Skin Cancer Tx

Question 1

What are some common sites of metastasis of skin cancer?

Answer 1

intestines, lung and brain

Question 2

What are the drugs for basal cell carcinomas?

Answer 2

-Aminolevulinic Acid-Porfimer-Sonidegib-Vismodegib

Question 3

What are BCCs typically caused by?

Answer 3

They are usually caused by a combination of cumulative and intense, occasional sunexposure.

Question 4

Are BCCs likely to metastasize?

Answer 4

BCC almost never spreads (metastasizes) beyond the original tumor site. Only inexceedingly rare cases can it spread to other parts of the body and become life-threatening.It shouldn’t be taken lightly, though: it can be disfiguring if not treatedpromptly.

Question 5

What are the treatment options for BCCs?

Answer 5

-surgical excision (Mohs surgery has the best cure rate)-cryotherapy-radiation-photodynamic therapy (aminolevulinic acid)-targeted therapy (for advanced BCCs)

Question 6

What is a common signaling mutation in BCCs?

Answer 6

Hedgehog signaling, animportant pathway inembryogenesis and organ maturation but one that is typically quiescent by adulthood except for minor tissue maintenance, butcan alsobecome dysregulated in some forms of cancer, including BCC.

Question 7

Hedgehog mutations have also been implicated in what kinds of cancers?

Answer 7

-rhabdomyosarcomas-medulloblastomas

Question 8

What are some of the pathological consequences of upregulated HH signaling?

Answer 8

-upregulation of anti-apoptotic protein Bcl-2, induction of VEGF and angiogenesis

Question 9

How do drugs attack abnormal HH signaling?

Answer 9

They (Vismodegib/Sonidegib) must act at or below the level of the transmembrane protein SMO (smoothened) because the pathway is ligand independent, so blocking HH binding to PTCH1 (protein patched homolog 1) is ineffective

Question 10

What are the AEs of Vismodegib and Sonidegib

Answer 10

-Teratogenic female AND male(makes sense since HH is invovled in organ formation)- up to 20 months after use in women and 8 months in semen in men-alopecia-endocrine dysfunction-GI toxicity-elevated serum creatinine

Question 11

What drugs are available for squamous cell carcinoma?

Answer 11

-aminolevulinic acid-afatinib-Cetuximab

Question 12

What are squamous cell carcinomas?

Answer 12

“Squamous cell carcinoma (SCC) is an uncontrolled growth of abnormal cells arising inthe squamous cells, which compose most of the skin’s upper layers (the epidermis).SCCs often look like scaly red patches, open sores, elevated growths with a centraldepression, or warts; they may crust or bleed. They can become disfiguring andsometimes deadly if allowed to grow.

Question 13

What are the treatment options for SSCs?

Answer 13

-surgery-photodynamic therapy (aminolevulinic acid)-targeted (afatinib and Cetuximab)-conventional drugs (bleomycin, docetaxel, hydroxyurea, fluorouracil

Question 14

What is Afatinib? Cetuximab?

Answer 14

PO irreversible TKI for EGFR and HER2Cetuximab- EGFR monoclonal bloking phosphorylation and activation of kinases

Question 15

Toxicities of targeted drugs?

Answer 15

These drugs can affect virtually any organ in the body due to their chronic use resulting in accumulation. Make sure to monitor closely

Question 16

What are the major toxicities of EGFR ddrugs?

Answer 16

-derm rxns especially common (rash, dry skin, etc.)-GI toxicity-rarely CV toxicity

Question 17

What are the drug options of actinic keratosis?

Answer 17

-Diclofenac-Imiquimod-Ingenol Mebutate-Aminolevulinic acid-Methylaminolevulinic acid

Question 18

What is actinic keratosis?

Answer 18

Actinic keratosis, also known as a solar keratosis, is a scaly or crusty growth (lesion) that mostoften appears on areas of the body commonly affected by the sun.You’ll often see the plural, “keratoses,” because there is seldom just one. In thebeginning, actinic keratoses are frequently so small that they are recognized by touchrather than sight. It feels as if you were running a finger over sandpaper. Patients mayhave many times more invisible (subclinical) lesions than those appearing on thesurface.

Question 19

What is the typical progression of actinic keratoses?

Answer 19

Most often, actinic keratoses develop slowly and reach a size from an eighth to aquarter of an inch. Early on, they may disappear only to reappear later. Most becomered, but some will be light or dark tan, pink, red, a combination of these, or the samecolor as your skin. Occasionally they itch or produce a pricking or tender sensation.They can also become inflamed and surrounded by redness. In rare instances, actinickeratoses can even bleed.”

Question 20

If left untreated actinic keratoses can transform into what?

Answer 20

SCC

Question 21

Treatment options for actinic keratoses?

Answer 21

-cyrosurgery is most common-topical options (5-FU creams such as imiquimod creams and ingenol mebutate)

Question 22

How does Imiquimod (Aldara) work?

Answer 22

It is an immunostimulant that primarily affects Toll-like receptors (and maybe adenosine receptors) to increase immune responses

Question 23

AEs of Imiquimod?

Answer 23

-topical site irritation (avoid sunlight)-can compromise condom and diaphragm integrity when used to treat genital warts

Question 24

How does Ingenol Mebate work?

Answer 24

The drug produces an interesting biphasic effect. Rapid lesion necrosis begins 1to 2 hours after application. Specific neutrophil mediated antibody (Ab)-dependentcellular cytotoxicity (ADCC ) follows within several days of drug application. Recallthat, in neutrophil-mediated ADCC, Ab are produced by B cells and bind to specificantigens on dysplastic epidermal cells. These Ab also bind to receptors on infiltratingneutrophils. Occupation of receptors on neutrophils by specific Ab triggersneutrophils’ killing mechanisms, including release of cytotoxic agents such as ROS, which destroy dysplastic epidermal cells.

Question 25

AEs of Ingenol Mebate?

Answer 25

-erythema, skin peeling, swelling, superficial ulceration(not really systemic)

Question 26

Melanoma treatment options

Question 27

What are some roles of IL-2 agonism (aldesleukin)?

Answer 27

IL-2 possesses a potent ability to stimulate cytotoxic T cells and to expand and activate antitumor lymphocyte populations (formerly termed lymphokine-activated killer cells). However, IL-2 also stimulates TReg cells which can diminish the beneficial effects of stimulating tumor- or virus-specific T cell responses. Indiscriminate stimulation is also responsible for the array of adverse drug effects.

Question 28

AEs of Aldesleukin?

Answer 28

- vascular (capillary) leak syndrome (VLS) which is associated with increased vascular permeability, hypotension, pulmonary edema, liver cell damage and renal failure is considered due either to stimulation of CD122hi NK cells, leading to the release of pro-inflammatory cytokines (such as TNF) and the production of vasoactive mediators, or to the direct binding of IL-2 to CD25+ endothelial cells rather than to NK cells or other CD25−CD122+ cells.- must be administered (IV bolus) in a hospital setting-severe lethargy, somnolence, and come-infection risks due to impaired neutrophils

Question 29

Contraindications to Aldesleukin?

Answer 29

-restricted to patients with normal pulmonary (PFT normal) and CV function (stress test)-CNS impairment -hepatic or liver disease -organ transplant (may increase risk of rejection due to improved cellular immune function).-treat pre-existing infections before giving   

Question 30

Describe the use of the BCG vaccine in melanoma 

Answer 30

May be used to stimulation of the patient’s immune system to recognize and eradicate the tumor cells.

Question 31

How can exogenous interferon (Intron A) be used in melanoma treatment?

Answer 31

Type I interferons (IFNs) activate antitumor immunity. This extrinsic activity includes stimulation of the innate and adaptive cytotoxic lymphocyte populations (T cells, NK cells, dendritic cells, innate lymphoid cells (ILCs)) and the negative regulation of suppressive cell types known to dampen antitumor immunity (for example, myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells). Type I IFNs also have an intrinsic impact on tumor cells by inhibiting proliferation, and modulating apoptosis, differentiation, migration and cell surface antigen expression.Type I IFNs can be produced by both tumor and immune cells, resulting in activation of immune cells, the actions of which will depend on, or complement, tumor cell intrinsic effects, including antigen presentation, cytokine production and death signaling pathways. As such, the effect of type I IFNs on the reciprocal crosstalk between immune and tumor cells is key to their antitumor potential.

Question 32

What are the AEs of Intron A?

Answer 32

can affect many organsBBWs:-may aggrevate fatal neuropsychiatric, autoimmune, ischemic (CV), and infectious disorders-worsening of depression

Question 33

What to monitor with Intron A?

Answer 33

-LFTs can be elevated-CBCs (can be toxic to blood components)-pulmonary X-rays-ECGs 

Question 34

What are the 'checkpoint inhibitors' used in melanoma treatment?

Answer 34

-Ipilumumab-Nivolumab-Pembolizumab

Question 35

How are T-cells activated?

Answer 35

It depends on peptide presentation AND co-stimulatory signals to refine the response (CD28 binding by either CD80 or CD86) 

Question 36

How can T-cell response be downregulated normally?

Answer 36

a | The CTLA4-mediated immune checkpoint is induced in T cells at the time of their initial response to antigen. The level of CTLA4 induction depends on the amplitude of the initial T cell receptor (TCR)- mediated signalling. High-affinity ligands induce higher levels of CTLA4, which dampens the amplitude of the initial response. The key to the regulation of T cell activation levels by the CD28–CTLA4 system is the timing of surface expression. Naive and memory T cells express high levels of cell surface CD28 but do not express CTLA4 on their surface. Instead, CTLA4 is sequestered in intracellular vesicles. After the TCR is triggered by antigen encounter, CTLA4 is transported to the cell surface. The stronger the stimulation through the TCR (and CD28), the greater the amount of CTLA4 that is deposited on the T cell surface. Therefore, CTLA4 functions as a signal dampener to maintain a consistent level of T cell activation in the face of widely varying concentrations and affinities of ligand for the TCR. b | By contrast, the major role of the programmed cell death protein 1 (PD1) pathway is not at the initial T cell activation stage but rather to regulate inflammatory responses in tissues by effector T cells recognizing antigen in peripheral tissues. Activated T cells upregulate PD1 and continue to express it in tissues. Inflammatory signals in the tissues induce the expression of PD1 ligands, which downregulate the activity of T cells and thus limit collateral tissue damage in response to a microorganism infection in that tissue. The best characterized signal for PD1 ligand 1 (PDL1; also known as B7-H1) induction is interferon-γ (IFNγ), which is predominantly produced by T helper 1 (TH1) cells, although many of the signals have not yet been defined completely. Excessive induction of PD1 on T cells in the setting of chronic antigen exposure can induce an exhausted or anergic state in T cells.

Question 37

So what is the effect of Ipilumumab?

Answer 37

It targets CTLA4 to prevent downregulation of T cell activity for treatment of melanoma and NSCLC 

Question 38

What is the effect of Nivolumab? Pembolizumab?

Answer 38

Nivolumab- targets PD1 for treatment of melanoma and NSCLCPemoblizumab- targets PD1 for treatment of PD1

Question 39

AEs of checkpoint inhibitors?

Answer 39

BBWs- endocrinopathies diarrhea, serious rash, and peripheral neuropathy-avoid in pregnancy-immune-mediated AEs such as dermatitis including toxic epidermal necrolysis

Question 40

Signaling pathways in melanoma

Answer 40

Two important components, BRAF and MEK have been identified as having therapeutic importance. On the one hand we can use PO small molecular weight drugs that are effective against mutated (constitutively active) BRAF, and on the other, separate drugs to block the effects of an important downstream modulator, MEK1/2.

Question 41

Target of Cobimetinib and Trametinib?

Answer 41

MEK1/2

Question 42

What melanoma drug targets BRAF V600E?

Answer 42

-Vemurafenib-Debrafenib (and BRAF V600K/D and wild-type BRAF)

Question 43

What does sorafenib target?

Answer 43

multiple intracelular and cell surface kinases

Question 44

Some things to consider with oral drugs?

Answer 44

most of these kinase inhibitors are CYP substrates, some weak inhibitors, some interact with food or dependent on acidic environments for uptake

Question 45

AEs for PO MEK or BRAF inhibitors?

Answer 45

-rash in EGFR TKIs-decreased LVEF, HTH, thromboembolic states-eye problems-lung problems