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NCI/PDQ^® Health professionals: Melanoma Treatment (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 26 de octubre del 2012

TABLE OF CONTENTS

• General Information About Melanoma
  • Incidence and Mortality
  • Related Summaries

• Cellular and Molecular Classification of Melanoma

• Stage Information for Melanoma
  • Clark Classification (Level of Invasion)
  • Definitions of TNM

• Treatment Option Overview

• Stage 0 Melanoma
  • Current Clinical Trials

• Stage I Melanoma
  • Standard Treatment Options for Patients With Stage I Melanoma
  • Treatment Options Under Clinical Evaluation for Patients With Stage I Melanoma
  • Current Clinical Trials

• Stage II Melanoma
  • Standard Treatment Options for Patients With Stage II Melanoma
  • Adjuvant Treatment Options for Patients With Stage II Melanoma
  • Treatment Options Under Clinical Evaluation for Patients With Stage II Melanoma
  • Current Clinical Trials

• Stage III Melanoma
  • Standard Treatment Options for Patients With Stage III Melanoma
  • Adjuvant Treatment Options for Patients With Resected Stage III Disease
  • Treatment Options for Patients With Unresectable Stage III Disease
  • Treatment Options Under Clinical Evaluation for Patients With Stage III Melanoma
  • Current Clinical Trials

• Stage IV and Recurrent Melanoma
  • Standard Treatment Options for Patients With Stage IV and Recurrent Melanoma
    • Treatment Option Overview for Patients With Stage IV and Recurrent Melanoma
    • Immunotherapy
      • Ipilimumab
        • IL-2
    • Signal transduction inhibitors
      • BRAF inhibitors
        • Vemurafenib
      • Sorafenib
  • Chemotherapy
  • Palliative local therapy
  • Biochemotherapy

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

• Current Clinical Trials

• Changes to This Summary (10/26/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information About Melanoma

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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 [PUBMED Abstract]
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. 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. [PUBMED Abstract]
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 and Molecular Classification of Melanoma

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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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]

Stage Information for Melanoma

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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

^aReprinted 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	Melanoma in situ.
T1	Melanomas 1.0 mm in thickness.
T2	Melanomas 1.012.0 mm.
T3	Melanomas 2.014.0 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	1.012.0	a: w/o ulceration.
		b: with ulceration.
T3	2.014.0	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

^aReprinted 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.^bMicrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if performed).^cMacrometastases 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.
N13	Regional metastases based upon the number of metastatic nodes and presence or absence of intralymphatic metastases (in transit or satellite metastases).
Note: N13 and ac subcategories assigned as shown below:
N Classification	No. of Metastatic Nodes	Nodal Metastatic Mass
N1	1	a: micrometastasis.b
		b: macrometastasis.c
N2	23	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).
No = number.

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

^aReprinted 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.
LDH = lactate dehydrogenase.

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

^aReprinted 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.^bClinical 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.^cPathologic 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.

Stage	T	N	M	Stage	T	N	M
Clinical Stagingb				Pathologic Stagingc
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	T14a	N1a	M0
					T14a	N2a	M0
				IIIB	T14b	N1a	M0
					T14b	N2a	M0
					T14a	N1b	M0
					T14a	N2b	M0
					T14a	N2c	M0
				IIIC	T14b	N1b	M0
					T14b	N2b	M0
					T14b	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. [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: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44. [PUBMED Abstract]

Treatment Option Overview

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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 III; 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. [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. 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]
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. 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]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]

Stage 0 Melanoma

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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. [PUBMED Abstract]

Stage I Melanoma

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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-1MSLT-1 [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm3.5 mm in this study) primary melanomas. [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm3.5 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. 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: 1iiBLevel 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. [PUBMED Abstract]
2. 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]
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. [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. 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]
7. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]

Stage II Melanoma

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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. .001) and a reduction in the length of the hospital stay. 2 Depending Depending on the location of the melanoma, most patients can now have this surgery on the location of the melanoma, most patients can now have this surgery performed on an outpatient basis. 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], 1.001.59; 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], 1.001.59; P = .05), but no difference in survival was seen (HR, 1.24; 95% CI, 0.961.61; = .05), but no difference in survival was seen (HR, 1.24; 95% CI, 0.961.61; P = .1). = .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 The diagnostic accuracy of SLN biopsy has been demonstrated in several studies with a false-negative rate of biopsy has been demonstrated in several studies with a false-negative rate of 0% to 2%.0% to 2%. 8 13 14 15 16 17 Using a vital blue dye and a radiopharmaceutical agent, Using a vital blue dye and a radiopharmaceutical agent, which are injected at the site of the primary tumor, the first lymph node in 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 the lymphatic basin that drains the lesion can be identified, removed, and examined microscopically. If metastatic melanoma is detected, a complete examined microscopically. If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure. To regional lymphadenectomy can be performed in a second procedure. To ensure accurate identification of the SLN, lymphatic mapping ensure accurate identification of the SLN, lymphatic mapping and removal of the SLN should be performed prior to wide and removal of the SLN should be performed prior to wide excision of the primary melanoma. 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 Because this finding arose from a post hoc subset analysis of data from a randomized trial, it arose from a post hoc subset analysis of data from a randomized trial, it should be viewed with caution. should be viewed with caution.

  The International Multicenter Selective Lymphadenectomy Trial (MSLT-1MSLT-1 [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm3.5 mm in this study) primary melanomas. [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm3.5 mm in this study) primary me