melanoma Flashcards
epidemiology
5th common men, 6th common women. 10x more in whites than AA. 50% higher in white men than women. Worldwide incidence varies 100 fold. Death rates declining in white 50yo.
etiology
- UV radiation not proven but consistently strong association
- genetic (small % of overall) red hair, freckling
pathogenesis
- majority of melanocytes at epidermal-dermal junction and choroid of the eye
- progression involves series of steps
- secretes a variety of growth autocrine and paracrine factors-> proliferation
- tumor associated antigens
- oncogenes (ie. BRAF mutation)
risk factors
- lattitude, intesity of solar exposure
- whites fair hair (red and blond), light colored eyes (blue and green)
- blistering sunburns (especially during youth)
- intermittent, intense exposure worse than chronic, occupational
- previous non-melanoma skin CA, parent, increased atypical nevi >3, increased common nevi >101
pathophysiology
classified by histologice subtype (these do not determine tx)
- superficial spreading (>70%) - flat, irreg, spreading
- nodular (15-30%) pure vertical, aggressive, dark blue-black
- lentigo maligna - less propensity to metx
- acral lentiginous - more common in blacks, asians, hispanics, plantar surfaces
- uveal -most common intraocular
prevention
#minimize UV radiation #avoid sun 10am to 4pm #SPF 15 or higher, wide brim hats
screening
#predicated on relationship of tumor thickness / spread - CATCH EARLY - surgery highly successful if lesion yearly exam #suspicious lesions should be excised/biopsied by a professional (no shave bx)
signs and sx
usually asx
itch, ulceration, bleed
disease at presentation
local 84%, regional 8%, mets 4%, unstaged 4%
natural history
radial growth -> vertical growth -> lymph node spread -> mets (any organ in body, unlike non-melanoma)
Diagnosis
#Bx - plan as to not interfere with LN mapping and sentinel node bx #H&P -assess risk factors, FH, total body skin exam #stage III: CXR, LDH, CT (however, these are relatively insensitive at detecting distant mets) #stage IV: BRAF mutation testing
staging
#correlates size =T of lesion and N with likelihood of mets #ulceration, bleeding -> worse prognosis #Breslow TNM classification has replaced Clark
prognosis
#5yr OS = 98% local, 62% regional, 15% distant #larger than 4mm thick have 50% chance of relapse #older pt >70 and african am= worse prognosis
treatment principles
#according to stage of dz #surgery key #XRT limited to palliative setting #adjuvant chemo not recommended outside of clinical trial #immunotherapy
treatment -adjuvant immunotherapy - interferon alpha 2b (1yr, best duration unk) AND pegylated interferon alpha 2b (up to 5yr)
#primary lesions > 4mm (stage II) or involving regional LN rendered disease free by surgery (stage III) #low or intermediate NOT effective #OS risk reduction 11%
interferon alpha 2b AND pegylated interferon alpha 2b ADR
acute constituitional sx ( fever, chills, malaise, arthralgias), fatigue, HA, wt loss, myelosuppression, depression, hypothyroidism
management of interferon ADR’s - anorexia
calorie counts -> if miss 3meals /7 days HOLD for 1 week -> RED 33-50% with nutrition consult
management of interferon ADR’s - wt loss
> 10% wt loss -> HOLD 1 wk, RED 33-50% with nutrition consult
management of interferon ADR’s - fatigue
thyroid test-> if > or = to 2 pt decline in ECOG-> HOLD 1-2 wks, RED 33-50%
management of interferon ADR’s - depression
Beck’s inventory, moderate depression, HOLD 1-2 wks, RED 33-50% with psych eval
management of interferon ADR’s - AST
LFTs, when >10x ULN HOLD until <3x ULN, RED 33-50%
management of interferon ADR’s - WBC
ANC, 250, RED 33-50%
example inteferon alpha 2b dose
20MU/m2/d IV 5days/wk x4wk, THEN 10MU 3days/wk x48wk
example peg-interferon dose
6ug/kg/wk x8wks, THEN 2ug/kg/wk up to 5 yrs
treatment -adjuvant immunotherapy - node (-) pts 1-4mm thick or <1mm with ulceration
no std adjuvant recommended
treatment - metastatic - preferred regimens
ipilimumab (asx or more indolent), vemurafenib (sx, rapidly growing, quicker higher response rate), clinical trial, high dose IL-2
treatment - metastatic - other active (not preferred) regimens
dacarbazine, temozolomide, biochemotherapy, paclitaxel, imatinib (c-Kit mutation), paclitaxel/carboplatin
treatment - metastatic - aldesleukin (IL-2)
#RR 15-25%, CR 2-5% (some durable) #DO NOT use with untreated / active brain mets #tx related mortality 2.2%, need adherence to pt-eligibility criteria, well trained staff
treatment - metastatic - aldesleukin (IL-2) - ADR
cytokine induced capillary leak sx (hypotension, visceral edema, dyspnea, tachycardia, arrhythmia), visceral edema(= pulm congestion, pleural eff, edema), constitutional sx, pruitis, eosinophilia, BM suppression, inc LFTs, renal failure, N/V
treatment - metastatic - interferon
RR 15%, rare CR, unlike IL-2 CR not durable, not widely used
treatment - metastatic - combo interferon +IL-2
RR 18%, few CRs
treatment - metastatic - combo interferon +IL-2 +histamine
#phase III subset with hepatic mets appeared to respond #phase III trial though showed NO benefit over dacarbazine
ipilimumab MOA
blocks CTLA-4 (CTLA-4 turns off t cells)
ipilimumab - 1st line tx
compared ipi + dacarbazine vs dacarb
OS 11.2 vs 9.1mo
dose at 10mg/kg instead of 3 - cost is issue
no good monotherapy data
ipilimumab - 2nd line tx
OS 10.1 vs 6.4mo
some durable responses, 24mo OS 24%
3mg/kg q3wk x4oses (FDA and NCCN approved for primary and secondary)
ipilimumab response determination (1 of 4 categories)
different because based on activating the immune system to kill melanoma cells; because of this pts should receive ALL 4 doses unless severe or life threatening tox
A: response in baseline lesion
B: SD with slow, steady decline in total tumor volume
C: response after initial increase in total tumor volume
D: reduction in total tumor volume after the appearance of new lesions
Differences between WHO vs irRC criteria for response:
new, measurable lesions: always represent PD vs incorporated into tumor burden
new, nonmeasurable lesions (<5x5mm): PD vs do not define progression but preclude CR
non-index lesions: define response vs contribute to defining response
ipilimumab ADR
most common skin and GI track (think GVHD), treat with steroids until median resolution time of 2 weeks, mild may use topical; colitis grade 2-budesonide, grade 3 or 4 high dose steroid, if no response after one wk use infliximab
dacarbazine in metastatic dz
#only FDA approved chemo for metastatic melanoma #RR 20-25%, CR uncommon, lasts 5-7mo
temozolomide in metastatic dz
beneficial for pt with CNS mets
nitrosureas, cisplatin, and taxanes in metastatic dz
RR 10-20%, RR <10%, RR 6-18% respectively
combination chemo in metastatic dz
combo only increases toxicity, does NOT improve OS
biochemotherapy in metastatic dz
increases RR, but dose NOT improve OS
vemurafenib
BRAF v600e mutant, 81%RR
1st line: 6mo OS 84% vs 64% (dacarbazine)
2nd line: CR 6%, PR 47%
vemurafenib ADR
most common: rash, photosensitivity, hair loss, joint pain
grade III tox: cutaneous squamous cell CA (12%, remove surgically, continue tx), rash, GI, fatigue, joint pain
