PREVENTION AND MANAGEMENT OF SKIN TOXICITIES INCLUDING WHEN AND HOW TO COLLABORATE WITH DERMATOLOGISTS

Florian SCOTTE, MDPhD

Suresnes, France

Thanks to Vincent Sibaud for the pictures and teaching

DISCLOSURES

• Consultant / Advisory Boards / Speaker: Tesaro, Sanofi, Roche, MSD, TEVA, Norgine, Prostrakan, Leo pharma, Janssen, Hospira, Boehringer, AMGEN, Pierre Fabre Oncologie, Vifor Pharma

• Associations: ESMO, ASCO, MASCC, AFSOS, AESCO

A 58-year-old woman treated with eribulin therapy for a metastatic breast carcinoma. Two weeks after the second cycle, she developed blisters and painful bullous detachmentin axillary areas and groin.

Which is the most likely diagnosis? (choose the single best

response):

Quiz

1. Toxic epidermal necrolysis

2. Glucagonoma

3. staphylococcal scalded skin syndrome

4. Characteristic toxicity of chemotherapy

A 58-year-old woman treated with eribulin therapy for a metastatic breast carcinoma. Two weeks after the second cycle, she developed blisters and painful bullous detachmentin axillary areas and groin.

Which is the most likely diagnosis? (choose the single best

response):

Quizz

1. Toxic epidermal necrolysis

2. Glucagonoma

3. staphylococcal scalded skin syndrome

4. Characteristic toxicity of chemotherapy :

Toxic Erythema of Chemotherapy

Toxic erythema of chemotherapy

Bolognia JL, Cooper DL, Glusac EJ. Toxic erythema of chemotherapy: a useful clinical term. J Am Acad Dermatol 2008;59:524-9.

• New clinically descriptive term to emphasize the overlapping features of toxic reactions observed withchemotherapy. May enhance communication and patient care.

• Toxic -nonallergic- drug reaction. Dose-dependent.

• Confined in contact and occlusive areas.

• Docetaxel, paclitaxel, doxorubicin, etoposide, capecitabine, oxaliplatin, cytarabine, dactinomycin, thiotepa…..

• Overlapping terms (pubmed): intertrigo dermatitis,

intertriginous eruption of chemotherapy, flexural erythematous eruption, intertrigo-like eruption associated with chemotherapy, SDRIFE (symetric drug-related intertriginous and flexural exanthema), Chemotherapy-related bilateral dermatitis associated with eccrine squamous syringometaplasia……

Docetaxel, paclitaxel, doxorubicin, etoposide, capecitabine, oxaliplatin…..

Toxic erythema of chemotherapy

Sibaud V. Toxic erythema of chemotherapy. Ann Dermatol Venereol, 2015

Toxic erythema of chemotherapy

…..It is thought that accumulation/excretion of chemotherapy in sweat leads to direct toxic insults to eccrine glands and keratinocytes…..

Yeager A, et al. Unilateral Axillary Toxic Erythema of Chemotherapy in a Patient With Previous Axillary Lymph Node Dissection: Implications for Pathophysiology and Therapy. JAMA Dermatol 2016 ;152:727-8.

Rosen AC, Balagula Y, Raisch DW, Garg V, Nardone B, Larsen N, et al. Life-threatening dermatologic adverse events in oncology. Anticancer Drugs 2014;25:225-34.

Immune-mediated drug reactions…think about otherassociated drugs, or… !!!

Targeted therapies (sorafenib, regorafenib, dabrafenib, vemurafenib, bosutinib….), chemo(temozolomide, bendamustine), antibiotics, anticonvulsant drugs, analgesics…..

Chemo-induced (subacute) lupus erythematosus

5FU, capecitabine, pemetrexed, cisplatin, docetaxel……

Lowe GC. A systematic review of drug-induced subacute cutaneous lupus erythematosus. Br J Dermatol 2011; 164; 465-72.

UV-recall

Taxanes, methotrexate

Susser WS, et al. Mucocutaneous reactions to chemotherapy. J Am Acad Dermatol 1999; 40: 367-98.

Chemotherapy, scleroderma-like syndrome, pseudocellulitis

Gemcitabine, pemetrexed, taxanes, bleomycine……

Reyes-Habito C, Roh EK. Cutaneous reactions to chemotherapeutic drugs and targeted therapies for cancer. J Am Acad Dermatol 2014; 71: 203 e1-12.

Chemotherapy and inflammation of actinic keratoses

Fluorouracile, taxanes, cisplatine, capecitabine, doxorubicine……

Sibaud V, Lebœuf NR, Roche H, Belum VR, Gladieff L, Deslandres M, Montastruc M, Eche A, Vigarios E, Dalenc F, Lacouture ME.Dermatological adverse events with taxane chemotherapy. Eur J Dermatol 2016, Aug 22. [Epub ahead of print]

Toxic erythema of chemotherapy – key points

• TEC is one of the most common skin toxic effects of high-dose chemo: taxanes+++, lipsosomal

doxorubicin…..

• Site of predilection: intertriginous zones, under dressings, pressure areas….; sweating, occlusive phenomenon and

direct toxic effect

• Accurate diagnosis is critical for optimal management (topical steroids, dose reduction if needed…) and erroneous assignment of drug allergies (antibiotics…)

• Not every skin rash occurring with chemotherapy is a TEC….

Sibaud V, Lebœuf NR, Roche H, Belum VR, Gladieff L, Deslandres M, Montastruc M, Eche A, Vigarios E, Dalenc F, Lacouture ME. Dermatological adverse events with taxane chemotherapy. Eur J Dermatol 2016, Aug 22. [Epub ahead of print]

Bolognia JL, Cooper DL, Glusac EJ. Toxic erythema of chemotherapy: a useful clinical term. J Am Acad Dermatol 2008;59:524-9.

• High-potency corticosteroids,• celecoxib,• antiperspirants (?),• dose reduction,• patient education• and conselling……

Management: Toxic erythema of chemotherapy

Hand-Foot syndrome and chemotherapyLiposomal doxorubicin, capecitabine, cytarabine, cyclophosphamide…..

Sibaud V et al. HFS 14: a specific quality of life scale for patients suffering from hand-foot syndrome. The Oncologist 2011; 16: 1469-78.

Hand-foot skin reaction and targeted therapiesdual inhibition of VEGFR – PDGFR and/or BRAF protein

Macdonald JB et al. Cutaneous adverse effects of targeted therapies: Part I: Inhibitors of the cellular membrane. J Am Acad Dermatol 2015;72:203-18.

Hand-foot skin reaction and targeted therapies(-nib)

Balagula Y. The risk of hand foot skin reaction to pazopanib, a novel multikinase inhibitor: a systematic review of literature and meta-analysis. Invest New Drugs, 2011.Belum VR. The risk of hand foot skin reaction with the novel multikinase inhibitor regorafenib: a meta-analysis. Invest New Drugs, 2013.Fischer A. The risk of hand foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and meta-analysis. Invest New Drugs, 2013.

Incidence

all grades (%)

Incidence

High grades (%)

Molecular target indications

Regorafenib (Stivarga ®) 60,5 20,4 VEGFR 1-3; PDGFR α-β; c-KIT; RAF;TIE-2; RET; P38 MAPK, FGFR- 1

CRC

Sorafenib (Nexavar ®) 33,8 8,9 VEGFR 1-3; PDGFR β; c-KIT, RET, RAF Renal cell carcinoma, hepatocellular carcinoma

Sunitinib (Sutent®) 18,9 5,5 VEGFR 1-3; PDGFR β; c-KIT, RET; Flt3; CSF-1R

Renal cell carcinoma and GIST

Axitinib (Inlyta ®) 29,2 9,6 VEGFR 1-3; PDGFR α-β; c-KIT Renal cell carcinoma

Vemurafenib (Zelboraf®) 7-23 2 BRAF métastatic melanoma

Pazopanib (Votrient®) 4,5 1,8 VEGFR 1-3; PDGFR α-β; c-KIT; RAF Renal cell carcinoma

Hand foot syndrome – key points

• Chemotherapy and hand foot syndrome: symmetric diffuse erythema, inflammation, edema,

blistering. Palms more than soles. Capecitabine and liposomal doxorubicin.

• Targeted therapies and hand foot skin reaction: pressure-bearing areas (lateral aspect of the feet, heels, fingertips, interphalangeal joints…). Localized hyperkeratotic lesions, perilesional halo. Soles more than palms. Multitargeted angiogenesis inhibitors and anti-BRAF monotherapy.

Kristen K et al. Chemotherapy-induced hand-foot syndrome and nail changes: A review of clinical presentation, etiology, pathogenesis, and management . J Am Acad Dermatol 2014;71:787-94.

A 59-year-old man treated with platinum-based and fluorouracil chemotherapy incombination with anti-EGFR cetuximab, for a locally advanced Head and Neckcarcinoma. He developed bilateral periungual lesions, with a purulent discharge.

Quiz

What is the most likely diagnosis (choose the single best response):

1. Cetuximab toxic effect

2. Fluorouracil toxic effect

3. Cisplatin toxic effect

4. Paraneoplastic syndrome

A 59-year-old man treated with platinum-based and fluorouracil chemotherapy incombination with anti-EGFR cetuximab, for a locally advanced Head and Neckcarcinoma. He developed bilateral periungual lesions, with a purulent discharge.

Quiz

What is the most likely diagnosis (choose the single best response):

1. Cetuximab toxic effect

2. Fluorouracil toxic effect

3. Cisplatin toxic effect

4. Paraneoplastic syndrome

The Nail…

Damage to the nail folds: paronychia, periungual pyogenic granulomas

EGFR1 – MEK – mTOR inhibitors

afatinib, erlotinib, cetuximab, panitumumab, gefitinib, trametinib, selumetinib, everolimus, temsirolimus….

Targeted therapies, paronychia and pyogenic granuloma

1: All-grade nail toxicity overall incidence of EGFR inhibitors: 17,2% (95% CI: 13,8-21,3%, RR =77)

Overgrowing of friable granulation tissue on lateral and/or proximal nail folds, mimicking ingrown nails

Garden BC, et al. The risk of nail changes with epidermal growth factor recpetor inhibitors: a systematic review of the literature and meta-analysis. J Am Acad Dermatol 2012;67: 400-08.

Kiyohara Y. Erlotinb-related skin toxicities : treatment strategies in patients with metastatic non small cell lung cancer. J Am Acad Dermatol, 2013.

Liquid nitrogen, topical steroids/antibiotics in combination, silver nitrate…..

Pyogenic granuloma – correct nail curvature !

Pyogenic granuloma – supportive Oncodermatology !

Baseline W2 W4

D’andrea M, Casassa E, Fabbrocini G, Sibaud V. Efficacy and safety of topical blocking agents in the management of targeted therapy-related pyogenic granuloma. Support Care cancer, 2018 (in progress).

Fissures – skin cracking

Lacouture ME. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 2011; 19: 1079-1095.Thomas M, Robert C. Dermatologic manifestations of MEK inhibitors. In : Sibaud V, Robert C, eds. Skin side effects induced by targeted anticancer therapies : a new dermatology. Toulouse : Privat, 2010 ; 89- 94.

EGFR / MEK inhibitors

afatinib, erlotinib, cetuximab, panitumumab, gefitinib, trametinib, selumetinib, ….

Lacouture ME. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 2011; 19: 1079-1095.

Fissures –skin cracking

Supportive Oncodermatology

« Cyanoacrylate Liquidband » = « Superglue »

Lacouture ME. The PRIDE syndrome. Br J Dermatol, 2006.

Papulopustules and/or paronychia, regulatoryabnormalities of hair growth, itching, and drynessdue to epidermal growth factor receptor inhibitors

Robert C. cutaneous side effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005; 6: 491-500.

EGFR/MEK inhibitors -Dermatological toxicities

Onycholysis and chemotherapy

Taxanes (docetaxel, paclitaxel) +++, doxorubicin, etoposide, capecitabine……..

Separation of the nail plate from the nail bed – results from toxic effects to the bed epithelium, leading to plate detachment.

43% et 35% all-grade incidence with paclitaxel (95% CI:18-73,3%) and docetaxel (95% CI: 29,9-40,2%, RR 77,7), respectively.

Capriotti K, et al. The risk of nail changes with taxane chemotherapy: a systematic review of the literature and meta-analysis. Br J Dermatol 2015; 173: 842-45.

Onycholysis management –supportive care

Scotté F. Multicenter study of a frozen glove to prevent docetaxel-induced onycholysis and cutaneous toxicity of the hand. J Clin Oncol 2005; 23: 4424-29.Scotté F. Matched case-control phase 2 study to evaluate the use of a frozen sock to prevent docetaxel-induced onycholysis and cutaneous toxicity of the foot. Cancer 2008; 112: 1625-31.

Preventive measures: repeated nail trimming, frozen gloves 1/socks

Curative measures: partial removal of the nail plate and nail bed cleaned and cultured – dose reduction

1: Nail changes decreased from 51% to 11% of hands wearing frozen gloves

Grade 0*

Grade 1*Asymptomatic separation of the nail bed from the nail plate or

nail loss

Preventive nail care instructions given – frozen gloves should be considered

Continue drug at current dose and monitor for change in severity

If infection is suspected, apply topical antibiotics or antifungal agent

Reassess after 2/3 weeks. If reaction worsens proceed to next step

Continue drug at current dose and monitor for change in severity; obtain bacterial/viral/fungal cultures if infection is suspected;

If infection, start oral antibiotics with anti-Staphylococcus aureus and Gram + coverageIf painful haematoma or subungual abcess is suspected, partial or total nail avulsion is required

Pain control

Reassess after 2 weeks; if reactions worsen or do not improve Interrupt treatment until severity decreases to grade 0-1

*Adpted from nail loss clinical grading, CTCae, V4.02

Grade 2*symptomatic separation of the nail bed from the nail plate or nail

loss; limiting instrumental activitites of daily living (ADL)

Grade 3*Severe pain and/or superinfection ; limiting self-care ADL

Interrupt treatment until severity decreases to grade 0-1; obtain bacterial/viral/fungal cultures if infection is suspected; and continue treatment of nail reaction with the following:

If infection, start oral antibiotics with anti-Staphylococcus aureus and Gram + coverageIf painful haematoma or subungual abcess is suspected, partial or total nail avulsion is required

Pain control

Reassess after 2 weeks; if reactions worsen or do not improve, please consider dose interruption or discontinuation per protocole and switch to another antineoplastic agent

Sibaud V, Baran R, Piraccini BM, Lacouture ME (2016). « Drug-induced nail disorders - Anticancer therapies” in Baran & Dawber's Diseases of the Nails and theirManagement, Fifth Ed.216. Editors: R.Baran, DR de Berker, BM Piraccini, B.Richert, L.Thomas.

Check Point Inhibitors - Safety prevalence

Postow MA et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372: 2006-17. Larkin J et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015, may 31.

Anti-PD-1/PD-L1 and nonspecific maculopapular rash

- Most prevalent skin toxicity – Calculated all-grade incidence: 14.3% and 16.7% for nivolumab and pembrolizumab, respectively

- Develops after first cycles - shorter time to onset than other toxicities- Mainly located on trunk and extremities – macules, papules, scaling - Pruritus+++

- Aberrant targeting of self antigens into the dermis/epidermis by reactivated CD4+/CD8+ T cells?

Belum VR et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016; 60: 12-25.

Sibaud V, Lacouture ME. Dermatologic complications of immune checkpoint inhibitors. Am J Clin Dermatol, 2018 (in press)

Anti-PD-1/PD-L1 and nonspecific maculopapular rash

- Self limited - Less than 2% of grade 3 or higher

- Most relevant histopathological features: eczematiform pattern with spongiotic dermatitis and exocytosis

- Early management is required for limiting exacerbation of the lesions and treatment discontinuation(moderate to high-potency topical steroids, moisturizers, oral antihistamines…)

- A skin biopsy performed if atypical lesions or persistent/recurrent/intolerable grade 2 or grade 3

Boningen J, et al. Anti-PD-1-induced psoriasis. A study of 21 patients. J Eur Acad Dermatol 2016 oct 14.

Anti-PD-1/PD-L1 and psoriasiform eruptions

- Incidence currently unknown- Occurrence or exacerbation of a preexisting psoriasis

Hua C, Robert C. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 2016; 52:45-51.Nakamura Y, et al. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study. J Dermatol 2017;44:117-22.

- Associated hair depigmentation

- Does not require specific treatement other than photoprotective measures - Usually persists beyond immunotherapydiscontinuation

- Surrogate marker for treatment response (objective response or overall survival)

Anti-PD-1/PD-L1 and vitiligo

Belum VR, Zarbo A, Sibaud V, Oudard S, Leboeuf NR, Postow M, Busam KJ, Lacouture ME.:Immune-related alopecia (areata and universalis-type) in cancer patients receiving immune checkpoint inhibitors. Br J Dermatol 2017; 176: 1649-1652.Rivera N, et al. Hair Repigmentation During Immunotherapy Treatment With an Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Agent for Lung Cancer. JAMA Dermatol 2017 Jul 12.

Hair toxicities

- Uncommon toxicities (<2%)

- Alopecia areata (ipilimumab) – progressive hair repigmentation

Universalis-type

Belum VR, Zarbo A, Sibaud V, Oudard S, Leboeuf NR, Postow M, Busam KJ, Lacouture ME.:Immune-related alopecia (areata and universalis-type) in cancer patients receiving immune checkpoint inhibitors. Br J Dermatol 2017; 176: 1649-1652.

- Uncommon toxicities (<2%) – not published – histopathological findings not available

- Psoriasis,lichenoid reactions. Paronychia, onycholysis, Brittle nails?

Nail toxicities

Belum VR, Zarbo A, Sibaud V, Oudard S, Leboeuf NR, Postow M, Busam KJ, Lacouture ME.:Immune-related alopecia (areata and universalis-type) in cancer patients receivingimmune checkpoint inhibitors. Br J Dermatol 2017; 176: 1649-1652.

Oral lichenoid reactions

- reticulated white streaks consistent with Wickham’s striae- Papular, plaque-like, ulcerative or atrophic/erythematous lesions- either isolated or associated with skin or genital involvement

Sibaud V, Eid C, Belum VR, Combemale P, Lamant L, Motzer R, Vigarios E, Lacouture ME. Oral lichenoid reactions associated with anti-PD-1/PD-L1 therapies: clinicopathological findings. J Eur Acad Dermatol Venereol 2017, april 17.

Grade 1Macules/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)

*: A skin biopsy should be performed in the case of atypical lesions, persistent grade 2 and grade 3 or life-threatening skin reactions

Symptomatic management:

Continue anti-PD-1/PD-L1 antibodies

Reassess after 2 weeks and monitor for change in severity

Symptomatic management:

Continue anti-PD-1/PD-L1 antibodies, reassess after 1-2 weeks and monitor for change in severity:- If persistent (or intolerable grade 2), delay immunotherapy and consider oral corticosteroids (0.5-1 mg/kg/day). Once

improved, taper steroids over 1 month and resume immunotherapy when systemic steroid dose is < 10 mg prednisoneequivalent

- If worsened, manage as grade 3

Grade 3*Macules/papules covering >30% BSA with or without

symptoms (e.g. pruritus, burning, tightness); limiting self-care ADL

Symptomatic management: topical moisturizers (if tolerated), high or very high-potency topical steroids(e.g. clobetasol), oral antihistamines, oral steroids (1mg/kg/day)

Delay immunotherapy, reassess after several days and monitor for change in severity:-if persistent or worsened: permanently discontinue immunotherapy and supportive measures

-if improved to grade 1: taper steroids over 1 month and resume immunotherapy when systemic steroid dose is < 10 mg prednisone equivalent - close follow-up

Life-threatening reactions*(blisters and exfoliative rash, fever, mucosal ulcerations, facial

oedema, Nikolsky sign, etc.)

Permanently discontinue - supportive measures

Sibaud V, Delord JP. Dermatologic complications of anti-PD-1 / PD-L1 immune checkpoint antibodies. Curr Opin Oncol 2016; 28: 254-63.

Symptomatic Management:- Topical moisturizers applied to full

body surface (if tolerated),- Topical steroids applied to affected

areas, - Oral antihistamines

sibaud.vincent@iuct-oncopole.fr

sibaud.vincent@iuct-oncopole.fr