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

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Adjuvant therapy of malignant melanoma

, M.D.

Department of Surgical Oncology, University Hospital Rotterdam - Den Hoed Cancer Center, Netherlands

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.

Conclusions

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.

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