Stage III Melanoma

Overview

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 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.

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

Study

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

NCCTG

160

6.6

40%

30%

47%

39%

ECOG 1684

280

6.9

37%

26%

46%

37%

ECOG 1690

642

4.3

44%

35%

52%

55%

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.

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 III 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 III 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. In one multi-center clinical trial involving 642 patients with stage III melanoma, patients were treated with high-dose alpha interferon for one year, low-dose alpha interferon for two years, or no further treatment after surgery. Five years following treatment, the recurrence rate for patients who received high-dose alpha interferon was 56%, compared to 60% for those who received low-dose treatment and 65% for those who received no further adjuvant treatment after surgery. Another multi-center clinical trial involved 424 patients with stage III melanoma. Half of these patients were treated with surgery alone, while the other half were treated with surgery followed by 3 years of moderate-dose alpha interferon. Five years following treatment, 28% of patients treated with surgery alone survived without evidence of recurrence, compared to 27.5% of patients treated with adjuvant alpha interferon, indicating that moderate-dose alpha interferon does not decrease the chance of recurrence.

Research is ongoing to determine the role of alpha interferon in the treatment of melanoma. At this time, alpha interferon in high doses appears to be the most beneficial option; however, other doses and schedules of alpha interferon are being evaluated.

Proleukin®: Proleukin®  is a biologic agent that has been approved for the treatment of metastatic melanoma. Proleukin® has traditionally been given in high doses to patients with malignant melanoma, administered either intravenously by rapid infusion or by continuous infusion. Although high doses of Proleukin® historically have been associated with severe side effects, data analyses have demonstrated that the safety of high-dose Proleukin® has significantly improved over the past decade and the side effects are less severe. Clinical trials are ongoing in an attempt to establish optimal doses, schedules and treatment combinations producing the fewest side effects.

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.

Combination Treatment with Biologic Agents and Chemotherapy (Biochemotherapy): The administration of chemotherapy combined with immunotherapy appears to be the most promising currently available therapy for metastatic melanoma and several studies have been evaluating this approach for the treatment of high-risk stage III melanoma.

Researchers recently conducted a small trial evaluating the safety and efficacy of neoadjuvant biochemotherapy in patients with stage III melanoma. Of the participants, 12 did not have measurable disease at the time of enrollment due to diagnostic lymph node removal. The biochemotherapy included interleukin-2, interferon alpha, Platinol®, Velban® and dacarbazine. Patients initially received 2 cycles of biochemotherapy (neoadjuvant) and then a complete lymph node dissection followed by an additional 2 cycles of biochemotherapy. At 2.6 years (31 months) following therapy, 65% (31) of the patients remained free of disease progression. Of the 16 patients who did experience a recurrence, 14 recurred within the first 9 months. These results indicate that neoadjuvant biochemotherapy demonstrates anti-cancer activity for patients with stage III melanoma. Researchers caution that although the overall survival data is promising, its significance is not yet apparent due to the limited size of the study and the variation in prognostic factors of the participants.

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 been demonstrated to have 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.

Gene Therapy: Currently, there are no gene therapies approved for the treatment of melanoma. Gene therapy is defined as the transfer of new genetic material into a cell for therapeutic benefit. This can be accomplished by replacing or inactivating a dysfunctional gene or replacing or adding a functional gene into a cell to make it function normally. Many gene therapy studies are being carried out in patients with refractory melanoma. If successful, these therapies could be applied to patients with earlier stage cancer.

Antisense Treatment: Some advanced-stage cancers, including some melanomas, are resistant or can develop a resistance to chemotherapy drugs, making the drugs less effective or ineffective against the cancer. One factor in the development of disease resistance in some cancers (melanoma included) is thought to be an abnormal gene, called the bcl-2 gene. This defective gene produces an excess amount of protein, which in turn helps protect cancer cells from apoptosis, the process by which the body normally kills abnormal cancer cells. The overproduction of this protein gives cancer cells a survival advantage over normal cells and helps the cancer cells develop a resistance to radiation therapy and some chemotherapy drugs. Researchers have been working to develop drug products that may help overcome such resistance by targeting the bcl-2 gene, providing more effective treatment options to individuals with advanced melanoma and certain other cancers.

A new type of agent, called an antisense compound, is currently being studied for its potential ability to target the bcl-2 gene and slow the production of its protein. Genes use mRNA to carry the genetic information used to produce their proteins. The antisense compounds are synthetic DNA strands that bind to and destroy a gene’s mRNA, thereby preventing the gene from producing an excess amount of its protein. This would decrease the cancer cell’s resistance to therapy. Researchers recently treated patients with advanced melanoma with chemotherapy and a new antisense compound, currently named G3139.

Researchers in Austria treated 17 patients with advanced melanoma, most of whom had disease that was resistant to standard treatments. All patients received monthly cycles of the chemotherapy drug dacarbazine and the antisense compound G3139 for up to one year. The findings showed that this treatment regimen resulted in decreased bcl-2 protein levels and increased apoptosis of melanoma cells. Six of the 14 patients who could be evaluated experienced shrinkage of the cancer. One patient had a complete response to treatment. Two patients had more than a 50% reduction in cancer size and three patients had less than a 50% reduction in cancer size. For some patients, the responses to treatment have lasted for more than one year. The G3139 treatment was well tolerated.

These findings represent the first of their kind: the successful use of an antisense compound to decrease the amount of bcl-2 gene protein produced. The combination of dacarbazine and G3139 appears to produce responses in patients with advanced melanoma, despite resistance to other treatments. In addition, the bcl-2 gene protein is thought to play a role in the progression of several other cancers, including prostate cancer, leukemia, non-Hodgkin’s lymphoma and breast cancer. G3139 is currently undergoing further study in Europe and the United States for the treatment of melanoma and these other bcl-2–related cancers. Antisense G3139 has not yet been approved by the U.S. Food and Drug Administration and continues to be evaluated in clinical trials.

Side Effect Management (Supportive Care): Supportive care is treatment designed to prevent or control the side effects of cancer and its treatment. Side effects not only cause patients discomfort, but also may prevent the delivery of therapy at its planned dose and schedule. In order to achieve optimal outcomes from treatment and improve quality of life, it is imperative that treatment be delivered as planned and that side effects resulting from cancer and its treatment are appropriately managed. For more information, visit  Managing Side Effects.