melanoma interactive cancer cases discussion rome, april 3-4, 2009
TRANSCRIPT
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