Lecture 15 - Melanoma Flashcards by Alexa Carnahan

Epidemiology

mortality rates have declined rapidly

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Pathogenesis

melanocytes are dendritic pigmented cells that arise from neural-crest tissue furing early fetal development and migrate to sites within body
located in skin, uveal tract, meninges, and ectodermal mucosa
melanocytes synthesize melanin to protect tissues from UV radiation induced damage

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Melanoma results from

the malignant transformation of skin melanocytes or from the transformation of preexisting nevocellular nevi
number of growth factors, immune factors, and tumor antigens identified in progression of melanoma: BRAF, MEK, P13K/AKT, c-KIT, cytotoxic T lymphocytes, PD-1

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Cutaneous melanoma is characterized by growth patterns:

superficial spreading melanoma
nodular melanoma
lentigo maligna melanoma
acral lentiginous melanoma
uveal melanoma

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Superficial spreading melanoma

lesions arise from pre-existing nevus
initially appears flat but becomes irregular and asymmetrical
more common in women

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Nodular melanoma

strictly vertical growth, more aggressive tumors
appear dark blue-black in color and are raised and asymmetrical
more common in men

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Lentigo maligna melanoma

infrequent type, presents on face of elderly
tan lesion with areas of brown and black

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Acral lentiginous melanoma

frequently presents on palms, soles, or under nail beds; lesions have irregular convoluted borders
appear as brown stains
more common in african americans, asians, hispanics

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Uveal melanoma

arises from pigmented epithelium of choroid
most common ocular melanoma
often metastasis in liver

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Clinical presentation

ABCDE: asymmetric, irregular borders, wide variety of colors, diameter of >6mm, evolution of mole may be indicative of neoplastic transformation

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Diagnostic work up

biopsy of suspected lesion is gold standard
for suspicious lesions: wide-local excision with removal of underlying subcutaneous fat
sentinel-node biopsy for determining if melanoma has invaded lymph node beds
if melanoma is a clinical or pathologic stage IV, tumor tissue should be tested for BRAF V600E and K mutations

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Surgery

margins may need to accomodate anatomical or cosmetic consideration
Mohs surgery
surgery beyond localized disease is palliative

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Radiation

could be offered in adjuvant setting for select pts with + lymph nodes and high risk of relapse

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Adjuvant treatment

recommendations based on stage

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Treatment overview: stage IB or IIA (lymph node negative)

clinical trial or observation

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Treatment overview: stage IIB or IIC (lymph node negative)

clinical trial, observation, pembrolizumab

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Treatment overview: stage III

nivolumab, pembrolizumab, or dabrafenib/trametinib (if BRAF mutant), +/- radiation, or observation

Adjuvant nivolumab

categroy 1 recommendation (preferred immunotherapy) in adjuvant setting

Adjuvant pembrolizumab

improved recurrence free survival and reduced risk of distant metastases
similar to nivolumab in terms of efficacy and toxicity

Adjuvant dabrafenib/trametinib

in completely resected, stage III disease with BRAF V600E or V600K mutations
add MEK inhibitor to prevent resistance
toxicities: pyrexia, fatigue, nausea

First line treatment options

anti-PD-1 monotherapy: nivolumab, pembrolizumab
combination targeted therapy BRAF V600 mutation: dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib
certain circumstances: nivolumab/ipilimumab

Second line treatment options

anti-PD-1 monotherapy: nivolumab, pembrolizumab, nivolumab/ipilimumab, pembrolizumab/low dose ipilimumab for those that have progressed on prior anti-PD-1 therapy
combination targeted therapy BRAF V600 mutation: dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib
chemo: dacarbazine, temozolomide, paclitaxel, albumin bound paclitaxel, carboplatin/paclitaxel

Decision on treatment: what do we start with 1st: targeted therapy or immunotherapy?

targeted oral therapy for quicker onset of action - if pt has BRAF mutation

Targeted therapies

BRAF: vemurafenib, dabrafenib, encorafenib
MEK: trametinib, cobimetinib, binimetinib

Vemurafenib

BRAF kinase inhibitor rare toxicity: QT prolongation; unique toxicity: development of sqaumous cell carcinoma use in combo with cobimetinib

Cobimetinib

MEK inhibitor for the treatment of unresectable or metastatic melanoma in pts with BRAF V600E or V600K used in combo with vemurafenib to help prevent recurrence

Dabrafenib

BRAF kinase inhibitor toxicities: squamous cell carcinoma used in combo with trametinib

Trametinib

reversibly and selectively inhibits MEK 1 and 2 activation and kinase activity MEK 1 and 2 inhibition leads to decreased cellular proliferation, cell cycle arrest, and increased apoptosis used in combo with dabrafenib to help prevent BRAF resistance

Encorafenib

BRAF kinase inhibitor for BRAF V600E or V600K mutation, unresectable or metastatic disease less fevers!

Binimetinib

MEK-1 inhibitor approved for BRAF V600E or V600K mutated unresectable or metastatic melanoma in combo with encorafenib less fevers!

PD-1 inhibitors

nivolumab, pembrolizumab

CTLA-4 inhibitors

ipilimumab, tremelimumab

PD-L1 inhibitors

atezolizumab, durvalumab

Pembrolizumab

progression-free survival and overall survival longer with pembrolizumab has less toxicity than ipilimumab

Nivolumab/ipilimumab

for untreated, unresectable stage III or IV AEs: fatigue, diarrhea, pruritis, rash, N/V, pyrexia, decreased appetite, increased LFTs, colitis, hypothyroidism

Ipilimumab

CTLA-4: immune checkpoint molecule that down regulates pathways of T-cell activation fully humanized monoclonal antibody that blocks CTLA-4 to promote antitumor immunity in unresectable and 1st line metastatic setting toxicities: some pts have tumor growth prior to immune system activation

Immunotherapy response

immune related response criteria: response after initial increase in disease; reduction in total tumor burden after presence of new lesions need to understand so therapy isn't stopped based on what was thought to be progressing disease rash, diarrhea, colitis, neuropathy, pneumonitis, musckuloskeletal pain, endocrinopathy, diabetes, hypophysitis

Ipilimumab toxicities

skin: rash, vitiligo, pruritis GI: diarrhea, colitis liver: elevated enzymes, bilirubin, hepatitis endocrine: hypophysitis, hypothyroidism

Symptoms management of ipilimumab

grade 1: continue anti-CTLA-4 therapy, sx control grade 2: sx control, wait until resolution to grade 1 and continue anti-CTLA-4 therapy, if no resolution to grade 1, hold anti-CTLA-4 therapy and treat like grade 3/4 grade 3/4: hold anti-CTLA-4 therapy, start steroid - budesonide, methylprednisolone, dexamethasone

Chemo/immunotherapy

chemo rarely cures any pt in metastatic setting immunotherapy: interleukin 2 (fallen out of favor) - stimulator of cytotoxic T-cells, drug associated with life threatening capillary leak syndrome; interferon alfa (fallen out of favor)

Melanoma screening

montly self-exams of skin to serve as mechanism for recognizing moles or marks on skin that may be melanoma pts with strong family history should have clinical exam by physician high risk pts should receive yearly clinical exams

Melanoma prevention

sunscreen SPF >15 avoid tanning beds and sun lamps avoid direct exposure to sun between 10 am and 4 pm when IV rays are most intense