Melanoma Kari Kendra MD, PhD 9/18/2009

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. 2005. 2. Greenlee RT, Hill-Harmon MB, Murray T, et al. Cancer statistics, 2001. CA Cancer J Clin. 2001;51:15-36. [Erratum in: CA Cancer J Clin. 2001;51:144.] American Cancer Society, Cancer Facts and Figures. 2005.

SEER Age Adjusted Incidence Rates for Cutaneous Melanoma

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

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

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; 19:3635-3648 2001

What are the challenges?

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

Detect the disease early!

Benign Malignant Asymmetry Border

Benign Malignant Color Diameter

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

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

Prognostic indicators: Breslow depth Depth (mm) 5-year survival (%) <0.75 96 0.76 – 1.49 87 1.50 – 2.49 75 2.50 – 3.99 66 >4.00 47 Koh HK, et al 1991

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

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

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

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

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

Fifteen-year survival curves for the stage groupings of patients with localized melanoma Balch, C. M. et al. J Clin Oncol; 19:3635-3648 2001

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

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%

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

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; 19:3635-3648 2001

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

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

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

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)

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

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

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

(Newcki et al, 2008)

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

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

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

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

Depasquale et al, Histopathology 2005

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

Fifteen-year survival curves for the stage groupings of patients with localized melanoma Balch, C. M. et al. J Clin Oncol; 19:3635-3648 2001

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

Case 1

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

Case 1 What is the next step?

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

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

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

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

Adjuvant therapy with Interferon Alfa-2b (E1684) IFN-2b Observation median DFS 1.7 yr 1.0 yr OS 3.8 yr 2.8 yr benefit greatest in LN+ patients benefit most pronounced early during the treatment interval

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

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%

Adjuvant therapy with Interferon Alfa-2b (E1684) IFN-2b Observation median DFS 1.7 yr 1.0 yr OS 3.8 yr 2.8 yr benefit greatest in LN+ patients benefit most pronounced early during the treatment interval

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

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

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

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?

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

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

Adjuvant therapy with GM-CSF GM-CSF Observation median survival 37.5 mos 12.2 mos 1 yr 89% 45% 2 yr 64% 15% Well tolerated Results from large studies currently pending

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

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

Clinical trials CALGB 500103: 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

Clinical trial (closed to accrual) CALGB 500101: 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 500002: Phase III Trial of High Dose Interferon Alpha 2b vs cisplatin, vinblastine, DTIC plus IL2 and Interferon in Patients with High Risk Melanoma

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

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

Metastatic Disease

Case 2

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

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

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

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

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

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)

Prognosis: Metastatic Melanoma Resection can improve median survival with without resection resection (months)_ (months) Skin/sc nodules 24 11 GI 49 6 Brain 9 2 - 4 (Essner R, 2001, Fifth World Conference on Melanoma)

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

Case 2 Options: Resection Systemic chemotherapy Radiation therapy

Case 2 This patient chose: Surgery Followed by adjuvant therapy

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?

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

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

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

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)

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

Chemotherapy: Single agents Response Rate DTIC 20% Vindesine 14% Vinblastine 13% Carmustine 18% Taxanes 18% Cisplatin 23% Temozolamide 20%

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

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

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

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

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

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

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

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

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)

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)

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)

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 - 4 ) 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)

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)

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

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

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

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 gp100:209-217 (210M) peptide followed by high dose IL2 vs high dose IL2 alone in patients with metastatic melanoma OSU 04105 – A phase I study of PS-341 (bortezomib) and interferon – alpha- 2b in malignant melanoma

Clinical trials OSU 05122 – A phase 3, randomized, open label, comparative study of ticilimumab and either DTIC or temozolamide in patients with advanced melanoma