Melanoma Kari Kendra MD, PhD 9/18/2009. Melanoma Incidence and Mortality Incidence (US) Incidence...

MelanomaMelanoma

Kari Kendra MD, PhDKari Kendra MD, PhD

9/18/20099/18/2009

Melanoma Incidence and Melanoma Incidence and MortalityMortality

Incidence Incidence (US)(US) 59,580 new cases 59,580 new cases

33,580 new male cases 33,580 new male cases 26,000 new female cases26,000 new female cases 12 per 100,000 population 12 per 100,000 population

MortalityMortality (US) (US) 7,770 total7,770 total

4,910 males4,910 males 2,860 females2,860 females

American Cancer Society, Cancer Facts and Figures. 2005.

SEER Age SEER Age Adjusted Adjusted Incidence Incidence Rates forRates forCutaneous Cutaneous Melanoma Melanoma

Melanoma: risk factorsMelanoma: risk factors

Constitutional predispositionConstitutional predisposition Fair skin/hair color/ frecklingFair skin/hair color/ freckling Burn vs tanBurn vs tan >20 benign nevi (moles) or >3 atypical nevi>20 benign nevi (moles) or >3 atypical nevi Family history of dysplastic neviFamily history of dysplastic nevi Increasing ageIncreasing age ImmunosuppressionImmunosuppression Xeroderma pigmentosumXeroderma pigmentosum H/O solar keratosis, squamous cell H/O solar keratosis, squamous cell

carcinomacarcinoma

Melanoma: risk factorsMelanoma: risk factors

Risk behaviorsRisk behaviors >3 sunburns>3 sunburns Episodic Episodic

excessive excessive sunlight exposuresunlight exposure

Long term Long term continuous continuous sunlight exposuresunlight exposure

UV exposure at UV exposure at tanning salonstanning salons

Copyright © American Society of Clinical Oncology

Balch, C. M. et al. J Clin Oncol; 19:3635-3648 2001

Fifteen-year survival curves comparing localized melanoma (stages II and I), regional metastases (stage III), and distant metastases (stage IV)

What are the challenges?What are the challenges?

MelanomaMelanoma

The challenge The challenge (historically):(historically): Early detectionEarly detection Rapid growth/high Rapid growth/high

proliferation rate proliferation rate Chemotherapy Chemotherapy

resistantresistant Radiation resistantRadiation resistant Short anticipated Short anticipated

survivalsurvival

Detect the disease early!Detect the disease early!

AAsymmetry symmetry BBorderorder

BenignBenign

MalignaMalignantnt

MalignaMalignantnt

CColor olor DDiameteriameter

BenignBenign

MalignaMalignantnt

MalignaMalignantnt

Prognostic indicatorsPrognostic indicators

Thickness (Breslow depth)Thickness (Breslow depth) Nodal statusNodal status UlcerationUlceration MitosisMitosis Satellite lesionsSatellite lesions In transit lesionsIn transit lesions

Prognostic indicators: Prognostic indicators: Breslow depthBreslow depth

Depth (mm)Depth (mm) 5-year survival (%)5-year survival (%) <0.75<0.75 9696 0.76 – 1.490.76 – 1.49 8787 1.50 – 2.491.50 – 2.49 7575 2.50 – 3.992.50 – 3.99 6666 >4.00>4.00 4747

Koh HK, et al 1991Koh HK, et al 1991

Biopsy techniquesBiopsy techniques

Excisional biopsyExcisional biopsy 1-3 mm margins1-3 mm marginsavoid wider margins (accurate avoid wider margins (accurate lymphatic mapping) lymphatic mapping)

Full thickness incisional/punch biopsyFull thickness incisional/punch biopsy for large lesionsfor large lesionslesions of the palms, soles, digits, face, lesions of the palms, soles, digits, face, earsears

Deep shave biopsiesDeep shave biopsiesWhen suspicion for melanoma is lowWhen suspicion for melanoma is low

NCCN Guidelines 2005NCCN Guidelines 2005

Surgical Treatment of Surgical Treatment of MelanomaMelanoma

In Situ:In Situ: 0.5 mm margin wide 0.5 mm margin wide excisionexcision

<< 1.0 mm: 1.0 mm: 1 cm margin wide 1 cm margin wide excision excision

1.0 - 4.0 mm: 1-2 cm margin wide 1.0 - 4.0 mm: 1-2 cm margin wide excisionexcision

> 4.0 mm:> 4.0 mm: 2 cm margin wide 2 cm margin wide excisionexcision

Nodal evaluationNodal evaluation

Tumors with depth >1 mmTumors with depth >1 mm Sentinel node evaluationSentinel node evaluation

Tumors with depth < 1 mmTumors with depth < 1 mm No nodal evaluation recommendedNo nodal evaluation recommended

NCCN Guidelines 2005NCCN Guidelines 2005

Negative Sentinel Lymph Negative Sentinel Lymph NodesNodes

5 year survival >80% for Clarks level IV 5 year survival >80% for Clarks level IV primariesprimaries

OS is 89%OS is 89% Of the 11% who failedOf the 11% who failed

2.7% in the draining basin2.7% in the draining basin 7.3% distant disease7.3% distant disease

Essner et al 2001Essner et al 2001



Fifteen-year survival curves for the stage groupings of patients with localized melanoma

Prognostic Indicators: Prognostic Indicators: Nodal status Nodal status

OS for patients with 1 OS for patients with 1 positivepositive sentinel node is 60% at 5 yearssentinel node is 60% at 5 years

OS for patients with a single OS for patients with a single palpablepalpable node is 40% at 5 years node is 40% at 5 years

• Gershenwald et al, 2001Gershenwald et al, 2001

Negative Sentinel Lymph Negative Sentinel Lymph NodesNodes

Key prognostic indicators - ulceration Key prognostic indicators - ulceration and tumor thicknessand tumor thickness T1 lesions (T1 lesions (<<0.75 mm) - 86% alive at 10 0.75 mm) - 86% alive at 10

yearsyears T4 lesions with ulceration (>4mm) – 10 T4 lesions with ulceration (>4mm) – 10

year survival 41%year survival 41%



Photomicrograph of a typical ulcerated melanoma

Mitotic IndexMitotic Index N = 3661 from the Sydney Melanoma DatabaseN = 3661 from the Sydney Melanoma Database CorrelatedCorrelated

clinical information (survival)clinical information (survival) primary tumor thickness (Breslow depth)primary tumor thickness (Breslow depth) ulcerative state (infiltrative, attenuative, and ulcerative state (infiltrative, attenuative, and

traumatic)traumatic) tumor mitotic rate (TMR) (at the tumor mitotic rate (TMR) (at the invading front, deep invading front, deep

borderborder)) Conclusion: TMR is a more powerful prognostic Conclusion: TMR is a more powerful prognostic

indicator than ulceration in patients with indicator than ulceration in patients with primary cutaneous melanomaprimary cutaneous melanoma

Azzola et al, Cancer 2003Azzola et al, Cancer 2003

Survival curves of 3661 patients with Survival curves of 3661 patients with localized, cutaneous melanoma when tumor localized, cutaneous melanoma when tumor

mitoses/mmmitoses/mm22 were grouped into four were grouped into four categories .categories .

Azzola et al Cancer 2005Azzola et al Cancer 2005

Azzola et al, 2003Azzola et al, 2003

Tumor thickness and Tumor thickness and Mitotic IndexMitotic Index

Clarks level vs Mitotic IndexClarks level vs Mitotic Index Clark level of invasion failed to have a significant prognostic Clark level of invasion failed to have a significant prognostic

impact by multivariate analysis after adjusting for TMR. impact by multivariate analysis after adjusting for TMR. The number of patients with a Clarks level IV was too small for The number of patients with a Clarks level IV was too small for

adequate comparisonadequate comparison..

(Azzola et al: (Azzola et al: Cancer 2005)Cancer 2005)

Risk of In-Transit Risk of In-Transit MetastasisMetastasis

In- transit metastasisIn- transit metastasis Cutaneous / subcutaneous tissueCutaneous / subcutaneous tissue Between the primary tumor and the draining Between the primary tumor and the draining

lymph node basinlymph node basin 5 yr survival rates: 12% - 37%5 yr survival rates: 12% - 37% Risk factors:Risk factors:

Thicker primaryThicker primary Lower extremityLower extremity Regional LN metastasisRegional LN metastasis

Other prognostic factors:Other prognostic factors: LDHLDH

Elevated levels correlate with: Elevated levels correlate with: Early recurrenceEarly recurrenceShorter survival (Newcki Shorter survival (Newcki et al, 2008)et al, 2008)

Serum S100 levelSerum S100 level Early studies suggest: Early studies suggest:

Shorter survivalShorter survivalEarly distant relapseEarly distant relapsePoorer response to treatment (Smith Poorer response to treatment (Smith et al, 2008)et al, 2008)

Microvessel DensityMicrovessel Density

(Newcki et al, 2008)(Newcki et al, 2008)

Other prognostic factors:Other prognostic factors: LDHLDH

Elevated levels correlate with: Elevated levels correlate with: Early recurrenceEarly recurrenceShorter survival (Newcki Shorter survival (Newcki et al, 2008)et al, 2008)

Serum S100 levelSerum S100 level Early studies suggest: Early studies suggest:

Shorter survivalShorter survivalEarly distant relapseEarly distant relapsePoorer response to treatment (Smith Poorer response to treatment (Smith et al, 2008)et al, 2008)

Microvessel DensityMicrovessel Density

Microvessel Density Microvessel Density (MVD)(MVD)

N= 244N= 244 Histology: superficial spreading (59.3%), nodular Histology: superficial spreading (59.3%), nodular

(21.1%), lentigo maligna melanoma (9.8%), acral (21.1%), lentigo maligna melanoma (9.8%), acral lentiginous (4.4%)lentiginous (4.4%)

Breslow thickness: 0.1 mm – 14.8 mmBreslow thickness: 0.1 mm – 14.8 mm Duration of follow-up : minimum of 2 yearsDuration of follow-up : minimum of 2 years Immunostain: with CD31 antibody to identify Immunostain: with CD31 antibody to identify

endotheliumendothelium Vessel count performed at the tumor edge and in Vessel count performed at the tumor edge and in

the peritumoral host tissue and in the tumor the peritumoral host tissue and in the tumor center for depth >2mmcenter for depth >2mm

Depasquale et al Histopathology Depasquale et al Histopathology 20052005

Microvessel Density Microvessel Density (MVD)(MVD)

Conclusion: microvessel assessment of primary Conclusion: microvessel assessment of primary melanoma using the Chalkley score technique melanoma using the Chalkley score technique provides reliable prognostic information on the provides reliable prognostic information on the risk of recurrence of the tumor, particularly for risk of recurrence of the tumor, particularly for melanomas deeper than 2 mm.melanomas deeper than 2 mm.

Chalkley score – total number of microvessels and Chalkley score – total number of microvessels and relative area occupied by vasculaturerelative area occupied by vasculature

Depasquale et al Histopathology Depasquale et al Histopathology 20052005

Depasquale et al, Histopathology 2005Depasquale et al, Histopathology 2005

MelanomaMelanoma

The challenge The challenge (historically):(historically): Early detectionEarly detection Rapidly growing Rapidly growing Chemotherapy Chemotherapy

resistantresistant Radiation resistantRadiation resistant Short anticipated Short anticipated

survivalsurvival



Fifteen-year survival curves for the stage groupings of patients with localized melanoma

Adjuvant therapy for high Adjuvant therapy for high risk patientsrisk patients

What therapies are available?What therapies are available?

How do we identify patients for How do we identify patients for treatment?treatment?

Case 1Case 1

Case 1Case 1

34 y/o female presented with a 34 y/o female presented with a bleeding mole on her arm. bleeding mole on her arm.

BiopsyBiopsy: nodular melanoma, 4.1 mm : nodular melanoma, 4.1 mm deep, with ulceration, mitotic rate deep, with ulceration, mitotic rate 15/10 HPF15/10 HPF

Wide excisionWide excision: no residual tumor: no residual tumor Sentinel NodeSentinel Node: positive for 2/2 LN: positive for 2/2 LN Axillary LN dissectionAxillary LN dissection: 0/20 LN: 0/20 LN

Case 1Case 1

What is the next step?What is the next step?

Systemic Therapy:Systemic Therapy:AdjuvantAdjuvant

Biologic AgentsBiologic Agents IL2IL2 IFNIFN GM-CSFGM-CSF

Chemotherapeutic agentsChemotherapeutic agents CisplatinCisplatin VinblastineVinblastine DTICDTIC

BiochemotherapyBiochemotherapy

Adjuvant therapy with Adjuvant therapy with Interferon Alfa-2b Interferon Alfa-2b (E1684)(E1684)

FDA approvedFDA approved IFN-alpha 2b for adjuvant treatment of IFN-alpha 2b for adjuvant treatment of

melanoma patients with thick primary melanoma patients with thick primary tumors (> 4mm) or resected nodal diseasetumors (> 4mm) or resected nodal disease

positive response data is for node + positive response data is for node + patients onlypatients only


Patient populationPatient population Breslows depth >4mmBreslows depth >4mm LN+ after ELNDLN+ after ELND clinical LN+ with synchronous primaryclinical LN+ with synchronous primary regional LN recurrence after surgery regional LN recurrence after surgery

for primaryfor primary

Kirkwood et al, JCO 1996;14:7Kirkwood et al, JCO 1996;14:7


TreatmentTreatment high-dose IFNhigh-dose IFNαα-2b-2b : 20 MU/m : 20 MU/m22 IV, IV,

5 days per week for 4 weeks 5 days per week for 4 weeks (induction phase) followed by 10 (induction phase) followed by 10 MU/mMU/m22 SC TIW for 48 weeks SC TIW for 48 weeks

observationobservation


IFNIFN-2b-2b ObservationObservation median DFS 1.7 yr 1.0 yrmedian DFS 1.7 yr 1.0 yr

OS 3.8 yr 2.8 yrOS 3.8 yr 2.8 yr

* benefit greatest in LN+ patientsbenefit greatest in LN+ patients* benefit most pronounced early during the benefit most pronounced early during the

treatment intervaltreatment interval


TOXICITIES:TOXICITIES:constitutionalconstitutional

myelosuppressionmyelosuppression

hepatotoxocityhepatotoxocity

neurologicneurologic

* 67% of all patients had severe (grade 3) 67% of all patients had severe (grade 3) toxicity at some point during treatmenttoxicity at some point during treatment


Time from patients receiving Time from patients receiving 80% of80% of

randomizationrandomization target dosetarget dose

inductioninduction 67%67%

3 months3 months 62%62%





IFNIFN-2b-2b ObservationObservation median DFS 1.7 yr 1.0 yrmedian DFS 1.7 yr 1.0 yr

OS 3.8 yr 2.8 yrOS 3.8 yr 2.8 yr

* benefit greatest in LN+ patientsbenefit greatest in LN+ patients* benefit most pronounced early during the benefit most pronounced early during the

treatment intervaltreatment interval

Adjuvant therapy with Adjuvant therapy with Interferon Interferon -2b-2b

(E1690)(E1690)Patient population:Patient population:

T4cN0 T4cN0

T1-4cN0pN1T1-4cN0pN1

T1-4cN1T1-4cN1

recurrent LN+recurrent LN+* lymphadenectomy not requiredlymphadenectomy not required

Kirkwood et at, JCO 2000;18:2444Kirkwood et at, JCO 2000;18:2444

Adjuvant therapy with Interferon Adjuvant therapy with Interferon -2b-2b(E1690)(E1690)

Treatment:Treatment:

1. high-dose IFN1. high-dose IFNαα-2b-2b

2. low dose IFN2. low dose IFNαα-2b-2b

3. observation3. observation


high-dose IFNhigh-dose IFNαα-2b-2b : 20 MU/m : 20 MU/m22 IV, IV, 5 days per week for 4 weeks 5 days per week for 4 weeks (induction phase) followed by 10 (induction phase) followed by 10 MU/mMU/m22 SC TIW for 48 weeks SC TIW for 48 weeks

low dose IFNlow dose IFNαα-2b-2b: : 3 MU/m3 MU/m22 SC SC TIW - maintenance phase for 2 yearsTIW - maintenance phase for 2 years

observationobservation


RESULTSRESULTS (642 patients) (642 patients) relapsed free survival relapsed free survival

HD > observation HD > observation 5-year estimate RFS5-year estimate RFS (44%, 35%) (44%, 35%)

overall survivaloverall survival HD = LD = observationHD = LD = observation

* Post relapse survival effected by salvage Post relapse survival effected by salvage therapy?therapy?

Adjuvant therapy with GM-Adjuvant therapy with GM-CSFCSF

Patient population: Patient population: stage III stage III ( >4 positive LN or nodal mass ( >4 positive LN or nodal mass > 3 cm) > 3 cm)

stage IVstage IV* all rendered clinically disease-free by all rendered clinically disease-free by

surgery before enrollmentsurgery before enrollment

* Spitler et al, JCO 2000;18:1614Spitler et al, JCO 2000;18:1614


Treatment:Treatment:

GM-CSF 125 mcg/mGM-CSF 125 mcg/m22 sc days 1-14 sc days 1-14 followed by 14 days of restfollowed by 14 days of rest

duration - 1 yearduration - 1 year


GM-CSFGM-CSF ObservationObservation

median survivalmedian survival 37.5 mos 12.2 mos 37.5 mos 12.2 mos

1 1 yryr 89%89% 45%45%

2 yr2 yr 64%64% 15%15%

* Well toleratedWell tolerated* Results from large studies currently pendingResults from large studies currently pending

Adjuvant Therapy Adjuvant Therapy

Currently recommended for:Currently recommended for:

1. 1. ulceratedulcerated primary lesions of any primary lesions of any depth with or without a positive depth with or without a positive sentinel nodesentinel node

2. 2. positivepositive lymph nodes lymph nodes

Current optionsCurrent options

ObservationObservation IFN IFN (1 yr of therapy)(1 yr of therapy) Clinical trialsClinical trials

Clinical trialsClinical trials

CALGB 500103CALGB 500103: Phase III : Phase III Randomized Study of Four Weeks Randomized Study of Four Weeks High Dose IFN-alpha 2b in Stage High Dose IFN-alpha 2b in Stage T3-T4 or N1 (microscopic) T3-T4 or N1 (microscopic) MelanomaMelanoma

OSU 07033OSU 07033: A Pilot Study of IFN-: A Pilot Study of IFN-alpha-2b Dose Reduction with alpha-2b Dose Reduction with Dose Optimization Dose Optimization

Clinical trial Clinical trial (closed to accrual)(closed to accrual)

CALGB 500101CALGB 500101: A Randomized Placebo-: A Randomized Placebo-Controlled Phase III Trial of Yeast Controlled Phase III Trial of Yeast Derived GM-CSF vs Peptide Vaccination Derived GM-CSF vs Peptide Vaccination vs GM-CSF plus Peptide Vaccination vs vs GM-CSF plus Peptide Vaccination vs Placebo in patients wth “no evidence of Placebo in patients wth “no evidence of disease” after compete surgical disease” after compete surgical resection of “locally advanced” and/or resection of “locally advanced” and/or stage IV melanomastage IV melanoma

CALGB 500002CALGB 500002: Phase III Trial of High : Phase III Trial of High Dose Interferon Alpha 2b vs cisplatin, Dose Interferon Alpha 2b vs cisplatin, vinblastine, DTIC plus IL2 and vinblastine, DTIC plus IL2 and Interferon in Patients with High Risk Interferon in Patients with High Risk MelanomaMelanoma

Can we better define those who might Can we better define those who might benefit from adjuvant therapy?benefit from adjuvant therapy?

Can we better define those tumors Can we better define those tumors and high risk for recurrence?and high risk for recurrence?


Thickness (Breslow depth)Thickness (Breslow depth) Nodal statusNodal status UlcerationUlceration Mitotic Index Mitotic Index Satellite lesionsSatellite lesions In transit lesionsIn transit lesions

Metastatic DiseaseMetastatic Disease

Case 2Case 2

Case 2Case 2

75 y/o man diagnosed with: 75 y/o man diagnosed with: superficial spreading melanoma (1999)superficial spreading melanoma (1999) s/p wide excision, SLN evaluations/p wide excision, SLN evaluation Original depth of 6.3 mm, node negative, no Original depth of 6.3 mm, node negative, no

ulceration, mitotic rate 4/10 HPFulceration, mitotic rate 4/10 HPF Presents with non-productive coughPresents with non-productive cough

CT chest demonstrates a solitary pulmonary CT chest demonstrates a solitary pulmonary nodule, 3.0 cm in the RLLnodule, 3.0 cm in the RLL

CT abdomen is clearCT abdomen is clear MRI head is clearMRI head is clear

Case 2Case 2

What is his prognosis?What is his prognosis?

What do we have to offer this patient?What do we have to offer this patient?

MetastasisMetastasis

Most frequent first distant sites Most frequent first distant sites include:include: skin skin subcutaneous tissues subcutaneous tissues distant lymph nodesdistant lymph nodes

Surveillance is importantSurveillance is important

Metastatic melanomaMetastatic melanoma

Treatment approaches:Treatment approaches:• LocalizedLocalized

• Surgery – isolated metastases, limited in Surgery – isolated metastases, limited in size and number, rendered disease freesize and number, rendered disease free

• RadiationRadiation

• Systemic therapySystemic therapy• ChemotherapyChemotherapy• Biotherapy (Immunotherapy)Biotherapy (Immunotherapy)

• Palliative carePalliative care


Surgery:Surgery:

isolated metastases, isolated metastases,

limited in size and number, limited in size and number,

rendered disease freerendered disease free

Prognosis: Metastatic Prognosis: Metastatic

MelanomaMelanoma

Single institution data (John Wayne Institute)Single institution data (John Wayne Institute)

(548 patients)(548 patients)

Site of metastasisSite of metastasis Skin/sc nodule (median survival 11 months)Skin/sc nodule (median survival 11 months) GI (median survival 6 months)GI (median survival 6 months) Liver, bone, or brain (median survival 2 – 4 Liver, bone, or brain (median survival 2 – 4

months)months)

((Essner R, 2001, Fifth World Conference Essner R, 2001, Fifth World Conference on Melanoma)on Melanoma)

Prognosis: Metastatic Prognosis: Metastatic

MelanomaMelanoma

Resection can improve median survival Resection can improve median survival

with without with without resection resection resectionresection

((months)_months)_ (months) (months)

Skin/sc nodules 24 11Skin/sc nodules 24 11

GIGI 49 6 49 6

Brain Brain 9 2 - 4 9 2 - 4

((Essner R, 2001, Fifth World Conference on Essner R, 2001, Fifth World Conference on Melanoma)Melanoma)

Radiation TherapyRadiation Therapy

Likelihood of local CR dependent on:Likelihood of local CR dependent on: Size of dose per fractionSize of dose per fraction Volume of diseaseVolume of disease

(Overgaard et al, 1985)(Overgaard et al, 1985)

CNS metastasesCNS metastases Vertebral metastases with cord Vertebral metastases with cord

compressioncompression

Case 2Case 2

Options:Options:

ResectionResection

Systemic chemotherapySystemic chemotherapy

Radiation therapyRadiation therapy

Case 2Case 2

This patient chose:This patient chose: SurgerySurgery Followed by adjuvant therapyFollowed by adjuvant therapy

Case 3Case 3

20 y/o male:20 y/o male: Presents with SOB, CT: bilateral Presents with SOB, CT: bilateral

pulmonary nodules and axillary masspulmonary nodules and axillary mass Biopsy of axillary mass: melanomaBiopsy of axillary mass: melanoma

What is his prognosis?What is his prognosis?

What treatments are available?What treatments are available?


Systemic therapy:Systemic therapy:

• ChemotherapyChemotherapy – directly target – directly target the tumorthe tumor

• ImmunotherapyImmunotherapy –activates the –activates the immune system to recognize and immune system to recognize and destroy the cancerdestroy the cancer

Biologic therapy:Biologic therapy: HD IL2 HD IL2

Cycle: 600,000 IU/kg every 8 hours x 14 Cycle: 600,000 IU/kg every 8 hours x 14 doses, repeated after 6 – 9 days of restdoses, repeated after 6 – 9 days of rest

Course: repeated after 6 – 12 weeks of restCourse: repeated after 6 – 12 weeks of restRR 16%RR 16%CR 6%, PR 10%CR 6%, PR 10%Median response duration for CR, not reached Median response duration for CR, not reached

6 years after completion of the study6 years after completion of the study28% of responding patients remained disease 28% of responding patients remained disease

freefree

Atkins et al, JCO 1999Atkins et al, JCO 1999

Biologic therapy:Biologic therapy: HD IL2 HD IL2

Cycle: 600,000 IU/kg every 8 hours x 14 Cycle: 600,000 IU/kg every 8 hours x 14 doses, repeated after 6 – 9 days of restdoses, repeated after 6 – 9 days of rest

RR 16%RR 16%CR 6%, PR 10%CR 6%, PR 10%

Median response duration for CR, not reached Median response duration for CR, not reached 6 years after completion of the study6 years after completion of the study

28% of responding patients remained disease 28% of responding patients remained disease freefree

Atkins et al, JCO 1999Atkins et al, JCO 1999

Biologic therapy:Biologic therapy:IFN IFN αα

RR 10 – 24%RR 10 – 24% Dose: Dose:

10 MU/m10 MU/m22 TIW TIW 20 MU/m20 MU/m22 QD x 5 /week QD x 5 /week

Delayed responses observedDelayed responses observed Initial progression, CR at 12 monthsInitial progression, CR at 12 months

(Kirkwood et at, Ann Int Med 1985)(Kirkwood et at, Ann Int Med 1985)

Biologic TherapyBiologic Therapy(IL2, IFN)(IL2, IFN)

Potential benefits:Potential benefits: Durable responsesDurable responses

Limitations:Limitations: ToxicityToxicity

Chemotherapy:Chemotherapy:Single agentsSingle agents

Response Response

RateRate DTICDTIC 20%20% VindesineVindesine 14%14% VinblastineVinblastine 13%13% CarmustineCarmustine 18%18% TaxanesTaxanes 18%18% CisplatinCisplatin 23%23% TemozolamideTemozolamide 20%20%


Best studied:Best studied: DTICDTIC NitrosoureasNitrosoureas

RR 10% – 20%RR 10% – 20% Responders survive longer than Responders survive longer than

nonrespondersnonresponders Responses most frequent in skin, Responses most frequent in skin,

subcutaneous tissue, lymph node, and subcutaneous tissue, lymph node, and lung metastaseslung metastases


Best studied:Best studied: DTICDTIC

RR 10% – 20%RR 10% – 20% Responders survive longer than Responders survive longer than

nonrespondersnonresponders Responses most frequent in skin, Responses most frequent in skin,

subcutaneous tissue, lymph node, and subcutaneous tissue, lymph node, and lung metastaseslung metastases

Single Agent: Single Agent: DTICDTIC

Schedule/Dose: Schedule/Dose: D1 q 3 weeks, 850 - 1000 mg/mD1 q 3 weeks, 850 - 1000 mg/m22

D1 – 5 q3 weeks, 250 mg/mD1 – 5 q3 weeks, 250 mg/m22/d/d

RR and duration not effected by RR and duration not effected by schedule or daily doseschedule or daily dose

Hematologic toxicities are not Hematologic toxicities are not cumulativecumulative


RR 20%RR 20% Liver, bone, and brain, respond Liver, bone, and brain, respond

infrequentlyinfrequently Median duration of response is 5 – 6 Median duration of response is 5 – 6

monthsmonths CR 5% (phase III trials with 580 pt)CR 5% (phase III trials with 580 pt) CR predominantly in sc nodules and CR predominantly in sc nodules and

lymph node metastaseslymph node metastases


RR 20%RR 20% Median duration of response is 5 – 6 Median duration of response is 5 – 6

monthsmonths CR 5% (phase III trials with 580 pt)CR 5% (phase III trials with 580 pt) CR predominantly in sc nodules and CR predominantly in sc nodules and

lymph node metastaseslymph node metastases Liver, bone, and brain, respond Liver, bone, and brain, respond

infrequentlyinfrequently

Single Agent:Single Agent:TemozolamideTemozolamide

OralOral CNS penetrationCNS penetration Spontaneously converted to Spontaneously converted to

mitozolomide (active metabolite of mitozolomide (active metabolite of DTIC)DTIC)

Phase II studies show similar RR to Phase II studies show similar RR to DTICDTIC

Dose: 150 mg/mDose: 150 mg/m22/d, D 1 – 5, q 28 days/d, D 1 – 5, q 28 days

Single Agent: Single Agent: nitrosoureasnitrosoureas

BCNU, CCNU, methylCCNU, BCNU, CCNU, methylCCNU, fotemustinefotemustine

Lipid solubleLipid soluble CNS penetrationCNS penetration Fotemustine - responses noted in Fotemustine - responses noted in

CNS disease (9/36 patients)CNS disease (9/36 patients)(Khayat et al, 1987)(Khayat et al, 1987)

Chemotherapy:Chemotherapy:Combination regimensCombination regimens

Dartmouth regimenDartmouth regimen DTIC, BCNU, cisplatin, tamoxifenDTIC, BCNU, cisplatin, tamoxifen

CVDCVD Cisplatin, vinblastine, dacarbazineCisplatin, vinblastine, dacarbazine

CVTCVT Cisplatin, vinblastine, temodarCisplatin, vinblastine, temodar

Taxol/carboplatinTaxol/carboplatin

Combination:Combination:Dartmouth regimenDartmouth regimen

DTIC: 220 mg/mDTIC: 220 mg/m22 iv, D 1 – 3 and 22 – 24 iv, D 1 – 3 and 22 – 24 Cisplatin: 25 mg/mCisplatin: 25 mg/m22 iv, D 1 – 3 and 22 – iv, D 1 – 3 and 22 –

2424 Carmustine: 150 mg/mCarmustine: 150 mg/m22 iv D1 iv D1 Tamoxifen 10 mg po BID starting on D4Tamoxifen 10 mg po BID starting on D4

1 cycle = 6 weeks1 cycle = 6 weeks(DelPrete et al, Cancer Treat Rep 1984)(DelPrete et al, Cancer Treat Rep 1984)

Combination: Combination: CVDCVD

Cisplatin: 20 mg/mCisplatin: 20 mg/m22 iv D1 – 5 iv D1 – 5 Vinblastine: 1.6 mg/mVinblastine: 1.6 mg/m22 iv, D1 – 5 iv, D1 – 5 DTIC: 800 mg/mDTIC: 800 mg/m22 iv D1 iv D1

1 cycle = 21 days1 cycle = 21 days

(Legha et al, Cancer 1989)(Legha et al, Cancer 1989)

Combination Combination chemotherapy:chemotherapy:

Paclitaxel and carboplatinPaclitaxel and carboplatinN = 31 patientsN = 31 patients 2 previous therapies, incuding temodar or 2 previous therapies, incuding temodar or

DTICDTIC Taxol 100 mg/mTaxol 100 mg/m22, carboplatin AUC 2 , carboplatin AUC 2

on day 1, 8, and 15 of a 28 day cycleon day 1, 8, and 15 of a 28 day cycle 26% PR, 19% SD = clinical benefit of 45%26% PR, 19% SD = clinical benefit of 45% Median TTP 3 months, median OS of 7.9 Median TTP 3 months, median OS of 7.9

months months in responders median OS = 5.7 monthsin responders median OS = 5.7 months

(Rao et al, (Rao et al, Cancer 2006)Cancer 2006)


CVD + IL2 + IFNCVD + IL2 + IFN Cisplatin (20 mg/mCisplatin (20 mg/m22 iv days 1 - 4) iv days 1 - 4) Vinblastine (1.2 mg/m2 on days 1 – 4)Vinblastine (1.2 mg/m2 on days 1 – 4) Dacarbazine (800 mg/mDacarbazine (800 mg/m22/d iv days 1)/d iv days 1) IFN IFN α (5 mU/mα (5 mU/m22/day sc days 1 – 5, 8, 10, and /day sc days 1 – 5, 8, 10, and

12)12) IL2 (9.0 MU/m2/ day CI, on days 1 - 4 )IL2 (9.0 MU/m2/ day CI, on days 1 - 4 ) 1 cycle = 21 days, max of 4 cycles1 cycle = 21 days, max of 4 cycles Responses in 19/40 patients (22%)Responses in 19/40 patients (22%) 8 CR (20%)8 CR (20%)Response duration 7+ monthsResponse duration 7+ months (McDermott et al, Clin Cancer Res 2000)(McDermott et al, Clin Cancer Res 2000)


CVT +IL2 +IFNCVT +IL2 +IFN(48 pts), median follow-up 414 days(48 pts), median follow-up 414 days Temezolomide, 150 mg/m2/d, po, days 1 Temezolomide, 150 mg/m2/d, po, days 1

– 4, replaces the DTIC– 4, replaces the DTIC RR 47%, 7/48 CRRR 47%, 7/48 CR Median response duration 6 months Median response duration 6 months Of responders: 36% relapsed in CNSOf responders: 36% relapsed in CNS

(63% of responders developed CNS relapse (63% of responders developed CNS relapse with CVD, IL2, IFN) with CVD, IL2, IFN)

(Atkins et al, Clin Cancer (Atkins et al, Clin Cancer Res 2002)Res 2002)

Current optionsCurrent options

Participation in a clinical trialParticipation in a clinical trial Standard therapyStandard therapy

Biologic therapy Biologic therapy ChemotherapyChemotherapy Radiation therapyRadiation therapy SurgerySurgery

Symptom managementSymptom management


OSU 06006OSU 06006: A Phase I Study of Bolus High : A Phase I Study of Bolus High Dose IL2 with Sorafenib in Patients with Dose IL2 with Sorafenib in Patients with Unresectable or Metastatic MelanomaUnresectable or Metastatic Melanoma

OSU 09023OSU 09023: An Open-label, Multicenter, : An Open-label, Multicenter, Phase I/II Study of Pazopanib in Phase I/II Study of Pazopanib in Combination with Paclitaxel in First-line Combination with Paclitaxel in First-line Treatment of Subjects with Stage Treatment of Subjects with Stage IIIBwet/IV Non-small Cell Lung Cancer IIIBwet/IV Non-small Cell Lung Cancer


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

Clinical trials and newer Clinical trials and newer agentsagents

OSU 0132OSU 0132 – A phase 2 study of – A phase 2 study of bevacizumab and interferon-alpha-2b in bevacizumab and interferon-alpha-2b in metastatic melanomametastatic melanoma

OSU 0351OSU 0351 – A phase III multi- – A phase III multi-institutional randomized study of institutional randomized study of immunization with the gp100:209-217 immunization with the gp100:209-217 (210M) peptide followed by high dose (210M) peptide followed by high dose IL2 vs high dose IL2 alone in patients IL2 vs high dose IL2 alone in patients with metastatic melanomawith metastatic melanoma

OSU 04105OSU 04105 – A phase I study of PS-341 – A phase I study of PS-341 (bortezomib) and interferon – alpha- 2b (bortezomib) and interferon – alpha- 2b in malignant melanomain malignant melanoma

Clinical trialsClinical trials OSU 05122OSU 05122 – A phase 3, randomized, open – A phase 3, randomized, open

label, comparative study of ticilimumab label, comparative study of ticilimumab and either DTIC or temozolamide in and either DTIC or temozolamide in patients with advanced melanomapatients with advanced melanoma

Melanoma Kari Kendra MD, PhD 9/18/2009. Melanoma Incidence and Mortality Incidence (US) Incidence...

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Transcript of Melanoma Kari Kendra MD, PhD 9/18/2009. Melanoma Incidence and Mortality Incidence (US) Incidence...