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Title: MELANOMA


1
MELANOMA
  • Lawrence Flaherty M.D.
  • Professor of Medicine and Oncology
  • Karmanos Cancer Institute
  • General Surgery Educational Conference
  • April 23rd 2008

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Melanoma Incidence RatesUS, 1975-2000
White Men
All Men
Overall
Women
Ries LAG, et al, eds. SEER Cancer Statistics
Review, 19752000. Bethesda, MD National Cancer
Institute 2003 Tables XVI-19.
8
Melanoma Incidence by Age and Gender US,
1996-2000
Ries LAG, et al, eds. SEER Cancer Statistics
Review, 19752000. Bethesda, MD National Cancer
Institute 2003 Tables XVI-19.
9
Cancer Mortality Rates by State Economic Area
(Age-adjusted 1970 US Population)Melanoma of
Skin White Males, 1970-94
US 2.96/100,000
3.65-5.13 (highest 10)
3.42-3.64
3.25-3.41
3.07-3.24
2.87-3.06
2.73-2.86
2.55-2.72
2.36-2.54
2.09-2.35
1.27-2.08 (lowest 10)
Sparse data (5 SEAs 0.06 of deaths)
Devesa SS et al. Atlas of Cancer Mortality in the
U.S., 195094. Washington, DC US Govt Print Off
1999.
10
MELANOMACLINICAL CHARACTERISTICS
  • A Asymmetry
  • B Border Irregularity
  • C Color Change
  • D Diameter ( 6mm )
  • E Evolution/Excise

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Morphologic Types of Melanoma
Type Frequency Features
Superficial 60-70 Flat during early phase
notching,spreading scalloping, areas of
regression Nodular 15-30 Darker and thicker
than superficial spreading, rapid onset
commonly blue-black or blue-red (5
melanotic) Lentigo 5 Enlarge slowly usually
large, flat, tan maligna or
brown Acral Uncommon On soles, palms, beneath
nail beds lentiginous Asians (46), usually
large, tan or brown irregular Blacks (70)
border subungual melanoma more common in
older, dark-skinned people Desmoplastic 1.7 Rare,
locally aggressive, occur primarily on head
and neck in elderly
Data from Lotze MT, et al. Cutaneous Melanoma.
In DeVita VT Jr,. et al, eds. Cancer
Principles Practice of Oncology. 6th ed.
Philadelphia, PA Lippincott-Raven 2001.
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Biopsy Principles - NCCN
  • - Excisional Preferred - narrow margins
    (1-3mm) preserves accuracy for possible SLNBx
  • - Incisional (full thickness) or Punch (of
    thickest region) for large, anatomically
    difficult or uncertain lesions
  • - Shave may compromised full path and depth
    assessment low index of suspicion lesions

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Biopsy Principles - NCCN
  • Pathologic Assessment required
  • - depth - Breslows Thickness (mm)
  • - ulceration (presence or absence)
  • - Clark Level (lesions lt 1mm)
  • - mitotic rate
  • - margin status peripheral and deep
  • - satellitosis, if present
  • - encouraged by AAD (location, regression,
    TIL, VGP, LVI, neurotropism, subtype)

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SURGICAL MANAGEMENTNon-Invasive Melanomas
  • Dysplastic Nevus Complete Excision
  • Melanoma in-situ 5 mm Margins

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Wide Excision Prospective Randomized Trials
  • Cascinelli N, Belli F, Santinami M, et al.
    Ann.Surg.Oncol. 20007(6)469-474
  • Balch CM, Soong SJ, Smith T, et al.
    Ann.Surg.Oncol. 20018(2)101-108
  • Grob JJ, Dreno B, de la Salmoniere P, et al.
    Lancet 6-27-1998351(9120)1905-1910
  • Cohn-Cedermark G et al. 2000 ASCO Annual Meeting.
    Abstract 2240
  • Roberts DL, Anstey AV, Barlow RJ, et al.
    Br.J.Dermatol. 2002146(1)7-17

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Recommended excision marginsNCCN Guidelines
  • Thickness of Primary
  • In situ
  • lt 1.0 mm
  • 1.01 - 2 mm
  • 2.01 - 4 mm
  • gt 4. mm
  • Margin of Excision
  • 0.5 cm
  • 1.0 cm
  • 1 -- 2 cm
  • 2.0 cm
  • gt 2.0 cm

Maximal achievable with primary closure
Where anatomically feasible
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AJCC STAGING
  • Database 30,450 Patients
  • Clinical Path 17,659 Patients
  • 5 Year Follow-up 73
  • 10 Year Follow-up 49
  • 15 Criteria Applied

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AJCC STAGING
  • T- STAGE
  • Variable Chi-Square Value
  • Thickness 252.4
  • Ulceration 199.0
  • Age 50.9
  • Site 40.0
  • Level 35.4
  • Gender 15.5

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AJCC STAGING
  • T-STAGE
  • 5 Year Survival
  • Depth No Ulcer Ulceration
  • lt 1.0 mm 95 83
  • 1.01 2.00 89 77
  • 2.01 4.00 78 63
  • gt 4.00 mm 67 45
  • 10 year survivals 10-15 worse depending on
    category

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AJCC NEW STAGING SYSTEM
  • T CLASSIFICATION
  • T1 ltor 1.0mm a w/o ulceration IA
  • b with ulceration IB
  • T2 1.01 2.0mm a w/o ulceration
  • b with ulceration IIA
  • T3 2.01 4.0mm a w/o ulceration
  • b with ulceration IIB
  • T4 gt 4.0mm a w/o ulceration
  • b with ulceration IIC

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First Things First
  • Level is not Stage
  • Clarks Levels refer to skin anatomy
  • Levels I, II, III, IV, and V
  • Stage refers to Depth, Nodes, and Organs
  • Stage I, II, III, IV
  • Most Stage I melanomas are between Clarks
    Levels I ? IV

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First Things First
  • Stage 0 in-situ (pre-invasive melanoma)
  • I 0.0 2.00 mm
  • II 2.0 4.00 mm
  • III Lymph Node Involvement
  • IV Organ Involvement

Skin Only
The Good News 80-90 of individuals The Better
News 95 remain cancer free
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MelanomaLymph Node Involvementand Management
31
Surgical Lymph Node Evaluation
  • Therapeutic Dissection
  • Elective Regional Lymph Node Dissection
  • Sentinel Lymph Node Biopsy (SLNBx)

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Randomized Trial of Elective Node Dissection in
Melanomas 1 to 4 mm Thick
100
Overall Survival ()
Regional Node Dissection (n 379)
90
80
70
Observation (n 361)
5-yr Survival 86 82
60
Arm ELND Obs
50
P 0.25
40
1
2
3
4
5
6
7
8
10
12
0
9
11
Years
Balch et al, Ann Surg 1996224255
Elective regional lymph node dissection
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Sentinel Lymph Node Biopsy
  • Concept
  • Identify initial draining lymph node/s
    (Sentinel)
  • Remove - if positive Regional LND
  • - if negative No Regional LND
  • Value
  • Therapeutic Benefit ? (ongoing trials)
  • Prognostic information
  • Defines potential for adjuvant therapy/trials

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Sentinel Lymph Node Biopsy
  • Technique
  • Developed and reported by Morton et al
  • Lymphoscintigraphy
  • Defines drainage pattern (nodal basins)
  • Identifies 1st draining nodes/s (sentinel)
  • SLND done at the time of WLE
  • Intradermal injection using
  • Isosulfan blue (visual identification)
  • Technesium sulfur colloid (gamma probe)
  • Sentinel Lymph Node/s identifiied and removed

(Arch Surg 1992 127392-399)
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Sentinel Lymph Node Biopsy
  • Results (Morton et al)
  • 237 lymph node basins identified
  • 80 of basins had a SLN identified
  • 18 positive for melanoma
  • 12 by H and E
  • 9 by immunohistochemistry
  • All patients underwent a complete RLND
  • among 82 that were SLN
  • 3079 additional nodes removed
  • Only 2 , lt0.1

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Optimal SN Sampling For Melanoma
Practical Aspects
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HE
9
Spare
8
Spare
Meridian Section
Subcapsular
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Control
6
Mart-1
5
HE
Heroic Evaluation
4
HMB-45
3
HE
2
S-100
Am J Surg Pathol 1999
1
HE
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Sentinel Lymph Node Biopsy
  • How often and in which patients can we expect to
    find a positive node?

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SENTINEL LYMPH NODE BIOPSYThin Melanomas
  • Retrospective review of 512 patients with
    melanomas 1.50 mm selected to undergo sentinel
    node biopsy
  • Positive node rate by thickness
  • 0.75 mm 1.7
  • 0.75-1.00 mm 3.9
  • 1.01-1.50 mm 7.1
  • Younger patients (lt44) significantly more likely
    to have a positive sentinel node

Bleicher et al, Proc ASCO 2002 abstract 1355
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Impact of Tumor Thickness on Sentinel Node Status
Moffitt Cancer Center Experience 2075 patients
?
?
?
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Sentinel Lymph Node Biopsy
  • Does a sentinel lymph node have a prognostic
    value?

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Sentinel Lymph Node Biopsy Rationale?
  • SLN status is the most powerful independent
    prognostic factor for predicting survival and
    individualizing treatment

Disease-free survival stratified by SLN status
Gershenwald J et al. J Clin Oncol. 199917976983
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AJCC STAGING
  • N Stage
  • Variable Chi- Square Value
  • Number 66.1
  • Micro vs. Macro 50.5
  • Ulceration 25.4
  • Thickness 6.2

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AJCC STAGING
  • N Stage
  • 5 year survival
  • Number micro macro
  • 1 61 46
  • 2 56 38
  • 3 56 27
  • 4 36 23
  • gt4 34 22
  • 10 year survival 5-15 worse depending on
    category

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NEW AJCC STAGING SYSTEM
  • N CLASSIFICATION
  • N1 1 NODE a micrometastasis III A
  • b macrometastasis III B
  • N2 2-3 NODES a micrometastasis
  • b macrometastasis III C
  • c in transit/satellite
  • w/o lymph nodes
  • N3 4 or gt Nodes,
  • matted, in-transit/
  • satellite/ or ulceration
  • metastatic lymph nodes

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  • Is there a God?

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  • Is there a God?
  • What is the meaning of Life?

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  • Is there a God?
  • What is the meaning of Life?
  • Is there a benefit to a lymph node dissection?

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SENTINEL LYMPH NODE BIOPSYIs earlier node
dissection better?
Kretschmer et al, Eur J Cancer 200440212
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Multicenter Selective Lymphadenectomy Trial MSLT
-1
1.2 3.5 mm thickness cutaneous melanoma (n1269)
Wide local excision Sentinel Node Biopsy (60)
Wide local excision (40)
SLN Positive
SLN Negative
Perform lymphadenectomy
Follow for survival
NEJM 20063551307-17
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MSLT 1 (SLNBx) - Con
  • - No survival benefit
  • - False (SLN) may exist - ?proven concept
  • - MSLT 1 trial (2000 pts)
  • - publication based on 1264 sub-group
    analysis with intermediate risk (1.5
    3.5mm)
  • - Australian investigators used US nodal
    evaluation in observation group

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MSLT 1 (SLNBx) - Pro
  • - Prognostic test
  • - little additional toxicity to WLE
  • - f/u can be more risk dependent, i.e.
  • - node neg less frequent
  • - node pos more freq, Rx opprtunities
  • - DFS of 5 may be beneficial to patients
  • - earlier nodal dissection may reduce morbidity
  • - OS benefit may emerge with longer f/u

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Multicenter Selective Lymphadenectomy Trial-II
MSLT-II will determine, in patients with
histopathological or RT-PCR SN metastases,
whether there is an outcome difference comparing
SLNB plus complete lymphadenectomy (CLND) vs.
SLNB alone
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Sentinel Lymph Node Biopsy
  • Present Status and Questions
  • 1. Strongly prognostic with limited morbidity
  • 2. Incorporated into new AJCC staging system
  • 3. Done at time of WLE (? After WLE)
  • 4. Employs blue dye and TSC (95-98 yield)
  • 5. Who is a candidate ?
  • gt than 1.0 mm (.76 1.5mm), ulcerated
    primary, or Clark IV?
  • 6. Serial sectioning HE, IHC, RT-PCR ?
  • 7. Positive SLN complete RLND

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Melanoma Evaluation
  • Low Risk - lt 1.00mm, no ulceration, lt Clark IV
  • 1. No SLNBx
  • 2. Complete History and PE - Skin Exam
  • 3. No Chest X-ray or labs necessary
  • 4. Follow-Up q 6 months for 2 yrs then yrly
  • Intermediate Risk - gt 1.00mm, or ulceration, or
    IV
  • 1. SLNBx
  • 2. Chest X-ray, CBC, SMA
  • 3. Follow-up q 3-6 mos for 5 yrs, ? yearly
    x-rays and labs

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Adjuvant Therapy for Malignant Melanoma
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Approaches to Adjuvant Therapy
  • Agents/Modality Evaluated
  • BCG
  • Corynebacterium parvum
  • Levamisole
  • Transfer factor
  • Vaccinia oncolysate
  • Isolated limb perfusion
  • Radiotherapy

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Approaches to Adjuvant Therapy
  • Agents/Modality Evaluated
  • DTIC
  • DTIC BCG or C. parvum
  • DTIC Nitrosoureas
  • Autologous Bone Marrow Transplant
  • Interferon gamma
  • Interferon alpha 2B

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E-1684
  • Objectives to assess the effects of interferon
    alfa-2b as adjuvant therapy after surgery in
    patients at high risk
  • Overall survival
  • Relapse free survival
  • Eligibility Patients with either
  • gt 4.00 mm melanoma
  • lymph node involvement after resection

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E-1684
  • Arm A Observation x 52 weeks
  • Randomization
  • Arm B Induction Maintenance
  • Interferon Alfa 2b (Intron A) Dosing
  • Induction 20 MIU/m2 IV 5 x weekly x 4 weeks
  • Maintenance 10 MIU/m2 SC TIW x 48 weeks

IFN alfa 2b
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E1690 Relapse-Free Survival by Treatment Group
J Clin Oncol. 2000182444-2458.
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E1690 Overall Survival byTreatment Group
1.00
Median OS 5.12 yr 5.96 yr
Arm HDI Obs
0.85
0.70
Probability
0.55
Observation (n202)
HDI (n203)
0.40
0.25
1
3
0
2
4
5
6
7
8
Years
PNS
J Clin Oncol. 2000182444-2458.
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E-1694/S-9514Phase III Adjuvant GM2 v HD-IFN
  • Background
  • GM2-KLH/QS21
  • - development of IgM Abs favorable
  • - GM2-BCG in Phase III trial in 122 pts at
    MSKCC prolonged RF survival for
  • - pre-existing IgM Abs (control)
  • - developing IgM Abs (vaccine) p 0.02 -
    conjugating with KLH augmented IgM
  • - addition of QS-21 increases IgG and IgM (8X)

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E-1694/S-9514Phase III Adjuvant GM2 v HD-IFN
  • Randomization 11
  • Treatment
  • Arm A GM2-KLH/QS21
  • SC - Weekly X 4 then
  • Week 12 and every 12 weeks X 7
  • (12 vaccinations over 2 years)
  • Arm B High Dose IFN alfa 2b
  • IV 20 MU/m2 M-F x 4 weeks
  • SC 10 MU/m2 M,W,F x 11 months

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E1694/S9512/C509801 Relapse-free Survival
Eligible Patients
1.0
GMK
IFN
0.8
0.6

Probability
0.4
0.2
0.0
0
5
10
15
20
25
30
35
40
45
Months


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E1694/S9512/C509801 Overall Survival Eligible
Patients
1.0
GMK
IFN
0.8
0.6

Probability
0.4
0.2
0.0
0
5
10
15
20
25
30
35
40
45

Months
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Adjuvant IFN - Summary
  • - 3 large cooperative group randomized phase III
    trials, 2 intergroup
  • Trial PTS/arm Control RFS OS
  • 1684 123 Obs
  • 1690 220 Obs 0
  • 1694 440 GM2
  • Conclusion - High dose IFN is the standard of
    care for with high risk melanoma

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Adjuvant InterferonLow-Dose European Trials
  • Trial Total pts IFN dose RFS OS
  • DKG 203 1 MU
    0.6 0.8
  • EO-18871 281 1 MU 0.9
    0.8
  • Scot-MG 96 3 MU 0.4
    0.4
  • Aus-MMCG 311 3 MU 0.02
    0.6
  • French-CGM 499 3 MU 0.04 0.06
  • UKCCR 654 3 MU 0.2 0.8
  • WHO-16 444 3 MU 0.5 0.7
  • EO-18952 1418 5 MU 0.02
    0.7
  • 10 MU 0.2 0.6
  • Cancer Treatment Reviews 2003 29 241-252

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Meta-analysis of Adjuvant IFN 12 Trials 14
comparisons
  • 4 High Dose (20 MU/m2) 6 Low Dose (3 MU)
  • E-1684 WHO - 16
  • E-1690 (HD arm) E-1690 (LD-arm)
  • E-2696 UKCCCR AIM
  • NCCTG -83 French CGM
  • Austrian MMCG
  • 2 Intermed Dose (5-10 MU) Scottish MG
    EORTC 18952 (1 yr)
  • EORTC 18952 (2 yr) 2 Very Low Dose (1 MU)
  • EORTC 18871
  • excludes E-1694 DKG 80
  • Cancer Treatment Reviews 2003 29 241-252

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Meta-analysis of Adjuvant IFN Treatment for
Malignant Melanoma
  • Results All trials (excluding E-1694)
  • Relapse Free Survival improved with IFN
  • p0.000003 HR 0.83 (.77-.90)
  • High-dose IFN (26 reduction)
  • Significant trend for increased benefit with
    increased dose (p 0.02)
  • Overall Survival benefit less clear
  • p0.1 HR 0.93 (.85-1.02)
  • compatible with both no benefit and a moderate
    but clinically worthwhile benefit

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Meta-analysis of Adjuvant IFN Treatment for
Malignant Melanoma
  • Results High-dose IFN including E-1694
  • Relapse free survival
  • - improved as seen in meta-analysis
  • Overall survival
  • - p 0.06 HR 0.85 (.72 1.01)
  • with addition of NCCTG-83
  • - p 0.05 HR 0.86 (.74 1.00)

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Adjuvant IFN Whos a Candidate
  • Based on Trials
  • 1. gt 4.0mm melanomas
  • 2. Nodal involvement (macro -palpable)
  • Other Groups
  • 1. Nodal involvement (micro- SLNBx)
  • 2. 2.0-4.0mm with ulceration
  • 3. Stage IV resected disease free
  • 4. Mucosal and Ocular primaries

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Canvaxin Trials
  • Phase III Randomized Double Blind Trials (2)
  • 1) Resected Stage III (nodal) patients
  • 2) Resected Stage IV (metastatic NED) pts

Canvaxin (Vaccine) BCG
Placebo BCG
Intradermal injections of vaccine or placebo,
weeks 0, 2, 4, 6, 8, then monthly x 12, then
every 2 months x 6, then every 3 months X 12
(total 35/5 yrs). BCG given on week 0 and 2 only
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Canvaxin Stage IV Trial ResultsOverall Survival
Morton DL, et al, presented at SSO San Diego, 2006
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Canvaxin Stage III Trial ResultsOverall Survival
Morton DL, et al, presented at SSO San Diego, 2006
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Intergroup Trial E-1697
  • Intermediate Risk Melanoma
  • Eligibility 1.5mm N1a
  • Phase III 11 Randomization
  • Trial Arms
  • A Observation
  • B High-dose IFN
  • 20 MU/m2 IV, M-F x 4 weeks

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Intergroup Node Trial - S-0008
  • Schema Arm A (High Dose Interferon)
  • Induction-IFN-20 MU/m2 IV M F x 4
    weeks
  • Maintenance IFN 10 MU/m2 SC, M, W, F x
    48 weeks
  • 11 Randomization
  • Arm B - (Biochemotherapy)
  • Cisplatin 20 mg/m2 IV d 1-4
  • Velban 1.2 mg/m2 IV d 1-4
  • DTIC 800 mg/m2 IV d 1
  • IFN ? 2B - 5 MU/m2 SC d, 1-5, 8, 10, 12
  • IL-2 9MU/m2/d CIV d 1-4 (96o)
  • Every 3 weeks x 3 cycles

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S-0008 Trial Background / Rationale
  • 1). Despite HD-IFN, approximately 50 or more of
    node pts die within 5 years.
  • 2). Young group - median age 49-51
  • 3). Biochemotherapy regimens in Stage IV
  • - RRs - 30-60
  • - 10 durable CRs
  • - meta analysis BCT superior to cytokines
  • 4). BCT has activity in patients that fail
    adjuvant IFN

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Intergroup Node Trial S0008
  • Eligibility
  • Includes Cutaneous and Unknown Primaries
  • 1 node (macro) if palpable
  • - (micro) if primary is ulcerated
  • 2 or more nodes (micro or macro)
  • satellite and intransit metastasis
  • recurrence in a previous resected nodal basin
  • at initial diagnosis or at relapse
  • High overall risk group 50-90 likelihood of
    relapse/death

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Management ofMetastatic Melanoma
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Prognosis for Metastatic Melanoma
1.0
0.8
Skin, SQ or distant LN
0.6
Proportion Surviving
Lung
0.4
Visceral sites excluding lung
0.2
0.0
2
0
1
3
Survival (years)
Balch, JCO 193622, 2001.
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SURGERY - ISOLATED METASTASIS
  • Metastatic Site pts. Median Survival Range
  • Skin/Subcutaneous 114 17-32 months
  • Lung 74 13-26 months
  • Brain 42 5-15 months
  • G.I. (non-liver) 39 3-12 months
  • Adrenal 13 24.0 months

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SURGERY - ISOLATED METASTASIS
  • Survival - 2 Year - 15-31 - 5 Year - 10
  • Requires Complete Resection
  • Liver Generally Excluded
  • No Known Prognostic Factors for Long-Term
    Survival
  • Treatment Options Post-Surgery
  • Observation
  • High-dose Interferon
  • Protocols - SWOG-9430/31
  • Vaccine Trials

97
SWOG-9430
  • Patients had to be randomized PRIOR to attempted
    resection of stage IV disease
  • Goals were to determine rate of resectability,
    outcome after resection
  • 77 patients entered from 18 SWOG institutions,
    1996-2005
  • 63 came from seven institutions accruing at least
    4 cases
  • Results
  • 4 patients had no evidence of metastatic melanoma
    at resection
  • 10 patients were unresectable
  • 63 patients (82) were resected free of disease
  • 61 skin/soft tissue/lymph nodes 13 lung, 8
    liver, 5 CNS, 27 other visceral sites
  • 1 patient had a nonfatal postoperative pulmonary
    embolus

98
SWOG-9430Progression Free Survival after
Resection
99
SWOG-9430Overall Survival after Resection
33
29
15
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Metastatic Melanoma
  • Systemic Treatment Options
  • Single Agent Chemotherapy
  • Multi Agent Chemotherapy
  • Chemotherapy Biologic Therapy
  • Interferon Chemotherapy
  • Interleukin-2 Chemotherapy

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Single Agent Therapies
  • Evaluable Agent Patients CRPR 95 CI
    ()
  • Chemotherapy
  • Dacarbazine 1936 20 18-22
  • Carmustine 122 18 11-25
  • Cisplatin 188 23 17-29
  • Vincristine 52 12 3-20
  • Vinblastine 62 13 5-21
  • Paclitaxel 65 18 9-28
  • Biologic Agents
  • Interferon ? 380 16 N/A
  • Interleukin-2 270 16 12-21

102
DTIC Combination ChemotherapySingle Institution
Phase II Trials
  • Regimen Response Rate
  • DTIC Cisplatin 20-53
  • DTIC Cisplatin Velban (CVD) 20-40
  • Bleomycin Vincristine CCNU DTIC (BOLD)
    22-44
  • DTIC Cisplatin BCNU Tamoxifen (Dartmouth)
    15-55

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BiochemotherapyInpatient Regimens-IL-2 Based
  • Author Regimen Route N RR CRs
  • Atkins CVD/IL-2/IFN CIV 42 45 6
  • Khayat C/IL-2/IFN CIV 127 49 13
  • Richards DCBT/IL-2/IFN IVPB 42 57 10
  • Legha CVD/IL-2/IFN CIV 114 60 24
  • Keiholz C/IL-2/IFN CIV 60 33 3
  • Atkins CD/IL-2 IVPB 38 42 3
  • ODay CVDT/IL-2/IFN CIV 35 57 7
  • 458 66 (14.4)
  • CCisplatin, DDTIC (dacarbazine), VVelban,
    TTamoxifen, IL-2Interleukin-2,
  • IFNInterferon Alfa, CIVContinuous infusion
    intravenous, IVPBIntravenous Piggyback

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Biochemotherapy
  • Summary Observations
  • - over 1500 patients have been reported
  • - vast majority, single institution, phase II
    trials
  • - response rates in the 40-60 range
  • - complete responses of 10-20, majority
    durable
  • - responses have been identified in all organ
    sites
  • - experience being gained with outpatient
    regimens
  • - CNS relapses remain a significant problem

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CONCURRENT BCT vs CVDPROTOCOL E3695
  • Randomization
  • Arm A Arm B
  • DTIC 800 mg/m2 day 1 DTIC 800 mg/m2 day 1
  • CDDP 20 mg/m2 day 1-4 CDDP 20 mg/m2/d day 1-4
  • VBL 1.2 mg/m2/d day 1-4 VBL 1.2 mg/m2/d day 1-4
  • IFN alpha 2b 5 MU/m2 SC day 1-5, 8,
    10, 12
  • IL-2 9 MU/m2/d by CIV x 4 days
  • G-CSF 5 mcg/kg SC days 7-16
  • cycle q21 days assess response day 42 max 4
    cycles

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E3695 Preliminary Results
Accrued 416 Eligible 405 (CVD 201/ BCT 204)
Efficacy

There were no statistically significant
differences between the treatment arms
109
E3695 Preliminary TTP Data
110
Metastatic Melanoma
  • Off Protocol Back to Basics
  • Single Agent Chemotherapy (DTIC)
  • Single Agent Biologics (IL-2)
  • New Directions
  • B-Raf inhibitors chemotherapy
  • Targeted agents

111
Interleukin 2 Therapy for Melanoma
112
HD IL-2 TREATMENT REGIMEN
IL-2 600,000 or 720,000 IU/kg Q8H by 15 min
infusion Over 5-6 days Max 14-15 doses
IL-2 600,000 or 720,000 IU/kg Q8H by 15 min
infusion Over 5-6 days Max 14-15 doses
Rest
7-10 days
Repeat at 8-12 weeks if responding Maximum 2-5
courses
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TUMOR RESPONSE
  • N Evaluated 270
  • CR 17 ( 6)
  • PR 26 (10)
  • CR PR 43 (16)
  • (95 CI12 to 21)

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High Dose IL-2 Therapy
  • RR 16 (43 / 270)
  • Durable responses
  • Median 8.9 mos
  • CR not reached

Atkins et al JCO, 1999 (N270)
115
SUMMARY / CONCLUSIONS
  • HD bolus IL-2 therapy produces durable responses
    in approximately 5 of patients with metastatic
    melanoma
  • 44 of responders are currently disease or
    progression free
  • Relapse remains unlikely in patients in response
    for gt 30 months

116
SUMMARY / CONCLUSIONS
  • 11 of pts remain alive _at_ gt 5 years
  • Late death from disease is rare
  • Local salvage therapy may produce durable disease
    free survival
  • Results comparable to those in RCCA patients
    receiving this same regimen

117
Melanoma
20
B-Raf
60
118
BAY 43-9006
  • Orally available inhibitor of c-Raf and b-Raf
    kinases
  • (IC50 2 nM and 21nM, respectively)
  • - IC50 for V559E b-Raf 38nM
  • Raf inhibition not competitive with ATP
  • Recommended phase II dose 400 mg BID
  • Major adverse effects rash, hand-foot
    syndrome, diarrhea

119
BAY 43-9006/carboplatin/paclitaxelStudy design
  • carboplatin carboplatin
    carboplatin
  • paclitaxel paclitaxel
    paclitaxel
  • Day 1 2 3 19 20 21 22 23
    40 43
  • BAY 43-9006 BAY 43-9006
  • Patients who maintain PR or SD for six months
    may be treated with
    BAY 43-9006 alone

120
BAY 43-9006/carboplatin/paclitaxelBest
responses in melanoma
  • 7 of 13 Partial response
  • 15, 10, 8, 8, 7, 6 6 months
  • 5 of 13 Stable disease
  • Progression after 3 to 5 months
  • 1 of 13 Progression after 2 cycles

121
New Treatment Opportunities
  • E 2603 - Phase III Trial of Taxol
    Carboplatin /- Sorafenib (Bay 43-9006)

Taxol Carboplatin Sorafenib
Stage IV
Taxol Carboplatin
122
Summary Points
  • 1. New Staging emphasis on
  • ulceration of primary disease
  • of nodes, micro or macro
  • 2. Sentinel Lymph Node Bx
  • gt 1.00 mm, or ulceration, or Clark level IV
  • 3. IFN (high-dose) is standard adjuvant therapy
  • 1684 RFS OS (10 absolute benefit)
  • 1690 RFS no OS (pub 5/00 JCO)
  • 1694 RFS OS

123
Summary Points
  • 4. Biochemotherapy in Stage IV disease
  • - encouraging phase II data
  • - based on Phase III not the standard
  • 5. Biochemotherapy in Stage III disease
  • - high risk node pts
  • 6. Stage IV Disease
  • - resect solitary metastasis
  • - evaluate for brain metastasis (gt 50)
  • - durable CRs with HD IL-2
  • - best option trial, then IL-2, then
    chemotherapy

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