Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information

Clark Classification (Level of Invasion) TNM Definitions Clinical Staging         AJCC stage groupings Pathologic Staging         AJCC stage groupings

Treatment Option Overview
Stage 0 Melanoma

Current Clinical Trials

Stage I Melanoma

Current Clinical Trials

Stage II Melanoma

Current Clinical Trials

Stage III Melanoma

Current Clinical Trials

Stage IV Melanoma

Current Clinical Trials

Recurrent Melanoma

Current Clinical Trials

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Changes to This Summary (11/04/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of melanoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Prognostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system ² in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version ³, written in less technical language, and in Spanish ⁴.

General Information

Note: Separate PDQ summaries on Skin Cancer Treatment ⁵; Skin Cancer Prevention ⁶; and Skin Cancer Screening ⁷ are also available.

Note: Estimated new cases and deaths from melanoma in the United States in 2008:[1]

• New cases: 62,480.
• Deaths: 8,420.

Melanoma is a malignant tumor of melanocytes, which are the cells that make the pigment melanin and are derived from the neural crest. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate. Melanoma occurs predominantly in adults, and more than 50% of the cases arise in apparently normal areas of the skin. Early signs in a nevus that would suggest malignant change include darker or variable discoloration, itching, an increase in size, or the development of satellites. Ulceration or bleeding are later signs. Melanoma in women occurs more commonly on the extremities and in men on the trunk or head and neck, but it can arise from any site on the skin surface. A biopsy, preferably by local excision, should be performed for any suspicious lesions, and the specimens should be examined by an experienced pathologist to allow for microstaging. Suspicious lesions should never be shaved off or cauterized. Studies show that distinguishing between benign pigmented lesions and early melanomas can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered.[2]

Prognosis is affected by clinical and histological factors and by anatomic location of the lesion. Thickness and/or level of invasion of the melanoma, mitotic index, presence of tumor infiltrating lymphocytes, number of regional lymph nodes involved, and ulceration or bleeding at the primary site affect the prognosis.[3-6] Microscopic satellites in stage I melanoma may be a poor prognostic histologic factor, but this is controversial.[7] Patients who are younger, female, and who have melanomas on the extremities generally have a better prognosis.[3-6]

Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. For disease clinically confined to the primary site, the greater the thickness and depth of local invasion of the melanoma, the higher the chance of lymph node or systemic metastases and the worse the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites. The risk of relapse decreases substantially over time, though late relapses are not uncommon.[8,9]

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. ⁸ Last accessed October 1, 2008. 
   
   
2. Corona R, Mele A, Amini M, et al.: Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions. J Clin Oncol 14 (4): 1218-23, 1996.  [PUBMED Abstract]
   
   
3. Balch CM, Soong S, Ross MI, et al.: Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 7 (2): 87-97, 2000.  [PUBMED Abstract]
   
   
4. Manola J, Atkins M, Ibrahim J, et al.: Prognostic factors in metastatic melanoma: a pooled analysis of Eastern Cooperative Oncology Group trials. J Clin Oncol 18 (22): 3782-93, 2000.  [PUBMED Abstract]
   
   
5. Balch CM, Buzaid AC, Soong SJ, et al.: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19 (16): 3635-48, 2001.  [PUBMED Abstract]
   
   
6. Liu ZJ, Herlyn M: Melanoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1745-1824. 
   
   
7. León P, Daly JM, Synnestvedt M, et al.: The prognostic implications of microscopic satellites in patients with clinical stage I melanoma. Arch Surg 126 (12): 1461-8, 1991.  [PUBMED Abstract]
   
   
8. Shen P, Guenther JM, Wanek LA, et al.: Can elective lymph node dissection decrease the frequency and mortality rate of late melanoma recurrences? Ann Surg Oncol 7 (2): 114-9, 2000.  [PUBMED Abstract]
   
   
9. Tsao H, Cosimi AB, Sober AJ: Ultra-late recurrence (15 years or longer) of cutaneous melanoma. Cancer 79 (12): 2361-70, 1997.  [PUBMED Abstract]
   
   

Cellular Classification

Following is a list of clinicopathologic cellular subtypes of malignant melanoma. These should be considered descriptive terms of historic interest only as they do not have independent prognostic or therapeutic significance.

• Superficial spreading.
• Nodular.
• Lentigo maligna.
• Acral lentiginous (palmar/plantar and subungual).
• Miscellaneous unusual types:
  • Mucosal lentiginous (oral and genital).
  • Desmoplastic.
  • Verrucous.

Stage Information

Agreement between pathologists in the histologic diagnosis of melanomas and benign pigmented lesions has been studied and found to be considerably variable. One such study found that there was discordance on the diagnosis of melanoma versus benign lesions in 37 of 140 cases examined by a panel of experienced dermatopathologists.[1] For the histologic classification of cutaneous melanoma, the highest concordance was attained for Breslow thickness and presence of ulceration, while the agreement was poor for other histologic features such as Clark level of invasion, presence of regression, and lymphocytic infiltration. In another study, 38% of cases examined by a panel of expert pathologists had two or more discordant interpretations. These studies convincingly show that distinguishing between benign pigmented lesions and early melanoma can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered.[2]

The microstage of malignant melanoma is determined on histologic examination by the vertical thickness of the lesion in millimeters (Breslow classification) and/or the anatomic level of local invasion (Clark classification). The Breslow thickness is more reproducible and more accurately predicts subsequent behavior of malignant melanoma in lesions larger than 1.5 mm in thickness and should always be reported. Accurate microstaging of the primary tumor requires careful histologic evaluation of the entire specimen by an experienced pathologist. Estimates of prognosis should be modified by sex and anatomic site as well as by clinical and histologic evaluation.

• Level I: Lesions involving only the epidermis (in situ melanoma); not an invasive lesion.
• Level II: Invasion of the papillary dermis but does not reach the papillary-reticular dermal interface.
• Level III: Invasion fills and expands the papillary dermis but does not penetrate the reticular dermis.
• Level IV: Invasion into the reticular dermis but not into the subcutaneous tissue.
• Level V: Invasion through the reticular dermis into the subcutaneous tissue.

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define melanoma.[3]

Primary tumor (T)

• TX: Primary tumor cannot be assessed (e.g., shave biopsy or regressed melanoma)
• T0: No evidence of primary tumor
• Tis: Melanoma in situ
• T1: Tumor 1.0 mm or less in thickness with or without ulceration
  • T1a: Tumor 1.0 mm or less in thickness and Clark level II or III with no ulceration
  • T1b: Tumor 1.0 mm or less in thickness and Clark level IV or V or with ulceration
• T2: Tumor more than 1.0 mm but 2.0 mm or less in thickness with or without ulceration
  • T2a: Tumor more than 1.0 mm but 2.0 mm or less in thickness with no ulceration
  • T2b: Tumor more than 1.0 mm but 2.0 mm or less in thickness with ulceration
• T3: Tumor more than 2.0 mm but 4.0 mm or less in thickness with or without ulceration
  • T3a: Tumor more than 2.0 mm but 4.0 mm or less in thickness without ulceration
  • T3b: Tumor more than 2.0 mm but 4.0 mm or less in thickness with ulceration
• T4: Tumor more than 4.0 mm in thickness with or without ulceration
  • T4a: Tumor more than 4.0 mm in thickness without ulceration
  • T4b: Tumor more than 4.0 mm in thickness with ulceration

Regional lymph nodes (N)

• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Metastasis to one lymph node
  • N1a: Clinically occult (microscopic) metastasis
  • N1b: Clinically apparent (macroscopic) metastasis
• N2: Metastasis to two or three regional nodes or intralymphatic regional metastasis without nodal metastases
  • N2a: Clinically occult (microscopic) metastasis
  • N2b: Clinically apparent (macroscopic) metastasis
  • N2c: Satellite or in-transit metastasis without nodal metastasis
• N3: Metastasis in more than four regional nodes, or matted lymph nodes, or in-transit metastasis or satellite(s) with metastatic regional node(s)

   [Note: Micrometastases are diagnosed after elective or sentinel lymphadenectomy; macrometastases are defined as clinically detectable lymph nodes metastases confirmed by therapeutic lymphadenectomy, or when any lymph node metastasis exhibits gross extracapsular extension.]

Distant Metastasis (M)

• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis
  • M1a: Metastasis to skin, subcutaneous tissues, or distant lymph nodes
  • M1b: Metastasis to lung
  • M1c: Metastasis to all other visceral sites or distant metastasis at any site associated with an elevated serum lactic dehydrogenase

Clinical staging includes microstaging of the primary melanoma and clinical and/or radiologic evaluation for metastases. By convention, it should be assigned after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.[3]

Stage 0

• Tis, N0, M0

Stage IA

• T1a, N0, M0

Stage IB

• T1b, N0, M0
• T2a, N0, M0

Stage IIA

• T2b, N0, M0
• T3a, N0, M0

Stage IIB

• T3b, N0, M0
• T4a, N0, M0

Stage IIC

• T4b, N0, M0

Stage III

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

Stage IV

• Any T, any N, M1

With the exception of clinical stage 0 or stage IA patients (who have a low risk of lymphatic involvement and do not require pathologic evaluation of their lymph nodes), pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after sentinel node biopsy and, if indicated, complete lymphadenectomy.[3]

Stage 0

• Tis, N0, M0

Stage IA

• T1a, N0, M0

Stage IB

• T1b, N0, M0
• T2a, N0, M0

Stage IIA

• T2b, N0, M0
• T3a, N0, M0

Stage IIB

• T3b, N0, M0
• T4a, N0, M0

Stage IIC

• T4b, N0, M0

Stage IIIA

• T1–4a, N1a, M0
• T1–4a, N2a, M0

Stage IIIB

• T1–4b, N1a, M0
• T1–4b, N2a, M0
• T1–4a, N1b, M0
• T1–4a, N2b, M0
• T1–4a/b, N2c, M0

Stage IIIC

• T1–4b, N1b, M0
• T1–4b, N2b, M0
• T1–4b, N2c, M0
• Any T, N3, M0

Stage IV

• Any T, any N, M1

References

1. Corona R, Mele A, Amini M, et al.: Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions. J Clin Oncol 14 (4): 1218-23, 1996.  [PUBMED Abstract]
   
   
2. Farmer ER, Gonin R, Hanna MP: Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists. Hum Pathol 27 (6): 528-31, 1996.  [PUBMED Abstract]
   
   
3. Melanoma of the skin. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 209-220. 
   
   

Treatment Option Overview

Melanomas that have not spread beyond the site at which they developed are highly curable. Most of these are thin lesions that have not invaded beyond the papillary dermis (Clark level I–II; Breslow thickness ≤1 mm). The treatment of localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion; for most lesions 2 mm or less in thickness, this means 1 cm radial re-excision margins.[1,2]

Melanomas with a Breslow thickness of 2 mm or more are still curable in a significant proportion of patients, but the risk of lymph node and/or systemic metastasis increases with increasing thickness of the primary lesion. The local treatment for these melanomas is surgical excision with margins based on Breslow thickness and anatomic location. For most melanomas more than 2 mm to 4 mm in thickness, this means 2 cm to 3 cm radial excision margins. These patients should also be considered for sentinel lymph node biopsy followed by complete lymph node dissection if the sentinel node(s) are microscopically or macroscopically positive. Sentinel node biopsy should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping. Patients with melanomas that have a Breslow thickness more than 4 mm should be considered for adjuvant therapy with high-dose interferon.

Some melanomas that have spread to regional lymph nodes may be curable with wide local excision of the primary tumor and removal of the involved regional lymph nodes.[3-6] In a prospective randomized controlled trial (EST-1684) ⁹, adjuvant high-dose interferon was shown to increase relapse-free survival and overall survival (OS) when compared to observation.[7] A subsequent randomized trial (EST-1690) ¹⁰ conducted by the same group of investigators using the same high-dose interferon regimen confirmed the relapse-free survival but not the OS advantage.[8] A third randomized trial (E-2696) ¹¹again demonstrated both a disease-free survival and OS advantage to high-dose interferon when compared to a ganglioside vaccine.[9] Clinicians should be aware that high-dose interferon regimens have substantial side effects, and patients should be monitored closely. Adjuvant therapy with lower doses of interferon have not been consistently shown to have an impact on either relapse-free survival or OS.[10] Adjuvant chemotherapy does not improve survival. A multicenter phase III randomized trial (EORTC-18832 ¹²) of patients with high-risk primary limb melanoma did not show a benefit from isolated limb perfusion with melphalan in regard to disease-free survival or OS when compared to surgery alone.[11]

Melanoma that has spread to distant sites is rarely curable with standard therapy, though high-dose interleukin-2 (IL-2) has been reported to produce durable responses in a small number of patients.[12,13] In patients with systemic metastasis confined to one anatomic site, long-term survival is occasionally achieved by complete resection of all metastatic disease.[14-17] All patients with distant metastasis are appropriately considered candidates for clinical trials exploring new forms of treatment, including combination chemotherapy, biological response modifiers (such as specific monoclonal antibodies, interferons, IL-2, or tumor necrosis factor-alpha), vaccine immunotherapy, or biochemotherapy (chemoimmunotherapy).

Malignant melanoma has been reported to spontaneously regress; however, the incidence of spontaneous complete regressions is less than 1%.[18]

Patients with all stages of melanoma may be considered candidates for ongoing clinical trials. Information about ongoing clinical trials is available from the NCI Web site ¹³.

References

1. Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991.  [PUBMED Abstract]
   
   
2. 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. N Engl J Med 318 (18): 1159-62, 1988.  [PUBMED Abstract]
   
   
3. Shen P, Wanek LA, Morton DL: Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol 7 (8): 554-9; discussion 560-1, 2000.  [PUBMED Abstract]
   
   
4. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998.  [PUBMED Abstract]
   
   
5. Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.  [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. 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]
   
   
8. 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]
   
   
9. Kirkwood JM, Ibrahim J, Lawson DH, et al.: High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696. J Clin Oncol 19 (5): 1430-6, 2001.  [PUBMED Abstract]
   
   
10. 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]
    
    
11. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk 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 16 (9): 2906-12, 1998.  [PUBMED Abstract]
    
    
12. Atkins MB, Lotze MT, Dutcher JP, et al.: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17 (7): 2105-16, 1999.  [PUBMED Abstract]
    
    
13. Atkins MB, Kunkel L, Sznol M, et al.: High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6 (Suppl 1): S11-4, 2000.  [PUBMED Abstract]
    
    
14. Lee ML, Tomsu K, Von Eschen KB: Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Res 10 (1): 81-92, 2000.  [PUBMED Abstract]
    
    
15. Leo F, Cagini L, Rocmans P, et al.: Lung metastases from melanoma: when is surgical treatment warranted? Br J Cancer 83 (5): 569-72, 2000.  [PUBMED Abstract]
    
    
16. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999.  [PUBMED Abstract]
    
    
17. Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001.  [PUBMED Abstract]
    
    
18. Wang TS, Lowe L, Smith JW 2nd, et al.: Complete spontaneous regression of pulmonary metastatic melanoma. Dermatol Surg 24 (8): 915-9, 1998.  [PUBMED Abstract]
    
    

Stage 0 Melanoma

Stage 0 melanoma is defined by the following clinical stage grouping:

• Tis, N0, M0

Patients with stage 0 disease may be treated by excision with minimal, but microscopically free, margins.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage 0 melanoma ¹⁴. 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 ¹⁵.

Stage I Melanoma

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 ² for more information.)

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

• T1a, N0, M0
• T1b, N0, M0
• T2a, N0, M0

Standard treatment options:

• Current evidence suggests that lesions 2 mm or less in thickness may be treated conservatively with radial excision margins of 1 cm. A randomized trial compared narrow margins (1 cm) with wide margins (at least 3 cm) in patients with melanomas no thicker than 2 mm.[1,2] No difference was observed between the two groups in respect to the development of metastatic disease, disease-free survival, or overall survival (OS). Two other randomized trials have compared 2 cm margins with wider margins (i.e., 4 cm or 5 cm), and found no statistically significant difference in local recurrence, distant metastasis, or OS, with a median follow-up of 10 years or more for both trials.[3-5][Level of evidence:1iiA] In the Intergroup Melanoma Surgical Trial, 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.[5] Depending on the location of the melanoma, most patients can now have this procedure performed on an outpatient basis.

  Elective regional lymph node dissection is of no proven benefit for patients with stage I melanoma. Lymphatic mapping and sentinel lymph node biopsy for patients who have tumors of intermediate thickness and/or ulcerated tumors, however, may allow the identification of individuals with occult nodal disease who might benefit from regional lymphadenectomy and adjuvant therapy.[6-9]

  The International Multicenter Selective Lymphadenectomy Trial (MSLT-1) ¹⁶ included 1,269 patients with intermediate-thickness (defined as 1.2 mm-3.5 mm in this study) primary melanomas.[10] 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.[10][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.[10]

Treatment options under clinical evaluation:

• Because of the higher rate of treatment failure in the subset of clinical stage I patients with occult nodal disease, clinical trials are evaluating new techniques to detect submicroscopic sentinel lymph node metastasis to identify those patients who may benefit from regional lymphadenectomy with or without adjuvant therapy. One of the objectives of the currently ongoing phase III Sunbelt Melanoma Trial (UAB-9735 ¹⁷) 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 ¹⁸) is testing the combination of reverse transcription and PCR in the detection of melanoma tumor antigen transcripts in lymph nodes and peripheral blood samples.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I melanoma ¹⁹. 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 ¹⁵.

References

1. Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991.  [PUBMED Abstract]
   
   
2. 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. N Engl J Med 318 (18): 1159-62, 1988.  [PUBMED Abstract]
   
   
3. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al.: Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer 89 (7): 1495-501, 2000.  [PUBMED Abstract]
   
   
4. Balch CM, Soong SJ, Smith T, et al.: Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 8 (2): 101-8, 2001.  [PUBMED Abstract]
   
   
5. 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]
   
   
6. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998.  [PUBMED Abstract]
   
   
7. Essner R, Conforti A, Kelley MC, et al.: Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early-stage melanoma. Ann Surg Oncol 6 (5): 442-9, 1999 Jul-Aug.  [PUBMED Abstract]
   
   
8. 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]
   
   
9. Mraz-Gernhard S, Sagebiel RW, Kashani-Sabet M, et al.: Prediction of sentinel lymph node micrometastasis by histological features in primary cutaneous malignant melanoma. Arch Dermatol 134 (8): 983-7, 1998.  [PUBMED Abstract]
   
   
10. 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]
    
    

Stage II Melanoma

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 ² 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) ¹⁶ 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) ⁹ 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) ¹⁰ 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) ²⁰randomized 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 ¹⁷) 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) ¹⁸ 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 ²¹) 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 ²²) 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 ²³. 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 ¹⁵.

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]
    
    

Stage III Melanoma

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 ² 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.[1-7] Skin grafting may be necessary to close the resulting defect.

  A multicenter, randomized controlled study (EST-1684) ⁹has 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) ¹⁰by 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]

Treatment options under clinical evaluation:

• Because of the higher rate of treatment failure in this group, clinical trials exploring adjuvant chemotherapy and/or adjuvant biologic therapy, or immunologically active agents to prevent recurrences after control of the primary tumors with standard therapy are especially appropriate for newly diagnosed patients.

  An ongoing phase III trial (ECOG-1697 ²¹) 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, with or without a single microscopically positive lymph node. Another ongoing phase III trial (EORTC-18991 ²⁴) is evaluating adjuvant phenylated interferon-alpha-2b versus observation. Results are pending from a phase III study (EORTC-18952 ²²) that randomly assigned 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.




• For patients with high-risk stage III disease, phase III clinical trials such as the SWOG-S0008 ²⁵ and MDA-ID-95196 ²⁶ trials, for example, are evaluating interferon-alpha-2b versus chemoimmunotherapy.



• For patients with in-transit and/or satellite lesions (stage IIIC) of the extremities, hyperthermic isolated limb perfusion (ILP) with melphalan (L-PAM) with or without tumor necrosis factor-alpha (TNF-alpha) has resulted in high tumor response rates and palliative benefit.[3] Results from a multicenter randomized phase II study showed no benefit from adding interferon-gamma to a regimen of L-PAM plus TNF-alpha.[13] Clinical trials such as the ACOSOG-Z0020 ²⁷ and MSKCC-99047 ²⁸trials, for example, are evaluating ILP using L-PAM in combination with TNF or other chemotherapeutic agents.



• A recently completed phase I/II study (MCC-11543 ²⁹) evaluated interferon-alpha-2b in combination with radiation therapy; results are pending.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III melanoma ³⁰. 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 ¹⁵.

References

1. Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991.  [PUBMED Abstract]
   
   
2. 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. N Engl J Med 318 (18): 1159-62, 1988.  [PUBMED Abstract]
   
   
3. Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.  [PUBMED Abstract]
   
   
4. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al.: Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer 89 (7): 1495-501, 2000.  [PUBMED Abstract]
   
   
5. Balch CM, Soong SJ, Smith T, et al.: Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 8 (2): 101-8, 2001.  [PUBMED Abstract]
   
   
6. Heaton KM, Sussman JJ, Gershenwald JE, et al.: Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma. Ann Surg Oncol 5 (4): 322-8, 1998.  [PUBMED Abstract]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. Liénard D, Eggermont AM, Koops HS, et al.: Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study. Melanoma Res 9 (5): 491-502, 1999.  [PUBMED Abstract]
    
    

Stage IV Melanoma

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 ² for more information.)

Stage IV melanoma is defined by the following clinical stage grouping:

• Any T, any N, M1

Standard treatment options:

• Melanoma metastatic to distant, lymph node-bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or occasionally the brain may be palliated by resection with occasional long-term survival.[1-3] Radiation therapy may provide symptomatic relief for metastases to brain, bones, and viscera.

  Advanced melanoma is refractory to most standard systemic therapy, and all newly diagnosed patients should be considered candidates for clinical trials. Although advanced melanoma is relatively resistant to therapy, several biologic response modifiers and cytotoxic agents have been reported to produce objective responses.

  The objective response rate to dacarbazine (DTIC) and the nitrosoureas, carmustine (BCNU) and lomustine, is approximately 10% to 20%.[4-7] Responses are usually short-lived, ranging from 3 to 6 months, though long-term remissions can occur in a limited number of patients who attain a complete response.[4,7] Other agents with modest single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[4,5,8]

  Phase II studies of three-drug combinations showed higher response rates (ranging from 22% to 45%) than were seen with single agents.[4,5] Randomized trials comparing two-drug or three-drug combination regimens with DTIC alone have not consistently demonstrated any advantage for the combination, though these trials had limited sample sizes and insufficient power to detect small but clinically relevant differences in response or survival.[4]

  The addition of tamoxifen to the three-drug combination regimen of cisplatin, BCNU, and DTIC (i.e., the Dartmouth regimen) showed high response rates in phase II studies, with a 20% complete response rate in several trials.[4] A phase III trial testing the three drugs with and without tamoxifen showed no benefit for the addition of tamoxifen, and the response rates in both study arms were once again in the 20% to 30% range.[9]

  One trial directly compared DTIC alone to the three-drug regimen plus tamoxifen.[6] Results from this trial indicated no difference in tumor response or overall survival (OS) between the two treatment groups. The tumor response rate to DTIC was 10.2% compared with 18.5% for the three-drug combination plus tamoxifen (P = .09). Pending the outcome of further randomized, controlled trials, no combination regimen has yet been proven to be superior to DTIC alone.

  The two biologic therapies that appear most active against melanoma are interferon-alpha and interleukin-2 (IL-2). Response rates for interferon range from 8% to 22%, and long-term administration on a daily or a three-times-per-week basis appears superior to once per week or more intermittent schedules.[10] Response to IL-2 regimens is similar and is in the 10% to 20% range.[11-13] Attempts to improve on this with the addition of lymphokine-activated killer cells (autologous lymphocytes activated by IL-2 ex vivo) and by tumor-infiltrating lymphocytes (lymphocytes derived from tumor isolates cultured in the presence of IL-2) have not improved response rates or durable remissions sufficiently to merit the expense and complexity of this therapy. Phase II studies testing combinations of interferon and IL-2 have demonstrated high response rates, but a phase III comparison of interferon and IL-2 compared with IL-2 alone in 85 patients did not show any benefit for the combination.[8]

  Combinations of chemotherapy and biologics (chemoimmunotherapy or biochemotherapy) have been tested against chemotherapy alone. Four small phase III studies comparing DTIC and interferon with DTIC alone yielded conflicting results.[4] In a larger randomized trial involving 271 patients, 258 eligible patients received either DTIC alone; DTIC plus interferon; DTIC plus tamoxifen; or DTIC, interferon, and tamoxifen (2 × 2 factorial design).[14] No statistically significant differences were found in response rates, time-to-treatment failure, or survival among the different groups. Toxic effects were increased in the groups who received interferon.[14][Level of evidence: 1iiA] IL-2 has also been combined with cisplatin in several phase II trials [15-17] with encouraging response rates, but data supporting an improvement in survival are lacking. One prospective trial randomly assigned 102 patients to either chemotherapy (DTIC, cisplatin, and tamoxifen) alone or chemotherapy plus IL-2 and interferon-alpha-2b.[18] No statistically significant differences were found in objective response rate or OS between the treatment groups, and toxic side effects were increased in the group that received biochemotherapy.

  A meta-analysis of 20 randomized trials (involving 3,273 patients) that compared single-agent DTIC to combination chemotherapy with or without immunotherapy found that the combination of DTIC and interferon-alpha produced a tumor response rate 53% greater (95% confidence interval, 1.10–2.13) than that seen with DTIC alone;[19] however, no difference in OS was found.

  Ongoing phase II and III trials such as the EORTC-18951 ³¹, UCCRC-9372 ³², SFMH-BB-IND-5301 ³³, and E-E3695 ³⁴ trials, for example, are comparing complex biochemotherapy regimens (interferon, IL-2, and chemotherapy) to chemotherapy alone. Pending the results of these and future trials, no proof exists that biochemotherapy is superior to chemotherapy.

Treatment options under clinical evaluation:

1. Patients should be considered appropriate candidates for clinical trials evaluating new forms of chemotherapy and/or biologic therapy (specific monoclonal antibodies, interleukin, and interferons) or vaccines.
2. Palliative radiation therapy for bone, spinal cord, or brain metastases.
3. Complete surgical resection of all known disease (SWOG-9430 ³⁵).

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV melanoma ³⁶. 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 ¹⁵.

References

1. Leo F, Cagini L, Rocmans P, et al.: Lung metastases from melanoma: when is surgical treatment warranted? Br J Cancer 83 (5): 569-72, 2000.  [PUBMED Abstract]
   
   
2. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999.  [PUBMED Abstract]
   
   
3. Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001.  [PUBMED Abstract]
   
   
4. Anderson CM, Buzaid AC, Legha SS: Systemic treatments for advanced cutaneous melanoma. Oncology (Huntingt) 9 (11): 1149-58; discussion 1163-4, 1167-8, 1995.  [PUBMED Abstract]
   
   
5. Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.  [PUBMED Abstract]
   
   
6. Chapman PB, Einhorn LH, Meyers ML, et al.: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17 (9): 2745-51, 1999.  [PUBMED Abstract]
   
   
7. Mays SR, Nelson BR: Current therapy of cutaneous melanoma. Cutis 63 (5): 293-8, 1999.  [PUBMED Abstract]
   
   
8. Sparano JA, Fisher RI, Sunderland M, et al.: Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 11 (10): 1969-77, 1993.  [PUBMED Abstract]
   
   
9. Rusthoven JJ, Quirt IC, Iscoe NA, et al.: Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 14 (7): 2083-90, 1996.  [PUBMED Abstract]
   
   
10. Agarwala SS, Kirkwood JM: Interferons in melanoma. Curr Opin Oncol 8 (2): 167-74, 1996.  [PUBMED Abstract]
    
    
11. Atkins MB, Lotze MT, Dutcher JP, et al.: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17 (7): 2105-16, 1999.  [PUBMED Abstract]
    
    
12. Atkins MB, Kunkel L, Sznol M, et al.: High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6 (Suppl 1): S11-4, 2000.  [PUBMED Abstract]
    
    
13. Rosenberg SA, Yang JC, Topalian SL, et al.: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271 (12): 907-13, 1994 Mar 23-30.  [PUBMED Abstract]
    
    
14. Falkson CI, Ibrahim J, Kirkwood JM, et al.: Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 16 (5): 1743-51, 1998.  [PUBMED Abstract]
    
    
15. Demchak PA, Mier JW, Robert NJ, et al.: Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma: a pilot study. J Clin Oncol 9 (10): 1821-30, 1991.  [PUBMED Abstract]
    
    
16. Flaherty LE, Robinson W, Redman BG, et al.: A phase II study of dacarbazine and cisplatin in combination with outpatient administered interleukin-2 in metastatic malignant melanoma. Cancer 71 (11): 3520-5, 1993.  [PUBMED Abstract]
    
    
17. Atkins MB, O'Boyle KR, Sosman JA, et al.: Multiinstitutional phase II trial of intensive combination chemoimmunotherapy for metastatic melanoma. J Clin Oncol 12 (8): 1553-60, 1994.  [PUBMED Abstract]
    
    
18. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al.: Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 17 (3): 968-75, 1999.  [PUBMED Abstract]
    
    
19. Huncharek M, Caubet JF, McGarry R: Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials. Melanoma Res 11 (1): 75-81, 2001.  [PUBMED Abstract]
    
    

Recurrent Melanoma

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 ² for more information.)

Recurrent melanoma is resistant to most standard systemic therapy, and all newly diagnosed patients should be considered candidates for clinical trials. Deciding on further treatment depends on many factors, including prior treatment and site of recurrence, as well as individual patient considerations. Surgery is the most efficacious therapy for isolated recurrence in sites where it can be accomplished (including lymph node, skin, brain, lung, liver, and gastrointestinal sites).[1-3] Although advanced melanoma is relatively resistant to therapy, several biologic response modifiers and cytotoxic agents have been reported to produce objective responses.

The objective response rate to dacarbazine (DTIC) and the nitrosoureas, carmustine (BCNU) and lomustine, is approximately 10% to 20%.[2,4-6] Responses are usually short-lived, ranging from 3 to 6 months, though long-term remissions can occur in a limited number of patients who attain a complete response.[4,6] Other agents with modest single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[2,4]

Phase II studies of three-drug combinations showed higher response rates (ranging from 22%–45%) than were seen with single agents.[2,4] Randomized trials comparing two-drug or three-drug combination regimens with DTIC alone have not consistently demonstrated any advantage for the combination, though these trials had limited sample sizes and insufficient power to detect small but clinically relevant differences in response or survival.[4]

The addition of tamoxifen to the three-drug combination regimen of cisplatin, BCNU, and DTIC (i.e., the Dartmouth regimen) showed high response rates in phase II studies with a 20% complete response rate in several trials.[4] A phase III trial testing the three drugs with and without tamoxifen showed no benefit for the addition of tamoxifen, and the response rates for both study arms were once again in the 20% to 30% range.[7]

One trial directly compared DTIC alone with the three-drug regimen plus tamoxifen.[5] Results from this trial indicated no difference in tumor response or overall survival (OS) between the two treatment groups. The tumor response rate to DTIC was 10.2% compared with 18.5% for the three-drug combination plus tamoxifen (P = .09). Pending the outcome of further randomized controlled trials, no combination regimen has yet been proven to be superior to DTIC alone.

The two biologic therapies that appear most active against melanoma are interferon-alpha and interleukin-2 (IL-2). Response rates for interferon range from 8% to 22% and long-term administration on a daily or a three-times-per-week basis appears superior to once per week or more intermittent schedules.[8] Response to IL-2 regimens is similar and is in the 10% to 20% range.[9-11] Attempts to improve on this with the addition of lymphokine-activated killer cells (autologous lymphocytes activated by IL-2 ex vivo) and by tumor-infiltrating lymphocytes (lymphocytes derived from tumor isolates cultured in the presence of IL-2) have not improved response rates or durable remissions sufficiently to merit the expense and complexity of these therapies. Phase II studies testing combinations of interferon and IL-2 have demonstrated high response rates, but a phase III comparison of interferon and IL-2 compared with IL-2 alone in 85 patients did not show any benefit for the combination.[12]

Combinations of chemotherapy and biologics (chemoimmunotherapy or biochemotherapy) have been tested against chemotherapy alone. Four small phase III studies comparing DTIC and interferon with DTIC alone yielded conflicting results.[4] In a larger randomized trial involving 271 patients, 258 eligible patients received either DTIC alone; DTIC plus interferon; DTIC plus tamoxifen; or DTIC, interferon, and tamoxifen (2 × 2 factorial design).[13] No statistically significant differences were found in response rates, time-to-treatment failure, or survival among the different groups. Toxic side effects were increased in the groups that received interferon.[13][Level of evidence: 1iiA]

IL-2 has also been combined with cisplatin in several phase II trials [14-16] with encouraging response rates, but data supporting an improvement in survival are lacking. One prospective trial randomly assigned 102 patients to either chemotherapy (DTIC, cisplatin, and tamoxifen) alone or chemotherapy plus IL-2 and interferon-alpha-2b.[17] No statistically significant differences were found in objective response rate or OS between the treatment groups, and toxic side effects were increased in the group that received biochemotherapy.

A meta-analysis of 20 randomized trials (involving 3,273 patients) that compared single-agent DTIC to combination chemotherapy with or without immunotherapy found that the combination of DTIC and interferon-alpha produced a tumor response rate 53% greater (95% confidence interval, 1.10–2.13) than that seen with DTIC alone.[18] No difference in OS was found, however.

Two ongoing phase III trials (E-E3695 ³⁴ and SWOG-S0008 ²⁵) are comparing complex biochemotherapy regimens (interferon, IL-2, and chemotherapy) to chemotherapy alone. Pending the results of these and future trials, no proof exists that biochemotherapy is superior to chemotherapy.

For patients with recurrent melanoma presenting in the extremities as in-transit or satellite metastases, surgical resection remains standard treatment for limited-volume disease. For multiple in-transit and/or satellite lesions, hyperthermic isolated limb perfusion (ILP) with melphalan has been associated with overall tumor response rates of approximately 80% to 90%, with complete response rates ranging from 7% to 82%.[19,20] Small, single-institution studies have suggested that the addition of tumor necrosis factor-alpha (TNF-alpha) to melphalan-based ILP may further increase complete response rates (54%–90%).[20-24] A prospective, randomized multicenter study (ACSOG-Z0020 ²⁷) comparing hyperthermic ILP with melphalan alone to ILP with melphalan plus TNF demonstrated no statistically significant difference in 3-month complete response rates (25% melphalan vs. 26% melphalan plus TNF) or overall response (64% melphalan vs. 69% in melphalan plus TNF).[25][Level of evidence: 1iiDiv] Furthermore, ILP with melphalan plus TNF was associated with increased adverse events, including musculoskeletal complications of the perfused extremity resulting in two toxicity-related amputations.

Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that patients with multiple brain metastases, bone metastases, and spinal cord compression may achieve symptom relief and some shrinkage of the tumor with radiation therapy.[26,27] The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. A recently completed phase I and II clinical trial (MCC-11543 ²⁹) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma, and results are pending.

Treatment options:

1. Resection of isolated single or localized metastases from skin, visceral, or brain sites in selected patients is sometimes associated with prolonged survival.
2. Hyperthermic isolated limb perfusion for in-transit and/or satellite extremity recurrences.[25] Isolated limb infusion is being studied as a minimally invasive regional chemotherapy technique for extremity recurrences.[28,29]
3. Palliative radiation therapy for bone, spinal cord, or brain metastases.
4. Palliative biologic therapy and/or chemotherapy in phase I and II clinical trials.
5. Palliative treatment with interleukin-2 or interferon can occasionally result in prolonged survival.

(For more information on symptom relief, refer to the Pain ³⁷ summary.)

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent melanoma ³⁸. 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 ¹⁵.

References

1. Wong JH, Skinner KA, Kim KA, et al.: The role of surgery in the treatment of nonregionally recurrent melanoma. Surgery 113 (4): 389-94, 1993.  [PUBMED Abstract]
   
   
2. Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.  [PUBMED Abstract]
   
   
3. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999.  [PUBMED Abstract]
   
   
4. Anderson CM, Buzaid AC, Legha SS: Systemic treatments for advanced cutaneous melanoma. Oncology (Huntingt) 9 (11): 1149-58; discussion 1163-4, 1167-8, 1995.  [PUBMED Abstract]
   
   
5. Chapman PB, Einhorn LH, Meyers ML, et al.: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17 (9): 2745-51, 1999.  [PUBMED Abstract]
   
   
6. Mays SR, Nelson BR: Current therapy of cutaneous melanoma. Cutis 63 (5): 293-8, 1999.  [PUBMED Abstract]
   
   
7. Rusthoven JJ, Quirt IC, Iscoe NA, et al.: Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 14 (7): 2083-90, 1996.  [PUBMED Abstract]
   
   
8. Agarwala SS, Kirkwood JM: Interferons in melanoma. Curr Opin Oncol 8 (2): 167-74, 1996.  [PUBMED Abstract]
   
   
9. Atkins MB, Lotze MT, Dutcher JP, et al.: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17 (7): 2105-16, 1999.  [PUBMED Abstract]
   
   
10. Atkins MB, Kunkel L, Sznol M, et al.: High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6 (Suppl 1): S11-4, 2000.  [PUBMED Abstract]
    
    
11. Rosenberg SA, Yang JC, Topalian SL, et al.: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271 (12): 907-13, 1994 Mar 23-30.  [PUBMED Abstract]
    
    
12. Sparano JA, Fisher RI, Sunderland M, et al.: Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 11 (10): 1969-77, 1993.  [PUBMED Abstract]
    
    
13. Falkson G, Gelman RS, Pandya KJ, et al.: Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol 16 (5): 1669-76, 1998.  [PUBMED Abstract]
    
    
14. Demchak PA, Mier JW, Robert NJ, et al.: Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma: a pilot study. J Clin Oncol 9 (10): 1821-30, 1991.  [PUBMED Abstract]
    
    
15. Flaherty LE, Robinson W, Redman BG, et al.: A phase II study of dacarbazine and cisplatin in combination with outpatient administered interleukin-2 in metastatic malignant melanoma. Cancer 71 (11): 3520-5, 1993.  [PUBMED Abstract]
    
    
16. Atkins MB, O'Boyle KR, Sosman JA, et al.: Multiinstitutional phase II trial of intensive combination chemoimmunotherapy for metastatic melanoma. J Clin Oncol 12 (8): 1553-60, 1994.  [PUBMED Abstract]
    
    
17. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al.: Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 17 (3): 968-75, 1999.  [PUBMED Abstract]
    
    
18. Huncharek M, Caubet JF, McGarry R: Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials. Melanoma Res 11 (1): 75-81, 2001.  [PUBMED Abstract]
    
    
19. Skene AI, Bulman AS, Williams TR, et al.: Hyperthermic isolated perfusion with melphalan in the treatment of advanced malignant melanoma of the lower limb. Br J Surg 77 (7): 765-7, 1990.  [PUBMED Abstract]
    
    
20. Fraker DL, Alexander HR, Ross M, et al.: A phase III trial of isolated limb perfusion for extremity melanoma comparing melphalan alone versus melphalan plus tumor necrosis factor (TNF) plus interferon-gamma (IFN). [Abstract] Society of Surgical Oncology 55th Annual Cancer Symposium, Denver Co, 2002. A-1, S-8, 2002. 
    
    
21. Liénard D, Lejeune FJ, Ewalenko P: In transit metastases of malignant melanoma treated by high dose rTNF alpha in combination with interferon-gamma and melphalan in isolation perfusion. World J Surg 16 (2): 234-40, 1992 Mar-Apr.  [PUBMED Abstract]
    
    
22. Liénard D, Eggermont AM, Koops HS, et al.: Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study. Melanoma Res 9 (5): 491-502, 1999.  [PUBMED Abstract]
    
    
23. Fraker DL, Alexander HR, Andrich M, et al.: Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Oncol 14 (2): 479-89, 1996.  [PUBMED Abstract]
    
    
24. Vaglini M, Belli F, Ammatuna M, et al.: Treatment of primary or relapsing limb cancer by isolation perfusion with high-dose alpha-tumor necrosis factor, gamma-interferon, and melphalan. Cancer 73 (2): 483-92, 1994.  [PUBMED Abstract]
    
    
25. Cornett WR, McCall LM, Petersen RP, et al.: Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020. J Clin Oncol 24 (25): 4196-201, 2006.  [PUBMED Abstract]
    
    
26. Rate WR, Solin LJ, Turrisi AT: Palliative radiotherapy for metastatic malignant melanoma: brain metastases, bone metastases, and spinal cord compression. Int J Radiat Oncol Biol Phys 15 (4): 859-64, 1988.  [PUBMED Abstract]
    
    
27. Herbert SH, Solin LJ, Rate WR, et al.: The effect of palliative radiation therapy on epidural compression due to metastatic malignant melanoma. Cancer 67 (10): 2472-6, 1991.  [PUBMED Abstract]
    
    
28. Lindnér P, Doubrovsky A, Kam PC, et al.: Prognostic factors after isolated limb infusion with cytotoxic agents for melanoma. Ann Surg Oncol 9 (2): 127-36, 2002.  [PUBMED Abstract]
    
    
29. Brady MS, Brown K, Patel A, et al.: A phase II trial of isolated limb infusion with melphalan and dactinomycin for regional melanoma and soft tissue sarcoma of the extremity. Ann Surg Oncol 13 (8): 1123-9, 2006.  [PUBMED Abstract]
    
    

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Editorial changes were made to this summary.

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• PDQ® Cancer Information Summaries: Adult Treatment ⁴³

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Glossary Terms

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with cause-specific mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with tumor response rate as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.