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Estimated new cases and deaths from melanoma in the United States in 2011: [1]
Melanoma is a malignant tumor of melanocytes, which are the cells that make the pigment melanin and are derived from the neural crest. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate. Melanoma occurs predominantly in adults, and more than 50% of the cases arise in apparently normal areas of the skin. Early signs in a nevus that would suggest malignant change include darker or variable discoloration, itching, an increase in size, or the development of satellites. Ulceration or bleeding are later signs. Melanoma in women occurs more commonly on the extremities and in men on the trunk or head and neck, but it can arise from any site on the skin surface. A biopsy, preferably by local excision, should be performed for any suspicious lesions, and the specimens should be examined by an experienced pathologist to allow for microstaging. Suspicious lesions should never be shaved off or cauterized. Studies show that distinguishing between benign pigmented lesions and early melanomas can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered. [2]
Prognosis is affected by clinical and histological factors and by anatomic location of the lesion. Thickness and/or level of invasion of the melanoma, mitotic index, presence of tumor infiltrating lymphocytes, number of regional lymph nodes involved, and ulceration or bleeding at the primary site affect the prognosis. [3] [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]
Other PDQ summaries containing information related to melanoma include the following:
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.
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.
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define melanoma. [3]
| 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 1.01–2.0 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. | ||
| 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. | ||
|---|---|---|
| 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). | |
| No = number. | ||
|---|---|---|
| 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. | ||
| 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. | ||
|---|---|---|
| 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. | ||
| 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 | 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 |
| 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. | |||||||
Melanomas that have not spread beyond the site at which they developed are highly curable. Most of these are thin lesions that have not invaded beyond the papillary dermis (Clark level I–II; Breslow thickness ≤1 mm). The treatment of localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion; for most lesions 2 mm or less in thickness, this means 1 cm radial re-excision margins. [1] [2]
Melanomas with a Breslow thickness of 2 mm or more are still curable in a significant proportion of patients, but the risk of lymph node and/or systemic metastasis increases with increasing thickness of the primary lesion. The local treatment for these melanomas is surgical excision with margins based on Breslow thickness and anatomic location. For most melanomas more than 2 mm to 4 mm in thickness, this means 2 cm to 3 cm radial excision margins. These patients should also be considered for sentinel lymph node biopsy followed by complete lymph node dissection if the sentinel node(s) are microscopically or macroscopically positive. Sentinel node biopsy should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping. Patients with melanomas that have a Breslow thickness more than 4 mm should be considered for adjuvant therapy with high-dose interferon.
Some melanomas that have spread to regional lymph nodes may be curable with wide local excision of the primary tumor and removal of the involved regional lymph nodes. [3] [4] [5] [6] In a prospective randomized controlled trial (EST-1684), adjuvant high-dose interferon was shown to increase relapse-free survival (RFS) and overall survival (OS) when compared to observation. [7] A subsequent randomized trial (EST-1690) conducted by the same group of investigators using the same high-dose interferon regimen confirmed the RFS but not the OS advantage. [8] A third randomized trial (SWOG-8593) again demonstrated both a disease-free survival (DFS) and OS advantage to high-dose interferon when compared to a ganglioside vaccine. [9] Clinicians should be aware that high-dose interferon regimens have substantial side effects, and patients should be monitored closely. Adjuvant therapy with lower doses of interferon have not been consistently shown to have an impact on either RFS or OS. [10] Adjuvant chemotherapy does not improve survival. A multicenter phase III randomized trial of patients with high-risk primary limb melanoma did not show a benefit from isolated limb perfusion with melphalan in regard to DFS or OS when compared to surgery alone. [11]
Melanoma that has spread to distant sites is rarely curable with standard therapy, though high-dose interleukin-2 (IL-2) has been reported to produce durable responses in a small number of patients. [12] [13] In patients with systemic metastasis confined to one anatomic site, long-term survival is occasionally achieved by complete resection of all metastatic disease. [14] [15] [16] [17] All patients with distant metastasis are appropriately considered candidates for clinical trials exploring new forms of treatment, including combination chemotherapy, biological response modifiers (such as specific monoclonal antibodies, interferons, IL-2, or tumor necrosis factor-alpha), vaccine immunotherapy, or biochemotherapy (chemoimmunotherapy).
Malignant melanoma has been reported to spontaneously regress; however, the incidence of spontaneous complete regressions is less than 1%. [18]
Patients with all stages of melanoma may be considered candidates for ongoing clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Stage 0 melanoma is defined by the American Joint Committee on Cancer's TNM classification system: [1]
Patients with stage 0 disease may be treated by excision with minimal, but microscopically free, margins.
Check for U.S. clinical trials from NCI's 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.
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]
Standard treatment options for patients with stage I melanoma include the following:
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 include the following:
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.
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]
Standard treatment options for patients with stage II melanoma include the following:
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 (from 46% to 11%; 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 thick 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 thick. Few data are available to guide treatment in patients with melanomas more than 4 mm thick; however, most guidelines recommend margins of 3 cm whenever anatomically possible. Although prophylactic regional lymph node dissections (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, potentially identifying 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 include the following:
Treatment options under clinical evaluation for patients with stage II melanoma include the following:
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.
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]
Standard treatment options for patients with stage III melanoma include the following:
Clinical trials exploring adjuvant therapy after control of the primary tumor with standard therapy are especially appropriate because of the higher rate of treatment failure in this group.
Adjuvant treatment options for patients with resected stage III disease include the following:
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.
Clinicians should be aware that the high-dose regimens have significant toxic effects.
Treatment options for patients with unresectable disease include the following:
Treatment options under clinical evaluation for patients with stage III melanoma include the following:
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.
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]
Standard treatment options for patients with stage IV and recurrent melanoma include the following:
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. [2] [3] [4]
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. [5] [6] (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.
Melanoma has been refractory to most standard systemic therapy. The two approved treatments, dacarbazine (DTIC) and interleukin-2 (IL-2), have not demonstrated an impact on overall survival (OS) in randomized trials. Attempts over the past two decades to develop novel regimens (e.g., multiagent chemotherapy; [7] [8] combinations of chemotherapy and tamoxifen; [9] [10] [11] combinations of chemotherapy and immunotherapy or biochemotherapy; [7] [12] [13] [14] [15] [16] [17] vaccines; antisense bcl-2 oligonucleotide oblimersen; a reactive-oxide species inhibitor, elesclomol; and others) have also not impacted OS. [18]
However, drug development in melanoma is changing. Significant strides have been made in cataloguing the genetic abnormalities that permit the formation and dissemination of melanoma and in better understanding immunologic checkpoints. The discovery of activating mutations in BRAF in 2002 [19] was followed by the discovery of other mutations, which allowed melanoma to be classified into a group of diseases, and created the opportunity to develop therapies that target the activating molecules and their pathways. The most frequently mutated pathway, the mitogen-activated protein (MAP) kinase pathway, involves the BRAF, NRAS and KIT genes. The single most frequent mutation is in the BRAF gene, with 60% to 70% of malignant melanomas harboring a single nucleotide transversion. In smaller subsets of melanoma, activating mutations may occur in NRAS (15%–20%), c-kit (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), CDK4 (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target these mutations are currently in clinical trials.
Advances in immunotherapy include development of novel monoclonal antibodies such as anti-CTLA-4 and anti-PD-1, which can prevent down regulation of T cells and modifications in adoptive cell transfer (ACT). Pilot data of ACT regimens have yielded promising results when incorporating lymphodepletion in single-institution studies, but confirmatory trials are needed.
Finally, antiangiogenesis agents in conjunction with relevant therapies for melanoma are under active development. Because of the rapid development of novel therapies, all newly diagnosed patients should be considered candidates for clinical trials.
The objective response rate to DTIC and the nitrosoureas, carmustine (BCNU) and lomustine, is approximately 10% to 20%. [7] [8] [9] [20] 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. [7] [20] A randomized trial of DTIC versus temozolomide showed an OS of 6.4 months versus 7.7 months, respectively (hazard ratio [HR] = 1.18; 95% confidence interval [CI] 0.92–1.52). These data suggested similarity to DTIC; however, no benefit in survival has been demonstrated for either DTIC or temozolomide, and therefore, temozolomide did not receive approval from the U.S. Food and Drug Administration. [21][Level of evidence: 1iiA] Other agents with modest single-agent activity include vinca alkaloids, platinum compounds, and taxanes. [7] [8] [22]
IL-2. Response to IL-2 regimens is in the 10% to 20% range. [11] [23] [24] Approximately 5% of patients may obtain a complete remission and be long-term survivors; however, phase III confirmatory trials have not been conducted. 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 report suggests that ACT with lymphodepletion (using cyclophosphamide plus fludarabine with or without total-body irradiation) followed by autologous TIL transfer and high-dose IL-2 have improved durable response rates in a single-institution study. [25][Level of evidence: 3iiiDiv] There are no confirmatory phase III trials.
Ipilimumab. 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. [26] 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 (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 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 adverse events. [26][Level of evidence: 1iA]
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. [27][Level of evidence:1iiA]
Sorafenib. The multikinase inhibitor sorafenib (Nexavar) has activity against both the vascular endothelial growth factor signaling and the Raf/MEK/ERK pathway at the level of Raf kinase. However, 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. [28] [29]
BRAF inhibitors. Thirty-two patients with metastatic melanoma characterized by the BRAF V600E mutation were entered into the phase II component of a phase I and II trial and received PLX4032, an orally available inhibitor of mutated BRAF, at the recommended phase II dose of 960 mg twice daily. The number of prior treatments ranged from zero to more than three regimens. Twenty-four patients had a partial response and two had a complete response (i.e., an 81% response rate), with responses lasting from 2 months to 18 months and with four responses ongoing. The most common side effects included the following: [30]
There were no grade 4 adverse events. [30][Level of evidence: 3iiiDiv] A randomized phase III trial of DTIC versus PLX4032 (NCT01006980) is ongoing with patients who have unresectable stage III and stage IV melanoma but who have not received prior therapy for advanced disease. The primary endpoint is OS, and accrual is expected to be completed shortly.
A number of phase II trials of signal transduction inhibitors that have potential for the treatment of melanoma are ongoing, including single-agent trials or combination trials of MEK, AKT, and PI3 kinase inhibitors. (Information about ongoing clinical trials is available from the NCI Web site.)
Kit inhibitors. A number of phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-kit mutation. (Information about ongoing clinical trials is available from the NCI Web site.)
Treatment options under clinical evaluation for patients with stage IV and recurrent melanoma include the following:
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.
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.
Added text about pegylated interferon alpha-2b, which was approved by the U.S. Food and Drug Administration in 2011 for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of complete surgical resection, including complete lymphadenectomy. Also stated that approval was based on EORTC-18991 and that relapse-free survival was improved for patients receiving interferon. Added that one-third of the patients receiving pegylated interferon discontinued treatment because of toxicity.
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.
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board. Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Melanoma Treatment are:
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.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
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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