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NEWER CHEMOTHERAPEUTIC AGENTS – ADVERSE MUCOCUTANEOUS MANIFESTATIONS.pptx
- 1. Qualifications M.B.B.S., M.D.Dermatology Present affiliation(s) Assistant Professor, SCB Medical college and Hospital, Cuttack Publications & Presentations (Number) Publications: National – 16, International – 14 Presentations - 14 Academic achievements •2nd prize in Award paper session in 2nd AESTHETIC ASIA 2017 •1st prize in TYSA quiz zonal round (east zone). •2nd prize in TYSA quiz national round. •2nd prize in Award paper session in 37th CUTICON ODISHA 2018 •1st prize in Free paper session in 37th CUTICON ODISHA 2018 •MANORAMA DEVI PG ACADEMIC AWARD for post graduate in 37th CUTICON ODISHA 2018. •1st prize in QUIZ in 7th ONYCHOCON PURI 2018. Areas of interest Leprosy, Clinical dermatology, Dermoscopy Name: Siddhartha Dash Email ID: siddharth101990 @gmail.com FACULTY CV
- 2. NEWER CHEMOTHERAPEUTIC AGENTS –ADVERSE MUCOCUTANEOUS MANIFESTATIONS Dr. Siddhartha Dash Assistant Professor SCBMCH, Cuttack
- 3. Introduction Three broad categoriesof anticancer therapies: • Cytotoxic chemotherapy • Targeted therapies • Immunotherapies
- 4. Dermatologic Toxicities ofCytotoxic Chemotherapy Drug class Agents within class Dermatologic toxicities Alkylating agents • Classic alkylating agents: cyclophosphamide, ifosfamide, thiotepa • Platinum agents: cisplatin, carboplatin, oxaliplatin • Hyperpigmentation, • Type I hypersensitivity reactions • Alopecia • Radiation recall Antimetabolites Cladribine, gemcitabine, pemetrexed, fludarabine, 5-fluorouracil, tegafur, capecitabine • Maculopapular or bullous reactions • Hand Foot Syndrome • Hyperpigmentation • Nail changes • Alopecia Antitumor antibiotics • Anthracyclines: doxorubicin, daunorubicin • Bleomycin • HFS & Extravasation injury (vesicant type) • Flagellate dermatitis, Localized scleroderma, Raynaud’s phenomenon
- 5. Dermatologic Toxicities ofCytotoxic Chemotherapy Drug class Agents within class Dermatologic toxicities Mitotic inhibitors • Taxanes: paclitaxel, docetaxel • Vinca alkaloids: vincristine, vinblastine, vinorelbine • Atypical (taxane-induced) HFS, nail changes, serpentine supravenous pigmentation • HFS, maculopapular rash, alopecia Antimetabolites • Topoisomerase - I inhibitors: topotecan, irinotecan • Topoisomerase-II inhibitors: etoposide, teniposide, amsacrine • Reversible hair loss • HFS (type II inhibitors) • Paronychia (type II inhibitors) • Perianal irritation (type II inhibitors)
- 7. Targeted therapies • Preciselyintervene on distinct mechanistic effectors. • Includes: • EGFR inhibitors • Specific tyrosine kinase inhibitors • Multikinase inhibitors • RAS-RAF-MEK-ERK pathway inhibitors • Antiangiogenic agents • mTOR inhibitors • Hedgehog signaling pathway (HhSP) inhibitors • Proteasome inhibitors
- 8. EGFR inhibitors • Twoclasses of EGFR inhibitors exist: • Monoclonal antibodies (e.g. cetuximab, panitumumab, trastuzumab, pertuzumab, afatinib, dacomitinib) • Small-molecule tyrosine kinase inhibitors (e.g. gefitinib, erlotinib, lapatinib, canertinib) • Wild-type EGFR is critical for homeostatic regulation in keratinocytes and cutaneous adnexal cells.
- 9. Papulopustular eruptions: • Mostcommon and characteristic • Dose-dependent • Folliculocentric papules pustules crusting erythematotelangiectatic changes and PIH. • Common sites: Head, neck, chest and back • M/M: sunscreen, topical steroids, and topical or systemic antibiotics, systemic retinoids.
- 10. Xerosis andfissures: • Second most common cutaneous toxicity • Dryness and skin fragility of extremities acral fissuring and asteatotic eczema Hair changes: • Kinky, brittle, and slow growing scalp hair, scarring and non scarring alopecia. • Trichomegaly, or thickening, elongation, and curling of the eyelashes and eyebrows. • Hirsutism (rarely)
- 11. Mucosal changes: • Mucositis,stomatitis, aphthous-like ulcers of the oral and genital mucosa, vulvovaginitis, balanitis, and conjunctivitis. Nail changes: • Onycholysis, paronychia, pyogenic granuloma-like lesions, and changes in matrix pigmentation and texture
- 12. Specific Tyrosine KinaseInhibitors • Imatinib, dasatinib, ponatinib, bosutinib and nilotinib: Malignancies driven by BCR-Abl, c-kit, and PDGF receptor aberrancies • Facial edema and morbilliform rash • Reversible dose-dependent hypopigmentation in darker-skinned individuals due to imatinib. • T/t: low sodium diets for edema topical & oral corticosteroids for rash
- 13. Multikinase Inhibitors • Sorafenib,Sunitinib, Pazopanib, Vandetanib, Regorafenib: used to treat multiple solid tumors, including renal cell, colon, breast and hepatocellular carcinomas. • Hand foot skin reaction: • Symmetric hyperkeratotic plaques with serious inflammation over sites of pressure/friction. • Low-grade disease: emollients, keratolytic agents, topical corticosteroids, topical anesthetics, and antiseptic soaks • High-grade disease: Dose reduction/stoppage.
- 14. • Hair changes: •Brittle hair with kinking, depigmentation, and slow growth • Alopecia • Others: • Splinter subungual hemorrhages, stomatitis, xerosis, inflammatory eruptions, and reversible yellow discoloration of the skin (sunitinib). • Keratoacanthoma and invasive squamous cell carcinoma(SCC).
- 15. RAS-REF-MEK-ERK Pathway Inhibitors •The RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway: Responsible for cellular proliferation, survival, and differentiation. • Two categories of targeted therapies specific for this pathway: • BRAF inhibitors (e.g., vemurafenib, encorafenib and dabrafenib) • MEK inhibitors (e.g., trametinib, cobimetinib, Binimetinib).
- 16. BRAF inhibitors: •Non-malignant cutaneous adverse events: • Non specific rash: Maculopapular Papulopustular Grover disease like Keratosis-pilaris like • Others: HFSR, pruritus, hyperkeratosis, photosensitivity, alopecia, panniculitis, xerosis, and paronychia • Malignant cutaneous adverse events: • Squamoproliferative lesions: ranges from verrucous keratoses to invasive SCC. • Melanocytic lesions: • Can induce dynamic changes in existing melanocytic lesions. • New eruptive lesions, including dysplastic nevi and BRAF wild type second primary melanoma
- 17. MEK inhibitors: • EGFR-inhibitorlike toxicities: papulopustular eruption, xerosis, hair and nail changes, and pruritus. • Exanthematous morbilliform rash. • No reports of secondary cutaneous malignancy.
- 18. Antiangiogenic Agents • VEGFreceptor inhibitors (e.g. bevacizumab): targeted therapies that interfere with this obligatory neovascularization. • Adverse effects: • Mucocutaneous hemorrhage (epistaxis) • Delayed wound healing
- 19. mTOR Inhibitors • mTORinhibitors: rapamycin/sirolimus and everolimus • Mucocutaneous adverse effects: 1. Stomatitis: • isolated discrete aphthae on non-keratinizing epithelium. • Pain, odynophagia, and dysphagia can result in therapy limiting dehydration and malnutrition. 2. Morbilliform, eczematoid and EGFR inhibitor like acneform eruptions. 3. Nail: Paronychia and pyogenic granuloma (similar to EGFR inhibitors).
- 20. Hedgehog Pathway Inhibitors •HhSP inhibitors (e.g. vismodegib and erismodegib): advanced, metastatic, or unresectable basal cell carcinoma as well as for basal cell nevus syndrome. • Mucocutaneous toxicities: 1. Alopecia: Reversible 2. Dysgeusia: Reversible with treatment termination
- 21. Proteasome Inhibitors • E.g.Bortezomib – used in hematological malignancy • Mucocutaneous toxicity: morbilliform rash, erythematous papules and nodules, or malignancy-associated Sweet’s syndrome. • Cause: large drug-induced proinflammatory cytokine efflux. • Treatment: systemic corticosteroids
- 22. IMMUNOTHERAPY • Downregulate surfacereceptors of cytotoxic T – cells. • Adjunctive anticancer therapy for multiple solid tumors. • Three classes: CTLA-4 inhibitors: ipilimumab, tremelimumab anti–PD-1 protein: nivolumab, pembrolizumab anti–PD-L1 protein: atezolizumab, durvalumab, avelumab
- 23. Dermatologic toxicity: 1. Maculopapularrash: • MC • centrifugal spread • T/T: oral antihistamines and topical and systemic corticosteroids. 2. Pruritus: • 2nd MC • May occur with or preceding maculopapular rash or can occur on normal appearing skin. • T/t: gabapentin, doxepin, mirtazapine 3. Lichenoid reactions (mostly occurs with anti PD-1/PDl-1 agents), classic LP, LSA and lichen planus pemphigoides.
- 24. 4. Autoimmune disorders: •Reactivation of pre-existing disorders, as well as de novo disease. • Dermatomyositis, vasculitis, Sjogren’s syndrome, Crohn’s disease, rheumatoid arthritis, thyroiditis, and autoimmune thrombocytopenic purpura. 5. Vitiligo: • Seen most commonly in patients with melanoma. • Bilateral and symmetric distribution. • Depigmentation of existing nevi, eyelashes, eyebrows, or scalp hair. • Seldom reversible with treatment termination. • Positive prognostic factor for treatment response and overall survival. 6. Bullous pemphigoid
- 25. 7. Exacerbation ofpsoriasis and sarcoidosis. 8. Hair changes: alopecia, depigmentation, and change in texture 9. Nail changes: onychomadesis, onycholysis, and paronychia 10. Xerostomia and dysgeusia 11. SJS, TEN and DRESS 12. Secondary eruptive squamo-proliferative lesions, including invasive cutaneous SCC
- 26. References • Deutsch A,Leboeuf NR, Lacouture ME, McLellan BN. Dermatologic Adverse Events of Systemic Anticancer Therapies: Cytotoxic Chemotherapy, Targeted Therapy, and Immunotherapy. Am Soc Clin Oncol Educ Book. 2020 May;40:485-500. • Das A, Sil A, Khan IA, Bandyopadhyay D. Dermatological adverse drug reactions to tyrosine kinase inhibitors: a narrative review. Clin Exp Dermatol. 2023 Feb 20:llad070. • Haraszti S, Polly S, Ezaldein HH, etal. Eruptive squamous cell carcinomas in metastatic melanoma:an unintended consequence of immunotherapy.JAADCase Rep.2019;5:514-517. • Sibaud V, Meyer N, Lamant L,etal. Dermatologic complications of anti-PD-1/PD-L1 immune check point antibodies.CurrOpinOncol.2016;28:254-263. • Plachouri KM,Vryzaki E, Georgiou S.Cutaneous adverse events of immune checkpoint inhibitors:a summarized overview.CurrDrugSaf.2019;14:14-20. • Wozel G, Sticherling M, Sch¨on MP.Cutaneous sideeffects of inhibition of VEGF signal transduction.JDtschDermatolGes.2010;8:243-249.
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