Total body topical 5-fluorouracil for extensive non-melanoma skin cancer.

Abstract

Topical 5-fluorouracil 5% cream is one of the treatment modalities for non-melanoma skin cancer (NMSC). There is a lack of suitable therapies to treat patients with extensive NMSC. In this paper we report two patients with extensive NMSC treated by total body application of topical 5-fluorouracil 5% cream.
Topical 5-fluorouracil 5% cream was applied twice daily to the total body, including normal appearing skin. During the treatment, weekly blood samples were taken for measurement of 5-fluorouracil levels. All samples showed a 5-fluorouracil level less than the detection level of 10 microg/l. Total body 5- fluorouracil 5% cream was shown to be an effective treatment in our patients; the majority of lesions cleared in both patients.
In conclusion, total body topical 5- fluorouracil 5% cream application was successful in two patients with extensive NMSC. No detectable serum level of 5-fluorouracil could be determined. Pain and secondary infections were important side effects in our patients. However, in patients with extensive NMSC this treatment may be considered.

Full text

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Abstract
Background
of the treatment modalities for non-melanoma skin
cancer (NMSC). There is a lack of suitable therapies to
treat patients with extensive NMSC. In this paper we
reporttwopatientswithextensiveNMSCtreatedbytotal
body application of topical 5-fluorouracil 5% cream.
ObservationsTopical 5-fluorouracil 5% cream was
applied twice daily to the total body, including normal
appearing skin. During the treatment, weekly blood
samples were taken for measurement of 5-fluorouracil
levels. All samples showed a 5-fluorouracil level less
than the detection level of 10 lg/l. Total body 5-
fluorouracil 5% cream was shown to be an effective
treatment in our patients; the majority of lesions
cleared in both patients.
ConclusionsIn conclusion, total body topical 5-
fluorouracil 5% cream application was successful in
Topical 5-fluorouracil 5% cream is one
two patients with extensive NMSC. No detectable
serum level of 5-fluorouracil could be determined.
Pain and secondary infections were important side
effects in our patients. However, in patients with
extensive NMSC this treatment may be considered.
Keywords
Non-melanoma skin cancer Æ Systemic absorption Æ
Topical 5-fluorouracil
Basal cell carcinoma Æ Cancer Æ
Impact of this article on practice
•
Total body topical 5-fluorouracil cream can be
considered in the treatment of extensive non-mel-
anoma skin cancer.
Total body topical 5-fluorouracil is associated with
minimal systemic absorption. Further research is
warranted to this treatment in non-melanoma skin
cancer.
•
Introduction
There are several treatment modalities for non-
melanomaskin cancer
cryotherapy, topical 5-fluorouracil and radiation ther-
apy are the mainstay of treatment. Newer modalities
are photodynamic therapy (PDT) and imiquimod.
Treatment of thin (superficial) basal cell carcinomas
with topical 5-fluorouracil is widely accepted despite
the absence of published 5-year cure rates. The pro-
ducer advices to treat a limited body surface area
(approximately 500 cm2) to reduce the risk of systemic
absorption. From the doctors perspective there are
cases when treating larger areas or even total body
(NMSC)[1].Surgery,
S. van Ruth Æ C. J. Sanders
Department of Dermatology and Allergology, University
Medical Centre Utrecht, Utrecht, The Netherlands
F. G.A. Jansman (&)
Department of Social Pharmacy, Pharmacoepidemiology
and Pharmacotherapy, Groningen University Institute for
Drug Exploration (GUIDE), Antonius Deusinglaan 1, 9713
AV Groningen, The Netherlands
e-mail: f.g.a.jansman@isala.nl
F. G.A. Jansman
Department of Clinical Pharmacy, Isala klinieken, Zwolle,
The Netherlands
Pharm World Sci (2006) 28:159–162
DOI 10.1007/s11096-006-9030-x
123
CASE REPORT
Total body topical 5-fluorouracil for extensive non-melanoma
skin cancer
Serge van Ruth Æ Æ Frank G.A. Jansman Æ Æ
Cornelis J. Sanders
Received: 14 March 2006/Accepted: 16 May 2006/Published online: 27 September 2006
? Springer Science+Business Media B.V. 2006

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application is desirable, because there is a lack of
suitable therapies to treat patients with extensive
NMSC. In this paper we report two patients with
extensive NMSC treated by total body application of
topical 5-fluorouracil 5% cream. Total body applica-
tion was chosen in order to treat both obvious carci-
nomas and minimal or subclinical NMSC.
Case report one
This case represents a 73-year-old man with a past
medical history of ichthyosis vulgaris and mycosis
fungoides. He had been treated before with topical
nitrogen mustard application, topical steroids, UVB
therapy and, for the past 10 years, with photo chemo-
therapy (PUVA) in order to control the mycosis fun-
goides. He received a cumulative dose of 8300 J/cm2
which is far beyond the general accepted maximum
cumulative dose of 2000–4000 J/cm2. In recent months
the patient developed more than one hundred epithe-
lial tumours at his atrophic skin. Histopathology of
several skin biopsies showed mainly superficial basal
cell carcinomas, several actinic keratoses, occasional
squamous cell carcinomas and mycosis fungoides le-
sions. His PUVA therapy was stopped and he received
acitretin 20 mg daily and topical steroids.
Topical 5-fluorouracil 5% cream (Efudix?) was ap-
plied, wearing gloves, twice weekly to the total body on
an outpatient clinic base, using 20 g per application.
Inactive ingredients were methyl- and propyl-para-
hydroxybenzoate, propylene glycol (1520), polysorbate
60, stearylalcohol, white paraffin and purified water.
The treatment period was 6 weeks. Blood samples
were taken before, 30-60-90-120-240 min after and
24 h after application in order to measure the 5-fluo-
rouracil level. During treatment analgesics were
administered to reduce pain. After 6 weeks erosions
had developed and topical 5-fluorouracl 5% cream
application was stopped. He developed shaking chills,
fever and a staphyloccal aureus sepsis. He was admit-
ted to hospital. At that time no leucopenia was ob-
served. There was a full recovery after 14 days
administration of flucloxacillin intravenously.
Measurement of 5-fluorouracil blood levels was
performed by a validated reversed-phase high-perfor-
mance liquid chromatographic analysis according to
reference [2]. The detection level was 10 lg/l. The
minimal therapeutic level was 25 lg/l. All samples
showed a 5-fluorouracil level less than 10 lg/l.
No epithelial tumours were present several months
later. After a follow-up of 3 years he has developed
localized actinic keratoses and basal cell carcinomas,
controlled by topical 5-fluorouracil 5% cream or
excision. His mycosis fungoides is managed by topical
application of nitrogen mustard ointment.
Case report two
A 30-year-old man with nevoid basal cell carcinoma
syndrome presented with progressive basal cell carci-
nomas, both nodular and superficial. His past medical
history disclosed an inguinal hernia and repeated
extirpation of jaw cysts. Previous therapy of basal cell
carcinomas included surgical excision, cryotherapy and
topical 5-fluorouracil 5% cream. In order to slow down
the progress of developing new basal cell carcinomas,
acitretin in a dose of 35 mg daily had been taken for
5 years. More than 70 basal cell carcinomas were
diagnosed and the patient was admitted to the hospital
(Fig. 1). The majority of the basal cell carcinomas were
of the superficial type and about 10% were nodular
types, mainly located on the neck and arms.
Topical 5-fluorouracil 5% cream was applied twice
daily to the total body, including normal appearing
skin. The total quantity of topical 5-fluorouracil 5%
cream used during admission was 400 g (13 g daily).
During the treatment, weekly blood samples were ta-
ken for measurement of 5-fluorouracil levels. All
samples showed a 5-fluorouracil level less than the
detection level of 10 lg/l.
Some nodular basal cell carcinomas were treated
with photodynamic therapy or excision. During the
Fig. 1 Before therapy
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treatment, analgesics and antiseptics were prescribed
and special attention was given to local wound dress-
ings to prevent infection and alleviate pain. After
4 weeks of treatment the majority of lesions were
eroded and therapy was stopped. Because of secondary
infection,systemic antibiotics
(erythromycin 250 mg four daily for 2 weeks). A few
days after discontinuation of the topical 5-fluorouracil
5% cream therapy, our patient could be discharged.
Six weeks after, patient was evaluated on the out-
patient clinic. The majority of lesions had cleared
(Fig. 2). Six months after starting therapy, patient is
doing well without active epithelial tumours (Fig. 3).
were administered
Discussion
Topical 5-fluorouracil has been used widely for (pre)
malignancies, such as actinic keratoses, superficial ba-
sal cell carcinomas and Bowen’s disease [3, 4]. Less
experience has been gained for treating squamous cell
carcinomas [5]. There are different concentrations of
topical 5-fluorouracil cream in use, but the majority of
studies deals with topical 5-fluorouracil 5% cream. In
the majority of people one or a few lesions are treated
at the same time. In certain cases, however, patients
exhibit extensive numbers of basal cell carcinomas for
example in nevoid basal cell carcinoma syndrome,
after total body radiation therapy or after repeated
courses of PUVA. In those particular cases the re-
stricted area that is advised for topical 5-fluorouracil
5%creamisa significantproblem. Systemic
administration of 5-fluorouracil would be an option in
those cases, however intensive topical treatment for
widespread NMSC seems more attractable [6]. To our
knowledge this is the first paper reporting total body
topical 5-fluorouracil 5% cream therapy.
Total body 5-fluorouracil 5% cream was shown to be
an effective treatment in our patients; the majority of
lesions cleared in both patients. The first patient was
treated twice weekly. Because the subsequent plasm-
aconcentrations indicated that systemic absorption was
minimal, the second patient was treated more aggres-
sively, i.e. twice daily.
In the literature there are a few reports dealing with
topical 5-fluorouracil 5% cream in nevoid basal cell
carcinomas, where (partial) unresponsiveness was no-
ticed [7, 8]. Addition of cryotherapy has been sug-
gested toimprove the
carcinomas and actinic keratoses[8, 9]. The addition of
retinoids to 5-fluorouracil 5% cream has been reported
in the treatment of disseminate actinic keratoses and
was found to be highly effective [10]. The therapy in
our both patients was highly effective for multiple
superficial basal cell carcinomas, and even for squa-
mous cell carcinomas. Several nodular basal cell car-
cinomas in our second patient were treated by excision
or photodynamic therapy.
Analysis of blood samples showed, in our patients,
that systemic absorption did not lead to detectable
blood levels or systemic side effects. Pharmacokinetic
evaluation by Levy et al. [11] showed that topical
application results in a minimal systemic absorption
(10%), however, absorption can be up to 75 times
greater in diseased skin. Notwithstanding the limited
systemic absorption, myocardial ischemia was reported
by Rozenman et al. [12] and even life-threatening
toxicity occurred in one patient, however this was the
case in a dihydropyrimidine dehydrogenase deficient
person [13].
An important side effect is irritation, especially in
combination with the erosions that occur during
treatment. Analgesics and the application of proper
wound dressings resulted in an acceptable situation and
did not alter the mobility of the patient. Our first pa-
tient developed a sepsis and admission was necessary.
In order to prevent this side effect, our second patient
was given prophylactic systemic antibiotics when im-
petiginisation was noticed. Known possible side effects
of topical 5-fluorouracil therapy include local effects
like irritation and infection, but also contact dermatitis
and, as mentioned before, also systemic side effects
have been reported in literature [12–14].
In conclusion, total body topical 5-fluorouracil 5%
cream application was successful in two patients with
clearanceof basalcell
Fig. 2 After 6 weeks of therapy
Pharm World Sci (2006) 28:159–162161
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extensive NMSC. No detectable serum level of 5-
fluorouracil could be determined. Pain and secondary
infections were important side effects in our patients.
However, in patients with extensive NMSC this treat-
ment may be considered.
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Fig. 3 After 6 months of therapy
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