Cutaneous Side Effects of Recently Launched Anti-Cancer Agents
Wednesday, July 05, 2006
When most dermatologists of my generation were growing up, solid
tumor neoplasia was treated with surgery and/or radiotherapy, and
chemotherapy was mainly used for hematologic malignancies such as
leukemias and lymphomas. Therefore, dermatologists were familiar
with cutaneous reactions to the limited number of drugs given in
hemopathies, such as cyclophosphamide, anthracyclines, cytarabin,
nitrogen mustard, alkaloids, and bleomycin.
Later on, we became familiar with fluorouracile and platin
derivatives and learned of the cutaneous localized or disseminated
eruptions that these medications could induce.
However, in the last decade, medical practice has changed,
particularly in treating solid tumors. Several types of drugs were
developed that weren't acting only as classical cytotoxic agents.
Indeed, monoclonal antibodies targeting oncogenes were launched as
well as other molecules acting on signaling pathways. In addition,
the majority of patients now receive ambulatory treatment, which
means that delayed complications - including those involving the
skin - usually develop when patients are at home. Therefore,
private-practice dermatologists are often the first to diagnose
In this overview, I have limited the data to taxanes,
capecitabin, gemcitabine, imatinib, and epidermal growth factor
receptor (EGFR) inhibitors, all of which can cause adverse skin
reactions (Table 1).
Taxanes are mainly responsible for acral, erythema, and
sclerodermatous changes. Paclitaxel (Taxol®) and
docetaxel (Taxotere®) constitute a class of cytotoxic
drugs largely used in tumors such as breast, non-small cell
bronchial, and ovarian cancers. They are efficient and widely
Docetaxel is responsible for many more adverse skin reactions
than paclitaxel. Indeed, cutaneous eruptions develop in 70% of
patients treated with docetaxel.1 Most often, these
eruptions consist of palmar-plantar erythema and, more rarely,
disseminated exanthems. This acral syndrome - otherwise known as
hand and foot syndrome, acral erythema, or erythrodysesthesia - can
be associated with painful sensations in the affected areas.
Tingling and/or even burning pain may also develop. Of note, the
severity of these reactions can vary, ranging from a few red
plaques to diffuse edematous erythematosus lesions that sometimes
blister and then ulcerate. This cutaneous toxicity develops
anywhere from 2 days after infusion to 21 days. Pathogenesis of
this reaction remains unknown, as histology may display either
syringometaplasia, evoking the toxic effects of secreted drugs
through the eccrine coils or vasculitis, perhaps by another
Acral erythema may recur during later courses of treatment with
similar offending drugs, and it is considered to be dose-dependent.
Interestingly, a recent study showed that in a multivariate
analysis, skin toxicity was the only independent factor predictive
of grade 3-4 infection in docetaxel-treated patients.3
Curative treatment is poor. Treatment with topical or systemic
steroids is sometimes effective, but it remains controversial. A
2005 French study showed that use of frozen gloves reduced the skin
toxicity score, demonstrating that as for alopecia this could be a
useful prevention tool.
Sclerodermatous-like changes in various sites, mainly hands or
lower limbs, have been reported with docetaxel and more recently
with paclitaxel. Clinical features usually appear within days after
infusion and improve if the drug is withdrawn. There is an initial
edema followed by cutaneous thickening. Skin biopsy shows only
Nail changes are another "toxic" effect of taxanes and occur in
up to 30-40% of treated patients. These changes are characterized
essentially by distal onycholysis, developing with or without
subungual hemorrhage and acute paronychia. The later may progress
to subungual abscess of distal fingers. Patients should be
instructed about these events, and nail polish should be
applied.4 As with palmoplantar erythema, frozen gloves
in the same study cited above were able to reduce the incidence of
nail changes significantly.
Finally, patients with erythema multiforme, subacute lupus
erythematosus, and even radiation recall dermatitis have all been
reported. The latter is a peculiar and unexplained phenomenon
characterized by the development of an inflammatory cutaneous
reaction after infusion chemotherapy (such as taxanes) that
develops specifically at the site of prior radiotherapy although
there was no skin toxicity at the time of that treatment.
Gemcitabine (Gemzar®) is a cytidin analog, chemically
similar to cytarabin, acting in the cell through 2 phosphorylated
metabolites. This molecule is effective in a wider spectrum of
malignancies than cytarabin, being used in pancreatic cancer,
non-small cell lung cancer, and, to a lesser degree, breast and
ovarian tumors. Gemcitabine appears to be a "safe skin drug" but
may induce erysipeloid localized inflammatory plaques.
Development of exanthema after gemcitabine infusion is possible
but rare. In a series of 40 cases, treatment with this drug and
cisplatin led to a unique grade 2 skin "rash".5 In
another series in which 52 patients received gemcitabine and
vinorelbin for non-small cell lung cancers, the authors noted a 2%
incidence skin rash grade 3-4.6 This is therefore lower
than what was seen with cytarabin. In my experience with similar
patients, there is a low incidence. Other types of cutaneous
reactions may occur. Interestingly, some patients with an
intriguing erysipeloid erythema developing only in the areas of
previous lymphoedema have been reported.7 Authors
postulated that impaired lymphatic drainage had altered
pharmacokinetics of the drug in these skin sites, allowing
increased toxicity. However, a case in which the reaction developed
without any previous history of such events has been published,
suggesting a possible peculiar event linked to
One patient with scleroderma-like change of the lower
extremities has been reported with an initial inflammatory edema,
which may correspond to the same phenomenon.9
Finally, a series of patients presenting with recall radiation
changes induced by gemcitabine has been described, involving mainly
the skin but also deep organs.10
Capecitabine (Xeloda®) is an oral prodrug that is
metabolized into 5-fluorouracil - a pyrimidine analog. It is
used for treating cancer of the colon after surgery but also in
colorectal and breast tumors and sometimes in other
The main problem that one should be aware of with capecitabine
is a high frequency of acral erythema, also called hand and foot
syndrome. In data obtained from 179 patients (4 series), hand and
foot syndrome developed in 65% of treated patients, with grade 3
reactions noted in 4.5%.11 The most frequent occurrence
was during cycle 2 of treatment. Analysis of these cases showed
that combined use of docetaxel - already known as an inducing drug
- and preceding chemotherapy-related stomatitis were significant
risk factors for the development of this reaction. However, other
data from 2 large phase III trials showed that the incidence of
acral erythema was similar when capecitabine was administered as
monotherapy or in combination.12
As stated above, treatment with corticosteroids remains
controversial, relying mainly on isolated case reports. Therefore,
the only proven method is dose reduction or even
In chronic myeloid leukemia (Philadelphia chromosome), the
BCR-ABL fusion gene, created by the Philadelphia
chromosome (Ph+), displays a tyrosine kinase activity not linked to
a membrane receptor. This leads to a constitutive phosphorylation
of cellular proteins, with consecutive mitosis. Imatinib is the
first member of an important new class of drugs, tyrosine kinase
inhibitors (TKIs), part of the signal transduction inhibitors
(STIs). It has been designed to link to the BCR-ABL fusion gene. It
is a major oral drug in this disease, but now other indications
such as gastrointestinal stromal tumors (GIST), hypereosinophilic
syndromes, or even some mastocytoses may be treated with
One of the most common side effects seen in patients receiving
treatment with imatinib is skin rash, which occurs in 3-30% of
treated cases.13,14 In a prospective study done in a
dermatologic ward, the rash was considered severe in 5/36 eruptions
and responsible for treatment withdrawal in 3/36
patients.15 This rash may be maculopapular and of
variable severity. However, authors have reported that these
eruptions are sometimes characterized as dark purple, pruritic
papules suggestive of lichen planus. Histopathology also revealed
features of lichen planus. Withdrawal of the drug has led to
Other cutaneous reactions have been described. Some were severe,
such as Stevens-Johnson syndrome, exfoliating dermatitis, acute
generalized exanthematic pustulosis, and generalized erythema with
chills and fever. Others have presented with features of pityriasis
Periorbital edema and peripheral edema are other frequently
noted adverse reactions to imatinib, noted in 21-40% of
cases.13,14 The common hypothesis explaining this
symptom is the effect of platelet-derived growth factor receptor
(PDGFR) inhibition on interstitial-fluid homeostasis, given that
blockade of PDGFR signalling in transgenic mice induces
dysregulation of the tension between endothelial cells and the
extracellular matrix. Highly significant relationships have been
observed between the daily dose of imatinib and both rashes and
edema. In a multivariate analysis, female sex and the daily dose of
imatinib were independent risk factors for the development of
Pigment modifications may occur with TKIs. Recently, patients
who developed skin hypopigmentation within the first month of
treatment have been reported.17 This has included the
skin and hair. The hypopigmentation was reversible and potentially
dose-related. C-Kit and its ligand stem cell factor have a
regulatory role in melanocyte development and survival, suggesting
a rational mechanism of action for imatinib in the pathogenesis of
hypopigmentation. However, despite this pharmacological mechanism,
development of hypopigmentation does not appear to predict leukemic
cell response or clinical outcome.17 Paradoxically, hair
repigmentation was noted in 9 of 133 patients given imatinib for
Sorafenib is another TKI. It blocks a product of RAF
(serine-threonine kinases). The drug has yielded very encouraging
results in renal-cell carcinoma. Sunitinib is a new oxindole agent
with antiangiogenic properties that inhibits vascular endothelial
growth factor receptor 2, c-Kit, FLT-3, and PDGFR. It has shown
potent, broad-range anti-tumor activity in many mouse models and is
being tested in renal cancer. These molecules are, like imatinib,
responsible for generalized rashes, hair modifications, and edema
but with differences in incidences. Hand and foot syndrome may
develop 2-4 weeks after treatment. Subungual splinter hemorrhages
have been reported with these 2 molecules mainly on the hands.
These lesions are asymptomatic.
Epidermal Growth Factor Receptor Inhibitors
EGFR is aberrantly overexpressed in some neoplastic conditions.
This overexpression was previously associated with resistance to
chemotherapy and poor prognosis. But now, several investigative
groups have conducted trials using various drugs acting on the
signaling pathways in lung and colon carcinomas as well as
colorectal, ovarian, head and neck, breast, and bladder
Two types of agents acting against EGFR have been developed:
monoclonal antibodies to prevent EGF binding and small-molecule
inhibitors of tyrosine kinase enzymatic activity and downstream
intracellular signaling. The chimeric monoclonal blocking antibody
is cetuximab (Erbitux®). The 2 small molecules that
inhibit the tyrosine kinase of EGFR are gefitinib
(Iressa®) and erlotinib (Tarceva®).
Unexpectedly, a frequent occurrence of cutaneous adverse
reactions -characterized by acneiform eruptions - has been reported
with all EGFR inhibitors tested. These acne or follicular eruptions
are characterized by inflammatory lesions (papules and pustules)
without retentional lesions. They may involve the face and upper
trunk as well as sites not usually involved by classical acne (such
as the extremities and lower back), and they are sometimes
pruritic. Bacterial culture of pus is negative or yields only
P. acnes. With cetuximab, the drug that appears to induce
folliculitis most frequently, the figure reached 75-91% of
patients.19 The length of time until lesions appeared
was very short, with a mean delay of 10 days after initiating
therapy, but it occurred as early as 2 days after cetuximab was
started. With gefitinib, skin lesions occurred 5-12 days after
beginning treatment. Authors have found that the intensity of the
folliculitis was related to the tumor response and survival. This
positive association was recorded in clinical trials with
erlotinib, cetuximab, and gefitinib but is still controversial.
Various treatments have been found to be efficient, mainly topical
antibiotics, oral doxycyclin and even topical steroids.
Paronychia may occur after administration of any of the EGFR
inhibitor. It is characterized by an erythematous painful lateral
nail-fold, which may evolve to become a pyogenic granuloma-like
lesion. Paronychia can affect any finger or toe, single or
multiple. It occasionally recurs around the same nail or another
one. It can sometimes resolve spontaneously and always disappears
within a few days of discontinuing EGFR inhibitor treatment.
Patients should be instructed to avoid trauma, and if lesions
appear, use of antiseptics is recommended.
Apart from the special side effects observed with TKIs and EGFR
inhibitors, the cutaneous adverse reactions to chemotherapy
management remain difficult to treat. Indeed, patients are nearly
always given a combination of drugs and therefore imputability to a
single molecule is complicated. In addition, manuscripts reporting
large series of chemotherapy patients often identify skin toxicity
with few or no details since these are written by oncology teams.
Much data remains controversial, such as the dose dependence of
disseminated exanthema and/or the steroid responsiveness of hand
and foot syndrome.
The major question that is asked is whether it is possible to
continue treatment despite the cutaneous reaction. Decision making
is always difficult and requires a discussion with the oncologists
in order to weigh the severity of the reaction relative to the
benefit from the regimen used in tumor management. Dermatologists
should invest themselves fully in this essential clinical task and
not leave it to other specialists.
Table 1. Major Cutaneous Reactions to Recently Launched
||Rash "erysipeloid" reaction (RARE)
Hand and foot syndrome
Hand and foot syndrome
||Disseminated rash, sometimes lichenoid
- Zimmerman GC, Keeling JH, Burris HA, et al. Acute cutaneous
reactions to docetaxel, a new chemotherapeutic agent. Arch
- Karam A, Metges JP, Labat JP, et al. Squamous syringometaplasia
associated with docetaxel. Br J Dermatol.
- Poikonen P, Sjostrom J, Klaar S, et al. Skin toxicity as a risk
factor for major infections in breast cancer patients treated with
docetaxel. Acta Oncol. 2004;43(2):190-5.
- Wasner G, Hilpert F, Schattschneider J, et al.
Docetaxel-induced nail changes--a neurogenic mechanism: a case
report. J Neurooncol. 2002 Jun;58(2):167-74.
- Shepherd FA, Cormier Y, Burkes R, et al. Phase II trial of
gemcitabine and weekly cisplatin for advanced non-small cell lung
cancer. Semin Oncol. 1997;24(3 Suppl 8):S8-27-S8-30.
- Katakami N, Sugiura T, Nogami T, et al. Combination
chemotherapy of gemcitabine and vinorelbine for patients in stage
IIIB-IV non-small cell lung cancer: a phase II study of the West
Japan Thoracic Oncology Group (WJTOG) 9908. Lung Cancer.
- Brandes A, Reichmann U, Plasswilm L, et al. Time- and
dose-limiting erysipeloid rash confined to areas of lymphedema
following treatment with gemcitabine--a report of three cases.
Anticancer Drugs. 2000;11(1):15-7.
- Kuku I, Kaya E, Sevinc A, et al. Gemcitabine-induced
erysipeloid skin lesions in a patient with malignant mesothelioma.
J Eur Acad Dermatol Venereol. 2002;16(3):271-2.
- Bessis D, Guillot B, Legouffe E, et al. Gemcitabine-associated
scleroderma-like changes of the lower extremities. J Am Acad
Dermatol. 2004;51(2 Suppl):S73-6.
- Jeter MD, Janne PA, Brooks S, et al. Gemcitabine-induced
radiation recall. Int J Radiat Oncol Biol Phys.
- Heo YS, Chang HM, Kim TW, et al. Hand-foot syndrome in patients
treated with capecitabine-containing combination chemotherapy.
J Clin Pharmacol. 2004;44(10):1166-72.
- Scheithauer W, Blum J. Coming to grips with hand-foot syndrome.
Insights from clinical trials evaluating capecitabine. Oncology
(Williston Park). 2004;18(9):1161-8, 1173; discussion 1173-6,
- Cervantes F, Hernandez-Boluda JC, Odriozola J, et al. Imatinib
mesylate (STI571) treatment in patients with chronic-phase chronic
myelogenous leukaemia previously submitted to autologous stem cell
transplantation. Br J Haematol. 2003;120(3):500-4.
- van Oosterom AT, Judson IR, Verweij J, et al. Update of phase I
study of imatinib (STI571) in advanced soft tissue sarcomas and
gastrointestinal stromal tumors: a report of the EORTC Soft Tissue
and Bone Sarcoma Group. Eur J Cancer. 2002 Sep;38 Suppl
- Valeyrie L, Bastuji-Garin S, Revuz J, et al. Adverse cutaneous
reactions to imatinib (STI571) in Philadelphia chromosome-positive
leukemias: a prospective study of 54 patients. J Am Acad
Dermatol. 2003 Feb;48(2):201-6.
- Roux C, Boisseau-Garsaud AM, Saint-Cyr I, et al. [Lichenoid
cutaneous reaction to imatinib]. Ann Dermatol Venereol.
2004 Jun-Jul;131(6-7 Pt 1):571-3.
- Tsao AS, Kantarjian H, Cortes J, et al. Imatinib mesylate
causes hypopigmentation in the skin. Cancer. 2003 Dec
- Robert C, Soria JC, Spatz A, et al. Cutaneous side-effects of
kinase inhibitors and blocking antibodies. Lancet Oncol.
- Molinari E, De Quatrebarbes J, Andre T, et al.
Cetuximab-induced acne. Dermatology.