Current Clinical Trials

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 II melanoma is defined by the following clinical stage groupings:

• T2b, N0, M0
• T3a, N0, M0
• T3b, N0, M0
• T4a, N0, M0
• T4b, N0, M0

Standard treatment options:

• Current evidence suggests that for melanomas with a thickness between 2 mm and 4 mm, the surgical margins need to be 2 cm or less. The Intergroup Melanoma Surgical Trial Task 2b compared 2-cm versus 4-cm margins for patients with 1-mm to 4-mm thick melanomas. With a median follow-up of more than 10 years, no significant difference was observed between the two groups in terms of local recurrence or survival. The reduction in margins from 4 cm to 2 cm was associated with a statistically significant reduction in the need for skin grafting (from 46% to 11%; P < .001) and a reduction in the length of the hospital stay.[1] Depending on the location of the melanoma, most patients can now have this surgery performed on an outpatient basis. A study conducted in the United Kingdom randomly assigned patients with melanomas more than 2 mm thick to excision with either 1-cm or 3-cm margins.[2] Patients treated with 1-cm margins of excision had a higher rate of local regional recurrence (hazard ratio [HR] = 1.26; 95% confidence interval [CI], 1.00–1.59; P = .05), but no difference in survival was seen (HR = 1.24; 95% CI, 0.96–1.61; P = .1). This suggests that 1-cm margins may not be adequate for patients with melanomas more than 2 mm thick. Few data are available to guide treatment in patients with melanomas more than 4 mm thick; however, most guidelines recommend margins of 3 cm whenever anatomically possible. Although prophylactic regional lymph node dissections have been used in patients with stage II melanomas, four prospective randomized trials have failed to show a benefit for this procedure in terms of survival.[3-6]

  Lymphatic mapping and sentinel lymph node biopsy have been used to assess the presence of occult metastasis in the regional lymph nodes of patients with stage II disease, potentially identifying individuals who may be spared the morbidity of regional lymph node dissection and individuals who may benefit from adjuvant therapy.[7-11] The diagnostic accuracy of sentinel lymph node biopsy has been demonstrated in several studies with a false-negative rate of 0% to 2%.[7,12-16] Using a vital blue dye and a radiopharmaceutical agent, which are injected at the site of the primary tumor, the first lymph node in the lymphatic basin that drains the lesion can be identified, removed, and examined microscopically. If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure. To ensure accurate identification of the sentinel lymph node, lymphatic mapping and removal of the sentinel lymph node should be performed prior to wide excision of the primary melanoma.

  To date, no published data from prospective trials are available on the clinical significance of micrometastatic melanoma in regional lymph nodes, but some evidence suggests that for patients with tumors of intermediate thickness and occult metastasis, survival is better among those patients who undergo immediate regional lymphadenectomy than it is among those who delay lymphadenectomy until the clinical appearance of nodal metastasis.[6] Because this finding arose from a posthoc subset analysis of data from a randomized trial, it should be viewed with caution.

  The International Multicenter Selective Lymphadenectomy Trial (MSLT-1) included 1,269 patients with intermediate-thickness (defined as 1.2 mm–3.5 mm in this study) primary melanomas.[17] There was no melanoma-specific survival advantage (the primary endpoint) for those patients randomly assigned to wide excision plus sentinel lymph node biopsy followed by immediate completion lymphadenectomy for node positivity versus patients randomly assigned to nodal observation and delayed lymphadenectomy for subsequent nodal recurrence at a median of 59.8 months.[17][Level of evidence: 1iiB]

  This trial was not designed to detect a difference in the impact of lymphadenectomy in patients with microscopic lymph node involvement.[17]

Adjuvant therapy:

• 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.[18] 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 OS (P = .023) 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.[18][Level of evidence: 1iiA] A subset analysis of the stage II patients 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) 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.[19] 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 for low-dose interferon was seen when compared with 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 (HR = 1.0; P = .995).[19][Level of evidence: 1iiA]

  Another multicenter prospective trial (E-1694) 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).[20] Of the 880 patients who were randomly assigned, 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].) For the population eligible for efficacy analysis, the greatest benefit was seen in the node-negative (stage IIB) subset (relapse-free survival [HR = 2.07]; OS [HR = 2.71]).[20][Level of evidence: 1iiA]

  Clinicians should be aware that the high-dose regimens have substantial side effects and patients must be monitored closely.

  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.[21]

Treatment options under clinical evaluation:

• Because of the higher rate of treatment failure in this group, clinical trials exploring adjuvant chemotherapy and/or biologic therapy, or immunotherapy, are appropriate choices when possible for newly diagnosed patients. Other clinical trials are evaluating new techniques to detect submicroscopic sentinel lymph node metastasis to identify the patients who may benefit from regional lymphadenectomy with or without adjuvant therapy. One of the objectives of the ongoing phase III Sunbelt Melanoma Trial (UAB-9735) is to determine the effects of lymphadenectomy with or without adjuvant high-dose interferon-alpha-2b versus observation on disease-free survival and OS in patients with submicroscopic sentinel lymph node metastasis detected only by the polymerase chain reaction (PCR) (i.e., sentinel lymph node negative by histology and immunohistochemistry). No survival data have been reported from this study. An ongoing diagnostic study (UCCRC-9308) is testing the combination of reverse transcription and PCR in the detection of melanoma tumor antigen transcripts in lymph nodes and peripheral blood samples.

  An ongoing phase III trial (ECOG-1697) is evaluating the effect of 1 month of high-dose adjuvant interferon-alpha-2b versus observation on relapse-free survival and OS in patients with melanomas more than 1.5 mm in thickness and with or without a single microscopically positive lymph node. Results are pending from another phase III study (EORTC-18952) that randomized patients with stage II or stage III disease to adjuvant intermediate high-dose interferon-alpha-2b versus intermediate low-dose interferon-alpha-2b versus observation.

  Autologous bone marrow transplantation with high-dose chemotherapy has not been shown to improve survival.[22]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Balch CM, Urist MM, Karakousis CP, et al.: Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg 218 (3): 262-7; discussion 267-9, 1993.  [PUBMED Abstract]
   
   
2. Thomas JM, Newton-Bishop J, A'Hern R, et al.: Excision margins in high-risk malignant melanoma. N Engl J Med 350 (8): 757-66, 2004.  [PUBMED Abstract]
   
   
3. Veronesi U, Adamus J, Bandiera DC, et al.: Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer 49 (11): 2420-30, 1982.  [PUBMED Abstract]
   
   
4. Sim FH, Taylor WF, Ivins JC, et al.: A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results. Cancer 41 (3): 948-56, 1978.  [PUBMED Abstract]
   
   
5. Balch CM, Soong SJ, Bartolucci AA, et al.: 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 (3): 255-63; discussion 263-6, 1996.  [PUBMED Abstract]
   
   
6. Cascinelli N, Morabito A, Santinami M, et al.: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351 (9105): 793-6, 1998.  [PUBMED Abstract]
   
   
7. Gershenwald JE, Thompson W, Mansfield PF, et al.: Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17 (3): 976-83, 1999.  [PUBMED Abstract]
   
   
8. McMasters KM, Reintgen DS, Ross MI, et al.: Sentinel lymph node biopsy for melanoma: controversy despite widespread agreement. J Clin Oncol 19 (11): 2851-5, 2001.  [PUBMED Abstract]
   
   
9. Cherpelis BS, Haddad F, Messina J, et al.: Sentinel lymph node micrometastasis and other histologic factors that predict outcome in patients with thicker melanomas. J Am Acad Dermatol 44 (5): 762-6, 2001.  [PUBMED Abstract]
   
   
10. Essner R: The role of lymphoscintigraphy and sentinel node mapping in assessing patient risk in melanoma. Semin Oncol 24 (1 Suppl 4): S8-10, 1997.  [PUBMED Abstract]
    
    
11. Chan AD, Morton DL: Sentinel node detection in malignant melanoma. Recent Results Cancer Res 157: 161-77, 2000.  [PUBMED Abstract]
    
    
12. Morton DL, Wen DR, Wong JH, et al.: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127 (4): 392-9, 1992.  [PUBMED Abstract]
    
    
13. Reintgen D, Cruse CW, Wells K, et al.: The orderly progression of melanoma nodal metastases. Ann Surg 220 (6): 759-67, 1994.  [PUBMED Abstract]
    
    
14. Thompson JF, McCarthy WH, Bosch CM, et al.: Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res 5 (4): 255-60, 1995.  [PUBMED Abstract]
    
    
15. Uren RF, Howman-Giles R, Thompson JF, et al.: Lymphoscintigraphy to identify sentinel lymph nodes in patients with melanoma. Melanoma Res 4 (6): 395-9, 1994.  [PUBMED Abstract]
    
    
16. Bostick P, Essner R, Glass E, et al.: Comparison of blue dye and probe-assisted intraoperative lymphatic mapping in melanoma to identify sentinel nodes in 100 lymphatic basins. Arch Surg 134 (1): 43-9, 1999.  [PUBMED Abstract]
    
    
17. Morton DL, Thompson JF, Cochran AJ, et al.: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355 (13): 1307-17, 2006.  [PUBMED Abstract]
    
    
18. Kirkwood JM, Strawderman MH, Ernstoff MS, et al.: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14 (1): 7-17, 1996.  [PUBMED Abstract]
    
    
19. Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12): 2444-58, 2000.  [PUBMED Abstract]
    
    
20. Kirkwood JM, Ibrahim JG, Sosman JA, et al.: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19 (9): 2370-80, 2001.  [PUBMED Abstract]
    
    
21. Hancock BW, Wheatley K, Harris S, et al.: Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22 (1): 53-61, 2004.  [PUBMED Abstract]
    
    
22. Meisenberg BR, Ross M, Vredenburgh JJ, et al.: Randomized trial of high-dose chemotherapy with autologous bone marrow support as adjuvant therapy for high-risk, multi-node-positive malignant melanoma. J Natl Cancer Inst 85 (13): 1080-5, 1993.  [PUBMED Abstract]
    
    

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