MEK/BRAF inhibitors and the implications on patients and health care providers

Transcription

1 MEK/BRAF inhibitors and the implications on patients and health care providers Tara McKeown NP Paediatric Neuro Oncology Hospital for Sick Children Adjunct Lecturer, Lawrence S. Bloomberg, Faculty of Nursing, University of Toronto

2 Agenda Overview of low grade glioma Previous & current treatment What are BRAF & MEK inhibitors Side effects and management More questions

3 Pediatric low grade gliomas (PLGG) Most common pediatric brain tumours Grade I & II astrocytic tumour They can arise anywhere in the CNS Predisposing factors Neurofibromatosis I Tuberous Sclerosis

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6 Morbidity Visual compromise Endocrine dysfunction Precocious puberty Growth hormone Diencephalic syndrome Hypothalamic obesity Neurological deficits Neurocognitive issues Grabenbauer G, Oncology 2000, Grill J, Eur J Pediatr 2000, Gayre G, J Neuro-Ophthalmol 2001

7 Management of Pediatric Low grade gliomas

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9 Non surgical management of Pediatric LGG Traditionally, radiation has been the standard treatment Merchant. JCO 2009

10 Chemotherapy history First publication in 1976 (pre CT era): broad phase II study of vincristine in recurrent brain tumours Then in 1988 Vincristine-actinomycin (Packer) In 1993: Vincristine-carboplatin (Packer) In 1997: TPCV (Petronio-Prados) In 2005: Vinblastine (Bouffet) In 2011: Vinorelbine (Cappellano) Other: Combination with Avastin (Bevacizumab)

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14 Treatment Treatment and management for PLGG is complex Most children often require more then one line of chemotherapy PLGG IS A CHRONIC DISEASE

15 Biology of PLGG The mitogen activated protein kinase (MAPK) activity

16 BRAF & MEK inhibitors What are they? Why do/should they work? Trametinib mitogen activated protein (MAP) kinase inhibitor Inhibits MEK1 & MEK 2 Dabrafenib inhibitor of BRAF kinase activity Where did these drugs come from?

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24 Side effect management Drastic difference in how we manage the side effect profile of BRAF and MEK inhibitors compared to other chemotherapeutics Skin management and prophylaxis is key

25 Prophylaxis skin measures Daily short baths/showers with lukewarm water, after bath pat dry and apply moisturizer to body (thicker the better, ointments and creams over lotion). Avoid hot showers or baths, harsh soaps and bubble bath Itchiness can be avoided with frequent moisturizing Daily sunscreen (broad spectrum >SPF 50) and frequent reapplication, wide brim hats and good skin coverage Keep nails short and trim Baseline dermatology assessment

26 Skin Grading Grade I observe and treat topically, <10% BSA Grade II observer more carefully and consider systemic treatment, BSA >10%-<30% Grade III - stop/decrease medication, BSA >30% Grade IV admit for management BSA rule of 9's (divide body into regions of 9% areas or palmar method (palmar surface 1% BSA)

27 Dabrafenib Side effects Clinical Features Treatment Keratosis pilaris Morbilliform eruption Pinpoint follicular papules, typically on face, posterior arms and legs Pink macules and papules, trunk and extremities 1) Moisturize 2)Emollients with keratolytics 3)Low potency steroids for puritis 1) Gentle skin care 2) Sx<30% BSA topical steroids 3) Sx >30% BSA topical steroids? Addition systemic steroids Seborretic Dermatitis Puritis, erythematous, groin, face, head, axilla 1)Topical imidazole & topical steroids Palmoplantar Hyperkeratotis Thickening of palms/soles, yellowish colour 1)Gentle skin care 2)Keratolytics Photosensitivity Sunburn with minimal exposure 1)Education 2)Sun protective clothing and sunscreen Panniculitis Red or bruise like nodules that are tender on fat layers of skin 1)NSAIDS 2)Mid-high potency topical steroids 3)dermatology if suspect infection Melanocytic lesions/eruptic nevi Occur weeks to months 1) importance baseline photography 2) Full body exam by patient and team 3) Fast referral to derm to r/u malignancy Keratinocytic neoplasm (warts, SCC) None reported in kids yet, Dermatology expedited Hair curling

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30 Dabrafenib Side effects Clinical Features Treatment Keratosis pilaris Morbilliform eruption Pinpoint follicular papules, typically on face, posterior arms and legs Pink macules and papules, trunk and extremities 1) Moisturize 2)Emollients with keratolytics 3)Low potency steroids for puritis 1) Gentle skin care 2) Sx<30% BSA topical steroids 3) Sx >30% BSA topical steroids? Addition systemic steroids Seborretic Dermatitis Puritis, erythematous, groin, face, head, axilla 1)Topical imidazole & topical steroids Palmoplantar Hyperkeratotis Thickening of palms/soles, yellowish colour 1)Gentle skin care 2)Keratolytics Photosensitivity Sunburn with minimal exposure 1)Education 2)Sun protective clothing and sunscreen Panniculitis Red or bruise like nodules that are tender on fat layers of skin 1)NSAIDS 2)Mid-high potency topical steroids 3)dermatology if suspect infection Melanocytic lesions/eruptic nevi Occur weeks to months 1) importance baseline photography 2) Full body exam by patient and team 3) Fast referral to derm to r/u malignancy Keratinocytic neoplasm (warts, SCC) None reported in kids yet, Dermatology expedited Hair curling

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32 Dabrafenib Side effects Clinical Features Treatment Keratosis pilaris Morbilliform eruption Pinpoint follicular papules, typically on face, posterior arms and legs Pink macules and papules, trunk and extremities 1) Moisturize 2)Emollients with keratolytics 3)Low potency steroids for puritis 1) Gentle skin care 2) Sx<30% BSA topical steroids 3) Sx >30% BSA topical steroids? Addition systemic steroids Seborretic Dermatitis Puritis, erythematous, groin, face, head, axilla 1)Topical imidazole & topical steroids Palmoplantar Hyperkeratotis Thickening of palms/soles, yellowish colour 1)Gentle skin care 2)Keratolytics Photosensitivity Sunburn with minimal exposure 1)Education 2)Sun protective clothing and sunscreen Panniculitis Red or bruise like nodules that are tender on fat layers of skin 1)NSAIDS 2)Mid-high potency topical steroids 3)dermatology if suspect infection Melanocytic lesions/eruptic nevi Occur weeks to months 1) importance baseline photography 2) Full body exam by patient and team 3) Fast referral to derm to r/u malignancy Keratinocytic neoplasm (warts, SCC) None reported in kids yet, Dermatology expedited Hair curling

33 Hyperkeratotic hand and foot reaction

34 Dabrafenib Side effects Clinical Features Treatment Keratosis pilaris Morbilliform eruption Pinpoint follicular papules, typically on face, posterior arms and legs Pink macules and papules, trunk and extremities 1) Moisturize 2)Emollients with keratolytics 3)Low potency steroids for puritis 1) Gentle skin care 2) Sx<30% BSA topical steroids 3) Sx >30% BSA topical steroids? Addition systemic steroids Seborretic Dermatitis Puritis, erythematous, groin, face, head, axilla 1)Topical imidazole & topical steroids Palmoplantar Hyperkeratotis Thickening of palms/soles, yellowish colour 1)Gentle skin care 2)Keratolytics Photosensitivity Sunburn with minimal exposure 1)Education 2)Sun protective clothing and sunscreen Panniculitis Red or bruise like nodules that are tender on fat layers of skin 1)NSAIDS 2)Mid-high potency topical steroids 3)dermatology if suspect infection Melanocytic lesions/eruptic nevi Occur weeks to months 1) importance baseline photography 2) Full body exam by patient and team 3) Fast referral to derm to r/u malignancy Keratinocytic neoplasm (warts, SCC) None reported in kids yet, Dermatology expedited Hair curling

35 Panniculitis Althralgias Painful Nodular Treatment NSAID, short course of steroids

36 Dabrafenib Side effects Clinical Features Treatment Keratosis pilaris Morbilliform eruption Pinpoint follicular papules, typically on face, posterior arms and legs Pink macules and papules, trunk and extremities 1) Moisturize 2)Emollients with keratolytics 3)Low potency steroids for puritis 1) Gentle skin care 2) Sx<30% BSA topical steroids 3) Sx >30% BSA topical steroids? Addition systemic steroids Seborretic Dermatitis Puritis, erythematous, groin, face, head, axilla 1)Topical imidazole & topical steroids Palmoplantar Hyperkeratotis Thickening of palms/soles, yellowish colour 1)Gentle skin care 2)Keratolytics Photosensitivity Sunburn with minimal exposure 1)Education 2)Sun protective clothing and sunscreen Panniculitis Red or bruise like nodules that are tender on fat layers of skin 1)NSAIDS 2)Mid-high potency topical steroids 3)dermatology if suspect infection Melanocytic lesions/eruptic nevi Occur weeks to months 1) importance baseline photography 2) Full body exam by patient and team 3) Fast referral to derm to r/u malignancy Keratinocytic neoplasm (warts, SCC) None reported in kids yet, Dermatology expedited Hair curling

37 Melanocytic lesions Changes in nevi Explosive new nevi

38 Trametinib MEK inhibitors Side effects Clinical Features Treatments Papulopustular rash Pustules on face, chest, back 1) low potency steroids 2) Clindamycin lotion 3)Bleach baths 4) Oral antibiotics (tetracycline or biaxin) Morbilliform eruption Pink macules and papules, trunk and extremities 1) Gentle skin care 2) Sx<30% BSA topical steroids 3) Sx >30% BSA topical steroids? Addition systemic steroids Xerosis Hair changes Angular chellitis Dryness with puritis, commonly on distal extremities Thinning, coarse quality of hair, blonde/whitish Corner of the mouth are raw, crusted, itching pain 1) Gentle skin care, emollients, avoid bubble baths, hot water and harsh soap 1. Vaseline 2. Mix low potency steroid with mupirocin+/- nystatin Paronychia Red distal fingers toes inflammed 1. Anti-septic baths or salt soaks 2. Fucidin H or mupirocin+/- nystatin with steroids 3. Anti-biotics 4. chiropidist Diarrhea Mucositis 1. BRAT diet 2. Rule out infection - immodium Betaderm and steroids - paste

39 Papulopustular reaction Acneiform Head, neck and upper torso Puritis, erythema, weeping, crusting or infection

40 Trametinib MEK inhibitors Side effects Clinical Features Treatments Papulopustular rash Pustules on face, chest, back 1) low potency steroids 2) Clindamycin lotion 3)Bleach baths 4) Oral antibiotics (tetracycline or biaxin) Morbilliform eruption Pink macules and papules, trunk and extremities 1) Gentle skin care 2) Sx<30% BSA topical steroids 3) Sx >30% BSA topical steroids? Addition systemic steroids Xerosis Hair changes Angular chellitis Dryness with puritis, commonly on distal extremities Thinning, coarse quality of hair, blonde/whitish Corner of the mouth are raw, crusted, itching pain 1) Gentle skin care, emollients, avoid bubble baths, hot water and harsh soap 1. Vaseline 2. Mix low potency steroid with mupirocin+/- nystatin Paronychia Red distal fingers toes inflammed 1. Anti-septic baths or salt soaks 2. Fucidin H or mupirocin+/- nystatin with steroids 3. Anti-biotics 4. chiropidist Diarrhea Mucositis 1. BRAT diet 2. Rule out infection - immodium Betaderm and steroids - paste

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42 Weight gain??

43 Other side effects and considerations Folliculitis, pyogenic granuloma, fissuring of digists Cardiac valvular and function Optho uveitis and risk of retinal venus NPO guidelines and storage of meds

44 Combination BRAF and MEK inhibitors Significant less skin toxicities But only for a smaller subgroup of the population, BRAF V600E mutated

45 So why do we do this??

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49 Final take home points Most patients with low grade gliomas will need more than one line of therapy Response to treatment does not mean cure Biological predictors of the future changing how we treat Low grade Glioma is a long term chronic disease MEK and BRAF inhibitors provide a potential promising new treatment for this population Uncertain of when to stop and if we stop can we restart with same effect Side effect management Partnering with Dermatology, opthalmology Partnering together Long term side effects in children is unknown