NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

Cover of Surgical Treatment

Surgical Treatment: Evidence-Based and Problem-Oriented.

Show details

Adjuvant therapy of malignant melanoma

, M.D.

Author Information

Adjuvant therapies in the management of primary malignant melanoma can be locoregional or systemic in nature.

Locoregional adjuvant therapies are surgical procedures that are performed in addition to the simple excision of the primary melanoma in the absence of clinical evidence of the presence of locoregional disease. These procedures are: 1) re-excision of the excisional biopsy area to obtain wide excision margins; 2) elective lymph node dissection (ELND) of the regional lymph nodes; 3)adjuvant isolated limb perfusion (ILP) with cytostatic drug(s).

Systemic adjuvant therapies are systemic treatments that are administered with the goal to eradicate micrometastatic deposits throughout the body after surgical management of primary melanomas with a high risk of systemic dissemination without clinical evidence of the presence of metastatic disease.

Adjuvant surgical procedures in the management of primary melanoma

(Re)Resection to obtain Wide Margin

The dogma of wide excision of ≥ 5 cm lost its rationale when Breslow demonstrated that prognosis correlated with thickness of the primary melanoma. The concept of the necessity of a 5 cm margin was challenged and evaluated in a number of phase-III-trials. Three trials were conducted in patients with thin melanomas < 2 mm. In the French Trial (1) (319 patients) and the Scandinavian Trial (2) (769 patients) patients were randomized to undergo an excision with margins of 2 vs. 5 cm, while in the WHO-Melanoma Program Trial #10 (34) (623 patients) margins were 1 cm vs. 3 cm. The Intergroup Trial in the USA (56) (486 patients) compared different margins (2 vs. 4 cm) in the management of thicker melanomas (1–4 mm melanomas). Table I demonstrates that all trials had very similar results: local recurrence rates, diseasefree survival (DFS) and overall survival (OS) were virtually identical in the narrow excision and the wide excision arm in all 4 trials. The conclusion from these trials is that a 1 cm margin is sufficient for melanomas < 2 mm and that a margin of 2 cm is adequate for melanomas 1–4 mm. A nonrandomized study based on 278 cases (7) demonstrated a lack of impact of wider than 2 cm excision margins on the local recurrence rate, DFS and OS in patients with melanomas thicker than 2 mm. Taken together it shows that a 2 cm margin can be considered adequate for all melanomas thicker than 2 mm. This means that virtually all melanomas at any site can be treated by excision and primary closure.

Table I. Surgical margins and outcome in primary melanoma.

Table I

Surgical margins and outcome in primary melanoma.

Elective lymph node dissection

Elective lymph node dissection (ELND) has been practiced widely based on the hypothesis that micrometastases from the primary melanoma disseminate sequentially from the primary tumor to regional lymph nodes and then to distant sites. As in breast cancer lymphatic and haematogenic spread occur commonly simultaneously and it is therefore unlikely that removal of lymph nodes containing micrometastases changes the prognosis as most often widespread micrometastatic disease is present.

Retrospective studies using historic controls (selection bias, stage migration) usually demonstrated a survival benefit in patients treated by ELND but three large studies comprising some 10,000 patients, that did not compare results between different time periods and were without these pit falls failed to show an overall benefit for ELND (810) Thusfar 4 randomized phase-III-trials have been conducted. These trials have failed to demonstrate a significant effect of ELND on overall survival. In the first 2 trials, the large WHO-1 Trial (1112) and in the much smaller Mayo Clinics Trial (1314) no benefit was observed for ELND. Patients with microscopically involved lymph nodes in the ELND arm did not fare better than the patients who underwent a delayed lymph node dissection for clinically positive nodes. The overall outcome of the USA Intergroup trial in patients with intermediate primaries of 1–4 mm thickness was also negative (15). No benefit of ELND did occur in the 2–3 mm or 3–4 mm thick melanomas but only in the patients with relatively thin melanomas of 1–2 mm in thickness. The recently reported WHO-trial in patients with truncal melanomas thicker than 1.5 mm did also not show a significant benefit of ELND overall. In this trial, however, patients with micrometastases in the lymph nodes discovered after ELND fared better than the patients who underwent a delayed lymph node dissection for clinically positive nodes. Routine ELND is overtreatment of the patient population and must be abandoned. Sentinel lymph node mapping is the elegant solution to the problem.

The sentinel node procedure (or selective lymph node dissection: SLND) presents an attractive option to circumvent the problem of overtreatment and of inflicting morbidity on the whole patient population. It is unlikely that selective lymph node dissection (SLND) will improve survival. The use of SLND will dissect heterogeneous groups of patients (stage IIA-IIB) into node-positive and node- negative populations with clearly different prognosis and thereby lead to cleaner phase-III-trials to identify therapeutic systemic regimens in high risk melanoma patients to treat the concomitant systemic micrometastatic disease

Adjuvant isolated limb perfusion

Isolated limb perfusion was believed to have an impact on survival in the treatment of high risk primary melanoma through the mechanism of ridding the extremity of in-transit micrometastases, being in-transit on their way to form regional lymph node metastases and established in transit metastases in the (sub-)cutaneous compartment. Macroscopic in-transit metastases are known to develop in 5–8% of the patients with a high risk primary melanoma.

Retrospective (again) studies suggested that a prophylactic ILP improved outcome in patients with high risk primary melanoma, which was not observed in a large matched-controlled study (16). Two very small and inadequate phase-III-trials claimed a benefit for ILP (1718). The only valid and definitive trial addressing the question of the value of a prophylactic ILP with melphalan in the management of high risk primary melanoma of the extremity is the intergroup trial of the EORTC-WHO and NAPG (North American Perfusion Group) conducted in 832 patients which shows not even a hint of a survival benefit (19). Prophylactic ILP should no longer be performed. It is a harmful procedure with significant morbidity and costs and without any impact on survival.

Systemic adjuvant therapy

Results of various adjuvant therapy trials in high risk stage II-III melanoma

Adjuvant therapy of stage IIA-IIB/IIIB malignant melanoma with various agents have been performed. With the exception of only one, possibly two trials with interferon-α, virtually all trials have been negative. Eleven negative reports on efficacy or adjuvant therapy with DTIC (CCNU or BCNU) and/or BCG or Levamisole were published (2030). The 1991 study report by Quirt et al. showed a benefit of adjuvant levamisole treatment, but no impact of BCG alone or BCG+Levamisole adjuvant therapy (29) Since two other trials on adjuvant therapy with levamisole have been negative (28, 30) levamisole is not regarded as an active agent. Three randomized trials with adjuvant Corynebacterium Parvum have been reported, all three with negative results (3133). Five reports on sizable “active specific immunotherapy” trials with either whole tumor cell vaccines (3436) or viral lysates of melanoma cells (3738) have shown no impact on survival by any of these adjuvant regimens. Finally phase-III-trials by the SWOG on adjuvant treatment with vitamin A (39) and yet another SWOG trial on adjuvant therapy with interferon-gamma (40) have been reported, results being negative. One negative report has been made on the use of s.c. IL2 (in combination with IFN-alpha) in the adjuvant setting in high risk melanoma (41). One randomized phase-III-trial report on the use of GM2-ganglioside report has shown that in a rather small trial a benefit could be observed in those patients that were seronegative prior to the vaccination and became seropositive after vaccination (42).

Adjuvant IFNα trials

Results in moderate risk melanoma stage IIA-IIB (> 1.5 mm; node negative)

Most recent phase III adjuvant trials have investigated the efficacy of various regimens with IFNα. In patients with primary melanomas > 1.5 mm, clinically node negative, three trials in Europe have completed accrual. These three trials are similar in design, all using IFNα2a at low doses of 3MU for 6 months (Scottish Trial), 12 months (Austrian Trial) or 18 months (French Trial).The results of the Austrian trial have been reported so early that no survival data could be presented but only a benefit in terms of DFS (43). The French trial has reached maturity and a significantly prolonged DFS was observed in the IFNarm and a favorable trend for survival (44).

Very high risk melanoma (stage IIB-IIIB)

In one rather small trial in 280 patients (ECOG 1684) a significant benefit on DFS and OS has been reported after high dose treatment with IFN-2b for one year (45). In the NCCTG Trial (262 patients) it was demonstrated that a the same high dose when administered intramuscularly, tiw, for only 12 weeks, resulted only in a trend towards prolonged survival in the TxN1M0 melanoma patients (46). Both regimens were associated with significant toxicity. No DFS or OS benefit was observed in the low dose IFN (3MU, tiw, for 3 years) WHO-16 trial in 444 stage IIIB patients (47). Another low dose IFNalpha one year regimen was evaluated in the EORTC-18871 trial showing not even a trend for a benefit (48). Unfortunately the impact on overall survival by high dose IFN-alpha therapy was not confirmed by the recently unblinded ECOG 1690 study, in spite of a significant benefit on DFS (49). Low dose IFN-alpha treatment in the ECOG 1690 trial did not demonstrate a benefit just like in the WHO-16 trial. Overall it can be stated that observations have been inconsistent on the efficacy of IFN-alpha in the adjuvant setting for high risk melanoma. Dose intensity as well as duration of treatment are not clearly defined and the efficacy of any regimen has yet to be demonstrated or confirmed by more than one trial.

Table II summarizes the experience with IFN-alpha in adjuvant phase-III-trials up till 1999.

Table II. IFN-alpha adjuvant therapy studies in patients with stage (IIA-IIB)-IIIB melanoma.

Table II

IFN-alpha adjuvant therapy studies in patients with stage (IIA-IIB)-IIIB melanoma.


Phase-III-trials have demonstrated that extensive surgical procedures such as margins wider than 2 cm, elective lymph node dissections and prophylactive isolated limb perfusions, bring no survival benefit in comparison to limiting the surgery of the primary melanoma to an excision with a relatively narrow margin of maximally 2 cm and primary closure. The prognosis of patients with primary melanomas depends on the presence or absence of systemic micrometastatic disease. This can not be changed by extended locoregional surgical procedures. The sentinel node procedure provides us with the best information regarding the prognosis of the patient. In case of a positive node, full regional lymph node dissection by itself is unlikely to improve the prognosis of the patient significantly. In the absence of a standard adjuvant therapeutic regimen of proven efficacy for lymph node positive patients the value of the sentinel node procedure is limited to providing us with the best staging system to perform clean phase-III-trials to discover an effective adjuvant systemic therapy. Unfortunately no standard adjuvant systemic treatment with confirmed activity has been identified thusfar in malignant melanoma.


Banzet P, Thomas A, Vuillemin E. et al. Wide versus narrow surgical excision in thin (< 2 mm) stage I primary cutaneous malignant melanoma: long term results of a french multicentric prospective randomized trial on 319 patients. Proc Am Assoc Clin Oncol. (1993);12:387.
Ringborg U, Andersson R, Eldh J. et al. Resection margins of 2 versus 5 cm for cutaneous malignant melanoma with a tumor thickness of 0.8 to 2.0 mm: randomized study by the Swedish Melanoma Study Group. Cancer. (1996);77:1809–1814. [PubMed: 8646678]
Veronesi U, Cascinelli N, Adamus J. et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm [published erratum appears in N Engl J Med 1991 Jul 25; 325 (4) 292] N Engl J Med. (1988);318:1159–1162. [PubMed: 3079582]
Cascinelli N (1995) Update WHO-10 trial. WHO-program meeting, May 1995, Albany, NY, USA: 317–321 .
Balch CM, Urist MM, Karakousis CP et al (1993) Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial [see comments]. Ann Surg 218: 262–267; discussion 267–269 . [PMC free article: PMC1242959] [PubMed: 8373269]
Karakousis C P, Balch C M, Urist M M. et al. Local recurrence in malignant melanoma: long-term results of the multiinstitutional randomized surgical trial. Ann Surg Oncol. (1996);3:446–452. [PubMed: 8876886]
Heaton K M, Sussman J J, Gershenwald J E. et al. Surgical margins and prognostic factors in patients with thick (> 4 mm) primary melanoma. Ann Surg Oncol. (1998);5:322–328. [PubMed: 9641453]
Drepper H, Kohler C O, Bastian B. et al. Benefit of elective lymph node dissection in subgroups of melanoma patients. Results of a multicenter study of 3616 patients. Cancer. (1993);72:741–749. [PubMed: 8334626]
Slingluff C L Jr, Stidham K R, Ricci W R. et al. Surgical management of regional lymph nodes in patients with melanoma. Ann Surg. (1994);219:120–130. [PMC free article: PMC1243113] [PubMed: 8129482]
Coates A S, Ingvar C I, Petersen-Schaefer K. et al. Elective lymph node dissection in patients with primary melanoma of the trunk and limbs treated at the Sydney Melanoma unit from 1960 to 1991 [see comments] J Am Coll Surg. (1995);180:402–409. [PubMed: 7719543]
Veronesi U, Adamus J, Bandiera D C. et al. Inefficacy of immediate node dissection in stage 1 melanoma of the limbs. N Engl J Med. (1977);297:627–630. [PubMed: 895764]
Veronesi U. Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer. (1982);49:2420–2430. [PubMed: 7074555]
Sim F H. A prospective randomized study of the efficacy of routine elective lymphadenopathy in management of malignant melanoma; preliminary results. Cancer. (1985);41:948– 951. [PubMed: 638981]
Sim F H. Lymphadenectomy in the management of stage I malignant melanoma: a prospective randomized study. Mayo Clin Proc. (1986);61:697–705. [PubMed: 3747613]
Balch CM, Soong SJ, Bartolucci AA et al (1996) Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 224: 255–263; discussion 263–266 . [PMC free article: PMC1235362] [PubMed: 8813254]
Franklin H R, Schraffordt Koops H, Oldhoff J. et al. To perfuse or not to perfuse? A retrospective comparative study to evaluate the effect of adjuvant isolated regional perfusion in patients with stage I extremity melanoma with a thickness of 1.5 mm or greater. J Clin Oncol. (1988);6:701–708. [PubMed: 3357008]
Ghussen F, Nagel K, Groth W. et al. A prospective randomized study of regional extremity perfusion in patients with malignant melanoma. Ann Surg. (1984);200:764–768. [PMC free article: PMC1250596] [PubMed: 6508407]
Fenn N J, Horgan K, Johnson R C. et al. A randomized controlled trial of prophylactic isolated cytotoxic perfusion for poor-prognosis primary melanoma of the lower limb. Eur J Surg Oncol. (1997);23:6–9. [PubMed: 9066739]
Schraffordt Koops H, Vaglini M, Suciu S. et al. Prophylactic isolated limb perfusion for localized, highrisk limb melanoma: results of a multicenter randomized phase-III-trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol. (1998);16:2906–2912. [PubMed: 9738557]
Hill G J II, Moss S E, Golomb F M. et al. DTIC and combination therapy for melanoma. Cancer. (1981);47:2556–2562. [PubMed: 7020916]
Pinsky C M, Oettgen H F. Surgical adjuvant for malignant melanoma. Surg Clin North Am. (1981);61:1259–1266. [PubMed: 7031933]
Veronesi U, Adamus J, Aubert C. et al. A randomized trial of adjuvant chemotherapy and immunotherapy in cutaneous melanoma. N Engl J Med. (1982);307:913–916. [PubMed: 7050717]
Quirt I C, DeBoer G, Kersey P A. et al. Randomized controlled trial of adjuvant chemoimmunotherapy with DTIC and BCG after complete excision of primary melanoma with a poor prognosis or melanoma metastases. Can Med Assoc J. (1983);128:929–936. [PMC free article: PMC1875390] [PubMed: 6339024]
Fisher R I, Terry W D, Hodes R J. et al. Adjuvant immunotherapy or chemotherapy for malignant melanoma: Preliminary report of the National Cancer Institute randomized clinical trial. Surg Clin North Am. (1981);61:1267–1277. [PubMed: 7031934]
Loutfi A, Shakr A, Jerry M. et al. Double blind randomized prospective trial of levamisole/placebo in stage I cutaneous malignant melanoma. Clin Invest Med. (1987);10:325–328. [PubMed: 3308241]
Tranum B L, Dixon D, Quagliana J. et al. Lack of benefit of adjunctive chemotherapy in stage I malignant melanoma: A Southwest Oncology Group study. Cancer Treat Rep. (1987);71:643–644. [PubMed: 3581104]
Czarnetzki B M, Macher E, Suciu S, Thomas D, Steerenberg P A, Rümke P h. Long-term adjuvant immunotherapy in stage I high risk malignant melanoma, comparing two BCG preparations versus non-treatment in a randomised multicentre study (EORTC PROTOCOL 18781). Eur J Cancer. (1993);29A:1237–1242. [PubMed: 8343260]
Lejeune F J, Macher E, Kleeberg U R. et al. An Assessment of DTIC versus Levamisol and placebo in the treatment of high risk stage I patients after removal of a primary melanoma of the skin, A phase III adjuvant study (EORTC PROTOCOL 18761). Eur J Cancer Clin Oncol. (1988);24:881–890.
Quirt I C, Shelley W E, Pater J L. et al. Improved survival in patients with poor prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the national cancer institute of Canada clinical trials group. J Clin Oncol. (1991);9:729–735. [PubMed: 2016615]
Spitler L E. A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma. J Clin Oncol. (1991);9:736–740. [PubMed: 2016616]
Karakousis C P, Didolkar M S, Lopez R. et al. Chemoimmunotherapy (DTIC and Corynebacterium parvum) as adjuvant treatment in malignant melanoma. Cancer Treat Rep. (1979);63:1739–1743. [PubMed: 393377]
Balch C M, Smalley R V, Bartolucci A A. et al. A randomized prospective trial of adjuvant C. Parvum immunotherapy in 260 patients with clinically localized melanoma (stage I): prognostic factors analysis and preliminary results of immnotherapy. Cancer. (1982);49:1079–1084. [PubMed: 7037155]
Thatcher N, Mene A, Banerjee S S. et al. Randomized study of Corynebacterium parvum adjuvant therapy following surgery for (stage II) malignant melanoma. Br J Surg. (1986);73:111–115. [PubMed: 3512025]
Morton DL, Holmes EC, Eilber FR et al (1982) Adjuvant immunotherapy: Results of a randomized trial in patients with lymph node metastases. In: Terry WD, Rosenberg SA (eds) Immunotherapy of Human Cancer. Elsevier North Holland, New York, pp 245–249 .
Terry WD, Hodes RJ, Rosenberg SA et al (1982) Treatment of stage I and II malignant melanoma with adjuvant immunotherapy or chemotherapy: Preliminary analysis of a prospective randomized trial. In: Terry WD, Rosenberg SA (eds) Immunotherapy of Human Cancer. Elsevier North Holland, New York, pp 252–257 .
Morton D L. Adjuvant immunotherapy of malignant melanoma: Status of clinical trials at UCLA. Int J Immunother. (1986);2:31–36.
Wallack M K, Sivanandham M, Balch C M. et al. A phase III randomized, double-blind, multiinstitutional trial of vaccinia melanoma oncolysate-active specific immunotherapy for patients with stage II melanoma. Cancer. (1995);75:34–42. [PubMed: 7804974]
Hersey P, Coates P, Tyndall L (1997) Is adjuvant therapy worthwhile? Melanoma Res 7 (suppl): 78 (abstract)
Meyskens FL, Liu PY, Tuthill RJ et al (1994) Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group Study J Clin Oncol 12: 2060–2065 . [PubMed: 7931474]
Meyskens F L, Kopecky K J, Taylor C W. et al. Randomized trial of adjuvant human Interferon-gamma versus observation in high risk cutaneous melanoma: a Southwest Oncology Group Study. J Natl Cancer Inst. (1995);87:1710–1713. [PubMed: 7473820]
Hauschild A, Burg G, Dummer R (1997) Prospective randomized multicenter trial on the oupatient use of subcutaneous interleukin 2 and interferon α2b in high risk melanoma patients. Melanoma Res 7 (suppl 1): 401 (abstract)
Livingstone P O, Wong G Y C, Adluri S. et al. Improved survival in stage III melanoma patients with GM2 antibodies: a randomised trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol. (1994);12:1036–1044. [PubMed: 8164027]
Pehamberger H, Soyer P, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Auböck J, Fritsch P, Kerl H, Wolff K. Adjuvant interferon α-2a treatment in resected primary stage II cutaneous melanoma. J Clin Oncol. (1998);16:1425–1429. [PubMed: 9552047]
Grob J J, Dreno B, Chastang C, Guillot B, Cupissol B, Souteyrand P, Sassolas B, Cesarini J P, Thivolet J, Denoeux J P, Ortonne J P, Thomas T, Beylot C, Truchetet F, Lorette G, Chemaly C, Meynadier J, Amblard P, Thyss P, Avril M F, Prigent F, Bonerandi J J. Randomised trial of interferon α-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. The Lancet. (1998);351:1905–1910.
Kirkwood J M, Strawderman M H, Ernstoff M S, Smith T J, Borden E C, Blum R H. Interferon-α2b adjuvant therapy of high-risk resected curaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. (1996);14:7–17. [PubMed: 8558223]
Creagan E T, Dalton R J, Ahmann D L. et al. Randomized surgical adjuvant clinical trial or recombinant interferon-alpha-2a in selected patients with malignant melanoma. J Clin Oncol. (1995);13:2776–2783. [PubMed: 7595738]
Cascinelli N (1995) Evaluation of efficacy of adjuvant rIFNα 2A in regional node metastases. Proc Am Soc Clin Oncol 14: 410 (abstr)
Kleeberg U, Broecker EB, Chartier C et al (1999) EORTC 18871 adjuvant trial in high risk melanoma patients IFNa vs. IFNgamma vs. Iscador vs. Observation. Eur J Cancer 35 (S4): 264 (abstr)
Kirkwood JM, Ibrahim J, Sondak V et al: (1999) Preliminary analysis of the E 1690/ S9111/C9190 Intergroup Postoperative Adjuvant Trial of High- and Low-Dose IFNalpha2b (HDI and LDI) in High-Risk Primary or Lymph Node Metastatic Melanoma. Proc Am Soc Clin Oncol; 18: 2072 (abstr)
Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6912


  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...