Melanoma Overview 2009

Frances Collichio Associate Professor, University of North Carolina, Chapel Hill

What is Melanoma?
A Cancer of Melanocytes All Melanomas are malignant Melanocytes?
Cells that Make Pigment

Melanoma therefore can start from any pigmented cell.

Extracutaneous Melanomas,
Mucosal
GI tract, Head and Neck, vagina Older pts Poorer px Disporportionally non-white

Ocular
Ciliochoroidal
Poor prognosis

Iris
Better px

Unknown Primary
2-4% of all melanoma 9% of melanoma with lymph node involvement Search for the primary
Ocular exam when there are liver mets

When you cannot find the primary, treat these as if they started in the skin.

Silent National Epidemic

18 16 14 12 10 8 6 4 2 0 1935
1:1500

Rate/100,000

1950
1:600

1980
1:250

1985
1:150

1987
1:135

2000
1:75

2005
1:65

2010
1:60

estimated

Lifetime Risk

The incidence per year is rising faster than any other cancer!

New Melanoma Patients to UNC

375 350 325 300 275 250

# of Patients

225 200 175 150 125 100 75 50 25 0 98 99 0 1 2 3 4 5 6 7

Year

2007 Estimated US Cancer Cases*

Men 766,860
Prostate Lung & bronchus Colon & rectum Urinary bladder Non-Hodgkin lymphoma Melanoma of skin Kidney Leukemia Oral cavity Pancreas All Other Sites 29% 15% 10% 7% 4% 4% 4% 3% 3% 2% 19%

Women 678,060 26% Breast 15% Lung & bronchus 11% Colon & rectum 6% Uterine corpus 4% Non-Hodgkin lymphoma 4% 4% Melanoma of skin Thyroid

3% Ovary 3% Kidney 3% Leukemia 21% All Other Sites

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2007.

Melanoma US 2008
108,000 estimated new cases 62,480 invasive 48,290 in situ 8,420 deaths
www.cancer.org

Etiology
Inheritance -Chromosome 9 (10-40%) Environment
Sun Tanning Booths

Genes-Environment Interactions

Melanoma AAsymmetry BBorder CColor DDiameter EEvolution: A changing mole

Types of Melanoma

Nodular Amelanotic Melanoma

Invasive Melanoma

www.NCCN.org

After diagnosing a skin lesion as melanoma, what is next?

Surgery on the primary by an experience surgeon or dermatologist The margins of resection around the primary depend on the depth of the primary
Less than 1mm deep, 1cm margin 1 to 2mm deep, a 1 to 2cm margin Greater than 2 mm deep, a 2 cm margin

Staging, 2002 AJCC

T
Breslow depth Clark level---used only in T1 melanomas Ulceration

N
N1 one node is involved N2 one to three N3 4 or more, matted nodes, in transit disease, or satellites (tumor w/in 5cm of the primary). Micro or Macro in all three cases

M
M1a-skin, subcutaneous tissue or distant lymph nodes M1b-lung M1c-other sites

Staging and Survival

Stage 4 Melanoma

Example
Stage IIB
T is 4mm without ulceration Or T is 2 to 4 mm with ulceration No nodes are involved. No mets

Patients often think that 4mm tumor is not stage 4

In Transit Melanoma

Sentinel Lymph Node Procedure

Sentinel Lymph Node Evaluation

Lymph node serially sectioned while fresh Alternate sections paraffin-embedded; remainder snap frozen
MS01-1234
Level 1 S-100

MS01-1234
Level 2 H&E

MS01-1234
Level 3 H&E

MS01-1234
Level 4 H&E

MS01-1234
Level 5 H&E

MS01-1234
Level 6 H&E

MS01-1234
Level 7 S-100

Doe, John

Doe, John

Doe, John

Doe, John

Doe, John

Doe, John

Doe, John

Five H&E-stained sections flanked by two S-100 sections

Morton, NEJM 2006

Nodal relapse in the observation 15.6% Nodal relapse in the treated group 3.4% 5 year survival 72.3% for patients with sentinel node involvement treated with immediate lymphadenectomy vs 52.4% for those with recurrent disease

Morton, NEJM 2006

Sentinel lymph node biopsy identifies patients who would otherwise require lymph node surgery at relapse The earlier initiation of complete lymph node dissection may improve overall survival Accurately predicts prognosis

Indications for the Sentinel Lymph Node Procedure

Thin melanomas (< 1 mm) Risk: 5% (Annals of Surgical Oncology Oct 2004) UNC: balanced discussion 0.5-1.0 mm Intermediate thickness melanomas (1-4 mm) Risk: 18-20% UNC: All patients (NEJM 2006) Thick melanomas (>4 mm) Risk: 40%+ nodal, 15-20% systemic UNC: All patients

Patients with Postive Lymph Nodes

Have completion Lymph node surgery.

After treating the primary and completing lymph node surgery, what is next?

Now
You know the T stage You know the N stage You base the extent of additional studies on those two facts.

Additional Studies?
Stage I to IIA: (up to a 4mm thick with no ulceration) No additional Studies Stage IIB, IIC: Additional Studies as clinically indicated Stage III: Baseline studies for staging or symptoms---Chest x-ray, CT + PET, MRI brain

Why PET/CT
CT commonly used alone
Can miss visceral/lung metastases
Sensitivity Specificity

Initial CT PET CT/PE T

P-Value
CT v P

.734 .890 .988

.882 .952 .976

<0.01 <0.01 CT v C/P <.00001 <.00001

Reinhardt, MJ et al. J Clin Oncol 2006;24:1178 P

v C/P

<0.01

NS

Treatment of Stage III Melanoma when all of the visible tumor has been removed
Observation Clinical Trial Or Interferon alpha

Treatment of Stage III Melanoma

Only one FDA Approved Therapy Interferon-a 2b (Brand Name: Intron) Meta-Analysis ~ 10% Absolute Benefit in RFS Improved QoL versus Observation Cost Effective Patient Preference compared to increased risk 3% survival benefit
Cole, BF et al. J Clin Oncol 1996;14:2666 Hillner, BE et al. J Clin Oncol 1997;15:2351 Killbridge, KL et al. J Clin Oncol 2001;19:812

Adjuvant Radiation Therapy

Consider RT to the nodal basin when there are multiple nodes involved or extranodal extension

(category IIb evidence NCCN)

Treatment of Stage III melanoma that cannot be surgically removed

In transit disease Matted Lymph nodes
Clinical trials Local infusions of chemotherapy or immune therapy Radiation Chemotherapy

Management of Stage IV
Median survival is 9 months and less than 5% probability of survival beyond 5 years. Surgery
Best for skin/lymph nodes>lung>GI tract

Radiation
Palliation of symptomatic sites High dose fractions (?) Brain Mets

Standard Systemic Treatments

Clinical Trial Small Molecule Targets Immune modulating agents
High-dose IL-2 Vaccines

Chemotherapy
DTIC or temozolamide Paclitaxel with or without platinum New agents

Immune Modulating Agents High Dose IL 2

Increases CD 4 positive cells Pooled analysis ORR 14% CR 5% Highly selected patients Most durable response of the known therapies Toxic. Requires ICU care and expert personnel

Any hope for Vaccines ?

Stage IIIB and IV OncoVEXGM-CSF will be administered by injection into all injectable cutaneous, subcutaneous or nodal lesions lesions, every two weeks. This vaccine uses Herpes virus proteins as a co-stimulant

After 3 Injections

Resolution of un-injected disease in the lung. Injection sites in the knee/thigh

Targeting the CTLA-4

Blocking CTLA-4 Augments Immune Responses
T cell Inactivation T cell Activation

T cell

T cell
TCR MHC B7 CD28 B7 CTLA-4

TCR MHC CD28

CTLA-4

MDX-010

APC APC

Anti-tumor immune responses are turned off

Mechanism to promote antitumor immune responses

CTLA -4 Blockade: Clinical Development

Fully human monoclonal antibodies Ipilimumab (MDX-010)IgG Ticilimumab (CP-675,206)--IgG

Durable Complete Response in Metastatic Melanoma

Complete resolution of 2 subcutaneous nodules, 31 lung metastases and 0.5 cm brain metastasis. Patient previously failed chemotherapy and surgery. Response ongoing at 40+ months

Sources: Phan et al. PNAS. 2003 Jul;100(14):8372-8377 and Medarex unpublished data Duration as of 1/10/05.

Our Case
53 year old Resection
of brain melanomas 4/2005 in the small intestine 9/2005 under the skin 11/2005

Six months of temodar Disease free for one year CTLA 4 inhibitor
Recurrence in the skin, lung and bone summer 2007 Severe joint pain and decrease in performance status. Prednisone

After initial increase in skin mets, he went into a complete remission and has been in remission for over a year

Chemotherapy
Gold Standard Dacarbazine [Alkylator]
Response Rate: 10-20% Complete Remission Rate 5% IV Regimen No Phase III Data

Chemotherapy
Temozolomide [Temodar]
Oral agent converts to active metabolite of dacarbazine Penetrates CNS FDA Approved for Brain Tumors only Middleton et al: Phase III trial showing no difference from dacarbazine UNC: Current First Line Therapy off Trial
Middleton MR, Grob JJ, et al. J Clin Oncol 2000;18:158

Temodar Targets
Transmethylation of the O-6 site of guanine in DNA leads to profound cytotoxicity

Other active chemotherapy?

Chemotherapy Alternatives
Taxol 80mg/m2/week for 6 of 7 weeks MTP 13 weeks, RR 22% Cisplatin 150 mg/m2 RR 16.3%; OS 7 months

Collichio F, Ollila D, Huck K, et al Proc Am Soc Clin Oncol, 2005:23:726s Glover D, Ibrahim J, et al. Melanoma Res 2003;13:619

SYMMETRY
All patients received paclitaxel and got Elescomol First Line Measurable disease LDH less than 2.5 times normal No brain mets

Symmetry
Better response with Elesclomol and paclitaxel than paclitaxel alone Better time to disease progression But more deaths with the combination and the research is currently on hold

Small Molecule Targets

MAPK and PI3K/AKT pathways

Cell Membrane--------------------------------------------------------SHC PI3KAKT RAS PTEN BRAF MEK CCND1 MAPK3 MAPK1 CDK4/6 VEG CFOS
Proliferation

ELK
Proliferation

Cell cycle progression

MAPK and PI3K/AKT pathways

Ras/Ras
Cutaneous Not chronically sun exposed
Proliferative pathway

PI3/AKT
Cutaneous, Chronically sun exposed Mucosal, Acral Antiapototic pathway CDKN2A gene mutations CDK4 amplifcation in acral and mucosal

KIT
Receptor tyrosine kinase Critical regulator of growth of melanocytes. Dysfunctional KIT pigmentary defects. Expression is lost in nevi Amplification in chronically sun exposed melanoma Amplification in KIT exons 11, 13, 17 and 18 may correlate with Rx response

KIT
Case 2 79 yo rectal melanoma 12/06 recurrence, anal rectal junction and near the kidney Strong staining for KIT KIT exons 11, 13, 17 were amplified Additional peak in exon 11 Imatinib 400mg daily Marked improvement in all disease J Clin Oncol 2008

Conclusions
Epidemiology
Sun Tanning Booths

Epidemic Types of Melanoma

Mucosal, Ocular, Cutaneous

Recognition

Conclusion
Surgery
With appropriate margins

Sentinel Lymph node

For most cases except very thin Positive nodes are followed by a completion dissection

Tests to do after knowing the T stage and nodal stage

Conclusion
Treatment of Resectable Stage III
Clinical trial, observation, interferon

Treatment of non resectable Stage III

Clinical trial, local therapies, chemotherapy

Conclusions
Treatment of Stage IV
Standards are interleukin II, chemotherapy (temodar, taxol), surgery when appropriate, palliative radiation

Research -Targeted therapy

small molecules if KIT amplified -Immune therapy CTLA research Vaccine therapy -Chemotherapy new agents