ARTICLE
Auteur(s) : Joanna Mangana1, Marie C
Zipser1, Curdin Conrad1, Patrick A
Oberholzer1, Antonio Cozzio1, Alexander
Knuth2, Lars E French1, Reinhard Dummer1
1Department of Dermatology,University Hospital of
Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland
2Department of Oncology, University Hospital of Zurich,
Gloriastrasse 31, 8091 Zurich, Switzerland
accepté le 30 Avril 2005
Delivery systems have been developed to exploit tumor
microphysiology and have aimed at improving the tropism of
chemotherapeutic agent towards tumor cells [1]. Therefore
macromolecular carriers have been used during recent years
providing the single drugs with specific characteristics, such as
long circulating time capacity, preferential extravasation and
accumulation in tumor stroma. Liposomal anthracyclines, such as
pegylated liposomal doxorubicin (PLD) have accomplished
considerable and prolonged circulation within the body based upon
unique drug encapsulation, which in turn results in significant
anticancer activity with reduced adverse effects, such as
cardiotoxicity and neutropenia [2].
PLD is encapsulated into polyethylene-glycol coated liposome
variants of doxorubicin with a reduced uptake by the
reticulo-endothelial system. The volume of distribution of this
drug is close to blood volume and the area under the
concentration-time curve (AUC) is increased at least 60 fold
compared with free doxorubicin [3]. PLD has an eliminated half-life
around 40-60 hours in the human body and a circulation time of 2-3
weeks in the blood and the drug remains encapsulated in the
liposomes during this time [4].
PLD acts in a completely different manner when compared to
doxorubicin in a non liposomal form. After extravasation into tumor
tissue, liposomes remain within tumor cells, but they do not
interact with plasma proteins and mononuclear phagocytes.
Consequently, liposomes undergo enzymatic degradation, which leads
to the release of the drug into the tumor tissue. During
encapsulation within the liposomes, the drug is not bioavailable,
hence has no anti-tumor effect and thus no therapeutic ability. On
the other hand, the therapeutic results of the medication itself
and differences in them may not vary much compared to doxorubicin
when the liposomes have not yet reached to the target tissues [5].
Therefore there is a correlation between efficacy and toxicity of
liposomal doxorubicin and the different liposomal leakage rates.
Liposomes with the best therapeutic activity are those with the
slowest drug release rate [6].
The pegylated liposomal form of doxorubicin has been
investigated and is used today for the treatment of metastatic
breast cancer, aggressive Non-Hodgkin lymphoma, non small cell lung
cancer, multiple myeloma, gastrointestinal malignancies [7].
Moreover, it is more and more often accepted as a treatment option
for the acquired immunodeficiency syndrome-related Kaposi sarcoma
[8] and refractory ovarian cancer [9]. There are many side effects
reported, which are connected to PLD treatment, nevertheless, skin
toxicities are the most important dose limiting side effects.
We report 6 consecutive patients with different malignancies who
were referred to or treated by the Department of Dermatology of
Zurich University hospital with PLD, and in turn developed
cutaneous side effects, including palmoplantar erythrodysesthesia
syndrome (PPE), also called hand foot syndrome (HFS) or acral
erythema (AE). PPE is characterised as a patchy erythema of hands
and soles, whose primary lesions can sometimes become painful, can
lead to erosions and to desquamation, ulceration, blister formation
and can also cause functional limitation during daily activity.
Materials and methods
Medical records of six patients treated with PLD at the University
hospital of Zurich from 2005 until 2007, were retrospectively
reviewed. Laboratory data including histological findings and
clinical information of the skin manifestation, such as clinical
symptoms, location and severity of clinical signs, as well as
treatment regimen were collected. Toxicity was graded using the
basic scale from the common toxic effects criteria of the National
Cancer Institute for evaluation of the skin lesions (table 1) [10].
All six patients were Caucasian women with ages ranging from 23
to 73 years. They received PLD in different dose-schedules as a
treatment for different malignancies: three of them for
metastasized breast cancer, one for ovarian cancer, one for tumor
stage mycosis fungoides [11] and one for cutaneous B-cell lymphoma
(table 2). All six patients had
diagnosed disease evaluated with standard criteria. Dermatologic
examination was conducted in all cases and any evidence of skin
toxicity was classified and documented.
Before receiving PLD five of six patients were treated with at
least one chemotherapeutic agent. Only one patient had received
anthracyclines in the past, with no reported side effect. Also no
allergic side effects occurred during infusion of PLD. PLD was
administered as a 1-2 hour intravenous infusion. The cycles were
repeated every four weeks, except in two cases, in which they
repeated every two weeks. One patient received oral
corticosteroids, as prophylactic treatment of PPE, before the
infusion.
Table 1 Grading of skin lesions according to National
Cancer Institute common toxicity criteria (NCI CTC) version 3
|
Terminology
|
Grade 1
|
Grade 2
|
Grade 3
|
Grade 4
|
Grade 5
|
|
Macular or papular eruption or erythema without associated
symptoms
|
Macular or papular eruption or erythema with pruritus or other
associated symptoms. localized desquamation or other lesions
covering < 50% of body surface area (BSA)
|
- Severe, generalized erythroderma or macular papular or
vesicular eruption;
- desquamation
- Covering > 50% BSA
|
Generalised exfoliative, ulcerative or bullous dermatitis
|
Death
|
Table 2 Patients’ demographic and clinical
characteristics, dose intensity and impact of skin reactions on
chemotherapy continuation
|
Age in years
|
PLD dose (mg/m2)
|
Intervals (weeks)
|
Localization
|
PPE grade
|
Onset of toxicity after cycles
|
Consequences
|
Diagnosis
|
Other observations
|
|
1
|
73
|
50
|
4
|
S, I, P,C
|
IV
|
5
|
-
|
PPE
|
PN
|
|
2
|
40
|
50
|
2
|
S, P, A, E
|
III
|
3
|
Stop
|
ELR
|
|
|
3
|
56
|
30
|
4
|
P, S
|
II
|
3
|
Reduction
|
PPE
|
|
|
4
|
72
|
40
|
2
|
P, S, T
|
II
|
2
|
Prolongation
|
PPE
|
SG inv.
|
|
5
|
56
|
50
|
4
|
I, E, P, S
|
III
|
3.5
|
Reduction
|
PPE
|
|
|
6
|
29
|
85
|
4
|
I, OM
|
II
|
2
|
Reduction
|
ILD
|
Stom.
|
Results
Clinical presentations and severity
Three of six patients in this study developed classical PPE, one
PPE associated with bullous disease on pre-existing scars due to
prurigo nodularis, one developed eruptions of lymphocyte recovery
(ELR) and one showed intertrigo-like dermatitis with stomatitis. In
five of six patients the manifestations were located on the palms
and soles, in three patients they were located also at the
intertriginous areas of the body and one showed infiltration of the
oral mucosa (table 2). Two of the
patients developed Grade III skin lesions, one of which was
compatible with PPE and the other with ELR. One of the patients
developed Grade IV PPE (table 2). We now
would like to present two of the six clinical cases, based on their
special clinical features.
Clinical case 1
A 73-year-old woman with breast cancer first diagnosed in 2003 with
bone metastases, received 5 cycles of PLD, 50 miligrammes per
square metre of body surface area (mg/m2) every four
weeks for five cycles, two years after she underwent bilateral
mastectomy. She was diagnosed with prurigo nodularis in 2000.
Prurigo nodularis is a chronic eczematous process of unknown
aetiology, characterized by a papulonodular pruriginous eruption
and subsequent scar formation [12]. Five days after the last
infusion of PLD, the patient presented with a generalised erythema
with erosions and bullae formation, preferentially at the sites of
mechanical pressure. Skin eruptions were not restricted to hand and
feet areas, but they were spread over the whole body including the
capillitium and the axilla region. Due to prurigo nodularis the
patient also later developed bullae in the regions of pre-existing
scars and traumatized skin areas (figure 3). Tenderness,
oedema as well as painful erythema and desquamation on both palms
and soles were also observed (figures 1 and 2).
Two weeks after the fifth cycle of PLD the patient was diagnosed
with cardiomyopathy with a left ventricular ejection fraction
(LVEF) of 31%. Cardiological assessment was made by clinical
examination, serial echocardiogram (ECG) and the measurement of
LVEF obtained by echocardiography. Due to lack of previous clinical
data, the unknown initial LVEF and pre-existing atrial fibrilation
(AF), no secure correlation to the PLD therapy could be
determined.
Clinical case 2
A 40-year-old woman was diagnosed with breast cancer in 1989 and
underwent bilateral mastectomy in the same year. During the
following years the patient received multiple cycles of other
chemotherapeutic agents, including anthracyclines. In 2006 lung
metastases were diagnosed and patient was treated with capecitabine
until April 2007. A few weeks later she received PLD
50 mg/m2 infused in three cycles. One week after
the third cycle, the patient developed painful redness with
desquamation, vesicules, macules and papules confined to the hands
and soles. The skin of the hands begun to peel. A few days later
the maculopapular rash had spread to the axilla, trunk and
extremities and the patient had difficulty in picking up objects
with her fingers, due to swelling and pain. At this stage, the
patient was hospitalised and a low fever was recorded.
The diagnosis of ELR was established based on the histological
findings, the subsequent blood tests which showed excessive
lymphopenia and decreased white blood cells (WBC) coinciding with
the rash, the negative immunofluorecence and the clinical
signs.
Histological features
In four of six patients skin biopsies were performed to evaluate
the clinical diagnosis in two papular, one papulovesiclar and one
erythematous lesion. In connection with PPE, biopsies revealed
unspecific changes, such as mild spongiosis, sub-epidermal oedema,
perivascular lymphocytic infiltration, dilated blood vessels,
keratinocyte necrosis and presentation of eosinophils in the
dermis. In one case there was also evidence of neutrophilic
infiltrates of the sweat glands, compatible with neutrophilic
eccrine hidradenitis. In the case of ELR, a biopsy showed an
atrophic epidermis with apoptotic keratinocytes, perivascular
lymphocytic infiltration and interface dermatitis in the absence of
eosinophils.
Therapy of skin reactions
All six patients required short-term hospitalization and treatment
for these skin reactions. The treatment consisted of supportive
measures and various modalities during the hospitalization, such as
rest, avoidance of vigorous exercise and skin re-hydrating
therapies. The medications included topical and systemic steroids,
vitamin B6, topical antiseptic agents, urea 10% ointment and
emollient creams. These interventions led to a relief of the
symptoms in all cases.
Management and outcome
Dose reduction was necessary in three patients, while only one
patient was unable to continue the treatment due to painful skin
eruptions and transient functional impairment. In one of the cases,
PPE presented at the end of the therapy with PLD (clinical case 1).
Delays in administration of the chemotherapy for periods more than
1 week occurred in none of the patients. In one case an adjustment
of the treatment intervals was required, and the time between the
intravenous infusions of PLD 40 mg/m2 was increased from
every two weeks to every four weeks. Two of the patients have since
died. The patient described in case one, died of multiple organ
failure due to septicaemia several months after developing PPE.
Discussion
PPE is the most common cumulative toxicity experienced by patients
treated with PLD and appears to be dose-interval related. In their
study, Lyass et al. evaluated different incidences of PPE among
patients during various treatment schedules and doses. Shorter
schedules of drug administration lead to more severe symptoms and
greater toxicity, which is not related to the dosage of PLD given
at each cycle. At the dose schedule of 35 mg/m2
administered every 3 weeks 17.7% of the patients developed PPE,
while only 2.22% developed PPE at the dose of
50 mg/m2 every 4 weeks and at the dose of
65 mg/m2 every 5 weeks [13]. Wollina et al. resumed
that of the 34 patients who received PLD in different dosages,
grade 2 and 3 PPE was observed in only 5.88% and 2.94% of the
patients respectively [11]. Two out of 3 patients who developed PPE
were on a 2-week schedule.
PPE was first reported in 1974 by Zuelke, during mitotane
therapy [14]. It has been described that once PPE develops, it can
be retriggered after treatment with other chemotherapeutic agents
also known to cause this adverse effect [15]. It affects most
commonly the palms and soles, with the hands being affected to a
greater degree [16].
It is intriguing that pre-existing skin disease may facilitate
the involvement of skin areas, other than the hands and feet, as we
have seen in the patient with pre-diagnosed prurigo nodularis. The
patient described in clinical case one developed bullae and
vesicles on pre-existing scars, which implies that compressed and
damaged skin areas are faster and more intensely affected than
normal skin. Preferential recruitment of liposomes to inflammatory
areas was demonstrated in a murine model where liposomes were
highly concentrated in areas around psoriatic lesions, which might
be explained by the leakage of superficial post capillary venules
in inflammatory areas [17].
In addition, areas exposed to friction and to higher pressure
such as the axilla, groin, inner side of the knees, sacral area,
bra line, elbow and wrist can be involved. This was also seen in
the patient depicted in case one. The contribution of local trauma
or pressure to the skin was reported in the study by Lyass et al.
[13]. PPE manifested in skin areas subjected to frequent contact
pressure or microtrauma among 45 patients receiving PLD in
different schedules and dosages, due to breast cancer [13].
Reduction of the dose of PLD is a standard approach to eliminate
the risk of PPE [18]. Patient education can also be very helpful
[18]. Supportive treatment measures must start as soon as possible
when the first signs of PLD adverse skin side effects occur, in
order to relieve the symptoms and to avoid and/or reduce the
severity of PPE [18]. Usually mild symptoms recede in one to three
weeks. Non-pharmacological interventions consist of sitting on
padded surfaces, wearing loose clothing, and keeping the skin well
hydrated. In addition, avoidance of jogging or vigorous exercise
and sunlight and use of regional cooling may have a positive effect
in relieving the symptoms [19-21]. Emollient creams are of great
value [22] while, though corticosteroids and pyridoxine are used in
clinical practice, their effects still remain to be shown [23].
The eruption of lymphocyte recovery concurs with the return of
the lymphocytes to the peripheral circulation and skin. It occurs
more commonly after bone marrow ablative antineoplastic
chemotherapy in leukaemia patients with a decrease in WBC count in
a febrile patient [24]. The diagnosis of ELR should be based on
both clinical and histological findings, as both are not specific
[25]. It manifests as a generalised macular or papular rash, which
reveals a non specific dermatitis in the biopsy. The histological
features of ELR consist of a scan of moderate superficial
perivascular mononuclear infiltrate consisting predominantly of
T-cells, followed by mild epidermal changes including slight basal
vacuolization, intercellular oedema, atypical keratinocytes and
dysmaturation [26]. With this article we depict for the first time
a case of ELR in connection with therapy with PLD. The
differentiation between ELR and a drug eruption is of great
significance since patients are often given multiple essential
drugs when the rash occurs, especially in regard to initiating
appropriate therapeutic measures.
Stomatitis was only present in one of the patients presented
here, after two intravenous infusions of 85 mg/m2
of PLD (clinical case 6). The severity of stomatitis correlates
strongly with the dose and maximum plasma concetration (Cmax) and
it is most often seen at doses around 60-70 mg/m2.
In the report of Al Batran et al., 22 of 45 enrolled patients
developed grade 1-4 mucositis [27]. In addition
Hamilton et al. showed that the reduction in the dose of PLD
by administering higher doses at prolonged intervals (i.e. 60-70
mg/m2 every 6 weeks) was associated with significantly
less PPE but higher rates of mucositis, ranging between 53 to
100%, including grade 3-4 mucositis in 12.5-85% of patients
[28].
Intertrigo-like dermatitis describes the development of rather
painful erythematous patches in areas of skin folding, such as the
axilla, belt region, groin and waist, and resembles the
manifestations of intertrigo. A case of a 60-year-old woman treated
with PLD who developed erythema at her axilla and groin, compatible
with intertrigo-like dermatitis has also been reported. The biopsy
revealed interface dermatitis with epidermal dysmaturation
[29].
In the literature, other skin reactions also correlated with PLD
treatment are described. Harrison et al. reported alopecia in 8.8%
of 34 patients receiving treatment with liposomal doxorubucin due
to Acquired Immune Deficiency Syndrome (AIDS) related Kaposi
sarcoma while Uzielly et al. described no cases of alopecia in two
separate phase I studies of 56 patients [30]. Other skin
manifestations of minor clinical significance include diffuse
follicular rash, melanotic spots in unusual areas such as the
finger and toes webs, palms and soles, trunk, nail pigmentation,
radiation-recall responses, hyperkeratosis and dry skin [13, 31,
32].
Conclusion
Pegylated liposomal doxorubicin induces various skin reactions
including palmar plantar erythrodysesthesia syndrome. The exact
clinical presentations might depend on pre-existing skin diseases.
When skin reactions appear they may alter or affect a patient’s
quality of life. However, they often respond to dose reduction and
do not usually limit the duration of the therapy. Finally palmar
plantar erythrodysesthesia syndrome is frequent among patients
treated with liposomal doxorubucin and as a result all physicians
should be familiar with its clinical and histological
manifestations, so that they can easily distinguish it from
allergic drug reactions.
Acknowledgements
The authors would like to thank Dr Maria B. Karpova for critical
reading. Financial support: none. Conflict of interest: none.
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