1. Melanoma
INTERACTIVE CANCER CASES DISCUSSION
Rome, April 3-4, 2009

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. Pincipali differenze AJCC 2002 vs 1992
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

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

10. Limits of Clark’s level of invasion
Buzaid et al, J Clin Oncol 15: , 1997

11. Prognostic value of ulceration

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

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

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

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

16. Can J Surg 46: , 2003

17. NEJM 350: , 2004

18. Principles of surgical margins for wide excision of primary melanoma
American Society of Plastic Surgeons
Principles of surgical margins for wide excision of primary melanoma
Tumor thickness Recommendend clinical margins
in situ cm
≤ 1 mm cm
mm cm
mm cm
> 4 mm cm

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

20. Morton et al, NEJM 355: , 2006

21. Incidence of positive SLN according to thickness
Wong, Ann Surg Oncol 13: , 2006
≥ 4 mm %
Gershenwald, Ann Surg Oncol 7: , 2000
Gutzmer, J Dtsch Dermatol Ges 6: , 2008

22. In situ (0) not indicated
Recommendations on the use of SLNB
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

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. should not be staged by imaging
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: , 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
Eggermont (EORTC 18952, Lancet 2005):
N 1388, 10 MU 5dd/w for 4 wks followed by 10MU 3 dd/w for 1 y

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, fever 20-25%
Depression %
Suicidal ideation %
Autoimmune disorders %
(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: , 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.
JCO 20: , 2002

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. Retrospective, 400 pts
JCO 16: , 1998

39. AJCC 2002

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

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: , 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. R Dacarbazine Temozolomide 305 PATIENTS (250 mg/m2/d for 5 days, q21d
(200 mg/m2/d for 5 dd q28d)
JCO 18: , 2000

48. Median PFS: 1.9 vs 1.5 mos (p= 0.012)
Median OS: 7.9 vs 5.7 mos (p= 0.06)
JCO 18: , 2000

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
Drug Target
Sorafenib Raf, VEGFR, PDGFR
Bevacizumab VEGF
Bortezomib proteasome inhibitor
Ipilumumab CTLA-4 mAb
Vitaxin v3 integrin mAb
Oblimersen bcl-2 antisense
MS histone 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