Melanoma. Lynn Schuchter, M.D. Associate Professor of Medicine Abramson Cancer Center of the University of Pennsylvania

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1 Melanoma Lynn Schuchter, M.D. Associate Professor of Medicine Abramson Cancer Center of the University of Pennsylvania WHAT IS MELANOMA? Melanoma is a type of skin cancer (a serious skin cancer because it can be fatal) which begins when colorproducing cells (melanocytes) grow unregulated. Melanoma can appear in normal appearing skin or develop from or near a mole. EPIDEMIOLOGY AND RISK FACTORS Melanoma is relatively uncommon. For the year 2003, projections are that there will be 54,200 new cases of melanoma, with 7,600 deaths from melanoma. By comparison, there are approximately 200,000 new cases of breast cancer each year and 185,000 new cases of lung cancer each year. Approximately 1 in 67 individuals in the U.S. will be diagnosed with melanoma. This is a 2000% increase from Melanoma accounts for 4% of all skin cancer cases and 79% of skin cancer deaths. Melanoma is the sixth most common cancer among men and the seventh most common cancer among women. The incidence of melanoma continues to rise. This rise in the incidence rate is thought to be related to increasing sun exposure, especially early in life. Melanoma is the leading cause of death from skin cancer and accounts for 1-2% of all cancer deaths in the United States. Melanoma affects all age groups; the median age at diagnosis is 50. Exposure to sunlight (ultraviolet radiation) has been strongly implicated as a causative factor in the development melanoma. Individuals with a tendency to burn rather than tan when exposed to sunlight have higher rates of melanoma, including those with fair complexion, blond or red hair, blue eye color, and freckles. The pattern of sun exposure may also be important; intermittent intense exposure, rather than chronic exposure, may carry more risk of melanoma. Blistering sunburns, particularly in childhood, are associated with an increased risk of melanoma. Other factors linked to melanoma risk include: an increased number of moles (melanocytic nevi), atypical moles or dysplastic nevi, a family history of melanoma, a personal history of melanoma, and other skin cancers. Approximately 10% of patients with melanoma have a family history of melanoma.

2 PREVENTION AND SCREENING: The most important preventative measures are to reduce excessive sun exposure and avoid sunburns. Safe sun strategies include reducing sun exposure, particularly avoiding the midday sun, use of sunscreen products with an SPF > 15 on a regular basis, and wearing protective clothing. Patients with clinically atypical moles, particularly if there is family history of melanoma, require a regular surveillance program. Regular skin examinations should be performed every 6-12 months, which can be assisted by the use of photography of atypical moles. CLINICAL CHARACTERISTICS OF MELANOMA: Early detection and recognition of melanoma is key to improving overall survival in patients with malignant melanoma. Most patients report a preexisting mole at the site of the melanoma. The signs of early melanoma are based on the color, shape and size of a mole. Most melanomas are varying shades of brown, but black, blue, or pink may be found in melanomas. In particular, a history of change in an existing mole, including change in shape, color, or surface is an important clue that a skin spot may represent melanoma. Itching, burning, or pain in a mole should increase suspicion of melanoma although melanomas are often not associated with local discomfort. Bleeding and ulceration are signs of a more advanced melanoma. The A,B,C,D s for the recognition of melanoma are useful for public education and clinicians to identify pigmented lesions suspicious for melanoma: Asymmetry: One half does not match the other half; Border irregularity: The edges are ragged, notched, or blurred; Color variation: The color is uneven. Shades of tan, brown, black with dashes of red, white, or blue; Diameter: > 6mm about the size of a pencil eraser. Melanoma can occur on any part of the body. In men, melanomas are most commonly found on the trunk and in women, melanoma often develops on the arms and legs. DIAGNOSIS OF MELANOMA: Any skin lesion suspicious for melanoma should be biopsied. The proper biopsy is essential not only to establish a diagnosis but also to allow precise histological interpretation which will determine the prognosis and plan of therapy. Most clinically suspicious skin lesions are best biopsied by complete excision taking a 1-2 mm margin of normal skin. PROGNOSTIC FACTORS: When detected in its earliest stages, melanoma is highly curable. The average 5 year survival rate for individuals with melanoma is 89%. A number of factors have been identified that predict the overall prognosis of melanoma. The single most predictive factor is the depth of invasion (thickness) of the melanoma, measured in millimeters (mm) from the top of the skin to the underlying skin. Increasing thickness is associated with an increase risk of recurrence from melanoma and therefore death. In addition, the thicker the primary melanoma the more likely there is to be local lymph node involvement. Other poor prognostic factors include ulceration of the melanoma, increasing level of invasion (Clark s level), and high mitotic rate.

3 The presence of regional lymph node involvement is a poor prognostic sign regardless of the thickness. In addition, the number of involved lymph nodes correlates with risk of distant metastatic disease and therefore survival. For example, a patient with one local lymph node involved has 50% risk of dying from melanoma and a patient with many lymph nodes involved has a 75% chance of dying from melanoma. STAGING SYSTEM FOR MELANOMA Clinical staging is based on whether the tumor has spread to lymph nodes or distant sites. The staging system for melanoma is determined by the American Joint Committee on Cancer (AJCC), updated in 2002, it now more accurately classifies patients into groups with similar survival. Stage I and Stage II melanoma are localized to the skin (Stage I is less than 1 mm thick and Stage II melanoma is greater than 2 mm thick), and Stage III indicates spread to local lymph nodes (i.e. if the melanoma was on the forearm, and spread to lymph nodes in the armpit, that would be stage III melanoma). Stage IV spread to distant sites such as lung, liver, or brain metastases. Table 1 indicates the 5-year survival rates associated with each of the four stages. PATIENT EVALUATION: The initial evaluation of a patient with melanoma includes a history, a family history, and a complete physical examination that includes a total skin examination. Melanoma can spread by local extension through lymph channels and through the blood stream. Any organ can be involved by metastases, but lung and the liver are the most common sites. Therefore, in practice, a chest x-ray, liver blood tests, and LDH (a blood test) are also done to determine if the melanoma has metastasized. The majority of patients who present with melanoma do not have a distant metastatic disease at presentation; therefore, x-rays (computerized tomography scans -CT scans) to search for distant metastases (spread beyond the primary site) have an extremely low yield and consequently are not indicated in patients who do not have symptoms. More extensive staging evaluation with CT scans of the chest/abdomen/pelvis can be considered in patients with high risk disease (thick primary melanoma > 4 mm thick or in those patients who have lymph nodes involved with melanoma) where the risk of spread to distant sites is higher. SURGICAL TREAMENT OF THE PRIMARY MELANOMA Once melanoma is diagnosed, the standard treatment is surgical removal. After the initial biopsy to diagnose the melanoma, than a wide excision is done. The wide excision removes an area of normal tissue around the melanoma. The extent of the surgery depends upon the thickness (depth) of the melanoma. Large surgical excisions are no longer required. Current recommendations for surgical margins are as follows: For melanoma in situ, excision with a 0.5 cm border of clinically normal skin is sufficient. For melanomas < 1 mm thick, a 1 cm margin is recommended. If the thickness is between 1 and 4 mm, a 2 cm margin is recommended. For melanomas thicker than 4 mm, at least a 2 cm margin should be taken. Sentinel lymph node mapping is a new surgical technique that can identify the draining lymph node most likely to be involved with melanoma and can be considered in patients with newly diagnosed melanoma. Sentinel lymph node mapping may be considered in patients with melanomas > 1 mm thick and who have no

4 evidence of clinically enlarged regional lymph nodes. The purpose of this surgical procedure is to identify regional lymph nodes in which microscopic melanoma cells may be present. This procedure is done only for patients that have a significant like hood of metastasis to lymph nodes. Patients with melanoma < 1mm have a low likelihood of regional lymph node involvement (<5%), and thus generally, sentinel node mapping is not indicated. If the sentinel lymph node is negative for melanoma, no further lymph node surgery is required. If melanoma is detected in the sentinel lymph node, a complete lymph node dissection is recommended. In those patients who have enlarged local lymph nodes than a complete lymph node surgery should be done to potentially cure the melanoma. A sentinel lymph node procedure would be inappropriate in patients who have clinically enlarged local lymph nodes. TREATMENT ADJUVANT THERAPY: Adjuvant therapy is treatment given to reduce the risk of metastasis or recurrence after surgery for melanoma clinically confined to the skin or lymph nodes. This therapy is adjunctive or extra, following surgery. Patients who are at increased risk for spread of melanoma to distant sites in the body (lung, liver, brain) are those patients with deep (thick) melanomas (> 4mm thick) or those patients with local lymph node involvement. These patients have at least a 50-75% chance of dying from melanoma. Therefore, these patients are appropriate candidates for adjuvant therapy. Current options for adjuvant therapy include interferon or participation in clinical trials with melanoma vaccines and other forms of immunotherapy alone or combined with chemotherapy. Adjuvant Interferon: In 1995 the FDA recommended approval for interferon-alpha 2b based on a study (E1684) conducted by the Eastern Cooperative Oncology Group (ECOG). In that study, patients with high risk melanoma (thick primary melanoma,>4mm or node positive disease, Stage III), were treated with interferon for one year or were observed without treatment. An intensive regimen was deliberately chosen in order to deliver interferon at the maximally tolerated dose to achieve peak drugs levels. Patients were treated with an intravenous induction

5 phase of 20 million units/m 2, 5 days a week for 1 month, followed by 11 months of 10 mu/m 2 given subcutaneously three days a week. Patients who received the interferon a small, but significant improvement in survival. This was the first melanoma adjuvant study which demonstrated an improvement in overall survival. Based upon these results, the FDA approved high dose interferon for patients with high risk melanoma. There are side effects associated with IFN. Patient s experience flu-like symptoms such as fatigue, fever, chills, myalgia, anorexia, nausea, vomiting and headache. IFN may cause or exacerbate depression. Suicidal ideation and suicide have been associated with IFN therapy. Significant laboratory abnormalities include elevated hepatic transaminases, neutropenia, elevated triglycerides, and anemia. It is critical that patients undergoing treatment with IFN be monitored closely and that the dose of IFN is modified appropriately for toxicity. High dose IFN is the only treatment approved by the FDA for melanoma patients who are high risk for recurrence (Adjuvant therapy). SURVEILLANCE Patients with a history of melanoma should be followed regularly for evidence of local regional recurrence, distant, metastatic disease and a second primary melanoma. The most important component is the history and physical examination. The physical examination should include a thorough skin exam as the risk of second primary melanoma is increased. At least 3% of patients will develop an additional melanoma within 3 years of diagnosis; this risk is higher in patients with atypical moles. Regional lymph nodes should be thoroughly examined, especially in those patients without prior nodal surgery. The remainder of the examination should be comprehensive, keeping in mind frequent metastases to lung, liver, and brain. Follow up studies generally include, complete blood count, chemistries with liver function tests and a serum LDH. An elevated LDH is suggestive of metastatic melanoma. Since the lungs are the most frequent sites of distant disease, periodic chest x-rays are recommended. The routine use of screening CT scans, MRI s, PET scans or bone scans is not justified for follow-up. Patient education is an integral part of the management of patients with melanoma. Patients should be instructed on how to perform monthly self-skin examinations for detection of new primary melanomas and recurrent disease. They should be educated on the clinical characteristics of melanoma and the importance of safe sun strategies.

6 The intensity of the surveillance and the extent of the investigation are related risk of recurrence. For low risk melanoma (< 1mm), visits every 6 months for 2 years than annually. The surveillance guidelines for patients with high risk melanoma include evaluation every 3-4 months for 2 years, then every 6 months for 3 years. At 5 years, patients are seen once a year. Patients are followed for 10 years. Those patients with dysplastic nevi or family history of melanoma are followed annually, indefinitely. A history and physical examination is performed at each visit, a chest radiograph is obtained every other visit, and laboratory studies are performed at the discretion of the treating physician. TREATMENT OF METASTATIC MELANOMA The treatment of a patient with metastatic melanoma depends upon multiple factors including the overall condition and age of the patient, the sites and number of metastases, pace of the disease, and the patient s wishes for treatment. Currently, the goals of treatment are directed toward improving or reducing symptoms. There is no evidence that treatment of metastatic melanoma has any impact on prolonging survival. Metastatic melanoma can metastasize to virtually any organ of the body. The most common site of distant metastases is the lung. The skin, liver, and brain are also common sites of metastases. The overall survival for patients with metastatic melanoma ranges from 4.7 to 11 months, with a median survival of 8.5 months. The estimated 5 year survival rate for patients with Stage IV disease is 5%. In highly selected patients, long term survival has been reported. The range of treatment options includes observation, surgery when feasible, chemotherapy, immunotherapy or participation in a clinical trial of biochemotherapy or other experimental approaches including vaccines. Single Agent Chemotherapy: Numerous chemotherapy medications have demonstrated activity in the treatment of metastatic melanoma including dacarbazine, cisplatinum and taxanes. However, no single chemotherapy has consistently shown response rates (shrinkage rate) greater than 20%. Dacarbazine (DTIC) remains the only chemotherapeutic agent approved by the FDA for the treatment of metastatic melanoma. Clinical trials have demonstrated overall response rates of approximately %. Responses are not long-lasting, generally only 3 to 6 months. Long-term complete responses are seen in only 1-2 % of the patients. The most commonly used regimen of DTIC is mg/m2 intravenously and repeated every 3 weeks. DTIC is generally well tolerated. The most frequent side effect is nausea and vomiting which can be severe. Mild to moderate drop in the WBC is a common side effect. Temozolomide (Temodar) (TMZ) Temodar is oral chemotherapy agent that is chemically converted in the body to MTIC, which is the active metabolite of DTIC. It has a wide volume of distribution, including the brain. This is an advantage because the brain is so frequently involved with melanoma metastases. Results from recent phase II studies of Temodar in patients with metastatic melanoma show an overall response rate of 21%, including 5% complete response. Responses in patients with brain metastases have also been reported. The results from several phase II studies suggest that temozolomide is at least as effective as DTIC in metastatic disease. Since TMZ is administered orally it is easy to administer and it is extremely well tolerated. The standard dose is mg/m2/d orally on days 1 to 5. Courses are repeated every 4 weeks. The major side effect is a mild to drop in WBC counts. Mild nausea and vomiting is also common, but can be readily controlled with standard anti-nausea medications. This drug has not been approved by the FDA for the treatment of melanoma. However, because of its ease of administration and lack of toxicity compared to other melanoma therapies, Temodar is frequently used as first line therapy for patients with metastatic melanoma.

7 Combination Chemotherapy: A variety of combination chemotherapy regimens have produced response rates in the 30-50% range. The Dartmouth regimen, which includes Cisplatin, DTIC, BCNU and tamoxifen (CBDT) has been one of the standard regimens for patients with Stage IV melanoma. This combination requires hospitalization, has greater side effects and recent studies show no difference in response rate or survival compared with DTIC alone. This treatment program has been routinely covered by insurance companies for the treatment of advanced melanoma. Only the DTIC in this regimen is approved by the FDA for the treatment of melanoma, the use of the other agents in this regimen is all off-label use. Another combination chemotherapy regimen frequently used in patients with metastatic melanoma is the CVD regimen. This includes the chemotherapy drugs cisplatin, vinblastine, and DTIC. However, the regimen has not been shown to be superior to DTIC alone. Based upon these data, at the present time there in no evidence that any combination regimen is superior to single agent DTIC and overall, DTIC appears to equivalent to Temodar. Immunotherapy: Interferon has been evaluated extensively in patients with metastatic melanoma. A series of phase II studies have been conducted using a variety of doses and schedules. The response rates range from 10-25%. Most of the responses have been partial, with a complete response rate less than 5%. While interferon has been approved by the FDA for the adjuvant treatment of high risk melanoma, it is designated on orphan drug by the FDA for use in combination with IL-2. Roferon (Hoffman LaRoche interferon alpha) in combination with IL-2 was designated as on orphan drug combination for the treatment of metastatic melanoma on 5/11/90. IL-2 (aldesleukin), a potent T cell activator is approved by the FDA for the treatment of metastatic melanoma. Reponses have been reported as well as some durable complete responses in a small percentage of patients receiving IL-2. Median response duration was 8.9 months (range 1.5 months to more than 106 months). Because the adverse effects of IL-2 are frequent, often serious, and sometimes fatal, the potential benefit of the drug to the patient must be weighed carefully against the possible risks involved.

8 The currently approved regimen by the FDA for patients with metastatic melanoma consists of two 5 day courses of IL-2 separated by a rest period. Two high dose regimens have been used, 600,000 IU/kg or 720,000 IU/kg given q 8 h over 15 minutes for doses per cycle. This is followed by 7-10 day rest period between the two cycles. Repeat courses can be given at 8-12 weeks if the patient is responding to treatment. Typically, 2 or 3 courses are given to patients with a good response, with a maximum of 5 courses. Other dosing regimens include continuous IV infusion or subcutaneous administration with lower doses of IL-2. Some studies report less serious side effects with these alternative methods of delivery or doses of IL-2, but it remains unclear whether there is comparable efficacy. The most common side effects include hypotension (low blood pressure), diarrhea, kidney and breathing problems, fever, chills, and vomiting. Because of low response rates and substantial toxicity of high dose IL- 2, its use should be restricted to carefully selected patients and administered by experienced clinicians at established cancer treatment centers. Careful assessment of cardiac and pulmonary function is mandatory prior to initiation of therapy. Experimental approaches to melanoma include: Vaccine Therapy: Vaccine therapy for the treatment of melanoma is a new, promising area for the treatment of melanoma, particularly in the adjuvant setting. There are generally two approaches currently undergoing clinical investigation, whole cell vaccines (autologous or allogeneic) and peptide-based or defined antigens. Currently, vaccine approaches should be considered experimental. Biochemotherapy: Combines immunotherapy with chemotherapy and has been studied in patients with metastatic melanoma. Multiple phase II studies demonstrated response rate of 50%, with a 10% complete response rate. The recent results of randomized phase III clinical trials comparing biochemotherapy either to IL-2 and IFN or to chemotherapy have been disappointing with no evidence to date that this very toxic therapy improves overall survival in patients with metastatic disease. This therapy is associated with significant toxicity. Until prospective randomized clinical trials demonstrate a benefit of biochemotherapy, this approach remains investigational.

9 Table 1 New AJCC Stage Groupings for Cutaneous Melanoma Stage TNM classification Definition 5-year survival rate, % ± SE IA IB IIA IIB IIC IIIA IIIB IIIC IV T1a N0 M0 T1b N0 M0 T2a N0 M0 T2b N0 M0 T3a N0 M0 T3b N0 M0 T4a N0 M0 T4b N0 M0 T1-4a N1a M0 T1-4a N2a M0 T1-4a N1b-2c M0 T1-4b N1a-2a M0 T1-4b N1b-2b M0 AnyT N3 M0 AnyT anyn M1a-1b 1b AnyT anyn M1c 1 mm; no ulceration (Clark level II/III) 95.3 ± mm with ulceration or Clark level IV/V 90.9 ± to 2 mm; no ulceration 89.0 ± to 2 mm with ulceration 77.4 ± to 4 mm; no ulceration 78.7 ± to 4 mm with ulceration 63.0 ± 1.5 > 4 mm; no ulceration 67.4 ± 2.4 > 4 mm with ulceration 45.1 ± 1.9 Single micro node; no ulceration 69.5 ± to 3 micro nodes; no ulceration 63.3 ± to 3 macro nodes or in-transit mets; no ulcer to 3 micro nodes; ulceration to 3 macro nodes; ulceration nodes, matted, or nodes + in-transit mets 26.7 ± 2.5 Distant skin, SC, nodal, or lung metastasis 5 20 All visceral mets or elevated LDH with mets 9.5 ± 1.1 AJCC = American Joint Committee on Cancer; TNM = Tumor, node, metastases; SE = Standard error; SC = Subcutaneous; LDH = Lactic acid dehydrogenase. Adapted with permission from Balch CM, Buzaid AC, Soong S-J, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19(16): Helpful Web sites about melanoma OncoLink : ASCO web site: American Academy of Dermatology:

Melanoma: The Basics. What is a melanocyte?

Melanoma: The Basics. What is a melanocyte? Melanoma: The Basics What is a melanocyte? A melanocyte is a normal cell, found in the skin, which produces melanin. Melanin is a black or dark brown pigment that is seen in the skin, hair, and parts of