Melanoma Flashcards
Prognostic factors of melanoma
Tumour thickness #1 most important
Mitotic rate #2 most important
Ulceration
Primary tumour location
Older age, male
Lymph node
Define stage 0, 1, 2, 3 melanoma
Stage 0: melanoma doesn’t invade the dermis
Stage 1: <2mm with no ulceration, <1mm with ulceration
Stage 2: >2mm with no ulceration, >1mm with ulceration
Stage 3: LN involvement
How common are BRAF mutations in melanoma?
40%
Typically skin with little chronic skin-induced damage
2 types of BRAF mutation in melanoma?
V600E (most) and V600K
How does BRAF mutation cause melanoma?
BRAF mutation –> downstream uninhibited activation of MEK and ERK pathways –> cell proliferation, survival
MOA of vemurafenib and dabrafenib
BRAF inhibitors
Used in unresectable melanoma with BRAF mutation
Why can’t we use BRAF inhibitors alone in melanoma with BRAF mutation?
> 80% will develop resistance
Adding a MEK inhibitor will increase time to resistance and reduce toxicity of BRAF inhibitor (reduce paradoxical activation of the MAPK pathway)
Treatment of unresectable melanoma with BRAF mutation
BRAF inhibitor (vemurafenib or dabrafenib)
PLUS
MEK inhibitor (trametinib)
How do CTLA4 inhibitors work?
Normally B7 (APC) binds to CD28 (T cell) to provide costimulation signal to activate T cell so it can kill the tumour cell
With time, T cell expresses CTLA4 which preferentially binds to B7 on APC, which has an inhibitory signal and therefore inhibits the T cell
By inhibiting CTLA4, we allow B7 and CD28 to continue binding and for T cells to be activated so it can do its job.
List a CTLA4 inhibitor we use in melanoma
Ipilimumab
How do PD1 inhibitors work?
PDL1 (found on many cells) bind to PD1 (on T cells) to provide an inhibitor signal on the T cell. Important in prevent chronic inflammation and tissue damage and promoting peripheral tolerance.
Tumour cells over express PDL1 so it will inhibit T cells from attacking them.
By inhibiting PD1 on T cells, it is unable to bind to the excess PDL1 on tumour cells so T cells can continue to be activated.
List 2 PD1 inhibitors we use in melanoma
Pembrolizumab
Nivolumab
Are CTLA4 inhibitors or PD1 inhibitors superior in melanoma?
PD1 inhibitors
Both combination is most superior
Treatment of unresectable BRAF negative and fit patient
PD1 inhibitor (pembrolizumab or nivolumab)
PLUS
CTLA4 inhibitor (ipilimumab)
*Very toxic combination but highest survival
Treatment of unresectable BRAF negative and less fit patient
PD1 inhibitor (pembrolizumab or nivolumab)
Treatment of CNS metastasis in melanoma
Surgery or targeted radiotherapy or whole brain radiotherapy
What’s pseudoprogression?
Tumour can get bigger before getting smaller
Can happen in immunotherapy
If patient is well, continue treatment then repeat CT in 4-6/52 to assess progression
Are PD1 inhibitors or CTLA4 inhibitors more likely to have immunotoxicity?
CTLA4 inhibitors
BUT combination is the worst! (1 in 2 will need to stop treatment)
List tissues/organs commonly affected by immunotoxicity (from immunotherapy)
Skin GIT Liver Endo: Adrenals, thyroid, pituitary Lung
Why does immunotoxicity occur with immunotherapy?
By inhibiting CTLA4 and PD1, you prevent the inhibition of T cells and you upset the balance of the immune system = results in unopposed immune activation, inflammation, tissue damage
Management of mild immunotoxicity (from immunotherapy)
Treat symptomatically
Continue the drug
Management of persistnet mild or moderate immunotoxicity (from immunotherapy)
Oral pred 1mg/kg
Omit/reduce next dose until symptoms resole or return to baseline
Management of severe/life threatening immunotoxicity
High dose IV pred. If symptoms improve, do steroid taper over at least 4 weeks
If symptoms do not improve within 5-7 days, consider alternative immunosuppressant
Cease immunotherapy permanently
Which type of immunotoxicity is most likely to be permanent?
Endocrinopathy - thyroid, adrenals
Will need hormone replacement lifelong
Do we do adjuvant immunotherapy in melanoma?
Not standard of care at the moment but this is a growing space
What’s actinic keratosis at risk of?
Becoming invasive SCC
Progress at an unpredictable rate to invasive disease
