1. Melanoma
Kari Kendra MD, PhD
9/18/2009

2. Melanoma Incidence and Mortality
Incidence (US)
59,580 new cases
33,580 new male cases
26,000 new female cases
12 per 100,000 population
Mortality (US)
7,770 total
4,910 males
2,860 females
Key Point: The incidence of malignant melanoma in the United States
is increasing.
An estimated 59,580 new cases of melanoma occurred in the United States in 2005 (26,000 new cases among women; 33,580 new cases among men). Melanoma in situ is also showing an increased incidence.
Nearly 8,000 Americans succumb to malignant melanoma each year.1,2
References
1. American Cancer Society. Cancer Facts and Figures
2. Greenlee RT, Hill-Harmon MB, Murray T, et al. Cancer statistics, CA Cancer J Clin. 2001;51: [Erratum in: CA Cancer J Clin. 2001;51:144.]
American Cancer Society, Cancer Facts and Figures

3. SEER Age Adjusted Incidence Rates for Cutaneous Melanoma

4. Melanoma: risk factors
Constitutional predisposition
Fair skin/hair color/ freckling
Burn vs tan
>20 benign nevi (moles) or >3 atypical nevi
Family history of dysplastic nevi
Increasing age
Immunosuppression
Xeroderma pigmentosum
H/O solar keratosis, squamous cell carcinoma

5. Melanoma: risk factors
Risk behaviors
>3 sunburns
Episodic excessive sunlight exposure
Long term continuous sunlight exposure
UV exposure at tanning salons

6. Fifteen-year survival curves comparing localized melanoma (stages II and I), regional metastases (stage III), and distant metastases (stage IV)
Balch, C. M. et al. J Clin Oncol; 19:

7. What are the challenges?

8. Melanoma The challenge (historically): Early detection
Rapid growth/high proliferation rate
Chemotherapy resistant
Radiation resistant
Short anticipated survival

9. Detect the disease early!

10. Benign
Malignant
Asymmetry Border

11. Benign
Malignant
Color Diameter

12. Prognostic indicators
Thickness (Breslow depth)
Nodal status
Ulceration
Mitosis
Satellite lesions
In transit lesions

13. Prognostic indicators
Thickness (Breslow depth)
Nodal status
Ulceration
Mitosis
Satellite lesions
In transit lesions

14. Prognostic indicators: Breslow depth
Depth (mm) 5-year survival (%)
<
0.76 –
1.50 –
2.50 –
>
Koh HK, et al 1991

15. Biopsy techniques Excisional biopsy 1-3 mm margins
avoid wider margins (accurate lymphatic mapping)
Full thickness incisional/punch biopsy
for large lesions
lesions of the palms, soles, digits, face, ears
Deep shave biopsies
When suspicion for melanoma is low
NCCN Guidelines 2005

16. Surgical Treatment of Melanoma
In Situ: 0.5 mm margin wide excision
< 1.0 mm: 1 cm margin wide excision
mm: cm margin wide excision
> 4.0 mm: 2 cm margin wide excision

17. Prognostic indicators
Thickness (Breslow depth)
Nodal status
Ulceration
Mitosis
Satellite lesions
In transit lesions

18. Nodal evaluation Tumors with depth >1 mm
Sentinel node evaluation
Tumors with depth < 1 mm
No nodal evaluation recommended
NCCN Guidelines 2005

19. Negative Sentinel Lymph Nodes
5 year survival >80% for Clarks level IV primaries
OS is 89%
Of the 11% who failed
2.7% in the draining basin
7.3% distant disease
Essner et al 2001

20. Fifteen-year survival curves for the stage groupings of patients with localized melanoma
Balch, C. M. et al. J Clin Oncol; 19:

21. Prognostic Indicators: Nodal status
OS for patients with 1 positive sentinel node is 60% at 5 years
OS for patients with a single palpable node is 40% at 5 years
Gershenwald et al, 2001

22. Negative Sentinel Lymph Nodes
Key prognostic indicators - ulceration and tumor thickness
T1 lesions (<0.75 mm) - 86% alive at 10 years
T4 lesions with ulceration (>4mm) – 10 year survival 41%

23. Prognostic indicators
Thickness (Breslow depth)
Nodal status
Ulceration
Mitosis
Satellite lesions
In transit lesions

24. Photomicrograph of a typical ulcerated melanoma
The epidermis above the primary melanoma is absent, with a
tapering of the epidermis at the periphery of the lesion.
Balch, C. M. et al. J Clin Oncol; 19:

25. Prognostic indicators
Thickness (Breslow depth)
Nodal status
Ulceration
Mitosis
Satellite lesions
In transit lesions

26. Mitotic Index N = 3661 from the Sydney Melanoma Database Correlated
clinical information (survival)
primary tumor thickness (Breslow depth)
ulcerative state (infiltrative, attenuative, and traumatic)
tumor mitotic rate (TMR) (at the invading front, deep border)
Conclusion: TMR is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma
Azzola et al, Cancer 2003

27. Survival curves of 3661 patients with localized, cutaneous melanoma when tumor mitoses/mm2 were grouped into four categories Azzola et al Cancer 2005
Azzola et al, 2003

28. Tumor thickness and Mitotic Index
Clarks level vs Mitotic Index
Clark level of invasion failed to have a significant prognostic impact by multivariate analysis after adjusting for TMR.
The number of patients with a Clarks level IV was too small for adequate comparison.
(Azzola et al: Cancer 2005)

29. Prognostic indicators
Thickness (Breslow depth)
Nodal status
Ulceration
Mitosis
Satellite lesions
In transit lesions

30. Risk of In-Transit Metastasis
Cutaneous / subcutaneous tissue
Between the primary tumor and the draining lymph node basin
5 yr survival rates: 12% - 37%
Risk factors:
Thicker primary
Lower extremity
Regional LN metastasis

31. Other prognostic factors:
LDH
Elevated levels correlate with:
Early recurrence
Shorter survival (Newcki et al, 2008)
Serum S100 level
Early studies suggest:
Shorter survival
Early distant relapse
Poorer response to treatment (Smith et al, 2008)
Microvessel Density

32. (Newcki et al, 2008)

33. Other prognostic factors:
LDH
Elevated levels correlate with:
Early recurrence
Shorter survival (Newcki et al, 2008)
Serum S100 level
Early studies suggest:
Shorter survival
Early distant relapse
Poorer response to treatment (Smith et al, 2008)
Microvessel Density

34. Other prognostic factors:
LDH
Elevated levels correlate with:
Early recurrence
Shorter survival (Newcki et al, 2008)
Serum S100 level
Early studies suggest:
Shorter survival
Early distant relapse
Poorer response to treatment (Smith et al, 2008)
Microvessel Density

35. Microvessel Density (MVD)
Histology: superficial spreading (59.3%), nodular (21.1%), lentigo maligna melanoma (9.8%), acral lentiginous (4.4%)
Breslow thickness: 0.1 mm – 14.8 mm
Duration of follow-up : minimum of 2 years
Immunostain: with CD31 antibody to identify endothelium
Vessel count performed at the tumor edge and in the peritumoral host tissue and in the tumor center for depth >2mm
Depasquale et al Histopathology 2005

36. Microvessel Density (MVD)
Conclusion: microvessel assessment of primary melanoma using the Chalkley score technique provides reliable prognostic information on the risk of recurrence of the tumor, particularly for melanomas deeper than 2 mm.
Chalkley score – total number of microvessels and relative area occupied by vasculature
Depasquale et al Histopathology 2005

37. Depasquale et al, Histopathology 2005

38. Melanoma The challenge (historically): Early detection Rapidly growing
Chemotherapy resistant
Radiation resistant
Short anticipated survival

39. Fifteen-year survival curves for the stage groupings of patients with localized melanoma
Balch, C. M. et al. J Clin Oncol; 19:

40. Adjuvant therapy for high risk patients
What therapies are available?
How do we identify patients for treatment?

41. Case 1

42. Case 1 34 y/o female presented with a bleeding mole on her arm.
Biopsy: nodular melanoma, 4.1 mm deep, with ulceration, mitotic rate 15/10 HPF
Wide excision: no residual tumor
Sentinel Node: positive for 2/2 LN
Axillary LN dissection: 0/20 LN

43. Case 1
What is the next step?

44. Systemic Therapy: Adjuvant
Biologic Agents
IL2
IFN
GM-CSF
Chemotherapeutic agents
Cisplatin
Vinblastine
DTIC
Biochemotherapy

45. Adjuvant therapy with Interferon Alfa-2b (E1684)
FDA approved
IFN-alpha 2b for adjuvant treatment of melanoma patients with thick primary tumors (> 4mm) or resected nodal disease
positive response data is for node + patients only

46. Adjuvant therapy with Interferon Alfa-2b (E1684)
Patient population
Breslows depth >4mm
LN+ after ELND
clinical LN+ with synchronous primary
regional LN recurrence after surgery for primary
Kirkwood et al, JCO 1996;14:7

47. Adjuvant therapy with Interferon Alfa-2b (E1684)
Treatment
high-dose IFNα-2b : 20 MU/m2 IV, 5 days per week for 4 weeks (induction phase) followed by 10 MU/m2 SC TIW for 48 weeks
observation

48. Adjuvant therapy with Interferon Alfa-2b (E1684)
IFN-2b Observation
median DFS yr yr
OS yr yr
benefit greatest in LN+ patients
benefit most pronounced early during the treatment interval

49. Adjuvant therapy with Interferon Alfa-2b (E1684)
TOXICITIES:
constitutional
myelosuppression
hepatotoxocity
neurologic
67% of all patients had severe (grade 3) toxicity at some point during treatment

50. Adjuvant therapy with Interferon Alfa-2b (E1684)
Time from patients receiving 80% of
randomization target dose
induction 67%
3 months 62%
6 months 40%
9 months 30%
11 months 25%

51. Adjuvant therapy with Interferon Alfa-2b (E1684)
IFN-2b Observation
median DFS yr yr
OS yr yr
benefit greatest in LN+ patients
benefit most pronounced early during the treatment interval

52. Adjuvant therapy with Interferon -2b (E1690)
Patient population:
T4cN0
T1-4cN0pN1
T1-4cN1
recurrent LN+
lymphadenectomy not required
Kirkwood et at, JCO 2000;18:2444

53. Adjuvant therapy with Interferon -2b (E1690)
Treatment:
1. high-dose IFNα-2b
2. low dose IFNα-2b
3. observation

54. Adjuvant therapy with Interferon -2b (E1690)
high-dose IFNα-2b : 20 MU/m2 IV, 5 days per week for 4 weeks (induction phase) followed by 10 MU/m2 SC TIW for 48 weeks
low dose IFNα-2b: 3 MU/m2 SC TIW - maintenance phase for 2 years
observation

55. Adjuvant therapy with Interferon -2b (E1690)
RESULTS (642 patients)
relapsed free survival
HD > observation
5-year estimate RFS (44%, 35%)
overall survival
HD = LD = observation
Post relapse survival effected by salvage therapy?

56. Adjuvant therapy with GM-CSF
Patient population:
stage III ( >4 positive LN or nodal mass > 3 cm)
stage IV
all rendered clinically disease-free by surgery before enrollment
Spitler et al, JCO 2000;18:1614

57. Adjuvant therapy with GM-CSF
Treatment:
GM-CSF 125 mcg/m2 sc days followed by 14 days of rest
duration - 1 year

58. Adjuvant therapy with GM-CSF
GM-CSF Observation
median survival mos mos
1 yr 89% 45%
2 yr 64% 15%
Well tolerated
Results from large studies currently pending

59. Adjuvant Therapy Currently recommended for:
1. ulcerated primary lesions of any depth with or without a positive sentinel node
2. positive lymph nodes

60. Current options
Observation
IFN (1 yr of therapy)
Clinical trials

61. Clinical trials
CALGB : Phase III Randomized Study of Four Weeks High Dose IFN-alpha 2b in Stage T3-T4 or N1 (microscopic) Melanoma
OSU 07033: A Pilot Study of IFN-alpha-2b Dose Reduction with Dose Optimization

62. Clinical trial (closed to accrual)
CALGB : A Randomized Placebo-Controlled Phase III Trial of Yeast Derived GM-CSF vs Peptide Vaccination vs GM-CSF plus Peptide Vaccination vs Placebo in patients wth “no evidence of disease” after compete surgical resection of “locally advanced” and/or stage IV melanoma
CALGB : Phase III Trial of High Dose Interferon Alpha 2b vs cisplatin, vinblastine, DTIC plus IL2 and Interferon in Patients with High Risk Melanoma

63. Can we better define those who might benefit from adjuvant therapy?
Can we better define those tumors and high risk for recurrence?

64. Prognostic indicators
Thickness (Breslow depth)
Nodal status
Ulceration
Mitotic Index
Satellite lesions
In transit lesions

65. Metastatic Disease

66. Case 2

67. Case 2 75 y/o man diagnosed with: Presents with non-productive cough
superficial spreading melanoma (1999)
s/p wide excision, SLN evaluation
Original depth of 6.3 mm, node negative, no ulceration, mitotic rate 4/10 HPF
Presents with non-productive cough
CT chest demonstrates a solitary pulmonary nodule, 3.0 cm in the RLL
CT abdomen is clear
MRI head is clear

68. Case 2
What is his prognosis?
What do we have to offer this patient?

69. Metastasis Most frequent first distant sites include:
skin
subcutaneous tissues
distant lymph nodes
Surveillance is important

70. Metastatic melanoma Treatment approaches: Localized Systemic therapy
Surgery – isolated metastases, limited in size and number, rendered disease free
Radiation
Systemic therapy
Chemotherapy
Biotherapy (Immunotherapy)
Palliative care

71. Metastatic melanoma Surgery: isolated metastases,
limited in size and number,
rendered disease free

72. Prognosis: Metastatic Melanoma
Single institution data (John Wayne Institute)
(548 patients)
Site of metastasis
Skin/sc nodule (median survival 11 months)
GI (median survival 6 months)
Liver, bone, or brain (median survival 2 – 4 months)
(Essner R, 2001, Fifth World Conference on Melanoma)

73. Prognosis: Metastatic Melanoma
Resection can improve median survival
with without resection resection
(months)_ (months)
Skin/sc nodules GI
Brain
(Essner R, 2001, Fifth World Conference on Melanoma)

74. Radiation Therapy Likelihood of local CR dependent on: CNS metastases
Size of dose per fraction
Volume of disease
(Overgaard et al, 1985)
CNS metastases
Vertebral metastases with cord compression

75. Case 2
Options:
Resection
Systemic chemotherapy
Radiation therapy

76. Case 2
This patient chose:
Surgery
Followed by adjuvant therapy

77. Case 3
20 y/o male:
Presents with SOB, CT: bilateral pulmonary nodules and axillary mass
Biopsy of axillary mass: melanoma
What is his prognosis?
What treatments are available?

78. Metastatic melanoma Systemic therapy:
Chemotherapy – directly target the tumor
Immunotherapy –activates the immune system to recognize and destroy the cancer

80. Biologic therapy: HD IL2
Cycle: 600,000 IU/kg every 8 hours x 14 doses, repeated after 6 – 9 days of rest
Course: repeated after 6 – 12 weeks of rest
RR 16%
CR 6%, PR 10%
Median response duration for CR, not reached 6 years after completion of the study
28% of responding patients remained disease free
Atkins et al, JCO 1999

81. Biologic therapy: HD IL2
Cycle: 600,000 IU/kg every 8 hours x 14 doses, repeated after 6 – 9 days of rest
RR 16%
CR 6%, PR 10%
Median response duration for CR, not reached 6 years after completion of the study
28% of responding patients remained disease free
Atkins et al, JCO 1999

83. Biologic therapy: IFN α
RR 10 – 24%
Dose:
10 MU/m2 TIW
20 MU/m2 QD x 5 /week
Delayed responses observed
Initial progression, CR at 12 months
(Kirkwood et at, Ann Int Med 1985)

84. Biologic Therapy (IL2, IFN)
Potential benefits:
Durable responses
Limitations:
Toxicity

85. Chemotherapy: Single agents
Response
Rate
DTIC %
Vindesine %
Vinblastine %
Carmustine %
Taxanes %
Cisplatin %
Temozolamide 20%

86. Chemotherapy: Single agents
Best studied:
DTIC
Nitrosoureas
RR 10% – 20%
Responders survive longer than nonresponders
Responses most frequent in skin, subcutaneous tissue, lymph node, and lung metastases

87. Chemotherapy: Single agents
Best studied:
DTIC
RR 10% – 20%
Responders survive longer than nonresponders
Responses most frequent in skin, subcutaneous tissue, lymph node, and lung metastases

88. Single Agent: DTIC Schedule/Dose: D1 q 3 weeks, 850 - 1000 mg/m2
D1 – 5 q3 weeks, 250 mg/m2/d
RR and duration not effected by schedule or daily dose
Hematologic toxicities are not cumulative

89. Single Agent: DTIC RR 20% Liver, bone, and brain, respond infrequently
Median duration of response is 5 – 6 months
CR 5% (phase III trials with 580 pt)
CR predominantly in sc nodules and lymph node metastases

90. Single Agent: DTIC RR 20% Median duration of response is 5 – 6 months
CR 5% (phase III trials with 580 pt)
CR predominantly in sc nodules and lymph node metastases
Liver, bone, and brain, respond infrequently

91. Single Agent: Temozolamide
Oral
CNS penetration
Spontaneously converted to mitozolomide (active metabolite of DTIC)
Phase II studies show similar RR to DTIC
Dose: 150 mg/m2/d, D 1 – 5, q 28 days

92. Single Agent: nitrosoureas
BCNU, CCNU, methylCCNU, fotemustine
Lipid soluble
CNS penetration
Fotemustine - responses noted in CNS disease (9/36 patients)
(Khayat et al, 1987)

93. Chemotherapy: Combination regimens
Dartmouth regimen
DTIC, BCNU, cisplatin, tamoxifen
CVD
Cisplatin, vinblastine, dacarbazine
CVT
Cisplatin, vinblastine, temodar
Taxol/carboplatin

94. Combination: Dartmouth regimen
DTIC: 220 mg/m2 iv, D 1 – 3 and 22 – 24
Cisplatin: 25 mg/m2 iv, D 1 – 3 and 22 – 24
Carmustine: 150 mg/m2 iv D1
Tamoxifen 10 mg po BID starting on D4
1 cycle = 6 weeks
(DelPrete et al, Cancer Treat Rep 1984)

95. Combination: CVD Cisplatin: 20 mg/m2 iv D1 – 5
Vinblastine: 1.6 mg/m2 iv, D1 – 5
DTIC: 800 mg/m2 iv D1
1 cycle = 21 days
(Legha et al, Cancer 1989)

96. Combination chemotherapy: Paclitaxel and carboplatin
N = 31 patients
2 previous therapies, incuding temodar or DTIC
Taxol 100 mg/m2, carboplatin AUC 2
on day 1, 8, and 15 of a 28 day cycle
26% PR, 19% SD = clinical benefit of 45%
Median TTP 3 months, median OS of 7.9 months
in responders median OS = 5.7 months
(Rao et al, Cancer 2006)

97. Biochemotherapy CVD + IL2 + IFN Cisplatin (20 mg/m2 iv days 1 - 4)
Vinblastine (1.2 mg/m2 on days 1 – 4)
Dacarbazine (800 mg/m2/d iv days 1)
IFN α (5 mU/m2/day sc days 1 – 5, 8, 10, and 12)
IL2 (9.0 MU/m2/ day CI, on days )
1 cycle = 21 days, max of 4 cycles
Responses in 19/40 patients (22%)
8 CR (20%)
Response duration 7+ months
(McDermott et al, Clin Cancer Res 2000)

98. Biochemotherapy CVT +IL2 +IFN
(48 pts), median follow-up 414 days
Temezolomide, 150 mg/m2/d, po, days 1 – 4, replaces the DTIC
RR 47%, 7/48 CR
Median response duration 6 months
Of responders: 36% relapsed in CNS
(63% of responders developed CNS relapse with CVD, IL2, IFN)
(Atkins et al, Clin Cancer Res 2002)

99. Current options Participation in a clinical trial Standard therapy
Biologic therapy
Chemotherapy
Radiation therapy
Surgery
Symptom management

100. Clinical trials
OSU 06006: A Phase I Study of Bolus High Dose IL2 with Sorafenib in Patients with Unresectable or Metastatic Melanoma
OSU 09023: An Open-label, Multicenter, Phase I/II Study of Pazopanib in Combination with Paclitaxel in First-line Treatment of Subjects with Stage IIIBwet/IV Non-small Cell Lung Cancer

101. Clinical trials
 OSU 08059: A Phase II Trial of Intravenous Administration of Reovirus Serotype 3 - Dearing Strain (Reolysin®) in Patients with Metastatic Melanoma.

102. Clinical trials and newer agents
OSU 0132 – A phase 2 study of bevacizumab and interferon-alpha-2b in metastatic melanoma
OSU 0351 – A phase III multi-institutional randomized study of immunization with the gp100: (210M) peptide followed by high dose IL2 vs high dose IL2 alone in patients with metastatic melanoma
OSU – A phase I study of PS-341 (bortezomib) and interferon – alpha- 2b in malignant melanoma

103. Clinical trials
OSU – A phase 3, randomized, open label, comparative study of ticilimumab and either DTIC or temozolamide in patients with advanced melanoma