Skin Cancers Study Notes

EI Skin Cancers Gauri Sabnis, PhD 5thmostcommoncancer inbothin andI Reading: Katzung et al, Basic and Clinical Pharmacology, Chapter 54 Goodman and Gilman’s Pharmacological Basis of Therapeutics, Chapter 37 Dipiro et al, Pharmacotherapy: A pathophysiologic Approach, Chapter 116 madrone ✥Largest organ of the integumentary system mainly Skin divided into ❊ Epidermis ❊ Dermis arrightendertheskin ❊ Hypodermis (subcutaneous tissue) ✥Serves 3 functions bacteria helpagainst ❊ Protection, sensation and regulation ✥4 cell types present in epidermis I I ❊ Keratinocytes Hair soovofskin goingto ❊ Melanocytes ❊ Langerhans cells Immure byconer ❊ Merkel cells cells for responsible sensation 4 harmful A beast deadlistinhumaneval Bus C ✥UV radiation can cause todeadlistsurfaced ❊ Pigmentation, degradation of collagen, ❊ DNA damage/mutagenesis ❊ Immunosuppression ✥Major cause of skin cancers including melanoma is sunlight ⇥ Ultra-violet rays coming from the sun ❊ UV-A (310 – 410 nm) Photoaging ⇥ Most of the UV radiation reaching earth surface is UV-A ⇥ Least harmful of the 3 types ⇥ But can cause premature aging of the skin, physical damage and skin cancer ❊ UV-B (280 – 310 nm) ⇥ Most likely cause of skin burns ⇥ Majority (up to ~300 nm) absorbed by ozone O widow UV-C (100 – 280 nm) ⇥ Involved in photobiosynthesis of vitamin D asturnotes ⇥ Most harmful to all living things Feely's ⇥ Filtered out by stratospheric ozone feelit ❊ ✥Ozone depletion and 1988 Vienna Convention for the protection of the ozone layer ❊ Ban on CFCs 5 Types of skin cancers ✥Actinic Keratoses (pre-cancerous) ❊ Dry, scaly patches or spots ❊ Mostly fairer skin ❊ Usually from sun exposure ❊ Can progress to cancer – squamous cell carcinoma ✥Squamous cell carcinoma ❊ 2nd most common type of skin cancer ❊ Mostly fairer skins, but also darker skins ❊ Part of skin that is exposed to sun ✥Basal cell carcinoma 8 ❊ Most common type of skin cancer ❊ Fair skins but also darker skins ❊ Develops years after sun exposure or tanning beds ❊ Early diagnosis and Rx is important ❊ Can invade the surrounding tissue and grow into nerves, bones causing damage see 6 Types of skin cancers ✥Melanoma ❊ Deadliest form of skin cancers ❊ Rarer form of skin cancer ❊ Frequently develops as a mole or a dark spot ❊ Early diagnosis and Rx are crucial ❊ Cutaneous and uveal melanoma woo eye sancerinthe ✥Other “skin” cancers happensinptwho op Mostly haveAlot ❊ Kaposi sarcoma ❊ Cutaneous lymphoma 7 Asymnty DDonator B Border E C color Wowing ABCDEs of melanoma ✥A= Asymmetry ✥B = Border ✥C = Color Mabmmor ✥D = Diameter bigger ✥E = Evolving 8 Age 6 Day Typedskintype Risk factors pave AtainorOAns ✥Caucasians; pale white skin, red or blond hair, blue or green eyes, high degree of freckling set ❊ Fitzpatrick skin type I ✥Sun sensitive skin ❊ Rarely tans and/or burns easily ❊ Had 5 or more sunburns between the ages of 15 and 20 763Me ✥Age – cumulative sun damage ✥Moles ❊ 50 or more moles ❊ Large moles ❊ Atypical mole(s) ✥Melanoma history (self) or family ❊ History of other cancers such as breast or thyroid ✥Weakened immune system ❊ AIDS ❊ Receiving medicine for auto-immune disease or organ rejection prevention ✥Living in sunny locations (CA, FL, AZ, LV etc.) ✥Using tanning beds ❊ Individuals who spent time in tanning beds before the age of 35 have 75% increased risk of melanoma 10 Prevention ✥Sun protections ❊Avoid exposure to UV radiation ⇥ Natural and artificial so ❊Seek shade – 10 am to 2 pm ❊Protective clothing – long sleeved shirts, longer pants, wide-brimmed hat, shades ❊Extra caution near water, sand or snow ❊Sunscreens ⇥ SPFs, UVA and UVB protection ⇥ Reapplication, water-resistance 12 Sun protectionj important re applying isvery ✥Active ingredients include – ❊ Chemical agents that absorb incident solar radiation – sunscreens ❊ Physical agents containing particulate materials that block or reflect incident energy and reduce transmission to skin ✥Ideal sunscreen – ❊ Photostable, remain intact for sustainable period, non-irritating, invisible and nonstaining to clothes ❊ Block both UVA and UVB radiation e so see ✥Approved UVA blockers include ❊ Avobenzone (Parsol 1789) , oxybenzone – sunscreen ❊ Titanium dioxide, zinc oxide – sunblocks ⇥ Word “sunblock” – not allowed anymore! ✥Approved UVB filters include ❊ Octorylene, salicylates (octisalate, ✥Sun protection factors (SPFs and UPFs) ❊ SPF: for lotions, creams ❊ SPF-15 means only 1/15th of the rays reach the skin – it will take 15 times as long for the skin to burn compared to unprotected skin ✥SPF rating is useful for UVB rays e but not useful in UVA protection ❊ Star rating for UVA rays ❊ UPF: UV protection factor – mainly used for clothing ⇥ Skiers, winter sports, water sports ⇥ Tighter the weave – greater protection ⇥ Wide brimmed hats to protect, nose, ears and neck homosalate) 13 Sun protection ✥Apply 30 minutes before sun exposure ✥Reapply every 2 hours, after swimming and perspiring heavily ✥About 1 oz (palm-ful) to cover arms, I legs, neck and face ✥Must be used regularly, not just when expecting prolonged exposure ✥Outside temperature is not indicative of sun’s damaging rays ❊ First of the season sunburns ✥“Slip! Slop! Slap! Seek and Wrap” ❊ Slip on a shirt ❊ Slop on sunscreen ❊ Slap on a hat ❊ Seek shade between the hours of 12 to 4 pm ❊ Wrap on sunglasses to protect the eyes and sensitive skin around them 14 Diagnosis ✥Biopsy posentiremassisremoed Pfrtion as ❊Incisional or excisional ✥Pathologic evaluation ❊Cancer diagnosis ❊Staging ✥Other diagnostic tests ❊B-RAF and c-Kit ❊Abdomen, chest, pelvic CT or PET/CT, bone scans and brain MRI ✥Systemic symptoms – shortness of breath, abdominal or bone pain, headaches and mental status change (hallucinations) ❊Metastatic site SHABM 15 comeBod Systemic therapy ✥Immunotherapy ❊ Anti-PD-1 pembrolizumab (Keytruda) OR nivolumab (Opdivo) ❊ Nivolumab + ipilimumab (Yervoy) ✥Targeted therapy ❊ B-RAF V600E mutation – Vemurafenib (Zelboraf), dabrafenib (Tafinlar) and encorafenib (Braftovi) ❊ MEK inhibitor – trametinib (Mekinist), cobimetinib (Cotellic) and binimetinib (Mektovi) ✥Other regimens ❊ Cytotoxic regimens ⇥ Dacrabazine Dtr ⇥ Temozolomide codbazine go.pro Alkyla&ng Agents - Triazenes ⇥ Paclitaxel (or Abraxane) ⇥ Carboplatin/paclitaxel ❊ Bio-chemotherapy ⇥ Dacarbazine or temozolamide and a platinum ± vinblastin/nitrosurea and IL-2 + intrferon-2b 16 Alkylating Agentst ✥Produce highly reactive ion intermediates which transfer alkyl groups to cellular macromolecules ❊ N7 or O6 of guanine is highly susceptible g ✥Alkylated DNA can undergo ❊ Cross-linking of bases, with other strand of DNA, cross-linking of DNA with proteins ❊ Excision of guanine from the DNA backbone ⇥ BER or NER pathway ❊ Abnormal base pairing ⇥ MMR pathway ❊ Unfixed errors can lead to mutations ⇥ Oncogenes and secondary malignancies ✥Anticancer actions of alkylating agents ❊ Cytotoxic effect – cell death ⇥ Not dependent on multiplying DNA - not cell cycle specific ❊ Radiomimetic actions 18 DNA Damage by Alkylating Agents 19 Aziridines R Bis(chloroethyl)amines Where R = Cyclophosphamide Nitrosureas Where R = Thiotepa BCNU (carmustine) Triethylenemelamine Chlorambucil CCNU (lomus=ne) Alkylsulfonates Melphalan CH3 Mechlorethamine Methyl – CCNU (semustine) Busulfan 20 Alkylating agents traced Enter S Mato Mo ✥Thio-TEPA is a tertiary aziridine Aziridines ❊ Weaker than quaternary aziridinium - weaker alkylator ❊ Can enter CNS ❊ Severe myelosuppression - infections and hemorrhage Thiotepa ✥Busulfan - one/both methylsulfonate ester moieties can be displaced by nucleophilic attack on N7 of G ❊ Exerts myelosuppressive action and was used primarily for chronic phase of CML before imatinib (Gleevec) Triethylenemelamine ❊ Now used only to prep for stem cell transplant ❊ Toxicity: a Alkylsulfonates ⇥ Pulmonary fibrosis (busulfan lung), hepatic injury and GI mucosal damage ⇥ Skin: alopecia, pruritis, hyperpigmentation of skin (busulfan tan) 88 Busulfan 21 ✥Unstable structures - readily decompose in Mirco Nitrosoureas redefine aqueous inside of a cell ❊ Fragmentation due to loss of H+ from the urea moiety ❊ Cyclization of resultant anion to unstable oxazolidine ❊ Decomposes to release N2 and CO2 and cytotoxic electrophiles ⇥ Vinyl carbocation ⇥ Acetaldehyde ⇥ 2-chloroethylamine ❊ Alkylate DNA at N7 of G ❊ A 2nd pathway to generate electrophile 2-chloroethyl Nitrosureas Where R = carbocation ✥Both highly lipophilic ❊ Precludes complete aqueous solution — made with 10% ethanol (BCNU) BCNU (carmustine) ❊ Can penetrate BBB but degrades in blood in 15 minutes ⇥ Wafer formulation - implanted directly into the brain (Grand mal seizures) ✥Resistance due to upregulation of OCCNU (lomustine) Methyl – CCNU (semustine) methylguanine DNA-methyl transferase with subsequent repair of the DNA ✥Toxicity: profound and delayed myelosuppression (up to 6 weeks) ❊ Thrombocytopenia and leukopenia - hemorrhage and infections ❊ Acute and delayed pulmonary toxicity is also a risk 22 Triazines ✥Slightly different MOA - methylate O6 of guanine ❊O6 O guanine alkylation leads to mispairing (G-T) during subsequent DNA replication ❊Cell destruction due to post-replication mismatch repair system ⇥ Patients who can repair this - through O6-methylguanine DNA-methyl transferase are resistant • MGMT gene silencing can be used to predict response to temozolamide ⇥ Enzyme is irreversibly damaged during this repair - subsequent loss of DNA repair capability is lost 23 Activation of Triazenes Md Dacarbazine MTIC Cacticate AIC They Temozolamide Carbonium ion Alkylated DNA AttachtheDNA 24 Triazines Oba ✥Procarbazine: Inhibits DNA, RNA and protein synthesis, prolongs interphase and produces chromosomal breaks ❊ Oxidative metabolism generates azoprocarbazine, H2O2 and other metabolites (a weak MAO inhibitor) ⇥ DDI ⇥ Disulfiram-like reaction when combined with ethanol ❊ Secondary cancers – higher than other alkylating agents ✥Dacarbazine: Prodrug, activated in vivo CYP1A ❊ Generates carbonium ion (CH3+) ❊ Potent vesicant ❊ Myelosuppression - thrombocytopenia and leukopenia most common and can be fatal ❊ Increased risk of hepatotoxicity and hepato-cellular necrosis ✥Temozolamide: prodrug, activated in non-enzymatic manner to generate CH3+ ion t ❊ Women clear temozolamide ~5% less than men ❊ MGMT gene silencing is a good indicator of response fgenesilenceiptrespond vemygoodtothedng 25 Stage IV Melanoma Treatment Evolution Pre-1998 1998-2011 2011 – 2014 Approvals with no positive trials No new drugs 7 New regimens approved Vemurafenib 1975-DTIC 1998-HD-IL2 19982011 2011 Ipilimumab Cytotoxic chemotherapy Immunotherapy Targeted therapy 2012 Debrafenib 2013 Trametinib Debrafenib + Trametinib 2014 Nivolumab Pembrolizumab 26 Immunotherapy ✥Immunosuppressive for transplants, allergic reactions of drugs ❊Suppress immune system’s activity ❊Examples – GCs, methotrexate etc. ⇥NOT anticancer immunotherapy ✥Immune modulation for anti-tumor action ❊Cytokines ❊Interferons ❊TNF ❊Immune checkpoint modulators 27 Immunotherapy ✥Interferons ❊ High dose IFN-α, pegylated IFN-α ❊ Response rates range from 10-30% usedenymore really mom ✥IL-2 - Aldesleleukin (Proleukin) O 00 ❊ Produced by activated T cells and a growth factor for T-cells, NK cells ❊ Can stimulate cytotoxic activities of NK cells, CTLs, monocytes, LAK cells and TILs ⇥ Promotes activated T-cell proliferation and enhanced killing by NK-cells ⇥ Resting T-cells and tumor cells lack expression of IL-2 receptor ❊ Response rates of 15-25%, but durable response (median 70 mo.) even w/ large tumor burden ❊ Given at high dose 600,000 IU/kg every 8 hours (max 14 doses in 5 days) for 2 cycles O soo ❊ Cytokine induced capillary leak syndrome (BBW) – loss of vascular tone and extravasation of proteins and fluid into extravascular space ⇥ Hypotension, visceral edema, dyspnea, tachycardia, arrhythmia ⇥ Requires extensive supportive care! 28 IthappensBagour immune systemis activated Capillary Leak Syndrome 29 Immune Checkpoints ✥Inhibitory pathways ❊ Maintain self-tolerance IN ❊ Modulate duration of immune response ✥Expression of immune checkpoint proteins is dysregulated by tumors – imp immune resistance mechanism ✥T – cells: ability to recognize peptides from all cellular compartments 05 4 0 5s 4❊0Ability to orchestrate diverse immune response – helper T cells – integrateno adaptive and innate ❊ Ability to recognize and kill antigen expressing cells – CD8+ T cells – CTL immunity ✥Inhibitory ligands – regulate effector functions of T cells – commonly overexpressed on tumors/tumor microenvironment ✥Antibodies targeting these pathways target not only the tumor cells but the lymphocyte receptor or their ligands ❊ Enhance endogenous anti-tumor immunity ✥2 immune checkpoints – utilized for anticancer drug therapy ❊ CTLA – 4 (CD 152) Cytotoxic T Lymphocyte associated antigen 4 ❊ PD – 1 (CD 279) – Programed cell Death 1 Theyarebreaksonourimmune system keepourimmunisin 3 cheek ✥Both inhibitory receptors, regulate immune response at different levels and mechanisms 30 wewantthetoadtoattach terrorcell CTLA – 4 ✥CTLA-4 – Cytotoxic T Lymphocyte Associated antigen 4 ❊ Expressed exclusively on T cells ✥Regulates the amplitude of early stages of T cell activation ✥When antigen is presented to T-cell and binds to TCR, ✥CD28 signaling strongly amplifies TCR signaling to activate T cell ✥CTLA-4 counteracts the activity of CD28 ❊ Both CD28 and CTLA-4 have the same ligand (CD80 and CD86) ❊ CTLA-4 out-competes CD28 for the ligands psst i the T-cell activation ✥CTLA-4 dampens 31 MHC TCR Signal 1 Phagocytotic vesicle Amplification of Signal MHC TCR CTLA-4 Signal 1 to cell surface Amplification of Signal Dampening of Signal CD28 B7 Dendritic Cell (APC) Phagocytotic vesicle Resting T cell Dendritic Cell (APC) CTLA4 B7 Dampened T cell Activated T cells No anti-tumor response Attack the cancer cells 32 Hodi et al ournal of Clinical Oncology, March 2018; 36(9) 850-858 Ipilimumab (Yervoy) ✥Anti-CTLA4 antibody – broad enhancement of immune response ✥Immunogenic tumors respond Weber et al Journal of Clinical Oncology, 2012; 30(21) 2691-2697 better ❊ Chemo and radiation mediated tumor cell death may increase immunogenicity ✥Response kinetics ❊ RECIST vs. imRECIST ✥BBW: Severe immune reactions (irAEs) ❊ Dermatitis, enterocolitis, hepatitis and endocrinopathies ⇥ Monitor – ACTH, TSH, A1c ❊ Initiate high dose GCs So InflammationofBoth smallandlarge intestines 34 ✥Major role is to limit the activity of T-cells in the peripheral tissues at the time of inflammation to limit 555collateral tissue damage Programmed Death Ligand (PD-L1) ✥Activated T- cells express PD-1 and continue to express it d ✥Inflammatory signals in the tissues induce expression of PD-1 ligands such as PD-L1 PIE ❊ PD-L1 downregulates activity of PD-1 ❊ Limits tissue damage ✥Oncogenic signaling inside the tumor cell such as PI3K/Akt can increase expression of PD-L1 on the tumor cells ❊ Usually adaptive in response to presence of TILs ❊ Suppress immune response MHC TCR Signal 1 MHC Phagocytotic vesicle TCR Phagocytotic vesicle Signal 1 Amplification of Signal CD28 CD80 or CD86 Dendritic Cell (APC) Trafficking of T-cells periphery tissues Tissue Resting T cell Dampening of Signal PD-L1 PD-1 Antigen-activated T cell Inflammation 35 I Cancer cells evade T-cells by expressing PD-L1 on their surface MHC TCR Signal 1 Phagocytotic vesicle Phagocytotic vesicle Signal 1 Amplification of Signal CD28 CD80 or CD86 Dendritic Cell (APC) Trafficking of T-cells periphery tissues Dampening of Signal PD-L1 PD-1 Resting T cell Muted T cell Activated T-cells arrive at location Phagocytotic vesicle PD-L1 Signal 1 Dampening of Signal PD-1 Pembrolizumab Antigen-activated T cell Nivolumab 36 PD-1 Targeted ℞ ✥Blocks binding of PD-L1 to PD-1 ❊ Anti-PD-1 antibodies ⇥ Pembrolizumab (Keytruda) ⇥ Nivolumab (Opdivo) ✥Inhibit negative immune regulation ✥Approved for melanoma, NSCLC, MSI-H cancers ❊ Requires expression of PD-L1 on the tumors for NSCLC ✥Significantly reduced immune toxicity compared to ipilimumab J. Hamanishi et al, PNAS 2007 37 Schachter J et al, Lancet 2017; 390: 1853–62 PD-1 Targeted Agents ✥Pembrolizumab ✥Nivolumab (alone or + Yervoy) ✥Used for various indications including GI Ia ❊ Metastatic (IV), unresectable and adjuvant – melanoma ✥IV infusion given over 30 minutes with low-protein binding filter ❊ Volume administered must not es exceed 4 mL/kg or 160 mL (whichever is lower) - Nivolumab ❊ Contains polysorbate 80 – Pembro ✥Spartalizumab (in phase III) 38 Anti-PD-L1 Not indicated for melanoma ✥Antibodies against the PD-L1 that is expressed on the tumors ✥Block the same pathway but the target in the ligand (PD-L1 instead of the receptor (PD-1) ❊ Atezolizumab (Tecentriq) ⇥ For melanoma with V600E mutation of MEK in combination with cobimetinib and vemurafenib ❊ Durvalumab (Imfinzi) ⇥ Approved for unresectable stage III NSCLC ❊ Avelumab (Bavencio) 39 ADRs ✥Immune related adverse events (irAEs) ❊ Due to hyperactivation of immune system ❊ Resemble auto-immune disease manifestation ⇥ Colitis, enterocolitis, GI toxicity ⇥ Dermatologic toxicity – immune mediated rash including SJS, toxic epidermal necrolysis ⇥ Hepatitis, encephalitis, pneumonitis, nephritis, ocular (uveitis, irisitis) ❊ Pts w/ auto-immune disease, transplants – worsening of symptoms and rejection ✥All immunotherapy agents produce varying degree of endocrine toxicity (endocrinopathies) ❊ Hypophysitis - inflammation of the pituitary ❊ Thyroid, adrenal, gonadal insufficiency ❊ T1DM, worsening of existing diabetes ⇥ Majority appear soon after treatment starts but can be delayed ✥Toxicity: Ipilumumab (BBW) > Nivolumab, pembrolizumab, atezolizumab ❊ Due to excessive immune system stimulation 40 Vitiligo whogotit survivedmuchInger PI por ✥Vitiligo is condition where skin loses its pigmentation in patches ❊ Leukoderma ✥Normally considered an auto-immune disease ❊ Risk factors include family history of auto-immune conditions such as T1DM, Hashimoto’s, Grave’s, RA, SLE etc. ✥Immune mediated destruction of melanocytes after anti-cancer immunotherapy ❊ Linked to outcomes of therapy Nakamura Y et al, Journal of Dermatology 2017; 44: 117–122 41 MAPK pathway ✥Oncogenic mutations of Ras is common ❊ Inhibition of Ras is difficult ❊ Fernesylation of ras (imp for activity) can be inhibited ✥Immediately downstream of Ras is Raf → ❊ phosphorylates MEK → ❊ phosphorylates MAPK → ✥Activating mutations (V600E) in BRaf in significant fraction of melanomas ❊ Vemurafenib and dabrafenib ✥MEK inhibitor ❊ Tremetinib and cobimetinib ⇥ Vertical sequential inhibition 42 Growth Factor Receptor PI(4,5)P2 PI(3,4,5)P3 PI3-K Shc Grb2 SHP-2 Akt PTEN SHP-2 P P P P SOS RAS-GDP RAS-GTP mTOR RAF 4E-BP1 S6K elF-4E p90RSK Ribosomal Synthesis mRNA Translation Nucleus DNA Polymerase MAPK MEK Cyclin D1 Cell proliferation Suppress apoptosis TRANSCRIPTION 43 ✥Oncogenic BRAF mutations present in B-Raf inhibitors ~50% melanomas – Ser/Thr kinase ✥V600E mutations allows ❊ Dimeric and monomeric activation ❊ Inhibits negative feedback from pMEK Vemurafenib ⇥ Addictively activate the MAPK pathway – promote malignant transformation and cell proliferation ✥BRAF inhibitors ❊ Dabrafenib ❊ Vemurafenib ❊ Encorafenib ✥Inhibition of mutated B-Raf (V600E) Dabrafenib allows activation of wild-type B-Raf and turns the MAPK pathway on again ❊ Dual inhibition of B-Raf and MEK ✥ADRs: Cardiotoxicity (QT prolongation, HTN, ↓ LVEF), dermatologic toxicity ✥Paradoxical activation of C-Raf and wt BRaf leading to secondary skin cancers Encorafenib ❊ Squamous cell carcinoma (SCC) ✥CYP3A4 mediated metabolism ❊ DDI 44 MEK inhibitors ✥MEK is the kinase that activates MAPK (ERK) ✥Dual specificity kinase – Y and S/T kinase ✥MEK inhibitors ❊ Trametinib ❊ Cobimetinib ❊ Binimetinib ✥Given with B-Raf inhibitors for a stepwise inhibition of the pathway ✥ADRs: Cobimetinib ❊ CV – HTN, cardiomyopathy (↓LVEF) Trame0nib ❊ ↑ CPK, rhabdomyolysis ❊ Derm – photosensitivity, PPE, xeroderma including secondary skin cancers ❊ GI – diarrhea, stomatitis, ulcers ❊ Ocular – retinal detachment, visual impairment, retinopathy Binimetinib ✥B-RAF testing is required 45 Brain Metastases ✥Metastasis is the most common “cancer” affecting the brain ❊ # of primary brain tumors vs. brain mets ✥Brain is most common site of metastasis for melanoma ✥New blood vessels or lymphatics to drain into the venous circulation ✥Why and how brain? ❊ Grow in the lung, seed pulmonary venous circulation ❊ Traverse lung capillary bed to enter the right side ❊ Cross patent foramen ovale directly (?) ✥15-20% of body’s blood flow goes to the brain ✥Improved systemic Rx ❊ Does not cross BBB ❊ Sanctuary site 46 Rx of brain metastasis ✥Supportive ❊ Corticosteroids ❊ Anticonvulsants ❊ Antibiotic prophylaxis ❊ Anticoagulants ✥Curative intent ❊ Surgery (1-3 lesions) ❊ Whole brain radiation therapy (WBRT) – multiple lesions and postoperative ❊ Stereotactic radiosurgery (Gamma knife, linear accelerator, single dose vs. fractionated) ❊ Chemotherapy (chemo sensitive primary) 47 Pregnancy and Melanoma ✥Cancer is not contagious, so it is usually not passed on to others ✥Cancer cells are big and do not cross placenta ✥However, rarely melanoma may cross placenta (stage IV) ❊Dermatologists will evaluate the placenta 48