Pazopanib

SPAEN 2012 Florence
Skin toxicities
Mark David Anliker
Fachbereich Dermatologie/Allergologie
Kantonsspital St.Gallen
1
SPAEN 2012 Florence
How do chemotherapeutics work?
Different groups
Alkylating substances (Alk): Adriblastine®, Temozolomide, Alkeran®
(hämatotox) Ifosfamide, Dacarbazine
Pyramidine analogs (Pyr): Gemzar®, Cytosar®
Anti tumor-antibiotics: Anthracyclins: doxorubicin, epirubicin
Platinum containing: Cisplatin
Topoisomerase 2-inhibitors (Top): Etoposid
Taxanes (Tax): Taxol®, Taxotere®
Antimetabolites (AM): MTX, 5-FU, Gemcitabine
Immunmodulators (IM): Thalidomid
Tyrosin Kinase Inhibitors (TKI): Sunitinib, pazopanib
Epidermal Growth Factor Receptor antagonists (EGFR):Erbitux ®
SPAEN 2012 Florence
Adjuvant Therapies in soft tissue sarcoma

Single-agent chemotherapy recommendations for metastatic disease

Doxorubicin

Liposomal pegylated doxorubicin:

Ifosfamide

Ifosfamide plus mesna

Gemcitabine

ET-743 (trabectedin)is available in the US

Epirubicin

Dacarbazine

Temozolomide

Pazopanib 800 mg PO qd (indicated for those who have received prior chemotherapy)

Combination chemotherapy recommendations for metastatic disease*

Combination chemotherapy regimens consist of any one of the regimens described below, including doxorubicin,
ifosfamide, and mesna; doxorubicin and dacarbazine; mesna, doxorubicin, ifosfamide, and dacarbazine; or gemcitabine
and docetaxel.
SPAEN 2012 Florence
Cytostatic agents:
Side effects
Toxic side effect
Substance related side effect
Side effects through immunosuppression
Allergic reactions
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Toxic reactions
3 Groups:
Reaction due to paravasate
Vesicants: Intravasal irritation,
necrosis, ulcerationen, scars i.e.
Doxorubicin, Paclitaxel
Irritants: lokale irritation pain,
Phlebitis, no necrosis i.e.
Carboplatin Dacarbacin, short
lived
Non-vesicants: not or weak
irritation i.e. liposomal Doxorubicin, Docetaxel
Therapy: Aspiration of rest of
medication, intralesional NaCl
or Glucose5%, Hyaluranidase,
cooling thrombosis prophylaxis,
lokal steroids, DMSO 99%,
debridement
Medical emergencies following dermatological
injections and infusions]
Dill-Müller D.
Hautarzt. 2006;57:195-201.
SPAEN 2012 Florence
Toxic reactions
Alopecia due to alkylating CT
Direct toxic effects on the
germinative hair follicules and
epidermal basal cells
Protective cooling with constant
temperature of -4Grad C, during
the infusion
Scalp cooling to prevent chemotherapy-induced
hair loss: practical and clinical considerations.
Mols F, van den Hurk CJ, Vingerhoets AJ,
Breed WP. Support Care Cancer. 2009
SPAEN 2012 Florence
Toxic effects
Alopecia
L-cystein 0,125mg/ml und Vit
B6 0,015mg/ml 3 days
before doxorubicine reduces
der apoptose(death)-rateof
the keratincytes
Prevenir lAlopecie chimio-induite
Humbert.P. Ann Dermatol veneréol.
Suppl 2009 2.Mai
diffuse Alopecia:
Total Alopecia:
Cyclophosphamid
Bleomycine
Vinblastine
Razoxane
Cytarabin
5-FU
Paclitaxel (Taxol)
Doxorubicin
Esorubicin, Idarubicin
Vincristine
Cisplatin (hemialopecia,
unilateral!)
Levamisole (scarring)
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Substance spezific side-effects
Palmoplantar scharply demarcated painful and obscure erythematous
plaques, ca. 2 W after CT in repeted and higher doses. CT can be
detected in the epidermis!
Erythrodysaesthesie syndrome
Detection of doxorubicin in the horny layer in a patient
suffering from palmar-plantar erythrodysaesthesia.
Schmook T, Jacobi U, Lademann J, Worm M, Stockfleth E.
Dermatology. 2005
SPAEN 2012 Florence
Substance specific side-effects
Fixed od palmoplantar
Erythrodysaesthesiesyndrome
Known for following
therapeutics:
Disturbed maturation of epidermis
.
Fixed erythrodysaesthesia plaque due to intravenous
injection of docetaxel.
Chu CY, Yang CH, Yang CY, Hsiao GH, Chiu HC.
Br J Dermatol. 2000;142:808-11.
Docetaxel (Taxotere)(Tax)
Tapotecam
Capecitabine
Doxorubicine(Alk)
Tegafur
SPAEN 2012 Florence
Bleomycine
Erythema flagellatum
Hyperpigmentierungen
Sclerodermia
Bleomycin-induced "flagellate dermatitis".
Arseculeratne G et al. Arch Dermatol. 2007;143:1461
SPAEN 2012 Florence
Paclitaxel
(Taxol®)
70j female patient, metastasizing ThymusCA
Therapy with carboplatin und taxole for 2
weeks. Exanthema 1 day after sun
exposure
Photo recall phenomenon: an
adverse reaction to taxanes.
Ee HL, Yosipovitch G.
Dermatology. 2003;207(2):196-8.
.
SPAEN 2012 Florence
Paclitaxel
(Taxol®) PTReaction
Photosensitivy-reaction
UV protection,
protect the finger nails !!
Photosensitivity in following
cytostatic agents:
Cyclophosphamid
Chlorambucil
Procarbazine
Azathioprin PA
MTX
5-FU
PT
Vinblastin
Mitomycine
Amsacrine
Mercaptopurine
PA: photoallergisch PT: phototoxisch
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Side effects of the skin due to
immunosuppression
Atypical infections
Side effects due to aplasia
Immunosuppression and skin tumors (i.e. melanoma risk
elevated by factor 4-8x)
Positive effects on inflammatory dermatoses (Psoriasis,
eczema, pemphigus etc.) und paraneoplastic syndromes
Psoriasis disappearance after the first phase of an oncologic treatment:
Cagiano R, Bera I et al. Clin Ter. 2008;159:421-5. Review.
Life-long dermatological follow-up
TKI und Haut
Malignant Melanoma
Dermatoskopy
Malignant melanoma is a killer
Early peak at age 40-45
40 deaths per million people/year
Anliker
SPAEN 2012 Florence
Control your skin according to
the A-B-C-D rule
• A = Asymmetry:
irregular, not round form
• B = Border:
irregular cloudy
• C = Color :
different colors, spots
• D = Dynamics:
changes(size, color, thickness)
Anliker
Find skin cancer early
•
•
•
•
Look for the ugly dukcling
Old elevated nevi rarely turn malign
New spots are to be monitored
In case of insecurity :Fotograph and compare
to it in 3 months
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Diagnosis
Scaly rough spots on
back of hands since
months
Kryotherapy
actinic precanceroses
19
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Diagnosis
60-y bump on nose since 4
4 mths
Sclerodermiform
Basalioma
Basalioma multiloculare
20
nodular Basalioma
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Benign tumors
Little angiomas
Seborrhoic warts
Naevus bleu
Lentigines
21
SPAEN 2012 Florence
Side effects of the skin due to
immunosuppression
24
Atypical infections
Verrucous tumor dorsum of the
right hand after working in the
garden
75j f, Endoxane for muliple
myeloma
Granulating inflammation
Differential diagnosis:
Deep mycosis
Leishmaniosis
Verrucous tumor Ackerman
Atypical bacterial infection
Histopathologie
Kultur:
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asteroides!
Gartenarbeit und
Hautverletzung
HE
grocott
PAS
gram
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2012 Florence
Reaction
in aplasia!
Allergic drug reaction!!
obscure maculopapular exanthema, starting in the
skin folds, 60% of body surface!
SPAEN 2012 Florence
Reaction in aplasia!
Allergic reactions can Allergic drug reaction
be masqueraded by
immunosuppression
TEN/Lyell-Sy in cytostatic
agents:
Cyclophosphamide
Chlorambucil
Procarbazine
MTX
Mercaptopurine
Actinomycine
Streptozocin
Azathioprine
SPAEN 2012 Florence
32
conclusions
Implications of cytostatic agents for the skin:
Toxic side effect
Substance related side effect
Side effects through immunosuppression
Allergic reactions
UV-Prophylaxis und Infect prophylaxis (keep skin intact,
protect hands, use gloves in dirt, with animals, protect nails,
cool skin, hands and feet in chemotherapy)
Skin tumors are a lot more common: life-long dermatological
follow up
Allergies due to cytostatic agents are possible even in aplasia
SPAEN 2012 Florence
How do TKI/VEGF inhibitors act?
From inhibition of the cell
cycle to inhibitng the
signal tranduction: ATPpocket is blocked,
Phosphorylation is
hindered
Anliker 2012
SPAEN 2012 Florence
Pazopanib
Pazopanib (trade name Votrient) is a potent
and selective multi-targeted receptor tyrosine
kinase inhibitor of VEGFR-1, VEGFR-2,
VEGFR-3, PDGFR-a/β, and c-kit that blocks
tumor growth and inhibits angiogenesis. It
has been approved for renal cell carcinoma
and soft tissue sarcoma by the U.S. Food and
Drug Administration
Pazupanib (Votrient®)
Target is VEGF
Anliker/Fritsche KSSG 2012
TKI und Haut
Observed side effects under treatment with
pazopanib
50% of patients suffer skin reactions
-prolonged wound healing
-Infections of the skin
-Pigmentation disorders of skin and hair 39%
-Aphtous lesions of the mouth, stomatitis 4%
-Hand-foot reaction 6%
-alopecia 9%
-rash 9%
-hyperhidrosis 2%
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Anliker 2012
2010
TKI und Haut
How does the skin become involved?
Tyrosinkinase are distributed
heavily in
• melanocytic nevi
• cornifying skin
• warts, keratoses
• hair roots (pigmentation)
• nails
And therefore are targeted by
TKIs
Anliker 2012
SPAEN 2012 Florence
Pazopanib (Votrient®)
 Hand-foot-reactions + Acral Erythema (MA)
Psoriasiform plaques
painful callositas
Sharp borders
Splinter hemorrhage
Anliker 2012
TKI und Haut
The most common problem in TKI treatment
Callositas,
Hyperkeratosis and
fissures
Sorafenib 43%,
after 1-8 weeks
Sunitinib 52% after
1 to 12 weeks
Pazopanib 6%
Anliker 2012
TKI und Haut
on areas under pressure
paradoxical reaction of skin
• hands and feet
• hyperproliferative
hyperkeratosis, possible
counter mechanism due to
inflammatory attack
Anliker 2012
SPAEN 2012 Florence
Two destinctive reactions
Hand-foot reaction= Keratosis and
callositas
Hand and foot syndrome= acral
dysaesthesia syndrome under
conventinal chemotherapy= toxic
reaction-- different treatment
Anliker 2012
TKI und Haut
Prophylaxis
•
Reduce mechanical stress/ activities
•
No tight foot wear, avoid areas of pressure,
avoid friction (gloves, thick socks,
decompression)
•
Cut nails short
•
Regular use of emollients, urea, steroids early
•
UV-protectioon
Anliker 2012
SPAEN 2012 Florence
Pazopanib: Depigmentation +Alteration of Hair
Skin discolorations

White skin 1w- yellowish skin (without Hepatitis),
urine, vitiligo described

Dark skin  depigmentation (macular or
generalized)

Depigmentation (white during treatment, original
color during therapy-free intervals, resulting in zebralike pattern!)
Hair
Therapy: dye hair?
Anliker 2012
TKI und Haut
Observed side effects under treatment with
pazopanib
Very rarely do allergic reactions occur
Patient mal 47y, pazopanib for renal cell
Carcinoma
7days after begin
Itching purpuric lesions
on the extremities
Biopsy revealed allergic vasculitis
Anliker
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2010
TKI und Haut
Observed side effects under treatment with
pazopanib
Stomatitis 4%
Induction by dentistry, trauma
Treatment with topical steroids (Kenacort orobase) 2x per
day or clobetasol dipropionate soution 0,05%
Prophylaxis agains infection: regular mouth rinsing with
chlorhexidine
Anliker
Anliker 2012
2010
TKI und Haut
Observed side effects under treatment with
pazopanib
How to avoid additional problems of the skin I
UV protection 50+ apply twice daily
T-shirts have a protection factor of only 6-10- dark synthetic
fabrics are better- look for labeling SPF
Apply UV protection on the whole skin!
Avoid midday sun 11-16h
Sunglasses
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2010
SPAEN 2012 Florence
Chronic UV-exposure leads to skin aging
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UV intensity during the day
Quelle: Prof. Ch. Surber, Uni Basel / Spirig
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Intensity: Reflection makes a difference
25%
50%
90%
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Behavior: In Italy noone makes a siesta anymore
earlier
today
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Behavior hasnt changed. With sunscreen
an knowledge. People stay till the skin
burns
Bauer J, et al. Interventional study in 1,232 young German children to
prevent the development of melanocytic nevi failed to change sun exposure
and sun protective behavior. Int J Cancer. 2005 Sep
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SPAEN 2012 Florence
Clothing can protect
•
•
•
•
Densly fabricated material
Wide and dark clothes protect better
Articifial fibers protect better
Wet clothes dont protect very well
Tip:Hold clothing against
the light: If it shines
through- no good
protection.
CE-Signs«100 % UV» oder «100 UV 400
nm» offer 100 % protection
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TKI und Haut
Observed side effects under treatment with
pazopanib
How to avoid additional problems of the skin II
Moisturizer for dry skin: containing lactic acid, urea or
glycerine- hydrated the skin better
Protect hair from UV, no procedures with heat, chemicals
No excessive activation of circulation with hot baths, sauna,
infra red etc.
Anliker
Anliker 2012
2010
TKI und Haut
Observed side
effects under treatment with
pazopanib
How to avoid additional problems of the skin III
Protect skin from trauma, wair gloves in household, garden
and mechanical work
Regular moisturizer will make skin less vulnerable
In case of cuts, wounds use of antiseptic ointments,
bepanthenol on regular base
Anliker
Anliker 2012
2010
TKI und Haut
Observed side effects under treatment with
pazopanib
What do patients report?

Cancer Survivors Network
I have been on votrient since July 2011 with very few
side effects. I started out on 4 tablets (800mg) a day for
a couple of months and then had to drop down to 2
tablets due to liver enzymes being elevated and some
mouth issues. I also have a decreased appetite and
some nausea but still mange to eat and only lost about
10 pounds in the last six Months. I was diagnosed in
April 2011 with stage iv with mets to lung. I just
completed abdominal,pelvic,chest, and brain scans that
were all read as normal and no evidence of metastatic
disease. He plans for me to stay on votrient for another
6 months and will repeat scans again afew months after
stopping. For me the votrient was an answered prayer. It
was also kind of ironic I because insurance wouldn't pay
for onconolgist's first choice of Affinitor.
Anliker
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2010
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Barbara Gaus MD
Dermatology/Allergolo
gy
KS St. Gallen
Thank you for your
attention
Tobias Gertsch MD
Dermatology/Allergolo
gy
KS St. Gallen
Selina Thurneyesen MD
Dermatology/Allergolog
y KS St. Gallen
Andre Surovy MD
Dermatology/Allergolog
y KS St. Gallen
Birgit Ichters MD
Dermatology/Allergolog
y KS St. Gallen
Philipp Fritsche MD
Dermatology/Allergolo
gKS St. Gallen
Damian Bühler MD
DermatologyAllergolog
y KS St. Gallen
Anliker/Fritsche KSSG 2012