Transcript Clinical signs, pathophysiology and management of skin toxicity

Clinical signs, pathophysiology and management
of skin toxicity during therapy
with epidermal growth factor receptor inhibitors
S. Segaert1 & E. Van Cutsem
Department of Dermatology, University Hospital, Katholieke Universiteit Leuven;
Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium
종양혈액내과
노태준
Introduction
Epidermal growth factor receptor (EGFR)
Neoplastic cell proliferation
Migration
Stromal invasion
Resistance to apoptosis
Angiogenesis.
Inhibition of EGFR
Impair tumour growth
Have made EGFR an attractive target for the development of
cancer therapeutics.
epidermal growth factor receptor
Iressa
EGFR inhibitors
Monoclonal Ab. against the EGFR
Cetuximab (ErbituxTM)
Panitumumab (ABX-EGF)
Matuzumab (EMD72000)
EGFR tyrosine kinase inhibitors
Gefitinib (IressaTM)
Erlotinib (TarcevaTM)
EKB-569 antibody
Skin toxicity
EGFR inhibitors
Generally well tolerated. (do not have the severe systemic sideeffects usually seen with cytotoxic drugs)
Most often an acneiform eruption.
A correlation has been suggested between the acneiform
eruption and EGFR inhibitor antitumour activity
Prospective studies including skin and tumour biopsies are,
however, needed to clarify and explain this possible relationship.
Acneiform eruption
The most frequently reported side-effect
Both monoclonal antibodies and tyrosine kinase inhibitors
The rash seems to be dose dependent
in more than 50% up to 100% of patients
The eruption : seborrheic areas (rich in sebaceous glands)
the face, the neck and retroauricular area, the shoulders, the upper
trunk (V-shaped), the scalp.
Acneiform eruption
(A) papular lesions on the chest
(B) V-shaped papulopustular eruption on the back
(C) close up of follicular pustules (D) confluent pustules on the nose
Incidence
Simplified classification
National Cancer Institute Common Toxicity Criteria version 2.0 (NCI CTC v2.0)
National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI
CTCAE v3.0)
Acneiform eruption
The acneiform eruption arises a few days after treatment with the
EGFR inhibitor.
to reach a maximum after 2 to 3 weeks following commencement of
the therapy.
Some spontaneous improvement can be seen even when treatment
is continued.
The eruption disappears in a few weeks time when treatment is
discontinued leaving sometimes residual hyperpigmentation and
xerosis.
Xerosis
Patients receiving EGFR inhibitors can
gradually develop a dry skin over weeks
resembling the xerosis in atopic eczema.
Patient’s old age, previous therapy with
cytotoxics and history of atopic eczema
will accentuate the cutaneous dryness
Dry, scaly, itchy skin especially of the
limbs and of skin areas that were affected
by acneiform eruption.
When secondary infection of the xerotic
skin with Staphylococcus aureus occurs,
a flare-up of acute oozing dermatitis and
sometimes yellow crusting may be seen.
Xerosis, dry eczema and fissure over the
interphalangeal joint of the finger
Nail changes
Nail changes are seen in 10%–
15% of patients and are a late
event (starting usually not earlier
than 4–8 weeks) during the
treatment course.
Paronychia manifesting with
inflammation of the nail fold
(mainly of the great toe; other toes
and fingers may be involved as
well) is usually the first sign.
This paronychia can be very
painful and mimics an ingrown
toenail in the severe cases where
pyogenic granuloma of the nail
fold develops.
Paronychia and pyogenic
granuloma of the nail fold of the
big toe
Hair changes
During prolonged treatment
with EGFR inhibitors,
changes of the hairs can be
noticed.
Very characteristic are the
long, curly, rigid eyelashes,
also named trichomegaly.
The scalp hairs grow more
slowly and adopt a finer,
more brittle and curly aspect.
Trichomegaly (long curly eyelashes).
Telangiectasia
Early during the development of
acneiform eruption or with
subsequent flares of the rash,
scattered telangiectasia may
appear
On the face, on and behind the ears,
on the chest, back and limbs,
usually in the vicinity of a follicular
pustule.
Unlike other telangiectasia, the
lesions tend to fade over months
usually leaving some
hyperpigmentation.
Telangiectasia.
Hyperpigmentation
Post-inflammatory
hyperpigmentation is
typically seen following
acneiform eruption or other
causes of skin inflammation
such as eczema or an
inflamed sebaceous cyst.
Sun exposure aggravates
the hyperpigmentation.
Hyperpigmentation following acneiform eruption
with also some new erythematous lesions.
Pathophysiology
Side effect that is directly linked to specific inhibition of the EGFR.
First, similar cutaneous effects develop regardless of the
mechanism of action of the EGFR inhibitor as a monoclonal
antibody or as an EGFR-specific tyrosine kinase inhibitor.
Secondly, the cutaneous effects appear to be dosedependent as shown for gefitinib and panitumumab.
Thirdly, there is growing evidence for a possible correlation
between tumour response and the presence or extent of
skin rash
Pathophysiology
In the spectrum of drug-induced skin changes
The combination of the itchy acneiform eruption, xerosis,
paronychia, hair changes and telangiectasia is entirely
unique.
Corticosteroids, vitamin B and antiepileptics
- this rash usually does not itch and is not accompanied by
the other skin findings elicited by EGFR inhibitors.
Oral retinoids
- xerosis and paronychia but not acneiform changes.
Pathophysiology
EGFR is known to be expressed,
basal epidermal cells
sebaceous glands, hair follicle outer root sheath, hair shaft
capillary system.
EGFR activation
promotion of keratinocyte proliferation
regulation of differentiation and keratinisation
EGFR central role in
Carcinogenesis
Psoriasis
Wound healing
Management (general)
Maximal hydration of the skin
the use of bath oil or shower oil (instead of shower gel or
soap), tepid water
To prevent xerosis
an emollient cream (especially on the limbs)
Sun exposure should be avoided
minimise the risk of hyperpigmentation.
Acneiform eruption Management
For mild grade 1 reactions
no treatment
topical anti-acne (metronidazole gel, erythromycin or clindamycin
gel)
For grade 2 reactions
topical treatment
an oral antihistamine(cetirizine, loratadine, hydroxyzine)
an oral tetracycline (doxycycline 100 mg/day)
Acneiform eruption Management
For grade 3 reactions
Topicals treatment
Oral anti-histamines
oral tetracyclines at high doses (doxycycline 2100 mg/day)
For grade 4 reactions
although extremely seldom
should be treated in specialised burn care units
EGFR inhibitors should be immediately stopped for good.
Eczema Management
General hydrating measures
In this respect alcoholic lotions should be discontinued
Switched to oil in water creams instead
topical weak corticosteroids are recommended for a
short term (1–2 weeks)
Paronychia Management
Wearing shoes that are not too tight.
The nail folds very sensitive to infection.
Topical antiseptics or antibiotics should be used on a
regular basis.
In case of secondary bacterial infection, oral antibiotics
can be administered according to the antibiogram.
Telangiectasia Management
Telangiectasia will gradually disappear over months.
In selected cases electrocoagulation or pulsed dye laser
therapy can be applied to accelerate disappearance.
Hyperpigmentation Management
Prevention and treatment of acneiform eruption and
eczema is important.
Sun blocking creams.
Bleaching creams are not very helpful
The hyperpigmentation will fade spontaneously with time
(months)
Conclusion
Treatment efficacy and rash : marker for tumor response.
The acneiform eruption responds well to topical antiacne therapy and tetracycline antibiotics.
Future clinical research is required to meet the need for
a more accurate classification and for more evidencebased treatment of skin toxicity.