3/6/19 1 Skin toxicities from cancer treatments Resident Power Hour Cecilia Larocca, MD Centers for Melanoma and Cutaneous Oncology Brigham and Women’s Hospital/DanaFarber Cancer Institute Harvard Medical School Outline Topics Covered • Skin toxicities of: • Chemotherapy • Targeted therapies • Immunotherapy • Common skin toxicity syndromes • Hand foot syndrome • Hand foot skin reaction • Papulopustular (acneiform eruption) Sources: Literature Review • JAAD CMEs • JAMA Derm Case series • Case reports • Metaanalyses • 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 NOT an exhaustive list 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;366:21712179. Sekulic A. J Am Acad Dermatol. 2015 Jun;72(6):10216.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 Paronychia • Chemotherapy • EGFRi • MEKi • mTORi Onycholysis • Chemotherapy • EGFRi • Vandetanib • mTORi Drugs with well recognized nail toxicities: Chemotherapy Taxanes* EGFRi* MEKi mTORi Other: Vandetanib (EGFR/VEGF) Taxaneinduced: Subungal hemorrhage/ Onycholysis/ Abscess/ Onychomadesis Splinter hemorrhages • VEGFi • MTKi * Highest incidence of nail changes Robert C et al. Lancet Oncol. 2015 Apr;16(4):e1819. Stevenson R. BMJ Case Rep. 2011 Aug 11;2011. Negulescu M et al. 2017;2(34):146151. Peuvrel L et al. Dermatology. 2012;224(3):2048.
Transcript
3/6/19
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Skin toxicities from cancer treatments
Resident Power Hour
Cecilia Larocca, MDCenters for Melanoma and Cutaneous Oncology
Brigham and Women’s Hospital/Dana-‐Farber Cancer InstituteHarvard Medical School
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.
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Drug effects on distinct anatomic nail regions
Miller at al. J Am Acad Dermatol. 2014 Oct;71(4):787-‐94. Robert C et al. Lancet Oncol. 2015 Apr;16(4):e181-‐9.
A patient presents with these skin color changes, what therapy is he likely receiving?
A) Sorafenib: MTKiB) Sunitinib: MTKiC) Imatinib: bcr-‐abl iD) Erlotinib: EGFRiE) Abiraterone: Androgen i
Vigarios E et al. Support Care Cancer. 2017 May;25(5):1713-‐1739.
Yellow discoloration oral
Yellow discoloration: unique to sunitinib
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.
A patient with RCC presents with intense erythema and pain of the scrotum, what treatment is he likely receiving for his cancer?
A) Sunitinib: painful “toxic erythema”B) Everolimus: mucosal apthous-‐like
ulcerationC) Sorafenib: reports of scrotal eczemaD) VemurafenibE) Imatinib
Billemont B, et al. N Engl J Med. 2008 Aug 28;359(9):975-‐6; discussion 976.
Erythema, scale on scrotum
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
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.JAMA Dermatol. 2015 Feb 1;151(2):170-‐7.
This side effect is most commonly reported with what cancer treatment?
A) PembrolizumabB) BortezomibC) VemurafenibD) ImatinibE) Sunitinib
Bolognia, 3rd Edition
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This side effect is most commonly reported with what cancer treatment?
A patient was recently started on a cancer therapy and reported itching and redness at the site of prior radiation. What therapy is notassociated 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.
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.
Photo courtesy of N. LeBoeuf
Photo courtesy of N. LeBoeuf
Photo courtesy of N. LeBoeuf
(C. Larocca)
Mangold et al.
Carlos et al.
Piraccini et al.
Anforth et al.
phototox
Gingival hyperplasia
Grey culy hair
Brittle hair
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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.
• Grover’sCarlos 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.
Neutrophilic Panniculitis (EN-‐like)
Drug–induced:BRAFiMEKi
BRAFi + MEKiMTKi (sorafenib/regorafenib)
Must r/o cutaneous metastases
Early onset mean 60d, median 24d(7 days—16 months)
Mossner et al. J Eur Acad Dermatol Venereol. 2015 Sep;29(9):1797-‐806.
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-‐rasc) Mutant BRAFd) WT BRAFe) c-‐kitf) p53
Ø~21-‐60% had Ras mutationsØHras is the most common mutation
Bleomycin know to cause:
A) Sclerodermatous changesB) Flagellate hyperpigmentationC) Raynaud’s phenomenonD) Radiation recallE) 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 nota feature of hydroxyurea?A. Radiation sensitizerB. Megaloblastic anemiaC. Poikiloderma of handsD. Leg ulcersE. NeurotoxicityF. RA-‐like Inflammatory arthritis
Mechanism of Action:Impairs DNA synthesisInhibition of ribonucleotide diphosphate reductase(reduces nucleotides to deoxynucleotides)
Other cutaneous AE:PhotosensitivityRadiation recall reactionsAlopeciaDermatomyositis-‐like eruptionDrug-‐induced lupusLichenoid drug reactionsHyperpigmentation of skin/nails
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Voriconazole is associated with increased incidence of:
A) LentiginesB) MelanomaC) Cutaneous SCCD) De novo nevi-‐ not trueE) A, B, and CF) All of the aboveG) A and C
Racette et al. JAAD 2005
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. CapcitabineB. DocetaxelC. SorafenibD. TemsirolimisE. Vemurafenib
S. Liu et al. Palmoplantar Peeling Secondary to SirolimusTherapy. Am J Transplant. 2014; 14(1): 221–225. C. Larocca
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. PanniculitisB. Leukemia CutisC. Neutrophilic eccrine
Can be polymorphic:linear, annular, EM-‐like+/-‐ purpura
Keane FM et al Clin Exp Dermatol. 2001 Mar;26(2):162-‐5.
Herms F. et al.Br J Dermatol. 2017 Jun;176(6):1645-‐1648.
Srivastava M et al. JAAD 2007 Apr;56(4):693-‐6.
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:
A. Neutrophilic dermatosesB. Vacuolar interfaceC. Spongiotic dermatoses
After treatment with ipilimumab a patient notes the development of several depigmented macules. She asks what this means?
• 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
True or False?
Vitiligo-‐like depigmentation from ICI is associated with improved PFS and OS in melanoma
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.
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Eruptive KAs have been reported with all except:
A. SorafenibB. SunitinibC. VemurafenibD. PembrolizumabE. Dabrafenib
Anforth R. et al. Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013 Jan;14(1):e11-‐8.
Freites-‐Martinez A et al. Eruptive Keratoacanthomas Associated With Pembrolizumab Therapy. JAMA Dermatol. 2017 Jul 1;153(7):694-‐697.
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.
Arch Dermatol. 2004;140(3):367-‐368Cases J. 2009 Jul 2;2:6946.
Management of taxane-‐induced scleroderma?
A. Permanent discontinuation of taxaneB. Transient discontinuation of taxane and
dose reductionC. Continue therapy and start systemic
steroids and methotrexateD. Continue therapy, but no effective therapy
available
Photo courtesy of S. Liu
Scleroderma-‐Like Reaction to Taxanes
Photos courtesy of Stephanie Liu, MD
Preceded by edema
COX-‐2 inhibitors should be used for treatment of capecitabine induced hand foot syndrome.
• 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
Rosen A, et al. (2013) Management Algorithms, in Dermatologic Principles and Practice in Oncology: (ed M. E. Lacouture), John
Wiley & Sons, Ltd, Oxford, UK
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Pseudocellulitis
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.
GemcitabinePemetrexed
A patient on erlotinib presents with the following eruption 2 weeks after starting therapy. What would you use for treatment?
AVOID topical retinoids as they are irritatingUse topical steroidsUse topical clindamycin or oral doxycyclineIsotretinoin may be considered in severe cases
Reactions on the Hands and FeetNot 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
Hand foot skin reaction (HFSR) ≠ Hand foot syndrome (HFS)Skin
toxicityCancer
treatmentHistology Shared
featuresDistinct
morphology
HFSR
Targeted therapy
• MTKi(sorafenib)
• BRAFi
Bands of necrotic keratinocytes
(Late) Acanthosis + hyperkeratosis or parakeratosis
Sub-‐ or intra-‐epidermal or subcorneal blisters
LocationHands and
feet
SymptomsPain/
dysesthesia
Erythema+/-‐ Edema+/-‐ Blisters
Resolution with
stoppingdrug
Localized hyperkeratosis
to weight bearing areas with halo of erythema around plaques
HFS
Chemotherapy
• 5-‐FU• Capcitabine• Cytarabine• Doxil• Taxanes
Scattered necrotic/dyskeratotickeratinocytes
Mild spongiosis
Interface/ vacuolar degeneration of the basal layer
Desquamation (peeling skin) in areas of blisters
Lipworth et al Oncology 2009
C.Larocca
Immune Checkpoint Inhibitors
Ipilimumab
PembrolizumabNivolumab
SKIN TOXICITIES
PruritusXerosisEczematous dermatitisPsoriasisBullous pemphigoidCutaneous lupusLichenoid dermatitisSJS/TENMorbiliformEruptive KAsInflammation of SKs/AKsVitiligoVasculitisSweet’s syndrome
ConclusionDrug Papulo-‐
pustular(acneiformCTCAE)
Cysts/ comedones/ KP-‐like
Paronychia Onycholysis Xerosis HFSR Keratoses SCC/ KA Eruptive nevi Photo-‐sensitive
Panniculitis
EGFRi ✓ ✓ ✓* ✓ ✓*
VEGFi ✓folliculitis ✓
BRAFi ✓folliculitis ✓ ✓ ✓*** ✓ ✓ ✓ ✓ ✓
MEKi ✓ ✓ ✓ ✓ ✓
mTORi ✓ ✓ ✓ ✓ ✓*** ✓
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
