Treatment of localized melanoma

INTRODUCTION — Melanoma is a serious form of skin cancer that starts in the pigment-producing skin cells (melanocytes). Melanoma is the sixth most common cancer in the United States, and incidence rates (the number of melanoma cases diagnosed annually) are increasing faster than for any other cancer. Although the explanation for this is unknown, it may be related to increased recreational sun exposure and global changes such as ozone depletion.

In contrast to other types of skin cancers (eg, squamous cell or basal cell cancers) that usually develop on sun-exposed areas of the body, melanomas can develop anywhere on the skin surface (show figure 1), as well as on the mucous membranes lining the mouth, nose, and genital areas. If left untreated, melanoma can spread (metastasize) to other parts of the body much more frequently than is typical for other types of skin cancers. Fortunately, when detected at an early stage, treatment is often effective in limiting the spread of the disease.

This topic reviews the diagnosis and treatment of localized melanoma. A separate topic is available that discusses the treatment of advanced and metastatic melanoma (See "Patient information: Treatment of advanced or metastatic melanoma").

DIAGNOSIS

Appearance of lesion — Similar to other types of skin cancer, melanoma is diagnosed based upon the appearance of a skin lesion. Melanomas can occur anywhere on the skin surface, but it frequently develops on the back and other areas that may be easy to miss with self-inspection. Abnormal findings can be described with an acronym, ABCDE. A — Asymmetry (one side is different from opposite side) (show picture 1) B — Border irregularities (jagged, uneven edge) (show picture 2) C — Color variegation (ie, different colors within the same region, show picture 3) D — Diameter greater than 6 mm (if larger than a pencil eraser, evaluation recommended) E — Evolution (change) in color, shape, or symptoms over time (show picture 4)

Other abnormal features include inflammation (swelling) and bleeding or crusting. A person who notices any of these changes should make an appointment with a healthcare provider as soon as possible. Referral to a dermatologist (physician who specializes in skin conditions) may be recommended.

Biopsy — To determine if the abnormality is a melanoma, a small piece of the area (or if it is small, the entire area) is removed and examined under a microscope to determine if precancerous or cancerous cells are present.

CLINICAL STAGING — After melanoma is diagnosed, the next step is to determine the clinical stage or extent of disease spread. Accurate staging is important to determine the most appropriate treatment.

The American Joint Committee on Cancer has defined a staging system for melanoma that takes into consideration the following characteristics (show table 1): The thickness of the tumor The presence of ulceration (loss of skin) over the surface of the melanoma The presence and extent of tumor involvement of the draining lymphatics and/or "regional" lymph nodes The presence or absence of tumor spread beyond the lymph nodes (distant metastases)

A thorough physical examination, chest X-ray, and blood tests are typically performed to evaluate the possibility of lymph node or distant spread of the tumor.

Additional radiologic examinations (such as a CT scan) may also be recommended, particularly for patients with stage III disease, those with a previous melanoma, and those with signs or symptoms of metastasis. These scan are usually performed after the lymph nodes are evaluated and shown to be involved (see "Evaluating the lymph nodes" below).

Surgery — In most patients, surgery is required to remove (or excise) the entire tumor. Generally, one to two centimeters of normal skin surrounding the lesion must also be removed. This procedure is termed a wide local excision. This decreases the chance that the melanoma will recur at the same site. The amount of normal skin that is removed depends upon the thickness of the melanoma. However, it is rare to remove more than a 2 cm (around 1 inch) margin surrounding the melanoma.

The type of physician (eg, dermatologist or general surgeon) who will perform the surgery depends upon the location and size of the wide local excision. Most procedures are performed as a day surgery in a hospital or surgical center. Most patients are able to go home later the same day.

A dermatologist may be able to perform a wide local excision of small melanomas after the patient receives local anesthesia (numbing medication that is injected under the skin). For larger areas, a general surgeon or surgical oncologist may be needed and sedation may be necessary.

Occasionally, skin grafting may be necessary to promote healing and replace skin that has been removed. In some patients (such as those with a melanoma on the face or neck), it can be difficult to remove a sufficient amount of normal skin to ensure adequate margins. In this case, radiation therapy may be recommended after surgery.

If an enlarged lymph node (or gland) is present, it may be biopsied at the time of the wide local excision. Even if enlarged lymph nodes cannot be detected, the lymph nodes may be evaluated during or after the surgical removal of the melanoma.

Evaluating the lymph nodes — The most common site of melanoma spread is the surrounding lymph nodes (glands). Sometimes, lymph node involvement is obvious or strongly suspected because an enlarged lymph node can be felt. In this case, removal of all the lymph nodes in that lymph node basin (called a therapeutic node dissection) is considered the standard approach. Therapeutic node dissection provides an opportunity to cure the patient, particularly when used in conjunction with adjuvant systemic therapy (see "Adjuvant therapy" below).

In the majority of cases, enlarged lymph nodes are not visible, and the only way to determine if they are affected is to take a sample of the lymph node during surgery. The sample is then examined under a microscope to determine if abnormal cells are present. This is typically accomplished with a surgical technique known as sentinel lymph node (SLN) biopsy.

Sentinel lymph node biopsy — The sentinel lymph node (SLN) technique is based upon the theory that when tumor cells migrate, they spread to one or a few lymph nodes before involving other nodes. Further, these nodes can be identified by injecting a blue dye or radioactive material around the primary tumor before the wide local excision, and then searching for the node that has taken up the dye or the radioactive tracer at the time of surgery. This is known as lymphatic mapping.

Sentinel lymph node biopsy and lymphatic mapping are usually done at the time of the wide local excision. Most procedures are performed in a hospital after the patient is given general anesthesia to induce sleep and prevent pain. The patient may go home later the same day or the following day, after spending one night in the hospital.

The status of this first draining (sentinel) lymph node accurately predicts the status of the remaining regional lymph nodes. Because only one, or at most, a few lymph nodes, are removed at surgery and evaluated by the pathologist, the risk of this procedure is lower and the accuracy is greater than a full lymph node dissection.

The success of SLN biopsy is dependent upon the skill of the surgeon and the other physicians involved with the procedure. For optimal results, intraoperative lymphatic mapping and SLN biopsy requires coordination between a surgeon, nuclear medicine physician, and pathologist to achieve optimal results (see below). If later tests reveal that the cancer has spread to the SLN, a second procedure, termed a completion node dissection, is performed to remove the remaining lymph nodes. If the SLN is negative for tumor involvement, further lymph node dissection is usually not performed since the likelihood of finding tumor involvement is 5 percent or less.

SLN biopsy has become the standard technique for assessing the status of regional lymph nodes and is recommended for staging of most patients with newly diagnosed primary melanomas. However, patients whose melanomas are less than 1 mm in thickness (thin melanomas) may not require SLN, since the likelihood of tumor spread to the regional lymph nodes is less than 10 percent.

In contrast, SLN biopsy may be advised for thin melanomas with other high-risk features, such as ulceration, Clark's level IV or V (the tumor has invaded deeper levels of the skin, show table 1), or if there are significant areas of regression (spontaneous loss of tumor cells).

Clark's levels refer to how deeply the tumor has invaded the skin (show figure 2). Level II: the tumor invades the papillary dermis; level III: the tumor invades to the papillary-reticular dermal interface; level IV: the tumor invades the reticular dermis; level V: the tumor invades subcutaneous tissue.

PATHOLOGIC STAGING — Once the staging work-up is complete, a pathologic disease stage between I and IV is assigned (show table 2). A higher stage indicates more extensive disease. Stage I or IIA disease — The tumor is less than 4 millimeters thick without ulceration, or less than 2 millimeters thick if ulceration is present. This is considered to be localized disease. Surgery alone is curative in 70 to 90 percent of cases. Stage IIB or IIC disease — The tumor is 2.1 to 4 millimeters thick with ulceration, or 4 or more millimeters thick with or without ulceration. This is considered to be localized disease. Patients are at a higher risk of recurrence, even after the tumor has been completely surgically removed. For these patients, adjuvant (additional) therapy is often recommended (see "Adjuvant therapy" below). Stage III disease — There is evidence of melanoma spread in the lymphatic channels surrounding the tumor (called satellites) or nearby lymph nodes. The tumor may be any thickness. Adjuvant therapy is strongly recommended. Stage IV disease — The melanoma has metastasized to more distant locations in the body, which may or may not include the lymph nodes. The tumor may be any thickness. This is referred to as advanced disease. For a full discussion of treatment of advanced disease, see "Patient information: Treatment of advanced or metastatic melanoma").

Based upon the pathologic disease stage, the optimal treatment is chosen. For patients with localized disease who have no evidence of distant metastases, the goals of treatment are: Complete surgical removal of the primary melanoma Evaluation of regional lymph nodes for evidence of tumor involvement Preventing further spread or disease recurrence

ADJUVANT THERAPY — The term adjuvant therapy refers to any additional anticancer treatment that is given after a cancer is surgically removed. The objective of adjuvant treatment is to stop or slow the growth of any remaining cancer cells that were not removed during surgery.

Immunotherapy — Interferon alpha (IFN-a) is the agent most commonly used to treat patients with melanoma who are at high risk for recurrence. Research has shown that IFN-a, a form of immunotherapy, can help to decrease the chance of recurrence and increase the patient's chance of survival [3]. Immunotherapy may boost the patient's immune response so that it can more effectively fight the cancer.

Treatment with IFN-a begins after surgery, and may continue for up to twelve months. The best way of administering adjuvant IFN-a is not clear. The following IFN-a regimen is the standard for patients with high-risk melanoma. It includes two parts, which are given for up to 12 months. High dose intravenous therapy (at a dose of 20 MU/m2) five days per week for four weeks. A lower dose of IFN-a (10 MU/m2), is given under the skin (subcutaneously) three times weekly for up to 11 additional months. This injection can be given by the patient or a family member.

Although other regimens and doses have been studied, none has been shown to be as effective as this regimen. Because adjuvant IFN-a therapy helps only a minority of patients at risk for melanoma recurrence and is frequently associated with considerable side effects, patients should be encouraged, whenever possible, to enroll in clinical trials testing adjuvant strategies aimed at improving the outcomes of treatment with IFN-a (see "Clinical trials" below).

Benefits — In the first reported trial [3], benefit from IFN-a seemed to be limited to patients who had lymph node involvement (stage III disease). In this group of patients, there was an approximately two-fold increase in the number of patients who were free of disease recurrence at five years.

However, in subsequent trials, an improvement in recurrence-free survival (approximately 20 to 40 percent better than expected) was seen in patients with a lower risk of disease recurrence (stage IIB) as well [4].

We recommend adjuvant IFN-a therapy as the standard of care for patients with node-positive melanoma, and recommend that it be strongly considered for other patients whose risk of recurrence is estimated to be 30 to 40 percent or more (ie, those with stage IIB and IIC disease, show table 2).

Side effects — The problem with IFN-a is its risk of toxic side effects. Nearly all patients develop some side effects during treatment, although the type and severity are variable. Because patients have differing tolerances for side effects and differing ideas about the importance of quality versus quantity of life, the decision to pursue adjuvant IFN-a is an individual one, especially for patients who have node-negative but otherwise high-risk melanoma.

Side effects may include flu-like symptoms (low grade fever, muscle and joint aches, chills, fatigue), depression, mood changes, a drop in the number of white blood cells, and temporary liver enzyme abnormalities. The majority of these effects can be managed with appropriate supportive care and/or dose reduction. Most adverse reactions are completely reversible when treatment is stopped.

Future directions — Research is ongoing to identify other therapies that are effective in treating melanoma. It is hoped that combining interferon with a melanoma vaccine, radiation therapy, or other agents will yield a form of treatment that is more effective or equally effective and less toxic. As noted above, patients should be encouraged, when possible, to enroll in clinical trials testing different adjuvant strategies (see "Clinical trials" below).

MONITORING

Clinician monitoring — Because melanoma can recur in the same location or in new sites, routine follow-up and monitoring is very important. Seeing a healthcare provider regularly is the most important aspect of follow-up since most recurrences are discovered when the patient is seen and examined at regular intervals after treatment. Blood tests and a chest X-ray may be performed at periodic intervals to evaluate the possibility of distant spread of melanoma, while other imaging studies (eg, CT or PET scans) are usually recommended only if new symptoms or signs develop.

Self-examination — In addition to visits with a healthcare provider, monthly self-examination is recommended to identify any new or changing skin lesions. If a new or changing lesion is detected, contact a healthcare provider to determine if further evaluation is needed. To perform self-examination, stand in an area that is brightly lit. Use a hand-held mirror to examine the face, including the nose, lips, mouth, and ears. Face away from a full-length mirror and hold up the hand-held mirror to see the back of the head, ears, and neck. Examine both sides of the hands and arms, including between the findings and under the fingernails. Use the full-length mirror to examine the undersides and back of the arms and armpits. Examine the neck, chest, and abdomen. Women should lift the breasts to examine underneath. Using both mirrors, examine the shoulders, upper back, and upper arms. Scan the lower back, buttocks (including between the buttocks), and backs of both legs. Sit down, and rest one foot on a chair. Examine the legs, including the ankles, top and bottom of the feet, between the toes, and under the toenails. Switch legs and repeat. Use a hand-held mirror to examine the genitals.

CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/


WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute

1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Melanoma Center, University of Pittsburgh Cancer Institute

(www.melanomacenter.org)
Skin Cancer Foundation

(www.skincancer.org)
Melanoma Research Foundation

(www.melanoma.org)


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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Rivers, JK. Melanoma. Lancet 1996; 347:803.
2. NIH Consensus conference. Diagnosis and treatment of early melanoma. JAMA 1992; 268:1314.
3. Kirkwood, JM, Strawderman, MH, Ernstoff, MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol 1996; 14:7.
4. Kirkwood, JM, Ibrahim, JG, Sosman, JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the gm2-klh/qs-21 vaccine in patients with resected stage iib-iii melanoma: Results of intergroup trial e1694/s9512/c509801. J Clin Oncol 2001; 19:2370.
5. Kirkwood, JM, Bender, C, Agarwala, S, et al. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol 2002; 20:3703.