Download Cancer risk in people with epilepsy: the role of antiepileptic

Brain Advance Access published December 1, 2004
DOI: 10.1093/brain/awh363
Brain Page 1 of 11
INVITED REVIEW
Cancer risk in people with epilepsy: the role of
antiepileptic drugs
Gagandeep Singh,1 Pablo Hernáiz Driever2 and Josemir W. Sander1
1
Correspondence to: Ley Sander, Department of Clinical and
Experimental Epilepsy, UCL Institute of Neurology, Queen
Square, London WC1N 3BG, UK
E-mail: [email protected]
Summary
There has been considerable debate about the relationship
between epilepsy and cancer, in particular whether the
incidence of cancer is increased in people with epilepsy
and whether antiepileptic drugs promote or protect against
cancer. We review available evidence from animal experiments, genotoxicity studies and clinico-epidemiological
observations, and discuss proposed mechanisms underlying the association between epilepsy and cancer.
A carcinoma-promoting effect has been seen unequivocally in rodent models for phenobarbital and phenytoin;
phenobarbital promoted liver tumours and phenytoin
caused lymphoid cell and liver tumours in rats. Early
human epidemiological studies found an association
between phenobarbital and hepatocellular carcinoma,
and several subsequent studies suggested an association
with lung cancer. An association with brain tumours has
also been demonstrated. Phenytoin has been causally
implicated in three human cancers: lymphoma, myeloma
and neuroblastoma, the latter specifically in the setting of
foetal hydantoin syndrome. However, despite considerable
long-term pharmaco-epidemiological data being available
for both antiepileptic drugs, evidence for human carcinogenicity is not consistent and both are considered only
possibly carcinogenic to humans. Valproate, however,
has been found to exert an antiproliferative effect on certain cancer cell lines both in vitro and in vivo. A corresponding cancer-suppressive effect has not been studied in
human epidemiological studies, though there are now preliminary reports of the use of valproate in human haematological and solid tumours. The anticancer activity of
valproate appears to be driven by histone deacetylase inhibition and to be independent of hormone or multidrug
protein resistance dependant mechanisms. The newer
antiepileptic drugs appear to be safe, as no carcinogenicity
has been demonstrated either during regulatory testing or
in post-marketing surveillance. Nevertheless, the subject
of cancers and epilepsy constitutes a promising agenda for
clinical and experimental research in the future.
Keywords: epilepsy; cancer; co-morbidity; antiepileptic drugs; carcinogenicity
Abbreviations: AED = antiepileptic drug; GSK3=glycogen synthase kinase3; HDAC = histone deacetylase;
IARC = International Agency for Research in Cancer; SIR = standardized incidence ratio; SMR = standardized mortality ratio
Received September 9, 2004. Revised November 16, 2004. Accepted November 17, 2004
Introduction
People with a history of epilepsy represent a sizeable
proportion (1–2%) of the general population (Bell and
Sander, 2002; Sander, 2003). The challenge to improve
their overall health status is contingent not only upon controlling seizures but also on managing several concomitant
health conditions. Indeed, comorbidity is widespread in
Brain
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epilepsy and is a focus of much recent attention (Gaitatzis
et al., 2004). The concern that epilepsy or its treatment may
be causally implicated in the development and subsequent
course of several health conditions is an area of ongoing
interest. The spectrum of comorbidity encompasses not
only neuropsychiatric disorders such as dementia, learning
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Department of Clinical and Experimental Epilepsy, UCL
Institute of Neurology, London, UK and 2Department of
Pediatric Oncology and Hematology, Campus Virchow
Hospital, Charité Universitätsmedizin Berlin, Berlin,
Germany
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G. Singh et al.
Overview of carcinogenicity testing
The seminal event in carcinogenesis is often the mutational
transformation of proto-oncogenes, tumour-suppressor genes
or other genes controlling cell proliferation. In addition,
epigenetic events at translational and post-translational
level, such as DNA methylation, acetylation of nuclear
proteins, alternative splicing of mRNA and modification of
proteins by phosphorylation or nitrosylation, may initiate carcinogenesis (Hanahan and Weinberg, 2000). One of these,
regulation of acetylation of the nuclear proteins known as
histones (histone deacetylation and acetylation), is mechanistically relevant to the present review, as described later
(Fig. 1). The net result of the combination of these molecular
events is that cancer cells are rendered self-sufficient in growth
signals and insensitive to anti-growth signals, and are able to
evade apoptosis, sustain angiogenesis, replicate limitlessly
and invade neighbouring tissues as well as metastasize.
The list of pharmaceutical agents suspected or known to be
carcinogenic is long. In general, the carcinogenic potential
of pharmaceutical agents is inferred from three types of
Balance of genomic expression in cancer cells
HDAC sensitive promoter regions
Histone Acetyltransferase
Histone Deacetylase
Open gene /
Active
euchromatin
Closed gene /
Silent
heterochromatin
Histone Deacetylase
Histone Acetyltransferase
Arrest of cell growth
Differentiation
Apoptosis
Cell growth
Dedifferentiation
Survival
Valproate
Note:
Histone Deacetylase
Acetylated Histones
Deacetylated Histones
Histone Acetyltransferase
Fig. 1 Diagrammatic representation of the interaction between valproate and acetylation status of DNA-associated proteins known as
histones in development of cancer. Ac = acetyl group; HDAC = histone deacetylase).
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disabilities and depression, but also non-neurological
conditions such as cancer.
Cancer is the second most frequent cause of death worldwide. Naturally, it can complicate several chronic medical
conditions, including epilepsy, fuelling concerns about the
cancer risk or lack thereof associated with the underlying
disorder. Pertinent to this cancer risk is the carcinogenicity
of drugs used over long periods of time to treat these disorders,
particularly so because drug exposure is a potentially avoidable risk. Accordingly, testing for carcinogenicity is crucial in
the evaluation of drug safety.
The potential for antiepileptic drugs (AEDs) to be
carcinogenic was investigated in experimental, epidemiological and clinical research, particularly in the late 1960s and
1970s (Peraino et al., 1971; White et al., 1979). The issue is
far from settled, however, although it has not attracted much
attention recently. In this article, we review available experimental and human data on the occurrence of cancer in people
with epilepsy and present an argument for further studies in
this area.
Cancer risk and anticonvulsants
studies: (i) laboratory animal assays in which rodents are
exposed to the agent, either chronically to usual doses or,
more often, to discrete maximal tolerated doses; (ii) genotoxic
assays, where the agent’s potential to cause chromosomal
damage or aberrations is estimated in vitro; and (iii) longterm human epidemiological studies of users of the drug.
Rodent carcinogenesis is mechanistically simple and involves
a limited number of oncogenic events. Distinct from this,
human carcinogenesis is a complex process; in experimental
situations an array of at least five different genetic events is
required to render normal cells malignant (Hahn and
Weinberg, 2002). Not surprisingly, animal carcinogenicity
data, which suggested neoplastic development at a variety
of sites for several pharmaceutical agents, have not been
confirmed in human epidemiological data for many agents.
Carcinogenicity studies for AEDs may be carried out in
samples of people with either cancer or epilepsy. Studies
in samples of persons with cancer use a retrospective case–
control design. Though theoretically appealing, these are
rarely feasible, being complicated by recall bias and the
fact that epilepsy history is often not mentioned in records
of cancer registries or death certificates of people dying of
cancer (Bell et al., 2004). The alternative, estimating cancer
incidence or mortality in epilepsy cohorts, is used more often
(Clemmesen and Hjalgrim-Jensen, 1978; White et al., 1979;
Shirts et al., 1986; Olsen et al., 1989; Lamminpaa et al., 2002).
Ideally, such samples should be large, and prospectively
followed up for several decades in view of the time required
for the development of cancers and the low frequencies of
individual cancer types. Providing necessary information is
available and the sample size is sufficiently large, it might also
be possible to undertake nested case-control studies within
such cohorts. In reality, however, long prospective follow-ups
are logistically not very feasible. Most studies so far have
surmounted the problem of prospective follow-up by backdating follow-ups to several years previously (Clemmesen
and Hjalgrim-Jensen, 1978; White et al., 1979; Olsen et al.,
1989; Lamminpaa et al., 2002). Good examples of the latter
are cohorts of institutionalized epilepsy patients, whose
records may be traced back to the point of institutionalization
(Clemmesen and Hjalgrim-Jensen, 1978; White et al., 1979;
Olsen et al., 1989), of hospital clinic attendees, of persons
applying for driving privileges (D. Lowe, A. E. M. McLean
and J. Taylor, unpublished, 1986) and from prescription
records of pharmacies or insurance agencies (Friedman and
Ury, 1980, 1983; Selby et al., 1989; Lamminpaa et al., 2002).
Cancer incidence or mortality can then be ascertained through
cancer registries or demographic databases. However, it
may not be possible to confirm a diagnosis of epilepsy and
verify durations and compliance of AEDs taken in such
cohorts. Moreover, it is often not possible to make note of
the presence of confounding risk factors, such as smoking,
alcohol consumption and ages at menarche and menopause, in
backdated designs.
Given the methodological difficulties associated with the
study of cancer co-morbidity in people with epilepsy, the most
practical approach appears to be the follow-up of large cohorts
drawn from prescription records cross-checked against
records of cancer registries (Lamminpaa et al., 2002). The
ratios of observed cancer incidence or mortality to expected
figures for the community, region or country provide the
standardized incidence ratio (SIR) and standardized mortality
ratio (SMR), respectively. A SIR/SMR greater than 1 implies
a carcinogenic effect whilst a ratio less than 1 indicates a
cancer-protective effect. A positive drug–cancer association
should carry a large relative risk (>3), persist over time and be
statistically significant (Selby et al., 1989). However, it needs
to be borne in mind that a drug that is given for a condition
with symptoms that may mimic that of a particular neoplasm
shortly before its diagnosis may appear to be associated with
the neoplasm even if it is not carcinogenic. In order to offset
this apparent association, referred to as ‘protopathic bias’
(Horwitz, 1985), some authors have proposed including a
time lag from exposure, after which measurement of association is made (Selby et al., 1989). An association that increases
over time excludes the possibility of protopathic bias and
is in keeping with the concept that carcinoma risk increases
with age.
The International Agency for Research in Cancer (IARC)
continuously reviews experimental and human data regarding
potential carcinogens (International Agency for Research in
Cancer, 1987). On the strength of available evidence, the
agency classifies chemical carcinogens into four groups:
Group 1: definitely known to be carcinogenic to humans;
Group 2A: probably carcinogenic to humans; Group 2B: possibly carcinogenic to humans; Group 3: carcinogenicity
unclassifiable; Group 4: probably not carcinogenic to humans.
Carcinogenicity of antiepileptic drugs
Animal carcinogenicity
Conventional or older AEDs are drugs that have been
available since before the 1980s, and these include phenobarbital, phenytoin, carbamazepine and sodium valproate.
These drugs are still the mainstay of epilepsy treatment
(Sander, 2004). On a worldwide basis, over 85% of people
with epilepsy are treated with these drugs, and phenobarbital
is the most commonly used by far. Globally, however, the
majority of people with epilepsy are not treated, as there is a
huge treatment gap (Meinardi et al., 2001).
Phenobarbital
Phenobarbital was one of the first drugs for which
carcinogenicity was demonstrated in animal experiments.
In the original study, a high incidence of liver tumours was
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Epidemiological approaches to human
carcinogenicity
Page 3 of 11
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G. Singh et al.
Phenytoin
Anecdotal reports of lymphoma occurring in phenytoin users
(Salztein and Ackerman, 1959; Hyman and Sommers, 1966)
led to carcinogenicity studies in animals (Kruger, 1970;
Kruger and Harris, 1972). A few studies in selected rodent
strains demonstrated that phenytoin treatment led to the development of lymphoma through chronic antigenic stimulation
and immunosuppressive effects of the drug. Drug exposure
was also associated with liver tumours through a promoting
mechanism similar to that of phenobarbital (Chhabra et al.,
1993; Diwan et al., 2001). Other studies, however, did not
support a carcinogenic potential for phenytoin (Levo et al.,
1975; Maeda et al., 1988).
Valproate
Valproate administration caused uterine adenocarcinomas in
Wistar rats (Watkins et al., 1992). In contrast, an antitumour
effect of valproate was discovered serendipitously, when clinical experience with the drug raised concerns about its teratogenicity, specifically the development of human neural tube
defects (Blaheta et al., 2004). Its teratogenicity was then
studied in vitro using neuroectodermal cell lines, such as
neuroblastoma cells (Regan, 1985; Blaheta and Cinatl, 2002).
An antiproliferative and differentiating effect was revealed in
these experiments and was later extended to other
cell lines, such as glioma, breast cancer, prostate cancer and
teratocarcinoma cell lines and leukaemia progenitors (Cinatl
et al., 1997; Knupfer et al., 1998; Blaheta and Cinatl, 2002).
The effect was subsequently confirmed in vivo (Michaelis
et al., 2004).
Carbamazepine
Little has been published on the carcinogenicity of this drug. It
is known, however, that carbamazepine administered in doses
in excess of 25 mg/kg/day for more than 2 years caused
hepatocellular tumours in female, and benign interstitial
tumours of the testes in male, Sprague–Dawley rats
(Ciba Geigy, Product Information, 1987).
Newer AEDs
Newer AEDs are those that have been launched in the last
20 years. These include vigabatrin, lamotrigine, gabapentin,
felbamate, topiramate, tiagabine, zonisamide, levetiracetam
and pregabalin (Sander, 2004; Bialer et al., 2004).
While conventional AEDs were never formally tested for
carcinogenicity prior to clinical use, carcinogenicity was evaluated during drug development for these newer drugs.
Male Wistar rats fed on high doses (250–2000 mg/kg) of
gabapentin for long durations developed non-invasive, nonmetastatic, acinar pancreatic carcinoma (Sigler et al., 1995).
The effect, however, was not considered representative of
human carcinogenic risk since human pancreatic carcinomas
are ductal rather than acinar. Similarly, pregabalin, a drug
structurally similar to gabapentin, was shown to produce an
increased incidence of haemangiosarcoma in mice fed on high
doses of the drug. This was, however, felt to be speciesspecific and there is no evidence to suggest a related risk
in humans (European Medicines Evaluation Agency, 2003;
Pfizer, 2004). Felbamate was found to produce testicular
interstitial cell tumours in male rats (McGee et al., 1998).
None of the other newer AEDs have been found to be carcinogenic to animals in experiments that preceded their use in
human trials.
Genotoxicity studies
Several genotoxicity studies using a variety of approaches
have been performed for the conventional AEDs (phenobarbital, phenytoin and sodium valproate). The majority of these
did not show significant derangements in genotoxic assays for
these drugs (Schaumann et al., 1989a, b; Schaumann et al.,
1990; Whysner et al., 1996). However, others have found an
increased frequency of sister chromatid exchanges in
phenytoin-treated individuals with epilepsy (Hu et al.,
1990; Taneja et al., 1992; Kaul and Goyle, 1999; Kaul
et al., 2001). Genotoxicity testing is now a regulatory requirement for approval of all pharmaceutical agents and has been
performed ab initio for the newer AEDs.
Human carcinogenicity
Phenobarbital
We reviewed one large multidrug, community-based, screening study (Friedman and Ury, 1980, 1983; Selby et al.,
1989), five historical cohort studies that evaluated cancer
risk among people with epilepsy presumably given phenobarbital (Clemmesen and Hjalgrim-Jensen, 1978, 1981;
White et al., 1979; Olsen et al., 1989, 1995; Lamminpaa
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noted when phenobarbital administration followed exposure
to 2-acetyl-aminoflourene but not when given alone (Peraino
et al., 1971). The hepatocarcinogenicity was reproduced in
subsequent studies (Driver and McLean, 1986; Becker, 1985;
Diwan et al., 1988). However, it was influenced by species,
sex and age of the animal. On the basis of the above studies, it
was concluded that phenobarbital is not in itself carcinogenic
but is an indirectly acting, genotoxic, liver tumour promoter
(Yamagi et al., 1984; Diwan et al., 1995). Phenobarbital has
also been found to promote neoplasms of the thyroid (Becker,
1985). These initial animal experiments were significant
because they fuelled concerns about carcinogenicity among
clinicians prescribing barbiturates and led to epidemiological
studies that examined carcinoma incidence or mortality in
subjects receiving barbiturates (Clemmesen and HjalgrimJensen, 1978; Gold et al., 1978; Annegers et al., 1979;
White et al., 1979; Shirts et al., 1986; Olsen et al., 1989,
1990, 1995; Selby et al., 1989; Goldbaher et al., 1990; Gurney
et al., 1997; Lamminpaa et al., 2002).
Cancer risk and anticonvulsants
Phenytoin
In the past, several clinical case reports and series have
suggested an association between phenytoin treatment and at
least three cancers (lymphoma, myeloma and neuroblastoma).
An assessment of the carcinogenicity of phenytoin with
specific regard to lymphoreticular malignancies was complicated by its potential to cause a variety of lymph node lesions
that may mimic lymphoma upon presentation. In a review of
over 100 cases of lymphadenopathy secondary to anticonvulsant use, lymph node histology was reported to be consistent
with Hodgkin’s disease or even lymphoblastic lymphoma in a
small, unspecified proportion; treatment with radiotherapy
and chemotherapy followed, but the lymphadenopathy
regressed on withdrawal of phenytoin treatment (Anthony,
1970). In an earlier report, lymphadenopathy was described
in association with fever, skin rash and hepatosplenomegaly,
usually developing within 3 months of phenytoin treatment
(Salztein and Ackerman, 1959). The condition was characterized on histopathology by obliteration of lymph node architecture, hyperplasia and diffuse infiltration by atypical
lymphoid cells, and was appropriately termed ‘pseudolymphoma’. This closely mimics mycosis fungoides, a T-cell
lymphoma with cutaneous involvement, in its clinical and
pathological features (Rijlaarsden et al., 1991; Cooke et al.,
1998). Drug withdrawal, in order to document regression of
lymphadenopathy (Anthony, 1970), or immunohistochemical
studies for the demonstration of clonality (Jeng et al., 1996;
Choi et al., 2003), may be the only means of distinguishing the
two conditions.
An initial report described six cases of lymphoma in
association with phenytoin use (Hyman and Sommers,
1966). Since then, the development of lymphoma has been
noted in relation to long-term phenytoin use by several authors
(Gams et al., 1968; Li et al., 1975; Matzner and Polliack, 1978;
Garcia Suarez et al., 1996). It is difficult to infer carcinogenicity
on the basis of these clinical reports alone, particularly as some
of the early descriptions of lymphoma may have been pseudolymphoma or vice versa (Hyman and Sommers, 1966). The
issue is further complicated by reports of development of
frankly malignant lymphoma after a period of time in what
unequivocally is pseudolymphoma (Gams et al., 1968; Li et al.,
1975). The occurrence of lymphoma after a quiescent period
following phenytoin withdrawal for pseudolymphoma was
referred to as ‘pseudo-pseudolymphoma’ (Gams et al., 1968).
Recently, progression from paracortical and follicular
hyperplasia to frank malignant lymphoma in two out of five
cases of pseudolymphoma has been reported (Abbondanzo
et al., 1995). In a larger review of 25 cases of phenytoinassociated lymphadenopathy, it was observed that, whilst
benign lymphadenopathy occurred early, within weeks to
months, lymphomas typically occurred after long periods of
exposure.
A few epidemiological studies, in particular those performed in institutionalized cohorts of patients with epilepsy,
noted increased SIRs/SMRs due to lymphomas, but the
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et al., 2002) and four studies that assessed the association
between barbiturate exposure in the perinatal period and
childhood brain tumours (Gold et al., 1978; Annegers
et al., 1979; Goldbaher et al., 1990; Olsen et al., 1990;
Gurney et al., 1997). Three studies were in hospitalized or
institutionalized cohorts (Clemmesen and Hjalgrim-Jensen,
1978, 1981; White et al., 1979; Olsen et al., 1989, 1995),
two, including the screening study, were AED- or barbiturate
prescription-linked (Friedman and Ury, 1980, 1983; Selby
et al., 1989; Lamminpaa et al., 2002) and one study was
population incidence-based (Shirts et al., 1986). All except
one (Clemmesen and Hjalgrim-Jensen, 1978, 1981), reported
increased SIRs (from 1.1 to 1.5) for cancer, though the risk
was statistically significant in only one study (White et al.,
1979). Most of the increased risk was due to brain tumours,
and this was significant in all five studies (SIR 2.9–5.7). This
risk was, however, elevated only for the initial years of study,
conforming to a protopathic bias (Feinstein, 1985) and
implying that brain tumours were the cause of seizures
and not a drug effect.
Data regarding the risk of other systemic cancers associated
with phenobarbital administration are not consistent. The
Nordic studies (Clemmesen and Hjalgrim-Jensen, 1978, 1981;
Olsen et al., 1989, 1995; Lamminpaa et al., 2002) demonstrated increased SIRs for hepatocellular carcinoma; however,
in two of these studies the risk was confounded by other
known risk factors for hepatic carcinoma, including thorotrast
exposure and cirrhosis (Clemmesen and Hjalgrim-Jensen,
1978, 1981; Olsen et al., 1989, 1995). By contrast, in England,
an inverse association between epilepsy and hepatocellular
carcinoma was found (White et al., 1979). Several studies
have reported increased SIRs for lung cancers (White et al.,
1979; Friedman and Ury, 1980; Olsen et al., 1989, 1995;
Selby et al., 1989; Shirts et al., 1986; Lamminpaa et al.,
2002). Interestingly, in the multidrug screening community
study of North California, an association was noted between
prescriptions of most types of barbiturates (including
phenobarbital, pentobarbital and secobarbital) and lung
cancer (Friedman and Ury, 1980; Selby et al., 1989). An
increased SIR for lung cancer was also noted in one
population-based survey; however, smoking was a confounding factor in this study (Shirts et al., 1986). A few studies
noted decreased risk of cancer in certain sites, notably urinary
bladder and skin, in association with phenobarbital
administration (Clemmesen and Hjalgrim-Jensen, 1978,
1981; Olsen et al., 1989, 1995).
An early study reported a three-fold increased risk of childhood brain tumours with peri- or postnatal barbiturate exposure (Gold et al., 1978). Others have since questioned the
strength of the association owing to confounding factors
and wide confidence intervals (Annegers et al., 1979). The
association between in utero barbiturate exposure and paediatric brain tumours has not been replicated in several later
studies (Annegers et al., 1979; Goldbaher et al., 1990; Olsen
et al., 1990; Gurney et al., 1997).
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G. Singh et al.
Valproate
The lack of pharmacoepidemiological data in the specific case
of valproate notwithstanding, indirect evidence for a
cancer-protective effect was recently presented in the form
of a small, uncontrolled trial that reported therapeutic benefit
with valproate administration alone or in combination with
all-trans retinoic acid in myelodysplastic syndromes
(Kuendgen et al., 2004). Several Phase I and II trials evaluating the role of valproate alone and in combination with other
chemotherapeutic agents in malignant disorders are under
way. The German-Speaking Society of Paediatric Oncology
and Haematology is currently examining potential oncological benefits of valproate use in paediatric malignant glioma in
a multicentre trial (Driever et al., 1999).
Epilepsy and cancer survival
Since several AEDs, including phenobarbital, phenytoin and
carbamazepine are potent inducers of hepatic drugmetabolizing enzymes and many of the cancer chemotherapeutic agents are either metabolized in the liver or converted
from prodrugs to active drugs in the liver, an increased SMR
due to cancer and possibly decreased cancer survival may be
attributed to induction of metabolism of the chemotherapeutic
agents by enzyme-inducing AEDs (Vecht et al., 2003). Drug
interactions between AEDs and cytotoxic agents were the
subject of a few early anecdotal reports (Baker et al.,
1992; Hassan et al., 1993; Zamboni et al., 1998) and, more
recently, of systematic pharmacokinetic studies (Crews et al.,
2002; Grossman et al., 1998; Kuhn, 2002; Chang et al., 2003).
These interactions were recently reviewed elsewhere (Vecht
et al., 2003); those relevant to the efficacy of cancer
chemotherapeutic agents are summarized in Table 1.
Enzyme-inducing AEDs were shown to reduce the area
under the plasma concentration–time curves, decrease maximal plasma concentrations and enhance hepatic clearance of
many cytotoxic agents (Baker et al., 1992; Zamboni et al.,
1998; Villikka et al., 1999; Mathijssen et al., 2002;
Table 1 Cancer chemotherapeutic agents that are substrates
for enzyme-inducing action of AEDs
Agent
Reference
Methotrexate
Busulfan
Thiotepa*
Cyclophosphamide*
Ifosfamide*
CCNU*
Vincristine
Doxorubicin*
Tenoposide
Paclitaxel
Irinotecan
Relling et al., 2000
Hassan et al., 1993
Chang et al., 1995
Alberts et al., 1976, 1978
Lu et al., 1998
Levin et al., 1979
Villikka et al., 1999
Cusack et al., 1988; Sturgill et al., 2000
Baker et al., 1992; Relling et al., 2000
Fetell et al., 1997; Chang et al., 1998
Crews et al., 2002; Kuhn, 2002;
Mathijssen et al., 2002; Murry et al.,
2002
Zamboni et al., 1998
Grossman et al., 1998
Moorthy et al., 1997
Chang et al., 2004
Topotecan
9-Aminocampothecin
Tamoxifen*
y
CCI-779
*Demonstrated only in animal studies; y investigational drug.
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association with phenytoin exposure was not statistically
significant (White et al., 1979; Olsen et al., 1989). Moreover,
no association was observed in the Northern Californian multidrug screening, Finnish AED prescription and Rochester
community studies between phenytoin use and lymphoma
(Friedman and Ury, 1980; Shirts et al., 1986; Selby et al.,
1989; Lamminpaa et al., 2002).
Multiple myeloma was anecdotally reported following phenytoin use (Matzner and Polliack, 1978; Rymard et al., 1981).
However, two case–control studies of patients with multiple
myeloma did not find any association between prior phenytoin
use and development of myeloma (Friedman, 1986;
Linet et al., 1987).
Several reports describe the occurrence of neuroblastoma
among children with foetal hydantoin syndrome following
prenatal exposure to phenytoin (Pendergrass, 1976; Sherman
and Roizen, 1976; Seeler et al., 1979; Ramilo and Harris, 1979;
Allen et al., 1980; Ehrenbard and Chaganti, 1981; Jiminez
et al., 1981; Lipson and Bale, 1985; Koren et al., 1989;
Al-Shammri et al., 1992; Satge et al., 1998). Ten cases of
neuroectodermal tumours reported up to 1992 have been
reviewed (Al-Shammri et al., 1992). There were six cases
of neuroblastoma (Pendergrass, 1976; Sherman and Roizen,
1976; Ramilo and Harris, 1979; Allen et al., 1980; Ehrenbard
and Chaganti, 1981; Koren et al., 1989; Al-Shammri et al.,
1992), one ganglioblastoma of the adrenal gland (Seeler
et al., 1979), one ectodermal tumour of the cheek (Jiminez
et al., 1981) and one ependymoblastoma (Lipson and Bale,
1985). Tumours were diagnosed between 1 day and 36 months
after birth. They developed in the setting of a characteristic
foetal hydantoin syndrome in seven cases (Pendergrass, 1976;
Sherman and Roizen, 1976; Seeler et al., 1979; Ramilo and
Harris, 1979; Allen et al., 1980; Ehrenbard and Chaganti,
1981; Jiminez et al., 1981), one child had unclassifiable dysmorphic features (Lipson and Bale, 1985), another coincidentally had ornithine transcarbamylase deficiency and one was
apparently normal (Al-Shammri et al., 1992). In many of the
reported cases, however, there was antenatal exposure to multiple AEDs, smoking or alcohol (Sherman and Roizen, 1976;
Ramilo and Harris, 1979; Jiminez et al., 1981). The incidence
of both foetal hydantoin syndrome and neuroblastoma has been
calculated, and it was estimated that it would take 45 years for
four cases of the two to occur together by coincidence rather
than the four observed over 5 years (Ehrenbard and Chaganti
1981). However, other authors did not find prenatal phenytoin
exposure in any of 188 cases of childhood neuroblastoma seen
over 17 years in one centre in Canada (Koren et al., 1989). Our
review of the literature did not find any report of neuroblastoma
from 1992 onwards. Nonetheless, given the rarity of childhood
neuroectodermal tumours, these case reports of neuroblastoma
associated with phenytoin exposure assume significance.
Cancer risk and anticonvulsants
Mechanistic considerations
Cancer risk
The classical mechanistic view of hepatocarcinogenicity of
phenobarbital was that the agent, through its enzyme-inducing
properties on the cytochrome P450 system, induced the
conversion of xenobiotics to activated compounds that
were carcinogenic (White et al., 1979; Olsen et al., 1993).
Recently, however, the tumour-promoting action of phenobarbital was attributed to its effect on gap junction-mediated
intercellular communication, a process by which cells interact
with each other and inhibit the growth of surrounding cells
(Sugie et al., 1987). Indeed, phenobarbital was shown to
decrease gap junction intercellular communication, thereby
liberating tumour precursor cells from the inhibiting effects of
other cells (Warner et al., 2003).
Phenytoin can cause a spectrum of immunological
reactions in man. A reduction in immunoglobulin levels
has been noted in 20% of its long-term users (Bardana
et al., 1983). Moreover, it inhibits the endogenous production
of interferon-g (Fleischmann et al., 1990). The combination
of these effects is thought to be the basis of its carcinogenic
potential with specific regard to lymphoreticular neoplasia
(Kruger, 1972). Phenytoin also modulates immune milieu
in utero, as shown by increased glucocorticoid receptor
expression by peripheral blood lymphocytes of children
with the foetal hydantoin syndrome, perhaps explaining the
tendency of children with foetal hydantoin syndrome to
develop neuroectodermal tumours. Teratogenicity studies
suggest, however, that phenytoin modulates the cellular
responses to oxidative damage. Accordingly, oxidative
mechanisms have been proposed as inherent to phenytoin’s
carcinogenic and teratogenic potentials (Wells et al., 1997).
Consistent with this, phenytoin is found co-oxidized during
prostaglandin biosynthesis to a reactive free radical intermediate that is potentially culpable in embryopathies. The
generation of this intermediate is regulated by a microsomal
epoxide hydrolase, EPHX1.
If cancer incidence were truly increased among patients
with epilepsy, AEDs would be potential culprits. Other
mechanisms need to be considered, however, as patients’ lifestyles may render them more vulnerable to, or protect them
from, malignancies. Theoretically, cancer incidence would be
elevated if smoking rates were higher among people with
epilepsy, perhaps due to anxiety triggered by the unpredictability of seizures. The premise is supported by limited evidence of high smoking rates among people with epilepsy
(Kobau et al., 2004). On balance, however, there seems to
be insufficient explanation for an increased cancer incidence
from lifestyle patterns associated with epilepsy. Undoubtedly,
the association of brain cancers with epilepsy is a reflection of
the fact that brain tumours cause epilepsy, though there are
still some concerns about a milder persistent association being
due to tumour-promoting effects of AEDs (Shirts et al., 1986).
A biological basis—for instance, a genetic predisposition—
may in part underlie the association between epilepsies and
cancer. Indeed, mutations in the tumour suppressor gene,
leucine-glioma-inactivated-1, were recently found to be the
basis of autosomal dominant familial temporal lobe epilepsy
with either aphasic or auditory seizures (Gu et al., 2002; Fertig
et al., 2003). However, none of the families with this particular genotype showed an increased risk of malignancies
(Brodtkorb et al., 2003). Finally, there are certain disorders
that cause epilepsy and simultaneously predispose persons
with the disorder to cancers. Such conditions as Down’s
syndrome (Zipursky and Doyle, 1993; Ravindranath, 2003),
tuberous sclerosis (Fatihi et al., 2003) and neurofibromatosis
(Creange et al., 1999) are too rare to account for much of the
association between cancer and epilepsy.
Cancer protection
In some of the cohort studies reviewed, the observed cancer
incidence was found to be less than expected for certain sites.
Downloaded from http://brain.oxfordjournals.org/ by guest on October 12, 2016
Murry et al., 2002). For instance, in Phase I and II clinical
trials of paclitaxel, people with cancer who were on enzymeinducing AEDs were shown to tolerate maximal tolerated
doses that were 1.5–1.7 times routine doses (Fetell et al.,
1997; Chang et al., 1998). In addition, concomitant
administration of enzyme-inducing AEDs altered the profile
of toxicity of paclitaxel from myelosuppression and gastrointestinal toxicity to peripheral neuropathy (Chang et al., 1998).
On the basis of these studies, a 50% increase in the dose of
paclitaxel was recommended when administered in conjunction with enzyme-inducing AEDs (Baker and Dorr, 2001).
The clinical implications of these drug interactions are not
clear at the moment. A single study determined remission and
relapse rates in patients with acute lymphoblastic leukaemia
who received cancer chemotherapy and AEDs concomitantly,
the latter for control of seizures (Relling et al., 2000).
Subgroup analysis revealed that AED administration was
associated with significantly higher relapse rates in B-cell
leukaemias but not in the more aggressive T-cell leukaemias.
Drug interactions between AEDs and cytotoxic drugs are of
particular concern in the management of brain tumours, where
AEDs are commonly used to prevent seizures. It is possible
that the generally poor response of malignant brain neoplasia
to cytotoxic drugs may partly be due to low levels of the latter
owing to induction by AEDs. In recognition of these interactions, clinical trials of developing cytotoxic agents now
employ a different set of, usually higher, maximal tolerated
doses of the agents in people on enzyme-inducing AEDs
(Grossman et al., 1998; Kuhn, 2002; Chang et al., 2003).
Further studies are required to determine whether the drug
interactions between AEDs and cytotoxic agents translate into
reduced cancer survival. Of the newer AEDs, oxcarbazepine
and topiramate in higher doses have weak enzyme-inducing
properties (Benedetti, 2000). Other newer AEDs, such as
levetiracetam and gabapentin, may be preferable as firstline treatment in people with cancer who require treatment
with chemotherapeutic agents.
Page 7 of 11
Page 8 of 11
G. Singh et al.
similar functional effects by influencing signalling mechanisms upstream of GSK3 (Mai et al., 2002). Many of these
pathways are now recognized as being involved in the biological effects of several AEDs in mood disorders (Rogawski
and Loscher, 2004), but may also be relevant to potential
carcinoma-suppressing actions of these AEDs (Blaheta and
Cinatl, 2002).
Conclusions
Based on available evidence, phenobarbital is carcinogenic in
mice and rats and possibly carcinogenic to humans (Group
2B) (International Agency for Research on Cancer, 1987).
There is evidence of carcinogenicity of phenytoin in animals;
however, evidence in humans is inadequate and it also is
considered possibly carcinogenic to humans (Group 2B)
(International Agency for Research on Cancer, 1987). The
current view of the IARC, however, does not preclude further
carcinogenicity evaluation and the issue deserves more rigorous investigation. Studies so far have had limitations, particularly in view of the long duration needed to assess cancer
incidence and the lack of proper control for possible confounders. In addition, in the relatively small number of studies
available, selection of subjects, choice of controls, methods of
ascertaining cancer incidence, duration and type of AED treatment and coding procedures have varied. Although not based
upon carcinogenicity concerns, newer, non-hepatic drug
metabolizing enzyme-inducing AEDs should preferentially
be used rather than enzyme-inducing medications in people
with cancer who undergo treatment with cytotoxic drugs. The
issue of cancer incidence in people with epilepsy remains an
open question. In the specific case of valproate, epidemiological studies and clinical trials of an antiproliferative effect
are warranted.
Acknowledgements
The authors are grateful to Dr Jeremy Rees, UCL Institute of
Neurology, Queen Square, London for critically reviewing the
manuscript and Dr Gail Bell, University College London
Hospitals, NSH Foundation Trust for her help in preparing
the manuscript. No funding source was involved in the preparation of this review. G. S. is the recipient of a Commonwealth Fellowship.
Conflict of interest
The authors have declared no conflicts of interest.
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