US Pharm. 2006;31(7)(Oncology suppl):3-15.

Skin cancer is the most commonly diagnosed malignancy in the United States. Over one million cases of squamous cell and basal cell skin cancers are projected to be diagnosed in 2006.¹ The most deadly form of skin cancer is malignant melanoma. The American Cancer Society (ACS) estimated that 62,190 new cases of cutaneous melanomas would be diagnosed in the U.S. in 2006, with 7,910 deaths from the disease. Melanomas are responsible for about 4% of all new cancers and about 1% of cancer deaths per year.¹

The lifetime risk of developing a cutaneous melanoma is one in 63 for American men and women.² The age-adjusted incidence is 17.2 per 100,000 people annually, with a higher incidence in men (21.8 per 100,000) than in women (14 per 100,000). The median age at diagnosis is 57 years. The annual percentage increase of melanomas was 6.1% from 1975 to 1981 and 2.8% from 1981 to 2002. Melanomas are most common among white Americans (25.9 per 100,000 males, 17.2 per 100,000 females), followed by Hispanics (4.5 per 100,000 males, 4.4 per 100,000 females). They are least common among African-Americans (1.3 per 100,000 males, 0.8 per 100,000 females).

Risk Factors

Melanomas are usually found on sun-exposed areas. In men, the most common location for a melanoma is on the trunk, head, or neck, whereas women are most likely to develop lesions on their legs. Sun exposure is a well-known risk factor for melanomas. The nature of sun exposure influences the risk. A review of case-control studies on sun exposure and melanoma risk revealed a positive association with intermittent exposure, a history of sunburn at all ages, and a smaller link with total sun exposure.³ A reduced risk of melanoma is associated with occupational exposure, as reported in a recent meta-analysis examining sun exposure and melanoma risk.⁴ In addition, there is an association between melanomas and the use of tanning beds and sun lamps.⁵

Although melanomas are known to develop in a preexisting lesion, such as a mole, they can develop on any area of the skin. Risk factors for melanomas include skin type, environmental exposure, preexisting skin lesions, personal and family history, and immunosuppression (Table 1). Individuals with atypical moles (dysplastic nevi) have a higher risk of developing the cancer. Atypical moles are often large, flat, and asymmetrical and have ill-defined borders.⁶ Atypical moles can be located on any area of the skin but are most common on the upper back. These moles may be brown, tan, black, pink, or red. The risk of melanoma is directly correlated with the number of dysplastic nevi.

Prevention

There are two types of melanoma prevention: primary and secondary. The goal of primary prevention is to prevent the development of the disease. To reduce the risk of melanoma, it is important to be protected from the sun's damaging influence. Protection can be attained through the implementation of basic principles of safe sun practices:
1. During the peak midday period between 10 am and 4 pm, avoid exposure to strong sunlight. If outdoors, stay in the shade during these times. Avoid deliberate tanning with sun lamps and tanning beds.
2. Prevent sun damage with sunscreens that protect against ultraviolet light. Sunscreens should have an SPF rating of at least 15 and should be applied liberally and frequently during outdoor activities.
3. When outdoors, wear sunglasses and protective clothing (e.g., long-sleeved shirts and wide-brimmed hats).⁷

The goal of secondary prevention is to discover the disease in its earliest, most curable form. One of the best methods to detect melanomas is an examination of the skin. Professional assessments and self-examinations are important components of early melanoma detection. Self-examinations should be performed regularly in a private, well-lit area. A full-length mirror and a hand-held mirror are useful when examining areas difficult to see, and a blow dryer may be helpful when evaluating the scalp. Several organizations, such as the ACS and American Academy of Dermatology (AAD), have free brochures that describe and illustrate how to perform a self-examination for skin cancers. In addition, the ACS and AAD both demonstrate how to conduct a skin self-examination at their Web sites (www.cancer.org and www.aad.org, respectively).

Pathology

Most melanomas begin as superficial lesions within the epidermis and may remain there for years.⁸ They grow primarily in a horizontal manner, which is known as the radial growth phase. During the radial phase, melanomas grow slowly and are classified as a melanoma in situ, a lesion confined to the epidermis, or as a microinvasive melanoma, which grows horizontally in the epidermis but may also spread microscopically into the dermis. During the vertical growth phase, the melanoma begins to spread deeply into the dermis. This phase is more dangerous, since the disease can spread to other areas of the body, such as lymph nodes and other tissues. Most melanomas are characterized by a radial growth phase that may eventually evolve into a vertical growth phase. The major exception is nodular melanoma, which has no radial growth phase and starts in the vertical growth phase.

The four major melanoma subtypes, in order of frequency, are superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma.⁸ Superficial spreading melanomas account for 60% to 70% of all melanomas.⁹ Although this type can appear anywhere, it is commonly found on the trunk in men and on the legs in women. These melanomas appear as pigmented lesions that may contain a number of colors, including black and different shades of brown. Usually, superficial spreading melanomas have an irregular border with a notched or scalloped appearance.

Nodular melanomas represent 15% to 30% of all melanomas and are the most aggressive, exhibiting no radial growth.⁹ They may appear as a dark nodule on the skin. Nodular melanomas are common on the trunk or head and neck and are more common in men.

Representing 5% of all melanomas, lentigo maligna melanomas are often found on the face of elderly individuals.⁹ They may appear as a flat, brown or tan lesion that may be quite large.

The least common melanoma is acral lentiginous, which accounts for less than 5% of melanomas.⁹ Most often, this type is found on the palms of the hands and soles of the feet but can also be seen under fingernails or toenails. Acral lentiginous melanomas may be brown or black or contain color variations.^8,9

Presentation
Melanomas characteristically present as a pigmented lesion on the skin. Melanomas may develop in a preexisting lesion; however, the majority develop in previously normal areas of the skin. The ACS developed the "A-B-C-D" system to identify typical characteristics of a melanoma.¹⁰ "A," or asymmetrical, refers to the shape of the lesion. Most benign lesions are symmetrical, whereas melanomas are often asymmetrical. "B" refers to the lesion's border, which is usually irregular in melanomas. "C" refers to color, specifically color variation. The color of the melanoma may range from a solid, dark lesion to a lesion with several different shades, including blue, black, brown, pink, white, gray, or red. "D" refers to the diameter of the lesion. Most melanomas are more than 6 mm in diameter, which is about the size of a pencil eraser. Recently, "E" has been added to the scheme, representing evolution. Any change in a preexisting lesion, including a change in size, color, swelling, border, or raised area, should be evaluated.

Diagnosis

An accurate diagnosis of a suspicious lesion can be made only through a biopsy. Small lesions can be removed  through an excisional biopsy, which removes the lesion and a small margin of surrounding normal skin. If the lesion is too large to remove or is located in a delicate area, it may be examined through an incisional biopsy that removes only part of the lesion. The biopsy should be a full-thickness biopsy that includes subcutaneous tissue. The pathologist can then determine the thickness and depth of the lesion.

Varying levels have been established to identify the relationship between penetration depth and risk for metastasis. The deeper the penetration, the more likely it is to spread. Clark's system is used only to assess prognosis in patients with thin lesions and does not correlate with prognosis and tumor thickness. It comprises five levels:
Level I: Limited to the epidermis.
Level II: Extending to the papillary dermis but not filling it.
Level III: Filling the papillary dermis.
Level IV: Infiltrating into the reticular dermis.
Level V: Involving subcutaneous fat.

Breslow classified melanomas according to their thickness and reported a good correlation between thickness and prognosis. An additional negative prognostic factor is the presence of ulceration.⁸

Staging
After a diagnosis is made, the patient should be evaluated to determine the stage or extent of disease. Once the extent is known, the appropriate treatment can be initiated, and an estimation of the patient's prognosis can be made. Staging includes an evaluation of the entire skin surface, regional lymph nodes, chest/abdominal CT scans, and serum lactate dehydrogenase (LDH). Stages are defined according to the American Joint Committee on Cancer's TNM (tumor, node, metastasis) system (Tables 2 and 3).¹¹ "T" represents the primary tumor and is divided into substages based on thickness (T1 to T4) and the absence or presence of ulceration ("a" and "b," respectively). "N" represents lymph node involvement and contains three levels based on the number of nodes involved with disease. "M" indicates the presence or absence of distant metastases, with subsets based on the location of the lesion(s) and the serum LDH level.

Melanomas may be classified as localized disease (83% at diagnosis), regional disease (11%), and advanced disease (3%), with the stage of the remaining 3% unknown.² Localized disease, including stages I and II, has not spread beyond the area where it developed. Regional disease (stage III) occurs when the tumor has spread to local lymph nodes. Advanced disease (stage IV) is characterized by spread to distant parts of the body.

Surgery

Surgical removal of a melanoma is performed through a wide excision that removes the lesion and an area of surrounding normal tissue. The margin of tissue removed is determined by the thickness of the tumor. A margin of 1 cm is recommended for Ia lesions. Lesions that are 1.1 to 2 mm thick should be resected with margins of 1 to 2 cm; lesions that are greater than 2 mm in thickness require margins of 2 cm.¹²

Patients with stage Ia melanomas are usually managed with wide excision and careful follow-up. Wide excision is also appropriate for patients with stage Ib and stage II tumors. However, lymph node evaluation is often recommended for these patients. Evaluation of the sentinel lymph node is a means of evaluating one lymph node and, if negative, may spare the patient a more extensive lymph node dissection. The sentinel lymph node is considered the first node that the disease will spread to once malignant cells leave the tumor and enter the lymphatic system. The node is identified by injecting a blue dye and a radiopharmaceutical agent into the tissue surrounding the primary tumor. The sentinel lymph node will be the first node to take up the dye. If the node is negative, the patient can be assigned to observation or adjuvant therapy. If positive, dissection of regional nodes should be performed.

Patients with clinically positive nodes (stage III) undergo wide excision of the primary tumor with complete lymph node dissection, followed by close observation or adjuvant therapy. Patients who present with distant metastases (stage IV) can be treated with systemic therapy.

Adjuvant Therapy

After surgery, adjuvant therapy is administered. Systemic therapy is aimed to treat any remaining microscopic disease to prevent relapse. Adjuvant therapy for early-stage melanoma is controversial.

Interferon Alfa:Although a number of treatments have been used, there is no standard that has been definitively proven to extend overall survival. A commonly recommended adjuvant therapy is interferon alfa. The initial interest in adjuvant interferon alfa was sparked by the Eastern Cooperative Oncology Group (ECOG) E1684 trial (discussed in detail below).¹³ Based largely on the results of this trial, interferon alfa-2b was approved for adjuvant therapy in adults with melanoma who are disease-free but at high risk for recurrence.

Four phase III randomized trials evaluated the activity of high-dose interferon alfa.^14-17 The first study compared three months of high-dose interferon alfa-2a to observation.⁸ There was no difference in disease-free or overall survival between treatment and observation. This was followed by three studies of interferon alfa-2b conducted by the ECOG. In the first study (E1684), patients were randomized to high-dose interferon at doses of 20 million units (MU)/m² for five days per week intravenously for one month, followed by 10 MU/m² three days per week subcutaneously for 48 weeks, or observation.¹³ After a median follow-up of 6.9 years, a significant difference in respective overall survival (3.8 vs. 2.8 years) was seen between the interferon and observation groups. However, at a median follow-up of 12.6 years, the difference in overall survival was insignificant.¹⁵ Toxicity was significant and included neutropenia, flu-like symptoms, fatigue, depression, and hepatotoxicity. Dose reduction or delays were required in 37% of the patients during the induction phase and were required in 36% during the maintenance phase of the trial.

The E1684 trial was followed by a three-arm trial (E1690) that compared the same interferon dose and schedule to low-dose interferon and observation.¹⁶ High-dose interferon was associated with an increase in relapse-free survival, compared to observation, but there was no overall survival benefit in either interferon arm. A lack of survival benefit may have been due to the fact that patients in the observation arm were allowed to receive interferon therapy upon relapse.

The third study (E1694) randomly compared high-dose interferon to a melanoma vaccine called GMK,¹⁷ which contains ganglioside GM2, a melanoma antigen that is the most immunogenic ganglioside expressed on melanoma cells. The study was halted early when a midpoint analysis revealed a significantly higher disease-free and overall survival in the interferon arm. A pooled analysis of updated data from all three ECOG trials revealed no significant impact of high-dose adjuvant interferon on overall survival, compared to observation.¹⁵

Due to the toxicity encountered with high-dose interferon, a number of randomized trials compared low-dose interferon to observation. Interferon was primarily administered at a dose of 3 MU three times per week for six months to three years.¹⁸ Disease-free survival was significantly improved with interferon only in two studies,^19,20 and none of the studies demonstrated an improvement in overall survival.

Since high-dose interferon was associated with significant toxicity and low-dose interferon did not improve survival, a phase III study of intermediate-dose interferon was initiated.²¹ Patients received 13 or 25 months of interferon alfa-2b versus observation. The 13-month regimen had no significant impact on survival, and the 25-month regimen improved survival by only 5.4%.

These studies demonstrate that there is no compelling evidence to suggest interferon alfa as the adjuvant therapy of choice in patients with stage IIb/III disease at intermediate to high risk of recurrence. Guidelines proposed by the National Comprehensive Cancer Network suggest offering participation in a clinical trial, high-dose interferon alfa-2b, or observation to patients with localized lesions more than 4 mm thick who are at significant risk for recurrence or who have positive lymph nodes.¹⁰

Isolated Limb Perfusion
In-transit metastases are lesions that develop in cutaneous and subcutaneous lymphatic vessels between the primary tumor and lymph nodes. Their incidence is 5% to 8% in patients with high-risk melanomas.²² They are surgically excised if their number and location allow removal without excess morbidity. Relapse after surgical excision is common. Dong et al. reported that 55% of 648 patients experienced a second regional relapse after surgical excision within two years, and 82% relapsed by five years.²³

In-transit metastases located on extremities may be treated with isolated limb perfusion (ILP). In this procedure, which is performed under general anesthesia, the affected limb is surgically isolated from the rest of the body with a bypass system. Chemotherapeutic agents are infused into the limb, concentrating the drugs in the limb and sparing the rest of the body from the effects of the drugs. The limb is also heated (hyperthermia) to improve the activity of the drugs. The most commonly employed drug for ILP is melphalan. The overall response rate to melphalan with hyperthermia (>=40^oC) ranges from 80% to 90%, with complete response rates as high as 55% to 65%.²² Responses generally last about nine to 12 months. Toxicities include local skin erythema, peripheral neuropathy, and myopathy.

Distant Metastatic Disease
Patients with advanced-stage melanomas may be treated with chemotherapy, immunotherapy, or both. Responses to systemic therapy are classified as complete (no evidence of disease), partial (more than a 50% reduction in size of primary tumor), minor (less than a 50% reduction in size of primary tumor), or stable (no change). Overall response combines complete and partial responses.

Dacarbazine and Temozolomide:The most active chemotherapeutic agent is dacarbazine (DTIC). DTIC is associated with an overall response rate of about 20% (Table 4), and the duration of response to single-agent DTIC is about four to six months.⁹ DTIC is administered intravenously or by infusion. Major adverse effects associated with DTIC are anorexia, nausea and vomiting, myelosuppression, local tissue damage upon extravasation, and infrequent occurrence of a flu-like syndrome.

Temozolomide, a prodrug that degrades to the active agent MTIC, is also the active metabolite of DTIC. It has the advantages of oral administration and better penetration into the central nervous system. It has been administered as a single agent to over 400 patients with advanced melanoma and resulted in response rates of 6% to 26%, mostly in patients without prior therapy.^24-27 Median overall survival ranged from 5.5 to 11.5 months.

Temozolomide and DTIC were compared in a head-to-head trial of 305 patients and produced respective response rates of 13.5% and 12.1% and survivals of 7.7 and 6.4 months, respectively.²⁸ Temozolomide was also compared with combination temozolomide and cisplatin, and no significant differences were found in respective response rates (26% vs. 29%) or survival (11.5 vs. 12 months).²⁷ However, in another study, temozolomide plus cisplatin produced a response rate of 48.6% among 37 patients.²⁸ Temozolomide was administered with interferon in two trials involving a total of 87 patients, with response rates of 12.5% and 27.6%. Survivals were only 11.8 and 14.5 months, respectively.^29,30

Adverse effects with temozolomide include myelosuppression, mild to moderate nausea and vomiting, headache, and fatigue. Unfortunately, despite the advent of newer agents such as temozolomide, no single agent has demonstrated significantly better outcomes than DTIC. However, temozolomide, since it is administered orally, is more convenient and better tolerated than DTIC regarding nausea and vomiting and does not carry the risk of extravasation.

Combination Chemotherapy: DTIC has been combined with many agents for the management of advanced melanoma. One of the most active regimens is cisplatin, vinblastine, and DTIC (CVD). The first trial of this regimen produced an objective response rate of 40% over a nine-month median duration of response among 50 patients with advanced disease.³¹ This combination was then compared to DTIC alone in patients with advanced disease. The most recent data from this study revealed no significant differences in respective response rates (19% vs. 14%), median duration of response (21.5 vs. 17 weeks), or median survival (27 vs. 21 weeks) between CVD and DTIC alone.³²

A four-drug regimen, known as the Dartmouth regimen, contains cisplatin, DTIC, carmustine, and tamoxifen. The first study of this therapy indicated a response rate of 46%, including an 11% complete response rate.³³ In another small trial involving 20 patients, a response rate of 50% was reported. However, concern about the possibility of DVT and PE prompted researchers to delete tamoxifen from the regimen, and the response declined to 11%. When tamoxifen was reinserted into the regimen, the response was 52%.³⁴ A combined analysis of these trials is presented in Table 4.³⁴ A response rate of 51% was found in 45 patients who received CVD plus tamoxifen, whereas 20 patients who received CVD without tamoxifen achieved a 10% response.³⁴ Despite the differences in response with and without tamoxifen, there was no survival difference between the regimens.

Two randomized studies compared the original four-drug regimen to the three-drug regimen without tamoxifen and reported no significant difference in response or survival, thereby eliminating the need for tamoxifen in this combination.^35,36 A phase III study compared the Dartmouth regimen to single-agent DTIC and reported slightly higher response rates with the combination (18.5%) over DTIC alone (10.2%). However, the difference was not significant and there was no survival benefit with the combination regimen.³⁷

Interferon Alfa: Although the exact mechanism of action is unknown, interferon alfa is thought to exert its antineoplastic effects partly via modulation of the immune system. Over a dozen trials of single-agent interferon involved about 400 patients with advance melanomas. Doses ranged from 10 MU/m²/day to 50 MU/m² three times per week. Response rates ranged from 4% to 29%, with an average overall response of 16% (4% complete).⁹ The median duration of response was only four months. Interferon was no more active than DTIC and represented considerable toxicity and cost.

The combination of interferon and DTIC has produced response rates of 17% to 46%.^38-41 Several trials compared DTIC alone to DTIC plus interferon. Falkson randomized 73 patients to DTIC alone or DTIC plus interferon.³⁸ Seven patients responded to DTIC (19%) and 17 to the combination (46%)--a significant difference. The combination was also associated with a significantly longer time to treatment failure (nine vs. 2.5 months) and median survival (16.7 vs. eight months). However, the activity of DTIC plus interferon was not confirmed in three other comparative trials.^39-41 A major adverse effect is a flu-like syndrome that may begin in hours to days after administration. Signs and symptoms may include fever, chills, arthralgias, myalgias, fatigue, headache, and malaise. This reaction may be dose-related and is seen in most people who receive this drug.

Interleukin-2: Interleukin-2 (aldesleukin) is one of the few agents approved for management of metastatic melanoma. As with interferon, the exact antineoplastic mechanism of interleukin-2 is unknown but is thought to involve immunomodulation. A review of single-agent trials of 270 patients who received high-dose interleukin-2 (720,000 U/kg/dose) reported an overall response rate of 16%.⁴² The median duration of response for all who responded was 8.9 months, and the median overall survival for the entire population was 11.4 months. Twenty of the responding patients (47%) survived after a median follow-up of 62 months, including 15 who survived more than five years. Interleukin-2 is associated with significant toxicities that may limit its use. Combination interleukin-2 and interferon alfa has produced response rates of 11% to 24%.^43-45 A phase III study randomized 85 patients with advanced disease to interleukin-2 alone or in combination with interferon alfa-2a.⁴⁶ There was a 2% response among patients who received interleukin-2 alone, versus 10% among those who received interleukin-2 plus interferon--an insignificant difference. These studies report no survival benefit to combination interferon alfa and interleukin-2.

Interleukin-2 has been linked to serious and sometimes life-threatening side effects, which may limit its use to select young patients with a good performance status. Most patients with advanced melanoma do not fit this description and would likely not be candidates. The frequency and severity of these effects are dose-related. A black box warning in the prescribing literature states that an intensive care facility and specialists in cardiopulmonary or intensive care medicine must be available.⁴⁷

Biochemotherapy: Biochemotherapy combines chemotherapy and immunotherapy. Many of these regimens contained a chemotherapy base of DTIC to which other chemotherapy agents are added. The combination of DTIC plus interferon has produced response rates of 17% to 28% and median survivals of 4.5 to 17 months.⁴⁸ The addition of two to three more chemotherapeutic agents has increased response rates but has not had an impact on survival. DTIC and interleukin-2 has produced responses in 16% to 26% of patients, with survivals of nine to 13 months.⁴⁸ Combination interferon alfa and interleukin-2 has been administered with a variety of chemotherapeutic agents. Response rates have been as high as 64%, but survivals remain in the eight- to 12-month range.⁴⁸ Only two phase III trials of biochemotherapy reported significant differences in response with biochemotherapy, one over immunotherapy and the other over chemotherapy.^49,50 However, no significant differences in survival were found in any of the studies. The combination of chemotherapy plus immunotherapy may increase the response over either treatment alone but at a cost of greater toxicity with no clearly significant survival benefit.

Thalidomide: Thalidomide has demonstrated immunomodulatory and antiangiogenesis activity with benefit in patients with multiple myeloma and other malignancies.⁵¹ Although trials of single-agent thalidomide against metastatic melanomas reported no clinical responses,^52,53 it has been combined with temozolomide and interferon alfa with mixed results.^54-56 Adverse effects include constipation, peripheral neuropathy, dizziness, somnolence, edema, dry skin, dry mouth, tremor, and fatigue.

Summary

Malignant melanoma is the most dangerous form of skin cancer. The incidence of melanoma continues to increase. Exposure to ultraviolet light is a major risk factor that can be minimized through safe sun practices. Melanomas are readily detectable on the skin surface. People should be encouraged to perform self-examinations and to report any abnormality to their physician.

Surgical excision of early lesions offers the best opportunity for a cure. Interferon alfa is the only agent approved for adjuvant therapy in patients at risk for relapse after surgery, but recommendations for adjuvant therapy are controversial. Treatment of advanced disease remains disappointing. The most active single agent is DTIC, which is associated with about a 20% response rate. Although many combination regimens have been investigated, none offers superior survival benefits over DTIC. The addition of interferon alfa and/or interleukin-2 to chemotherapy may increase response rates but with no impact on survival. Five-year survivals are 98.3% with localized disease, 63.8% with regional disease, and 16% in patients with metastatic disease.

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