hypertension

Dexamethasone induces
sodium retention, which
antagonizes hypotensive
effects of captopril.

12/stable/completely
recovered.

Upper digestive
hemorrhage

Omeprazole inhibits
hepatic metabolism
of warfarin, enhancing
its anticoagulant
effect.

37/short-term unstable/
completely recovered.

Vol. 42 No. 3 September 2011

Definitely associated.

Cause of
Admission

Miranda et al.

Phenyoin warfarin
(Nappi, 1979)14

Medical History at
Admission

Definitely associated.

Post-surgical
bleeding
and melena

Hemorrhage from the

combination of an
anticoagulant and an
antiaggregation agent

Seven to 18 days/short-term
unstable/completely
recovered

INR international normalized ratio.

a
The 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 blood
pressure under control before admission.

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

Aspirin enoxaparin
(Macie et al., 2004)15

was admitted for upper

digestive hemorrhage and
INR 6. The dose of
omeprazole was increased to
40 mg/day po a few days
before admission.
Warfarin was discontinued until
INR was 3, and a low molecular
weight heparin was started.
63-year-old female with localized
breast cancer, arterial
hypertension controlled
with captopril and
hydrochlorothiazide, had
recent breast surgery and was
started on prophylactic low
molecular weight heparin.
Presented with surgical scar
bleeding after restarted
on aspirin.
72-year-old male with extensive
small-cell lung cancer, not on
chemotherapy, known history of
arterial hypertension and who
was taking long-term aspirin
and omeprazole, presented with
melena a few days after starting
dexamethasone for bone pain.
He was admitted, and a gastric
bleeding ulcer was diagnosed by
upper endoscopy. Red blood
cell transfusion was required.

347

348

Miranda et al.

captopril, and anti-inflammatory agents and

anticonvulsants (Table 4). The most frequent
ADRs were neutropenic fever (20 instances)
caused by cytotoxic chemotherapy (Table 5).
Most patients admitted for an ADE were
clinically stable (n 33/39, 84.6%) and recovered completely by the time of discharge
(n 34, 87.2%). Two of 20 patients who
were admitted for febrile neutropenia died
of sepsis (mortality rate 10%, 95%
CI 1.2%e31.6%). A 60-year-old male with
advanced non-small cell lung cancer who
had received carboplatin and paclitaxel two
weeks before admission was admitted to treat
febrile neutropenia; he developed hemodynamic instability and died on the ward after
three days. The other patient was a 32-yearold female with localized breast cancer who
was being treated with adjuvant cyclophosphamide, methotrexate, and leucovorin. She was
admitted because of febrile neutropenia and
hemodynamic instability. She died after 14
days. Both patients received standard care
with broad-spectrum antibiotics, blood transfusion, and granulocyte-colony stimulating
factors (G-CSF).
Univariable analysis (n 458) identified
the number of medications taken by patients,
receipt of systemic chemotherapy within four
weeks of admission, and cancer type as risk
factors for patients to be hospitalized for an
ADR (Table 6). In adjusted analysis, cancer
type and receipt of chemotherapy remained
significant. Patients with hematologic malignancies were 12 times more likely to be admitted for an ADR than were those with solid
tumors (odds ratio [OR]: 12.1, 95% CI
5.9e25.0; P < 0.0001). Patients who received
chemotherapy within four weeks before hospitalization had a tenfold risk of being admitted for an ADR than were those who did not
receive chemotherapy within this time frame
(OR: 10.8, 95% CI 5.3e22.1; P < 0.0001).

Discussion
The present study showed that one in 10
cancer patients was hospitalized to treat an
ADR. Although febrile neutropenia was obviously common, other ADEs, including DDIs
and ADRs, also were identified. Although
most patients recovered and were discharged

Vol. 42 No. 3 September 2011

from hospital in good clinical condition, two

patients admitted for febrile neutropenia
died despite receiving standard treatment.
We are unaware of studies on the frequency
of ADEs as causes of hospitalization in oncology. A recent systematic review of 25 studies
in general medicine conducted over the last
19 years demonstrated that approximately 6%
of adult patients and 11% of the elderly were
admitted to treat complications from ADRs,
with the drugs most commonly involved being
cardiovascular medications, nonsteroidal antiinflammatory drugs (NSAIDs), and central
nervous system drugs.7 A Dutch retrospective
cohort of more than 3500 patients with different illnesses also found a similar prevalence of
hospitalization for ADRs (5%), and in 0.3% of
patients, the outcome was fatal.11 In that study,
neutropenic fever was among the most common causes of admission.
Because cancer patients often receive chemotherapy with a substantial risk of side effects,12 their chance of being hospitalized
for ADEs is expected to be higher than that
for patients without cancer. Moreover, drug
pharmacokinetics may be altered in cancer
patients because of malnourishment, organ
dysfunction, and edema. Indeed, we found
that 12.7% of hospital admissions were associated with an ADE, roughly triple the 5% rate
reported for adult noncancer patients.7 This
is likely caused by cytotoxic chemotherapy,
which is known to be highly toxic. Our multivariable analysis showed that cancer patients
who received chemotherapy close to admission were at risk of being hospitalized for an
ADR in comparison with those who did not.
Similar to the Dutch cohort,11 we identified
febrile neutropenia as a common ADR leading to hospitalization.
Presence of hematological malignancies was
a risk factor for an ADR-associated hospitalization. Febrile neutropenia was responsible for
hospital admission for one in 29 U.S. cancer patients receiving cytotoxic chemotherapy from
1999 to 2005 and for one death for every 14 hospitalized patients.13 The mortality rate of febrile
neutropenia among our patients was 10%,
which does not differ significantly from that reported for the U.S. patients, despite probable
differences in socioeconomic status. The U.S.
study also found that hospitalization for neutropenia was more common in patients with a

Number of
Instances

Probability of an
ADE to be Associated
with Hospitalization

20

Definitely associated.

Mucositis after systemic

chemotherapy

Definitely associated.

Chemotherapy-induced
nausea and vomiting

Definitely associated.

Constipation and
abdominal pain
(Becouarn and
Rougier, 1998)27

Definitely associated.

ATRA syndrome
(De Botton
et al., 1998)28

Definitely associated.

Arterial hypertension
and seizures
(Chu et al., 2007)16

Definitely associated.

ADR
Febrile neutropenia
post systemic
chemotherapy

Medical History at Admission

Median of seven days (range 2e14)/17 patients

had a stable clinical course, one patient was
taken to the intensive care unit; all 18 were
discharged completely recovered. Two
patients died in hospital.
Median of seven days (range 5e8)/all patients
except one had a stable clinical course and
were discharged completely recovered. One
patient had hemodynamic instability because
of dehydration but recovered later after IV
fluids.
10 days/stable clinical course/completely
recovered.

Seven to 15 days/stable clinical course/

discharged in good clinical condition.

Spent seven days in hospital/stable clinical

course/discharged completely recovered.

Spent four days in hospital/good clinical course

but was discharged with high blood pressure.

349

Patients with various tumor types (nine had

hematological cancers) presented with fever
and neutropenia seven to 20 days after receipt
of cytotoxic chemotherapy. Patients did not
receive prophylactic colony stimulating
factors but all received it while in hospital to
treat febrile neutropenia.
Four patients with non-Hodgkins lymphomas
and two with gastric cancer developed oral
and/or intestinal mucositis after receiving
chemotherapy (methotrexate or
fluoropirimidines). Patients received local
oral mouthwash, painkillers, hydration, and
sometimes, antibiotics.
34-year-old male with colorectal cancer treated
with Folfox regimen. He took steroids for
chemotherapy-induced nausea and vomiting
prophylaxis, but four days after treatment, he
developed severe nausea and vomiting and
was admitted to receive IV fluids and IV
antiemetics.
Two patients (36 and 56 years old) with
advanced colorectal cancer were treated with
Folfox and a 70-year-old male also with
colorectal cancer not receiving chemotherapy
but tramadol 40 mg/daily po developed
severe constipation and abdominal pain. They
were treated with stool softeners, laxatives,
fluids, nonopioid analgesics; the dose of
tramadol was decreased to 300 mg/day po,
and stool softeners were given prophylatically.
75-year-old male with acute promyelocytic
leukemia who was receiving ATRA developed
ATRA syndrome with dyspnea, prolonged
fever, and asthenia. He was admitted and
treated with dexamethasone.
63-year-old male with advanced non-small cell
lung cancer, with no evidence of brain
metastasis and no known comorbid conditions
started treatment with platin-based
chemotherapy combined with bevacizumab.
After one month, the patient was admitted with
hypertensive crisis and seizures. He received

Length of Admissions (Days)/Evolution/

Clinical Status at Discharge

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

Table 5
Description of Hospital Admissions Associated with ADR

(Continued)

Folfox fluorouracil, leucovorin, and oxaliplatin; ATRA all trans-retinoic acid; IV intravenous.

Probably associated.
Cerebrovascular ischemia
(Czaykowski et al., 1998;29
Numico et al., 2005)30

antihypertensive agents and anticonvulsants,

and bevacizumab was stopped.
61-year-old male with advanced non-small cell
lung cancer, type II diabetes (taking
metformin), and arterial hypertension
controlled with atenolol and enalapril.
Developed cerebral vascular ischemia during
infusion of cisplatin 60 mg/m2.
Cisplatin was stopped, and the patient was
admitted and taken care of by a neurologist.
The vascular toxicity induced by cisplatin
coupled with chronic high blood pressure
and diabetes might have contributed to the
cerebral ischemia.

Medical History at Admission

ADR

Probability of an
ADE to be Associated
with Hospitalization
Number of
Instances

Table 5
Continued

Spent five days in hospital and was discharged

partially recoveredda neurological motor
deficit remained.

Miranda et al.

Length of Admissions (Days)/Evolution/

Clinical Status at Discharge

350

Vol. 42 No. 3 September 2011

hematological malignancy than for those with

solid tumors.13 These findings reflect the intense anticancer regimens coupled with the underlying aggressive nature of these diseases.
Cancer patients usually receive many medications to treat comorbid illness and/or as
supportive care. Two studies by Riechelmann
et al.4,5 showed that each additional drug
taken by patients increases the risk of DDIs,
although the number of medications taken
by patients was not a significant risk factor
for an ADR in the adjusted analysis. It is possible that type of drug is more important
than the number of medications in predisposing patients to experience ADRs.
The proportion of DDIs leading to hospital
admission of cancer patients is unknown.
Among our patients, six patients were hospitalized to treat the clinical consequences of
DDIs, such as thromboembolism resulting
from phenytoin-induced reduction in hepatic
metabolism of warfarin14 and hemorrhage
from the additive effects of NSAIDs and low
molecular weight heparin.15 Studies of potential DDIs showed that one-third of ambulatory
Canadian cancer patients take drug doublets
with the potential to interact,4,5 mostly not
involving chemotherapy but medications to
treat comorbid illnesses, such as warfarin, captopril, and phenytoin, the same drugs associated with hospitalization for a DDI in the
present analysis. Screening of cancer patients
medications to identify those taking these
agents could identify potentially dangerous
drug combinations and avoid hazardous clinical outcomes.
Our study has limitations. The study population came from a single institution, and although it is representative of the general
cancer patients seen in the public setting, selection bias was possible. Brazil is a developing
country, with heterogeneous access to health
care, such that 80% of the population, ours
included, does not have access to expensive
cancer treatments, including most molecular
targeted agents. Molecular targeted agents
are being prescribed increasingly in cancer
treatment, and although their side effects
are different from those of cytotoxic chemotherapy, they may lead to serious adverse
events. Clinically significant cardiotoxicity
has been reported in up to 15% of patients
treated with sunitinib, an agent that targets

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

351

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

OR (95% CI)
(0.4e1.3)
(1.7e6.4)
(6.1e24.6)
(2.3e8.6)
(0.5e3.0)

Multivariable
P-value

OR (95% CI)

P-value

0.26
0.001
0.0001
0.0001
0.632

d
2.0 (1.0e4.3)
10.8 (5.3e22.1)
12.1 (5.9e25.0)
d

d
0.065
0.0001
0.0001
d

Age
Number of medications taken by patient at admission
Receipt of chemotherapy
Type of cancer (hematologic vs. solid tumor)
Severity of comorbid illness (Charlson Comorbidity Index $2)

0.7
3.3
12.2
4.4
1.2

tyrosine kinase receptors, including the vascular endothelial growth factor receptor,16
and about 4% of breast cancer patients
treated with trastuzumab, a HER2/neu-target
monoclonal antibody, develop symptomatic
cardiac dysfunction.17 Although we identified
a patient who developed severe high blood
pressure after receiving bevacizumab, the
prevalence of hospitalizations associated
with ADEs from molecular targeted cancer
agents could not be evaluated. Another limitation was the lack of involvement from a clinical pharmacist, which might have hampered
the identification of ADRs and DDIs.
There is no established method to identify clinically significant ADEs, and chart reviews and/or patient interviews have been
used often; we identified ADEs by medical
record review. Also, although it has been estimated that 60%e70% of ADEs reported in
general medicine and about 20% of hospital
admissions of cancer patients for ADEs are
preventable,18,19 we did not evaluate preventability of ADEs. This is because criteria
used to define an ADE as avoidable include
patient compliance and a detailed medical
history20 (such as allergy history), which
could not be captured reliably in a retrospective study. Here, we focused on ADEs that
resulted in hospitalization, although we recognize the potentially large number of minor ADEs misdiagnosed because of cancer
symptomatology and comorbidities.
Cost analysis was not performed, but the
cost of morbidity and mortality associated
with hospitalizations for ADEs is substantial.
A U.S. study showed that the mean cost of hospitalization to treat febrile neutropenia was
$13,372 per admission.21
Cancer brings great physical and psychological burdens to patients and their caregivers.
Ways to minimize patient suffering include

the avoidance of futile interventions, such as

unnecessary prescriptions. Prevention of ADEs
in cancer patients requires increasing awareness by physicians of the pharmacology of
agents commonly prescribed. Because many
DDIs found here were the same ones found in
a study of potential DDIs, screening tools, such
as flyers listing the most dangerous combinations, or electronic programs, could help to
identify risky doublets and prevent their consequences. Avoidance of polypharmacy and medication reconciliation also can help to decrease
the risk of an ADE. Improved patient reporting
of ADEs is also pivotal. Studies that compare
patient self-reporting with physician capturing
ADEs have shown that patients do not always express their concerns about ADEs unless their
doctors inquire about them.22 Use of electronic
patient self-report tools to identify possible
ADEs seems useful,23 although not applicable
to many patients (illiterate and functionally impaired individuals); strengthening patientdoctor relationships may help cancer patients
to better report their symptoms. Cultural background also plays a role in determining how often patients report their symptoms.
Despite the strategies described above to reduce clinically significant ADEs, it is impossible to avoid all cancer therapy-induced ADEs.
There must be a balance between an acceptable rate of ADEs and dose-intensity of anticancer agents. For chemotherapy regimens
from which a 20% rate of febrile neutropenia
is anticipated, oncology guidelines advise on
the use of prophylactic G-CSF, when the cost
of such agents is not an issue.24 In our setting,
dose reductions and cycle delays of anticancer
agents are used as an alternative to prophylactic G-CSF because of reimbursement issues, although they may compromise drug efficacy,
especially in the adjuvant setting. Therefore,
the acceptable tradeoff between the risks of

352

Miranda et al.

a serious ADE vs. the dose-intensity delivered

has not yet been established. Recognizing
this limitation, we suggest more attention be
paid to patients with hematological malignancies and those receiving anticancer therapy. A
hospitalization for an ADE may decrease treatment efficacy because of treatment interruption, lead to life-threatening complications
and/or long term disability, and ultimately
have a fatal outcome.

Disclosures and Acknowledgments

No funding was received for this study, and
the authors have no conflicts of interest to
declare.

References
1. World Health Organization. International drug
monitoring: the role of national centres. Report of
a WHO meeting. World Health Organ Tech Rep
Ser 1972;498:1e25.
2. Hardman JG, Limbird LE, Gilman AG, eds.
Goodman and Gilmans the pharmacological basis
of therapeutics. Cedro, NM: McGraw-Hill Companies, Inc., 2001:903e952.
3. Lazarou J, Pomeranz BH, Corey PN. Incidence
of 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 patients
receiving supportive care exclusively. J Pain Symptom Manage 2008;35:535e543.
5. Riechelmann RP, Tannock IF, Wang L, et al. Potential drug interactions and duplicate prescriptions
among cancer patients. J Natl Cancer Inst 2007;99:
592e600.
6. Riechelmann RP, Moreira F, Smaletz O,
Saad ED. Potential for drug interactions in hospitalized cancer patients. Cancer Chemother Pharmacol
2005;56:286e290.
7. Kongkaew C, Noyce PR, Ashcroft DM. Hospital
admissions associated with adverse drug reactions:
a systematic review of prospective observational
studies. Ann Pharmacother 2008;42:1017e1025.
8. Ebbesen J, Buajordet I, Erikssen J, et al. Drugrelated deaths in a department of internal medicine. Arch Intern Med 2001;161:2317e2323.
9. Charlson ME, Pompei P, Ales KL, MacKenzie CR.
A new method of classifying prognostic comorbidity
in longitudinal studies: development and validation.
J Chronic Dis 1987;40:373e383.

Vol. 42 No. 3 September 2011

10. World Health Organization. International drug

monitoring. The role of the hospital. World Health
Organ 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. Pharmacoepidemiol Drug Saf 2008;17:365e371.
12. Riechelmann RP, Krzyzanowska MK, OCarroll A,
Zimmermann C. Symptom and medication profiles
among cancer patients attending a palliative care
clinic. Support Care Cancer 2007;15:1407e1412.
13. Caggiano V, Weiss RV, Rickert TS, LindeZwirble WT. Incidence, cost, and mortality of neutropenia 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 in
patients receiving enoxaparin for the treatment
of an acute coronary syndrome. Chest 2004;125:
1616e1621.
16. Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007;370:2011e2019.
17. Ewer SM, Ewer MS. Cardiotoxicity profile of
trastuzumab. Drug Saf 2008;31:459e467.
18. Franceschi M, Scarcelli C, Niro V, et al. Prevalence, clinical features and avoidability of adverse
drug reactions as cause of admission to a geriatric
unit: a prospective study of 1756 patients. Drug
Saf 2008;31:545e556.
19. McDonnell PJ, Jacobs MR. Hospital admissions
resulting from preventable adverse drug reactions.
Ann Pharmacother 2002;36:1331e1336.
20. Schumock GT, Thornton JP. Focusing on the
preventability of adverse drug reactions [letter].
Hosp Pharm 1992;27:538.
21. Bennett CL, Calhoun EA. Evaluating the total
costs of chemotherapy-induced febrile neutropenia:
results from a pilot study with community oncology
cancer patients. Oncologist 2007;12:478e483.
22. Basch E, Iasonos A, McDonough T, et al. Patient versus clinician symptom reporting using the
National Cancer Institute Common Terminology
Criteria for Adverse Events: results of a questionnaire-based study. Lancet Oncol 2006;7:903e909.
23. Basch E, Iasonos A, Barz A, et al. Long-term toxicity monitoring via electronic patient-reported outcomes in patients receiving chemotherapy. J Clin
Oncol 2007;25:5374e5380.
24. Smith TJ, Khatcheressian J, Lyman GH, et al.
2006 update of recommendations for the use of white
blood cell growth factors: an evidence-based clinical
practice guideline. J Clin Oncol 2006;24(19):
3187e3205.

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

353

25. Clarke PF, Kendall R, Hornby R, Kendall MJ.

Captopril and hydrochlorthiazideea safe antihypertensive for use in general practice? J Clin Pharm
Ther 1991;16(5):361e366.

retinoic acid syndrome in 413 cases of newly

diagnosed acute promyelocytic leukemia. The
European APL Group. Blood 1998;92(8):2712e
2718.

26. Unge P, Svedberg LE, Nordgren A, et al. A study

of the interaction of omeprazole and warfarin in anticoagulated patients. Br J Clin Pharmacol 1992;34(6):
509e512.

29. Czaykowski PM, Moore MJ, Tannock IF. High

risk of vascular events in patients with urothelial
transitional cell carcinoma treated with cisplatin
based chemotherapy. J Urol 1998;160(6 Pt 1):
2021e2024.

27. Becouarn Y, Rougier P. Clinical efficacy of

oxaliplatin monotherapy: phase II trials in advanced
colorectal cancer. Semin Oncol 1998;25(2 Suppl 5):
23e31.
28. De Botton S, Dombret H, Sanz M, et al. Incidence, clinical features, and outcome of all trans-

30. Numico G, Garrone O, Dongiovanni V, et al.

Prospective evaluation of major vascular events in
patients with nonsmall cell lung carcinoma treated
with cisplatin and gemcitabine. Cancer 2005;
103(5):994e999.