Dermatologists & Oncologists: Two important reasons we are getting closer. Ioanna Panoutsopoulou, MD. GAMC June 1 st 2016
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1 Dermatologists & Oncologists: Two important reasons we are getting closer Ioanna Panoutsopoulou, MD GAMC June 1 st 2016
2 Points of presentation Cutaneous adverse events from: Epidermal Growth Factor Receptor Inhibitors (EGFRi) Melanoma Treatments
3 Targeted oncologic treatments Side effects on skin, hair and nails are common affect quality of life May lead to antineoplastic treatment discontinuation Dermatologist s role is important in managing the cancer patients Average cost of managing the skin toxicities: $1920 per pt/year Borovicka JH et al. Arch Dermatol. 2011;147:
4 Epidermal Growth Factor Receptor Inhibitors (EGFR inhibitors) Monoclonal antibodies to EGFR: cetuximab, panitumumab Tyrosine Kinase inhibitors specific for EGFR: erlotinib, gefitinib Dual kinase inhibitors of EGFR and HER2: lapatinib Inhibitors of erbb receptors: canertinib Multikinase inhibitors: vandetanib
5 EGFR inhibitors Why so many cutaneous side effects? EGFR: Located in epidermis and appendages 1 Important in homeostasis of epidermis and pilosebaceous unit2, 3, 4 Inhibits IL-5 perifollicular inflammation 5 Affects IL Green MR et al. J Invest Dermatol. 1985;85: Lacouture ME. Nat Rev Cancer. 2006;6: Murillas R et al. EMBO J. 1995;14: Brodell LA et al. J Cutan Pathol. 2013;40: Rodeck U. J Cell Physiol. 2009;218: Bangsgaard N. PLoS One. 2012;7:e39706
6 50-90% of the pts receiving EGFRi will develop cutaneous side effects
7 EGFRi Papulopustular lesions Most common side effect Aseptic folliculitus Rapid onset: 75% of pts within 1-2 wks 1,2 Dose-dependent Milia are absent Associated pruritus Distribution: head, neck, trunk, proximal aspect of extremities Pustules may lead to: Crusted or hyperkeratotic papules Bacterial infection 1. Cunningham D et al. N Engl J Med. 2004;351: Lacouture ME et al. Support Care Cancer. 2011;19:
8 Panitumumab 61 yo colon Ca
9 9/3/15 9/3/15 30/3/15 11/5/15
10
11 s/p 2 wks doxycycline 100 mg BID + Methylprednisolone aceponate lot bid Panitumumab colon Ca while on same dose of panitumumab
12 Panitumumab colon Ca s/p 2 wks doxycycline 100 mg BID + Methylprednisolone aceponate lot bid while on same dose of panitumumab
13
14 Panitumumab (EGFRi) 43 yo F colon Ca
15 panitumumab (EGFRi) 60 yo M colon Ca Erlotinib (EGFRi) 81 yo M renal Ca
16 EGFR inhibitors Papulopustular lesions Flares when 1 : EGFRi dose EGFRi held and re-introduced Exposure to UV worsening 2 Irradiated areas not involved 3 Degree of lesion severity associated with: Creatinic kinase levels (CK) Maybe better prognosis 4,5 1. Segart S et al. Ann Oncol. 2005;16: Luu M et al. Photodermatol Photoimmunol Photomed. 2007;23: Bossi P et al. Ann Oncol. 2007;18: Perez-Soler R. Oncology. 2003;17(11 Suppl 12): Liu HB et al. PlosOne. 2013;8:e55128
17 EGFR inhibitors Papulopustular lesions Grading of severity: body surface area (BSA) affected Activities of daily living (ADL)
18 EGFR inhibitors Side effects Photosensivity photodermatitis telangiectasias xerosis 30% of pts Dose-dependent Skin fragility cracks Necitumumab + capecitabine
19 photosensitivity
20 2/2/15 26/2/15 Necitumumab + capecitabine Lung cancer
21
22 EGFR inhibitors Secondary skin infections Staph aureus Pseudomonas aeruginosa Herpes simples
23 Panitumumab 83 yo colon Ca Staph aureus
24
25 Pseudomonas aeruginosa infection Panitumumab colon Ca s/p amikacin gel BID
26 EGFRi & Hair Hair quality changes: after 2 nd 3 rd month 1. Scalp hair: thinner, fragile, curlier 1 hair growth rate Mild androgenetic alopecia Case reports: scarring alopecia by erlotinib, loss of pigment 2. Facial hair: Eyelashes: trichomegaly (elongated, thicker, curly 2,3 ) keratitis eyebrows: hypertrichosis, in-between the eyebrows and periorbital area 4 Hypertrichosis: upper lip and chin 1. Zheng et al. BMJ Case Rep. Published online 2009 Mar Criado PR et al. An Bras Dermatol. 2010;85: Rodriguez NA et al. J Clin Oncol. 2011;29:e532-e Pascual JC et al. Br J Dermatol. 2004;151:
27 Panitumumab (EGFRi) 43 yo F colon Ca
28 Panitumumab (EGFRi) 43 yo F colon Ca 6 months later while on panitumumab
29 Panitumumab (EGFRi) 43 yo F colon Ca
30 Panitumumab colon Ca
31 Afatinib lung Ca
32 EGFRi & mucosa Oral mucosa: Aphthae, dry mouth, geographic tongue Genital mucosa: Valanitis, vaginitis, aphthae eyes: Conjuctivitis & keratitis 1. Busam KJ et al. Br J Dermatol. 2001;144: Melichar B et al. Eur J Cancer Care. 2007;16:
33 EGFRi & nails 20% of pts 1 Paronychia Pyogenic granuloma like lesions Nail dyschromias onycholysis 1. Garden BC et al. J Am Acad Dermatol. 2012;67: Fox LP. J Am Acad Dermatol. 2007;
34 Erlotinib (EGFRi) Necitumumab + capecitabine Panitumumab (EGFRi) Cetuximab (EGFRi)
35 PG-like lesions Afatinib 22 y.o. lung Ca
36 Melanoma Treatments RAF inhibitors: vemurafenib, dabrafenib MEK inhibitors: trametinib, cobimetinib, selumetinib Immunomodulators: Anti-CTLA-4 : ipilimumab (tremelimumab) Anti-PD-1 inhibitors: nivolumab, pebrolizumab, (pidilizumab)
37 RAF inhibitors Folliculocentric smooth papules: 70% of pts extensive maculo-papular eruption plaques Location: trunk & extremities: (spares head/neck) vemurafenib
38 RAF inhibitors - Cutaneous neoplams SCCs (RAS mutation) 1 & Keratoacanthomas 1. Su F et al. N Enlg J Med. 2012;366:
39 Vemurafenib - Ακανθοκυτταρικά καρκινώματα
40 RAF inhibitors - Cutaneous neoplams verruca keratoses 1 Photo- exposed and non photo-exposed areas Minimal to no atypia HPV negative 1. Anforth RM et al. Br J Dermatol. 2012;167:
41 Vemurafenib 48 yo M melanoma verrucous keratoses
42 Dabrafenib 72 yo F melanoma
43 RAF inhibitors Palmo-plantar hyperkeratosis 1,2 60% of pts Friction Prevention: avoiding friction and pressure on skin 1. Huang V et al. Arch Dermatol. 2012;148: Anforth RM et al. Br J Dermatol. 2012;167:
44 Dabrafenib + trametinib 33 yo M melanoma Vemurafenib 48 yo M melanoma
45 RAF inhibitors Follicular keratosis 1 30% of pts pruritus Seborrheic dermatitis 2 pruritus 1. Harvey NT et al. Am J Dermatopathol. 2012;34: Huang V et al. Arch Dermatol. 2012;148:
46 RAF inhibitors - Photosensitivity vemurafenib > dabrafenib Sun burns Urticarial lesions Pain Sinha R et al. Br J Dermatol. 2012;167: Dummer R et al. N Engl J Med. 2012;366:
47 RAF inhibitors Non scarring alopecia Facial erythema Eruptive milia Epidermal cysts Radiation recall dermatitis Lobular panniculitis 1,2 (neutrophilic) Upper & lower extremities Arthralgia vemurafenib 1. Bussemart L et al. Ann Oncol. 2013;24: Kim GH et al. J Cutan Pathol. 2013;40:
48 Vemurafenib 35 yo F melanoma eruptive milia
49 RAF inhibitors & pigmented lesions Change of existing nevi 1 New nevi 1,2 Second primary melanoma 3,4 1. Haenssle HA et al. Arch Dermatol. 2012;148: Boussemart L et al. Ann Oncol. 2013;24: Dalle S et al. Br J Dermatol. 2013;168: Debarbieux S et al. Br J Dermatol. 2013;168:
50
51 MEK inhibitors trametinib, cobimetinib, selumetinib Side effects similar to EGFRi Combined therapy of MEK & RAF inhibitors fewer side effects 1. Adjei AA et al. J Clin Oncol. 2008;26: Davies BR et al. Mol Cancer Ther. 2007;6: Gadiot J et al. Onco Targets Ther. 2013;6:
52 MEK inhibitors Side Effects Maculopapular erythematous lesions 50-75% of pts 1 Dose-dependent 1,2 Papulopustular lesions 3 Head/neck/trunk pruritus infection with Staphylococcus aureus 1. Banerji U et al. Clin Cancer Res. 2010;16: Adjei AA et al. J Clin Oncol. 2008;26: Balagula Y et al. Invest New Drugs. 2011;29:
53 MEK inhibitors Xerosis - pruritus Alopecia (17% of pts) Skin hyperpigmentation Trichomegaly, hair de-pigmentation paronychia telangiectasias 1. Banerji U et al. Clin Cancer Res. 2010;16: Adjei AA et al. J Clin Oncol. 2008;26: Balagula Y et al. Invest New Drugs. 2011;29:
54 Dose-dependent Anti-CTLA-4 (Ipilimumab) side effects Maculopapular Alopecia pruritus vitiligo: maybe better prognosis 1 1. Cancer Biol Ther. 2015;16(5):662-70
55 Anti-PD-1 Nivolumab & Pebrolizumab Cutaneous side effects Pruritus Vitiligo JAMA Dermatol. 2016;152(1):45-51
56 Conclusions Numerous and frequent side effects from targeted antineoplastic treatments Important to diagnose and manage cutaneous side effects: Improve pts quality of life Not decrease the dose of antineoplastic tx Not discontinue the antineoplastic tx
57 Thank you!
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