Stage III Melanoma


Stage III melanoma includes cancers of any thickness with tumor spread to regional lymph nodes. The extent or amount of tumor in the lymph nodes is the most important prognostic factor for patients with stage III melanoma. The presence of micrometastases, defined as tumor detected by sentinel lymph node biopsy, is more favorable than the presence of macrometastases, which are defined as clinically detectable nodal metastases. Similarly, one lymph node that contains tumor is more favorable than having four or more involved lymph nodes. The following is a general overview of the diagnosis and treatment of melanoma. Each person with melanoma is different, and the specific characteristics of your condition will determine how it is managed. The information on this Web site is intended to help educate you about treatment options and to facilitate a shared decision-making process with your treating physician.

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The following is a general overview of treatment for stage III melanoma. Treatment may consist of surgery, radiation, chemotherapy, biological therapy, or a combination of these treatment techniques. Multi-modality treatment, which utilizes two or more treatment techniques, is increasingly recognized as an important approach for improving a patient’s chance of cure or prolonging survival. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient’s situation may influence how these general treatment principles are applied. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

Surgical Treatment of Stage III Disease

Outcomes of patients with stage III melanoma relates primarily to the extent of lymph node metastasis. Standard surgical treatment for patients with stage III melanoma is removal of the primary cancer with up to 2-centimeter (over an inch) margins of the adjacent skin, depending on the thickness of the primary tumor, and removal of all of the regional lymph nodes. Regional lymph node dissection may be performed in the neck, armpit or groin, depending on the site of the primary tumor and presence of palpable nodes. Chronic side effects of removing lymph nodes vary, depending on the extent of disease, body habits of the patient, and inclusion of postoperative radiation to site, but may include numbness, and swelling of the associated extremity, which is called lymphedema.

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Historically, patients with locoregional spread of melanoma (stage III disease) and thick primary tumors have been considered appropriate candidates for adjuvant therapy because of high rates of distant recurrence and subsequent death from disease. Our ability to detect micrometastatic locoregional disease has improved over the past decade with the adoption of new techniques such as sentinel lymph node (SLN) biopsy. In addition, the pathologic assessment of sentinel lymph nodes have improved with the availability of immunohistochemical staining which allows detection of nodal metastases as small as 0.1 mm or even aggregates of a few cells.   For this reason, the current era can be viewed as one of transition, in which patients are being diagnosed with stage III disease earlier with a much better prognosis and lower risk of relapse. The significance of these technologic advances is reflected in the new American Joint Committee on Cancer (AJCC) staging system, which now incorporates pathologic nodal staging.

One of the challenges facing oncologists is assessing the risks for individual patients on the basis of data from previously published studies. Five-year overall survival rates for patients with stage III melanoma have been reported as ranging from 70% for stage IIIA to 27% for stage IIIC disease. In this group of patients, assembled largely during the pre-sentinel lymph node era, patients with stage I and II disease were reported to have 5-year recurrence-free survival rates of 90% and 70%, respectively. The 10% to 30% recurrence rates likely reflect unidentified microscopic disease, which can be detected with present-day techniques.

Adjuvant Treatment of Stage III Disease

It is important to understand that many patients with stage III melanoma are at high risk for disease recurrence. Undetectable areas of cancer are referred to as micrometastases. The presence of micrometastases causes cancer recurrence following treatment with surgery alone. The delivery of cancer treatment following local treatment with surgery is referred to as “adjuvant” therapy and may include radiation therapy, biologic therapy, combination chemotherapy/biologic therapy and/or vaccines.

Radiation Therapy: A subset of patients is known to have a significant risk of locoregional relapse of melanoma following surgery. Features associated with a high risk of recurrence at the primary site are positive microscopic margins, recurrent disease, and thick primary tumors with ulceration or satellitosis. Features associated with high risk for lymph node recurrence following surgical removal of the lymph nodes have also been defined and include involvement of 4 or more lymph nodes, lymph nodes measuring at lease 3 cm, lymph nodes in the neck (cervical region) and evidence of extracapsular extension (tumor beyond the capsule of the normal lymph node). In these circumstances, a short course of radiotherapy to the region is believed to be effective in controlling and “killing” possible residual microscopic disease, decreasing the incidence of recurrence in the region.

Biologic Therapy: High-dose alpha interferon is a biologic therapy that stimulates the immune system and has been approved by the U.S. Food and Drug Administration for adjuvant treatment of stage III melanoma. Three clinical trials have been completed in which patients with high-risk melanoma and stage III melanoma were treated with either high-dose alpha interferon for one month and lower doses for 48 weeks or no adjuvant therapy. In all 3 trials, there was a 9% to 11% reduction in the incidence of recurrence and in 2 of the 3 trials there was an 8% to 9% improvement in 5-year overall survival. Increasing emphasis has been placed on the “relative value” that patients place on side effects of treatment, in part because of the significant toxicity experienced by 78% of patients in the ECOG 1684 trial.

Table 1: Randomized phase III trials of high-dose interferon alpha adjuvant therapy for patients with high-risk (stage IIB and III) melanoma


Total No. of Patients

Median Follow-up (years)

5-year Disease Free Survival: Interferon Arm

5-year Disease Free Survival: Observation Arm

5-year Overall Survival: Interferon Arm

5-year Overall Survival: Observation Arm








ECOG 1684







ECOG 1690







There have been no benefits associated with using lower doses of alpha-interferon.

Patients with stage III disease appear to have some benefit from adjuvant interferon therapy. There are a number of ongoing clinical trials evaluating alpha interferon, vaccines and other anti-cancer therapies alone or in combination. It is important to consider all of these options before beginning treatment. For patients who do not wish to participate in a clinical trial, the standard treatment is high-dose alpha interferon.

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