Targeted therapies and adverse drug reactions in oncology: the role of clinical pharmacist in pharmacovigilance
International Journal of Clinical Pharmacy
Targeted therapies and adverse drug reactions in oncology: the role of clinical pharmacist in pharmacovigilance
G. Fornasier 0 1 2
M. Taborelli 0 1 2
S. Francescon 0 1 2
J. Polesel 0 1 2
M. Aliberti 0 1 2
P. De Paoli 0 1 2
P. Baldo 0 1 2
0 Scientific Directorate, CRO Aviano National Cancer Institute - IRCCS , Via F. Gallini 2, 33080 Aviano, PN , Italy
1 Unit of Cancer Epidemiology, CRO Aviano National Cancer Institute - IRCCS , Via F. Gallini 2, 33080 Aviano , Italy
2 Pharmacy Unit, CRO Aviano National Cancer Institute - IRCCS , Via F. Gallini 2, 33080 Aviano, PN , Italy
Background The majority of adverse drug reactions (ADRs) reported in the summary of product characteristics (SPCs) are based on pivotal clinical trials, performed under controlled conditions and with selected patients. Objectives (1) to observe ADRs in the real-world setting and to evaluate if the supervision of the pharmacist impacts on the management of ADRs and on the satisfaction of patients; (2) to sensitise health professionals and patients on the need to increase the reporting of ADRs, in compliance with Pharmacovigilance. Setting CRO Aviano, Italian National Cancer Institute. Method From February 2013 to April 2015, we conducted an observational study enrolling 154 patients (≥ 18 years) undergoing treatment with at least one of ten targeted-therapies included in the study. Main outcome ADR reporting in the real-world setting. Patient satisfaction with clinical pharmacist support. Results Reported ADRs in the real setting do not always correspond with data described in the respective SPCs. Unknown ADRs were also identified such as hyperglycaemia with lenalidomide and sorafenib; and hypomagnesaemia with bevacizumab. We also observed a 124.3% increase in spontaneous reports. Conclusion This study shows the high value of active pharmacovigilance programs, and our results might be a starting point for developing a randomised trial which should aim to demonstrate the impact of the pharmacist on improving patient's adherence and in measuring the difference in ADRs reports in the different arms followed or not by the pharmacist.
Adverse drug reaction; Italy; Oncology; Pharmacist; Pharmacovigilance; Safety; Targeted-therapies; Underreporting
G. Fornasier and M. Taborelli have equally contributed to this
• Pharmacovigilance studies are essential in oncology,
because the under-reporting phenomenon is especially
relevant in this field. In particular, physicians often
underestimate the adverse reactions caused by
oncological drugs, because they consider them common and they
rather focus on efficacy of the drugs.
• Pro-active pharmacovigilance is important to improve
spontaneous reporting that can generate new signals on
adverse drug reactions (ADRs). These signals can lead
the Competent Authority to make a decision on each
single drug (alerts, recommends…).
• Real life conditions are needed to detect the real
incidence of the ADRs;
• Individual patient monitoring improves their compliance,
because patients receive more information and they are
directly involved in treatment.
In recent years, anticancer treatments have seen an
enormous evolution. Targeted therapies are a new generation of
anticancer drugs which interfere with specific molecules
that are involved in the growth, progression, and spread of
cancer, and are expressed by specific cancer types. These
drugs have introduced the concept of individually-tailored
cancer treatment. The specific mechanism of action of target
therapies should cause less toxic effects than conventional
chemotherapy drugs [
]. The specific safety profile of each
new drug, which is the information known about its safety
at the time of marketing, has always been based on pivotal
clinical trials. For this reason, the adverse drug reactions
(ADRs) reported in the Summary of Product Characteristics
(SPC) cannot be exhaustive [
], because the potential new
drugs are tested under controlled conditions, with a small
sample of selected patients, and often with a short follow-up
time. The differences between selected patients enrolled in
clinical trials and the real-world patients regard the
characteristics of the latter [
]. Often, the real-world patients in
oncology are represented by elderly patients which may be
considered as a “special population”. Elderly patients are at
a high risk of ADRs, medical errors, and drug interactions,
because of comorbidities, polypharmacy, greater
vulnerability, and age-related changes in pharmacokinetics and
In everyday clinical practice, there is a significant list of
side-effects that can be ascribed to targeted drugs; indeed,
although they are different from the well-known side effects
caused by chemotherapy, they can severely compromise
patients’ quality of life, and can even cause discontinuation
of therapy or changes in the therapeutic strategy [
Pharmacovigilance aims to improve patients’ safety
through the detection of ADRs. Spontaneous reporting is the
best method for highlighting adverse drug reactions outside
clinical trials [
In oncology, under-reporting of adverse reactions is a
common phenomenon, because ADRs are generally
considered inevitable [
]. In addition, there is a relevant decrease
of patient’s satisfaction during anticancer treatment as a
consequence of ADRs. A shift in the trend of reporting ADRs
by health professionals and patients is considered to be an
important element to improve patient’s safety and
adherence to targeted therapies. The involvement of patients in
Pharmacovigilance reporting systems (PVRS) is a potential
strategy to increase the knowledge of oncological ADRs,
increase patient’s satisfaction, and reduce the phenomenon
of under-reporting [
Aims of the study
The main objective of this study was to observe the ADRs
caused by ten anticancer targeted-therapies in the real-world
oncology setting and to detect the differences with the ADRs
reported in SPCs. As secondary outcome, this study
investigated the role and the impact of the clinical pharmacist in
reducing under-reporting of ADRs and in improving their
management. Moreover, patients’ satisfaction with the
support provided by the clinical pharmacist was investigated at
the conclusion of the study.
The study was approved by CRO National Cancer Institute
Ethical Committee (Project No. 199/Sc).
The present study was conducted at the National Cancer
Institute “Centro di Riferimento Oncologico—CRO” in
Aviano, north-eastern Italy, between February 2013 and April
2015, enrolling 154 patients, aged 18 years and older. We
performed a prospective, observational pilot study to
evaluate the safety profile of 10 anticancer targeted-therapies.
All patients were treated with at least one targeted-therapy
at the doses reported in SPC. The study focused on eight
oral drugs: erlotinib, everolimus, gefitinib, imatinib,
lapatinib, lenalidomide, sorafenib, sunitinib, and two injectable
drugs: bevacizumab and cetuximab. To avoid biases caused
by concomitant administered drugs, we enrolled patients in
monotherapy with the studied drugs (excluding cetuximab).
Indeed, to remove the effect of earlier treatment, patients
previously treated with other drugs underwent a wash-out
period of 12 weeks. The recruitment phase started in
February 2013 and lasted 18 months.
Eligible patients who fulfilled the inclusion criteria
(age ≥ 18 years, patients treated at CRO of Aviano with at
least one of the study drugs) and signed the informed
consent, were interviewed by a clinical pharmacist using a
structured questionnaire to collect data on socio-demographic
characteristics, drug schedule, and ADRs. Particular
attention was paid to the evaluation of patient’s interactions with
the adverse events occurring during treatment, assessing
whether patients had ever heard of PVRS, if they knew how
it works, and if they had ever reported any ADRs to PVRS.
Patients not using these ten target-therapies or not treated at
CRO Aviano were excluded. Every 30 days, patients were
contacted by a clinical pharmacist for the follow-up
interview to evaluate their health condition and ADRs observed
during therapy. Metabolism and nutrition disorders
(hyperglycaemia, hypomagnesaemia, according to MedDRA
dictionary) were also reported, since patients in treatment with
target therapies have to perform routinely analysis every
month. These interviews were conducted face-to-face or
by telephone, according to the patients’ preferences, using
a structured questionnaire (see additional downloadable
material). In the final interview, patient’s compliance and
satisfaction were further assessed. Patients’ compliance was
also observed for oral drugs through the hospital pharmacy
service. Indeed, we gave another medicine pack only if the
patient had actually taken the drugs given before.
Furthermore, in the final interview, patients were asked whether
they appreciated the monthly monitoring, if they would have
liked to be monitored after the study, and whether
pharmacist monitoring impacted on the therapy adherence and
management of ADRs. The answers to the final interview
were anonymously collected by the nurses, in order to avoid
biases. The ADRs observed were compared with those
reported in SPC. We could not analyze the data concerning
erlotinib, gefitinib, and lapatinib because there were< 10
ADR terminology was firstly classified according to
MedDRA dictionary [
]. Information on ADRs were then
analysed using the World Health Organization-Uppsala
Monitoring Center (WHO-UMC) criteria and the Naranjo
algorithm to evaluate whether they were connected to the
drug or not (causality assessment) [
Overall, 154 patients were enrolled (Table 1). The
majority were female (n = 83, 54%) and were 65 years or
older (n = 60, 39%) (median age: 61 years; interquartile
range 52–69 years). The therapy with bevacizumab was
the most frequent (n = 49, 32%), followed by Sunitinib
(n = 27, 18%), and Sorafenib (n = 20, 13%). Therefore, the
most common pathology was breast cancer (n = 34, 22%),
followed by colorectal cancer (n = 31, 20%), and renal cell
carcinoma (n = 25, 16%). Six patients were sequentially
treated with two drugs (Sunitinib/Everolimus or Sunitinib/
Sorafenib) and three patients with three drugs (Sunitinib,
Everolimus, and Sorafenib). The majority of patients
presented comorbidities (n = 110, 71%), and received
oncology pre-treatment (n = 94, 61%). For the specific purpose
to the pilot study, we collected and reported data relative
to detection of both “known” ADRs (reported by SPCs
]) and “unknown” ADRs (not listed in SPCs by
Compared to the values of ADRs reported in SPC, we
observed (Table 2) a higher frequency of increased
lacrimation (41.7%, 95% CI 13.8–69.6% vs. 1 to < 10% in SPC), and
eyelid oedema (66.7%, 95% CI 40.0–93.3% vs. 1 to < 10% in
SPC) among patients treated with imatinib. Patients being
treated with sorafenib reported a higher frequency of
neuropathy (40.0%, 95% CI 18.5–61.5%) and skin desquamation
(35%, 95% CI 14.1–55.9%) than that reported in SPCs (i.e., 1
to < 10%). Many differences emerged with sunitinib: 96.3%
of patients reported hypothyroidism (95% CI 89.2–100 vs.
1 to < 10% in SPC); 55.6% reported musculoskeletal pain
(95% CI 36.8–74.3% vs. 1 to < 10%), 44.4% cited increased
blood creatinine and abdominal discomfort (95% CI
25.7–63.2% vs. 1 to < 10%); 37.0% indicated
hypertriglyceridemia and hypercholesterolaemia (95% CI 18.8–55.3%
vs. 1 to < 10% and 95% CI 18.8–55.3% vs. 0.1 to < 1%,
respectively). In addition, a higher frequency of myalgia/
arthralgia and headache (42.9%, 95% CI 29.0–56.7% and
28.6, 95% CI 15.9–41.2, respectively vs. 1 to < 10% in SPC)
was detected among patients treated with bevacizumab.
Finally, a difference in the incidence of mucositis (58.3%,
95% CI 30.4–86.2% vs. 1 to < 10% in SPC) was observed
among patients treated with cetuximab. We did not notice
differences between the ADRs observed with everolimus
compared to ADRs reported in the SPC.
Detection of “unknown” ADRs
Table 3 summarises several “unknown” ADRs (which are
not reported by respective SPCs released by market
holders) observed during the study. Among the patients treated
with lenalidomide, the unknown ADRs were:
hyperglycaemia (50.0%) and hypercholesterolaemia (28.6%). The same
ADRs (25.0 and 15.0%, respectively), together with
hypertriglyceridemia (10.0%), were also observed with sorafenib.
Finally, patients treated with bevacizumab developed
Follow up (months)
hypomagnesaemia (12.2%), while patients treated with
cetuximab developed neutropenia (25.0%).
We also observed several ADRs which are reported as
“uncommon” in SPCs (data not shown). The uncommon
ADRs observed were deep vein thrombosis with everolimus
(n = 3, 20.0%), eye disorders like blepharitis and keratitis
with cetuximab (n = 3, 25.0%), and a transient ischaemic
attack (TIA) with sorafenib (n = 1, 5.0%). A Doppler
echocardiography was performed and showed a right carotid
artery stenosis of 30% and left carotid artery stenosis of
50%. It must be highlighted that, due to the small number
of known cases of adverse effects, the dosage of the drugs
was not revised. Thus, this could result in higher health risks
Impact of this study on patient satisfaction and on under‑reporting of ADRs
The results of satisfaction questionnaire (see downloadable
additional material) showed that this approach was
appreciated by patients. Indeed, almost all of the patients (99%)
appreciated the presence of the clinical pharmacist in the
cancer care team and 99% considered the clinical
pharmacist’s role essential for improving the quality of
pharmaceutical care and patient’s adherence to the therapy. Furthermore,
96% of patients immediately contacted the pharmacist if
there were any changes in the treatment or ADRs;
moreover, 98% of patients would have wanted to be monitored
after the end of the study. The adherence was not measured;
however, through the clinical pharmacy service (direct
hospital dispensation of drugs to outpatients) we observed that
enrolled patients (95%) effectively took the entire medicine
pack before taking another one. Comparison between
pharmacovigilance reports received at CRO Aviano, National
Cancer Institute, in 2013 (start of the study) and 2015 (end
of the study) showed an increase (124%) of spontaneous
reports (37 vs. 83 individual case reports).
The real conditions of clinical daily practice are needed to
detect all of the possible “real” toxicities imputable to drugs,
because ADRs reported in SPCs are essentially based on
clinical trials. Patients often present comorbidities,
polypharmacy, a greater vulnerability, and age-related changes
in pharmacokinetics and pharmacodynamics. Indeed, the
self-administration of oral drugs increases the risk of ADRs
because of the improper use of drugs [
patients often suspend or self-regulate the dose of the drug
when they experienced an important adverse drug reaction,
with a possible decrease of therapy’s effectiveness.
Furthermore, ADRs are the major problem of pharmacovigilance,
especially in the oncology setting, as the anticancer drug
toxicity is considered common, and a normal consequence
of these therapies [
]. Health professionals do not report
ADRs because they generally think that there could be
negative consequences for the patients’ therapy if they fill out
PV reports or complaints by the pharmaceutical industry [
]. Moreover, they often have several doubts about how to
appropriately complete the PV report. Often, patients are
not informed about the existence of the PV report and about
the possibility of directly completing this report. Motivating
health professionals and patients to report ADRs to improve
the knowledge of pharmacovigilance activities is an effective
approach against under-reporting .
In this study, we showed the importance of pro-active
pharmacovigilance in order to efficiently highlight adverse
drug reactions, and the fundamental role of the pharmacist
in ensuring patient’s safety. Most patients (71%) enrolled in
the study presented comorbidities, and were therefore more
vulnerable. The median age of patients enrolled in our study
was 61 years old and the majority (54%) were female; in
clinical trials, patients enrolled are young, male, and with
Furthermore, it is also worth noting that even with a
small number of patients, it has been possible to observe
a difference in the incidence of some ADRs and to identify
unknown ADRs. 28.6% of patients in monotherapy with
bevacizumab had headaches but none had high blood pressure.
Indeed, 42.9% of patients being treated with bevacizumab
reported myalgia/arthralgia without disease progression. In
patients treated with sunitinib, the collected data showed
a significant difference in the incidence between ADRs
observed in patients and those reported in SPC. All patients
taking sunitinib followed the drug’s therapeutic scheme: 4
consecutive weeks, followed by a 2 week rest period. Thus,
we considered the rest period to be a de-challenge and the
drug re-intake as a re-challenge. We observed ADRs only
during the drug intake period. Applying the PV principles,
the correlation between ADRs reported and sunitinib was
]. In particular, 96% of patients showed
hypothyroidism during the treatment with sunitinib and 56%
patients showed musculoskeletal pain without progression
of the disease. We also observed 44% of patients with
hypercholesterolaemia and hypertriglyceridemia, which improved
during the interruption of sunitinib’s administration. In total,
8 of the 20 patients who took sorafenib showed neuropathy,
so the drug had to be suspended because of this toxicity.
Imatinib caused eyes toxicity; in particular, 67% of patients
presented eyelid oedema, and 42% showed increased
lacrimation. We observed unknown ADRs and searched for them
in the Eudravigilance and AIFA databases to verify whether
there were other reported cases other than ADRs [
The results from our study showed that 12% of patients
being treated with bevacizumab developed
hypomagnesaemia and this adverse reaction was also reported in the
Eudravigilance database. In the literature, this adverse effect
is linked to anti-epidermal growth factor receptor (EGFR)
monoclonal antibodies or to chemotherapy, but it is not
linked to bevacizumab [
]. Patients that used
lenalidomide presented hyperglycaemia and hypercholesterolaemia
as unknown adverse reactions. Those adverse effects have
also been reported in the Eudravigilance database, but they
could be associated with the concomitant use of
dexamethasone. The unknown ADRs observed with sorafenib are also
reported in the Eudravigilance database and we observed
an improvement in adverse reactions with the suspension of
sorafenib. Finally, although we observed neutropenia with
cetuximab and there are some cases in the Eudravigilance
and AIFA databases, the concomitant use of chemotherapy
could affect this adverse effect. We also observed
uncommon adverse effects with these ten targeted-therapies. These
adverse events are not generally associated with the drugs
and are consequently not reported to the regulatory agencies,
causing a non-revised therapeutic administration of drugs.
This can lead to serious health risks for the patient. It is
important to report unknown and uncommon ADRs to the
regulatory agency, in order to improve safety information
about these new generations of drugs [
The results of the present study are also important for
clinical practice. The monthly semi-structured interview
allowed to understand if the drug had been taken correctly
by the patient and intervened if there was any case of
nonadherence. The review of Lam and Fresco [
that patient interviews and pill count are indirect measures
used in routine clinical practice to verify patient’s
non-adherence. Indeed, the monitoring of patients and the
information gave them about the management of ADRs increase the
satisfaction of patients and the dialogue between patients,
health professionals, and pharmacists. Patients contacted
the pharmacist if ADRs were present; if patients contacted
their pharmacist before taking other substances
(supplementations, herb, medical devices, etc.) or to understand how to
take the drugs, the risk of interactions and adverse effects
could decrease. Finally, the involvement of pharmacists in
this study increased the pharmacovigilance reports from the
beginning to the end of the study (37 vs. 83 individual case
Strengths and limitations
The most important strength of the present study is that we
observed the occurrence of ADRs in real-world conditions.
Moreover, the structured interview, done every 30 days,
allowed the close monitoring of ADRs. Study limitations are
inherent to the observational nature of the study, which only
permitted to retrieve a small number of adverse drug
reactions. Furthermore, in regard to “known” ADRs, we used
the data reported in specific SPCs as term of comparison
of ADRs observed in the study, but obviously this can lead
to potential biases correlated with the differences between
the subjects recruited in the pre-registration trials and the
population group participating to this study. So this may
render to an impoverishment of the statistical design, and
somehow arbitrary comparisons. Another limitation is the
use of non-validated questionnaire forms. Regarding this,
it is necessary to make a distinction between the methods
used in the standard or “passive” pharmacovigilance
activities—passive because based on the mere respect of reporting
methods established by national or international legislation
(e.g. CIOMS forms)—and methods used by “proactive”
Pharmacovigilance studies—carried out with the
educational purpose of citizens, patients, and health
professionals in order to reduce underreporting of ADRs and detect
potentially serious hazards for patients. To our knowledge,
one of the future challenges involving PVRS will be the
validation of questionnaires forms to be proposed as
standard documentation during medication reviews activities and
Another limitation of the study was that blood and
lymphatic system disorders (according to MedDRA dictionary)
were underestimated because patients did not understand
haematological exams, so we decided not to consider
haematological toxicity in our analysis.
During the study, we observed a difference of ADRs between
the SPC and patients enrolled in the study as well as some
unknown ADRs. This observational study also highlighted
that there was an increase in pharmacovigilance reports,
and therefore a decrease in the under-reporting
phenomenon. This improved the information about ADRs of these
ten targeted-therapies. Patient’s monitoring improved their
satisfaction and decreased the autonomous suspension of
drugs or self-regulation, and consequently adverse effects.
Indeed, patients immediately contacted the pharmacist if
there were changes in the treatment or ADRs. These results
have given a high value to pharmacovigilance studies and
the presence of clinical pharmacists in the treatment team
to reduce the phenomenon of under-reporting. Results from
the present study might be a starting point for developing a
randomised trial which aims to confirm the impact of the
pharmacist on improving patient’s adherence and in
measuring the difference in ADRs reports with the intervention of
Funding The study was supported by Agenzia Italiana del Farmaco
(AIFA) and Regione Autonoma Friuli Venezia-Giulia (Active
Pharmacovigilance projects art.1, comma 819 Lex 27/12/2006, n.296 Financial
2007 - Number: H25E11000000005).
Conflicts of interest None.
Open Access This article is distributed under the terms of the
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