Recent modalities in the

management of Malignant
Melanoma
Essay
Submitted for partial fulfillment of the Master’s Degree
in
Clinical Oncology and Nuclear Medicine

Presented by
Mohamed Mohamed Alhefny
(M.B.B., Ch)
Faculty of Medicine
Ain- Shams University
ACKNOWLEDGEMENT
Prof. Dr. Tarek Hussein Kamel Taha
Professor of Clinical Oncology and Nuclear Medicine
Faculty of Medicine – Ain Shams University
 

Prof. Dr. Nivine Mahmoud Ahmed Gado

Professor of Clinical Oncology and Nuclear Medicine
Faculty of Medicine – Ain Shams University

Dr. Khaled Naguib Abdel-Hakim Mohamed

Lecturer of Clinical Oncology and Nuclear Medicine
Faculty of Medicine – Ain Shams University
 Malignant Melanoma

is a neoplastic disorder produced by malignant

transformation of the normal melanocyte.

 In the National Cancer Database (NCDB), 91.2% of

melanomas are cutaneous, 5.3% are ocular, 1.3% are
mucosal, and 2.2% are of unknown primary site.
EPIDEMIOLOGY
There were an estimated 62,480 new cases of melanoma,
The 16th and 15th most commonly diagnosed cancer in males
and females, respectively
More common in white populations
Malignant melanoma is the sixth-most-common United States
cancer diagnosis.
 The actual incidence of melanoma is increasing more rapidly
than that of any other cancer.
Overall 5-year survival rates for melanoma have increased
from 82% in the late 1970s (1975 to 1977) to 92% in the more
recent era (1996 to 2002).
Melanomas represent the third most common skin cancer in
Egypt after BCCs and SCCs,
Melanoma in Egypt represents about 8% of skin tumors
contributing about 0.65 % of all cancers.
Risk factors for developing melanoma

• Intrinsic factors
• family history and
• inherited genotypes
• Environmental factor
• the most relevant is sun exposure .
 Genetic Susceptibility
Genes involved are:
1- MC1R (Melanocortin 1 Receptor)
2-DNA repair genes .

Two genes have been discovered in melanoma families:

1-CDKN2A (p16) on chromosome 9p21
2-CDK4 on chromosome 12.
Pathway systems for melanoma transformation:
1)Mitogen-activated protein kinase pathway (MAPK), a
cell cycle regulator
2)Bcl-2 family of apoptosis related proteins . 3)PTEN, a
tumour suppressor gene .
4)c-Kit, which is an important tyrosine kinase pathway .
 Melanoma tumor formation
Normal Benign/premalignant Malignant / Locally Invasive Metastasis

Normal
p16
Melanocytes Integrins
p53 c-kit ↓
E-cadherin ↓
Dysplastic
N-cadherin ↑
Nevi MUC18/MCAM ↑ Angiogenesis,
CREB/ATF-1 ↑ Invasion & Apoptosis:
Early Primary
Radial e.g., bFGF, IL-8,
Growth MMP-2, EGF-R,
Phase PAR-1, FAS/APO-1
Advanced
Primary
Vertical
Growth
Phase Metastatic
Melanoma
 Characteristics of Cutaneous Melanoma:

using the mnemonic ABCDE.

A stands for asymmetry,
B for borders that are irregular or diffuse,
C for color variegation,
D for diameter more than 5 mm, and
E signifies enlargement of the lesion.

 Bleeding and ulceration occurs in 10% of localized

melanomas and 54% of late melanomas and is a poor
prognostic finding
 Cutaneous Melanoma Subtypes

1.Superficial Spreading Melanoma.

2.Nodular Melanoma.
3.Lentigo Maligna Melanoma.
4.Acral Lentiginous Melanoma.
5.Lentiginous Melanoma.
6.Desmoplastic Melanoma.
 Prognostic Factors of Cutaneous
Melanomas
Localized melanoma: Stage I and II
I)Thickness
(1) Breslow Thickness:
The Breslow depth of a primary cutaneous melanoma is the most powerful
independent prognostic factor for clinically localized disease (stage I and II).
(2) Clark Level:
The Clark level is defined as the depth based on the layer of skin to which
the melanoma has invaded.
II)Ulceration

III)Mitotic Rate

IV)Site of Primary Melanoma : trunck , head

and neck associated with worse prognosis

V)Age older age associated with worse prognosis

VI)Level of Invasion

VII) Sex Men in general have a worse prognosis

VIII) Other Prognostic Factors: Satellitosis ,

lymphovascular invasion
PROGNOSTIC FACTORS for Stage III

The most powerful predictive factor in patients

with stage III melanoma is the number of
metastatic nodes. They have been grouped, 1, 2-3
and 4 nodes.

PROGNOSTIC FACTORS for Stage IV

Stage IV melanoma has a dismal prognosis with a median

survival of 4-6 months, and an overall 5-year survival rate
between 9 and 19%. Most important prognostic factors is
site of metastases, number of metastatic sites and elevated
serum LDH.
RECENT MARKERS WHICH CORRELATE
WITH PROGNOSIS:

I) VEGF
II) S100
III) Galectin-1
IV) TRP-1
V) Discs Large Homolog 5 (Dlg5)
VI) Syntaxin 7 (STX7)
VII) SOX 10
VIII) Ki67
IX) Melan-A
 DIAGNOSIS
of
Malignant Melanoma
 DIAGNOSIS of Malignant Melanoma

1)History
2) Physical exam
3) Biopsy (excisional biopsy, incisional biopsy, punch biopsy)
4)Baseline chest x-ray
5) CBC, liver function tests, & LDH level.
6) Hepatobiliary ultrasound or CT abdomen
7) PET with FDG has become available and has rapidly gained
an appropriate role in staging patients

CT scans, PET, magnetic resonance imaging [MRI] of the

brain, etc.) should be limited to those patients with thick
melanomas (greater than 2mm) and macrometastases
CLINICAL INDICATIONS OF PET/CT IN
CUTANEOUS MELANOMA:

1-Initial Staging of Cutaneous Malignant Melanoma:

PET/CT has little or no role in the T staging of melanoma FDG
PET/CT is of limited use in patients with early-stage disease
without nodal or distant metastases (stage I–II), because of the
superficial nature of the tumor and the background activity
normally present in the skin.
2)Regional lymph node metastasis:
PET/CT is not as sensitive as sentinel lymph node biopsy in the
initial evaluation of patients with no palpable regional
lymphadenopathy , However, in patients with palpable regional
lymphadenopathy (macrometastasis), PET/CT scanners have the
same sensitivity as (SLN) in detection of metastasis with over
advantage of detecting occult metastasis
3)Distant metastasis of cutaneous melanoma:

Malignant melanoma is well known for its propensity to spread

to unusual sites. Because of the high tumor-to-background
ratio, PET can highlight metastases at unusual sites that are
easily missed with conventional imaging modalities. When
PET/CT is used for M staging the overall sensitivities and
specificities are more than 90% compared with approximately
50% for conventional staging with CT or MRI.

4)Evaluation of tumor response to therapy:

As metabolic changes precede anatomic changes, functional

imaging with FDG PET is better suited to this task than
anatomical modalities such as computer tomography (CT).
Malignant Melanoma:
treatment approaches
 Overview on different treatment approaches:
(1) The use of high dose Interferon Alpha-2b in stages IIB, IIC and III
melanomas that improves the overall survival and relapse-free survival of the
patients.
(2) Systemic chemotherapy For stage IV (distant metasteses ) melanoma.
The chemotherapeutic agents used are :
Dacarbazine, Temozolomide (the active metabolite of Dacarbazine) or
combination chemotherapy , in head to head comparison the OS was 6.4 months
with Dacarbazine and 7.7 months with Temozolomide.
 Combination chemotherapy regimens includes:
• cisplatin, vinblastine, and DTIC
• Paclitaxel , carboplatin / cisplatin .
• Docetaxel , carboplatin / cisplatin .
 Biochemotherapy :
 At M.D. Anderson -Cancer Center, CVD was compared with CVD plus IL-2 and
interferon alfa-2b given sequentially. The overall response rate and median
survival rate were superior in the biochemotherapy arm (48% vs. 25% and 11.8
months vs. 9.5 months, respectively.
 (3) Immunotherapy
Peptide vaccines targeted commonly expressed cancer antigens (e.g.,
MAGE) , melanoma differentiation antigens (e.g., tyrosinase, gp100)

M-Vax , an autologous whole-cell melanoma vaccine modified by the

hapten dinitrophenol and then irradiated, improved survival in
patients with stage III disease and demonstrated that development of a
delayed type-hypersensitivity response (DTH) correlated with improved
DFS and OS. A phase III study of M-vax in metastatic melanoma is
ongoing , the objective response rates is only about 5% - 10% .
An oncolytic herpes simplex virus type 1 encoding granulocyte
macrophage colony-stimulating factor (GM-CSF; OncovexGM-CSF) for
direct injection into accessible melanoma lesions resulted in a 28%
objective response rate in a Phase II clinical trial. Responding patients
demonstrated regression of both injected and noninjected lesions.

The intravenous administration of high-dose interleukin-2 has no

apparent direct cytotoxic or cytostatic effect on melanoma, and all of its
antitumor activity is a function of its ability to modulate the immune
system against melanoma.
 4-Anti-Angiogenic Agents
Melanoma is a highly vascular tumor ,recent clinical trials have
investigated the activity of thalidomide in combination with extended
dosing of temozolomide. In a phase II trial which excluded patients
with brain metastases or prior chemotherapy, an objective response
rate of 32% was observed among patients with advanced stage IIIC or
IV disease .
Newer anti-angiogenic agents evaluated includes lenalidomide , and
anti-vascular endothelial growth factor (anti-VEGF, bevacizumab) the
results was disease stabilization, rather than objective tumor
regression .
Targeted Therapies-5

BRAF is a member of the MAPK pathway, which promote cell

activation and proliferation.
The multikinase inhibitor sorafenib, which targets mutant and wild-
type BRAF as well as c-Kit, VEGFR-2, VEGFR-3 , recently was shown to
be ineffective against advanced melanoma as a single agent but
ongoing trials show some hope about its combination with
carboplatin and paclitaxel .
Methylthioadenosine (MTA) is a naturally occurring
nucleosidase, MTA demonstrated to promote anti-
proliferative and pro-apoptotic responses in different cell
types. In vitro experiments showed that MTA treatment
inhibited melanoma cell proliferation and viability in a dose
dependent manner, where BRAF mutant melanoma cell lines
appear to be more sensitive.

In melanoma, the (MAPK) and the PI3K-AKT-mTOR  (AKT)

signaling pathways are constitutively activated and have  key
functions in tumor progression, so that , combination of the
nonselective RAF inhibitor sorafenib with the mTOR inhibitor
sirolimus significantly potentiated growth inhibition and led
to an approximately 2-fold increase of apoptosis of melanoma
cells in monolayer culture compared with
sorafenib monotreatment , the initial results suggest that
mTOR inhibitors enhance sorafenib-induced endoplasmic
reticulum stress and apoptosis in melanoma cells .
In phase II study, the activity and tolerability of the combination of
bevacizumab, (Anti-angiogenesis), and everolimus (mTOR inhibitor),
was evaluated in metastatic melanoma,This combination was found to
have moderate activity and was well tolerated in the treatment of patients
with metastatic melanoma with an OS about 12 month .

Imexon is an aziridine compound that increases reactive oxygen

species, disrupts mitochondrial membranes, and induces apoptosis ,
Study of Imexon Plus Dacarbazine in Patients With Unresectable ,
Metastatic Melanoma reveals partial response in about 25% of 67
patients with metastatic melanoma.
A total of 676 patients with unresectable stage III or IV melanoma,
were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100
(glycoprotein 100 )(403 patients), ipilimumab alone (137), or gp100 alone
(136). The primary end point was overall survival, The median OS was
10.0 months among patients receiving ipilimumab plus gp100, 6.4 months
with gp100 alone , and with ipilimumab alone was 10.1 months, So
Ipilimumab, as compared with gp100 alone,improved overall survival in
patients with previously treated metastatic melanoma.
In March 25, 2011, the US Food and Drug Administration (FDA) approved
ipilimumab for the treatment of unresectable or metastatic melanoma.
 6-Isolated Limb Perfusion and Infusion:

An option for management of some patients with extensive regional

recurrences in an extremity is isolated limb perfusion with melphalan or
isolated limb infusion. Isolated limb perfusion can lead to complete
responses in 60% to 90% of patients, with complete responses reported in
25% to 69% of patients.
7-Radiotherary
adjuvant radiation to 1ry lesion:
1-DM histology 2- tumor thickness >4 mm with ulceration or satellite
3-positive resection margins 4- locally recurrent disease
Adjuvant radiation for LNs:
1-extracapsular extension 2-four or more involved nodes
3- lymph node size >3 cm 4-cervical node location
5-recurrent nodal disease .
elective node irradiation is recommended for head and neck melanomas
of 1.50 mm or Clark level IV .
definitive treatment approach remains an option for large LMM lesions
of the face and for inoperable patients.
Radiation therapy e as a palliative treatment for LN , skin ,
subcutaneous ,and brain metastasis.
After finishing treatment melanoma
patients must commit to a follow up
schedule of visits every 3 months for
2 years, followed by every 6 months
for 3 years, then yearly for at least 5
years.
THANK YOU