Skin and genitourinal Cancers Flashcards
What are the four types of melanoma and the associated demographics / risk factors?
Superficial spreading
- Typically younger pts
- lower sun exposed areas
- Often associated with precursor nevus
- more associated with BRAF mutations
Lentigo maligna
- typically older pts
- High sun exposed areas
- Usually ass with actinic (solar) keratosis
- Rarley associated with BRAF mutations
Desmoplastic melanoma
- Older pts, very sun exposed skin
- High tumour mutational burden, responds well to immunotherapy
Non solar exposure related melanoma
- Eg uveal melanoma, acral melanoma, mucosal melanoma, melanoma in blue nevus
Melanoma risk factors?
In order of most risk to least risk
- Xeroderma pigmentosum (east asian and subcontinent)
- Prievious melanoma
- High nevus count
- Red hair and blue eyes
- Male sex
- first degree relative with melanoma
- Sun exposure - >10 sunburns <13yrs old
What are acceptable margins for a <1mm thickness, 12mm thickness, and >2mm thickness melanoma?
<1mm thickness - 1cm margin
1-2mm thickness 1cm or 2cm margins (evidence for both)
>2mm thickness - 2 cm margin
What has a worse prognosis? Stage 2C and stage 2B melanoma or stage 3A melanoma?
Stage 2B and 2C have worse prognosis that 3A
- it is now routine to offer adjuvant immunotherapy to stage 2C and 2B
Which stages of melanoma are offered adjuvant immunotherapy? and what agents are used?
Stage 2B and 2C
Stage 3B-C
PD1 or PDL1 inhibitors are used primarily, usually pembrolizumab or nivolumab
What systemic therapies are used for melanoma?
Immunotherapy
- PD1 and PDL1 inhibitors
Targeted therapies
- RAF/MEK inhibitors
Chemotherapy
- Dacarbazine (historically, but not so relevant anymore)
Give an example of a common mutation in melanoma?
B-RAF mutation is found in 40-50% of melanomas
- more common in superfical spreading type
- V600E in 3/4 of these, V600K in 1/5 of these
- Not prognostic but predictive of response to RAF/MEK inhibitors
What is the mechanism of action of BRAF mutation in melanoma
RAF is park of the RAF/MEK pathway
- activating mutations in b-RAF results in downstream signalling (MEK)
What are some common RAF inhibitors used in melanoma?
Dabrafenib, Vemurafenib, Encorafenib
RAF inhibitor toxicities?
Rash
Fatigue
Photosensativity rash
Arthralgias
SCC (in pts with activating RAS mutations)
What are some common MEK inhibitors used in melanoma?
Trametinib, Cobimetinib, binimetinib
MEK inhibitor toxicities?
Rash
Fatigue
Diarrhoea
Arthralgias
Peripheral oedema
No increase in SCC as inhibits down stream MEK
Why is immunotherapy better for intracranial melanoma mets compared to other systemic therapies?
Immunotherapy trains the immune system outside of the blood brain barrier, which results in enhanced immune response in the brain
Other systemic therapies have trouble crossing the blood brain barrier
Combined CTLA4 and PDL1 blockade is preferred
Mechanism of LAG3 inhibition in melanoma?
LAG 3 is a cell surface molecule on immune cells
- It negatively regulates T cell proliferation - and effector T cell function
- It is upregulated in melanoma
- It is distinct from the PD1 pathway
LAG3 inhibition works synergistically with immunotherpy
Give an example of a LAG3 inhibitor?
Relatlimab
How is metastitic melanoma treated?
Single agent immunotherapy usually
- Can consider adding LAG3 inhibitor Relatlimab given well tolerated
- Can consider ipilimumab + nivolumab in those with poor prognosis, liver mets, Braf positive disease, mucusal/acral melanomas
Immunotherapy generally preferred over targeted therapies RAF/MEKi even if BRAF positive
- RAF/MEK result in more rapid reduction in tumour size so can consider in pts who need rapid tumour size reduction initially (ie mass effect)
What are the two main types of keratinocyte carcinomas?
Basal cell carcinoma
Squamous cell carcinoma
Local therapies ar the mainstay of treatment for keratinocyte carcinomas. What are some local therapies types?
- Surgery (Mohs surgery, Standard Excision)
- Radiation therapy for non surgical candidates
- Topical or photodynamic therapy for in situ or low risk cancers
What is the main molecular pathway in BCC?
BCCs usually arrise from dysfunction in the hedghod signalling pathway
Explain the Hedghog pathway in BCC?
Membrane PTCH1 normally suppresses membrane SMO. Without this suppression SMO leads to downstream signalling
In BCC, PTCH1 is mutated. leading to SMO activation and downstream signalling. Drugs that suppress SMO directly can be used
What are some drugs that suppress SMO for BCCs?
Vismodegib, Sonidegib
General treatment for Met cutaneous SCC?
PD1 inhibitors
- gold standard for tumors that cannot be treated with local therapy (surg, radio) alone
- Cemiplimab (noval PD1i), pembrilizumab
Platinum based chemo - can still be effective for distant mets
General treatment for locally advanced cutaneous SCC?
Neoadjuvant therapy, then definitve surgery
- neoadjuvant with noval PD1i Cemiplimab
What is the precursor leision to cutaneous SCC?
Actinic keratosis
What is treatment for actinic keratosis?
Cryotherapy OR topical therapies (if cosmetic region)
- cosmetic therapies inc flurouracil, imiquimod
What are merkel cells in the skin?
they are the mechanoreceptors in the top layer of skin
Treatment of merkel cell carcinoma?
Highly immunogenic cancer, so treat with immunotherapies
Does PSA screening work? what is the main downside of PSA screening?
Yes it does work
Main down side is the opportunity cost - more medical intervention for pts with positive result, many people would not have had symptoms or effects of PrCa in their life
Risk stratification guide Pr Ca Rx. How is prostate cancer risk stratified?
Risk stratification, then treat by risk category
- risk stratification based on tumour grade, size and extension (MRI), volume (no. core Bx involved), PSA lvl, predicted survical from other co-morbidities
How is low risk Pr Ca treated?
Observation
How to determine of Pr Ca is organ confined or metastatic?
CTAP, PSMA PET imaging
How is organ confined intermediate or high risk Pr Ca treated?
Radical prostatectomy or Pr radiotherapy
WHat are some risks of radial prostatectomy?
Erectile dysfunction
Urinary incont (may actually improved if already had prostatomegaly related sx)
What are some risks of Pr radiotherapy?
Erectile dysfunction
Faecal incont
Is there a role for neoadjuvant therapy in organ confined Pr cancer?
Yes
- can use adjuvant androgen deprivation therapy prior to radical prostatectomy
How is Pr Ca monitored post surgery? What is the main salvage therapy?
Monitored with PSA post op. If PSA rising post op then this indicates cancer recurrance
Salvage therapy with adjuvant local radiotherapy
- can do PSMA PET first to see if met, because no point doing local radio if it is met
Treatment for recurrant Pr Ca if there is no role for local radio therapy (ie if distant recurrance)?
Watchful waiting, aiming for PSA doubling time >12/12
Androgen deprivation therapy is mainstay of treatment
What are some examples of GnRH agonists and how do they work?
Goserelin, leuprorelin, Tritorelin
Cointinue stimulation of the anterior pit by exogenous GnRH agonists results in down regulation of GnRH receptors and therefor down regulation of LH and FSH and therefore testosterone
Why are pts covered with additional anti androgen when initially being treated with GnRH agonists?
GnRH agonists can initially flare Pr disease due to initial increase in FSH and LH die to stimulation of ant pit by the exogenous GnRH agonist.
Therefore pts are covered with additional anti-androgen initially
What are some examples of GnRH antagonists and how do they work?
Degarelix
Relugolix (oral equivilant of degarelix)
Work by antagonising the GnRH receptors on teh ant pituitary resulting in down regulation of LH and FSH and therefore testosterone
What is the major risk factor for androgen deprivation therapies?
cardiovascular events
- use GnRHG antagonists in pts with CVD as these have the lowest relative risk compared to other forms of androgen deprivation
What are some examples of 1st gen androgen pathway inhibitors and how do they work?
Bicalutamide, Nilutamide
Stop DHT (dihydrotestosterone) from binding to androgen receptors (ARs)
When are 1st gen androgen pathway inhibitors used in Pr Ca?
As an adjunct of GnRH therapies, or as second line in non met or met Pr Ca
Given an example of an androgen metabolism inhibitor and how does it work?
Abiraterone
Irreversibly inhibits CYP17 in adrenals and possible in the tumor itself
What are some side effects of Abiraterone?
Causes upstream accumulation of steroids precursors (similar to CAH)
leads to hypokalaemia and hypertension
How are the side effects of Abiraterone in isolation managed?
Need to give indefinite prednisolone 10mg to compensate. This can have significant steroid side effects
When are 2nd gen androgen pathway inhibitors indicated?
Non metastatic locally advance castrate resistant Pr Ca
When is chemo used in Pr Ca?
Distant met disease, castrate resistant disease
Overview of Pr Ca chemotherapies?
Docetaxel - taxane, first line
Cabazitaxel - taxane, used second line when docetaxel resistance develops
Carboplatinin, Etoposide - used when neuroendocrine differentiator
Does BRCA 1 or BRCA 2 gene defects confer higher risk of Pr Ca in men?
BRAC2
however both increase risk of Pr Ca
When are antiresorptive (ie DMAB or zol) used in Pr Ca?
Should be used in cases of endocrine therapy related osteoporosis
Given some examples of other metastatic Pr Ca disease treatments?
PSMA labelled lutetium
- THERANOSTIC
- Not currently covered by gov, but ongoing research
Radium-223 (Alpharadin)
- used for symptomatic bone mets only
- Binds preferentially to hydroxyappetite in bone mets, local alpha radiation to area
Risk factors for endometrial cancer?
Obesity / metabolic syndrome
Excess estrogen (especially unopposed estrogen)
Tamoxifen
MSH6 germline mutations
Lynch syndrome
What is the major change to endometrial cancer recently?
Has recently be reclassified to include molecular subtypes.
this is due to teh PORTEC3 study that showed the response to adjuvant chemo-radiotherapy depended on the molecular subtype
THerefore we are now routinely molecular subtyping endometrial cancer to guide therapy
What are 4 common molecular subtypes of endometrial cancer?
POLE Mutation
MMR deficient
NSMP (no specific mutation present)
p53 abnormality
Which molecular subtype of endometrial cancer responds best to neoadjuvant chemoradio? WHich does not respond?
Responds best - p53 abn
Does not respond - POLE mutation -> de-escalation
General approach to management of endometrial cancers?
Management by staging
- Consider conservative management for very low risk women (ie stage 1A, low grade)
- if stage 1A but have p53 mutation then need to be upstaged and managed as such
- For everyone else, they are statified as low to high risk based on molecular subtype. this then guides adjuvant therapy
- POLE mut is low risk, de-escalate therapy
- MMRd - iummunotherapy mainstay
- p53 - chemo
Histological subtypes of ovarian cancer?
High grade serous - 70%
Endometrioid - 11%
clear cell - 1%
Low grade serous - 5%
mucinous - 3%
Features of high grade serous ovarian cancer?
- Arrise from fibrinated end of fallopian tube
- Ca 125 elevated in 70%. Ca 125 can also be elevaterd in preg or ascites
- Ultrasound is best, MRI can be useful but unnec. Dont Bx until definitive surg (avoid spillage into peritoneal cavity)
Check BRCA upfront - will guide management after chemo
General approach to high grade serous ovarian cancer?
Surgical resection, adjuvant chemo
What chemo is used for high grade serous ovarian cancer?
Platinum doublet + Bevacizumab
Management of high grade serous ovarian cancer in BRCA pos pts?
Surgical resection, adjuvant chemo
If found to have good response (complete response or deep partial response) then can treat with PARP post chemo
Some features of mucinous ovarian cancers?
Usually Dx early as they grow very large before met
Histo very similar to GI cancers, therefor usually CEA and CA19.9 pos and can use GI cancer therapies
Lower rates of response to platinum doublet than high grade serous
What is the primary risk factors for cervical cancer?
HPV infection
How is cervical cancer screened?
HPV testing 5 yearly from age of 25
- if found to have high risk HPV strain, then for pap smear test
How is cervical cancer diagnosed?
Usually dx early due to screening
- Dx based on cytology from colposcopy usually
Can be Dx due to symptomatic disease (usually advanced if symptomatic)
What are some symptoms of advanced cervical cancer?
- Post coital or dysfunctional vaginal bleeding or discharge
- Pelvic side wall invasion - classic triad of lower limb oedema, flank pain and sciatica
General management of cervical cancer?
Very early stage - surgery (extent of surgery dep on risk of spread, from conisation to radial hysterectomy with lymphadenectomy
All other pts - combination chemoradio OR palliative chemo
Chemotherapy option for cervical cancer?
Platinum doublet with bevacizumab
Treatment for RCC organ confined?
Surgery
Potentially some role for adjuvant pembrolizumab
Treatment for RCC metastatic?
Treatment stratified according to favourable prognosis vs intermidiate-poor prognosis
Treatment usually involved Sunitinib (VEGFR inhibotor) or lenvatinib (FGFR inhibitor) with immunotherapy
What is Von Hippel Landau disease?
Auto dom disease
Associated with clear cell RCC, pancreatic NET, and haemangioblastomas in retina/CNS
Due to a VHL deficiency.
- VHL usually degrades HIF. thus abnormal VHL mean HIF pathways are always active
Non muscule invasive bladder cancer treatment?
- TURBT via cystoscopy
- single dose of intravescicular chemo (gemcitabine or mitomycin C)
- Subsequent adjuvant or maintainence intravesicular chemo for 1-3 years if high grade Ta / TIS, or T1 disease
- Adjuvant intravesicular immunotherpy with BCG
- Causes local immune reaction
- Risk of systemic absorption (BCG-osis)
- given weekly for 6 weeks
Muscle invasive bladder cancer treatment?
Neoadjuvant chemo, cystectomy and radical radiotehrapy
- many different regimes for chemo
What are the two types of testicular cancer and some features of each?
Seminoma
- AFP always normal, May have elevated LDH or bHCG
- more common than non seminoma, slower growing then non seminoma
Non seminoma
- histologies include: yolk sac, embryonal, teratome, choriocarcinoma
- AFP associated with embryonal and yolk sac tumours. If elevated in pure seminoma, then indicates that there is occult non-seminoma (yolk sac or embryonal) component
-
Management of stage 1 (confined to testis) seminoma?
- Orchidectomy
- Adjuvant chemotherapy (carboplatin) OR radiotherapy (para-aortic) OR active survailence
Management of stage 1 (confined to testis) non-seminoma?
- Orchidectomy
- Adjuvant chemotherapy (BEP) OR active survailence
Radiotherapy not recommended
Management of stage 2 and 3 (regional LN spread and distant spread) testicular cancer (both seminoma and non seminoma)?
Usually chemo with BEP
Only seminoma are radiosensative
