Article

Dummer R, Hauschild A, Pentheroudakis GCutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 20(Suppl 4):129-131

Department of Dermatology, University of Kiel, Kiel, Germany.
Annals of Oncology (Impact Factor: 7.04). 05/2009; 20 Suppl 4(Supplement 4):129-31. DOI: 10.1093/annonc/mdp152
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Available from: George Pentheroudakis, Aug 26, 2014
Annals of Oncology 19 (Supplement 2): ii86–ii88, 2008
doi:10.1093/annonc/mdn100
clinical recommendations
Cutaneous malignant melanoma: ESMO Clinical
Recommendations for diagnosis, treatment and follow-
up
R. Dummer
1
, A. Hauschild
2
& L. Jost
3
On behalf of the ESMO Guidelines Working Group*
1
Department of Dermatology, University of Kiel, Kiel, Germany;
2
Department of Dermatology, University of Kiel, Germany;
3
Department of Oncology, Kantonsspital,
Bruderholz, Germany
incidence
The incidence of malignant melanoma varies from 3–5/100
000/year in Mediterranean countries to 12–20/100 000 in
Nordic countries. The mortality rate is 2/100 000 for females
and 3/100 000/year for males with a lesser variation with
geography. Melanoma mortality has doubled in males over the
last 25 years. Increased ultraviolet-B ray exposure of
a genetically predisposed population seems responsible for an
ongoing increase in incidence over recent decades.
diagnosis
Suspicious lesions are characterized by asymmetry, border
irregularities, color heterogeneity, dynamics (evolution of
color, elevation or size) (‘ABCDE rule’). Diagnosis should be
based on a full-thickness excisional biopsy with a small side
margin [B]. Processing by an experienced pathology institute is
mandatory. The histology report should follow the WHO
classification and include maximum thickness in millimeters
(Breslow), level of invasion (Clark level I–V), presence of
ulceration, presence and extent of regression and clearance of
the surgical margins.
staging
Physical examination with special attention to other suspicious
pigmented skin lesions including head and genitalia, tumor
satellites, in-transit metastases, regional lymph node and
systemic metastases is mandatory. Today, many primary
melanomas have a diameter of <5 mm. In low-risk melanomas
(tumor thickness <1 mm) no other investigations are necessary.
In higher stages imaging is recommended in order to exclude
regional or distant metastatic disease. The refined version of the
ASCC staging and classification system, which includes the
staging of microscopically positive lymph nodes, is the
classification system of choice (Table 1).
treatment for localized disease
Wide excision of primary tumors with a normal skin margin of
0.5 cm for in situ melanomas, of 1 cm for tumors with
a Breslow thickness up to 2 mm and 2 cm for thicker tumors is
recommended [II, B]. Modifications may be needed for
preservation of function in melanomas of the fingers and toes
or those of the face and the ear.
Routine elective lymphadenectomy or irradiation to the
regional lymph nodes is not recommended [II, B].
Sentinel lymph node biopsy in melanoma with a tumor
thickness of >1 mm is necessary for precise staging and is
followed by complete clearance of regional lymph nodes, if the
sentinel node was positive for micro-metastases [C]. This
procedure should be performed only by skilled teams in
experienced centers.
There is no generally accepted adjuvant therapy to date for
patients with high-risk primary melanoma or completely
resected lymph node metastases (stage III). Adjuvant
immunotherapy with interferon-a (IFN-a) leads to
a significant prolongation of disease-free survival in some but
not all randomized trials. Positive effects of high-dose IFN-a on
overall survival have been demonstrated in two out of three
randomized trials [C]. The optimal timing and dosing
schedules and the best type of interferon (pegylated versus
conventional) are not yet defined. Therefore, adjuvant
interferon treatment is preferentially applied in the context of
randomized clinical trials in specialized centers.
Adjuvant chemotherapies, mistletoe extracts, viscum album
and hormone therapies are not beneficial. Adjuvant
immunotherapy with other cytokines including interleukin-2,
tumor vaccination and immunochemotherapy are experimental
and not to be used outside of controlled clinical trials.
Radiotherapy for local tumor control should be considered
in case of inadequate resection margins of lentigo maligna
melanoma or R1 resections of melanoma metastases when
re-excision is not feasible [B].
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.
Taddei 4, CH-6962 Viganello-Lugano, Switzerland
Approved by the ESMO Guidelines Working Group: August 2002, last update
September 2007. This publication supercedes the previously published version—Ann
Oncol 2007; 18 (Suppl 2): ii71–ii73.
Conflict of interest: Dr Dummer has reported no conflicts of interest. Dr Hauschild has
reported that he is member of the advisory board for Schering-Plough, Synta, Pfizer,
BMS, Bayer and that he receives study grants from Bayer, Essex Pharma, Roche,
Pharma.
ª 2008 European Society for Medical Oncology
Page 1
treatment for locoregional metastatic
disease
In the case of isolated loco-regional lymph node metastases,
surgical removal, including the surrounding lymph node
region, is indicated; removal of the tumor-bearing lymph node
alone is insufficient. Surgical removal is also recommended in
the case of an isolated metastasis in a parenchymal organ,
including the central nervous system. However, before
undertaking additional aggressive local surgical treatments,
a detailed staging investigation, including imaging techniques
such as CT or positron emission tomography (PET) scans, are
necessary to exclude the presence of further metastases [B].
Non-resectable in-transit metastases or inoperable primary
tumors of the limbs without additional metastases may be
treated with isolated limb perfusion using e.g. melphalan and
tumor necrosis factor [II–III, C]. However, such treatment
requires major surgery and should be restricted to a few
experienced centers. Radiation therapy may be used instead [V,
D], although there are no data showing a positive effect on
any outcome measure.
Adjuvant systemic therapy after complete resection as
mentioned above.
treatment for systemic metastatic
disease (stage IV ASCC)
Palliative therapy for advanced disease with several metastases
in different anatomical regions should initially use cytostatics
such as dacarbazine, vinca alkaloids, nitrosurea or
temozolomide alone or in combination with cytokines like
IFN-a or, in the case of aggressive metastastic disease,
polychemotherapy [C]. Since the overall impact of systemic
therapy on survival in advanced melanoma patients is
questionable, these patients should be treated preferentially in
controlled clinical trials evaluating new approaches. Surgery of
visceral metastases may be appropriate for selected cases with
good performance status and isolated tumor manifestation.
In all surgically treated patients R0 resections must be the goal.
Palliative radiotherapy should be considered especially for
symptomatic brain or localized bone metastases.
patient information and follow-up
The patient and his/her family, in particular small children,
should be instructed in avoidance of sunburn, extended
unprotected solar or artificial ultraviolet exposure and in
lifelong regular self-examination of the skin and peripheral
lymph nodes. The patient must be aware that her/his family
members have an increased risk of melanoma [B]. A secondary
melanoma develops in 8% of all melanoma patients within 2
years of their initial diagnosis. Melanoma patients also have
increased risks for other skin tumors. In patients with lentigo
maligna melanomas, 35% of the patients developed another
cutaneous malignancy within 5 years.
During melanoma follow-up, patients are clinically
monitored in order to detect a relapse and to recognize
additional skin tumors, especially a second melanoma, as early
as possible [B].
Recommendations for follow-up depend upon the risk of
relapse over time. Follow-up relies primarily on clinical
examinations every 3 months during the first 3 years and every
6–12 months thereafter. Since patients with a thin primary
melanoma have only a small risk of relapse, imaging techniques
are not necessary for this patient population. In contrast,
ultrasound of lymph nodes, CT or whole body PET/PET–CT
scans may be considered in the follow-up of high-risk patients,
i.e. those with thick primary tumors or following treatment of
metastases. However, there is currently no consensus on the use
of imaging techniques or blood tests. Rising serum S100 has
a higher specificity for disease progression than lactate
Table 1
AJCC TNM stage 10-year
survival (%)
Criteria for staging
IA T1a N0 M0 87.9 T1a = Breslow £1 mm, no
ulceration (U–) and Clark
level £III
IB T1b N0 M0 83.1 T1b = Breslow £1 mm with
ulceration (U+) or Clark
level IV
T2a N0 M0 79.2 T2a = Breslow
1.01–2.0 mm U–
IIA T2b/T3a N0 M0 64.4/63.8 T2b = Breslow 1.01–2.0 mm,
U+/T3 = 2.01–4.0 mm U–
IIB T3b/T4a N0 M0 53.9/50.8 T3b = Breslow 2.01–4.0 mm
U+/T4 =>4.0 mm U–
IIC T4b N0 M0 32.3 T4b = Breslow > 4.0 mm U+
IIIA Any Ta N1a/N2a M0 63.0/56.9 U–, N1a = 1 lymph
node microscopically
+/N2 = 2–3 nodes
IIIB Any Tb N1a/N2a M0 47.7/35.9 U+, N1a = 1 lymph
node microscopically
+/N2 = 2–3 nodes
IIIC Any Tb N1b/N2b M0 24.4/15.0 U+, N1b = 1 lymph
node macroscopically
+/N2 = 2–3 nodes
Any T N3 M0 18.4 U– or U+,N3=‡4 nodes,
satellite or in transit
metastases
IV Any T any N M1a 15.7 M1a = nodal
metastases with normal
LDH; distant
skin, subcutaneous
metastases with normal
LDH
Any T any N M1b 2.5 M1b = lung
metastases with normal
LDH
Any T any N M1c 6.0 M1c = LDH elevated
and/or any non-
pulmonary
visceral metastases
Percentage figures are median values for disease-specific survival with
a standard deviation between 1% and 7%. AJCC, American Joint
Committee on Cancer; TNM. Tumor–node–metastasis; LDH, lactate
dehydrogenase.
Annals of Oncology
clinical recommendations
Volume 19 | Supplement 2 | May 2008 doi:10.1093/annonc/mdn100 | ii87
Page 2
dehydrogenase (LDH) and therefore is the most accurate blood
test in the follow-up of melanoma patients if any blood test is
done at all [D].
Psychosocial guidance and rehabilitation—if
needed—constitute an important task of the caring physician.
Reporting follow-up results to Clinical Cancer Registries
secures quality control of surgical and medical interventions.
note
Levels of evidence [I–V] and grades of recommendation [A–D]
as used by the American Society of Clinical Oncology are given
in square brackets. Statements without grading were considered
justified standard clinical practice by the expert authors and the
ESMO faculty.
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clinical recommendations
Annals of Oncology
ii88 | ESMO Guidelines Working Group Volume 19 | Supplement 2 | May 2008
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    [Show abstract] [Hide abstract] ABSTRACT: Purpose The aim of this systematic review was to systematically assess the potential patient-relevant benefit (primary aim) and diagnostic and prognostic accuracy (secondary aim) of positron emission tomography (PET) and PET/computed tomography (CT) in primary staging of malignant melanoma. This systematic review updates the previous evidence for PET(/CT) in malignant melanoma. Materials and methods For the first aim, randomized controlled trials (RCTs) investigating patient-relevant outcomes and comparing PET and PET(/CT) with each other or with conventional imaging were considered. For the secondary aim, a review of reviews was conducted, which was amended by an update search for primary studies. MEDLINE, EMBASE and four databases of the Cochrane Library were searched. The risk of bias was assessed using a modified QUADAS tool. Results No RCTs investigating the patient-relevant benefit of PET(/CT) and no prognostic accuracy studies were found. Seventeen diagnostic accuracy studies of varying quality were identified. For patients with American Joint Committee on Cancer (AJCC) stages I and II, sensitivity mostly ranged from 0 to 67%. Specificity ranged from 77 to 100%. For AJCC stages III and IV, sensitivity ranged from 68 to 87% and specificity from 92 to 98%. Conclusion There is currently no evidence of a patient-relevant benefit of PET(/CT) in the primary staging of malignant melanoma. RCTs investigating patient-relevant outcomes are therefore required. The diagnostic accuracy of PET(/CT) appears to increase with higher AJCC stages.
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    • "NSCLC: proportion of T1-3N0M0 cases receiving surgery [20]. Melanoma: proportion of cases with Breslow thickness > 1 mm receiving sentinel node biopsy [21]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Population-based cancer registry studies of care patterns can help elucidate reasons for the marked geographic variation in cancer survival across Italy. The article provides a snapshot of the care delivered to cancer patients in Italy. Methods: Random samples of adult patients with skin melanoma, breast, colon and non-small cell lung cancers diagnosed in 2003-2005 were selected from 14 Italian cancer registries. Logistic models estimated odds of receiving standard care (conservative surgery plus radiotherapy for early breast cancer; surgery plus chemotherapy for Dukes C colon cancer; surgery for lung cancer; sentinel node biopsy for >1mm melanoma, vs. other treatment) in each registry compared to the entire sample (reference). Results: Stage at diagnosis for breast, colon and melanoma was earlier in north/central than southern registries. Odds of receiving standard care were lower than reference in Sassari (0.68, 95%CI 0.51-0.90) and Napoli (0.48, 95%CI 0.35-0.67) for breast cancer; did not differ across registries for Dukes C colon cancer; were higher in Romagna (3.77, 95%CI 1.67-8.50) and lower in Biella (0.38, 95%CI 0.18-0.82) for lung cancer; and were higher in Reggio Emilia (2.37, 95%CI 1.12-5.02) and lower in Ragusa (0.27, 95%CI 0.14-0.54) for melanoma. Conclusions: Notwithstanding limitations due to variations in the availability of clinical information and differences in stage distribution between north/central and southern registries, our study shows that important disparities in cancer care persist across Italy. Thus the public health priority of reducing cancer survival disparities will not be achieved in the immediate future.
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