Patients with stage II melanoma have cancer that is 1 to 2 millimeters with ulceration or greater than 2 mm with or without ulceration. Stage II melanoma has spread to the lower part of the inner layer of skin (dermis), but not into the tissue below the dermis or into nearby lymph nodes. Ulceration refers to the microscopic presence of continuous epidermis in the tissue overlying the melanoma and is an important prognostic factor for stage II melanoma.
The following is a general overview of treatment for stage II melanoma. 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 II Melanoma
Patients with primary cutaneous melanoma with a thickness of 1 millimeter or more historically were reported to have a 60% to 70% chance of survival 5 years after surgery. These statistics represent data that came from the era prior to sentinel lymph node biopsy. In other words, some of the patients thought to have stage II melanoma actually had more advanced disease involving the lymph nodes. Today it is recognized that one of the most important aspects of the management of stage II melanoma is adequate assessment for cancer involvement of local lymph nodes. Both the American Joint Committee on Cancer and the World Health Organization recommend a sentinel lymph node biopsy as a staging procedure for patients with a primary melanoma greater than 1 mm.
The surgical treatment of stage II melanoma typically involves a single procedure in which a local excision of the cancer is performed as well as a SLN biopsy. During a SLN biopsy, a physician injects a tracer (radioactive isotope and/or blue dye) into the area of the primary tumor. The tracer, which is taken up by the lymph system, identifies the so-called “sentinel lymph node”, which is the first lymph node that could be potentially involved with melanoma. Lymphatic mapping can be performed prior to surgery to aid the physician in determining which lymph node group is the primary drainage basin for any particular area of skin and it can also be used on the day of surgery to identify which lymph node is the “sentinel” lymph node.
Once the SLN has been identified, the physician removes the SLN through a small incision and then a pathologist examines the SLN under the microscope to detect whether or not there is any evidence of melanoma cells. Patients who have a positive sentinel node (tumor identified) are counseled to undergo removal of all the lymph nodes in the region, while patients who have a negative sentinel node do not undergo further surgery. Approximately 15% of patients undergoing SLN biopsy have a positive SLN (pathologically stage III).
Most surgeons recommend a surgical margin (healthy tissue surrounding the cancer) of 2 centimeters (almost 1 inch). The need for skin grafting occurs in approximately 10% of patients who undergo a 2-cm-wide local excision. Clinical trials have demonstrated that larger surgical margins are no more effective and require skin grafting in a higher fraction of patients (up to 50%). In one large study, patients with melanoma of 1-4 millimeters were randomized to receive surgery with 2-centimeter or 4-centimeter margins. The overall local recurrence rate was 3.8%, with no difference between the two groups. The incidence of skin grafting was 10% for the patients with 2-centimeter surgical margins and 45% for patients with 4-centimeter surgical margins.
Adjuvant Treatment of Stage II Melanoma
Despite undergoing sentinel lymph node evaluations that are negative, some patients with stage II melanoma are at increased risk for having small amounts of cancer that have not been detected. Undetectable areas of cancer are often referred to as micrometastases. The presence of micrometastases causes cancer recurrence following treatment with surgery alone. Patients with thick melanomas (> 4 mm) who have evidence of ulceration are considered at high risk for recurrence. The delivery of cancer treatment aimed at killing micrometastases following local treatment with surgery is referred to as “adjuvant” therapy.
Alpha interferon is a biologic therapy that stimulates the immune system and is the only agent currently approved by the U.S. Food and Drug Administration for use as adjuvant therapy in patients with high-risk melanoma. Clinical studies evaluating adjuvant interferon following surgery generally show that interferon therapy decreases cancer recurrences and improves survival compared to surgery alone. In one randomized clinical trial in the US, only 60% of patients with stage II melanoma receiving alpha interferon (three times a week for 12 weeks) developed recurrent melanoma, compared to 72% of patients not receiving alpha interferon. The average duration of survival for patients receiving alpha interferon was 4.1 years, compared to only 2.7 years for patients not receiving alpha interferon.
French and Austrian trials appear to support these results. In the French trial, patients with melanomas larger than 1.5 millimeters treated with alpha interferon after surgery experienced a recurrence rate of 32%, compared to 44% in the patients not treated with interferon. In the Austrian trial, patients without clinical evidence of nodal involvement (no lymph node dissection) received surgery plus adjuvant alpha interferon or surgery only. Twenty-four percent of patients treated with alpha interferon developed recurrences, compared to 36% of patients treated with surgery only. The majority of relapses in both groups were local and/or regional.
Questions to ask your physician
The main questions to ask your physician relate to staging to determine whether there is involvement of lymph nodes and whether or not the risk of a recurrence warrants treatment with interferon or participation in a clinical trial evaluating adjuvant therapy.
Strategies to Improve Treatment
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of stage II melanoma will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the treatment of stage II melanoma include the following:
Alpha Interferon: Alpha interferon is a biologic therapy that stimulates the immune system and is the only agent currently approved by the U.S. Food and Drug Administration for adjuvant therapy of melanoma. Several recent studies have evaluated alpha interferon in patients with melanoma, with results indicating that high doses of alpha interferon are more beneficial than low or moderate doses. Research is ongoing to determine the role of alpha interferon in the treatment of melanoma. At this time, alpha interferon in higher doses appears to be the most beneficial option; however, other doses and schedules of alpha interferon are being evaluated.
Chemotherapy: Chemotherapy has not been extensively evaluated as adjuvant therapy for patients with stage I-III melanoma. Chemotherapy in combination with biologic agents is being evaluated in more advanced disease, and if successful, will be evaluated in earlier stages of melanoma.
Vaccines: One strategy for stimulating the immune system to attack cancer cells is the use of vaccines. Cancer cells often display certain small proteins and/or carbohydrates (antigens) on their surface that are not displayed by healthy cells. Vaccines are often comprised of these specific antigens, which can be taken directly from the patient’s cancer cells, other patient’s cells or produced in a laboratory. If these antigens are injected into the patient, the immune system recognizes them as “foreign” and will attack the cancer cells displaying the antigens. Researchers are now evaluating various strategies to enhance the immune response against the injected antigens, including combining the patient’s own immune cells with the specific antigens in a laboratory prior to injection.
Currently, no vaccine is approved by the U.S. Food and Drug administration for the treatment or prevention of melanoma. Melanoma vaccines have demonstrated anti-cancer activity in some patients, but this benefit has typically been limited to the minority of patients who generate a measurable immune response following vaccination. Generally, vaccines are made from crude mixtures of whole cells or cell products from removed melanomas, with or without other immune stimulating agents. They are usually produced locally in small quantities, not easily shipped and cannot be tested in large clinical trials. More recently, synthetic or semi-synthetic vaccines have been produced that can be tested in large-scale clinical trials.