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Evidence and interdisciplinary consensus-based German guidelines: surgical treatment and radiotherapy of melanoma

Garbe, Clausa; Hauschild, Axelb; Volkenandt, Matthiasc; Schadendorf, Dirkd; Stolz, Wilhelmi; Reinhold, Uwej; Kortmann, Rolf-Dieterk; Kettelhack, Christopho; Frerich, Bernhardl; Keilholz, Ulrichm; Dummer, Reinhardp; Sebastian, Günthere; Tilgen, Wolfgangf; Schuler, Geroldg; Mackensen, Andreasn; Kaufmann, Rolandh

doi: 10.1097/CMR.0b013e3282f0c893
REVIEW
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The primary treatment of a melanoma is surgical excision. An excisional biopsy is preferred, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for higher tumor thickness should be applied either at primary excision or in a two-step procedure. When dealing with facial, acral or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. The sentinel lymph node biopsy should be performed in patients whose primary melanoma is thicker than 1.0 mm and this operation should be performed in centers where both the operative and nuclear medicine teams are experienced. In clinically identified lymph node metastases, radical lymph node dissection is considered standard therapy. If distant metastases involve just one internal organ and operative removal is feasible, then surgery should be seen as therapy of choice. Radiation therapy for the primary treatment of melanoma is indicated only in those cases in which surgery is impossible or not reasonable. In regional lymph nodes, radiation therapy is usually recommended when excision is not complete (R1 resection) or if the nodes are inoperable. In distant metastases, radiation therapy is particularly indicated in bone metastases, brain metastases and soft tissue metastases.

aUniversity Department of Dermatology, Tübingen

bUniversity Department of Dermatology, Kiel

cUniversity Department of Dermatology, München

dUniversity Department of Dermatology, Mannheim

eUniversity Department of Dermatology, Dresden

fUniversity Department of Dermatology, Homburg

gUniversity Department of Dermatology, Erlangen

hUniversity Department of Dermatology, Frankfurt

iDepartment of Dermatology, München Schwabing

jDivision of Dermatology, Medical Center Bonn Friedensplatz, Bonn

kUniversity Department of Radiotherapy

lUniversity Department of Maxillo-Facial Surgery, Leipzig

mUniversity Department of Medical Oncology, Charité Berlin

nUniversity Department of Medical Oncology, Regensburg, Germany

oUniversity Department of Surgery, Basel

pUniversity Department of Dermatology, Zürich, Switzerland

Correspondence to Dr Claus Garbe, MD, Professor of Dermatology Head, Division of Dermatooncology, Department of Dermatology, University Medical Center, Liebermeisterstr. 25, 72074 Tuebingen, Germany

Tel: +49 7071 298 7110; fax: +49 7071 29 5187;

e-mail: claus.garbe@med.uni-tuebingen.de

Received 3 July 2007 Accepted 25 July 2007

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Purpose

These guidelines have been written under the auspices of the German Cancer Society and its working groups and the German Dermatologic Society to help clinicians to treat melanoma patients. It is hoped that it will assist caregivers in improving the management of melanoma patients. The guidelines are also intended to promote the integration of care between medical and paramedical specialties for the benefit of the patient.

These guidelines reflect the best published data available at the time the report was prepared. Caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations in this report. It may be necessary or even desirable to depart from the guidelines in the interests of specific patients and special circumstances. Just as adherence to the guidelines may not constitute defense against a claim of negligence, so deviation from them should not necessarily be deemed negligent.

The evidence cited in the guidelines has been classified as accurately as possible into five levels according to the proposal of the Canadian Medical Association: Level I evidence is based on randomized, controlled trials (or meta-analysis of such trials) of adequate size to ensure a low risk of incorporating false-positive or false-negative results. Level II evidence is based on randomized, controlled trials that are too small to provide level I evidence. These may show either positive trends that are not statistically significant or no trends, and are associated with a high risk of false-negative results. Level III evidence is based on nonrandomized, controlled or cohort studies, case series, case-controlled studies or cross-sectional studies. Level IV evidence is based on the opinion of respected authorities or that of expert committees as indicated in published consensus conferences or guidelines. Level V evidence expresses the opinion of those individuals who have written and reviewed these guidelines, on the basis of their experience, knowledge of the relevant literature and discussion with their peers.

These five levels of evidence do not directly describe the quality or credibility of evidence. Rather, they indicate the nature of the evidence being used. In general, a randomized, controlled trial has the greatest credibility (level I); however, it may have defects that diminish its value, and these should be noted. Evidence that is based on too few observations to give a statistically significant result is classified as level II. In general, level III studies carry less credibility than level I or II studies, but credibility is increased when consistent results are obtained from several level III studies carried out at different times and in different places.

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General principles of operative therapy

The primary treatment of a biopsy-proven melanoma is surgical excision. An excisional biopsy is preferred, both to give the dermatopathologist an optimal specimen and to allow evaluation of the excision margins for residual tumor. Incisional biopsies should not be performed when an excisional biopsy is technically possible. On occasion they are necessary, such as when dealing with a large lentigo maligna on the face, acral-lentiginous lesions or mucosal lesions. Incisional biopsies are more difficult to interpret histologically, and the risk remains that the worst area of the tumor has not been sampled. In contrast, large studies have shown that patients with incisional biopsies or incomplete excisional biopsies do not have a worse prognosis than those evaluated with a complete excisional biopsy [1,2]. Prospective randomized studies addressing this point cannot be performed, so all information on the topic is derived from retrospective evaluations (level of evidence III).

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Operative therapy of primary melanoma

An excisional biopsy with local anesthesia should be performed. If an invasive melanoma is suspected, a safety margin of 10 mm should be used. Larger margins in the primary excision may interfere with a sentinel lymph node biopsy with scintigraphy. The size of the excision margin for melanoma has long been controversial (Table 1) [3–5]. In comparison to older studies, newer data indicate that smaller excision margins are appropriate; the values given below are in concord with the American and British recommendations.

Table 1

Table 1

A 2 cm excision margin can also be considered for melanomas less than 2 mm in thickness but with ulceration or areas of regression.

The current recommendations are based on both prospective, randomized studies and international consensus conferences (level of evidence II) [6–10]. The studies show that the excision margin does not have a significant influence on the risk of distant metastases and thus on the overall survival [11]. In contrast, thicker tumors have a greater risk for satellite metastases, which may not be addressed by excisions with smaller margins [10].

Most excisions of primary melanomas can be accomplished in one or two sessions under local anesthesia. Most defects can be closed primarily or with a flap, so that a skin graft is only rarely required [12].

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Special cases: lentigo maligna melanoma/acral-lentiginous melanoma

When dealing with facial, acral or anogenital melanomas, micrographic control of the surgical margins may be preferable. Micrographic surgery working with paraffin-fixed tissue often allows a reduced safety margin and conservation of tissue, especially on the face [13]. Similarly on the hands and feet, the micrographic technique serves to conserve tissue by often making smaller margins possible (level of evidence III) [14].

In special clinical situations, such as older patients with multiple systemic diseases who are poor surgical risks, primary radiation therapy (either soft radiographs or electron beam) can be considered an alternative to surgery for lentigo maligna melanoma (LMM) (level of evidence IV) [15].

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Elective lymph node dissection/sentinel lymph node biopsy

Since the introduction of the sentinel lymph node biopsy, elective lymph node dissection no longer plays a role in melanoma management except in selected clinical studies (level of evidence II) [5,16]. The sentinel lymph node biopsy was developed to make possible the evaluation of the first draining lymph node in the regional lymphatic system [17]. The procedure is appropriate for patients in whom neither palpation nor sonography has suggested the presence of lymph node metastases. Metastatic melanoma ‘jumps over’ the sentinel lymph node in less than 5% of cases [17]. Multicenter studies have shown that the recurrence-free survival time correlates clearly with the status of the sentinel lymph node (level of evidence III) [18].

The evaluation of the sentinel lymph node is not well standardized, so that the risk of missing a micrometastasis depends heavily on the techniques used (number of sections; H&E stain; immunohistochemical stains; reverse transcription-PCR for melanoma-associated molecules) [19,20]. A source of error is an inexperienced surgeon. Various studies have shown that a detection accuracy of 90% is first obtained after 50 procedures have been performed. Thus it seems appropriate to concentrate sentinel lymph node biopsies in larger centers where such experience can be acquired. Sentinel lymph node biopsy in the head and neck region is particularly demanding [21] and requires surgical experience in this field. Special attention must be paid to sentinel lymph nodes in the parotid gland, which occur in up to a third of patients with head and neck melanomas [22,23]. A superficial parotidectomy is advocated by some authors in deep sentinel nodes adjacent to branches of the facial nerve [24].

The value of the sentinel lymph node biopsy in the treatment of melanoma is not universally agreed upon [4,25–28]. In the USA the sentinel lymph node biopsy is incorporated into the therapeutic plan as a procedure offering prognostic information; in contrast the latest British guidelines for melanoma state ‘Sentinel node biopsy can be used for staging in stage II melanoma in specialist centers in clinical trials but unless evidence emerges for a role in determining outcome it should not be routine’ [4].

On the basis of considerable experience in a number of German centers, we recommend the following approach (level of evidence III). The sentinel lymph node biopsy should be performed in patients whose primary melanoma is thicker than 1.0 mm. Sentinel lymph node biopsies should be performed in centers where both the operative and nuclear medicine teams are experiencedin the procedure. If there are other unfavorable prognostic parameters (Clark level IV–V; ulceration; regression), a sentinel lymph node biopsy can be considered for thinner tumors. At this time, we consider the sentinel lymph node biopsy as a supplementary staging procedure (pathologic staging), not as a therapeutic measure with proven value in increasing survival time (level of evidence III).

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Procedure in patients with negative sentinel lymph node biopsy

No further lymph node surgery is required (level of evidence III).

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Procedure in patients with micrometastases on sentinel lymph node biopsy

Studies have not confirmed that radical lymph node dissection improves survival. Nonetheless, when the sentinel lymph node biopsy shows micrometastases, radical lymph node dissection is recommended (level of evidence III) [29–31]. Any other approach should be carefully discussed with the patient and carried out in the setting of a controlled clinical study.

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Clinically identified lymph node metastases

Radical lymph node dissection is considered standard therapy (level of evidence IV) [32–36].

Metastasis of melanoma in the head and neck region depends on tumor location (facial, scalp, neck). Thus dissection of the lymphatic drainage for facial and scalp melanomas might include superficial parotidectomy or retroauricular and suboccipital lymph nodes in addition to comprehensive neck dissection [24,37]. Melanomas of parietal/frontal scalp, temple, lateral forehead, lateral cheek or ear located anterior to a virtual plane through the external auditory canal drain via parotid lymph nodes to the cervical nodal basins, thus requiring superficial parotidectomy and neck dissection. Melanomas located dorsally to this plane may require dissection of the retroauricular and occipital lymph nodes (posterolateral neck dissection), which is not addressed by classical cervical dissection procedures [38]. For melanomas of the chin and the neck, however, parotidectomy is not necessary and a comprehensive neck dissection is the treatment of choice. The radical neck dissection with resection of the jugular vein, spinal accessory nerve and sternocleidomastoid muscle has classically been considered the gold standard for treating regional disease. Cohort studies and case series, however, suggest that modified radical neck dissection does not bear a higher risk of nodal recurrence and is considered the appropriate treatment in microscopic disease, in the absence of gross tumor disease, tumor infiltration of the aforementioned structures or earlier surgical disturbance such as an open biopsy or earlier dissection [37–39].

An axillary dissection for melanoma should include the level I and II lymph nodes, as well as the level III nodes medial to the lesser pectoral muscle [40,41]. To facilitate the dissection of the level III nodes, the muscle can be retracted or separated from its origin and later reinserted. The median pectoral nerve branches serving the greater pectoral muscle must be spared to avoid atrophy. If the level III nodes are extensively involved, the lesser pectoral muscle may have to be removed.

When inguinal nodes are involved, the dissection should extend from the femoral triangle and the lower part of the abdominal rectus muscle from the pubic tubercle to the anterior iliac crest including the saphenous foramen and the inguinal ligament [33,35,42,43]. If there are no contraindications, the great saphenous vein is also removed. If there is preoperative suspicion or proof of iliac node involvement, the dissection should also include these nodes, which are removed to the level of the iliac bifurcation, along with the obturator group. After a complete inguinal dissection, the femoral vessels lie relatively unprotected under the skin, so a sartorius muscle transfer should be considered. When operating on recurrent disease, the approach is dictated by both the stage of the disease and the local conditions.

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Skin metastases

Treatment of choice for skin metastases is excision. If distant metastases are identified at the same time, one can discuss with the patient the approach of not treating the skin lesions and instituting systemic therapy. If multiple satellite or in-transit metastases are present on a limb and not amenable to surgical treatment, limb perfusion with melphalan [perhaps combined with tumor necrosis factor (TNF-α)] is the best approach (level of evidence III) [44,45]. Alternatives include cryotherapy, laser therapy and experimental approaches (level of evidence IV).

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Distant metastases

If operable metastases involve only one internal organ (e.g. lungs or brain), then operative removal of the metastases should be seen as therapy of choice (with brain metastases, stereotactic radiation therapy is equally effective) [46,47]. The possibility of first using neoadjuvant therapy and then excising the metastases should be considered. Many studies show that excision of solitary metastases can be associated with a surprisingly good prognosis for stage IV patients. When a patient with distant metastases is tumor-free following the surgery, about 5% will have long-term complete remission or even be cured (level of evidence IV) [47]. In addition, excision of metastases at certain sites may contribute greatly to the quality of life; included in this group are symptomatic brain metastases, gastrointestinal lesions causing obstruction, and bony lesions that seem likely to fracture (level of evidence IV). The removal of soft tissue metastases that are symptomatic, pressing on or displacing vital structures may also be worthwhile.

The value of debulking operations must be viewed critically, as there is no evidence that they improve survival time (level of evidence III).

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Radiation therapy in primary melanoma

Radiation therapy is indicated for the primary treatment of melanoma only in those cases in which surgery is impossible or not reasonable. Local control of the tumor is somewhat less satisfactory with radiation therapy, but still acceptable [48]. Even in high-risk situations, radiation therapy seems to bring therapeutic benefits [49,50]. The choice of radiation parameters (target volume, dosage and type of rays) must be individually determined. In general, electron beam therapy allows more radiation to be delivered to the tumor, especially at its depth, while still sparing the normal adjacent structures.

When macroscopic residual tumor is present, the operative site should be irradiated with a 3 cm margin with 70 Gy, fractionated as 2 Gy 5×weekly. When microscopic residual tumor (R1) is present, 60 Gy are recommended (level of evidence III). Higher single doses can be used, especially for palliative therapy. The regional lymph node drainage areas are not irradiated.

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Radiation therapy in lentigo maligna and lentigo maligna melanoma

Even though excision is the treatment of choice for lentigo maligna, radiation therapy can achieve adequate tumor control with good cosmetic and functional results in difficult areas on the face, especially in elderly individuals. The local tumor control rate for LMM in newer series is over 90% [15,51] (level of evidence III). The cosmetic results are almost always very good. Either electron beams or soft radiographs can be used in conventional fractions with a total dose of 50–60 G and individual doses of 2–6 Gy. Grenz ray therapy (12 kV) is recommended for lentigo maligna (100–120 Gy; 10 Gy 2×weekly for 5–6 weeks) [15].

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Radiation therapy in regional lymph nodes

When excision is not complete (R1 resection) or a lesion inoperable, radiation therapy of the relevant lymph nodes is usually recommended, although the literature is contradictory (level of evidence III) [52–55]. When the tumor is extensive, a debulking operation can be performed prior to radiation therapy, paying special attention to sparing vessels and nerves. In some instances, hyperthermia can also be used (see below). When the regional lymph nodes are involved and the primary tumor is inoperable or high risk (extensive primary tumor, second recurrence, postoperative macroscopic residual tumor), radiation therapy achieves a local control rate of 74–87%, as compared with 50–70% for surgery alone [53,55]. The median survival time is not increased, as in this stage (III AJCC) the risk of distant metastases is high and the prognosis guarded. Newer studies do suggest that local control can improve the survival time for high-risk tumors [56]. The total dosage and fractionation scheme should be based on the tolerance of the adjacent normal tissues, with special attention paid to radiation-sensitive organs to avoid side effects such as plexus paralysis and lymphedema. Higher single doses, as used in other regions, should be avoided for lymph nodes (see below). A total dose of 50–54 Gy with individual doses of 1.8–2.0 Gy is recommended. A retrospective analysis suggested that the side-effect profile was tolerable if the single doses were kept at a moderate level [57]. Higher single doses offered no advantages [58].

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Radiation therapy in skin metastases

In-transit metastases, which are too extensive for a surgical approach, can be controlled effectively by radiation therapy alone. Electron beams with quantum energy of 6–8 MeV are used. Postoperative radiation therapy should be considered after excision of recurrent in-transit metastases (Level of evidence III) [48]. A total dose of 50–60 Gy with conventional fractionation is appropriate. Depending on the extent and location, hyperthermia may be added.

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Radiation therapy in bone metastases

Bone metastases can be effectively palliated with radiation therapy (level of evidence III). The response rate is 67–85%; improvement is often noted during the therapy [59–61]. The major indications are pain, loss of structural stability (fracture risk), and compression of the spinal canal with or without neurological symptoms. In one series, radiation therapy achieved complete remission of symptoms in 47% and partial remission in 24% of cases with spinal cord compression [60], in another, the symptoms were controlled in 67% of cases [61]. Neurological deficits in melanoma patients should be investigated promptly so that those related to bone metastases can be treated promptly with radiation therapy, thus minimizing permanent damage.

A total dose of 35–36 Gy with individual doses of 2.5–3.0 Gy is recommended. In cases with a limited life expectancy and no threat to structural stability, considerably higher single doses (up to 8 Gy) can be used to shorten the total treatment time. If there is adjacent soft tissue involvement, a total dose of 45 Gy with single doses of 2.5 Gy is ideal; if the spinal cord is in the radiation field, the total dose should be limited to 40 Gy. Higher doses lead to better tumor control [48].

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Radiation therapy in brain metastases

Melanoma has a marked propensity to metastasize to the brain. Between 12 and 20% of patients with advanced disease develop brain metastases, whereas in autopsy series, central nervous system involvement has been found in up to 80% of cases.

Patients with brain metastases have a life expectancy of 1–3 months if not treated. With radiation therapy, the neurologic deficits can be improved in 50–75% of cases, usually associated with an overall improvement. A headache responds to radiation therapy 80% of the time [61,62]. The median survival time can be increased from 1.5 to 4 months, whereas the 1-year survival is 8–15% [61,62]. If multiple brain metastases are present, whole brain radiation is indicated; 30 Gy in 10 fractions over 2 weeks is recommended. Higher doses seem to increase the median survival time, so that in individual cases, if higher doses are tolerated, they may be used [63].

Retrospective analyses show that treatment of solitary brain metastases clearly prolongs the survival time [61,62,64,65]. Both stereotactic single-dose radiation therapy and operative resection are appropriate for solitary or few (≤3) lesions. The sterotactic treatment has much less toxicity. Treating individual lesions (surgery or stereotactic radiation) along with total brain radiation doubles the median survival time, from 4 to 10 months (level of evidence III) [64,66]. In another series, the value of the additional whole brain treatment was not clear [67–69]. Whole brain radiation alone without treating individual lesions specially has a median survival of 3–4 months. Good prognostic factors are the absence of extracranial metastases, the presence of a single lesion and the possibility for resection [61,62,64,65]. In a prospective, randomized study, the addition of fotemustine did not increase either the remission or survival rate [70].

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Thermoradiotherapy

The combination of radiation therapy with hyperthermia (thermoradiotherapy) may be a reasonable therapeutic option, but it is still under study. The results from retrospective and prospective clinical studies all show that the combined procedure is more effective than radiation therapy alone. Local tumor control is improved with combined therapy [71,72]. The hyperthermia increases the effectiveness of the radiation therapy by a factor of 1.4–4.8, so that 88% of macroscopic tumors respond [71,72]. This experience was confirmed in a multicenter, randomized study with 134 patients (level of evidence II) [73]. The addition of hyperthermia and a sufficient radiation therapeutic dose were the most important prognostic factors. The use of hyperthermia is limited by technical factors and restricted to relatively superficial tumors, such as inoperable primary tumors, as well as cervical, axillary and inguinal lymph nodes.

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Consensus-building process and participants

These guidelines were prepared under the auspices of the German Cancer Society and its working groups, and the German Dermatologic Society. In addition, the Working Group of German Tumor Centers, the Medical Center for Quality Assurance, the Working Group for Support for Quality Assurance in Medicine were involved, as were all the groups mentioned below. Professor Claus Garbe, Tübingen, coordinated the activities of the various groups, the selected experts, and the final authors.

An expert consensus conference with 20 experts from different medical specialties was held 14–15 February 2003. Agreement was reached on all the essential questions concerning this guideline. The details of the guideline were refined by multiple exchanges of the manuscript between the expert groups. Approval was likewise obtained from other scientific specialty groups, coordinated by the Information Center for Standards in Oncology (ISTO, German Cancer Society). Eight different working parties of the German Cancer Society took part in this process. The Association of the Scientific Medical Societies in Germany organized the process of approval with 11 different scientific medical societies. Last changes were added to this guideline in March 2006 and it remains valid until February 2009.

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Acknowledgements

The authors thank the following individuals for their participation in the expert conference and the subsequent process of approval by manuscript exchanges: Jürgen Becker, Würzburg, Jörg Böttjer, Minden, Helmut Breuninger, Tübingen, Reinhard Dummer, Zürich, Alexander Enk, Heidelberg, Claus Garbe, Tübingen, Sylke Gellrich, Berlin, Axel Hauschild, Kiel, Roland Kaufmann, Frankfurt, Ulrich Keilholz, Berlin, Christoph Kettelhack, Basel, Hans Christian Korting, München, Rolf-Dieter Kortmann, Leipzig, Ruthild Linse, Erfurt, Andreas Mackensen, Regensburg, Cornelia Mauch, Köln, Peter Mohr, Buxtehude, Dorothée Nashan, Freiburg, Rolf Ostendorf, Möchengladbach, Uwe Reinhold, Bonn, Michael Reusch, Hamburg, Dirk Schadendorf, Mannheim, Martin Schläger, Oldenburg, Helmut Schöfer, Frankfurt, Gerold Schuler, Erlangen, Volker Schwipper, Hornheide, Günther Sebastian, Dresden, Rudolph Stadler, Minden, Wolfram Sterry, Berlin, Wilhelm Stolz, München, Wolfgang Tilgen, Homburg, Uwe Trefzer, Berlin, Selma Ugurel, Mannheim, Jens Ulrich, Quedlinburg, Matthias Volkenandt, München, Michael Weichenthal, Kiel.

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Keywords:

consensus-based; evidence; German; guidelines; interdisciplinary; melanoma; radiotherapy; surgical treatment

© 2008 Lippincott Williams & Wilkins, Inc.