US Pharm. 2012;37(4):HS-4-HS-7.
Melanoma, the fifth most common cancer in the United States, accounts
for fewer than 5% of skin cancer cases but is the most serious form of
the disease, causing up to 75% of skin cancer–related deaths.1-3
The incidence of cutaneous melanoma increased tremendously from 1970 to
the late 1990s; however, rates have remained relatively stable since
2000.3,4 Five-year survival rates for melanoma increased from
82% in 1975 to 92% in 2004, but the overall mortality rate remains
unchanged.3 Although melanoma is curable if detected in its
early localized form, metastatic melanoma continues to be a therapeutic
A melanoma is a malignant tumor that arises from melanocytes, dendritic cells that produce melanin,
a pigment that protects the body from damaging ultraviolet (UV)
radiation. Melanocytes use tyrosine to synthesize melanin. A cluster of
melanocytes form nevi (pigmented lesions or moles), and melanoma results when these melanocytes undergo a malignant transformation.3,4
Melanocytes may be found in various areas of the body; however, they
are primarily located in the epidermis, and more than 90% of all
melanomas are cutaneous.
Incidence Rates and Epidemiology
The incidence of melanoma varies worldwide, with the highest rates in
Northern Europe, New Zealand, Australia, and North America.3
Melanoma has one of the fastest-growing incidence rates in the U.S. The
U.S. incidence rate increased from 7.9 to 17.7 per 100,000 persons
between 1975 and 2000.4 The American Cancer Society (ACS)
estimates that, in 2012, approximately 76,250 new melanoma cases (44,250
men, 32,00 women) will be diagnosed and about 9,180 individuals (6,060
men, 3,120 women) will die from the disease.2 Unfortunately,
these rates may be underestimated because superficial and in situ
melanomas are often managed in outpatient settings, which do not
routinely report cases to the cancer registries.4
Unlike many other cancers, melanoma affects people of all ages.
Incidence increases with age, and people in their 80s have the highest
rate of occurrence; however, melanoma is one of the most common cancers
in young adults and can occur in those under 30 years of age.2 Melanoma is rare in children and adolescents; only about 2% of cases are diagnosed in patients younger than 20 years.3 Overall, the median age of diagnosis is 53 years.4
Men are affected slightly more than women, with a ratio of 1.3 to 1,
but melanoma remains the leading cause of cancer in women aged 20 to 29
years.1,4 Although mortality rates have declined in younger
populations, men aged older than 65 years continue to have the highest
mortality rate.3 Melanoma mortality rates vary from state to state, with the highest rates seen in the northwestern U.S. (FIGURE 1).5
Melanoma is predominantly a malignancy of light-skinned,
fair-complexioned people. White populations are most often affected,
accounting for 98% of cases.1,4 People of darker complexion,
such as East Asian and Indian individuals, develop melanoma at a rate 10
to 20 times lower than that for white individuals.1 In the
U.S., approximately 1 in 50 (2%) white, 1 in 200 (0.5%) Hispanic, and 1
in 1,000 (0.1%) African American individuals are at risk for developing
melanoma in their lifetime.2
Etiology and Risk Factors
The etiology of melanoma is not fully understood, but many intrinsic
and extrinsic factors have been identified that contribute to the
occurrence of cutaneous melanoma. Physical characteristics such as blue
or green eyes, red or blond hair, pale complexion, high degree of
freckling, and tendency to sunburn put one at greater risk for
developing melanoma. The number of melanocytic nevi on the body and the
presence of atypical melanocytic nevi increase the risk of melanoma.3
Family history and personal history of melanoma are two important
factors for diagnosis. If a patient has at least one family member who
was diagnosed with melanoma, the risk of diagnosis increases 2.2-fold.
The risk is 100% if the patient has two or more family members with
dysplastic nevi and/or melanoma.6 Immunosuppression is also a
risk factor for melanoma. Maternal–fetal transfer of melanoma is rare
but should be noted, as melanoma is the cancer most likely to
metastasize from the placenta to the fetus. Congenital melanocytic nevi
are also considered precursors for melanoma. External risk factors
include geographic location and increased exposure to sunlight and UV
Several gene mutations that relate to melanoma risk have been
identified. Cyclin-dependent kinase inhibitor 2A and melanocortin-1
receptor gene have been associated with an increased risk of hereditary
melanoma.1 Familial atypical multiple mole melanoma syndrome (also known as dysplastic nevus syndrome),
a hereditary disease that increases the risk of melanoma 400- to
1,000-fold, is characterized by a predisposition to develop dysplastic
nevi and cutaneous melanoma.3 The mitogen-activated protein
kinase pathway is a major signaling pathway that has been associated
with the development of melanoma. A high prevalence of BRAF gene
mutations appears to be an epidemiologic link between UV radiation and
melanoma. Alterations in melanoma-specific pathways such as NEDD9, MITF, and NRAS
also play a role in the development of melanoma. Studies continue to
explore the relationship between molecular genetics and melanoma risk in
the hope of better understanding the disease and identifying new
targets for pharmacologic therapy.3
The developmental pathway of melanoma involves a series of distinct
steps; however, not all steps must occur in order for melanoma to
develop. Morphologic stages include melanocytic atypia, atypical
melanocytic hyperplasia, radial growth phase, primary melanoma in the
vertical growth phase with or without in-transit metastases, regional
lymph node metastatic melanoma, and distant metastatic melanoma.3
The main goal is to diagnose melanoma early to prevent tumor invasion
and metastasis. The classic clinical presentation of melanoma varies by
type. Early detection may be facilitated by using the ABCDE mnemonic to
assess a mole: Asymmetry; Border irregularity; Color variation or recent color change; Diameter (increasing or >6 mm); Evolving
lesion, including surface changes (i.e., any change in shape, size,
color, or elevation) and the development of new symptoms (e.g.,
bleeding, itching). Several characteristics are used to help distinguish
benign nevi from atypical nevi, including size, shape, color, location,
and number. If any abnormality is suspected, a dermatologist should
perform a comprehensive skin examination, and a biopsy may be warranted.3
This step is critical for evaluating a patient with multiple or
atypical nevi, a history of excessive sun exposure, or melanoma.4
Classification and Staging
Melanoma is classified into four major types: superficial spreading
melanoma, lentigo maligna melanoma, acral lentiginous melanoma, and
nodular melanoma. The types differ in appearance, site, and population
affected. Superficial spreading, lentigo maligna, and acral lentiginous
melanomas have a period of superficial growth and, if identified early,
may be cured by surgical excision. However, nodular melanoma usually
presents as a deeply invasive lesion that is highly capable of early
metastasis and is difficult to cure.3
Melanoma staging is important to help determine prognosis and
treatment options. The American Joint Committee on Cancer TNM staging
system for melanoma contains three major components that define the
extent of disease: Tumor size, lymph Node involvement, and Metastasis.
A stage 0 melanoma is defined as a melanoma in situ that has not yet
spread from the epidermis to the dermis. Stages I and II are localized
to a specific area. Stage III encompasses lymph nodes, but there is no
distant spread. Stage IV indicates metastasis to distant sites. Tumor
thickness, level of tumor invasion, and ulceration are powerful
predictors of survival, and TNM status and stage are used to determine
prognosis and survival. Other predictors include serum lactate
dehydrogenase, presence and site of distant metastases, evidence of
nodular involvement, and regression of primary melanoma.1-4
Melanoma has become a worldwide public health concern, and awareness
is the key factor in early detection and prevention of the disease. ACS
recommendations for prevention include limiting direct sun exposure
between the hours of 10 AM and 4 PM, when UV rays are the most intense;
wearing protective clothes that cover the arms, legs, and torso,
sunglasses that protect the eyes, and a broad-brimmed hat that shields
the face; avoiding tanning beds and sunlamps; and using sunscreen and
lip balm on sun-exposed areas.7-9
The American Academy of Dermatology recommends using sunscreen with a
sun protection factor of 30 or more. Sunscreen products labeled as broad spectrum
shield against both UVA and UVB rays and are a good source of
protection. One ounce (about a palmful) of sunscreen should be applied
to the arms, legs, neck, and face every 2 hours, or sooner after
sweating or swimming. Sunscreen should also be applied on cloudy days
because UV rays are still present.3,7-9
The treatment of melanoma depends upon the stage of disease. The
stage of cutaneous melanoma is directly associated with the development
of metastatic disease. If the melanoma is diagnosed at an earlier stage,
surgical excision is the treatment of choice. For melanomas that have
lymphatic involvement, surgical excision may not be enough, and lymph
biopsy may be warranted.3,4
Surgery: The surgical excision margin is the
most important determinant of outcome in early-stage melanoma. Thin
(<1 mm) melanomas require an incision of less than 1 cm. The cure
rate for melanomas smaller than 1 mm is as high as 98%.10
Midsize melanomas (1-2 mm) usually require an incision of 2 cm. Larger
melanomas (>4 mm) may have lymphatic involvement and are associated
with a high rate of recurrence. These tumors also require a maximum
surgical incision margin of 2 cm.
Surgery is usually limited to patients with early-stage disease.
Patients with stage III melanoma usually have lymph node involvement or
in-transit metastasis. In-transit metastasis is when a tumor develops in the lymph vessel between the primary melanoma and the regional lymph node basin.11
In-transit metastases occur more than 2 cm from the original site and
are more common in individuals with thick, ulcerated lesions. Surgery is
also used to manage these distinct melanoma-associated lesions.
Immunotherapy: Melanoma is one of the most
immunogenic solid tumors. Immunotherapy appears to be a viable treatment
option, as more traditional cancer treatments do not always yield
positive results in cases of melanoma. Complete response rates to
immunotherapy vary in patients with melanoma, but generally they are
Interferon (IFN) alfa is approved for adjuvant therapy in metastatic
melanoma. For patients who have undergone surgical resection for lesions
larger than 2 mm, with or without regional lymph node metastases, the
only effective adjuvant therapy is IFN.12 Various trials have
evaluated different doses and schedules of IFN therapy for metastatic
melanoma. The optimal IFN treatment modality has not been established
for the management of metastatic melanoma. Some of the disadvantages of
IFN therapy are high cost, unclear long-term benefit, and toxicities
(e.g., liver toxicity). IFN is known to cause constitutional symptoms
manifesting as fever, chills, myalgia, and fatigue. These symptoms have
been treated with acetaminophen, nonsteroidal anti-inflammatory drugs,
and meperidine. The most common dosages of IFN alfa therapy are listed
in TABLE 1.13,14
Interleukin-2 (IL-2), a glycoprotein produced by activated
lymphocytes, may be immunosuppressive. The role of immunosuppressive
properties in melanoma is not fully understood. IL-2 does not have a
direct effect on the tumor; rather, it works to regulate immunologic
activity. Because of severe multiorgan toxicity associated with IL-2
therapy, treatment with higher doses of IL-2 is reserved for patients
with good organ function who are being closely monitored by experienced
clinicians. The high-dose regimen of recombinant IL-2 (aldesleukin) used
to treat metastatic melanoma is 600,000 IU/kg/dose every 8 hours, for a
maximum of 14 doses in a 5-day period, given for two cycles, with a 10-
to 14-day rest period between cycles.11 Common side effects
of IL-2 include hypotension, arrhythmias, severe infections, and
shortness of breath; these effects are reversible.
Patients with stage IV malignant melanoma require cytotoxic, single-
or double-agent, systemic therapy. Single-agent chemotherapy with
dacarbazine, temozolomide, or fotemustine should be used in selected
patients who are not candidates for treatment with high-dose IL-2. Poor
response to chemotherapy or immunotherapy alone has led to the evolution
of combination therapy. Biologic therapy has been combined to increase
overall activity and, perhaps, response rates.3
Ipilimumab: Ipilimumab (Yervoy) was approved by the FDA in March 2011 to treat advanced or metastatic melanoma.15
Ipilimumab is a human immunoglobulin G1 monoclonal antibody that exerts
its action by blocking cytotoxic T lymphocyte–associated antigen 4,
thereby increasing T-cell activation and proliferation. Ipilimumab
activates the immune system, causing antitumor action.11 The
National Comprehensive Cancer Network recommended ipilimumab as a
category 1 treatment option for metastatic melanoma following a phase
III trial that showed an overall survival benefit.16 The usual dosage of ipilimumab in metastatic melanoma is 3 mg/kg IV every 3 weeks for four doses.
Melanoma is one of the few cancers whose incidence is on the rise.
Older adults are mainly affected, with a higher incidence later in life.
The primary treatment for melanoma is surgery with adjuvant IFN,
depending upon the melanoma’s size and grade. Treatment for advanced
melanoma is limited, and toxicities may limit its overall benefit. The
key focus for the prevention of melanoma is sunscreen application and
regular skin examinations for the detection of suspicious moles.
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2. American Cancer Society. What are the key statistics about
Accessed February 21, 2012.
3. O’Bryant CL, Poust JC. Melanoma. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill Medical; 2011.
4. Kazerooni R, Madden T. Melanoma. In: Schumock GT, Brundage DM, Richardson M, eds. Pharmcotherapy Self-Assessment Program: Hematology/Oncology I and II (Book 10). 5th ed. Kansas City, MO: American College of Clinical Pharmacy; 2006:55-80.
5. National Cancer Institute. Cancer mortality maps. http://ratecalc.cancer.gov. Accessed March 13, 2012.
6. Goldstein AM, Tucker MA. Genetic epidemiology of cutaneous melanoma: a global perspective. Arch Dermatol. 2001;137:1493-1496.
7. American Cancer Society. Melanoma skin cancer.
Accessed February 18, 2012.
8. Robinson JK. Sun exposure, sun protection, and vitamin D. JAMA. 2005;294:1541-1543.
9. American Academy of Dermatology. Be Sun Smart.
Accessed February 18, 2012.
10. Slinluff CL Jr, Flaherty K, Rosenberg SA, Read PW. Cutaneous melanoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:1897-1951.
11. CDC. United States Cancer Statistics (USCS). 1999–2007 incidence
and mortality data. www.cdc.gov/uscs. Accessed February 18, 2012.
12. Molife R, Hancock BW. Adjuvant therapy of malignant melanoma. Crit Rev Oncol Hematol. 2002;44:81-102.
13. PegIntron (peginterferon alfa-2b) product information. Whitehouse Station, NJ: Schering Corp; December 2011.
14. Intron A (interferon alfa-2b, recombinant) product information. Whitehouse Station, NJ: Schering Corp; September 2011.
15. Eggermont AM, Robert C. New drugs in melanoma: it’s a whole new world. Eur J Cancer. 2011;47:2150-2157.
16. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Melanoma. Version 3.2012.
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