33. Malignant Melanoma
33.1 General considerations
|
Stage of primary cutaneous melanoma |
AJCC T N M Clinicopathological details |
|
Stage IA T1 N0 M0 <0.75 mm Breslow thickness |
|
Stage IB T2 N0 M0 0.76-1.5mm |
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Stage IIA T3 N0 M0 1.51-4.0mm |
|
Stage IIB T4 N0 M0 >4.0mm |
|
Stage III Any T N1 M0 Nodal disease |
|
Stage IV Any T any N M1/2 Metastatic disease |
Clark’s system (based on a qualitative description of the increasing levels
of penetration through the dermis to the subcutaneous fat)
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Level I Tumor remains above the intact basal lamina; melanoma in situ (0mm) |
|
Level II Tumor invades into the papillary dermis(≤ 0.75mm) |
|
Level III Tumor reaches the papillary-reticular derims interface(0.76-1.5mm) |
|
Level IV Tumor invades into the reticular dermis(1.6-3.9mm) |
|
Level V Tumor invades into the subcutaneous fat(≥4mm) |
Breslow’s system
|
Quantifies the vertical depth of invasion (in mm) from the granular layer of the epidermis(or the base of an ulcer) to the deepest identifiable contiguous melanoma cell. |
Therapeutic excision is the accepted primary treatment for localized disease. If surgery is not possible, radiotherapy with curative intention can also be applied. Regional lymph node dissection must be conducted in case of regional lymph node metastases.
Isolated regional parfusion is indicated for inoperable tumor confined to an extremity.
High-risk patients(primaries ≥4 mm deep, regional lymph node involvement) often require adjuvant therapy in addition to surgery (interferon, radiotherapy, systemic therapy is still experimental).
Systemic therapy for metastatic melanoma includes chemotherapy and biological therapy. In some studies combined immuno-chemotherapy (biochemotherapy) has shown high objective response rates and a small proportion of longterm CRs, but also a substantial increase in toxicity.
Therapeutic vaccines have also started to show some evidence of clinical effectiveness.
Literature: for review e.g.
BECKER et al, Clin.Exp.Dermatol.25 (2000):503-508(classical
chemotherapy)
BONACCORSI et al,Dermatol.Clin. 19(2001): 727-735 (high-risk
melanoma)
CHOWDHURY et al,Cancer Treat.Rev.25(1999):259-270(new
approaches to systemic treatment).
DURAN GARCIA et al,Ann.Pharmacother.33(1999):730-738
EGGERMONT, Recent Results Cancer Res.157(2000): 178-
189(adjuvant therapy)
KROON et al, Melanoma Res. 9(1999):207-212 (consensus of the
Dutch Melanoma Working Party)
MA and ARIYAN,Clin.Plast.Surg.27(2000):441-450 (isolated
limb perfusion)
MARCHAND et al, Expert Opin. Biol. Ther.1(2001):497-
510(melanoma vaccines)
MARGOLIN, Curr.Oncol.Rep.3 (2001):338-343(high-dose
therapy)
PHILIP and FLAHERTY, Curr.Oncol.Rep.2(2000):314-
321(biochemotherapy)
WHITTAKER, Clin.Exp.Dermatol.25(2000):497-502(adjuvant
therapy)
33.2 Single agent therapy: chemotherapy
33.2.1 Dacarbazine (DTIC)
|
Dacarbazine 850-1000mg/m² i.v.(short inf) d1 or 250mg/m² i.v.(short inf) d1-5 |
To be repeated every 3-4 weeks
Literature:
CHAPMAN et al,J.Clin.Oncol. 17(1999):2745-2751 (randomized
phase III study of dacarbazine 1000mg/m² vs the Dartmouth
regimen)
HUNCHAREK er al,Melanoma Res.11(2001):75-81(meta-analysis
from 20 randomized trials of DTIC vs combination chemotherapy
+/ -immunotherapy)
LEGHA,Semin.Oncol.16(Suppl 1)(1989):34-44
LUCE et al, Cancer Chemother. Rep. 54(1970):119-124 (5-day
regimen)
MIDDLETON et al,J.Clin.Oncol.18(2000):158-166(randomized
phase III study of dacarbazine vs temozolomide) PRITCHARD et al,Cancer Treat.Rep.64(1980):1123-1126(1-day
regimen)
33.2.2 Temozolomide
|
Temozolomide 200mg/m² p.o. d 1-5 |
To be repeated every 4 weeks
Literature:
MIDDLETON et al, J.Clin.Oncol. 18(2000): 158-166(randomized phase III study of dacarbazine vs temozolomide)
33.2.3 Fotemustine
|
Fotemustine 100mg/m² i.v.(1 h inf) d 1,8,15 |
To be repeated every 3 weeks
Literature:
JACQUILLAT et al, Cancer 66 (1990):1873-1878
33.2.4 Vindesine
|
Vindesine 3mg/m² i.v. d 1 |
To be repeated every 2 weeks for 1 year, then every 3 weeks for 6 months and finally every 4weeks for 6 months as adjuvant therapy.
Literature:
RETSAS et al,Cancer 73 (1994):2129-2130
33.3 Single agent therapy: biological therapy
33.3.1 Interferon alpha
Literature: for review e.g.
AGARWALA and KIRWOOD,Forum 10(2000):230-239
EGGERMONT, Eur.J.Cancer 37(2001):2147-2153
HANCOCK et al,Cancer Treat.Rev. 26(2000):81-89(adjuvant
therapy)
Only little activity of interferon alpha has been demonstrated for metastatic stage IV melanoma. In the adjuvant setting for stage II and III disease a preliminary meta analysis has demonstrated a positive impact of interferon alpha on relapse free but not on long-term overal survival. Before final results from a number of large randomized studies are available interferon alpha should not be considered as standard therapy.
Low- dose interferon alpha
|
Interferon alpha 3MU s.c.3x weekly 6-36months |
Literature:
CASCINELLI et al,Lancet 358(2001) : 866-869(WHO Melanoma
Program Trial 16)
GROB et al, Lancet 351(1998):1905-1910(French trial)
KIRKWOOD et al,J.Clin.Oncol.18(2000):2444-2458(first analysis
of Intergroup trial E1690/S9111/C9190 comparing high-and low-
dose interferon alpha).
LAFUMA et al, Eur.J.Cancer 37(2001):369-375 (economic
analysis of the French trial reported by Grob et al 1998)
PEHAMBERGER et al,J.Clin.Oncol.16(1998):1425-1429(co-
operative Austrian study ).
Intermediate-dose interferon alpha
|
Interferon alpha 10MU s.c.5 d/wk for 4 wks followed by 5MU s.c.3x weekly for 2 years |
Literature:
EGGERMONT et al, American Society of Clinical Oncology 2001
Educational Book: 88-93 (preliminary results from EORTC
study18952)
High-dose interferon alpha
|
Interferon alpha 20MU/m² i.v.(or i.m.) 5 d/wk for 4 wks followed by 10MU/m² s.c. 3 x weekly for 48 wks |
Literature:
KIRKWOOD et al, J.Clin.Oncol.18(2000): 2444-2458 (first
analysis of Intergroup trial E 1690/S9111/C9190 comparing high-
and low-dose interferon alpha)
33.3.2 Interleukin –2
Literature: for review
KEILHOLZ and EGGERMONT ,Cancer J.Sci.Am.6(Suppl 1)
(2000):99-103(information from 27 trials of the EORTC programs
on the use of interlookin 2 in stage IV melanoma patients)
PHILIP and FLAHERTY,Semin.Oncol.24(Suppl 4)(1997):32-38
|
Interleukin-2 600000 or 720000 IU/kg i.v.(15min)every 8hours for 14 consecutive doses over 5 days,as tolerated |
After a six-to nine-day rest period,an additional 14 doses were scheduled
over the next five days.Courses of therapy were usually separated by six-
to twelve-week intervals(max five).
Literature:
ATKINS et al,J.Clin.Oncol.17(1999): 2105-2116(analysis of 270
patients from eight clinical trials).
33.4 Combination chemotherapy
33.4.1 Dartmouth regimen(CBDT)
|
Cisplatin 25mg/m² i.v.(30-45min inf) d1-3 |
|
BCNU 150mg/m² i.v.(short inf) d1* |
|
Dacarbazine 220mg/m² i.v.(short inf) d1-3 |
|
Tamoxifen** 20-40mg p.o. starting 1 wk before chemotherapy and continued as long as patient is on treatment |
To be repeated every 3 weeks
* BCNU repeated every odd 3-week cycle
** The addition of tamoxifen did not provide a meaningful clinical
advantage
Literature:
CHAPMAN et al,J.Clin.Oncol.17(1999):2745-2751 (randomized
phase III trial of the Dartmouth regimen vs dacarbazine
monotherapy)
CREAGAN et al,,J.Clin.Oncol.17(1999):1884-1890 (phase III trial
of cisplatin dacarbazine, and BCNU with or without tamoxifen)
MIDDLETON et al, Br.J.Cancer 82(2000):1158-1162
(randomized phase III study of the Dartmouth regimen vs
dacarbazine + interferon alpha)
RUSTHOVEN et al,J.Clin.Oncol.14(1996):2083-2090(National
Cancer Institute of Canada Clinical Trials Group randomized,
double-blined , placebocontrolled trial comparing cisplatin,
dacarbazine ,and BCNU with or without tamoxifen)
33.4.2 DVP
|
Dacarbazine 250mg/m² i.v.(30 min inf) d1-5 |
|
Vindesine 3mg/m² i.v.((bolus) d1,8,15 |
|
Cisplatin* 100mg/m² i.v.(30 min inf) d1 |
To be repeated every 4 weeks (total of 3 cycles)
* The addition of cisplatin to dacarbazine/vindesine increased the
median time to progression, but not overall survival. Toxicity was
increased as well.
Literature:
JUNGNELIUS et al,Eur.J.Cancer 34(1998):1368-1374
33.5 Biochemotherapy
The addition of immunotherapy to chemotherapy is still experimental and can not be recommended for routine treatment in the absence of confirmatory randomized studies showing the benefit of that approach.Only a few illustrating examples for such protocol regimes are given.
33.5.1 Dacarbazine + interferon alpha
|
Dacarbazine 800mg/m i.v.(short inf) d 1 |
|
Interferon alpha 9 MU s.c. 3 x weekly |
To be repeated every 3 weeks
Literature:
MIDDLETON et al,J Cancer 82(2000):1158-1162 (randomized phase III study of the Dartmouth regimen vs dacarbazine + interferon alpha)
33.5.2 Dacarbazine + cisplatin + interleukin-2 + interferon alpha
|
Dacarbazine 250mg/m² i.v.(30 min inf) d1-3 after |
|
Cisplatin 25mg/m² i.v.(1 h inf) d1-3 |
|
Interferon alpha 5MU/m² s.c. d6,8,10,13,15 |
|
Interleukin-2 18MU/m² i.v.(15 min inf) d6-10,13-15 |
To be repeated every 4 weeks (outpatient treatment possible)
Literature:
FLAHERTY et al,J.Clin.Oncol.19(2001):3194 -3202