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Presentation on theme: "Melanoma INTERACTIVE CANCER CASES DISCUSSION Rome, April 3-4, 2009."— Presentation transcript:


2 Antonio DR: 65 aa. Anamnesi: - ipertensione (in trattamento) -Non- fumatore -Lieve ipercolesterolemia (220 md/dl)

3 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

4 Stadio sec AJCC 1992 pT3N0M0 (stadio IIa) * * American Joint Commitee on Cancer Staging (AJCC) 1992

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

6 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)

7 Quale sarebbe stato il tasso di sopravvivenza a 5 anni stimato secondo AJCC 2002? A)Invariato B)80% C)20% D)circa 50% ?

8 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

9 Optimal cut-off for thickness Buzaid et al, J Clin Oncol 15: 1039-1051, 1997

10 Limits of Clarks level of invasion Buzaid et al, J Clin Oncol 15: 1039-1051, 1997

11 Prognostic value of ulceration

12 Stadio sec. AJCC 2002 AJCC Cancer staging manual, 6 th edition, 2002

13 Survival rates according to the AJCC 2002 staging system Balch et al, JCO 19: 3635-3648, 2001

14 !5 yrs survival curves for the stage groupings for patients with localized melanoma Balch et al, JCO 19: 3635-3648, 2001

15 Da valutare: Appropriatezza dei margini chirurgici Staging linfonodale (SLNB) Imaging Terapia adiuvante

16 Can J Surg 46: 419-426, 2003

17 NEJM 350: 757-766, 2004

18 Principles of surgical margins for wide excision of primary melanoma Tumor thickness Recommendend clinical margins in situ0.5 cm 1 mm1.0 cm 1.01-2 mm1-2 cm 2.01-4 mm2.0 cm > 4 mm2.0 cm American Society of Plastic Surgeons

19 3 rd interim analysis of the MSLT-I trial 1400 pts. Breslow 1.2-3.5 mm

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

21 Incidence of positive SLN according to thickness 4 mm30-50% Wong, Ann Surg Oncol 13: 302-309, 2006 Gershenwald, Ann Surg Oncol 7: 160-165, 2000 Gutzmer, J Dtsch Dermatol Ges 6: 198-203, 2008

22 Stageindication 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

23 ? Ritenete che le indagini radiologiche eseguite fossero sufficienti a definire lo stadio? A)No B)Si

24 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

25 Stage I and IIA should not be staged by imaging Stage IIB* and over Chest x-ray and liver US or CT scan chest, adbomen ± pelvis Liver function tests, LDH, full blood count * It may be reasonable to omit

26 Yankovitz, Cancer 110: 1107-1113, 2007

27 ? 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

28 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

29 Adjuvant HD IFN in stage IIb-III melanoma Kirkwood (ECOG 1684, JCO 1996): HDI vs observation Benefit in DFS and OS at 7 yrs Benefit in OS disappeared at 13 yrs Kirkwood (ECOG 1690, JCO 2000): HDI vs observation Benefit in DFS not in OS Kirkwood (ECOG 1694, JCO 2001): HDI vs GMK vaccine HDI better for DFS and OS (only 2y FU and no observation arm)

30 Toxicities of Adjuvant HD IFN Overall G3-4 toxicity:78% Fatigue,Flu-like symptoms, myalgias, fever20-25% Depression40-70% Suicidal ideation5-10% Autoimmune disorders 10% (hypo-hyperthiroidism, vitiligo, LES, rheumatoid arthritis ecc) Associated with improved PFS and OS.

31 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)

32 JCO 20: 18181-1825, 2002

33 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.

34 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

35 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

36 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

37 ? Quale dei seguenti parametri ematochimici ritenete abbiano valore prognostico nel melanoma metastatico? 1)Albumina 2)Emoglobina 3)Transaminasi 4)LDH

38 JCO 16:1103-1111, 1998 Retrospective, 400 pts

39 AJCC 2002

40 Trattamento melanoma metastatico ChemioterapiaORR 5-20% Immunoterapia (HD IL-2)ORR 10-25% (CR 6%) BiochemioterapiaORR10-30%

41 ? Ritenete che una polichemioterapia offra un vantaggio di sopravvivenza rispetto ad una mono-chemioterapia? A)NO B)SI

42 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

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

44 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

45 Marzo 2005:quale trattamento? Dacarbazina 250 mg/m2/d for5 q21dd Somministrati 6 cicli con SD Principale tossicità: piastrinopenia G3

46 Settembre 2005 TAC torace-addome-encefalo: Comparsa di multiple localizzazioni cerebrali a carico di entrambi gli emisferi

47 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)

48 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)

49 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

50 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

51 Nuove possibilità terapeutiche DrugTarget SorafenibRaf, VEGFR, PDGFR BevacizumabVEGF Bortezomibproteasome inhibitor IpilumumabCTLA-4 mAb Vitaxin v 3 integrin mAb Oblimersenbcl-2 antisense MS-275histone deacetylase inhibitor

52 ORR 13.5 vs 7.5 DFS 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)


54 Stage migration (the Will Rogers phenomenon)

55 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

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