Melanoma

INTERACTIVE CANCER CASES DISCUSSIONRome, April 3-4, 2009

Antonio DR: 65 aa.

Anamnesi:

- ipertensione (in trattamento)

- Non- fumatore

- Lieve ipercolesterolemia (220 md/dl)

1999

Asportazione di “nevo displastico” della spalla sx

Es. ISTOLOGICO: “melanoma maligno a cellule epitelioidi, ulcerato. Margini liberi per 2 cm. Spessore sec. Breslow = 2,1 mm. Livello sec. Clark= IV”

TAC torace-addome: negativa

Stadio sec AJCC 1992

pT3N0M0 (stadio IIa) *

* American Joint Commitee on Cancer Staging (AJCC) 1992

Buzaid et al, J Clin Oncol 15: 1039-1051, 1997

McCain had Stage IIA melanoma in 2000

“Melanoma History Suggests McCain Has 22% Odds of Not Surviving a First Term”

Lancet 372: 1462, 2008 (Correspondence by J. Alam)

Quale sarebbe stato il tasso di sopravvivenza a 5 anni stimato secondo AJCC 2002?

A) Invariato

B) 80%

C) 20%

D) circa 50%

?

• Thickness thresholds of 1.0, 2.0 and 4.0 mm

• Level of invasion is used only for defining T1 melanomas

• Ulceration included as a second determinant of T and N staging

Pincipali differenze AJCC 2002 vs 1992

Optimal cut-off for thickness

Buzaid et al, J Clin Oncol 15: 1039-1051, 1997

Limits of Clark’s level of invasion

Buzaid et al, J Clin Oncol 15: 1039-1051, 1997

Prognostic value of ulceration

Stadio sec. AJCC 2002

AJCC Cancer staging manual, 6th edition, 2002

Survival rates according to the AJCC 2002 staging system

Balch et al, JCO 19: 3635-3648, 2001

!5 yrs survival curves for the stage groupings for patients with localized melanoma

Balch et al, JCO 19: 3635-3648, 2001

Da valutare:

• Appropriatezza dei margini chirurgici

• Staging linfonodale (SLNB)

• Imaging

• Terapia adiuvante

Can J Surg 46: 419-426, 2003

NEJM 350: 757-766, 2004

Principles of surgical margins for wide excision of primary melanoma

Tumor thickness Recommendend clinical margins

in situ 0.5 cm

≤ 1 mm 1.0 cm

1.01-2 mm 1-2 cm

2.01-4 mm 2.0 cm

> 4 mm 2.0 cm

American Society of Plastic Surgeons

3rd interim analysis of the MSLT-I trial

1400 pts.

Breslow 1.2-3.5 mm

Morton et al, NEJM 355: 1307-1318, 2006

Incidence of positive SLN according to thickness

≥ 4 mm 30-50%

Wong, Ann Surg Oncol 13: 302-309, 2006

Gershenwald, Ann Surg Oncol 7: 160-165, 2000Gutzmer, J Dtsch Dermatol Ges 6: 198-203, 2008

Stage indication

In situ (0) not indicated

IA (≤ 1 mm) consider in case of adverse prognostic features (high mitotic index, linfovascular invasion, > 0.75 mm)

IB (≤ 1 mm, Clark ≥ IV ulcerated or >1 mm) use encouraged

Recommendations on the use of SLNB

?

Ritenete che le indagini radiologiche eseguite fossero sufficienti a definire lo stadio?

A) No

B) Si

• Stage I (≤ 2mm, no ulceration)

Routine imaging not recommended

• Stage II (> 4 mm ± ulceration)

As clinically indicated

• Stage III (N+)

Extend of imaging left at the discretion of the physician

Pelvic CT for inguinophemoral lymphoadenopathy

• Stage IV (M+)

LDH + chest X-ray recommended

Abdominal/pelvic CT ± PET should be considered

Brain CT or MRI in symptomatic patients

• Stage I and IIA• should not be staged by imaging

• Stage IIB* and overChest x-ray and liver US

orCT scan chest, adbomen ± pelvisLiver function tests, LDH, full blood count

* It may be reasonable to omit

Yankovitz, Cancer 110: 1107-1113, 2007

?

Ritenete che in questo caso un trattamento adiuvante con IFN-a avrebbe garantito un vantaggio in termini di PFS e OS?

A) No

B) Si

Main trials on low-intermediate dose IFN in stage IIb-III patients

• Cascinelli (WHO trial, Lancet 2001): N. 444, 3MU 3dd/w for 3 yrs

No improvement in DFS or OS

• Grobb (French trial, Lancet 1998): N. 449, 3MU 3dd/w for 18 mos

Improved PFS, trend for OS (not confirmd at 41 mos)

• Hancock (AIM-HIGH trial, JCO 2004): N. 674, 3MU 3dd/w for 2 yrs

No improvement in DFS or OS

• Eggermont (EORTC 18952, Lancet 2005): N 1388, 10 MU 5dd/w for 4 wks followed by 10MU 3 dd/w for 1 y

No improvement in DFS or OS

Adjuvant HD IFN in stage IIb-III melanoma

• Kirkwood (ECOG 1684, JCO 1996): HDI vs observationBenefit in DFS and OS at 7 yrsBenefit in OS disappeared at 13 yrs

• Kirkwood (ECOG 1690, JCO 2000): HDI vs observationBenefit in DFS not in OS

• Kirkwood (ECOG 1694, JCO 2001): HDI vs GMK vaccineHDI better for DFS and OS(only 2y FU and no observation arm)

Toxicities of Adjuvant HD IFN

• Overall G3-4 toxicity: 78%

• Fatigue,Flu-like symptoms, myalgias, fever 20-25%

• Depression 40-70%

• Suicidal ideation 5-10%

• Autoimmune disorders 10%

(hypo-hyperthiroidism, vitiligo, LES, rheumatoid arthritis ecc)

Associated with improved PFS and OS.

“ On the basis of the published data, adjuvant HDI therapy does not seem to reduce risk of death from melanoma in those patients at highest risk of this outcome” (Nature Clin Pract Oncol 5: 4-5, 2008)

“ Among all the trials of adjuvant therapy for intermediate or high risk melanoma reported to date, no therapy has ever achieved the durable RFS and independently significant OS benefits that have been observed with HDI” (Nature Clin Pract Oncol 5: 2-3, 2008)

JCO 20: 18181-1825, 2002

JCO 20: 18181-1825, 2002

“Although ECOG 1684 and ECOG 1690 (HDI vs observation) reported statistically significant benefit for DFS…our analysis confirmed this only for EOTC 1684.

For OS, ECOG 1684 trial reported benefit for IFN-a, but our analysis did not confirm it.

• Stage 0, IA

no adjuvant therapy recommended

• Stage IB, IIA

clinical trial or observation

• Stage IIB-C, III

IFN, clinical trial or observation

• Patients rendered free of disease after surgery

(stage III in-transit metastasis or stage IV)

consideration of adjuvant treatment is appropriate

“Decision on the appropriateness of adjuvant IFN should be made on an individual basis, after discussion with the patient, including an explanation of the potential benefits and side effects”

Marzo 2005

TAC TORACE:

“multiple lesioni polmonari bilaterali, noduli sottocutanei in regione mammaria sx e nodulo in regione ascellare sx”

BIOPSIA NODULO SOTTOCUTANEO:

Metastasi da melanoma

?

Quale dei seguenti parametri ematochimici ritenete abbiano valore prognostico nel melanoma metastatico?

1) Albumina

2) Emoglobina

3) Transaminasi

4) LDH

JCO 16:1103-1111, 1998

Retrospective, 400 pts

AJCC 2002

Trattamento melanoma metastatico

• Chemioterapia ORR 5-20%

• Immunoterapia (HD IL-2) ORR 10-25% (CR 6%)

• Biochemioterapia ORR 10-30%

?

Ritenete che una polichemioterapia offra un vantaggio di sopravvivenza rispetto ad una mono-chemioterapia?

A) NO

B) SI

Different polychemiotherapy regimens have not shown prolongation of survival in comparison with dacarbazine.

Objective response rates 5-28% were obtained with single agent dacarbazine, while the polychemiotherapy schedules achieved slightly higher response rates (12-37%)

Lancet Oncol, 4: 748-759, 2003

“The increased response observed with biochemiotherapy (chemo ± IFN ± IL-2) associated with increased toxicity and no significant improvement in survival”.

However…

“.. In certain clinical situations, an increased response rate may be an important therapeutic outcome, perhaps leading to better symptom control or rendering a tumor mass operable.This needs to be balanced against the increased toxicity associated with the approach”

Marzo 2005:quale trattamento?

• Dacarbazina 250 mg/m2/d for5 q21dd

Somministrati 6 cicli con SD

Principale tossicità: piastrinopenia G3

Settembre 2005

• TAC torace-addome-encefalo:

“ Comparsa di multiple localizzazioni cerebrali a carico di entrambi gli emisferi”

JCO 18: 158-166, 2000

305 PATIENTS R

Dacarbazine(250 mg/m2/d for 5 days, q21d

Temozolomide(200 mg/m2/d for 5 dd q28d)

JCO 18: 158-166, 2000

Median PFS: 1.9 vs 1.5 mos (p= 0.012)

Median OS: 7.9 vs 5.7 mos (p= 0.06)

Settembre 2005

• WBRT 30 gray in 10 frazioni (gg 1-5, 8-12) + Temozolomide 75 mg/m2/d dal g1 per 6 settimane (come glioblastoma)

• Dopo 4 settimane: temozolomide 200 mg/m2/die per 5 gg q28 per 3 cicli

Dicembre 2005

• TAC torace-addome-encefalo:

“Comparsa di lesioni epatiche multiple. Aumentate di volume lesioni polmonari”

• Il paziente viene arruolato in un trial clinico per trattamento con Talidomide

• Progressione di malattia a marzo 2006

Nuove possibilità terapeutiche

Drug Target

• Sorafenib Raf, VEGFR, PDGFR• Bevacizumab VEGF• Bortezomib proteasome inhibitor• Ipilumumab CTLA-4 mAb• Vitaxin v3 integrin mAb• Oblimersen bcl-2 antisense• MS-275 histone deacetylase inhibitor

ORR 13.5 vs 7.5DFS 2.6 mos vs 1. 6 mos (HR= 0.75; p= 0.02)OS 9 vs 7.8 mos (HR= 0.87, p= 0.077)

Stage migration (the Will Rogers phenomenon)

“ When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states”

R: {1, 2 } media= 1.5

S: {99,10000,20000} media= 10033

STAGE MIGRATION

R: {1, 2, 99 } media= 34

S: {10000,20000} media= 15000