Intertrigo-Like Dermatitis With Pegylated Liposomal Doxorubicin: Diagnosis and Management
- Corresponding author: A. Najem, MD, Department of Oncology, Dr Duchenne Hospital, Boulogne-sur-Mer, 62321, France; e-mail: abeernajem@gmail.com.
+ Author Affiliations
A 52-year-old woman was observed for
metastatic breast cancer, which had been diagnosed 14 years before and
was initially
treated with mastectomy, adjuvant chemotherapy,
and radiotherapy. During the following years, the patient presented with
multiple
local and lymph node recurrences that were
treated with surgical excision followed by several lines of
chemotherapy, including
anthracycline (epirubicin), taxane, vinorelbine,
and capecitabine. No skin toxicity was observed as a result of
treatment
with these different types of chemotherapy.
Following the occurrence of lung metastases, treatment with pegylated liposomal doxorubicin (PLD) was initiated at a dose
of 40 mg/m2 intravenously every 4
weeks. A preventive treatment for palmar-plantar eythrodysesthesia (PPE)
was initiated at the start
of chemotherapy with the use of frozen gloves
and socks during the infusion and daily application of emollient creams.
Three weeks after the third cycle, the patient developed erosive and desquamative erythematous lesions that were located in
the abdominal and axillary regions, sparing the bottom of the folds (Fig 1).
Neither mucosal lesions nor palmar or plantar involvement were
observed. The patient was apyretic. The lesions were nonpruriginous
but were painful and caused an alteration in
quality of life and functional limitations during daily activities
(toxicity
grade 2, according to the basic scale from the
Common Terminology Criteria for Adverse Events, version 4).
Fig 1.
Histology from a biopsy specimen of a lesion in the axillary area revealed unspecific changes: parakeratosis and moderate
neutrophil infiltrate in the stratum corneum (Fig 2A), vacuolar degeneration at the basal layer of the epidermis, dermal edema with perivascular lymphocytic infiltrate within
papillary dermis (Fig 2B). Periodic acid staining was negative, excluding a fungal infection. Our diagnosis was cutaneous toxicity caused by PLD,
which is described in the literature using the term intertrigo-like dermatitis.
Fig 2.
The fourth cycle of chemotherapy was
delayed for a week. Curative treatment with topical and systemic
corticosteroids was
initiated for a total duration of 1 week:
topical clobetasol propionate twice daily and oral prednisone at a dose
of 2 mg/kg
per day with a rapid gradual discontinuation (Table 1). The lesions responded well to treatment with complete remission after 1 week.
Table 1.
Treatment With Topical and Systemic Corticosteroids
To continue the chemotherapy without
dose reduction, we proposed a prophylactic treatment during all
subsequent cycles: oral
corticosteroid at a dose of 1 mg/kg per day with
rapid discontinuation for a total duration of 6 days, and topical
corticosteroids
(clobetasol propionate) applied systematically
on the morning before the PLD infusion and for 3 weeks in the previously
involved
areas (axilla and abdominal belt region), even
in the absence of a recurrence of skin lesions (Table 1).
With these preventive measures, new
skin adverse effects were not observed and the chemotherapy was
continued without dose
reduction or lengthening of the treatment
intervals for three additional cycles. PLD was then discontinued because
of cancer
progression.
Discussion
The polyethylene glycol-coated
(pegylated) liposomal form of doxorubicin allows for an increase in the
concentration of the
molecule in the tumor tissue and, conversely, it
reduces toxicity in healthy tissues, especially cardiotoxicity.1,2 However, PLD increases the frequency of skin toxicity, specifically hand-foot syndrome, which is also called PPE or acral
erythema.3
The physiopathology of PPE is still
not well understood. The long circulating half-life of pegylated
liposome and the hydrophilic
coating of the liposomes may facilitate
accumulation of the molecule in skin,3 especially in the sweat glands.4
Local microtrauma and vasodilatation may result in the extravasation of
the molecule in the stratum corneum, where it is
hypothesized that PLD may cause a local
inflammatory reaction that is mediated by cyclooxygenase-2 or a direct
cytotoxic reaction.5
This toxicity mainly occurs on the
palms of the hands and soles of the feet. But in rare cases, other areas
can be affected,
particularly areas that are prone to friction
and warm areas, such as the axillary folds and the inguinal and
abdominal belt
regions.6 Symptoms range from simple erythema to edema, desquamation, ulceration, and functional impairment.
Histologically, PPE presents with few
specific findings, which vary from epidermal atrophy to hyperkeratosis,
keratinocyte
necrosis, vacuolar degeneration of the basal
layer of the epidermis, and perivascular lymphocytic infiltration in the
papillary
dermis.6–9 Recently, Martorell-Calatayud et al10 described an erythematous eruption affecting the intertriginous areas and associated with syringometaplasia.
In the absence of typical
palmar-plantar involvement, diagnosis may be difficult. Inflammatory
lesion of the folds should
not be mistaken for infectious intertrigo, in
particular, fungal infection. Clinically, the spearing of the bottom
folds does
not favor a diagnosis of mycosis.
Skin toxicities are the most
significant dose-limiting adverse effects of PLD. Depending on the
severity, PPE or its variant,
intertrigo-like dermatitis, requires a dose
reduction or a change in the line of chemotherapy, with consequences
with respect
to treatment efficacy.5
Supportive treatment measures for the
palm and sole lesions include having the patient wear frozen gloves and
socks during
the infusion, daily application of emollient
creams, and avoidance of trauma, pressure, and heat exposure.
Administration
of pyridoxine and application of topical 99%
dimethylsulfoxide and systemic corticosteroids have been described in
the literature.5,11,12 For intertrigo-like dermatitis, preventive and curative treatments are poorly defined in the literature.
We report severe skin toxicity as a
result of treatment with PLD that affected axillary and abdominal areas,
with sparing
of palms and soles, probably because of the
efficacy of the preventive treatment for hands and feet (use of frozen
gloves
and socks). But the appearance of painful
erosive lesions in other areas could have affected continuation of
chemotherapy.
We propose here an effective and curative
treatment, and we believe that topical corticosteroids can be used to
reduce the
dose of systemic corticosteroids and thus limit
their adverse effects.
In conclusion, skin toxicity that
affects areas other than the palms and soles as a result of PLD
treatment has been described,
but is not well known. The diagnosis might be
difficult to make, especially in the absence of lesions in the
palmoplantar
area. Supportive treatment measures must be
begun as soon as possible after the first symptoms of PLD-induced
adverse skin
effects occur. This may allow the continuation
of chemotherapy without dose reduction and without changing the line of
chemotherapy.
We suggest that a combination of short oral
corticosteroids with topical corticosteroids is effective as a curative
treatment
for skin lesions and also as a secondary
preventive treatment.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
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