Cindy L. O’Bryant and Jamie C. Poust
KEY CONCEPTS
Cutaneous melanoma is an increasingly common malignancy, but it is a cancer that can be cured if detected early. Public education about screening and early detection is one strategy for controlling the increase in incidence and the mortality associated with cutaneous melanoma.
Surgical resection can cure patients with early-stage melanoma.
The toxicities associated with interferon-α2b (IFN-α2b) therapy are significant and require patient education, close patient monitoring, and appropriate dose modification based on toxicity.
Patients with locally advanced disease should be evaluated for adjuvant therapy; recommended options include IFN-α2b or participation in a clinical trial.
Metastatic melanoma remains a clinical challenge. At this time, there is not a single standard treatment approach for individuals with metastatic disease. Dacarbazine and temozolomide are considered the most active chemotherapies and can be used as single agents. Combination chemotherapy has not been shown to be superior to single-agent therapy with dacarbazine.
As the biology of melanoma has been further delineated, a growing number of potential targets for drug therapy have been identified. BRAF mutations appear in up to 70% of melanoma patients. Vemurafenib is a BRAF inhibitor that has been shown to improve overall survival in patients with this mutation.
Ipilimumab is an option for some individuals with metastatic melanoma. The immune-related toxicities associated with the use of this drug are significant and warrant close patient selection. Individuals require close monitoring and management by an experienced healthcare team. Clinical trials using this drug showed a significant improvement in overall survival.
Treatment of melanoma is determined by many factors. As the number of treatment options for patients with metastatic melanoma grows, it will be important to consider disease- and patient-related aspects when determining appropriate therapy.
INTRODUCTION
Melanoma is the seventh most common cancer in the United States. The incidence of melanoma has steadily increased from the 1970s, and today it is increasing at a faster rate than most other cancer types.1Although nonmelanoma skin cancers (NMSCs) are the most common malignancies of the skin, cutaneous melanoma accounts for up to 75% of all skin cancer–related deaths. With the rise in the number of melanoma skin cancer and the associated mortality, it is essential to consider issues of care beyond that of disease treatment. Skin cancer prevention and screening have a major impact on public health and on the success of treatment for those individuals diagnosed with both NMSC and melanoma. Skin cancers tend to occur more frequently in older individuals. Therefore, as the population continues to age, effective strategies to prevent, detect, and treat individuals with these cancers are needed.
The incidence of melanoma varies worldwide with the highest rates found in Australia, New Zealand, North America, and Northern Europe. In the United States, about one in every 50 Americans will be diagnosed with melanoma in their lifetime. The lifetime risk is greater in men (2.9%) than women (1.8%) and varies with ethnicity.1,2 The median age at diagnosis is 61 years old.3 In 2013, it was estimated that 76,690 new cases of melanoma would be diagnosed in the United States. Unfortunately, this estimate may not be accurate because many superficial and in situ melanomas are managed in facilities that do not routinely report their cases to cancer registries.4 Childhood and adolescent melanoma is rare with 2% of cases being diagnosed in individuals younger than 20 years old. The incidence in this age group is increasing by 2.9% per year. Young adults between the ages of 15 and 19 years account for about 75% of childhood melanomas. Different than the adult population, the incidence of melanoma appears to be the same between genders except in the 10- to 19-year-old age group in which the incidence is higher in girls than boys.5
The estimated number of individuals expected to die of melanoma in 2013 in the United States is 9,480.4 Survival rates have gradually increased over the past 4 decades. At present, the 5- and 10-year relative survival rates are 91% and 89%, respectively, but survival rates decline with more advanced disease. The overall mortality rate has remained stable.1 Men older than 65 years old have the highest mortality rates from melanoma. Death rates have declined in younger patients. The stabilization of mortality rates appears to be related to efforts at both primary and secondary prevention of melanoma in addition to advances in the treatment and management of melanoma patients.
ETIOLOGY AND EPIDEMIOLOGY
The etiology of melanoma, similar to most other malignancies, is not fully understood. A number of patient-specific factors and environmental factors have been identified (Table 116-1), and it is likely that these factors alone or in combination increase the occurrence of cutaneous melanomas.
TABLE 116-1 Risk Factors for Melanoma
Individual physical characteristics can determine responses to ultraviolet (UV) radiation. Caucasians with fair-colored hair (red or blond), light-colored eyes (blue or green), high degrees of freckling, and those who have a tendency to burn and rarely tan with exposure to sunlight appear especially at risk.5 Clinical and epidemiologic research shows a higher rate of melanoma in those who have extensive or repeated intense sun exposure.5 Intermittent intense sun exposure, blistering sunburns, and the time of life of exposure to the sun now are believed to be critical factors for development of cutaneous melanoma. Individuals with a history of these are at this highest risk. The risk is lower in individuals who had chronic sun exposure without a history of burning and those with occupational exposure. The risk with sunlight and UV radiation seems to be greatest during childhood and adolescence and is more hazardous than exposure during adult life.
One of the most important risk factors for melanoma is the number of melanocytic nevi (pigmented lesions or moles) on the body. The formation of these nevi has been shown to be directly related to cumulative sun exposure. The relative risk of developing melanoma increases with the greater number of typical nevi an individual has. A second risk factor is the presence of atypical melanocytic nevi. Atypical nevi may progress from a normal nevus or be dysplastic from the onset. Up to 20% of melanomas develop from atypical nevi, and individuals with these have an increased risk of developing melanoma compared with the general population. Small congenital melanocytic nevi may be present at birth or within the first few months after birth. About 1% to 3% of newborns are born with pigmented lesions, and the lifetime risk of developing melanoma is related to the size of the nevus.6
Immunocompromised patients are at an increased risk for development of cutaneous melanoma.5,6 Immunodeficiency includes individuals with ataxia telangiectasia, chronic lymphocytic leukemia, Hodgkin lymphoma, and immunosuppression after organ transplant. Acquired immunodeficiency syndrome has been shown to increase the risk of developing cutaneous melanoma and the disease often is more aggressive.7 A personal history of nonmelanoma or melanoma skin cancers is a risk factor for subsequent melanoma and may be associated with a poor prognosis. Xeroderma pigmentosum is a rare skin disorder but does carry an increased risk for melanoma.
A rare but important risk for melanoma is maternal–fetal transfer of melanoma. Although melanoma is not the most common cancer in pregnancy, it is the cancer most likely to metastasize to the placenta and the fetus.6Maternal–fetal transmission of melanoma is commonly lethal. However, neonates delivered with concomitant placental involvement but without clinical evidence of disease still are considered to be at increased risk for development of disease.
A number of genes have been implicated in melanoma development and progression, and molecular profiling studies have identified several distinct molecular subclasses of melanoma.8 Familial atypical multiple mole syndrome (FAMMS) or dysplastic nevus syndrome is a hereditary disease characterized by a predisposition to develop dysplastic nevi and cutaneous melanoma. About 8% to 10% of cases of melanoma are associated with a family history or hereditary dysplastic nevus syndrome. Patients with FAMMS suggest a risk for melanoma of 400- to 1,000-fold higher than that seen in the general population. The mode of inheritance is somewhat controversial and is believed to be polygenic.
Genetic studies of this heritable trait in families led to the identification of CDKN2A as the familial melanoma gene, located at chromosome 9p21. CDKN2A encodes two distinct proteins: inhibitor of cyclin-dependent kinase 4 (INK4A [inhibitor of cyclin-dependent kinase 4] or p16INK4a) and ARF (alternative reading frame; p14ARF). INK4A regulates cell cycle progression at the G1/S checkpoint by inhibiting the G1 cyclin-dependent kinases that phosphorylate and inactivate the retinoblastoma protein. ARF inhibits p53 degradation; therefore, loss of ARF inactivates p53. The frequencies of CDKN2A mutations vary in melanoma but are found more commonly in individuals with familial inheritance patterns and are associated with multiple cases of melanoma in a family, young age at diagnosis, multiple primary melanomas among family members, and pancreatic cancer.9
One of the major signaling pathways found to be associated with the development of melanoma is the mitogen-activated protein kinase pathway (MAPK), which mediates receptor tyrosine kinases, resulting in activation of RAS and downstream BRAF. Activating BRAF mutations are the most common somatic genetic event in human melanoma, occurring in 25% to 70% of melanoma patients and primarily noted by a single point mutation BRAF (V600E). BRAF does not appear to be an inherited disposition gene, but the high prevalence of BRAF mutations in cutaneous melanoma appears to be an epidemiologic link between UV radiation and melanoma. BRAF mutations are common in melanomas arising from skin with intermittent sun exposure and not as common in melanomas in chronically sun-exposed areas. This may be an early event in the damage to the melanocytes because these mutations are also found in benign and dysplastic nevi.5
Upstream of BRAF, mutations in NRAS and c-Kit have also been found as molecular drivers in the development of melanoma. Mutations in NRAS are found in 15% to 20% of patients. These tumors are associated with more advanced disease at diagnosis, high growth rates, and shorter survival times than those with BRAF mutations.10 c-Kit is a transmembrane receptor tyrosine kinase that when activated signals the MAPK and phosphatidyl-inosital-3-OH kinase (PI3K) pathways, resulting in transcription and cell proliferation. Mutations in c-Kit are commonly found in acral and mucosal melanomas.10
Other genetic alterations involved with the development of melanoma include MITF (microphthalmia-associated transcription factor), a gene that is important to the survival of melanocytes and has been shown to play a key role in melanoma signaling. The melanocortin 1 receptor gene (MC1R), which is associated with the red hair and fair skin phenotype, is involved in melanin synthesis and is more prevalent in individuals with melanoma. NEDD9modulates metastatic activity and has been found to be unregulated in melanoma. These melanoma-specific pathways give better understanding of the biology of the disease and may lead to better more directed treatment. A variety of other molecular pathways and receptor tyrosine kinases are also being studied to identify their role in the development of melanoma.5
Sunlight is one of the most important environmental factors in the pathogenesis of melanoma. The incidence of melanoma has been associated with latitude and the intensity of solar exposure among susceptible populations. Radiation in the ultraviolet B (UVB) range (280–320 nm) is historically considered to be the critical factor linking sunlight and melanoma, although prolonged exposure to ultraviolet A (UVA) radiation (320–400 nm) also may be important. Use of older UVB-blocking sunscreens may not be as protective as once thought because they allow more sustained sun exposure without any clinical symptoms of burn (e.g., erythema or pain), ultimately resulting in intense irradiation of the skin by UVA light.
PATHOGENESIS
Melanomas most often arise within epidermal melanocytes of the skin, although they can also arise from noncutaneous melanocytes. Human melanocytes are dendritic pigmented cells that arise from the neural crest tissue during early fetal development and migrate over a predictable route to a variety of sites within the body including the skin, uveal tract, meninges, and ectodermal mucosa. In adults, most melanocytes are located at the epidermal–dermal junction of the skin and the choroid of the eye, but they can also be found in other tissues such as the meninges and the alimentary and respiratory tracts. Primary melanoma can arise in any area of the body with melanocytes. The skin is the most frequent site of melanoma; cutaneous melanoma constitutes 90% of all melanomas. Primary melanoma can arise in the eye (ocular melanoma) and less frequently the mucosa and metastatic disease with unknown primary site.5
Normal melanocytes arise from melanoblasts. They undergo a series of differentiation events before reaching a final end-cell differentiation state and can be arrested in their differentiation process at any given state of maturation without loss of their proliferation capacity. Melanocytes adhere to the basement membrane of the epidermis and, despite a resting state, maintain a lifelong proliferation potential. The existence of melanoma stem cells has been suggested from work with melanoma cell lines.8
Melanocytes synthesize melanin to protect various tissues, such as the skin, from UV radiation–induced damage and reach the keratinocytes in the upper layers of the epidermis via dendrites. Tyrosinase is an essential enzyme within melanosomes that synthesizes melanin. They are resistant to severe UV radiation, unlike keratinocytes, and their survival leads to the proliferation of mutated genes.5
Skin melanocytes transform from preexisting nevocellular nevi in the development of melanoma. A series of distinct steps are involved in the development and progression of melanoma from melanocytes. The pathologic components of the progression in human melanoma involve a series of morphologic stages: melanocytic atypia, atypical melanocytic hyperplasia, radial growth phase in which limited growth and radial expansion of the nevi may occur without metastatic competence, primary melanoma in the vertical growth phase with or without in-transit metastases, regional lymph node metastatic melanoma, and distant metastatic melanoma.5 Primary melanoma is characterized by radial growth and limited vertical thickness (<0.75 mm). Primary melanoma demonstrates little tendency to metastasize. Melanoma has a potential for metastasis formation with the onset of a vertical growth phase. Therefore, the thickness of a primary melanoma is an important prognostic factor and is used in the staging classification of cutaneous melanoma. Of note, melanomas can skip steps in this development pathway.
Normal melanocytes require growth factors for proliferation, but melanoma cells can proliferate without growth factors. Melanoma cells secrete a variety of growth autocrine and paracrine factors that may facilitate proliferation. Additionally, with disease progression, melanoma cells increase production of certain growth factors and cytokines. The PI3K–AKT pathway often is overactive in melanoma. Integrins and growth factors promote growth and survival of melanoma through these pathways.
Basic fibroblast growth factors (bFGFs) are thought to be important mediators of growth stimulation and cell survival, act as motility factors for melanoma cells, and upregulate serine proteinases and metalloproteinases. Melanoma cells are strong producers of chemoattractive proteins such as interleukin-8. Vascular endothelial growth factor (VEGF) can be triggered in the vertical growth phase.11 Most of these changes occur between the radial growth phase and vertical growth phase of primary melanoma, and metastatic cells often show the highest cytokine production.
Understanding the biology of melanoma has provided potential targets for drug therapy.12 For example, the role of bFGF in the pathogenesis of melanoma has led to investigation of antisense oligonucleotides to block bFGF. Other pathways, such as MAPK pathway, have been targeted by RAF and MEK inhibitors and the PI3K/AKT pathway by mTOR (mammalian target of rapamycin) inhibitors. As pathways are identified and as agents that inhibit these pathways enter clinical trials and practice, there is growing excitement about the opportunities to impact treatment of melanoma in new and effective ways.
Immune factors appear to be involved in the progression of melanoma more often than in most other solid tumors.5 Spontaneous cancer regressions are rare but are a well-documented phenomenon seen in melanoma. Focal regression in primary melanoma has been reported. Tumor regression appears to be associated with host immunity.
A number of different tumor antigens have been identified in the cellular membrane and cytoplasm of melanoma cells and are referred to as melanoma-associated antigens. Ganglioside antigens have been of particular interest in the development of immunotherapy for melanoma. A large number of monoclonal antibodies to melanoma-associated antigens have been developed and are being evaluated in clinical trials for diagnosis of and therapy for melanoma.
The humoral and cellular responses of individuals with melanoma that express melanoma-associated antigens have been described and provide the rationale for immunotherapy in the management of metastatic melanoma.5Melanoma-directed antibodies have been isolated in the sera of patients with melanoma. The presence of antimelanoma antibodies in the sera of patients correlates with the clinical status of the patients, and the antibodies gradually disappear from the serum as the disease progresses. This phenomenon may be explained by the possible formation of anti-idiotype antibodies directed against the antimelanoma antibodies, an increase in the circulation of soluble tumor antigens that saturate all antibody combining sites, increased levels of immunosuppression, or absorption of antibodies on the tumor mass.
Interest has focused on the role of cell-mediated immune response in melanoma. Specific cell-mediated responses may play a role in tumor regression, but the role of specific cells, such as cytotoxic T lymphocytes (CTLs), is not fully understood. Tumor-infiltrating lymphocytes (TILs) have been shown in vivo and in vitro to possess antitumor reactivity. TILs contain a large number of mature tumor-specific lymphocytes and have been a target for manipulation in immunotherapeutic approaches for melanoma.5 Two identified targets are cytotoxic T lymphocyte antigen 4 (CTLA-4) and toll-like receptor 9 (TLR9). CTLA-4 is a glycoprotein expressed on the surface of activated T cells that appears to have an inhibitory effect on T cells. Blocking the effect of CTLA-4 is an effective strategy for increasing the T-cell antitumor response.
HISTOLOGIC SUBTYPES
Cutaneous melanomas are categorized by growth patterns. Four major histologic subtypes or growth patterns of primary cutaneous melanoma have been identified: superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. Clinical outcomes of the four major melanoma subtypes are similar if the comparison controls for depth of penetration or tumor thickness. Any of the four subtypes can present as an amelanotic variant. Amelanotic melanomas appear to be devoid of clinically apparent pigmentation. Two less common types of melanoma include desmoplastic melanoma and lentiginous melanoma. Desmoplastic melanoma is more commonly seen in older individuals, and its clinical presentation is similar to that seen in NMSCs. If a biopsy of the lesion is not obtained, the disease may be mismanaged. Lentiginous melanoma is histologically different than the four major subtypes. Uveal melanoma is considered a separate disease from cutaneous melanoma.
Superficial spreading melanoma is the most common morphologic type of cutaneous melanoma, accounting for about 70% of all melanomas.5 The lesions usually arise from a preexisting nevus, known as a precursor lesion, and evolve slowly over 1 to 5 years. At some point, superficial spreading melanoma may progress to a more rapid growth phase. Early in lesion development, the superficial spreading melanoma is flat, but the surface becomes irregular and asymmetrical as the lesion progresses. The lesion enlarges when it enters into a rapid growth phase, and the edges appear notched or lacy. The lesions can be blue, black, or pink. Areas within the lesion may be hypopigmented. These patches of color variation, specifically the hypopigmented areas, are thought to be associated with tumor regression within the lesion or pigment inconsistency. The clinical differential diagnosis of superficial spreading melanoma includes both benign and malignant skin disease. This subtype is sometimes confused with seborrheic keratoses or pigmented basal cell carcinoma. Superficial spreading melanomas may occur at any anatomic site on the body, but they are more commonly seen on the back in men and on the legs in women. This subtype of melanoma is more common in women. The mean age of diagnosis of superficial spreading melanoma is 51 years, which is earlier than that seen for other subtypes. Superficial spreading melanoma usually occurs after puberty.
Lentigo maligna melanoma represents 10% to 20% of melanomas and is commonly found on the head and neck. It is unique from other histologic subtypes; because of its prolonged radial growth phase, it does not have the same propensity to metastasize.5 Lentigo maligna melanoma arises on chronically sun-exposed sites in older individuals and presents as a freckle-like lesion. Lentigo maligna melanomas are generally large (>3 cm), flat, and tan-colored lesions with shades of brown and black. The lesions gradually grow and develop darker, with asymmetric flecks in areas. Lentigo maligna melanoma is uncommon before age 50 years and may have been present for more than 5 years. Only about 5% to 8% of lentigo maligna melanomas evolve into invasive melanoma, which is characterized by nodular development within the flat precursor lesion. Lentigo maligna melanoma can be difficult to distinguish from solar lentigo, which typically is a smaller and evenly pigmented flat-appearing lesion.
Nodular melanoma is the second most common growth pattern of melanoma, occurring in 15% to 30% of patients. Nodular melanoma is a pure vertical growth phase disease. In nodular melanoma, a small, expansive nodule in the papillary dermis invades the reticular dermis and subcutis. The radial growth phase is absent at all times. Nodular melanomas are more aggressive and develop more rapidly than superficial spreading melanoma. Nodular melanomas are dark blue–black and often uniform in color with a shiny surface, although a small percentage of nodular melanomas are amelanotic and have a fleshy appearance. Nodular melanomas are raised and often symmetric. They can occur at any age, typically around 50 years of age, and are most common on the trunk, head, and neck. Nodular melanomas are more common in men. Of note, nodular melanomas can resemble traumatized nevi.
Acral lentiginous melanoma makes up about 5% of melanomas and is most likely not related to UV exposure. It presents as three distinct clinical subtypes: melanoma on the palms of the hands or soles of the feet, subungual melanoma, and mucosal melanoma.6 Most acral lentiginous melanomas are located on the soles of the feet and look like a large tan or brown stain. The lesions often have irregular convoluted borders. The initial macular component of palmar/plantar melanomas can be masked by the thickened stratum corneum at these sites. Many of these lesions look verrucous in appearance making them difficult to distinguish from warts by the untrained eye. Suspicious lesions on the palms or soles of the feet should be evaluated. Acral lentiginous melanoma includes subungual melanoma, which arises in the nail matrix or nail bed. The most common presentation is a brown or black line in the great toe or the thumbnail. Mucosal melanoma is rare but can occur on any mucosal surface. Mucosal melanoma occurs most commonly in the oropharyngeal mucosa followed by the anal and rectal mucosa, genital mucosa, and urinary mucosa. Unfortunately, mucosal melanoma often does not become clinically apparent until the mass is large or the lesion bleeds. Acral lentiginous melanoma occurs in fewer than 10% of Caucasians with melanoma but is the most common type of melanoma reported in individuals with a dark complexion (e.g., African Americans, Asians, and Hispanics). Similar to lentigo maligna melanomas, this subtype is characterized by a protracted radial growth phase.
Uveal melanoma is the most common primary intraocular malignancy seen in adults but is an uncommon tumor.13 Unlike cutaneous melanoma, the frequency and mortality rates of uveal melanoma have remained steady. This melanoma arises from the pigmented epithelium of the choroid. Iris melanoma is a subset of uveal melanoma and tends to have a more benign course. The risk of metastasis varies with the histologic type and size of the tumor as well as the location in the eye. Metastases occur most frequently in the liver but have been documented in a variety of tissues.
The ability to predict the metastatic potential of melanomas would be a valuable prognostic tool. An attempt to predict the likelihood for metastasis is based on radial and vertical growth phases. Radial growth phase describes the early stage of melanoma when the tumor is thin and primarily intraepidermal in location. By definition, malignant melanoma in situ is a form of radial growth phase melanoma. Vertical growth phase is the stage of melanoma with clear metastatic potential.
CLINICAL PRESENTATION
Benign nevi often occur in sun-exposed areas and typically are 4 to 6 mm in diameter (about the size of a pencil eraser), raised or flat, uniform in color and round in shape. Dysplastic nevi are believed to be a link between benign nevi and melanoma. Dysplastic nevi tend to be larger than common nevi (>5 mm), appear as flat macules with asymmetry, have a fuzzy or ill-defined shape, and vary in color. Compared with melanoma lesions, dysplastic nevi appear less evolved.
The initial clinical presentation of melanoma often is a cutaneous lesion and depends on the histologic subtype and the stage of development of the lesion. The lesion can be located anywhere on the body but is most commonly discovered on the lower extremities in women and on the back and trunk in men. The cardinal clinical feature of a cutaneous melanoma is a pigmented skin lesion that changes over a period of time. Any changes in the skin surrounding a nevus, including redness or swelling, are important clinical signs. Uncommonly, the sensation of the lesion may become itchy or tender and painful. Friability of the lesion, resulting in bleeding or oozing, is a danger sign. Perhaps the most important warning sign of danger is the evolution in any characteristic of a lesion. A biopsy of the lesion is critical to establish diagnosis of melanoma. Subsequent pathologic interpretation of the biopsy will help provide information on prognosis and treatment options. An excisional biopsy with a 1- to 2-mm margin of normal-appearing skin is recommended for a suspicious lesion and should include a portion of underlying subcutaneous fat for microstaging. For larger lesions with which an excisional biopsy is impractical, an incisional or punch biopsy can be performed and should include a core of full-thickness skin and subcutaneous tissue. When excisional biopsies are not appropriate, as with the face or palmar surface of the hands, a full-thickness incisional or punch biopsy is preferred. A shave biopsy is never appropriate because it can underestimate the thickness of the lesion and may not fully remove the lesion. Additionally scarring may mask the remaining tumor.
CLINICAL PRESENTATION
General
• Any lesion that changes in appearance over time.
Local Signs and Symptoms
• The clinical features used to describe questionable lesions are highlighted with the mnemonic “ABCDE.”
(A) Asymmetry: Melanoma lesions are often asymmetric.
(B) Border: Melanoma lesions have irregular boarders.
(C) Color: Color is often variegated in a melanoma ranging from tan, blue-black, red, purple, or white.
(D) Diameter: Melanoma lesions are frequently greater than 6 mm.
(E) Enlargement or evolution: A sudden enlargement or change in lesion is concerning for melanoma.
• Other signs of melanoma include a lesion that swells, bleeds, or oozes.
Systemic Disease Signs and Symptoms
• Palpable lymph nodes.
• Depending on the site of metastases, shortness of breath, abdominal pain, bone pain, headache, and mental status changes.
Laboratory Tests
• In addition to a comprehensive metabolic panel, LDH should be evaluated.
Other Diagnostic Tests
• Biopsy and pathology review for staging with molecular testing for BRAF and c-Kit.
• When applicable, SLNB.
• Systemic staging should include chest, abdomen, and pelvic CT scan or CT/PET bone scan, and brain MRI.
CT, computed tomography; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PET, positron emission tomography; SLNB, sentinel lymph node biopsy.
Evaluation of any individual with a suspected melanoma includes a complete history and total-body skin examination. The focus of the patient history is identifying potential risk factors. Risk-related questions include an assessment of family history of melanoma, personal history of skin cancer or nevus excisions, sun exposure, and phenotype. Total dermatologic examination is necessary to determine melanoma risk factors (e.g., mole pattern, mole type, or freckling) and for staging. Melanoma commonly spreads to the lymph nodes; therefore, individuals suspicious for advanced disease should have their lymph nodes examined for lymphadenopathy. Lactate dehydrogenase (LDH) should be measured because elevated serum levels have been shown to be an independent predictor of decreased survival.14 In addition, any other signs or symptoms suggestive of metastatic disease should be completely evaluated.
The diagnosis of melanoma is complicated by the number of pigmented moles (melanocytic nevi) and nonmelanocytic lesions that resemble melanoma. An average of 10 to 40 ordinary nevi can be found on the skin of white adults. Nonmelanocytic pigmented lesions, such as seborrheic keratoses, pigmented basal cell carcinoma, and vascular lesions, also can appear similar to a melanoma lesion. In childhood melanoma, commonly the lesions are thicker at the time of diagnosis. This may be in part due to the low level of suspicion by pediatricians, the fact that many melanomas associated with congenital nevi develop in the dermis rather than the epidermis, and histologic uncertainty.6
Improved survival rates for melanoma have been attributed to the identification and treatment of disease at an early stage when the disease is limited and has not yet metastasized. It follows that one strategy to improve survival rates would be to increase efforts to identify early-stage melanoma. The cost effectiveness of massive screening for all adults by a physician has never been demonstrated. However, routine examination of the skin by physicians is recommended for individuals, adults, and children who are at high risk. The entire cutaneous surface, including the scalp, should be examined.
It has been estimated that about 50% of the initial melanoma lesions found are discovered by self-examination. Therefore, one of the most direct strategies to improve early detection would be a method to increase effective skin self-examination (SSE) by the individual, the individual’s partner, or a caregiver. Identification of early melanoma allows the opportunity to treat the lesions when they are thin and curable. Persons who perform SSE present for care at an earlier stage in the disease process and have 50% less advanced melanoma and lower mortality rate from the disease.5 Healthcare individuals who routinely work with the public, such as community pharmacists, have an opportunity to increase public awareness concerning the benefits and appropriate methods for SSE. Educational pamphlets describing SSE (Table 116-2) for the public are widely available through the American Cancer Society, American Academy of Dermatology, and Skin Cancer Foundation. If a newly discovered pigmented lesion is identified or if a preexisting pigmented lesion changes, the individual should be evaluated by a physician immediately.
TABLE 116-2 Self-Examination of Suspicious Moles
Skin self-examination is of special interest in elderly adults. As the population of older adults (≥65 years of age) increases, it is expected that the mortality rate from melanoma also will increase. Barriers to successful SSE in elderly adults, such as failing eyesight, lack of partners, and poor memory, impact older adults in detecting new or changing lesions. These barriers, coupled with the higher incidence of melanoma in men, present challenges and opportunities for healthcare professionals to target education on this growing segment of our population.
STAGING AND PROGNOSTIC FACTORS
The size of a primary melanoma lesion is associated with the likelihood of metastases. As such, Breslow tumor thickness of the primary melanoma lesion is commonly used as prognostic factor to determine predicated outcomes.15Tumor thickness is quantified to the nearest tenth of a millimeter with an ocular micrometer, measuring from the top of the granular layer of the overlying epidermis to the deepest contiguous invasive melanoma cell. The correlation between tumor thickness and probability of tumor metastases is strong but does not include aspects such as tumor satellites, defined rather arbitrarily as skin involvement within 2 cm of the primary lesion, and vascular invasion. It was once thought that the presence of satellite nodule(s) had the same impact on prognosis as a high-risk primary lesion (tumor thickness >4 mm). It is now known that patients with satellitosis have a worse prognosis than patients with thick primary lesions, and prognosis is more similar to that of patients with nodal metastases. Mitotic rate has now emerged as another important prognostic factor for developing metastatic disease. Mitotic rate is defined as the number of mitosis per square millimeters. Increasing mitotic rate represents a more aggressive lesion and is associated with a poorer survival rate despite tumor size. Ten-year survival rates drop by 8% for a nonulcerated T1melanoma with a mitotic rate of less than 1/mm2 compared with a lesion with a mitotic rate of greater than 1/mm2.16 The American Joint Committee on Cancer (AJCC) developed a staging system for melanoma that divides patients with localized melanoma into four stages according to microstaging criteria of Breslow.17 In addition to consideration of the primary lesion, the AJCC staging system includes aspects of the tumor satellite, extent of lymph node involvement, and presence of metastatic disease.17 Analysis of several large databases worldwide identified areas in which the AJCC staging system, which was published in 1997, did not reflect the natural history of melanoma. Issues such as the appropriate cutoff values for primary tumor thickness, ulceration of the melanoma, and satellite lesions of the primary tumor should be considered when making decisions about therapy.17 The cutoff values initially proposed by Breslow for primary tumor thickness were initially used in the AJCC staging system, but it appears that cutoff depths of 1, 2, and 4 mm of thickness may better predict overall survival. Melanoma ulceration and increased mitotic rate within a primary melanoma are both associated with decreased survival and thus are the most considerable prognostic factors in patients with localized disease.14 The revised AJCC staging system for cutaneous melanoma was published in 2002 and updated in 2009.14,17 It is important to carefully examine older clinical trials to determine which staging system was used to determine patient inclusion and exclusion criteria, as results may differ based on these patient criteria. Revisions of the new melanoma staging system include (a) principal prognostic factors for localized disease includes melanoma thickness, ulceration, and mitotic rate; (b) mitotic rate replaces invasion as primary criterion for T1b tumors ; (c) number of metastatic nodes, tumor burden, and ulceration define the nodes (N) category for patients with regional metastasis; (d) presence of microscopic nodal metastasis classifies a patient as stage III; and (e) two dominant components are site of distant metastases and presence of elevated serum LDH for metastatic disease.14 Clinical staging includes microstaging of the primary melanoma and clinical and radiologic evaluation. It is used after complete excision of the primary melanoma with clinical assessment for regional and distant metastasis. Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional nodes after partial or complete lymphadenectomy. At this time, it appears that patients with very limited disease (in situ or stage 0) do not require pathologic evaluation of lymph nodes (Tables 116-3and 116-4). As with other solid tumors, the presence of regional lymph node involvement is a powerful predictor of tumor burden and patient outcome. In the past, the primary method for determining nodal status was surgical resection and analysis of the lymph nodes via a regional lymph node dissection. The extent of lymph node dissection was determined by the anatomy of the area of the lesion. In recent years, preoperative lymphoscintigraphy and intraoperative sentinel node mapping have become more widely used methods for identifying the first or sentinel lymph node in the direct pathway of lymph drainage from the primary cutaneous melanoma. Sentinel lymph node biopsy (SLNB) is a minimally invasive procedure that determines if a patient is a candidate for a complete lymph node dissection. The rationale for lymphatic mapping and subsequent SLNB is based on the observation that regions of the skin have patterns of lymphatic drainage to specific lymph nodes in the regional lymphatic basin. The sentinel lymph node is believed to be the first node in the lymphatic basin into which the primary melanoma drains. Unlike other solid tumors, melanoma appears to progress in an orderly nodal distribution. Evaluation of sentinel nodes has been used for detection of micrometastases in breast cancer and in melanoma. SLNB allows for more thorough examination of a single sentinel node than is possible when examining multiple lymph nodes with a lymph node dissection and may be most useful for melanomas located in ambiguous drainage sites such as the head and neck areas. SLNB is associated with low false-negative rates and low complication rates.18 Detection of clinically undetectable disease in a lymph node basin that is not directly adjacent to the primary lesion may allow for upstaging of patients who initially are believed to have node-negative disease. The American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guidelines now recommend SLNB for patient with any intermediate-thickness melanoma.19
TABLE 116-3 Melanoma Tumor, Node, Metastasis Classification
TABLE 116-4 American Joint Committee on Cancer Tumor (T), Node (N), Metastasis (M) Stage Grouping for Cutaneous Melanoma
The stage of melanoma at the time of diagnosis is one of the primary indicators of the natural history of the disease and contributes to prognosis. Tumor thickness, level of tumor invasion, and ulceration all contribute to the stage of a patient and the overall outcome. Other factors such as tumor growth pattern or histological subtype, mitotic rate, density of TILs infiltrating the tumor tissue, elevated LDH level, satellite lesions, angiolymphatic invasion, gender, and age also have been reported to influence survival (Table 116-5). The location of the primary tumor on the skin is also important because individuals with tumors of the extremities have an increased survival compared with those with axial, neck, head, and trunk tumors. In addition, a number of additional prognostic factors have been identified in patients with advanced disease. The number of metastatic sites, disease involvement of the gastrointestinal tract, liver, pleura, or lung, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or greater, male sex, and prior immunotherapy have been associated with poor prognosis.20
TABLE 116-5 Prognostic Factors for Cutaneous Melanoma
TREATMENT
Desired Outcomes
Treatment of cutaneous melanoma depends on the stage of disease. Local disease is managed and often cured with surgical ablation. Regional disease is treated with surgical resection of the primary lesion and, depending on the risk of recurrence, possibly adjuvant therapy in an effort to eradicate any residual disease and cure the patient. The use of adjuvant therapy after surgical resection and the role of interferon-α (IFN-α) as adjuvant therapy remain controversial. When disease becomes metastatic, the treatment goals are to slow tumor progression, prolong life, and improve quality of life. The approvals of ipilumumab and vemurafenib have dramatically changed the management of metastatic melanoma. Both agents are more efficacious than standard chemotherapy treatment options, dacarbazine and temozolomide. Numerous clinical trials have evaluated single-agent and combination chemotherapy, immunotherapy, targeted therapy, and biochemotherapy regimens. Patients with advanced disease should have their tumors tested to document mutational status in an effort to direct appropriate therapy.
Surgery
Patients who present with a suspicious pigmented lesion should undergo a full-thickness excisional biopsy, if possible. Sites for which excisional biopsy is inappropriate include the face, palm of the hand, sole of the foot, distal digit, and subungual lesions. A full-thickness incisional or punch biopsy is preferred in these cases to provide microstaging and ultimately to determine therapy.
Localized cutaneous melanoma can often be cured with surgical excision. The cure rates for melanomas smaller than 1 mm are as high as 98%.5 The extent of the excision margin is important in preventing local recurrence and ultimate survival. For melanoma in situ, excision of the visible lesion or biopsy site with a 0.5 to 1 cm border of clinically normal skin and a layer of subcutaneous tissue with confirmation of histologically negative peripheral margins is recommended. The recommended clinical margin for invasive melanoma depends on the tumor thickness. Excision with a 1 cm margin of clinically normal skin and underlying subcutaneous tissue is recommended for invasive melanomas 1 mm or smaller thick.20,21 The appropriate margin of excision for melanomas between 1 and 2 mm in thickness is controversial. A study suggests the risk of locoregional recurrence is higher when melanomas that are at least 2 mm thick are excised with a 1-cm margin rather than a 2 cm margin.22 Current National Comprehensive Cancer Network (NCCN) guidelines recommend a 1 to 2 cm margin for melanoma with tumor thickness of 1.01 to 2 mm.20 Lesions that are 2 to 4 mm thick should be excised with a 2 cm margin. Primary tumors more than 4 mm thick require at least a 2 cm margin, but whether a larger margin is beneficial is not clear. Surgical management of lentigo maligna melanoma is problematic because subclinical extension of atypical junctional melanocytic hyperplasia may extend beyond the visible margins. Complete excision of these lesions is important.
When isolated regional lymph nodes are detected via physical examination in the absence of distant disease, therapeutic lymphadenectomy is recommended. The extent of therapeutic lymph node dissection often is modified according to the anatomic area of the lymphadenopathy. Prophylactic lymphadenectomy in all patients is not recommended. Although a subgroup of patients with early-stage melanoma will have microscopic metastatic disease in nonpalpable lymph nodes, prophylactic regional lymph node dissection does not prolong survival or decrease time to relapse in randomized clinical trials.5,23 Selective regional lymphadenectomy performed after scintigraphic and dye lymphographic identification of the affected sentinel draining lymph node(s) is the standard of care for melanomas more than 1 mm thick. If the sentinel node is found to have micrometastatic melanoma, regional dissection of the involved nodal basin is performed. If the lesion is 0.75 to 1 mm in thickness with ulceration or is Clark level IV or V, lymphatic mapping with SLNB may be considered based on patient characteristics such as ulceration of the tumor.24 Of note, the likelihood of detecting metastatic disease in the sentinel lymph node depends on tumor thickness. The likelihood of detecting metastatic disease is about 1% in tumors that are smaller than 0.8 mm but increases to more than 30% in tumors 4 mm thick.24 The Multicenter Selective Lymphadenectomy Trial II is currently enrolling patients to assess whether or not a complete lymph node dissection after a positive SLNB improves overall survival. SLNB results are important for accurate staging, for therapeutic lymphadenectomy, and to aid in the decision to offer adjuvant treatment.18,23
One of the most important aspects of surgical management of cutaneous melanoma is the role of patient follow-up.20 Postsurgical follow-up of patients who have had a melanoma excised is essential to monitor for undetected metastatic disease and the development of a second primary cutaneous melanoma or nonmelanoma primary malignancy. Scheduled screening in addition to routine surgical follow-up is required for any patient with a melanoma; the recommended frequency and duration depend on the stage of melanoma. The optimal duration of follow-up remains controversial. Most patients who develop recurrent disease do so in the first 5 years after treatment, but late recurrences more than 10 years after surgery have been observed. The increased lifetime risk of developing a second primary melanoma supports lifetime dermatologic surveillance for all patients.
Curative surgery usually is limited to patients with early-stage disease. A patient with stage III melanoma commonly has lymph node involvement, but in-transit metastases also may occur. In-transit metastasis is the clinical manifestation of tumor that develops in lymphatics between the primary melanoma and the regional lymph node basin.5 In-transit metastases are more than 2 cm from the original lesion. In-transit metastases are more common in individuals with thick, ulcerated lesion. Surgery is used for management of in-transit lesions, and the goal is complete resection. Unfortunately, subsequent recurrence in the same extremity often occurs after initial resection of in-transit metastases.
The role of surgery beyond that of cure is less clear, although surgery may offer palliation for patients with isolated metastases.23 Resection of isolated lesions in the brain and lungs may be appropriate in certain cases and should be evaluated based on individual patient criteria. Surgery can be an option when the lesion is accessible and when the lesion may cause problems if not removed. Surgery can extend survival time in select patients with metastatic disease. Patients whose metastases can be completely resected may experience improved quality of life, improved overall survival, and occasionally long-term disease control.23
Brain metastasis is a frequent complication of advanced melanoma. About 20% to 50% of patients with stage IV disease develop clinically apparent central nervous system (CNS) involvement. Surgical resection, with or without radiation, has been used in select individuals. More recently, high control rates of brain metastases have been achieved with focal radiation therapy such as linear accelerator–based stereotactic radiosurgery or gamma-knife technologies.25 Melanoma in the gastrointestinal tract can lead to bowel obstruction, and appropriate resection or bypass may provide significant relief of symptoms. Despite the lack of controlled clinical trials, the impact on palliative surgery should be evaluated in the context of a patient’s comfort and quality of life. Surgery may be an appropriate option if the perceived outcome is to provide patient comfort. On the other hand, surgery may constitute a significant physical challenge or financial burden to a patient with a limited life expectancy. The clinical scenarios involving surgical resection should be fully evaluated in terms of overall quality of life.
The risk of relapse and death after resection of a local or regional cutaneous melanoma is the primary determinant for use of adjuvant therapy after primary resection. Adjuvant trials have focused on patients at intermediate or high risk for recurrence.
Immunotherapy
Melanoma is considered one of the most immunogenic solid tumors, and it appears to interact with and respond to the immune system of the host in which it arises. Spontaneous regressions of melanoma suggest the importance of the immune system in disease modulation. Lymphoid infiltration into the primary melanoma also suggests that immunomodulation may impact the biology of melanoma. Early work showed that nonspecific immunomodulators, such as levamisole and bacillus Calmette-Guérin (BCG), for treatment of melanoma were associated with some regression of the tumor, although many of these responses were limited and short-lived. Because melanoma is generally resistant to traditional treatment modalities such as radiation and chemotherapy, immunotherapy offers an avenue of treatment. Although the complete response rate seen in patients with melanoma treated with biotherapy is relatively low, the durability of responses in individuals who respond can be significant. Remaining unanswered questions include what is the best approach to biotherapy in a patient with melanoma and can biotherapy be combined with other available and emerging antineoplastic therapy.
Interferon
One of the oldest, and most controversial, immunotherapy approach-es for the treatment of melanoma is the use of IFNs. The IFNs are a group of proteins with diverse immunomodulatory and antiangiogenic properties. A number of studies have evaluated various doses and schedules of recombinant IFN for treatment of metastatic melanoma. Response rates in metastatic melanoma range from 10% to 30%, and overall response rates are about 15% for IFN-α. Unfortunately, the optimal dose, treatment schedule, and treatment combinations and regimens have not been established for management of metastatic melanoma.5
In clinical trials of IFN therapy for patients with metastatic melanoma, response rates were highest in patients with minimal disease. Responses were seen at all sites of disease but were most frequent in subcutaneous, lymph node, and pulmonary metastases. The success of IFN in patients with minimal disease encouraged investigators to evaluate the role of adjuvant IFN after curative surgical resection in patients who were at high risk for recurrent disease (bulky disease or regional lymph node involvement). Early trials of short-term or low-dose regimens of IFN-α did not demonstrate a survival benefit in the adjuvant setting. In an attempt to optimize response in the adjuvant setting, maximum tolerated doses of IFN-α were administered for 1 month followed by prolonged therapy of IFN-α at more tolerable doses for 48 weeks. The rationale for the intensive induction phase was to provide peak IFN levels sufficient to inhibit tumor growth and avoid the development of anti-IFN antibodies. A large, multicenter cooperative group trial (E1684) of adjuvant IFN-α2b versus observation was designed for 287 patients with high-risk (stages IIB and III disease based on the 1997 AJCC staging criteria) melanoma after curative surgical resection. IFN-α2b was given IV as an induction therapy at maximum tolerated doses of 20 million IU/m2 per dose 5 days per week for 4 weeks in an outpatient setting; treatment was continued for 48 weeks with subcutaneous IFN-α2b 10 million IU/m2 per dose 3 times per week at home. This therapy now is often referred to as high-dose interferon (HDI). With a median followup period of 6.9 years, patients treated with HDI had significantly longer relapse-free and overall survival compared with patients who were observed after surgical resection (1.72 vs. 0.98 years and 3.8 vs. 2.8 years, respectively).26 Both the 5-year relapse-free and overall survival rates were higher with HDI. With longer follow-up (median, 12.6 years), however, the difference in overall survival was no longer significant.27 Further analysis showed that the greatest reduction in melanoma recurrence occurred during the first few months of treatment. Subgroup analysis of this study indicated that patients with large primary tumors and node-negative disease (T4N0M0) did not receive the same benefit from therapy, but the small number of patients in this group made it difficult to draw definite conclusions about the role of IFN for adjuvant therapy in this setting.
Pegylated IFN-α2b has also been evaluated in the adjuvant setting. The European Organization for Research and Treatment of Cancer (EORTC) 18991 trial evaluated 1,256 patients with resected stage III melanoma. Patients were randomized to observation or pegylated IFN. Pegylated IFN was given less frequently (once weekly) compared with nonpegylated IFN. Updated results demonstrated an improvement in relapse-free survival but no difference in overall survival or distant metastasis-free survival.28 Based on these data, the Food and Drug Administration (FDA) approved pegylated IFN-α2b(Sylatron) as an option for adjuvant treatment.
High-dose interferon treatment is associated with multiple toxicities, including flulike syndrome. Other toxicities include depression, nausea, weight loss, fatigue, myelosuppression, elevations in liver function tests, and renal insufficiency. Toxicities of IFN therapy in the adjuvant HDI trials were common and severe, and most patients required dose reductions or delays at some point during treatment. Dose modifications were required for dose-limiting constitutional symptoms, myelosuppression, and hepatic toxicities. Approximately three-quarters of patients were able to complete the year of therapy in an outpatient setting.
One of the strategies for reducing the toxicities associated with IFN was to modify the dose and duration. A subsequent ECOG trial (E1690) of low-dose IFN (LDI; 3 million IU per dose given subcutaneously three times weekly) for 24 months compared with the HDI regimen described earlier versus observation did not demonstrate an overall survival advantage of HDI versus observation.29 At a median followup period of 52 months, the 5-year estimated relapse-free survival rates for HDI, LDI, and observation were 44%, 40%, and 35%, respectively. Relapse-free survival was significantly longer in the HDI group, prolonging the median time to relapse by 10 months compared with observation and LDI. With longer follow-up, however, the difference in relapse-free survival was no longer significant.29 A significant overall survival benefit was not seen for HDI or LDI compared with observation, although the investigators speculated that this analysis of survival was affected by the number of patients in the observation arm who received IFN therapy after disease progression.29
The use of IFN in the adjuvant setting remains controversial. Although the HDI regimen is used in the United States, the LDI strategy remains standard in many European countries. In a pooled analysis of 713 patients who participated in two randomized controlled trials (E1684 and E1690), HDI was associated with a significant reduction in relapse-free survival compared with observation (P <0.006).27 No benefit in overall survival was observed in the pooled analysis. The results of nine randomized clinical trials of adjuvant HDI or LDI versus observation in melanoma were included in a systematic review. The systematic review observed a trend toward reduced risk of recurrence of melanoma and of death among the IFN-treated patients in nearly all studies.30 Because of differences in dose, frequency, and duration of IFN-α treatment in the various trials, the review was not able to compare LDI versus HDI. Furthermore, the wide variability in number of patients enrolled, end points, patient selection, quality, type of therapy, duration of treatment, and follow-up precluded statistical analysis of the pooled results. Although the differences in overall survival were not always statistically significant, HDI remains the only adjuvant treatment shown to prolong survival in prospective randomized trials. IFN-α2b is approved by the United States FDA for treatment of patients with primary melanomas larger than 4 mm (stages IIB and IIC) and in patients with melanoma involving regional lymph nodes who are disease-free after lymph node dissection (stage III).
Although IFN is widely used in the adjuvant setting, there are concerns over the considerable treatment toxicities and the lack of consistent overall survival advantage of a toxic and expensive regimen. In addition, whether the results from the HDI trials should be extrapolated to patients with local recurrences, satellite lesions, or in-transit metastases is not clear. Remaining questions include the following: (a) Are the toxicities associated with HDI treatment worth the potential benefits for patients? (b) What are the mechanism(s) and best approaches to managing IFN toxicity? (c) Is the regimen or schedule of IFN used in the initial positive trial necessary to achieve the benefits seen in this study? Aggressive toxicity evaluation and individualized management are essential to help preserve quality of life in individuals receiving IFN therapy.
A mechanism for optimizing the care of patients receiving IFN is to effectively prevent and manage treatment-related toxicities. A common syndrome seen with IFN-α therapy is a diverse group of side effects referred to as constitutional symptoms, which can include acute symptoms such as fever, chills, myalgia, and fatigue, and can encompass some of the more chronic toxicities such as fatigue, anorexia, and depression.31 Acetaminophen can be used to prevent or minimize acute dose-related symptoms such as fever, myalgia, and chills. Opiates, such as meperidine, are often required when patients experience severe chills or rigors, most commonly during the initial month of the HDI induction phase. Nonsteroidal antiinflammatory drugs (NSAIDs) have been used to manage IFN-related myalgia but may have overlapping side effects with IFN, such as a decrease in renal blood flow. Some NSAIDs, such as acetaminophen, may mask fevers that occur in patients who experience neutropenia while undergoing therapy. Additionally, NSAIDs may increase the risk of bleeding in the setting of thrombocytopenia caused by IFN. Fatigue is one of the most frequently observed dose-limiting toxicities seen with IFN therapy, occurring in 70% to 100% of patients.31 The mechanisms of IFN-induced fatigue are not fully understood and may be multifactorial in individual patients. IFN-induced fatigue appears to be dose related and may worsen with continued therapy. Pharmacologic (e.g., methylphenidate) and nonpharmacologic (e.g., exercise, psychosocial techniques, distraction, energy management, and dietary modifications) interventions for treatment of cancer-related fatigue and now IFN-related fatigue are being evaluated.31 Depression is common and should be fully evaluated. Contributing factors such as IFN-induced hypothyroidism or concomitant IFN symptoms (e.g., nausea and fatigue) should be evaluated concurrently with depression symptoms to optimize treatment decisions.32 Antidepressants, such as selective serotonin reuptake inhibitors, have been studied in IFN-induced depression with notable benefit.31 Anorexia was reported in about 70% of patients receiving adjuvant IFN therapy for melanoma and is thought to be mediated through direct effects on hypothalamic neurons, modification of normal hypothalamic neurotransmitters or neuropeptides, or effects from stimulation of other cytokines.31 Taste alterations may contribute to anorexia. Investigational strategies for ameliorating IFN-induced anorexia include nutritional intervention, use of appetite stimulants such as megestrol acetate, and patient education. Glucocorticoids should not be used for appetite stimulation or as part of an antiemetic therapy because they may adversely impact the immunomodulatory effects of IFN. Other toxicities such as hematologic or hepatic toxicities require monitoring and appropriate dose modification.
Because of the associated toxicity and adverse effects seen with IFN-α therapy, many experts have questioned the usefulness of intensive adjuvant therapy for melanoma despite the possible benefits in relapse-free and overall survival. A subsequent report from the cooperative group study demonstrated a quality-of-life benefit with IFN therapy based on the quality-of-life–adjusted survival analysis.33 This analysis calculates the quality-of-life–adjusted years gained as a result of IFN-α treatment or the clinical benefit of time without toxicities and without disease. Another approach that has been investigated is the use of a pegylated product. Unfortunately, pegylated IFN has been evaluated in an attempt to improve the benefit-toxicity ratio without much success.34
The role of IFN as adjuvant therapy is not clear at this time. If adjuvant IFN is given, it is not clear what product (e.g., pegylated IFN), dose, and duration of therapy should be used. The issues of patient side effects and cost must be carefully weighed against the potential disease-free survival benefit. Because HDI is the only therapy to demonstrate benefit in large comparative trials, it should be considered for patients with high-risk disease. The 2013 NCCN guidelines for melanoma list IFN-α as one of several options for select patients with high-risk disease.20 Other options include observation and probably, most importantly, clinical trials. Individuals should be prescreened for potential problems associated with therapy; relative contraindications to HDI therapy include autoimmune diseases, immunosuppression, decompensated liver disease, severe neuropsychiatric diseases, and life-threatening infection.31 Efforts continue to better define the optimal treatment regimen for HDI versus other strategies in well-designed clinical trials.
Clinical Controversy…
The role of IFN-α as adjuvant therapy for high-risk patients after surgical resection of melanoma is controversial. Assessment of patient risk factors, availability of clinical trials, and cost of therapy should be evaluated before initiation of therapy.
The role of IFN in advanced disease is even less clear, especially for patients whose disease has recurred after treatment with adjuvant IFN therapy. IFN-α has been used as a single agent in patients with metastatic disease who have not received adjuvant therapy and in combination with chemotherapy or other biotherapy for metastatic melanoma. The challenges of combination therapy are that many of the toxicities seen with IFN can be exacerbated by concomitant chemotherapy (e.g., nausea, vomiting, and neutropenia).
Interleukin-2
Interleukin-2 (IL-2) is a glycoprotein produced by activated lymphocytes.35 IL-2 was first identified as a T-cell growth factor, but now IL-2 clearly is a growth factor for a variety of cells, including lymphocytes, T cells, and natural killer (NK) cells. IL-2 also may be immunosuppressive. The role of each of these effects of IL-2 on disease control in melanoma is not clear.
The precise mechanism of cytotoxicity of IL-2 is unknown. High IL-2 concentrations have not been shown to have a direct antitumor effect on cancer cells in vitro. In vitro and in vivo, IL-2 stimulates the production and release of many secondary monocyte-derived and T-cell–derived cytokines, including IL-4, IL-5, IL-6, IL-8, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor, and IFN-γ, which may have direct or indirect antitumor activity. In addition, IL-2 stimulates the cytotoxic activities of NK cells, monocytes, lymphokine-activated killer (LAK) cells, and CTLs. IL-2 also appears to activate endothelial cells, which results in increased expression of adhesion molecules.35
Based on preclinical studies that demonstrated a dose–response relationship between recombinant IL-2 (aldesleukin) and tumor response, initial clinical trials of aldesleukin in patients with melanoma used relatively high doses of the drug as a single agent or in combination with LAK cells. The response rates seen in these trials ranged from 15% to 25%, and 2% to 5% of patients achieved complete responses, some of which were durable (median response, 70 months).35 Responses were seen at a number of metastatic sites such as the lung, liver, bone, lymph nodes, and subcutaneous tissue. Based on reevaluation of early clinical trials, aldesleukin received FDA approval for treatment of metastatic melanoma. Overall, objective response rates were about 16%, but 4% to 6% of responses were durable and were observed in patients with large tumor burdens.36 The high doses of aldesleukin used in the initial clinical trials and recommended in the drug label are associated with serious toxicities and may limit the practicality of therapy for individual patients and broad application in certain healthcare systems. The high-dose aldesleukin regimen used for treatment of metastatic melanoma is 600,000 IU/kg per dose every 8 hours for 14 doses maximum in a 5-day period given for two cycles, with a 10- to 14-day rest period between cycles. At these doses, cytokine-induced capillary leak syndrome is a common problem and often is accompanied by significant hypotension, visceral edema, dyspnea, tachycardia, and arrhythmias. Increased permeability of capillary walls allows for a fluid shift from the intravascular space into tissue. As the patient becomes intravascularly dehydrated, hypotension may occur, resulting in reflex tachycardia and arrhythmias. In addition, the decrease in blood volume may result in decreased renal blood flow and urine output, manifesting as increases in blood urea nitrogen, serum creatinine, edema, and weight gain and a decrease in urine output (input greater than output). Visceral edema can result in pulmonary congestion, pleural effusions, and edema. The management of patients receiving high-dose aldesleukin requires extensive supportive care medications, careful monitoring, and a staff trained in aspects of critical care such as hypotension management. Although patients initially receiving high-dose aldesleukin are treated in an intensive care unit, most patients can be managed on a designated oncology unit if the staff is familiar with the toxicities and management strategies of the toxicities. Constitutional symptoms are a frequent complication of aldesleukin therapy and become more intense as therapy progresses. Additional side effects seen with aldesleukin include pruritus, eosinophilia, bone marrow suppression (including thrombocytopenia), increased liver function test results, neurologic disturbances, diarrhea, and nausea.
In an attempt to reduce treatment-related toxicities, a number of studies have evaluated continuous-infusion aldesleukin and lower doses of aldesleukin given either alone or combined with chemotherapy and IFN therapy. Although initial reports were encouraging, survival has not been significantly affected. At this time, direct comparisons of various dosing schedules and regimens are needed to determine the optimum approach to aldesleukin therapy in metastatic melanoma. Coadministration of LAK cells with aldesleukin does not appear to significantly improve clinical response.
One of the greatest treatment challenges in treatment of metastatic melanoma is determining the role of aldesleukin therapy for each patient. Pretreatment factors such as performance status, site of metastases, and LDH may predict who will respond and are currently being assessed in clinical trials. Based on reports of long-term responses (>10 years) experienced by some patients, the risk certainly is worth the benefit for those individuals. Unfortunately, at this time, it is difficult to determine which individuals will respond to aldesleukin therapy because no biologic or immunologic parameters have been found to correlate with response. The decision to treat an individual with high-dose aldesleukin should be based on an analysis of an individual patient’s risk versus potential benefit. Patients with inadequate pulmonary function, cardiac function, renal insufficiency, active infection, or poor performance status are poor candidates for this therapy. Aldesleukin can be safely administered with a properly trained healthcare team and is one of only two approved therapies for treatment of metastatic melanoma.
Clinical Controversy…
Although aldesleukin has been associated with long-term durable responses in a small subset of patients with metastatic melanoma, the toxicity profile, intensity of therapy, and cost have limited its acceptance in the United States. Patients should be evaluated for treatment before initiation of therapy.
Chemotherapy
A number of antineoplastic agents have demonstrated in vitro activity against melanoma, but only a few drugs have consistently shown a response rate greater than 10% in individuals with metastatic melanoma. Most clinical trials of new agents in melanoma measure antitumor activity in terms of response rates, which usually include complete and partial response rates. It is important to understand that these response rates do not always correlate with survival and do not evaluate benefit to the patient. Complete responses can be durable in a small number of patients.
Dacarbazine, a cytotoxic drug thought to exert its antitumor effect through alkylation, currently is the most effective single agent for treatment of melanoma. Dacarbazine remains the only FDA-approved chemotherapeutic agent for treatment of metastatic melanoma in the United States.37 Prospective controlled clinical trials have observed response rates of 10% to 25%, with an average duration of response of 5 to 7 months. Randomized trials in large numbers of patients have confirmed that response rates are closer to 7%.38 Complete responses are uncommon, with fewer than 5% of patients treated with single-agent dacarbazine sustaining long-term complete responses. There does not appear to be a survival benefit for dacarbazine relative to other treatments or supportive care. Patients with skin, subcutaneous tissue, and lymph node involvement respond most frequently, but patients with metastatic disease to the liver, bone, and CNS often are unresponsive. The optimum dose schedule of dacarbazine has never been determined; therefore, single-dose regimens are often preferred for patient convenience. Doses of 250 mg/m2/day for 5 days or 800 to 1,000 mg/m2 every 3 weeks are seen in practice. Common adverse effects of dacarbazine therapy include myelosuppression, severe nausea and vomiting, and a flulike syndrome after high doses. Nausea and vomiting can be prevented and managed with available antiemetics and is not a major complication. At this time, dacarbazine has no defined role in the adjuvant setting.
Temozolomide is one of a series of imidazole tetrazine derivatives that was developed as a potential alternative to dacarbazine.37 Temozolomide is an oral prodrug of the active metabolite of dacarbazine. Dacarbazine requires hepatic transformation to its active intermediate, but at physiologic pH, temozolomide chemically degrades to the cytotoxic monomethyltriazenoimidazole carboxamide (MTIC). Temozolomide is administered orally and appears to be less emetogenic than dacarbazine, although nausea can be a challenging chronic toxicity. Temozolomide appears to cross into the CNS and so initially was thought to have benefit for patients with CNS metastases. In a phase III trial of chemotherapy-naïve individuals with metastatic melanoma, temozolomide showed efficacy at least equivalent to that of dacarbazine in terms of objective response rates, time to progression, and overall and disease-free survival.39 Temozolomide appeared to be associated with improvement in some aspects of quality of life, although overall disease control was similar to dacarbazine.40
A potential advantage of temozolomide is the convenience of oral dosing, which allows a potentially more effective dosing schedule. Low-dose intermittent dosing schedules with a rest period are being evaluated. This schedule allows for a threefold increase in drug exposure and may overcome some drug resistance mechanisms. The active metabolite of dacarbazine and temozolomide, MTIC, methylates guanine residues in DNA at the O6 position. Resistance to agents that produce O6 methylation is partly due to increased levels of O6-alylguanine-DNA alkyltransferase. Temozolomide administration results in the depletion of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), which is a major mechanism of tumor resistance.40 Clinical evaluations of prolonged administration of temozolomide are ongoing, often in combination with other agents such as IFN.
The nitrosoureas are active against melanoma. Nitrosoureas, such as carmustine and lomustine, have antitumor activity similar to that of dacarbazine, with reported response rates between 10% and 20%. Sites of responses are similar to those seen with dacarbazine. It was initially hoped that use of the lipophilic nitrosoureas would provide added benefit against a malignancy that can metastasize to the brain. Unfortunately, despite the ability of these agents to cross the blood–brain barrier, the commercially available nitrosoureas have not been shown to have increased activity against melanoma in the CNS. Fotemustine, a nitrosourea available in Australia and some European countries, appears to cross the blood–brain barrier more rapidly than do other nitrosoureas. Response rates of 30% have been reported in previously untreated patients, with response rates of 25% of patients who had cerebral metastases. Fotemustine is considered standard therapy in some countries.41 The most common toxicities of the nitrosoureas are nausea and vomiting and delayed myelosuppression, particularly thrombocytopenia. Leukopenia and thrombocytopenia may be seen as long as 3 to 5 weeks after drug administration and may limit the inclusion of these agents to multidrug regimens.
Cisplatin and related compounds have been evaluated in the management of metastatic melanoma. The effectiveness of platinum compounds as single agents is limited, with reported response rates of 10% to 15% with a short median duration. The activity of cisplatin in melanoma may be dose dependent, and higher response rates have been seen with higher doses of cisplatin in single-institution studies.42 The toxicities of cisplatin can be problematic, especially in higher doses, and include acute and delayed nausea and vomiting, renal toxicity, and neurotoxicity. Carboplatin, another platinum analog, has been evaluated in small trials for treatment of melanoma. Results demonstrated similar response rates to cisplatin with differing toxicities.39 Carboplatin has been studied in combination with paclitaxel for treatment of melanoma in the second-line setting and this combination as has shown activity.43,44
Taxanes have demonstrated encouraging results in initial trials of metastatic melanoma. Response rates of 15% to 17% have been seen in initial phase II trials with paclitaxel and docetaxel. In a small phase II trial, the albumin-bound nanoparticle formulation of paclitaxel (Abraxane®), showed encouraging results.45 A phase III trial comparing Abraxane with dacarbazine in chemotherapy-naïve melanoma patients reported an increase in progression-free survival (PFS) and a trend in overall survival in patients receiving Abraxane. As would be expected, neuropathy and neutropenia were more common in the Abraxane arm.46 At this time, these agents are not routinely used as single-agent therapy for melanoma but are being incorporated into multidrug strategies against metastatic melanoma.
In an attempt to improve the limited responses seen with single-agent chemotherapy, a variety of combination chemotherapy regimens (Table 116-6) have been evaluated in both small and large clinical trials. Response rates as high as 30% to 50% were reported in single-institution phase II trials of patients with metastatic melanoma. The combination of dacarbazine with other chemotherapy, most commonly cisplatin, increased the response rates reported with dacarbazine alone, but the survival benefit has been minimal. Responses often were limited to metastases in soft tissue, lymph nodes, and the lung, the sites most likely to respond to single-agent dacarbazine therapy. The concern with combination chemotherapy is increased toxicity, and any reports of increased response rates should be weighed against the effect of toxicities on overall quality of life. The initial reports with the cisplatin, vinblastine, and dacarbazine (CVD) regimen were exciting, with reported response rates greater than 50%, a 4% complete response rate, a median response duration of 9 months, and acceptable toxicities.47 Comparisons of this regimen to dacarbazine alone have been conflicting. Subsequent reports showed no difference in response rates or survival.
TABLE 116-6 Combination Chemotherapy Regimens for Metastatic Melanoma
The Dartmouth regimen is a combination that includes carmustine, dacarbazine, cisplatin, and tamoxifen. Initial reports from uncontrolled phase II trials of this combination have demonstrated high response rates of 20% to 50%, but few patients achieve long-term survival. The benefit of tamoxifen to this regimen is controversial, but a controlled clinical trial from the National Cancer Institute of Canada demonstrated no benefit in response or survival from tamoxifen in this combination.48 Careful analysis of the initial studies demonstrates that the criteria used to measure response were not the same as those used in large multicenter studies. Phase III trials showed no benefit of the Dartmouth regimen compared with single-agent dacarbazine.49,50 Response rates were 15%, and median survival was about 7 months in both studies. Of concern, toxicities were higher with the combination study and included bone marrow suppression, nausea, vomiting, and fatigue.
Biochemotherapy
Low overall response rates and toxicity have limited the routine use of chemotherapy alone or immunotherapy alone in the management of metastatic disease. Over the past decade, the strategy of a combination of chemotherapy (dacarbazine, platinum agents, or vinca alkaloids) and cytokines, aldesleukin, or IFN, often termed biochemotherapy, has been a major focus of investigation in the management of metastatic melanoma and more recently in the adjuvant setting. The primary rationale is to combine two therapies with some biologic activity to increase overall activity and perhaps response rates. In addition, some preclinical trials suggest potential synergistic interactions between cytokines and some chemotherapy agents. As with other treatment strategies in melanoma, the results from initial trials suggested a higher response rate with biochemotherapy than the rates seen with either chemotherapy or biotherapy alone. Although several studies have suggested an increase in response rate with the addition of IFN-α to chemotherapy, results of most studies have shown that the addition of IFN-α does not increase the antitumor effect of dacarbazine but does increase toxicity and cost. Similarly, the combination of aldesleukin to chemotherapy has not been consistently shown to increase response or survival. The most encouraging results have been seen with combination chemotherapy and combination biotherapy, but the results of phase III studies have not demonstrated a clear advantage of biochemotherapy compared with chemotherapy alone.51 A recently published meta-analysis of 18 randomized trials of chemotherapy versus biochemotherapy showed that biochemotherapy was associated with a significantly higher response rate in treatment of metastatic melanoma. However, these differences in response rates did not translate into a significant difference in overall survival. Toxicities can be severe and are consistent with the individual agents in the regimen.52
One of the problems with most studies of biochemotherapy is the relatively short duration of response. Recurrence rates among patients who respond to therapy are as high as 50% within 18 to 24 months. Strategies such as subcutaneous low-dose aldesleukin are being investigated in an effort to prolong overall survival and time to progression in patients who do respond to treatment. Initial response rates, durable complete remission, and activity in patients in whom HDI therapy was not successful have stimulated interest in evaluating biochemotherapy in the adjuvant setting for high-risk patients with node-positive disease compared with HDI.
Biochemotherapy has also been evaluated in the adjuvant setting. Phase II data in a neoadjuvant approach provided promising results in terms of response rates, relapse-free survival, and overall survival.51Results from a phase III study that compared biochemotherapy with IFN as adjuvant therapy in high-risk stage III disease were recently published. This trial demonstrated that biochemotherapy significantly improved relapse-free survival, but no difference in overall survival was observed.53
Vaccines
The rationale for vaccination as a therapeutic modality is based on the observation that antigens expressed on the surface of tumor cells differ from normal cells and the hope that vaccines might induce effective tumor-specific immune responses with fewer toxicities than conventional chemotherapy or other immunotherapies. Greater knowledge about tumor antigens and the mechanism of antigen presentation and immune response to antigens has led to the development of several vaccination strategies for treatment of early and advanced melanoma.
A variety of melanoma vaccines based on whole tumor cells, peptides, proteins, and tumor lysates have been evaluated for treatment of patients with metastatic disease and for intermediate- and high-risk patients after surgical resection of disease.54,55 Although tumor responses with some of these approaches have been observed in phase I and II trials, none of the vaccine responses have been confirmed in phase III trials.55 These early trials have focused on the safety, feasibility, and immunogenicity of the vaccine. Vaccines are a promising but still experimental approach in the treatment of melanoma.
Vaccination is a form of active specific immunotherapy directed against a particular cellular target or specific membrane antigen. The ideal tumor vaccine would generate an active, systemic, long-lived immune response in the cancer-bearing host against tumors; protect against primary development or subsequent relapse of cancer; or induce regression of established cancer. Obstacles in the development of a vaccine include identifying appropriate antigens to target and generating immune responses against tumor antigens to which the immune system has been already exposed.
Whole-cell tumor vaccines can be derived from cell lines that are already established (allogeneic vaccines) or from the patient’s own tumor cells (autologous). Whole-cell vaccines are challenging to produce for several reasons: a new vaccine must be prepared for each patient, patients must have sufficient tumor available to provide adequate material, and considerable delay may exist between time of tumor removal and vaccine administration. In addition, there are technical challenges to producing the vaccine in a laboratory.54 Currently, no autologous tumor cell vaccine has been successfully studied in a phase III randomized clinical trial. An example of a whole-cell tumor vaccine that is being studied is Canvaxin. Canvaxin™ (CancerVax, Carlsbad, CA) is an allogeneic whole-cell vaccine that uses BCG as an immune adjuvant. Small trials have shown improvements in survival compared with historical control participants, and some objective clinical responses have been seen in patients with metastatic melanoma. The results from two large phase III trials that compared Canvaxin with observation in stage III and IV melanoma demonstrated a survival disadvantage for patients who received the vaccine.56
Antigen vaccines use individual antigens to stimulate immune responses compared with whole-cell vaccines, which contain many thousands of antigens.55 These antigens usually are proteins or pieces of proteins called peptides. Antigen vaccines may be specific for a certain type of cancer, but they are not made for a specific patient. Vaccines against GM2 ganglioside, a glycolipid expressed on most melanomas, are examples of vaccines targeted against an antigen. Two randomized controlled trials with anti-GM2 vaccines have failed to show any benefit with the vaccine.55
Peptide antigen vaccines match the patient’s haplotype with the spectrum of immunity that he or she expresses. T cells recognize antigens as peptide epitopes on the surface of major histocompatibility complex (MHC) molecules. Antigenic peptides can be mixed with an immunologic adjuvant and administered with the goal of loading empty MHC molecules in vivo. To date, the most commonly used peptides have shown activity only in patients who express human leukocyte antigen (HLA)-A2. However, many patients would not be eligible for this vaccine because not all patients express this HLA antigen. Additional peptide antigens that are compatible in other haplotypes have been identified, and eventually this disadvantage may be overcome. Peptide vaccination can generate quantifiable and functional tumor-reactive T cells, but clinical responses are rare and do not consistently correlate with CTL response.
Because protein antigen vaccines have a slightly broader spectrum of antigen diversity, all patients with melanoma potentially could be eligible for vaccination with this particular type of vaccine. Whereas proteins intrinsically produced by the cell are presented only to CD8+ T cells, proteins taken up by antigen-presenting cells (APCs) are presented only to CD4+ T cells. Under certain conditions, APCs can present protein-derived antigens to both CD4+and CD8+ in a process known as cross-presentation.55
Tumor lysates can be generated from tumor cells by mechanical disruption or enzymatic digestion. Tumor cells that shed antigens in culture can be purified and used as an antigen source for vaccines. Production of a vaccine from these sources raises concern because standardization of production and verification of purity and biological activity are more difficult.
Vaccines in combination with other biologic therapies are being evaluated. In a randomized trial of 604 patients with resected stage III cutaneous melanoma, LDI combined with an allogeneic melanoma lysate vaccine (2 years) was compared with HDI alone (1 year).57 The median overall survival was not significantly different between the two treatment arms. Five-year relapse-free and overall survival were similar in the two treatment arms. The incidence of serious treatment-related adverse events was similar in the two arms, but more severe neuropsychiatric toxicity was observed in patients receiving HDI. Although the results of this trial suggest that the vaccine has some activity in melanoma, the study was not powered sufficiently to show either equivalency or small differences in efficacy. HLA typing was optional based on whether the centers were able to perform the typing. With ongoing research, additional trials performed with this vaccine, specifically in patients with certain HLA types, may prove promising.
Occasional clinical responses have been observed in clinical trials of melanoma vaccines, which demonstrate the potential of this form of treatment. Many clinical trials with vaccine therapy in melanoma patients are ongoing. The results of completed clinical trials have not yet shown definitive evidence of improved survival. Further research is needed to improve vaccine responses and to determine how to apply treatment to melanoma patients.
Targeted Therapy
The role of protein kinases in the regulation and proliferation signals in cancer cells is becoming a key focus for anticancer agents. The role of protein kinase inhibitors has emerged as standard therapy for malignancies such as renal cell carcinoma, chronic myelogenous leukemia, and gastrointestinal stromal tumors. As the biology of melanoma continues to unfold, there is increasing excitement about the development of targeted therapies against targets important for the development and progression of melanoma.58 There now is greater interest in identifying potential targets in melanoma and determining the applicability in specific patients or patient subsets.
The MAPK pathway and Akt pathway are involved in tumor cell growth and differentiation and are activated in melanoma. BRAF is downstream in the MAPK pathway. Mutations of BRAF have been described in melanoma cell lines, and it appears that about 70% of melanomas exhibit BRAF alteration.59 In a phase I/II trial, vemurafenib, an orally available inhibitor of mutated BRAF, showed activity in patients with melanoma that had BRAF with the V600E mutation. In the V600E mutation, a valine is substituted for glutamic acid at codon 600. Among the 16 patients with melanoma that had BRAF with the V600E mutation and who received 240 mg or more of vemurafenib twice daily, 10 had a partial response, and one had a complete response.60 In a phase III trial comparing vemurafenib with dacarbazine in patients with unresectable, previously untreated stage IIIC or IV melanoma with a BRAFV600E mutation, vemurafenib significantly improved response rate and overall survival.61 Patients treated with vemurafenib 960 mg orally twice a day demonstrated an overall survival rate at 6 months of 84% as compared with 64% in the dacarbazine arm. The estimated median PFS times were 5.3 months with vemurafenib and 1.6 months with dacarbazine. The vemurafenib arm showed a significant higher objective response rate of 48% compared with 5% in the dacarbazine arm. The median time to response was also shorter with vemurafenib than dacarbazine (1.45 months vs. 2.7 months). Vemurafenib was associated with cutaneous squamous cell carcinoma or keratoacanthoma in 18% of the patients. Unfortunately, patients developed resistance to vemurafenib, typically after 5 to 6 months of therapy. Resistance is potentially caused by mutations in MEK, dependency on MEK/ERK antiapoptotic signaling, PI3/AKT pathway involvement, NRAS mutation, or MAPK pathway reactivation.61,62 The use of intermittent, rather than continuous, dosing has been shown to delay resistance to vemurafenib in animal models, and studies of combination therapy to minimize resistance are ongoing.61–63 Dabrafenib, another oral selective BRAF inhibitor, demonstrated similar responses in profession-free survival and response rates in a phase II study in patients with previously untreated BRAF V6000E mutated melanoma. The incidence of cutaneous squamous cell carcinoma was much lower at 6%.64
Other drugs targeted toward mutated BRAF have not reported encouraging results. Sorafenib is a multikinase inhibitor that inhibits both wild-type and mutant BRAF in addition to other tyrosine kinases involved in angiogenesis and tumor progression. Preclinical studies demonstrated activity against human melanoma tumor xenografts in preclinical trials, but minimal activity was observed in phase I and II clinical trials in refractory metastatic melanoma. However, sorafenib may be active when given in combination with chemotherapy. In phase I to II studies, 27% of patients responded to sorafenib when given in combination with carboplatin and paclitaxel, and 73% of patients maintained a response at a 6-month follow-up.59 However, results from two phase III trials with this same combination failed to show an improvement in PFS and overall survival.43,44 But the trials did report a higher than expected response rate for the chemotherapy only (carboplatin and paclitaxel) arm, thus making this combination a viable treatment option for this patient population.
Another agent of interest is imatinib mesylate, an oral agent that inhibits c-Kit and platelet-derived growth factor receptor. c-Kit is expressed primarily on acral and mucosal melanomas. Imatinib suppressed melanoma cell growth in preclinical studies. In phase II trials, imatinib was shown to be inactive in metastatic melanoma despite downregulation of phosphorylated c-Kit, but this patient population was not selected for c-Kit mutations.59 A phase II trial in patients with c-Kit mutations reported partial response in 23% of patients, 30% with stable disease, and a PFS of 3.5 months.10
Other targeted therapies such as MEK inhibitors have been studied in the treatment of metastatic melanoma and have shown modest activity. Trametinib is an inhibitor of MEK1/2. Compared with chemotherapy (dacarbazine or paclitaxel) in BRAF-mutated patients in a phase II trial, patients treated with trametinib had improved progression-free survival, overall survival, and response rates. MEK162 is also a MEK1/2 inhibitor but preclinically showed activity against NRAS-mutated melanomas. In patients with NRAS mutations, more than half of the patients had a response (partial response or stable disease) when given MEK-162.10 Both of these agents are currently being studied in combination with other BRAF and PI3K inhibitors.
Other Approaches
Dendritic cells are potent APCs that initiate antigen-specific immune responses. Dendritic cells express high levels of MHC class I and class II molecules, which are essential in antigen presentation. Activation of T cells and recruitment of non–antigen-specific effectors, such as NK cells and macrophages, result in a broad immune response. One strategy that uses dendritic cells for inducing antitumor immune responses is peptide-pulsed dendritic cells. Antimelanoma CTLs can be generated from healthy donors and patients with melanoma with dendritic cells pulsed with melanoma-derived peptides. A number of clinical trials have evaluated dendritic cell–based immunotherapy, and its clinical benefit is yet to be substantiated. The immunosuppressive role of regulatory T cells may be affecting the success of these agents. Trials with dendritic cells given with high dose IL-2, chemotherapy, and anti-inflammatory agents demonstrated disease stabilization in patients with metastatic melanoma.65
Monoclonal antibodies have been used for diagnosis and treatment of melanoma. Monoclonal antibodies can be used to target biologic pathways that are associated with tumor progression and as a delivery system for antineoplastic drugs. Monoclonal antibodies have been conjugated to cytotoxic agents, radioisotopes, and toxins. More recently, monoclonal antibodies have been developed to target processes that are involved in the host immune response to melanoma. CTLA-4 is a transmembrane protein expressed on T lymphocytes that is a homodimer that functions as an inhibitory receptor for the costimulatory molecule B7. Crosslinking of CTLA-4 by B7 inhibits T-cell activation, transcription, translation, and transduction. CTLA-4 blockage overcomes this inhibition and results in activation and proliferation of T cells.66 CTLA-4 blockade may represent a novel approach to enhance the immune response against melanoma antigens. Ipilimumab and tremelimumab are two fully human monoclonal antibodies against CTLA-4. Preliminary results of clinical trials showed promising activity in malignant melanoma. Results from phase I and II trials with ipilimumab and tremelimumab demonstrate up to 20% response rates in advanced disease.67 In a phase III trial of 676 HLA-A*0201-positive patients with refractory metastatic melanoma, ipilumumab (3 mg/kg) plus a glycoprotein 100 (gp100) peptide vaccine was compared with ipilumumab (3 mg/kg) alone or gp100 alone.68 The median overall survival time was significantly longer in patients treated with ipilimumab either alone or combined with gp100 as compared with patients treated with gp100 alone (10.0 or 10.1 months vs. 6.4 months). No difference in overall survival was observed between the two ipilimumab groups. Another phase III trial compared a higher dose of ipilimumab (10 mg/kg) plus dacarbazine with dacarbazine alone in patients previously untreated for metastatic melanoma.69 Ipilimumab plus dacarbazine demonstrated significantly longer overall survival (11.2 vs. 9.1 months) and higher survival rates at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) than dacarbazine alone. The potential role of ipilimumab in the adjuvant setting was evaluated in a phase II trial that reported encouraging results; a phase III trial is ongoing to further assess its role in this setting.70 Unfortunately, a phase III study of tremelimumab reported no difference in overall survival compared with dacarbazine or temozolamide.71 CTLA-4 antibodies produce several immune-mediated adverse events that are distinct from the typical adverse events associated with conventional cancer treatments. Many of these adverse effects are autoimmune in nature and can occur in up to 40% of patients.66 Antibodies against CTLA-4 may cause autoimmune-mediated adverse events by promoting the activation of self-reactive T cells. The most common serious adverse events included dermatitis, enterocolitis, and diarrhea. Less common adverse effects include autoimmune thyroiditis, adrenal disease, or hepatitis.67–68 Close monitoring for immune-related adverse events and participation in a risk evaluation and mitigation strategy (REMS) program while on therapy is necessary.20 Ipilimumab therapy should be held for moderate immune-related events. High-dose systemic corticosteroids are initiated for patients who do not improve from withholding therapy or for grade 3 immune-related events. Ipilimumab can be restarted when adverse events improve to grade 0 or 1 and systemic corticosteroid doses have been minimized. Infliximab can be used for patients who do not respond to steroids.68 In cases of severe or life-threatening immune-related adverse events, permanent discontinuation of therapy is recommended. In the clinical studies reported to date, patients who experienced grade 3 or 4 autoimmune toxicities were also the most likely to exhibit tumor regression and increased time to relapse.66 The timing of adverse effects is variable and may occur several months after the cessation of treatment.
Clinical Controversy…
The optimal dose of ipilumumab for the treatment of metastatic melanoma is currently unknown. The FDA-approved dosing is 3 mg/kg IV every 3 weeks for a total of four doses. Clinical studies that dosed ipilumumab at 10 mg/kg have shown slightly higher response rates but also greater toxicity. An ongoing clinical trial comparing the outcomes of the 3 mg/kg and 10 mg/kg dosing will help to answer this question.
Antibodies directed against programmed death 1 (PD-1), which is upregulated on activated T cells, block the binding of program death-ligand 1 and 2 to the receptor on tumor cells, thus allowing T cells to remain stimulated and the immune response to continue.10 Early-stage clinical trials with these agents show potential, and they are associated with less frequent immune-related adverse events compared to ipilumumab.10
Gene therapy of human melanoma is in its infancy but suggests several exciting approaches to management of metastatic melanoma. Several strategies for gene therapy are under investigation for the treatment of melanoma. One approach to gene therapy for melanoma is adoptive therapy. In this process, T lymphocytes are removed from the patient and are genetically altered to target specific antigens on the cancer cell. They are then expanded to large numbers and given back to the patient along with IL-2 after receiving an immunosuppressive preparative chemotherapy regimen.10 In a very small clinical trial in which T cells were engineered with a receptor against the cancer-testis antigen NY-ESO-1, found in about 25% of melanoma patients, response rates of 45% were seen in patients with treatment refractory metastatic melanoma.72 The challenges to this type of therapy are determining a patient population that can tolerate the intensity of treatment and who do not need immediate treatment because cell processing takes several week to complete.10
Antiangiogenic agents are also being evaluated for the management of metastatic melanoma. Thalidomide, given either as a single agent or in combination with chemotherapy or cytokines, was the initial agent studied. Thalidomide analogs are now being studied in an attempt to avoid toxicities associated with the parent compound. The thalidomide analogs are grouped into two classes: selective cytokine inhibitory drugs and immunomodulatory derivatives. Both classes appear to have antiangiogenic and antiinflammatory properties, but the selective cytokine inhibitory drugs are phosphodiesterase inhibitors. Immunomodulatory derivatives also have effects on T-cell stimulation and inhibition of TNF-α. Other antiangiogenic agents such as integrins and VEGF inhibitors are also being investigated. As seen in other cancer using these therapies, disease stabilization rather than tumor response is most likely to be the best outcome.5
Radiation
The role of radiation for the adjuvant treatment of melanoma is being investigated based on retrospective data that suggest that patients treated with therapeutic lymphadenectomy for lymph node field relapse benefit from postoperative adjuvant radiation to the nodal basins. Overall, these data demonstrate improvement in locoregional control with reasonable toxicity but with no impact on overall survival. A recently completed phase III trial reported that adjuvant radiotherapy reduced the risk of lymph node field relapse in patients who had undergone therapeutic lymphadenectomy for metastatic melanoma in regional lymph nodes.73 No difference in relapse-free survival was observed. For patients with metastatic melanoma, radiation is limited to the palliative setting to symptomatic areas of disease progression.
Limb Perfusion and Limb Infusion
Isolated limb perfusion is a surgical procedure of regional intravascular delivery of chemotherapy or biotherapy (or both) into an extremity with cutaneous melanoma.74 When in-transit metastases occur in extremities, local therapy with isolated limb perfusion or isolated limb infusion has been used.5 Isolated limb perfusion is a method for escalating the dose of chemotherapeutic drugs to a specific region of the body while limiting the systemic toxicities of the agent. Most perfusions can be performed with drug exposures of less than 2%. The most significant side effect of isolated limb perfusion is regional toxicity; all of the skin, subcutaneous tissue, and tissue of the extremity receives the same dose and is subjected to the same perfusion conditions as the tumor located within the extremity. After regional perfusions, objective response rates greater than 50% in treated limbs have been reported, with overall response rates possibly as high as 80%. The role of hyperthermia (39°C to 40°C [102°F to 104°F]) with regional isolated perfusion is not clearly defined. Although most clinical trials have used melphalan, whether the combination of melphalan with other agents may improve results is not known.75 Agents that have been combined with melphalan include actinomycin D, nitrogen mustard, thiotepa, and cisplatin. Work with biologic response modifiers, such as TNF-α, has been encouraging.76 A simplified form of isolated limb perfusion, called isolated limb infusion, is a low-flow isolated limb perfusion performed under hypoxic conditions via small-caliber arterial and venous catheters. It has been proposed that the hypoxia that develops during isolated limb infusion may be beneficial with certain cytotoxic agents such as melphalan.
PREVENTION AND DETECTION
The results of early treatment emphasize the role of early detection and prevention. There are three different strategies for chemoprevention for melanoma. Primary chemoprevention is used to prevent occurrences of melanoma in healthy individuals. Secondary chemoprevention is used to prevent premalignant melanoma precursors from becoming melanoma. Tertiary chemoprevention is used to prevent melanoma recurrence in individuals who were treated for melanoma and have no evidence of disease. The mainstay of melanoma prevention remains strategies to protect individuals from harmful effects of the sun77 (Table 116-7).
TABLE 116-7 Options for Sun Protection Sunscreens
Ultraviolet light exposure plays a major role in melanoma development. Childhood sunburns and intermittent sun exposure correlate positively with melanoma risk. Studies have shown that a decrease in recreational sun exposure is associated with a reduction of a second primary melanoma in individuals diagnosed with primary melanoma.78 Education and reeducation about the importance of sun protection have the potential to help decrease the rising incidence of this disease. Strategies, such as sun avoidance, especially during peak hours of sun intensity (10 AM to 4 PM), and staying in the shade when outdoors, are important education concepts for individuals who are in the sun for prolonged periods or who are at high risk for burning. Skiers and winter sports enthusiasts should be cautioned about exposure to UV radiation because the reflection off snow and high altitude contribute to increased UV exposure. There is also the use of protective clothing to minimize damage to the skin for individuals who spend time in the sun. Clothing designed to protect an individual from sun exposure but allows for physical activities such as water sports and hiking is widely available. The clothes are designed for skin protection, but it is important to realize that not all clothing provides sufficient protection from UV radiation. Clothes with tight weaves provide the greatest protection. In addition to protective clothing, wide-brimmed hats to protect ears, the neck, and the nose as wells as sunglasses with both UVA and UVB protection are important. Additionally, the use of tanning beds over the past 3 decades has led to an increased exposure of individuals to UVA light. Observational studies show that individuals who spent time in tanning devices before the age of 35 years have a 75% increase in risk of melanoma.79 As a result, the World Health Organization International Agency for Research on Cancer declared in 2009 that UV light emitted from tanning beds was a human carcinogen.80 A recent report from the Centers for Disease Control and Prevention found that 5.6% of people in the United States reported indoor tanning in the last 12 months. The highest rates, 12.3%, were seen in young women 18 to 25 years old. Evidence suggests that behavioral counseling in the primary care setting can decrease UV exposure, including tanning beds, in younger patients. To aid in the prevention skin cancers, laws such as bans or requiring parental consent have been put in place to restrict minors’ access to indoor tanning in 33 states.81
It is important to counsel patients about the appropriate use of sunscreens to optimize benefits from these products. Sunscreens should be applied 15 to 30 minutes before going into the sun and should be reapplied every 2 hours, after swimming, and after perspiring heavily. About 1 oz of sunscreen (a “palmful”) should be used to cover the arms, legs, neck, and face of the average adult. Sun protection must be used regularly and not limited to times of recreation or anticipated “prolonged” exposure. Times of season changes, when the potential for sun exposure can be perceived as erratic, are possible times for the “first-of-the-season sunburn.”
Historically, patients have been counseled that the risk of skin cancer can be limited by the use of sunscreens with a sun protection factor (SPF) of 15 or greater. SPF is a measure of protection from UVB radiation only. Although some studies have found a decreased risk of melanoma in sunscreens users, others have demonstrated no association and even increased melanoma risk with sunscreen use. Methodologic difficulties may explain the discrepancy in study results. Factors that include variables in sun exposure, sunscreen use, and sun sensitivity are very difficult to control in these trials. In addition, all sunscreens are not the same. It is important that people understand that no sunscreen provides complete protection and that the SPF scale is not linear; the higher the SPF, the smaller the difference in sun protection. For example, whereas SPF 15 sunscreens filter out about 93% of UVB rays, SPF 30 sunscreens filter out about 97%, SPF 50 sunscreens about 98%, and SPF 100 about 99%.
Sunscreens traditionally have been designed to prevent erythema by blocking UVB, leaving users relatively unprotected from wavelengths such as UVA. As a result, the use of sunscreens, especially those with higher SPFs, may lead to the ability of individuals to increase their time in the sun without clinical indication of sunburn. Newer forms of sunscreens combine protection for UVA and UVB. Unfortunately, no currently approved system rates products for UVA protective capabilities, but the FDA has proposed new sunscreen rules that will establish an UVA testing and labeling system. It is unclear when this system will be put into place. The impact of the use of high-potency sunscreens on the incidence of melanoma is not clear at this time because the lag time for melanoma is about 2 decades, and high-potency sunscreens have only been popular for about 10 years.
Thickness and stage of the disease are inversely related to melanoma survival. Early detection can play a large part in the secondary prevention of melanoma. Many healthcare organizations and skin cancer groups recommend monthly SSE to serve as a mechanism for recognizing moles or marks on the skin that may be melanoma. Patients with a strong family history should additionally have a clinical examination and, in some cases, screening photography to document the size, shape, and location of moles. Both patients and clinicians need to be properly educated in the clinical features of the disease to ensure more appropriate diagnosis. Currently, there are no consistent recommendations for the screening and early detection of melanoma.
PERSONALIZED PHARMACOTHERAPY
Treatment of cutaneous melanoma is determined by many factors including disease-related and patient-related issues. Most available reviews and guidelines provide treatment recommendations based on stage of disease.20 Most patients present with localized disease.20 Treatment of localized disease is surgical excision, with the extent of excision based on the tumor size. Wide excision is recommended for in situ melanoma and wide excision with SLNB for stage IA, IB, and II disease. The long-term survival of individuals with early-stage disease and thin tumors (<1 mm) is good, but survival is negatively impacted as tumor thickness increases.
The role of adjuvant therapy in the management of individuals at high risk for recurrence remains controversial. One controversy is determination of which patients are appropriate candidates for treatment after resection of the primary tumor. Although adjuvant therapy has been considered historically in patients with locally advanced disease (stages II and III), it is increasingly being considered after surgical resection of an isolated distant metastases.
Another controversy with adjuvant therapy is the choice of therapy. HDI has the most evidence supporting its use and is FDA approved for this indication. The challenges with this therapy have been discussed, and the therapy has limited worldwide acceptance. With the encouraging data of ipilimumab in the metastatic setting, clinical trials are now underway as an adjuvant treatment option. New therapies and combinations must be evaluated to help answer the questions that remain about adjuvant therapy in melanoma. The most appropriate option is a clinical trial, if available. Clinical trials of chemotherapy, immunotherapy, vaccines, and emerging therapies are ongoing.
Another treatment challenge is the management of patients with advanced disease. The 2013 NCCN guidelines list a variety of preferred systemic therapies for advanced or metastatic melanoma, including ipilimumab, vemurafenib, high-dose aldesleukin, and clinical trial. Dacarbazine, temozolomide, combination chemotherapy, or biochemotherapy are also included as treatment options.20 The choice of drug therapy should be based on BRAF mutational status, the aggressiveness of the disease, and disease-related symptoms. Patients with a more indolent clinical picture may respond better to immunotherapy. Patients with a documented BRAF mutation are candidates for vemurafenib. Vemurafenib may be particularly beneficial in patients with BRAF mutations who are symptomatic from their disease because of the rapid response rates that are seen. In patients who harbor the c-KIT mutation, imatinib can be offered as first-line therapy.20 Combination chemotherapy or biochemotherapy provides a treatment option for most patients. Furthermore, these modalities may be particularly beneficial in patients with rapid disease progression. Patients who have predominantly visceral disease and have appropriate organ function may be eligible for high-dose aldesleukin therapy. Best supportive care is also an option in some individuals. Data suggest that surgical treatment of metastatic melanoma should be considered in select individuals based on the extent and location of disease and performance status.
In patients who develop brain metastases, treatment of CNS disease is independent of systemic therapy. Depending on the size and location of metastases, surgical resection can be offered as the first-line treatment modality in patients with a favorable prognosis. Stereotactic radiosurgery is an acceptable alternative for patients who are unable to undergo resection. Whole-brain radiotherapy is generally reserved for patients with a large volume of metastases because of the concern of cognitive decline.82 In many cases, after brain metastases have been treated, patients can continue with their systemic treatment. As previously mentioned, temozolamide may also be a treatment option for patients with brain metastases. An important consideration for treatment of melanoma is the presentation of the disease. As discussed, treatment of melanoma isolated to the limb may be most appropriately treated with regional therapy. Treatment options for metastatic uveal melanoma include strategies for managing hepatic metastasis, such as chemoembolization to the liver and intrahepatic chemotherapy.13
EVALUATION OF THERAPEUTIC OUTCOMES
The outcome of patients treated with melanoma depends on the stage of disease at presentation. The prognosis of patients with thin tumors (<1 mm in thickness) and localized disease is good with long-term survival in more than 90% of patients. The risk of regional nodal involvement increases with increasing tumor thickness, so survival rates decrease in patients with nodal involvement. Long-term survival in patients with distant metastases is even lower. Therefore, early diagnosis and appropriate treatment of early disease are essential. Patients with suspicious pigmented lesions should be evaluated and the lesion excised whenever possible. Treatment is determined by patient factors and stage of disease.
Clinical practice guidelines published by the NCCN and ESMO provide some guidance for follow-up of patients with melanoma.20,83 Intensive surveillance has the benefit of early detection of recurrent disease, which may lead to better options of surgical resection. Emphasis on evaluation of locoregional areas is important. For patients with in situ melanoma, periodic skin examinations for life are recommended, although frequency is determined based on patient risk factors. Local recurrence is associated with aggressive tumor biology and frequently is a manifestation of an aggressive primary tumor. If a local recurrence occurs after inadequate primary disease, the patient should undergo a workup based on the lesion thickness of the original melanoma. Patients with nodal recurrence should be evaluated for lymph node metastases. Patients with systemic recurrence should be evaluated and treated in a fashion similar to patients presenting with systemic disease.
ABBREVIATIONS
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