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Melanoma Overview 2009. Frances Collichio Associate Professor, University of North Carolina, Chapel Hill Disclosure: OncoVex Novartis. What is Melanoma?. A Cancer of Melanocytes All Melanomas are malignant Melanocytes? Cells that Make Pigment

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Melanoma overview 2009

Melanoma Overview 2009

Frances Collichio

Associate Professor, University of North Carolina, Chapel Hill

Disclosure: OncoVex

Novartis


What is melanoma

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

Extracutaneous Melanomas,

  • Mucosal

    • GI tract, Head and Neck, vagina

    • Older pts

    • Poorer px

    • Disporportionally non-white


Ocular

Ocular

  • Uveal

  • Ciliary body/Choroidal

    • Poor prognosis

    • Iris

    • Better px


Unknown primary

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

“Silent”NationalEpidemic

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

Rate/100,000

1:1500 1:600 1:250 1:150 1:135 1:75 1:65 1:60

estimated

Lifetime Risk


New melanoma patients to unc

New Melanoma Patients to UNC


2007 estimated us cancer cases

2007 Estimated US Cancer Cases*

Men766,860

Women678,060

  • 26%Breast

  • 15%Lung & bronchus

  • 11%Colon & rectum

  • 6%Uterine corpus

  • 4%Non-Hodgkin lymphoma

  • 4%Melanoma of skin

  • 4% Thyroid

  • 3%Ovary

  • 3%Kidney

  • 3%Leukemia

  • 21%All Other Sites

Prostate29%

Lung & bronchus15%

Colon & rectum10%

Urinary bladder7%

Non-Hodgkin4% lymphoma

Melanoma of skin4%

Kidney4%

Leukemia 3%

Oral cavity3%

Pancreas2%

All Other Sites19%

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.

Source: American Cancer Society, 2007.


Melanoma us 2008

Melanoma US 2008

  • 108,000 estimated new cases

    • 62,480 invasive

    • 48,290 in situ

    • 8,420 deaths

www.cancer.org


Etiology

Etiology

  • Inheritance

    -Chromosome 9 (10-40%)

  • Environment

    • Sun

      • Greater than 3 blistering sunburns under age 20

      • Freckles on the back

    • Tanning Booths

  • Genes-Environment Interactions


Melanoma

Melanoma

A—Asymmetry

B—Border

C—Color

D—Diameter

E—Evolution: A changing mole


Melanoma overview 2009

Types of Melanoma


Nodular amelanotic melanoma

Nodular Amelanotic Melanoma

Invasive Melanoma


After diagnosing a skin lesion as melanoma what is next

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 and survival

Staging and Survival


Stage 4 melanoma

Stage 4 Melanoma


Staging 2002 ajcc

Staging, 2002 AJCC

  • T

    • Breslow depth

    • Clark level---used only in T1 melanomas

    • Ulceration

  • N

    • N1: Metastasis to one node

    • N2: Metastasis to two or three nodes

    • N3: Mets to 4 or more, or matted nodes, or in transit disease, or satellites (tumor w/in 5cm of the primary).

    • Micromets are defined by sentinel node. Macro mets are clinically detectable.

  • M

    • M1a-skin, subcutaneous tissue or distant lymph nodes

    • M1b-lung

    • M1c-other sites


T stage

T stage

  • TX: Primary cannot be assessed (shave bx)

  • T0: no evidence of primary

  • T1 1mm or less

    • T1a: 1mm or less and Clarks level II or III w/o ulceration

  • T2 >1mm and <2mm

  • T3 >2mm and <4mm

  • T4 >4mm

    • A:w/o ulceration

    • B:w ulceration


Nodal stage

Nodal Stage

  • N

    • N1: Metastasis to one node

      • N1a:micromet

      • N1b: Macromet

    • N2: Metastasis to two or three nodes

      • N2a: Micromet

      • N2b: Macromet

      • N2c:in-transit met(s)/satellite(s) without metastatic lymph nodes

    • N3: Mets to 4 or more, or matted nodes, or in transit disease, or satellites (tumor w/in 5cm of the primary).


Sentinel node procedure

Sentinel Node procedure

  • Stages the patient

  • Directs further diagnostic studies

  • May have a therapeutic impact

  • Avoid unnecessarily complex

    dissections.


Sentinel lymph node evaluation

Sentinel Lymph Node Evaluation

Lymph node serially

sectioned while fresh

Alternate sections

paraffin-embedded;

remainder snap frozen

MS01-1234

Level 1 S-100

Doe, John

MS01-1234

Level 2 H&E

Doe, John

MS01-1234

Level 3 H&E

Doe, John

MS01-1234

Level 4 H&E

Doe, John

MS01-1234

Level 5 H&E

Doe, John

MS01-1234

Level 6 H&E

Doe, John

MS01-1234

Level 7 S-100

Doe, John

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


Indications for the sentinel lymph node procedure

Indications for the Sentinel Lymph Node Procedure

  • Thin melanomas (< 1 mm)

    • Consider for ulcerated primaries or Clarks IV, V

  • Intermediate thickness melanomas (1-4 mm)

    • Risk: 18-20%

  • Thick melanomas (>4 mm)

    • Risk: 40%+ nodal, 15-20% systemic


  • Patients with postive lymph nodes

    Patients with Postive Lymph Nodes

    • Have completion Lymph node surgery.


    In transit melanoma

    In Transit Melanoma


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

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


    Melanoma overview 2009

    Now

    • You know the T stage

    • You know the N stage

    • You base the extent of additional studies on those two facts.


    Additional studies

    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 (CT, PET, MRI)

    • Stage III: Baseline studies for staging or symptoms---Chest x-ray, CT + PET, MRI brain


    Why pet ct

    Why PET/CT

    • CT commonly used alone

      • Can miss visceral/lung metastases

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


    Treatment of stage iib t4 iic and iii melanoma when all of the visible tumor has been removed

    Treatment of Stage IIb (T4), IIc, and III Melanoma when all of the visible tumor has been removed

    • Observation

    • Clinical Trial

    • Or Interferon alpha


    Adjuvant therapy

    Adjuvant Therapy

    • 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 but not statistically significant

          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


    Interferon regimen

    Interferon Regimen

    IFNa 2b

    20 Million Units/m2/Day IV

    (15MU often new starting point)

    5 Days per week for 4 weeks

    10 Million Units/m2/Day Subcutaneous

    3 times per week for 11 months

    Side Effects:

    Flu-like Sx, Hepatic Transaminitis, Fatigue, HA, Nausea, Wt Loss, Myelosuppression, Depression


    Adjuvant radiation therapy

    Adjuvant Radiation Therapy

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

      (category IIb evidence NCCN)


    Stage iv

    Stage IV

    • Median survival is 9 months and less than 5% probability of survival beyond 5 years.


    Stage iv disease local therapies

    Stage IV disease local Therapies

    • Surgery

      • Best for skin/lymph nodes>lung>GI tract

    • Radiation

      • Palliation of symptomatic sites

      • High dose fractions (?)

      • Brain Mets


    Systemic treatments

    Systemic Treatments

    • Where is this going

      • Genetic Footprint

    • What Categories of treatment do we see?

      • Immune-therapy sensitive

      • Chemotherapy

      • Targetted Therapy


    Mapk and pi3k akt pathways

    MAPK and PI3K/AKT pathways

    Cell Membrane---------------------------------------------------------SHCPI3K→AKT

    RASPTEN ↓

    BRAF

    MEK ½CCND1

    MAPK3 ↓

    MAPK1 CDK4/6

    ↓ ↓ ↓

    VEG CFOS ELK

    Proliferation Proliferation ↓

    Cell cycle progression


    Mapk and pi3k akt pathways1

    MAPK and PI3K/AKT pathways

    • Ras/RasPI3/AKT

      Cutaneous Not chronically sun exposedCutaneous, Chronically sun exposed

      Mucosal, Acral

      Proliferative pathwayAntiapototic pathway

      CDKN2A gene mutations

      CDK4 amplifcation in acral and mucosal


    Melanoma overview 2009

    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


    Melanoma overview 2009

    KIT

    Case

    • 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


    Imatinib study

    Imatinib Study

    • For patients with KIT amplification or mutation

    • Gleevac 400mg PO daily


    Immunotherapy

    Immunotherapy

    • IL2

    • Vaccines

    • Other Modulators of the immune system

      • CTLA 4

      • New agents


    Immune modulating agents high dose il 2

    Immune Modulating AgentsHigh 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

    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

    After 3 Injections


    Resolution of un injected disease in the lung injection sites in the knee thigh

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


    Targeting the ctla 4

    Targeting the CTLA-4


    Ctla 4 blockade clinical development

    CTLA -4 Blockade: Clinical Development

    • Fully human monoclonal antibodies

    • Ipilimumab (MDX-010)—IgG

    • Ticilimumab (CP-675,206)--IgG


    Melanoma overview 2009

    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.


    Immune breakthrough events

    Immune Breakthrough Events

    • Colitis

    • Hepatitis

    • Vitiligo

    • Any autoimmune


    Our case

    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 two years


    Chemotherapy

    Chemotherapy

    • Gold Standard – Dacarbazine [Alkylator]

      • Response Rate: 10-20%

      • Complete Remission Rate 5%

      • IV Regimen

      • No Phase III Data


    Chemotherapy1

    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

    Middleton MR, Grob JJ, et al. J Clin Oncol 2000;18:158


    Temodar targets

    Temodar Targets

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


    Other active chemotherapy

    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

    SYMMETRY

    • All patients received paclitaxel and ½ got Elescomol

    • First Line

    • Measurable disease

    • LDH less than 2.5 times normal

    • No brain mets


    What were the results of symmetry

    What were the results of 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

    • UNC was number 2 in the USA for accrual


    Conclusions

    Conclusions

    • Epidemiology

      • Sun

      • Tanning Booths

    • Epidemic

    • Types of Melanoma

      • Mucosal, Ocular, Cutaneous

    • Recognition


    Conclusion

    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

    • Reviewed Adjuvant Interferon Rx


    Conclusions1

    Conclusions

    • “Genetic footprint is the future”

    • Currently

      • Targetted

      • Immune

      • Chemotherapy

    • Research at UNC

      -KIT amplified or mutated

      -Vaccine Study of Oncolytic Virus


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