Lecture 15 - Melanoma Flashcards
Epidemiology
mortality rates have declined rapidly
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
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
Cutaneous melanoma is characterized by growth patterns:
superficial spreading melanoma
nodular melanoma
lentigo maligna melanoma
acral lentiginous melanoma
uveal melanoma
Superficial spreading melanoma
lesions arise from pre-existing nevus
initially appears flat but becomes irregular and asymmetrical
more common in women
Nodular melanoma
strictly vertical growth, more aggressive tumors
appear dark blue-black in color and are raised and asymmetrical
more common in men
Lentigo maligna melanoma
infrequent type, presents on face of elderly
tan lesion with areas of brown and black
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
Uveal melanoma
arises from pigmented epithelium of choroid
most common ocular melanoma
often metastasis in liver
Clinical presentation
ABCDE: asymmetric, irregular borders, wide variety of colors, diameter of >6mm, evolution of mole may be indicative of neoplastic transformation
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
Surgery
margins may need to accomodate anatomical or cosmetic consideration
Mohs surgery
surgery beyond localized disease is palliative
Radiation
could be offered in adjuvant setting for select pts with + lymph nodes and high risk of relapse
Adjuvant treatment
recommendations based on stage
Treatment overview: stage IB or IIA (lymph node negative)
clinical trial or observation
Treatment overview: stage IIB or IIC (lymph node negative)
clinical trial, observation, pembrolizumab
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
