Melanoma Flashcards
Histology
Superficial spreading melanoma
- Initially appears flat but subsequently becomes irregular and ___
Nodular melanoma
- strictly vertical growth, more aggressive tumors
- Appear dark ___ in color and are usually raised and asymmetrical
Lentigo maligna melanoma
- Presents on the face of ___ patients
- Tan lesion with areas of brown and black
- Has low propensity to metastasize
Acral lentiginous melanoma
- Frequently presents on the palms, soles, or under nail beds
- “brown stains”
Uveal melanoma
- Arises from pigmented epithelium of the choroid
- Most common ___ melanoma
- Often metastasis in ___
- asymmetrical
- blue/black
- elderly
- ocular, liver
Pathogenesis
- Majority of melanocytes are located at the epidermal-dermal junction of the skin and choroid of the ___
- Melanocytes synthesize melanin to protect tissues from ___ 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 the progression of melanoma
– ___ , MEK, PI3K/AKT, c-KIT, Cytotoxic T, lymphocytes, PD-1
- eye
- UV
- BRAF
Clinical Presentation - ABCDE
- Asymmetric
– Have irregular ___
– With a wide variety of ___ (from black to yellow to purple)
– With a ___ of > 6mm
– ___ of a mole may be indicative of neoplastic transformation
- borders
- colors
- diameter
- evolution
Diagnostic Work Up
- Biopsy of a suspected lesion is the gold standard
- If a melanoma is a clinical or pathologic stage IV, the tumor tissue should be ___ and __ mutations
- Sentinel-node biopsy is useful to determine if the melanoma has invaded lymph node beds
- CT scans may be indicated with strong
evidence of metastatic disease
- BRAF V600E and K
Surgery
Margins may need to accommodate
anatomical or cosmetic consideration
- Mohs surgery
- Patients with clinical lymph nodes without metastases, should have wide excision of primary site and lymph nodes involved ( ___ dissection if sentinel lymph node is positive)
- Surgery beyond localized disease is thought to be ___
- full
- palliative
Radiation and Chemotherapy
___ : Could be offered in the
adjuvant setting for select patients with
positive lymph nodes and high risk of
relapse
Adjuvant treatment
– Recommendations are based on ___
radiation
stage
Treatment Overview
Stage IB or IIA (lymph node negative)
- Clinical trial or observation
Stage IIB or IIC (lymph node negative)
- Clinical trial, observation, ___
Stage III
- ___ , pembrolizumab, or ___ / ___
(if BRAF mutant), +/- radiation, or observation
Unresectable stage III with in-transit lesions
- ___ (T-VEC), topical ___ , consider radiation, isolated limb perfusion
- pembrolizumab
- nivolumab, dabrafenib/trametinib
- Talimogene Laherparepvec, imiquimod
Adjuvant Nivolumab
Checkmate 238 trial
- Toxicities were ___ in the ipilimumab arm compared to nivolumab
- this made nivolumab the preferred
immunotherapy in the adjuvant setting
higher
Adjuvant Pembrolizumab
KEYNOTE-054
- Pembrolizumab was compared to placebo in Stage III resected melanoma
- Data ___ to be like nivolumab in this setting in terms of efficacy and toxicity
extrapolated
Adjuvant Dabrafenib/Trametinib
Used in patients with BRAF V600 mutations with stage ___ disease and SLN metastasis > 1 mm (category 1 recommendation by NCCN)
Toxicities
– Most common: ___ , fatigue, nausea
- III
- Pyrexia
Metastatic Treatment Options - 1st line
- anti PD-1 monotherapy (3)
- Combination targeted therapy BRAF V600 mutation (3)
- Certain circumstances (1)
Metastatic Treatment Options - 2nd Line
T or F: In general, immunotherapy and targeted therapy are preferred for
treatment of unresectable or distance metastases. For patients who
are not eligible for any of the recommended immunotherapy or targeted therapy options (due to progression on prior therapy, unacceptable toxicity, or comorbidities), cytotoxic therapy can be considered on a case-by-case basis
T
Decision on Treatment
What do we start with first: Targeted
therapy or immunotherapy?
- For a quicker onset of action, ____ should be started initially
* If the patient has a ___ mutation
* All patients with metastatic disease should be tested for BRAF mutations
- ~ 40-50% of cutaneous melanomas
- Immunotherapy can take ___ to see effect
- targeted oral therapy
- weeks
- BRAF
Vemurafenib
___ kinase inhibitor
- V600E mutation
Common toxicities:
- Fevers, peripheral edema, fatigue, headache, rash/skin disorders, photosensitivity, nausea/vomiting, diarrhea, arthralgias
- Unique toxicities: Development of ___ cell carcinoma
- BRAF
- squamous
Cobimetinib
Indicated: In treatment of unresectable or metastatic melanoma in patients with BRAF V600 __ or V600 __ mutations
* Used in combination with ___
- E, K
- Vemurafenib
Dabrafenib
BRAF kinase inhibitor
– Used in BRAF V600E mutations (single agent)
– Used in BRAF V600E or V600K mutations (in combination with ___ )
Toxicities:
* Fevers, headache, hyperkeratosis, hyperglycemia,
hand foot syndrome, arthralgia, alopecia, ___ cell carcinoma (up to 10%)
- trametinib
- squamous
Trametinib
Reversibly and selectively inhibits MEK 1 and 2 activation and kinase activity
- Inhibition of MEK 1 and 2 leads to decreased cellular proliferation, cell cycle arrest, and increased ___
- For use in BRAF V600__or V600 __ mutations
- apoptosis
- E, K
Dabrafenib and Trametinib
BRAF resistance to single agent therapy
typically occurs around __ - __ months
- With use of combination therapy
(BRAF/MEK) these agent may suppress
the downstream ___ mechanism
Preferred now:
* Dabrafenib and Trametinib
* ___ and Cobimetinib
* Encorafenib and ___
- 6-7
- resistance
- Vemurafenib
- Binimetinib
Encorafenib
BRAF Kinase Inhibitor:
– FDA approved for BRAF V600E or V600K mutation, unresectable or metastatic disease
Common toxicities:
- Fatigue, hand foot syndrome, rash, nausea/vomiting, anemia, ↑’d transaminases, arthralgias, ↑’d serum creatinine
- Less ___
fevers
Binimetinib
MEK-1 inhibitor
- FDA approved for BRAF V600E or V600K mutated unresectable or metastatic melanoma in combination with ___
Common toxicities
- Fatigue, rash, nausea/vomiting, anemia, ↑’d transaminases, visual impairment
* Less ___
- Encorafenib
- fever
___ and ___ : The Brakes
CTLA-4
PD-1
Pembrolizumab
KEYNOTE-006 - compared pembrolizumab and ipilimumab
Results:
– Both PFS and OS were statistically significantly longer with ___ arms
Toxicities:
– ___ arms had less toxicities
- pembrolizumab
- Pembrolizumab
Nivolumab
CheckMate 06734: 1st Line
- Compared single agent nivolumab with single agent ipilimumab or the combination of both
AE
- combo > ___ > ___
- Fatigue, diarrhea, pruritis,
rash, nausea/vomiting, pyrexia, decreased appetite, increased LFT’s, colitis, hypothyroidism
Median PFS
- combo > ___ > ___
- ipilimumab > nivolumab
- nivolumab > ipilimumab
Ipilimumab
Fully humanized monoclonal antibody that blocks CTLA-4 to promote antitumor immunity
- Since response is based on the patient’s immune system to kill the melanoma, some patients will have tumor growth prior to immune system ___
- All patients should receive all __ doses unless experiencing life threatening toxicities
___ and __ toxicities are the most common toxicities with Ipilimumab
- Endocrine toxicities take the longest to reverse (and may not)
activation
4
skin, GI
Immunotherapy Response
Immune related response criteria (irRC)
- Response after initial ___ in disease
- Reduction in total tumor burden ___ presence of new lesions
- Very important to understand so therapy isn’t stopped based on what was thought to be progressing disease
- increase
- after
immune mediated colitis, diabetes, and hypophysitis can occur
Chemotherapy/Immunotherapy
Chemotherapy ___ cures any patient in the metastatic setting, either single agent or combination therapy
Immunotherapy - ___ (really fallen out of favor)
– Stimulator of ___ __ -cells
– Demonstrated activity against melanoma cells
– Response rates range from 15 - 25
- rarely
- Interleukin 2
- cytotoxic
Immunotherapy
Interleukin 2
- Drug is associated with life threatening ___ ___ syndrome:
- Hypotension, visceral edema, dyspnea
- Tachycardia, arrhythmias, acute renal failure
- Patients typically receive therapy in the ICU
Interferon alfa (fallen out of favor)
capillary leak
Prognosis
Patients with melanoma > 4 mm thick have a __ % risk of relapse
- Patients with ___ ___ involvement have a 50 - 85% risk of relapse
- 5-year overall survival: 94%
* Local disease: > 99%
* Distant stage disease ~35%
- 50%
- lymph node
