Antineoplastic therapy-induced palmar plantar erythrodysesthesia ('hand-foot') syndrome: Incidence, recognition and management

Abstract

Palmar plantar erythrodysesthesia (PPE) is a distinctive and relatively frequent toxic reaction related to some chemotherapeutic agents. Doxorubicin, cytarabine, docetaxel, and fluorouracil are the most frequently implicated agents. PPE seems to be dose dependent and both peak drug concentration and total cumulative dose determine its occurrence. PPE presents as a painful erythema, often preceded by paresthesia, located on the palms and soles in the context of treatment with chemotherapy. Histologically, PPE shows few specific findings. Mild spongiosis, scattered necrotic and dyskeratotic keratinocytes and vacuolar degeneration of the basal layer is seen. Dermal changes in most cases include dilated blood vessels, papillary edema, and a sparse superficial perivascular lymphohistiocytic infiltrate can be found in varying degrees in the epidermis. Withdrawal or dose reduction of the implicated drug usually gives rise to amelioration of the symptoms. Supportive treatments such as topical wound care, elevation, and cold compresses may help to relieve the pain. Use of systemic corticosteroids, pyridoxine (vitamin B6), blood flow reduction, and, recently, topical 99% dimethyl-sulfoxide have been used with variable outcomes. It could be of interest to consider them as preventive measures when drugs with a strong association with PPE are going to be administered.

Full text

Antineoplastic Therapy–Induced
Palmar Plantar Erythrodysesthesia
(‘Hand-Foot’) Syndrome
Incidence, Recognition and Management
Eduardo Nagore,
1
Amelia Insa
2
and Onofre Sanmartín
1
1 Instituto Valenciano de Oncología, Valencia, Spain
2 Hospital Universitario Dr Peset Aleixandre, Valencia, Spain
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
1. Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
2. Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
3. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
5. Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
6. Specific Comments on Relevant Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
6.1 Fluorouracil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
6.2 Fluorouracil Analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
6.2.1 Capecitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
6.2.2 Tegafur . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
6.3 Cytarabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
6.4 Doxorubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
6.4.1 Liposome-Encapsulated Doxorubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
6.5 Docetaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
6.6 Other Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
7. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
Abstract
Palmar plantar erythrodysesthesia (PPE) is a distinctive and relatively frequent toxic reaction related to some
chemotherapeutic agents. Doxorubicin, cytarabine, docetaxel, and fluorouracil are the most frequently implicated
agents. PPE seems to be dose dependent and both peak drug concentration and total cumulative dose determine
its occurrence.
PPE presents as a painful erythema, often preceded by paresthesia, located on the palms and soles in the
context of treatment with chemotherapy. Histologically, PPE shows few specific findings. Mild spongiosis,
scattered necrotic and dyskeratotic keratinocytes and vacuolar degeneration of the basal layer is seen. Dermal
changes in most cases include dilated blood vessels, papillary edema, and a sparse superficial perivascular
lymphohistiocytic infiltrate can be found in varying degrees in the epidermis.
Withdrawal or dose reduction of the implicated drug usually gives rise to amelioration of the symptoms.
Supportive treatments such as topical wound care, elevation, and cold compresses may help to relieve the pain.
Use of systemic corticosteroids, pyridoxine (vitamin B6), blood flow reduction, and, recently, topical 99%
dimethyl-sulfoxide have been used with variable outcomes. It could be of interest to consider them as preventive
measures when drugs with a strong association with PPE are going to be administered.
REVIEW ARTICLE
Am J Clin Dermatol 2000 Jul-Aug; 1 (4): 225-234
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1. Incidence
Palmar plantar erythrodysesthesia (PPE) is a cutaneous drug
reaction that is most often induced by chemotherapeutic agents.
It is important to be aware of this reaction since it can be a dose-
limiting toxicity.
PPE was firstly described by Zuehlke in 1974 associated with
mitotane therapy for hypernephroma.
[1]
Subsequently, many re-
ports, using different terms for the condition (acral erythema,
hand-foot syndrome, palmar-plantar erythema, Burgdorf’s reac-
tion, and toxic erythema of the palms and soles), have appeared
in the literature.
[2]
Many drugs have been implicated as causing PPE. Cytarab-
ine, doxorubicin, fluorouracil, and docetaxel are the most com-
monly involved drugs, although many others have also been re-
ported to cause this condition (table I).
[1-89]
Nevertheless, it is
very difficult to assess the real relationship between PPE and
some agents since most cases are described in the context of dif-
ferent multidrug regimens.
The actual incidence of PPE is very difficult to determine
because most reports in literature are isolated case reports or short
case series, and when a drug is evaluated by oncologists in large
series, its cutaneous reactions are usually mentioned with few
details. However, an estimation can be made by considering some
case series in which PPE has been found to occurs in 6 to 64% of
patients treated with different chemotherapy regimens.
[34,89]
In
most cases (nearly 80%), patients present with less severe grades
of PPE [1 and 2 of WHO criteria and 1 of the National Cancer
Institute (NCI) criteria (these criteria are described in section
2)],
[18,62]
although the severity is very variable depending on the
chemotherapy regimen, and some series have reported more fre-
quent severe toxicity.
[57]
We review herein some of the major aspects of PPE and
detailed information in those drugs which are more frequently
associated with this reaction. To this end, we have systematically
reviewed articles obtained from MEDLINE published between
1966 and March 2000 using all the synonymous for PPE men-
tioned earlier as key words.
2. Clinical Presentation
Whatever the causative agent, the clinical presentation of
PPE is very similar and is distinct from other adverse skin reac-
tions.
[8,19,23,26,27,34,38,55,59,65,66,73,88-91]
Most patients present with a prodrome of dysesthesia, usually
a tingling sensation of the palms and soles. In a few days, it pro-
gresses to a burning pain in conjunction with well-defined swell-
ing and erythema. The erythema is symmetric, and sometimes
more marked over the pads of the distal phalanges. Some patients
may develop alternating bands of erythema over joint surfaces or
have periungual skin involvement. The hands are usually more
severely affected than the feet, and may be the only area involved
(figs 1 and 2). Rarely, erythema may also be noted outside the
palmar and plantar regions.
[29,47]
Some patients may only present
with fine desquamation with or without erythema. A bullous vari-
ant has also been described, specifically associated with cytarab-
Table I. Agents that have been associated with palmar plantar erythro-
dysesthesia
Most frequently associated
Cytarabine
Docetaxel
Doxorubicin and liposome-encapsulated doxorubicin
Fluorouracil
Less frequently associated
Capecitabine
Cisplatin
Cyclophosphamide
Daunorubicin
Doxifluridine
Etoposide
Floxuridine
Hydroxyurea (hydroxycarbamide)
Mercaptopurine
Methotrexate
Mitotane
Paclitaxel
Tegafur
Vinorelbine
Fig. 1. Palmar edema and erythema, with fine desquamation (palmar plantar
erythrodysesthesia WHO grade 2).
226 Nagore et al.
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ine or methotrexate.
[39,76]
However, in our experience, bullous PPE
may appear with other agents such as fluorouracil or doxorubicin
(fig. 3). Bullous PPE is merely a severe form of this entity. The
lesions tend to worsen if therapy is continued, and tenderness and
associated edema may cause restriction of the fine movements of
the fingers.
[37]
The erythema becomes darker or violaceous, and
spreads to involve the entire surface of the palms and soles. The
pain may be so severe that daily activities are limited. If the drug
responsible is stopped within a few days of the reactions appear-
ing a gradual clearing of symptoms will occur over a period of 2
weeks. Areas of pallor with blisters develop, and eventually des-
quamate with extensive, but superficial, exfoliation. In some pa-
tients, when treatment is continued despite the appearance of the
PPE, lesions may evolve into a palmoplantar keratoderma.
[44,65]
In rare instances, long term sequelae may occur despite cessation
of chemotherapy, with persistence of abnormal sensation and ap-
pearance of the affected digits.
[7]
PPE seems to be dose dependent. Both peak drug concentra-
tion and total cumulative dose determine its occurrence because
regimens with either bolus (short term) infusions or continuous
low dosage administration can induce the reaction in a dose-de-
pendent manner.
[6,40,47,51]
In general, the reaction happens sooner
(from 24 hours to 2 or 3 weeks) and more severely with bolus or
short term chemotherapy than with low-dose continuous infu-
sions (up to 2 to 10 months). Rechallenge of patients with the
causative chemotherapeutic agents using similar dosage sched-
ules has lead to recurrence of the reaction in most but not all
patients.
[25,29,52,61]
There are a number of different classifications for grading the
degree of severity of PPE, but the two most often used are those
from WHO and NCI (table II). These classifications are of interest
because, according to some protocols, a high degree of severity
may necessitate a dose reduction for some drugs. When WHO
grade 3 or 4 or NCI grade 3 toxicity first appears, or WHO grade
2 toxicity appears repeatedly, the dosage should be decreased to
50 or 75% of the initial dosage, or the drug discontinued. Drug
withdrawal is preferable if toxicity of these grades recurs even
after the dosage is decreased.
3. Pathology
There are no studies with a large series which describe his-
tologic findings. However, some case reports include histologic
evaluation (table III).
[8,15,19,23,24,26,27,34,38,50,59,63,65,66,73,79,87-90,92]
PPE is a clinical variant of a cytotoxic reaction that primarily
affects keratinocytes, and the histopathologic findings are similar
to those seen with direct toxic reactions, such as radiation recall
dermatitis, localized epidermal necrolysis or generalized epider-
mal necrolysis. All these adverse skin reactions demonstrate the
same basic histologic pattern of an interface dermatitis with a
cell-poor infiltrate and a variable degree of epidermal necrosis.
[92]
Early or mild cytotoxic reactions (PPE WHO grades 1 and
2) show isolated necrotic basal keratinocytes (fig. 4). In severe
cytotoxic reactions (WHO grades 3 and 4) the entire basal layer
is destroyed, and a blister may form together with complete epi-
dermal necrosis (fig. 5).
[15]
Dermal changes in most cases include dilated blood vessels,
papillary edema, and a sparse superficial perivascular lympho-
histiocytic infiltrate. Eccrine glands may also be involved in some
Fig. 2. Palmar erythema, with fissuration (palmar plantar erythrodysesthesia WHO
grade 3).
Fig. 3. Palmar edema, erythema, and blisters in the lateral aspects of the digits
(palmar plantar erythrodysesthesia WHO grade 4).
Palmar Plantar Erythrodysesthesia 227
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cases. Eccrine squamous syringometaplasia may also be seen in
some cases of severe PPE (WHO grades 3 and 4) (fig. 6).
[66,90]
4. Pathogenesis
The cause of PPE is currently unknown. Formerly, as there are
some clinical and histologic similarities between PPE and acute
graft-versus-host disease (AGVHD) it has been suggested that
chemotherapeutic drug-induced changes in cell surface receptors
might be able to induce host-versus-altered host changes.
[9]
How-
ever, currently, the most likely and accepted hypothesis is a direct
toxic effect of the chemotherapeutic drug against epidermal cells
because of the dose-relationship and the common histopathologic
findings with other entities produced by direct toxicity.
[92,93]
It is
of interest that PPE is a dose-limiting factor in some treatment
regimens, when other toxicities can be modulated. Nevertheless,
there is not a clear explanation for its particular distribution. Spe-
cific features of the hands and feet could play a role in its location.
The thick stratum corneum, the temperature gradient, the vascular
anatomy, the rapidly dividing epidermis, the absence of seba-
ceous glands and hairs follicles, the high concentration of eccrine
glands, and wide dermal papillae may all be important in the
pathogenesis.
[88,89]
Other traits must be involved since there is no
direct relationship between drug, dosage, and severity in all pa-
tients. Concomitant drug therapy, transfusions, blood transfu-
sions, and the metabolic status of the patient may contribute as
well.
[24,89]
5. Differential Diagnosis
Although the diagnosis is usually evident, it may be difficult
to differentiate PPE from AGVHD when the reaction occurs in a
patient who has received a bone marrow transplant.
[89-90]
More-
over, both disorders may occur simultaneously. Other signs of the
disease may provide clues in the case of AGVHD, such as gas-
trointestinal abnormalities (including diarrhea and abdominal
pain), elevated liver enzymes levels, and a rapid decline in the T
helper cell/suppressor cell ratio.
[90]
However, in the absence of
extracutaneous involvement, AGVHD can appear identical to
PPE.
[89]
The involvement of the palms and soles in AGVHD is
usually a diffuse macular erythema which may form papules, in
contrast to the areas of well-defined intense erythema and edema
that are seen in PPE.
[90]
Histologically, both PPE and AGVHD
are indistinguishable in their early stages. Serial biopsies may
sometimes be needed to differentiate between them.
[24]
The pre-
sence of degenerate keratinocytes, at all levels of the epidermis
and associated with adjacent lymphocytes (satellite cell necrosis),
are characteristic of AGVHD.
[94]
In contrast, the finding of squa-
mous syringometaplasia suggests PPE.
[90]
It is important to distinguish between these 2 entities because
they require different treatment. Moreover, cyclosporine infu-
sion, which is one of the most important treatments for AGVHD,
is reported to worsen the pain of PPE possibly due the alcohol
present in the infusion.
[45]
6. Specific Comments on Relevant Drugs
In this section we describe the more relevant and specific
characteristics displayed by the drugs associated with a high in-
Table II. Classification of palmar plantar erythrodysesthesia severity according to WHO and National Cancer Institute (NCI) criteria
WHO criteria NCI criteria
grade definition grade definition
1 Dysesthesia/paresthesia, tingling in the hands and feet 1 Skin changes or dermatitis without pain (e.g., erythema,
peeling)
2 Discomfort in holding objects and upon walking, painless
swelling or erythema
3 Painful erythema and swelling of palms and soles,
periungual erythema and swelling
2 Skin changes with pain, not interfering with function
4 Desquamation, ulceration, blistering, severe pain 3 Skin changes with pain interfering with function
Table III. Histologic grades with their corresponding clinical expression (related to WHO criteria)
Grade Clinical lesion Histologic findings
1 Erythema Dilated blood vessels of the superficial dermal plexus
21 + edema
32 + fissuration Isolated necrotic keratinocytes in higher layer of the epidermis
43 + blister Complete epidermal necrosis
228 Nagore et al.
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cidence of PPE. Tegafur, which has a relatively low incidence of
PPE, has also been included to emphasize its different clinical
behaviour to that of fluorouracil despite being one of its deriva-
tives.
6.1 Fluorouracil
Fluorouracil is a fluoropyrimidine antimetabolite that under-
goes complex intracellular metabolic activation to fluorodeoxy-
uridine monophosphate (FdUMP), which inhibits thymidylate
synthetase, and to fluoridine triphosphate (FTUP), which is in-
corporated into RNA as a false base. The cytotoxicity of fluoro-
uracil is relatively specific to the S-phase and the agent has been
found to be effective in treating numerous types of solid tu-
mors.
[80]
Dermatitis has been reported during treatment with fluoro-
uracil and leucovorin (calcium folinate) in 10 to 24% of pa-
tients,
[11,18,41]
but the incidence of PPE is variable and may range
from 6 to 67%.
[20,33,49,51,62]
PPE occurs more often with pro-
tracted infusion schedules of fluorouracil than when the agent is
given as a bolus infusion.
[51]
However, it may also be seen in
patients receiving a high dose leucovorin-modulated fluorouracil
bolus.
[56]
A recent meta-analysis of all randomized trials that compared
fluorouracil bolus with fluorouracil continuous infusion (CI),
based on individual data from 1219 patients, was conducted to
compare the toxicity of the 2 schedules of fluorouracil adminis-
tration and to identify predictive factors for toxicity.
[54]
The over-
all proportion of PPE was 34% for patients assigned to fluoroura-
cil CI and 13% for patients assigned to fluorouracil bolus. The
adjusted PPE relative risk was 1.87, which indicates that the risk
of PPE was almost doubled when fluorouracil was given by CI.
Interestingly, female patients and older patients had a signifi-
cantly higher risk of PPE.
[54]
Popescu et al.
[62]
also reported an
overall higher incidence of PPE in women, however, they did not
observe any difference in age-related toxicity for PPE.
The mechanism by which fluorouracil causes PPE is un-
known. A strong correlation between this toxicity and high doses
of fluorouracil has been postulated by some authors, on the basis
of the incidence of PPE observed in high dose, short term, con-
tinuous fluorouracil infusion studies.
[30,77]
It has also been sug-
gested that fluorouracil has a cumulative effect on the skin, since
some authors have described PPE appearing after a median num-
ber of 9 treatment courses, corresponding to a median fluorouracil
cumulative dosage of 18500 mg/m
2
.
[18]
Development of PPE usually leads to discontinuation of flu-
orouracil, dosage reduction or delay of planned chemotherapy,
with resolution of the skin manifestations.
[18,25,81]
In fact, since
myelosuppresion can be modulated using CI regimen and
leucovorin, PPE is the dose-limiting toxicity. Sometimes PPE
occurring as a complication of fluorouracil therapy may result in
symptoms and signs that continue for many months after with-
drawal of the causative agent.
[7]
6.2 Fluorouracil Analogues
6.2.1 Capecitabine
Capecitabine is a rationally designed oral fluoropyrimidine
carbonate that is activated by tumor cells into fluorouracil. It has
been approved for the treatment of breast cancer that progresses
after standard chemotherapy with paclitaxel and an anthracy-
Fig. 4. Histopathologic findings in mild palmar plantar erythrodysesthesia (WHO grades
1 and 2): interface dermatitis, isolated necrotic keratinocytes, vascular dilatation, and
dermal edema can be seen.
Fig. 5. Histopathologic findings in severe palmar plantar erythrodysesthesia (WHO
grades 3 and 4): interface dermatitis, complete epidermal necrosis, blister formation, and
reticular desquamation of the dermis can be seen.
Palmar Plantar Erythrodysesthesia 229
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cline-containing regimen
[80]
and for the treatment of advanced
colon cancer.
[95]
The dose-limiting toxicity of this agent using a chronic divided
daily administration schedule is similar to long term fluorouracil
infusions with mucositis, diarrhea, and PPE.
[12,13,17,75]
WHO
grade 3 to 4 PPE has been reported in 10% of patients treated with
capecitabine at 2510 mg/m
2
/day given for 2 weeks followed by a
week rest period and repeated in 3-week cycles.
[10]
6.2.2 Tegafur
Tegafur is a fluoropyrimidine analogue of fluorouracil (1-2-
tetrahydrofluoril-5-fluorouracil), It is a fluorouracil prodrug
which is metabolized in liver to fluorouracil by cytochrome P450
and enzymatic hydrolysis. It is used in the treatment of advanced
gastrointestinal neoplasms. It is considered as an alternative oral
therapy to intravenous fluorouracil.
[65]
Cutaneous adverse effects of tegafur are frequent events.
However, only isolated cases of chemotherapy-induced PPE have
been reported to be associated with tegafur, and therefore the
exact incidence is not currently known. Most cases presented at
dosages of about 500 to 1600 mg/day.
[8,16,44,65]
It has been suggested that PPE in patients treated with tegafur
could be a fluorouracil dependent reaction as it results at serum
fluorouracil concentrations equivalent to very low dose fluoro-
uracil CI.
[44]
Another possible explanation for this cutaneous re-
action is that tegafur is metabolized not only to fluorouracil, but
also to dehydro-tegafur another hydroxilated metabolite, which
may be pharmacologically active and may be responsible for this
reaction.
[8]
6.3 Cytarabine
Cytarabine is an analogue of deoxycytidine that is phosphor-
ylated to an active metabolite, ara-C triphosphate. Ara-C triphos-
phate inhibits DNA polymerase and is incorporated into DNA,
resulting in strand breaks. Cytarabine is most active in hemato-
logic malignancies in combination with other drugs.
[80]
PPE associated with cytarabine was first described by
Burgdorf et al.
[14]
The incidence of this palmar-plantar reaction
has varied from 14 to 33% in patients treated with cytarabine at
dosages of 1000 mg/m
2
or more,
[40,61,78]
especially if 8 or more
doses at this level have been administered. Some patients treated
with conventional cytarabine dosages of 100 mg/m
2
have also
developed PPE.
[22,50,70]
The incidence at this lower drug dosage
level is not defined, but it is much lower than at high doses.
Dysesthesias often herald the onset of the erythema, and the
edema may be marked enough to limit finger motion. Some pa-
tients also have fever, facial edema and erythema, and erythem-
atous maculopapular rashes characteristic of a type I hypersensi-
tivity reaction.
[22,40,50]
In most cases, only the hands are involved,
but this reaction has also been described as involving only the
ears.
[48]
The skin usually heals without scarring, and patients have
been treated with cytarabine again without recurrence of this tox-
icity.
[70]
6.4 Doxorubicin
Doxorubicin is an anthracycline antibiotic that induces for-
mation of covalent topoisomerase-DNA complexes, and prevents
the enzyme from completing the relegation portion of the liga-
tion-relegation reaction. Doxorubicin can also intercalate in be-
tween base pairs of DNA and generate toxic oxygen free radicals.
It is effective in a large variety of tumors. Numerous solid tumors
are responsive, including neuroblastoma, soft tissue and bone sar-
comas, breast cancer, ovarian cancer, bladder cancer, thyroid can-
cer, small cell lung cancer, and gastric cancer. A large number of
hematologic malignancies also respond to doxorubicin.
[80]
Doxorubicin is usually given in combination therapy, and
mainly with drugs that also have been associated with the devel-
opment of PPE, therefore is quite difficult to assess the exact
incidence of PPE after doxorubicin administration. Some authors
have reported an incidence of PPE as high as 29% associated with
doxorubicin given as a monotherapy CI regimen.
[67,69]
PPE ap-
peared in 22% of patients treated with doxorubicin 30 mg/m
2
/day
by intravenous bolus on days 1 to 3 administered at 14-day inter-
vals.
[5]
A regimen of weekly doxorubicin and fluorouracil CI re-
sulted in 89% of patients developing PPE (WHO grade 1 to 3).
[36]
This incidence is higher than that reported for either doxorubicin
Fig. 6. Squamous syringometaplasia in palmar plantar erythrodysesthesia.
230 Nagore et al.
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or fluorouracil alone. The combination of these 2 drugs might
explain this high incidence.
6.4.1 Liposome-Encapsulated Doxorubicin
Liposome-encapsulated doxorubicin is a preparation of
doxorubicin encapsulated in a liposome formulation containing
polyethylene glycol. The liposome prevents binding of the drug
to plasma proteins and also inhibits its excretion. Therefore, these
preparations have a theoretical advantage when compared with
the free drug in tumor treatment because they have a significantly
longer circulation time and may provide an alternative for pro-
longed infusions.
[35]
Liposomal doxorubicin has been used in the
treatment of breast cancer, ovarian cancer, Kaposi’s sarcoma,
melanoma, and small cell lung cancer.
PPE is a significant adverse effect of therapy with liposomal
doxorubicin and may limit its use in some cases. In fact, patients
who experience PPE should have the drug discontinued until the
symptoms clear. PPE incidence has been reported in 3.4 to 40%
of patients treated with liposomal doxorubicin.
[32,37,46,57,83]
Pa-
tients are more likely to develop PPE after higher doses of lipo-
somal doxorubicin,
[37,57]
after higher dosage intensity,
[3]
and after
multiple cycles.
[57,72]
However, lengthening the interval between
treatments and dosage reductions decrease the incidence of
PPE.
[57,72]
PPE associated with liposomal doxorubicin is similar
to observations made in patients receiving protracted infusions of
doxorubicin.
[67]
Although the mechanism of skin damage in the PPE has not
been studied in detail, it has been suggested that it is a cumulative
but reversible effect of liposomal doxorubicin, depending on dos-
age and schedule. Given the prolonged circulation time of lipo-
somal doxorubicin, it is conceivable that a slow release of
doxorubicin takes place in the intravascular compartment, mim-
icking a continuous drug infusion. An alternative possibility is
that liposomes localize in mucous membranes and skin and
slowly release the drug in situ.
[72]
The skin elements most suscep-
tible to the toxic effect of a DNA replication inhibitor such as
doxorubicin would be the rapidly dividing keratinocytes of the
basal layer of the epidermis. A physical factor precipitating the
PPE is clearly involved, because palmar, plantar, and sacral skin
areas are the most commonly affected.
[57,72]
6.5 Docetaxel
Docetaxel is a semisynthetic derivative from the leaf extracts
of Taxus baccata. It has a similar mechanism of action as
paclitaxel, and actually is more potent in enhancing microtubule
assembly. It also promotes apoptosis. Clinical responses have
been observed in breast and ovarian cancer, non-small cell lung
cancer, pancreatic, and gastric carcinomas.
[80]
Skin toxicity may occur in 50 to 75% of patients receiving
docetaxel. Docetaxel also induces PPE although its incidence has
not been defined in the different studies published.
[80]
PPE asso-
ciated with docetaxel appears to be a more generalized form of
chemotherapy-induced PPE and it is seen in a significant percent-
age of patients receiving this drug; Zimmerman et al.
[79]
reported
PPE developing in 58% of patients treated with docetaxel at 100
mg/m
2
/day as either a 2- or a 3-hour infusion every 21 days. The
average time that elapsed between treatment and the development
of an eruption was from 2 to 4 days. Increased peak plasma con-
centrations did not correlate with severity of reaction, thus sug-
gesting that these reactions are either idiosyncratic or more prob-
ably related to tissue concentration via local blood flow or
sweat.
[79]
Docetaxel administered on a weekly basis might be
associated with a lowers incidence of PPE as less dermatologic
events have been described with this schedule.
[96]
Paradoxically, only one case of paclitaxel-induced PPE has
been reported in the literature.
[26]
6.6 Other Drugs
PPE has occasionally been related to other drugs (table I).
Most reports consisted of one or a few cases and large series show
that it is a low frequency secondary effect.
However, it is interesting to note the case of vinorelbine. PPE
has not been reported with vinorelbine given as a bolus. Recently,
a 7% incidence of PPE has been observed in a new treatment
schedule for metastatic breast cancer in which continuous 96 hour
infusions of high dosages of vinorelbine were used.
[42]
PPE will
be seen with greater frequency in the future because this modality
may be used more widely.
7. Treatment
Other than dose reduction, lengthening of the drug adminis-
tration interval and ultimately, drug withdrawal, there is no ther-
apy for PPE that has been proven to be effective in large-scale
clinical trials.
Some treatments have been proposed in small series or as
isolated cases although they need to be corroborated in large se-
ries (table IV). Symptomatic relief may be obtained with wound
care to prevent infection, elevation to reduce edema, cold com-
presses, and pain medications.
[88,89]
Cooling the hands and feet
during treatment to decrease blood flow to these areas may atten-
uate the severity of the reaction.
[87]
Potent topical corticosteroids have been used with variable
success, and a better outcome is obtained if the affected areas are
cooled or emollients are also applied.
[2,37,73,81,91]
Systemic ther-
apy with corticosteroids may help in some cases.
[39,42,82,83,91]
In-
Palmar Plantar Erythrodysesthesia 231
 Adis International Limited. All rights reserved. Am J Clin Dermatol 2000 Jul-Aug; 1 (4)

terestingly, sequential corticotherapy was effective in some cases
to prevent PPE caused by high dose fluorouracil and liposome-
encapsulated doxorubicin.
[82,83,91]
In those cases, premedication
with oral prednisolone (1 mg/kg/day)
[82,91]
or dexamethasone (8
mg/12 hours)
[83]
24 hours prior to chemotherapy, and then con-
tinued for 3 or 5 days at the same dose and tapered over the
following 48 hours, prevented the appearance of PPE and permit-
ted administration of an adequate chemotherapy dose.
Pyridoxine (vitamin B6) seems to be the most useful treat-
ment. It has been used successfully at doses of 100 to 300 mg/day
for treating and preventing fluorouracil-, docetaxel-, etoposide-,
and doxorubicin-related PPE.
[7,33,37,56,59,63,81,86]
Pyridoxine usu-
ally helps to alleviate the pain and, consistently, allows the dose
of chemotherapy to be maintained. It has been successful even in
some instances where there has been a bad response to topical or
systemic corticosteroids.
[37,81]
Recently, a double-blind clinical
trial using a canine model has proved the efficacy of pyridoxine
in delaying the onset and severity of PPE during doxorubicin-
containing pegylated liposome chemotherapy.
[84]
The mecha-
nism is unknown, although some models have established that
pyridoxine may help to regenerate cold damaged nerve fibers,
[97]
and this drug is the treatment of choice in isoniazide neurotoxic-
ity.
[98]
Nevertheless, prophylactic use of pyridoxine does not pre-
vent neurotoxicity due to cytarabine or to vincristine.
[99-100]
Al-
though a negative effect on response duration was reported in a
study when pyridoxine was given at 300 mg/m
2
to prevent
hexamethylmelamine-related neurotoxicity,
[101]
other studies
have not observed this event.
[56,86]
Topical 99% dimethyl-sulfoxide 4 times daily for 14 days
has been reported to resolve some cases of pegylated liposomal
doxorubicin-induced PPE.
[85]
This treatment has also shown
strong activity in treating tissue extravasation reactions during
intravenous administration of doxorubicin.
[102]
8. Conclusion
PPE is a relatively frequent toxic reaction related to some
chemotherapeutic agents. It presents with variable severity and
can necessitate modification of the chemotherapy treatment
schedule (dosage reduction, lengthening of the drug administra-
tion interval and even, drug withdrawal). Many treatments have
been proposed to provide symptomatic relief and there use can be
considered once the eruption has appeared. Since some of these
agents have shown efficacy in preventing the appearance or re-
ducing the severity of PPE, they could be used prophylactically
with those drugs associated with a high incidence of this cutane-
ous reaction.
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Correspondence and offprints: Dr Eduardo Nagore, C/ Denia, 20-6
a
, 46006
Valencia, Spain.
E-mail: eduyame@meditex.es
234 Nagore et al.
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