Transcript Slide 1

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.
Rate/100,000
“Silent” National Epidemic
18
16
14
12
10
8
6
4
2
0
1935
1:1500
1950
1980
1:600
1:250
1985
1:150
1987
1:135
2000
2005
1:75
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
# of Patients
250
225
200
175
150
125
100
75
50
25
0
98
99
0
1
2
3
Year
4
5
6
7
2007 Estimated US Cancer Cases*
Men
766,860
Women
678,060
Prostate
29%
•26% Breast
Lung & bronchus
15%
•15% Lung & bronchus
Colon & rectum
10%
•11% Colon & rectum
Urinary bladder
7%
Non-Hodgkin
lymphoma
4%
Melanoma of skin
4%
Kidney
4%
•4%
Leukemia
3%
• 4%
Oral cavity
3%
• 3% Ovary
Pancreas
2%
• 3% Kidney
All Other Sites
19%
•6%
Uterine corpus
• 4% Non-Hodgkin
lymphoma
•3%
Melanoma of skin
Thyroid
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
A—Asymmetry
B—Border
C—Color
D—Diameter
E—Evolution: 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
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Level 1 S-100
Level 2 H&E
Level 3 H&E
Level 4 H&E
Level 5 H&E
Level 6 H&E
Level 7 S-100
Doe, John
Doe, John
Doe, John
Doe, John
Doe, John
Doe, John
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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
.734
.890
.988
.882
.952
.976
P-Value
CT v P
<0.01
<0.01
CT v C/P <.00001 <.00001
Reinhardt, MJ et al. J Clin Oncol 2006;24:1178P 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
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•
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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
TCR
MHC
T cell
CTLA-4
TCR
CTLA-4
MHC
CD28
B7
CD28
B7
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]
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•
•
•
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 ½ 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
PI3K→AKT
RAS
PTEN
↓
BRAF
MEK ½
CCND1
MAPK3
↓
MAPK1
CDK4/6
↓
↓
VEG
CFOS
Proliferation
↓
ELK
Proliferation
↓
Cell cycle
progression
MAPK and PI3K/AKT pathways
• Ras/Ras
PI3/AKT
Cutaneous Not chronically sun exposed
Cutaneous, Chronically sun exposed
Mucosal, Acral
Antiapototic pathway
CDKN2A gene mutations
CDK4 amplifcation in acral and mucosal
Proliferative pathway
KIT
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•
•
•
•
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