Skin toxicities from cancer treatments

Outline Skin toxicities from cancer treatments Resident Power Hour Cecilia Larocca, MD Centers for Melanoma and Cutaneous Oncology Brigham and Women s Hospital/Dana- Farber Cancer Institute Harvard Medical School Topics Covered Skin toxicities of: Chemotherapy Targeted therapies Immunotherapy Common skin toxicity syndromes Hand foot syndrome Hand foot skin reaction Papulopustular (acneiform eruption) NOT an exhaustive list JAAD CMEs Sources: Literature Review JAMA Derm Case series Case reports Meta- analyses Supportive Oncology journals Clinical trial publications (NEJM/JCO) Pearl for the Boards: Know downstream targets of drug in addition to direct drug mechanism of action A 75 year old female with a large locally advanced BCC is started on vismodegib what side effect is she most likely to experience? A) Diarrhea #7 B) Dysgeusia #3 C) Weight loss #4 D) Alopecia # 2 E) Muscle spasms # 1 F) Fatigue #5 Vismodegib: ERIVANCE trial Most common AEs that led to discontinuation (with n 2): o Muscle spasm, Weight decreased, Dysgeusia AE caused tx discontinuation in 17.3% AE typically occur within 6 months, if not they are unlikely to occur later on Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012;366:2171-2179. Sekulic A. J Am Acad Dermatol. 2015 Jun;72(6):1021-6.e8. Which drug is not associated with paronychia? A) Docetaxel: Taxane (microtubulin inhibitor) chemotherapy B) Bevacizumab: VEGFi C) Erlotinib: EGFRi D) Everolimus: mtori E) Trametinib: MEKi Nail changes caused by chemotherapy and targeted therapies Drugs with well recognized nail toxicities: Chemotherapy Taxanes* EGFRi* MEKi mtori Other: Vandetanib (EGFR/VEGF) * Highest incidence of nail changes Paronychia Chemotherapy EGFRi MEKi mtori Splinter hemorrhages VEGFi MTKi Onycholysis Chemotherapy EGFRi Vandetanib mtori Taxane- induced: Subungal hemorrhage/ Onycholysis/ Abscess/ Onychomadesis Robert C et al. Lancet Oncol. 2015 Apr;16(4):e181-9. Stevenson R. BMJ Case Rep. 2011 Aug 11;2011. Negulescu M et al. 2017;2(3-4):146-151. Peuvrel L et al. Dermatology. 2012;224(3):204-8. 1

Drug effects on distinct anatomic nail regions A patient presents with these skin color changes, what therapy is he likely receiving? Yellow discoloration oral A) Sorafenib: MTKi B) Sunitinib: MTKi C) Imatinib: bcr- abl i D) Erlotinib: EGFRi E) Abiraterone: Androgen i Robert C et al. Lancet Oncol. 2015 Apr;16(4):e181-9. Miller at al. J Am Acad Dermatol. 2014 Oct;71(4):787-94. Vigarios E et al. Support Care Cancer. 2017 May;25(5):1713-1739. Yellow discoloration: unique to sunitinib A patient with RCC presents with intense erythema and pain of the scrotum, what treatment is he likely receiving for his cancer? Erythema, scale on scrotum A) Sunitinib: painful toxic erythema B) Everolimus: mucosal apthous- like ulceration C) Sorafenib: reports of scrotal eczema D) Vemurafenib E) Imatinib Lee WJ. et al. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib. Br J Dermatol. 2009 Nov;161(5):1045-51. Billemont B, et al. N Engl J Med. 2008 Aug 28;359(9):975-6; discussion 976. Scrotal toxicities from TKI ONSET: ~2 weeks after the initiation of therapy Maximal intensity: ~ week 4 Disappears: during off weeks Could reappear after reintroduction of the drug Reports affecting labia majora as well This side effect is most commonly reported with what cancer treatment? A) Pembrolizumab B) Bortezomib C) Vemurafenib D) Imatinib E) Sunitinib JAMA Dermatol. 2015 Feb 1;151(2):170-7. Billemont B, Barete S, Rixe O. Scrotal cutaneous side effects of sunitinib. N Engl J Med. 2008 Aug 28;359(9):975-6; discussion 976. Bolognia, 3 rd Edition 2

This side effect is most commonly reported with what cancer treatment? A) Pembrolizumab: rare <3% B) Bortezomib: Sweet s Syndrome C) Vemurafenib D) Imatinib: rare E) Sunitinib Bolognia, 3 rd Edition A patient was recently started on a cancer therapy and reported itching and redness at the site of prior radiation. What therapy is not associated with this reaction? A) Tamoxifen B) Methotrexate C) Sorafenib D) Pemetrexed E) Erlotinib F) Docetaxel G) Vemurafenib H) Trametinib: MEKi Boussemart L et al. JAMA Dermatol. 2013 Jul;149(7):855-7. Radiation Recall Dermatitis Pemetrexed 5- Fluorouracil Methotrexate Gemcitabine Doxorubicin Hydroxyurea Vinblastine Paclitaxel Docetaxel Adriamycin Etoposide Bleomycin Capecitabine Pralatrexate Trastuzumab Tamoxifen A 68 YO F on vemurafenib for ovarian cancer present with the following eruption after spending time at an outdoor picnic. What is the etiology? Inflammatory/Disorders of abnormal cellular function BRAF Inhibitors Vemurafenib Dabrafenib Neoplastic/Disorder of proliferation A) Radiation recall phenomenon B) Photosensitivity C) UV recall phenomenon Vemurafenib causes UVA- induced photosensitivity C. Larocca Inflammatory/ Neutrophilic Abnormal epidermal function Abnormal follicular epithelium function Papulopustular eruption Folliculitis Neutrophilic eccrine hidradenitis Neutrophilic panniculitis Psoriasiform dermatitis Paronychia Acantholytic dermatoses (Darier s/grover s) Plantar hyperkeratosis (HFSR?) Xerosis Fissures Photosensitivity KP- like/follicular erythema Cysts/Milia- like lesions Telogen effluvium/diffuse alopecia Curly hair regrowth Benign Malignant Melanocytic Eruptive nevi Involuting nevi Changing nevi Melanoma Keratinocytic Verrucous keratosis Gingival hyperplasia SCC/KA Mangold et al. JAAD 2014; 71(5):e205-6 Carlos et al. JAMA Dermatol. 2015 Oct;151(10):1103-9. BRAF Inhibitors BRAF Inhibitors Folliculitis KP- like/follicular erythema Cysts/Milia- like lesions Acantholytic dermatoses (Darier s/grover s Disease) Photosensitivity Xerosis Fissures Plantar hyperkeratosis (HFSR?) Gingival hyperplasia Carlos et al. phototox (C. Larocca) Telogen effluvium Diffuse alopecia Grey, Curly hair Gingival hyperplasia Mangold et al. Brittle hair Piraccini et al. Images of Dariers presenation Grey culy hair Chu et al. JAAD 2012. Dec;67(6):1265-72. Anforth et al. Lancet Oncol. 2013 Jan;14(1):e11-8. Anforth et al. Lancet Oncol. 2013 Jan;14(1):e11-8. Mangold et al. JAAD 2014; 71(5):e205-6. Carlos et al. JAMA Dermatol. 2015 Oct;151(10):1103-9. Piraccini et al. JAAD 2015 Apr;72(4):738-41. Anforth et al. 3

Most common side effects due to vemurafenib Rash Grover- like eruption Other rashes Darier- like Seborrheic dermatitis- like eruption Morbiliform Carlos G et al. Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma. JAMA Dermatol. 2015 Oct;151(10):1103-9. CombiDT Decrease incidences of: AK/SCC/KA/BCC Melanoma Hyperkeratosis Plantar hyperkeratoses Verrucal keratoses/vv Hair changes Grover s Carlos G et al. Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma. JAMA Dermatol. 2015 Oct;151(10):1103-9. Drug induced: BRAFi MEKi BRAFi + MEKi MTKi (sorafenib/regorafenib) Neutrophilic Panniculitis (EN- like) Must r/o cutaneous metastases Early onset mean 60d, median 24d (7 days 16 months) BRAF inhibitors can cause SCC/KA in 15-30% of patients due to which pre- existing mutation in lesional skin? a) H- ras* b) N- ras c) Mutant BRAF d) WT BRAF e) c- kit f) p53 Ø ~21-60% had Ras mutations Ø Hras is the most common mutation Mossner et al. J Eur Acad Dermatol Venereol. 2015 Sep;29(9):1797-806. Bleomycin know to cause: A) Sclerodermatous changes B) Flagellate hyperpigmentation C) Raynaud s phenomenon D) Radiation recall E) All of the above Inaoki M. Case of bleomycin- induced scleroderma J Dermatol. 2012 May;39(5):482-4. Mendonça FM. et al. Flagellate dermatitis and flagellate erythema: report of 4 cases. Int J Dermatol. 2017 Apr;56(4):461-463. Which of the following is not a feature of hydroxyurea? A. Radiation sensitizer B. Megaloblastic anemia C. Poikiloderma of hands D. Leg ulcers E. Neurotoxicity F. RA- like Inflammatory arthritis Mechanism of Action: Impairs DNA synthesis Inhibition of ribonucleotide diphosphate reductase (reduces nucleotides to deoxynucleotides) Other cutaneous AE: Photosensitivity Radiation recall reactions Alopecia Dermatomyositis- like eruption Drug- induced lupus Lichenoid drug reactions Hyperpigmentation of skin/nails 4

Voriconazole is associated with increased incidence of: A) Lentigines B) Melanoma C) Cutaneous SCC D) De novo nevi- not true E) A, B, and C F) All of the above G) A and C Racette et al. JAAD 2005 C. Larocca A patient presents with a painful dermatitis after his initiating cancer treatment, which was made worse after using topical steroids. What agent is he likely on? A. Capcitabine B. Docetaxel C. Sorafenib D. Temsirolimis E. Vemurafenib S. Liu et al. Palmoplantar Peeling Secondary to Sirolimus Therapy. Am J Transplant. 2014; 14(1): 221 225. Inhibition of mtor pathway The bad Associated with skin fragility Impaired epidermal barrier Impair wound healing The good Reduced incidence in SCCs in patients with organ transplantation (preferred immunosuppressive agent in patients with high risk NMSC/numerous SCCs) A 35 YO M developed several painful papules and plaques on the trunk and extremities in the second week after initiation of induction chemotherapy with cytarabine for AML. What is the most likely diagnosis? A. Panniculitis B. Leukemia Cutis C. Neutrophilic eccrine hidradenitis D. Cellulitis E. Sweet s Syndrome Bolognia, 3 rd edition Neutrophilic eccrine hidradenitis Srivastava M et al. JAAD 2007 Apr;56(4):693-6. Herms F. et al.br J Dermatol. 2017 Jun;176(6):1645-1648. Keane FM et al Clin Exp Dermatol. 2001 Mar;26(2):162-5. Drugs: Cytarabine Anthracyclines Mitoxantrone Methotrexate Cyclophosphamide 5- fluorouracil Bleomycin Vinca alkaloids Imatinib mesylate Vemurafenib Can be polymorphic: linear, annular, EM- like +/- purpura After 7 days of imiquimod for tx of AKs the patient developed painful erythematous annular plaques, fever, arthalgias and malaise. What is likely seen on skin pathology: Maguiness SM, et al. Imiquimod- induced subacute cutaneous lupus erythematosus- like changes. Cutis. 2015 Jun;95(6):349-51. A. Neutrophilic dermatoses B. Vacuolar interface C. Spongiotic dermatoses 5

Imiquimod cutaneous autoimmune adverse events SCLE- like changes Vitiligo Pemphigus foliaceous GVHD Mechanism: TLR 7 signaling increases interferon alpha signaling Keratosis soles of feet Diagnosis? (TLR/IFN alpha thought to be important in pathophysiology of SLE) Wong et al. JAAD 1998 Chronic Arsenic Palmar- plantar keratoses Macular hypopigmentation Bowen s disease/nmsc Doxil Cytarabine 5- FU Cyclphosphamide Etoposide MTX Busulfan Melphalan Thiotepa Carmustine Mitoxantrone Intertriginous eruption Often confused for infectious intertrigo Eccrine squamous syringometaplasia Arch Dermatol 2008; 144(10): 1402-1403 Wong et al. JAAD 1998 An Bras Dermatol 85(5) Sept- Oct 2010 After treatment with ipilimumab a patient notes the development of several depigmented macules. She asks what this means? Vitiligo- like depigmentation from ICI is associated with improved PFS and OS in melanoma True or False? Four times less risk of death in patients with vitiligo development compared with patients without vitiligo. TRUE Patient is at higher risk for developing other immune mediate AE FALSE Teulings HE et al. Vitiligo- like depigmentation in patients with stage III- IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta- analysis. J Clin Oncol. 2015 Mar 1;33(7):773-81. 6

Eruptive KAs have been reported with all except: A. Sorafenib B. Sunitinib C. Vemurafenib D. Pembrolizumab E. Dabrafenib Neoplastic lesions Benign Malignant u Verrucous Keratoses KA/SCC BRAFI u BRAFi TGFb I u Sorafenib Sorafenib Pembrolizumab Melanocytic nevi u Melanoma BRAFi u BRAFI Sorafenib Sunitinib Erlotinib Regorafenib Rituximab Anforth R. et al. Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013 Jan;14(1):e11-8. Perier- Muzet et al. Melanoma patients under vemurafenib: prospective follow- up of melanocytic lesions by digital dermoscopy. J Invest Dermatol. 2014 May;134(5):1351-8. Freites- Martinez A et al. Eruptive Keratoacanthomas Associated With Pembrolizumab Therapy. JAMA Dermatol. 2017 Jul 1;153(7):694-697. Inflammation of Actinic Keratoses 5- Fluorouracil Capecitabine Cisplatin Cytarabine Vincristine Docetaxel Doxorubicin Dacarbazine Dactinomycin 6- Thioguanine Pemetrexed Management of taxane- induced scleroderma? A. Permanent discontinuation of taxane B. Transient discontinuation of taxane and dose reduction C. Continue therapy and start systemic steroids and methotrexate D. Continue therapy, but no effective therapy available Arch Dermatol. 2004;140(3):367-368 Cases J. 2009 Jul 2;2:6946. Photo courtesy of S. Liu Scleroderma- Like Reaction to Taxanes COX- 2 inhibitors should be used for treatment of capecitabine induced hand foot syndrome. Preceded by edema True Rosen A, et al. (2013) Management Algorithms, in Dermatologic Principles and Practice in Oncology: (ed M. E. Lacouture), John Wiley & Sons, Ltd, Oxford, UK Photos courtesy of Stephanie Liu, MD Rosen A, et al. (2013) Management Algorithms, in Dermatologic Principles and Practice in Oncology: (ed M. E. Lacouture), John Wiley & Sons, Ltd, Oxford, UK 7

Pseudocellulitis Gemcitabine Pemetrexed A patient on erlotinib presents with the following eruption 2 weeks after starting therapy. What would you use for treatment? A. Topical tazorac, topical clindamycin B. Topical hydrocortisone 1%, topical dapsone C. Topical triamcinolone, doxycycline D. Topical tretinoin, hydrocortisone, doxycycline E. Isotretinoin, topical triamcinolone, sunscreen Singh A, et al. J Gen Intern Med. 2012 Dec;27(12):1721. Bessis D, et al. J Am Acad Dermatol. 2004 Aug;51(2 Suppl):S73-6. AVOID topical retinoids as they are irritating Use topical steroids Use topical clindamycin or oral doxycycline Isotretinoin may be considered in severe cases Reactions on the Hands and Feet Not all reactions on the hands and feet are the same Periarticular thenar erythema and onycholysis (PATEO) Dorsal hand foot syndrome Taxanes Hand foot syndrome Palmoplantar erythrodysesthesia Acral erythema Chemotherapy Hand- foot skin reaction Targeted therapies Callous and inflammation over sites of pressure and friction Slide courtesy of N. Leboeuf Skin toxicity HFSR HFS Cancer treatment Targeted therapy MTKi (sorafenib) BRAFi Chemotherapy 5- FU Capcitabine Cytarabine Doxil Taxanes Hand foot skin reaction (HFSR) Hand foot syndrome (HFS) Histology Bands of necrotic keratinocytes (Late) Acanthosis + hyperkeratosis or parakeratosis Sub- or intra- epidermal or subcorneal blisters Scattered necrotic/dyskeratotic keratinocytes Mild spongiosis Interface/ vacuolar degeneration of the basal layer Shared features Location Hands and feet Symptoms Pain/ dysesthesia Erythema +/- Edema +/- Blisters Resolution with stopping drug Distinct morphology Localized hyperkeratosis to weight bearing areas with halo of erythema around plaques Desquamation (peeling skin) in areas of blisters Lipworth et al Oncology 2009 C.Larocca Immune Checkpoint Inhibitors Ipilimumab Pembrolizumab Nivolumab Pruritus Xerosis Eczematous dermatitis Psoriasis Bullous pemphigoid Cutaneous lupus Lichenoid dermatitis SJS/TEN Morbiliform Eruptive KAs Inflammation of SKs/AKs Vitiligo Vasculitis Sweet s syndrome SKIN TOXICITIES Drug Papulo- pustular (acneiform CTCAE) Cysts/ comedones / KP- like Conclusion Paronychia Onycholysis Xerosis HFSR Keratoses SCC/ KA Eruptive nevi Photo- sensitive EGFRi * * VEGFi folliculitis BRAFi folliculitis *** MEKi mtori *** Panniculitis MTKi ** ** ** ** Her2i (rare) (rare) * Also seen with Vandetinib (EGFR/VEGFi) ** Unique to sorafenib and/or regorafenib (likely due to RAF inhibition) ***Hand foot eruption in mtori and BRAFi have different morphology, likely distinct toxicity from HFSR Thank you! 8