General Information About Melanoma

Incidence and Mortality

Estimated new cases and deaths from melanoma in the United States in 2012:[1]

• New cases: 76,250.
• Deaths: 9,180.

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, it occurs most commonly 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.[3,4,5,6] 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.[3,4,5,6]

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 are, the higher the chance of lymph node or systemic metastases, and the worse the prognosis is. 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]

Related Summaries

Other PDQ summaries containing information related to melanoma include the following:

• Skin Cancer Prevention
• Skin Cancer Screening
• Skin Cancer Treatment

References:

1.	American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online. Last accessed September 24, 2012.
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.
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.
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.
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.
6.	Slingluff CI Jr, Flaherty K, Rosenberg SA, et al.: Cutaneous melanoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1643-91.
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.
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.
9.	Tsao H, Cosimi AB, Sober AJ: Ultra-late recurrence (15 years or longer) of cutaneous melanoma. Cancer 79 (12): 2361-70, 1997.

Cellular and Molecular Classification of Melanoma

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.

Molecular characterization of melanoma is an active area of research. Activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) gene, first reported in 2002, are the most frequent mutation in cutaneous melanoma. Approximately 40% to 60% of malignant melanomas harbor a single nucleotide transversion. The majority have a mutation that results in a substitution from valine to glutamic acid at position 600 (BRAF V600E); less frequent mutations include valine 600 to lysine or arginine residues (V600K/R).[1] Drugs that target this mutation by inhibiting BRAF are under evaluation in clinical trials. One such drug, vemurafenib, was approved by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of unresectable or metastatic melanoma in patients who test positive for the BRAF mutation as detected by an FDA-approved test (e.g., cobas® 4800 BRAF V600 Mutation Test).

In smaller subsets of cutaneous melanoma, other activating mutations have been described, including NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], c-KIT, and CDK4 (cyclin-dependent kinase 4).

• Approximately 15% to 20% of melanomas harbor an oncogenic NRAS mutation.[2,3]
• A c-KIT mutation, or increased copy number, is associated with mucosal and acral melanomas (which comprise 6% to 7% of melanomas in Caucasians but are the most common subtype in the Asian population).[4,5]
• CDK4 mutations have been described in approximately 4% of melanomas and are also more common in acral and mucosal melanomas.[6,7]

Drugs developed to target these mutations are currently in clinical trials. Additional oncogenes and tumor-suppressor gene candidates currently under evaluation include P13K, AKT, P53, PTEN, mTOR, Bcl-2, MITF.

Uveal melanomas differ significantly from cutaneous melanomas; in one series, 83% of 186 uveal melanomas were found to have a constitutively active somatic mutation in GNAQ or GNA11.[8,9]

References:

1.	Pollock PM, Meltzer PS: A genome-based strategy uncovers frequent BRAF mutations in melanoma. Cancer Cell 2 (1): 5-7, 2002.
2.	Edlundh-Rose E, Egyházi S, Omholt K, et al.: NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res 16 (6): 471-8, 2006.
3.	Goel VK, Lazar AJ, Warneke CL, et al.: Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol 126 (1): 154-60, 2006.
4.	Hodi FS, Friedlander P, Corless CL, et al.: Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (12): 2046-51, 2008.
5.	Guo J, Si L, Kong Y, et al.: Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29 (21): 2904-9, 2011.
6.	Curtin JA, Fridlyand J, Kageshita T, et al.: Distinct sets of genetic alterations in melanoma. N Engl J Med 353 (20): 2135-47, 2005.
7.	Stark M, Hayward N: Genome-wide loss of heterozygosity and copy number analysis in melanoma using high-density single-nucleotide polymorphism arrays. Cancer Res 67 (6): 2632-42, 2007.
8.	Van Raamsdonk CD, Bezrookove V, Green G, et al.: Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457 (7229): 599-602, 2009.
9.	Van Raamsdonk CD, Griewank KG, Crosby MB, et al.: Mutations in GNA11 in uveal melanoma. N Engl J Med 363 (23): 2191-9, 2010.

Stage Information for Melanoma

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.

Clark Classification (Level of Invasion)

• 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.

Definitions of TNM

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

Table 1. 1. Primary Tumor (T)^a

a Reprinted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.
TX	Primary tumor cannot be assessed (e.g., curettaged or severely regressed melanoma).
T0	No evidence of primary tumor.
Tis	Melanomain situ.
T1	Melanomas ≤1.0 mm in thickness.
T2	Melanomas 1.01–2.0 mm.
T3	Melanomas 2.01–4.0 mm.
T4	Melanomas >4.0 mm.
Note: a and b subcategories of T are assigned based on ulceration and number of mitoses per mm2 as shown below:
T classification	Thickness (mm)	Ulceration Status/Mitoses
T1	≤1.0	a: w/o ulceration and mitosis <1/mm2.
		b: with ulceration or mitoses ≥1/mm2.
T2	1.01–2.0	a: w/o ulceration.
		b: with ulceration.
T3	2.01–4.0	a: w/o ulceration.
		b: with ulceration.
T4	>4.0	a: w/o ulceration.
		b: with ulceration.

Table 2. 2. Regional Lymph Nodes (N)^a

No = number.
a Reprinted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.
b Micrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if performed).
c Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.
NX	Patients in whom the regional nodes cannot be assessed (e.g., previously removed for another reason).
N0	No regional metastases detected.
N1–3	Regional metastases based upon the number of metastatic nodes and presence or absence of intralymphatic metastases (in transit or satellite metastases).
Note: N1–3 and a–c subcategories assigned as shown below:
N Classification	No. of Metastatic Nodes	Nodal Metastatic Mass
N1	1	a: micrometastasis.b
		b: macrometastasis.c
N2	2–3	a: micrometastasis.b
		b: macrometastasis.c
		c: in transit met(s)/satellites(s)without metastatic nodes.
N3	≥4 metastatic nodes, or matted nodes, or in transit met(s)/satellite(s)with metastatic node(s).

Table 3. 3. Distant Metastasis (M)^a

LDH = lactate dehydrogenase.
a Reprinted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.
M0	No detectable evidence of distant metastases.
M1a	Metastases to skin, subcutaneous, or distant lymph nodes.
M1b	Metastases to lung.
M1c	Metastases to all other visceral sites or distant metastases to any site combined with an elevated serum LDH.
Note: Serum LDH is incorporated into the M category as shown below:
M Classification	Site	Serum LDH
M1a	Distant skin, subcutaneous, or nodal mets.	Normal.
M1b	Lung metastases.	Normal.
M1c	All other visceral metastases.	Normal.
	Any distant metastasis.	Elevated.

Table 4. 4. Anatomic Stage/Prognostic Groups^a

Stage	T	N	M	Stage	T	N	M
Clinical Stagingb	Pathologic Stagingc
a Reprinted with permission from AJCC: Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.
b Clinical staging includes microstaging of the primary melanoma and clinical and/or radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.
c Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic Stage 0 or Stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes.
0	Tis	N0	M0	0	Tis	N0	M0
IA	T1a	N0	M0	IA	T1a	N0	M0
IB	T1b	N0	M0	IB	T1b	N0	M0
	T2a	N0	M0		T2a	N0	M0
IIA	T2b	N0	M0	IIA	T2b	N0	M0
	T3a	N0	M0		T3a	N0	M0
IIB	T3b	N0	M0	IIB	T3b	N0	M0
	T4a	N0	M0		T4a	N0	M0
IIC	T4b	N0	M0	IIC	T4b	N0	M0
III	Any T	≥N1	M0	IIIA	T1–4a	N1a	M0
					T1–4a	N2a	M0
	IIIB	T1–4b	N1a	M0
		T1–4b	N2a	M0
		T1–4a	N1b	M0
		T1–4a	N2b	M0
		T1–4a	N2c	M0
	IIIC	T1–4b	N1b	M0
		T1–4b	N2b	M0
		T1–4b	N2c	M0
		Any T	N3	M0
IV	Any T	Any N	M1	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.
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.
3.	Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.

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.

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.[3,4,5,6] A completed, multicenter, phase III randomized trial (SWOG-8593) 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 (DFS) or overall survival (OS) when compared to surgery alone.[7] Systemic treatment with high dose and pegylated interferon alpha-2b are approved for the adjuvant treatment of patients who have undergone a complete surgical resection but are considered to be at high risk for relapse. Prospective randomized controlled trials with both agents have shown an increase in relapse-free survival (RFS) but not OS when compared to observation.[8] Clinicians should be aware that high-dose and pegylated 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 RFS or OS.[9]

Although melanoma that has spread to distant sites is rarely curable, both ipilimumab and vemurafenib have demonstrated an improvement in progression-free survival (PFS) and OS in international, multicenter, randomized trials in patients with unresectable or advanced disease, resulting in U.S. Food and Drug Administration (FDA) approval in 2011. Vemurafenib is a selective BRAF V600E kinase inhibitor, and its indication is limited to patients with a demonstrated BRAF V600E mutation by an FDA-approved test.

Interleukin-2 (IL-2) was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (0% –8%) with previously treated metastatic melanoma in eight phase I and II studies. No improvement in OS has been demonstrated in randomized trials.

Dacarbazine (DTIC) was approved in 1970 based on overall response rates. Phase III trials indicate an overall response rate of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[10,11,12,13,14] Temozolomide, an oral alkylating agent, appeared to be similar to DTIC (intravenous administration) in a randomized phase III trial with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.[11]

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.

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.
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.
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.
4.	Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998.
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.
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.
7.	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.
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.
9.	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.
10.	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.
11.	Middleton MR, Grob JJ, Aaronson N, et al.: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18 (1): 158-66, 2000.
12.	Avril MF, Aamdal S, Grob JJ, et al.: Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22 (6): 1118-25, 2004.
13.	Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011.
14.	Robert C, Thomas L, Bondarenko I, et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364 (26): 2517-26, 2011.

Stage 0 Melanoma

Stage 0 melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

• Tis, N0, M0

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

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 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.	Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.

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 for more information.)

Stage I melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

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

Standard Treatment Options for Patients With Stage I Melanoma

• 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.[2,3] No difference was observed between the two groups in respect to the development of metastatic disease, disease-free survival (DFS), or overall survival (OS). Two other randomized trials 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.[4,5,6][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 (46% to 11%, P < .001) and a reduction in the length of the hospital stay.[6] 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 (SNL) 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.[7,8,9,10]

  The International Multicenter Selective Lymphadenectomy Trial (MSLT-1 [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm–3.5 mm in this study) primary melanomas.[11] There was no melanoma-specific survival advantage (the primary endpoint) for those patients randomly assigned to wide excision plus SLN biopsy followed by immediate complete 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.[11][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.[11]

Treatment Options Under Clinical Evaluation for Patients With Stage I Melanoma

• 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 SLN metastasis to identify those patients who may benefit from regional lymphadenectomy with or without adjuvant therapy. One of the objectives of the phase III Sunbelt Melanoma Trial (UAB-9735) was to determine the effects of lymphadenectomy with or without adjuvant high-dose interferon-alpha-2b versus observation on DFS and OS in patients with submicroscopic SLN metastasis detected only by the polymerase chain reaction (PCR) (i.e., SLN negative by histology and immunohistochemistry). No survival data have been reported from this study. An ongoing diagnostic study (UCCRC-9308) tested the combination of reverse transcription and PCR in the detection of melanoma tumor antigen transcripts in lymph nodes and peripheral blood samples.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I 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.	Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.
2.	Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991.
3.	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.
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.
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.
6.	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.
7.	Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998.
8.	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.
9.	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.
10.	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.
11.	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.

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 for more information.)

Stage II melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

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

Standard Treatment Options for Patients With Stage II Melanoma

• 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 compared 2-cm margins versus 4-cm margins for patients with 1-mm thick melanomas 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 (46% to11%; P < .001) and a reduction in the length of the hospital stay.[2] 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 in thickness to excision with either 1 cm margins or 3 cm margins.[3] 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 that are more than 2 mm in thickness. 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 (LNDs) 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.[4,5,6,7]

  Lymphatic mapping and sentinel lymph node (SLN) biopsy have been used to assess the presence of occult metastasis in the regional lymph nodes of patients with stage II disease, which potentially identifies individuals who may be spared the morbidity of regional LND and individuals who may benefit from adjuvant therapy.[8,9,10,11,12] The diagnostic accuracy of SLN biopsy has been demonstrated in several studies with a false-negative rate of 0% to 2%.[8,13,14,15,16,17] 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 SLN, lymphatic mapping and removal of the SLN 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.[7] Because this finding arose from a post hoc subset analysis of data from a randomized trial, it should be viewed with caution.

  The International Multicenter Selective Lymphadenectomy Trial (MSLT-1 [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm–3.5 mm in this study) primary melanomas.[18] There was no melanoma-specific survival advantage (the primary endpoint) for those patients randomly assigned to wide excision plus SLN biopsy followed by immediate complete 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.[18][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.[18]

Adjuvant Treatment Options for Patients With Stage II Melanoma

• Adjuvant treatment after resection (e.g., with interferons) has not been shown to impact survival.

Treatment Options Under Clinical Evaluation for Patients With Stage II Melanoma

• Clinical trials testing adjuvant treatment following surgery.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.	Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.
2.	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.
3.	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.
4.	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.
5.	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.
6.	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.
7.	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.
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.
9.	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.
10.	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.
11.	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.
12.	Chan AD, Morton DL: Sentinel node detection in malignant melanoma. Recent Results Cancer Res 157: 161-77, 2000.
13.	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.
14.	Reintgen D, Cruse CW, Wells K, et al.: The orderly progression of melanoma nodal metastases. Ann Surg 220 (6): 759-67, 1994.
15.	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.
16.	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.
17.	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.
18.	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.

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 for more information.)

Stage III melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

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

Standard Treatment Options for Patients With Stage III Melanoma

1.	Wide local excision of the primary tumor with 1 cm to 3 cm margins, depending on tumor thickness and location.[2,3,4,5,6,7,8] Skin grafting may be necessary to close the resulting defect.
2.	High-dose or pegylated interferon alpha-2b as adjuvant treatment for patients who have undergone a complete surgical resection but are considered to be at high risk for relapse.
3.	Ipilimumab for patients with unresectable disease.
4.	Vemurafenib for patients with unresectable disease who test positive for the BRAF V600 mutation in a U.S. Food and Drug Administration-approved test.

Adjuvant Treatment Options for Patients With Resected Stage III Disease

1.

High-dose interferon. High-dose interferon alpha-2b was approved in 1995 for the adjuvant treatment of patients with melanoma who have undergone a complete surgical resection but who are considered to be at a high risk of relapse. Evidence was based on a significantly improved relapse-free survival (RFS) and marginally improved overall survival (OS) that were seen in the completed EST-1684 trial. Subsequent large, randomized trials have not been able to reproduce a benefit in OS. A multicenter, randomized, controlled study, (EST-1684), 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.[9] 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 RFS (P = .002) and 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.[9][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 RFS 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) conducted by the same investigators compared the same high-dose regimen of interferon alpha-2b to either a low-dose regimen (3 mU/m2 of body surface per day given subcutaneously 3 times a week every week for 104 weeks) or observation.[10] The stage entry criteria for this trial were the same as for the initial study. This three-arm trial entered 642 patients. At a median follow-up of 52 months, a statistically significant RFS 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 RFS advantage was seen for low-dose interferon when compared with the observation group. The 5-year estimated RFS rates for the high-dose interferon, low-dose interferon, and observation groups were 44%, 40%, and 35%, respectively. Neither high-dose interferon nor low-dose interferon yielded an OS benefit when compared with observation (hazard ratio [HR], 1.0; P = .995).[10][Level of evidence: 1iiA] Pooled analyses of the two high-dose arms versus the two observation arms from both studies (EST-1684 and EST-1690) suggest that treatment confers a significant RFS advantage but not a significant benefit for survival.[10][Level of evidence: 1iiA] E-1697, a randomized, multicenter, national trial evaluated high-dose intravenous interferon for a short duration (1 month) versus observation in patients with node-negative melanoma at least 2 mm in thickness or with any thickness and positive sentinel nodes. This trial was closed at interim analysis because of the lack of benefit from treatment with interferon. Clinicians should be aware that the high-dose regimens have significant toxic effects.

2.

Pegylated Interferon. Pegylated interferon alpha-2b, which is characterized by a longer half-life and can be administered subcutaneously, was approved by the FDA in 2011 for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of complete surgical resection, including complete lymphadenectomy. Approval was based on EORTC-18991, which randomly assigned 1,256 patients with resected stage III melanoma to observation or weekly subcutaneous pegylated interferon alpha-2b for up to 5 years. RFS, as determined by an Independent Review Committee, was improved for patients receiving interferon (34.8 months vs. 25.5 months in the observation arm; HR, 0.82; 95% confidence interval [CI], 0.71–0.96; P = .011). No difference in median OS between the arms was observed (HR, 0.98; 95% CI, 0.82–1.16).[11][Level of evidence: 1iiDii] One-third of the patients receiving pegylated interferon discontinued treatment because of toxicity.

Treatment Options for Patients With Unresectable Stage III Disease

1.	Ipilimumab. (Refer to the Standard Treatment Options for Patients with Stage IV and Recurrent Melanoma section of this summary for more information.)
2.	Vemurafenib for patients who test positive for the BRAF V600 mutation by an FDA-approved test. (Refer to the Standard Treatment Options for Patients with Stage IV and Recurrent Melanoma section of this summary for more information.)
3.	Local therapy for extremity melanoma. 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.[4] No impact on OS has been convincingly demonstrated in randomized controlled studies.[12,13]

Treatment Options Under Clinical Evaluation for Patients With Stage III Melanoma

• Clinical trials exploring the following:
  • Adjuvant therapy after local control of the tumor in high-risk tumors.
  • Intralesional therapies for local control of lesions.
  • Isolated limb perfusion for unresectable extremity melanoma.
  • Systemic therapy for unresectable disease.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III 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.	Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.
2.	Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991.
3.	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.
4.	Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.
5.	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.
6.	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.
7.	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.
8.	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.
9.	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.
10.	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.
11.	Eggermont AM, Suciu S, Santinami M, et al.: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 372 (9633): 117-26, 2008.
12.	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.
13.	Lens MB, Dawes M: Isolated limb perfusion with melphalan in the treatment of malignant melanoma of the extremities: a systematic review of randomised controlled trials. Lancet Oncol 4 (6): 359-64, 2003.

Stage IV and 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 for more information.)

Stage IV melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

• Any T, any N, M1

Standard Treatment Options for Patients With Stage IV and Recurrent Melanoma

1.	Immunotherapy. Ipilimumab. Interleukin-2 (IL-2).
2.	Signal transduction inhibitors. Vemurafenib (for patients who test positive for the BRAF V600 mutation).
3.	Chemotherapy.
4.	Palliative local therapy.

Treatment Option Overview for Patients With Stage IV and Recurrent Melanoma

Although melanoma that has spread to distant sites is rarely curable, both ipilimumab and vemurafenib have demonstrated an improvement in progression-free survival (PFS) and overall (OS) in international, multicenter, randomized trials in patients with unresectable or advanced disease, resulting in U.S. Food and Drug Administration (FDA) approval in 2011. Ipilimumab is an antibody against the cytotoxic T-lymphocyte antigen (anti-CTLA-4). Vemurafenib is a selective BRAF V600E kinase inhibitor, and its indication is limited to patients with unresectable or metastatic melanoma with a demonstrated BRAF V600E mutation.

Interleukin-2 (IL-2) was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (0%–8%) with previously treated metastatic melanoma in eight phase I and II studies. No improvement in OS has been demonstrated in randomized trials.

Dacarbazine (DTIC) was approved in 1970 based on overall response rates. Phase III trials indicate an overall response rate of 10% to 20% with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[2,3,4,5,6] Temozolomide, an oral alkylating agent, appeared to be similar to DTIC (intravenous administration) in a randomized phase with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.[3]

Attempts over the past two decades to develop combination regimens, for example, multiagent chemotherapy;[7,8] combinations of chemotherapy and tamoxifen;[9,10,11] and combinations of chemotherapy and immunotherapy;[7,12,13,14,15,16,17] have not demonstrated an improvement of the combination on OS. However, advances in understanding of key molecular pathways are enabling rational development of combination therapy.

In smaller subsets of melanoma, activating mutations may occur in NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog] (15%–20%), c-KIT (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), and CDK4 (cyclin-dependent kinase 4) (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target these mutations are currently in clinical trials.

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

Immunotherapy

Ipilimumab

Ipilimumab is a human monoclonal antibody that blocks the activity of cytotoxic T-lymphocyte antigen 4 (CTLA-4), blocking the function of CTLA-4 as a down regulator of T-cell activation. It is approved for the treatment of unresectable or metastatic melanoma and supported by two prospective, randomized, international trials, one each in previously untreated and treated patients.[6,19]

Previously treated patients. A total of 676 patients with previously treated, unresectable stage III or stage IV disease, who were HLA-A*0201-positive patients, were entered into a three-arm, multinational, randomized, double-blind trial comparing ipilimumab with or without glycoprotein 100 (gp100) peptide vaccine to the gp100 vaccine plus placebo.[19] Patients were stratified by baseline metastases and prior receipt or nonreceipt of IL-2 therapy. Of the patients, 82 had metastases to the brain at baseline. The median OS was 10 months and 10.1 months among patients receiving ipilimumab alone or with the gp100 vaccine, respectively, versus 6.4 months for patients receiving the vaccine alone (hazard ratio [HR], 0.68; P < .001; HR, 0.66; P <.003).

An analysis at 1 year showed that among those patients treated with ipilimumab, 44% and 45% of them were alive compared to 25% of the patients who received vaccine only. Grade 3 to grade 4 immune-related adverse events occurred in 10% to 15% of patients treated with ipilimumab. These immune-related, adverse events (AEs) most often included diarrhea or colitis, and endocrine-related events (i.e., inflammation of the pituitary) and required cessation of therapy and institution of anti-inflammatory agents such as corticosteroids or in four cases, infliximab (i.e., an anti-tumor necrosis factor-alpha antibody). There were 14 deaths related to study drugs (2.1%), and seven were associated with immune-related AEs.[19][Level of evidence: 1iA]

Previously untreated patients. A multicenter, international trial randomly assigned 502 patients untreated for metastatic disease (adjuvant treatment was allowed) in a 1:1 ratio to ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m²) or placebo plus dacarbazine (850 mg/m²) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22.[6] Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary endpoint was survival.

Patients were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic stage. Approximately 70% of the patients had an ECOG PS of 0, and the remainder of the patients had an ECOG PS of 1. Approximately 55% of patients had stage M1c disease. The median OS was 11.2 months (95% confidence interval [CI], 9.4–13.6) versus 9.1 months (95% CI, 7.8–10.5). Estimated survival rates in the two groups respectively were 47.3% and 36.3% at 1 year; 28.5% and 17.9% at 2 years; and 20.9% and 12.2% at 3 years (HR for death with ipilimumab-dacarbazine, 0.72; P < .001). The most common study-drug-related AEs were those classified as immune related. Grade 3 to 4, immune-related AEs were seen in 38.1% of patients treated with ipilimumab plus dacarbazine versus 4.4% in patients treated with placebo plus dacarbazine, the most common being hepatitis and enterocolitis. No drug-related deaths occurred.[6][Level of evidence: 1iA]

Clinicians and patients should be aware that immune-mediated adverse reactions may be severe and fatal. Early identification and treatment, including potential administration of systemic glucocorticoids or other immunosuppressants according to the immune-mediated– adverse reaction management guide provided by the manufacturer, is necessary.[20]

IL-2

Response to high-dose IL-2 regimens generally ranges from 10% to 20%.[12,13,21] Approximately 4% to 6% of patients may obtain a durable complete remission and be long-term survivors, the basis for approval by the FDA in 1998. However, phase III confirmatory trials have not been conducted, and there are currently no predictive biomarkers to select who is likely to respond to treatment.

Attempts to improve on this therapy have included the addition of lymphokine-activated killer cells (i.e., autologous lymphocytes activated by IL-2 ex vivo) and tumor-infiltrating lymphocytes (TIL) (i.e., lymphocytes derived from tumor isolates cultured in the presence of IL-2). A single-institution trial reports that adoptive cell therapy (ACT) with lymphodepletion (using cyclophosphamide plus fludarabine with or without total-body irradiation) followed by autologous TIL transfer and high-dose IL-2 may improve durable response.[22][Level of evidence: 3iiiDiv] A multicenter, randomized trial of high-dose IL-2 with and without a peptide vaccine [gp100:209–217(210M)] in patients with locally advanced stage III or stage IV melanoma who were HLA*A0201-positive reported an increase in response rate with the combination.[23][Level of evidence:1iiDiv] Multicenter, phase III trials powered for an assessment on OS are needed for validation, since response rates are not known to be a surrogate for OS in melanoma.

Signal transduction inhibitors

BRAF inhibitors

Vemurafenib

Vemurafenib is an orally available, selective BRAF (V-raf murine sarcoma viral oncogene homolog B1) inhibitor that is approved by the FDA for patients with unresectable or metastatic melanoma that tests positive for the BRAF V600E mutation. Treatment with vemurafenib is discouraged in wild-type BRAF melanoma because data from preclinical models has demonstrated that BRAF inhibitors can enhance rather than downregulate the MAPK (mitogen-activated protein kinase) pathway in tumor cells with wild-type BRAF and upstream RAS mutations.[24,25,26,27]

Previously untreated patients. The approval of vemurafenib was supported by an international, multicenter trial that screened 2,107 patients with previously untreated, stage IIIC or IV melanoma for the BRAF V600 mutation and identified 675 patients by the cobas® 4800 BRAF V600 Mutation Test.[5] Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m² IV every 3 weeks). Coprimary endpoints were rates of OS and progression-free survival (PFS).[5][Levels of evidence: 1iiA and 1iiDiii]

At the planned interim analysis, the Data and Safety Monitoring Board determined that both the OS and PFS endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib. A total of 675 patients were evaluated for OS; although the median survival had not yet been reached for vemurafenib and the data were immature for reliable Kaplan-Meier estimates of survival curves, the OS in the vemurafenib arm was clearly superior to that in the dacarbazine arm. The HR for death in the vemurafenib group was 0.37 (95% CI, 0.26–0.55; P<.001). The survival benefit in the vemurafenib group was observed in each prespecified subgroup, for example, age, sex, ECOG PS, tumor-stage lactic dehydrogenase, and geographic region. The HR for tumor progression in the vemurafenib arm was 0.26 (95% CI, 0.20–0.33; P<.001). The estimated median PFS was 5.3 months versus 1.6 months in the vemurafenib and dacarbazine arms, respectively.

Twenty patients had non-V600E mutations: 19 with V600K and 1 with V600D. Four patients with a BRAF V600K mutation had a response to vemurafenib.

AEs required dose modification or interruption in 38% of patients receiving vemurafenib and 16% of those receiving dacarbazine. The most common AEs with vemurafenib were cutaneous events, arthralgia, and fatigue. Cutaneous squamous cell carcinoma, keratoacanthoma, or both, developed in 18% of patients and were treated by simple excision. The most common AEs with dacarbazine were fatigue, nausea, vomiting, and neutropenia.

Previously treated patients. A total of 132 patients with a BRAF V600E or BRAF V600K mutation were enrolled in a multicenter phase II trial of vemurafenib, which was administered as 960 mg orally twice daily.[28] Of the enrolled patients, 61% percent had stage M1c disease, and 49% had an elevated lactate dehydrogenase level. All patients had received one or more prior therapies for advanced disease. Median follow-up was 12.9 months. An Independent Review Committee (IRC) reported a 53% response rate (95% CI, 44–62) with eight patients (6%) achieving CR. Median duration of response per IRC assessment was 6.7 months (95% CI, 5.6–8.6). Most responses were evident at the first radiologic assessment at 6 weeks; however, some patients did not respond until more than 6 months on therapy.[28][Level of evidence: 3iiiDiv]

Sorafenib

The multikinase inhibitor sorafenib has activity against both the vascular endothelial growth-factor signaling and the Raf/MEK (mitogen-activated ERK-activating kinase/ERK (extracellular signal-regulated kinase) pathway at the level of RAF kinase. This agent had minimal activity as a single agent in melanoma and two large, multicenter, placebo-controlled, randomized trials of carboplatin and taxol plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[29,30]

Chemotherapy

The objective response rate to DTIC and the nitrosoureas, carmustine (BCNU) and lomustine, is approximately 10% to 20%.[2,31,32,33] 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.[31,33] A randomized trial of DTIC versus temozolomide showed an OS of 6.4 months versus 7.7 months, respectively (HR, 1.18; 95% CI, 0.92–1.52). These data suggested similarity to DTIC; however, no benefit in survival has been demonstrated for either DTIC or temozolomide; therefore, temozolomide did not receive approval from the FDA.[3][Level of evidence: 1iiA] Other agents with modest single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[31,32,34]

Palliative local therapy

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.[15,16,17]

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.[35,36] (Refer to the PDQ summary on Pain for more information.) 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 phase I and II clinical trial (MCC-11543) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma and results are pending.

Biochemotherapy

A published data meta-analysis of 18 randomized trials (15 of which had survival information) comparing chemotherapy with biochemotherapy (i.e., the same chemotherapy plus interferon alone or with IL-2) demonstrates no impact on OS.[37][Level of evidence:1iiA]

Treatment Options Under Clinical Evaluation for Patients With Stage IV and Recurrent Melanoma

Despite the recent approved therapies that impact OS, the vast majority of patients are not cured. Therefore, clinical trials remain a compelling option for treatment.

1.	Immunotherapy.
2.	Signal transduction inhibitors for patients with mutations, including BRAF, MEK, AKT, and PI3 kinase inhibitors.
3.	KIT inhibitors. Early data suggest that mucosal or acral melanomas that have activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[38,39] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.
4.	Antiangiogenesis agents.
5.	Palliative radiation therapy for bone, spinal cord, or brain metastases.
6.	Intralesional injections, for example, oncologic viruses.
7.	Complete surgical resection of all known disease versus best medical therapy (NCT01013623).

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV melanoma and recurrent 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.	Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44.
2.	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.
3.	Middleton MR, Grob JJ, Aaronson N, et al.: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18 (1): 158-66, 2000.
4.	Avril MF, Aamdal S, Grob JJ, et al.: Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22 (6): 1118-25, 2004.
5.	Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011.
6.	Robert C, Thomas L, Bondarenko I, et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364 (26): 2517-26, 2011.
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.
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.
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.
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.
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.
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.
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.
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.
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.
16.	Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999.
17.	Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001.
18.	Wang TS, Lowe L, Smith JW 2nd, et al.: Complete spontaneous regression of pulmonary metastatic melanoma. Dermatol Surg 24 (8): 915-9, 1998.
19.	Hodi FS, O'Day SJ, McDermott DF, et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363 (8): 711-23, 2010.
20.	Yervoy (Ipilimumab): Serious and Fatal Immune-Mediated Adverse Reactions [Medication Guide]. Princeton, NJ: Bristol-Myers Squibb, 2011. Available online. Last accessed January 23, 2012.
21.	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.
22.	Dudley ME, Yang JC, Sherry R, et al.: Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26 (32): 5233-9, 2008.
23.	Schwartzentruber DJ, Lawson DH, Richards JM, et al.: gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 364 (22): 2119-27, 2011.
24.	Heidorn SJ, Milagre C, Whittaker S, et al.: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140 (2): 209-21, 2010.
25.	Hatzivassiliou G, Song K, Yen I, et al.: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464 (7287): 431-5, 2010.
26.	Poulikakos PI, Zhang C, Bollag G, et al.: RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464 (7287): 427-30, 2010.
27.	Su F, Viros A, Milagre C, et al.: RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366 (3): 207-15, 2012.
28.	Sosman JA, Kim KB, Schuchter L, et al.: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366 (8): 707-14, 2012.
29.	Hauschild A, Agarwala SS, Trefzer U, et al.: Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 27 (17): 2823-30, 2009.
30.	Flaherty KT, Lee SJ, Schuchter LM, et al.: Final results of E2603: A double-blind, randomized phase III trial comparing carboplatin ©/paclitaxel (P) with or without sorafenib (S) in metastatic melanoma. [Abstract] J Clin Oncol 28 (Suppl 15): A-8511, 2010.
31.	Anderson CM, Buzaid AC, Legha SS: Systemic treatments for advanced cutaneous melanoma. Oncology (Huntingt) 9 (11): 1149-58; discussion 1163-4, 1167-8, 1995.
32.	Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.
33.	Mays SR, Nelson BR: Current therapy of cutaneous melanoma. Cutis 63 (5): 293-8, 1999.
34.	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.
35.	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.
36.	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.
37.	Ives NJ, Stowe RL, Lorigan P, et al.: Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin Oncol 25 (34): 5426-34, 2007.
38.	Hodi FS, Friedlander P, Corless CL, et al.: Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (12): 2046-51, 2008.
39.	Guo J, Si L, Kong Y, et al.: Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29 (21): 2904-9, 2011.

Changes to This Summary (10 / 26 / 2012)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Stage IV and Recurrent Melanoma

Added text to state that treatment with vemurafenib is discouraged in wild-type BRAF melanoma because data from preclinical models has demonstrated that BRAF inhibitors can enhance rather than downregulate the MAPK (mitogen-activated protein kinase) pathway in tumor cells with wild-type BRAF and upstream RAS mutations (cited Heidorn et al., Hatzivassiliou et al., Poulikakos et al., and Su et al. as references 24, 25, 26, and 27, respectively).

Added text to include levels of evidence 1iiA and 1iiDiii.

Added text about the results of a multicenter phase II trial of vemurafenib in which 132 patients with a BRAF V600E or BRAF V600K mutation were enrolled (cited Sosman et al. as reference 28 and level of evidence 3iiiDiv).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of melanoma. It 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.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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• be cited with text, or
• replace or update an existing article that is already cited.

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The lead reviewers for Melanoma Treatment are:

• Russell S. Berman, MD (New York University School of Medicine)
• Alison Martin, MD (Martin and Associates Consulting)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

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National Cancer Institute: PDQ® Melanoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2012-10-26