Oncology

Pharmacy
Practice
Journal of
Case Report
Docetaxel-associated palmar-plantar
erythrodysesthesia: A case report
and review of the literature
Christy S Harris
Department of Pharmacy Practice, Massachusetts College of Pharmacy and Health Sciences,
Boston, MA, USA
Dorothy Wang
School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA
Alison Carulli
School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA
Abstract
Docetaxel-associated palmar-plantar erythrodysesthesia is rarely reported in literature, particularly when used in the
treatment of sarcomas. Here, we report a case of docetaxel-related palmar-plantar erythrodysesthesia in a 28-year-old
male with recurrent Ewing sarcoma. Although palmar-plantar erythrodysesthesia has been seen in the literature for
30 years, there has still been little progress in understanding and appropriately addressing this adverse effect. This case
report and literature review illustrates an infrequently documented adverse skin reaction and discusses the etiology,
presentation, and available treatment options for palmar-plantar erythrodysesthesia.
Keywords
Palmar-plantar erythrodysesthesia, hand-foot syndrome, docetaxel, acral erythema, gemcitabine
Introduction
Palmar-plantar erythrodysesthesia (PPE), also known
as hand-foot syndrome or acral erythema, is a localized
skin reaction that presents with erythematous plaques
and edematous patches symmetrically on the palms of
the hands and soles of the feet. It can include tingling,
numbness, rash, dryness, increased pigmentation, or
pruritis and can lead to epidermal necrosis if the oend-
ing agent is not stopped.
13
It is often associated with
certain chemotherapeutic agents, most notably capeci-
tabine (5463%), liposomal doxorubicin (40%), and
continuous infusion 5-uorouracil (34%).
1,4,5
Other
cancer therapies that have been known to cause PPE
include doxorubicin, cytarabine, and paclitaxel.
1,3,6
This adverse event is also being seen with the targeted
agents such as pazopanib and sorafenib.
7,8
PPE is considered to be widely underreported with
varying descriptions of presentation and grading.
3
A literature search of OVID, PubMed and IPA
revealed that the majority of case reports describe
instances of PPE associated with malignancies such as
breast or ovarian cancer.
913
To date, there have been
very few studies or case reports documenting PPE
related to soft tissue sarcoma or bone sarcoma treat-
ment. Of these, the majority report liposomal doxoru-
bicin-associated PPE.
5,14,15
The low number of
sarcoma-related case reports could be attributed to
the relatively rare incidence of sarcomas, which account
for <1% of all cancers.
16
There are few systemic ther-
apy options for patients with sarcomas not amenable
to surgery.
17
In these cases, doxorubicin and ifosfamide
Corresponding author:
Christy S Harris, Department of Pharmacy Practice, Massachusetts
College of Pharmacy and Health Sciences, 179 Longwood Ave,
Room W355, Boston, MA 02115, USA.
Email: Christy.harris@mcphs.edu
J Oncol Pharm Practice
2014, Vol. 20(1) 7380
! The Author(s) 2013
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DOI: 10.1177/1078155213475466
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are the mainstays of treatment. Other commonly
accepted and utilized chemotherapy regimens for meta-
static sarcomas include dacarbazine, temozolomide,
pazopanib, gemcitabine, and docetaxel.
18
PPE has been associated with docetaxel although
reports are rare with tertiary literature reporting a
<1% incidence in docetaxel monotherapy.
1113
However, a prospective study of 2186 patients receiving
chemotherapy revealed 44 cases of PPE of which 6
(13.6%) were felt to be docetaxel-related.
10
When
reviewing the literature, there are no reports of PPE
developing with gemcitabine. It is unknown whether
combining gemcitabine with docetaxel increases the
risk of PPE. In studies that utilized the two agents
together in other cancers, the reported occurrence of
PPE ranged from 0% to 2%.
19,20
Sensory neuropathies,
including PPE, are rarely mentioned in sarcoma treat-
ment studies but most of these are retrospective in
design.
2128
Here, we report a case of PPE related to docetaxel
administration in a patient with metastatic refractory
Ewing sarcoma of the bone receiving a combination
regimen with docetaxel and gemcitabine.
Case description
The patient is a 28-year-old male heavily treated for
multiple recurrences of Ewing sarcoma of the bone
over a 4-year time period. His prior treatments con-
sisted of radiation therapy and systemic therapy,
including several investigational agents. His traditional
chemotherapy regimens included cyclophosphamide,
doxorubicin, and vincristine alternating with ifosfamide
and etoposide (CAV/IE); cyclophosphamide and topo-
tecan; and temozolomide and irinotecan with vincris-
tine. He began a new regimen consisting of gemcitabine
900 mg/m
2
as an extended infusion over 90 min on day
1 and 8 with docetaxel 100 mg/m
2
added on day 8 fol-
lowed by peglgrastim on day 9 (Table 1). The rst
cycle was well-tolerated with minimal complaints. The
patient noted some mild nausea, fatigue, and pain,
which responded well to oxycodone. For the second
cycle, gemcitabine was dose-reduced due to these
adverse eects while docetaxel remained at 100 mg/m
2
.
Upon returning to the clinic for initiation of cycle 3,
the patient stated that he had developed erythema on
the palms of his hands and soles of his feet approxi-
mately 48 h after day 8 of cycle 2 with gemcitabine and
docetaxel. The patient described the pain as walking
on needles and said that it lasted approximately 4 days.
He applied petrolatum-based emollients such as
Eucerin

cream and occasional Aquaphor

. The pain
was not particularly bothersome to him although he felt
that it aected his gait slightly. At the visit, the aected
skin, primarily on the palms and soles, had begun to
peel. The area also had some surrounding hyperpig-
mentation (Figure 1). However, the pain had resolved.
This was felt to be consistent with PPE due to docetaxel
and was classied as grade 2. The patient reported no
other adverse eects.
In response to PPE development, the patients doc-
etaxel dose was reduced to 75 mg/m
2
on cycle 3 day 8.
When returning to begin cycle 4 of chemotherapy, the
patient reported worsening of his PPE with peeling of
the skin and erythema about 13 days after receiving
the dose. The pain lasted for several days and again
impacted his gait to a small extent. He used heavy mois-
turizers and also began applying cocoa butter to soothe
the peeling skin. At the return visit, he reported that it
was no longer impacting his gait.
The docetaxel was discontinued at that time as it was
felt that the PPE was docetaxel-related with a Naranjo
score of 3 and the patient continued on gemcitabine
675 mg/m
2
as monotherapy for cycle 4. Three weeks
after discontinuing the docetaxel his symptoms were
resolving (Figure 2) and there were no further recur-
rences of PPE. He went on to receive two additional
cycles of gemcitabine alone on day 1 and 8 before being
enrolled in a new clinical trial.
Discussion
PPE is normally preceded by prodromal dysesthesia
and paresthesias, which manifests as tingling and
numbness in the palms and soles within 2 to 12 days
of treatment.
1,3,1113,29
This is followed by painful swel-
ling and erythema and can lead to cracking of the skin
and desquamation.
5
The onset is variable, occurring
anywhere from 24 h to 10 months after the initiation
of therapy.
3
These symptoms can progress over the next
3 to 4 days into painful erythema, burning, and sym-
metrical swelling, which occurs more commonly on the
hands than the feet. Further progression can lead to
blistering and desquamation. While PPE is often lim-
ited to the hands and feet, it can also be seen in other
areas such as the neck, chest, and trunk.
1,30
It has also
Table 1. Patient therapy summary.
Cycle, day Treatment
C1D1 Gemcitabine 900 mg/m
2
C1D8 Gemcitabine 900 mg/m
2
Docetaxel 100 mg/m
2
C2D1 Gemcitabine 900 mg/m
2
C2D8 Gemcitabine 675 mg/m
2
Docetaxel 100 mg/m
2
C3D1 Gemcitabine 675 mg/m
2
C3D8 Gemcitabine 675 mg/m
2
Docetaxel 75 mg/m
2
C, cycle; D, day.
Pegfilgrastim was used on day 9 of each 21 day cycle.
74 Journal of Oncology Pharmacy Practice 20(1)
been associated with other pressure-points on the body.
Even though it is not considered life-threatening, failure
to treat PPE can be debilitating and result in decreased
quality of life.
Several factors are associated with the development
of PPE including drug, dose, schedule, and duration of
infusion.
3,5
It is interesting to note that PPE rarely
occurs when 5-uorouracil is given as a bolus while
continuous infusion 5-uorouracil and capecitabine
are associated with PPE development. This illustrates
the idea that PPE development correlates with the dur-
ation of drug exposure.
3
The pathophysiology of PPE is unknown. One
theory proposes that the epidermis of the palms and
soles has a greater number of capillaries, which creates
higher concentrations of the chemotherapeutic agent,
resulting in drug accumulation and toxicity. PPE may
also be caused by drug extravasation from the micro-
capillaries of the hands and feet following local trauma
such as walking, ill-tting shoes, tight tting clothing,
or excessive exercise. Other irritants that may cause
local trauma include extreme temperatures, topical
anesthetics, and creams containing diphenhydramine.
Another hypothesis is that after the extravasation
occurs, the drug can enter the stratum corneum and
cause local inammation, most likely mediated by
cyclooxygenase (COX)-2.
1,3,4
A dierent explanation
states that the local inammation is due to direct cyto-
toxicity.
1,9
Another theory is that the basal cells of the
palms contain more Ki67, a cell proliferation marker,
than the back of the hand. This higher proliferation
rate in the palms could make them more sensitive to
cytotoxic drugs. Dihydropyridine dehydrogenase, the
rate-limiting step of 5-uorouracil catabolism, or thy-
midine phosphorylase, an activating enzyme, may also
be absent in the palms and soles.
31
Others propose that
the accumulation of certain cytotoxic drugs in areas
containing a high density of eccrine glands, such as
the palms and soles, can cause PPE.
1
Finally, a trial
of bevacizumab indicates that angiogenesis may play
Figure 1. Development of PPE in patients hands and feet occurring approximately 48 h after cycle 2 day 8 therapy.
PPE: palmar-plantar erythrodysesthesia.
Figure 2. Resolving PPE approximately 3 weeks after last dose of docetaxel.
PPE: palmar-plantar erythrodysesthesia.
Harris et al. 75
a possible role due to the higher incidence of PPE in the
bevacizumab plus chemotherapy arm versus chemo-
therapy alone.
32
PPE severity can be divided into three grades
according to the Common Terminology Criteria for
Adverse Events (CTCAE) version 4.
33
Grade 1 includes
minimal skin changes or dermatitis without pain.
Grade 2 includes skin changes with pain or limiting
activities of daily living. Grade 3 consists of severe
skin changes with pain or limiting self-care activities
of daily living (Table 2).
Very few treatments for PPE have been identied in
clinical trials, with most of the existing data found only
in case reports. Due to the limited information avail-
able, there are no guidelines that recommend an eect-
ive form of treatment. Currently, treatment generally
consists of creams and emollients, cold compresses
(applied 20 min at a time), wound care, and elevation
of the aected extremities.
9,34
Pharmacological thera-
pies for prophylaxis include pyridoxine, dexametha-
sone, and COX-2 inhibitors
1,5
(Figure 3). To date, the
only proven PPE treatment is dose reduction or treat-
ment interruption until symptoms improve.
3,35
PPE treatment
A number of case reports have indicated that vitamin E
may be an eective treatment for PPE. Although its
mechanism has not been extensively studied in PPE, it
has been postulated that its antioxidant properties
result in the stabilization of the cell membrane through
the prevention of lipid peroxidation. A case report of
ve patients who developed grade 2 or 3 PPE were
started on 300 mg/day of oral vitamin E without
chemotherapy dose reductions. These patients began
to notice improvement in their symptoms within
1 week of treatment, indicating some ecacy.
30
The
use of vitamin E was also assessed in a study of 42
patients who developed capecitabine-associated PPE
with oral vitamin E taken twice daily (dose unknown)
without dose reductions or delays. The patients
reported a decrease in pain, desquamation and
neurological symptoms, and an increase in comfort
level within 7 days of starting therapy.
36
Nevertheless,
more research and studies are needed to establish its
mechanism of action and role in the treatment of PPE.
A series of four cases discussed the use of topical
psoralen and UV-A light therapy (PUVA) treatment
for patients experiencing grade 2 PPE from tyrosine
kinase inhibitor therapy. The rst patient experienced
PPE while on imatinib and was given topical methox-
salen 0.01% followed by PUVA therapy for 23 treat-
ments and achieved sustained remission without an
imatinib dose reduction. The other three patients all
developed PPE while on sunitinib for renal cell
cancer. The rst of these three patients was given pred-
nisone 30 mg/day and PUVA therapy. The prednisone
was discontinued after 4 days and the patient received a
total of 30 PUVA treatments resulting in PPE remis-
sion and no sunitinib dose reductions. Topical PUVA
therapy was initiated in the other two patients receiving
40 and 23 treatments, respectively. Both achieved sus-
tained remission by their last treatment but eventually
required a dose reduction from other adverse eects.
37
A prospective case study of 23 patients being treated
for recurrent gynecologic cancers demonstrated that an
oral dexamethasone taper is eective for decreasing or
eliminating liposomal doxorubicin-induced PPE. The
oral dexamethasone taper regimen consisted of 8 mg
twice daily on days 14, 4 mg twice daily on day 5,
and 4 mg once daily on day 6. Of the 23 patients who
received liposomal doxorubicin 50 mg/m
2
, 9 developed
grade 2 or 3 PPE. Six of these patients were started on
the oral dexamethasone taper and were all able to
achieve a signicant decrease in PPE symptoms without
any treatment delays or dose reductions. Of note, the
three patients with PPE who elected not to receive the
oral dexamethasone regimen all required dose delays
and reductions.
38
Some other treatments that may be of some benet
include dimethyl sulfoxide, thalidomide, nicotine
patches to constrict vessels in the extremities, and ami-
fostine.
3942
Urea-containing moisturizing ointment,
topical heparin, and the Chinese herbal extract LC09
Table 2. Grading of PPE.
33
Grade Cancer Therapy Evaluation Program CTCAE version 4.0
Grade 1 Minimal skin changes or dermatitis (e.g. erythema, edema, or hyperkeratosis) without pain
Grade 2 Skin changes (e.g. peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting instrumental activities of
daily living
Grade 3 Severe skin changes (e.g. peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting self-care activities of
daily living
PPE: palmar-plantar erythrodysesthesia; CTCAE: Common Terminology Criteria for Adverse Events.
76 Journal of Oncology Pharmacy Practice 20(1)
have also reportedly been used.
4346
However, the
majority of the evidence consists of case reports or
observational trials.
PPE prophylaxis
Several small studies and case reports have
reported that varying doses of pyridoxine reduce sever-
ity and delay the onset of PPE.
5
Pyridoxine was origin-
ally studied in rodents and was found to treat
acrodynia, a skin condition similar to PPE. This data
were then extrapolated to PPE by researchers and
tested in several studies.
1
The results of one animal
study demonstrated a decrease in the frequency and
severity of PPE in the arm treated with 150 mg/day of
oral pyridoxine versus placebo.
47
Analysis of ve
patients from a larger trial of 25 patients with meta-
static colon cancer showed that the administration
of oral pyridoxine 50 or 150 mg/day enabled patients
to continue their 5-uorouracil treatment for a
median of 6 months versus 2.5 months in the non-
pyridoxine group.
48
However, two recent studies
reported no signicant dierence in capecitabine-
associated PPE development between the placebo-
treated groups and the 200 mg/day pyrixodine-treated
groups.
34,48
The COX-2 inhibitor, celecoxib, has been reported
to reduce the frequency of PPE in several studies.
50,52,53
Table 3. Summary of selected trials and case reports in the prophylaxis and treatment of PPE.
Study author Study design Study results
Pyrixodine
Fabian et al.
49
Five patients developed PPE while on 5-fluorouracil
and were given oral pyridoxine 50 or 150 mg/day
when PPE toxicity reached grade 2
Pyridoxine untreated group was able to continue 5-
fluorouracil treatment for a median 2.5 months
after PPE development versus the pyridoxine
treated group, which was able to continue treat-
ment for a median of 6 months after PPE
development
Kang et al.
34
Randomized, double-blind, placebo-controlled trial
of 360 capecitabine-treated patients randomized
to receive placebo or prophylactic oral pyridoxine
100 mg twice/day with treatment and followed
until discontinuation of chemotherapy or grade
23 PPE development
No statistically significant difference in PPE develop-
ment between the groups: 76.1% in placebo
versus 64% in pyridoxine (p 0.13)
Vail et al.
47
Forty one dogs treated with liposomal doxorubicin
(Doxil

) were randomized to placebo or

prophylactic pyridoxine 50 mg three times a day
for 15 weeks or until dose limiting toxicity
Placebo group was 4.2 times more likely to develop
PPE than the pyridoxine group; PPE occurred in
the pyridoxine group later and with less severity,
causing less treatment delays and discontinuations
Celecoxib
Zhang et al.
50
Prospective randomized clinical trial of 150 patients
with colorectal cancer being treated with capeci-
tabine were given either celecoxib 200 mg twice
daily or placebo
Celecoxib reduced the incidence of PPE by 17%
compared to the placebo group: 57.4% with
celecoxib versus 74.6% without celecoxib
(p 0.034)
Vitamin E
Kara et al.
30
Five patients with metastatic breast cancer who
developed grade 2 or 3 PPE during treatment with
either docetaxel or capecitabine were given
300 mg/day of oral vitamin E
Patients experienced no dose reductions and PPE
symptoms began to disappear within 1 week of
starting vitamin E
Yamamoto et al.
36
Forty two patients on capecitabine developed PPE
symptoms and were given oral vitamin E twice a
day (dose not reported)
Patients experienced no dose reductions or delays;
pain, desquamation, comfort level, and neuro-
logical symptoms improved within 7 days of
starting vitamin E
Bag Balm

Chin et al.
51
Among 39 patients receiving chemotherapy,
13 developed PPE and were given Bag Balm

three times daily

Twelve of thirteen patients reported symptomatic
improvement; 6 of 11 required no chemotherapy
dose delays or reductions; no patients discontin-
ued their chemotherapy due to PPE
PPE: palmar-plantar erythrodysesthesia.
Harris et al. 77
As previously stated, a possible cause of PPE is the
overexpression of COX-2 in the palms and soles.
Therefore, using celecoxib could reduce COX-2 expres-
sion and the resulting inammation. The only prospect-
ive, randomized, clinical trial consisted of 150 patients
with stage II or III colorectal cancer and demonstrated
that prophylactic celecoxib 200 mg twice daily can
reduce the incidence of PPE (57.4% with celecoxib
compared to 74.6% without celecoxib, p 0.034) in
capecitabine-treated patients.
50
However, more studies
are needed to assess its ecacy and place in therapy.
Bag Balm

, a topical ointment containing petrol-

atum, lanolin, and hydroxyquinolone sulfate, has also
been studied in the prevention of PPE. One group eval-
uated the use of this agent applied three times daily in
39 patients. In this study, 13 patients developed PPE: 12
of the 13 patients reported symptomatic improvement,
6 patients did not require a dose reduction or delay, and
none discontinued the chemotherapy.
51
A phase II, multicenter, matched case-control study
of 45 patients found that the use of frozen gloves may
help prevent skin toxicity. Each patient acted as their
own control, with the frozen glove applied to the right
hand 15 min prior to the docetaxel infusion for a total
of 90 min. Of the 41 patients assessed, 53% experienced
skin toxicity in the left hand versus 24% in the right
hand. The dierence in grade 0 toxicity was statistically
signicant (p 0.001) with 38% experiencing grade 0 in
the left hand and 67% in the right hand with the frozen
glove. Four patients had incomplete data and could not
be assessed.
54
A number of other non-pharmacological options
have been utilized. It is recommended that patients
avoid certain possible triggers and irritants such as
high temperatures (increased sun exposure and hot
showers), excessive exercise, and unnecessary pres-
sure/vigorous rubbing. They should also try to wear
loose-tting clothing and shoes, gloves, and apply ice
packs/cool compresses. In addition, patients can elevate
their hands and feet when resting.
9
Conclusion
Our patient presented with typical symptoms of doce-
taxel-associated PPE, developing erythema on the
palms of his hands and soles of his feet approximately
2 days after his second exposure to docetaxel, roughly 3
weeks after his rst docetaxel dose. This is consistent
with the typical timeline of progression of appearing
212 days after drug administration.
PPE is now being seen with the newer oral small
molecule inhibitors, such as sorafenib and pazopa-
nib.
1,3
As these agents are taken on a continuous
basis for longer periods of time, there is increased inter-
est in minimizing this adverse eect that can range from
being troublesome to debilitating to patients. An inter-
esting nding is the possibility that the development of
PPE may predict the ecacy of therapy, as shown in a
preliminary study with sunitinib.
55
Currently, there is a lack of ecacious treatments
available for the prevention or treatment of PPE.
Pyridoxine, our most studied agent, has had mixed
results in clinical trials. Other agents, such as celecoxib,
vitamin E, and Bag Balm

have not been extensively

researched and their ecacy is unclear. As a result, our
patient was dose reduced from 100 to 75 mg/m
2
for
cycle 3. However, his symptoms did not resolve and
continued to worsen. Docetaxel was discontinued in
cycle 4, at which point his symptoms began to improve.
Due to the lack of data on rechallenging patients with
chemotherapy-induced PPE, it was decided not to rein-
itiate docetaxel after symptom resolution.
In conclusion, PPE is a self-limiting toxicity that can
aect a patients quality of life and potentially impact
cancer treatment. With the lack of controlled trials on
PPE, optimal treatment or prevention of this adverse
eect is still unknown. At present, only dose reduction
and/or discontinuation of the chemotherapeutic agent
have been shown to alleviate and resolve PPE symp-
toms. Therefore, more research is needed to understand
its etiology and to develop agents for treatment or pre-
vention to better optimize patient care.
Informed consent was obtained from the patient for
all pictures.
Funding
This research received no specic grant from any funding
agency in the public, commercial, or not-for-prot sectors.
Conflict of interest
The authors declare that there is no conict of interest.
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