oncologic review of the skin cancers

1. Cancers of the Skin
Saeed Salman MD
Radiotherapy Unit
Oncology Institute
Rambam Health Care Campus
Sa_Salman@RMC.gov.il

2. 1. NONMELANOMA
2. MELANOMA
27-Feb-20 2

3. NONMELANOMA skin cancer (NMSC)
• 1/5 Americans will develop NMSC during his or her lifetime
• The most common human cancer
• Higher than the incidence of lung, breast, prostate and colon cancer
combined
• Risk factors: solar radiation, UV exposure, age
27-Feb-20 3

4. Diagnosis of Nonmelanoma Skin Cancer
• Clinical findings:
• Nodularity
• Tissue friability
• Erythema
• Definitive diagnosis can be established only by tissue biopsy
• A: Shave biopsy : raised lesions such as nodular
basal cell carcinoma
• B: Punch biopsy : lesions with a deeper dermal
or subcutaneous extension such as
dermatofibrosarcoma protuberans (DFSP)
27-Feb-20 4
- clean (nonsterile) conditions - local anesthesia
DeVita, Hellman, and Rosenberg's Cancer Principles & Practice of Oncology

5. NMSC Surgical Excision
• C: excisional biopsy : under sterile conditions
• Excisional surgery involves the removal of the cancer and a margin of clinically
uninvolved skin
• Procedure types:
• In office : effective and cost efficient, poor pathological assessment
• MMS : potential for irregular subclinical extension, better pathological
assessment
27-Feb-20 5

6. NMSC Surgical Excision.. cont.…
• Mohs Micrographic Surgery:
• staged excision with intraoperative
microscopic analysis that facilitates
optimal margin control
• Immediately processed frozen
sections for microscopic examination
• cure rate of >97% to 99% for primary
BCC and SCC
27-Feb-20 6
DeVita, Hellman, and Rosenberg's Cancer Principles & Practice of Oncology

7. NMSC Surgical Excision.. cont.…
• Surgical Destruction:
• curettage and cautery or electrodessication C&D:
Curettage of Visible tumor with 2 to 4 mm margins, then cautery or electrodesiccation to
destroy another 1 mm at the lateral and deep margins
• Cryotherapy:
using liquid nitrogen
Requires −50°C to −60°C at the deep and lateral margins of the tumor
Complications: delayed wound healing, hypertrophic scarring, hypo- and
hyperpigmentation, paresthesia if superficial nerves are injured
Limitation: inability to evaluate treatment margins
27-Feb-20 7

8. Radiation Therapy
• Can be used to treat : BCC and SCC, Merkel cell carcinoma (MCC),
angiosarcoma (AS), cutaneous lymphomas, some adnexal carcinomas, and
other primary and metastatic cutaneous neoplasms.
• Primary modality for:
• overall health status precludes surgery
• unwilling or unable to undergo surgery
• Size and extent of the tumour precludes surgical extirpation
• Adjuvant treatment:
• Positive surgical margins
• Perineural invasion (PNI)
• Local regional nodal metastasis
• Limitation: assess and control the tumor margins, postradiation dermatitis
and future skin cancers
27-Feb-20 8

9. Radiation Therapy.. Cont..
• Radiation type:
• Electron external beam: superficial tumors
• Photons beam (x-rays) : for deeper tumors
• Radiation dose:
• 2- to 2.5-Gy fractions to a total of 50 to 66 Gy
• Acceptable local control and late toxicity
• Accelerated / hypo-fractionated treatment protocols provide excellent local
control but have an increased risk of fibrosis, atrophy, telangiectasias, and
poor cosmesis
• Local control : BCC, 90% to 95% at 5 years; SCC, 80% to 95% at 5 years
27-Feb-20 9

10. Topical Therapy
• Imiquimod, functions as a topical immune-response modifier :
• Activates intracellular toll-like receptors 7 and 8 
• Induction of cytokines : IFN-α and IFN-γ and interleukin (IL)-6, IL-8 
• A T-helper type 1–dominant inflammatory response driven by CD4 T cells
• Inferior outcome compared to surgery or RT
• A.E.: site reactions, fatigue, myalgias, fever and chills or flu-like symptoms,
headache, diarrhea, nausea, and tender lymphadenopathy
• 5-FU:
• Chemotherapeutic agent that interferes with DNA synthesis by inhibiting
thymidylate synthetase
• Outcome and adverse event same as imiquimod.
27-Feb-20 10

11. BASAL CELL CARCINOMA
• Slow-growing neoplasm
• Originating from the basal cell layer of the epidermis
• The most common human cancer
• Half of all human cancers and 75% of skin malignancies
• Sun-exposed areas of lighter skinned individuals
• locally invasive
• The incidence continues to increase, doubling of the number of cases every 10
years
• More common in older individuals
• Increasing incidence in each decade of life that peaks after age 80 years
• Men are affected more often than women (3/2)
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12. BCC .. CONT. ..
• Primary carcinogen is UVR:
• sun exposure
• Indoor tanning (NOT “safer”)
• Other carcinogens:
• Ionizing radiation
• Chemicals (e.g., arsenic, polyaromatic hydrocarbons)
• Psoralen plus UVA (PUVA) therapy
• Genetic syndromes with inherited mutations in tumor suppressor genes (TSG)
• Alterations in immune surveillance (i.e., organ transplantation, underlying
hematologic malignancy, immunosuppressive medications, or HIV infection)
27-Feb-20 12

13. BCC Genomic analysis
• BCC is associated with mutations in the PTCH1 regulatory gene, which
maps to chromosome 9q22.3
• Loss of heterozygosity at this site is seen in both sporadic and hereditary
BCC
• The PTCH1 protein is part of a receptor complex that regulates the
hedgehog signaling pathway, a key regulator of embryonic development
and cellular proliferation
• Loss-of-function mutations in PTCH1 thus permit unopposed Smoothened
activity and cellular proliferation
• This understanding of the molecular pathogenesis of BCC has led to the
development of targeted medical therapy for BCC with small-molecule
inhibitors of Smoothened
27-Feb-20 13

14. BCC Clinical and Pathologic Features
• slowly growing solitary lesion on sun-exposed skin
• Typically asymptomatic
• May bleed or ulcerate
• Half of BCCs occur on the face and ears, 30% on the nose
• Subtypes: nodular, superficial, and infiltrative
27-Feb-20 14

15. BCC NODULAR subtype
• most common BCC subtype
• >60% of all tumors
• Clinically, it presents as a raised, translucent,
pearly, skin-toned to pink papule or nodule
with prominent telangiectasias
• easy bleeding and/or crusting
• sun-exposed areas of the face in individuals
over the age of 60 years
27-Feb-20 15

16. BCC Superficial subtype
• second most common subtype of BCC
• up to 15% of all BCCs
• younger patients at a mean age of 57 years
• well-defined, pink to erythematous, scaly or
eroded macule or plaque commonly with a thin
pearly border
• predominately on the trunk
• Histologically, superficial BCC may be a broad
lesion characterized by basophilic buds extending
from an atrophic epidermis into the papillary
dermis
• limited to the upper dermis
27-Feb-20 16

17. BCC Infiltrative subtype
• 5% to 15% of all BCCs
• predominately in the head and neck region of older adults
• Clinically : flat or indurated, slightly firm lesion, without well-
demarcated borders, with a white to yellowish hue, and may be
difficult to differentiate from a scar
27-Feb-20 17

18. Staging, Prognosis, and Management
• overall prognosis is excellent
• mortality for BCC is far less than 1%, with less than 1,000 deaths per
year in the United States
• traditional tumor-node-metastasis (TNM) staging in not necessary
• High risk features: infiltrative and morpheaform subtypes of BCC;
recurrent BCC; anatomic location on the nose, ear, eyelid, or temple;
and increasing preoperative size
27-Feb-20 18

19. BCC Management
• Low-risk tumors: surgery or C&D
• high-risk tumors:
• MMS
• RT
• Combination MMS + RT for deep destructive tumors
• Topical 5-FU is twice-daily application for 3 to 6 weeks irrespective of tumor
size or location
27-Feb-20 19

20. BCC Management
• Very high risk, metastatic, multiple, not eligible for RT / MMS:
• Vismodegib:
• once-daily oral dosing of 150 mg
• adverse events:
• muscle spasms
• Alopecia
• dysgeusia leading to weight loss
• Fatigue
• diarrhea, and hyponatremia
• between 12% and 54% of patients discontinued therapy because of adverse effects
27-Feb-20 20

21. SQUAMOUS CELL CARCINOMA - SCC
• Risk factors:
• Age : 10-fold greater in people aged >70
• Chronic UVR: 5- to 10-fold greater in geographic regions of high environmental UVR
• fair skin complexion and light-colored hair and eyes
• Men are affected twofold more commonly than women
• UV light therapy
• chemical carcinogens (e.g., petroleum, coal tar)
• ionizing radiation
• HPV : anogenital and periungual regions
• Heritable conditions : xeroderma pigmentosum
• Drugs: Immunosuppressive therapy, photosensitizing drugs (voriconazole),
Vemurafenib,
27-Feb-20 21

22. SCC Clinical and Pathologic Features
• Invasive SCC may present as a slightly
raised papule plaque or nodule that is
skin-colored, pink, or red
• surface of the tumor may be smooth
, keratotic, or ulcerated
• Bleeding with minimal trauma is
common
• Verrucous carcinoma, a variant of SCC,
includes oral florid papillomatosis, giant
condyloma of Buschke-Lowenstein (on
the genitalia), and epithelioma
cuniculatum (on the plantar foot)
27-Feb-20 22

23. SCC histologically
• large cellular size, nuclear hyperchromatism, lack of
maturation, nuclear atypia, and the presence of
mitotic figures
• Well-differentiated SCC, cytoplasmic keratinization
is manifested by the presence of keratin pearls (horn
cysts)
• Poorly differentiated or undifferentiated SCC shows
decreased evidence of keratinization, higher degree
of cytologic atypia, and increased number of mitotic
figures.
27-Feb-20 23

24. SCC Staging and Prognosis
• Cutaneous SCCIS is a stage 0: indolent, enlarge slowly over years,
seldom progresse to invasive carcinoma
• Overall prognosis is good to excellent
• 2% to 4% of patients will develop nodal metastasis
• 1% to 2% of patients will die from disease (4,000 to 9,000 deaths per year in the United States)
• risk for local recurrence and metastasis: location, size, depth,
histologic differentiation, PNI, immunosuppression
• no universally accepted staging system
27-Feb-20 24

25. SCC Management
• destruction by C&D
• removal by excisional surgery or MMS
• RT
• Adjuvant postoperative RT:
• residual disease
• positive margins
• PNI (especially if symptomatic)
• multiple recurrences
• underlying tissue invasion
27-Feb-20 25

26. Management of Regional, Distant, or
Inoperable SCC
• Local RT : Definitive doses 60 to 66 Gy
• Lymph node dissection
• A combination of both (parotid nodes)
• Metastatic disease:
• Cetuximab: chimeric monoclonal antibody directed against the EGFR
• chemotherapy,
• Immunotherapy with nivolumab or pembrolizumab:
• monoclonal antibodies to the immune checkpoint receptor programmed death 1 (PD-1)
27-Feb-20 26

27. MERKEL CELL CARCINOMA
• Rare and aggressive tumor
• Neuroendocrine cell origin
• Frequent metastasis and poor overall prognosis
• Men twice that in women
• whites are more than 20 than blacks
• Risk factors:
• Immunosuppression
• UV
• Merkel cell polyomavirus (MCPyV)
27-Feb-20 27

28. Management of Merkel Cell Carcinoma
• MMS with 1- to 2-cm margins is generally recommended
• With surgery alone 25% recure within 2 years and 47% within 5 years
• Relapses pattern:
• local 9%
• Nodal 53%
• Distant metastasis 38%
• Adjuvant RT?
• Positive surgical margins (RT dose of 56 to 60 Gy)
• 60 to 66 Gy can be considered for primary RT
27-Feb-20 28

29. MCC Systemic therpay
• nodal, metastatic, and recurrent MCC
• Chemotherapy: cyclophosphamide, anthracyclines, and cisplatin
• 3-year survival rate was 17% in metastatic disease
• Immunotherapy:multicenter, phase II, noncontrolled study of
pembrolizumab (anti–PD-1) 2 mg/kg every 3 weeks(1)
• 25 patients evaluated objective response rate was 56%, and 4 patients (16%)
showed a complete response
• 2019 update: At 24 months, progression-free survival was 48.3% and overall
survival was 68.7%.
27-Feb-20 29
1- https://www.nejm.org/doi/full/10.1056/NEJMoa1603702

30. More to mention..
• DERMATOFIBROSARCOMA PROTUBERANS
• 1 in 4 million
• Locally aggressive – low grade
• MMS, chemotherapy, RT
• ANGIOSARCOMA(malignant hemangioendothelioma, hemangiosarcoma, and lymphangiosarcoma)
• 0.1 per million
• violaceous to red, ill-defined patch commonly on the face or forehead
• mortality rate of 50% at 15 months after diagnosis
• MICROCYSTIC ADNEXAL CARCINOMA (sweat gland carcinoma)
• smooth-surfaced, nonulcerated, flesh-colored to yellowish asymptomatic nodule, papule, or
plaque
• surgically remove the tumor
• SEBACEOUS CARCINOMA
• Sebaceous glands
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31. Cutaneous Melanoma
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32. Cutaneous Melanoma
• Malignant transformation of the melanocyte
• >70% of the deaths attributable to skin cancer each year
• 5.2% of new cancer diagnoses
• Incidence is rising 3% per year
• Is the fifth most common U.S. cancer diagnosis
• 1/28 men and 1/44 women will be diagnosed with melanoma of the skin during
their lifetime
• 91.2% of melanomas are cutaneous, 5.3% ocular, 1.3% mucosal, and 2.2%
metastases from unknown primary site
• More in whites
• For women aged 25 to 35 years, melanoma is the leading cause of cancer-related
death
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33. Melanoma ANATOMIC DISTRIBUTION
27-Feb-20 33

34. Molecular Biology of Cutaneous
Melanoma
• THE RAS-RAF-MAPK PATHWAY ( Driver Mutations)
• RAF Kinases
• BRAF mutations are detected in 40% to 45% of cutaneous
melanoma
• MEK
• constitutive signaling leading to oncogenic cell
proliferation and escape from apoptosis
27-Feb-20 34

35. Cellular Changes in Melanocyte to
Melanoma Progression
Early cutaneous melanomas usually proceed
to grow radially, and this is called the radial
growth phase (RGP) of melanoma, which
may continue for years before progressing to
the vertical growth phase (VGP)
27-Feb-20 35

36. Melanoma ETIOLOGY AND RISK FACTORS
• Ultraviolet Light Exposure:
• Both UVA and UVB have immunosuppressive effects on the skin, which are implicated in melanoma induction, Thus, sun protection
should address both UVA and UVB rays
• Tanning bed (UVA)
• Physical Traits
• Blond or red hair
• Green or blue eyes
• Familial Predisposition
• Pregnancy and Estrogen Use
• Incidence of melanoma is higher in pregnant females
• They have a particularly bad outcome
27-Feb-20 36

37. Melanoma PREVENTION AND SCREENING
• Sun Protection
• clinical trial in Australia, March 1992 to August 1996 of 1,621 randomly
selected adults
• sun protection factor (SPF) 16 sunscreen every morning
• 10-year follow-up
• invasive melanoma decreased by 73% in the intervention
• Recommendations:
• The best protection from the sun is a building, the next best is protective
clothing, and the third best is sunscreen
• Avoiding midday sun from about 11 a.m. to 3 p.m.
27-Feb-20 37

38. Melanoma Screening for Early Diagnosis
• Self-examination
• decrease incidence and mortality
• It is more common for women to detect melanomas, for themselves or for
their partners
• ½ of melanomas are identified by the patient or family
• Patients with melanoma or at high risk should be seen regularly by a
dermatologist
27-Feb-20 38

39. DIAGNOSIS OF PRIMARY MELANOMA
• Characteristics
• ABCD :
• Asymmetry
• Border irregularity
• Color variation
• Diameter >6 mm
• High-risk patients  low threshold for biopsy
• Symptoms:
• bleeding, itching, pain, and ulceration
• deep vertical growth and are hallmarks of a late diagnosis
27-Feb-20 39

40. DIAGNOSIS OF PRIMARY MELANOMA
• Biopsy:
• full-thickness biopsy of the entire lesion with 1-2 mm margins
• 35% of U.S. dermatologists favour shave biopsy, 12% favor scoop or
saucerization biopsy, and 11% favour punch biopsy
• with only 31% favouring the recommended excisional biopsy
27-Feb-20 40

41. Melanoma Subtypes: Histologic Growth
Patterns
• Superficial Spreading Melanoma
• 70% of primary cutaneous melanomas
• trunk and extremities
• associated with sun exposure
• Nodular Melanoma
• may be nonpigmented
• commonly are diagnosed when relatively thick
• carry the worst prognosis
• 20% of cutaneous melanomas
• Acral Lentiginous Melanoma
• <5% of melanomas
• acral sites (subungual, palmar, plantar)
• mucosal surfaces (anorectal, nasopharyngeal, female genital tract)
• independent of UV light exposure
27-Feb-20 41
• Lentigo Maligna Melanoma
• older individuals
• chronically sun-damaged skin – face
• 10% to 20% of melanomas

42. Prognostic Factors for Primary Melanomas
• Depth of Invasion
• Breslow thickness:
• T1 lesions are ≤1 mm thick
• T2 lesions are 1.1 to 2 mm thick
• T3 lesions are 2.1 to 4 mm thick
• T4 lesions are >4 mm thick
• Clark level : not used anymore
• Ulceration
• important negative prognostic feature
• T1a, T2a, T3a, and T4a melanomas are nonulcerated
• T1b, T2b, T3b, and T4b melanomas are ulcerated
• An ulcerated lesion is comparable to that of a nonulcerated lesion one T level higher
(e.g., T2b and T3a are both stage IIA)
27-Feb-20 42

43. Prognostic Factors for Primary Melanoma
• Patient Sex :
• prognosis is better for women than men
• Sex and Location:
• Women  more on the extremities
• men  more on the trunk and head and neck
• Location:
• clinical outcome for patients with melanomas on extremities is better than
that for patients with truncal or head and neck melanomas
• Mucosal melanoma is the worst location
27-Feb-20 43

44. Prognostic Factors for Primary Melanoma
• Patient Age
• Mortality risk increases with age
• Growth Pattern
• Nodular melanomas have the worst prognosis
• Lesser risk with superficial spreading melanoma
• Mitotic Rate
• Six or more mitoses per square millimetre  worse prognosis
• 10-year survivals of 97%, 96%, 91%, 86%, and 77% for 0, 1, 2 to 3, 4 to 10, and
≥11 mitoses per
27-Feb-20 44

45. 27-Feb-20 45

46. 27-Feb-20 46

47. 27-Feb-20 47

48. MANAGEMENT of MELANOMA
27-Feb-20 48

49. Melanoma In Situ (Clinical TISN0M0, Stage 0)
• Wide excision alone - curable in the vast majority of cases
• Margin of 5 to 10 mm
• No need to perform radiologic staging studies
• Follow up annually
27-Feb-20 49

50. Thin Primary Melanoma (Clinical T1A – T3A)
• <0.8 mm thick
• Excision with a appropriate margin (usually 1 to 2 cm) (including skin
and all underlying subcutaneous tissue to the deep muscle fascia)
• risk of metastasis for thin melanomas is in the 5% to 10% range
• Follow-up:
• Annually for many years
27-Feb-20 50

51. REGIONALLY METASTATIC MELANOMA (STAGE III):
LYMPH NODE METASTASIS, SATELLITE LESIONS,
AND IN-TRANSIT METASTASES
• Regional metastases are defined:
• Local recurrence is best defined as recurrence of melanoma in the scar from
the original excision or at the edge of the skin graft if that was used for
closure.
• Satellites metastases may occur either simultaneously with the original
diagnosis or arise subsequent to original excision. Typically, recurrences that
are separate from the scar but within 2 to 5 cm of it are considered satellite
metastases (Fig. 92.10).
• Regional recurrences beyond 5 cm of the scar but proximal to regional nodes
are considered in-transit metastases (Fig. 92.11).
• Regional node metastases are typically in a draining nodal basin that is near
the lesion
27-Feb-20 51

52. 27-Feb-20 52

53. • mortality in the range of 50% over 5 to 10 years – old data
• Initial workup:
• History and physical examination
• Serum LDH
• more aggressive: radiologic imaging as indicated by signs and symptoms
• Consider: CT scans of the chest, abdomen, and pelvis plus MRI of the head
• Wide excision with at least a 2-cm margin
• SNBx node negative:
• Chance of sentinel node positivity approximately 35% to 40% in STAGE II
• Palpable Metastatic Melanoma in Regional Nodes:
• Axillary Dissection
• Inguinal and Iliac Dissection
• Cervical Dissection + adjuvant RT
27-Feb-20 53

54. STAGE III Adjuvant treatment -
Immunotherapy
• High-Dose Interferon-α2B
• Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) Blockade
• Ipilimumab (fully human immunoglobulin G1 monoclonal antibody
that blocks CTLA-4)
• improved OS in the treatment of metastatic melanoma in two randomized
clinical trials
• EORTC 18071 trail : ipilimumab vs placebo
• OS rate at 5 years was 65.4% in the ipilimumab group compared with 54.4% in
the placebo group (HR for death, 0.72; 95.1% CI, 0.58 to 0.88; P = .001)
27-Feb-20 54

55. STAGE III Adjuvant treatment -
Immunotherapy
• PD-1 Blockade In Adjuvant Therapy
• Checkmate-238 was a randomized, double-blind, phase III trial
• nivolumab VS ipilimumab
• RFS 70.5% in the nivolumab group and 60.8% in the ipilimumab group
• ONGOING:
• S1404 : HDI VS EPI NIVU
• Keynote-054: pembrolizumab VS placebo
27-Feb-20 55

56. STAGE III Adjuvant treatment - MAB
• COMBI-AD -Adjuvant Dabrafenib plus
trametinib for Resected Stage III BRAf V600–
Mutant melanoma
• Axel Hauschild et al, NEJM sep.2017,
• PRESENTED AT ESMO 2017-MADRID
• In phase 3 trials (COMBI-d and COMBI-v),
treatment with the BRAF inhibitor dabrafenib
plus the MEK inhibitor trametinib improved
survival in patients with unresectable or
metastatic BRAF V600E/K–mutant melanoma
27-Feb-20 56
pERK
Proliferation, Survival, Invasion, Metastasis
RAS
MEK
mutBRAF Dabrafenib
MAPK Pathway
Trametinib

57. Relapse-free survival
(primary endpoint)
27-Feb-20 Salman 57
438 413 405 392 382 373 355 336 325 299 282 276 263 257 233 202 194 147 116 110 66 52 42 19 7 2 0
432 387 322 280 263 243 219 203 198 185 178 175 168 166 158 141 138 106 87 86 50 33 30 9 3 0 0
Months From Randomization
Dabrafenib plus trametinib
Placebo
No. at Risk
0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
ProportionAliveandRelapseFree
1 y, 88%
2 y, 67%
3 y, 58%
1 y, 56%
2 y, 44%
3 y, 39%
 NR, not reached.
Group
Events,
n (%)
Median
(95% CI), mo
HR
(95% CI)
Dabrafenib
plus
trametinib
166 (38)
NR
(44.5-NR) 0.47
(0.39-0.58);
P < .001
Placebo 248 (57)
16.6
(12.7-22.1)
P = .0000000000000153

58. Overall survival - (first interim analysis)
27-Feb-20 Salman 58
438 426 416 414 408 401 395 387 381 376 370 366 362 352 328 301 291 233 180 164 105 82 67 28 12 5 0
432 425 415 410 401 386 378 362 346 337 328 323 308 303 284 269 252 202 164 152 94 64 51 17 7 1 0
0
0
0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54
ProportionAlive 1 y, 97%
2 y, 91%
3 y, 86%
1 y, 94%
2 y, 83%
3 y, 77%
 a Prespecified significance boundary (P = .000019).
Months From Randomization
Group
Events,
n (%)
Median
(95% CI), mo
HR
(95% CI)
Dabrafenib
plus
trametinib
60 (14)
NR
(NR-NR) 0.57
(0.42-0.79);
P = .0006a
Placebo 93 (22)
NR
(NR-NR)
Dabrafenib plus trametinib
Placebo
No. at Risk

59. Common adverse events
• One fatal pneumonia (SAE) in the combo group
27-Feb-20 Salman 59
Dabrafenib Plus Trametinib (n = 435) Placebo (n = 432)
AEs, n (%) All Grades Grade 3/4 All Grades Grade 3/4
Any AE (> 20% with dabrafenib plus
trametinib)a
422 (97) 180 (41) 380 (88) 61 (14)
Pyrexia 273 (63) 23 (5) 47 (11) 2 (< 1)
Fatigue 204 (47) 19 (4) 122 (28) 1 (< 1)
Nausea 172 (40) 4 (1) 88 (20) 0
Headache 170 (39) 6 (1) 102 (24) 0
Chills 161 (37) 6 (1) 19 (4) 0
Diarrhoea 144 (33) 4 (1) 65 (15) 1 (< 1)
Vomiting 122 (28) 4 (1) 43 (10) 0
Arthralgia 120 (28) 4 (1) 61 (14) 0
Rash 106 (24) 0 47 (11) 1 (< 1)

60. 27-Feb-20 Salman 60

61. STAGE III MELANOMA Clinical Follow-up
• No studies have shown a clear benefit in terms of survival with closer
follow-up
• decreases psychological stress
27-Feb-20 61

62. MELANOMA Clinical Follow-up
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63. STAGE IV MELANOMA
• Any patient with distant metastases is considered stage IV
• skin and subcutaneous tissue metastases M1a (better prognosis) - median
survival of 15months
• Lung metastases  M1b - median survival of 12 months
• Other distant metastases  M1c (poor prognosis) - survival of 6 to 9 months
• Timing of Distant Metastases:
• initially with stage IV disease is uncommon
• Often, within 2 to 3 years of diagnosis
• Can accrue after disease-free intervals of decades
• Patterns of Metastases:
• 60% to 80% of first metastases are at local or regional sites
• Most common first sites of visceral metastasis are lung and liver (about 10% each)
27-Feb-20 63

64. Clinical Evaluation of Melanoma (Stage IV)
• MRI scan of the brain
• total-body PET/CT scan (not in uveal melanoma)
• Bone scan, soft tissue MRI, ultrasound, or plain films may be
indicated to evaluate known areas of metastasis
27-Feb-20 64

65. Histologic or Cytologic Diagnosis
• Biopsy is better than FNA
• Immunohistochemical stains: S100, HMB45, tyrosinase, and MART-
1/MelanA
• Testing for BRAF:
• It is best to test a metastatic lesion
27-Feb-20 65

66. Surgery for Distant Metastases (Stage IV)
• Cases in Which the Benefit of Surgery Is Clear:
• Anemia due to occult bleeding from intestinal metastasis
• Bowel obstruction due to small bowel metastasis
• Cutaneous or subcutaneous metastasis with ulceration, pain, or impending ulceration
• Lymph node metastasis with neurologic symptoms
• Symptomatic brain metastasis
• Life-threatening hemorrhage from metastasis
• Cases in Which the Benefit of Surgery Is Likely, Especially if Patients Have
Progressed on Available Systemic Therapy:
• Solitary asymptomatic visceral metastasis resectable with minimal morbidity
• Bony metastasis with pain or joint involvement, unresponsive to radiation
• Solitary brain metastasis without symptoms
• Large, asymptomatic nodal metastasis with concurrent low-volume systemic disease
• Extensive skin and soft tissue metastases in the absence of visceral metastases
• Isolated growing metastasis in the setting of stable or regressing metastases after therapy
27-Feb-20 66

67. Treatment of Unresectable Metastatic (Stage
IV) Melanoma
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68. 27-Feb-20 68

69. Thank You
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