Malignant Melanoma

Melanomas have two growth phases, radial and vertical. During the radial growth phase, malignant cells grow in a radial fashion in the epidermis. With time, most melanomas progress to the vertical growth phase, in which the malignant cells invade the dermis and develop the ability to metastasize. (See Etiology and Workup.)

Clinically, lesions are classified according to their depth, as follows:

• Thin: 1 mm or less]
• Moderate: 1-4 mm
• Thick: >4 mm

Histologic types of melanoma

There are five different forms, or histologic types, of melanoma:

• Superficial spreading
• Nodular
• Lentigo maligna 
• Acral lentiginous
• Mucosal lentiginous 

Superficial spreading melanomas

Approximately 70% of cutaneous malignant melanomas are the superficial spreading melanoma (SSM) type. Many SSMs arise from a pigmented dysplastic nevus, often one that has long been stable. Typical changes include ulceration, enlargement, or color changes. An SSM may be found on any body surface, especially the head, neck, and trunk of males and the lower extremities of females.

Nodular melanomas

Nodular melanomas (NMs) represent approximately 10-15% of melanomas and also are found commonly on all body surfaces, especially the trunk of males. These lesions are the most symmetrical and uniform of the melanomas and are dark brown or black. The radial growth phase may not be evident in NMs; however, if this phase is evident, it is short-lived, because the tumor advances rapidly to the vertical growth phase, thus making the NM a high-risk lesion. Approximately 5% of all NMs are amelanotic melanomas.

Lentigo maligna melanomas

Lentigo maligna melanomas (LMMs) also account for 10-15% of melanomas. They typically are found on sun-exposed areas (eg, hand, neck). LMMs may have areas of hypopigmentation and often are quite large. LMMs arise from a lentigo maligna precursor lesion. (See the image of lentigo maligna melanoma below.)

Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ). Image courtesy of Susan M. Swetter, MD.

Acral lentiginous melanomas

Acral lentiginous melanomas (ALMs) are the only melanomas that have an equal frequency in blacks and whites. They occur on the palms, soles, and subungual areas. Subungual melanomas often are mistaken for subungual hematomas (splinter hemorrhages). Like NM, ALM is extremely aggressive, with rapid progression from the radial to vertical growth phase.

Mucosal lentiginous melanomas

Mucosal lentiginous melanomas (MLMs) develop from the mucosal epithelium that lines the respiratory, gastrointestinal, and genitourinary tracts. These lesions account for approximately 3% of the melanomas diagnosed annually and may occur on any mucosal surface, including the conjunctiva, oral cavity, esophagus, vagina, female urethra, penis, and anus.

Noncutaneous melanomas commonly are diagnosed in patients of advanced age. MLMs appear to have a more aggressive course than cutaneous melanomas, although this may be because they commonly are diagnosed at a later stage of disease than the more readily apparent cutaneous melanomas.

Sites other than the skin

The majority of melanomas are in the skin, but other sites include the eyes, mucosa, gastrointestinal tract, genitourinary tract, and leptomeninges. Metastatic melanoma with an unknown primary site may be found in lymph nodes only.

Melanomas originate from melanocytes, which arise from the neural crest and migrate to the epidermis, uvea, meninges, and ectodermal mucosa. The melanocytes, which reside in the skin and produce a protective melanin, are contained within the basal layer of the epidermis, at the junction of the dermis and epidermis.

Melanomas may develop in or near a previously existing precursor lesion or in healthy-appearing skin. A malignant melanoma developing in healthy skin is said to arise de novo, without evidence of a precursor lesion. Many of these melanomas are induced by solar irradiation. Melanoma also may occur in unexposed areas of the skin, including the palms, soles, and perineum.

Certain lesions are considered to be precursor lesions of melanoma. These include the following nevi:

• Common acquired nevus
• Dysplastic nevus
• Congenital nevus
• Cellular blue nevus

Genetics

Many genes are implicated in the development of melanoma, including CDKN2A (p16), CDK4, RB1, CDKN2A (p19), PTEN/MMAC1, and ras. CDKN2A (p16) appears to be especially important in both sporadic and hereditary melanomas. This tumor suppressor gene is located on band 9p21, and its mutation plays a role in various cancers.

Ultraviolet radiation

Exposure to ultraviolet radiation (UVR) is a critical factor in the development of most melanomas. Ultraviolet A (UVA), wavelength 320-400 nm, and ultraviolet B (UVB), 290-320 nm, potentially are carcinogenic and actually may work in concert to induce a melanoma.

UVR appears to be an effective inducer of melanoma through many mechanisms, including suppression of the immune system of the skin, induction of melanocyte cell division, free radical production, and damage of melanocyte DNA.

Interestingly, melanoma does not have a direct relationship with the amount of sun exposure because it is more common in white-collar workers than in those who work outdoors.

Sunburn

Acute, intense, and intermittent blistering sunburns, especially on areas of the body that only occasionally receive sun exposure, are the greatest risk factor for the development of sun exposure–induced melanoma. This sun-associated risk factor is different than that for squamous and basal cell skin cancers, which are associated with prolonged, long-term sun exposure.

LMM is an exception to this rule, because it frequently appears on the head and neck of older individuals who have a history of long-term sun exposure.

Parkinson disease

Retrospective case-control analyses from the Mayo Clinic concluded that patients with Parkinson disease (PD) have about a 4-fold increased risk of having preexisting melanoma, and patients with melanoma have a similar risk of developing PD. The results support studies by other researchers showing an increased risk for melanoma in patients with PD.[7]

In the Mayo Clinic study, Dalvin et al found 32 cases of melanoma in 974 patients with PD (with 26 of the 32 diagnosed before the onset of PD), versus 63 cases in the control group of 2922 persons without PD; thus, the likelihood of having a history of melanoma was 3.8-fold higher in patients with PD compared with controls (95% confidence interval [CI], 2.1 - 6.8; P< 0.001).

In a second analysis, Dalvin et al found 43 cases of PD in 1544 patients diagnosed with melanoma, compared with 14 cases of PD in a control group of 1544 persons without melanoma. This translated to a 4.2-fold increased risk for PD after being diagnosed with melanoma, compared with controls (95% CI, 2.0 - 8.8; P< 0.001).[7]

Additional risk factors

Importantly, other factors exist that may predispose an individual to melanoma; chemicals and viruses are 2 etiologic agents that also have been implicated in the development of melanoma.

Greatly elevated risk factors for cutaneous melanoma include the following:

• Changing mole
• Dysplastic nevi in familial melanoma
• More than 50 nevi, 2 mm or greater in diameter

Moderately elevated risk factors for cutaneous melanoma include the following:

• One family member with melanoma
• Previous history of melanoma
• Sporadic dysplastic nevi
• Congenital nevus

Slightly elevated risk factors for cutaneous melanoma include the following:

• Immunosuppression
• Sun sensitivity
• History of acute, severe, blistering sunburns
• Freckling

Occurrence in the United States

The American Cancer Society estimates that 97,610 cases of invasive cutaneous melanoma will be diagnosed in the United States in 2023 (58,120 in men and 39,490 in women), along with 89,070 cases of in situ melanoma. Since the early 2000s, incidence rates of melanoma in persons younger than age 50 years have stabilized in women and declined by about 1% per year in men; in adults age 50 and older, rates increased in women by about 1% per year from 2015 to 2019 but stabilized in men.[8]

Although melanoma accounts for only about 1% of skin cancers, it is responsible for the vast majority of deaths from skin cancers. The American Cancer Society estimates that 7990 people in the US (5420 men and 2570 women) will die of melanoma in 2023.[8]

However, a review of Surveillance, Epidemiology, and End Results data from 1975 to 2014 identified discrepancies in incidence and mortality trends that suggest considerable overdiagnosis of melanoma in White persons. During that period, in Blacks, the incidence of melanoma increased by almost 25%, while mortality due to melanoma decreased by approximately 25%. In Whites, melanoma incidence increased approximately 4-fold in women and 6-fold in men, while mortality was stable in women and increased by less than 50% in men. These researchers calculate that had medical care not improved, estimated mortality would have increased 60% in White women and more than doubled in White men. They estimate that 59% of White women and 60% of White men with melanoma were overdiagnosed in 2014.[9]

International statistics

Worldwide, the incidence of malignant melanoma has increased rapidly over the past 50 years, with the highest incidence in fair-skinned populations and in geographic areas closest to the equator. Australia and New Zealand have the highest incidence of melanoma in the world, at an age-standardized rate of 32.5 cases per 100,000 population.[10]

Racial demographics

Melanoma is more common in Whites than in Blacks and Asians. The rate of melanoma in Blacks is estimated to be one twentieth that of Whites. White people with dark skin also have a much lower risk of developing melanoma than do those with light skin. The typical patient with melanoma has fair skin and a tendency to sunburn rather than tan. White people with blond or red hair and profuse freckling appear to be most prone to melanomas. In Hawaii and the southwestern United States, Whites have the highest incidence, approximately 20-30 cases per 100,000 population per year.

Sex- and age-related demographics

Overall, melanoma is the fifth most common malignancy in the US population, accounting for 6% of all new cancer cases in men and 4% of all new cases in women. However, the relative incidence of melanoma in men and women varies markedly by age: in people younger than 50 years of age, incidence rates are higher in women than in men, but by age 65, they are twice as high in men as in women, and by age 80 they are three times as high as in men. Those differences primarily reflect differences in occupational and recreational sun exposure, which have changed over time.[8] Women tend to have lesions that are nonulcerated and thinner than those in men.

Melanoma may occur at any age, although children younger than age 10 years rarely develop a de novo melanoma. The median age at diagnosis is 65 years, and 79% of patients are 45 to 84 years old.[11] Nevertheless, melanoma is the most common malignancy in women aged 25-29 years and accounts for more than 7000 deaths annually in that age group. Melanoma is notorious for affecting young and middle-aged people, unlike other solid tumors, which mainly affect older adults. It is commonly found in patients younger than 55 years, and it accounts for the third highest number of lives lost across all cancers.

Malignant melanomas usually present at 2 extremes: at one end of the spectrum are patients with small skin lesions that are easily curable by surgical resection, and at the other are patients with widely metastatic disease, in whom the therapeutic options are limited and the prognosis is dismal, with a median survival of only 6-9 months. For this reason, physicians must be aware of the clinical characteristics of melanoma to make an early diagnosis.

Prognosis also is related to the type of melanoma. Superficial spreading and nodular types of melanoma are the 2 most common fatal melanomas, based on a review of data from the original 9 registries of the Surveillance, Epidemiology, and End Results (SEER) program from 1978-2007.[12] This confirms prior studies.

The most important prognostic factors include the following[1] :

• Thickness and/or level of invasion
• Mitotic index (mitoses per millimeter)
• Ulceration or bleeding at the primary site
• Number of regional lymph nodes involved, with distinction of macrometastasis and micrometastasis
• Systemic metastasis, including the site (nonvisceral versus lung versus all other visceral sites) and serum lactate dehydrogenase (LDH) level elevation

In general, positive prognostic factors include the following[1] :

• Younger age
• Female sex
• Melanoma located on the extremities

In a review of 3,872 cases of lymph node–positive melanoma, the proportion of examined lymph nodes found to be positive (the lymph node ratio) independently predicted disease-specific survival. These researchers concluded that the lymph node ratio consistently improved the prognostic accuracy of the TNM system.[13]

Prognosis is also worse in patients with immune compromise.[14] A study of patients who developed melanoma after solid organ transplantation found that their overall survival was worse than the rate reported in a national sample of patients with melanoma. In transplant recipients with thicker melanomas, disease-specific survival was significantly poorer than in patients without a prior history of transplantation.[15]

In patients with mucosal melanoma, a multivariable analysis determined that anatomic primary site was an independent predictor of overall survival and disease-specific survival. Tumors in the nasal cavity and oral cavity were associated with survival superior compared with tumors in the nasopharynx and paranasal sinuses. Age older than 70 years, tumor size, nodal status, and distant metastasis status were also predictive of outcome.[16]

Stage and prognosis

Prognosis depends on the disease stage at diagnosis. According to SEER data from 2012-2018, 5-year relative survival rates are as follows[11] :

• Localized (confined to primary site) -  99.5%
• Regional (spread to regional lymph nodes) - 70.6%
• Distant (metastatic)  - 31.9%

For stage IV melanoma, prognosis varies according to the site of metastasis; survival is progressively worse with metastasis to extra-regional lymph nodes or distant skin, lung, digestive tract, or brain, respectively.[17] Prognosis is also poorer in older patients and those with immune compromise (eg, organ transplant recipients, persons with HIV infection).[14]

Also see Malignant Melanoma Staging.

The focus of melanoma prevention and patient education is avoidance of sun exposure; see Treatment/Prevention. For patient education information, see Melanoma.

Family history

Carefully obtain any family history of melanoma or skin cancer. Also, a family history of irregular, prominent moles is important. Approximately 10% of all patients with melanoma have a family history of melanoma. These patients typically develop melanoma at an earlier age and tend to have multiple dysplastic nevi. These patients also are more likely to have multiple primaries.

Presence of a familial melanoma syndrome should be considered in patients with a family history of pancreatic cancer or astrocytoma. Mutations in the CDKN2A tumor suppressor gene (also known as p16) are the most common genetic abnormalities found in these families.

Patient history

Any previous history of melanoma must be elicited from patients, because those patients are at increased risk of developing a second melanoma. Patients have reported as many as 8 or more primary melanomas. Multiple primaries especially are prevalent in patients with multiple dysplastic nevi. The term familial atypical mole or melanoma (FAMM) syndrome is used to describe this hereditary tendency to develop multiple dysplastic nevi and melanomas.

Sun exposure

Question the patient extensively about previous sun exposure, including severe sunburns in childhood. The capacity to tan is also important, because individuals who tan easily are less likely to develop a melanoma than those who burn easily.

Moles

Question the patient about any changes noted in moles. Any history of change in size, color, or symmetry, as well as knowledge of bleeding or ulceration of the lesion must be obtained. Also elicit any history or family history of multiple nevus syndrome.

Total body examination

A total-body skin examination is crucial when evaluating a patient with an atypical nevus or a melanoma. The skin examination should be performed on initial evaluation of the patient and during all subsequent visits. A study from a general dermatology practice found that most melanomas diagnosed during a 3-year period were not the presenting complaint but were discovered only because a dermatologist performed a total-body skin examination; moreover, these incidentally discovered melanomas were more likely to be thinner or in-situ lesions.[18]

Crucial to a good skin examination is a well-lit examining room and a completely disrobed patient.

Serial photography and new techniques, such as epiluminescence microscopy and computerized image analysis, are useful adjuncts. Epiluminescence microscopy uses a magnifying lens to examine a lesion that has had oil applied. Computerized image analysis stores images of the lesions and makes them available for comparison over time.

Skin examination

During a skin examination, assess the total number of nevi present on the patient's skin. Attempt to differentiate between typical and atypical lesions. (The images below depict examples of melanomas.) The ABCDs for differentiating early melanomas from benign nevi include the following:

• A - Asymmetry (melanoma lesion more likely to be asymmetrical)

• B - Border irregularity (melanoma more likely to have irregular borders)

• C - Color (melanoma more likely to be very dark black or blue and to have variation in color than would a benign mole, which more often is uniform in color and light tan or brown)

• D - Diameter (mole < 6 mm in diameter usually benign)

  A 1.5-cm melanoma with characteristic asymmetry, irregular borders, and color variation.

  Malignant melanoma. Image courtesy of Hon Pak, MD.

  Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ). Image courtesy of Susan M. Swetter, MD.

Lymph node examination

If a patient is diagnosed with a melanoma, examine all lymph node groups. Melanoma may disseminate through the lymphatics, leading to the involvement of regional lymph nodes, and hematogenously, leading to the involvement of any node basin in the body.

Mucosal melanoma

CKIT mutations have been described in 39% of mucosal melanoma, 36% of acral lentiginous melanoma, 28% of cutaneous melanomas arising in areas of chronic sun-damaged skin, and none in melanomas of skin without chronic sun damage. (98)

The diagnosis of melanoma is confirmed by excisional biopsy. Sentinel lymph node biopsy or gene profile assay may be appropriate as prognostic studies in selected patients, but there is little evidence that they affect longevity.

In early-stage disease, laboratory and imaging studies are rarely indicated. In all stages, they are generally appropriate when prompted by signs or symptoms. Routine testing can lead to frequent false-positive results and a cascade of unnecessary tests.

Preoperative imaging studies have significant costs and offer minimal benefit in most patients with melanoma.[19] One meta-analysis of diagnostic tests used in staging melanoma has shown that ultrasonography is the best imaging study to diagnose lymph node involvement and that positron emission tomography computed tomography scanning (PET/CT) is the best imaging study to look for other sites of metastasis.[20]  In general, these studies are appropriate in high-risk patients or when localizing signs or symptoms are present.

A complete excisional biopsy is preferred. The sample should have a 1-3 mm margin of healthy skin and should include all layers of skin and some subcutaneous fat. Inclusion of fascia is no longer standard.

If the suggestive lesion is large or situated in a cosmetically sensitive area, an incisional or punch biopsy may be appropriate. The incisional biopsy specimen should be taken from the most abnormal area of the lesion.

Shave biopsy should generally not be done, as it can lead to inadequate staging and diagnosis. The National Comprehensive Cancer Network acknowledges that superficial shave biopsy may compromise pathologic diagnosis and complete assessment of Breslow thickness, but considers shave biopsy acceptable when the index of suspicion is low, and advises that a broad shave biopsy may be optimal for histologic assessment of melanoma in situ, lentigo maligna (LM) type (ie, melanoma on skin with high cumulative sun damage).[21] In cases where a shave biopsy was done inappropriately, a complete excisional biopsy of the lesion should be performed, if possible, to determine the depth and extent of the lesion.

Because failure to perform a reexcision after biopsy of a melanoma is associated with a local recurrence rate of as high as 40%, a reexcision must be performed. Recommendations are evolving.

Current recommendations for surgical margins of excision are as follows[21] :

• In situ lesions - 0.5-1 cm margin
• Lesions ≤ 1 mm in thickness - 1 cm margin
• Lesions 1.01 - 2 mm in thickness - 1-2 cm margin
• Lesions 2.01-4 mm in thickness - 2 cm margin
• Lesions greater than 4 mm in thickness - At least 2 cm margin

A study by Gillgren et al determined that a 2-cm excision provided a safe and reliable resection margin to treat lesions thicker than 2 mm.[22]

Although no single histologic feature is pathognomonic for melanoma, many characteristic features exist. Cytologic atypia virtually always is noted, with enlarged cells containing large, pleomorphic, hyperchromic nuclei with prominent nucleoli. Numerous mitotic figures often are noted.

Immunohistochemical stains usually are not necessary for diagnosis; they may be necessary in cases with indeterminate findings on routine histology. Both S-100 and homatropine methylbromide (HMB45) stains are positive in melanocytes and the latter shows a gradient in most benign nevi other than blue nevi. S-100 and SOX-10 are highly sensitive, although not specific, for melanocytes. They are particularly helpful in poorly differentiated or spindled tumors. 

PRAME (preferentially expressed antigen in melanoma) can stain the junctional component of benign nevi but dermal staining is suggestive of melanoma. It is not completely specific and stains other tumors, including testicular tumors and cellular neurothekeoma. It is particularly helpful in distinguishing preexisting nevus remnants from melanoma.[23, 24, 25, 26]

Mart-1/MelanA as well as MITF are sometimes used to establish the pattern of melanocytes, but all 3 may stain pseudonests in lichenoid tissue reactions. S100 is often poorly expressed in the nail matrix; HMB-45 and Mart-1 may be superior in that location. Next-generation gene sequencing and microarray genomic hybridization are becoming commonplace for the diagnosis of unique types of nevi and difficult melanocytic lesions.  Fluorescent in situ hybridization (FISH) assays also have evolving applications and molecular predictors of biologic response to targeted immunotherapy are in common use, with BRAF testing being the most frequent.[27, 28, 29, 30]

Patients with clinically enlarged lymph nodes and no evidence of distant disease should undergo a lymph node biopsy. For years, patients without clinically enlarged nodes underwent lymph node dissection (LND). However, studies show that in patients with melanomas that are 1-4 mm thick, LND may not yield a significant survival advantage.

The only patients who seem to benefit from LND are those with lesions 1.1–2 mm thick and who are younger than 60 years. Patients with lesions greater than 4 mm in thickness are widely considered not to benefit from removal of clinically negative nodes.

Lymphatics from any given region on the skin drain to a single lymph node. This node is called the sentinel lymph node and almost always is the first site of nodal involvement when melanoma spreads to regional nodes.

To determine which node is the sentinel node, the following two techniques, often in combination, are used. The combination of the two techniques allows detection of the sentinel node in as many as 98% of cases.

The first technique involves injecting a blue dye at the site of the primary melanoma and, through a small incision over the nodal basin, determining the location of the sentinel node. The second technique involves a radiolabeled solution injected into the site of the primary and the use of a hand-held gamma detector to determine the location of the sentinel node. The node is then removed for pathologic evaluation. Removal of the node should precede wide excision of the primary.[1]

Sentinel lymph node biopsy (SLNB) is now known to offer important prognostic, diagnostic, and therapeutic information.[31]

Guidelines from the National Comprehensive Cancer Network (NCCN) recommend discussing and offering SLNB to patients with stage IB or stage II melanoma that is 0.76-1 mm thick with ulceration or with a mitotic rate ≥1/mm2, or > 1 mm thick with any characteristic adverse features. The NCCN recommends discussing and considering SLNB in patients with stage IA melanoma that is 0.76-1 mm thick, with no ulceration and a mitotic rate of 0/mm3.[21] SLNB may be offered either as standard care or in the context of a clinical trial.

The NCCN does not recommend SLNB for patients whose melanoma is 0.75 mm or less in thickness. The NCCN advises that SLNB may be considered if conventional risk factors such as ulceration, high mitotic rate, or lymphovascular invasion are present, but notes that those are very uncommonly found with melanomas that thin.[21]

Joint guidelines from the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) recommend SLNB for patients with intermediate-thickness melanomas (Breslow thickness 1–4 mm) of any anatomic site. There is less evidence for patients with thick melanomas (T4; Breslow thickness >4 mm), but sentinel lymph node biopsy is recommended for staging and facilitating regional disease control. Evidence supporting routine sentinel lymph node biopsy for patients with thin melanomas (T1; Breslow thickness < 1 mm) is lacking, but it may be an option in selected patients with high-risk features in whom the benefits of staging outweigh the risks of the procedure.

Cadili et al reported that the likelihood of non–sentinel lymph node metastasis can be predicted on the basis of total metastasis within the sentinel lymph node. Their data showed that patients with ≥5 mm of metastasis have a 30% risk of metastasis. In contrast, those with less than 2 mm of total sentinel lymph node metastasis are unlikely (< 3.67% likelihood) to harbor metastasis in non-sentinel nodes, and those patients may not benefit from additional nodal dissection.[32]

Go to Sentinel Lymph Node Biopsy in Patients With Melanoma for complete information on this topic.

The chemistry panel may give a clue to possible metastatic disease. For example, an elevated alkaline phosphatase level may signal metastasis to the bone or liver, while elevated levels on liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) may represent metastasis to the liver.

Total protein and albumin provide information concerning the overall health and nutritional status of the patient and may afford prognostic information.

Many chemotherapy regimens may be toxic to the kidneys; therefore, a creatinine level is necessary prior to initiation of any treatment.

The lactate dehydrogenase (LDH) level is elevated in many conditions, including many malignancies. Although LDH elevation is not specific for melanoma, it may be useful in the follow-up care of some patients with melanoma. A markedly elevated LDH at diagnosis or at a follow-up visit may indicate distant metastases, especially in the lung and liver.

Although the specificity and sensitivity of this test are low, multiple studies show an elevated LDH level to be an independent predictive factor for poor prognosis. LDH level now is considered part of the staging system for melanoma.

To date, no studies support obtaining a routine radiograph in patients with melanoma. However, a normal chest radiograph finding at diagnosis provides a baseline for future comparison.

Patients with stage III disease, in-transit disease, or local recurrence should have a chest radiograph or computed tomography (CT) scan of the chest, because the lungs often are the first site of metastatic disease.

Magnetic resonance imaging (MRI) of the brain should be obtained during the workup of a patient with known distant metastases to detect additional asymptomatic metastatic disease. This is especially true for patients being considered for high-dose interleukin-2 treatment. MRI of the brain in patients without known metastatic disease should be done only in those who have neurologic symptoms. 

A chest CT scan should be included in the staging workup of a patient with stage IV disease (ie, the patient with known distant metastases) to detect asymptomatic metastatic lesions. In patients with stage I, II, or III disease, a chest CT scan should be performed only if clinically indicated.

A CT scan of the abdomen often is obtained when evaluating a patient with stage III, locally recurrent, or in transit disease. Although the yield is low, a negative CT scan provides a baseline study for future comparison.

CT scan of the pelvis is indicated only if a patient has local regional recurrence below the waist, is symptomatic, or has known metastatic disease with a history of primary tumors below the waist.

PET/CT is currently the most sensitive tool for the diagnosis of metastatic disease. PET scans are not indicated in early-stage disease (stage I or II), but a PET scan may aid in staging patients with known node involvement or in-transit or satellite lesions. Many studies report that PET scans have greater sensitivity than conventional radiographic studies for the detection of metastatic disease.

One meta-analysis found PET/CT scanning to be the best imaging study for finding other sites of metastasis.[20] In particular, fluorodeoxyglucose (FDG) PET/CT scans are a valuable tool for detecting additional metastasis as part of the preoperative evaluation of patients with advanced and metastatic melanoma.[33] Finally, PET scans often are useful in evaluating the response of metastatic disease to therapy.

The American Joint Committee on Cancer (AJCC) tumor/node/metastasis (TNM) classification and staging systems for cutaneous melanoma are provided below.[34]  The TNM system has incorporated the older Breslow classification of melanoma thickness, whose four classes of lesion depth correspond with levels T1-4. Clark levels, another older classification of melanoma, are now largely used for historical reference.

T classification (thickness) is as follows:

• TX: Primary tumor cannot be assessed (shave biopsy)
• T0 : No evidence of primary tumor
• Tis: Melanoma in situ
• T1: ≤1.0 mm (ulceration unknown or unspecified)
• T1a: < 0.8 mm without ulceration
• T1b: < 0.8 mm with ulceration; 0.8-1.0 mm with or without ulceration
• T2 : >1.0-2.0 mm (ulceration unknown or unspecified)
• T2a: >1.0-2.0 mm without ulceration
• T2b: >1.0-2.0 mm with ulceration
• T3: >2.0-4.0 mm (ulceration unknown or unspecified)
• T3a: >2.0-4.0 mm without ulceration
• T3b: >2.0-4.0 mm with ulceration
• T4: >4.0 mm (ulceration unknown or unspecified)
• T4a: >4.0 mm without ulceration
• T4b: >4.0 mm with ulceration

N classification (regional lymph node and/or lymphatic metastasis) is as follows:

• NX: Regional nodes not assessed
• N0: No regional metastases detected
• N1: One tumor-involved node; or in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes
• N1a: One clinically occult (ie, detected by sentinel lymph node biopsy); no in-transit, satellite, or microsatellite metastases
• N1b: One clinically detected; no in-transit, satellite, or microsatellite metastases
• N1c: No regional lymph node disease; in-transit, satellite, and/or microsatellite metastases found
• N2: Two or three tumor-involved nodes; or in-transit, satellite, or microsatellite metastases
• N2a: Two or three clinically occult (ie, detected by sentinel lymph node biopsy); no in-transit, satellite, or microsatellite metastases
• N2b: Two or three clinically detected; no in-transit, satellite, or microsatellite metastases
• N2c: One clinically occult or clinically detected; in-transit, satellite, and/or microsatellite metastases found
• N3: ≥4 tumor-inolved nodes or  in-transit, satellite, and/or microsatellite metastases with ≥2 tumor-involved nodes or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases 
• N3a: ≥4 clinically occult (ie, detected by sentinel lymph node biopsy); no in-transit, satellite, or microsatellite metastases
• N3b: ≥4, at least one of which was clinicallly detected, or presence of any matted nodes; no in-transit, satellite, or microsatellite metastases
• N3c: ≥2 clinically occulr or clinically detected and/or presence of any matted nodes, with presence of in-transit, satellite, and/or microsatellite metastases

Note that micrometastases are diagnosed after elective or sentinel lymphadenectomy. Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.

M classification is as follows:

• M0: No evidence of distant metastasis
• M1a: Distant skin, subcutaneous, or nonregional nodal metastases; 
• M1a: Distant skin, subcutaneous, or nonregional nodal metastases
• M1b: Lung metastasis, with or without M1a involvement
• M1c - Distant metastasis to non–central nervous system (CNS) visceral sites, with or without M1a or M1b involvement
• M1d: Distant metastasis to CNS, with or without M1a-c involvement

Cases (beyond M0)  in which the lactate dehydrogenase (LDH) level is known are given the suffix (0), for normal LDH level, or (1), for elevated LDH level.

AJCC prognostic staging is as follows:

• Stage 0 - Tis/N0/M0
• Stage IA - T1a,/N0/M0
• Stage IB - T1b, T2b/ N0/ M0
• Stage IIA - T2b, t3a/N0/M0
• Stage IIB - T3b, T4a/N0/M0
• Stage IIC - T4b/N0/M0
• Stage III (clinical staging) - Any T, Tis/≥N1/M0
• Stage IIIA (pathologic staging) - T1a/b, T2a/N1a, N2a/M0
• Stage IIIB (pathologic staging) - T0/N1b, N1c/M0; T1a-b, T2a/N1b-c, N2b/M0; T2b,T3a/N1a-c, N2a-b/M0
• Stage IIIC (pathologic staging) -  T0/N2b-c, N3b-c/M0; T1a-T3a/N2c, N3a-c/M0; T4b/N1a-c, N2a-c/MO
• Stage IV - Any T/Any N/M1t

Also see Malignant Melanoma Staging.

Surgery is the definitive treatment for early-stage melanoma. In patients with solitary or acutely symptomatic brain metastases, surgical management or treatments such as gamma knife radiation may alleviate symptoms and provide local control of disease.[35]

Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy of patients with advanced melanoma. Less than one half of patients with deep primaries (> 4 mm) or regional lymph node involvement have long-term disease-free survival; consequently, these patients are classified as high risk and should be considered for adjuvant therapy.

By stage, standard treatment options for melanoma are as follows[1]

• Stage 0 - Excision
• Stage I - Excision, with or without lymph node management
• Stage II - Excision, with or without lymph node management
• Resectable stage III - Excision, with or without lymph node management; adjuvant therapy and immunotherapy
• Unresectable stage III, stage IV, and recurrent melanoma - Intralesional therapy, immunotherapy, signal transduction inhibitors, chemotherapy, palliative local therapy

Multiple options for adjuvant treatment of node-positive melanoma have become available. A critical question for guiding the choice of regimens is whether the tumor contains a BRAF V600 mutation. BRAF and BRAF/MEK inhibitor combinations are useful in some patients to slow the progression of disease.

In patients with no BRAF mutation (ie, wild-type BRAF), current guidelines from the National Comprehensive Cancer Network (NCCN) recommend single-agent immunotherapy with the programmed cell death–1 (PD-1) inhibitor pembrolizumab or nivolumab or combination therapy with nivolumab plus ipilimumab.[21]  

For patients with a BRAF mutation, the NCCN recommends targeted combination therapy with dabrafenib/trametinib or vemurafenib/cobimetinib.[21] ​ Targeted therapy is preferred if clinically needed for early response. Current targeted therapies can slow tumor growth (eg, BRAF inhibition) or release the brakes on the immune response, resulting in tumor lysis (eg, PD-1 inhibition).

Interferon alfa-2b was approved in 1995 for adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence. However, while high-dose interferon alfa-2b and pegylated interferon have been shown to improve relapse-free survival, neither improves overall survival.[1] This is not currently offered to patients unless there are contraindications to giving PD-1 inhibitors or BRAF/MEK inhibitor combinations.

Neoadjuvant therapy for high-risk resectable melanoma has demonstrated significant efficacy in early clinical trials.[36, 37] Current NCCN guidelines recommend consideration of neoadjuvant therapy, preferably in the context of a clinical trial, in patients with gross resectable nodal disease and the following:[21]

• Very high risk of recurrence after complete resection
• High risk of perioperative morbidity due to extent of resection or underlying comorbidities
• Uncertain likelihood of achieving gross complete resection of nodal disease

Also see Lentigo Maligna Melanoma, Oral Malignant Melanoma, and Head and Neck Mucosal Melanomas.

A joint practice guideline from the American Society of Clinical Oncology and the Society of Surgical Oncology recommends completion lymph node dissection (CLND) for patients with a positive sentinel lymph node biopsy (SLNB), but the risk of morbidity must be weighed for each patient. CLND has not been shown to affect overall survival, but does help with regional disease control. Careful observation with removal of enlarged nodes is an option.The second Multicenter Selective Lymphadenectomy Trial (MSLT-II) confirmed that immediate CLND in patients with metastases found on SLNB increases the rate of regional disease control and provides prognostic information. However, immediate CLND did not increase melanoma-specific survival.[38]

In MSLT-II, patients who had sentinel node metastases detected via standard pathologic assessment or a multimarker molecular assay were randomized to receive either immediate CLND (n = 971) or nodal observation with ultrasonography (n = 968). At a median follow-up of 43 months, the mean 3-year rate of melanoma-specific survival (the primary endpoint for the study) was similar in the dissection group and the observation group (86 ± 1.3% and 86 ± 1.2%, respectively; P = 0.42).[38]

Secondary endpoints slightly favored CLND over observation, with 3-year rates of disease control of 92 ± 1.0% versus 77 ± 1.5%, respectively (P < 0.001) and 3-year disease-free survival of 68 ± 1.7% versus 63 ± 1.7%, respectively (P = 0.05). However, lymphedema developed in 24.1% of the dissection group versus 6.3% of the observation group (P< 0.001). Lymphedema was mild in 64% of cases, moderate in 33%, and severe in 3%.[38]

In patients whose SLNB reveals micrometastases, a randomized phase III trial by Steiner et al found no survival benefit with CLND. No statistically significant differences (ie, 10% or higher) in 5-year recurrence-free survival, distant metastases–free survival, or melanoma-specific survival were evident between 242 patients who underwent CLND and 241 patients who received observation only. At a median follow-up of 35 months, however, regional lymph node metastases developed in 14.6% of patients in the observation group versus 8.3% of those in the CLND group.[39]

Adjuvant therapy is used for locally advanced melanoma (stage III) melanoma, and most recently, resected advanced-stage disease. Although observation rather than adjuvant therapy is standard for stage II melanoma at this time, those patients are encouraged to enroll in clinical trials. Gould Rothberg et al developed and validated a multimarker prognostic assay for determining survival in stage II melanoma, which these researchers suggest might be beneficial in improving the selection of patients for adjuvant therapy.[40]

Immune therapy and targeted therapy (eg, in cases with BRAF mutations) are preferred for treatment of unresectable or distant metastatic disease.[41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52]  Isolated limb perfusion and intralesional therapy with talimogene laherparepvec (T-VEC) therapy may be appropriate for some patients with localized metastases.[53, 54, 55, 56]

Dabrafenib plus trametinib

In 2018, the US Food and Drug Administration (FDA) approved dabrafenib in combination with trametinib for adjuvant treatment, following complete resection, of patients with melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s).

Approval was based on COMBI-AD, an international, multicenter, randomized, double-blind, placebo-controlled trial in 870 patients with stage III melanoma with BRAF V600E or V600K mutations and regional lymph node involvement. Patients in the treatment arm (dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily) had significantly longer relapse-free survival (RFS) compared with those in the placebo arm. The estimated median RFS was not reached for patients who received the combination therapy, compared with 16.6 months (95% confidence interval [CI]: 12.7, 22.1) for those receiving placebo. Patients in the treatment arm also had experienced fewer recurrences/deaths by the time of data cutoff: 38% (n=166), compared with 57% (n=248) in the placebo arm (hazard ratio [HR] 0.47; 95% CI 0.39, 0.58; P < 0.0001).[57]

Five-year follow-up of COMBI-AD confirmed the long-term benefit of dabrafeinb plus trametinib in this setting. RFS was 53% in the treatment arm versus 36% in the placebo arm. Distant metastasis-free survival rates were 65% versus 54%, respectively.[58]

Pembrolizumab

Pembrolizumab, a monoclonal antibody to programmed cell death-1 protein (PD-1), has FDA approval for adjuvant treatment of resected, high-risk stage III melanoma. Approval was based on data from the EORTC1325/KEYNOTE-054 trial (n=1019) showing a significantly prolonged 1-year RFS compared with placebo (75.4% vs 61%; P < 0.001).[59]

On 3-year median follow-up of KEYNOTE-054, pembrolizumab continued to produce a sustained, clinically meaningful improvement in RFS across subgroups. In the overall population, the 3-year cumulative incidence of distant metastasis as the first recurrence was 22.3% with pembrolizumab  versus 37.3% with placebo group (HR 0.55, 95% CI 0.44-0.69). In the pembrolizumab arm, 3-year RFS was superior in PD-L1 positive patients, at 65%, versus 57% for PD-L1 negative patients.[60]

In 2021, the FDA expanded the approval of pembrolizumab to the adjuvant treatment of stage IIB or IIC melanoma following complete resection, in patients age 12 years and older. Approval was based on data from the KEYNOTE-716 trial, which demonstrated a statistically significant improvement in RFS at the time of the first interim analysis for patients randomized to the pembrolizumab arm compared with placebo, with an HR of 0.65 (95% CI 0.46-0.92; P=0.0132). The median RFS was not reached in either arm.[61]

Pembrolizumab is also indicated for first-line treatment of unresectable or metastatic melanoma.

Nivolumab

The PD-1 inhibitor nivolumab (Opdivo) is approved for adjuvant treatment in patients with lymph node involvement or metastatic melanoma who have undergone complete resection. Approval was based on findings from the phase III CheckMate-238 trial, in which 906 patients with completely resected stage IIIB/C or stage IV melanoma received either nivolumab or ipilimumab for up to 1 year. The 12-month RFS rate was 70.5% in the nivolumab arm compared with 60.8% in the ipilimumab arm (HR for disease recurrence or death, 0.65; 97.56% CI, 0.51-0.83; P < 0.001).[62] Based on this study, nivolumab is the current drug of choice in the adjuvant setting.

A study by Weber et al in patients with advanced melanoma that had progressed after treatment with ipilimumab or ipilimumab and a BRAF inhibitor reported a greater proportion of patients achieving an objective response and fewer toxic effects in patients treated with nivolumab (n=272) than in those treated with dacarbazine, or paclitaxel plus carboplatin (objective response rates 31.7 versus 10.6, respectively).[4]

Ipilimumab

In a phase III trial in patients with high-risk stage III melanoma, adjuvant therapy with the checkpoint inhibitor ipilimumab resulted in significantly higher rates of RFS, overall survival, and distant metastasis–free survival compared with placebo.[63] The study included 951 patients with stage III cutaneous melanoma who had adequate resection of lymph nodes and were randomized to receive ipilimumab at 10 mg/kg (IV) or placebo every 3 weeks for 4 doses, then every 3 months for up to 3 years, or until disease recurrence or unacceptable toxicity.

Median RFS—the primary endpoint—was 26.1 months with ipilimumab versus 17.1 months with placebo. However, 52% of patients (245 of 475) who started ipilimumab discontinued treatment due to adverse events—38.6% within 12 weeks. Grade 3-4 immune-related adverse events occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. Five patient deaths were linked to immune-related adverse events in the ipilimumab arm.[63]

Intralesional therapy

In 2015, the FDA approved the oncolytic immunotherapeutic vaccine talimogene laherparepvec (Imlygic) for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery. It is administered by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.[64]

Talimogene laherparapvec is a live-attenuated herpes simplex type I virus that has been genetically modified by deleting the gene that encodes infected cell protein 34.5(ICP 34.5) and replacing it with the coding sequence for the immune stimulatory protein granulocyte-macrophage colony-stimulating factor (GM-CSF). Once injected into a tumor, the modified virus replicates and produces GM-CSF.

A phase III clinical trial by Andtbacka et al demonstrated therapeutic benefit of talimogene laherparepvec against melanoma. The study compared 295 patients treated with talimogene laherparepvec and141 patients treated with GM-CSF. The primary endpoint was the durable response rate (DRR), defined as the rate of complete response plus partial response continuously lasting ≥6 months and beginning within the first 12 months. Secondary endpoints included overall survival (OR) and the overall response rate (ORR).[65]

The DRR was significantly higher among patients who received talimogene laherparepvec compared with those given GM-CSF (16.3% vs 2.1%; odds ratio, 8.9; P < 0.001). Of the patients who experienced a durable response, 29.1% had a durable complete response and 70.8% had a durable partial response. The median time to response was 4.1 (range: 1.2 to 16.7) months in the arm receiving talimogene laherparepvec.[65]

The ORR was also higher with talimogene laherparepvec (26.4% vs 5.7%; P < 0.001). In all, 32 (10.8%) patients receiving talimogene laherparepvec experienced a complete response, compared with just one (< 1%) patient receiving GM-CSF. The median time to treatment failure was 8.2 months with talimogene laherparepvec and 2.9 months with GM-CSF (hazard ratio [HR], 0.42). Median OS was 23.3 months and 18.9 months, respectively (HR, 0.79; P = 0.051), which just missed being statistically significant.[65]

The use of talimogene laherparepvec in combination with immune checkpoint inhibitors is currently being assessed. Early results  indicate that the combination of talimogene laherparepvec with ipilimumab or pembrolizumab has greater efficacy in melanoma than either therapy alone, and without additional safety concerns above those expected for each monotherapy.[66]

Interferon alfa

This drug is mentioned for completeness. It is no longer prescribed for melanoma.

Interferon (IFN) alfa-2b was the first drug approved by the FDA, in 1995, for adjuvant treatment of melanoma after excision in patients who are free of disease but are at high risk for recurrence. Approval was based on the results of Eastern Cooperative Group (ECOG) 1684, a large multicenter study of high-dose IFN that showed improvement in disease-free survival and survival benefit (time to progression improvement of 8 months, with a 1-year survival benefit).[67] A subsequent pooled analysis of 1016 patients and 716 observational controls from all ECOG trials showed a significant increase in relapse-free survival (P = 0.006) but not overall survival (P = 0.42).[68]

To investigate the possibility that the survival benefit seen in ECOG-1684 had to do with its incorporation of an induction phase of maximally tolerated dosages of IFN given intravenously for the initial 4 weeks, Pectasides et al conducted a prospective, randomized study in 364 patients with stage IIB, IIC, or III melanoma who had undergone curative surgery. Patients were randomized to receive IFN-alpha-2b IV for 5/7 days weekly for 4 weeks (arm A) versus the same induction regimen followed by IFN-alpha-2b administered subcutaneously 3 times a week for 48 weeks (arm B). At a median follow-up of 63 months, there were no significant differences in overall survival and relapse-free survival between the 2 arms, and patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity.[69]

On the other hand, Hauschild et al found that the addition of a 4-week modified high-dose IFN-alpha induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome.[70]

Hauschild et al also studied optimal duration of treatment of malignant melanoma with low-dose IFN alfa-2a and concluded that prolonging treatment with conventional low-dose IFN alfa-2a from 18 to 60 months showed no clinical benefit in patients with intermediate- and high-risk primary melanoma. Patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness and lymph node negative were included in this prospective, randomized, multicenter trial (n=850). Patients were randomly assigned to receive 3 MU IFN alfa-2a SC 3 times/wk for either 18 or 60 months. Median follow-up was 4.3 years. Relapse-free survival and distant-metastasis-free survival did not differ between the 2 groups.[71]

Meta-analysis data show that ulceration and tumor stage are important predictors of response to interferon alfa/pegylated-interferon.[72]

Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. It was approved by the FDA in 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy. The drug’s approval was based on a 5-year, open-label, multicenter trial in which cancer recurrence was delayed about 9 months longer in patients who took peginterferon alfa-2b than in patients who did not take the drug.[2]

Granulocyte-macrophage colony-stimulating factor

In addition to its approved indication—accelerating bone marrow recovery in diverse settings of bone marrow failure—granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used as adjuvant treatment of high-risk melanoma.[73] GM-CSF is no longer used in this setting, due to the availability of more effective treatments.[74] However, GM-CSF continues to be studied for its possible benefit as an immune modulator when used in combination with conventional therapies.[75]

In addition to intralesional therapy with talimogene laherparepvec (see Treatment/Adjuvant Therapy), increasing numbers of biologic therapies are available for the treatment of patients with advanced-stage (stage IV) melanoma. Chemotherapy is used less frequently due to the more efficacious drugs have been developed, including immunotherapy and BRAF and MEK inhibitors. The use of immune checkpoint inhibitors for the treatment of advanced melanoma has evolved beyond monotherapies to combination strategies.

Treatment of melanoma with BRAF mutations

BRAF mutations are present in 40-60% of cutaneous melanomas, and of those, about 90% are BRAF V600E mutations. Detection of BRAF mutations is important prior to starting treatment in any melanoma patient. First-line treatment of patients with BRAF V600 wild-type or mutation-positive, unresectable or metastatic melanoma is with nivolumab as a monotherapy or in combination with ipilimumab.[76, 77]

Vemurafenib

Vemurafenib (Zelboraf) was approved by the US Food and Drug Administration (FDA) in 2011. It is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF V600E. This agent is indicated for the treatment of unresectable or metastatic melanoma with the BRAF V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.

Phase III trial results for vemurafenib included a 63% relative reduction in the risk of death as well as a 74% relative reduction in the risk of tumor progression in patients with previously untreated metastatic melanoma with the BRAF V600E mutation, compared with dacarbazine. In addition, the overall survival rate at 6 months in the vemurafenib group was 84%, versus 64% in the dacarbazine group.[78]  Despite the short follow-up period, these results have significant clinical implications, given the frequency of BRAF V600E mutations in cutaneous melanomas. Moreover, a response to vemurafenib in four of 10 patients with the BRAF V600K mutation was noted, suggesting sensitivity of this mutation variant to vemurafenib.[78]

Vemurafenib was generally well tolerated, with cutaneous events (squamous cell carcinoma, keratoacanthoma, or both; all were treated with simple excision), arthralgia, fatigue, and photosensitivity the most common adverse events; such events led to dose modification or interruption in 38% of patients.[78]  Adverse events seen with dacarbazine were primarily fatigue, nausea, vomiting, and neutropenia and led to dose modification or interruption in 16% of patients.

Dabrafenib

In 2013 the FDA approved dabrafenib (Taflinar), a BRAF inhibitor in the same class as vemurafenib, for patients with unresectable or metastatic melanoma with BRAF V600E mutation confirmed by the THxID BRAF mutation test.[79]  In a multicenter, open-label, phase III randomized controlled trial, treatment with dabrafenib significantly improved progression-free survival (PFS) in patients with BRAF-mutated metastatic melanoma, compared with dacarbazine (5.1 vs 2.7 mo).[80]

Trametinib

Trametinib (Mekinist) is a mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that was approved by the FDA in 2013 for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by the THxID BRAF mutation test.[79]  Approval was based on a phase III open-label trial in which median PFS was 4.8 months with trametinib versus 1.5 months in patients receiving dacarbazine or paclitaxel. At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% confidence interval [CI], 0.32 to 0.92).[81]

Dabrafenib plus trametinib

In 2014, the FDA approved trametinib for use in combination with dabrafenib for treating patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Approval was based on the demonstration of response rate and median duration of response in a phase I/II study. Median PFS in the full-dose combination therapy group was 9.4 months, compared with 5.8 months in the dabrafenib monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval [CI], 0.25 to 0.62). The rate of complete or partial response with combination therapy was 76%, compared with 54% with monotherapy. Improvement in disease-related symptoms or overall survival was demonstrated for this combination.[82, 83]

Cobimetinib

In 2015, the FDA approved cobimetinib, a MEK1 and MEK2 inhibitor, for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafenib. Approval was based on results in 495 patients with advanced melanoma from the phase III coBRIM study, in which median PFS was longer with cobimetinib plus vemurafenib than with vemurafenib monotherapy (12.3 vs 7.2 months; HR, 0.58; 95% CI, 0.46 - 0.72). Additionally, the objective response rate was higher with the combination than with vemurafenib alone (70% vs 50%; P < 0.0001).[84]

Binimetinib plus encorafenib

The combination of binimetinib (Mektovi), a MEK inhibitor, plus encorafenib (Braftovi), a BRAF inhibitor, was approved by the FDA in 2018 for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. Approval was based on results from the phase III COLUMBUS trial, which demonstrated that the combination doubled median PFS compared with vemurafenib alone (14.9 months versus 7.3 months, respectively (P < 0.0001).[85]

Triple therapy

In 2020, the FDA approved the triple-therapy combination of the programmed cell death ligand–1 protein (PD-L1) inhibitor atezolizumab (Tecentriq), the MEK inhibitor cobimetinib (Cotellic), and vemurafenib for the treatment of BRAF V600 mutation–positive advanced melanoma. Approval was based on results of the double-blind, randomized, placebo-controlled, multicenter trial IMspire150 trial (n=514) in which median PFS was 15.1 months (95% CI: 11.4-18.4) with triple therapy, versus 10.6 months (95% CI: 9.3-12.7) with cobimetinib/vemurafenib plus placebo.[86]

The most common adverse reactions (≥ 20%) with atezolizumab in combination with cobimetinib and vemurafenib in patients with melanoma were rash, musculoskeletal pain, nausea, fatigue, hepatotoxicity, pyrexia, nausea pruritus, edema, stomatitis, hypothyroidism, and photosensitivity reaction.

The recommended atezolizumab dose, following completion of a 28-day cycle of cobimetinib and vemurafenib, is 840 mg every 2 weeks with cobimetinib 60 mg orally once daily (21 days on /7 days off) and vemurafenib 720 mg orally twice daily.

Treatment of BRAF V600 wild-type melanoma

For patients with BRAF V600 wild-type, unresectable or metastatic melanoma, nivolumab plus ipilimumab is a preferred choice for first-line treatment.[21] The FDA approved nivolumab plus ipilimumab for this indication in 2015. Approval was based on results from the phase II CheckMate 069 study. Of the 142 patients enrolled, 109 had BRAF wild-type melanoma. In patients with BRAF wild-type melanoma treated with the combination regimen, the objective response rate (the primary study endpoint) was 61% (95% CI: 48-71), compared with 11% (95% CI: 3-25) in patients given ipilimumab monotherapy (P < 0.001).[87]

Additional analysis of CheckMate 069 showed that complete responses were seen in 22% of patients in the combination therapy arm but in none of the patients in the ipilimumab arm. Partial responses were seen in 43% of the combination group and 11% of the ipilimumab monotherapy group. The combination group had a 60% reduction in the risk of progression compared with ipilimumab alone (HR=0.40; 95% CI: 0.22-0.71; P < 0.002). Median PFS was 8.9 months with the combination (95% CI: 7.0-NA) and 4.7 months with ipilimumab alone (95% CI: 2.8-5.3).[87]

Additional analysis showed that complete responses were seen in 22% of patients. Partial responses were seen in 43% of the combination group and 11% of the ipilimumab monotherapy group. The combination group had a 60% reduction in the risk of progression compared with ipilimumab alone (HR=0.40; 95% CI: 0.22-0.71; P < 0.002). Median PFS was 8.9 months with the combination (95% CI: 7.0, NA) and 4.7 months with ipilimumab alone (95% CI: 2.8-5.3). [94]

In pharmacovigilance studies, myocarditis occurred in 0.27% of patients treated with the combination of ipilimumab and nivolumab. Johnson et al reported fatal myocarditis in two patients with melanoma who were receiving treatment with ipilimumab and nivolumab. Both patients developed myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates.[88]

The phase III CheckMate 067 study in previously untreated patients with unresectable or metastatic melanoma randomized patients into three arms: combination therapy with nivolumab plus ipilimumab, monotherapy with nivolumab, and ipilimumab monotherapy. On 6.5-year follow-up, overall survival in patients with BRAF wild-type tumors was 46% in the nivolumab-plus-ipilimumab group, compared with 42% in the nivolumab group and 22% in the ipilimumab group. OS rates in patients with BRAF-mutant tumors were 57%, 43%, and 25%, respectively.[89]

Nivolumab monotherapy

Nivolumab was first approved for use in melanoma in 2014, when the FDA granted accelerated approval for treatment of unresectable or metastatic melanoma unresponsive to other drugs. Approval was based on interim results of a randomized clinical trial in patients with unresectable or metastatic melanoma that had progressed after ipilimumab. Interim analysis confirmed objective responses in 38 of the first 120 patients treated with nivolumab (31.7%; 95% CI 23.5-40.8) versus five of 47 patients who received investigator's choice of chemotherapy (10.6%; CI, 3.5-23.1).[4]

Nivolumab monotherapy was approved in 2015 on the basis of data from the randomized phase III CheckMate-066 trial, which compared nivolumab monotherapy with dacarbazine in the first-line treatment of 418 patients with advanced BRAF wild-type melanoma. In an interim analysis, nivolumab demonstrated superior overall survival, which was the primary outcome. The overall survival rate at 1 year with nivolumab versus dacarbazine was 72.9% versus 42.1%, respectively. In addition, median progression-free survival was longer in the nivolumab-treated patients compared with dacarbazine (5.1 vs 2.2 months; HR, 0.43; P < 0.001).[90] In 2016, the indication for nivolumab was expanded to include mutation-positive metastatic melanoma, making nivolumab effective across BRAF status.[76]

Pembrolizumab

Programmed cell death–1 protein (PD-1) and the related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. The PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells.

In 2014, the FDA granted accelerated approval for pembrolizumab (Keytruda). Pembrolizumab is the first monoclonal antibody for inhibition of PD-1.[91]  It was initially indicated for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on data including a study in which approximately 24% of patients experienced tumor shrinkage.[3]

In 2015, the FDA approved pembrolizumab as first-line treatment for unresectable or metastatic melanoma. Approval was based on the phase 3 KEYNOTE-006 trial. Patients with advanced melanoma were randomized to receive either pembrolizumab 10 mg/kg every 2wk or every 3wk, or 4 doses of ipilimumab (3 mg/kg every 3wk). Progression-free survival for the pembrolizumab groups were 47.3% and 46.4% respectively and 26.5% for ipilimumab. Note that the trial used a higher dose of pembrolizumab than the dose that is approved by the FDA, which is 2 mg/kg every 3 wk.[92]

Ipilimumab

Ipilimumab is an inhibitor of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). It is a humanized antibody directed at a down-regulatory receptor on activated T cells.[93]  The proposed mechanism of action is inhibition of T-cell inactivation, allowing expansion of naturally developed melanoma-specific cytotoxic T cells.

Ipilimumab was approved by the FDA in 2011 for unresectable or metastatic melanoma. In 2017, ipilimumab was approved in adolescents aged 12 years or older for treatment of unresectable or metastatic melanoma.[94]

Hodi et al reported improved survival with ipilimumab in patients with metastatic melanoma. In a phase III study, 676 patients with unresectable stage III or IV melanoma whose disease had progressed while receiving therapy for metastatic disease were randomly assigned in a 3:1:1 ratio to ipilimumab plus a glycoprotein 100 (gp100) peptide vaccine, ipilimumab, or gp100 alone. Ipilimumab was given at a dose of 3 mg/kg and was administered with or without gp100 every 3 weeks for up to 4 treatments; subsequently, patients would receive reinduction therapy.[95]

The median overall survival was 10 months in patients receiving ipilimumab plus gp100, compared with 6.4 months in those receiving gp100 alone. There was no difference in survival in the other ipilimumab arm compared with the ipilimumab plus gp100 arm. Because of these findings, ipilimumab was approved as a treatment for metastatic melanoma.[95]

In a phase III study of ipilimumab and dacarbazine compared with dacarbazine and placebo, survival in patients with metastatic melanoma was improved by 2 months (11 mo vs 9 mo) in the ipilimumab arm; however, those patients had more grade 3 and 4 toxicity.[96]

In the MDX010-20 trial, researchers evaluated immune-related adverse events (AEs) in 676 patients previously treated for metastatic melanoma who were randomly assigned to receive 1 of the following 3 treatment regimens (in a 3:1:1 ratio): (1) ipilimumab plus gp100; (2) ipilimumab plus placebo; or (3) gp100 plus placebo.[97]  Most of the immune-related AEs developed within 12 weeks of initial dosing, typically resolving in 6-8 weeks. Fewer than 10% of patients receiving any ipilimumab treatment experienced an immune-related AE more than 70 days after their last drug dose, and all of these AEs were grade 1 or 2 in severity. Most immune-related AEs, even grade 3/4 events, were readily managed with monitoring and early corticosteroid therapy; only 5 patients needed infliximab for gastrointestinal AEs, and all 5 subsequently improved.[97]

Ipilimumab is also approved in the adjuvant setting. See Adjuvant therapy, above.

Relatlimab plus nivolumab

Opdualag, a fixed-dose combination of nivolumab and the LAG-3-blocking antibody relatlimab, was approved by the FDA in March 2022 for treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. Efficacy was demonstrated in the phase III RELATIVITY-047 trial, a randomized, double-blind study in 714 patients with previously untreated metastatic or unresectable stage III or IV melanoma.[98]

In RELATIVITY-047, patients were randomized to receive nivolumab 480 mg and relatlimab 160 mg by intravenous (IV) infusion every 4 weeks or nivolumab 480 mg by IV infusion every 4 weeks until disease progression or unacceptable toxicity. Patients receiving nivolumab plus relatlimab had significantly longer PFS than those receiving nivolumab alone (10.1 versus 4.6 months, respectively), but also had a higher rate of grade 3 or 4 treatment-related adverse events (18.9% vs 9.7%). The final analysis of OS did not show a statistically significant difference (HR=0.80; 95% CI: 0.64-1.01) with median OS not reached (NR) in the Opdualag arm (95% CI: 34.2-NR) and 34.1 months (95% CI: 25.2-NR) in the nivolumab arm.[98]

In patients receiving nivolumab plus relatlimab, the most common laboratory abnormalities (≥20%) were decreased hemoglobin, decreased lymphocytes, increased liver transaminase values, and decreased serum sodium..The recommended dosage for patients 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks until disease progression or unacceptable toxicity.[98]

KIT inhibitor therapy

In a multicenter phase II trial, targeted therapy with imatinib was effective in patients with advanced melanoma harboring mutations and/or amplification of the KIT proto-oncogene.[99, 100] Hodi et al reported that in patients with metastatic melanomas arising from acral, mucosal, or chronically sun-damaged sites and containing KIT amplifications, mutations, or both, 7 of 24 patients achieved a partial response to therapy, with five patients' responses confirmed on subsequent imaging studies, for an overall confirmed response rate of 21%.[99] These findings reinforce similar findings in two earlier studies.[6, 101] Japanese researchers are currently recruiting patients for a study of imatinib combined with pembrolizumab in patients with advanced KIT-mutant melanoma that has progressed on standard therapy.[102]

Vaccines

Various vaccines have been studied in the treatment of melanoma. A phase III trial found that multiepitope peptide vaccination did not significantly improve relapse-free survival or overall survival in patients with high-risk resected melanoma.75  In contrast, several small studies using a personalized peptide-based DNA or RNA vaccine targeting a number of tumor neoantigens reported that some treated patients remained recurrence-free for up to 25 months, while other patients experienced recurrences but responded to treatment with pembrolizumab.[103] Phase I trials of vaccination against telomerase human telomerase reverse transcriptase (hTERT), in combination with checkpoint inhibitors, have suggested clinical efficacy with negligible added toxicity.[104]

Less frequently used therapies

With the advent of biologic therapies—most notably, agents that inhibit PD-1, BRAF, and MEK—the role of cytotoxic and immunotherapy agents such as dacarbazine and interleukin-2 (IL-2) has steadily diminished. For example, current NCCN guidelines recommend that use of cytotoxic agents (eg, carboplatin plus paclitaxel, or single-agent temozolomide) may be considered in symptomatic patients who are not candidates for further standard, immune-based, BRAF/MEK inhibitor therapy. However, the NCCN notes that cytotoxic therapy has a limited impact on overall survival in this setting.[21]

Dacarbazine

Dacarbazine was the first drug approved by the FDA for the treatment of metastatic melanoma. In the initial studies with dacarbazine, the overall response rate was 22%, with no impact on survival. In a phase III study of dacarbazine compared with temozolomide, the response rate was 12% versus 13%, respectively.[105] On the basis of this trial, and the greater ease of administration of temozolomide versus dacarbazine (oral versus intravenous), most oncologists prefer temozolomide for melanoma chemotherapy. Temozolomide has orphan drug designation for treatment of advanced metastatic melanoma.

Interleukin 2

The second drug approved by the FDA for the treatment of metastatic melanoma was interleukin-2 (IL-2), a recombinant hormone of the immune system originally described as a T-cell–derived growth factor and used as a lymphokine-activated cell killer therapy. A pooled analysis of 270 patients treated with a high-dose IL-2 bolus (600,000-720,000 units/kg every 8 hours for 5 days) resulted in an objective response rate of 16% (complete response of 6%) with the best response in patients with soft tissue and lung metastases. Median overall median survival was 11.4 months.[106]

The treatment was quite toxic, with some patients requiring intensive care unit support. The more common toxicities included hypotension (45%), vomiting (37%), diarrhea (32%), and oliguria (39%). Consequently, this therapy is offered only in centers that have adequately trained staff and facilities. To qualify for IL-2 therapy, patients must have normal results on pulmonary function testing, brain imaging, and cardiac stress testing, plus adequate kidney and liver function.

Carboplatin plus paclitaxel

Combination therapy with carboplatin and paclitaxel has been tested in two small phase II studies, and when used together with sorafenib, the response rate was 11-17%. This regimen sometimes is used by clinicians in clinical practice because of lesser toxicity than dacarbazine and also as a second- or third-line regimen.

However, a randomized, placebo-controlled phase III study by Hauschild et al found that the addition of sorafenib to carboplatin and paclitaxel did not improve outcome in patients with unresectable stage III or IV melanoma; these investigators recommend against this combination in the second-line setting for patients with advanced melanoma.[107, 108]

Treatment of brain metastases

The brain is a common site of metastasis in malignant melanoma. Brain metastases are associated with a poor prognosis; they tend to progress rapidly and display resistance to conventional therapies.

Stereotactic radiosurgery is used increasingly in patients with a limited number of brain metastases (fewer than 3); it is less invasive than craniotomy. External-beam radiation alone appears effective in palliating symptoms. Chemotherapy alone is relatively ineffective, although the combination of chemotherapy with external-beam radiation is being investigated.[35]

Investigational Treatments

In a phase Ib/II clinical trial in 24 patients with stage IV melanoma, Tobin et al reported favorable tolerability and a high response rate to treatment with the combination of all-trans retinoic acid (ATRA) and pembrolizumab. The overall response rate was 71%, with 50% of patients experiencing a complete response. Median PFS was 20.3 months and  1-year OS was 80%. The combination effectively lowered the frequency of circulating myeloid-derived suppressor cells—immature myeloid cells that accumulate in the circulation and at tumor sites, where they suppress antitumor immunity.[109]

In a randomized, open-label phase III trial in 168 patients with unresectable stage IIIC or IV melanoma, Rohaan et al demonstrated the survival benefit of therapy with tumor-infiltrating lymphocytes (TILs), compared with ipilimumab. For this personalized autologous treatment, tumor-resident T cells from the patient undergo ex vivo outgrowth and expansion, with subsequent intravenous adoptive transfer after preparative lymphodepleting chemotherapy,  supported by treatment with interleukin-2 to enhance expansion of the cells in the patient and augment their antitumor responses.[110]

Median PFS was 7.2 months (95% CI, 4.2-13.1) in the TIL group and 3.1 months (95% CI, 3.0-4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P< 0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median OS was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8-32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab. In the TIL group, most of those events were chemotherapy-related myelosuppression.[110]

The focus of melanoma prevention is avoidance of sun exposure. Everyone, especially those individuals at high risk of developing a melanoma, should wear protective clothing, avoid peak sun hours, protect children against exposure to ultraviolet radiation, avoid tanning booths, and wear sunscreen with a sun protection factor (SPF) of at least 15.

This last recommendation is considered somewhat controversial, because no study has shown sunscreen to reduce the incidence of melanoma.[111] Moreover, a systematic review found that sunscreen use leads to longer duration of intentional sun exposure, and sunburns tend to be more frequent among sunscreen users.[112]

In addition, a study of 499 white children who were enrolled at birth or at age 6 and stratified colorimetrically by skin tone found no association between sunscreen use and the overall number of moles at the age of 15 years. The only significant association was for lighter-skinned children who had at least three sunburns at 12 to 14 years old, who had fewer moles if they used sunscreen. However, even that association might have occurred by chance.[113]

First-degree relatives of a patient diagnosed with familial melanoma should be encouraged to have annual skin examinations. Individuals with other risk factors for melanoma (see Overview/Etiology) should seek regular screening or do self-screening.

A patient with a suggestive lesion should be referred to a dermatologist or surgical oncologist for excisional biopsy.

If the diagnosis of melanoma is made, the patient should be referred to an oncologist after definitive surgery is performed.

Follow-up care of a patient with melanoma is based on the stage of the primary. The follow-up examination should be performed with the knowledge that the patient has an increased risk for a second primary and that, of all solitary sites of visceral recurrence, the lungs are the most frequent.

Follow-up guidelines from the National Comprehensive Cancer Network are listed below.[21]

Follow-up for stage 0 in situ is as follows:

• At least annual skin examination for life
• Educate patient in monthly self-examination of skin

Follow-up for stage IA is as follows:

• History and physical examination (H&P) (with emphasis on nodes and skin) every 3-12 mo for 5 y, then annually as clinically indicated
• At least annual skin examination for life
• Educate patient in monthly self-examination of skin and lymph nodes

Follow-up for stage IB-IV (patients with no evidence of disease) is as follows:

• H&P (with emphasis on nodes and skin) every 3-6 mo for 2 y, then every 3-12 mo for 2 y, then annually as clinically indicated
• Chest radiography, lactate dehydrogenase (LDH) level, and complete blood cell count (CBC) every 6-12 mo (optional)
• Routine imaging is not recommended for stage IB or IIA disease
• CT scans to follow up for specific signs and symptoms
• Consider CT scans to screen stage IIB and higher for recurrent/metastatic disease
• At least annual skin examination for life
• Educate patient in monthly self-examination of skin and lymph nodes

Investigational studies suggest that neoadjuvant therapy with checkpoint inhibitors may be superior to adjuvant therapy. Blank et al randomized 20 patients with palpable stage III melanoma to receive ipilimumab/nivolumab in either four courses after surgery (adjuvant arm) or two courses before surgery and two courses after surgery (neoadjuvant arm). Neoadjuvant therapy proved feasible, with all patients undergoing surgery at the preplanned time point; 78% of patients achieving pathological response; and on median follow-up of 25.6 months, no patient experiencing relapse. However, in both the adjuvant and neoadjuvant arms, 9 of the 10 patients experienced one or more grade 3/4 adverse events. These authors concluded that neoadjuvant therapy appears promising, but further investigation is needed into reducing toxicity while preserving efficacy.[114]

OpACIN-neo, a multicenter phase II trial by Rozeman et al in 86 patients with macroscopic stage III melanoma, identified an effective and tolerable dosing schedule for neoadjuvant therapy. In this randomized comparison of three neoadjuvant dosing schedules, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously was associated with the lowest rate of grade 3-4 immune-related adverse events (20%). Of patients receiving this schedule, 57% achieved a radiologic objective response and 77% achieved a pathological response. Rozeman et al suggest that this schedule might be suitable for broader clinical use.[115]

Unlike advanced cutaneous melanoma, metastatic uveal melanoma does not respond to standard immunotherapies. However, a new class of immunotherapy agents, immune-mobilizing monoclonal T-cell receptors against cancer (ImmTACs), has shown benefit. ImmTACs enhance the function of tumor-specific T cells, which otherwise tend to have weak binding with tumor antigens.[116]

The first ImmTAC to become clinically available, tebentafusp-tebn (Kimmtrak), was approved by the FDA in 2022 for HLA-A*02:01–positive adult patients with unresectable or metastatic uveal melanoma. This agent is a bispecific fusion protein comprised of a soluble T-cell receptor fused to an anti-CD3 immune-effector function. It places T cells in proximity to melanoma cells by targeting the gp100 protein, a lineage antigen expressed in melanocytes and melanoma.

The efficacy of tebentafusp-tebn was demonstrated in IMCgp100-202 (NCT03070392), an open-label, multicenter trial in which patients with metastatic uveal melanoma were randomized to receive tebentafusp-tebn (n=252) or investigator’s choice (n=126) of pembrolizumab, ipilimumab, or dacarbazine. Median overall survival was 21.7 months for patients treated with tebentafusp-tebn versus 16 months in patients who received the investigator’s choice of therapy (hazard ratio [HR]=0.51, 95% CI: 0.37, 0.71, P < 0.0001), and progression-free survival was 3.3 versus 2.9 months (HR=0.73, 95% CI: 0.58, 0.94, P=0.0139).[117]

In the tebentafusp-tebn arm, the most common adverse reactions (≥30%) were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common laboratory abnormalities (≥50%) were decreased lymphocyte count, increased creatinine, increased glucose, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin, and decreased phosphate.

For full discussion of this form of melanoma, see Choroidal Melanoma.

Guidelines contributors: Wesley Wu, MD, Resident Physician, Department of Dermatology, Baylor College of Medicine; Mohsin R Mir, MD, Director, High Risk Skin Cancer Clinic, Assistant Professor, Mohs Surgery, Laser and Cosmetic Surgery, Department of Dermatology, Baylor College of Medicine

Screening

In 2016, the U.S. Preventive Services Task Force (USPSTF) concluded there is not enough evidence to recommend for or against routine screening (total body examination by a primary care physician or patient self-examination) for early detection of skin cancers in the adult general population.[118]  

The USPSTF did note the following clinical considerations:

• Skin cancer of any type occurs more commonly in men than in women and among persons with a fair complexion, persons who use indoor tanning beds, and persons with a history of sunburns or previous skin cancer. 
• Specific risk factors for melanoma include having an atypical mole, multiple (ie, ≥100) moles, and having a family history of melanoma.
• The risk of melanoma increases with age; the median age at diagnosis is 63 years, and the median age at death is 69 years.
• Clinical visual skin examination should assess skin lesions for asymmetry, border irregularity, color variability, diameter greater than 6 mm or evolution over time (ABCDE criteria)

The American Academy of Dermatology (AAD) promotes free skin examinations by volunteer dermatologists for the general population through the Academy's SPOTme™ Screening Program. The program also provides education about the importance of sun protection and early cancer detection.[119]

Guidelines from the American Academy of Dermatology (AAD), established in 2011 and updated in 2019, are as follows[120, 121] :

• Skin biopsy remains the first step to establish a definitive diagnosis of cutaneous melanoma.

• Preferred biopsy technique is a narrow excisional/complete biopsy with 1- to 3-mm margins that encompass the entire breadth of lesion and is of sufficient depth to prevent transection at the base. Diagnostic excisional biopsy can be accomplished by (1) elliptical (fusiform) excision, (2) punch excision around the clinical lesion, or (3) deep shave/saucerization to a depth below the anticipated plane of the lesion, usually extending to the deep reticular dermis.

• Partial/incomplete sampling (incisional biopsy) is acceptable for lesions whose large size or location in a challenging anatomic site (eg, facial, acral) precludes excisional biopsy, and for lesions with low clinical suspicion or uncertainty of diagnosis. Such biopsies should include the most clinically and/or dermoscopically atypical portion(s) of the lesion

• Narrow-margin excisional biopsy may be performed if an initial partial biopsy is inadequate for diagnosis or microstaging, but it should not generally be performed if the initial specimen meets the criteria for consideration of sentinel lymph node biopsy.

• Dermoscopy can improve diagnostic accuracy in lesions of clinical concern; it may help direct optimal and adequate tissue sampling of very large lesions or those in cosmetically or functionally sensitive areas.

• Prebiopsy photographs are an important aid to clinical/pathologic correlation and help to prevent wrong-site surgery if further treatment is required. Photographs may be taken by the patient and/or health care provider and should include a regional photograph that encompasses anatomic landmarks.

• Findings from history and physical examination should direct need for further studies to detect local, regional, and distant metastasis

• Ancillary diagnostic molecular techniques (eg, comparative genomic hybridization; fluorescence in situ hybridization, gene expression profiling [GEP]) may be used for equivocal melanocytic neoplasms, but routine molecular testing, including GEP, for prognostication is discouraged until better use criteria are defined. Testing of the primary cutaneous melanoma for oncogenic mutations (eg, BRAF, NRAS) is not recommended in the absence of metastatic disease.

The 2019 guidelines from the European Society for Medical Oncology (ESMO) require diagnosis based on a full-thickness excisional biopsy with a minimal side margin that has been processed by an experienced pathology institute. Histology reports should include the following[122] :

• Information on the type of melanoma
• Actinic damage
• Maximum vertical thickness in millimeters
• Information on mitotic rate 
• Presence of ulceration
• Presence and extent of regression
• Clearance of the surgical margins

ESMO guidelines consider mutation testing for actionable mutations mandatory in patients with resectable or unresectable stage III or stage IV, and highly recommended in high-risk resected disease stage IIC, but not for stage I or stage IIA–IIB. BRAF testing is mandatory.

Physical examination with special attention to other suspicious pigmented lesions, tumor satellites, in-transit metastases, regional lymph nodes, and distant metastases is requred. Imaging is not needed for low-risk melanomas but  in higher-stage tumors, US, CT, and/or PET scans are recommended to allow proper tumor assessment for accurate staging.[122]

The National Comprehensive Cancer Network (NCCN) guidelines recommend the following for biopsy of a suspicious pigmented lesion[21]

• Excisional/complete biopsy (elliptical, punch, or saucerization/deep shave) with 1- to 3-mm margins is preferred. Avoid wider margins to permit accurate subsequent lymphatic mapping.
• The orientation of an elliptical/fusiform excisional biopsy should be planned with definitive wide local excision in mind (eg, longitudinally [axially] and parallel to the underlying lymphatics on the extremities). 
• Full-thickness incisional or punch biopsy of clinically thickest or most atypical portion of lesion is acceptable in certain anatomic areas (eg, palm/sole, digit, face, ear) or for very large lesions. Multiple "scouting" biopsies may help guide management for very large lesions.
• Superficial shave biopsy may compromise pathologic diagnosis and complete assessment of Breslow thickness, but is acceptable when the index of suspicion is low. However, a broad shave biopsy may be optimal for histologic assessment for melanoma in situ (MIS), lentigo maligna (LM) type (ie, melanoma on skin with high cumulative sun damage).
• Repeat narrow-margin excisional biopsy is recommended if an initial partial biopsy is inadequate for diagnosis or microstaging but should not be performed if the initial specimen meets criteria for sentinel lymph node biopsy (SLNB).

The NCCN guidelines support the concept that most melanoma recurrences are diagnosed clinically. Current NCCN guidelines state that no further workup (ie, baseline laboratory tests and imaging studies) is required in stage 0 (melanoma in situ) and for asymptomatic patients with stage IA, IB, or IIA melanoma. (Physician Quality Reporting System [PQRS] measure #224 concerns overutilization of imaging studies in melanoma.)

Current NCCN guidelines do not recommend surveillance (follow-up) laboratory or imaging studies for asymptomatic patients with stage IA, IB, and IIA melanoma (ie, tumors ≤4 mm depth). Imaging studies (chest radiograph, CT and/or PET-CT) should be obtained as clinically indicated for confirmation of suspected metastasis or to delineate the extent of disease.[21]

The NCCN advises that imaging studies may be considered to screen for recurrent/metastatic disease in patients with stage IIB-IV disease, although this recommendation remains controversial. Routine laboratory or radiologic imaging in asymptomatic melanoma patients of any stage is not recommended after 5 years of follow-up.[21]

While abnormal laboratory test results are rarely the sole indicator of metastatic disease, serum lactate dehydrogenase (LDH) levels are incorporated into the American Joint Committee on Cancer (AJCC) melanoma staging guidelines for the classification of stage IV (distant) disease. Elevated LDH levels are associated with worse survival in this subgroup.[34]

Joint guidelines from the European Dermatology Forum, the European Association of Dermato-Oncology, and the European Organization for Research and Treatment of Cancer include the following recommendations on diagnosis of melanoma[123] :

• The 8 ^th edition of the AJCC staging manual should be used for classification into prognostic stages.
• When melanoma is suspected based on clinical findings, it should be confirmed using histopathology studies.
• Dermatoscopy should be used for assessing all nonpigmented and pigmented skin lesions. Training in dermatoscopy is considered mandatory.
• Use whole-body photography with sequential examinations when assessing high-risk patients for early melanoma detection.
• Use sequential digital dermatoscopy to help improve early melanoma detection; this technique should be used in high-risk patients in whom the total nevus count is high.
• The use of confocal laser microscopy can be considered for the further evaluation of clinically or dermatoscopically equivocal skin lesions.
• Ultrasonography on locoregional lymph nodes should be performed  as part of the initial workup for all primary melanomas staged pT1b or higher.

American Academy of Dermatology

American Academy of Dermatology (AAD) recommendations for surgical management of primary cutaneous melanoma are as follows[121] :

• Surgical excision with histologically negative margins is the recommended and first-line treatment for primary cutaneous melanoma of any thickness, as well as for melanoma in situ.
• Surgical margins should be based on tumor thickness. 
• Depth of excision is recommended to (but not including) the fascia.
• Sentinel lymph node biopsy, when indicated, should be performed before wide excision of the primary tumor, and in the same operative setting, whenever possible.
• Mohs micrographic surgery or staged excision with paraffin-embedded permanent sections may be utilized for melanoma in situ, lentigo maligna type, on the face, ears, or scalp for tissue-sparing excision and exhaustive histologic assessment of peripheral margins.

European Society for Medical Oncology

The European Society for Medical Oncology (ESMO) updated its guidelines on the management of locoregional melanoma in 2020.[124]

Wide local excision:

• In the context of resectable clinical stage III disease, primary melanomas should be removed with clear margins to ensure local control. Wide local excision (WLE), ideally with a clinical 1 cm margin, is advised, with primary closure to avoid reconstruction whenever possible.
• In the context of clinical stage IV disease, in the absence of symptoms or need for diagnostic tissue, there is no need to resect the primary tumor. If there is an indication to resect the primary lesion, resection should be with clear margins, but without additional safety margins.

Radical lymph node dissection:

• Radical lymph node dissection is recommended for cases of clinically detected lymph node metastases in resectable stage III disease after pathological assessment (cytology or histology of lesion preoperatively) and adequate staging.
• When lymph node surgery is indicated, radical node dissection is recommended over “node picking” (ie, removal of only lymph nodes with clinically apparent disease).
• Groin: If imaging does not show any iliac involvement, an inguinal dissection is sufficient. If iliac disease is also present, a combined ilio-inguinal dissection should be performed.
• Axilla: Complete clearance of the axilla, including level I–III, should be performed.
• Neck: Modified radical neck dissection is recommended. Parotidectomy should be performed only if there is evidence of involvement of the parotid.

Treatment of satellite or in-transit metastases:

• For resectable in-transit metastases that can comprise few, small, and non–rapidly-recurrent lesions, resection with clear margins—but without additional safety margins—is recommended. Extensive and multiple repeated resections and reconstructions should be avoided.
• Unresectable satellite/in-transit metastases, or inoperable primary tumors of the limbs without additional metastases, may be treated with locoregional treatments (eg, isolated limb perfusion or infusion, talimogene laherparepvec [T-VEC], electrochemotherapy, 10% rose Bengal solution [PV-10]).

Adjuvant radiotherapy after node dissection:

• For patients with advanced stage III disease that has been treated with lymphadenectomy, the primary recommendation is adjuvant systemic therapy and observation, reserving additional surgery and radiotherapy (RT) for any recurrent disease. However, adjuvant RT could be useful for high-risk patients where regional control is a major issue and/or where systemic therapy is not possible.

Neoadjuvant therapy:

• For easily resectable stage III disease with acceptable surgical morbidity, neoadjuvant strategies should be considered only in the context of a clinical trial. Outside of a clinical trial, neoadjuvant strategies should be considered for technically resectable but bulky nodal and/or in-transit disease when surgery will be associated with significant morbidity, likely to result in positive resection margin status, or necessitate postoperative RT.
• Continuing treatment after surgery should be considered based on the pathological response evaluation of the surgical specimen.
• In principle, the standard surgical approach should be used after neoadjuvant therapy until studies show that it is safe to omit or modify surgery. Tailoring of the extent of surgery can be considered if there is a major radiological or pathological response for disease that extends outside of the nodal basin.

BRAF-mutated melanomas:

• Current evidence suggests that patients with BRAF-mutated melanoma can derive a recurrence-free survival benefit from either adjuvant BRAF/MEK inhibition or adjuvant PD-1 blockade. In the absence of a direct efficacy comparison, individual treatment decisions should be made with the patient, factoring in the toxicity profiles for the different adjuvant treatment approaches.

Adjuvant therapy in stage IIIA melanoma:

• An absolute survival benefit of 5% at 5 years would be considered strong evidence to recommend adjuvant therapy in stage III melanoma. However, surrogate markers of overall survival benefit are currently acceptable.
• There is currently insufficient evidence to support the routine use of adjuvant therapy in stage IIIA melanoma.
• There may be some subsets of stage IIIA patients with a higher risk of relapse (eg, tumor burden in sentinel node >1 mm). In these patients, a balanced discussion of risk reduction and long-term side effects of adjuvant therapy can be considered.

Management of toxicity in the adjuvant setting:

• The management of toxicity from adjuvant therapy should be done according to the established management algorithms for metastatic disease.
• When adjuvant immunotherapy is withheld because of severe toxicity, the recommendation is neither to restart treatment nor to start an alternative adjuvant therapy.

Adjuvant therapy for in-transit metastases and resected stage IV disease:

• Adjuvant dabrafenib plus trametinib can be considered in patients with completely resected BRAF V600–mutated stage IV melanoma if there is a contraindication to immunotherapy.
• Adjuvant therapy may be considered for patients with completely resected in-transit melanoma or microsatellites, including patients without evidence of nodal metastasis.
• In cases of resectable locoregional relapse in patients receiving adjuvant therapy, whether to resume adjuvant therapy after complete resection remains controversial in the absence of prospective clinical data.

The melanoma guidelines from the National Comprehensive Cancer Network (NCCN) do not recommend sentinel lymph node biopsy for patients with in situ melanoma (stage 0).[21]

Evidence supporting routine sentinel lymph node biopsy for patients with thin melanomas (T1; Breslow thickness < 1 mm) is lacking and recommendations remain controversial. The NCCN does not recommend sentinel lymph node biopsy for patients with lesions 0.75 mm or thinner.[2]

The 2020 update of the European Society for Medical Oncology melanoma guidelines includes the following recommendations on sentinel lymph node biopsy[124] :

• Sentinel lymph node biopsy is recommended for staging in melanomas of stage pT2a or higher (> 1.0 mm Breslow thickness).
• Sentinel lymph node biopsy should be discussed with patients with a melanoma of stage pT1b (ie, with tumor thickness > 0.8–1.0 mm, or <  0.8 mm with ulceration).
• Sentinel lymph node biopsy is not routinely recommended for patients with a melanoma of stage pT1a (eg, with tumor thickness <  0.8 mm and no ulceration).
• Sentinel lymph node biopsy can be discussed in pT1a for special cases (eg, ≥3 mitoses/mm ², positive deep margin, or when Breslow thickness cannot be reliably determined [pTx]).

The American Academy of Dermatology (AAD) recommends consideration of sentinel lymph node biopsy in patients with lesions, including those less than 0.76 mm, with any of the following high-risk features[120, 121] :

• Ulceration
• Mitosis
• Angiolymphatic invasion
• Positive deep margin
• Young patient age

However, data suggest that the presence of a single mitotic figure may not correlate well with sentinel node status in thin lesions.[125]  In addition, the presence of regression in thin lesions is associated with a lower risk of nodal metastasis.[126]

The 2018 update of joint guidelines from the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) includes the following recommendations[127] :

• Routine sentinel lymph node biopsy is not recommended for patients with thin melanomas that are T1a (non-ulcerated lesions < 0.8 mm in Breslow thickness).
• Sentinel lymph node biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or < 0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure.
• Sentinel lymph node biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of >1.0 to 4.0 mm).
• Sentinel lymph node biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm.

In the case of a positive sentinel lymph node biopsy, completion lymph node dissection (CLND) or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathologic factors. For higher-risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND.[127]

The NCCN cites a study of Mohs micrographic surgery (MMS) that employed MMS enhanced by immunohistochemical staining as the primary treatment modality for melanoma in situ, which resulted in 99% removal of melanoma in situ when a total surgical margin of 9 mm was used, versus an 86% rate of removal with 6-mm margins. The stain comprised antibodies to a melanoma antigen recognized by T cells (MART-1).[21, 128]

The appropriate-use criteria for MMS from the AAD, American College of Mohs Surgery (ACMS), American Society for Dermatologic Surgery Association (ASDSA), and the American Society for Mohs Surgery (ASMS) further state that MMS is appropriate for all recurrent melanoma in situ and lentigo maligna, as well as primary lesions at the following sites[129] :

• Head
• Neck
• Hands
• Feet
• Pretibial surface
• Nails
• Ankles

For melanoma in situ, lentigo maligna type type, the AAD recommends permanent section analysis of the central MMS debulking specimen to identify and appropriately stage potential invasive cutaneous melanoma. If invasive cutaneous melanoma is identified on an MMS section intraoperatively, the tissue should be submitted for formal pathology review.[121]

For wide excision of primary melanoma, the NCCN, AAD, and ESMO practice guidelines agree on the following surgical margin recommendations for primary melanoma[21, 121, 122]

• Tumor in situ – Margin size 0.5-1.0 cm
• Tumor ≤ 1 mm – Margin size 1 cm
• Tumor > 1 to 2 mm – Margin size 1-2 cm
• Tumor > 2 mm – Margin size 2 cm

The AAD guidelines note that margins may be narrower to accommodate function and/or anatomic location.However, for primary invasive melanomas at anatomically constrained sites (eg, head and neck, acral), margins of < 1 cm (by either wide excision or Mohs micrographic surgery) are generally not recommended until further studies are available.[121]

NCCN guidelines recommend consideration of radiation therapy in the following situations[21] :

• Primary disease: As adjuvant treatment in selected patients with factors that include deep desmoplastic melanoma with narrow margins, extensive neurotropism, or locally recurrent disease

• Regional disease: As adjuvant treatment following resection of category 2B nodes and LDH < 1.5 times the upper limit of normal, and extranodal tumor extension; as palliative treatment for unresectable disease

• Metastatic disease: As either adjuvant or primary treatment for brain metastases

ESMO recommends considering stereotactic radiation of regional or single distant metastatic disease.[122]

NCCN recommendations for treatment of melanoma stage IV disease with distant metastasis include the following[21] :

• Treatment depends on whether melanoma is limited (resectable) or disseminated (unresectable)
• In limited disease, resection is recommended; alternatively, observation or systemic therapy may be chosen
• Treatment for limited disease includes clinical trial enrollment or systemic therapy 
• For patients with unresectable disease without brain metastases, treatment includes systemic therapy; patients with brain metastases require treatment of the central nervous disease

First-line immunotherapy regimens for systemic therapy (category 1), according to the NCCN guidelines, are as follows[21] :

• Anti–programmed cell death protein 1 (PD-1) monotherapy: Pembrolizumab or nivolumab 
• Nivolumab/ipilimumab 

If the tumor contains a BRAF V600 activating mutation, category 1 recommendations for first-line therapy are as follows[21] :

• Dabrafenib plus trametinib
• Vemurafenib plus cobimetinib
• Encorafenib plus binimetinib 

Second-line or subsequent therapy recommendations are as follows[21] :

• Anti PD-1 monotherapy: Pembrolizumab or nivolumab
• Nivolumab/ipilimumab
• Targeted therapy if a BRAF V600 activating mutation is present: Dabrafenib/trametinib or vemurafenib/cobimetinib
• Ipilimumab
• High-dose interleukin-2 (IL-2)
• Cytotoxic agents
• Imatinib for tumors with activating mutations of KIT 

Joint guidelines from the European Dermatology Forum, the European Association of Dermato-Oncology, and the European Organization for Research and Treatment of Cancer include the following recommendations on adjuvant therapy in stage III disease[130] :

• Stage IIIA-IIID and fully resected stage IV: Adjuvant therapy should be offered, with anti–PD-1 therapy or targeted therapy.
• Stage IIIA-IIID and fully resected stage IV, regardless of mutational status: Adjuvant therapy can be offered, with anti–PD-1 therapy or targeted therapy.
• Stage IIIA-IIID with BRAF-V600 E/K mutation: Adjuvant therapy can be offered, with BRAF/MEK inhibitor therapy.
• Stage IIIA with nodal metastasis of < 1 mm in diameter: Risk-to-benefit ratio should be carefully discussed with the patient.

The joint European guidelines include the following recommendations for stage IV melanoma[130] :

• First-line therapy in patients with stage IV disease is immunotherapy with checkpoint inhibitors; options include anti–PD-1 monotherapy and combination anti–PD-1 plus anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy.
• In certain situations, such as in patients with stage IV melanoma and BRAF-V600 E/K mutation, an alternative to immunotherapy is first-line therapy with BRAF/MEK inhibitors.
• Chemotherapy should only be considered if resistance to immunotherapy and targeted therapies is present.

The joint European guidelines include the following recommendations for brain metastases[130] :

• Treat brain metastases with stereotactic radiotherapy.
• Surgery is an option if stereotactic radiotherapy is not possible.
• Do not use whole-brain radiotherapy for melanoma brain metastases.
• Regarding systemic therapy for brain metastases, preferred therapy is combined immunotherapy. An alternative in patients with BRAF-V600 E/K mutations is targeted therapy.

Follow-up guidelines from the National Comprehensive Cancer Network are listed below.[21]

Follow-up for stage 0 in situ is as follows:

• At least annual skin examination for life
• Educate patient in monthly self-examination of skin
• Routine blood tests are not recommended
• Routine imaging to screen for asymptomatic recurrence or metastatic disease is not recommended

Follow-up for stage IA-IIA is as follows:

• History and physical examination (H&P), with emphasis on lymph nodes and skin, every 6-12 mo for 5 y, then annually as clinically indicated
• At least annual skin examination for life
• Educate patient in monthly self-examination of skin and lymph nodes
• Routine blood tests are not recommended
• Routine imaging to screen for asymptomatic recurrence or metastatic disease is not recommended
• Imaging as indicated to investigate specific signs or symptoms

Follow-up for stage IB-IV (patients with no evidence of disease) is as follows:

• H&P (with emphasis on nodes and skin) every 3-6 mo for 2 y, then every 3-12 mo for 2 y, then annually as clinically indicated
• Routine blood tests are not recommended
• Imaging as indicated to investigate specific signs or symptoms
• Consider imaging every 3–12 mo for 2 y, then every 6–12 mo for another 3 y (unless otherwise mandated by clinical trial participation) to screen for recurrence or metastatic disease
• Routine imaging to screen for asymptomatic recurrence or metastatic disease is not recommended after 5 y

Pharmacotherapy for melanoma—both as adjuvant therapy in locally advanced disease and first-line therapy in unresectable and stage IV melanoma—increasingly relies on biologic agents, often used in combination. Interferon and the chemotherapy agents dacarbazine, cisplatin, and vinblastine are approved by the US Food and Drug Administration (FDA) for use as adjuvant therapy in melanoma. However, those have largely been supplanted by biologic agents.

Current biologic agents for melanoma include the programmed cell death-1 protein (PD-1) inhibitors pembrolizumab and nivolumab; ipilimumab, which inhibits T-cell inactivation; and a growing number of biologic agents for targeted therapy, such as BRAF and MEK inhibitors (eg, vemurafenib, dabrafenib, trametinib), which are used for melanoma with BRAF V600E or V600K mutations. In addition, intralesional injection with talimogene laherparepvec is approved for skin metastasis.

Class Summary

A variety of agents are used, depending on melanoma stage, biomarkers, surgical resection. 

Dacarbazine

Although the mechanism of action for dacarbazine is unknown, possible actions include alkylating agent, purine metabolite, or interaction with sulfhydryl groups. The end result is inhibition of DNA, ribonucleic acid (RNA), and protein synthesis.

Cisplatin

Cisplatin is an alkylating agent that inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of the double helix.

Vinblastine

Vinblastine inhibits microtubule formation, which disrupts formation of the mitotic spindle, causing cell proliferation to arrest at metaphase. It is a component of the CVD regimen.

Ipilimumab (Yervoy)

Anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a humanized antibody that overcomes CTLA-4-mediated T-cell suppression to enhance the immune response against tumors. The marker CTLA-4 is associated with promoting a regulatory response by the immune system. This regulatory response has a dampening effect on the immune system. Ipilimumab is able to inhibit the effects of CTLA-4 on T cells and allows the expansion of naturally developed melanoma-specific cytotoxic T-cells. This agent is the first new agent to be approved for melanoma in over a decade.

It is indicated for the treatment of unresectable or metastatic melanoma in adults and adolescents aged 12 y or older. Additionally, it is indicated for the adjuvant treatment of adults with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy. It is also used off-label in previously untreated patients with BRAF V600 wild-type, unresectable or metastatic melanoma in combination with nivolumab. Note, nivolumab is approved in combination with ipilimumab.

Dabrafenib (Tafinlar)

Dabrafenib inhibits some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. It is indicated as a single agent for unresectable or metastatic melanoma with BRAF V600 E mutation. It is indicated in combination with trametinib for BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. Additionally, it is approved for adjuvant therapy in combination with trametinib for melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection.

Trametinib (Mekinist)

Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation, and of MEK1 and MEK2 kinase activity. It is indicated as a single agent or in combination with dabrafenib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by with the THxID BRAF mutation test. Additionally, it is approved for adjuvant therapy in combination with dabrafenib for melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection.

Pembrolizumab (Keytruda)

Pembrolizumab is a programed cell death-1 protein (PD-1) inhibitor. It is indicated as first-line treatment for unresectable or metastatic melanoma. It is also indicated for adjuvant treatment of resected, high-risk stage 3 melanoma.

Vemurafenib (Zelboraf)

Inhibits some mutated forms of BRAF serine-threonine kinase, including BRAF-V600E. The drug is indicated for unresectable or metastatic melanoma with BRAF-V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.

Nivolumab/relatlimab (Opdualag)

Fixed-dose combination indicated for treatment of adults and pediatric patients aged 12 years and older with unresectable or metastatic melanoma. Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody and relatlimab is a lymphocyte activation gene–3 (LAG-3) blocking antibody. The combination results in greater T-cell activation than with either antibody alone. 

Nivolumab (Opdivo)

Nivolumab is a monoclonal antibody to programmed cell death-1 protein (PD-1). It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is indicated as a single agent for unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. It is also indicated as a single agent in the first-line treatment of unresectable or metastatic BRAF V600 wild-type or mutation-positive melanoma. Combination therapy with ipilimumab for treatment of patients with BRAF V600 wild-type or mutation-positive unresectable or metastatic melanoma is superior to either drug alone.

Cobimetinib (Cotellic)

Reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.

Cobimetinib is indicated for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation in combination with vemurafenib. Cobimetinib and vemurafenib target 2 different kinases in the RAS/RAF/MEK/ERK pathway; compared with either drug alone, coadministration resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations.

Binimetinib (Mektovi)

Inhibits mitogen-activated extracellular signal regulated kinase (MEK) 1 and MEK 2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK)-related phosphorylation and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. It is indicated in combination with encorafenib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

Encorafenib (Braftovi)

Kinase inhibitor that targets BRAF V600E. This pathway regulates several key cellular activities, including proliferation, differentiation, survival, and angiogenesis; inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma. It is indicated in combination with binimetinib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

Class Summary

Immunotherapy (biotherapy) currently used to treat patients with melanoma includes IFN and interleukin (IL)-2. An oncologist should administer these treatments.

Interferon alfa 2b (Intron A)

IFN alfa-2b is a protein product manufactured by recombinant DNA technology. The mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. It is the drug of choice for adjuvant therapy in patients with high-risk melanoma. Its immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity.

IFN alfa-2b is generally initiated within 56 days of surgery and typically administered by medical oncologists.

Peginterferon alfa 2b (Sylatron)

Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. Alfa interferons act through high-affinity cell surface receptors, which, once activated, are known to inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase the phagocytic activity of macrophages, and enhance the cytotoxicity of lymphocytes for target cells.

A covalent attachment of polyethylene glycol polymer chains to interferon molecules (known as PEGylation) can significantly increase the time the drug remains in the bloodstream, which, in turn, can reduce the frequency of dosing and potentially reduce the severity and frequency of adverse effects.

It was approved by the FDA in March 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy. It is the first therapy approved for the adjuvant treatment of melanoma in 15 years.

Interleukin 2 (Proleukin)

IL-2 is the only therapy known to cure advanced-stage melanoma. It activates T cells and amplifies their responses. It enhances natural killer cell antitumor activity.

Class Summary

Local treatment of lesions or nodal lesions may be needed following resection.

Talimogene laherparepvec (Imlygic)

The exact mechanism of action is unknown. Talimogene laherparepvec is a genetically modified, live, attenuated herpes simplex virus programmed to replicate within tumors and to produce the immune stimulatory protein GM-CSF. Causes lysis of tumors, followed by release of tumor-derived antigens, which together with virally derived GM-CSF may promote an antitumor immune response. It is a solution for intralesional injection that may be considered for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery.

Tebentafusp (Tebentafusp-tebn, Kimmtrak)

Bispecific protein comprised of a soluble T-cell receptor fused to an anti-CD3 immune-effector function that specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma