Skin Side Effects Christiane Thallinger, M D U N I V E R S I T Y OF V I E N N A, D E P A R T M E N T OF O N C O L O G Y, G E N E R A L H O S P I T A L V I E N N A
Targets Substances 1 Multi Kinase Inhibitors Sorafinib Sunitinib Pazopanib... mtor Inhibitors Everolimus.... Morais et al, Journal of Kidney Cancer and VHL 2014
Targets Substances 2 Multi Kinase Inhibitors Sorafinib Sunitinib Pazopanib... mtor Inhibitors Everolimus.... Morais et al, Journal of Kidney Cancer and VHL 2014
Substances and Side Effects 3 EGFR-I MK-I BRAF-I MEK-I c-kit mtor maculapapular eruption (+) ++ ++ (+) ++ (+) acneiform rash ++ (+) (Sorafenib) - ++ - + HFSR - ++ + - - - alopecia + (+) (Sorafenib) + + - - paronychia ++ - - + - + hair changes trichomegaly, hypertrichoses, pigment changes hypopigmentation (Sunitinib) - - pigment changes - xerosis/pruritus + + (+) ++ + (+) skin tumors - + Sorafenib ++ - - - Degen et al, HAUTARZT 2011
Substances and Side Effects 4 EGFR-I MK-I BRAF-I MEK-I c-kit mtor maculapapular eruption (+) ++ ++ (+) ++ (+) acneiform rash ++ (+) (Sorafenib) - ++ - + HFSR - ++ + - - - alopecia + (+) (Sorafenib) + + - - paronychia ++ - - + - + hair changes trichomegaly, hypertrichoses, pigment changes hypopigmentation (Sunitinib) - - pigment changes - xerosis/pruritus + + (+) ++ + (+) skin tumors - + Sorafenib ++ - - - Degen et al, HAUTARZT 2011
Targets Substances 5 MK Inhibition Sorafinib Sunitinib Pazopanib... TKIs approved for treatment of of several malignancies TKIs treatment can be limited by poor tolerability TKI induced side effects include rash, alopecia, depigmentation, pruritus, xerosis, rash, and mucositis Most troublesome - hand-foot skin reaction different from hand-foot syndrome of cytotoxic chemotherapeutic
MKI induced HFSR Hand-Foot Skin Reaction (HFSR) 6 Diffuse painful oedema and redness of palms and sols Hyperkeratotic plaques develop predominantly over sites of pressure (heels, metatarsal heads, areas of friction caused by manual work) Lesions are sharply demarcated, erythematous, oedematous, painful Very tender blisters evolve into inflamed skin Distinct from the HFS (palmar-plantar erythrodysesthesia) associated with 5FU and capecitabine indicates different therapy strategies!
MKI induced HFSR 7 Common Terminology Criteria for Adverse Events Version 4.0 Grade 1 Minimal skin changes OR dermatitis (erythema, oedema, or hyperkeratosis without pain) Grade 2 Skin changes (peeling, blisters, oedema, or hyperkeratosis) with pain, slightly limiting instrumental ADL Grad 3 Severe skin changes (peeling, blisters, bleeding, oedema, or hyperkeratosis) with pain limiting self-care ADL
MKI induced HFSR 8 Hand-Foot Skin Reaction (HFSR) Grade 2 Grade 1 Grade 3
HFSR Facts Incidence of 1% to 45% in patients treated with multikinase inhibitors Include epidermal keratinocyte apoptosis, dyskeratosis and vacuolar degeneration with intraepidermal blister Initial symptoms of HFSR typically appear within the first 2 6 weeks of treatment. 9 Several weeks after initial symptoms, thickened or hyperkeratotic skin may appear, which may be painful and impair range of motion, and function, and weight bearing Gomez et al, The Oncologist 2011 Segaert et al, Eur J Cancer 2009
HFSR Pathogenesis 10 The remaining mechanisms are poorly understood HSFR does not appear to be related to increased excretion of the agent through sweat VEGF is not synthesized by keratinocytes or eccrine glands Alterations in keratinocytes by inhibition of c-kit may be hypothesized to cause HFSR - however the incidence of HFSR associated with Imatinib treatment is low! Possible VEGF inhibition in the vascular endothelium may be involved in HFSR (blocking VEGF via MKI increases tumor vessel regression via inhibition of endothelial cell survival) Meadows et al, Support Care Cancer 2015 Lai et al, J Clin Oncol 2007 Lee et al, BJD 2009
HFSR Pathogenesis 11 Limited dermatopathologic studies reported inflammatory and vascular changes changes consistent with wound healing Keratinocytes synthesize PDGF-α and PDGF-β, which bind PDGFRs on dermal fibroblasts, capillaries, and eccrine glands (Dermal eccrine glands express c-kit and PDGFR) Co-inhibition of VEGFR and PDGFR decrease vessels to repair Many endothelial functions vasodilatation, proliferation and survival are mediated by nitric oxide (NO) NO is downregulated by anti-vegf therapy Meadows et al, Support Care Cancer 2015 Lai et al, J Clin Oncol 2007 Erber et al, FASEB 2014
HFSR Treatment 12.moisturising creams, urea 20% cream, topical corticosteroid (clobetasol 0.05% cream)..modifying daily activities, reduce friction and heat exposure.dose reduction or dose interruption of the MK-inhibitor New approach: Sidenafil topically (1% sidenafil cream) Sidenafil approved by the FDA for the treatment of erectile dysfunction and pulmonary hypertension Sidenafil has been shown to improve wound healing Pilot study by Meadows et al mitigated HFSR symptoms
Substances and Side Effects 13 EGFR-I MK-I BRAF-I MEK-I c-kit mtor maculapapular eruption (+) ++ ++ (+) ++ (+) acneiform rash ++ (+) (Sorafenib) - ++ - + HFSR - ++ + - - - alopecia + (+) (Sorafenib) + + - - paronychia ++ - - + - + hair changes trichomegaly, hypertrichoses, pigment changes hypopigmentation (Sunitinib) - - pigment changes - xerosis/pruritus + + (+) ++ + (+) skin tumors - + Sorafenib ++ - - - Degen et al, HAUTARZT 2011
MKI induced RASH 14 Maculopapular rash is characterized by a flat, red area on the skin that is covered with small confluent papules, and also includes erythema
MKI induced RASH Common Terminology Criteria for Adverse Events Version 4.0 Grade 1 15 Macules/papules covering <10% BSA with OR without symptoms (e.g., pruritus, burning, tightness) Grade 2 Macules/papules covering 10-30% BSA with OR without symptoms (e.g., pruritus, burning, tightness); limiting instrumental activities of daily living (ADL). Grad 3 Macules/papules covering >30% BSA with OR without associated symptoms; limiting self-care ADL, majority of the cases associated with local superinfection (oral antibiotics indicated)
MKI induced RASH 16 Rash affects the upper trunk, spreading centripetally, associated with pruritus Rash is seen in 19% to 53% patients treated with multikinase inhibitors occurs early in therapy (within the first cycle of therapy) disappear without treatment in less than 2 months Pickert et al, J Drugs Dermatol 2011 Macdonald et al, J Am Acad Dermatol, 2015
RASH - Treatment 17 maculopapular rash is associated with skin inflammation that leads to pruritus oral antihistamine such as loratadine during the day and a sedative antihistamine such as hydroxyzine 25-50 mg at night Menthol creams for pruritus relief (Menthol cream 0.5-3%) Oral antiepileptic (gabapentin etc.) should be used only in exceptional cases of very resistant itch as second-or third-line treatment topical corticosteroid (e.g. clobetasol 0.05%) Macdonald et al, J Am Acad Dermatol, 2015
Skin Toxicity and Quality of Life 18 Cutaneous toxicities affect patient function and quality of life, which may lead to dose modification or discontinuation Toxicity grading correlated with health-related quality of life Cutaneous adverse effects are among the most frequently encountered, and significantly impact both quality of life and health care economics Nardone et al, J Drugs Dermatol 2012 Lee at al, BJD 2009 Macdonald et al, J Am Acad Dermatol, 2015
Economic Burden of SAEs (I) 19 Median cost by category of treatment as it relates to targeted drug. Borovicka et al, ARCH DERMATOL 2011
Economic Burden of SAEs (II) 20 Borovicka et al, ARCH DERMATOL 2011