Zusammenfassung
Molekular zielgerichtete Therapeutika und hier insbesondere die
Inhibitoren des epidermalen Wachstumsfaktorrezeptors (EGFRi) und
Multityrosinkinase-Inhibitoren (MTKi) gewinnen einen immer größeren
Stellenwert in der onkologischen Therapie. Die Nebenwirkungen unterscheiden
sich deutlich von denen der konventionellen Chemotherapie. Vor allem
kutane Nebenwirkungen stellen dosis- oder therapielimitierende Ereignisse
dar. Eine genaue Kenntnis der Nebenwirkungen sowie ein enger Austausch
des Dermatologen mit dem behandelnden Onkologen und dem Hausarzt,
eine detaillierte Patientenaufklärung und ein fundiertes
Nebenwirkungsmanagement sind Grundbausteine für eine erfolgreiche
Therapie mit EGFRi und MTKi. Gemeinsame dermatologische und onkologische Schwerpunktsprechstunden
helfen bei der Behandlung von schweren Fällen kutaner Toxizitäten,
der Entwicklung von neuen Therapiestrategien und sind insbesondere
zur Begleitbehandlung von Patienten in klinischen Studien essentiell.
Abstract
Molecular targeted therapies – particularly epidermal
growth factor receptor inhibitors (EGFRi) and multi tyrosine kinase-inhibitors
(MTKi) – continually gain importance in oncology treatment.
Adverse events differ greatly from those of conventional chemotherapy;
especially cutaneous adverse events often constitute dose-limiting
or therapy-limiting events. Knowledge of possible adverse events
and close interaction between the dermatologist, the oncologist
and the patient’s family physician, a detailed patient
education and a well-founded adverse event management are mandatory
for the treatment with EGFRi and MTKi. Interdisciplinary outpatient
clinics specialised on the treatment of these adverse events assist
with the treatment of severe cases, the development of new therapeutic strategies
and are essential for the concomitant treatment of patients treated
with new targeted drugs within clinical trials.
Schlüsselwörter
EGFRi - MTKi - Tyrosinkinaseinhibitoren - kutane Nebenwirkungen - targeted therapy
- Nebenwirkungsmanagement
Keywords
EGFRi - MTKi - tyrosinkinase inhibitors - cutaneous adverse events - targeted therapy
- adverse event management
Literatur
1
Arnault J P, Wechsler J, Escudier B, Spatz A, Tomasic G, Sibaud V, Aractingi S, Grange J D,
Poirier-Colame V, Malka D, Soria J C, Mateus C, Robert C.
Keratoacanthomas and squamous cell carcinomas
in patients receiving sorafenib.
J Clin Oncol.
2009;
27
e59-61
2
Boone S L, Rademaker A, Liu D, Pfeiffer C, Mauro D J, Lacouture M E.
Impact and
management of skin toxicity associated with anti-epidermal growth
factor receptor therapy: survey results.
Oncology.
2007;
72
152-159
3
Chou L S, Garey J, Oishi K, Kim E.
Managing dermatologic toxicities
of epidermal growth factor receptor inhibitors.
Clin Lung
Cancer.
2006;
8, Suppl 1
S15-22
4
Cortesi E, DePasquale C, D’Auria G. et al .
Management of cutaneous adverse effects
during treatment with ZD1838 in advanced non-small cell lung cancer
(NSCLC): surprising efficacy of early local treatment.
Proc
Am Assoc Cancer Res.
2004;
22
abstr 7100
5
Dancey J, Sausville E A.
Issues and progress
with protein kinase inhibitors for cancer treatment.
Nat
Rev Drug Discov.
2007;
2
296-313
6
Dasanu C A, Alexandrescu D T, Dutcher J.
Yellow skin discoloration associated with
sorafenib use for treatment of metastatic renal cell carcinoma.
South Med J.
2007;
100
328-330
7
Degen A, Alter M, Schenck F, Satzger I, Volker B, Kapp A, Gutzmer R.
The hand-foot-syndrome associated with medical tumor therapy – classification
and management.
J Dtsch Dermatol Ges.
2010;
8
652-661
8
Dubauskas Z, Kunishige J, Prieto V G, Jonasch E, Hwu P, Tannir N M.
Cutaneous squamous
cell carcinoma and inflammation of actinic keratoses associated
with sorafenib.
Clin Genitourin Cancer.
2009;
7
20-23
9
Eilers Jr R E, Gandhi M, Patel J D, Mulcahy M F, Agulnik M, Hensing T, Lacouture M E.
Dermatologic infections in cancer
patients treated with epidermal growth factor receptor inhibitor
therapy.
J Natl Cancer Inst.
2010;
102
47-53
10
Eiling E, Brandt M, Schwarz T, Hauschild A.
Pimecrolimus: a novel treatment
for cetuximab-induced papulopustular eruption.
Arch Dermatol.
2008;
144
1236-1238
11
Fox L P.
Nail toxicity associated with epidermal growth factor receptor
inhibitor therapy.
J Am Acad Dermatol.
2007;
56
460-465
12
Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard J Y, Nishiwaki Y, Vansteenkiste J,
Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A,
Feyereislova A, Dong R P, Baselga J.
Multi-institutional randomized phase II
trial of gefitinib for previously treated patients with advanced
non-small-cell lung cancer (The IDEAL 1 Trial) [corrected].
J Clin Oncol.
2003;
21
2237-2246
13
Golub L M, Lee H M, Ryan M E, Giannobile W V, Payne J, Sorsa T.
Tetracyclines
inhibit connective tissue breakdown by multiple non-antimicrobial
mechanisms.
Adv Dent Res.
1998;
12
12-26
14
Grandinetti C A, Goldspiel B R.
Sorafenib
and sunitinib: novel targeted therapies for renal cell cancer.
Pharmacotherapy.
2007;
27
1125-1144
15
Hong D S, Reddy S B, Prieto V G, Wright J J, Tannir N M, Cohen P R, Diwan A H, Evans H L,
Kurzrock R.
Multiple
squamous cell carcinomas of the skin after therapy with sorafenib
combined with tipifarnib.
Arch Dermatol.
2008;
144
779-782
16
Hu J C, Sadeghi P, Pinter-Brown L C, Yashar S, Chiu M W.
Cutaneous side effects of epidermal growth
factor receptor inhibitors: clinical presentation, pathogenesis,
and management.
J Am Acad Dermatol.
2007;
56
317-326
17
Jantzem H, Dupre-Goetghebeur D, Spindler P, Merrer J.
[Sorafenib-induced
multiple eruptive keratoacanthomas].
Ann Dermatol
Venereol.
2009;
136
894-897
18
Jatoi A, Rowland K, Sloan J A, Gross H M, Fishkin P A, Kahanic S P, Novotny P J, Schaefer P L,
Johnson D B, Tschetter L K, Loprinzi C L.
Tetracycline to
prevent epidermal growth factor receptor inhibitor-induced skin rashes:
results of a placebo-controlled trial from the North Central Cancer
Treatment Group (N03CB).
Cancer.
2008;
113
847-853
19
Kong H H, Cowen E W, Azad N S, Dahut W, Gutierrez M, Turner M L.
Keratoacanthomas
associated with sorafenib therapy.
J Am Acad Dermatol.
2007;
56
171-172
20
Krakauer T, Buckley M.
Doxycycline is anti-inflammatory
and inhibits staphylococcal exotoxin-induced cytokines and chemokines.
Antimicrob Agents Chemother.
2003;
47
3630-3633
21
Kwon E J, Kish L S, Jaworsky C.
The histologic spectrum of epithelial neoplasms induced by sorafenib.
J Am Acad Dermatol.
2009;
61
522-527
22
Lacouture M E.
Mechanisms of cutaneous toxicities to EGFR inhibitors.
Nat
Rev Cancer.
2006;
6
803-812
23
Lacouture M E, Basti S, Patel J, Benson A.
The SERIES clinic: an interdisciplinary
approach to the management of toxicities of EGFR inhibitors.
J
Support Oncol.
2006;
4
236-238
24
Lacouture M E, Boerner S A, Lorusso P M.
Non-rash skin toxicities associated with
novel targeted therapies.
Clin Lung Cancer.
2006;
8 Suppl 1
S36-42
25
Lacouture M E, Desai A, Soltani K, Petronic-Rosic V, Laumann A E, Ratain M J, Stadler W M.
Inflammation of actinic keratoses
subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase
inhibitor.
Clin Exp Dermatol.
2007;
31
783-785
26
Lacouture M E, Melosky B L.
Cutaneous
reactions to anticancer agents targeting the epidermal growth factor
receptor: a dermatology-oncology perspective.
Skin Therapy
Lett.
2007;
12
1-5
27
Lacouture M E, Wu S, Robert C, Atkins M B, Kong H H, Guitart J, Garbe C, Hauschild A,
Puzanov I, Alexandrescu D T, Anderson R T, Wood L, Dutcher J P.
Evolving strategies for the management
of hand-foot skin reaction associated with the multitargeted kinase
inhibitors sorafenib and sunitinib.
Oncologist.
2008;
13
1001-1011
28
Li T, Perez-Soler R.
Skin toxicities associated
with epidermal growth factor receptor inhibitors.
Target
Oncol.
2009;
4
107-119
29
LoRusso P.
Toward evidence-based management of the dermatologic effects
of EGFR inhibitors.
Oncology (Williston Park).
2009;
23
186-194
30
Marquez C B, Smithberger E E, Bair S M, Wenham R M, Fenske N A, Glass L F, Cherpelis B S.
Multiple
keratoacanthomas arising in the setting of sorafenib therapy: novel
chemoprophylaxis with bexarotene.
Cancer Control.
2009;
16
66-69
31
Melosky B, Burkes R, Rayson D, Alcindor T, Shear N, Lacouture M.
Management of skin
rash during EGFR-targeted monoclonal antibody treatment for gastrointestinal
malignancies: Canadian recommendations.
Curr Oncol.
2009;
16
16-26
32
Mitchell E P, Lacouture M, Shearer H. et al .
Updated results of STEPP, a phase 2, open-label
study of pre-emptive versus reactive skin toxicity treatment in
metastatic colorectal cancer (mCRC) patients receiving panitumumab+ FOLFIRI
or irinotecan-only chemotherapy as second-line treatment.
Ann
Oncol.
2008;
19
(suppl)
O-021
33
Perez-Soler R.
Can rash associated with HER1/EGFR inhibition be used
as a marker of treatment outcome?.
Oncology (Williston
Park).
2003;
17
23-28
34
Perez-Soler R, Chachoua A, Hammond L A, Rowinsky E K, Huberman M, Karp D, Rigas J,
Clark G M, Santabarbara P, Bonomi P.
Determinants of tumor
response and survival with erlotinib in patients with non – small-cell
lung cancer.
J Clin Oncol.
2003;
22
3238-3247
35
Perez-Soler R, Saltz L.
Cutaneous adverse effects
with HER1/EGFR-targeted agents: is there a silver lining?.
J Clin Oncol.
2005;
23
5235-5246
36
Perez-Soler R, Zou Y, Li T. et
al .
Topical vitamin K3 (Vit K3, Menadione) prevents
erlotinib and cetuximab-induced EGFR inhibition in the skin.
J
Clin Oncol.
2003;
24
3036a
37
Porta C, Paglino C, Imarisio I, Bonomi L.
Uncovering Pandora’s
vase: the growing problem of new toxicities from novel anticancer
agents.
The case of sorafenib and sunitinib Clin Exp Med.
2007;
7
127-134
38
Potthoff K, Hofheinz R, Hassel J C, Volkenandt M, Lordick F, Hartmann J T, Karthaus M,
Riess H, Lipp H P, Hauschild A, Trarbach T, Wollenberg A.
Interdisciplinary
management of EGFR-inhibitor-induced skin reactions: a German expert
opinion.
Ann Oncol.
2010;
[Epub
ahead of print]
39
Robert C, Soria J C, Spatz A, Le Cesne A, Malka D, Pautier P, Wechsler J, Lhomme C,
Escudier B, Boige V, Armand J P, Le Chevalier T.
Cutaneous side-effects
of kinase inhibitors and blocking antibodies.
Lancet Oncol.
2005;
6
491-500
40
Roe E, Garcia Muret M P, Marcuello E, Capdevila J, Pallares C, Alomar A.
Description
and management of cutaneous side effects during cetuximab or erlotinib
treatments: a prospective study of 30 patients.
J Am Acad
Dermatol.
2006;
55
429-437
41
Scope A, Agero A L, Dusza S W, Myskowski P L, Lieb J A, Saltz L, Kemeny N E, Halpern A C.
Randomized
double-blind trial of prophylactic oral minocycline and topical
tazarotene for cetuximab-associated acne-like eruption.
J
Clin Oncol.
2007;
25
5390-5396
42
Segaert S, Tabernero J, Chosidow O, Dirschka T, Elsner J, Mancini L, Maughan T, Morere J F,
Santoro A, Sobrero A, Van Cutsem E, Layton A.
The management of skin
reactions in cancer patients receiving epidermal growth factor receptor
targeted therapies.
J Dtsch Dermatol Ges.
2005;
3
599-606
43
Segaert S, Van Cutsem E.
Clinical signs, pathophysiology
and management of skin toxicity during therapy with epidermal growth
factor receptor inhibitors.
Ann Oncol.
2005;
16
1425-1433
44
Smith K J, Haley H, Hamza S, Skelton H G.
Eruptive keratoacanthoma-type
squamous cell carcinomas in patients taking sorafenib for the treatment
of solid tumors.
Dermatol Surg.
2009;
35
1766-1770
45
Tsao A S, Kantarjian H, Cortes J, O’Brien S, Talpaz M.
Imatinib mesylate causes hypopigmentation in the skin.
Cancer.
2003;
98
2483-2487
46
Valeyrie L, Bastuji-Garin S, Revuz J, Bachot N, Wechsler J, Berthaud P, Tulliez M,
Giraudier S.
Adverse cutaneous
reactions to imatinib (STI571) in Philadelphia chromosome-positive
leukemias: a prospective study of 54 patients.
J Am Acad
Dermatol.
2003;
48
201-206
47
Wollenberg A, Kroth J, Hauschild A, Dirschka T.
Hautreaktionen unter EGFR-Inhibitoren – Klinik
und Management.
Dtsch Med Wochenschr.
2010;
135
149-154
Prof. Dr. Dirk Schadendorf
Klinikdirektor Abteilung für Dermatologie Universitätsklinik
Essen
Hufelandstr. 55
45122 Essen
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