Melanoma overview 2009
This presentation is the property of its rightful owner.
Sponsored Links
1 / 68

Melanoma Overview 2009 PowerPoint PPT Presentation


  • 55 Views
  • Uploaded on
  • Presentation posted in: General

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

Download Presentation

Melanoma Overview 2009

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


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

  • 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

  • Uveal

  • Ciliary body/Choroidal

    • 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”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


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

  • 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

      • Greater than 3 blistering sunburns under age 20

      • Freckles on the back

    • Tanning Booths

  • Genes-Environment Interactions


Melanoma

A—Asymmetry

B—Border

C—Color

D—Diameter

E—Evolution: A changing mole


Types of Melanoma


Nodular Amelanotic Melanoma

Invasive Melanoma


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


Stage 4 Melanoma


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

  • 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

  • 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

  • Stages the patient

  • Directs further diagnostic studies

  • May have a therapeutic impact

  • Avoid unnecessarily complex

    dissections.


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

  • 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

    • Have completion Lymph node surgery.


    In Transit Melanoma


    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 (CT, PET, MRI)

    • 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

    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

    • Observation

    • Clinical Trial

    • Or Interferon alpha


    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

    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

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

      (category IIb evidence NCCN)


    Stage IV

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


    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

    • Where is this going

      • Genetic Footprint

    • What Categories of treatment do we see?

      • Immune-therapy sensitive

      • Chemotherapy

      • Targetted Therapy


    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 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


    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

    • 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

    • For patients with KIT amplification or mutation

    • Gleevac 400mg PO daily


    Immunotherapy

    • IL2

    • Vaccines

    • Other Modulators of the immune system

      • CTLA 4

      • New agents


    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 ?

    • 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


    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.


    Immune Breakthrough Events

    • Colitis

    • Hepatitis

    • Vitiligo

    • Any autoimmune


    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

    • 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

    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 ½ got Elescomol

    • First Line

    • Measurable disease

    • LDH less than 2.5 times normal

    • No brain mets


    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

    • 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

    • Reviewed Adjuvant Interferon Rx


    Conclusions

    • “Genetic footprint is the future”

    • Currently

      • Targetted

      • Immune

      • Chemotherapy

    • Research at UNC

      -KIT amplified or mutated

      -Vaccine Study of Oncolytic Virus


  • Login