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 byMohamed Mohamed Alhefny

(M.B.B., Ch)Faculty of Medicine

Ain- Shams University

ACKNOWLEDGEMENTProf. Dr. Tarek Hussein Kamel Taha

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

 

Prof. Dr. Nivine Mahmoud Ahmed Gado

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

Dr. Khaled Naguib Abdel-Hakim Mohamed

Lecturer of Clinical Oncology and Nuclear MedicineFaculty 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.

EPIDEMIOLOGYThere were an estimated 62,480 new cases of melanoma, The 16th and 15th most commonly diagnosed cancer in males and females, respectivelyMore 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 9p212-CDK4 on chromosome 12.

Pathway systems for melanoma transformation: 1)Mitogen-activated protein kinase pathway (MAPK), a cell cycle regulator2)Bcl-2 family of apoptosis related proteins . 3)PTEN, a tumour suppressor gene .4)c-Kit, which is an important tyrosine kinase pathway .

Normal Benign/premalignant Malignant / Locally Invasive Metastasis

NormalMelanocytes

DysplasticNevi

Early PrimaryRadial GrowthPhase

AdvancedPrimaryVertical Growth Phase

p16Integrinsp53 c-kit ↓

E-cadherin ↓ N-cadherin ↑MUC18/MCAM ↑CREB/ATF-1 ↑

MetastaticMelanoma

Angiogenesis, Invasion & Apoptosis:e.g., bFGF, IL-8,MMP-2, EGF-R,PAR-1, FAS/APO-1

Melanoma tumor formation

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 III)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) VEGFII) S100III) Galectin-1IV) TRP-1V) Discs Large Homolog 5 (Dlg5)VI) Syntaxin 7 (STX7)VII) SOX 10VIII) Ki67IX) Melan-A

DIAGNOSIS of

Malignant Melanoma

DIAGNOSIS of Malignant Melanoma

1)History2) Physical exam3) Biopsy (excisional biopsy, incisional biopsy, punch biopsy)4)Baseline chest x-ray5) CBC, liver function tests, & LDH level.6) Hepatobiliary ultrasound or CT abdomen7) 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) ImmunotherapyPeptide 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 AgentsMelanoma 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 .

5-Targeted Therapies

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-Radiotheraryadjuvant 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 nodes3- lymph node size >3 cm 4-cervical node location5-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.

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