Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage III melanoma is defined by the following clinical stage groupings:

• Any T, N1, M0
• Any T, N2, M0
• Any T, N3, M0

STANDARD TREATMENT OPTIONS:

• Wide local excision of the primary tumor with 1-cm to 3-cm margins, depending on tumor thickness and location.[1,2,3,4,5,6,7] Skin grafting may be necessary to close the resulting defect.

  A multicenter, randomized controlled study (EST-1684) has compared a high-dose regimen of interferon-alpha-2b (20 mU/m² of body surface per day given intravenously for 5 days a week every week for 4 weeks, then 10 mU/m² of body surface per day given subcutaneously 3 times a week every week for 48 weeks) to observation.[8] This study included 287 patients at high risk for recurrence after potentially curative surgery for melanoma (patients with melanoma >4 mm thick without involved lymph nodes or patients with melanomas of any thickness with positive lymph nodes). Patients who had recurrent melanoma involving only the regional lymph nodes were also eligible. At a median follow-up of 7 years, this trial demonstrated a significant prolongation of relapse-free survival (P = .002) and overall survival (OS) (P = .024) for patients receiving high-dose interferon.

  The median OS for patients who received the high-dose regimen of interferon-alpha-2b was 3.8 years compared with 2.8 years for those in the observation group.[8][Level of evidence: 1iiA] A subset analysis of the stage II patients, however, failed to show any benefit from high-dose interferon in terms of relapse-free survival or OS. Because the number of stage II patients was small in this subset analysis, it is difficult to draw meaningful conclusions from this study for this specific group.

  A subsequent multicenter randomized controlled study (EST-1690;CLB-9190;SWOG-9111) by the same investigators compared the same high-dose regimen of interferon-alpha to either a lower dose regimen (3 mU/m² of body surface per day given subcutaneously 3 times a week every week for 104 weeks) or observation.[9] The stage entry criteria for this trial were the same as for the initial study. This 3-arm trial entered 642 patients. At a median follow-up of 52 months, a statistically significant relapse-free survival advantage was shown for all patients who received high-dose interferon (including the clinical stage II patients) when compared with the observation group (P = .03); however, no statistically significant relapse-free survival advantage was seen for low-dose interferon when compared to the observation group. The 5-year estimated relapse-free survival rates for the high-dose interferon, low-dose interferon, and observation groups were 44%, 40%, and 35%, respectively. Neither high-dose nor low-dose interferon yielded an OS benefit when compared with observation (hazard ratio [HR] = 1.0; P = .995).[9][Level of evidence: 1iiA]

  Pooled analyses of the two high-dose arms versus the two observation arms from both studies suggest that treatment confers a significant relapse-free survival advantage but not a significant benefit for survival.[9][Level of evidence: 1iiA]

  Another multicenter prospective trial randomized patients with resected stage IIB or III melanoma to receive either the same high-dose interferon-alpha-2b regimen or a vaccine of conjugated GM2 melanoma antigen (GM2-KLH/QS-21)(GMK).[10] Of the 880 randomly assigned patients, 774 patients were eligible for efficacy analysis. This trial was closed after an interim evaluation indicated the inferiority of the GMK vaccine compared to treatment with interferon. A statistically significant relapse-free survival was found for high-dose interferon (HR = 1.47; P = .0015), as was a statistically significant OS benefit (HR = 1.52; P = .009). (In the intent-to-treat analysis, relapse-free survival [HR = 1.49]; OS [HR = 1.38].)

  Clinicians should be aware that the high-dose regimens have significant toxic effects.

  Several randomized trials using lower doses of interferon have been conducted in the adjuvant setting. To date, no consistent evidence is available that intermediate or low doses of interferon improve relapse-free survival or OS.[11]

  Autologous bone marrow transplantation with high-dose chemotherapy has not been shown to improve survival.[12]